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March 2013 Volume 162 Number 3 Supplement 1
Copyright 2013 by Mosby, Inc.
Global Neonatal Consensus Symposium: Feeding the Preterm Infant

Guest Editors Ricardo Uauy, MD, PhD
This Supplement is based on the Global Neonatal Consensus Symposium, Feeding the Preterm Infant, which was held in Chicago, Illinois, October 13-15, 2010. Sponsored by Mead Johnson Nutrition.
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March 2013 Volume 162 Number 3 Supplement 1

Introduction to the Symposium on Nutrition of the Preterm Infant
Copyright 2013 by Mosby, Inc.
Ricardo Uauy, MD, PhD and Carol Lynn Berseth, MD .....................................................................................................................................
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Growth Curves: How to Best Measure Growth of the Preterm Infant

Jatinder Bhatia, MD, FAAP ...................................................................................................................................................................................
Feeding Preterm Infants Today for Later Metabolic and Cardiovascular Outcomes
Alexandre Lapillonne, MD, PhD and Ian J. Grifn, MD....................................................................................................................................
Human Milk and the Nutritional Needs of Preterm Infants
David I. Tudehope, AM, MBBS, FRACP ............................................................................................................................................................. S17
Teresa Murgu a-Peniche, MD ............................................................................................................................................................................... S26 Jatinder Bhatia, MD, FAAP, Patricia Mena, MD, Scott Denne, MD, and Cecilia Garc a, MD....................................................................... S31
Vitamin D, Vitamin A, Maternal-Perinatal Considerations: Old Concepts, New Insights, New Questions Evaluation of Adequacy of Protein and Energy
Lipid Needs of Preterm Infants: Updated Recommendations

Alexandre Lapillonne, MD, PhD, Sharon Groh-Wargo, PhD, LD, RD, Carlos H. Lozano Gonzalez, MD, MPH, and Ricardo Uauy, MD, PhD ....................................................................................................................................................................................... S37
Selected Macro/Micronutrient Needs of the Routine Preterm Infant

Jatinder Bhatia, MD, FAAP, Ian Grifn, MD, Diane Anderson, PhD, RD, Neelam Kler, MD, and f, MD, PhD ................................................................................................................................................................................ S48 Magnus Domello
Intestinal Mucosal Defense System, Part 1. Consensus Recommendations for Immunonutrients

Josef Neu, MD, Walter A. Mihatsch, MD, MBA, Jaime Zegarra, MD, Sarayut Supapannachart, MD, FAAP, MBA, Zong-Yi Ding, MD, and Teresa Murgu a-Peniche, MD ..................................................................................................................................... S56 Teresa Murgu a-Peniche, MD, Walter A. Mihatsch, MD, MBA, Jaime Zegarra, MD, Sarayut Supapannachart, MD, FAAP, MBA, Zong-Yi Ding, MD, and Josef Neu, MD .............................................................................................................................................................. S64 David Tudehope, AM, MBBS, FRACP, Mary Fewtrell, MD, Sudha Kashyap, MD, and Enrique Udaeta, MD ............................................ S72
Intestinal Mucosal Defense System, Part 2. Probiotics and Prebiotics
Nutritional Needs of the Micropreterm Infant
Nutritional Requirements and Feeding Recommendations for Small for Gestational Age Infants
David Tudehope, AM, MBBS, FRACP, Maximo Vento, MD, PhD, Zulqar Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD, and Paulo Pachi, MD, PhD........................................................................................................................................................................................... S81
Alexandre Lapillonne, MD, PhD, Deborah L. OConnor, PhD, RD, Danhua Wang, MD, and Jacques Rigo, MD, PhD............................ S90
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Nutritional Recommendations for the Late-Preterm Infant and the Preterm Infant after Hospital Discharge
Feeding the Preterm Infant: Opportunities and Challenges of Bringing Science to the Bedside
Josef Neu, MD, Cristine L. Bradley, MSc, RD, Zong-Yi Ding, MD, Hugh N. Tucker, PhD, FACN, CNS, and Carol Lynn Berseth, MD......................................................................................................................................................................................S101
Aamer Imdad, MBBS and Zulqar A. Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD....................................................................................S107 Carol Lynn Berseth, MD and Ricardo Uauy, MD, PhD ...................................................................................................................................S115
Nutritional Management of the Low Birth Weight/Preterm Infant in Community Settings: A Perspective from the Developing World Symposium Summary: Looking Back and Looking Forward
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Vol. 162, No. 3, Supp. 1
Global Neonatal Consensus Symposium: Feeding the Preterm Infant

Guest Editors
Ricardo Uauy, MD, PhD Professor of Pediatrics INTA U of Chile Neonatology Division, Department of Pediatrics Catholic University, Santiago, Chile
Faculty
Diane Anderson, PhD, RD Associate Professor of Pediatrics Baylor College of Medicine Houston, Texas Carol Lynn Berseth, MD Medical Director for Global Innovation Mead Johnson Nutrition Evansville, Indiana Jatinder Bhatia, MD, FAAP Professor of Pediatrics Medical College of Georgia Augusta, Georgia Zulqar Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD Chair, Division of Women & Child Health Aga Khan University Karachi, Pakistan Cristine L. Bradley, MSc, RD Regulatory Sciences Mead Johnson Nutrition Evansville, Indiana Scott Denne, MD Professor of Pediatrics Indiana University School of Medicine Indianapolis, Indiana Zong-Yi Ding, MD Honor President 1st August Childrens Hospital afliated with the General Hospital of Beijing Military Defense Area Beijing, China f, MD, PhD Magnus Domello Associate Professor Department of Clinical Sciences, Pediatrics Ume a University Ume a, Sweden Mary Fewtrell, MD Head of Nutrition, Physiology & Metabolism University College London Institute of Child Health London, United Kingdom March 2013 Cecilia Garc a, MD Director, Neonatal Intensive Care Unit Hospital Sanatorio de la Trinidad Palermo Buenos Aires, Argentina Ian Grifn, MD Associate Professor of Pediatrics UC-Davis Medical Center Sacramento, California Sharon Groh-Wargo, PhD, LD, RD Associate Professor Case Western Reserve University MetroHealth Medical Center Cleveland, Ohio Aamer Imdad, MBBS Division of Women & Child Health The Aga Khan University Karachi, Pakistan Sudha Kashyap, MD Professor of Pediatrics Morgan Stanley Childrens Hospital Columbia University Medical Center New York, New York Neelam Kler, MD Head, Department of Neonatology President of the National Neonatology Forum (NNF) Sir Gangaram Hospital New Delhi, India Alexandre Lapillonne, MD, PhD Professor of Pediatrics Paris Descartes University APHP Necker Hospital Paris, France CNRC, Baylor College of Medicine Houston, Texas Carlos H. Lozano Gonzalez, MD, MPH Professor of Neonatology Academia Mexicana de Pediatr a Pediatr a Medicina Perinatal Monterrey, N.L. M exico
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Patricia Mena, MD Professor of Pediatrics lica de Chile Ponticia Universidad Cato Director of Newborn Unit Dr Sotero del Rio Hospital Santiago, Chile Walter A. Mihatsch, MD, MBA Head of the Department of Pediatrics Harlaching Munich Municipal Hospitals Munich, Germany Teresa Murgu a-Peniche, MD Infancy Area Director, National Center for Child and Adolescent Health, CeNSIA Secretary of Health, Mexico City Foege Fellow, Rollins School of Public Health Hubert Department of Global Health Emory University Atlanta, Georgia Josef Neu, MD Professor of Pediatrics University of Florida Gainesville, Florida Deborah OConnor, PhD, RD Associate Professor Department of Nutritional Sciences, University of Toronto Director, Clinical Dietetics, Hospital for Sick Children Toronto, Canada Paulo Pachi, MD, PhD Professor of Pediatrics Santa Casa de Misericordia de S~ ao Paulo S~ ao Paulo, Brazil Jacques Rigo, MD, PhD Professor of Neonatology and Nutrition Department of Neonatology University of Liege CHR Citadelle Li ege, Belgium
Sarayut Supapannachart, MD, FAAP, MBA Associate Professor of Pediatrics Ramathibodi Hospital School of Medicine Mahidol University Bangkok, Thailand Hugh N. Tucker, PhD, FACN, CNS Distinguished Research Fellow Mead Johnson Nutrition Evansville, Indiana David Tudehope, AM, MBBS, FRACP Professor of Paediatics and Child Health University of Queensland Queensland, Australia Enrique Udaeta, MD Chief, Division of Pediatrics Hospital Infantil de Mexico Mexico City, Mexico Maximo Vento, MD, PhD Professor of Pediatrics Hospital Universitario y Polit ecnico La F e Valencia, Spain Danhua Wang, MD Professor of Pediatrics Peking Union Medical College Hospital Beijing, P.R. China Jaime Zegarra, MD Pediatrician Hospital Nacional Cayetano Heredia Lima, Peru
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Vol. 162, No. 3, Suppl. 1
Faculty Disclosures
The authors who contributed to this publication have disclosed the following industry relationships: Diane Anderson, PhD, RD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Jatinder Bhatia, MD, FAAP, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Zulqar Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Carol Lynn Berseth, MD, is the Medical Director for Global Innovation at Mead Johnson Nutrition. She organized and facilitated the Symposium on Nutrition of the Preterm Infant, and received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Cristine L. Bradley, MSc, RD, is an employee of the sponsor, Mead Johnson Nutrition, and received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Scott Denne, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Zong-Yi Ding, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. f, MD, PhD, received an honorarium from Magnus Domello Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Mary Fewtrell, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Cecilia Garcia, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Ian Grifn, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Sharon Groh-Wargo, MD, LD, RD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation.
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Aamer Imdad, MBBS, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Sudha Kashyap, MD, serves as an advisor to Mead Johnson Nutritionals, and received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Neelam Kler, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Alexandre Lapillonne, MD, PhD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Carlos H. Lozano Gonzalez, MD, MPH, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Patricia Mena, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Walter A. Mihatsch, MD, MBA, is a recipient of a research grant from Mead Johnson Nutrition, and received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. In the past, he has acted as a scientic consultant to several infant formula companies. Teresa Murgu a-Peniche, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Josef Neu, MD, has received a research grant and honoraria for speaking from Mead Johnson Nutrition, is currently on its Scientic Advisory Committee, and received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Deborah L. OConnor, PhD, RD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Paulo Pachi, MD, PhD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation.
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Jacques Rigo, MD, PhD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Sarayut Supapannachart, MD, FAAP, MBA, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Hugh N. Tucker, PhD, FACN, CNS, is an employee of Mead Johnson Nutrition, and received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. David Tudehope, AM, MBBS, FRACP, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Enrique Udaeta, MD, is a consultant for Mead Johnson Nutrition, and received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation.
Ricardo Uauy, MD, PhD, chaired the Symposium on Nutrition of the Preterm Infant. Mead Johnson Nutrition paid his travel expenses. He also received an honorarium to compensate his time for contributing to, organizing and chairing the meeting and for his contribution to the nal editing of the supplement. Maximo Vento, MD, PhD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Danhua Wang, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Jaime A. Zegarra, MD, is a recipient of a research grant from Mead Johnson Nutrition, and received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation.
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Introduction to the Symposium on Nutrition of the Preterm Infant

t has been nearly a decade since the publication of Nutrition of the Preterm Infant, Second Edition.1 Numerous changes in neonatal care have occurred in the interim, and the need to rene nutritional care of the preterm infant is apparent. The science base indicates gaps in our knowledge of appropriate nutritional support and the need to establish new recommendations have evolved. Thus, we now have a better understanding about the requirements for specic nutrients and the need to address immaturity of host defenses, nutrient metabolism, and tissue repair mechanisms in preterm infants. Increasing numbers of infants survive birth and beyond at ever-lower gestational ages. At the same time, a broader range of the critical needs of the late preterm infant has become increasingly apparent. The nutritional requirements of very premature and late preterm infants differ from those of other preterm infants. In some geographic regions up to one-third of infants are classied as small for gestational age (SGA). The nutritional needs of this population also differ from those of appropriately sized preterm infants. Finally, as the world becomes smaller, there is a need to address health issues for all infants, and particularly preterm infants, in a more universal and global manner. This Supplement reports the deliberations and proceedings of the Global Neonatal Consensus Symposium, Feeding the Preterm Infant, held in Chicago, Illinois, on October 1315, 2010, which provided robust interactions among international academic neonatal nutritional experts in reviewing and updating the scientic literature concerning the needs of preterm infants. We identied 30 experts to participate in this task. We established 4 areas of work: (1) updating nutrient recommendations (protein, micronutrients, and lipids); (2) reviewing new science about the immaturity of host defense for the preterm infant; (3) recognizing the unique nutritional needs of specic subpopulations of preterm infants (the micropreterm infant, the SGA infant, the late preterm infant, and the postdischarge infant); and (4) identifying the challenges that prevent us from translating our understanding of science to practical application. Small teams were appointed to research each of these topics throughout the year, culminating in a 3-day interactive symposium where each teams work was reviewed and rened by the entire group at large. To focus this work, we dened: (1) micropreterm infant as one born at #27 weeks gestation and, commonly, <800 g at birth; (2) SGA infant as one born at $34 weeks gestation and weighing less than the third percentile; (3) late preterm infant as one born at 34-38 weeks gestation; and (4) the postdischarge infant as any preterm infant who survived to be discharged home, typically at a corrected gestational age of $37 weeks.
SGA Small for gestational age
The participating global experts developed consensus on nutritional recommendations and statements available in the current literature and identied a series of gaps in our knowledge. They highlighted the multiple challenges external to the science that limit our capacity to translate science into practical application. They also recognized a series of issues that apply to all patient groups. These issues were highlighted separately and include the use of breast milk, identifying appropriate growth curves, developing methodology to recommend nutrient intake, and a reconsideration of the importance of vitamin A and vitamin D for immature infants. What emerged among the participants as they progressed through the deliberations was a sense of global commitment to this altruistic effort. We anticipate the resulting synergy will help shape a global consensus on neonatal nutrition practices in the future.
Author Disclosures
Ricardo Uauy, MD, PhD, chaired the Symposium on Nutrition of the Preterm Infant. Mead Johnson Nutrition paid his travel expenses. He also received an honorarium to compensate his time for contributing to, organizing, and chairing the meeting and for his contribution to the nal editing of the Supplement. Carol Lynn Berseth, MD, is the Medical Director for Global Innovation at Mead Johnson Nutrition. She organized and facilitated the Symposium on Nutrition of the Preterm Infant. R.U. wrote the rst draft of this manuscript. n Ricardo Uauy, MD, PhD n y Tecnologia de los Alimentos Instituto de Nutricio University of Chile Neonatology Division Department of Pediatrics Catholic University Santiago, Chile Carol Lynn Berseth, MD Mead Johnson Nutrition Evansville, Indiana
n y Tecnologia Reprint requests: Ricardo Uauy, MD, PhD, Instituto de Nutricio de los Alimentos, University of Chile, PO Box 138-11, Macul 5540, Santiago, Chile. E-mail: uauy@inta.cl
Reference
1. Tsang RC, Uauy R, Koletzko B, Zlotkin S, eds. Nutrition of the Preterm Infant: Scientic Basis and Practical Guidelines. 2nd edition. Cincinnatti, OH: Digital Educational Publishing, Inc; 2005.
Please see the Author Disclosures at the end of this article.

0022-3476/$ - see front matter. Copyright 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.11.046
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Jatinder Bhatia, MD, FAAP
Birth weight is one of the most important anthropometric measures in the evaluation of an infant. For the full-term infant, birth weight is compared with reference or standard growth curves that are constructed by plotting weight, length, and head circumference against postnatal age. Following a similar approach for preterm infants is less effective for a variety of reasons. Birth weight and other anthropometric measures used to evaluate an infant at birth are inuenced by various maternal characteristics, the intrauterine milieu, and duration of gestation. Second, the causes of premature birth and their impact on birth weight are largely unknown. Third, gestational age is difcult to determine with full certainty. One approach that has been used to circumvent these issues is to use intrauterine growth reference curves. However, these curves do not really reect normal growth because they were constructed using cross-sectional data from infants born prematurely and, as such, do not reect the normal condition. Thus, there is a need to develop normative growth curves derived from healthy preterm infants that can be applied to neonates born prematurely. These should be updated periodically to reect secular trends in maternal body weight, height, and overall health. (J Pediatr 2013;162:S2-6). rowth is a sensitive indicator of postnatal health. The commonly used clinical measures of growth compare weight, length, and head circumference with postnatal age. Other measures of growth include mid-arm circumference, skin fold measurements, assessment of body composition, and biochemical markers. These measures of growth are used to dene nutritional strategies, educate caregivers, and enable early detection of growth alterations or failure. It is particularly important to have reliable measures of growth for premature infants because extrauterine growth restriction is common in small premature infants and is now recognized as a risk factor for poor neurodevelopmental outcomes.1,2 Two types of growth curves are used to monitor postnatal growth. A reference growth curve is based on a sample or population without exclusions or specifying the type of nutrition provided and describes how children actually grow. A standard growth curve follows a prescriptive approach based on how children should grow. A good example of the latter is the World Health Organization (WHO) Multicenter Growth Reference Study in which selection criteria includes predened, ideal maternal and environmental conditions; the resulting fetal and postnatal growth charts generated indicate how growth should occur under these ideal conditions.3
Growth Assessment of the Preterm Infant

The American Academy of Pediatrics and the Canadian Pediatric Society presently recommend that preterm infant growth should approximate intrauterine growth after allowing for a brief cessation in growth in the early neonatal period. However, the intrauterine environment differs markedly from the extrauterine environment. Postnatally, infants encounter temperature stress, feeding intolerance, insensible water loss, infectious agents, and medical interventions that increase energy expenditure and nutrient losses that affect measures of growth.4,5 Ehrenkranz et al have demonstrated this in infants less than 1500 g at birth (Figure 1).6 To assess growth of the preterm infant, a variety of intrauterine growth curves have been constructed by plotting growth measures at birth against gestational age. The rst birth weight per centile curves for gestational age were reported by Lubchenco et al.7 Intrauterine growth was estimated from 5635 live-born Caucasian infants at 24-42 weeks of gestation. Curves of the 10th, 25th, 50th, 75th, and 90th percentiles were compiled, smoothed and presented for male, female, and all infants. These curves represent infants who were born alive and survived to a particular gestational age. These curves may not represent normal growth rates because most of the infants were born prematurely and were likely affected by health conditions that induced premature birth. Subsequently, birth weights within a given gestational age were subdivided to classify infants as appropriate for gestational age, large for gestational age, and small for gestational age.8 Lubchenco et al later published curves that included measurements of length and head circumference.9 A number of investigators in other countries have constructed similar curves that describe observed fetal growth.10-19 From the Department of Pediatrics, Medical College of
Georgia, Georgia Health Sciences University, Augusta, GA Please see the Author Disclosures at the end of this article.
EFW WHO
Estimated fetal weight World Health Organization
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Vol. 162, No. 3, Suppl. 1 March 2013 age.24 Chauhan et al concluded that clinical and ultrasound methods provide poor estimates of birth weight.25 Hence, fetal weight curves derived from currently available technology may not be optimal guides to achieve target postnatal growth goals. Moreover, given that almost all preterm infants less than 29 weeks gestation have extrauterine growth restriction (Figure 1), use of fetal weight-based curves would make the infants appear to be more growth restricted. Because the error of estimating gestational age remains the same, the use of curves based on EFW does not appear to provide an advantage over the use of curves based on actual birth weight. Moreover, if there is a period of poor growth, subsequent weight gain would need to be greater to catch up, and the effects will be larger the later the growth alteration occurs. In addition, recent data indicate that birth weight appears to increase over time. Thus, it is appropriate to use updated curves when available. Growth rates have been estimated by a number of authors (Table).26 Although most practicing neonatologists aim for the best growth possible to avoid adverse metabolic effects, recent concerns about the late effects of earlyaccelerated growth have raised some caution (see Lapillonne and Grifn, in this supplement).27 There are insufcient data to construct robust ethnicspecic growth curves. Moreover, whenever this issue has been explored using appropriate methodologies, as with the Multicenter Growth Reference Study, the observed differences were found to be due to environmental conditions rather than truly genetic or ethnic differences. Despite this, some countries use area-specic growth charts to describe their populations.
Figure 1. Extrauterine growth restriction. Extremely low birth weight infants grow poorly after birth.6 Average body weight is plotted against postmenstrual age for infants born at 24-25 weeks (dotted line), 26-27 weeks (short dashes), and 28-29 weeks (long dashes). Reprinted with permission from Pediatrics.6 Copyright 1999 by the American Academy of Pedriatics.
Limitations of Currently Available Growth Estimates

The most common variable used to monitor growth of the preterm infant is gestational age estimated from the date of onset of the mothers last normal menstrual period. Errors in gestational age appear to be magnied at lower gestational ages. This is especially true if an obstetric estimate of gestational age is not available because an obstetricians estimate is closer to actual age than a neonatologists estimate in the delivery room.20 Ultrasound imaging studies of the fetus coupled with good maternal dating and history have been used to estimate gestational age and weight in longitudinal and cross-sectional studies.21,22 Weights predicted by these methods, compared with birth weights, place infants below the mean gestational age-related estimated fetal weight (EFW). Further, the incidence of fetal growth restriction based on EFW increases as gestational age decreases. More recently, body weight and EFW standards have been used to generate z-scores for body weight and for EFW. The z-scores for body weight are normally distributed around the mean whereas the z-scores for EFW are skewed towards fetal growth restriction, demonstrating signicant differences between the two approaches. Ideally, one would have liked a comparison of the same infants/fetuses studied using both methods. Cooke et al concluded that EFW would give more accurate information regarding fetal growth restriction.23 The drawback of using EFW curves is that fetal ultrasound is not very reliable in predicting birth weight. Ben-Haroush et al EFW in 840 pregnant women and concluded that EFW was correlated with birth weight but became less accurate at low gestational ages, high birth weights, and young maternal
Recent Advances
We believe that growth curves need to be updated periodically. Toward this end, Olsen et al has published a new growth curve.28 The investigators used a large data set from 248 US hospitals in 33 states for births in 1998-2006. Exact methods for measuring length and head circumference were not described, although the large number of infants in the data set may compensate for errors in measurements. Table. Comparison of growth rates
Authors Lubchenko et al 1963 Hoffman et al 197432
7
N 5635 1 164 871
Daily weight gain at 27-34 wk (g/kg) 14.9 11.2 13.7 15.4 15.7 16.3 16.9 20
Population Caucasian African American female African American male Caucasian male Caucasian female Male Female Not specied
Arbuckle et al 199316 Alexander et al 199618
1 087 629 3 134 879
Adapted from Grifn IJ. Nutritional assessment in preterm infants. In: Cooke RJ, Vandenplas Y, Wahn U, eds. Nutrition support for infants and children at risk. Nestle Nutr Workshop Ser Pediatr Program. Nestec Ltd, Vevey/S. Karger, Basel 2007;59:177-92.
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Vol. 162, No. 3, Suppl. 1 Lubchenco curves. Surprisingly, even though the data were obtained 3 decades later than Lubchencos and, presumably, were obtained from places closer to sea level, the new curves have lower birth weights at low gestational ages and higher birth weights from 36 weeks onwards. The most commonly used growth curves in neonatal units internationally are the Fenton curves (Figure 2) that are based on data from Nicklasson et al, Kramer et al, Beeby et al, and the US Centers for Disease Control.15,19,29,30 Fenton conducted a systematic review and meta-analysis and improved on the data of Babson and Benda.31 Three large
Gestational age was determined by neonatologist best estimate using obstetric history, obstetric examinations, prenatal ultrasound and postnatal physical examinations.28 The authors did not state whether a standardized scoring system was used or how a discrepancy between the obstetricians and neonatologists estimates was resolved. The nal sample of 257 855 data points included 57.2% male infants and 50.6% white, 15.7% black, 24.4% Hispanic, and 9.3% other infants, a distribution that is similar to US birth data. The curves were validated as sex-specic groups by gestational age. The sex-specic curves were then compared with the
Figure 2. Fetal-infant growth chart for preterm infants. The Fenton growth chart31 can be used to monitor growth of preterm infants from 22 weeks gestation through 20 weeks post-term. Reprinted with permission from: 2003 Fenton; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the articles original URL. Available at: http://www.biomedcentral.com/ 1471-2431/3/13.
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percentile on both curves. Intrauterine growth curves provide idealized guidelines to monitor the growth of preterm infants. Preterm birth is not normal, and many other variables related to preterm birth can affect growth. Nonetheless, we suggest that postnatal growth be adjusted by gestational age at birth, and all infants be followed using the WHO international growth standard. Two large population based international studies may provide more rened measures of fetal growth and truly international normative standards. The International Fetal and Newborn Growth Consortium for the 21st Century study (available at: http://www.intergrowth21.org.uk) provides normative data resulting from using a prescriptive approach that describes normal fetal growth, preterm growth, and newborn nutritional status from 8 geographically diverse populations and relates these standards to neonatal health risk. The worldwide use of these tools should improve infants healthcare and nutritional status. In addition, the INTERBIO-21st study, an extension of the International Fetal and Newborn Growth Consortium for the 21st Century project (available at: http://www.obs-gyn.ox.ac.uk/omphi/ studies/interbio-21st) may improve the phenotypic characterization of the intrauterine growth restriction/small for gestational age and preterm birth syndromes.
Figure 3. Olsen and Fenton curves. Lines indicate the 3rd, 50th, and 97th percentiles for weight of male infants born in the US from 1998-2006 at 23-42 weeks of gestation, adapted from Olson et al.28 The shaded area is bounded by the 3rd and 97th percentiles for weight of all infants described by Fenton.31 The closed circles represent the growth of an actual infant born at 27 weeks gestation.
Using Growth Curves to Manage Preterm Infants

The positive and negative consequences of more aggressive nutrition support need to be assessed over the short-and long-term because apparent gains can be offset by longterm adverse consequences. Equally, we should strive to achieve normal growth for adjusted age commensurate with feeding tolerance as soon as possible to support optimal brain development and linear growth. Both are potentially compromised if early feeding fails to deliver optimal nutrition. There remains uncertainty about the ideal growth and nutrient requirements of premature infants. Management of these infants over the past 2 decades has changed as have the nutrient preparations available for them. There is an increased use of human milk, and growth patterns of human milk-fed infants in the short term have been demonstrated to be similar to formula-fed cohorts with appropriate human milk fortication. We should strive to create reference charts for exclusively human milk-fed infants as we do for term infants and consider the relative gains and losses in terms of long-term growth, development, and overall health.
population-based surveys were identied. The data from different sources were averaged together to derive the per centiles and create a growth chart that combined both sexes. The Centers for Disease Control and Prevention growth curves were used to assess growth beyond 40 weeks corrected age. If a hypothetical infant born at 1500 g and 30 weeks is plotted on the Fenton and Olsen curves, it appears that for both boys and girls weight-for-age would be higher in the Olsen curves than in the Fenton curves. Figure 3 demonstrates the differences between the Olsen and Fenton curves. Although not apparent from Figure 3, the Olsen curves are sexspecic (the curves for males are shown) and range from the 3rd to the 97th percentile (similar to the Fenton curves), but the curves deviate from each other at both the lower and higher gestational ages (eg, the 3rd percentile on the Olsen curves are lower than the 3rd percentile of the Fenton curves throughout). The Fenton curves run through 50 weeks postmenstrual age, and the Olsen curves are limited to 41 weeks. More research and practical use are needed before recommendations can be made on the use of the new curves. Weights for an actual infant are plotted with the Olsen and Fenton curves (Figure 3). This example illustrates two issues of practical signicance. The differences in assessing growth by the two curves are small, and no demonstrable health consequences are suggested. Moreover, there is no difference in the classication of growth status. However, once growth falters after 37 weeks post-menstrual age, the infant falls below or near the 3rd
Summary
Numerous growth curves based on EFW are available. The utility of these curves is limited by our ability to determine the accurate estimates of fetal weight and gestational age. The errors associated with fetal weight-based curves are not different from those associated with body weight-based curves. It is unknown whether improved identication of
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12. Kitchen WH, Robinson HP, Dickinson AJ. Revised intrauterine growth curves for an Australian hospital population. Aust Paediatr J 1983;19: 157-61. 13. Yudkin PL, Aboualfa M, Eyre JA, Redman CW, Wilkinson AR. New birthweight and head circumference centiles for gestational ages 24 to 42 weeks. Early Hum Dev 1987;15:45-52. 14. Keen DV, Pearse RG. Weight, length, and head circumference curves for boys and girls of between 20 and 42 weeks gestation. Arch Dis Child 1988;63:1170-2. 15. Niklasson A, Ericson A, Fryer JG, Karlberg J, Lawrence C, Karlberg P. An update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age (1977-1981). Acta Paediatr Scand 1991;80:756-62. 16. Arbuckle TE, Wilkins R, Sherman GJ. Birth weight percentiles by gestational age in Canada. Obstet Gynecol 1993;81:39-48. 17. Amini SB, Catalano PM, Hirsch V, Mann LI. An analysis of birth weight by gestational age using a computerized perinatal data base, 1975-1992. Obstet Gynecol 1994;83:342-52. 18. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87: 163-8. 19. Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 2001;108:E35. 20. Platt RW. The effect of gestational age errors and their correction in interpreting population trends in fetal growth and gestational age-specic mortality. Semin Perinatol 2002;26:306-11. 21. Hadlock FP, Harrist RB, Martinez-Poyer J. In utero analysis of fetal growth: a sonographic weight standard. Radiology 1991;181:129-33. 22. Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr 1996;85:843-8. 23. Cooke RW. Conventional birth weight standards obscure fetal growth restriction in preterm infants. Arch Dis Child Fetal Neonatal Ed 2007; 92:F189-92. 24. Ben-Haroush A, Yogev Y, Bar J, Mashiach R, Kaplan B, Hod M, et al. Accuracy of sonographically estimated fetal weight in 840 women with different pregnancy complications prior to induction of labor. Ultrasound Obstet Gynecol 2004;23:172-6. 25. Chauhan SP, Hendrix NW, Magann EF, Morrison JC, Kenney SP, Devoe LD. Limitations of clinical and sonographic estimates of birth weight: experience with 1034 parturients. Obstet Gynecol 1998;91:72-7. 26. Grifn IJ. Nutritional assessment in preterm infants. Nestle Nutr Workshop Ser Pediatr Program 2007;59:177-88. 27. Lapillonne A, Grifn I. Feeding preterm infants today for later metabolic and cardiovascular outcomes. J Pediatr 2013;162:SXXX-XXX. 28. Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS. New intrauterine growth curves based on United States data. Pediatrics 2010; 125:e214-24. 29. Beeby PJ, Bhutap T, Taylor LK. New South Wales population-based birthweight percentile charts. J Paediatr Child Health 1996;32:512-8. 30. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11 2002;11:1-190. 31. Fenton TR. A new growth chart for preterm babies: Babson and Bendas chart updated with recent data and a new format. BMC Pediatr 2003;3:13. 32. Hoffman HJ, Stark CR, Lundin FE Jr, Ashbrook JD. Analysis of birth weight, gestational age, and fetal viability, U. S. births, 1968. Obstet Gynecol Surv 1974;29:651-81.
small-for-gestational age infants or fetal growth restriction at birth would lead to better postnatal care. Until more data are available, the use of currently published body weight charts, such as the Fenton charts, appears appropriate. An idealized population of preterm infants does not exist similar to the prescriptive growth of term infants demonstrated in the WHO infant-children curves and the recent fetal-infant growth curves. These latter charts describe growth as it should be, not as it actually occurs. n
Author Disclosure
Jatinder Bhatia, MD, FAAP, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. J.B. wrote this manuscript.
Reprint requests: Jatinder Bhatia, MD, FAAP, Department of Pediatrics, Medical College of Georgia, Georgia Health Sciences University, 1120 15th Street, BIW 6033, Augusta, GA 30912-3740. E-mail: jatindeb@georgiahealth. edu.
References
1. Casey PH, Whiteside-Mansell L, Barrett K, Bradley RH, Gargus R. Impact of prenatal and/or postnatal growth problems in low birth weight preterm infants on school-age outcomes: an 8-year longitudinal evaluation. Pediatrics 2006;118:1078-86. 2. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit inuences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006;117:1253-61. 3. WHO Multicenter Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight, and age. Acta Paediatrica Suppl 2006;450:76-85. 4. Canadian Paediatric Society Nutrition Committee. Nutrient needs and feeding of premature infants. Can Med Assoc J 1995;152:1765-85. 5. AAP, Committee on Nutrition. Pediatric nutrition handbook. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2004. 6. Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA, Donovan EF, Wright LL, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics 1999;104:280-9. 7. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics 1963;32:793-800. 8. Battaglia FC, Lubchenco LO. A practical classication of newborn infants by weight and gestational age. J Pediatr 1967;71:159-63. 9. Lubchenco LO, Hansman C, Boyd E. Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 1966;37:403-8. 10. Usher R, McLean F. Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969;74: 901-10. 11. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 1976;126:555-64.
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Alexandre Lapillonne, MD, PhD1,2, and Ian J. Grifn, MD3
Preterm birth continues to contribute disproportionately to neonatal morbidity and subsequent physical and neurodevelopmental disabilities. Epidemiologic studies have described additional long-term health consequences of preterm birth such as an increased risk of hypertension and insulin resistance in adult life. It is not known whether the inuence of infant and childhood growth rates and early nutrition on long-term outcomes is the same or different among preterm infants and neonates with intrauterine growth restriction. Our goal is to review the effects of fetal growth, postnatal growth, and early nutrition on long-term cardiovascular and metabolic outcomes in preterm infants. Present evidence suggests that even brief periods of relative undernutrition during a sensitive period of development have signicant adverse effects on later development. Our review suggests that growth between birth and expected term and 12-18 months post-term has no signicant effect on later blood pressure and metabolic syndrome, whereas reduced growth during hospitalization signicantly impacts later neurodevelopment. In contrast, growth during late infancy and childhood appears to be a major determinant of later metabolic and cardiovascular well being, which suggests that nutritional interventions during this period are worthy of more study. Our review also highlights the paucity of well-designed, controlled studies in preterm infants of the effects of nutrition during hospitalization and after discharge on development, the risk of developing hypertension, or insulin resistance. (J Pediatr 2013;162:S7-16). dvances in perinatal and neonatal care have resulted in improved survival for very low birth weight (VLBW) and extremely low birth weight (ELBW) infants,1,2 but preterm birth continues to contribute disproportionately to neonatal morbidity and subsequent physical and neurodevelopmental disabilities.2 Early nutrition is critical for brain develop3 ment, and protein and energy undernutrition in preterm infants during the early neonatal period is associated with later deficits in cognitive function and brain development.3 Low birth weight (LBW) status because of poor fetal growth increases the risk for hypertension and insulin resistance in adults,4,5 a concept known as fetal programming. When exposed to nutritional deprivation in utero, a fetus adapts to increase its chance of survival, albeit at the cost of intrauterine growth restriction (IUGR). However, when nutrient supply is no longer limited, these changes become maladaptative and can lead to an increased risk of insulin resistance, diabetes, and cardiovascular disease.4,5 It is tempting to extrapolate these observations to preterm infants as they, too, are usually born LBW (<2.5 kg). However, many preterm infants have normal or relatively normal growth prior to birth. Furthermore, most preterm infants have extrauterine growth restriction (EUGR)2 that might either mitigate or exacerbate the effects of IUGR, which occurs in 50% of all preterm infants. Most early epidemiologic studies used birth weight to identify infants and did not distinguish the effects of IUGR and preterm birth independently. Therefore, it is unclear whether or not LBW status because of preterm birth has the same metabolic and cardiovascular consequences as LBW status resulting from poor fetal growth (IUGR). As neonatal medicine advances, increasing numbers of preterm infants survive into adulthood. Thus, it is becoming critically important to dene the risk for abnormal cardiovascular and metabolic outcomes in this population. Issues that require clarication are: (1) the effect of neonatal, infant, and childhood growth on long-term metabolic and cardiovascular outcomes in preterm infants; (2) the effects of macronutrient and micronutrient intake and feeding practices on long-term metabolic and cardiovascular outcomes in preterm infants; and (3) whether nutritional and growth-related risk factors result in adverse metabolic and cardiovascular outcomes differently between term LBW and preterm infants and between IUGR/ small for gestational age (SGA) preterm
AGA BMI BP DBP ELBW EUGR HDL HOMA-IR Appropriate for gestational age Body mass index Blood pressure Diastolic blood pressure Extremely low birth weight Extrauterine growth restriction High-density lipoprotein Homeostasis Model of Assessment-Insulin Resistance IQ IUGR LBW LCPUFA SBP SGA VLBW Intelligence quotient Intrauterine growth restriction Low birth weight Long-chain polyunsaturated fatty acid Systolic blood pressure Small for gestational age Very low birth weight
From the 1Department of Neonatology, APHP Necker Hospital, Paris Descartes University, Paris, France; 2 CNRC, Baylor College of Medicine, Houston, TX; and 3 Department of Pediatrics, University of CaliforniaDavis, Sacramento, CA Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 rates of weight gain and head growth are associated signicantly with the incidence of cerebral palsy, mental development index <70, and neurodevelopmental impairment at 18 months corrected age. Gains in weight and body mass index (BMI) from birth to expected term are positively associated with neurodevelopment outcomes at 18 months in very preterm infants.19 Although considerable attention has focused on the effects of growth from birth to expected term on later development, less is known about the effects of postnatal growth after the due date and psychomotor development. Latal-Hajnal et al11 demonstrated that Bayley psychomotor development scores of former VLBW infants measured at 2 years were more closely related to postnatal growth than to the degree of growth retardation at birth. SGA children whose weights remained <10th percentile at age 2 years and AGA children whose weights had fallen below the 10th percentile by 2 years had signicantly lower psychomotor development indices and/or mental development index than SGA children with catch-up growth and AGA children with weights >10th percentile at age 2 years, respectively. A large multicenter study demonstrated that greater weight and length gain between expected term to 4 months post-term were positively, but modestly, related to neurodevelopmental outcomes at 18 months.19 However, increases in weight disproportionate to length provided no additional benet. Although there was no association between growth from 4-12 months and neurodevelopment outcomes at 18 months in the entire population, there was an association between BMI gain between 4-12 months and neurodevelopment at 18 months in the subgroup of SGA preterm infants. These data suggest that promoting growth during the whole rst year of life is important for SGA preterm infants. Moreover, poor postnatal growth in preterm infants, especially poor head growth, is associated with increased prevalence of motor and cognitive impairment at 3 to 8 years20-23 and a loss of 4.1 intelligence quotient (IQ) points in adults.24 Effects of Postnatal Nutrition VLBW infants routinely receive parenteral nutrition; this may have a signicant effect on the neurodevelopmental outcome of VLBW infants in subsequent years. Brandt et al studied 46 preterm infants25 and found that mean energy intake/ kg body weight per day correlated signicantly with developmental and IQs from 18 months to 6 years. Stephens et al26 demonstrated that energy and protein intakes during the rst week of life were strongly associated with developmental outcomes at 18 months in ELBW infants. Furthermore, we found a signicant association between the cumulative intake of lipids during the rst 2 weeks of life and the development quotient at 1 year corrected age in preterm infants who were born before 28 weeks of gestation and given adequate protein intake.27 All together, these ndings demonstrate that optimizing early nutrition by providing adequate parenteral nutrition during the rst weeks of life may limit the negative consequences of undernutrition on early neurodevelopment. Feeding mothers milk has a benecial effect on neurodevelopment, as assessed by developmental scores, in preterm
Lapillonne and Grifn
infants and appropriate for gestational age (AGA) preterm infants. We review the current knowledge on the effects of growth and nutrition on neurodevelopmental, metabolic, and cardiovascular outcomes of preterm infants in order to try to clarify these issues.
Effects of Prematurity, IUGR, Postnatal Growth, and Early Nutrition on Neurodevelopment

Long-term outcome data indicate that preterm infants are at increased risk for adverse neurodevelopmental outcomes, even in the absence of neonatal morbidities such as intraventricular hemorrhage and periventricular leukomalacia.6,7 The exact cause is not clear, but nutritional factors appear to be critically important for growth and neurodevelopment in the fetus and newborn.8 Effects of IUGR The risk for adverse outcomes is increased in IUGR (dened as an abnormal rate of fetal growth or failure to reach ones genetic potential) and SGA (dened by a birth weight <10th percentile for age) premature infants compared with their peers.9-11 Our data from a population of 2846 live births, demonstrate that SGA children born at 29-32 weeks gestation have a higher risk for minor cognitive disabilities, inattention/hyperactivity symptoms at 5 years of age, and a higher risk for poor school performance at 8 years relative to those born preterm but AGA.12 Furthermore, mildly-SGA infants (dened as those with births weights between the 10th and 20th percentiles) also have an increased risk for minor cognitive difculties and behavioral difculties.12 Effects of Postnatal Growth The majority of VLBW infants in the neonatal intensive care unit nursery fail to approximate in utero growth rates. Body size is typically below the 10th percentile by 36 weeks postconceptional age13 and often remains low throughout childhood and even into adolescence.14 This EUGR is attributable in part to inadequate intakes of energy and protein in the rst weeks of life.15 The causes of inadequate intakes during this period include acute neonatal illness and a clinicians concern for tolerance of enteral feeding, tolerance of parenteral macronutrient intake, and a desire to minimize morbidities, such as chronic lung disease, patent ductus arteriosus, and necrotizing enterocolitis. Macronutrients tend to be introduced slowly and increased cautiously out of concern for gastrointestinal or metabolic intolerance.16 Such concerns often lead to nutritional deciencies that, until recently, were considered to be inevitable.15 Studies have demonstrated an association between restricted postnatal growth and poor neurodevelopmental outcome.17-20 Lower developmental scores are associated with weights below the 10th percentile at 2 years in high-risk ELBW infants.17 In-hospital growth is positively related to neurodevelopmental outcome in ELBW infants.18 Lower
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March 2013 infants. Furthermore, the benets of breastfeeding on development seem to extend beyond the rst 2 years of life and into adolescence. Unfortunately, studies of the effect of mothers milk cannot be carried out as randomized trials and, thus are, affected by confounding variables that independently affect the supply of mothers milk and the outcome of the infant. In contrast, studies of donor human milk can be carried out as controlled studies. The few studies that have examined the effect of donor human milk on developmental outcome and neurologic impairment have failed to demonstrate a signicant effect of donor human milk.28 A detailed discussion about the benets of breast milk, breastfeeding, and supplements are presented in the chapter on human milk by Tudehope in this supplement.29 Early enteral intake and neurodevelopmental outcome vary with type of supplemented formulas. In large preterm infants, Lucas et al demonstrated higher cognitive and motor scores at 18 months corrected age and higher verbal IQs and lower rates of cerebral palsy at 7.5-8.0 years of age in preterm infants (<1850 g) fed preterm versus term formula.29,30 The follow-up of a subgroup of this cohort showed a persistent benet of using preterm versus term formula on verbal IQ up to adolescence.32 Furthermore, subsequent magnetic resonance imaging studies showed that infants fed preterm formula had signicantly larger caudate volumes.33 In contrast, the use of an enriched formula or multinutrient-fortied human breast milk after hospital discharge does not seem to provide any additional benets on later development 34,35 (see Lapillonne et al in this supplement).36
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is linked to metabolic responses that lead to insulin resistance and corresponding changes in glucose and lipid metabolism. A faster trajectory of childhood growth has also been linked with increased risk of adult chronic disease.38 These mechanisms could, together, explain why the risk of cardiovascular disease is greatest in those born small who subsequently become overweight; these infants are less able to adapt to a high metabolic burden.37 From a nutritional point of view, promoting catch-up growth in LBW term infants by providing an enriched formula similar to preterm formulas has not been shown to improve growth and neurodevelopment and may, in fact, be equivalent to overfeeding. In contrast, providing the preterm infant with a preterm formula is a very different situation. Preterm formulas are designed to maintain fetal growth rates, which are considered to be optimal for such infants.39 Therefore, feeding a preterm formula to preterm infants is appropriate when human milk is unavailable. Furthermore, once preterm infants are fed ad libitum and have some control over their nutritional intake, the use of preterm formulas does not seem to lead to increased energy intakes compared with other formulas. Instead, they provide greater amounts of specic nutrients (protein and calcium) and micronutrients (eg, zinc, iron and copper) without exceeding overall energy intake.40 Data from preterm infants and term infants born with IUGR should not be expected to be comparable because their stages of maturity, growth, and nutritional needs are very different, despite their similarities in birth weights. Whether or not poor growth, accelerated growth (ie, catch-up growth), and early nutrition produce similar effects in preterm and term IUGR infants remains unclear. To unravel this uncertainty, we analyzed the literature for preterm infants separately from LBW infants. We included only studies published after 2000, thereby including the period when modern methods of neonatal nutritional care were in place, as well as those of preterm or VLBW (<1500 g) infants. This approach excluded data from LBW term infants. Cardiovascular Health of Preterm Infants
Effects of Prematurity, IUGR, Postnatal Growth, and Early Nutrition on Cardiovascular Health, and the Metabolic Syndrome
The Model of the LBW Term Infant is Likely Inapropriate Most studies that have examined the relationship between early growth and adult chronic diseases have shown that being born LBW increases the risk of subsequent chronic disease. In many cases, the association between birth weight and later outcomes becomes clearly evident when adult size is included in the statistical analysis.4 Poor fetal and accelerated postnatal growth rates appear act in synergy. The worst outcome is often found in babies born small who subsequently become large.4 Growth during fetal life and infancy appear to inuence body composition later in life. LBW infants usually have the fastest rate of infant growth and gain proportionately more fat than lean body mass relative to AGA infants when a sufcient amount of energy is provided. This prole indicates that LBW infants respond to an energy-rich diet differently than normal preterm infants. Recent studies indicate that birth weight is strongly predictive of lean mass and has less of an impact on fat mass later in life.37 The rate of postnatal weight gain, particularly during childhood, appears especially important in the etiology of central adiposity, which
Effects of Prematurity. Numerous follow-up studies of blood pressure (BP) in children born prematurely exist.41 Prepubertal children who were born prematurely have similar or slightly elevated (0-4 mm Hg) mean systolic blood pressure (SBP) compared with those born at term.42 In a population based study including preterm infants born before 26 weeks of gestation, SBP and diastolic blood pressure (DBP) are lower by 2.3 mm Hg and 2.4 mm Hg, respectively, in extremely preterm children compared with term children, but these differences are explained by differences in height and BMI. When current height and BMI are taken into account, extremely preterm infants have SBPs and DBPs similar to their term classmates,43 even though they had experienced substantial postnatal growth restriction. This may not hold true at later ages. Teenagers and young adults born prematurely exhibit a more marked increase in SBP of 5 to 6 mm
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Table. Effects of IUGR, postnatal growth, and postnatal nutrition on metabolic and cardiovascular outcomes of adults born preterm*
Does IUGR affect the BP, the glucose tolerance, or the lipid prole of adults born preterm? References Irving et al 200044 Doyle et al 200346 Hack et al 200547 Hovi et al 201048 Johansson et al 200545 Mikkola et al 200750 Keijzer-Veen et al 200551 Hofman et al 200466 Dalziel et al 200767 Rotteveel et al 200871 Hovi et al 200976 References Irving et al 2000 Hack et al 200547 Hovi et al 201048 Keijzer-Veen et al 200551 Dalziel et al 2007
67 44
BP No No Questionable No Yes No No No Yes BP No No for growth <8 mo of age Yes for growth $8 mo of age No for growth <20 mo of age Yes for growth $20 mo of age No for growth <12 mo of age Yes for growth $12 mo of age
Glucose tolerance No No No No Glucose tolerance No No for growth <12 mo of age Yes for growth $12 mo of age No Glucose tolerance No study available
Lipid prole No No No No Lipid prole No Lipid prole No study available
Does postnatal growth affect the BP, the glucose tolerance, or the lipid prole of adults born preterm?
Does postnatal nutrition affect the BP, the glucose tolerance, or the lipid prole of adults born preterm? References BP No study available
*A study was included if: (1) published between 2000 and 2010, thereby demarcating the period of emerging modern methods of neonatal intensive care; (2) the study concerned young adults born preterm, AGA-LBW infants, and/or VLBW (<1500 g) infant to estimate the maximal impact of prematurity and VLBW and to avoid to include SGA (ie, LBW infants) term infants; (3) studies including a control group of normal weight term infants; and (4) the mean age at assessment was between 18 and 30 years.
Hg compared with those born at term.42 The shorter the gestation (ie, the more preterm the infant), the higher the BP is at adult age.44,45 Infants born prematurely or VLBW infants have a greater risk of hypertension compared with those born at term.45-48
Effects of IUGR. The effect of fetal growth on childhood or

adult BP remains controversial. Some studies suggest that children born prematurely and SGA have an increased SBP and pulse wave velocity, a measure of arterial stiffness,49 whereas others found no effect of IUGR on BP during childhood.50 Most studies of adults born prematurely do not support the hypothesis that IUGR increases the risk of high BP later in life (Table).44-48,51
Effects of Postnatal Growth. Fewer studies report associations between postnatal growth and BP.44,47,48,52 In a followup study of 19-year-old adults born as preterm infants, the incidence of hypertension was higher in the preterm group (gestational age <32 weeks and/or birth weight <1500 g) than in the general population of term infants. However, neither BP nor lipid proles in the former preterm infants were affected by birth weight, gestational age at birth, or early patterns of growth.51 Irving et al have shown that neither weight of preterm infants at 44 weeks post-menstrual age nor weight gain over any subsequent 4-week period up to 1 year of age was assoS10
ciated with adult BP.44 Similarly, Finken et al53 found no association between the carotid intima-media thickness in young adults born preterm and weight gain during the rst year of life. Hack et al47 found signicant correlations of adult SBP and DBP with length and weight z-scores in VLBW individuals at 20 months, 8 and 20 years, but not earlier (ie, 40 weeks and 8 months). Rotteveel et al51 showed that former preterm infants, the quartile with the highest adult SBP had a higher height SDS at 3 months of age and at ages 2, 5, 10, 19, and 21 years and a higher weight SDS at ages 1, 2, 5, 10, 19, and 21 years than those in the lowest SBP quartile, but not a higher weight SDS at 3 and 6 months. Finally, Hovi et al48 demonstrated that among all VLBW subjects, birth-weight z-score and weight z-score at term (40 weeks of postmenstrual age) were unrelated to 24-hour BPs in the adult. Interestingly, they found that a 1-unit decrease in z-score from birth to term was associated with a 1.9 mm Hg higher (0.0-3.7) 24hour SBP and a similarly higher DBP. Although this effect was attenuated when data were adjusted for gestational age at birth, these data indicate that poor early extrauterine growth may affect BP in the long term. Only one study describes a 4% lower ow-mediated endothelium dependent dilation in adolescents when the highest rate of weight gain in the rst 2 weeks after birth was compared with the lowest rate.54 The authors concluded that the accelerated neonatal growth may negatively affect long-term cardiovascular
March 2013 health, but whether or not the ow-mediated endothelium dependent dilation in adolescence is predictive of later cardiovascular health remains uncertain. The majority of studies (Table) do not, therefore, suggest that early postnatal growth has a signicant effect on BP in the adult. However, growth in later childhood and adolescence might affect BP.
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sign of metabolic syndrome. Studies show no signicant association between fasting plasma triglycerides, total cholesterol, or high-density lipoprotein (HDL) cholesterol and preterm birth or VLBW.44,67,68,70,72,73 In fact, a favorable lipid prole with a reduced circulating apolipoprotein- I level has been reported in preterm infants.74 Being overweight or obese also is a characteristic of the metabolic syndrome. However, young adults born prematurely have a similar or lower BMI than their counterparts born at term.44,52,68,71 Fewer VLBW males, but not females, were overweight or obese relative to term infants.14 In children, prematurity is associated with reduced body fatness.75 Total and central fat mass, assessed by bioelectric impedance, dual X-ray absorptiometry, and skin fold thickness, are similar in young adults born prematurely and at term.48,52,68,70,72,76 Very few data support the hypothesis that preterm infants have a higher risk of increased trunk fat mass.77 Although a recent study of young adults supports an association between preterm birth and greater total fat mass and trunk fat mass, limb fat mass and total lean mass were also elevated, which suggests that relative body fat proportions were not altered.74
Effects of Early Nutrition. Very few studies have reported the inuence of nutrition per se on BP. Breastfeeding is not associated with BP at the age of 7.5-8 years, but is at the age of 13-16 years.55,56 Two randomized, controlled trials examined this issue. One compared banked human milk with a preterm formula, and the other compared term with preterm formula. A 10% increase in human milk consumption decreased mean arterial BP by 0.3 mm Hg. Consistent with these ndings, data for term infants show that breastfeeding reduces BP in later life.57 It should be pointed out, however, that the data suggest feeding in infancy has, at most, only a modest effect on BP either in term or in preterm infants. Thus, the effect has limited clinical or public health signicance. Feeding an enriched formula versus a term formula does not alter long-term BP.56 The role of long-chain polyunsaturated fatty acids (LCPUFAs) on BP is also uncertain. Kennedy et al58 found no significant effect of LCPUFA supplementation during infancy in preterm infants on body composition and BP measured at 10 years. However, mean BP, SBP, and skin fold thickness were higher in girls who received LCPUFA supplementation. These data indicate that LCPUFA supplementation may have negative long term effects.59 However, because no adjustment for current height was made, no denite conclusion can be drawn from this study.60 Furthermore, these results are discordant with previous data for term infants showing that dietary supplementation with LCPUFAs during infancy is associated with lower BP in childhood.61
Metabolic Syndrome in Preterm Infants
Effects of Prematurity. Insulin resistance or glucose

intolerance may develop in VLBW patients during childhood,62-66 but is more likely observed during adulthood.52,67-69 Although differences in fasting serum glucose concentration or fasting insulin concentration are used as outcomes in some studies,44,68 more precise insulin resistance tests have been used in others.52,67-70 Hovi et al68 showed a 40% increase in the 2-hour insulin concentration (17.5-66.8) and a 19% increase in the insulin-resistance index (5.7-33.7), as determined by Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR), in VLBW young adults compared with controls. Rotteveel et al52,71 used the more precise hyperinsulinemic euglycemic clamp and conrmed that VLBW young adults had a signicantly greater insulin resistance that remained signicant even after adjusting for current weight, height, or indices of fat mass. An abnormal lipid prole is one feature of the metabolic syndrome. Indeed, elevated triglycerides may be the rst
Effects of IUGR in Preterm Infants. Although a few studies suggest a relationship,65 in most studies, long-term insulin sensitivity, lipid prole, and body fat mass are not affected by IUGR in VLBW patients (Table).44,52,53,68,78 Having had IUGR does not signicantly affect indices of glucose intolerance and insulin resistance of former preterm infants in adulthood.44,68 Insulin sensitivity, measured by the hyperinsulinemic euglycemic clamp method in young adults, is the same in SGA and AGA VLBW groups.52 In most studies of preterm infants, IUGR does not affect fasting serum concentrations of triglycerides, total cholesterol or HDL cholesterol.52,67,68,70,72-74 Postprandial hypertriglyceridemia is observed in the metabolic syndrome and may be related to the development of cardiovascular disease. In one study, a standardized mixed meal test performed in SGA VLBW patients showed that IUGR men had a higher triglyceride levels than controls.71 This pattern was not seen in SGA VLBW women or AGA VLBW patients. These data suggest that IUGR might induce specically a higher risk of cardiovascular disease in men born very prematurely. Finally, having IUGR when born preterm does not appear to increase the risk for increased adiposity in the adult.52,70,74 Effects of Postnatal Growth. Some studies have shown
an association between later but not early growth and insulin resistance during childhood and adulthood (Table). Insulin concentrations at 9-12 years of age are associated with childhood weight gain, but not with weight gain before 18 months of age.65 Similarly, Irving et al44 showed that weight at 44 weeks after the mothers last menstrual period and weights measured during any 4-week period for up to 1 year were not associated with later insulin sensitivity. Neither the SDS for weight at term nor the change in score
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Vol. 162, No. 3, Suppl. 1 in 2 randomized controlled studies. Contrary to what they observed for BP and for lipid proles, breastfeeding was not signicantly associated with any indices of insulin resistance.81 There was also no difference between the term versus preterm formula fed groups. In further analysis, the authors pooled the data into groups of infants assigned to a nutrient enriched diet (enriched formula) versus a diet lower in nutrients (human milk or standard formula).81 When the studies were combined, split32-33 proinsulin was signicantly lower in the slow-growing groups. However, there are a number of important caveats with this study: (1) diets were given for only 2 weeks; and (2) growth was very poor in all infants. The average change in weight of the combined groups over a 2-week period was a loss of 56 g. These investigators also published similar data for a reference cohort of term infants. They show that the more rapidly growing cohorts had split 32-33 proinsulin levels similar to term infants, and the slower growing cohort had split 3233 proinsulin levels less than the term infants (Figure). Taken on face value this would suggest that preterm birth followed by substantial postnatal growth failure produces more favorable long-term metabolic consequences that normal term birth. Even if this conclusion is correct, it would be untenable and unethical to attempt to replicate this growth pattern in preterm infants given the clear impact of early growth on long-term neurodevelopmental outcomes. Furthermore, whether or not the proinsulin concentration values during adolescence are predictive of later insulin resistance also remains to be determined. These investigators also examined the effects of these diets on lipid prole at 1316 years.82 Preterm infants who received human milk for just 4 weeks showed marked benets in their lipid prole and a reduction of 14% in the low-density lipoprotein:HDL cholesterol compared with those who received preterm formula, attributable largely to a decrease in low-density lipoprotein cholesterol and related to the volume of breast milk
from birth to term is related to either the glucose or insulin concentrations or the HOMA-IR index.68 Finally, weight gain from birth to 40 weeks gestation is not associated with increased insulin sensitivity in children aged 4-10 years born prematurely.79 In contrast, weight gain from expected term through childhood is signicantly associated with insulin sensitivity.79 Another study also suggests that rapid weight gain from birth to 3 months of age is a poor predictor of insulin resistance at adult age.78 Fewtrell et al65 measured fasting blood glucose and insulin in former preterm infants at 9-12 years of age. Growth during the immediate postnatal period was unrelated to later glucose or insulin. Furthermore, once current body size was taken into account, insulin, proinsulin, and split proinsulin concentrations were negatively correlated with weight SDS at 18 months of age. In other words, preterm infants who were relatively heavier at 18 months of age were less likely to have elevated insulin levels at 9-12 years of age than their relatively lighter peers. This nding does not support a relationship between more rapid weight gain in preterm infants during the rst 18 months of life and later risk of insulin resistance. In contrast, late weight gain and adult fat accumulation strongly predicts insulin resistance.78 Growth patterns during infancy and childhood are of great importance to insulin sensitivity in later life.52 Increased height gain between 1 and 5 years of age and increased weight gain between 2 and 21 years of age are strongly associated with lower insulin sensitivity whereas increased weight gain between birth and 1 year are not.52 The few studies that sought an association between early growth and later lipid prole do not support the hypothesis that early growth in AGA preterm infants may be detrimental.53,68,74 In particular, Hovi et al demonstrated that neither the weight SDS at term nor the change in the score from birth to term was related to the glucose or insulin concentrations or the HOMA-IR index.68 Similarly, Finken et al53 found no association between the lipid prole in young adults born preterm and weight gain during the rst year of life. We have examined the effect of weight gain in preterm infants during the rst year of life on body composition over the same period.80 The quartile of preterm infants with the most rapid weight gain during this period had a greater percentage whole body adiposity than the quartile with the slowest growth. However, even the faster growing quartile had a lower percentage whole body adiposity than the reference term infant.
Effects of Early Nutrition. Very few studies have assessed

the effect of nutrient supply on long-term metabolic outcomes. Regan et al79 showed no signicant association between macronutrient or energy intakes and insulin sensitivity in preterm infants at 4-10 years. It should be pointed out that when a narrow range of intakes are compared, as in this study, it may be difcult to nd a relationship between early nutrition and long-term outcomes.79 Singhal et al examined the effect of various diets and growth rate on subsequent measures of insulin resistance
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Figure. Early diet and fasting 32-33 split proinsulin concentrations in adolescents born preterm fed either a higher-nutrient versus lower-nutrient neonatal diet (data from Singhal81). Normative values observed in adolescents born at term are shown as a shaded band. Lapillonne and Grifn
March 2013 consumed.82 The effects of term formula and preterm formula were similar.
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only know, or suspect, that there are problems at both ends of the spectrum, as poor and rapid early growth result in unfavorable health outcomes. The current data indicate that growth measures, especially weight gain, are not perfect surrogates for nutritional status in preterm infants; they should not be the only measures used to dene optimal nutritional intakes.
Early Growth Is Not a Perfect Surrogate of Nutritional Status in Preterm Infants

Monitoring growth is an essential component of good clinical care that easily indicates health and nutritional status. In pediatrics, research and clinical practice have focused almost exclusively on achieving adequate growth and preventing growth failure. Deviations in growth, especially decreases in growth, are associated with an increased risk of diseases in the short- and long-term. Different organs grow at very different rates. The brain and head circumference grow mainly during the rst 2 years of life. Fat mass, expressed as percent of body weight, increases from birth to about 6-9 months, decreases for about 5-6 years, then increases again. Many factors inuence growth. Genetic inuences play an important role and can be modied by environmental factors. Nutrition, a marker of environmental inuences, has a marked inuence on growth. In preterm infants, growth, and particularly weight gain, has been widely used as a marker of adequate nutritional support. However, the relationship among growth, nutrition, and human milk feeding is complex in very preterm infants. Enhanced postnatal growth and increases in head circumference, in particular, are associated with improved neurodevelopmental outcomes.23,83 Interestingly, head growth catch-up occurs more often with breast milk feeding during hospitalization84 even though breastfed preterm infants exhibit slower rates of growth than formula fed preterm infants. Furthermore, preterm infants whose mothers choose to breastfeed reach a higher development or IQ even though they have slow rates of growth early in life.85,86 The studies by Lucas et al31,32,54,56,81,82 are puzzling because, on one hand, they show that human milk feeding has benecial effects not only on neurodevelopment but also on later BP, and lipid prole and may improve some indices of insulin resistance. On the other hand, they also show that preterm formula feeding improves growth and neurodevelopment33,34 but may not confer any benets with regards to cardiovascular health and metabolic outcomes. Lucas et al65 have shown no signicant association between early growth and cardiovascular health or insulin resistance. This suggests that nutrition may affect development, brain, and organ growth independently of total body growth. If energy and protein intake affect development and are also main determinants of growth, weight gain, and body composition, other nutrients such as LCPUFAs, iron, zinc, copper, iodine, selenium, vitamin A, choline, and folate may affect development with limited or no effect on growth variables.3 Although poor early growth is associated with adverse neurodevelopmental outcomes, it is not reasonable to assume that rapid growth provides neurodevelopmental advantages. The utility of growth as the sole or principal indicator of nutrition status in the preterm infant is limited because we do not know what denes optimal growth. We
Clinical Implications
Preterm infants are exposed to extrauterine life during a period that normally is characterized by rapid intrauterine growth. EUGR is a frequent clinical feature of very preterm infants, which results from several factors that include increased metabolic demand, poor early metabolic intolerance, poor feeding tolerance, infections, respiratory distress, pharmacologic effects (eg, of glucocorticoids), and inadequate nutritional supply.16,87,88 The picture is often complicated by maternal conditions such as preeclampsia that may cause IUGR. The preterm infant is born during a critical period for brain growth. The data cited above indicate that even brief periods of relative undernutrition during a sensitive period of development may have signicant adverse effects on later development. The effect of early nutrition on subsequent IQ and verbal IQ can be signicant (reaching 6-15 IQ points in some studies), clinically relevant, and likely to have a large population impact. A lot of attention has focused on the role of the early protein and energy decit because it alters brain development and weight gain, an easily accessible measure. However, efforts should continue to focus on improving nutritional care because deciencies of other nutrients, which may not affect the growth trajectory, are likely. Adults born prematurely have a signicantly greater risk of developing hypertension and insulin resistance than those born at term. In contrast to adults born IUGR or LBW at term, adults born prematurely do not have an increased propensity for developing the other features of metabolic syndrome (ie, dyslipidemia and obesity). These differences are not attributable to body size or composition or to fat distribution. Furthermore, fetal growth does not seem to play a significant role in the later risk of hypertension or insulin resistance in VLBW infants as it does in term infants. Very interestingly, current data suggest that growth velocity between birth and expected term and/or before 12-18 months post-term has no signicant effect on later BP and metabolic syndrome, and reduced growth during hospitalization or during the rst 4 months of life impacts later development signicantly. In contrast, growth during late infancy and childhood appears to be major determinant of later health, suggesting a nutritional intervention during this period would be effective. Our review also highlights the paucity of data on the effects of nutrition during hospitalization or after discharge on the risk of hypertension or insulin resistance. Therefore, at present, no data support the hypothesis that interventions aimed at discouraging weight gain during hospitalization and after discharge would improve adult body
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Vol. 162, No. 3, Suppl. 1 months post-term; 1-5 y growth for the period from 1-5 years; and so on. Finally, we recommend that future studies be designed to assess and dene growth in multiple time periods. The available data suggest that undernutrition or reduced growth during relatively short time frames can have significant impact on later development and health. Time periods are also clinically important because nutrition is administered by different routes (ie, intravenously, enterally, orally); in different forms (ie, parenteral nutrition, human milk, preterm formula, post-discharge formula, term formula, solid food); in different doses (xed dose when enterally fed, ad libitum when bottle fed or breastfed); and monitored by a variety of individuals (physicians in neonatal intensive care unit, general practitioners or primary care pediatricians after discharge) during critically-important periods in development. n
The authors thank the Association pour la Recherche et la Formation en N eonatologie (ARFEN) for providing technical assistance.
composition and reduce the chance of developing hypertension or type 2 diabetes. It is, therefore, vital that preterm infants receive sufcient nutrients to prevent EUGR and impaired neurodevelopment. Nutritional protocols and current practices do not always follow current guidelines.16,79,87,88 Provision of inadequate amounts of energy and protein are frequently noted, as discussed in other chapters of this issue. Alterations of dietary intake during the perinatal period affect metabolic programming and growth outcomes. In view of the documented effects of transient undernutrition on brain development and on metabolic outcomes, we encourage physicians to follow the most recent guidelines for preterm infants, which review and synthesize the best available nutritional knowledge. We strongly endorse human milk feeding as the preferred method to nourish preterm infants during hospitalization and after discharge. When human milk is not available, products designed to support growth rates similar to the intrauterine rate are recommended. Furthermore, we recommend that the term aggressive nutrition, a term coined to characterize nutrition support that follows guidelines but implies a potentially dangerous policy, should no longer be used. We believe that aggressive nutrition is the standard of care, and anything less is inadequate. To reect this, we suggest that the term adequate nutrition be used in place of the misnomer aggressive nutrition.
Author Disclosures
Alexandre Lapillonne, MD, PhD and Ian Grifn, MD, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. All authors have participated to the review of the available data and to the writing of the manuscript.
Reprint requests: Alexandre Lapillonne, MD, PhD, Department of Neonatology, Necker Hospital, 149 rue de Sevres, 75015 Paris, France. E-mail: alexandre.lapillonne@nck.aphp.fr.
Future Directions
We emphasize strongly that preterm infants be considered distinct from LBW term infants because they have unique medical vulnerabilities, states of maturation, and nutritional needs that predispose them to high rates of morbidity and alterations in development and long-term health. Furthermore, the nutritional decits of preterm infants are very specic and often iatrogenic. Extrauterine undernutrition of preterm infants can be confused with intrauterine malnutrition of IUGR term infants because both results in a similar early phenotype, but they differ quantitatively and qualitatively in many signicant ways. Therefore, we recommend that future studies in this area distinguish infants by weight and gestational age and not just by birth weight. Current nutritional practices applied to the preterm infant commonly result in undernutrition and poor growth. Future research should focus on the potential link between early nutrition and long-term neurologic and developmental outcomes and incidence of hypertension and type 2 diabetes in individuals born prematurely. Early growth appears frequently in the literature without denition and has been used to dene a wide spectrum that spans the rst 2 weeks to the rst 2 years of life. There is no agreement on the denitions of early growth and later growth for preterm infants and these terms should no longer be used. For clarity and ease of comparison among studies, we propose to clearly specify the period examined as follows: birth to term for the period between birth and the due date; term-6 mo growth for the period from expected term to 6
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55. 56.
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effects of early growth and current body composition. Pediatr Res 2006; 59:604-9. Singhal A, Cole TJ, Fewtrell M, Deaneld J, Lucas A. Is slower early growth benecial for long-term cardiovascular health? Circulation 2004;109:1108-13. Lucas A, Morley R. Does early nutrition in infants born before term programme later blood pressure? BMJ 1994;309:304-8. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet 2001;357: 413-9. Owen CG, Whincup PH, Gilg JA, Cook DG. Effect of breast feeding in infancy on blood pressure in later life: systematic review and meta-analysis. BMJ 2003;327:1189-95. Kennedy K, Ross S, Isaacs EB, Weaver LT, Singhal A, Lucas A, et al. The 10-year follow-up of a randomised trial of long-chain polyunsaturated fatty acid supplementation in preterm infants: effects on growth and blood pressure. Arch Dis Child 2010;95:588-95. Lapillonne A. Impact of LCPUFA supplementation on body composition of girls born preterm. Arch Dis Child 2011;96:206. author reply -7. Hoffman JP. Long-term health consequences of LCPUFA supplementation of preterm girls. Arch Dis Child 2011;96:205-6. author reply 6-7. Forsyth JS, Willatts P, Agostoni C, Bissenden J, Casaer P, Boehm G. Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised controlled trial. BMJ 2003;326:953. Bo S, Bertino E, Bagna R, Trapani A, Gambino R, Martano C, et al. Insulin resistance in pre-school very-low-birth weight pre-term children. Diabetes Metab 2006;32:151-8. Bazaes RA, Alegria A, Pittaluga E, Avila A, Iniguez G, Mericq V. Determinants of insulin sensitivity and secretion in very-low-birth-weight children. J Clin Endocrinol Metab 2004;89:1267-72. Darendeliler F, Bas F, Bundak R, Coban A, Sancakli O, Eryilmaz SK, et al. Insulin resistance and body composition in preterm born children during prepubertal ages. Clin Endocrinol 2008;68:773-9. Fewtrell MS, Doherty C, Cole TJ, Stafford M, Hales CN, Lucas A. Effects of size at birth, gestational age and early growth in preterm infants on glucose and insulin concentrations at 9-12 years. Diabetologia 2000;43: 714-7. Hofman PL, Regan F, Jackson WE, Jefferies C, Knight DB, Robinson EM, et al. Premature birth and later insulin resistance. N Engl J Med 2004; 351:2179-86. Dalziel SR, Parag V, Rodgers A, Harding JE. Cardiovascular risk factors at age 30 following pre-term birth. Int J Epidemiol 2007;36:907-15. Hovi P, Andersson S, Eriksson JG, Jarvenpaa AL, Strang-Karlsson S, Makitie O, et al. Glucose regulation in young adults with very low birth weight. N Engl J Med 2007;356:2053-63. Willemsen RH, de Kort SW, van der Kaay DC, Hokken-Koelega AC. Independent effects of prematurity on metabolic and cardiovascular risk factors in short small-for-gestational-age children. J Clin Endocrinol Metab 2008;93:452-8. Rotteveel J, van Weissenbruch MM, Delemarre-Van de Waal HA. Decreased insulin sensitivity in small for gestational age males treated with GH and preterm untreated males: a study in young adults. Eur J Endocrinol 2008;158:899-904. Rotteveel J, van Weissenbruch MM, Twisk JW, Delemarre-Van de Waal HA. Abnormal lipid prole and hyperinsulinaemia after a mixed
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David I. Tudehope, AM, MBBS, FRACP
Key principles underpinning feeding guidelines for preterm infants include support for developmental care, breastfeeding, milk expression, and creating feeding plans. Early trophic feeding with colostrum and transitional milk improves immune protection and promotes gut maturation. Studies of preterm infants demonstrate that feeding mothers milk (MM) decreases the incidence of infection and necrotizing enterocolitis and improves neurodevelopmental outcome but may decrease ponderal and linear growth. Standard practice in neonatal units is to promote mothers own milk as the feed of choice for all infants. However, it is not feasible or prudent to do so for all preterm infants. Mothers of preterm infants have lower rates of successful breastfeeding compared with those of term infants. MM can contain harmful bacterial or viral pathogens. Although preterm human milk (HM) contains higher concentrations of protein, sodium, zinc, and calcium than mature HM, it falls short of supplying adequate quantities of nutrients required by preterm infants. Therefore, HM supplemented with nutrients is recommended for all infants born before 32 weeks gestation and for certain infants born at 32-36 weeks of gestation. HM is the preferred feed, but preterm formula is an appropriate option when there is an inadequate supply of MM. (J Pediatr 2013;162:S17-25).
he American Academy of Pediatrics, World Health Organization (WHO), and United Nations Childrens Fund recommend that human milk (HM) be the exclusive nutritional source for full-term infants for the rst 6 months of postnatal life and provided in combination with complementary foods for at least 1 year.1-3 Breastfeeding and use of HM have many advantages for infants, mothers, families, and society.2-4 The role of HM in preterm infants is less well dened. Mothers of preterm infants encounter a variety of unique challenges that result in low rates of breastfeeding. Many of their infants are unable to breastfeed effectively for days, weeks, or even months after birth. These mothers must learn to establish and maintain milk production by expression and require support in the hospital and post-discharge to achieve and sustain exclusive breastfeeding. In the US, even though 69% of term infants and mothers initiate either partial or exclusive breastfeeding, the average rate of breastfeeding for preterm infants is 50% at hospital discharge and even lower if the infant is <1500 g birth weight.5 When lactation can be established, mothers preterm milk alone may not provide adequate nutrition. The estimated nutritional requirements of the preterm infant have been dened as those needed to support the rates of growth and nutrient accretion of the third trimester fetus. The amount of protein, sodium, phosphate, and calcium in preterm HM falls short of these needs.6 Therefore, it may be necessary to fortify mothers preterm milk with additional nutrients to meet requirements.1 Although HM is the preferred feed for premature infants, preterm formula is an appropriate option, especially if there is an inadequate supply of mothers milk (MM).
HM
HM is not a discreet entity, but one that varies with time after delivery, length of gestation, length of each lactation episode, and method of expression and collection. Colostrum is a pre-milk uid rich in immunoglobulins and immune cells that is produced during the rst 24-48 hours postpartum. Transitional milk is produced during the 3rd-14th day postpartum; it is rich in fat, lactose, and vitamins. Mature milk is produced after around 2 weeks postpartum. Mature milk is less concentrated than transitional milk, and its lower nutrient density is maintained throughout the rst postpartum year. The composition of HM varies with the length of gestation. Preterm breast milk, especially transitional milk, contains higher levels of protein, sodium, chloride, calcium, zinc, copper, and folate than term breast milk (Table).7
CMV DBM EBM HM ICU IQ NEC
Cytomegalovirus Donor breast milk Expressed breast milk Human milk Intensive care unit Intelligence quotient Necrotizing enterocolitis
MM LBW NICU RCT TPN VLBW WHO
Mothers milk Low birth weight Neonatal intensive care unit Randomized controlled trial Total parenteral nutrition Very low birth weight World Health Organization
From the Mater Medical Research Institute and the School of Medicine, The University of Queensland, Queensland, Australia Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 also contains lactoferrin, lysozyme, and secretory IgA that inuence host resistance of the preterm infant. Lipids and Fatty Acids Lipids in HM provide about 50% of the energy needs of the preterm infant. The lipids in HM include the long chain polyunsaturated fatty acids and gangliosides. The composition of fatty acids on the triglyceride molecule and the presence of bile salt-stimulated lipase allow the low birth weight (LBW) infant to absorb greater amounts of fat compared with formula,10 but only if the milk is not pasteurized. Carbohydrates Carbohydrates in HM include lactose and oligosaccharides. LBW infants absorb >90% of the lactose in HM. The nonabsorbed lactose remains in the gastrointestinal tract to soften stool, improve absorption of minerals, and support the growth of benecial intestinal ora. Approximately 10%-15% of the carbohydrate in HM are oligosaccharides, which also remain in the gastrointestinal tract and act as prebiotics that facilitate growth of bacteria such as Bidus spp. Oligosaccharides prevent bacterial attachment to the host mucosa and contribute in preventing systemic infection and necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants.11 Inositol is a component of membrane phospholipids, and compounds containing inositol are important in signal transduction. Breast milk, particularly colostrum, contains high concentrations of inositol (about 1.8 mmol/L). Other Components HM contains many trophic factors (insulin-like growth factor-1, epidermal growth factor, and transforming growth factor-a) that are believed to enhance development of the gastrointestinal tract.12 HM also contains numerous enzymes such as lipase, which improves lipolysis and fat absorption in the gut. Term and preterm HM contains a number of cells (macrophages, polymorphonuclear leucocytes, T and B lymphocytes), antimicrobial factors (secretory IgA, lactoferrin, lysozyme, B12 and folate-binding proteins, complement, bronectin, and mucin), and antiviral factors13 that confer local immunologic protection to an infants gastrointestinal tract.
Table. Composition of preterm transitional, mature preterm, and term mature milk
Nutrient (units/L) Macronutrient Total protein, g Energy, kcal Fat, g Carbohydrate, g Minerals Calcium, mmol Phosphorus, mmol Magnesium, mmol Sodium, mmol Chloride, mmol Potassium, mmol Trace elements Iron, mg Zinc, mmol Copper, mmol Manganese, mmol Iodine, mmol Vitamins Vitamin A, IU Vitamin D, IU Vitamin E, mg Vitamin K, mg Folate, mg Preterm* transitional 6-10 d 19 0.5 660 60 34 6 63 5 8.0 1.8 4.9 1.4 1.1 0.2 11.6 6.0 21.3 2.2 13.5 2.2 23 58 13 9.2 2.1 6 8.9 500-4000 40 2.9-14.5 0.7-5.3 33 Preterm mature 22-30 d 15 1 690 50 36 4 67 4 7.2 1.3 3.0 0.8 1.0 0.3 8.8 2.0 14.8 2.1 12.5 3.2 22 33 14 8.0 3.1 7.3 6.6 1.25 500-4000 40 2.9-14.5 0.7-5.3 33 Term mature $30 d 12 1.5 640 80 34 4 67 5 6.5 1.5 4.8 0.8 1.3 0.3 9.0 4.1 12.8 1.5 13 2.0 22 15-46 3.2-6.3 3-6 600-2000 2-3 1.2-9.2 1.8
*Values are mean SD. Adapted from Schanler RJ and Atkinson SA in Tsang et al.6
Composition of HM
The composition of HM varies with the time during each lactation episode. Foremilk is released initially. After about 2-3 minutes, hindmilk is produced. Hindmilk has a higher fat and energy content than foremilk8 and, thus, promotes weight gain better than foremilk or regular breast milk. Drip milk is the milk that drips from the opposite breast during breastfeeding. It was used extensively in the 1980s for feeding preterm infants until it was realized that drip milk had a low fat and energy content, similar to foremilk. The composition and volume of expressed breast milk (EBM) vary with the method used for expression. For example, sodium concentrations may be higher with hand pumping than mechanical pumping.7 Protein and Amino Acids HM contains a heterogenous mixture of bioavailable proteins and peptides that matches the needs of the developing infant. Colostrum is whey-dominant and contains high concentrations of growth and immune protective factors. As time from delivery increases, the abundance of these factors decreases, and mature milk has more casein as a source of amino acids. HM has a low protein level of only 0.9-1.2 g/100 mL, 70% of which is whey and 30% is casein.9 The whey protein in HM is predominantly a-lactalbumin, which is digested easily by the preterm infant and acts to promote gastric emptying. Human whey protein
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Methods Used to Meet the Nutritional Needs of the Preterm Infant

It is widely appreciated that breastfeeding provides a number of benets to a mother and her infant. However, initiating breastfeeding at the birth of a preterm infant is not always feasible, and MM may not be available in adequate amounts. There are other ways to meet the nutritional needs of preterm infants. Donor Breast Milk Donor breast milk (DBM) derives from donor milk banks, services that collect, screen, process, and dispense HM
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March 2013 donated by nursing mothers who are not related to the recipient infant. Guidelines for the establishment and operation of HM banks are available.14 Donors are required to be in good health, nonusers of drugs, alcohol, and cigarettes, and screened for HIV-1, hepatitis B and C, and syphilis. DBM is identied as being collected following a term or preterm delivery and < or $30 days from date of delivery. DBM is subjected to pasteurization, which removes potentially harmful bacteria but also lipase, lymphocytes, and other important components of HM. Nutritional Supplements Preterm infants fed solely preterm HM have poor rates of growth and nutritional decits. The nutritional decits of preterm HM can be corrected by adding nutrients such as glucose polymers, medium-chain fatty acids, vitamins (vitamin A, vitamin D, thiamine, riboavin, pyridoxine, nicotinamide, and ascorbic acid), or minerals (iron, zinc, calcium, and phosphate). Alternatively, HM fortiers that contain multiple components (macronutrients as well as minerals calcium, phosphorus, sodium, and vitamins A, D, E, K, riboavin, folic acid, and zinc) can be used. These fortiers are available in powdered or liquid form and must be prepared with care. It is important to mix powdered fortiers in HM thoroughly so that the nutrients can be absorbed easily. It should be appreciated that fortiers dilute HM, including nutrients, growth factors, and anti-infective agents, even though they provide adequate quantities of other types of essential nutrients. Formula When a mother cannot produce sufcient amounts of milk or her infant is not growing appropriately, preterm formulations are available to help meet the nutritional needs of a preterm infant. Preterm formulas are designed to provide nutrient intakes to match intrauterine accretion rates and are enriched with energy, typically 80-82 kcal/100 mL, protein, minerals, and trace elements.
SUPPLEMENT
fed formula. Preterm infants have reduced pancreatic and lingual lipase activities, a reduced bile pool and, therefore, decreased fat absorption and more steatorrhea relative to term infants. Providing HM to preterm infants increases fat absorption because it contains many enzymes, including lipase, that enhance intestinal lipolysis. In addition, HM contains hormones, peptides, amino acids, nucleotides, growth factors, and inhibitors of proinammatory cytokines15 that enhance maturation of the mucosal barrier and protects preterm infants from foreign proteins. Several randomized controlled trials (RCTs) that compare feeding HM or formula to preterm infants have reported a decrease in transient gastrointestinal intolerance, transient cessation of feeds, and NEC in HM-fed infants, but only when fed MM. In contrast, one meta-analysis found no signicant difference between the effects of unsupplemented, term DBM and formula on feed intolerance in preterm infants.16 Colonization of the gastrointestinal tract commences immediately after birth with the initiation of enteral feeding and becomes well established within a few days. Bidobacteria and Lactobacilli predominate in infants fed MM; other enteric organisms appear less frequently. Coliforms, Enterococci, and Bacteroides spp predominate in formula-fed infants. Preterm infants are susceptible to abnormal colonization because enteral feeds are often delayed and preterm infants are exposed to broad spectrum antibiotics and endemic organisms within the neonatal intensive care unit (NICU) environment.17 Infectious Diseases and NEC Preterm infants fed HM have lower incidence of late onset sepsis, urinary tract infection, diarrhea, and upper respiratory tract infection than those fed formula.18 Providing HM results in less pathogenic fecal ora and, importantly, offers the potential to reduce the quantity of fecal pathogens acquired in the nursery. Preterm infants fed MM have lower rates of NEC, diarrhea, and urinary tract infection than those fed term formula.19 Feeding MM signicantly decreases the incidence of systemic or local infections and NEC in LBW infants.7 Neurodevelopmental Outcomes Children classied as VLBW have poorer cognitive function and academic performance than those who have normal birth weights. Several studies indicate that feeding HM has a positive effect on neurodevelopmental outcomes in LBW infants. One prospective, nonrandomized study of 300 infants <1850 g birth weight compared intelligence quotient (IQ) scores at 7.5-8 years of age between those receiving DBM or formula.20 After correcting for social and educational factors, there was an 8.3 point IQ advantage for those receiving DBM and a dose-dependent relationship between proportion of DBM and IQ score. Breastfeeding was associated with signicantly higher IQ scores than formula feeding in a meta-analysis of 3 studies of LBW infants.21 The results from other studies are not as clear. A multicenter study of 463 preterm infants <33 weeks gestational age
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Benets of HM and Breastfeeding for Preterm Infants

Feeding HM to term infants provides nutritional, gastrointestinal, immunologic, developmental, and psychological benets that may impact their long-term growth and development. HM provides nutrients and energy as well as a range of substances that promote growth and development, protect the infant during its vulnerable early life, and prevent disease as an adult. These benets are likely to also apply to preterm infants, although less information is available about this population. Gastrointestinal Tract HM provides a number of benets to the developing gastrointestinal tract. HM promotes more rapid gastric emptying, improves gut motility, and usually results in more frequent stooling.15 Preterm infants fed HM tolerate full enteral feeds more rapidly and require less parenteral nutrition than those
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Vol. 162, No. 3, Suppl. 1 pitalization. There are many reasons to explain these decits. The concentrations of protein and fat in preterm milk vary widely. Protein content decreases throughout lactation. Serum albumin and blood urea nitrogen concentrations may decline in preterm infants as a result of inadequate dietary protein intake. Fat content varies from early to late lactation, throughout the day, from mother to mother, and within a single expression (eg, hind milk can contain up to 3 times as much fat as foremilk). Further variations in fat content can occur with collecting, mixing, storing, and mode of enteral feeding. Healthy preterm infants usually tolerate 160180 mL/kg/d of milk, whereas infants with chronic neonatal lung disease might only tolerate 120-140 mL/kg/d yet have higher energy requirements because of the increased work of breathing. Nutritional Supplements Specic nutrient deciencies of preterm HM can be corrected through appropriate supplementation with fortiers. The Cochrane Systematic Review of HM protein supplementation with approximately 1.5 g/kg/d evaluated a total of 90 VLBW infants in 4 RCTs (3 trials using HM protein and 1 using bovine casein). Protein-supplemented infants grew better by 3.6 g/kg/d weight gain, 0.18 cm/wk length, and 0.15 cm/wk head circumference compared with unsupplemented infants, but no outcomes past term were recorded.30 A separate Cochrane Systematic Review of studies concluded that multicomponent fortication of HM is associated with short-term improvements in weight gain (2.3 g/kg/d), linear growth (0.12 cm/wk), and head growth (0.12 cm/wk) in the short term.31 However, the sample size was too small to determine whether multicomponent fortication of HM provided long-term benet in growth or neurodevelopmental outcome or deleterious effects such as NEC or gastrointestinal intolerance. The authors concluded that it is unlikely that further studies evaluating fortication of HM versus no fortication will be performed and that further research should compare different proprietary preparations and evaluate short- and long-term outcomes, in search of the optimal composition of fortiers. It should be cautioned that adding a fortier that contains large amounts of calcium to preterm EBM has the potential to adversely affect fat absorption and the intrinsic host resistant properties of the milk. Some studies have demonstrated signicantly lower fat absorption, and therefore lower energy, and lower growth rates in infants fed fortied HM compared with preterm formula.
found no difference in IQ scores between groups fed supplemented HM or formula from birth to term chronological age.22 However, at 12 months chronological age, the duration of feeding supplemented MM was shown to be positively associated with Bayley Mental Development Index. In two other studies, LBW infants were randomized to receive unsupplemented drip donor term milk or calorie-enriched preterm formula from birth until hospital discharge. In one study, there was no difference in neurodevelopment at 18 months.23 In contrast, the other study reported higher scores at 37 weeks gestational age on the Neonatal Behavioral Assessment Scales for infants who received standard infant formula.24 More work needs to be done to delineate the effects of HM on neurodevelopment. Other Benets Breastfeeding has a protective effect against atopic disease for up to 4 years of age, but only when there is a high risk of atopy.25 HM fed infants have a decreased incidence and severity of retinopathy of prematurity compared with infants fed preterm formula.26 The ability to provide breast milk may be an important psychological benet for a mother who is able to provide little or none of the care needed by her critically ill preterm infant. Mothers who breastfeed are reported as having strong feelings of attachment, maternal empowerment, and self-condence and esteem.27
Potential Disadvantages of HM for Preterm Infants

Transmission of Infection via HM HM has been recognized as a source of transmission of several pathogens, including bacteria, viruses, and possibly parasites. Nonetheless, there are few infectious pathogens that pose risks to the newborn that outweigh the potential benets of breast milk. Maternal infection with HIV, tumor viruses, active tuberculosis, and untreated maternal bacteremia with a virulent pathogen are notable exceptions in the industrialized world. Holder pasteurization effectively removes cytomegalovirus (CMV) infectivity and should be used for DBM samples. Early studies indicated that freezing may be an effective technique, but late viral RNA and viral infectivity was shown to persist after freezing at 20 C for up to 10 days.28 Although not an ideal approach, a mother who is known to be infected with CMV may consider freezing her own milk to decrease the rate of CMV transmission. Although Herpes simplex types 1 and 2, Varicella zoster, and Epstein-Barr viruses have been detected in preterm breast milk, feeding with HM has not been shown to be a signicant route of transmission.29
Summary of Evidence
Data from meta-analyses and RCTs indicate that feeding with DBM rather than preterm or term formula may reduce the incidence of NEC. There are insufcient data to conclude whether there are neurodevelopmental advantages associated with DBM compared with preterm formula, although there is some evidence that DBM is better than term formula. Growth is slower in the short term in infants fed DBM than those fed formula. There are insufcient data to assess
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Nutritional Gaps with Feeding Mothers Unfortied Preterm Breast Milk

Preterm infants fed exclusively unfortied HM have poor rates of growth and nutritional decits during and after hosS20
March 2013 the effects on long-term growth outcomes or feed intolerance in VLBW infants, and there are no data available on specic nutrient deciencies. All trials were small, unblinded, and most used term drip milk, which has a lower calorie density than hindmilk. Further, all but one of the studies was initiated over 20 years ago. Since that time, formula and nutrient fortiers for HM have been adapted to meet the special needs of preterm infants. Overall, however, the available evidence suggests that providing LBW infants with DBM rather than formula, particularly term formula, may result in some advantages to the infant.
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assists the removal of breast milk. Early non-nutritive sucking from about 32 weeks postmenstrual age accelerates the transition from enteral feeding to full suck feeding. The use of galactogogues, such as the antidopaminergic drugs, metoclopramide, or domperidone, can be effective when milk supply dwindles. Domperidone is considered the ideal galactogogue because of its efcacy, lack of pediatric concerns, and only rare, mild side effects in lactating women.33 Major technological advances based on the pioneering work of lactation researcher Peter Hartmann have recently occurred in design and function of breast pumps that more nearly mimic the sucking of a mature infant on the breast. The latest innovation is a hospital-grade electric double pump with 2-phase expression pumping, which results in reduced pumping time through faster let-down and milk ow and has been proven to remove as much milk as a breastfeeding infant.34 Create a Protocol for Storing Breast Milk To ensure that an infant receives her MM, strict guidelines need to be established and followed. The protocol used at Mater Mothers Hospital is shown in the Figure. Milk should be collected in either glass or rigid plastic containers and not in plastic bags because milk stored in plastic bags may lose immune components or become contaminated. The mother is provided with computer printed labels to be used on every container of EBM including date and time of expression. Parents are not permitted to access refrigerator/ freezer for storage or retrieval of milk. Before feeding EBM to an infant, two authorized personnel must check the labeled storage container of EBM against the identication label on the feed chart and one of the infants attached identication tags to ensure appropriate matching. Establish a DBM Bank Given the many benets of providing HM to preterm infants, it makes sense to establish HM banks to serve mothers who are unable to provide sufcient amounts of milk to their infants. HM banking, popularized in the 1980s, received a major blow with the global reports of transmission of infectious diseases such as HIV, CMV, and tumor virus via breast milk. The WHO/United Nations Childrens Fund Global BabyFriendly Hospital Initiative subsequently led to a revival of interest in donor milk banks.2,3 A DBM bank is a service that collects, screens, processes, and dispenses HM donated by nursing mothers who are not related to the recipient infant. Breast milk banks are housed in hospitals or are free-standing. Guidelines and accreditation for HM banking established by state or local regulating agencies cover soliciting, donors, collecting, processing, and distributing the milk. Donors are healthy, nonusers of drugs, alcohol, and cigarettes, and are screened for HIV-1, hepatitis B and C, and syphilis. Donors, who are not paid, are separated into term or preterm delivery and < or $30 days from date of delivery. Each batch is tested for bacterial colony counts before and after Holder pasteurization. DBM is dispensed according to prescription by physician. Preterm infants are the most
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Feeding Plan for Preterm Infants

Availability of Breast Milk Mothers are usually very anxious and often unwell after preterm delivery, especially if the infant requires intensive care. Although feeding may not be seen as an immediate priority after admission, mothers must be educated that the provision of breast milk is a most important part of their infants care. For most mothers, breast milk is not available in large quantities until a few days after birth. Mothers need to be encouraged to continue with breast expression regularly as this may increase supply. Often only small amounts of colostrum are available in rst 1-5 days from a sick mother who has experienced a complex delivery. Even small amounts of colostrum are important to the preterm infant and must be fed. DBM can be used to supplement colostrum. After normal birth, initiation of lactation can take a few days. Enteral feeds should be started in preterm infants within 48 hours of birth, although they may be held for up to 72 hours after birth while waiting for breast milk to become available if the mother wishes. Milk volumes are low initially, and healthy, term babies receive little milk for the rst few days of life. Milk transfer rates have been reported to be 6-10 mL/kg on day 1 and 13-25 mL/kg on day 2. These rates are low relative to current uid management protocols, which recommend provision of up to 60-80 mL/kg on day 1. To create a feeding plan for late preterm infants, one should consider the low uid intake of healthy term infants and plan to monitor blood glucose. If breast milk is not available in sufcient quantity to provide an infants nutritional requirement, provision of supplementary intravenous uids or preterm formula should be discussed with the mother. Strategies to Increase Breast Milk Supply Mothers need to express frequently over the 24-hour day and cumulatively for more than 100 minutes per day for optimal milk production.32 Mothers need to be advised, shortly after delivery, about the benets of colostrum for their infant and be provided with written information. An electric breast pump is far quicker and more efcient than hand expression or a manual breast pump and should be made available with disposable items. Simultaneous pumping of both breasts is time-efcient for some women. Skin-to-skin contact (kangaroo care) can contribute to bonding, enhanced milk production, and successful exclusive breastfeeding.32 Breast massage
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Figure. Storage, defrosting, verication, and administration of EBM and articial baby milk. Used with permission from Mater Health Services, South Brisbane, Australia. (Continues)
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Figure. Continued.
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Vol. 162, No. 3, Suppl. 1 reached full enteral feeding at 150 mL/kg on day 20. EBM was half fortied with HM fortier on day 20 and fully fortied on day 24. Babys weight dropped to 965 g on day 9 and regained birth weight on day 18. On day 28 (32 weeks corrected age), baby weighed 1300 g (<10th centile) and on day 42 was 1585 g (5th centile). Babys rst suck feed was at 35 weeks corrected age and transition to full suck feeds took 21 days. She was discharged home fully breastfeeding at 38 weeks post-menstrual age with a weight of 2414 g (3rd percentile for corrected age). Observations of Case Study The hospital had a strong culture of breastfeeding VLBW infants and waited until MM milk was available and free of antibiotics before enteral feeding baby on day 5. This is not the best practice because the baby should have received trophic feeding on day 1or 2. Maternal antibiotics are rarely a contraindication for feeding colostrum to baby but if mother was too unwell to express her breasts or provide milk, a breast milk substitute, DBM if available or preterm formula, should have been offered to provide trophic benets. The lactation consultant should have interviewed mother in ICU before being transfered to the postnatal ward. Considering the mothers ill health post-cesarean delivery, an individualized feeding plan developed between staff in ICU and NICU most likely would have avoided much of delay in initiation and transitioning of breast milk feeding. Overall, a more aggressive approach to feeding and nutrition was required. Mother will need ongoing support in the community to continue exclusive breastfeeding for the undisputed longterm health benets for her VLBW infant. Careful monitoring of growth using the WHO chart is recommended and followup with a pediatrician and child health clinic with nursing staff familiar with extremely preterm infants. If babys weight does not exhibit catch up or falls below 3rd percentile, health professionals have a dilemma and nutritional options need to be discussed with mother. Again, a more aggressive approach to the introduction and advancement of enteral feeding may have provided better growth for this baby. n
frequent recipients of DBM, but term infants with gastrointestinal disorders and babies for adoption may have access to DBM, often at their parents expense. Monitor the Nutritional Adequacy of Preterm Breast Milk Preterm infants can require considerable medical care and have metabolic needs that exceed those of a normal term infant. When a nutrition plan is dened, it is necessary to monitor its effectiveness in maintaining appropriate rates and types of growth. The assessment of growth and nutrition of preterm infants, biochemical measures of growth, and postdischarge care strategies are discussed elsewhere in this issue.
Case Study
A secundagravid woman with mild hypertension of pregnancy has a very large painful, antepartum hemorrhage at 28 weeks gestation. Fetal monitoring shows non-reassuring fetal heart rate and an emergency cesarean delivery is performed under general anesthesia. Postoperatively mother continues to have bleeding because of a coagulopathy and requires several liters of blood transfusion and supportive mechanical ventilation in adult intensive care unit (ICU). The girl is born at 28 weeks gestation (1135 g [50th percentile on Fenton chart]) and is depressed at birth with Apgar scores 2 and 6 at 1 and 5 minutes, respectively (umbilical artery cord blood pH 7.14). She is resuscitated with intubation, positive pressure ventilation, and endotracheal surfactant and admitted to NICU where umbilical catheters were inserted and antibiotics gentamicin and amoxicillin commenced. She received 10% dextrose with electrolytes for 48 hours. She was weaned off mechanical ventilation at 60 hours and commenced on nasal continuous positive airway pressure at 8 cm H2O. Mother remained in ICU for 48 hours before being transferred to the postnatal ward, at which time she was seen by a lactation consultant. First colostrum was available on day 3 but discarded because of her antibiotic therapy. On day 5, she expressed 15 mL with aid of an electric breast pump, which was the rst milk fed to baby. Baby received starter solution of total parenteral nutrition (TPN) (protein 15 g/L) at 80 mL/kg on day 3, which was increased by 20 mL/kg/d and changed to maintenance TPN solution (protein 20g/L) on day 5. Fat emulsion was commenced on day 4 at 1 g/kg/d and increased by .05 g/kg/d up to 3 g/kg/d. Starter TPN solution (protein 15 g/L) was commenced at 100 mL/ kg on day 3 and increased by 20 mL/kg/d. On day 5 TPN was changed to maintenance (protein 20 g/L) and fat infusion reached maximum of 3 g/kg/d. Enteral feeds with mothers EBM were increased by increments of 10 mL/kg/ d from day 5. On day 7, baby was re-intubated and ventilated for increasing apnoea and coagulase negative Staphylococcus blood stream infection. Umbilical catheters were removed because of infection and replaced with a long peripheral cannula into superior vena cava for supplemental TPN. Feeds were withheld for 36 hours because of increase in light green aspirates. Feeds were recommenced at 20 mL/kg/d and nally
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Author Disclosures
David Tudehope, AM, MBBS, FRACP, received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. D. T. wrote this manuscript.
Reprint requests: David Tudehope, AM, MBBS, FRACP, Mater Medical Research Institute, Level 3 Quarters Building, Annerley Rd, Wooloongabba 4102, Queensland, Australia. E-mail: david.tudehope@mater.org.au.
References
1. Gartner LM, Morton J, Lawrence RA, Naylor AJ, OHare D, Schanler RJ, et al. Breastfeeding and the use of human milk. Pediatrics 2005;115:496506.
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2. WHO/UNICEF. Ten steps to successful breastfeeding. WHO/UNICEF Joint statement on the protection, promotion and support of breastfeeding: the special role of maternity services. Geneva and New York: World Health Organization and United Nations Childrens Fund; 1989. 3. WHO/UNICEF. WHO/UNICEF Joint statement on the protection, promotion and support of breastfeeding: the special role of maternity services. Geneva and New York: World Health Organization and United Nations Childrens Fund; 1989. 4. Kramer MS, Kakuma R. The optimal duration of exclusive breastfeeding: a systematic review. Geneva: World Health Organization; 2002. 5. Espy KA, Senn TE. Incidence and correlates of breast milk feeding in hospitalized preterm infants. Soc Sci Med 2003;57:1421-8. 6. Schanler RJ, Atkinson SA. Human milk. In: Tsang RC, Uauy R, Koletzko B, Zlotkin S, eds. Nutrition of the preterm infant. Cincinnati, OH: Digital Educational Publishing Inc; 2005. p. 333-56. 7. Edmond K, Bahl R. Optimal feeding of low birthweight infants. Technical review. Available at. Geneva: World Health Organization; 2006. p. 1-121, http://whqlibdoc.who.int/publications/2006/9789241595094_ eng.pdf. Accessed December 10, 2012. 8. Valentine CJ, Hurst NM, Schanler RJ. Hindmilk improves weight gain in low-birth-weight infants fed human milk. J Pediatr Gastroenterol Nutr 1994;18:474-7. 9. Atkinson SA. The effects of gestational age at delivery on human milk components. In: Jensen RG, ed. Handbook of milk composition. San Diego: Academic Press; 1995. p. 919. 10. AAP, Committee on Nutrition. Pediatric nutrition handbook. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2004. 11. Schanler RJ. Human milk for preterm infants: nutritional and immune factors. Semin Perinatol 1989;13:69-77. 12. Carver JD, Barness LA. Trophic factors for the gastrointestinal tract. Clin Perinatol 1996;23:265-85. 13. May JT. Antimicrobial factors and microbial contaminants in human milk: recent studies. J Paediatr Child Health 1994;30:470-5. 14. Human Milk Banking Association of North America. 2011 guidelines for establishment and operation of a donor human milk bank. Fort Worth, TX: Human Milk Banking Association of North America; 2003. 15. Donovan SM. Role of human milk components in gastrointestinal development: Current knowledge and future needs. J Pediatr 2006;149: S49-61. 16. Quigley MA, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2007;4:CD002971. 17. Yoshioka H, Iseki K, Fujita K. Development and differences of intestinal ora in the neonatal period in breast-fed and bottle-fed infants. Pediatrics 1983;72:317-21. 18. Narayanan I, Prakash K, Bala S, Verma RK, Gujral VV. Partial supplementation with expressed breast-milk for prevention of infection in low-birth-weight infants. Lancet 1980;2:561-3.
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19. Contreras-Lemus J, Flores-Huerta S, Cisneros-Silva I, OrozcoVigueras H, Hernandez-Gutierrez J, Fernandez-Morales J, et al. [Morbidity reduction in preterm newborns fed with milk of their own mothers]. Bol Med Hosp Infant Mex 1992;49:671-7. 20. Lucas A, Morely R, Cole TJ. Randomized trial of early diet in preterm babies and later intelligence quotient. Br Med J 1998;317:1481-7. 21. Anderson JW, Johnstone BM, Remley DT. Breast-feeding and cognitive development: a meta-analysis. Am J Clin Nutr 1999;70:525-35. 22. OConnor DL, Jacobs J, Hall R, Adamkin D, Auestad N, Castillo M, et al. Growth and development of premature infants fed predominantly human milk, predominantly premature infant formula, or a combination of human milk and premature formula. J Pediatr Gastroenterol Nutr 2003;37:437-46. 23. Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Arch Dis Child Fetal Neonatal Ed 1994;70:F141-6. 24. Tyson JE, Lasky RE, Mize CE, Richards CJ, Blair-Smith N, Whyte R, et al. Growth, metabolic response, and development in very-low-birth-weight infants fed banked human milk or enriched formula. I. Neonatal ndings. J Pediatr 1983;103:95-104. 25. Lucas A, Brooke OG, Morley R, Cole TJ, Bamford MF. Early diet of preterm infants and development of allergic or atopic disease: randomised prospective study. BMJ 1990;300:837-40. 26. Okamoto T, Shirai M, Kokubo M, Takahashi S, Kajino M, Takase M, et al. Human milk reduces the risk of retinal detachment in extremely low-birthweight infants. Pediatr Int 2007;49:894-7. 27. Bell EH, Geyer J, Jones L. A structured intervention improves breastfeeding success for ill or preterm infants. MCN Am J Matern Child Nurs 1995;20:309-14. 28. Hamprecht K, Maschmann J, Muller D, Dietz K, Besenthal I, Goelz R, et al. Cytomegalovirus (CMV) inactivation in breast milk: reassessment of pasteurization and freeze-thawing. Pediatr Res 2004;56:529-35. 29. Jones CA. Maternal transmission of infectious pathogens in breast milk. J Paediatr Child Health 2001;37:576-82. 30. Kuschel CA, Harding JE. Protein supplementation of human milk for promoting growth in preterm infants. Cochrane Database Syst Rev 2000;2:CD000433. 31. Kuschel CA, Harding JE. Multicomponent fortied human milk for promoting growth in preterm infants. Cochrane Database Syst Rev 2004;1: CD000343. 32. Conde-Agudelo A, Diaz-Rossello JL, Belizan JM. Kangaroo mother care to reduce morbidity and mortality in low birthweight infants. Cochrane Database Syst Rev 2011;3:CD002771. 33. Hale TW. Medications and mothers milk: a manual of lactational pharmacology. 14th ed. Amarillo, TX: Hale Pub; 2010. 34. Ramsay DT, Kent JC, Owens RA, Hartmann PE. Ultrasound imaging of milk ejection in the breast of lactating women. Pediatrics 2004;113: 361-7.
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Vitamin D, Vitamin A, Maternal-Perinatal Considerations: Old Concepts, New Insights, New Questions
Teresa Murgu a-Peniche, MD
Vitamins A and D are essential nutrients that play important roles in growth and development. Preterm and low birth weight infants have low levels of these nutrients and are at risk for developing detrimental health consequences associated with vitamin A and vitamin D deciencies. Preliminary data suggest that vitamin A and D supplementation is needed to prevent deciency. More work is needed to dene optimal doses, timing, and modes of administration to ensure that an adequate supply of these vitamins is available to meet the critical needs during pregnancy and in high-risk neonates. (J Pediatr 2013;162:S26-30).
he fat-soluble vitamins A and D play important roles in perinatal growth and development. Maternal concentrations of these vitamins directly affect concentrations in the fetus and neonate. Preterm infants have low stores and are at risk for vitamin deciency. Worldwide there is a silent epidemic of vitamin D deciency. This is an important public health problem that not only relates to bone disease in the population, but also may increase the risk of developing a wide range of common chronic diseases in adult life. Although vitamin A deciency is rarely seen in the US and other industrialized countries, it is a major nutritional concern in developing countries and is the leading cause of preventable childhood blindness.1
Vitamin D
Denition and Functions The term vitamin D refers to either vitamin D2 (ergocalciferol) or D3 (cholecalciferol). The major source of vitamin D3 is through the action of UV radiation from the sun on 7-dehydrocholesterol to form cholecalciferol in the dermal layers of the skin. Cholecalciferol is then enzymatically converted to 25-hydroxycholecalciferol [25(OH)D, or calcidiol]. The primary active form of vitamin D is 1,25-dihydroxycholecalciferol (calcitriol), which is formed from 25(OH)D by 1a-hydroxylase. Final activation of calcitriol occurs in the kidneys and in many other tissues throughout the body. Calcitriol circulates bound to a vitamin Dbinding protein to reach different organs. Calcitriol is also synthesized in or adjacent to regulated cellular targets, acting in an autocrine and paracrine fashion as well.2 Traditionally, the primary hormonal function of calcitriol is in controlling blood calcium concentrations by regulating the expression of genes involved in the intestinal absorption, renal excretion, and bone movement of this mineral. Many other functions of calcitriol have been identied as well, including immunomodulatory activity, insulin secretion, neuroprotective functions, and others. Maternal Vitamin D Status The best indicator of maternal vitamin D status is serum 25(OH)D concentration. New denitions of vitamin D sufciency have evolved based on functional biomarkers, and an optimal 25(OH)D level has not yet been determined. The Institute of Medicine has recently proposed the following denitions3: (1) Sufciency: 25(OH)D levels of at least 50 nmol/L (20 ng/ mL); however, serum 25(OH)D concentrations >75 nmol/L (>30 ng/mL) are not consistently associated with increased benet; (2) Risk of deciency: serum 25(OH)D level <30 nmol/L (<12 ng/mL); and (3) Potential risk for inadequacy: serum 25(OH)D level 30-50 nmol/L (12-20 ng/mL). Vitamin D deciency is highly prevalent in pregnant and lactating women and produces adverse consequences in these women, their fetuses and, ultimately, their growing infants and children.4,5 Several factors are responsible for this epidemic, including increased awareness of the injuries associated with sun exposure, insufcient vitamin D intake, and the rising prevalence of obesity. Adult obesity is associated with low 25(OH)D levels; whether vitamin D insufciency is a risk factor for increased body fat or body fat is a risk factor for vitamin D insufciency is not well understood.6
25(OH)D NbVAS ROP VLBW 25-hydroxycholecalciferol Newborn vitamin A supplementation Retinopathy of prematurity Very low birth weight
From the National Center for Child and Adolescent Health (CeNSIA), Mexico City, Mexico Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 March 2013 Data from the US National Health and Nutrition Examination Survey (2001-2006) revealed hypovitaminosis D (dened as a serum 25(OH)D level <50 nmol/L) in 80% of African American and 13% of white American women of reproductive age.5 Vitamin D deciency is widely prevalent in pregnant women, and mothers with vitamin D deciency mothers remain decient during lactation. In a study of American women at time of delivery, vitamin D deciency [dened as 25(OH)D of <37.5 nmol/L] and insufciency [dened as 25(OH)D of 37.5-80 nmol/L] were detected in 29.2% and 54.1% of black women, 45.6% and 46.8% of black neonates, 5.0% and 42.1% of white women, and 9.7% and 56.4% of white neonates. As recommended, 90% of mothers in the study had prenatal vitamin D intake of 400 IU/day.7 Similar results were reported in a study from northern India, where low levels of 25(OH)D (<22.5 ng/mL) were observed in >80% of women and >95% of infants.8 These studies highlight the high prevalence of vitamin D deciency in pregnant women and their neonates. Maternal Consequences of Vitamin D Deciency during Pregnancy Vitamin D deciency has been linked to bone disease (ie, rickets and osteomalacia). In malnourished populations, osteomalacia in mothers and abnormal skeletal metabolism in fetuses and infants have been reported.9 Nonclassical consequences of vitamin D deciency have been detected in pregnant women; experimental and observational studies have suggested that vitamin D deciency may be associated with increased risk of preeclampsia, insulin resistance, and gestational diabetes.10,11 Whether this association suggests causality cannot be determined based on the available data. Maternal Vitamin D Status and the Fetus There is a strong relationship between maternal and fetal (cord blood) 25(OH)D concentrations. 25(OH)D readily crosses the placenta and is metabolized to 1,25-dihydroxycholecalciferol by the fetal kidney as early as 24 weeks gestation. At birth, neonatal serum 25(OH)D concentration is 50%-70% of maternal serum 25(OH)D concentration.12 The signicance of maternal deciency during pregnancy is that the fetus develops in a state of hypovitaminosis D, which likely has short-term and longterm detrimental effects. Vitamin D deciency in newborns is associated with hypocalcemia and osteopenia, especially in preterm infants. These effects on bone are long-lasting. In a longitudinal study of 198 children followed up at age 9 years, Javaid et al13 concluded that low maternal vitamin D concentration during the third trimester of gestation was associated with reduced wholebody and lumbar spine bone mineral content. Different studies have suggested that vitamin D deciency also may be associated with an increased risk of nonbone diseases and/or abnormal development in the fetus. Vitamin D has critical functions that affect organs other than bone. Vitamin D receptors and 1-alpha hydroxylase have been detected in the developing brain. Calcitriol target gene products, including neurotrophins NGF, NT3, and NT4/5, which are critical for neurogenesis, have been identied.2 Epidemiologic data have conrmed associations between schizophrenia and winter birth and northern latitudes, which might result from low 25(OH)D levels.14 It remains to be seen whether vitamin D deciency can be shown to negatively impact cognitive or behavioral endpoints in experimental or epidemiologic studies. Whether vitamin D deciency in infants is associated with long-term risk of diabetes should be considered as well. A retrospective study of a birth cohort of 10 366 children suggested that postnatal vitamin D supplementation (2000 IU/ day) was associated with an 8-fold reduction in the incidence of type 1 diabetes mellitus.15 More studies are needed to analyze the role of hypovitaminosis D in the development of this public health problem. Vitamin D deciency also has been associated with an increased risk of autoimmune diseases, such as rheumatoid arthritis, allergy, multiple sclerosis, type 1 diabetes, and certain cancers.13 Evidence of causal relationships between vitamin D status and a disease or health outcome other than bone health remains elusive, however, owing to the multifactorial etiology of chronic diseases and the difculty of isolating the effects of a single nutrient from other confounding effects. Interventions to Improve Vitamin D in Pregnant Women Although vitamin D supplementation is effective in preventing vitamin D deciency, the optimal vitamin D requirement in women remains unknown. Studies evaluating plasma vitamin D status have shown that vitamin D supplementation of <2000 IU/day is not effective in achieving sufciency.16 The standard recommended daily allowance for vitamin D supplementation in adults is 400 IU/day; the same dose is recommended during pregnancy. However, studies in adults suggest that a daily dietary allowance of 1000-2000 IU/day is needed to achieve a target circulating 25(OH)D value of at least 75 nmol/L.17 In another study of lactating women, intake of 6400 IU/day postpartum resulted in signicantly higher levels of circulating vitamin D compared with controls.18 Higher amounts of vitamin D may be necessary, although the precise dose needed remains unknown. Previous studies have explored the role of vitamin D supplementation on perinatal outcomes. A study of 23 423 nulliparous Norwegian pregnant women found a 27% reduction in the risk of preclampsia in women receiving 10-15 mg/ day (600-800 IU/day) of vitamin D compared with women receiving no supplements.19 Another study suggested that vitamin D supplementation during pregnancy improved neonatal birth weight.20 There is an urgent need to determine the optimal dose of vitamin D to maintain vitamin D sufciency in pregnant women when sun exposure is inadequate or skin color limits the amount of vitamin D formed from UV radiation. Vitamin D deciency during pregnancy not only may impair
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Vol. 162, No. 3, Suppl. 1 infants, 54% of extremely low birth weight infants who did not receive intramuscular vitamin A had a plasma retinol concentration <0.70 mmol/L at 28 days.26 Role in Lung Development Vitamin A is required in the fetal lung for cellular differentiation and surfactant synthesis. Vitamin A and steroid hormones have similar effects on prenatal and postnatal lung development, operate through similar cell receptors, and may be interdependent. Administration of antenatal steroids may contribute to higher plasma vitamin A values measured soon after birth in the most immature preterm infants. In addition, postmortem studies have found larger lung and hepatic vitamin A stores in extremely low birth weight infants who received steroids. Indeed, the benecial pulmonary response to steroids may be mediated in part by vitamin A. Werkman et al27 reported a higher retinol:retinol-binding protein, reecting poorer vitamin A status, in preterm infants who later developed bronchopulmonary dysplasia compared with those who did not. Results from a meta-analysis of 8 eligible trials suggested that supplementation with vitamin A in VLBW infants was benecial in reducing the combined effect of death or oxygen requirement at age 1 month. Three studies reported outcomes at 36 weeks gestational age and showed a lower need for oxygen in infants who received vitamin A supplements. This benecial outcome was observed only in infants with a birth weight <1000 g.28 The lungs of the preterm infant may be decient in vitamin A at birth, but whether this can be modied by supplementation of either the mother or newborn infant is unknown. How lung concentrations of vitamin A relate (if at all) to plasma retinol is unclear. It is unknown whether providing the mother vitamin A in late pregnancy can decrease the risk of bronchopulmonary dysplasia and/or respiratory distress syndrome in newborns, or act as an effective adjunct to postnatal preventive therapy for respiratory morbidities. Role in Visual Development Low plasma vitamin A concentrations in preterm infants have been associated with the development of retinopathy of prematurity (ROP). However, there is insufcient evidence to support routine vitamin A supplementation to prevent ROP in preterm infants.28 Additional studies are needed to dene whether vitamin A supplementation might be benecial in preventing ROP in preterm infants and, if so, to establish the optimum dosing and timing of supplementation. Immune Function and Vitamin A There is an urgent need for vitamin A supplementation to improve survival from infectious diseases in children in countries where vitamin A deciency is prevalent. In these settings, the World Health Organization recommends periodic vitamin A supplementation in infants aged 6-59 months.29 Routine newborn vitamin A supplementation (NbVAS) has yielded controversial results, however. In
Murgu a-Peniche
maternal and fetal skeletal formation, but also may play a role in epigenetic imprinting that can affect other, extraskeletal functions later in life and even inuence reproductive outcomes.
Vitamin A
Functions Vitamin A is involved in regulating and promoting growth and cell differentiation and in maintaining the integrity of respiratory epithelial cells. Vitamin A is also part of the photosensitive visual pigment complex in the retina and plays a role in reproductive functions and immunocompetence. Carotenoids, dietary precursors of vitamin A, have potent antioxidant properties.21 Prenatal Considerations The mechanism of vitamin A transport across the placenta and its regulation are not fully understood. The estimated ratio of maternal to fetal plasma vitamin A concentrations in healthy pregnancies is roughly 2:1.22 Trials in women of reproductive age conducted in countries with a high prevalence of vitamin A deciency have reported conicting results in relation to outcomes associated with vitamin A supplementation. A study in Nepal found that supplementation with vitamin A or its precursor (b carotene) in women of reproductive age reduced pregnancy-related mortality by 44% (95% CI, 16%-63%).23 In contrast, a large-scale, randomized study performed in Ghana with more than 200 000 women of reproductive age found no improvement in perinatal or infant survival with vitamin A supplementation.24 The different outcomes in these two studies may be related to the higher incidence of severe vitamin A deciency in Nepalese women, as manifested by eye disease, compared with Ghanaian women. Large studies are needed to examine the role of vitamin A supplementation on reproductive outcomes. It is important to emphasize that an oversupply of vitamin A can be toxic. Excess retinoic acid in the rst trimester of pregnancy is reportedly teratogenic, leading to spontaneous abortions and fetal malformations, including microcephaly and cardiac anomalies.25 Postnatal Considerations: Prematurity and Vitamin A An adequate concentration of plasma vitamin A in very low birth weight (VLBW) infants has not yet been dened. Plasma concentration is not necessarily a good index of vitamin A status. Plasma concentrations can be normal even when tissue (liver, lungs, and other organs) stores are low. Nonetheless, a concentration <200 mg/L (0.70 mmol/L) is considered decient, and a concentration <100 mg/L (0.35 mmol/L) indicates severe deciency and depleted liver stores.1 Preterm infants have lower plasma concentrations of retinol and retinol-binding protein compared with their term counterparts. This decit is more severe in smaller babies, thus, in a multicenter study in extremely low birth weight
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March 2013 Indian children, administration of NbVAS (24 000 IU on days 1 and 2) reduced infant mortality at 6 months by almost 25%, with the greatest effect observed in infants with low birth weight. The prevalence of severe diarrhea and septicemia was lower in the infants who received vitamin A.30 In a study performed in Indonesia, a single dose of 50 000 IU given orally to term infants at birth reduced infant mortality at age 1 year by 64%. In contrast to the Indian study, the greatest impact was observed in infants with birth weight >2500 g; the prevalence of severe respiratory infections compared with placebo was also lower.31 Other studies have not conrmed these encouraging results, however, and systematic analyses of several trials have not documented any benet from NbVAS.32 Thus, at present, the World Health Organization does not recommend routine NbVAS to reduce infant morbidity or mortality as a public health intervention.33 More studies are needed to explore vitamin A status and neonatal outcomes in infants who receive vitamin A supplementation. Discrepancies among studies could be related to differences in the prevalence and severity of maternal vitamin A deciency, in the timing and mode of vitamin A administration, in the dose of vitamin A administered, or other as yet unexplored reasons. Role of Vitamin A in VLBW Infants There is a need to further analyze the role of vitamin A supplementation in decreasing the incidence and severity of infectious diseases in sick VLBW infants. Pooled data from 2 studies (n = 807) in VLBW infants who received intramuscular vitamin A supplementation showed a nonsignicant trend towards a reduced prevalence of sepsis in these infants (typical risk ratio, 0.89; 95% CI, 0.761.05).31 Trials to specically address this issue are still needed. In VLBW infants, the best results from vitamin A supplementation reported to date have been with intramuscular administration. One trial compared different intramuscular dosing regimens (5000 IU 3 times weekly for 4 weeks, 10 000 IU 3 times weekly for 4 weeks, or 15 000 IU weekly for 4 weeks) in infants weighing <1000 g. The optimal dose appeared to be 5000 IU 3 times weekly for 4 weeks; however, even with this dose, more than 25% of the infants had evidence of vitamin A deciency.33,34 Higher doses or a better mode of delivery may be needed. Other routes of administration have proven less effective. Vitamin A administered intravenous degrades in light and adheres to tubing. Administration via the enteral route also is not optimal. Administration by inhalation appears feasible, but more study is needed. In the future, it will be helpful to understand whether combining antenatal vitamin A supplementation of the mother with postnatal supplementation of the newborn can better prevent neonatal morbidity compared with postnatal supplementation alone. Moreover, it will be important to dene whether vitamin A supplementation in lactating women improves vitamin A status in their infants and, if so, to identify the optimal dosage for this effect. For these approaches to be effective, it will be necessary to identify appropriate bio-
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markers for vitamin A concentrations at the sites where biologically active vitamin A is stored.
Conclusion
Vitamin D deciency is a worldwide public health problem that can affect pregnant women and their children. Hypovitaminosis D has acute and long-term negative effects on bone health, and growing evidence suggests a possible association with chronic disorders and adverse reproductive outcomes. Many gaps remain in the knowledge of vitamin Ds modes of action, requirements, and appropriate levels. Vitamin A deciency is prevalent in developing countries. This nutrient is essential for normal development of the eye and immune system and apparently plays a role in lung function and maturation that is particularly important in preterm infants. Questions remain related to appropriate measures of sufciency and optimum dosages to promote health in pregnant women and preterm and term infants. Research to address these questions is urgently needed. n
Author Disclosures
Teresa Murgu a-Peniche has received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. T. M.-P. wrote this manuscript.
Reprint requests: Teresa Murgu a-Peniche, MD, Rollins School of Public Health, Hubert Department of Global Health, 1518 Clifton Road, Mail Stop 1518-002-7BB, Atlanta, GA 30322. E-mail: teresamurguiap@gmail.com.
References
1. World Health Organization. Global prevalence of vitamin A deciency in populations at risk, 1995-2005. WHO Global Database on Vitamin A Deciency. Geneva, Switzerland: World Health Organization; 2009. 2. McCann JC, Ames BN. Is there convincing biological or behavioral evidence linking vitamin D deciency to brain dysfunction? FASEB J 2008; 22:982-1001. 3. Institute of Medicine, Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press; 2011. 4. Dawodu A, Agarwal M, Hossain M, Kochiyil J, Zayed R. Hypovitaminosis D and vitamin D deciency in exclusively breast-feeding infants and their mothers in summer: a justication for vitamin D supplementation of breast-feeding infants. J Pediatr 2003;142:169-73. 5. Ginde AA, Sullivan AF, Mansbach JM, Camargo CA Jr. Vitamin D insufcency in pregnant and non-pregnant women of child beariing age in the United States. Am J Obstetr Gynecol 2010;202:436.e1-8. 6. Arunabh S, Pollack S, Yeh J, Aloia JF. Body fat content and 25hydroxyvitamin D levels in healthy women. J Clin Endocrinol Metab 2003;88:157-61. 7. Bodnar LM, Simhan HN, Powers RW, Frank MP, Cooperstein E, Roberts JM. High prevalence of vitamin D insufciency in black and white pregnant women residing in the northern United States and their neonates. J Nutr 2007;137:447-52. 8. Sachan A, Gupta R, Das V, Agarwal A, Awasthi PK, Bhatia V. High prevalence of vitamin D deciency among pregnant women and their newborns in northern India. Am J Clin Nutr 2005;81:1060-4. 9. Park W, Paust H, Kaufmann HJ, Offermann G. Osteomalacia of the mother, rickets of the newborn. Eur J Pediatr 1987;146:292-3. S29
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23. West KP Jr, Katz J, Khatry SK, LeClerq SC, Pradhan EK, Shrestha SR, et al., NNIPS-2 Study Group. Double-blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. BMJ 1999;318:570-5. 24. Kirkwood BR, Hurt L, Amenga-Etego S, Tawiah C, Zandoh C, Danso S, et al. Effect of vitamin A supplementation in women of reproductive age on maternal survival in Ghana (ObaapaVitA): a cluster-randomised, placebo-controlled trial. Lancet 2010;375:1640-9. 25. Soprano DR, Soprano KJ. Retinoids as teratogens. Annu Rev Nutr 1995; 15:111-32. 26. Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, et al. Vitamin A supplementation for extremely low birth weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 1999;340:1962-8. 27. Werkman SH, Peeples JM, Cooke RJ, Tolley EA, Carlson SE. Effect of vitamin A supplementation of intravenous lipids on early vitamin A intake and status of premature infants. Am J Clin Nutr 1994;59:586-92. 28. Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants. Cochrane Syst Rev 2011;10:CD000501. 29. WHO. Guideline: Vitamin A supplementation in infants 6-59 months of age. Geneva: World Health Organization; 2011. 30. Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community-based randomised trial in southern India. BMJ 2003;327:254. 31. Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128:489-96. 32. Kirkwood B, Humphrey J, Moulton L, Martines J. Neonatal vitamin A supplementation and infant survival. Lancet 2010;376:1643-4. 33. WHO. Guideline: Neonatal vitamin A supplementation. Geneva: World Health Organization; 2011. 34. Ambalavanan N, Wu TJ, Tyson JE, Kennedy KA, Roane C, Carlo WA. A comparison of three vitamin A dosing regimens in extremely low birth weight infants. J Pediatr 2003;142:656-61.
10. Lapillonne A. Vitamin D deciency during pregnancy may impair maternal and fetal outcomes. Med Hypotheses 2010;74:71-5. 11. Zhang C, Qiu C, Hu FB, David RM, van Dam RM, Bralley A, et al. Maternal plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus. PLoS ONE 2008;3:e3753. 12. Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr 2004;79:717-26. 13. Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, et al. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 2006;367:36-43. 14. Davies G, Welham J, Chant D, Torrey EF, McGrath J. A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophr Bull 2003;29:587-93. 15. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358:1500-3. 16. Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, Lemeur H. Vitamin D supplementation in pregnancy: a controlled trial of two methods. Obstet Gynecol 1986;68:300-4. 17. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC. Benet-risk assessment of vitamin D supplementation. Osteoporos Int 2010;21:1121-32. 18. Wagner CL, Hulsey TC, Fanning D, Ebeling M, Hollis BW. High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: a 6-month follow-up pilot study. Breastfeed Med 2006;1: 59-70. 19. Haugen M, Brantsaeter AL, Trogstad L, Alexander J, Roth C, Magnus P, et al. Vitamin D supplementation and reduced risk of preeclampsia in nulliparous women. Epidemiology 2009;20:720-6. 20. Marya RK, Rathee S, Lata V, Mudgil S. Effects of vitamin D supplementation in pregnancy. Gynecol Obstet Invest 1981;12:155-61. 21. Mactier H, Weaver LT. Vitamin A and preterm infants: what we know, what we dont know, and what we need to know. Arch Dis Child Fetal Neonatal Ed 2005;90:F103-8. 22. Jansson L, Nilsson B. Serum retinol and retinol-binding protein in mothers and infants at delivery. Biol Neonate 1983;43:269-71.
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Evaluation of Adequacy of Protein and Energy

Jatinder Bhatia, MD, FAAP1, Patricia Mena, MD2, Scott Denne, MD3, and Cecilia Garc a, MD4
Growth assessment is the most common measure of nutritional adequacy in pediatrics, especially when evaluating nutrition of preterm neonates. The American Academy of Pediatrics denes postnatal nutrient intake to promote growth as one that approximates the rate of growth.for a normal fetus of the same post-menstrual age.1 It is known that in the fetus, fat and lean body mass are accreted progressively as gestation progresses, whereas postnatal growth and observed accretion of fat and lean body mass differ. This review discusses anthropometric measures used to assess growth, biochemical markers used to monitor nutritional sufciency, and the effect of growth trajectory in preterm infants on health outcomes later in life. (J Pediatr 2013;162:S31-6). rowth is the most common measure of nutritional status in newborns, particularly in preterm infants. Growth is characterized by orderly short- and long-term coordinated changes in body size and tissue composition. The American Academy of Pediatrics recommends that postnatal nutrient intake in the preterm infant be designed to provide nutrients to approximate the rate of growth and composition of weight gain for a normal fetus of the same post-menstrual age, and to maintain normal concentrations of blood and tissue nutrients.1 It is unclear whether this goal is achievable or even desirable if we are unable to assess the short- and long-term consequences of specic growth rates in terms of survival and long-term health. It is known that the late gestation fetus accretes fat at a higher rate than earlier in gestation. The optimal composition of growth for preterm infants after birth is uncertain, however. The interpretation of growth-related variables depends strongly on the estimation of developmental stage used for the assessment, given that such variables are determined by gestational age, maturity, developmental processes, nutrient intake, programmed growth rate for each stage, and associated morbidities. The appropriateness of nutritional intake for infants in routine clinical practice is commonly monitored by changes in anthropometric measurements. Such measurements are easy to obtain and have proven useful for tracking an infants progress over time, but because they are assessed post hoc, their usefulness is limited. The opportunity to accomplish meaningful changes occurs days to weeks after the institution of the initial nutritional management plan. The accurate measurement of postnatal growth of very low birth weight (VLBW) infants is essential for both clinical care and research. The consequences of poor or excessive growth during hospitalization may affect these infants both acutely and over the course of life.
Weight
Using the currently available fetal growth reference data, most VLBW infants (<1500 g) accrue a "weight decit" of 198-335 g from birth until birth weight is regained at age 2-3 weeks.2 Very preterm infants can lose up to 15%-20% of their birth weight.3 Although this weight loss principally reects changes in hydration, up to one-half may be related to mobilization of lean tissue, glycogen, and fat stores to compensate for inadequate nutrient intake in the rst few days after birth. Weight growth velocity (GV; g/kg/day) summarizes infant weight gain over a specic time interval, smoothing the variability inherent in daily weight measures. Changes in GV are much more sensitive for identifying changes in growth compared with changes in absolute weight plotted on growth curves. Regular assessments of GV averaged over 5 or 10 days can help identify growth failure early and monitor the response to nutritional interventions.4 Calculated GVs vary based on the starting points (eg, birth weight, nadir, time to regain birth weight) and time intervals (eg, birth to 28 days, birth to discharge, nadir to discharge, time regained birth weight to discharge) used. Patel et al5 proposed a mathematical exponential model for GV assessment during the hospital stay that produced results comparable to a desirable growth rate, reported as 20 g/kg/day for intrauterine weight gain and 12.0-21.2 g/kg/day for postnatal weight gain in a large VLBW infant population.6 Kashyap et al7 reported that lean mass accretion is related directly to protein intake, and that fat accretion is related primarily to energy intake. The available preterm formulas and fortied human milk diets provide a protein intake of approximately 3.5-3.6 g/kg/day and an energy intake of approximately 120 kcal/kg/day when
BUN DEXA GV LBW SGA VLBW Blood urea nitrogen Dual emission x-ray absorptiometry Growth velocity Low birth weight Small for gestational age Very low birth weight
From the 1Medical College of Georgia, Georgia Health tero del Sciences University, Augusta, GA; 2Hospital So Rio, Santiago, Chile; 3Indiana University School of 4 Medicine, Indianapolis, IN; and Sanatorio de la Trinidad, Buenos Aires, Argentina Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 porating bone minerals, body fat, and the remaining soft tissues. Previous studies in term and preterm infants have reported body composition reference ranges based mainly on DEXA.13
fed at sufcient volume. These intakes support growth and protein accretion at or slightly greater than intrauterine rates, but lead to relatively increased fat deposition. Despite this, however, many VLBW infants who consume these diets remain below the 10th percentile of intrauterine growth standard at discharge. There is clear evidence indicating that, with respect to growth, VLBW infants are likely to benet from a higher protein intake and from an energy intake not exceeding 120-130 kcal/kg/day. Global scientic societies, in support of the World Health Organization and American Academy of Pediatrics, recommend the use of human milk in all infants, including preterm infants. In 2002, an expert panel convened by the Life Sciences Research Ofce of the American Society for Nutritional Sciences concluded that current scientic evidence is insufcient to identify the optimal protein content for preterm infant formulas.8
Biochemical Assessments
Serum measurements are of little use in assessing overall protein and energy status, but measurement of blood glucose, blood urea nitrogen (BUN), and some plasma proteins are clinically useful for identifying special conditions that require adjustment of protein and/or mineral intake. Urea is the nal end product of oxidation of amino acids and proteins and represents the irreversible loss of nitrogen from the body. BUN values in neonates are difcult to interpret, because an excess of protein intake in relation to requirements and an excess of ultimately oxidized amino acids lead to high levels of urea synthesis. An elevated BUN value may represent appropriate amino acid delivery, utilization, and subsequent appropriate oxidation, or may represent amino acid intolerance. However, considering that human milk is relatively low in protein, the potential use of BUN to adjust the use of fortiers is a valid option. In a prospective randomized study, Arslanoglu et al14,15 showed that adjusting the fortication of human milk using BUN concentrations as a marker of protein tolerance resulted in increased weight gain and head circumference growth. Visceral proteins, measured in the serum, are the product of protein anabolism, with the major site of production in the liver. Visceral protein synthesis and plasma levels depend on amino acid availability. Albumin is synthesized in the liver and is the most abundant plasma protein. Albumin concentrations are low in fetuses and preterm infants compared with term neonates. Once synthesized, approximately 40%-50% of body albumin resides in the extravascular space. Given its wide volume of distribution and a long half-life, albumin levels are slow to respond to changes in nutritional management or disease state. Transthyretin (prealbumin), along with retinol-binding protein, serves as the serum transport protein for vitamin A and thryoxine, and its synthesis in the liver is highly sensitive to protein and/or energy intake. Both prealbumin and retinol-binding protein have a shorter half-life (2-3 days) than albumin, and respond to changes in nutrient balance within 7 days. Prealbumin contains a high concentration of tryptophan and one of the highest ratios of essential to nonessential amino acids of any protein in the body. The serum concentration of prealbumin increases when more than 55% of assessed protein and energy needs are met. In adults, when protein is kept constant and energy is varied, prealbumin changes; if energy is maintained and protein is varied, retinol-binding protein changes.16 Several studies have included serial measurements of plasma and urinary amino acids.17-20 These measures may be useful for evaluating the effects of the level of protein intake and protein quality (eg, differences in whey:casein ratios), as well as the metabolic pathways involved in the synthesis of nonessential amino acids. Plasma amino acid
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Length
Weekly measurements of length are an excellent means of tracking linear growth; they are also the most accurate indices of lean body mass compared with weight or head circumference. In addition, length measurements have proven useful as components of a variety of indicators that compare body weight and length (eg, body mass index, ponderal index). Ehrenkranz et al9 reported an average rate of length gain of approximately 1 cm/week, signicantly greater than the 0.69-0.75 cm/week increase reported in term infants during the rst 3 months of life in other studies.
Head Circumference
Like length, head circumference measurements should be recorded on a weekly basis. Head circumference increases at a rate of 0.89-1.00 cm/week in VLBW infants.9 The rate of head circumference growth increases with postnatal age; infants with the lowest birth weights have the steepest rates of head circumference growth. Head circumference catch-up growth, an index of brain growth, has been associated with early, aggressive protein administration and better neurologic outcomes.6,10
Body Composition
In isolation, weight is an insensitive marker of growth unless matched with concomitant assessment of body composition. No good bedside measures of body composition are currently available.11 However, the advent of bedside whole-body air displacement plethysmography (pea pod; www.bodpod. com [Cosmed, Rome, Italy]) and possibly dual emission xray absorptiometry (DEXA) in the future could make it possible to measure body composition in a relatively easy and noninvasive fashion.12 With plethysmography, analysis of the whole-body density permits estimation of fat-free and fat mass, and with DEXA, a whole-body scan produces a pseudo3-compartment model of body composition incorS32
March 2013 patterns of low birth weight (LBW) infants may be inuenced not only by the quantity and quality of protein ingested, but also by the energy supply, gestational age, rate of growth, time of sampling with respect to feeding, and maturation of enzymes that synthesize and metabolize amino acids. The milk protein fractions whey and casein have different solubilities in acid. Approximately 70% of the proteins in human milk are in the soluble whey fraction, and 30% are in the insoluble casein fraction. The whey fraction provides lower concentrations of phenylalanine, tyrosine, and methionine and higher concentrations of taurine compared with the casein fraction, and these amino acid patterns are reected in blood concentrations. Preterm infants fed a whey:casein protein ratio of 60:40 (similar to breast milk) have reasonably well-balanced plasma amino acids and an adequate coefcient of protein utilization (protein gain:intake). Higher proportions of casein cannot be handled with the same efciency, as evidenced by the development of metabolic acidosis and higher plasma tyrosine and phenylalanine concentrations reported with commercial formulas derived from bovine milk with a 18:82 whey:casein.17-19 Lactoferrin, lysozyme, and secretory immunoglobulin are specic human whey proteins involved in host defense; these proteins are essentially absent in bovine milk.20
SUPPLEMENT
plasticity have a strong inuence on later, long-lasting variability in phenotype. Postnatal weight gain is an important component of the programming of adipose tissue growth and insulin sensitivity, both of which have major potential effects on the prevalence of adult chronic diseases.22 For example, the risk of metabolic syndrome is greatest in adults who were born small and experienced a high rate of catchup growth. The precise patterns of growth leading to obesity are unclear, with both infant size and infant growth implicated.23,24 Most infants born small for gestational age (SGA) experience rapid catch-up growth during the rst year of life. Fetal growth restriction followed by rapid weight gain early in postnatal life is implicated in promoting central adiposity, insulin resistance, type 2 diabetes, and cardiovascular diseases. Research studies have established that protein intake in excess of metabolic requirements may enhance the secretion of insulin and insulin-like growth factor-1, favor growth during the rst 2 years of life, and increase adipogenic activity and adipocyte differentiation.25,26 Meta-analyses of observational studies indicate that breastfeeding, relative to feeding of standard infant formulas, reduces the risk for obesity in breastfed infants owing to the lower protein content of breast milk (the early protein hypothesis).27 The relationship between early growth and later cardiovascular and metabolic risks has not yet been studied extensively. An observational study found that rapid weight gain during the rst 3 months of life was associated with more central adiposity, a higher percentage of body fat mass, and lower insulin resistance, all of which are important determinants of cardiovascular disease and type 2 diabetes later in life.28 According to DEXA body composition analyses in children, a predominant distribution of central fat rather than peripheral fat is associated with an unfavorable cardiovascular risk prole,29 although not all studies have supported this association. The SGA infant with catch-up growth presents a prole of higher adiposity, especially visceral fat, and its related metabolic differences of hyperinsulinemia and low adiponectin. Overall ndings also suggest a diminished capacity to store subcutaneous fat that may reect decits in skeletal muscle in SGA infants at birth, resulting in reduced glucose utilization, redirection of glucose to lipogenesis, and fat storage in adipose tissue.30 LBW is known to be associated with higher blood pressure later in life, but the association between weight gain in infancy and later blood pressure remains unclear. In a large 5-country study, Adair et al31 reported an increased risk for elevated blood pressure associated with each period of weight gain during infancy and childhood; however, higher systolic pressure in adulthood was related mainly to adult size. A cohort trial conducted by Singhal et al32 studied children born SGA and randomly assigned at birth to receive either a standard or a nutrient-enriched formula. Blood pressure was measured at age 6-8 years in 51% of the randomized children. Diastolic and mean arterial blood pressures were
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Trajectory of Weight Gain and Later Outcomes

Numerous studies have demonstrated that a suboptimal intrauterine environment, as well as undernutrition or overnutrition during the early neonatal period, has adverse affects on later outcomes. The fetal origins of adult health and disease and catch-up growth hypotheses, for example, have proposed that there are critical windows during growth that may reect genetic/nutrient/environmental interactions that translate to phenotype programming.13 There is concern that aggressive feeding in an effort to produce catch-up growth also may contribute to later adverse outcomes. Growth is a sensitive, but nonspecic, indicator of an infants overall health and well being. Optimal growth, based on a statistical approach, implies adherence to anthropometric development of healthy infants, with specic sex and age distributions as indicated by recommended reference curves. A new challenge has been added to the term optimal growtha pattern of early growth to prevent adverse outcomes, such as cardio-metabolic diseases, later in life. Nutritional conditions during key periods of development are of profound importance in determining the subsequent life-long growth trajectory of an organism. A period of nutritional decit can be followed by accelerated growth, compensating for the initial deprivation. Although this compensatory growth can bring quick benets, it is also associated with a number of unintended, potentially deleterious consequences that often do not become evident until much later in adult life.21 The concept of programming states that events occurring early in life during a period of critical sensitivity or
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Vol. 162, No. 3, Suppl. 1 weeks gestational age). Neurologic abnormalities, learning difculties, poor scholastic achievement, and behavioral problems have been reported.39 The prevalence of cerebral palsy is 3-fold greater in late preterm infants compared with full-term infants.40 Studies conducted over the last decade have indicated that a high incidence of growth failure or catch-down growth between birth and hospital discharge is associated with poorer neurodevelopment in the long term. The term catch-down growth was suggested by Ong et al41 to dene growth failure as a decrease in weight z score of >0.67 (ie, >0.67 SD). Lathal-Hajnal et al42 studied neurodevelopmental outcome in relation to growth status at birth and to postnatal growth in 219 VLBW infants. SGA children had a lower mean Bayley Scales of Infant Development Psychomotor Development Index score at age 2 years compared with SGA children who experienced catch-up growth. Appropriate for gestational age children with catch-down growth were more likely to have lower mean Bayley Psychomotor Development Index and Mental Development Index scores than those who remained at >10th percentile at age 2 years, and also had a higher incidence of severe cerebral palsy (22.9% vs 1.2%; P = .008). Ehrenkranz et al6 investigated the effect of growth rates on neurodevelopmental outcomes in a cohort of VLBW infants. In a subset of that study, extremely LBW infants were divided into quartiles of in-hospital growth rate and evaluated at 18-22 months corrected age. The mean rate of weight gain in the rst and fourth quartiles was 12.0 g/ kg/day and 21.2 g/kg/day, respectively. Comparing the lowest with the highest quartiles, the risk of cerebral palsy, Bayley Psychomotor and Mental Developmental Index scores <70, and neurodevelopmental impairment were signicantly correlated with growth rate. Current information indicates a clear relationship between pre- and postnatal undernutrition and disturbed structural and functional brain development.43 Outcome studies have documented impaired cognitive development in childhood among SGA preterm infants,44 and volumetric magnetic resonance imaging studies have found diminished overall brain volume, as well as decreased cerebral cortical gray matter and hippocampal volumes, in similar infants.45,46 More than 2 decades age, Lucas et al47 investigated neurodevelopmental outcomes related to different nutritional approaches in LBW preterm infants during hospitalization. The most valuable contribution of these studies was to open a new line of evidence that strongly supports a favorable and differential effect of human breast milk on neurodevelopment.
signicantly lower in children assigned to the standard formula group compared with the nutrient-enriched formula group. Despite several limitations, that study suggested that faster early growth can have negative effects on long-term health. Even though the underlying biological mechanisms are still unclear, prematurity, fetal and neonatal growth restriction, and catch-up growth are strongly associated with increased risks of developing hypertension, insulin resistance, and type 2 diabetesall components of the metabolic syndrome. Various hypotheses to explain this association have been proposed, pointing to a role of a detrimental fetal environment, a genetic susceptibility, or an interaction between them, as well as to the particular dynamic changes in adiposity that occur during catch-up growth. In neonates born at term, the association between small size at birth and impaired glucose regulation later in life is well established. VLBW preterm and SGA births are also associated with insulin resistance in childhood. Current nutritional strategies that promote catch-up growth should include monitoring of weight-for-length and adiposity, and the concept of healthy catch-up growth should be a goal of future research.33 Published studies have all tried to balance long-term side effects and potential benets resulting from rapid recovery growth. Weight-for-age decits markedly increase the risk of death in children aged <5 years.34 Given our current knowledge of child health in developing countries, as well as the risk of both poor growth and excessive growth in the early neonatal period, it seems quite reasonable to continue to promote growth of small infants and young children to match normal growth based on international norms (eg, World Health Organization Multicenter Growth Reference Study growth standards). A major priority, however, is to reanalyze existing datasets to assess the full impact of catch-up growth on health in both the short term and the long term.
Neurodevelopmental Outcome
Infants born preterm are at increased risk of developing cognitive and motor impairments compared with infants born at term. Several studies have demonstrated that inadequate early nutrition exerts an adverse inuence on long-term developmental outcome. Ultimate brain growth of preterm infants is less than that of normal infants born at term.35-37 Preterm birth during this critical stage with superimposed perinatal undernutrition might result in adverse neurocognitive function later in life. This reduced brain growth may be improved by nutritional strategies during hospitalization and the catch-up growth period.10 The rst year of life may provide an important opportunity for human somatic and brain growth to compensate for earlier prenatal and postnatal deprivation.38 Concern has focused principally on outcomes in the more vulnerable populations, such as extremely LBW infants; however, follow-up studies have also shown impairment in more mature preterm infants as well as late preterm infants (34-36
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Clinical Evaluation of Feeding Strategies

Once the negative impact of postnatal growth failure on neurodevelopment became evident, several studies were undertaken in attempts to elucidate the optimal nutritional strategy. The most recent evidence suggests that early high protein intake may improve growth in VLBW infants. Randomized controlled trials have suggested short-term safety
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March 2013 and efcacy of starting parenteral amino acid infusions at 2.5-3.5 g/kg/day as soon as possible after birth48-50 and then advancing up to 4 g/kg/day. Although data evaluating the longer-term effects of this strategy are limited, a large observational study has demonstrated that preterm infants receiving earlier and higher amounts of amino acids exhibited improved growth in the neonatal intensive care unit, lower rates of microcephaly in males at age 18-22 months, and neurodevelopmental outcomes similar to those in infants receiving lower amounts of early amino acids.10 Another observational study showed that increased protein intake during the rst week of life was associated with higher Mental Developmental Index scores and lower likelihood of length growth restrictions at age 18 months in extremely LBW infants.51 In contrast, a small randomized trial with limited follow-up suggested that higher early amino acid intake may be associated with abnormal neurocognitive outcome at age 18 months, but not at age 24 months.52 Variation in nutritional practices, especially those involving the initiation and advancement of enteral nutrition, largely explain the differences in growth reported in different newborn intensive care units. From the standpoint of optimizing growth, feeding preterm infants earlier and faster decreases the time to achieving full feeds and improves GV; as the available evidence suggests, growth and catch-up from birth to at least age 1 year are the primary variables related to favorable neurodevelopmental outcomes. Numerous benecial effects of breast milk in term and near-term infants have been demonstrated, including improved cognitive skills, improved behavior ratings, and decreased rates of infection. Improved neurodevelopment has been related to the presence of long-chain polyunsaturated fatty acids (eg, arachidonic acid, docosahexaenoic acid), found in human milk, but not in bovine milk. Recent extensive and detailed analyses of nutritional support and outcomes in preterm infants have yielded the following recommendations50,53: (1) early, aggressive parenteral nutrition; (2) early enteral nutrition; (3) feeding of human milk with appropriate fortication, especially in VLBW infants; and (4) feeding of premature infant formula when human milk feeding is not possible.
SUPPLEMENT
Author Disclosures
All authors have received honoraria from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. P. M. and S. D. wrote the rst draft of this manuscript.
Reprint requests: Jatinder Bhatia, MD, FAAP, Division of Neonatology, Medical College of Georgia, Georgia Health Sciences University, BIW-6033, Augusta, GA 30912. E-mail: jatindeb@georgiahealth.edu.
References
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Conclusions and Recommendations

The ideal nutritional management of preterm newborns emulates intrauterine growth. Evaluating the appropriateness of nutritional care remains an unresolved challenge. Many variables intervene in and interfere with theoretical calculations during the postnatal period, and nutritional goals should not be considered exclusively for the short term, but rather should be projected into childhood and adult life. Although the anthropometric components of growth (weight, height, and head circumference) provide very limited information, they remain the tools most commonly used to monitor growth. New measures are needed that provide more comprehensive information about growth and development during infancy, childhood, and beyond. n
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19. Jarvenpaa AL, Rassin DK, Raiha NC, Gaull GE. Milk protein quantity and quality in the term infant, II: effects on acidic and neutral amino acids. Pediatrics 1982;70:221-30. 20. Goldman AS, Chheda S, Keeney SE, Schmalstieg FC, Schanler RJ. Immunologic protection of the premature newborn by human milk. Semin Perinatol 1994;18:495-501. 21. Metcalfe NB, Monaghan P. Compensation for a bad start: grow now, pay later? Trends Ecol Evol 2001;16:254-60. 22. Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult disease: the hypothesis revisited. BMJ 1999;319:245-9. 23. Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002;31:1235-9. 24. Baird J, Fisher D, Lucas P, Kleijnen J, Roberts H, Law C. Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ 2005;331:929. 25. Karlberg J, Jalil F, Lam B, Low L, Yeung CY. Linear growth retardation in relation to the three phases of growth. Eur J Clin Nutr 1994;48(Suppl 1): S25-43. 26. Hoppe C, Udam TR, Lauritzen L, Molgaard C, Juul A, Michaelsen KF. Animal protein intake, serum insulin-like growth factor I, and growth in healthy 2.5-y-old Danish children. Am J Clin Nutr 2004;80: 447-52. 27. Koletzko B, Broekaert I, Demmelmair H, Franke J, Hannibal I, Oberle D, et al. Protein intake in the rst year of life: a risk factor for later obesity? The EU Childhood Obesity Project. Adv Exp Med Biol 2005;569: 69-79. 28. Leunissen RW, Kerkhof GF, Stijnen T, Hokken-Koelega A. Timing and tempo of rst-year rapid growth in relation to cardiovascular and metabolic risk prole in early adulthood. JAMA 2009;301:2234-42. 29. Stettler N, Iotova V. Early growth patterns and long-term obesity risk. Curr Opin Clin Nutr Metab Care 2010;13:294-9. 30. Beltrand J, Levy-Marchal C. Pathophysiology of insulin resistance in subjects born small for gestational age. Best Pract Res Clin Endocrinol Metab 2008;22:503-15. 31. Adair LS, Martorell R, Stein AD, Hallal PC, Sachdev HS, Prabhakaran D, et al. Size at birth, weight gain in infancy and childhood, and adult blood pressure in 5 low- and middle-income-country cohorts: when does weight gain matter? Am J Clin Nutr 2009;89:1383-92. 32. Singhal A, Cole TJ, Fewtrell M, Kennedy K, Stephenson T, Elias-Jones A, et al. Promotion of faster weight gain in infants born small for gestational age: is there an adverse effect on later blood pressure? Circulation 2007; 115:213-20. 33. Ong KK. Catch-up growth in small for gestational age babies: good or bad? Curr Opin Endocrinol Diabetes Obes 2007;14:30-4. 34. Pelletier DL, Frongillo EA Jr, Habicht JP. Epidemiologic evidence for a potentiating effect of malnutrition on child mortality. Am J Public Health 1993;83:1130-3. 35. Dobbing J, Sands J. Vulnerability of developing brain, IX: the effect of nutritional growth retardation on the timing of the brain growth spurt. Biol Neonate 1971;19:363-78.
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Alexandre Lapillonne, MD, PhD1,2, Sharon Groh-Wargo, PhD, LD, RD3, Carlos H. Lozano Gonzalez, MD, MPH4, and Ricardo Uauy, MD, PhD5
Long-chain polyunsaturated fatty acids (LCPUFAs) are of nutritional interest because they are crucial for normal development of the central nervous system and have potential long-lasting effects that extend beyond the period of dietary insufciency. Here we review the recent literature and current recommendations regarding LCPUFAs as they pertain to preterm infant nutrition. In particular, ndings that relate to fetal accretion, LCPUFA absorption and metabolism, effects on development, and current practices and recommendations have been used to update recommendations for health care providers. The amounts of long-chain polyunsaturated fatty acids (LCPUFAs) used in early studies were chosen to produce the same concentrations as in term breast milk. This might not be a wise approach for preterm infants, however, particularly for very and extremely preterm infants, whose requirements for LCPUFAs and other nutrients exceed what is normally provided in the small volumes that they are able to tolerate. Recent studies have reported outcome data in preterm infants fed milk with a docosahexaenoic acid (DHA) content 2-3 times higher than the current concentration in infant formulas. Overall, these studies show that providing larger amounts of DHA supplements, especially to the smallest infants, is associated with better neurologic outcomes in early life. We emphasize that current nutritional management might not provide sufcient amounts of preformed DHA during the parenteral and enteral nutrition periods and in very preterm/very low birth weight infants until their due date, and that greater amounts than used routinely likely will be needed to compensate for intestinal malabsorption, DHA oxidation, and early decit. Research should continue to address the gaps in knowledge and further rene adequate intake for each group of preterm infants. (J Pediatr 2013;162:S37-47). reterm infants are particularly susceptible to postnatal growth failure and nutrient deciencies. Dietary lipids provide preterm infants with most of their energy needs. Recent interest has focused on the quality of dietary lipid supply early in life as a major determinant of growth, infant development, and long-term health. In this regard, LCPUFAs are of concern because they are crucial for normal development of the central nervous system development and have the potential for long-lasting effects extending beyond the period of dietary insufciency.1 Furthermore, LCPUFAs also have potentially significant modulatory effects on developmental processes that affect short-term and long-term health outcomes related to growth, body composition, immune and allergic responses, and the prevalence of nutrition-related chronic diseases.1 Recommendations for intake of total fat, essential fatty acids (EFAs), and medium-chain triglycerides (MCTs) have not varied over the last decade, and to our knowledge, there are no new data that would cause us to modify the current recommendations.1 This is not to say that there have been no new developments in the area of LCPUFAs. Consequently, the aim of this article is to review the recent literature and current recommendations regarding LCPUFAs as they pertain to preterm infant nutrition. In particular, ndings related to fetal accretion, LCPUFA absorption and metabolism, effects on development, and current practices and recommendations are used to update recommendations for health care providers.
LCPUFA Fetal Accretion Rate

When data on intrauterine accretion are available, the amount of nutrient required to attain the mean rate of accretion can be used to estimate the minimum nutrient requirement for preterm infants. When there are adequate bioavailability data on the relative absorption of a nutrient from human milk or infant formulas and on oxidation rate and/or losses, a recommendation can be made regarding the minimum amount for absorption that will result in a net retention rate similar to the intrauterine accretion rate.
ALA ARA DHA EFA EPA LA LCPUFA MCT MDI a-linolenic acid Arachidonic acid Docosahexaenoic acid Essential fatty acid Eicosapentaenoic acid Linoleic acid Long-chain polyunsaturated fatty acid Medium-chain triglyceride Mental Development Index
From the 1Paris Descartes University, Assistance ^ pitaux de Paris Necker Hospital, Paris, Publique Ho France; 2Childrens Nutrition Research Center, Baylor College of Medicine, Houston, TX; 3Case Western Reserve University, MetroHealth Medical Center, Cleveland, a, Pediatr a OH; 4Academia Mexicana de Pediatr Medicina Perinatal, Monterrey, Mexico; and 5Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 cholesterol esters (0.5%). In breast milk, LCPUFAs are mainly triacylglycerols esteried at the sn-2 and sn-3 positions and can be part of the phospholipid fraction.6 Human milk contains bile salt-stimulated lipase and palmitic acid in the b position of the triglyceride molecule. These unique components increase the bioavailability of human milk fat by improving absorption and digestion. However, human milk for preterm infants is often pasteurized to suppress viral and bacterial activity. Heat inactivates bile saltstimulated lipase and changes the structure of the milk fat globule. These actions may be the reason why feeding pasteurized milk is associated with a 30% reduction in fat absorption and growth rate.7 Fortication of human milk, particularly with calcium, may further impair LCPUFA absorption. Overall, only 70%80% of ARA and DHA from pasteurized breast milk is absorbed by very preterm infants (Table I). The recombinant form of human bile saltstimulated lipase signicantly increases DHA and ARA absorption when added to pasteurized human milk.8 This approach can be potentially benecial, but the safety, efcacy, and cost-effectiveness of using recombinant human bile salt stimulated lipase as an additive must be fully characterized before routine use can be recommended. LCPUFAs from sh oils or from single-cell algae are added as triacylglycerols to the fat blend of preterm formulas. DHA in algal oils has a weak positional specicity and contains equal amounts of DHA in the sn-1, sn-2, and sn-3 positions, unlike the DHA triacylglycerols present in breast milk. These chemical differences may reduce absorption of DHA derived from algal sources. Although sh oil provides DHA with a bond located in the sn-2 position, it also contains eicosapentaenoic acid (EPA), which has not yet been proven safe in preterm infants (Table I). Phospholipids are not a common source of LCPUFAs in preterm formulas.9,10 However, it can be speculated that DHA derived from phospholipids offers potential advantages because it: (1) is one of the forms found naturally in human milk; (2) provides ARA and other LCPUFAs; and (3) may be one way to promote brain DHA uptake.11
Attention so far has focused mainly on DHA accumulation in the central nervous system. Whether the brain is protected when availability of DHA is limited is not known, but the ease with which fetal brain DHA is altered by maternal dietary n-3 fatty acid intake suggests that the membrane lipid composition of the fetal brain is sensitive to changes in DHA supply.2 Because most LCPUFAs accumulate in white adipose tissue and, to a lesser extent, in lean mass and the liver,3 it is important to consider the accumulation of DHA and other LCPUFAs in all relevant organs. Analyses of fetal autopsy tissue yielded the following estimates of intrauterine accretion of LCPUFAs during the last trimester: 106 mg/kg/day for linoleic acid (LA), 4 mg/kg/ day for a-linolenic acid (ALA), 212 mg/kg/day for arachidonic acid (ARA), and 43 mg/kg/day for DHA.3 It is likely that the accumulation of LCPUFAs is not linear over time during the last trimester of gestation. Thus, using these numbers to calculate an average daily rate of fatty acid accumulation will overestimate or underestimate tissue requirements during specic periods of growth. A more precise estimate of the fetal accretion rate cannot be determined until more data become available. The placenta selectively favors the transfer of DHA over other fatty acids, including ARA, during the last trimester of pregnancy.4 It is generally thought that the fetus does not synthesize LCPUFAs from their precursors at rates sufcient to support an adequate DHA accretion rate. However, evidence from stable isotope studies in preterm infants suggests that ARA and DHA synthesis occurs to some degree at an age when the infant would normally be dependent on placental transfer.5 Tracer studies indicate that the rate of ARA synthesis is signicantly greater than the rate of DHA synthesis, suggesting that the fetus has a greater ability to regulate ARA supply by de novo synthesis or placental reuptake compared with DHA supply.4 Overall, these data suggest that exogenous supply of DHA may be more critical than that of ARA during the perinatal period.
LCPUFA Absorption and Metabolism

The fetus does not accumulate appreciable amounts of fat until the last trimester of gestation. Thus, postnatally, adipose tissue cannot be a signicant source of LCPUFAs for brain growth of preterm infants as it is for term infants. The LCPUFAs used for organ growth, including brain growth, depend on the amount of LCPUFAs supplied exogenously, intestinal absorption of LCPUFAs, and, nally the capacity to synthesize and oxidize LCPUFAs.
LCPUFA Metabolism by Preterm Infants. Studies

using LCPUFA precursors labeled with stable isotopes have demonstrated that LCPUFA synthesis occurs even in small preterm infants.1 Using the novel stable isotope natural abundance approach, the estimated mean endogenous synthesis of ARA was reported as 27 mg/kg/day at 1 month and 12 mg/kg/day at 7 months, and that of DHA was 13 mg/kg/day at 1 month and 2 mg/kg/day at 7 months.12 Thus, endogenously synthesized LCPUFAs are insufcient to meet requirements dened by the fetal accretion rate. Whether conversion in human milk-fed preterm infants is similar to that in formula-fed preterm infants, or whether conversion is affected by the supply of dietary EFAs or LCPUFAs, remains to be established. Recent studies in adult populations have suggested that variability in biochemical and functional central nervous system responses to changes in diet are explained in part by
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Digestion and Absorption of LCPUFAs. Mechanisms

of fat absorption and digestion have been reviewed extensively elsewhere.1 MCTs and structured lipids (eg, synthetic b-palmitate) do not fall within the scope of this review, even though they may affect LCPUFA absorption and improve overall fat absorption. Human milk fat is provided in the form of a milk fat globule and consists mainly of triacylglycerols (98%), phospholipids (1%), and cholesterol and
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Table I. Comparison of intestinal absorption of fatty acids among formulas

Study I* Preterm breast milk Intestinal absorption (fatty acids, %) 18:2n-6 20:4n-6 18:3n-3 20:5n-3 22:6n-3 Metabolizable intake (fatty acids, mg/kg/day) 18:2n-6 20:4n-6 18:3n-3 20:5n-3 22:6n-3 Standard PTF1 PL PTF Study II TG-MO PTF Fortied preterm breast milk Standard PTF2 TG-FO PTF
88.1 3.0 81.1 3.6 90.3 2.6 57.0 6.9 78.4 4.0 608 61 26.0 2.1 35.2 3.8 2.7 1.0 14.1 1.2
69.7 0.3 NA 88.5 1.5 NA NA 585 29 NA 64.5 1.2 NA NA
91.3 1.7 84.7 1.7 94.4 1.1 64.3 9.5 88.3 1.8 601 13 16.4 0.4 51.0 0.8 1.4 0.4 12.0 0.3
68.9 4.0 80.4 2.3 90.5 1.6 NA 80.4 2.3 575 38 40.0 1.4 64.7 1.8 NA 30.6 1.1
83.5 13 76.6 12 85.3 12 81.0 25 76.9 18 453 231 20.1 6 29.9 9.0 10.0 10.0 15.9 7.0
97.8 1.6 NA 98.2 1.3 NA NA 906 213 NA 80.9 18.0 NA NA
95.9 3.0 75.9 10.2 96.7 2.7 92.5 3.3 94.8 4.2 878 152 1.7 0.2 54.2 6.9 4.6 1.0 18.2 3.7
NA, not applicable; PTF, preterm formula; PL, LCPUFAs from phospholipids; TG-MO PTF, triacylglycerols from microorganisms; TG-FO PTF, triacyglycerols from sh oil. Shown are intestinal absorption of fatty acids and metabolizable intake of fatty acids at age $4 weeks in preterm infants fed exclusively unfortied (study I) or fortied (study II) preterm breast milk, standard preterm formula with no LCPUFAs added (standard PTF1; standard PTF2), preterm formula with LCPUFA TG-MO PTF or from TG-FO PTF, or preterm formula with LCPUFA phospholipids from egg yolk (PL PTF). *Study I: data from Carnielli et al.9 Study II: balance study performed in a subset of 15 preterm infants from Lapillonne et al53; postnatal age $4 weeks, no signicant difference among groups for postnatal age, corrected age, and weight at time of the balance study (Picaud JC et al, unpublished data 2012).
single nucleotide polymorphisms in genes responsible for EFA desaturation. This nding adds complexity to dening LCPUFA requirements and establishing the extent of the effect of the intake other nutrients (eg, LCPUFA precursors, n-3/n-6 fatty acid ratio) that affect endogenous LCPUFA synthesis.13 These ndings explain much of the variance in ARA blood levels, but no association between polymorphism desaturase and DHA levels has yet been identied, suggesting a stronger role for the inuence of diet on DHA levels.14,15 To our knowledge, there is no similar evidence for preterm infants; however, because the conversion of EFA to LCPUFAs is highly variable, it is likely that the single nucleotide polymorphisms that play a regulatory role in LCPUFA formation may exist in preterm infants as well. In support of this concept, a large interindividual variability in the rate of conversion of EFAs to LCPUFAs has been measured in stable isotope studies of infants.16,17 The nal step in the synthesis of DHA is considerably more complex than that for ARA. DHA synthesis requires enzymes present in peroxisomes and the endoplasmic reticulum, along with the coordinated movement of fatty acids between these two organelles. A recent study of infants born at term found that, compared with dietary EPA, conversion of EPA to DHA is twice as efcient when EPA is formed from dietary ALA.16 Even though conversion of EPA to DHA is less efcient with EPA from the diet compared with EPA formed from ALA, EPA is present in the human milk and relatively well absorbed (Table I). Thus, when estimating ingested DHA equivalents, it may be appropriate to include approximately 45% of dietary EPA in the calculation.16 None of the estimated retention gures reported to date have taken into account DHA oxidation and endogenous biosynthesis. Present evidence suggests that DHA oxidation may occur in adults as well as in preterm infants. Signicant
b-oxidization of DHA in adults was reported recently.18 In addition, DHA in plasma phospholipids is decreased in preterm infants who receive 42 mg/kg/day of DHA (ie, a dose similar to the theoretical fetal accretion rate) through a lipid emulsion containing sh oil, suggesting that DHA oxidation may be signicant.19 Furthermore, some DHA oxidation likely occurs in preterm infants, when energy intake does not meet requirements, but the magnitude cannot be estimated based on the available data.
Effects of LCPUFAs Supplementation in Preterm Infants

Possible effects of LCPUFA supplementation include improving neurologic and visual development. These effects are numerous and signicant enough to serve in dening the need for and dosage of LCPUFAs for preterm infants. In contrast, effects on modulation of immune function in preterm infants are too scarce to add sufcient information for estimating requirements.
Data from Experimental Studies. LCPUFAs, particularly DHA, play important roles in central nervous system development. Complex neural functions affected by the composition of dietary fatty acid supply include neurogenesis, photoreceptor differentiation, activation of the visual pigment rhodopsin, protection from oxidative stress, synaptogenesis, activities of multiple enzymes, function of ion channels, neurotransmitter concentrations, and eicosanoid metabolism.20 In rodents and nonhuman primates, poor accumulation of retinal and brain DHA leads to abnormal retinal physiology, poor visual acuity, increased duration of visual xation, and increased stereotyped behaviors and locomotor activity.21 The evidence most relevant to the issue of causality showed that control performance levels were
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Vol. 162, No. 3, Suppl. 1 plasia.24,30 It has been 15 years since a sh oilenriched formula was rst shown to reduce growth in preterm infants. Since that time, very little new information has become available to conrm or refute the nding that high n-3 and low n-6 LCPUFA intake reduces growth in very low birth weight infants.24 However, it is likely that in this specic group of infants, the balance between n-3 and n-6 LCPUFAs is critical for growth, and it is prudent to minimize the decline of ARA status, which has been associated with reduced growth. Supplementation with n-3 and n-6 LCPUFAs has been shown to be safe and possibly even benecial in preterm infants when growth24,31 and body composition32 are used as the safety parameters.
restored when DHA was added to the diets of animals with severely reduced brain DHA concentrations.21 Nevertheless, the magnitude of these effects is not large, despite the fact that the studies were conducted under profound dietary restriction. The relevance of these ndings to human development is unclear.
Supplementation with Standard Doses of LCPUFAs.

The effects of LCPUFAs on the developing brain have been reported extensively,22-27 and are not reviewed here. Overall, studies in preterm humans indicate possible benets for retinal and cognitive development, as suggested by greater sensitivity to light on electroretinography, more mature visual acuity, and short-term effects on global developmental outcomes at 6-18 months after DHA supplementation of preterm infant formula. The effects in term infants are weaker but supported by sufcient data to merit consideration of enriching term formulas with LCPUFAs.28,29 Interestingly, two recent meta-analyses concluded that the available randomized controlled trials do not show clear benets of formula supplementation with LCPUFA on neurodevelopment in preterm infants.24,30 This nding is somewhat surprising, given that many studies have suggested that LCPUFAs play an important role in development. Several factors may explain these apparent discrepancies, as reviewed previously.3 In brief, meta-analyses are designed a priori to classify results as positive or negative relative to a dened clinical issue of interest. In other words, a treatment is deemed either to work and be recommended or to not work and thus not be recommended. This approach yields the most useful information when a given treatment is well dened. With regard to randomized controlled trials designed to assess the effects of DHA enrichment in preterm formulas, there obviously is extreme variability in study design. The assessment schedule and methodology, dose and source of fatty acid supplementation, and composition of the control formula vary considerably among studies. Other potential explanations for the difculty in demonstrating clinical benets of LCPUFA supplementation in preterm formulas by meta-analysis include variations in study endpoints, selection of relatively mature and healthy preterm infants, timing of the DHA decit as well as DHA provision, genetic background, maternal DHA status, single versus multiple pregnancy, in utero growth and maturation, and the ability of preterm infants to synthesize DHA from ALA or EPA. It has been shown that the DHA equivalent, which depends on the rate of conversion and amount of EFA in the diet, has a greater impact than DHA intake on the magnitude of visual acuity response at age 4 months.23 Clearly, the magnitude of these factors in modulating DHA status and development in preterm infants is not known and warrants further research. With regard to safety, adding LCPUFA to preterm formulas has no signicant effect on the relative risks of sepsis, necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage, or bronchopulmonary dysS40
Supplementation with High Dosages of LCPUFAs.

The dosages of LCPUFAs used in early studies were chosen to produce the same concentrations of ARA and DHA in formula as seen in term breast milk. This might not be a wise approach for preterm infants, particularly for very and extremely preterm infants, whose requirements for LCPUFAs and other nutrients exceed what is normally provided in the small volumes that they are able to tolerate during the rst days or weeks of life. Because the amount of DHA provided by ingesting breast milk is well below the in utero accretion rate, providing DHA at a dose higher than that of term human milk might better fulll requirements and confer health benets. Three studies report outcome data in preterm infants fed milk with a DHA content exceeding 0.2%-0.4% fatty acids, which are the levels most widely used in previous studies33-37 (Table II). One study examining the effect of providing DHA supplementation (0.5% of total fatty acids) for up to 9 months after term reported that DHA improved growth in the entire cohort of preterm infants and improved mental development in boys.33 It should be noted that g-linoleic acid, not ARA, was the n-6 PUFA source in the supplement used in that study. In another study, the objective was to evaluate effects on neurologic development of supplementing human milk with oils (DSM, Heerlen, The Netherlands) that provided an extra 32 mg of DHA and ARA per day.34 This intervention started 1 week after birth and continued until hospital discharge. Interestingly, DHA content of the control human milk was high (0.7% total fatty acids), probably related to the high sh consumption of the mothers. Combined with the LCPUFAs in human milk, infants received 59 mg/kg/day of DHA and 48 mg/kg/day of ARA. At the 6-month follow-up evaluation, the intervention group performed better than the control group in the problem-solving subscore of the Ages and Stages Questionnaire. An electrophysiological assessment of event-related potentials revealed that infants in the intervention group also had signicantly lower responses to a standard image, indicating better recognition memory. At 20 months postnatal age, no differences in the mental and motor development scores of the Ages and Stages Questionnaire or in the
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Table II. Visual acuity and development outcome results with DHA supplementation in preterm infants
Reference Fewtrell et al (2004)
33
Site United Kingdom Australia
Age, weeks 25-34
n 238
Groups DHA 0.5% + g-LA versus no LCPUFAs DHA 1% versus DHA 0.30% (no difference in ARA)
Duration Up to 9 months CA Days 2-5 until due date
Age 18 months CA
Outcomes No overall difference in Bayley MDI and Psychomotor Development Index; higher Bayley MDI in boys No difference in visual acuity at 2 months; higher visual acuity at 4 months No overall difference in Bayley MDI and Psychomotor Development Index; fewer severe mental delay; higher MDI in girls; higher MDI (unadjusted analysis only) and fewer mild mental delay in infants with birth weight <1250 g No difference in language development; no difference in behavior Higher problem solving subscore at the ages and stages questionnaire; better recognition memory at the event-related potential test No difference in Bayley MDI, but signicant correlation between plasma DHA concentration at discharge and MDI; better attention capacity at the free-play session test
Smithers et al (2008)30 Makrides et al (2009)35
27-31
657
2 and 4 months CA 18 months CA
Smithers et al (2010)39 Henricksen et al (2010)34 Norway 141 DHA 59 mg/kg/day + ARA 45 mg/kg/day versus DHA 32 mg/kg/day + ARA 22 mg/kg/day 1 week until discharge
26 months CA; 3-5 years CA 6 months CA
Westerberg et al (2011)38
20 months postnatal age
CA, corrected age. Shown are results of visual acuity and development outcome assessments of randomized controlled trials using DHA supplementation in preterm infants at a dose exceeding 0.4% of total fatty acids. DHA and ARA are expressed as % total fatty acids.
Mental Development Index (MDI) score of the Bayley Scales of Infant Development38 were observed; however, plasma DHA concentration at discharge was positively correlated with Bayley MDI score. The intervention group had better results at 20 months in the free-play sessions, suggesting positive effects from supplementation on functions related to attention. Furthermore, plasma DHA concentration at discharge was positively correlated with sustained attention.38 The third study was designed to compare the effects of a high versus a standard DHA intake (ie, 1% vs 0.35% total fatty acids as DHA) with ARA intake kept constant. This study included breastfed and formula-fed infants. Mothers who provided breast milk took capsules containing 3 g of either tuna oil (900 mg DHA) or soy oil (no DHA), resulting in milk with either high or standard DHA content. A formula with matching high versus standard DHA concentrations was used for infants who required supplementary feeds. The feeding regimen was started between days 2 and 5 after birth and maintained until expected term. All infants received a standard term formula with DHA after the expected term. Visual acuity was signicantly improved at 4 months corrected age in the high-DHA group.37 At 18 months there were no overall differences in the MDI or the Bayley Psychomotor Developmental Index, but fewer infants had an MDI score <70.35 Infants who weighed <1250 g
and were fed the high-DHA diet had a higher MDI score than controls (mean difference, 4.6; 95% CI, 0.1-9.0; P < .05), but the difference was not signicant when gestational age at delivery, sex, maternal education, and birth order were taken into account. Girls fed a high-DHA diet had higher MDI scores and were less likely to have mild or signicant developmental delay than control girls. This effect was not seen in boys. Finally, the early advantage in visual and cognitive functions did not translate into any clinically meaningful change in language development or behavior when assessed in early childhood.39 Giving very low birth weight infants larger doses of DHA appears to be safe and may provide further health benets for functions beyond development. One trial found a reduced incidence of oxygen treatment at 36 weeks in the high-DHA group compared with the standard-DHA group,35 which can be interpreted as a short-term benet of high DHA doses. Overall, the studies published to date indicate that greater DHA supplementation is associated with better neurologic outcomes. One study suggested that the smallest infants, which are the most vulnerable to DHA deciency, are those the most likely to reap the greatest benet from high-dose supplementation.35 The observation that a nonsignicant difference in mean MDI translates to fewer infants with a low MDI score suggests that low development score are at least in part, due to early nutritional deciencies.
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Vol. 162, No. 3, Suppl. 1 from colostrum to mature milk. There are no important differences between full-term and preterm human milk in terms of total fat, most saturated and monounsaturated fatty acids, or the EFAs LA and ALA.45 Preterm milk may contain a slightly higher proportion of medium- and intermediatechain fatty acids than term milk, which may be advantageous for fat and calcium absorption in preterm infants. Compositional differences in LCPUFA levels between term and preterm milk are of interest. As in full-term milk, concentrations of both DHA and ARA in preterm milk decrease over the rst 3-5 weeks of lactation. Some studies have reported more ARA and/or DHA in preterm milk than in full-term milk, whereas other studies have reported the opposite.45 In terms of percent contribution to total fatty acids, however, DHA is often higher in preterm milk than in fullterm milk.45 The reported ranges of DHA and ARA values in preterm human milk are summarized in Table III. Based on the values presented in Table III, the estimated mean (SD) concentration of DHA in preterm human milk (by weight) is 0.33% 0.10% (range, 0.22%-0.55%), and that of ARA is 0.55% 0.09% (range, 0.44%-0.69%). These values are very similar to those reported in full-term human milk.44 Banked human milk may be fed to preterm infants when their mothers own milk is unavailable or insufcient. The estimated mean fat content in banked human milk is 3.2 g/100 mL, somewhat lower than the generally accepted value for mature human milk.46,47 This may be related to inadequate emptying of the breast during pumping. The LCPUFA content of banked human milk appears to be similar to that of mature milk. Pasteurization and storage of banked human milk induces lipolysis, inactivates bile saltstimulated lipase and lipoprotein lipase, reduces fats, and increases the absolute amount of free fatty acids in pooled samples. These effects alter the integrity of human milk and may contribute to slower growth in preterm infants fed banked milk versus their mothers own milk.7 LCPUFA Composition: Infant Formula Products Commercial infant formulas marketed for preterm infants vary in fat quantity and quality. Total fat ranges between
Although DHA supplementation beyond discharge and/or expected term is recommended,40 one of the trials did not use such a strategy.35 This may explain, high-dose versus standard-dose DHA supplementation failed to signicantly improve the development outcome of the whole cohort, particularly when the assessment was performed long after the period of supplementation. It also should be noted that none of the regimens studied prevented the early DHA decit due to parenteral nutrition.41 This early DHA decit during the parenteral nutrition phase may have contributed to the impaired developement at 18 months of age.
Assessment of Status and Current Practices

LCPUFA Composition: Human Milk The fat and fatty acid content of human milk is known to be highly variable. For example, fatty acid composition varies among countries, from woman-to-woman, by duration of gestation and stage of lactation, throughout the day, and during a feeding. This variability may be of little signicance for a healthy term infant, but it presents more of a risk to the preterm infant, whose feedings are delivered articially and controlled by a medical team. The fatty acid composition of human milk is known to vary worldwide. Variability is greater for ALA and DHA than for LA and ARA.42,43 The LA content of human milk ranges from 7.9% in the Philippines to 17.8% in Chile, a <2.5-fold difference. ALA has a 5-fold disparity, ranging from 0.43% in the Philippines to 2% in China. The worldwide mean (SD) concentration of DHA in breast milk (by weight) is 0.32% 0.22% (range, 0.06%-1.4%), and that of ARA is 0.47% 0.13% (range, 0.24%-1%).44 Mothers who live in coastal areas or on islands produce milk with the highest DHA levels. Mothers who live away from the coast and/or in developed countries consume fewer marine foods and produce milk relatively low in DHA. Human milk responds to changes in the maternal diet, and LCPUFA supplementation increases DHA concentration in milk. Fatty acid composition of human milk varies by stage of lactation and duration of gestation. Total fat, LA, and ALA increase and DHA and ARA decrease as milk transitions
Table III. Composition of LCPUFA in milk from mothers of preterm infants

% total fatty acids Reference Smithers et al (2008)36 Clandinin et al (1997)54 Jacobs et al (1996)55 Carnielli et al (1998)9 Beijers and Schaafsma (1996)56 Bitman et al (1983)57 Luukkainen et al (1995)58 Genzel-Borovicz eny et al (1997)59 Rueda et al (1998)60 Kov acs et al (2005)61 S42 Site Australia Canada Netherlands Netherlands Netherlands US Finland Germany Spain Hungary Age, weeks <33 28-34 30-35 27-33 26-36 26-36 25-33 24-33 33-36 23-33 n 21 25 5 20 65 46 23 19 6 8 DHA 0.26 0.3 0.4 0.26 0.32 0.22 0.4 0.32 0.55 0.27 ARA 0.45 0.54 0.6 0.48 0.49 0.56 0.44 0.59 0.69 0.66 Sampling time point(s) Pooled; 26-40 weeks <42 days of life Third week of life 28 days of life Mean colostrum, 1 week; transitional, 2 weeks; mature, >2 weeks 42 days of life Mean, 5 samplings over 3 months Mean, 4 samplings over 1 month Mean colostrum, 1 week; transitional, 2 weeks; mature, >2 weeks Mean, 5 samplings over 3 weeks
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March 2013 3.8 and 4.2 g/dL, provided by a combination of long-chain triglycerides and MCTs. Up to 40%-50% of total fat may come from MCTs. Preterm infant formula is routinely supplemented with commercially available sources of LCPUFA, so that the fatty acid composition resembles that of human milk. Most of the LCPUFA oils added to infant formulas are derived from microorganisms; however, some are derived from a combination of low-EPA sh oil as a source of DHA and oil from microorganisms as a source of ARA. LCPUFA Intake from Infant Feedings The estimated DHA accretion rate is 45 mg/kg/day during the last trimester of gestation.3 Most contemporary intravenous lipid emulsions provide little if any LCPUFAs. Human milk and formulas designed for preterm infants contain DHA and ARA, but arguably in insufcient amounts to compensate for an accumulated decit. Consequently, preterm infants who receive many weeks of parenteral nutrition followed by human milk and/or commercial preterm formula may accumulate a DHA decit of up to 50% of the normal rate.41 Table IV compares DHA and ARA intakes from selected enteral feedings given to preterm infants. Assuming an average fat content of 3.9 g fat/dL in human milk, milk with 0.2%0.4% fatty acids as DHA would provide a 1-kg preterm infant fed at full enteral feeds of 180 mL/day with only 1428 mg DHA/kg/day, an amount clearly below the in utero accretion rate of 45 mg/kg/day. LCPUFA Status: Insights from Studies with High Doses of DHA The effect of milk DHA on preterm infant plasma or erythrocyte DHA depends largely on dose.36 Milk that contains $0.8% DHA provides an intake of 45 mg/kg/day, assuming a human milk fat content of 3.7% and a volume intake of 150 mL/kg/day. In the study by Smithers et al,36 milk DHA content ranged from 0.2% to 1.25% of total fatty acids (assumed to represent 11-67 mg/kg/day), and there was a di-
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rect relationship between milk DHA content and erythrocyte DHA content. At a milk DHA content of >0.8% of fatty acids ($45 mg/kg/day), none of the infants had an erythrocyte DHA concentration <6% at expected term, but at a milk DHA content of 1% ($54 mg/kg/day), the erythrocyte DHA concentration ranged between 6.5% and 9%, within the range expected in term infants at birth.2,3 The DHA intake of the control infants (ie, 32 mg/kg/day) in the study of Henriksen et al34 did not prevent a decline in plasma DHA concentrations, conrming that intake below the fetal accretion rate is inadequate to maintain normal DHA status in preterm infants.34 In the intervention group of the same study, preterm infants received 59 mg DHA/kg/day, which increased plasma DHA concentration by 12% from the time of study inclusion to hospital discharge. Assuming a DHA intestinal absorption rate of 80%, DHA intake between $55 and 60 mg/kg/day provides DHA at a rate matching the fetal accretion rate. In terms of ARA intake, the aforementioned studies differed greatly. In one study, ARA supplementation was given at a dose similar to that of DHA,34 whereas in another study no ARA supplementation was given.36 Consequently, changes in ARA status during the DHA supplementation period differed between these studies. A dramatic decline in ARA status was observed when milk ARA content was $0.5% of total fatty acids36; in contrast, ARA status was stable when similar doses of ARA and DHA were used.34 Additional studies are needed to determine the potential effects of these changes on ARA status, but because no decrease in ARA status is observed during fetal life, such biological effects in preterm infants probably should be avoided. Because the DHA:ARA ratio varies widely in term milk44 and preterm milk,48 future research should focus on dening individual DHA and ARA needs rather than an optimal DHA:ARA ratio. Finally, the studies cited here provide clues on how to increase LCPUFA intake in human milk-fed preterm
Table IV. Estimated LCPUFA intake at 120 kcal/kg/day from various forms of human milk and preterm infant formulas*
LCPUFA, % total fatty acids Total fat, g/100 mL Human milk Full-term Preterm Banked Fortied Formula Standard{{ Preterm{{ 4.2z 3.9z 3.2** 4.4zz 3.6 4.2 DHA 0.32x 0.33{ 0.32 0.33xx 0.24 0.3 ARA 0.47x 0.55{ 0.47 0.55xx 0.52 0.55 LCPUFA, mg/100 mL DHA 13.4 12.9 10.2 12.9 8.6 12.6 ARA 19.7 21.4 15.0 21.4 18.7 23.1 LCPUFA intake, mg/kg/day DHA 24.2 23.2 18.4 19.3 15.6 18.9 ARA 35.5 38.6 27.1 32.2 33.7 34.6 LCPUFA absorbed, mg/kg/day DHA 19 18 15 15 12 15 ARA 28 31 22 26 27 28
*Full-term, preterm, and banked human milk and standard formula assume 20 kcal/oz and 180 mL/kg/day; fortied and preterm formula assume 24 kcal/oz and 150 mL/kg/day. Intestinal absorption, 80%.9 zData from Lawrence (1995).62 xData from Brenna et al (2007).44 {See Table I. **Data from Wojcik et al (2009).46 Assuming fatty acid concentrations of full-term milk.63 zzAssuming the fat content of preterm milk62 plus 0.5 g fat/100 mL from non-LCPUFA-containing fortier xxAssuming fatty acid concentrations of preterm milk. {{Mean of preterm formula products available in the US.
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Vol. 162, No. 3, Suppl. 1 essentiality of ARA and DHA and proposed a minimum value for the requirements of preterm infants. More recently, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition did not change the recommendations, but rather expressed them as mg/kg/day instead of percentage of total fatty acids.50
infants. In one study, sh oil was given to lactating mothers to increase the DHA content of their milk. Supplementing mothers with the appropriate amount of tuna oil increased human milk DHA concentrations to the desired level with only a small increase in EPA and no change in ARA levels.48 However, despite its physiological basis, this strategy leads to large variations in the DHA content of human milk, with values as low as 0.3% and as high as 2.5% observed. Furthermore, this strategy does not allow supplementation with both ARA and DHA concomitantly. Adding DHA with or without ARA directly into the feeding is likely to be the most reliable technique for delivering adequate amounts of DHA to preterm infants.
Updated Recommendations for LCPUFA Intake in Preterm Infants

Breastfeeding In agreement with other reports, we strongly endorse human milk as the preferred food source for preterm infants. We emphasize, however, that fortiers and supplements must be used appropriately to meet the specic needs of preterm infants, especially very preterm infants. The DHA content in human milk is highly variable, mainly because of variations of maternal diets. Nutritional counseling during the lactation period is recommended to ensure optimal mothers intake of omega-3 fatty acids. Fat, EFA, and MCT Intake There are no new data since the recommendations of 2010 to modify the recommendations for total fat intake, EFAs, and MCTs for preterm infants.1 DHA Given the limited and highly variable formation of DHA from ALA, and the critical role of DHA in normal retinal and brain development in humans, DHA should be considered conditionally essential during early development. Early deprivation of DHA should be identied early and treated aggressively, because it is not known denitively if
Previous LCPUFA Recommendations

Various regulatory bodies, professional organizations, and expert panels have issued recommendations and consensus statements on LCPUFA intake for preterm infants. These recommendations rely on the composition of human milk and the results of decades of research related to LCPUFA intake and blood and tissue levels, anthropometric parameters, and visual and neurocognitive outcomes. Evidence supports the superiority of human milk and the safety of supplementing formulas with DHA and ARA in amounts similar to those found in human milk.49 Table V summarizes Previous recommendations. Interestingly, in 2002 the Expert Panel of the Life Sciences Research Organization did not recognize a need for LCPUFAs and did not recommend a minimum content of ARA, DHA, or EPA for preterm infant formulas at that time. Just 3 years later, Koletzko and Innis1 recognized the
Table V. Recommendations for enteral LCPUFA in preterm infants

Life Sciences Research Organization, 2002* LA (C18:3n-3) % total energy mg/100 kcal mg/kg/day % total fatty acids ALA (C18:2n-6) % total energy mg/100 kcal mg/kg/day % total fatty acids LA:ALA ARA (C20:4n-6) mg/100 kcal mg/kg/day % total fatty acids DHA (C22:6n-3) mg/100 kcal mg/kg/day % total fatty acids ARA:DHA EPA (C20:5n-3)
*Klein (2002).64 Koletzko and Innis (2005).1 zAgostoni et al (2010).50
Koletzko and Innis, 2005 3.2-12.8 352-1425 600-1680 8-25 0.7-2.1 77-228 1.75-4 6-16:1 0.3-0.7 0.2-0.5 1.2-2:1 #30% DHA
European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, 2010z 3.2-12.8 350-1400 385-1540 $0.45 $50 $55 $0.9 5-15:1 16-39 18-42 11-27 12-30 1-2:1 #30% DHA
Current 3.2-12.8 350-1400 385-1540 $0.45 $50 $55 $0.9 5-15:1 18-45 12-60 #20 mg/kg/day
352-1425 8-25 77-228 1.75-4 6-16:1 #0.6 #0.35 1.5-2:1 #30% DHA
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March 2013 a transient decit can be compensated for with regard to central nervous system growth and maturation. We emphasize that current nutritional management does not provide sufcient amounts of preformed DHA during the parenteral and enteral nutrition periods and in very preterm/ very low birth weight infants until the due date. Nutrient recommendations should be expressed as absolute amount per kg/day rather than as a proportion of total fatty acids, because the latter applies only if full enteral feeding is reached. The fetal accretion rate of DHA is approximately 45 mg/kg/day. Greater amounts may be needed to compensate for intestinal malabsorption, DHA oxidation, and early decit. On the other hand, the amount of DHA that can be synthesized endogenously by preterm infants is unclear. DHA intakes of 55-60 mg/kg/day from the time of preterm birth to expected term have been tested and appear to be safe, to promote normal DHA status, and to improve visual and neurocognitive functions. These values are likely to represent an adequate intake for very preterm infants, but further research is needed to conrm that they represent adequate intake for all infant groups (ie, extremely, very, and moderately preterm infants, with or without intrauterine growth restriction, and males and females). Because the maximum DHA content of human milk is >1.5% of fatty acids (equivalent to 84 mg/kg/day),51 and because no studies with such a high intake in preterm infants have been reported, no upper limit can be set with certainty. ARA Preformed ARA should be provided to ensure adequate ARA levels during the period of DHA supplementation. Limited data are available to dene the necessary ARA dose with certainty. When a high dose of DHA is provided, 45 mg/kg/day of ARA has been shown to support growth and normal ARA status. EPA Limited data are available to identify whether there is any benet to including EPA in the diet of preterm infants. Thus, we recommend an EPA intake not exceeding 20 mg/ kg/day, which is the mean + 1 SD amount of EPA provided daily by human milk when fed at 180 ml/kg/day.48 Duration of Supplementation The recommendations for DHA, ARA, and EPA specied above should be continued until the infant reaches the expected due date. After the expected due date, recommendations for term infants should be applied.52 Research is needed to examine whether LCPUFA supplementation after the due date may provide additional benets.
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the due date according to interindividual differences, such as genetic variations in fatty acid desaturase activities or sex. Investigators are encouraged to address subgroups that have specic needs and benets, such as extremely preterm infants and preterm infants with intrauterine growth retardation, extrauterine growth retardation, bronchopulmonary dysplasia, or prolonged parenteral nutrition. Supplementation studies should be designed to examine growth, body composition, visual and cognitive development, attention and behavioral disorders, and effects on immune outcomes and cardiovascular function. Studies evaluating the effects of different amounts of LCPUFAs and the specic effects of ARA supply, with sufcient duration of intake, adequate sample sizes, and standardized methodology for outcome measurements, warrant careful consideration. Future studies should evaluate various DHA levels to dene dose-response relationships and elucidate potential immediate and long-term benets and safety issues. The most effective mode of delivering LCPUFAs (ie, through supplementation of the mother, supplements mixed in milk, and/or enriched fortiers) also merit further evaluation. n
We thank Mrs Gretchen Duenas and the Association pour la Recherche et la Formation en N eonatologie (ARFEN) for providing technical assistance and Professors Jean-Charles Picaud, MD, PhD, and Bernard Salle, MD, for providing additional balance study data.
Author Disclosures
Ricardo Uauy, MD, PhD, chaired the Symposium on Nutrition of the Preterm Infant. Mead Johnson Nutrition paid his travel expenses and provided an honorarium for contributing to, organizing, and chairing the meeting and for his assisting with the nal editing of the supplement. All authors received honoraria from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. A. L. wrote the rst draft of this manuscript.
Reprint requests: Alexandre Lapillonne, MD, PhD, Professor of Pediatrics, Department of Neonatology, Necker Hospital, 149 rue de Sevres, 75015 Paris, France. E-mail: alexandre.lapillonne@nck.aphp.fr.
References
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Gaps in Knowledge and Recommendations for Future Research

Future research should consider short- and long-term effects of LCPUFA status of preterm infants before and after
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25. Georgieff MK, Innis SM. Controversial nutrients that potentially affect preterm neurodevelopment: essential fatty acids and iron. Pediatr Res 2005;57:99R-103R. 26. Heird WC, Lapillonne A. The role of essential fatty acids in development. Annu Rev Nutr 2005;25:549-71. 27. Fleith M, Clandinin MT. Dietary PUFA for preterm and term infants: review of clinical studies. Crit Rev Food Sci Nutr 2005;45:205-29. 28. Uauy R, Dangour AD. Fat and fatty acid requirements and recommendations for infants of 0-2 years and children of 2-18 years. Ann Nutr Metab 2009;55:76-96. hles H, Campoy C, Cetin I, et al. The 29. Koletzko B, Lien E, Agostoni C, Bo roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations. J Perinat Med 2008;36:5-14. 30. Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized controlled trials. Am J Clin Nutr 2008;87:912-20. 31. Clandinin MT, Van Aerde JE, Merkel KL, Harris CL, Springer MA, Hansen JW, et al. Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid. J Pediatr 2005;146:461-8. 32. Groh-Wargo S, Jacobs J, Auestad N, OConnor DL, Moore JJ, Lerner E. Body composition in preterm infants who are fed long-chain polyunsaturated fatty acids: a prospective, randomized, controlled trial. Pediatr Res 2005;57:712-8. 33. Fewtrell MS, Abbott RA, Kennedy K, Singhal A, Morley R, Caine E, et al. Randomized, double-blind trial of long-chain polyunsaturated fatty acid supplementation with sh oil and borage oil in preterm infants. J Pediatr 2004;144:471-9. 34. Henriksen C, Haugholt K, Lindgren M, Aurv ag AK, Rnnestad A, Grnn M, et al. Improved cognitive development among preterm infants attributable to early supplementation of human milk with docosahexaenoic acid and arachidonic acid. Pediatrics 2008;121:1137-45. 35. Makrides M, Gibson RA, McPhee AJ, Collins CT, Davis PG, Doyle LW, et al. Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA 2009;301: 175-82. 36. Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of two doses of docosahexaenoic acid (DHA) in the diet of preterm infants on infant fatty acid status: results from the DINO trial. Prostaglandins Leukot Essent Fatty Acids 2008;79:141-6. 37. Smithers LG, Gibson RA, McPhee A, Makrides M. Higher dose of docosahexaenoic acid in the neonatal period improves visual acuity of preterm infants: results of a randomized controlled trial. Am J Clin Nutr 2008;88:1049-56. 38. Westerberg AC, Schei R, Henriksen C, Smith L, Veierd MB, Drevon CA, et al. Attention among very low birth weight infants following early supplementation with docosahexaenoic and arachidonic acid. Acta Paediatr 2011;100:47-52. 39. Smithers LG, Collins CT, Simmonds LA, Gibson RA, McPhee A, Makrides M. Feeding preterm infants milk with a higher dose of docosahexaenoic acid than that used in current practice does not inuence language or behavior in early childhood: a follow-up study of a randomized controlled trial. Am J Clin Nutr 2010;91:628-34. 40. Aggett PJ, Agostoni C, Axelsson I, De Curtis M, Goulet O, et al., ESPGHAN Committee on Nutrition. Feeding preterm infants after hospital discharge: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2006;42:596-603. 41. Lapillonne A, Eleni dit Trolli S, Kermorvant-Duchemin E. Postnatal docosahexaenoic acid deciency is an inevitable consequence of current recommendations and practice in preterm infants. Neonatology 2010; 98:397-403. 42. Brenna JT, Lapillonne A. Background paper on fat and fatty acid requirements during pregnancy and lactation. Ann Nutr Metab 2009;55: 97-122. 43. Yuhas R, Pramuk K, Lien EL. Human milk fatty acid composition from nine countries varies most in DHA. Lipids 2006;41:851-8.
6. Straarup EM, Lauritzen L, Faerk J, Hy CE, Michaelsen KF. The stereospecic triacylglycerol structures and fatty acid proles of human milk and infant formulas. J Pediatr Gastroenterol Nutr 2006;42:293-9. 7. Andersson Y, S avman K, Bl ackberg L, Hernell O. Pasteurization of mothers own milk reduces fat absorption and growth in preterm infants. Acta Paediatr 2007;96:1445-9. 8. Montjaux N, Hascoet JM, Lapillonne A, Kermorvant-Duchemin E, Simeoni U, Saliba E, et al. A prospective, randomized, double-blind crossover study comparing rhBSSL (recombinant human bile salt stimulated lipase) and placebo added to pasteurized breast milk in preterm infants. PAS/ASPR meeting, Denver April 30-May 3 2011. Abstract 2855.7. 9. Carnielli VP, Verlato G, Pederzini F, Luijendijk I, Boerlage A, Pedrotti D, et al. Intestinal absorption of long-chain polyunsaturated fatty acids in preterm infants fed breast milk or formula. Am J Clin Nutr 1998;67: 97-103. 10. Chirouze V, Lapillonne A, Putet G, Salle BL. Red blood cell fatty acid composition in low-birth-weight infants fed either human milk or formula during the rst months of life. Acta Paediatr Suppl 1994;405:70-7. 11. Picq M, Chen P, Perez M, Michaud M, V ericel E, Guichardant M, et al. DHA metabolism: targeting the brain and lipoxygenatio. Mol Neurobiol 2010;42:48-51. 12. Carnielli VP, Simonato M, Verlato G, Luijendijk I, De Curtis M, Sauer PJ, et al. Synthesis of long-chain polyunsaturated fatty acids in preterm newborns fed formula with long-chain polyunsaturated fatty acids. Am J Clin Nutr 2007;86:1323-30. 13. Schaeffer L, Gohlke H, Mu ller M, Heid IM, Palmer LJ, Kompauer I, et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum Mol Genet 2006;15:1745-56. 14. Lattka E, Illig T, Heinrich J, Koletzko B. Do FADS genotypes enhance our knowledge about fatty acid related phenotypes? Clin Nutr 2010;29: 277-87. 15. Lattka E, Illig T, Koletzko B, Heinrich J. Genetic variants of the FADS1 FADS2 gene cluster as related to essential fatty acid metabolism. Curr Opin Lipidol 2010;21:64-9. 16. Lin YH, Llanos A, Mena P, Uauy R, Salem N Jr, Pawlosky RJ. Compartmental analyses of 2H5-a-linolenic acid and C-U-eicosapentaenoic acid toward synthesis of plasma-labeled 22:6n-3 in newborn term infants. Am J Clin Nutr 2010;92:284-93. 17. Pawlosky RJ, Lin YH, Llanos A, Mena P, Uauy R, Salem NJ. Compartmental analyses of plasma 13C- and 2H-labeled n-6 fatty acids arising from oral administrations of 13C-U-18:2n-6 and 2H5-20:3n-6 in newborn infants. Pediatr Res 2006;60:327-33. 18. Plourde M, Chouinard-Watkins R, Vandal M, Zhang Y, Lawrence P, Brenna JT, et al. Plasma incorporation, apparent retroconversion and b-oxidation of 13C-docosahexaenoic acid in the elderly. Nutr Metab (Lond) 2011;8:5. 19. DAscenzo R, DEgidio S, Angelini L, Bellagamba MP, Manna M, Pompilio A, et al. Parenteral nutrition of preterm infants with a lipid emulsion containing 10% sh oil: effect on plasma lipids and longchain polyunsaturated fatty acids. J Pediatr 2011;159:33-8. 20. Innis SM. Dietary (n-3) fatty acids and brain development. J Nutr 2007; 137:855-9. 21. McCann JC, Ames BN. Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals. Am J Clin Nutr 2005;82:281-95. 22. San Giovanni JP, Parra-Cabrera S, Colditz GA, Berkey CS, Dwyer JT. Meta-analysis of dietary essential fatty acids and long-chain polyunsaturated fatty acids as they relate to visual resolution acuity in healthy preterm infants. Pediatrics 2000;105:1292-8. 23. Uauy R, Hoffman DR, Mena P, Llanos A, Birch EE. Term infant studies of DHA and ARA supplementation on neurodevelopment: results of randomized controlled trials. J Pediatr 2003;143:S17-25. 24. Schulzke SM, Patole SK, Simmer K. Long-chain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database Syst Rev 2011;CD000375. S46
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44. Brenna JT, Varamini B, Jensen RG, Diersen-Schade DA, Boettcher JA, Arterburn LM. Docosahexaenoic and arachidonic acid concentrations in human breast milk worldwide. Am J Clin Nutr 2007;85:1457-64. 45. Bokor S, Koletzko B, Decsi T. Systematic review of fatty acid composition of human milk from mothers of preterm compared to full-term infants. Ann Nutr Metab 2007;51:550-6. 46. Wojcik KY, Rechtman DJ, Lee ML, Montoya A, Medo ET. Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc 2009;109:137-40. 47. Saarela T, Kokkonen J, Koivisto M. Macronutrient and energy contents of human milk fractions during the rst six months of lactation. Acta Paediatr 2005;94:1176-81. 48. Smithers LG, Markrides M, Gibson RA. Human milk fatty acids from lactating mothers of preterm infants: a study revealing wide intra- and inter-individual variation. Prostaglandins Leukot Essent Fatty Acids 2010;83:9-13. 49. American Acedemy of Pediatrics, Committee on Nutrition. Pediatric nutrition handbook. 6th ed. Elk Grove Village (IL): American Academy of Pediatrics; 2009. 50. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85-91. 51. Jensen RG. Lipids in human milk. Lipids 1999;34:1243-71. 52. Food and Agriculture Organization of the United Nations. Fat and fatty acids in human nutrition: report of an expert consultation. Available from: http:// foris.fao.org/preview/25553-0ece4cb94ac52f9a25af77ca5cfba7a8c.pdf. Accessed 2010. 53. Lapillonne A, Picaud JC, Chirouze V, Goudable J, Reygrobellet B, Claris O, et al. The use of low-EPA sh oil for long-chain polyunsaturated fatty acid supplementation of preterm infants. Pediatr Res 2000;48:835-41. 54. Clandinin MT, Van Aerde JE, Parrott A, Field CJ, Euler AR, Lien EL. Assessment of the efcacious dose of arachidonic and docosahexaenoic
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acids in preterm infant formulas: fatty acid composition of erythrocyte membrane lipids. Pediatr Res 1997;42:819-25. Jacobs NJ, van Zoeren-Grobben D, Drejer GF, Bindels JG, Berger HM. Inuence of long chain unsaturated fatty acids in formula feeds on lipid peroxidation and antioxidants in preterm infants. Pediatr Res 1996;40: 680-6. Beijers RJ, Schaafsma A. Long-chain polyunsaturated fatty acid content in Dutch preterm breast milk; differences in the concentrations of docosahexaenoic acid and arachidonic acid due to length of gestation. Early Hum Dev 1996;44:215-23. Bitman J, Wood L, Hamosh M, Hamosh P, Mehta NR. Comparison of the lipid composition of breast milk from mothers of term and preterm infants. Am J Clin Nutr 1983;38:300-12. Luukkainen P, Salo MK, Nikkari T. The fatty acid composition of banked human milk and infant formulas: the choices of milk for feeding preterm infants. Eur J Pediatr 1995;154:316-9. Genzel-Borovicz eny O, Wahle J, Koletzko B. Fatty acid composition of human milk during the 1st month after term and preterm delivery. Eur J Pediatr 1997;156:142-7. n JL, Maldonado J, Gil A. GestaRueda R, Ram rez M, Garc a-Salmero tional age and origin of human milk inuence total lipid and fatty acid contents. Ann Nutr Metab 1998;42:12-22. Kov acs A, Funke S, Marosvo lgyi T, Burus I, Decsi T. Fatty acids in early human milk after preterm and full-term delivery. J Pediatr Gastroenterol Nutr 2005;41:454-9. Lawrence RA. Storage of human milk and the inuence of procedures on immunological components of human milk. Acta Paediatr Suppl 1999; 88:14-8. Luukkainen P, Salo MK, Janas M, Nikkari T. Fatty acid composition of plasma and red blood cell phospholipids in preterm infants from 2 weeks to 6 months postpartum. J Pediatr Gastroenterol Nutr 1995;20: 310-5. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr 2002;132:1395S-577S.
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Jatinder Bhatia, MD, FAAP1, Ian Grifn, MD2, Diane Anderson, PhD, RD3, Neelam Kler, MD4, and Magnus Domell of, MD, PhD5
Requirements for optimal nutrition, especially for micronutrients, are not well dened for premature infants. The reference fetus, developed by Ziegler et al,1 has served as a model to dene nutritional needs and studies designed to determine nutrient requirements. Revision of nutrient requirements and provision of optimal nutrition may lead to improved outcomes in preterm infants. Appropriate provision of nutrients also may help prevent nutritional disorders, such as metabolic bone disease and anemia. In this review, we discuss calcium, phosphorus, magnesium, vitamin D, iron, and copper, and dene optimal intakes based on the available published data. (J Pediatr 2013;162:S48-55). ptimal micronutrient requirements for preterm infants are not well dened. Increasing numbers of these infants survive after birth at progressively lower gestational ages. It is important to dene micronutrient needs and provide appropriate amounts of these nutrients to prevent nutritional disorders, such as metabolic bone disease and neonatal anemias. In this article we review current data from preterm infants and recommend the micronutrient intake necessary to meet the estimated requirements for calcium, phosphorus, magnesium, vitamin D, copper, and iron. Calcium and phosphorus homeostasis and formation of bone matrix are complex processes that require an adequate supply of protein and energy, as well as calcium, phosphorus, magnesium, and vitamin D. Vitamin D is important for bone mineralization, supports physiological processes that affect neuromuscular and immune functions, and plays a role in the heart, lung, pancreas, and brain. Iron is the oxygen-binding moieity of hemoglobin and myoglobin, which are essential for oxygen transport. It is also a cofactor for cytochrome C and other enzymes, which are necessary for cellular energy metabolism. Iron is critically important for normal brain development, including myelin formation and neurotransmitter synthesis. Zinc is essential for multiple enzymes involved in gene expression, signal transduction, apoptosis, cellular proliferation, differentiation, and growth. Copper is essential for enzymes in the electron transport chain and the antioxidant systems; anemia, neutropenia, and osteoporosis may result from copper deciency.
Background: Calcium, Phosphorous, Magnesium, and Vitamin D

Physiology of Mineral Accretion and Bone Formation The majority of fetal mineral accretion occurs during the third trimester.1 Peak calcium accretion rate, typically 120-160 mg/kg/ day (3-4 mmol/kg/day) in late gestation, is maintained through active transplacental calcium inux. Parathyroid hormone (PTH), PTH-related peptide, and 25-hydroxy vitamin D [25(OH)D] play important roles in the transplacental transport of calcium and bone remodeling.2 After birth, dramatic physiological changes in bone metabolism result from disruption of the maternal mineral supply, stimulation of calciotropic hormone secretion, changes in the hormonal environment, and a relative reduction in mechanical stress. These events stimulate the remodeling process, leading to increased bone resorption and decreased bone density.3 Calcium, Phosphorus, and Magnesium Intake Low birth weight (LBW) infants, either preterm or infants with intrauterine growth restriction, have signicantly lower calcium and phosphorus stores compared with infants who are born at term and appropriate for gestational age. This might be the result of low total body mineral content at birth, which is subsequently worsened by a suboptimal postnatal dietary calcium supply, transient hypoparathyroidism, lack of mechanical stimulation, and the use of diuretics and other calciuric drugs. Estimated daily enteral calcium and phosphorus requirements in preterm infants are 120-230 and 60-140 mg/kg/day, respectively. These values may be overestimates, however, because the unique postnatal environment of preterm infants might modify their mineral needs. Bone accretion in early infancy is not likely to occur at rates observed during the third trimester in utero. Furthermore, bone remodeling increases after birth, and released minerals become available to the pool of precursors necessary for early postnatal bone From the Medical College of Georgia, Georgia Health growth and turnover. Recent studies suggest that calcium retention in the range Sciences University, Augusta, GA; University of
1 2
25(OH)D ELBW LBW PTH VLBW
25-hydroxy vitamin D Extremely low birth weight Low birth weight Parathyroid hormone Very low birth weight
California Davis Medical Center, Sacramento, CA; 3 Baylor College of Medicine, Houston, TX; 4Sir Gangaram Hospital, New Delhi, India; and 5Department of Clinical Sciences, Pediatrics, Ume a University, Ume a, Sweden Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 March 2013 of 60-90 mg/kg/day ensures appropriate bone mineralization in very low birth weight (VLBW) infants.4 An enteral intake of 120-140 mg/kg/day will support this level of calcium retention, given an estimated absorption rate of 50%-65%. Phosphorus accretion is linked to calcium and nitrogen retention. Phosphorus absorption is efcient (up to 90%) in infants fed either human milk or formula. If calcium retention is 60-90 mg/kg/day and nitrogen retention is 350-450 mg/kg/day, then phosphorus intake sufcient to meet accretion by bone and soft tissues can be achieved by an intake of 65-90 mg/kg/day of a highly absorbable phosphate source, and the resultant calcium:phosphorus would be 1.5-2.0:1. Similar to calcium, magnesium has a high accretion rate in utero during the third trimester. Thus, preterm infants have a higher magnesium requirement than term infant, estimated as 8-15 mg/kg/day. Requirement for Vitamin D The ideal denition of optimal vitamin D levels would be based on functional biomarkers, such as intestinal calcium absorption, extent of bone mineralization, and PTH concentrations. Recent studies based on adult vitamin D physiology indicate that a serum 25(OH)D concentration <50 nmol/L is consistent with vitamin D deciency, and a concentration 50-80 nmol/L is consistent with vitamin D insufciency. 25(OH)D concentrations >80 nmol/L are considered sufcient. However, because no similar studies in preterm infants are currently available, values from adult and pediatric populations are extrapolated to neonates. Low vitamin D level is not uncommon in neonates fed either breast milk or infant formula. Preterm neonates are at particular risk for metabolic bone disease, for reasons that include: difculty achieving adequate enteral intake of calcium, phosphorus, and vitamin D; relative immobility; dependence on total parenteral nutrition; use of unfortied human milk; and adverse effects of medications (ie, diuretics and steroids) administered during hospitalization. Metabolic bone disease may be present in >50% of extremely low birth weight (ELBW) infants and in up to 25% of VLBW infants. Impact of Vitamin D Supplementation in Preterm and Term Infants Total and free 25(OH)D concentrations in cord blood of preterm and full-term neonates are lower than those in maternal blood. Early supplementation with vitamin D has been studied in neonates. Salle et al5 evaluated 25(OH)D levels in 17 preterm infants who received 1000 IU of vitamin D daily from birth. Mean levels increased from 20 nmol/L (range, 10-40 nmol/L) at birth to 92 nmol/L (range, 71-116 nmol/L) at 6 months. This dosage is sufcient to raise vitamin D levels to the desired range when administered for 6 months. Whether this leads to any functional benets is unclear, however. Several other clinical studies have evaluated the relationship between vitamin D3 intake and 25(OH)D concentrations.6-12 These ndings support the consensus opinion that a vitamin D intake of 8001500 IU/day is necessary to increase 25(OH)D concentrations to above 75 nmol/L in preterm infants of mothers with vitamin D deciency. At best, 400 IU/day of vitamin Dthe amount recommended for term infantsis provided in some US neonatal intensive care units.13 It is likely that an intake far lower than this is currently provided, given that clear criteria for vitamin D sufciency in preterm infants have not yet been established. Evidence from Randomized Controlled Trials A randomized controlled trial investigating the effect of vitamin D supplementation on bone density and biochemical indices in preterm infants has demonstrated that doses of 200-400 IU/kg body weight/day is sufcient to maintain normal vitamin D status.14 However, a more recent trial that compared 3 doses (200, 400, or 800 IU/kg/day) led the authors to conclude that higher doses might accelerate bone turnover.15 Although vitamin D provides clear short-term benets to preterm infants, the benets of increased vitamin D intake on bone mineral status in preterm-born children are no longer evident at age 9-11 years.16 Factors Affecting Enteral Absorption of Calcium and Phosphorus Intestinal absorption of calcium and bone accretion are affected by numerous factors. Calcium phosphate has low solubility compared with calcium chloride, citrate, and carbonate. Organic calcium salts, such as calcium gluconate and glycerophosphate, are more soluble and readibly absorbed. A high palmitate content in fat reduces calcium absorption, secondary to the formation of insoluble calcium soaps. Supplementation of human milk with phosphorus improves calcium retention and reduces calciuria in infants. Human milk has an excellent calcium:phosphorus and, thus, high bioavailability; however, it is relatively low in calcium and phosphorus and requires fortication to achieve adequate mineralization in preterm infants. When human milk fortier is provided with adequate amounts of calcium and phosphorus, calcium retention reaches 60 mg/kg/day. The use of human milk fortiers containing highly soluble calcium glycerophosphate improves calcium retention by up to 90 mg/kg/day in formula-fed infants, although the percentage of net calcium absorption is less than that seen with human milk. Because the poor bioavailability of preterm formula is compensated for by a higher calcium and phosphorus content, routine mineral supplementation is not required in infants fed preterm infant formula. The reported effects of vitamin D supplementation on calcium absorption have been inconsistent due to differences in study design. Bronner et al17 showed that calcium absorption in LBW infants was directly proportional to daily calcium intake and independent of vitamin D supplementation. In contrast, Senterre et al18 reported that calcium absorption in preterm infants increased from 50% to 71% when human milk was supplemented with 1200 IU/day of vitamin D3 with no additional calcium. This latter result suggests that
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Vol. 162, No. 3, Suppl. 1 25(OH)D concentrations at 27.5 nmol/L. In contrast, in some parts of Europe there have been reports of low cord blood levels of 25(OH) D (<10 mg/mL) in preterm infants, suggesting a higher required daily intake of up to 1000 IU. The American Academy of Pediatrics guidelines, revised in 2008, recommend an increased minimal supplementation of 400 IU/day to mantain serum 25(OH)D levels at >50 nmol/L.13 However, this dose might not be sufcient in parts of world where dietary supplementation with vitamin D is not routine, and the prevalence of vitamin D deciency is higher. Considering the prevalence of vitamin D deciency in pregnant mothers, the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition guidelines issued in 2009 state that higher vitamin D supply in preterm infants could be necessary to correct rapidly the low fetal level.21 A vitamin D intake of 800-1000 IU/day during the rst months of life is recommended, as this dose may help achieve vitamin D sufciency without risk of toxicity. These guidelines were based on several reports that documented vitamin D doses in sufcient ranges with supplementation of 800-1000 IU/day. Gaps in Knowledge Few studies have dened vitamin D requirements objectively in neonates, particularly in preterm neonates. Future studies are needed to dene the threshold for adequate vitamin D levels in neonates based on physiological functions. Guidelines for optimal vitamin D intake in preterm infants should take into account maternal vitamin D intake and status, as well as geographic, racial, and other constraints.
vitamin D supplementation supports calcium absorption. Calcium absorption increases in a relatively low-pH environment and with a high-lactose, high-casein formula. Assessment of Bone Mineralization
Biochemical Markers. Plasma calcium and phosphorus,

serum alkaline phosphatase, and serum osteocalcin concentrations and urinary excretion of pyridium cross-links of collagen are used to screen for metabolic bone disease in preterm infants; however, these markers have limitations and cannot be considered diagnostic of osteopenia. Nevertheless, elevated serum osteocalcin concentration, coupled with high serum alkaline phosphatase activity and increased excretion of cross-linked collagen, has been proposed as a marker of osteopenia in preterm infants.
Radiologic Markers. Conventional radiologic evaluation

is an insensitive method for evaluating metabolic bone disease in preterm infants givens the variations in X-ray exposure, as well as quantication. Bone mineral loss must be signicant before it can be appreciated radiologically. Efforts to dene bone density objectively on standard radiography using a scoring system19 have been followed by more accurate estimations of bone mineral content by bone absorptiometry. Dual X-ray absorptiometry has been proven to provide the most accurate determination of bone mineral content in preterm and term infants, and numerous studies have established normative data. Previous Guidelines Early guidelines recommended a vitamin D dose of 200 IU/ day for : (1) all breastfed infants unless they are weaned to at least 500 mL/day of vitamin D-fortied formula or milk; (2) all non-breastfed infants who ingest <500 mL/day of vitamin D-fortied formula or milk; and (3) children and adolescents who do not get regular sunlight exposure, do not ingest at least 500 mL/day of vitamin Dfortied milk, or do not take a daily multivitamin supplement containing at least 200 IU of vitamin D20 (Table I). These recommendations were based on data from the US, Norway, and China that showed an intake of vitamin D of 200 IU/day prevents physical signs of vitamin D deciency and maintains serum Table I. Recommended vitamin D supplement for preterm infants by feeding method
Early breast milk only 20-70 IU/L Early breast milk with human milk fortier (4 g/100 mL) 903 IU/L Preterm formula 400-800 IU/L Suggested intake 400-1000 IU/day
Copper
In Utero Copper Accretion Factorial analysis suggests a net requirement of $30 mg copper/kg/day in preterm infants is adequate to maintain normal growth.22 Postnatal Copper Metabolism Concentration of copper is high in early milk and declines with lactation.23 Copper deciency at 5 weeks to 8 months postnatally has been reported in preterm infants.23-31 It is notable, however, that most of these case reports are of infants who received copper-free parenteral nutrition; there is a paucity of similar recent reports. Assessment of Copper Status Copper status is estimated by measuring the plasma concentration of copper or ceruloplasmin, the main copperbinding protein in plasma. Both of these indicators are decreased in severe copper deciency but are relatively insensitive to marginal copper deciency. The activity of the enzyme copper-zinc superoxide dismutase in erythrocytes may be a more sensitive indicator of copper deciency. The main clinical features of copper deciency are anemia, thrombocytopenia, neutropenia, apnea, osteoporosis and other, characteristic changes in bone.24-31 Serum copper concentrations are normally <35 mg/dL, and
Bhatia et al
Standard term formula in the US is supplemented with 400 IU/L of vitamin D. A term infant with formula consumption of 1 L/day will meet the daily requirement and needs no additional supplementation. A breastfed term infant should be supplemented with a liquid preparation of vitamin D at a dose of 400 IU/day. A preterm infant will not be able to achieve such a high daily intake even with preterm formula containing more than 1000 IU/L of vitamin D until he or she weighs more than 2 kg and achieves a daily enteral intake of 160 mL/kg. Thus, a preterm infant, whether breastfed or formula-fed, will require vitamin D supplementation in the form of an oral liquid preparation.
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March 2013 the ceruloplasmin concentration is <15 mg/dL in copper deciency.24,27,28 Previous Guidelines The currently recommended enteral copper intake is 120-150 mg/kg/day.21,32-34 In a comprehensive review of the nutrient composition of preterm infant formulas, Klein22 recommended a copper concentration of 100-250 mg/100 kcal. At an energy intake is 120 kcal/kg/day, this recommendation is equivalent to 120-300 mg/kg/day. Newer Guidelines The 9 published studies of copper balance in preterm infants present summary data for 28 different groups of preterm infants.35-43 Copper intake (mean SD) was 162 128 mg/kg/day (range, 54-528 mg/kg/day), zinc intake was 1226 653 mg/kg/day (range, 511-2360 mg/kg/day), and the zinc:copper ratio (mg/mg) was 8.62 3.14 (range, 3.9-16.9). To assess the effect of zinc intake on copper retention, we performed a multiple regression analysis, weighted by the number of subjects in each of the 28 groups. Copper retention was positively related to copper intake (P < .0001), negatively related to zinc intake (P < .0001) and postnatal age (P = .0012), and unaffected by feeding type (human milk vs formula; P = .83). Zinc and copper intake accounted for most of the variability in copper retention (R2 = 0.776), as did the full model (R2 = 0.787). Our analysis yielded the following equation: Copper retention (mg/kg/day) = 7.8148 + [0.5871 copper intake (mg/kg/day)] [0.0508 zinc intake (mg/ kg/day)]. From this model, the copper intake required to produce copper retention of 30 mg/kg/day increases linearly with increasing zinc intake (Figure 1). This retention would be expected at a copper intake of 210 mg/kg/day if zinc intake
SUPPLEMENT
were 2000 mg/kg/day, and at a copper intake of 232 mg/kg/ day if zinc intake were 2250 mg/kg/day. Gaps in Knowledge The main gaps in our current knowledge regarding copper requirements for preterm infants involve the effects of copper retention from diets containing a higher zinc intake (>1.5-2 mg/kg/day) and high intake of enteral copper on liver function and serum transaminase levels in preterm infants with and without cholestasis.
Zinc
Zinc is essential for a multitude of enzymes and plays an important role in cellular growth and differentiation. Zinc deciency leads to stunted growth (poor length gain), increased risk for infection, skin rash, and possibly poor neurodevelopment.44 Assessment of Status Marginal zinc deciency is notoriously difcult to diagnose, owing to the lack of a reliable biomarker.44 Even though serum or plasma zinc is the most commonly used biomarker, it is not a sensitive indicator of marginal zinc deciency.44 Current Recommendations Most studies of zinc requirements in preterm infants have recommended intakes in the range of 1-2 mg/kg/day.21,32 For formulas, these intakes are equivalent to a minimum zinc content of 1.1 mg22 to 1.2 mg/100 kcal,21 and a maximum content of 1.522 to 1.8 mg/100 kcal.21 Intakes as high as 3 mg/kg/day are sometimes recommended,23 especially for infants who weigh <1000 g.32 There are concerns about higher zinc intake because of the potential adverse effect of zinc on copper absorption, however,44 and a zinc:copper of <20:1 is recommended for preterm infants.21 Gaps in Knowledge There remain large gaps in our knowledge of zinc requirements in preterm infants. Areas of uncertainty include: (1) the in utero zinc accretion rate in the fetus; (2) the optimal accretion rate in postnatal preterm infants; (3) bioavailability and retention of zinc contained in human milk fortied with modern human milk fortiers and in modern formulas; (4) effects of zinc intake on the absorption of other minerals (eg, iron and copper) in preterm infants; (5) effect of other minerals (eg, iron, copper) on the absorption of zinc intake in preterm infants; and (6) effect of fat absorption on zinc absorption in preterm infants.
Figure 1. Interrelationship of copper and zinc intake. The copper intake (mean and 2 SD) required to achieve a copper retention of 30 mg/kg/day is shown for different zinc intakes. Also shown are the current range of intakes recommended by Tsang et al,32 Agostoni et al,21 and Klein.22
In Utero Zinc Accretion In a comprehensive appraisal of nutrient requirements in preterm infants, Klein22 estimated zinc requirements in preterm infants using a factorial method. The requirement for retained zinc (ie, the amount by which that zinc absorption must exceed zinc losses) was estimated to be
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approximately 400 mg/kg at 1500-2500 g (30-32 weeks of postconceptional age).22 Metabolic Balance Studies The 14 reports on zinc balance in preterm infants published to date35-43,45-49 present summary data for a total of 35 different groups from studies examining infants at several distinct time points or with several different diets. When the analysis is weighed for the number of individuals in each group, zinc retention is positively correlated with zinc intake (P = .0401), is greater in formula-fed infants compared with human milk-fed infants (P = .0085), and is unaffected by either gestational age (P = .44) or postnatal age (P = .30) (Figure 2). If we assume that a zinc retention of 400 mg/kg/day is optimal, based on Kleins data for infants weighing 15002500 g, then a zinc intake of 2200 mg/kg/day is required in formula-fed infants and an intake of 2025 mg/kg/day is required in human milk-fed infants to meet that requirement for absorbed zinc. These intakes are equivalent to 1.7-1.9 mg/ 100 kcal. Assuming an energy intake of 120 kcal/kg/day, this is equal to 1.3-1.5 mg/100 mL of an 80-kcal/100 mL formula or 1.1-1.3 mg/100 mL of a 67-kcal/oz formula. Supplementation Trials Few studies have examined the effect of zinc supplementation in preterm infants (Table II).50-54 The most relevant of these is the study by Friel et al,54 who randomized 52 VLBW infants to receive 66 kcal/100 mL of formula containing either 0.67 or 1.1 mg/100 mL zinc starting at 1 month before discharge and continuing until 6 months after discharge. These formulas would be expected to provide approximately 1.2 or 2.0 mg/kg/day zinc (assuming an energy intake of 120 kcal/kg/ day). The group with the higher zinc intake demonstrated improved linear growth (but no differences in weight gain
Table II. Summary of signicant ndings from zinc supplementation trials in preterm infants
Low zinc intake, mg/kg/day 0.17* 0.3-0.4 0.55-0.71 1.1-1.2 High zinc intake, mg/kg/day 0.48* 0.6 0.94-1.43 1.9-2.2 Signicant differences, high versus low intake \ serum zinc None \ serum zinc \ red cell zinc \ linear growth \ serum zinc \ linear growth \ motor scores
Reference Haschke et al (1985)51 Loui et al (2004)52 Diaz-Gomez et al (2003)53 Friel et al (1993)54
Trials are ranked in increasing order of zinc intake in the high-zinc group. *Assuming calorie intake of 120 kcal/kg/day. At 6 weeks and at 3 weeks. At 3 months and at the start of the study.
or head circumference increase), higher motor scores, and (at some time points) higher plasma zinc concentrations.54 These results suggest that the higher zinc intake (in line with our estimate from metabolic balance data) is preferred over a lower zinc intake. Safety of Higher Zinc Doses Zinc is a relatively nontoxic mineral.44 The Institute of Medicine reviewed dietary reference intakes and identied the potential adverse effect of oral zinc on copper absorption as the most likely adverse effect of high zinc intake.44 Based on data from balance studies,35-43,45-49 we conclude that a zinc intake of 2.0-2.25 mg/kg/day is required to ensure an adequate zinc retention of 400 mg/kg/day.
Iron
Preterm and LBW infants are at high risk for iron deciency. Iron is necessary for brain development, and iron deciency anemia in infants is associated with poor neurodevelopment. In contrast to most other nutrients, however, there is no mechanism for excretion of iron from the human body. Excessive iron supplementation may increase the risk of infections, cause poor growth, and interact with absorption and metabolism of other minerals. Furthermore, iron is a potent pro-oxidant, and iron overload may lead to free radical disorders. Thus, it is important to avoid both iron deciency and iron overload in preterm infants. Estimated Iron Requirements Owing to the physiological shift of iron from hemoglobin into iron stores that occurs in newborns, a healthy term infant is initially independent of exogenous iron and is able to double its birth weight before iron stores are depleted. Preterm and LBW infants have higher iron requirements because of more rapid postnatal growth; small preterm infants double their birth weight at 6-8 weeks, whereas term infants do not achieve this until approximately 4-6 months of age.
Bhatia et al
Figure 2. Relationship between zinc intake and zinc retention. Mean zinc intake (mg/kg/day) and zinc retention (mg/ kg/day) reported in previous studies.35-43,45-49 For formulafed infants, y = 0.1358x + 100.6 (R2 = 0.12); for human milkfed infants, y = 0.450x 510.2 (R2 = 0.12).
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March 2013 Using a factorial approach, estimated iron requirements for preterm infants with a birth weight of 1 kg are 1.4-2 mg/kg/day during the rst year of life. However, these estimates do not consider blood losses and blood transfusions, which greatly inuence iron status and iron requirements in small preterm infants. Delayed umbilical cord clamping causes blood to ow from the placenta to the newborn and is associated with fewer blood transfusions and reduced incidence of intraventricular hemorrhage in preterm infants. Local practice regarding umbilical cord clamping, blood sampling, blood transfusions, and erythropoietin treatment greatly inuences iron requirements of preterm infants during the rst months of postnatal life. Iron Absorption Preterm infants absorb 25%-40% of iron from iron supplements given between feedings and 11%-27% of iron from iron-fortied preterm formula, rates exceeding those seen in term infants. Studies on iron bioavailability from multinutrient-fortied human milk are lacking. Randomized Controlled Trials Relatively few randomized studies comparing different doses of iron supplements or fortication of human milk or formula given to preterm or LBW infants have been published to date.
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mately 3 and 2 mg/kg/day, respectively, at age 3-9 months. That study found no difference in neurodevelopment or in the prevalence of anemia at age 12 months, but the highiron group had higher glutathione peroxidase concentrations (a marker of oxidative stress), lower plasma zinc and copper levels, and a higher rate of respiratory tract infections, suggesting possible adverse effects of the higher iron concentrations.60 In an iron supplementation trial in LBW infants (average birth weight 2000 g), iron intake ranged from 1.0-1.6 mg/ kg/day to 3.6-6.8 mg/kg/day. Serum ferritin level was higher at 20 weeks, but erythrocyte superoxide dismutase activity was reduced in the high-iron group, suggesting that high iron intake could alter copper metabolism. Furthermore, there was no signicant difference in hemoglobin concentration between the groups at 20 weeks.61 The study by Berglund et al56 found signicant differences in iron status at 6 months between marginally LBW infants (2000-2500 g) who had received 1 or 2 mg/ kg/day of iron between 6 weeks and 6 months of life. However, there were no signicant differences in the proportion of infants with iron deciency or iron deciency anemia in the 2 groups. Furthermore, a secondary analysis taking compliance and diet into account showed that an actual dietary iron intake of 1 mg/kg/day effectively prevented iron deciency.
Iron versus Placebo. A meta-analysis of studies published before 1992 showed that prophylactic iron given as a supplement or in iron-fortied formula leads to signicantly reduced incidence of anemia at 6 months in preterm infants.55 An enteral iron dose of $2 mg/kg/day was used in that study. In a recent randomized controlled, blinded trial (n = 285), Berglund et al56 showed that iron supplements of 2 mg/kg/day given from 6 weeks of age reduced the risk of iron deciency anemia at age 6 months in marginally LBW infants (2000-2500 g). No adverse effects with regard to infant growth, infection, or other morbidity were reported. A recent follow-up of these children found that those supplemented with 1-2 mg of iron per kg/day up to age 6 months exhibited signicantly fewer behavioral problems at age 3 years.57 Different Iron Doses. Several randomized controlled trials have investigated the effects of preterm formulas containing different amounts of iron. All of these trials included preterm infants with an average birth weight of 1.4-1.5 kg. In one trial, an iron intake of 1.3 mg/kg/day resulted in higher iron stores compared with an intake of 0.3 mg/kg/day, even though the incidence of iron deciency (dened as serum ferritin <19 mg/L) at 2 months postdischarge was similar in both groups (32%).58 A similar study found no difference in iron status between preterm infants receiving 0.9 mg/kg/day or 1.2 mg/kg/day, and there were no cases of iron deciency anemia at age 6 months.59 In another study, the 2 intervention groups (high-iron and low-iron) had iron intakes of 5.9 and 3.0 mg/kg/day, respectively, at discharge and approxi-
Timing of Iron Supplementation. Older studies have

shown that early iron supplementation does not improve early anemia of prematurity (before 2 months), which is believed to be caused by immature erythropoiesis rather than by iron deciency.55 However, 2 recent studies have suggested that initiation of iron supplementation or fortication at age 2 weeks, compared with 6-8 weeks, leads to a reduced need for blood transfusions in VLBW infants.62,63 Previous Guidelines In 2002, Klein22 recommended an iron intake of 2-3.6 mg/kg/ day (1.7-3.0 mg/100 kcal based on 120 kcal/kg/day). In 2005, Tsang et al32 recommended an intake of 2-4 mg/kg/day (1.33.1 mg/100 kcal based on 130 kcal/kg/day for ELBW infants and 1.5-3.6 mg/100 kcal based on 110 kcal/kg/day for VLBW infants). In 2010, European Society of Pediatric Gastroenterology, Hepatology, and Nutrition recommended an intake of 2-3 mg/kg/day (1.8-2.7 mg/100 kcal based on 110 kcal/kg/day) for infants with a birth weight <1800 g.21 The World Health Organization recommends 2-4 mg/kg/day for all LBW infants aged 2-24 months,64 and the American Academy of Pediatrics recommends 2 mg/kg/day at age 1-12 months for all LBW infants.65 Gaps in Knowledge To date, no studies have examined the effects of different doses of iron supplementation or fortication in ELBW infants, even though these infants are likely to be at increased risk for iron deciency and iron overload. In addition, there
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References
are no data on the long-term health consequences of different dietary iron intakes in preterm and LBW infants.
Recommended Intakes for Preterm and VLBW Infants

Calcium: 120-160 mg/kg/day; phosphorus: 60-90 mg/kg/day; magnesium: 8-15 mg/kg/day; vitamin D: 400-1000 IU/day; copper: 150-200 mg/kg/day; zinc: 2-2.25 mg/kg/day; iron: 2-3 mg/kg/day (birth weight < 1500 g); 2 mg/kg/day (birth weight 1500-2500 g).
Conclusion
Traditionally, the high calcium and phosphorus requirements of preterm neonates have been proposed to match the intrauterine accretion rate in the third trimester. However, recent studies suggest that a lower postnatal mineral accretion (enteral calcium intake of 120-140 mg/kg/day and phosphorus intake of 60-90 mg/kg/day) is sufcient to maintain adequate retention of these minerals. The goal of vitamin D supplementation should be to achieve an intake of 4001000 IU/day. In countries and geographical areas with a higher risk and/or prevalence of vitamin D deciency, intake should be targeted at the higher end of the range, and populations at low risk for vitamin D deciency should receive vitamin D at the lower end of the range. We recommend a dietary iron intake of 2 mg/kg/day for infants with a birth weight of 1500-2500 g and 2-3 mg/kg/ day for infants with a birth weight of <1500 g. Prophylactic iron should be started at age 2-6 weeks (at 2 weeks in VLBW infants). Infants receiving erythropoietin treatment and those with signicant, uncompensated blood losses will need a higher dose initially, requiring a separate iron supplement in addition to preterm formula or fortied human milk. A prolonged dietary iron intake of >3 mg/kg/day should be avoided in most cases because of possible adverse effects. In infants who have received multiple blood transfusions, serum ferritin concentration should be determined before starting iron supplementation/fortication, and prophylactic iron should not be given while serum ferritin is above normal levels for newborns.66 Iron supplements or intake of ironfortied formula in the recommended doses should be continued after discharge, at least until age 6-12 months, depending on diet. Hemoglobin and serum ferritin should be checked at follow-up visits, taking the physiological changes of iron status during infancy into consideration. n
Author Disclosures
All authors received honoraria from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. I. G. wrote the rst draft of this manuscript.
Reprint requests: Jatinder Bhatia, MD, FAAP, Division of Neonatology, Medical College of Georgia, Georgia Health Sciences University, BIW-6033, Augusta, GA 30912. E-mail: jatindeb@georgiahealth.edu.
1. Ziegler EE, ODonnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976;40:329-41. 2. Care A. Unique aspects of calcium and vitamin D metabolism in the placenta and fetus. In: Gluckman PD, Heymann MA, eds. Pediatrics and perinatology: the scientic basis. 2nd ed. London: Arnold; 1996. p. 540-2. 3. Rigo J, Pieltain C, Salle B, Senterre J. Enteral calcium, phosphate and vitamin D requirements and bone mineralization in preterm infants. Acta Paediatr 2007;96:969-74. 4. Mize CE, Uauy R, Waidelich D, Neylan MJ, Jacobs J. Effect of phosphorus supply on mineral balance at high calcium intakes in very low birth weight infants. Am J Clin Nutr 1995;62:385-91. 5. Salle BL, David L, Glorieux FH, Delvin E, Senterre J, Renaud H. Early oral administration of vitamin D and its metabolites in premature neonates: effect on mineral homeostasis. Pediatr Res 1982;16:75-8. 6. Glorieux FH, Salle BL, Delvin EE, David L. Vitamin D metabolism in preterm infants: serum calcitriol values during the rst ve days of life. J Pediatr 1981;99:640-3. 7. Robinson MJ, Merrett AL, Tetlow VA, Compston JE. Plasma 25-hydroxyvitamin D concentrations in preterm infants receiving oral vitamin D supplements. Arch Dis Child 1981;56:144-5. 8. Markestad T, Aksnes L, Finne PH, Aarskog D. Plasma concentrations of vitamin D metabolites in premature infants. Pediatr Res 1984;18:269-72. 9. Hillman LS, Hoff N, Salmons S, Martin L, McAlister W, Haddad J. Mineral homeostasis in very premature infants: serial evaluation of serum 25-hydroxyvitamin D, serum minerals, and bone mineralization. J Pediatr 1985;106:970-80. 10. Hillman LS, Hollis B, Salmons S, Martin L, Slatopolsky E, McAlister W, et al. Absorption, dosage, and effect on mineral homeostasis of 25-hydroxycholecalciferol in premature infants: comparison with 400 and 800 IU vitamin D2 supplementation. J Pediatr 1985;106:981-9. 11. Evans JR, Allen AC, Stinson DA, Hamilton DC, St John Brown B, Vincer MJ, et al. Effect of high-dose vitamin D supplementation on radiographically detectable bone disease of very low birth weight infants. J Pediatr 1989;115:779-86. 12. Delvin EE, Salle BL, Claris O, Putet G, Hascoet JM, Desnoulez L, et al. Oral vitamin A, E and D supplementation of pre-term newborns either breast-fed or formula-fed: a 3-month longitudinal study. J Pediatr Gastroenterol Nutr 2005;40:43-7. 13. Wagner CL, Greer FR. Prevention of rickets and vitamin D deciency in infants, children, and adolescents. Pediatrics 2008;122:1142-52. 14. Backstrom MC, Maki R, Kuusela AL, Sievanen H, Koivisto AM, Ikonen RS, et al. Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants. Arch Dis Child Fetal Neonatal Ed 1999;80:F161-6. 15. Kislal FM, Dilmen U. Effect of different doses of vitamin D on osteocalcin and deoxypyridinoline in preterm infants. Pediatr Int 2008;50:204-7. 16. Backstrom MC, Maki R, Kuusela AL, Sievanen H, Koivisto AM, Koskinen M, et al. The long-term effect of early mineral, vitamin D, and breast milk intake on bone mineral status in 9- to 11-year-old children born prematurely. J Pediatr Gastroenterol Nutr 1999;29:575-82. 17. Bronner F, Salle BL, Putet G, Rigo J, Senterre J. Net calcium absorption in premature infants: results of 103 metabolic balance studies. Am J Clin Nutr 1992;56:1037-44. 18. Senterre J, Putet G, Salle B, Rigo J. Effects of vitamin D and phosphorus supplementation on calcium retention in preterm infants fed banked human milk. J Pediatr 1983;103:305-7. 19. Koo WW, Gupta JM, Nayanar VV, Wilkinson M, Posen S. Skeletal changes in preterm infants. Arch Dis Child 1982;57:447-52. 20. Gartner LM, Greer FR. Prevention of rickets and vitamin D deciency: new guidelines for vitamin D intake. Pediatrics 2003;111:908-10. 21. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85-91.
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22. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr 2002;132:1395S-577S. 23. American Academy of Pediatrics, Committee on Nutrition. Pediatric nutrition handbook. 6th ed. Elk Grove Village (IL): American Academy of Pediatrics; 2009. 24. Ashkenazi A, Levin S, Djaldetti M, Fishel E, Benvenisti D. The syndrome of neonatal copper deciency. Pediatrics 1973;52:525-33. 25. Manser JI, Crawford CS, Tyrala EE, Brodsky NL, Grover WD. Serum copper concentrations in sick and well preterm infants. J Pediatr 1980; 97:795-9. 26. Allen TM, Manoli A 2nd, LaMont RL. Skeletal changes associated with copper deciency. Clin Orthop Relat Res 1982;126:206-10. 27. Sutton AM, Harvie A, Cockburn F, Farquharson J, Logan RW. Copper deciency in the preterm infant of very low birthweight: four cases and a reference range for plasma copper. Arch Dis Child 1985;60:644-51. 28. Al-Rashid RA, Spangler J. Neonatal copper deciency. N Engl J Med 1971;285:841-3. 29. Seely JR, Humphrey GB, Matter BJ. Copper deciency in a premature infant fed on iron-fortied formula. N Engl J Med 1972;286:109-10. 30. Blumenthal I, Lealman GT, Franklyn PP. Fracture of the femur, sh odour, and copper deciency in a preterm infant. Arch Dis Child 1980;55:229-31. 31. Halliday HL, Lappin TR, McMaster D, Patterson CC. Copper and the preterm infant. Arch Dis Child 1985;60:1105-6. 32. Tsang RC, Uauy R, Koletzko B, Zlotkin S. Nutrition of the preterm infant: scientic basic and practical guidelines. Cincinnati (OH): Digital Educational Publishing; 2005. 33. American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatrics 1985;75:976-86. 34. European Society of Paediatric Gastroenterology and Nutrition, Committee on Nutrition of the Preterm Infant. Nutrition and feeding of preterm infants. Acta Paediatr Scand Suppl 1987;336:1-14. 35. Dauncey MJ, Shaw JC, Urman J. The absorption and retention of magnesium, zinc, and copper by low birth weight infants fed pasteurized human breast milk. Pediatr Res 1977;11:1033-9. 36. Mendelson RA, Bryan MH, Anderson GH. Trace mineral balances in preterm infants fed their own mothers milk. J Pediatr Gastroenterol Nutr 1983;2:256-61. 37. Cooke RJ, Paule C, Ruckman K. Nutrient balance in the preterm infant, 3: effect of balance duration on outcome measurements. J Pediatr Gastroenterol Nutr 1989;8:355-8. 38. Ehrenkranz RA, Gettner PA, Nelli CM. Nutrient balance studies in premature infants fed premature formula or fortied preterm human milk. J Pediatr Gastroenterol Nutr 1989;8:58-67. 39. Ehrenkranz RA, Gettner PA, Nelli CM, Sherwonit EA, Williams JE, Ting BT, et al. Zinc and copper nutritional studies in very low birth weight infants: comparison of stable isotopic extrinsic tag and chemical balance methods. Pediatr Res 1989;26:298-307. 40. Fairey AK, Butte NF, Mehta N, Thotathuchery M, Schanler RJ, Heird WC. Nutrient accretion in preterm infants fed formula with different protein:energy ratios. J Pediatr Gastroenterol Nutr 1997;25:37-45. 41. Martinez FE, Sieber VM, Jorge SM, Ferlin ML, Mussi-Pinhata MM. Effect of supplementation of preterm formula with long-chain polyunsaturated fatty acids on mineral balance in preterm infants. J Pediatr Gastroenterol Nutr 2002;35:503-7. 42. Tyrala EE. Zinc and copper balances in preterm infants. Pediatrics 1986; 77:513-7. 43. Wirth FH Jr, Numerof B, Pleban P, Neylan MJ. Effect of lactose on mineral absorption in preterm infants. J Pediatr 1990;117:283-7. 44. Institute of Medicine Food and Nutrition Board, Standing Committee on the Scientic Evaluation of Dietary Intervals. Dietary reference intervals for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molydbenum, nickel, silicon, vandium and zinc. Zinc. Washington, DC: National Academies Press; 2000. p. 442-501. 45. Voyer M, Davakis M, Antener I, Valleur D. Zinc balances in preterm infants. Biol Neonate 1982;42:87-92.
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46. Higashi A, Ikeda T, Iribe K, Matsuda I. Zinc balance in premature infants given the minimal dietary zinc requirement. J Pediatr 1988;112:262-6. 47. Friel JK, Andrews WL, Simmons BS, Miller LV, Longerich HP. Zinc absorption in premature infants: comparison of two isotopic methods. Am J Clin Nutr 1996;63:342-7. 48. Wastney ME, Angelus PA, Barnes RM, Subramanian KN. Zinc absorption, distribution, excretion, and retention by healthy preterm infants. Pediatr Res 1999;45:191-6. 49. Loui A, Raab A, Obladen M, Bratter P. Nutritional zinc balance in extremely low-birth-weight infants. J Pediatr Gastroenterol Nutr 2001; 32:438-42. 50. Rajaram S, Carlson SE, Koo WW, Braselton WE. Plasma mineral concentrations in preterm infants fed a nutrient-enriched formula after hospital discharge. J Pediatr 1995;126:791-6. 51. Haschke F, Singer P, Baumgarter D, Steffan I, Schilling R, Lothaller H. Growth, zinc and copper nutritional status of male premature infants with different zinc intake. Ann Nutr Metab 1985;29:95-102. 52. Loui A, Raab A, Wagner M, Weigel H, Gruters-Kieslich A, Bratter P, et al. Nutrition of very low birth weight infants fed human milk with or without supplemental trace elements: a randomized controlled trial. J Pediatr Gastroenterol Nutr 2004;39:346-53. 53. Diaz-Gomez NM, Domenech E, Barroso F, Castells S, Cortabarria C, Jimenez A. The effect of zinc supplementation on linear growth, body composition, and growth factors in preterm infants. Pediatrics 2003; 111:1002-9. 54. Friel JK, Andrews WL, Matthew JD, Long DR, Cornel AM, Cox M, et al. Zinc supplementation in very-low-birth-weight infants. J Pediatr Gastroenterol Nutr 1993;17:97-104. 55. Doyle JJ, Zipursky A. Neonatal blood disorders. In: Sinclair JC, Bracken MB, eds. Effective care of the newborn infant. Oxford, UK: Oxford University Press; 1992. 56. Berglund S, Westrup B, Domellof M. Iron supplements reduce the risk of iron deciency anemia in marginally low birth weight infants. Pediatrics 2010;126:e874-83. 57. Berglund SK, Westrup B, Hagglof B, Hernell O, Domellof M. Effects of iron supplemantation of LBW infants on cognition and behavior at 3 years. Pediatrics 2012. in press. 58. Hall RT, Wheeler RE, Benson J, Harris G, Rippetoe L. Feeding ironfortied premature formula during initial hospitalization to infants less than 1800 grams birth weight. Pediatrics 1993;92:409-14. 59. Grifn IJ, Cooke RJ, Reid MM, McCormick KP, Smith JS. Iron nutritional status in preterm infants fed formulas fortied with iron. Arch Dis Child Fetal Neonatal Ed 1999;81:F45-9. 60. Friel JK, Andrews WL, Aziz K, Kwa PG, Lepage G, LAbbe MR. A randomized trial of two levels of iron supplementation and developmental outcome in low birth weight infants. J Pediatr 2001;139:254-60. 61. Barclay SM, Aggett PJ, Lloyd DJ, Duffty P. Reduced erythrocyte superoxide dismutase activity in low birth weight infants given iron supplements. Pediatr Res 1991;29:297-301. 62. Berseth CL, Van Aerde JE, Gross S, Stolz SI, Harris CL, Hansen JW. Growth, efcacy, and safety of feeding an iron-fortied human milk fortier. Pediatrics 2004;114:e699-706. 63. Franz AR, Mihatsch WA, Sander S, Kron M, Pohlandt F. Prospective randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams. Pediatrics 2000;106: 700-6. 64. Stoltzfus RJ, Dreyfuss ML. Guidelines for the use of iron supplements to prevent and treat iron deciency anemia: International Nutritional Anemia Consultative Group (INACG), World Health Organization (WHO), United Nations Childrens Fund (UNICEF). Washington, DC: ILSI Press; 1998. 65. American Academy of Pediatrics, Committee on Nutrition. Pediatric nutrition handbook. 5th ed. Elk Grove Village (IL): American Academy of Pediatrics; 2004. 66. Siimes AS, Siimes MA. Changes in the concentration of ferritin in the serum during fetal life in singletons and twins. Early Hum Dev 1986;13:47-52.
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Josef Neu, MD1, Walter A. Mihatsch, MD, MBA2, Jaime Zegarra, MD3, Sarayut Supapannachart, MD, FAAP, MBA4, a-Peniche, MD6 Zong-Yi Ding, MD5, and Teresa Murgu
When microbial communities colonize in the developing intestinal tract after birth, microrganisms interact with specic apical surface receptors on the enterocytes. This interaction triggers a response that prevents overexpression of inammatory cytokines, thus providing protection from pathogen-induced mucosal damage. Multiple immune modulatory factors in human milk and innate humoral factors also control inammatory responses, providing additional protective effects. Our understanding of the role of the luminal microbial communities or microbiota is growing rapidly as novel technologies provide new insights into their taxonomy, function during early development, and impact on life-long health. Multiple studies have evaluated the effects of the specic nutrients, glutamine, arginine, nucleotides, polyunsaturated fatty acids, and lactoferrin, on disease outcomes in premature infants. These studies support a role for nutrients to modulate host defense mechanisms in premature infants, to develop normal digestive function, to protect from bacterial translocation, and to preserve mucosal barrier integrity. These effects are clearly important. However, not enough is yet known to design specic clinical care practices that support a healthy microbiota. (J Pediatr 2013;162:S56-63). he mucosa of the small intestine is an interface between the external environment and the internal milieu and the site of selective assimilation of certain nutrients and molecules and exclusion of others. The rst line of host defense is the innate immune system, which is present at birth. It works in association with the adaptive immune system, which develops postnatally following exposure to various antigens and the microbiome to modulate the immune response. Infants, particularly those who are undernourished, may be at increased risk of harm caused by microbial pathogens and dietary antigens. Potentially harmful bacteria proliferate and facilitate bacterial translocation and/or mucosal invasion. Several factors promote the creation of a hostile gastrointestinal (GI) environment and predispose the preterm infant to disease.1 These include the use of feeding tubes, routine use of broad-spectrum antibiotics, and the subsequent proliferation of antibioticresistant pathogens, colonization of the gut with multi-resistant commensal local ora in the neonatal intensive care unit, and poor nutrition status secondary to the functional immaturity of an infants GI tract. This paper reviews several aspects of host defenses in the newborn and external factors affecting the intestinal mucosa such as type of feeding, the role of the intestinal microbiome, physical and chemical factors in the intestine, and the immune system, particularly the innate immune system.
Human Milk
Human milk protects the intestinal tract from infection and damage induced by dietary antigens. It also contains protective agents, including immunoglobulins, lactoferrin, lysozyme, glycoconjugates, oligosaccharides, and various cell types.2 Biologically-active antibodies appear in human milk as the result of maternal exposure to antigens and confer protection to her infant.3 This is particularly relevant because the mothers fecal bacteria commonly colonize the infant at birth and, thus, generate a shared microbiome specic to the maternal-infant dyad.4
Physical and Chemical Protective Factors

Intestinal motility can be a critical factor in clearing antigens presented to the mucosa. The time available for transport to the brush border and absorption depends on the rate at which luminal contents ow through the GI tract. Migratory motor
From the 1University of Florida, Gainesville, FL; 2Munich Municipal Hospitals, Munich, Germany; 3Hospital Nacional Cayetano Heredia, Lima, Peru; 4Ramathibodi Hospital School of Medicine, Mahidol University, Bangkok, Thailand; 51st August Childrens Hospital, Afliated with the General Hospital of Beijing Military Defense Area, Beijing, China; and 6National Center for Child and Adolescent Health (CeNSIA), Mexico City, Mexico Please see the Author Disclosures at the end of this article.
ARA DHA GI IL LA LCPUFA NEC PUFA TPN
Arachidonic acid Docosahexaenoic acid Gastrointestinal Interleukin Linoleic acid Long chain polyunsaturated fatty acid Necrotizing enterocolitis Polyunsaturated fatty acid Total parenteral nutrition
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Vol. 162, No. 3, Suppl. 1 March 2013 complexes act as housekeepers to propel luminal contents caudally through the intestinal tract. In preterm infants, motility is immature because coordinated motor complexes that are important for digestion and absorption are not mature until 34 to 35 weeks gestational age.5 Immature motility promotes bacterial overgrowth and, thus, reduces absorption of key dietary nutrients. Gastric acid secretion increases in preterm infants during the rst weeks after birth.6 Normal gastric acid and pancreaticobiliary secretions decrease the amount of viable microorganisms and intact dietary protein antigens that reach the small intestine. Pancreatic insufciency in the preterm infant can last throughout the rst year of life. Low gastric acid and pancreaticobiliary secretions, coupled with the common use of histamine-blockers to prevent gastric ulcers, allow a greater bacterial or antigenic load to reach the distal intestine and colon, thus predisposing the infant to sepsis and necrotizing enterocolitis (NEC).7 Intestinal mucus plays a signicant role in intestinal defense.8 Mucus is a complex viscous gel that covers the surface of the villous epithelium. It is mainly composed of water and electrolytes, but it also contains mucins, glycoproteins, immunoglobulins, glycolipids, and albumin. Bioactive factors, such as lactoferrin, lysozyme, and glycolipids from human milk, may also be present within the mucus gel. Mucus is secreted into the lumen of the intestine from storage vacuoles in goblet cells that are interspersed among enterocytes along the villus-to-crypt axis. Once secreted, mucus envelops foreign antigens, which helps propel them caudally within the lumen. The intestine responds quickly to insults by secreting copious amounts of mucin. Mucin from the small intestine of newborn rats contains more protein than that of adult rats; carbohydrate composition also changes with age. Newborn mucin contains less fucose and N-acetyl-cysteine than adult mucin.9 Developmental aspects of mucin in the human small intestine remain poorly understood. Improved understanding of mucin function in the future may lead to preventative actions treatments designed to protect the developing GI tract. and present antigens to CD 4+ T cells and B cells. In response to an antigen signal, naive T cells differentiate into effector or regulatory (tolerance-inducing) T cells and, thereby, play a central role in the maintenance of local immune homeostasis. Peyer patches are aggregations of lymphoid tissue located in the lamina propia and submucosa of the GI tract. They rst appear at about 19 weeks of gestation, spread throughout the jejunum and ileum from 24 to 40 weeks gestation, and remain prominent in the terminal ileum in the adult.
Innate Humoral Factors

Numerous innate humoral factors (lysozyme, peroxides, lactoferrin, trefoil peptides, other bioactive proteins, and glycoproteins) are secreted by exocrine glands and cover mucosal surfaces. They contribute to mucosal protection in conjunction with phagocytes in the absence of specic antibodies. These factors are present in mucosal secretions and act synergistically to protect from pathogens and other insults before the adaptive immune system has the opportunity to mount an antigen-specic response. Although a complete review of innate humoral factors is beyond the scope of this paper, lactoferrin deserves special attention because it is in relatively high concentrations in human milk and may provide some protection to the developing infant. Lactoferrin is a multifunctional protein produced in neutrophils and stored in an iron-free state. Anti-infective properties of lactoferrin include bacteriostatic, bactericidal, antifungal, and antiviral actions.
Inammatory Response Cells and Mediators: Cytokines and Chemokines

The role of cytokines produced by intestinal epithelial cells is presently being elucidated. Interleukin (IL)-6 has important proinammatory functions such as inducing secretion of acute-phase proteins by the liver and enhancing T-cell proliferation and B-cell antibody secretion. Intestinal epithelial cells also secrete various types of chemokines in response to inammatory stimuli. The rst chemokine found to be produced by intestinal epithelial cells was IL-8, which is induced by tumor necrosis factor-alpha. IL-8 is known to stimulate leukocytic inltration of tissues. The most obvious function of intestinal epithelial cells is to maintain a barrier to intestinal luminal contents. The cytokine-related inammatory response drastically reduces this barrier function. Interferon gamma, another pro-inammatory cytokine, reduces the epithelial barrier function in cells grown in culture. Transforming growth factor-beta, a mediator that participates in cell restitution and wound healing, counteracts this action.
Intestinal Epithelium
The enterocyte develops from the same undifferentiated stem cell that gives rise to the goblet, enteroendocrine, and, probably, M cells in the intestine. Goblet cells are found throughout the small and large intestine. Special tight junctions and interdigitations join the intestinal epithelial cells and serve as a permeability barrier between the external and internal milieus.10 Intestinal permeability is controlled by the tight junctions and altered by lack of enteral nutrition, various microbes and cytokines, cortisol, and stress. These intercellular junctions are exquisitely sensitive to modulation by small molecules, such as the short-chain fatty acid butyrate and glutamine, which act to preserve them.
Immunomodulatory Nutrients
Glutamine Glutamine, the most abundant amino acid in the human body, plays a central role in inter-organ carbon and nitrogen ux. Glutamine has not traditionally been used as
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Subepithelial Cells
Follicular dendritic cells are important nonphagocytic antigen-presenting cells. They reside in lymphoid follicles
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Vol. 162, No. 3, Suppl. 1 have no effects.12 In contrast, enteral glutamine supplementation improved tolerance to enteral feedings.13 In addition, enteral supplementation also decreased the incidence of intraventricular hemorrhage and periventricular leukomalacia.13 These preliminary results indicate that glutamine supplementation may be benecial, but additional large-scale controlled studies are needed to provide more detailed information about whether and how glutamine should be provided to preterm infants. Arginine Arginine is an essential amino acid for the fetus and neonate and a conditionally essential nutrient for adults. L-arginine is a versatile and critical component of nutrition and metabolism. It is a precursor for the synthesis of nitric oxide, creatine, polyamines, urea, ornithine, proline, glutamate, and other molecules with biologic importance. Arginine also stimulates the secretion of insulin and growth hormone. A certain concentration of arginine may be necessary not only for tissue growth but also for normal physiological function. Arginine concentrations can decrease when metabolic demand increases or when endogenous synthesis decreases or becomes limited. Premature infants who develop NEC
a nutritional supplement because it is synthesized endogenously and considered a non-essential amino acid. However, glutamine supply can be depleted rapidly, particularly in response to injury, infection, or chronic glucocorticoid treatment. Glutamine also is an important fuel for rapidly dividing cells such as enterocytes and immune cells. The amide nitrogen of glutamine is critical for the biosynthesis of nucleotides required for cell replication and hexosamines. Glutamine and nucleotides act synergistically to promote differentiation and proliferation of intestinal epithelial cells. The key antioxidant peptide, glutathione, is also formed from glutamine. Glutamine is not currently contained in total parenteral nutrition (TPN), and many premature infants do not feed enterally for weeks. The sudden cessation of maternal glutamine supply at birth may be detrimental to preterm infants who are highly stressed and/or undergoing rapid growth. Preterm infants may need exogenous glutamine for optimal growth and normal development of the intestinal mucosa and immune function, among other things. Premature neonates who develop NEC have reduced plasma glutamine and arginine concentrations.11 Two large multicenter trials have evaluated the safety and efcacy of glutamine supplementation. Parenteral glutamine supplementation was shown to Table. Characteristics of Included Studies
Source Amin, 200225 Costalos, 200326 Neu, 199727 n 152 87 68 Birth weight/ gestational age #1250 g #32 wk 28-32 wk 500-1250 g 24-32 wk #1500 g <32 wk 500-1250 g 580-1250 g 26-32 wk 401-1000 g
Prebiotics Parenteral L-arginine Saccharomyces boulardii and polyamine Enteral glutamine in premature formula Enteral glutamine Enteral glutamine Parenteral glutamine
Dosage and duration 1.5 mmoL/kg/d (26 mg/kg/d) during the rst 28 d of life 2 109/kg and 2 340 mmoL/kg/d from rst feed to 30 d 0.08 mg/k/d initially to 0.31 mg/k/d by day 13 of life 0.3 g/k/d from d 3 to d 30 of life 0.3 g/k/d during the rst 28 d Solution with 20% of total amount of amino acids from d 4 to d 14 of life Solution 20% of total amount of amino acids from d 3 to d 120 of life, death, or discharge 2.5% L-glutamine solution, 16% of total amount of amino acids. Amino acids started on rst d of life at 1 g/kg/d and increased by 0.5 g/kg/d to a maximum of 3 g/kg/d BLF 100 mg/d alone or in combination with LGG 6 109 CFU/d from birth to d 30 of life (d 45 for ELBW)
Primary outcome Incidence of NEC all stages Gut function and stool colonization Nosocomial sepsis, tolerance to subsequent feeding and length of hospitalization Time to achieve $120 mL/k/d of enteral feeding Incidence of culture-proven nosocomial sepsis Incidence of NEC all stages, nosocomial sepsis, and length of hospitalization Death or late onset sepsis
Van den Berg, 200528 Vaughn, 200313 Bober-Olesinska, 2002

29
102 649 55
Poindexter, 200430
721
Parenteral glutamine
Thompson, 200331
35
<1000 g and <1500 g who required O2 >40% or ventilated within 24 h
Parenteral glutamine
Time to establish full enteral feeding
Manzoni, 200924
472
#1500 g
Oral BLF alone or in combination with LGG
Incidence of late onset sepsis
BLF, bovine lactoferrin; CFU, colony forming units; ELBW, extremely low birth weight; O2, fraction of inspired oxygen; LGG, Lactobacilus GG.
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web 4C=FPO Figure 1. LCPUFA supplementation versus control. Outcome: neonatal sepsis.
have signicantly lower plasma concentrations of arginine than infants who do not.11,14 Low concentrations of arginine in premature infants may reduce the formation of nitric oxide, a critical mediator that regulates intestinal blood ow in response to inammation or injury. Hypoargininemia (plasma arginine <32 mol/L) is associated with increased severity of respiratory distress syndrome and hypoxemia in preterm infants who are dependent upon TPN.15 Enteral nutrition is essential for maintaining mucosal mass and integrity, and infants on TPN fail to synthesize citrulline and arginine from glutamine, glutamate, and proline in the small intestine. Several investigators are exploring the differences between enteral versus TPN feeding on endogenous arginine synthesis. Nucleotides Nucleotides, nucleosides, and nucleobases are components of the non-protein nitrogen fraction in human milk. Nucleotides, derived from endogenous biochemical sources, de novo synthesis, the salvage pathway, or from the diet, provide purines and pyrimidines for nucleic acid synthesis. Many recent studies have suggested that nucleotides may be conditionally essential nutrients for the GI tract under conditions of stress (eg, infection, post-intestinal resection, or trauma). There is a strong interaction between glutamine and nucleotides in the intestinal epithelium.16 A study of 311 full-term healthy infants showed that term formula fortied with nucleotides enhanced infant immunity, as indicated by
Haemophilus inuenzae and diphtheria humoral antibody responses. Nucleotide-supplemented formula was also associated with a reduction in the number of infants with diarrhea; however, this outcome was not assessed in all study infants.17 Omega-3 Polyunsaturated Fatty Acids Dietary fatty acids such as linoleic acid (LA) (18:2n-6) and a-linolenic acid (18:3n-3) of the n-6 and n-3 series of polyunsaturated fatty acid (PUFA), respectively, are considered to be essential because they are not formed endogenously. Once ingested, essential fatty acids are converted to longer-chain, highly unsaturated fatty acids, including arachidonic acid (ARA) from LA and eicosapentaenoic acid and docosahexaenoic acid (DHA) from a-linolenic acid. Modulation of immune and inammatory responses is related to the balance between omega6 and omega-3 PUFAs; a high omega-6:omega-3 is pro-inammatory. A systematic review of randomized controlled trials in premature newborn infants who received infant formula supplemented with DHA or control formula found no difference in incidence of sepsis or NEC between the groups. The incidence of retinopathy of prematurity and bronchopulmonary dysplasia was also similar in both groups. However, the sample sizes were small, and the effect of DHA doses was not clearly demonstrated.18 DHA and other n-3 long chain polyunsaturated fatty acid (LCPUFA) may play signicant roles in anti-
web 4C=FPO Figure 2. LCPUFA supplementation versus control. Outcome: neonatal NEC. Intestinal Mucosal Defense System, Part 1. Consensus Recommendations for Immunonutrients
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web 4C=FPO Figure 3. Supplementation with other immunonutrients versus control. Outcome: neonatal sepsis.
inammatory processes and have long-term positive effects on allergic illnesses. One study evaluated 1342 newborn infants enrolled in a multicenter, prospective, open-label, trial. Infants who received formula supplemented with DHA and ARA had a lower incidence of bronchiolitis in the rst year of life.19 Another study found similar outcomes in a randomized controlled trial in infants receiving formula supplemented with DHA and ARA or placebo.20 The infants who received formula with DHA early in life had a lower incidence of upper respiratory infection, wheezing/asthma, and allergies up to 3 years of age compared with the control group. Manley et al showed that
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preterm infants who received a high DHA supplement had a signicantly lower incidence of chronic lung disease than those who did not.21 Additionally, Martin et al have shown that healthy preterm infants have signicantly better DHA status than their counterparts who have chronic lung disease.22 Fish oil-based intravenous lipid emulsions are now being used to treat parenteral nutrition-associated liver disease, a severe inammation of the liver that occurs following prolonged TPN. It is a serious complication in premature infants and in children with short bowel syndrome who receive prolonged parenteral nutrition. Infants
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web 4C=FPO Figure 4. Supplementation with other immunonutrients versus control. Outcome: neonatal necrotizing enterocolitis.
who receive sh oil-based intravenous lipid emulsions have lower rates of death and liver transplantation compared with infants who receive a soybean-based product that contain more n-6 LCPUFA and no preformed n-3 LCPUFA.23 Further, infants who receive sh oil-based intravenous lipid emulsions recover from cholestasis 6 times faster than control infants. No adverse side effects were found. Lactoferrin In addition to being an innate humoral protein, the ironbinding protein lactoferrin is the most abundant whey protein in human milk. As implied by its name, lactoferrin was
rst isolated from milk. Subsequently, it was found to be in most exocrine uids such as saliva, bile, pancreatic secretions, and tears. Lactoferrin also is in plasma. Bovine lactoferrin has been shown to decrease late onset sepsis in premature infants.24
Clinical Strategies to Enhance Intestinal Immunity and Host Defense: Evidence-Based Clinical Practices
Numerous studies have evaluated the effects of immunonutrients on outcomes in premature and low birth weight infants. Characteristics of relevant clinical trials from the
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7. Canani RB, Terrin G. Gastric acidity inhibitors and the risk of intestinal infections. Curr Opin Gastroenterol 2010;26:31-5. 8. Schenk M, Mueller C. The mucosal immune system at the gastrointestinal barrier. Best Pract Res Clin Gastroenterol 2008;22: 391-409. 9. Snyder JD, Walker WA. Structure and function of intestinal mucin: developmental aspects. Int Arch Allergy Appl Immunol 1987;82: 351-6. 10. Marchiando AM, Graham WV, Turner JR. Epithelial barriers in homeostasis and disease. Annu Rev Pathol 2010;5:119-44. 11. Becker RM, Wu G, Galanko JA, Chen W, Maynor AR, Bose CL, et al. Reduced serum amino acid concentrations in infants with necrotizing enterocolitis. J Pediatr 2000;137:785-93. 12. Poindexter BB, Langer JC, Dusick AM, Ehrenkranz RA. Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcome. J Pediatr 2006; 148:300-5. 13. Vaughn P, Thomas P, Clark R, Neu J. Enteral glutamine supplementation and morbidity in low birth weight infants. J Pediatr 2003;142: 662-8. 14. Zamora SA, Amin HJ, McMillan DD, Kubes P, Fick GH, Butzner JD, et al. Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis. J Pediatr 1997;131:226-32. 15. Zamora SA, Amin HJ, McMillan DD, Fick GH, Butzner JD, Parsons HG, et al. Plasma L-arginine concentration, oxygenation index, and systemic blood pressure in premature infants. Crit Care Med 1998; 26:1271-6. 16. Tuhacek LM, Mackey AD, Li N, DeMarco VG, Stevens G, Neu J. Substitutes for glutamine in proliferation of rat intestinal epithelial cells. Nutrition 2004;20:292-7. 17. Pickering LK, Granoff DM, Erickson JR, Masor ML, Cordle CT, Schaller JP, et al. Modulation of the immune system by human milk and infant formula containing nucleotides. Pediatrics 1998;101: 242-9. 18. Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized controlled trials. Am J Clin Nutr 2008;87:912-20. 19. Pastor N, Soler B, Mitmesser SH, Ferguson P, Lifschitz C. Infants fed docosahexaenoic acid- and arachidonic acid-supplemented formula have decreased incidence of bronchiolitis/bronchitis the rst year of life. Clin Pediatr (Phila) 2006;45:850-5. 20. Birch EE, Khoury JC, Berseth CL, Castaneda YS, Couch JM, Bean J, et al. The impact of early nutrition on incidence of allergic manifestations and common respiratory illnesses in children. J Pediatr 2010;156: 902-6. 21. Manley BJ, Makrides M, Collins CT, McPhee AJ, Gibson RA, Ryan P, et al. High-dose docosahexaenoic acid supplementation of preterm infants: respiratory and allergy outcomes. Pediatrics 2011; 128:71-7. 22. Martin CR, Dasilva DA, Cluette-Brown JE, Dimonda C, Hamill A, Bhutta AQ, et al. Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J Pediatr 2011;159:743-9. 23. Puder M, Valim C, Meisel JA, Le HD, de Meijer VE, Robinson EM, et al. Parenteral sh oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg 2009;250:395-402. 24. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009;302: 1421-8. 25. Amin HJ, Zamora SA, McMillan DD, Fick GH, Butzner JD, Parsons HG, et al. Arginine supplementation prevents necrotizing enterocolitis in the premature infant. J Pediatr 2002;140: 425-31. 26. Costalos C, Skouteri V, Gounaris A, Sevastiadou S, Triandalidou A, Ekonomidou C, et al. Enteral feeding of premature infants with Saccharomyces boulardii. Early Hum Dev 2003;74:89-96.
US National Medical Library Medline database (through February 2010) are shown in the Table. The role of specic immunonutrients on the incidence of NEC and sepsis is summarized in Figures 1-4. Based on these studies, no conclusions and recommendations can be made on the use of immunonutrients such as glutamine, arginine, nucleotides, omega-3 PUFA, and lactoferrin, in preterm infants. There is convincing and exciting preclinical evidence that immunonutrients have the capability to improve host defense and the possibility to prevent diseases such as NEC, bronchopulmonary dysplasia, and hospital-acquired sepsis. Encouraging data from one randomized controlled trial suggest that lactoferrin may prevent neonatal sepsis or NEC. There are insufcient data available to recommend the routine use of glutamine, arginine, nucleotides, omega-3 LCPUFA, or lactoferrin for improvement of host defense in preterm infants. Well-designed, randomized, controlled clinical studies with sound scientic basis (eg, those based on animal studies and other experimental models) are needed. n
Author Disclosures
T. M. in the past has acted as scientic consultant of one formula company. Josef Neu, MD has received a research grant and honoraria for speaking from Mead Johnson Nutrition and is currently on its Scientic Advisory Committee. Walter A. Mihatsch, MD, MBA, is a recipient of a research grant from Mead Johnson Nutrition. In the past, he has acted as a scientic consultant to several infant formula companies. Jaime Zegarra, MD, is a recipient of a research grant from Mead Johnson Nutrition. All authors received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Teresa Murgu a-Peniche, MD, in the past, has acted as a scientic consultant for an infant formula company. J. N. wrote the rst draft of this manuscript.
Reprint requests: Teresa Murgu a-Peniche, MD, Foege Fellow, Rollins School of Public Health, Hubert Department of Global Health, 1518 Clifton Road, Mail Stop 1518-002-7BB, Atlanta, GA 30322. E-mail: teresamurguiap@gmail.com.
References
1. Caicedo RA, Schanler RJ, Li N, Neu J. The developing intestinal ecosystem: implications for the neonate. Pediatr Res 2005;58:625-8. 2. Newburg DS, Walker WA. Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatr Res 2007; 61:2-8. 3. Brandtzaeg P. The mucosal immune system and its integration with the mammary glands. J Pediatr 2010;156:S8-15. 4. Silverstein AM. The most elegant immunological experiment of the XIX century. Nat Immunol 2000;1:93-4. 5. Berseth CL. Gastrointestinal motility in the neonate. Clin Perinatol 1996; 23:179-90. 6. Hyman PE, Clarke DD, Everett SL, Sonne B, Stewart D, Harada T, et al. Gastric acid secretory function in preterm infants. J Pediatr 1985;106: 467-71. S62
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27. Neu J, Roig JC, Meetze WH, Veerman M, Carter C, Millsaps M, et al. Enteral glutamine supplementation for very low birth weight infants decreases morbidity. J Pediatr 1997;131:691-9. 28. van den Berg A, van Elburg RM, Westerbeek EA, Twisk JW, Fetter WP. Glutamine-enriched enteral nutrition in very-low-birth-weight infants and effects on feeding tolerance and infectious morbidity: a randomized controlled trial. Am J Clin Nutr 2005;81:1397-404. 29. Bober-Olesinska K, Kornacka MK. [Effects of glutamine supplemented parenteral nutrition on the incidence of necrotizing enterocolitis, noso-
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comial sepsis and length of hospital stay in very low birth weight infants]. Medycyna wieku rozwojowego 2005;9:325-33. 30. Poindexter BB, Ehrenkranz RA, Stoll BJ, Wright LL, Poole WK, Oh W, et al. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics 2004;113:1209-15. 31. Thompson SW, McClure BG, Tubman TR. A randomized, controlled trial of parenteral glutamine in ill, very low birth-weight neonates. J Pediatr Gastroenterol Nutr 2003;37:550-3.
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Teresa Murgu a-Peniche, MD1, Walter A. Mihatsch, MD, MBA2, Jaime Zegarra, MD3, Sarayut Supapannachart, MD, FAAP, MBA4, Zong-Yi Ding, MD5, and Josef Neu, MD6
The interplay between microorganisms and the intestine of newborn infants is associated with diverse functional and clinical outcomes that result from the specic interactions among microbial communities, their products, and the unique characteristics of the gastrointestinal tract. Multiple mechanisms of action for infant formula ingredients with probiotic activity appear to exist. These mechanisms are thought to protect the host not only from intestinal diseases but also from systemic infection. However, questions about the safety of probiotics for preterm infants remain unanswered, particularly with regard to sepsis, immunomodulatory effects, and microbial resistance. Few well-designed studies have been conducted to evaluate the effects of probiotic, prebiotic, and synbiotic ingredients on relevant clinical outcomes in preterm infants. Although existing data are encouraging, there is insufcient evidence to recommend the routine use of these ingredients in all preterm infants. (J Pediatr 2013;162:S64-71). ommensal microbes in the gastrointestinal tract play an important role in nutrition, angiogenesis, and mucosal immunity. The interaction of luminal microbes with cells of the intestinal epithelium also inuence the balance of mucosal inammatory and anti-inammatory processes, which play a signicant role in gastrointestinal illness and health status. Gut colonization starts immediately after birth, and the pattern of microbial colonization differs between formula-fed and breastfed infants. Preterm infants are particularly susceptible to abnormal colonization for many reasons, including delayed feeds, antibiotic use, and others. Provision of probiotics or prebiotics may change this abnormal pattern and confer health benets through different mechanisms. On the other hand, use of probiotics and prebiotics may introduce and/or stimulate innappropriate colonization of microbes at an inopportune time and, thereby, negatively affect the microbial ecology and immune system of an individual for a lifetime. Herein, we describe the most relevant modes of action of probiotics and the primary results reported for their use in preterm infants.
The Intestinal Microbial Environment

Current understanding of intestinal colonization in neonates is derived largely from studies using culture-based techniques. Recent studies suggest that many preterm infants are exposed to microbes in utero via the amniotic uid, even those without a history of rupture of membranes or culture-positive chorioamnionitis.1 Thus, the conceptual framework that the intestine is sterile at birth and the possibility that intestinal microorganisms play a role in intestinal development, especially in regards to mucosal immunology, may need to be reevaluated. With regard to initial postnatal colonization, studies using ribosomal DNA and RNA microarray-based assays showed that the patterns of microbial communities vary widely over time in healthy term infants, which suggests that the current denition of healthy colonization is too narrow.2 By 1 year of age, the prole of microbial communities in the infant changes to resemble that of the adult. Further, the composition and temporal patterns of intestinal microbial development in fraternal twins is strikingly similar, which suggests that genetic factors of the host contribute in shaping this development. Strikingly, Bidobacteria are not detected in these infants. This nding may have far-reaching implications because most studies of probiotic and prebiotic agents have targeted the propagation of these organisms, believed to be benecial for the developing intestinal tract. A few studies of microbial ecology in premature infants have used non-culture-based techniques to characterize the microbiota. Recently, microbial DNA has been detected in meconium. This indicates that microbiota have an intrauterine origin and that the intrauterine environment is not sterile.3 Lower microbial diversity has been detected in infants whose mothers had intended to breastfeed and in infants born at <30 weeks gestation. The implications of these ndings remain unclear. Fecal samples taken from infants diagnosed with necrotizing enterocolitis (NEC) have reduced diversity, increased From the National Center for Child and Adolescent Health (CeNSIA), Mexico City, Mexico; Munich abundance of gammaproteobacteria, and decreased numbers of other bacterial Municipal Hospitals, Munich, Germany; Hospital Nacional Cayetano Heredia, Lima, Peru; Ramathibodi species.4 Of note, infants who receive antibiotics prior to the onset of NEC for Hospital School of Medicine, Mahidol University, a higher mean number of days have decreased microbial diversity. Whether these Bangkok, Thailand; 1st August Childrens Hospital, afliated with General Hospital of Beijing Military Defense differences in diversity and bacterial strains relate to predisposition to NEC Area, Beijing, China; and University of Florida,
1 2 3 4 5 6
Gainesville, FL Please see the Author Disclosures at the end of this article.
NEC RCT
Necrotizing enterocolitis Randomized controlled trial
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Vol. 162, No. 3, Suppl. 1 March 2013 requires further research. The evaluation of the microbiota and its interaction with the gut mucosa during development, in both health and disease conditions, could yield information that might revolutionize our current thinking and lead to a more rational, mechanistically based approach to the use of pre- and probiotics. microbes can decrease nuclear factor kB activation to preserve the inhibitor, IkB.10 This function is important because high nuclear factor kB activity has been associated with development of NEC.11 The small intestine contains the major part of the gutassociated lymphoid tissue, which interacts with intestinal microbes to mediate responses in the small intestine to these microbes. Within the large intestine, probiotics ferment carbohydrates to produce short chain fatty acids, which act to alter innate immunity.12 Immunomodulatory effects associated with probiotics may also confer protection to the liver, specically by preventing production and/or uptake of lipopolysaccharides in the gut and thereby reducing levels of low-grade inammation.6 Other Antiviral activity has been demonstrated in the culture uid of probiotics. This raises interest in the role of probiotics against viral infections such as enteroviruses.13 Also, cytoprotective effects of probiotics have been suggested through activation of heat shock protein.10
Probiotics
It has been proposed that probiotics protect the host not only from intestinal diseases, but also from allergic disorders, liver inamation, and other systemic conditions.5,6 Probiotics or their metabolites interact with the host and with microbes, as do benecial commensal intestinal microbes, which makes the study of their mode of action unique and complex. Mode of Action Little is known about whether probiotics exert a benecial effect only in the presence of preexisting commensal intestinal microbiota. Commensal microbes in the intestinal tract provide a number of benets for the host. Probiotics act in synergy to exert similar effects. Probiotics are also thought to simulate commensal microbes. They compete for nutrient binding sites to provide a protective barrier against incoming bacteria and have, in some cases, antimicrobial action. Probiotics may also interfere with the adherence of pathogenic bacteria, increase the physical and immunological barrier function of the intestine, increase mucus production, decrease ischemic injury through nitric oxide production, and modulate the inamatory response. In addition, there is some evidence linking probiotic use with improved intestinal motility.7 Adherence Experimental evidence has shown that different strains of probiotics interfere with the adherence of pathogenic bacteria. There is now evidence that this effect may be mediated by soluble molecules secreted by probiotic strains.8 Immunomodulation There is evidence that probiotics have immunomodulatory actions, which may be benecial for diseases with high proinamatory activity in the bowel such as inammatory bowel disease and NEC. The immunomodulatory effect may be mediated by strengthening the intestinal barrier, whereby bacterial translocation across the epithelium and activation of the secondary inammatory cascade are reduced. In addition, there is a specic immune stimulation by probiotics through processes involving dendritic cells that present antigens to undifferentiated T-cells, directing their differentiation to effector versus regulatory phenotypes. Dendritic cells also sample commensal organisms, incorporate them, and transport them to mesenteric lymph nodes where they induce a local immune response by activating specic B-cells to produce specic secretory IgA.9 It has also been demonstrated that a combination of probiotic organisms and toll receptor agonists derived from
Safety of Probiotics
Infection The most important area of concern with probiotic use is the risk of sepsis. Probiotic therapy has been associated occasionally with adverse effects, including bacteremia, sepsis, or endocarditis in a select subset of patients who were immunocompromised or severely debilitated.10,14-16 Sepsis related to probiotic use in children has also been reported. In many cases, strain homology has been detected by molecular typing. There are now several reports of Lactobacillus bacteremia and Saccharomyces boulardii fungemia related to probiotic use in children with underlying risk factors such as short gut syndrome, immune deciency, complex cardiac diseases, or antibiotic-related diarrhea.17,18 Probiotic nosocomial Saccharomyces cerevisiae sepsis and, more recently, a case of Bidobacterium breve sepsis, thought to have low pathogenic potential, have been reported as well.19,20 The bacteremia/fungemia most likely originates from the probiotic strain through translocation and may be attributable to gut ischemia due to poor cardiac function and/or catheter contamination.18 Boyle et al have proposed the following risk factors for probiotic sepsis21: immune compromise, prematurity, catheter in place, impaired intestinal barrier, jejunostomy (gastric acid bypass), concomitant administration of broad spectrum antibiotics to which probiotics are resistant, probiotics of high mucosal adhesion, and cardiac valvular disease. It is clear that sick, premature infants are at increased risk. Metabolic Activities The intestinal microbiota play an important role in many metabolic activities, including digestion of complex carbohydrates, lipid metabolism, and glucose homeostasis. Mice colonized with microbiota store more fat than those not exposed
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Vol. 162, No. 3, Suppl. 1 tance; changes in growth, development, immune function, and allergic diseases and long-term changes must be monitored. Further, to document possible associations between the supplemented probiotic and sepsis, it will be important to use molecular probes to identify infectious agents because they are more sensitive and strain-specic than culture-based methods and may be less prone to bias.
to microrganisms.22 Although improved energy storage may be benecial in selected populations such as low birthweight infants, the ability of probiotics to promote weight gain is controversial at this time. Luoto et al23 demonstrated that early gut microbiota modulation with probiotics modied the growth pattern and restrained excessive weight gain during the rst years of life in a selected group of children. Excessive weight gain during the rst months of life may be a consequence of failure to establish anti-inammatory and tolerance responses to the initial environmental challenge presented by indigenous gut microbes, thus creating a lowgrade inammatory state characteristic of obesity and metabolic disorders.24 Modulation of this phenomenon through external interventions may explain, in part, the results of these studies. The importance of these experimental ndings remains to be substantiated by future results of well-designed clinical studies, particularly as we face a global obesity epidemic. It is possible that only microbes with specic metabolic and immunomodulatory activities may be benecial. Thus, care needs to be taken to nd the most effective and safe strains. Immune Activities of Probiotics. Potential Risk? Intestinal microbiota are necessary for a range of immune functions, including antibody production, development and persistence of oral tolerance to food antigens, and formation of germinal centers within lymphoid follicles.25,26 Manipulations of the microbiota in newborns may have signicant immunomodulatory effects. The long-term effects of these manipulations are difcult to predict but particularly important because there is potential risk of modifying immune responses in the adult. Microbial Resistance Another potential risk is the transfer of antimicrobial resistance from probiotic strains to pathogenic bacteria present in the intestinal microbiota. Many Lactobacillus strains are resistant to vancomycin, for example; this resistance could be transferred potentially to staphylococci or enterococci. Despite this concern, conjugation studies have not found the vancomycin-resistant genes of lactobacilli to be transferable to other genera.27 Delivery Risks The mode of probiotic delivery must be designed to ensure that microbes maintain probiotic activity and stability without compromising infant formula safety. Warming formula containing probiotics to temperatures above 40 C will change the natural balance of the culture. This is in contrast to World Health Organization recommendations to mix infant formula with hot water (>70 C) to minimize the risk of potentially deadly infections caused by Enterobacter sakazakii, which has been found in powdered infant formula.28 Monitoring If probiotics are to be used in newborns, the incidence of sepsis secondary to probiotic translocation and antibiotic resisS66
Evidence-Based Clinical Practices: Clinical Strategies to Enhance Intestinal Immunity or Host Defense with Probiotics, Prebiotics, and Synbiotics
Extensive research using a variety of approaches has been conducted thoughout the world in relation to the supplementation of preterm infant feedings with probiotics. This review provides information from the US National Medical Library Medline database through February 2010. With regard to host defense, 13 randomized controlled trials (RCTs) report on the effect on sepsis or NEC incidence, although the methodological quality of these studies varies. A summary of the most relevant studies is presented in the Table. There is no convincing evidence of a benecial effect with regard to sepsis incidence. Most of the studies showed no effect, one presented an increased risk, and one showed a decreased risk. Individual results and references are presented in Figure 1. In contrast, some of the available RCTs support the hypothesis that certain probiotics prevent NEC (Figure 2). Because the majority of probiotic-containing products have been evaluated in single sites, independent replication of these results in adequately powered, large, multicenter trials is essential before a particular product can be recommended for routine use in preterm infants.
Prebiotics
Prebiotics are selectively fermented ingredients that allow changes in the composition in the gastrointestinal microora, that confer benets upon host well-being. Prebiotics are not fully digested in the small intestine and, thus, can act in the lower intestinal tract to preferentially promote the growth of non-pathogenic organisms such as bidobacteria and lactobacilli. Human milk contains considerable amounts of a variety of different oligosaccharides, which are fermented, in part, in the infants colon. The concentration of oligosaccharides changes with the duration of lactation. Levels are highest in colostrum at 20-23 g/L then decline to about 20 g/L on day 4 of lactation and to 9 g/L on day 120 of lactation.29 Some absorption of intact human milk oligosaccharides occurs in preterm infants, but most oligosaccharides resist digestion in the small intestine and undergo fermentation in the colon.30 Oligosaccharides are implicated in maintaining normal gut ora and inhibiting growth of pathogenic bacteria. Their fermentation products, short-chain fatty acids, provide nutrition and energy for colonocytes and for the body following absorption. Other evidence suggests that human milk oligosaccharides may
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Table. Characteristics of included studies

Source Kitajima, 199741 Bin Nun, 200542 Samanta, 200943 Lin, 200844 Lin, 2005
45
n 91 145 186 434 367 183 69 69 80 94 585 80 20
Birthweight/gestational age <1500 g <1500 g <1500 g and <32 wk <1500 g <34 wk <1500 g <1500 g and <30 wk <37 wk <37 wk 27-36 wk <1500 g and <32 wk <1500 g or <33 wk <1500 g 800-2560 g and <33 wk
Probiotics Bidobacterium breve Bidobacterium infantisStreptococcus thermophylusLactobacillus acidophilus Bidobacterium bidusBidobacterium lactisBidobacterium infantisLactobacillus acidophilus Bidobacterium bidusLactobacillus acidophilus Lactobacillus acidophilus Bidobacterium infantis Bidobacterium lactis Bidobacterium lactis Bidobacterium lactis Bidobacterium lactis Bidobacterium longum Lactobacillus GG Lactobacillus GG Lactobacillus casein sp. rhamnosus Lactobacillus GG
Dosage and duration 0.5 109 organisms once daily from rst feed for 28 d 0.35 109 CFU of each from rst feed to 36 wk corrected age 2 2.5 109 CFU/d until discharge 125 mg/k/do twice daily for 6 wk 125 mg/k/do twice daily from d 7 until discharge 6 2 109 CFU/kg/d (12 billion CFU/kg/d) for rst 6 wk 1.6 109 CFU once daily from d 1 to d 3; 4.8 109 CFU once daily from d 4 to d 21 1.6 109 CFU once daily from d 1 to d 3; 4.8 109 CFU once daily from d 4 to d 21 Preterm formula 2 107 CFU/g formula powder started within 48 h, for 30 d Each 2 2.5 109 CFU/d until discharge 6 10 CFU once daily from rst feed until discharge
9
Primary outcome Gut colonization by Bidobacterium breve NEC all stages NEC, sepsis, death, and hospital stay NEC $ stage II Death or NEC $ stage II Nosocomial infections Gut colonization by Bidobacterium lactis and enteric pathogens Weight gain, fecal pH, fecal calprotectin, lactate, IgA Intestinal permeability (lactulose/mannitol ratio) Percent of infants with >50% enteral feed intake at d 14 Urinary tract infections, sepsis, NEC $ stage II after 7 d of probiotics Gut colonization by Candida species Fecal colonization, pathogenic ora, clinical symptoms
Mihatsch, 201046 Mohan, 200647 Mohan, 200848 Stratiki, 2007

49
Rouge, 200950 Dani, 2002

51
Manzoni, 200652 Millar, 199353
6 109 CFU once daily from d 3 to 6 wk or discharge from NICU 2 108/d for 2 wk
CFU, colony forming unit; IgA, immunoglobulin A; NICU, neonatal intensive care unit. Data derived from references: [41-53].
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web 4C=FPO Figure 1. Inuence of probiotics on the incidence of culture-proven sepsis. References for Figure 1: [41-54].
have anti-infective roles in the intestinal, respiratory, and urinary tracts. Finally, sialic acid is a structural and functional component of brain gangliosides and could play a role in neurotransmission and memory. Animal data suggest that early supplementation with sialic acid increases brain ganglioside sialic acid concentration and improves learning ability.31
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Techniques to synthesize human milk oligosaccharides in quantities sufcient to supplement infant formula are not available currently. A variety of prebiotics that are thought to mimic clinical effects attributed to human milk oligosaccharides have been studied in preterm infants. These include fructo-oligosaccharides from plants, galactooligosaccharides, acidic oligosaccharides from carrots, and
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web 4C=FPO Figure 2. Inuence of probiotics on the incidence of NEC (Bell stage $2). References for Figure 2: [41-54].
lactulose.32-39 Supplementation of pretem infant formula with prebiotics did not have a signicant effect on fecal bidobacteria counts, stool pH, stool viscosity, or gastrointestinal transport.38,39 Early feeding tolerance in extremely immature infants may be improved by prebiotics, although conclusive evidence for this effect is lacking.38,39 It has been hypothesized that prebiotics increase host defense in pre-
term infants and, thereby, reduce the incidence of gastrointestinal complications (eg, NEC, reduce the incidence of hospital-acquired infections, and improve long-term outcome. However, clinical research is insufcient to conrm these hypotheses. So far, no convincing effect on sepsis incidence32,35-37 or on the incidence of NEC32,35,37,38 has been found in RCTs. In summary, based on available
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during preterm labor: a molecular and culture-based investigation. PLoS One 2008;3:e3056. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol 2007;5:e177. Mshvildadze M, Neu J, Shuster J, Theriaque D, Li N, Mai V. Intestinal microbial ecology in premature infants assessed with non-culturebased techniques. J Pediatr 2010;156:20-5. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, et al. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J 2009;3: 944-54. Ouwehand AC. Antiallergic effects of probiotics. J Nutr 2007;137: 794S-7S. Gratz SW, Mykkanen H, El-Nezami HS. Probiotics and gut health: a special focus on liver diseases. World J Gastroenterol 2010;16:403-10. Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. Effects of probiotic and prebiotic on gastrointestinal motility in newborns. J Physiol Pharmacol 2009;60(Suppl 6):27-31. Lazar V, Miyazaki Y, Hanawa T, Chiriuc MC, Ditu LM, Marutescu L, et al. The inuence of some probiotic supernatants on the growth and virulence features expression of several selected enteroaggregative E. coli clinical strains. Roum Arch Microbiol Immunol 2009;68:207-14. Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004;303:1662-5. Petrof EO, Kojima K, Ropeleski MJ, Musch MW, Tao Y, De Simone C, et al. Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology 2004;127:1474-87. Chung DH, Ethridge RT, Kim S, Owens-Stovall S, Hernandez A, Kelly DR, et al. Molecular mechanisms contributing to necrotizing enterocolitis. Ann Surg 2001;233:835-42. Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology 2009;136:65-80. Mikhailova NA, Nagieva FG, Grinko OM, Zverev VV. Experimental study of antiviral activity of spore-forming bacterium Bacillus pumilus Pashkov. Zh Mikrobiol Epidemiol Immunobiol 2010;69-74. Bayer AS, Chow AW, Betts D, Guze LB. Lactobacillemiareport of nine cases. Important clinical and therapeutic considerations. Am J Med 1978;64:808-13. Rautio M, Jousimies-Somer H, Kauma H, Pietarinen I, Saxelin M, Tynkkynen S, et al. Liver abscess due to a Lactobacillus rhamnosus strain indistinguishable from L. rhamnosus strain GG. Clin Infect Dis 1999;28: 1159-60. Mackay AD, Taylor MB, Kibbler CC, Hamilton-Miller JM. Lactobacillus endocarditis caused by a probiotic organism. Clin Microbiol Infect 1999; 5:290-2. De Groote MA, Frank DN, Dowell E, Glode MP, Pace NR. Lactobacillus rhamnosus GG bacteremia associated with probiotic use in a child with short gut syndrome. Pediatr Infect Dis J 2005;24:278-80. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005;115:178-81. Ohishi A, Takahashi S, Ito Y, Ohishi Y, Tsukamoto K, Nanba Y, et al. Bidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele. J Pediatr 2010;156: 679-81. Perapoch J, Planes AM, Querol A, Lopez V, Martinez-Bendayan I, Tormo R, et al. Fungemia with Saccharomyces cerevisiae in two newborns, only one of whom had been treated with ultra-levura. Eur J Clin Microbiol Infect Dis 2000;19:468-70. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 2006;83:1256-64. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004;101:15718-23. Luoto R, Kalliomaki M, Laitinen K, Isolauri E. The impact of perinatal probiotic intervention on the development of overweight and obesity:
data, routine use of prebiotics in all preterm infants can not be recommended. Synbiotics refer to nutritional supplements that contain probiotics and prebiotics. The one preliminary RCT designed to measure the effect of certain synbiotic products in preterm infants on sepsis and NEC incidence was too underpowered for sound conclusions.40
2. 3.
4.
Conclusions and Recommendations Regarding Use of Prebiotics, Probiotics, and Synbiotics in Preterm Infants
There is no conclusive evidence (Level of Evidence 1a) to recommend the routine use of probiotics, prebiotics, or synbiotics in all preterm infants. There are encouraging preliminary data (Level of Evidence 2b) that indicate specic probiotics may be safe and effective where the incidence of NEC is high. However, these studies need to be repeated in RCTs. The available trials do not indicate that an optimal probiotic or prebiotic strain, dosing regimen, or protocol have been identied. The available evidence does not indicate whether products that contain a single strain of probiotic are more or less effective than those that contain multiple strains. Safety and efcacy of each probiotic strain must be tested separately. Data generated with one probiotic strain do not necessarily apply to another strain. Outside of clinical studies, clinicians should only use probiotics that have been shown to be safe. Conrmation of efcacy and safety is required in large, adequately-powered, multi-center, well-designed RCTs in low- and very low-birthweight infants. The incidence of severe NEC (Bell stage $2) and mortality should be monitored as primary outcomes. n
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9. 10.
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12. 13.
14.
Author Disclosures
Teresa Murgu a-Peniche, MD, has acted, in the past, as scientic consultant for one infant formula company. Walter A. Mihatsch, MD, is a recipient of research grants from Mead Johnson Nutrition. In the past, he has acted as a scientic consultant to several infant formula companies. Jaime A. Zegarra, MD, is a recipient of research grants from Mead Johnson Nutrition. Josef Neu, MD, has received a research grant and honoraria for speaking from Mead Johnson Nutrition and is currently on its Scientic Advisory Committee. All authors received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. T.M.-P. wrote the rst draft of this manuscript.
Reprint requests: Teresa Murgu a-Peniche, MD, Foege Fellow, Rollins School of Public Health, Hubert Department of Global Health, 1518 Clifton Road, Mail Stop 1518-002-7BB, Atlanta, GA 30322. E-mail: teresamurguiap@gmail.com.
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follow-up study from birth to 10 years. Int J Obes (Lond) 2010;34:15317. Hotamisligil GS. Inammation and metabolic disorders. Nature 2006; 444:860-7. Gaboriau-Routhiau V, Moreau MC. Gut ora allows recovery of oral tolerance to ovalbumin in mice after transient breakdown mediated by cholera toxin or Escherichia coli heat-labile enterotoxin. Pediatr Res 1996;39:625-9. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science 2005;307:1915-20. Tynkkynen S, Singh KV, Varmanen P. Vancomycin resistance factor of Lactobacillus rhamnosus GG in relation to enterococcal vancomycin resistance (van) genes. Int J Food Microbiol 1998;41:195-204. WHO/FAO Guidelines: Safe preparation, storage, and handling of powdered infant formula. Geneva, Switzerland: Department of Food Safety, Zoonoses and Foodborne Diseases, World Health Organization, in collaboration with Food and Agriculture Organization of the United Nations; 2007. p. 32. Coppa GV, Gabrielli O, Pierani P, Catassi C, Carlucci A, Giorgi PL. Changes in carbohydrate composition in human milk over 4 months of lactation. Pediatrics 1993;91:637-41. Brand-Miller JC, McVeagh P, McNeil Y, Messer M. Digestion of human milk oligosaccharides by healthy infants evaluated by the lactulose hydrogen breath test. J Pediatr 1998;133:95-8. Miller JB, McVeagh P. Human milk oligosaccharides: 130 reasons to breast-feed. Br J Nutr 1999;82:333-5. Westerbeek EA, van den Berg JP, Lafeber HN, Fetter WP, Boehm G, Twisk JW, et al. Neutral and acidic oligosaccharides in preterm infants: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 2010;91:679-86. Boehm G, Lidestri M, Casetta P, Jelinek J, Negretti F, Stahl B, et al. Supplementation of a bovine milk formula with an oligosaccharide mixture increases counts of faecal bidobacteria in preterm infants. Arch Dis Child Fetal Neonatal Ed 2002;86:F178-81. Knol J, Boehm G, Lidestri M, Negretti F, Jelinek J, Agosti M, et al. Increase of faecal bidobacteria due to dietary oligosaccharides induces a reduction of clinically relevant pathogen germs in the faeces of formula-fed preterm infants. Acta Paediatr Suppl 2005;94:31-3. Mihatsch WA, Hoegel J, Pohlandt F. Prebiotic oligosaccharides reduce stool viscosity and accelerate gastrointestinal transport in preterm infants. Acta Paediatr 2006;95:843-8. Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J Pediatr 2008;152:801-6. Riskin A, Hochwald O, Bader D, Srugo I, Naftali G, Kugelman A, et al. The effects of lactulose supplementation to enteral feedings in premature infants: a pilot study. J Pediatr 2010;156:209-14. Modi N, Kulinskaya E. A double-blind, randomised, controlled trials of the effect of prebiotic bidogenic oligosaccharides on enteral tolerance in preterm infants. Proceedings of the Eastern Society for Pediatric Research (ESPR) Annual Meeting, Philadelphia, PA, 2008. Modi N, Uthaya S, Fell J, Kulinskaya E. A randomized, double-blind, controlled trial of the effect of prebiotic oligosaccharides on enteral tolerance in preterm infants (ISRCTN77444690). Pediatr Res 2010; 68:440-5.
SUPPLEMENT
40. Underwood MA, Salzman NH, Bennett SH, Barman M, Mills DA, Marcobal A, et al. A randomized placebo-controlled comparison of 2 prebiotic/probiotic combinations in preterm infants: impact on weight gain, intestinal microbiota, and fecal short-chain fatty acids. J Pediatr Gastroenterol Nutr 2009;48:216-25. 41. Kitajima H, Sumida Y, Tanaka R, Yuki N, Takayama H, Fujimura M. Early administration of Bidobacterium breve to preterm infants: randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 1997;76: F101-7. 42. Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 2005;147:192-6. 43. Samanta M, Sarkar M, Ghosh P, Ghosh J, Sinha M, Chatterjee S. Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. J Trop Pediatr 2009;55:128-31. 44. Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 2008;122: 693-700. 45. Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2005;115:1-4. 46. Mihatsch WA, Vossbeck S, Eikmanns B, Hoegel J, Pohlandt F. Effect of Bidobacterium lactis on the incidence of nosocomial infections in verylow-birth-weight infants: a randomized controlled trial. Neonatology 2010;98:156-63. 47. Mohan R, Koebnick C, Schildt J, Schmidt S, Mueller M, Possner M, et al. Effects of Bidobacterium lactis Bb12 supplementation on intestinal microbiota of preterm infants: a double-blind, placebo-controlled, randomized study. J Clin Microbiol 2006;44:4025-31. 48. Mohan R, Koebnick C, Schildt J, Mueller M, Radke M, Blaut M. Effects of Bidobacterium lactis Bb12 supplementation on body weight, fecal pH, acetate, lactate, calprotectin, and IgA in preterm infants. Pediatr Res 2008;64:418-22. 49. Stratiki Z, Costalos C, Sevastiadou S, Kastanidou O, Skouroliakou M, Giakoumatou A, et al. The effect of a bidobacter supplemented bovine milk on intestinal permeability of preterm infants. Early Hum Dev 2007; 83:575-9. 50. Rouge C, Piloquet H, Butel MJ, Berger B, Rochat F, Ferraris L, et al. Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 2009;89:1828-35. 51. Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study. Biol Neonate 2002;82:103-8. 52. Manzoni P, Mostert M, Leonessa ML, Priolo C, Farina D, Monetti C, et al. Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Clin Infect Dis 2006;42:1735-42. 53. Millar MR, Bacon C, Smith SL, Walker V, Hall MA. Enteral feeding of premature infants with Lactobacillus GG. Arch Dis Child 1993;69:483-7. 54. Uhlemann M, Heine W, Mohr C, Plath C, Pap S. [Effects of oral administration of bidobacteria on intestinal microora in premature and newborn infants]. Z Geburtshilfe Neonatol 1999;203:213-7.
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David Tudehope, AM, MBBS, FRACP1, Mary Fewtrell, MD2, Sudha Kashyap, MD3, and Enrique Udaeta, MD4
We have used an expansive denition of a micropreterm infant as <30 weeks gestation to provide a global perspective to a high risk group of preterm infants for which there are little published data to guide nutritional management. Consensus nutritional guidelines for preterm infants have been developed for infants >1000 g birth weight and >28 weeks gestational age. Micropreterm infants have greater nutritional decits at birth than more mature preterm infants and accumulate greater postnatal decits. Nutritional guidelines based on the needs of preterm infants born >28 weeks gestation are unlikely, on a theoretical basis, to meet nutritional requirements of micropreterm infants. Unfortunately, very few good quality studies have addressed the nutritional requirements of this group specically; this makes it difcult to formulate solid, evidence-based nutritional recommendations for these neonates. Nutritional management of micropreterm infants is based on recommendations established for preterm infants, which are adjusted after considering an infants gestational age, birth weight, and clinical status. Minimal enteral feeding should commence on the rst or second day of life, with incremental advancement and fortication of human milk when 100 mL/kg is tolerated. Early use of parenteral nutrition is recommended, ideally initiated within the rst hours of life and enteral feeds are being established; this will help prevent the accumulation of nutritional decits and incidence of growth failure. Fortied human milk should be given in order to meet nutritional requirements. When human milk is not available in sufcient quantity, a preterm formula should be given. (J Pediatr 2013;162:S72-80). lthough the more commonly accepted classications of preterm infants are extremely low birth weight (ELBW) and extremely preterm (<28 weeks gestation), we dened micropreterm as <30 weeks gestation. A subset of this population is small for gestational age (GA); these infants weigh <10th percentile at birth at <30 weeks gestation. This expanded denition was selected to gain a global perspective of a high risk group of preterm infants. We were unable to locate substantial information about this population. This discussion addresses the current state of knowledge and clinical practice on the nutritional requirements of the micropreterm infant.
Developmental Physiology and Biology

The composition of weight gained by the fetus changes with GA. The difference in body composition between a micropreterm and a more mature infant impact decisions about nutritional management. For example, body water as a percentage of body weight decreases rapidly during the last trimester. Water comprises about 80% of weight gained between 24 and 28 weeks of gestation but only 60% of weight gained between 36 and 40 weeks. The proportion of weight gained as fat increases markedly from 8% at 24-28 weeks to nearly 20% near term.1 The fetal intestine is capable of digesting and absorbing milk feeds by 25 weeks gestation, but not as well as that of a more mature infant. Gastrointestinal motor activity develops later and may limit tolerance to enteral feeds. Motility is described as being disorganized between 25 and 30 weeks of gestation. This can cause nutrients to remain in the intestine, especially if digestion is suboptimal, and may increase the risk of necrotizing enterocolitis (NEC).2 Antenatal steroids accelerate the maturation of the gut and reduce the incidence of NEC (relative risk: 0.46; 95% CI 0.29-0.74).3 Swallowing activity begins to develop during the second trimester, and enteral ingestion of amniotic uid contributes to fetal nutrition and development of the gastrointestinal tract. Postnatally, ingestion of colostrum and milk plays an important role in stimulating gut maturation. Accompanying the development of the gastrointestinal tract, there is also progressive development of different enzymes throughout fetal life.4 Gastric pepsin and brush-border enzymes, including sucrase, aminopeptidase, and lactase, develop in parallel and are present in low concentrations in infants born prematurely. Lactase activity remains low throughout fetal life but increases markedly with the rst enteral feed, regardless of age. Shulman et al5 initiated feeds on
From the 1Mater Medical Research Institute and the School of Medicine, The University of Queensland, Queensland, Australia; 2University College London Institute of Child Health, London, United Kingdom; 3 Morgan Stanley Childrens Hospital, Columbia University Medical Center, New York, NY; and 4Hospital Infantil de Mexico, Mexico City, Mexico Please see the Author Disclosures at the end of this article.
BW DBM ELBW GA NEC P:E PDF PTF
Birth weight Donor breast milk Extremely low birth weight Gestational age Necrotizing enterocolitis Protein:energy Post-discharge formula Preterm formula
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Table I. Summary of theoretical concerns and available data from micropreterm infants for specic enteral nutrients
Nutrient Fluid Energy Theoretical concerns Increased requirements due to immature skin Vulnerable to uid overload with worsening cardiovascular disease, patent ductus arteriosus Low energy stores. Intake often inadequate due to concomitant illness restricting supply Concern regarding NEC Increased requirement for growth, especially if decits accumulate Greater risk of overload, metabolic acidosis, increased BUN and urea Some amino acids conditionally essential Published data for micropreterm infants? No Intakes of 150-180 mL/kg/d tolerated in enteral studies EE of 60-75 kcal/kg/d by indirect calorimetry and by doubly labeled water in stable ELBW infants30,31 Higher levels of EE of 88-96 kcal/kg/d by doubly labeled water method in infants with sepsis31 and chronic lung disease31 ELBW infants (generally >750 g) included as subjects along with VLBW infants in enteral feeding studies dening protein requirements. Factorial method33 ELBW infants randomized and treated for 7 days with IV amino acids starting at 0.5 g/kg/d and increased by 0.5-3.0 or starting 2 g/kg/d and increased by 1.0-4.0 daily; infants receiving higher amino acids in rst week had lower NDI at 18 mo [not 2 y] and lower z-scores for weight, length, and head circumference at 2 y34 P:E 3.6 g/100 kcal with protein intake 4.6 g/kg/d tolerated for 1 wk35 P:E 3.6 g/100 kcal with protein intake 4.3 g/kg/d for longer periods reported some evidence of protein overload36 24-31 weeks GA infants (n=20): Formula supplementation with oligosaccharides reduced stool viscosity and accelerated GI transit37 No Current recommendations Range 135-200 mL/kg/d 130-150 kcal/kg/d12
12,13
New recommendations
120-140 kcal/kg/d
Protein
Factorial approach31: 3.5-4.0 g/kg/d Tsang et al12: 3.8-4.4 g/kg/d (26-30 wk PCA) ESPGHAN13: 4.0-4.5 g/kg/d ELBW 3.8-4.4 g/kg/d VLBW
3.6-4.5 g/kg/d Larger trials than Blanco, et al.34 necessary to assess best IV amino acid advancement and dosage
P:E
Tsang et al12: 3.3-3.4 g/100 kcal ESPGHAN13: 3.6-4.1 g/100 kcal Tsang et al12: 9-20 g/kg/d for enteral feeding of growing ELBW infant Tsang et al12: 6.2-8.4 g/kg/d for enteral feeding of growing ELBW infant, or 4.1-6.5 g fat/ 100 kcal DHA: 20-62 mg/kg/d ARA: 30-36 mg/kg/d EPA: #23 mg/kg/d
3.0-3.6 g/100 kcal
Carbohydrate Lipids
LCPUFA
Provides 40%-50% of calories PTF has 23%-50% glucose polymers and some have Gos and Fos oligosaccharides as prebiotics May have increased requirements due to high energy needs and restricted uid intake Absorption may be reduced with resultant steatorrhoea Provides 50% energy in human milk Greater decit at birth. LCPUFA oxidized if energy supply insufcient
10.5-14 g/kg/d 5-7 g/kg/d for enteral feeding of growing micropreterm, or 4.4-6.0 g fat/100 kcal Some evidence to suggest higher intake of DHA (1% of total fatty acids) might have particular benets to micropreterm infants
Sodium
High fractional excretion of sodium in rst 10-14 d
In a multicenter trial of infants <33 weeks maternal diet high in DHA and infant DHA dose of 1% total fatty acids increased MDI of females <1250 g38 For infants <1250 g, supplementation was associated with higher MDI in unadjusted, but not in adjusted, analyses For males overall, and for all infants with bodyweight <1250 g the risk of BPD was lower in supplemented infants39 No
Vol. 162, No. 3, Suppl. 1 March 2013
Calcium and phosphorus
Greater mineral decit at birth (majority of mineral accretion occurs in last trimester). Greater risk of metabolic bone disease. Calcium absorption rate 50%-65%, phosphate absorption 90%
No
Tsang et al12: Calcium 100-220 mg/kg/d Phosphorus 60-140 mg/kg/d
4-5 mmol/kg/d in rst 10-14 d and 2.5-3.0 mmol/kg/d thereafter Calcium intake of 120-180 mg/kg/d Phosphorus intake of 60-90 mg/kg/d; (maintain phosphorus levels $1.8 mmol/L) (continued )

800-1000 IU/d 2-4 mg/kg/d from 2-4 wk of age adjusted for transfusions and EPO 2.0-2.25 mg/kg/d
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ARA, arachidonic acid; BPD, bronchopulmonary dysplasia; BUN, blood urea nitrogen; DHA, docosahexaenoic acid; EE, energy expenditure; EPA, eicosopentaeoic acid; EPO, erythropoietin; ESPGHAN, European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; Fos, fructo-oligosaccaride; GI, gastrointestinal; Gos, galacto-oligosaccharide; IV, intravenous; LCPUFA, long chain polyunsaturated fatty acids; MDI, Mental Development Index; NDI, neurodevelopmental index; PCA, postconceptual age; RCT, randomized controlled trial; VLBW, very low birth weight.
Vol. 162, No. 3, Suppl. 1 day 4 or day 15 in 135 infants at 26-30 weeks gestation and found that early feeding was associated with increased lactase activity. Macronutrient transporters are present by the third trimester.2 Certain enzymes of amino acid metabolism develop late in gestation, including those involved in: (1) the synthesis of cysteine from methionine, taurine from cysteine, and tyrosine from phenylalanine; (2) the degradation of tyrosine; and (3) the production of urea.6 Based on these observations, micropreterm infants might be expected to require certain amino acids (eg, cysteine and taurine), which are not essential later in life, and may be at risk for accumulating excessive amounts of others (eg, phenylalanine, tyrosine, and methionine). Enzymes used in gluconeogenesis such as phosphoenolpyruvate carboxykinase may not develop until just before or just after term delivery. This is not surprising because the fetal liver stores glucose as glycogen, and there is a steady ow of glucose to the fetal circulation via the placenta. Immediately after birth, glycogen phosphorylase and glucose 6-phosphatase act to release glucose from liver glycogen. Gluconeogenesis is not necessary to maintain blood glucose concentrations until 24-48 hours after birth. The micropreterm neonate is born with low stores of liver glycogen,7 a reduced gluconeogenic ability, and is, thus, at particular risk for developing hypoglycemia.
Tsang et al12: 700-1500 IU/kg/d
Tsang et al12: 25-50 mg/kg/d
Tsang et al : 150-400 IU/kg/d 2-3 mg/kg/d from 2-4 wk of age adjusted for transfusions and EPO Tsang et al12: 1000-3000 mg/kg/d
12
Current recommendations
Folate: 64 infants (BW 801-1300 g) on EPO randomized to B12 + folate 100 mg/kg/d versus folate 60 mg/d had enhanced erythropoiesis and lower fall in hemoglobin40 Folate, iron, B12: ELBW infants (BW <800 g) randomized to EPO, B12, iron, and folate had signicantly lower transfusion requirement than controls40 ELBW infants: meta-analysis reported supplementation associated with reduction in death or oxygen requirement at 36 wk gestation41
ELBW infants: observational study (101/226 in time period 1 and 220/338 in time period 2) reported signicant reduction in NEC, sepsis, and death after introducing probiotics mixed in breast milk or formula42
Published data for micropreterm infants?
190-230 mg/kg/d Only off label products available outside of RCT
New recommendations
1330-3330 IU/kg/d
At least 100 mg/d
Current Practice
Perhaps reecting the lack of specic data and nutritional recommendations, the nutritional management of micropreterm infants varies markedly among neonatal units and countries. In 2006, neonatal practitioners were surveyed and reported that they provided parenteral and enteral nutrition sooner and in larger volumes than they had previously, indicating improved nutritional management as a result of increased knowledge.8 Regardless, postnatal growth failure is virtually inevitable in micropreterm infants. It is important to act promptly to secure an adequate nutrient supply because early growth failure is associated with adverse neurodevelopmental outcomes. In a review from the National Institute of Child Health and Human Development that evaluated ELBW infants, 89% of infants weighed <10th percentile for GA at 36 weeks post-menstrual age, and 40% of infants had weight, length, and head circumference <10th percentile at 18-22 months corrected age.9 The many causes of growth failure include complications of extreme prematurity; extended time to meet recommended dietary intakes; and failure to provide adequate nutrients for recovery or catch-up growth.10
Born with lower body stores, especially of fat-soluble vitamins. May have reduced absorptive capacity for some vitamins. May benet from pharmacological doses of some vitamins.
Insufcient vitamin D in breast milk Decient stores at birth, sufcient to synthesize 18 g of hemoglobin in 1 kg infant Human milk low in iron Zinc: greater decit at birth; transitional breast milk has sufcient zinc but not mature milk Copper: deciency is a potential problem during rapid growth Gut rapidly colonizes with bacteria after birth Formula-fed infants colonize with Gram negative bacilli
Insufcient vitamin A in preterm breast milk
Theoretical concerns
No
No
Table I. Continued
Evidence Base for Dening Nutritional and Feeding Practices for Micropreterm Infants
Nutrient Requirements Very few studies have examined the nutrient requirements of micropreterm infants, and most published studies do not stratify by birth weight (BW) or GA or include subgroup analyses. The available data for specic nutrients are summarized in Table I.
Tudehope et al
Trace elements
Nutrient
Vitamins
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Probiotics

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Table II. Preterm nutrient recommendations (per 100 kcal) by expert group
Nutrient Protein Fat Linoleic a-Linolenic LA:ALA ARA DHA Carbohydrate Vitamin A Vitamin D Vitamin E Vitamin K Thiamin Riboavin Vitamin B6 Vitamin B12 Niacin Folic acid Pantothenic acid Biotin Vitamin C Choline Inositol Taurine Carnitine Calcium Phosphorus Ca:P Magnesium Iron Zinc Manganese Copper Iodine Selenium Sodium Potassium Chloride Chromium Molybdenum Fluoride Total Nucleotides AMP CMP Unit g g mg mg mg mg g IU mg RE IU IU mg a-TE mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg:mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg ESPGHAN, 201013 3.2-4.1 4.4-6.0 350-1400 >50 5-15 16-39 11-27 10.5-12 [1199-2464] 360-740 800-1000** [3.0-14.9] 2-10 4-25 125-275 180-365 41-273 0.08-0.7 345-5000 32-90 300-1900 1.5-15 10-42 7-50 4-48 NS NS 110-130 55-80 NS 7.5-13.6 1.8-2.7 1.0-1.8 6.3-25 90-120 10-50 4.5-9 63-105 60-120 95-161 0.027-1.12 0.27-4.5 1.4-55 #5 NS NS Tsang et al, 200512 <1000 g BW 2.5-3.4 4.1-6.5 467-1292 NS 5-15 $22 $16 6.0-15.4 467-1154 [140-347] 100-308 4.0-9.2 [2.7-6.2] 5.3-7.7 120-185 167-277 100-162 0.20-0.23 2400-3700 17-38 800-1300 2.4-4.6 12-18.5 9.6-21.5 21-62 3.0-6.9 1.9-2.2 67-169 40-108 NS 5.3-11.5 1.333-3.077 0.667-2.308 0.5-5.8 80-115 6.7-46.2 0.9-3.5 46-88 52-90 71-192 0.07-1.73 0.20-0.23 NS NS 0.23-0.62 1.4-3.2 Tsang et al, 200512 >1000 g BW 2.6-3.8 4.1-6.5 462-1309 NS 5-15 $22 $16 5.4-15.5 538-1364 [162-410] 115-364 4.6-10.9 [3.1-7.3] 6.2-9.1 138-218 192-327 115-191 0.23-0.27 2800-4400 19-45 900-1500 2.8-5.5 13.8-21.8 11.1-25.5 25-74 3.5-8.2 2.2-2.6 77-200 46-127 NS 6.1-13.6 1.538-3.636 0.769-2.727 0.5-6.8 92-136 7.7-54.5 1.0-4.1 53-105 60-106 82-226 0.08-2.05 0.23-0.27 NS NS 0.27-0.73 1.6-3.7 LSRO, 200211 (preterm) 2.5-3.6 4.4-5.7 [350-1425]z [77-228]x 6-16 [0-34]{ [0-20]jj 9.6-12.5 [680-1270] 204-380 75-270 [3.0-11.9] 2-8 4-25 30-250 80-620 30-250 0.08-0.7 550-5000 30-45 300-1900 1.0-37 8.3-37 7-23 4-44 5-12 2-5.9 123-185 82-109 1.7-2.0:1 6.8-17 1.7-3.0 1.1-1.5 6.3-25 100-250 6-35 1.8-5.0 39-63 60-160 60-160 NS NS 0-25 NS NS NS WHO >1000 g BW (Birth to 7 d)* [1.3-4.0] [0.7-4.8] NS NS NS NS NS [6.7-26.7] [933-2000] [280-601] [40-260]** [8.0-16.0] [5.4-10.7] [10.7-13.3] [53-67] [480-613] [15]zz [0.15]** [720] [50]** [1067-1733] [2.0] [8-13] NS NS NS NS [80-107] [41-62] NS [6.5-8.1] 0.0 [0.57] [0.7-1.5] [93-161] [34] [4.2-6.3] [31-92] [130-182] [47-142] [0.07-0.13] [0.26-0.51] NS NS NS NS WHO >1000 g BW (stabilization to term)* [2.5-3.0] [3.8-5.7] NS NS NS NS NS [6.3-12.9] [583-1250] [175-375] [400-800]** [5.0-10.0] [3.4-6.7] [6.7-8.3] [33-42] [300-383] [15]zz [0.15]** [720] [50]** [667-1083] [1.3] [5-8] NS NS NS NS [134-200] [65-98] NS [4.1-8.1] [1.7-2.5] [0.42-0.67] [0.5-0.9] [58-101] [26-53] [2.6-3.9] [48-77] [81-114] [74-118] [0.04-0.08] [0.16-0.32] NS NS NS NS WHO >1000 g BW (term to 1 y)* [2.0] [4.0-6.6] NS NS NS NS NS [6.8-14.1] [545-1273] [164-382] [400]** [5.5-10.9] [3.7-7.3] [7.3-9.1] [45] [45] [15]zz [0.15]** [720] [25]** [727-1182] [1.4] [18] NS NS NS NS [253]xx [105]xx NS [4.4-13.3] [1.8-2.7] [0.89] [0.5-1.0] [64-110] [29-58] [2.9-4.3] [42-63] [89-124] [64-97] [0.05-0.09] [0.17-0.35] NS NS NS NS (continued )
SUPPLEMENT

WHO >1000 g BW (term to 1 y)*
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Vol. 162, No. 3, Suppl. 1 Recently, several expert groups have reviewed the available scientic evidence and formulated consensus guidelines for the nutritional management of preterm infants. In 2002, the Life Sciences Research Ofce of the American Society for Nutritional Sciences made recommendations for the nutrient content of formulas for preterm-low BW infants based on current scientic knowledge and expert opinion. The examples and sample calculations were based on a 1000 g preterm infant and dened for different stages of postnatal life (transition, stable growing, and post-discharge stages). The Life Sciences Research Ofce pointed out that it was not known whether these recommendations would meet the needs of infants weighing less 750 g because so few data concerning their nutritional requirements were available.11 Tsang et al12 dened reasonable nutrient intakes for ELBW and VLBW infants and for different stages of postnatal life: day 0; transition (the period of metabolic and physiologic instability after birth); and the stable, growing period. The authors highlighted the vulnerability of ELBW infants, who are likely to have greater needs for many nutrients, be more susceptible to excess, and be a more heterogeneous population in terms of their clinical status than other infants. The authors noted that almost no data relate directly to this sub-group. In 2010, the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition published updated guidelines on enteral nutrition supply for preterm infants.13 No specic recommendations were provided for infants with BWs below 1000 g because only data for protein were available. Despite the lack of data for ELBW infants, all expert groups recognized the importance of supplying sufcient protein and energy to compensate for the accumulated decits seen in almost all ELBW/micropreterm infants during the early postnatal period. Recommended intakes by the three expert groups are listed in Table II. Use of Human Milk for Micropreterm Infants Although human milk is accepted as the gold standard for feeding healthy term infants, it cannot be assumed that this is the case for micropreterm infants who have higher requirements for most nutrients. Hence, it is important to critically evaluate the nutritional adequacy and health effects of human milk for this specic population in order to make evidence-based recommendations for optimal nutrition. A detailed discussion of the use of human milk for preterm infants is provided elsewhere (see the discussion of human milk by Tudehope et al, in this supplement); the discussion here focuses specically on data relevant to the use of human milk and infant formulas in the micropreterm infant.14 Term infant formulas are not suitable for feeding preterm infants and are certainly inappropriate for micropreterm infants. Unmodied human milk is unlikely to meet the nutritional requirements of micropreterm infants for several key nutrients, including protein and energy (especially when mature donor milk is used), sodium, calcium, phosphorus,
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ALA, alpha-linolenic acid; AMP, adenosine monophosphate; Ca:P, calcium to phosphorous ratio; CMP, cytosine monophosphate; GMP, guanosine monophosphate; LA, linoleic acid; LSRO, Life Sciences Research Ofce; NS, none specied; PUFA, polyunsaturated fatty acids; RE, retinol equivalents; TE, tocopherol equivalents; UMP, uridine monophosphate; WHO, World Health Organization. Single values indicate a minimum recommendation. Values in brackets have been calculated. *Calculated based on the average of the maximum and minimum energy recommendations for the indicated population; 75, 120, and 110 kcal/kg/d for birth to 7 days, stabilization to term, and term to 1 year, respectively. 3.6-4.1 g/100 kCal for infants <1 kg body weight; 3.2-3.6 g/100 kCal for infants 1-1.8 kg body weight. zMinimum: 8% of total fatty acids. Maximum: 25% of total fatty acids. xMinimum: 1.75% of total fatty acids with the further stipulation that the LA:ALA not exceed 16:1. Maximum: 4.0% of total fatty acids with the further stipulation that the LA:ALA not be less than 6:1. {A minimum recommendation for ARA was not established. Maximum: 0.6% of total fatty acids with the further stipulation that the ARA:DHA is within the range of 1.5-2.0:1. jjA minimum recommendation for DHA was not established. Maximum: 0.35% of total fatty acids with the further stipulation that the ARA:DHA is within the range of 1.5-2.0:1. **Recommendation given per day, independent of body weight and energy intake. The ratio of vitamin E to PUFA (mg of a-TE per g PUFA) should exceed 1.5 mg/g. zzRecommendation per gram protein fed. xxRecommendation in mg/d for breast fed infants. Formula fed infants should receive at least 377 mg/d of calcium and 273 mg/d of phosphorous.
WHO >1000 g BW (stabilization to term)* WHO >1000 g BW (Birth to 7 d)* LSRO, 200211 (preterm) Tsang et al, 200512 >1000 g BW Tsang et al, 200512 <1000 g BW ESPGHAN, 2010 Unit Nutrient
13
Table II. Continued
GMP UMP
mg mg
NS NS
0.03-0.54 0.6-0.9
0.04-0.64 0.7-1.1
NS NS
NS NS
NS NS
NS NS
March 2013 magnesium, trace elements, and certain vitamins. However, human milk does have theoretical advantages compared with formulas, including the composition and absorbability of its fats and the bioavailability of certain trace metals. Human milk also has a lower renal solute load than formulas designed to meet the needs of preterm infants and contains specic components that enhance mucosal maturation, provide protection from bacteria, and modulate gut inammation and motility.
SUPPLEMENT
intervention. There were no differences among groups in growth or rates of late-onset sepsis.18 Use of DBM in the Micropreterm Infant To make appropriate choices about the use of DBM in the micropreterm infant, it is important to consider the relative advantages and disadvantages. A recent Cochrane systematic review19 compared outcomes in preterm infants fed DBM or formula. None of the 8 studies analyzed focused specically on micropreterm infants, and most were 20-30 years old and from an era when DBM was fed without fortication or mineral supplements, often as the sole diet. Only 1 study compared the effects of nutrient-fortied DBM versus PTF as a supplement to mothers breast milk in micropreterm infants.20 This study was unable to establish any short-term benet for DBM over PTF.
Health Effects of Human Milk in Micropreterm Infants

Few studies have examined the benets to health provided by human milk in micropreterm infants. Many of the longer-term benets reported with human milk in preterm infants, (eg, improved developmental outcome, cardiovascular health, and bone health) might be anticipated to be greater in micropreterm infants who have a greater risk for sub-optimal, long-term outcomes, but no specic data are available to conrm or refute this hypothesis. Growth and Brain Development A number of studies have reported slower growth, in both weight and length, in preterm infants <32 weeks gestation who were fed unsupplemented breast milk before hospital discharge, compared with those who were fed formula.15,16 An observational study reported that infants <30 weeks GA who were fed fortied human milk had slower weight gain (22 vs 26 g/kg/d), smaller length increments, and lower discharge weights (2428 g vs 2998 g) than those fed preterm formula (PTF) but were discharged home earlier [22 vs 26 days].15 However, ELBW infants who were fed human milk shortly after birth had higher mental development scores at 30 months than did infants who were not.16 An observational trial compared outcomes for preterm infants <30 weeks gestation who were fed mothers milk exclusively with those who received supplemental donor breast milk (DBM) or PTF as a supplement to maternal milk when volume was inadequate15 Those who received only mothers milk had fewer episodes of late onset sepsis [23% vs 36%, OR 0.47 (0.25-0.7)] and total infection-related events; shorter durations of hospital stay (73 vs 88 days); fewer gram-negative organisms isolated from blood cultures; but the same incidence of NEC (6% vs 9%) compared with those who needed to be supplemented. The addition of DBM to mothers milk when volume was inadequate offered limited shortterm advantages over PTF.15 Infection and NEC A recent study compared a complete human milk-based diet with a diet of DBM fortied with bovine milk fortier or PTF and found that infants with BWs of 500-1250 g who received a complete human milk-based diet had a signicant reduction in NEC (P < .02) and, especially, NEC requiring surgical
Fortication of Human Milk for the Micropreterm Infant

A recent Cochrane review concluded that the use of multinutrient fortiers in infants weighing <1500 g is associated with short-term improvements in weight gain, linear growth, head growth, nitrogen retention, and blood urea levels.21 The review did not consider micropreterm infants separately. A small randomized controlled trial22 showed that adjustable fortication of human milk (based on the infants blood urea concentration) resulted in greater weight and head circumference gains, which were signicantly correlated with protein intake compared with standard fortication.
Consensus Position on Feeding Micropreterm Infants

What to Give: Nutrient Requirements Because so few studies have focused specically on the micropreterm infant, evidence-based guidelines cannot be formulated for the majority of nutrients for this group. Our consensus position is that the recommendations for preterm infants should be applied to micropreterm infants for most nutrients. Although the reasonable nutrient intakes provide an indication of nutrient requirements, they cannot and should not be followed rigidly. Each infants nutrient requirements should be determined on an individual basis after considering GA, BW, presence or absence of growth restriction, and clinical factors. Absorption and bioavailability of nutrients from different types of milk vary widely and generally are higher when human milk is used rather than infant formula or other breast milk substitutes. Furthermore, nutrient requirements change over time; micropreterm infants, in particular, accumulate nutritional decits during rst few weeks of life. Thus, nutritional management of these infants should include requirements for catch-up growth. Available Enteral Feedings In practice, the main options for enteral feeds are human milk or PTF. There is strong and convincing evidence that
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Vol. 162, No. 3, Suppl. 1 fants may have abnormalities in splanchnic blood ow before and after birth that may become less marked during the rst week of life. In these infants, there may be justication for a delayed and careful introduction of enteral feeding, preferably with colostrum. One of the goals of providing postnatal nutrition for micropreterm infants is to ensure that the transfer of nutrients to the fetus and neonate is maintained. Because immaturity of the gastrointestinal tract precludes provision of substantial nutritional support via the enteral route, nearly all micropreterm and very low BW infants receive parenteral nutrition. This liberal approach to parenteral nutrition, adopted over the last decade, has markedly improved nutritional intakes of ELBW infants. However, parenteral nutrition is associated with risks, mainly sepsis and metabolic complications, and the risk-benet ratio must be considered. Parenteral nutrition must be started early to maintain a continuous nutrient supply during the transition from the fetus in utero to the preterm infant ex utero, preferably within the rst 24 hours of life, for micropreterm infants. Many neonatal intensive care units now have the ability to place central lines and initiate total parenteral nutrition. Post-Discharge Feeding It is unlikely that unsupplemented breast milk meets the nutritional requirements of micropreterm infants after discharge. Although the proportion of these infants who are breastfed exclusively after discharge varies in different settings and is sometimes low, the majority of infants receive some breast milk for at least the rst few weeks after discharge. There are various possible methods to increase nutrient (and particularly protein) intake of micropreterm infants who breastfeed after discharge, although none has been formally evaluated. Mothers can mix expressed breast milk with fortiers for each feed, or a number of breast feeds can be replaced with a preterm or post-discharge formula (PDF). Both strategies are likely to increase nutrient intakes, but they may interfere to some degree with breastfeeding and increase the risk of infection. However, these risks must be weighed against the risks of malnutrition and poor growth. The timely introduction of foods rich in energy, protein, iron, and zinc should be encouraged in this group of infants. Ideally, micropreterm infants who are fed formula after discharge should receive a nutritionally enriched PDF. These formulas are considered as stepping-stones between preterm and term formulas. They have an energy content of 71-74 kcal/100 mL and are enriched with more protein, minerals, vitamins, and trace minerals per 100 kcal than term formula. A 2012 Cochrane systematic review (including 10 randomized controlled trials of good methodological quality and 762 infants) was limited because the measured outcomes differed.23 No subgroup analyses were conducted for micropreterm infants, and most studies enrolled preterm infants under 1850 g. Infants fed PDF consumed less formula, the same amount of energy, but more protein, calcium, and phosphorus than those fed term formula. A meta-analysis of 4 trials reported a signicant difference in weight and
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feeding human milk to preterm infants has benecial effects for short-term (risk of infection and NEC, feed tolerance) and longer-term (neurodevelopmental outcome, cardiovascular risk, bone health) outcomes. Given the generally poorer outcomes for micropreterm infants, it is reasonable to hypothesize that this group may gain even greater benets from human milk than other preterm infants. However, feeding unsupplemented human milk is associated with slower ponderal and linear growth, higher risk of metabolic bone disease, and deciencies of micronutrients; these concerns are likely to be greater in micropreterm infants, who generally have higher nutrient requirements. Thus, although human milk is preferred over formula feeding, supplementation or fortication of human milk is required for this group of infants. When mothers breast milk is unavailable or in short supply, DBM or PTF can be used. The short-term use of breast milk substitutes for preterm babies has not been shown to have demonstrable adverse effects on risks of allergy, bowel microora, duration of breastfeeding, or childhood or adult diseases. PTFs are designed to meet the estimated nutrient requirements for routine preterm infants but may not necessarily meet the requirements for micropreterm infants. For example, when volumes sufcient to provide an energy intake of 120 kcal/kg/d are fed, the available preterm infant formulas and fortied human milk diets provide protein intakes of approximately 3.2-3.6 g/kg/d, which are below the recommended higher protein intakes for micropreterm infants (especially ELBW infants). When higher energy intakes of 130-140 kcal/kg/d are provided, some PTFs will support the recommended protein intakes for these infants, but the higher energy intakes might result in increased fat deposition. The more immature the infant, the greater is the need for enteral feeding regimens with a higher protein:energy (P:E) to meet the goal of greater protein gain relative to fat. Supplementation of current PTF (P:E 2.7-3.0 g/100 kcal) with protein will increase the P:E and result in more lean mass and relatively less fat deposition. Recently PTFs with P:E of 3.33.6 g/100 kcal have become available in several countries. A PTF with relatively high P:E may be desirable for the micropreterm infant. However, at present, safety and efcacy of formulas with higher P:E (>3.6/100 kcal) for micropreterm infants are not known and need to be studied. Feeding Schedules The objectives of feeding right after birth are to stimulate gut maturation and hormone release and test gut motility. Trophic feeding or minimal enteral feeding, dened as <24 mL/kg/d, should commence on day 1 if possible or day 2 at the latest. Gastric residues should not be allowed to interfere with feeding. Feeding volumes of 1-2 mL/feed should be provided every 3-6 hours for infants <30 weeks gestation on days 1-2. When these feeds are tolerated and the infant is well, volumes can be increased by about 20 mL/kg/d. However, this approach may not be reasonable for all infants. For example, infants who have no or reversed end diastolic blood ow before delivery may be more likely to develop NEC, especially when they are growth-restricted. These inS78
March 2013 length but not head circumference at 9 months corrected age. In 2001, Lucas reported no difference in Bayley Mental Development Index and Psychomotor Development Index scores at 18 months in the two groups.24 Four trials reported no difference in bone mineralization. The review concluded that available data did not provide strong evidence that feeding preterm infants with nutrient-enriched formula following hospital discharge affects growth rates or development up to 18 months post-term compared with standard term formula.24 However, this conclusion was criticized for the limited ability to combine the summary data available in the published manuscripts.26 Cooke pointed out that in studies with adequate sample size and duration of 6-12 months, infants fed PTF or PDF (particularly males) had enhanced growth.
SUPPLEMENT
making it impossible to formulate evidence-based recommendations for most nutrients. Nutritional management of micropreterm infants should be based on existing recommended intakes for preterm infants, individualized according to an infants GA, BW, and clinical status. Early use of parenteral nutrition is recommended while establishing enteral feeds to avoid the accumulation of nutrient decits and growth failure. Human milk should be used when available but should be fortied to meet requirements, ideally based on measurement of milk composition. When human milk is not available in sufcient quantities, a PTF should be used. n
Author Disclosures
Mary Fewtrell, MD, has received research funding and performed advisory or consultant work Philips Advent and Pzer. Sudha Kashyap, MD, has served on an advisory board for Mead Johnson Nutrition. He has also, in the past, served on advisory boards as a consultant for Abbott and Baxter. Enrique Udaeta, MD, is a consultant for Nestle and Mead Johnson Nutrition and is an academic speaker for Mead Johnson Nutrition. All authors received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. D. T. wrote the rst draft of this manuscript.
Reprint requests: David Tudehope, AM, MBBS, FRACP, Mater Medical Research Institute, Level 3, Quarters Building, Annerley Rd., Wooloongabba, Queensland 4102, Australia. E-mail: david.tudehope@mater.org.au.
Monitoring of Nutritional Practices and Status

Growth Growth monitoring is an integral part of the medical and nutritional assessment and management of micropreterm infants, who are at high risk for intrauterine and extrauterine growth restriction. The ideal postnatal growth rate for micropreterm infants is not known. Lean body mass gain (nitrogen retention) could be measured in addition to weight gain to derive better estimates of macronutrient requirements, but this approach is difcult to apply outside of research settings.27 Without a universally-accepted growth standard for monitoring longitudinal growth of preterm infants in hospital, the goal is to replicate the fetal growth rate of at least 1520 g/kg/d. The International Fetal and Newborn Growth Consortium [INTERGROWTH-21] study currently is monitoring longitudinal growth in a cohort of preterm infants 2336 weeks gestation to provide new growth standard curves.28 The World Health Organization Multi-Center Growth Reference Group created sex-specic growth curves,29 which should be used to plot longitudinal growth for micropreterm infants from the expected date of delivery.
References
1. Ziegler EE, ODonnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976;40:329-41. 2. Commare CE, Tappenden KA. Development of the infant intestine: implications for nutrition support. Nutr Clin Pract 2007;22:159-73. 3. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006;(Issue 3). Art. No.: CD004454, 10.1002/ 14651858.CD004454.pub2; 2006. 4. Greengard O. Enzymic differentiation of human liver: comparison with the rat model. Pediatr Res 1977;11:669-76. 5. Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou CN, Smith EO. Early feeding, feeding tolerance, and lactase activity in preterm infants. J Pediatr 1998;133:645-9. 6. Boehm G, Muller DM, Beyreiss K, Raiha NC. Evidence for functional immaturity of the ornithine-urea cycle in very-low-birth-weight infants. Biol Neonate 1988;54:121-5. 7. Widdowson EM. Nutrition. In: Davis JA, Dobbing J, eds. Scientic Foundations of Paediatrics. London: Heinemann; 1981. p. 41-3. 8. Hans DM, Pylipow M, Long JD, Thureen PJ, Georgieff MK. Nutritional practices in the neonatal intensive care unit: analysis of a 2006 neonatal nutrition survey. Pediatrics 2009;123:51-7. 9. Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 2001;107:E1. 10. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107:270-3. S79
Discussion
Future research should focus either on micropreterm/ELBW infants or stratify subjects by GA or BW to allow balanced sub-group analyses. Ideally, a standard denition should be used (based on GA or BW) so data across studies can be compared. It is important to dene optimal protein and energy intakes and P:E, and measure lean mass, not just weight gain, as an outcome. The specic nutritional needs of micropreterm infants with postnatal growth restriction before and after discharge need to be dened. Micropreterm infants have greater nutritional decits at birth than more mature preterm infants and accumulate greater postnatal decits. Recommendations for routine preterm infants are not likely on a theoretical basis to meet requirements for micropreterm infants. Only a few good-quality studies have addressed this group specically,
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26. Cooke RJ. Postdischarge nutrition of preterm infants: more questions than answers. Nestle Nutr Workshop Ser Pediatr Program 2007;59:213-24. 27. Rigo J. Protein, amino acid, and other nitrogen compounds. In: Tsang RC, Uauy R, Koletzko B, Zlotkin S, eds. Nutrition of the Preterm Infant Scientic Basis and Practical Aspects. Cincinnati, OH: Digital Educational Publishing, Inc; 2005. p. 45-80. 28. Villar J, Knight HE, de Onis M, Bertino E, Gilli G, Papageorghiou AT, et al. Conceptual issues related to the construction of prescriptive standards for the evaluation of postnatal growth of preterm infants. Arch Dis Child 2010;95:1034-8. 29. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight, and age. Acta Paediatrica Suppl 2006;450:76-85. 30. Bauer J, Maier K, Hellstern G, Linderkamp O. Longitudinal evaluation of energy expenditure in preterm infants with birth weight less than 1000 g. Br J Nutr 2003;89:533-7. 31. Torine IJ, Denne SC, Wright-Coltart S, Leitch C. Effect of late-onset sepsis on energy expenditure in extremely premature infants. Pediatr Res 2007;61:600-3. 32. Leitch CA, Ahlrichs J, Karn C, Denne SC. Energy expenditure and energy intake during dexamethasone therapy for chronic lung disease. Pediatr Res 1999;46:109-13. 33. Ziegler EE, Thureen PJ, Carlson SJ. Aggressive nutrition of the very low birthweight infant. Clin Perinatol 2002;29:225-44. 34. Blanco CL, Gong AK, Schooleld J, Green BK, Daniels W, Leichty EA, et al. Impact of early and high amino acid supplementation on ELBW infants at 2 years. J Pediatr Gastroenterol Nutr 2012; 54:601-7. 35. Cooke RJ. Postnatal growth in preterm infants. In: Thureen PJ, Hay WW, eds. Neonatal nutrition and metabolism. Cambridge: Cambridge University Press; 2006. p. 47-57. 36. Kashyap S, Heird WC. Protein requirements of low brithweight, very low birthweight, and small for gestational age infants. In: Raiha NC, ed. New York/Vevey: Raven Press, Ltd./Nestle, Ltd.; 1994. p. 133-46. 37. Mihatsch WA, Hoegel J, Pohlandt F. Prebiotic oligosaccharides reduce stool viscosity and accelerate gastrointestinal transport in preterm infants. Acta Paediatr 2006;95:843-8. 38. Makrides M, Gibson RA, McPhee AJ, Collins CT, Davis PG, Doyle LW, et al. Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA 2009;301: 175-82. 39. Manley BJ, Makrides M, Collins CT, McPhee AJ, Gibson RA, Ryan P, et al. High-dose docosahexaenoic acid supplementation of preterm infants: respiratory and allergy outcomes. Pediatrics 2011;128:71-7. 40. Haiden N, Klebermass K, Cardona F, Schwindt J, Berger A, KohlhauserVollmuth C, et al. A randomized, controlled trial of the effects of adding vitamin B12 and folate to erythropoietin for the treatment of anemia of prematurity. Pediatrics 2006;118:180-8. 41. Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birthweight infants. Cochrane Database of Systematic Reviews 2011;(Issue 10):CD000501. Art No: CD000501, http://dx.doi.org/101002/14651858CD000501pub 32011; 2011. 42. Satoh Y, Shinohara K, Umezaki H, Shoji S, Satoh H, Ohtsuka Y, et al. Bidobacteria prevents necrotising enterocolitis and infection in preterm infants. Int J Probiot Prebiot 2007;2:149-54.
11. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr 2002;132:1395S-577S. 12. Tsang RC, Uauy R, Koletzko B, Zlotkin S. Nutrition of the preterm infant, Scientic basic and practical guidelines. Cincinnati, OH: Digital Educational Publishing Inc; 2005. 13. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85-91. 14. Tudehope D, Vento M, Bhutta Z, Pachi P. Nutritional requirements and feeding recommendations for small for gestational age infants. J Pediatr 2012;162:SXXX-XXX. 15. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: benecial outcomes of feeding fortied human milk versus preterm formula. Pediatrics 1999;103:1150-7. 16. OConnor DL, Jacobs J, Hall R, Adamkin D, Auestad N, Castillo M, et al. Growth and development of premature infants fed predominantly human milk, predominantly premature infant formula, or a combination of human milk and premature formula. J Pediatr Gastroenterol Nutr 2003;37:437-46. 17. Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Higgins RD, Langer JC, et al. Persistent benecial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics 2007;120:e953-9. 18. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, KiechlKohlendorfer U, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010;156:562-567 e1. 19. Quigley M, Henderson G, Anthony MY, McGuire W. Formula milk vs donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2007;(Issue 4). Art. No.: CD002971, 10.1002/14651858.CD002971.pub2; 2007. 20. Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers own milk in the feeding of extremely premature infants. Pediatrics 2005; 116:400-6. 21. Kuschel CA, Harding JE. Multicomponent fortied human milk for promoting growth in preterm infants. Cochrane Database of Systematic Reviews 2004;(Issue 1). Art No: CD000343, http://dx.doi.org/101002/ 14651858CD000343pub2; 2004. 22. Arslanoglu S, Moro GE, Ziegler EE. Adjustable fortication of human milk fed to preterm infants: does it make a difference? J Perinatol 2006;26:614-21. 23. Young L, Morgan J, McCormick FM, McGuire W. Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2012;(Issue 3). Art No: CD004696, http://dx.doi.org/101002/14651858CD004696pub4; 2012. 24. Lucas A, Fewtrell MS, Morley R, Singhal A, Abbott RA, Isaacs E, et al. Randomized trial of nutrient-enriched formula vs standard formula for postdischarge preterm infants. Pediatrics 2001;108:703-11. 25. Henderson G, Fahey T, McGuire W. Nutrient-enriched formula milk versus human breast milk for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2007;(Issue 4). Art. No.: CD004862, 10.1002/14651858.CD004862.pub2; 2007.
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David Tudehope, AM, MBBS, FRACP1,2, Maximo Vento, MD, PhD3, Zulqar Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD4, and Paulo Pachi, MD, PhD5
We dene the small for gestational age (SGA) infant as an infant born $35 weeks gestation and <10th percentile on the Fenton Growth Chart. Policy statements from many organizations recommend mothers own milk for SGA infants because it meets most of their nutritional requirements and provides short- and long-term benets. Several distinct patterns of intrauterine growth restriction are identied among the heterogeneous grouping of SGA infants; each varies with regard to neonatal morbidities, requirements for neonatal management, postnatal growth velocities, neurodevelopmental progress, and adult health outcomes. There is much we do not know about nutritional management of the SGA infant. We need to identify and dene: infants who have true growth restriction and are at high risk for adverse metabolic outcomes in later life; optimal growth velocity and catch-up growth rates that are conducive with life-long health and well being; global approaches to management of hypoglycemia; and an optimal model for postdischarge care. Large, rigorously conducted trials are required to determine whether aggressive feeding of SGA infants results in improved nutritional rehabilitation, growth, and neurodevelopmental outcomes. Before birth, maternal supplementation with specic nutrients reduces the rate and severity of growth restriction and may prevent nutrient deciency states if infants are born SGA. After birth, the generally accepted goal is to provide enough nutrients to achieve postnatal growth similar to that of a normal fetus. In addition, we recommend SGA infants be allowed to room in with their mothers to promote breastfeeding, motherinfant attachment, and skin-to-skin contact to assist with thermoregulation. (J Pediatr 2013;162:S81-9). mall for gestational age (SGA) newborns have a birth weight lower than expected for a given duration of gestation regardless of its cause. Newborns with intrauterine growth restriction (IUGR) have a birth weight less than a predetermined cut-off value due to nutritional restrictions during pregnancy. Low birth weight (LBW) newborns have a birth weight <2500 g. The SGA infant is dened as $35 weeks gestation and <10th percentile on the Fenton Growth Chart.1 Technological advances in industrialized countries enable obstetricians to detect growth-restricted fetuses antenatally. Babies who are SGA may be constitutionally small and at no greater risk than normally sized babies or small due to IUGR. SGA infants can be term or preterm; for the latter category, the combination of SGA and prematurity signicantly increases the risk of neonatal and infant mortality.2 Infants with IUGR receive reduced amounts of critical nutrients in utero, which results in chronic growth failure. This vulnerable group of infants with IUGR is at high risk for perinatal morbidity and mortality and constitutes 50% of perinatal deaths occurring preterm and 20% of deaths at term.3 Each year, more than 20 million infants worldwide are born with LBW. The global average incidence is 16% of all births, varying between 7% in industrialized countries, 16% in developing countries, and 19% in the least developed countries.4 This incidence is likely to be an underestimate because two-thirds of infants born in many parts of Africa, Asia, and Latin America are not reported or not weighed at birth.5 Because of uncertainties with the assessment of gestational age in many countries, it is difcult to be sure of the true proportion of LBW that are preterm and SGA, but the World Health Organization (WHO) estimates that 69% of all LBW infants have IUGR. Low maternal socioeconomic status is predictive of infant growth restriction at birth; commonly associated and interrelated factors include poverty, high parity, malnutrition, smoking, poor personal and sexual hygiene, and maternal drug use. The likelihood of IUGR increases when pregnancy is complicated by an underlying medical condition that imposes stress on the fetus such as restricted umbilical artery ow, microvascular thrombi, and reduced uterine perfusion. Constitutional growth restriction relates to parental stature and racial or ethnic factors. Typically, these infants have symmetrical growth restriction at birth, do not reach normal growth
From the 1Mater Medical Research Institute, South Brisbane; 2School of Medicine, University of Queensland, Brisbane, Queensland, Australia; 3Hospital cnico La Fe , Valencia, Spain; 4Aga Universitario y Polite Khan University, Karachi, Pakistan; and 5Santa Casa de ~o Paulo, Sa ~o Paulo, Brazil Misericordia de Sa Please see the Author Disclosures at the end of this article.
AGA BMI DBM IUGR IV LBW NEC
Appropriate for gestational age Body mass index Donor breast milk Intrauterine growth restriction Intravenous Low birth weight Necrotizing enterocolitis
PI RCT RR SGA UNIMAP WHO
Ponderal index Randomized controlled trial Relative risk Small for gestational age United Nations Multiple Micronutrient Preparation World Health Organization
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Vol. 162, No. 3, Suppl. 1 consistent in dening the variables that should be included in the adjustment (ie, maternal height, weight, ethnicity, and parity). There is evidence that SGA infants dened using the corrected growth reference are truly at greater risk in terms of morbidity and mortality than those dened by growth references for the normal population. The use of customized growth standards in high- and low-risk populations has been shown to improve the prediction of abnormal 5minute Apgar scores, length of hospital stay, admission to the neonatal intensive care unit, hypoglycemia, need for resuscitation, and perinatal death. Consequently, the Royal College of Obstetricians and Gynaecologists in the United Kingdom recommended the use of customized interpretation of birth weight adequacy in the identication and management of SGA fetuses.11,12 Classication of SGA Infants The commonly used classications focus on the timing of the prenatal insult. In infants with proportionate growth restriction, all anthropometric variables (weight, length, head circumference) are below the 10th percentile, whereas in those with disproportionate growth restriction head circumference is preserved, length is somewhat affected, and weight is compromised to a greater degree.13 Miller and Hassanein14 rst described the use of Rohrers Ponderal Index (PI, equal to mass/height3) in 1971. A normal PI is $2.41 and equates to no length sparing and chronic IUGR, whereas a low PI (<2.41) represents length sparing and acute or subacute IUGR.14 The classication of SGA as intrinsic implies onset of IUGR at the time of conception or in rst trimester; classication as extrinsic implies later onset of IUGR. Earlyonset growth restriction, which tends to give rise to an SGA infant who is proportionate, symmetrical, hypoplastic, and has a normal PI, is more likely to have an intrinsic cause of growth restriction such as poor maternal nutritional status, chromosomal anomalies, and exposure to teratogens. Lateonset growth restriction can result from disorders of the placenta or from maternal problems that impair delivery of oxygen and nutrients to the placenta. The infant with lateonset growth restriction (extrinsic type) has disproportionate growth that affects weight more than length and much more than head circumference. Patterns of Growth Restriction at Birth Several distinct patterns of IUGR are identied among the heterogeneous grouping of SGA infants with different neonatal morbidities, requirements for neonatal management, growth velocities in childhood, neurodevelopment, and adult health outcomes. A mild decrease in fetal growth, 3rd to 10th percentile for gestational age, represents the lower end of the normal distribution of growth for gestational age, with growth restriction usually attributed to constitutional factors. A moderate decrease in fetal growth, <3rd percentile for gestational age, is usually of late onset. These infants often exhibit maladaptation after birth, with catch-up growth in the rst 6 months, although as a group these infants remain below the 50th
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percentiles postnatally, are not prone to metabolic disorders, and should receive normal newborn care. Several factors are involved in other forms of IUGR, including racial/ethnic backgrounds, maternal age (<18 or >40 years), maternal height, weight at booking, socioeconomic and marital status, altitude of residence, poverty, parity, malnutrition, smoking, poor personal and sexual hygiene, maternal drug use, and complications of pregnancy. Follow-up of these children indicates that they display high rates of school failure, behavioral problems, attention decit, language delay, subtle neurological decits, and sudden infant death syndrome. SGA infants have reduced linear growth in infancy and excess abdominal fat gain in childhood. This growth pattern is associated with increased rates of cardiovascular disease, hypertension, and insulin resistance later in adult life.6-9
Determinants of Nutritional Requirements of SGA Infants

Fetal Adaptation and Maladaptation to Uteroplacental Failure When intrauterine nutrient supply is compromised, the fetus responds in a characteristic manner that increases the chances of survival: (1) overall size is decreased; (2) brain growth is spared; (3) lung maturation is accelerated; and (4) red blood cell production increases. Blood ow is selectively redistributed from less vital structures such as the splanchnic bed, musculoskeletal structures, and pulmonary and urogenital systems to more vital organs such as the brain, heart, adrenal glands, and placenta. The relative hypoxemia to which growth-restricted fetuses are exposed stimulates erythropoiesis as a compensatory response that increases hematocrit and the appearance of nucleated red blood cells.10 One-half of all infants with IUGR have a venous hematocrit > 60%; in 17% of infants, it is >65%. The increased red cell mass increases energy and glucose consumption. These adaptations can become pathologic if deprivation is severe. Chronic hypoxemia can lead to metabolic acidosis, which is commonly present in the growthrestricted fetus before the onset of labor. Transient reductions in maternal blood ow during labor can further decrease oxygen supply. The fetus becomes dependent on anaerobic glycolysis and lactic acid accumulates, further compromising potential for survival. Antenatal detection of fetal growth restriction often is associated with abnormal Doppler ow studies that reveal high resistance in umbilical vessels and low resistance in cerebral vessels. Further research in the pre- and postnatal periods is required to identify markers of blood ow redistribution and characterize the related metabolic complications in IUGR infants. Customized Fetal/Birth Weight Models Customized fetal birth weight models derived from combining data from populations in several countries improves identication of SGA infants at increased risk for adverse outcomes.3,10 All customized growth charts are remarkably
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March 2013 percentile and are at risk of metabolic syndrome. A severe intrauterine growth failure indicates weights less than 3 SDs below the mean for gestational age or <60% of expected weight. Infants with early-onset growth restriction have high risks for perinatal mortality, continued growth failure, and impaired neurodevelopment. Composition and Metabolism of SGA Compared with Appropriate for Gestational Age Infants The main nutrients for the healthy fetus are glucose, lactate, ketone bodies, and amino acids. The growth-restricted fetus receives fewer of these nutrients, which reduces lean mass, body fat, bone mineral content, and glycogen stores and increases the risk of hypoglycemia.15 Growth-restricted neonates have less body fat and greater proportions of body water than their gestational-age matched peers. Neonatal water turnover increases with the clinical degree of IUGR; this test has been used as a putative measure of true growth restriction and susceptibility to postnatal morbidities. The meager reserves of energy in these infants can become exhausted during a stressful labor and delivery. Protein turnover in SGA infants compared with their appropriate for gestational age (AGA) peers range from 2% to 30% greater to 20% lesser. Oxygen consumption and energy expenditure in SGA infants are high, secondary to a large brain:body and the need for catch-up growth. Fat and protein absorption is 11%-14% lower in SGA infants than AGA infants. Major problems in interpreting studies and drawing conclusions about metabolism of SGA infants are the heterogeneous groups studied, inconsistency in selection of controls (whether gestational age or birth weight), and variability in feeding schedules.15
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is proposed as being superior to traditional iron-folic acid combinations.19,20 Compared with iron-folate supplementation, multiple micronutrient supplementation has comparable effects on maternal anemia in the third trimester (RR 1.03; 95% CI 0.87-1.22) but is associated with a 9% reduction in the risk of SGA births (RR 0.91; 95% CI 0.86-0.96).21
UNIMAP Nutrient Content

The UNIMAP formulation contains 30 mg of iron, 400 mg of folic acid, 15 mg of zinc, 2 mg of copper, 65 mg of selenium, 800 mg of retinal equivalents vitamin A, 1.4 mg of vitamin B1, 1.4 mg of vitamin B2, 18 mg of niacin, 1.9 mg of vitamin B6, 2.6 mg of vitamin B12, 70 mg of vitamin C, 5 mg of vitamin D, 10 mg of vitamin E, and 150 mg of iodine.
Feeding SGA Infants: Balancing Benets and Risks

In supplying postnatal nutrient supply to SGA infants, one must consider the balance of risks associated with underand overfeeding. The global epidemic of metabolic syndrome in adults, especially in low-income countries in which the prevalence of IUGR is high, demands a more careful approach in which the risks and benets of nutritional practices are assessed adequately with both short- and long-term consequences in mind. There is clearly no gain from iatrogenic malnutrition and insufcient catch-up growth induced by inadequate nutrient supply; consequences on brain development and later educational performance are well dened. There is also no gainand potential long-term consequences on adult healthby promoting fat tissue gain, especially if abdominal fat is being laid down. Specic Nutritional Requirements for SGA Infants $35 Weeks The generally accepted goal is to provide sufcient nutrients to achieve postnatal growth similar to that of a normal fetus because specic requirements of most nutrients for SGA infants are unknown. In 2006, WHO evaluated studies of infants with birth weights <2500 g or gestation lengths <37 weeks from developing and developed countries.13 Infants were classied into 3 groups; birth weight <1500 g or gestation <32 weeks; birth weight 1500-1999 g or 32-36 weeks; and term infants <2500 g. The nutritional requirements for AGA preterm infants were not distinguished from those for SGA infants. The Recommended Nutrient Intakes have been calculated from fetal accretion rates, factorial equations, and published values (Canada Paediatric Society Nutrition in 1995,22 American Academy of Pediatrics Committee on Nutrition in 1985,23 and European Society for Paediatric Gastroenterology, Hepatology, and Nutrition in 198724). These recommendations are summarized in the Table.13,20,24-33 Which Milk Should Be Fed to the SGA Infant? Breastfeeding is recommended as the optimal feeding method and nutrition for all infants but is particularly important for
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Maternal Nutrition and IUGR

The associations between maternal undernutrition, chronic energy decits, and micronutrient deciencies with IUGR and SGA births are well recognized. Maternal undernutrition (body mass index [BMI] <18.5 kg/m2) ranges from 10% to 19% in most low-income countries.16 The nutritional status of a woman before and during pregnancy is important for a healthy pregnancy, and low maternal BMI is associated with IUGR.17 The exact comparative risks associated with low maternal BMI, poor weight gain in pregnancy, and maternal micronutrient deciencies and the occurrence and severity of IUGR are poorly quantied; however, there is a growing body of evidence that supports the importance of maternal nutrition before conception. Thus, interventions to ameliorate IUGR/SGA should focus on malnourished adolescent girls, especially those likely to become pregnant. A meta-analysis of studies indicate that balanced protein energy supplementation in pregnancy is associated with a 31% reduction in risk of giving birth to SGA infants (relative risk [RR] 0.69; 95% CI 0.56-0.85).18 Given the high prevalence of multiple micronutrient deciencies in pregnancy in most developing countries,19 the administration of a multiple micronutrient supplement (eg, United Nations Multiple Micronutrient Preparation [UNIMAP]) during early pregnancy
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Table. Summary of theoretical concerns and available evidence for special nutritional needs of SGA infants
Nutrient Fluid Theoretical issues Increased proportion of total body water; clinical comorbidities such as polycythemia and hypoglycemia Reduced energy stores, especially fat and glycogen; depletion of catecholamines; increased O2 consumption and total energy expenditure Reduced muscle mass and increased catabolism from catecholamines; increased losses in stools (11%-14%) compared with AGA infants; increased amino acid turnover and more efcient protein synthesis Decreased glycogen stores in liver and muscle and in fat stores increases vulnerability for hypothermia and hypoglycemia (<2.6 mmol/L), especially in late-onset IUGR; insulin levels may be high or low Decreased deposition in subcutaneous tissue/brown fat; use and -oxidation; attenuated ketone bodies; decreased absorption (11%-14%) compared with AGA infants Depleted stores at birth due to impaired placental transfer Increased compared with gestational age peer group Low phosphate levels at birth; breast milk may not meet needs but breast milk may adapt to needs25 Decreased whole-body density and content compared with AGA infants Vitamin D29 Vitamin A (1 mg3.33 IU)29 Normal serum iron but low stores at birth High cord blood hematocrit and hemoglobin, but ferritin <10 m/L Deciencies at birth due to maternal deciency and decrease placental transfer; cumulative decit due to low levels in mature human milk but adequate levels in transitional milk32 Published data and/or previous recommendations RCT: infants fed 200 mL/kg on day 2 regained birth weight faster and had more rapid weight gain than those fed 170 mL/kg on day 725 None 110-135 kcal/kg/d24 None 3.0-3.6 g/kg/d13 None 5-20 g/kg/d13 None 4.5-6.8 g/kg/d13 DHA 1% of total fat for LBW26 None 1-3 mmol/kg/d13 Calcium 60-90 mg/kg accretion Phosphorus supplementation adjusted to nitrogen and calcium supplementation28 800-1000 IU/day 400-1000 IU/day Multivitamin supplementation recommendations by many countries RCT: 0, 1, or 2 mg/kg/d iron for 2000-2500 g infants30 RCT: 2-3 mg/kg/d31 RCT of 5 mg in SGA >36 weeks, no benet33 Serum sodium levels as necessary Monitoring/outcomes Edema, excessive weight gain, urine output and specic gravity, serum electrolytes Anthropometric data, PI, skin folds Research: Body composition Weight, length, head circumference skinfolds, BUN, creatinine, albumin Blood glucose levels as necessary Recommendation based on birth weight 60 mL/kg [>2000 g]- 80 mL/kg [<2000 g] on day 1 and increase to 160-200 mL/kg/d13 110-135 kcal/kg/d24 3.0-3.6 g/kg/d provides 12-15 kcal/kg/d or 9%-13% of calories13 P:E 2.2-3.3 g/100 kcal 10-12 g/kg/d (40-48 kcal/kg/d) or 40%-45% of energy; 6-10 mg/kg/minimum Calculated from macronutrients 4.4-6.0 g/kg/d (40%-54% of energy based on energy provided by macronutrients) DHA 1% of total fat for LBW26; Preterm not SGA studies 63 mg/100 kcal (2.7 mmol/100 kcal; maximum 86 mg/100 kcal [4.6 mmol/100 kcal])27 Calcium 120-160 mg/kg/d Phosphorus 60-90 mg/kg/d Multivitamin supplementation for breastfed SGA infants FBCs with reticulocytes before starting iron; ferritin and transferrin to assess iron stores (if available) Mortality, infection, cognitive outcomes Supplementation with 2 mg/kg/d from 8 weeks and continue to 1 year or until iron-fortied food intake Use of liquid multiple micronutrient mixture20
Energy Protein
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Carbohydrate
Lipids
Anthropometric data, skin folds, PI Research: Body composition studies
LCPUFA Sodium Calcium/phosphorus
Vitamins
Iron Zinc
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BUN, blood urea nitrogen; DHA, docosahexaenoic acid; FBC, full blood count; LCPUFA, long chain polyunsaturated fatty acids; P:E, protein to energy ratio.
March 2013 LBW infants, as research shows increased cognitive development in this population with feeding human milk.34 Mothers breast milk is the rst choice of feed for SGA infants because it meets most of their nutritional requirements and provides short- and long-term benets. Breastfeeding and expressed breast milk reduce the incidence and/or severity of a wide range of infectious diseases, including necrotizing enterocolitis (NEC), bacterial meningitis, bacteremia, gastroenteritis, respiratory tract infection, otitis media, and urinary tract infection.34,35 Breastfeeding decreases the rate of sudden infant death syndrome/sudden unexpected death in infancy in the rst year of life, and the incidence of insulin-dependent (type 1) and noninsulin-dependent (type 2) diabetes mellitus, obesity, certain cancers, hypertension, hypercholesterolemia, and asthma in older children and adults.34 Breastfeeding is also associated with better speech and jaw development and improved visual acuity.25 Despite methodologic difculties and challenges, the use of breast milk substitutes for growth-restricted neonates is associated with increased short- and long-term adverse outcomes, including mortality and serious morbidity. Epidemiologic studies25,26 and randomized controlled trials (RCTs)36,37 in high-risk environments have found that the incidence of invasive infection is greater in LBW infants who are fed formula. A meta-analysis of RCTs38 has shown that formula-fed LBW infants have 5 times the risk of NEC, a condition associated with a mortality of approximately 20% and signicant long-term health care costs among survivors.39,40 In a meta-analysis, formula feeding resulted in later transition than breast milk in LBW infants.38 It should be noted, however, that all trials cited were performed in the 1980s and 1990s with the use of standard term formulas lacking the immunological advances in formula that have occurred in the past two decades. Mothers Breast Milk for the SGA Infant: Outcomes of Trials
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for term SGA infants.43 The group fed enriched formula had better length and head circumference growth than the group fed term formula, with the larger benet in females. Breastfed infants showed no advantage over term formula when confounding factors were considered.44 Another study assessed 1-year olds who were born SGA and found that breastfed infants had higher motor development scores than formula-fed infants; no other differences between the groups were detected.45
Growth. Most studies show that term SGA infants remain

smaller than their AGA peers at 7-8 years of age. One study showed that although only 6%-7% of term SGA infants were below the 5th percentile for height at 18 years, they accounted for 14%-21% of short 18 year-olds.35 However, the authors of a cohort study from the United Kingdom of term SGA infants (n = 474) reported no signicant differences in mean weight, length, and head circumference in breastfed compared with formula-fed infants at 18 months of chronological age.44 Summary of Studies on Breastfeeding SGA Infants There are limited data on most outcomes in SGA infants. The available data suggest that the benets of feeding mothers milk to SGA infants, such as feed tolerance, infection, NEC, and neurodevelopment, are similar to those for preterm infants. There seems to be no adverse effect of this modality of feeding on growth. Breast milk feeding is preferred over formula feeding because of benets related to reduced infection and improved neurodevelopment. Although most published studies are from developed countries, the few available studies from developing countries show similar results. Breastfeeding and feeding mothers expressed breast milk are likely to have an even greater impact in reducing infections in developing countries due to the higher incidence of infections in these settings. Donor Breast Milk for SGA Infants No studies describing the use of donor breast milk (DBM) for SGA infants were found. Although almost all studies on DBM have been conducted in developed countries, the results are unlikely to be different in developing country settings. Because of the proven benets of mothers breast milk in preventing infection in SGA infants and for DBM in studies with preterm infants in developed countries, it is tempting to suggest that increased efforts to establish and maintain donor milk banks in developing countries might be as or even more benecial than in developed countries.
Neurodevelopment. Most studies show that SGA infants

have poorer neurodevelopment than AGA infants, especially SGA infants who do not exhibit catch-up growth. One study showed that infants who were breastfed exclusively for >12 weeks scored 5.0 points (range, 0.7-9.30) greater on the Wechsler Preschool and Primary Scales than those breastfed for <12 weeks.41 Another study compared outcomes in term SGA infants at 18 months of age whose mothers chose to breastfeed (n = 137) with those whose mothers chose to formula feed (n = 235).42 Mean scores on the Bayley Mental Development Index and Psychomotor Development Index were 8.2 points greater (95% CI 5.0-11.4) and 5.8 points greater (95% CI 2.88.7), respectively, for the breastfed group. In an RCT of term SGA infants who received a 76 kcal/100 mL enriched formula had a signicantly lower Psychomotor Development Index (99.5 vs 102.0) scores at 9 months than infants fed the standard term formula. From this, the authors concluded that an enriched formula should not be promoted
Consensus Position on Feeding SGA Infants

Assessment and Patterns of Growth in the Hospital The ideal postnatal growth rate for SGA infants is not known. The current goal of current nutritional management is to achieve a postnatal growth rate similar to normal intrauterine growth. Compared with this standard, postnatal
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Vol. 162, No. 3, Suppl. 1 continued poor feeding or for extra volume to keep blood glucose levels >2.6 mmol/L.
growth failure and associated poor neurodevelopmental outcomes occur commonly in SGA infants. A fetus grows in utero at a rate of at least 15-20 g/kg/day. To attain this rate, the SGA infant would need approximately 110-135 kcal/kg/day with additional energy for catch-up growth. The slower the rate of intrauterine growth, the less likely the infant will exhibit catch-up growth. Less-affected and healthier SGA infants are more likely to respond to nutritional intervention and exhibit catch-up growth during the rst 6 months. Gestational age also inuences growth recovery; the lower the gestational age, the longer it takes to achieve nal catch-up growth and the worse the long-term prognosis. When possible it is recommended that catch-up growth be gradual: not too much and not too fast. If an infant is SGA at birth and subsequently has a discharge weight AGA, this represents early postnatal catch-up growth and may be a risk factor for metabolic syndrome in adult life. Healthy catch-up growth is paralleled by an increase in linear growth and lean body mass, and unhealthy catch-up growth is associated with an increase in fat mass, central adiposity, and insulin resistance.46 Population studies show that the majority of SGA infants achieve catch-up growth during the rst 2 years of life, and a failure to show early compensatory growth in that time period predicts permanently decreased growth.47,48 SGA infants are prone to persistent decits in muscle mass but normal or excessive gains in fat. Feeding SGA Infants
Role of Parenteral Fluids for Nutrition. Intravenous

(IV) uids are commenced with 10% dextrose at 60 mL/ kg/d if enteral feeding is not possible or problematic hypoglycemia occurs with difculty maintaining normal blood glucose levels with enteral feeds. IV uids may be required to support a more gradual increase in enteral volume intake and may be reduced as feed volume increases. This is often the preferred option for the mother who wants her baby to be fed exclusively with breast milk when donor milk is not available. In term or near-term infants with severe IUGR (<2000 g), especially when absent or reversed umbilical artery end diastolic ow has been demonstrated on antenatal Doppler studies, a more conservative approach to enteral feeding should be adopted with a low threshold for IV uids while waiting for the mothers colostrum and immature milk to become available. The infant should be carefully monitored for signs of feed intolerance (vomiting, increasing/large residual gastric aspirate if tube feeding). SGA is a risk factor for NEC in term babies, but the risk is very low in the absence of other problems, and the limited information available suggests that feeding volume is not a factor.51-53 However, an Australian study from 2007-2009 reported infants >33 weeks gestation contributed 24.5% to mortality from NEC.54 All literature reports of absent or reversed umbilical artery end diastolic ow and NEC are in preterm infants.53 From a nutritional point of view, the liberal approach to parenteral nutrition adopted during the last two decades has markedly improved nutritional intakes of infants with severe IUGR.
Model of Care. Standard practice in neonatal units is to promote mothers own milk as the feed of choice for all LBW infants. Breastfeeding should be promoted and actively supported for SGA infants. In the absence of any perinatal compromise, it is recommended to encourage kangaroo mother-baby skin-to-skin contact, attempt breastfeeding as early as feasible,49 and initiate feeds within 30 minutes of birth50 with breastfeeding or expressed breast milk (mother or donor). If the SGA infant is reluctant to feed or does not feed well, the mother may need encouragement to express her breasts up to 8 to 10 times per day. Many of these initiatives are interrelated, and it is unlikely that specic clinical interventions will be effective if used alone.10 For SGA infants who require admission to the nursery, allowing parents to spend at least 24 hours with their infant in a parent room before discharge provides a smooth transition to home. Complementary infant formula feeds should be given only if medically indicated with consent from the mother. If the mother plans to formula feed, feeds should commence at 60 mL/kg on day 1 (80 mL/kg if <2000 g) in infants with moderate-to-severe IUGR. The infant should be encouraged to demand feed, but not less than every 3 hours or more than 4 feeds hourly. The passage of an enteral tube should be considered for gavage feeding of expressed breast milk and/or infant formula in the event of
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Special Care Nursery Versus Rooming In with the Mother on the Postnatal Ward. Most SGA infants
should room in with their mothers on the postnatal ward to enhance the success of breastfeeding, promote motherinfant attachment, and initiate skin-to-skin contact to assist with thermoregulation.44 Whether the infant should room in with mother or be admitted to the neonatal nursery must be a decision based on neonatal and maternal factors and on hospital policy. Hospital policy will be inuenced by physical environment (eg, proximity of the postnatal ward to the nursery), staff ratios and competence, and feeding guidelines. Key principles underpinning feeding guidelines include developmentally supportive care, support of breastfeeding, and the individual feeding plan developed by parents and a multidisciplinary team. The requirement for admission to a neonatal unit will depend on evaluating the perinatal history (eg, asphyxia, congenital anomaly, severity of growth restriction [<2000 g], and the ongoing need for specialized care [eg, IV uids]). Moderate-to-severe growth restriction and abnormal Doppler umbilical blood ow measurements antenatally might dictate a more conservative approach to enteral feeding, with need for IV uids while awaiting breast milk to become available.53 With the assistance of supportive and skilled nursing, term babies of birth
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March 2013 weight >2000 g cope well with rooming in and breastfeeding on the postnatal ward. Provision of specialized, individualized care for the motherbaby dyad can mitigate the need for transfer to the nursery on occasion. Additional supports include performance of blood glucose estimations, occasional gavage feeds, nursing baby on a heated water bed, and permitting additional hospital admission days when necessary.
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economically afuent, healthy women from diverse ethnic and cultural settings.59 After reaching postmenstrual term age, growth of preterm and SGA infants should be monitored with the use of these new prescriptive postnatal standards for term infants, which have been adopted by more than 100 countries. The WHO growth charts provide globally applicable standards of growth for children under optimal conditions of breastfeeding in 6 countries from birth until 2 years of age. These sex-specic growth curves should be used to plot longitudinal growth for preterm and SGA infants after the expected date of delivery. More controversial is the choice of growth chart to use for monitoring growth trajectory for SGA babies who are born preterm. The INTERGROWTH-21st study currently is monitoring longitudinal growth in a cohort of infants 23-36 weeks gestation to provide new growth standard curves.60
Discharge Criteria. Each motherbaby dyad should be

evaluated individually to determine the optimal time for discharge. Early discharge can be practiced safely and may promote attachment. Weight by itself should not be a criterion for decision-making about suitability for discharge. Discharge may be considered providing the following criteria are satised: physiological stability (maintains temperature in open incubator), no clinical illness, feeding is progressing well, not losing weight, and steady weight gain. Most importantly, the mother and family need to be assessed for their readiness, competence, and willingness to accept social support and access the health care system and resources if necessary.55
Recommendations for SGA Infants >34 Weeks Gestation

Breastfeed within the rst 30 minutes and prevent hypothermia. Breastfeeding is preferred; alternative feeding method if necessary. Feed according to gestational age; consider supplements for iron and other micronutrients. Do not promote rapid weight gain because it increases risk for metabolic syndrome. Maternal nutritional interventions (including iron and micronutrients) must be focused during preconception or pregnancy to prevent SGA birth.
Postdischarge Nutrition and Growth for SGA Infants: Possible Adult Disorders Resulting from IUGR.
There is a strong association between LBW and insulin resistance. The thrifty phenotype hypothesis, which postulates that fetal programming for adaptation to an adverse intrauterine environment results in lower insulin sensitivity in utero, is one of the hypotheses to explain this association. Later in life, metabolic syndrome may develop, featuring hypertension, dyslipidemia, central obesity, and type 2 diabetes associated with excessive weight gain. Recent epidemiologic evidence indicates that obesity, insulin resistance, diabetes, and cardiovascular disease are more common among adults who were smaller than normal at birth and very likely were SGA, and particularly among those with a high placental:fetal weight.56 These examples suggest that certain adult pathologies may be unavoidable complications of environmentally imposed conditions such as severe and prolonged fetal malnutrition leading to fetal growth restriction to ensure fetal survival. Such conditions may represent examples of programming in which an insult applied at a critical or sensitive stage in development may result in a lifelong effect on the structure and development of the individual.57 An RCT from Honduras randomized SGA infants who were breastfeeding at 4 months to continue exclusive breastfeeding until 6 months or to introduction of complementary feeds at 4 months; this study found no difference in developmental outcome at 12 months.58
Case Study
A 31-year-old primigravid woman developed pregnancyinduced hypertension and poor fetal growth from 35 weeks gestation. She was treated with antihypertensive agents and fetal monitoring with growth assessments, and tests for fetal well-being were performed by maternal-fetal medicine specialists. At 37 weeks, with absent end-diastolic ow on Doppler studies and progressive growth failure, a cesarean delivery was performed. Baby boy D measured 1950 g in weight (<3rd percentile); 45.8 cm in length (10th percentile); and 33.4 cm in head circumference (35th percentile) and was vigorous at birth with Apgar scores of 7 at 1 minute and 9 at 5 minutes. There were no dysmorphic features, but there was evidence of muscle wasting and decreased subcutaneous fat tissue. The clinical team decided to provide care on the postnatal ward with mother and infant rooming in. The infant was nursed initially in an open cot with a heated water mattress to prevent hypothermia, and breastfeeding was attempted at 2 hours. Blood glucose estimation was 2.4 mm/L at 4 hours of age just before the second feed. The infant received 2 complementary feeds of 25 mL of a partially hydrolyzed formula on day 1 when blood glucose estimations were again <2.8 mmol/L. With support from a lactation consultant, skin-to-skin contact (kangaroo cuddling), and feeding every 2-3 hours, the mother rapidly established
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Monitoring of Nutritional Practices and Status

Growth Charts The WHO Multicenter Growth Reference Group growth curves are based on healthy, breastfed children of socio-
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Author Disclosures
a transitional milk supply. By day 3, blood glucose estimations were all >3.0 mmol/L; complementary feeds were ceased, and the baby was completely breastfed. Weight loss was minimal, the nadir was 1890 g on day 4; the infant had regained his birth weight when weighed on day 6 and was discharged home, with midwifery follow-up on day 7 with a weight of 1980 g.
All authors received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. D. T. wrote the rst draft of this manuscript.
Reprint requests: David Tudehope, AM, MBBS, FRACP, Mater Medical Research Institute, Level 3 Quarters Building, Annerley Rd, Wooloongabba 4102, Queensland, Australia. E-mail: david.tudehope@mater.org.au.
Discussion
Was Rooming-In on a Postnatal Ward an Acceptable Model of Care? Considerable variation in practice exists depending on facilities and rigor of glucose monitoring. In developing countries, this model is the norm and such infants do better when kept with mother in a mother-baby unit. Kangaroo care for mother and father should be practiced as early as possible. Should the Baby Have Received IV Dextrose Infusion and/or Gavage Feeding for 3 Blood Glucose Levels 2.3-2.7 mmol/L on day 1? Consensus opinion is that IV dextrose is not indicated unless baby is symptomatic, has blood glucose estimation< 2.4 mmol/L, or has little prospect of sucking and swallowing properly in the short term. Continue to place on breast frequently plus express and administer colostrum. Was Partially Hydrolyzed Formula the Most Appropriate Complimentary Feed? Pasteurized DBM is preferred if available; otherwise, there is a diversity of practice among term, preterm, and partially hydrolyzed formulas. Should the Baby Have Been Discharged Home on Day 7 Weighing Only 1980 Grams? Weight should not be the major consideration for discharge but rather physical stability, feeding well, starting to gain weight, maternal competency, and adequate community support. If weight were the arbiter it would be about 1800 g. What Feeding and Monitoring Regime Is Recommended after Discharge? As breastfeeding was well established, this should be continued and home visitation from a pediatric nurse is desirable. Supplementation or hospital readmission is rarely required. What Is the Optimal Growth Velocity and Who Should Oversee Follow-Up? Weight loss <10% within the rst week and a weight gain of 15-20 g/day in the rst 4 weeks is expected. Health care professionals who are familiar with follow-up of LBW infants should plot growth on a WHO growth chart. Catch-up growth should not be too rapid or too slow. n
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References
1. Fenton TR. A new growth chart for preterm babies: Babson and Bendas chart updated with recent data and a new format. BMC Pediatr 2003;3:13. 2. Marchant T, Willey B, Katz J, Clarke S, Kariuki S, Ter Kuile F, et al. Neonatal mortality risk associated with preterm birth in East Africa, adjusted by weight for gestational age: individual participant level meta-analysis. PLoS Med 9: e1001292. 3. Figueras F, Gardosi J. Should we customize fetal growth standards? Fetal Diagn Ther 2009;25:297-303. 4. Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter L, et al. Maternal and child undernutrition: consequences for adult health and human capital. Lancet 2008;371:340-57. 5. United Nations Childrens Fund. Special edition: Celebrating 20 years of the Convention on the Rights of the Child, The state of the worlds children. New York: United Nations Childrens Fund; 2010. p. 1-100. 6. Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002;31: 1235-9. 7. McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005;85: 571-633. 8. Reinehr T, Kleber M, Toschke AM. Small for gestational age status is associated with metabolic syndrome in overweight children. Eur J Endocrinol 2009;160:579-84. 9. Reinehr T, Kleber M, Toschke AM. Former small for gestational age (SGA) status is associated to changes of insulin resistance in obese children during weight loss. Pediatr Diabetes 2010;11:431-7. 10. Rosenberg A. The IUGR newborn. Semin Perinatol 2008;32:219-24. 11. Coomarasamy A, Fisk NM, Gee H, Robson SC. The investigation and management of the small-for-gestational-age fetus. Guideline No 31. Nov 2002 ed. London: Royal College of Obstetrics and Gynaecology; 2002. p. 1-16. 12. Pain S, Chang AM, Flenady V, Chan FY. Customised birthweight: coefcients for an Australian population and validation of the model. Aust N Z J Obstet Gynaecol 2006;46:388-94. 13. Edmond K, Bahl R. Optimal feeding of low birthweight infants. Technical review. Geneva: World Health Organization; 2006, http://whqlibdoc. who.int/publications/2006/9789241595094_eng.pdf. p. 1-121. Accessed December 5, 2012. 14. Miller HC, Hassanein K. Diagnosis of impaired fetal growth in newborn infants. Pediatrics 1971;48:511-22. 15. Anderson MS, Hay WW. Intrauterine growth restriction and the smallfor-gestational-age infant. In: Avery GB, MacDonald MG, Seshia MMK, Mullett MD, eds. Averys neonatology: pathophysiology and management of the newborn. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 490-522. 16. Black RE, Allen LH, Bhutta ZA, Cauleld LE, de Onis M, Ezzati M, et al. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 2008;371:243-60. 17. Fishman SM, Cauleld L, de Onis M. Childhood and maternal underweight. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL, eds. Comparative quantication of health risks: global and regional burden of disease attributable to selected major risk factors. Geneva: World Health Organization; 2004. p. 39-161.
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18. Imdad A, Yakoob MY, Bhutta ZA. Effect of balanced protein energy supplementation during pregnancy on birth outcomes. BMC Public Health 2011;13(suppl 3):S17. 19. Yakoob MY, Khan YP, Bhutta ZA. Maternal mineral and vitamin supplementation in pregnancy. Expert Rev Obstet Gynecol 2010;5:241-56. 20. UNICEF/WHO/UNU. Composition of a multi-micronutrient supplement to be used in pilot programmes among pregnant women in developing countries. New York: UNICEF; 1999. 21. Haider BA, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev 2012 Nov 14; 11:CD004905. 22. Canadian Paediatric Society. Promoting optimal monitoring of child growth in Canada: using the new World Health Organization growth charts Executive Summary. Paediatr Child Health 2010;15:77-83. 23. American Academy of Pediatrics Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatrics 1985;75:976-86. 24. European Society of Paediatric Gastroenterology and Nutrition. Nutrition and feeding of preterm infants. Committee on Nutrition of the Preterm Infant. Acta Paediatr Scand Suppl 1987;336:1-14. 25. Baumgart S. Whats new from this millennium in uids and electrolyte management for VLBW and EBW prematures. J Neonatal-Perinat Med 2009;2:1-9. 26. Makrides M, Gibson RA, McPhee AJ, Collins CT, Davis PG, Doyle LW, et al. Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA 2009;301: 175-82. 27. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr 2002;132:1395S-577S. 28. Rigo J, Pieltain C, Salle B, Senterre J. Enteral calcium, phosphate and vitamin D requirements and bone mineralization in preterm infants. Acta Paediatr 2007;96:969-74. 29. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85-91. 30. Bergland S, Westrup B, Domellof M. Iron supplements reduce the risk of iron deciency anaemia in marginally low birth weight infants. Pediatrics 2010;2010:e873-83. 31. Aggarwal D, Sachdev HP, Nagpal J, Singh T, Mallika V. Haematological effect of iron supplementation in breast fed term low birth weight infants. Arch Dis Child 2005;90:26-9. 32. Diaz-Gomez NM, Domenech E, Barroso F, Castells S, Cortabarria C, Jimenez A. The effect of zinc supplementation on linear growth, body composition, and growth factors in preterm infants. Pediatrics 2003; 111:1002-9. 33. Black RE. Micronutrients in pregnancy. Br J Nutr 2001;85(suppl 2): S193-7. 34. Horta BL, Bahl R, Martin es JC, Victora CG, WHO. Evidence on the long-term effects of breastfeeding: systematic reviews and meta-analysis. Geneva: World Health Organization; 2007. p. 1-52. 35. Schanler RJ. The use of human milk for premature infants. Pediatr Clin North Am 2001;48:207-19. 36. Narayanan I, Prakash K, Bala S, Verma RK, Gujral VV. Partial supplementation with expressed breast-milk for prevention of infection in low-birth-weight infants. Lancet 1980;2:561-3. 37. Narayanan I, Prakash K, Verma RK, Gujral VV. Administration of colostrum for the prevention of infection in the low birth weight infant in a developing country. J Trop Pediatr 1983;29:197-200. 38. Anderson JW, Johnstone BM, Remley DT. Breast-feeding and cognitive development: a meta-analysis. Am J Clin Nutr 1999;70:525-35. 39. Kashyap S, Forsyth M, Zucker C, Ramakrishnan R, Dell RB, Heird WC. Effects of varying protein and energy intakes on growth and metabolic response in low birth weight infants. J Pediatr 1986; 108:955-63.
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40. Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Arch Dis Child Fetal Neonatal Ed 1994;70:F141-6. 41. Rao MR, Hediger ML, Levine RJ, Nacy AB, Vik T. Effect of breastfeeding on cognitive development of infants born small for gestational age. Acta Paediatr 2002;91:267-74. 42. Morley R, Cole TJ, Powell R, Lucas A. Mothers choice to provide breast milk and developmental outcome. Arch Dis Child 1988;63:1382-5. 43. Morley R, Fewtrell MS, Abbott RA, Stephenson T, MacFadyen U, Lucas A. Neurodevelopment in children born small for gestational age: a randomized trial of nutrient-enriched versus standard formula and comparison with a reference breastfed group. Pediatrics 2004;113:515-21. 44. Fewtrell M, Morley R, Abbott RA, Singhal A, Stephenson T, MacFadyen UM, et al. Catch-up growth in small-for-gestational-age term infants: a randomized trial. Am J Clin Nutr 2001;74:516-23. 45. Ounsted M, Moar VA, Scott A. Neurological development of small-forgestational age babies during the rst year of life. Early Hum Dev 1988; 16:163-72. 46. Ong KK. Catch-up growth in small for gestational age babies: good or bad? Curr Opin Endocrinol Diabetes Obes 2007;14:30-4. 47. Yau KI, Chang MH. Growth and body composition of preterm, smallfor-gestational-age infants at a postmenstrual age of 37-40 weeks. Early Hum Dev 1993;33:117-31. 48. Hediger ML, Overpeck MD, Kuczmarski RJ, McGlynn A, Maurer KR, Davis WW. Muscularity and fatness of infants and young children born small- or large-for-gestational-age. Pediatrics 1998;102:E60. 49. Lawn JE, Mwansa-Kambafwile J, Horta BL, Barros FC, Cousens S. Kangaroo mother care to prevent neonatal deaths due to preterm birth complications. Int J Epidemiol 2010;39(suppl 1):i144-54. 50. Hay WW Jr. Strategies for feeding the preterm infant. Neonatology 2008; 94:245-54. 51. Wilson R, del Portillo M, Schmidt E, Feldman RA, Kanto WP Jr. Risk factors for necrotizing enterocolitis in infants weighing more than 2,000 grams at birth: a case-control study. Pediatrics 1983;71:19-22. 52. Wiswell TE, Robertson CF, Jones TA, Tuttle DJ. Necrotizing enterocolitis in full-term infants. A case-control study. Am J Dis Child 1988;142: 532-5. 53. Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch Dis Child 2005; 90:F359-63. 54. ANZNN (Australian and New Zealand Neonatal Network). Report of the Australian and New Zealand Neonatal Network 2007. Sydney: ANZNN; 2011, http://www.preru.unsw.edu.au/PRERUWeb.nsf/resources/ AnnualReports/$le/ANZNNAnnualReport_2007_WEB.pdf. Accessed January 1, 2012. 55. American, Academy of Pediatrics, Committee on Fetus and Newborn. Hospital stay for healthy term newborns. Pediatrics 2010;125:405-9. 56. Misra DP, Salaa CM, Miller RK, Charles AK. Non-linear and genderspecic relationships among placental growth measures and the fetoplacental weight ratio. Placenta 2009;30:1052-7. 57. Cooke RJ. Postnatal Growth and Development in the Preterm and Small for Gestational Age Infant. In: Lucas A, Makrides M, Ziegler EE, eds. Importance of Growth for Health and Development Nestl e Nutr Inst Workshop Ser Pediatr Program. Basel: Vevey/S. Karger AG; 2010. p. 85-98. 58. Dewey KG, Cohen RJ, Brown KH, Rivera LL. Effects of exclusive breastfeeding for four versus six months on maternal nutritional status and infant motor development: results of two randomized trials in Honduras. J Nutr 2001;131:262-7. 59. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight, and age. Acta Paediatr Suppl 2006;450:76-85. 60. Villar J, Knight HE, de Onis M, Bertino E, Gilli G, Papageorghiou AT, et al. Conceptual issues related to the construction of prescriptive standards for the evaluation of postnatal growth of preterm infants. Arch Dis Child 2010;95:1034-8.
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Alexandre Lapillonne, MD, PhD1,2, Deborah L. OConnor, PhD, RD3, Danhua Wang, MD4, and Jacques Rigo, MD, PhD5
Early nutritional support of preterm infants is critical to life-long health and well being. Numerous studies have demonstrated that preterm infants are at increased risk of mortality and morbidity, including disturbances in brain development. To date, much attention has focused on enhancing the nutritional support of very low and extremely low birth weight infants to improve survival and quality of life. In most countries, preterm infants are sent home before their expected date of term birth for economic or other reasons. It is debatable whether these newborns require special nutritional regimens or discharge formulas. Furthermore, guidelines that specify how to feed very preterm infants after hospital discharge are scarce and conicting. On the other hand, the late-preterm infant presents a challenge to health care providers immediately after birth when decisions must be made about how and where to care for these newborns. Considering these infants as well babies may place them at a disadvantage. Latepreterm infants have unique and often-unrecognized medical vulnerabilities and nutritional needs that predispose them to greater rates of morbidity and hospital readmissions. Poor or inadequate feeding during hospitalization may be one of the main reasons why late-preterm infants have difculty gaining weight right after birth. Providing optimal nutritional support to late premature infants may improve survival and quality of life as it does for very preterm infants. In this work, we present a review of the literature and provide separate recommendations for the care and feeding of late-preterm infants and very preterm infants after discharge. We identify gaps in current knowledge as well as priorities for future research. (J Pediatr 2013;162:S90-100). uch attention has focused on enhancing the nutritional support of very low birth weight (VLBW) and extremely low birth weight (ELBW) infants to improve survival and quality of life. Signicant efforts have been made to provide adequate nutrition to VLBW/ELBW (henceforth VLBW) infants before discharge and for term infants during the rst months of life. Nutritional requirements of VLBW infants have been dened to prevent cumulative nutritional decits soon after birth.1,2 The goal of these efforts is to improve growth early so that preterm and VLBW infants reach normal weight and length by the expected date of delivery or, at most, by the time they are discharged from the hospital. In most countries, preterm infants are sent home before their expected date of term birth for economic or other reasons. It is debatable whether these newborns require special nutritional regimens or discharge formulas. Guidelines that specify how to feed VLBW infants after hospital discharge are scarce and conicting. Furthermore, the nutritional support provided during hospitalization has improved and decreased the incidence of acquired nutritional decits. Thus, the systematic use of special nutrient-enriched discharge formulas must be considered carefully. Similarly, the nutritional requirements of term infants during the early months of life may need to be re-evaluated to prevent excess protein and energy intakes and more strictly mimic intakes of breastfed term infants.3 Feeding regimens designed specifically to meet the nutritional requirements of late-preterm newborn infants have not been established and ought to be considered. We present a review of the literature and provide recommendations for the care and feeding of late-preterm infants and VLBW infants after discharge, separately. We identify gaps in current knowledge as well as priorities for future research.
Nutritional Requirements for the Late-Preterm Infant

A variety of terms have been used to describe preterm infants born at a number of different intervals between 32 and 36 weeks gestation (ie, late preterm, near term, marginally preterm, moderately preterm, minimally preterm, and mildly preterm). Only the terms moderately preterm and late preterm are dened
AAP DHA ELBW EUGR GA HM LCPUFA NICU VLBW American Academy of Pediatrics Docosahexaenoic acid Extremely low birth weight Extrauterine growth retardation Gestational age Human milk Long-chain polyunsaturated fatty acid Neonatal intensive care unit Very low birth weight
From the 1Paris Descartes University, APHP Necker Hospital, Paris France; 2CNRC, Baylor College of Medicine, Houston, TX; 3Department of Nutritional Sciences, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada; 4Department of Pediatrics, Peking Union Medical College Hospital, Beijing, China; and 5Department of Neonatology, University of Liege, CHR Citadelle, Liege, Belgium Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 March 2013 well and should be used. The term late-preterm infants describes infants born between 34.0 and <37.0 weeks gestation, and moderately preterm describes infants born between 32.0 and <37.0 weeks gestation.4 Late-preterm births comprised 8.8% of all live births in the US in 2008 and close to 10% of all births in developing countries. Late-preterm infants are at risk for mortality and perinatal morbidity. Although severe illness may be uncommon, latepreterm infants are 2 to 3 times more likely than term infants to experience mild-to-moderate morbidities such as hypothermia, hypoglycemia, respiratory distress and delayed lung uid clearance, jaundice, infection, feeding intolerance, nutritional compromise in the early neonatal period, and greater rates of readmission after hospital discharge.5 Presently, long-term neurologic and developmental outcomes of late-preterm infants are a major concern. The brain of the late-preterm infant is less mature than that of the term infant. Given that late-preterm infants comprise 9%-10% of all births, even minor increases in the incidence of neurologic disability and/or school failure in this group can have a huge impact on the effectiveness of educational systems and health care needs. Current Nutritional Practices The late-preterm infant presents a challenge to health care providers immediately after birth when decisions must be made about how and where to care for these newborns. Triage of late-preterm infants varies among hospitals. Some institutions admit these infants directly to a newborn nursery, and others admit them to a neonatal intensive care unit (NICU). In many institutions, the limited availability of acute care beds in the NICU and established clinical practices determine that these infants are admitted to the well-baby nursery or to mothers rooms in accordance with roomingin practices. However, considering these infants as well babies may place them at a disadvantage. For example, mothers of preterm infants who are admitted to a NICU are more likely to initiate and continue breastfeeding than mothers of infants placed in the well-baby nursery.6 Late-preterm infants have signicantly greater medical risks and require specic support more often than term infants.7 Late-preterm infants can develop hypoglycemia and have difculty feeding, situations that may require intravenous treatment, which is a relatively labor-intensive treatment for a well-baby nursery.8 Striking variations in the clinical care of late-preterm infants in 10 NICUs located in California and Massachusetts were reported.9 Five percent to 66% of infants received hyperalimentation, and 4%-72% of infants were sent home with recommendations to be fed a postdischarge formula. Weight gain by moderately premature infants (30-35 weeks gestational age [GA]) during hospitalization falls well below intrauterine norms.10 In a study of 15 NICUs, 98% of moderately premature infants (30-35 weeks GA) failed to gain at least 15 g/kg/d, the recommended intrauterine growth rate.10 The z-score for weight decreased from birth to discharge by 0.45 to 0.93 (average, 0.67) across all NICUs. The NICUs that reported optimal growth worked to minimize postnatal weight loss so that birth weight was regained more quickly, and better mid-term growth was achieved.10 The provision of protein and energy supplements increased the growth velocity of moderately preterm infants.10,11 In one study, shorter duration of gavage feeding correlated with growth velocity, suggesting that terminating gavage feeding may reect variation in the recognition, rather that true attainment, of mature feeding ability. In fact, gavage often may be discontinued too early to allow for proper growth.10 The advantages of breastfeeding for late-preterm infants appear to be even greater than those for term infants. However, establishing breastfeeding in this group frequently is more problematic than in term infants. Late-preterm infants may be sleepier, have less muscle strength, and, thus, have more difculty with latch, suck, and swallow. Furthermore, they are more likely to be separated from their mothers, who may have medical conditions that interfere with breastfeeding.12 Any one or a combination of these conditions places the mothers and infants at risk for breastfeeding failure. Breastfeeding initiation in the US is 59%-70% in the latepreterm population, and the likelihood of breastfeeding beyond 4 weeks or the recommended 6 months is signicantly less than for term infants, and, possibly, less than for infants born before 34-35 weeks gestation.13 Consequences of Poor Feeding in the Late-Preterm Population
Growth. Poor or inadequate feeding during hospitalization

may be one of the main reasons why late-preterm infants have difculty gaining weight right after birth.10 When physical growth was measured in a population-based cohort of late-preterm and term infants,14 late-preterm infants were found to be at increased risk of being underweight and stunted at 12 and 24 months of age (aOR: 2.57 and 2.35, and 3.36 and 2.30, respectively). Wasting was signicantly different between the groups in the rst year of life, but only a small number of infants were reported to have wasting at 12 and 24 months. Whether or not poor growth of latepreterm infants during the rst years of life is linked to inadequate early nutrition remains to be determined.
General Health and Readmission. Late-preterm infants

are 2 to 3 times more likely to be readmitted than term infants.5,13 The main presenting diagnoses are jaundice, suspected sepsis, and feeding difculties. Feeding may be successful during the birth hospitalization but can become problematic after discharge. Feeding difculties secondary to poor oral-motor tone, function, and neural maturation predispose the infants to dehydration and hyperbilirubinemia. Late-preterm infants also may be discharged home after successful transition to the extrauterine environment, but before lactation is established and problems with latch and milk transfer are identied and addressed adequately. Parental education and timely outpatient follow-up by a provider
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Vol. 162, No. 3, Suppl. 1 in proportion during this time. Resting energy expenditure is 45 kcal/kg/d in VLBW infants and 50 kcal/kg/d in larger preterm infants. The additional energy requirements needed for heat generation and physical activity (eg, movement, crying) are slightly less in VLBW infants (15 kcal/kg/d) than in larger preterm infants (20 kcal/kg/d). Fat accumulation increases as a proportion of the weight gain from 12% at 28 weeks GA to 20% at term and 40% in breast-fed term infants.22 Fetal energy deposition per gram of weight gain also increases from 1.8 kcal/g at 28 weeks GA to 2.3 kcal/g at term and 3.8 kcal/g in breast-fed term infants. Therefore, energy requirements vary across all preterm groups. Mineral requirements are controversial. On one hand, mineral requirements for bone development can be estimated exclusively from placental transport. Accordingly, the American Academy of Pediatrics (AAP) and other groups23 recommend that preterm infants receive relatively large amounts of mineral supplements. On the other hand, smaller amounts of highly bioavailable calcium and phosphorous are recommended if adaptation to extrauterine life is taken into account.2 After birth, bone turnover is stimulated, and calcium and phosphorous are released to the mineral pool. Thus, activation of bone turnover reduces the need for exogenous calcium and phosphorus and, therefore, on that basis the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition recommended recently smaller amounts of highly bioavailable calcium and phosphorus. Mineral requirements are relatively high in late-preterm infants because bone mineralization lags bone growth in all preterm infants, and their bones contain smaller mineral stores than those of similar GA newborn infants. Nutritional stores of essential nutrients in newborn infants (ie, LCPUFAs, iron, trace elements) are derived from transplacental transfer and related to GA. To date, no data justify providing late-preterm infants with different amounts of these nutrients than those recommended for other preterm infants. Therefore, similar intakes are recommended. The nutritional requirements of late-preterm and earlyterm infants are shown to be greater than those of full-term infants. The values do not take into account the nutrient supply needed to compensate for any nutritional decit and, therefore, may not apply to the very preterm infant at time of or after hospital discharge. Recommendations, Gaps in the Literature, and Research Priorities The nutritional needs of late-preterm infants differ from those of term infants, especially with regard to energy, protein, calcium, and phosphorous requirements. Late-preterm infants have unique and often-unrecognized medical vulnerabilities and nutritional needs that predispose them to greater rates of morbidity and hospital readmissions. Breastfeeding is the preferred way to feed late-preterm infants. However, donor or mothers milk often does not meet the theoretical nutritional needs of the late-preterm infant. When late-preterm infants have a signicant comorbidity and/or when the gap between actual and recommended
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knowledgeable in breastfeeding should be included in the proper management of these motherinfant dyads.15
Development. The risk of adversely affecting brain development during the last trimester is well known. Although most attention has focused on VLBW infants, moderately preterm infants are also at risk of impaired development. The preterm infant brain weighs approximately two-thirds that of the term infant at 34 weeks GA, and the relative percentages of gray matter and myelinated white matter to total brain volume increase exponentially between 34 and 40 weeks gestation.16 Late-preterm infants can have various neonatal complications, such as poor feeding, that increase the risk of brain injury and abnormal neurodevelopmental outcome. Long-chain polyunsaturated fatty acids (LCPUFAs) play an important role in early infant development and visual acuity in preterm infants (see article on lipid needs by Lapillonne et al in this Supplement).17 They may be important in late-preterm infants as well. Supplementation of formula with docosahexaenoic acid (DHA) and arachidonic acid improves visual acuity and cognitive development in moderately preterm infants (ie, 30-37 weeks GA).18 Late-preterm infants may require preformed DHA in early life for optimal neurologic development. Late-preterm infants are at more risk of adverse developmental outcomes and academic difculties for up to 7 years of age than term infants.19 Late-preterm infants have a greater risk of cerebral palsy, speech disorders, neurodevelopment handicaps, behavioral abnormalities, and competence issues (behavioral, scholastic, social, and global). Given the known relationship among poor early growth, inadequate nutrition during hospitalization, and long-term development of VLBW infants, it may be speculated that similar risks exist for late-preterm infants. Large population-based studies that evaluate long-term neurodevelopmental and behavioral outcomes in relation to nutritional intake, feeding performances, and early growth are needed to test this hypothesis. Changes in Nutritional Needs in Late Gestation Nutritional requirements for late-preterm infants can be evaluated in the same manner applied to VLBW infants and with a similar goal.20 Specic data about late-preterm infants are scarce. However, extrapolation from data for VLBW and term infants can be made with a reasonable degree of condence. In general, nutritional recommendations for preterm infants need to: (1) consider fetal growth as appropriate for a particular GA; (2) focus on lean body mass deposition; (3) consider age-appropriate accretion rates of protein, minerals, and various essential constituents; (4) incorporate an understanding of gastrointestinal tract development; (5) consider the cumulative nutrient decit that may accrue during the early days or weeks of life; and (6) adapt recommendations relative to postconceptional age. Growth velocity decreases dramatically from 18-20 g/kg/ d at 28 weeks GA to 10 g/kg/d at term.21,22 Protein accretion and, therefore, requirements related to body weight decrease
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March 2013 nutrient intakes is signicant, fortiers and supplements may be necessary to meet a particular infants needs. Presently, clinical judgment is applied to balance the benets (improved nutrition) with the risks (interruption of breastfeeding and transient undernutrition) associated with providing nutrient-enriched supplements or formula to late-preterm infants. Studies designed to determine the best way to provide optimal nutrition to late-preterm infants, the largest subgroup of preterm infants, are needed. Late-preterm infants appear to have poorer rates of breastfeeding initiation and duration than term and, possibly, earlier preterm infants. Health care providers should monitor breast milk supply, nutrient transfer, and problems related to poor intake. Individualized feeding plans should be promoted and include special considerations to compensate for immature feeding skills and inadequate breast milk production, including the need to stimulate lactation. Mothers of late-preterm infants should receive qualied, extended lactation support, frequent follow-up, and due consideration of delayed hospital discharge. Current nutritional practices are likely to induce transient undernutrition in late-preterm infants, the magnitude and consequences of which are unknown. The possible link between early nutrition and long-term neurologic and developmental outcomes in late-preterm, moderately preterm, and early-term infants needs to be dened.
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Figure 1. Weight growth status categorization (ie, weight-forage vs weight-for-length) at discharge from hospital of preterm infants born at 26 to 29 weeks GA (n = 1214). The discordance at discharge between the weight-for-age and weight-for-length methods of weight growth status assessment is primarily caused by the small-for-age infants being mostly appropriate-for-length (adapted from Olsen et al36).
Nutritional Requirements for the Preterm Infant after Discharge

Nutritional Status at Discharge from the Hospital
Growth and Quality of Growth. Extrauterine growth retardation (EUGR) describes postnatal growth of preterm infants that is less than the expected growth of a fetus at the same postconceptional age. It is a major problem that occurs in 60%-100% of preterm births globally.24-28 EUGR has been dened at discharge as growth values <10th percentile or <2 SD from the mean of intrauterine growth expectation. It has also been dened as a change in z-score of >1 SD or >2 SD from birth to discharge.29 The latter denition was a better predictor of neurodevelopmental outcomes than the former denition.30 Body composition and bone mineral content at discharge can be measured reliably in research settings.31-35 There is no standard for these measures in preterm infants because neonatal disease and undernutrition occur commonly and inuence body composition strongly. Indeed, most studies show that body composition is abnormal at discharge and marked by a reduction in fat-free mass32 and increased total31-33 and intra-abdominal adiposity.32,35 This predominant fat mass deposition among preterm infants is believed to be due to imbalances in protein/energy nutrition during hospitalization and recovery from early malnutrition, especially in the ELBW groups.20 It is important to assess lean-to-fat mass or lean-to-total body mass routinely. Monitoring only weight-for-age may
result in an inappropriate classication of nutritional adequacy (Figure 1).36 Therefore, the assessment of growth status of preterm infants in the NICU and at the time of discharge should include weekly measurements of length and recordings of weight-for-length or other measures of body proportion. It remains to be determined how type of growth and body proportion are associated with optimal outcomes. Finally, poor growth of head circumference postnatally is associated with poor brain development, cerebral palsy, Mental Development Index score <70, and Psychomotor Index <70 at 18 months corrected age,37 motor and cognitive impairment at 3 and 7 years,38,39 and a detriment of 4.1 IQ points in adults.40 Accordingly, assessments of growth should include measurements of head circumference.
Effects of the Nutrition Strategies during Hospitalization. The goal of providing nutrition to the
preterm infant is to ensure that the rate of growth and body composition equal those of a fetus at the same GA. This goal also can apply to the growing preterm infant after discharge through the rst year of life. EUGR is attributed to an early nutritional decit and poor growth during the stable growing period. Aggressive enteral and parenteral nutrition for very preterm infants reduces cumulative energy and protein decits, promotes postnatal growth, optimizes body composition,21,41-45 and may, improve neurodevelopmental outcomes.37,42,45-49 When infants are fed human milk (HM), they should also receive fortiers.50 There is considerable interest in individualizing the nutrient fortication of HM to address each preterm infants unique nutritional
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Vol. 162, No. 3, Suppl. 1 that demonstrate many advantages of HM.60-62 Despite awareness of these advantages, rates of HM feeding among preterm infants fall signicantly below those of term infants for a variety of reasons such as maternal illness, stress, lack of adequate staff support, and other factors related to preterm birth.63 Premature infants are at greater risk for morbidity, malnutrition, and likelihood that not all nutrient decits will be resolved before discharge. Therefore, VLBW preterm infants, and particularly those born ELBW, have the greatest nutrient needs, especially if they: (1) are discharged well before their expected delivery date; fed predominantly HM; (2) have fallen below the 3rd or 5th percentile in growth indices; or (3) have persistent morbidities that elevate nutritional requirements or limit the volume of feeds consumed. The goals for VLBW preterm infants should be to promote HM feeding, minimize nutrient decits, promptly address decits when identied, and avoid overnourishing or promoting postnatal growth acceleration beyond normal for postconceptional age. Because the nutritional status of preterm infants varies widely, creating individualized feeding plans is the best approach. Ideally, the pre- and postdischarge nutritional concerns should be closely coupled, although it generally is not achieved. VLBW infants are discharged at younger ages and lower body weights than ever before. Once home, they are cared for by health care providers who had not been involved with their inpatient care. Close nutritional monitoring of infants after hospital discharge frequently is not accomplished because high-risk neonatal follow-up clinics are concerned more with neurodevelopmental than nutritional status. Therefore, it is important to establish postdischarge feeding guidelines to care for these infants.
requirements and differences in milk composition.51,52 The variability in the protein and/or fat content of HM may be responsible for slow growth in some HM-fed infants when fortiers are provided in a consistent manner, regardless of differences in milk composition.51-54 When infants are fed formula, it is necessary to stress that the use of hydrolyzed protein and/or bottled or canned sterilized preterm formula has a reduced nutrient bioavailability that needs to be compensated. A prospective study of preterm infants with birth weights <1250 g demonstrated that initiating aggressive nutritional support early (ie, energy and protein intakes of 50 kcal/kg/ d and 2.5 g/kg/d at day 1; increased to 120 kcal/kg/d and 4 g/kg/d at day 6; and to 120-130 kcal/kg/d and 4-4.5 g/kg/ d during the stable growing period) signicantly reduced growth restriction at the time of discharge. The incidence of infants with a weight <2 SD did not change between birth and discharge, and postnatal growth restriction was observed in only 9% of infants.55 Effect of Postdischarge Nutrition on Development and Growth Few published studies have tested the hypothesis that a proactive approach to feeding VLBW infants after hospital discharge (eg, feeding VLBW infants differently than term infants) improves growth and development better than a reactive approach (eg, intervening when growth failure has occurred). This gap in our knowledge is particularly pronounced for VLBW infants fed HM predominantly after hospital discharge and for VLBW infants with persistent morbidities. It is difcult to establish universal postdischarge feeding guidelines because growth and nutritional status of preterm infants vary considerably. Furthermore, the volume of feeds consumed at discharge varies greatly and may reach 200 mL/kg/day or more if the infants are fed ad libitum. It is important to consider caloric density because infants on less calorie-dense formulas ingest 22%-23% more formula than those on more calorie-dense formulas.56 Therefore, the caloric density of feeds will determine the intake not only of energy but also of micronutrients and proteins, which are important for physical growth.
Evidence in Support of the Need for NutrientEnriched Formula after Hospital Discharge. Infants
who weigh less than expected for their postconceptional ages are at increased risk of long-term growth failure and require particular attention.64 Breastfeeding and providing fortied HM should be promoted. If an infant is formula-fed, a preterm formula or a special postdischarge formula that contains more protein, minerals, trace elements, and LCPUFAs than standard term formula should be provided until the preterm infant reaches 40 weeks postconceptional age and, possibly, until the infant reaches 52 weeks postconceptional age.64,65 Henderson et al66 identied 7 good-quality controlled trials (N = 631 infants) in which the authors compared the effects of feeding preterm infants either a nutrient-enriched formula or standard term formula after hospital discharge. The authors found little evidence that nutrient-enriched formula affected the growth or development of preterm infants up to 18 months corrected age. However, this analysis was limited because preterm infants at most nutritional risk were either excluded or underrepresented. For example, in all but 1 of the 6 trials (n = 20 infants), a signicant proportion of infants weighed >1500 g. In one trial, preterm infants (n = 103) were included only if they were growing well at
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Current Practices for Feeding after Hospital Discharge. Postdischarge practices regarding breastfeeding
and nutrient enrichment of feedings vary widely by country, NICU, and caregiver. Infants are sent home on HM alone, partially or fully nutrient-fortied HM, nutrient-enriched formula, or conventional term formula. Although there is a lack of evidence to suggest a prescriptive approach to feeding all VLBW infants after discharge, there is general consensus that HM should be fed in preference to infant formula and that certain subgroups of infants will be at risk for poor nutritional status after discharge. Many organizations recommend that mothers own milk be the exclusive source of nutrition for the rst 6 months of life.57-59 These endorsements are based on abundant data
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March 2013 discharge (25 g/kg/d). In another, infants with an abnormal suck and swallow were not included (n = 89). In yet another, infants with chronic lung disease were not included (n = 125). Thus, future research efforts should study subgroups of preterm infants who are not able to feed ad libitum after hospital discharge or who have extra metabolic demands secondary to growth restriction or chronic lung disease.66 Another limitation is that the growth could not be evaluated until 6 months postterm because of lack of data. It is important to evaluate growth before 6 months because most preterm infants are at greatest nutritional risk soon after hospital discharge. Recent studies indicate that nutrient-enriched discharge formulas can provide advantages to preterm infants. Growth at 4 and 12 months and mineralization at 4 months after discharge are better in VLBW infants fed preterm formula during the rst 2 months after discharge than in those fed term formula.67 Nutrient-enriched formula provided after term does not change the quantity of growth but improves the quality of growth in preterm infants. Infants fed nutrientenriched formula have lower fat mass, corrected for body size at 6 months corrected age, than infants fed standard formula or HM.68 Preterm infants fed nutrient-enriched formula after discharge exhibit an increase in fat-free and peripheral fat mass but not central adiposity compared with infants fed term formula.69 These data indicate that nutrient-enriched formulas do not promote central adiposity in preterm infants, a feature that is associated with metabolic syndrome later in life.
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mental increase in the nutrition and the rate of breastfeeding may play a role.
Nutritional Deciencies Other than Protein/Energy.

Considerable attention has focused on the macronutrient content of feedings that contribute to caloric intake such as protein, which has a direct effect on growth. Less attention has focused on other nutrients, particularly minerals, iron, LCPUFAs, and vitamin A. Feeding postdischarge preterm infants formulas or HM with greater concentrations of calcium and phosphorus than those contained in term formula improves bone mineralization, particularly if the special formulas used during hospitalization are continued after hospital discharge.65,73 Provision of large amounts of calcium and phosphorous for long periods may not be necessary. Relative osteopenia of preterm infants resolves spontaneously during the rst months after discharge in a manner similar to that induced by the acceleration of growth at the rst stage of adolescence. Bone mineral content improves spontaneously in most infants, and rapid catch-up mineralization is observed after discharge in VLBW infants. At 3 to 6 months corrected age, spine and total bone mineral density, corrected for anthropometric values, are found to be in the range of normal term newborn infants.74,75 Nevertheless, potential long-term effects of supplementation after discharge on peak bone mass are not known. Bone mass may be reduced at adulthood, but this is mainly the result of a persistent growth restriction because it is appropriate for the body size achieved. Furthermore, early diet or HM feeding does not affect bone mass during childhood.75,76 Therefore, on the basis of the limited data available, it is likely that mineral intake after discharge should exceed that of term infants when catch-up growth occurs and is supported by enriched feeds, but it is unlikely that extra mineral supplementation is necessary when a mineralrich postdischarge or preterm formula or enriched HM is used. With regard to vitamin D intake, there is no evidence that preterm infants after discharge should receive greater doses that term infants to maintain a normal plasma 25-hydroxy vitamin D concentration. Body iron stores are highly variable at discharge, so it is important to screen for iron deciency at discharge and during the rst year of life. The AAP and European Society of Pediatric Gastroenterology, Hepatology, and Nutrition recommend that preterm infants receive iron supplements for up to 1 year after discharge.2,77 The AAP recommends at least 2 mg/kg/day, which is the amount of iron provided by iron-fortied formulas. Preterm infants fed HM should receive an iron supplement of 2 mg/kg/day by 1 month of age, and this should be continued at least until the infant is weaned to iron-fortied formula or begins eating complementary foods that supply 2 mg/kg of iron per day. Infants who receive iron loads from multiple transfusions of packed red blood cells do not require supplements. Lapillonne et al discuss providing LCPUFAs to preterm infants (see article on lipid needs by Lapillonne et al in
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Evidence in Support of the Need for NutrientEnriched HM after Hospital Discharge. Although
HM is purported to be superior to formula, HM-fed infants often accrue the greatest nutritional decits before hospital discharge.64 To determine whether the provision of nutrient supplements after discharge is benecial, VLBW (750-1800 g) preterm infants fed predominantly HM were randomly assigned at discharge (38 weeks postconceptional age) to a control group (unfortied HM) or an intervention group (half of HM feeds nutrient-enriched).70,71 Both groups received intensive lactation support. The infants fed nutrientenriched HM grew more rapidly during the 12-week study period than infants fed HM alone. The observed differences in absolute weight and length, and, among smaller babies, head circumference were sustained for the rst year.71 In addition, the duration of HM feeding for both groups was signicantly longer than had been reported previously for preterm infants.63 A larger, randomized controlled trial studied HM-fed preterm infants (535-2255 g, n = 207) randomized to receive 20-50 mL of expressed breast milk containing a multinutrient fortier (17.5 kcal and 1.4 g of protein) each day from the time of discharge to 4 months corrected age or HM alone.72 In this study, the breast milk supplement did not inuence breastfeeding, nor did it have a signicant impact on growth. It is not clear why the results of the 2 studies differ, but it is possible that differences in the incre-
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Vol. 162, No. 3, Suppl. 1 Selection of a Growth Chart Two types of growth charts can be used to monitor the growth of preterm infants after hospital discharge. One is based on fetal growth until term and growth of preterm infants thereafter; the other tracks growth of term infants. Most growth charts describe how infants actually grow, rather than how they should grow to promote optimal neurodevelopment and achieve the best long-term health outcomes. For a detailed discussion of growth charts, see the article on growth curves by Bhatia, in this Supplement82; for the effects of early growth on optimal neurodevelopment and long-term health outcomes, see the article on metabolic and cardiovascular outcomes by Lapillonne and Grifn, in this Supplement.83 A single chart cannot be used to monitor and plot the growth of infants during their initial hospital course and through the early discharge period when the risk of nutrient decits is greatest. To address these issues, the Fenton charts84 were designed to commence monitoring infants at 22 weeks postconceptional age and continue for 10 weeks postterm. However, intrauterine and postnatal growth in term infants are sex-related. The use of sex-related intrauterine growth charts such as those of Olsen et al85 reduces the false detection of intra-uterin growth retardation, especially in girls. Therefore, we have created new sex-related fetal-infant growth charts from 22 wks GA to 66 or 92 weeks postconceptional age to evaluate the growth adequacy during the rst year of life in preterm infants according to sex (Figure 2).
this issue) and recommend that DHA and arachidonic acid be provided until the expected due date in amounts greater than had been previously recommended. After the due date, preterm infants should receive the same quantity of LCPUFAs as term infants until more data become available. Vitamin A status may be suboptimal in formula-fed VLBW infants for many months after discharge.78 It has been shown that preterm infants who ingest 3000 IU of vitamin A per day for 90 days fail to exhibit plasma vitamin A concentrations at levels characteristic of repletion status.79 This observation is in contrast to previous studies of term infants, in which a similar supplementation protocol was sufcient to maintain plasma vitamin A concentrations.80 The failure to achieve optimal vitamin A concentrations may be due to immaturity of fat digestion mechanisms in premature infants. Additional studies are needed to determine the dose and duration of vitamin A supplementation that allows infants to reach full repletion values.
How to Monitor the Postdischarge Infant

Accurate serial measurements of weight, length, and head circumference plotted precisely on validated growth charts facilitate early identication of potential nutritional or health problems after hospital discharge. To ensure accuracy, measurements should be made by trained personnel who use standardized techniques. Expensive equipment is not necessary.81
14.0 13.0 12.0 11.0 10.0
14.0 13.0
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+ 2 SD
12.0 11.0 10.0

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+ 1 SD Mean - 1 SD - 2 SD
+ 1 SD Mean + 1 SD - 2 SD
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24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92
Postconceptional Age (Weeks)
Postconceptional Age (Weeks)
Figure 2. Examples of sex-related fetalinfant growth charts from 22 weeks GA to 92 weeks postconceptional age by combining the Olsen et al85 and the World Health Organization growth curves.86 Body weight versus GA for A, boys and B, girls.
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of nutritional decits occurring during the early days or weeks of life. A paucity of data exists on the effects of a poor nutrition supply at different stages of gestation, and we stress the need for future research in this area. At the present time, good clinical judgment is required to balance the benets (improved nutrition) versus risks (interruption of breastfeeding and transient undernutrition) and provide appropriate, nutrient-enriched feeds to all preterm infants including the moderately preterm infants. Monitoring Close monitoring of growth (weight-, length-, and head circumference-for-age, indexes of body proportionality) and feed intake should be performed at discharge, at expected term, and every 2 to 4 weeks after discharge until indexes of growth are >2 SD on an appropriate growth curve (ie, World Health Organization growth standard). Predominantly breast-fed infants, infants with persistent morbidities, and infants who were recently transitioned to a different type/mode of feeding should be monitored closely immediately after discharge and during the rst week after discharge. Selective biological indexes (ie, blood urea nitrogen, ferritin, retinol binding protein, alkaline phosphatase, 25[OH] vitamin D) may be useful in assessing selective nutrient deciencies but should be determined on an individual risk basis. Nutritional Counseling Because of the heterogeneity in nutritional status, postnatal age, and corrected age of preterm infants at the time of hospital discharge, an individualized approach is highly recommended over the use of general guidelines. Individualized nutritional plans should be based on growth, quality of growth, and selective nutrient deciencies. As a rule of thumb, however, infants who weigh <1000 g at birth and those who weigh <2000 g at discharge require detailed instructions at discharge, close monitoring and, potentially, nutritional intervention.
Monitoring During the First Weeks after Discharge.

As a general rule, infants should be transitioned to the feed that they will go home consuming several days before discharge to assess tolerance and growth. Close monitoring of feeding and growth is recommended after hospital discharge, especially for infants at risk for nutritional decit (ie, those who have an uncoordinated suck swallow, have persistent comorbidities, or are predominantly breast fed). Parents should be reminded that breastfeeding is the optimal way to feed their infants. Breast-fed infants should be fed every 1.5-3 hours and allowed no more than one period of prolonged sleep (5 hours) to maintain mothers milk supply. Ad libitum feeding is encouraged to optimize infant growth. Infants should be weighed within 48 hours of discharge to assess intake and provide reassurance to families. This is particularly important for families that had been transitioned from nasogastric or enriched feedings to breastfeeding just before discharge. A complete feeding assessment should be conducted within the rst week of discharge. Parents should be made aware how to contact a dietitian and/or lactation consultant, ideally one who has experience working with mothers of preterm infants.
Recommendations for Preterm Infants after Hospital Discharge

Guidelines for all preterm newborn infants should be similar because postconceptional nutritional needs are very similar. Therefore, the recommendations below are appropriate for all groups of preterm infants, except where indicated otherwise. Prevention We strongly emphasize the importance of proactive nutritional support during hospitalization to prevent nutritional decits and reduce the incidence and the degree of growth failure. Proactive support limits the need for specialized feeding after discharge. Nutrient intake and growth should be monitored in all groups of preterm infants (ELBW, VLBW, moderately preterm) after birth to reduce the risk
Table. Nutritional needs by GA (weeks)

GA, weeks Variables (per kg/d) Fetal growth Weight gain, g Lean body mass gain, g Protein gain, g Requirements Energy, kcal Proteins, g Calcium, mg Phosphorus, mg <28 20 17.8 2.1 125 4 120-140 60-90 28-31 17.5 14.4 2 125 3.9 120-140 60-90 32-33 15 12.1 1.9 130 3.5 120-140 60-90 34-36 13 10.5 1.6 127 3.1 120-140 60-90 37-38 11 7.2 1.3 115 2.5 70-120 35-75 39-41 10 6.6 1.2 110 2 70-120 35-75
Weight gain, lean body mass, and protein gain during the last trimester of pregnancy and theoretical energy and protein requirements for enteral nutrition are indicated by GA group. Before 39 weeks GA, requirements are based on fetal growth, fetal accretion rate, and intestinal absorption; after 40 weeks GA, requirements are based on the composition of HM (adapted from Rigo20 and Ziegler 21). The values indicated in this table are theoretical values per GA groups. They show that both the late-preterm infant (ie, 34-36 weeks GA) and the early-term infant (ie, 37-38 weeks GA) have nutritional requirements that are different than the full-term infant (ie, 39-41 weeks GA). The values indicated do not take into account the nutrient supply needed to compensate for any nutritional decit and therefore are not applicable as such for the very preterm infant at time of, or after, hospital discharge.
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5. Engle WA, Tomashek KM, Wallman C. Late-preterm infants: a population at risk. Pediatrics 2007;120:1390-401. 6. Colaizy TT, Morriss FH. Positive effect of NICU admission on breastfeeding of preterm US infants in 2000 to 2003. J Perinatol 2008;28: 505-10. 7. Ma H, Li Z, Meng QH, Li XH, Wang XH, Li H, et al. Relativity of nuclear factor-kappaB (P65/Rel-A) and angiotensin II type 1 receptor expression in early stage of lesions of adriamycin nephrosis in young rats and the effects of intervention [in Chinese]. Zhonghua Er Ke Za Zhi 2004;42: 275-9. 8. Garg M, Devaskar SU. Glucose metabolism in the late preterm infant. Clin Perinatol 2006;33:853-70. 9. McCormick MC, Escobar GJ, Zheng Z, Richardson DK. Place of birth and variations in management of late preterm (near-term) infants. Semin Perinatol 2006;30:44-7. 10. Blackwell MT, Eichenwald EC, McAlmon K, Petit K, Linton PT, McCormick MC, et al. Interneonatal intensive care unit variation in growth rates and feeding practices in healthy moderately premature infants. J Perinatol 2005;25:478-85. 11. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107:270-3. 12. Adamkin DH. Feeding problems in the late preterm infant. Clin Perinatol 2006;33:831-7. 13. Radtke JV. The paradox of breastfeeding-associated morbidity among late preterm infants. J Obstet Gynecol Neonatal Nurs 2011;40:9-24. 14. Santos IS, Matijasevich A, Domingues MR, Barros AJ, Victora CG, Barros FC. Late preterm birth is a risk factor for growth faltering in early childhood: a cohort study. BMC Pediatr 2009;9:71. 15. Academy of Breastfeeding Medicine Protocol Committee. ABM clinical protocol #10: breastfeeding the late preterm infant (34(0/7) to 36(6/7) weeks gestation) (rst revision June 2011). Breastfeed Med 2011;6:151-6. 16. Adams-Chapman I. Neurodevelopmental outcome of the late preterm infant. Clin Perinatol 2006;33:947-64. 17. Lapillonne A, Groh-Wargo S, Lozano Gonzalez CH, Uauy R. Lipid needs of preterm infants: updated recommendations. J Pediatr 2013;162: SXXX-XXX. 18. Fang PC, Kuo HK, Huang CB, Ko TY, Chen CC, Chung MY. The effect of supplementation of docosahexaenoic acid and arachidonic acid on visual acuity and neurodevelopment in larger preterm infants. Chang Gung Med J 2005;28:708-15. 19. McGowan JE, Alderdice FA, Holmes VA, Johnston L. Early childhood development of late-preterm infants: a systematic review. Pediatrics 2011;127:1111-24. 20. Rigo J. Protein, amino acid, and other nitrogen compounds. In: Tsang RC, Uauy R, Koletzko B, Zlotkin S, eds. Nutrition of the preterm infant. Scientic basis and practical aspects. Cincinnati, OH: Digital Educational Publishing, Inc.; 2005. p. 45-80. 21. Ziegler EE. Protein requirements of very low birth weight infants. J Pediatr Gastroenterol Nutr 2007;45(Suppl 3):S170-4. 22. Leitch CA, Denne SC. Energy. In: Tsang RC, Uauy R, Koletzko B, Zlotkin S, eds. Nutrition of the preterm infant. Scientic basic and practical guidelines. Cincinnati, OH: Digital Educational Publishing Inc.; 2005. p. 23-44. 23. Atkinson SA, Tsang RC. Calcium, magnesium, phosphorus, and vitamin D. In: Tsang RC, Uauy R, Koletzko B, Zlotkin S, eds. Nutrition of the preterm infant. Scientic basis and practical guidelines. Cincinnati, OH: Digital Educational Publishing, Inc.; 2005. p. 245-77. 24. Bertino E, Coscia A, Mombro M, Boni L, Rossetti G, Fabris C, et al. Postnatal weight increase and growth velocity of very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2006;91:F349-56. 25. Roggero P, Gianni ML, Amato O, Orsi A, Piemontese P, Cosma B, et al. Postnatal growth failure in preterm infants: recovery of growth and body composition after term. Early Hum Dev 2008;84:555-9. 26. Sakurai M, Itabashi K, Sato Y, Hibino S, Mizuno K. Extrauterine growth restriction in preterm infants of gestational age < or =32 weeks. Pediatr Int 2008;50:70-5.
To avoid creating nutritional decits after discharge, preterm infants should at least receive the nutrient intake of their respective corrected age (Table) until they reach full term (ie, 39-41 weeks). This strategy does not take into account the nutrient supply needed to compensate for any nutritional decit. We strongly endorse HM feeding as the preferred method of nourishing preterm infants after discharge and recognize that providing mothers with lactation support is an important component of care for the preterm infant. Nutrient decits should be identied, promptly corrected, and afterwards, nutrition should be normalized as soon as possible to avoid overnourishing or promoting growth acceleration. Close monitoring of growth as outlined here and select follow-up of biochemical deciencies should accomplish these objectives. HM fortiers and enriched formulas are effective nutrition adjuvants that can be used to improve growth. These agents should be discontinued as soon as possible after expected term to avoid overfeeding. The recommendations for DHA, and arachidonic acid, supply for preterm infants should be continued until full term. Thereafter, recommendations for term infants should be applied. We recommend that iron status be measured. Iron supplementation should be continued after discharge from the hospital, at least until 6-12 months of age, depending on diet. n
Author Disclosures
All authors received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. All authors have participated to the review of the available data and to the writing of the manuscript.
We thank Gretchen Duenas and the Association pour la Recherche et la Formation en Neonatologie for their technical assistance.
Reprint requests: Alexandre Lapillonne, MD, PhD, Professor of Pediatrics, Department of Neonatology, Necker-Enfants Malades Hospital, 149 rue de Sevres, 75015 Paris, France. E-mail: alexandre.lapillonne@nck.aphp.fr.
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27. Wang DH. Multicenter study of the nutritional status of premature infants in neonatal intensive care unit in China: report of 974 cases [in Chinese]. Zhonghua Er Ke Za Zhi 2009;47:12-7. 28. Bertino E, Coscia A, Boni L, Rossi C, Martano C, Giuliani F, et al. Weight growth velocity of very low birth weight infants: role of gender, gestational age and major morbidities. Early Hum Dev 2009;85:339-47. 29. Euser AM, de Wit CC, Finken MJ, Rijken M, Wit JM. Growth of preterm born children. Horm Res 2008;70:319-28. 30. Shah PS, Wong KY, Merko S, Bishara R, Dunn M, Asztalos E, et al. Postnatal growth failure in preterm infants: ascertainment and relation to long-term outcome. J Perinat Med 2006;34:484-9. 31. Roggero P, Gianni ML, Amato O, Orsi A, Piemontese P, Morlacchi L, et al. Is term newborn body composition being achieved postnatally in preterm infants? Early Hum Dev 2009;85:349-52. 32. Cooke RJ, Grifn I. Altered body composition in preterm infants at hospital discharge. Acta Paediatr 2009;98:1269-73. 33. Ahmad I, Nemet D, Eliakim A, Koeppel R, Grochow D, Coussens M, et al. Body composition and its components in preterm and term newborns: a cross-sectional, multimodal investigation. Am J Hum Biol 2010; 22:69-75. 34. Rigo J. Body composition during the rst year of life. Nestle Nutr Workshop Ser Pediatr Program 2006;58:65-76. 35. Uthaya S, Thomas EL, Hamilton G, Dore CJ, Bell J, Modi N. Altered adiposity after extremely preterm birth. Pediatr Res 2005;57:211-5. 36. Olsen IE, Lawson ML, Meinzen-Derr J, Sapsford AL, Schibler KR, Donovan EF, et al. Use of a body proportionality index for growth assessment of preterm infants. J Pediatr 2009;154:486-91. 37. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit inuences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006;117:1253-61. 38. Powers GC, Ramamurthy R, Schooleld J, Matula K. Postdischarge growth and development in a predominantly Hispanic, very low birth weight population. Pediatrics 2008;122:1258-65. 39. Cooke RW, Foulder-Hughes L. Growth impairment in the very preterm and cognitive and motor performance at 7 years. Arch Dis Child 2003;88: 482-7. 40. Weisglas-Kuperus N, Hille ET, Duivenvoorden HJ, Finken MJ, Wit JM, van Buuren S, et al. Intelligence of very preterm or very low birthweight infants in young adulthood. Arch Dis Child Fetal Neonatal Ed 2009;94: F196-200. 41. Janeiro P, Cunha M, Marques A, Moura M, Barroso R, Carreiro H. Caloric intake and weight gain in a neonatal intensive care unit. Eur J Pediatr 2010;169:99-105. 42. Valentine CJ, Fernandez S, Rogers LK, Gulati P, Hayes J, Lore P, et al. Early amino-acid administration improves preterm infant weight. J Perinatol 2009;29:428-32. 43. Premji SS, Fenton TR, Sauve RS. Higher versus lower protein intake in formula-fed low birth weight infants. Cochrane Database Syst Rev 2006 Jan 25;CD003959. 44. Smolkin T, Diab G, Shohat I, Jubran H, Blazer S, Rozen GS, et al. Standardized versus individualized parenteral nutrition in very low birth weight infants: a comparative study. Neonatology 2010;98:170-8. 45. Collins CT, Chua MC, Rajadurai VS, McPhee AJ, Miller LN, Gibson RA, et al. Higher protein and energy intake is associated with increased weight gain in pre-term infants. J Paediatr Child Health 2010;46:96-102. 46. Stephens BE, Walden RV, Gargus RA, Tucker R, McKinley L, Mance M, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics 2009;123:1337-43. 47. Ehrenkranz RA. Early nutritional support and outcomes in ELBW infants. Early Hum Dev 2010;86(Suppl 1):21-5. 48. Ziegler EE, Carlson SJ. Early nutrition of very low birth weight infants. J Matern Fetal Neonatal Med 2009;22:191-7. 49. Poindexter BB, Langer JC, Dusick AM, Ehrenkranz RA, National Institute of Child Health and Human Development Neonatal Research Network. Early provision of parenteral amino acids in extremely low birth
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weight infants: relation to growth and neurodevelopmental outcome. J Pediatr 2006;148:300-5. Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Higgins RD, Langer JC, et al. Persistent benecial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics 2007;120:e953-9. Arslanoglu S, Moro GE, Ziegler EE, The Wapm Working Group On Nutrition. Optimization of human milk fortication for preterm infants: new concepts and recommendations. J Perinat Med 2010;38:233-8. Polberger S. New approaches to optimizing early diets. Nestle Nutr Workshop Ser Pediatr Program 2009;63:195-204. de Halleux V, Close A, Stalport S, Studzinski F, Habibi F, Rigo J. Advantages of individualized fortication of human milk for preterm infants [in French]. Arch Pediatr 2007;14(Suppl 1):S5-10. Reali A, Greco F, Fanaro S, Atzei A, Puddu M, Moi M, et al. Fortication of maternal milk for very low birth weight (VLBW) pre-term neonates. Early Hum Dev 2010;86(Suppl 1):33-6. Senterre T, Rigo J. Optimizing early nutritional support based on recent recommendations in VLBW infants and postnatal growth restriction. J Pediatr Gastroenterol Nutr 2011;53:536-42. Cooke RJ, McCormick K, Grifn IJ, Embleton N, Faulkner K, Wells JC, et al. Feeding preterm infants after hospital discharge: effect of diet on body composition. Pediatr Res 1999;46:461-4. Health Canada. Exclusive Breastfeeding Duration - 2004 Health Canada Recommendation. 2004. AAP, Committee on Nutrition. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. Agostoni C, Decsi T, Fewtrell M, Goulet O, Kolacek S, Koletzko B, et al. Complementary feeding: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2008;46:99-110. Gartner LM, Morton J, Lawrence RA, Naylor AJ, OHare D, Schanler RJ, et al. Breastfeeding and the use of human milk. Pediatrics 2005;115:496-506. Kramer MS, Aboud F, Mironova E, Vanilovich I, Platt RW, Matush L, et al. Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psychiatry 2008;65:578-84. Morales Y, Schanler RJ. Human milk and clinical outcomes in VLBW infants: how compelling is the evidence of benet? Semin Perinatol 2007; 31:83-8. Callen J, Pinelli J. A review of the literature examining the benets and challenges, incidence and duration, and barriers to breastfeeding in preterm infants. Adv Neonatal Care 2005;5:72-88. Aggett PJ, Agostoni C, Axelsson I, De Curtis M, Goulet O, Hernell O, et al. Feeding preterm infants after hospital discharge: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2006;42:596-603. Lapillonne A, Salle BL, Glorieux FH, Claris O. Bone mineralization and growth are enhanced in preterm infants fed an isocaloric, nutrientenriched preterm formula through term. Am J Clin Nutr 2004;80: 1595-603. Henderson G, Fahey T, McGuire W. Nutrient-enriched formula milk versus human breast milk for preterm infants following hospital discharge. Cochrane Database of Systematic Reviews 2007 Oct 17;CD004862. Picaud JC, Decullier E, Plan O, Pidoux O, Bin-Dorel S, van Egroo LD, et al. Growth and bone mineralization in preterm infants fed preterm formula or standard term formula after discharge. J Pediatr 2008;153: 616-21. 21.e1-2. Amesz EM, Schaafsma A, Cranendonk A, Lafeber HN. Optimal growth and lower fat mass in preterm infants fed a protein-enriched postdischarge formula. J Pediatr Gastroenterol Nutr 2010;50:200-7. Cooke RJ, Grifn IJ, McCormick K. Adiposity is not altered in preterm infants fed with a nutrient-enriched formula after hospital discharge. Pediatr Res 2010;67:660-4. OConnor DL, Khan S, Weishuhn K, Vaughan J, Jefferies A, Campbell DM, et al. Growth and nutrient intakes of human milk-fed preterm infants provided with extra energy and nutrients after hospital discharge. Pediatrics 2008;121:766-76. S99
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79. Delvin EE, Salle BL, Claris O, Putet G, Hascoet JM, Desnoulez L, et al. Oral vitamin A, E and D supplementation of pre-term newborns either breast-fed or formula-fed: a 3-month longitudinal study. J Pediatr Gastroenterol Nutr 2005;40:43-7. 80. Delvin EE, Salle BL, Reygrobellet B, Mellier G, Claris O. Vitamin A and E supplementation in breast-fed newborns. J Pediatr Gastroenterol Nutr 2000;31:562-5. 81. Canadian Paediatric Society. Promoting optimal monitoring of child growth in Canada: using the new World Health Organization growth chartsExecutive Summary. Paediatr Child Health 2010;15:77-83. 82. Bhatia J. Growth curves: how to best measure growth of the preterm infant. J Pediatr 2013;162:SXXX-XXX. 83. Lapillonne A, Grifn IJ. Feeding preterm infants today for later metabolic and cardiovascular outcomes. J Pediatr 2013;162:SXXX-XXX. 84. Fenton TR. A new growth chart for preterm babies: Babson and Bendas chart updated with recent data and a new format. BMC Pediatr 2003;3:13. 85. Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS. New intrauterine growth curves based on United States data. Pediatrics 2010; 125:e214-24. 86. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight, and age. Acta Paediatr Suppl 2006;450:76-85.
71. Aimone A, Rovet J, Ward W, Jefferies A, Campbell DM, Asztalos E, et al. Growth and body composition of human milk-fed premature infants provided with extra energy and nutrients early after hospital discharge: 1-year follow-up. J Pediatr Gastroenterol Nutr 2009;49:456-66. 72. Zachariassen G, Faerk J, Grytter C, Esberg BH, Hjelmborg J, Mortensen S, et al. Nutrient enrichment of mothers milk and growth of very preterm infants after hospital discharge. Pediatrics 2011;127:e995-1003. 73. Cooke RJ, Embleton ND, Grifn IJ, Wells JC, McCormick KP. Feeding preterm infants after hospital discharge: growth and development at 18 months of age. Pediatr Res 2001;49:719-22. 74. Lapillonne AA, Glorieux FH, Salle BL, Braillon PM, Chambon M, Rigo J, et al. Mineral balance and whole body bone mineral content in very lowbirth-weight infants. Acta Paediatr 1994;405:117-22. 75. Rigo J, Senterre J. Nutritional needs of premature infants: current issues. J Pediatr 2006;149:S80-8. 76. Fewtrell MS, Cole TJ, Bishop NJ, Lucas A. Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease? J Pediatr 2000;137:668-73. 77. Baker RD, Greer FR. Diagnosis and prevention of iron deciency and iron-deciency anemia in infants and young children (0-3 years of age). Pediatrics 2010;126:1040-50. 78. Peeples JM, Carlson SE, Werkman SH, Cooke RJ. Vitamin A status of preterm infants during infancy. Am J Clin Nutr 1991;53:1455-9.
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Josef Neu, MD1, Cristine L. Bradley, MSc, RD2, Zong-Yi Ding, MD3, Hugh N. Tucker, PhD, FACN, CNS4, and Carol Lynn Berseth, MD5
Designing an optimal feeding program for preterm infants is particularly challenging. These infants require individualized feeding plans and frequent medical interventions, and their health status and physical limitations necessitate specialized products. This review highlights the challenges of translating new understandings into practical application and, specically, the challenges of translating scientic knowledge into available nutritional products that can be used to meet the special needs of preterm infants. All infant formula products are developed for use in a heavily regulated environment, which is not integrated internationally. The regulatory framework for preterm nutrition products can be particularly complex in the areas of composition and the degree of scientic and clinical support required across countries. Registration and approval of products for preterm infants in most countries must address the complexities for a population for which no well-recognized nonclinical safety or efcacy models exist. Mandatory regulatory review for science-based innovative product improvements may require two or more years. In addition, throughout years of development, industry must justify the nancial support of programs that serve a small specialty segment of the market. These industry-specic challenges may be neither visible nor appreciated by the general public or health care professionals, and, yet, they are integral to the development process. Effective collaborations among academic scientists, regulatory authorities, and the industry are essential to bring science to the bedside. Without such collaborations, preterm infants, and particularly very low birth weight infants, in the neonatal intensive care unit will not be able to benet from innovative nutrition interventions designed to improve short- and long-term clinical outcomes. (J Pediatr 2013;162:S101-6). he preceding articles present a comprehensive view of the challenges clinicians face when making decisions about providing optimal nutritional support to the heterogeneous population of patients described as preterm or low-birth-weight infants. These infants require individualized feeding plans and frequent medical intervention, and their health status and physical limitations necessitate the creation of specialized products. Several phases are involved in developing new products during which clinicians, academics, industry, and regulatory agencies play key roles. The process begins with the emergence of product concepts that stem from clinicians who identify unmet needs in their patients and basic scientists who make novel discoveries. Next, basic and translational scientists in academics and industry consider various concepts and test novel hypotheses in the context of current knowledge to dene which of many possible concepts is the most reasonable to pursue. Considerable research is required to create the scientic rationale required to build broad consensus. Additional work is required to meet regulatory requirements and provide evidence of product safety and efcacy. Regulatory agencies oversee the new product development process to protect patient safety. Thus, bringing a product to the bedside requires years of close interplay among academics, industry, and regulatory bodies, and many challenges arise during the process. Our goal is to improve understanding of the process involved in developing innovative products in an effort to speed the delivery of new discoveries to the bedside.
Product Conception
The preceding articles make it abundantly clear that there is no lack of ideas for new products to serve the preterm infant population. For every current need that is met by available human milk fortiers or formulas, clinicians identify 3 or 4 unmet needs that evolve continually from the diverse and burgeoning preterm infant population. The investigators who participated in the Global Neonatal Consensus Symposium identied more than a dozen unmet needs during 3 days of discussions.
ARA DHA FDA NICU NIH VLBW Arachidonic acid Docosahexaenoic acid Food and Drug Administration Neonatal intensive care unit National Institutes of Health Very low birth weight
From the 1Department of Pediatrics, University of Florida, Gainesville, FL; 2Regulatory Sciences, Mead Johnson Nutrition, Evansville, IN; 3The 1st August Childrens Hospital, Afliated to The General Hospital of Beijing Military Defense Area, PLA, Beijing, China; 4Mead Johnson Nutrition, Evansville, IN; and 5Medical Affairs, Mead Johnson Nutrition, Evansville, IN Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 research but mostly from industry-sponsored research. Support for patient-oriented studies is needed to provide regulatory agencies the necessary substantiation that demonstrates the safety and efcacy of new products. Interactions between Academics and Industry Overall, academics and industry have a longstanding collaborative relationship that has successfully brought innovative ideas to patient care. However, the relationship between these two sectors has been uneasy at times. Concerns about potential conicts of interest have led to the creation of university and corporate policies that dene their interactions. Awareness of these concerns stems from certain sales activities and publication practices of some pharmaceutical companies. First, pharmaceutical sale practices are geared toward inuencing physician drug recognition so that their drug is the rst one that comes to mind when prescriptions are written. Small gifts and free lunches have been shown to inuence prescribing practices. Second, some companies have supported the conduct and publication of research that selectively favors new products, including those in which an author has a nancial stake. Hence, conict of interest policies have been developed to regulate product promotions, dene what industry can provide to academicians and clinicians, and protect patients from promotional activities that could have detrimental effects on the quality of their care. In the US, legislation has been proposed that would establish government regulation of the vendorhealth care provider relationship. The National Institutes of Health (NIH)-supported Clinical Trials site (clinicaltrials.gov) is a clearinghouse of information in which journal editors and others can determine the source of support and potential for conict of interest for clinical investigators. Although the intent of these regulations is focused on marketing activities, there is a risk that stringent regulations could limit the industry from providing direct or indirect
It is not possible to create a new product for every unmet need. Ideas for new products arise organically from astute clinicians, basic researchers, and industry scientists. Once a concept emerges, it can take years before it is developed into a product ready for market. For example, it has been known since 1980 that the long-chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and arachidonic acid (ARA) accumulate in the fetal brain during the third trimester.1 It has been appreciated for almost 40 years that DHA is the primary fatty acid in membranes of the rods of the retina and that n-3 polyunsaturated fatty acids are essential for normal visual development in rodents,2 but it was not until 1987 that the relationship between DHA and visual development of premature infants was rst investigated3 and 2002 that a formula containing DHA and ARA was made available in the US.
Product Denition
A product becomes dened and rened through the coordinated efforts of basic and clinical academic research and applied industry research. The key element of this phase is the accumulation of a critical mass of knowledge that indicates the potential for a unique and specic clinical application. It is not uncommon for it to take 5 or more years before broad concurrence develops among academic and clinical scientists. This sound knowledge base is required before a period of more rapid accumulation of evidence can occur. Figure 1 illustrates the long development cycle required to create nutritional products. For example, to gain consensus that formulas or human milk did not meet the nutritional needs for DHA and ARA of infants in some regions required the collection of substantial long-term data regarding the minimum daily dietary intake of these fatty acids. Research support during the denition phase of product development derives partially from public funding of basic
web 4C=FPO Figure 1. Building consensus. The early accumulation of knowledge is not linear and accelerates only after the basic research phase has evolved. The decision to move forward with required product development tasks must start several years before general awareness and acceptance.
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March 2013 support to academic institutions for research activities. Some consideration should be given to the potential impact on the ability of academia and industry to collaborate in a collegial manner. Continued success is dependent, in part, upon the development of a regulatory environment that does not hinder progress. The growing drive to protect intellectual property poses additional new challenges. Many interactions between university and industry are now subject to formal, contractual exchanges dened by codied rules and regulations. The recent emergence of University Technology Transfer Ofces and the increasing attempts of universities to capture intellectual property formally have had a profound impact on industryacademia collaborations, often thwarting the open collaboration that is the basis of scientic endeavors and strangling the very activities that they hope to prot from. Some academic institutions now view patenting and the creation of new commercial focus as a source of nancial gain. Universities that create too many barriers to collaboration may cause the industry to avoid interacting with their faculty and, thus, delay the application of new knowledge. Academia and the industry often have different, but important, complementary goals. Academics often conduct basic research that may not have an immediate clinical application, and the industry focuses on the practical application of a commercial product. Academic research is based primarily on the impact it will have on the global research community, and academic advancement often is based on success in procurement of NIH funding rather than industry support. Academic research often is focused on identifying and elucidating the mechanisms involved in a biological or disease process, and the industry is focused on translating that understanding into products that benet patients. Thus, both parties provide valuable efforts to the translating of science to the bedside. Bridging these apparently disparate goals of academia and industry often presents a challenge that requires a great deal of solid support. The NIH has supported these types of interactions through their Small Business Innovation Research grant mechanism. However, these grants are limited to small companies. More efforts are necessary to create a broader working relationship and improved mutual understanding.
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quent industrial development of specic products that embody these innovations require many years to complete. When products specically for preterm infants are considered, the challenge becomes even greater because only a small segment of patients are available for the important and required clinical studies. Regulations Governing the Infant Formula Industry Government authorities establish regulations to ensure foods are safe and nutritionally adequate. Regulations governing infant formula, and preterm infant nutrition products in particular, are even more strict because of the specic medical and nutritional needs of preterm infants. Because specialized infant formula is the only source of nutrition for many preterm infants, rigorous safeguards have been established for these products. Codex Alimentarius, the US Food and Drug Administration (FDA), the European Commission, Food Standards Australia New Zealand, and others have established regulatory provisions to assess preterm infant formulas. However, some countries still lack a regulatory framework for foods and formulas for this patient population, which may create a barrier to the healthy development of infants born prematurely in those regions. Where integrated regulatory frameworks for preterm nutrition products exist, specic approaches to product composition and scientic substantiation are provided. Composition The general approach of competent authorities is to recognize that the design of products created to meet the particular nutritional needs of preterm infants differs from the compositional provisions for infant formulas designed for healthy term infants. Most regulatory authorities have distinguished the unique requirements for preterm formulas by creating a regulation for infants with special needs, referred to as formula for special medical purposes or exempt infant formula, a term unique to the US. These regulations require that the nutrient composition of the formula be adapted to meet specic nutritional needs of the target infant population. As such, preterm infant nutrition products can be different from normal (term-born) infant formulas if there is sufcient scientic evidence to support healthy development of preterm infants. Except those for China, virtually all global regulations are absent of an explicit required range (minimum/maximum) for nutrients in preterm formula. Across all major regulatory bodies, regulations have incorporated the requirement for scientic substantiation to dene the appropriate composition of preterm formula. The Table provides a summary of the general regulatory approach for preterm infant nutrition products, applicable to formula and human milk fortiers. Scientic Substantiation Preterm infant nutrition products have evolved since their rst commercial introduction in the early 1980s. The accumulation of new knowledge drives continual revision of nutritional guidelines. Hence, there are now several sets of
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Product Testing
Once a product is dened, considerable research and testing is required to satisfy regulatory requirements before a product gains approval for market. Because of the unique preclinical, clinical, and regulatory requirements of products designed for premature infants, many years of research and large funding commitments are required to get a product ready for market approval and commercial launch. Even as the need for a scientic nutritional intervention begins to be acknowledged by experts, industry may be expected to have new, alternative interventions commercially available as soon as possible. This product demand may emerge well before the development of adequate scientic consensus, and subse-
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Vol. 162, No. 3, Suppl. 1 example, a research and development program for a new addition to the infant formula product category requires toxicology and safety studies, nonclinical modeling, clinical studies, and regulatory submissions. The ability to change the order of these steps or to shorten the time needed to accomplish each step is quite limited. Once the decision to develop a specic product is made, there is an obligatory time requirement of ve to seven years prior to commercial realization and clinical availability. Even product improvements that appear to be simple modications of a current neonatal intensive care unit (NICU) nutrition intervention may take several years to become available in this heavily regulated environment (Figure 2). Because the timeline required to conduct additional research and fulll regulatory requirements is long, industry must begin developing a new product several years ahead of the learning curve to be perceived as responsive to the needs of health care professionals and consumers. If product development has not begun well before an unmet need is identied, the clinical innovation will lag far behind the time that demand for a product is at its height. This disparity between the time required to meet all of the requisite development milestones and the desire to have immediate clinical improvements produces a perception that the industry is unresponsive or slow to meet clinical needs. On the opposite end of the timeline spectrum, there is risk for the industry to create a product before the development of scientic consensus around the need for that product. If the product becomes available before consensus has developed, industry may be viewed as promoting unnecessary innovations solely for commercial gain. Because there is little way to predict the speed of the knowledge accumulation process or shorten the development timeline, industry and its academic partners must become adept at anticipating unmet clinical needs and understanding the realistic time requirements for general acceptance. Product decisions must be made with less than an ideal amount of information, and industry must assume the risk that scientic consensus may evolve differently as more data are generated. Fostering an atmosphere of early collaboration and trust among industry, clinicians, and regulators will facilitate more rapid consensus on possible directions for therapeutic improvement, relative priority, and nutrition interventions that will ultimately be of greatest benet. Complexity of Establishing Nonclinical Safety and Suitability The resource-intensive toxicology and nonclinical modeling studies needed to meet early development safety requirements are sometimes invisible to academic scientists and clinical practitioners. A critical rst step in product development is to demonstrate the safety of the new intervention. There are few models, if any, that can be relied upon routinely to simulate the response of VLBW humans in the NICU. This lack of nonhuman models relevant to the VLBW infant creates a void that is not found in other clinical populations.
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Table. General approach to regulation of preterm infant nutrition products

Principles Globally, very few national regulations include specic compositional provisions (regulated minimum/maximum nutrient ranges) for preterm infant formulas and human milk fortiers. Major regulatory authorities apply principles of Formulas for Special Medical Purposes (FSMP) for infants, or exempt infant formula. FSMP formulas for infants are intended for use only under medical supervision and advertising to the general public is prohibited. FSMP products designed for preterm infants may deviate from the normal (term) infant formula compositional standard to meet the unique nutritional needs of the preterm patient population. Sound medical and nutritional principles are required to justify such compositional deviations from normal infant formula and to support nutritional safety and adequacy of the formula. Expert recommendations for feeding preterm infants such as those elaborated by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; Life Sciences Research Organization; American Academy of Pediatrics; and Tsang et al [6] are the strongest form of widely accepted scientic substantiation. Most regulatory bodies have no explicit regulatory requirements for the clinical testing of formula for preterm infants; however, it is well recognized that clinical studies are essential to ensure the safety of these products.
widely recognized expert recommendations for preterm infant nutrition on the basis of reviews of available scientic reports or on expert consensus. The European Society for Pediatric Gastroenterology Hepatology and Nutrition (2010), the American Academy of Pediatrics (2009), Life Sciences Research Ofce of the American Society for Nutritional Sciences (2002), Tsang et al in 2005 and other expert groups, including the current meeting of international experts, have all proposed that nutrient requirements for preterm infants differ from those of term infants.4-6 These recommendations provide the most recent knowledge on neonatal nutrition and are used by regulatory authorities as a preferred source of scientic substantiation for appropriate deviations from the composition of normal (term born) infant formula. Industry Challenges Challenges arise between industry and its regulators, who may be more accustomed to the product development path typically followed by pharmaceutical companies, which is neither optimal nor appropriate for nutritional interventions aimed at preterm and very low birth weight (VLBW) infants. The mandatory sequence of milestones needed to meet regulatory requirements and long lead times associated with bringing infant products to market can lead to the perception that industry is not responsive. The continual emergence of new concepts makes it risky for industry to invest in development of new products before the emergence of genuine scientic consensus that a particular product is most likely to improve clinically relevant outcomes. Industrys Challenge of Meeting Regulatory Requirements After a specic nutritional intervention has been dened, several additional steps remain on the development timeline. For
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web 4C=FPO Figure 2. Product denition and testing. The challenge for industry, health care professionals, and regulators is to satisfy the risk-avoidance environment in an emotional and politically sensitive population. In addition, clinical investigations must be completed well before the accumulation of knowledge curve has crossed the line to general awareness and agreement. GRAS, Generally Regarded as Safe.
The timeline for development for any new or novel nutrient for the infant formula category must account for the requirement of a formal notication of safety based on information considered available to the general public. The notication to the US FDA that an ingredient is Generally Regarded as Safe requires that all data in the submission have been published in peer-reviewed journals that have been available to the public for at least six months. This portion of the development timeline is dependent on manuscript acceptance and publication, data review by an assembled third-party expert panel, and, nally, review by the US FDA Ofce of Food Additive Safety. This publication and review process can last 2 years or longer after data are available to health care professionals. Once the decision is made to go forward with nonclinical evaluations of a nutrient or nutrition intervention, the development path and resulting product are largely determined and unchangeable. It is understandable that new scientic discoveries can justify a change to a product in development. The impact of such a change must be evaluated carefully relative to the work done and resources invested to date. Although scientic debate and challenge are healthy to advance knowledge, there comes a time in the development pathway that further unproductive debate is not in the best interest of public health. Continuing debate and scientic challenge become problematic for regulators who must make risk-benet decisions regarding patient care. Clinical Trial Conduct Conducting clinical trials in the VLBW NICU patient population presents substantial challenges. These patients have high morbidity and mortality, which can complicate the interpretation of suitability data and understanding of adverse events in a clinical trial setting. Frequently, clinical practice for these special patients is not consistent across units or
even within subsegments of infants in the NICU. This inconsistency in patient management makes it difcult to develop clinical trial protocols intended to mimic standard of care and increases the requirement for large numbers of study subjects to account for variability. It is not uncommon for a clinical trial to require two years to complete. Most regulatory bodies have no explicit regulatory requirements for clinical testing of preterm infant formula; however, it is recognized that clinical studies are essential to ensure the safety of these products. Return on Investment There may be a perception that for-prot companies reap large nancial benets from the research, development, and commercialization of nutrition products for the NICU. This perception is unfounded, however, because of the very small market segment and volume of product usage compared with the large expense of development. Anticipated future revenues from specialized nutritional products cannot be expected to support the investment required to accomplish all of the required development tasks. Company business managers must balance reporting requirements for corporate expenses with duciary responsibilities to the company shareholders. Those companies that continue to invest in nutrition research and development to benet patients in the NICU environment do so primarily from a desire to provide philanthropic contributions to the eld of clinical nutrition rather than to generate prots.
Recommendations
The Global Neonatal Consensus Symposium has dened nutrient requirements for VLBW premature infants as they progress through their clinical course and has recommended adjustments in nutrient intake to meet their changing
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Vol. 162, No. 3, Suppl. 1 MSc, RD, and Hugh N. Tucker, PhD, FACN, CNS, are employees of Mead Johnson & Company. Carol Lynn Berseth, MD, is the Medical Director for Global Innovation at Mead Johnson Nutrition. She organized and facilitated the Symposium on Nutrition of the Preterm Infant. All authors received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. All authors wrote portions of the rst draft and reviewed the nal version of this manuscript.
Reprint requests: Dr. Carol Lynn Berseth, MD, Mead Johnson Nurtitionals, GR&D, 2500 Lloyd Expressway, Evansville, IN 47721-001. E-mail: carol.berseth@mjn.com.
nutritional needs. The preterm infant population comprises a number of subgroups that require different amounts and proportions of nutrients, and it is a challenge to meet their unique and varied needs. Academicians, clinical specialists, industry scientists, and regulators who create and deliver innovative products to this population have common goals and much common ground. To better meet the needs of this diverse patient population, they must leverage opportunities to develop a collaborative approach. The best possible innovation must be identied quickly and accepted broadly; regulations must not be so cumbersome that they interfere with healthy scientic discovery and debate nor should they unnecessarily prolong the approval process. To assist in this process, it is incumbent upon academic and industry scientists to continue to rene guidelines that address the needs of the evolving and burgeoning preterm infant patient population. These activities must be conducted on a global scale to effectively bring new innovations quickly and safely to the bedside. Since the time the Global Neonatal Consensus Symposium took place, China published new regulations applicable to preterm infant formula products (GB 25596-2010). The regulations specify a permitted range for nutrients essential in the composition of preterm formulas. This unique regulatory approach for formula for special medical purposes for infants may offer challenges to the implementation of new scientic ndings that may expand the nutrient targets for preterm infant nutrition. n
References
1. Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW. Intrauterine fatty acid accretion rates in human brain: implications for fatty acid requirements. Early Human Development, 1980 acid requirements. Early Human Development 1980;4:121-9. 2. Belkonen RM, Anderson RE, Wheeler TG. Membrane fatty acids associated with the electrical response in visual excitation. Science 1973;182: 1253-4. 3. Uauy RD, Birch DG, Birch EE, Tyson JE, Hoffman DR. Effect of dietary omega-3 fatty acids on retinal function of very-low-birth-weight neonates. Pediatr Res 1990;28:485-92. 4. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85-91. 5. American Academy of Pediatrics, Committee on Nutrition. Pediatric nutrition handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. 6. Tsang RC, Uauy R, Koletzko B, Zlotkin S. Nutrition of the preterm infant. Scientic basic and practical guidelines. Cincinnati, OH: Digital Educational Publishing Inc.; 2005.
Author Disclosures
Josef Neu, MD, has received a research grant and honoraria for speaking from Mead Johnson Nutrition and is currently on its Scientic Advisory Committee. Cristine L. Bradley,
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Nutritional Management of the Low Birth Weight/Preterm Infant in Community Settings: A Perspective from the Developing World
Aamer Imdad, MBBS and Zulqar A. Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD
Globally, about 20 million infants are born with low birth weight (LBW; <2500 g). Of all LBW infants, approximately 95% are born in developing countries. The greatest incidence of LBW occurs in South-Central Asia; the second greatest is in Africa. The two main reasons for LBW are preterm birth (<37 weeks) and intrauterine growth restriction (IUGR), which are risk factors for increased morbidity and mortality in newborn infants. Maternal nutrition status is one of the most important risk factors for LBW/IUGR. Providing balanced protein energy and multiple micronutrient supplements to pregnant women will reduce incidence of IUGR. Calcium supplementation during pregnancy will reduce the incidence of pre-eclampsia and preterm birth in developing countries. Exclusive breastfeeding is protective for a mother and her infant and has been shown to reduce morbidity and mortality in infancy. Kangaroo mother care for preterm infants will reduce severe morbidity and mortality as well. Community-based intervention packages are among the most effective methods of reducing morbidity and mortality in mothers and children. Future research should focus on improving triage of preterm and IUGR infants. Exclusive breastfeeding should be promoted, and appropriate alternative food supplements should be provided when breastfeeding is not possible. (J Pediatr 2013;162:S107-14). uring the past decade, child mortality before the age of 5 years has decreased markedly. The child death rate was 10.6 million/year in 2000-2003; it decreased to 8.8 million in 2008.1,2 A reduction in mortality among children 1 to 59 months of age accounts for most of this decline. This may be because child-survival programs have focused primarily on important causes of death after the rst 4 weeks of life (ie, pneumonia, diarrhea, malaria, and vaccine-preventable disorders).3 At the same time, little progress has been made in reducing neonatal mortality.4 Neonatal deaths now account for 41% of deaths compared with 37% from 2000 to 2003.1,2 To achieve the Millennium Development Goal 4 to reduce child mortality by two-thirds by 2015, it is important to reduce neonatal deaths.3 Low birth weight (LBW) increases morbidity and mortality in neonates and is a common feature in most neonatal deaths.3,5,6 LBW may result from preterm birth, intrauterine growth restriction (IUGR), or both.7 Preterm infants are 7 to 13 times more likely to die during the neonatal period than full-term infants.8-10 Infants who are preterm with IUGR have an even greater risk of death.11 A term LBW infant is likely to have growth failure and an increased risk of morbidity and mortality in infancy.12 It has been estimated that the risk for neonatal death is 2.8 or 8 times greater for term infants who weigh 1500 to 1999 g at birth than for infants who weigh 2000 to 2499 g or 2500 to 2999 g, respectively.13 LBW infants who survive are likely to remain small and more likely to experience developmental decits than normal-term infants.14 Adults who had LBWs have a greater incidence of chronic diseases such as type 2 diabetes, hypertension, and other cardiovascular disease.14,15 According to the United Nations Childrens Fund (UNICEF), an estimated 15.5% (>20 million infants) of all births were LBW (<2500 g) worldwide in the year 2000.5 The prevalence of LBW infants in developing countries (16.5%) is more than double than in developed countries (7%). The vast majority (95%) of LBW infants are born in developing countries, with the greatest incidence in South-Central Asia (27%) followed by Africa, where incidence ranges from 13% to 15%, with little variation across the region as a whole. Overall, 70% all LBW births occur in Asia.5 The causes of LBW are different in developing and developed countries.16 Preterm birth is major cause of LBW in developed countries, whereas most LBW newborns are born at term but small for gestational age (SGA) in developing nations.17 SGA infants are dened as infants whose weight is below the 10th percentile or 2 SD below the mean in growth charts for their estimated gestational age.18 Accurate assessment of gestational age is required to screen SGA infants. Because it is relatively difcult to get accurate gestational age estimates, birth weight is the most commonly used variable used to compare different populations.16 Infants born with LBW at term have IUGR, whereas the subcategory very LBW comprises mainly preterm
BMI IUGR LBW MgSO4 RR SGA UNICEF
Body mass index Intrauterine growth restriction Low birth weight Magnesium sulfate Relative risk Small for gestational age United Nations Childrens Fund
From the Division of Women & Child Health, The Aga Khan University, Karachi, Pakistan Please see the Author Disclosures at the end of this article.
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Vol. 162, No. 3, Suppl. 1 der inequality, inadequate educational opportunities, malnutrition, marriage and conception at a young age, short birth intervals, and undesirably large families. Figure 2 helps us to understand the cycle of malnutrition that runs among LBW, childhood/adolescent stunting, and maternal undernutrition and how repeated pregnancies with inadequate recovery between pregnancies can lead to maternal depletion syndrome.21 Maternal undernutrition is widespread in low and middleincome countries, especially in South-Central Asia where more than 10% of women 15 to 49 years old are <145 cm tall and show evidence of maternal wasting (BMI <18.5) in most countries.13 A serious problem of maternal undernutrition (more than 20% of women with BMI <18.5) is evident in most countries in sub-Saharan Africa, South-Central/SouthEastern Asia. Yemen, India, Bangladesh, and Eritrea have a critical problem because BMI is low in about 40% of all women.13 Low prepregnancy weight and BMI are important risk factors for LBW.13,22 A recent meta-analysis of 78 studies that included 1 025 794 women has shown that maternal underweight is associated with an overall increased risk of preterm birth by 29% (relative risk [RR] 1.29; 95% CI 1.15-1.46) and that of LBW by 64% (RR 1.64; 95% CI 1.38-1.94).23 A subgroup analysis showed that underweight women have an increased risk of preterm birth in developing countries (RR 1.22; 95% CI 1.15-1.30) but not in developed countries (RR 0.99; 95% CI 0.67-1.45). In both developed and developing countries, underweight women are at increased risk of LBW births (RR 1.48; 95% CI 1.29-1.68 and RR 1.52; 95% CI 1.25-1.85, respectively). In addition to maternal nutrition status, increased physical activity performed by women, such as farming or gathering water, is reported to be associated with lower birth weights and smaller head and mid-arm circumferences in infants.24 Malaria during pregnancy is associated with LBW,16 and malaria chemoprophylaxis increases maternal hemoglobin levels and infant birth weights.25 In addition, women in
infants. Indeed, these 2 categories overlap because some preterm infants exhibit features of IUGR and other newborn infants with evidence of IUGR may weigh more than 2500 g at birth, and, thus, are not considered LBW.16 In developing countries, it is difcult to assess and evaluate LBW infants and monitor rates of neonatal mortality because data are incomplete. It is estimated that 58% of newborn infants are not even weighed at birth in developing countries.5 The incidence is greatest in south Asia and sub-Saharan Africa, where 74% and 65% of births are not weighed, respectively.5 We reviewed the evidence base for strategies designed to manage LBW/preterm infants in community settings in the developing world to make specic recommendations for action. We searched PubMed, Cochrane Library, World Health Organization/UNICEF data bases and guidelines by using a combination of terms for low birth weight, community, nutrition, etc, and synthesized up-to-date evidence on nutritional management of LBW infants in the community.
Etiology of LBW
The causes of fetal growth restriction and prematurity in developing countries are well known.16,19 Some of the most important maternal risk factors include: low prepregnancy weight or body mass index (BMI); inadequate energy intake and gestational weight gain; cigarette smoking; and specic complications of pregnancy, such as genital tract infections, pregnancy-induced hypertension, and incompetent cervix.3,16,19 Fetuses with certain genetic or chromosomal disorders are also at greater risk for IUGR.20 The Table summarizes the main known risk factors in the pathogenesis of LBW/IUGR.16,19 Figure 1 describes the interaction of social, economic, and behavioral factors that can result in LBW/IUGR.16 The nutritional status of a woman before and during pregnancy is important for a healthy pregnancy outcome. Pregnancy is just one stage of a womans life, and women living in a developing country become pregnant in a context of gen-
Table. Selected risk factors for LBW

Prepregnancy Low weight for height Short stature Chronic medical illness Poor nutrition Low maternal weight at mothers birth Previous infant of LBW Uterine or cervical anomalies Parity (none or more than 5) Pregnancy Multiple gestation Birth order Anemia Elevated hemoglobin concentration Fetal disease Pre-eclampsia and hypertension Infections Placental problems Premature rupture of membranes Heavy physical work Altitude Renal disease Assisted reproductive technology Exposure to indoor air pollution Maternal psycho-social stress Mental health Social and environmental Low socioeconomic status Low educational status Smoking No care or inadequate prenatal care Poor gestational weight gain Alcohol abuse Illicit and prescription drugs Short interpregnancy intervals (<6 months) Age (<16 or >35 years) Unmarried Stress (physical and psychological)
Data derived from Qadir and Bhutta16 and Valero De Bernabe et al.19
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Figure 1. Factors associated with LBW. Figure used with permission from Qadir A et al.16
developing countries may suffer from chronic and communicable diseases, which further aggravate their already poor nutritional status. Certain social factors like drug abuse, poor nutritional habits, and cigarette smoking are interrelated and covary with poor socioeconomic status.16 Some of the other key risk factors associated with LBW are indoor air pollution, environmental tobacco smoke, and maternal mental health.16,25,26
intervals of 18-23 months (OR 1.40; 95% CI 1.24-1.58), LBW (OR 1.61; 95% CI 1.39-1.86), and SGA (OR 1.26; 95% CI 1.18-1.33). A retrospective study of 45 000 women has shown that the women who use family planning services are less likely to deliver a LBW infant than those who do not.34 Maternal Nutrition Interventions Low folate levels are associated with LBW, preterm birth, and IUGR.35-39 Folic acid supplementation around the time of conception reduces the incidence of neural tube defects and other congenital anomalies.40,41 Folate supplementation reduces the incidence of preterm birth and LBW.35,42,43 Most of this evidence is based on observational and nonrandomized studies; any recommendation for providing folate supplements to preterm and/or LBW infants should be made after the intervention has been tested in randomized trials. Balanced protein energy supplementation is considered one of the most promising macronutrient interventions for the prevention of adverse perinatal outcomes, including IUGR.44,45 A recent meta-analysis of randomized studies indicate that balanced protein energy supplementation in pregnancy is associated with a 31% reduction in the risk of giving birth to an SGA infant (RR 0.69; 95% CI 0.56-0.85).46 It also increases mean birth weight (mean difference, +59 g; 95% CI 33-86). This effect is more pronounced in malnourished women than adequately nourished women. The authors of a Cochrane review of balanced protein energy supplementation has also concluded showed that risk of stillbirth was significantly reduced for women given balanced energy and protein
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Interventions to Prevent LBW

Prevention and management of LBW in the community requires a continuum of care and coordination among reproductive health services that provide family planning support, such as antenatal care for pregnant women, skilled attendance and emergency obstetric care during birth, and postnatal care services.6,16 Figure 3 summarizes evidence-based interventions that can help prevent and manage morbidity and mortality in LBW infants. We focus on nutrition interventions that can help to prevent or manage the LBW and/ or preterm infant in the community. Birth Spacing The relationship of adequate birth spacing (>36 months) and neonatal and infant outcomes is well known.27-30 Short birth intervals increase the risk of LBW, preterm birth, neonatal mortality, and stunting.27,31-33 A meta-analysis by Conde-Agudelo et al32 has shown that inter-pregnancy intervals shorter than 6 months are associated with an increased risk of preterm birth compared with interpregnancy
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Figure 2. Nutrition across the life cycle. Figure created by United Nations Administrative Committee on Coordination, SubCommittee on Nutrition and reproduced per United Nations Administrative Committee on Coordination, Sub-Committee on Nutrition policy.21
supplementation (RR 0.62, 95% CI 0.40-0.98), mean birth weight was signicantly increased (mean difference +40.96 g; 95% CI 4.66-77.26).45 There also was a signicant reduction in the risk of SGA (RR 0.79, 95% CI 0.69-0.90). No signicant effect was detected for preterm birth or neonatal death.45 Micronutrient deciency is common in most low- and middle-income countries.13,47,48 Iron deciency is one of the leading micronutrient deciencies among pregnant women in these countries.49 For example, anemia affects 41.8% of all pregnancies globally,50 and iron deciency accounts for half of these cases.51 Intermittent or daily iron or iron-folic acid supplementation during pregnancy increases hemoglobin levels and decreases the incidence of anemia at term.52 Because maternal micronutrient deciencies during pregnancy in developing countries are common, there is interest in administering multiple micronutrients during pregnancy as an alternative to traditional iron-folic acid combinations.53 UNICEF has developed such a formulation called the United Nations Multiple Micronutrient Preparation in close collaboration with the United Nations University and the World Health Organization.48 The authors of a Cochrane review showed that multiple micronutrient supplementation has comparable effects on maternal anemia in the third trimester (RR 1.03; 95% CI 0.87-1.22) and reduces the risk of SGA births by 9% (RR 0.91; 95% CI 0.86-0.96) compared
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with iron-folate supplementation.54 A meta-analysis of 12 randomized, controlled trials has shown that multiple micronutrient supplementation is associated with an increase in mean birth weight (mean difference, 22.4 g; 95% CI 8.336.4 g); a reduction in the prevalence of LBW (OR 0.89; 95% CI 0.81-0.97) and SGA (OR 0.90; 95% CI 0.82-0.99); and an increase in the prevalence of large-for-gestationalage babies (OR 1.13; 95% CI 1.00-1.28).53 Another recent meta-analysis that included 17 trials has shown that multiple micronutrient supplements reduces incidence of SGA by 9% (RR 0.91; 95% CI 0.86-0.96 [xed model]).55 Recently, there has been an increased interest in providing combined macro/micronutrient supplements because deciencies for both exist concurrently. A study from Burkina Faso has shown that supplementation with balanced protein energy and multiple micronutrients increases length at birth more than supplementation with multiple micronutrients alone.56 Future research efforts should focus on validating these results in other parts of the world. Calcium and Magnesium Supplementation during Pregnancy Hypertensive disorders of pregnancy increase maternal morbidity and mortality and are associated with preterm birth and IUGR.57,58 Women with pre-eclampsia are 2.7 times more likely than normotensive women to have infants with
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infants.66 Partially breastfed infants have 3 times the risk of all-cause mortality, and those who do not breastfeed have 14 times the risk of death in the rst 6 months of life compared with those who breastfeed exclusively.13 A study from Ghana has shown that the risk of neonatal death is 4fold greater in children given milk-based uids or solids in addition to breast milk.67 There is increasing risk of neonatal mortality with increasing delay in initiation of breastfeeding from 1 hour to day 7. Late initiation of breastfeeding (after day 1) is associated with a 2.4-fold increase in risk of mortality. Another study from Bangladesh has shown that partial or no breastfeeding is associated with a 2.23-fold greater risk of infant deaths resulting from all causes and 2.40- and 3.94fold greater risk of deaths attributable to acute respiratory infections and diarrhea, respectively, compared with exclusive breastfeeding in the rst few months of life.68 Exclusive breastfeeding is not common in most countries.69,70 Exclusive breastfeeding rates vary from 20% in central and eastern European countries to 44% in South Asia.71 Exclusive breastfeeding for 6 months might be difcult, particularly where maternal malnutrition is common.72 One of the main contributing factors is the lack of assistance to mothers who wish to breastfeed.73 Education and support is, therefore, the cornerstone for the promotion of breastfeeding.74 The Baby Friendly Hospital Initiative and peer counselors are considered the two most effective strategies to promote exclusive breastfeeding, especially when infants are delivered at home.65 Comprehensive and culturally appropriate breastfeeding education provided by counselors (physicians, nurses, midwives, lactation consultants, or peer counselors) in the hospital during the prenatal period and continued support in the mothers home is critical for facilitating breastfeeding among mothers, especially those who have low incomes.75-77 Prenatal and postnatal education is important because the incidence of breastfeeding is affected primarily by prenatal education, whereas prenatal and postpartum management affects the duration and exclusivity of breastfeeding.78,79 The authors of a Cochrane review have evaluated support for the breastfeeding mother and show that all forms of extra support increases the duration of any breastfeeding (RR 0.91; 95% CI 0.86-0.96) and increases likelihood of exclusive breastfeeding compared with any breastfeeding (RR 0.81; 95 % CI 0.74-0.89).80 A review published in the Lancet Undernutrition series shows that individual counseling increases the odds of exclusive breastfeeding substantially during the neonatal period (OR 3.45; 95% CI 2.20-5.42) and at 6 months after delivery (OR 1.93; 95% CI, 1.18-3.15).65 Group counseling is also effective during the neonatal period (OR 3.88; 95% CI 2.09-7.22) and at 6 months after delivery (OR 5.19; 95% CI 1.90-14.15). Mass media campaigns have been shown to increase rates of exclusive breastfeeding. Kangaroo Mother Care Kangaroo mother care is a simple and cost-effective method to promote the health and well-being of preterm infants.81 It
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Figure 3. Proposed nutrition related interventions for prevention and management of LBW/preterm birth in community settings. MMN, maternal multiple micronutrient.
IUGR.57 Calcium supplementation during pregnancy reduces gestational hypertensive disorders and risk of preterm birth. A Cochrane review by Hofmeyr et al59 has shown that calcium supplementation during pregnancy signicantly reduces the incidence of gestational hypertension (RR 0.65; 95 % CI 0.53-0.81), preeclampsia (RR 0.45; 95% CI 0.31-0.65), and preterm birth (RR 0.76; 95% CI 0.60-0.97). Another recent review of studies from developing countries shows similar results for reduction in risk of gestational hypertension (RR 0.55; 95% CI 0.36-0.85), pre-eclampsia (RR 0.41; 95% CI 0.24-0.69), and preterm birth (RR 0.88; 95% CI 0.78-0.99).60 Magnesium sulfate (MgSO4) supplementation effectively prevents eclampsia in women with pre-eclampsia.51 A Cochrane review that included 6 trials for MgSO4 analysis shows that MgSO4 supplementation reduces the risk of pre-eclampsia (RR 0.41; 95% CI 0.290.58) and placental abruption (RR 0.64; 95% CI 0.50-0.83).61 Breastfeeding Breast milk is the natural and ideal rst food for infants, including those born with LBW; it provides many immunologic, psychological, and social, economic, and environmental benets.62-64 Breastfeeding should be initiated within 2448 hours after birth and continued as the sole source of nutrition for the rst 6 months of life.65 Suboptimal breastfeeding is a risk factor for increased morbidity and mortality in
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Vol. 162, No. 3, Suppl. 1 nancy intervals may also reduce maternal depletion and improve birth weight. On the basis of current evidence and the context of nutritional management and thermal care of these infants, early and exclusive breastfeeding is of key importance. Strategies to address maternal antenatal care and promotion of breastfeeding include providing education and support through community support groups and trained health workers. Outreach services provided by lay health workers and community structures offer the best platform for promoting contextspecic packages of early newborn care and for reaching those in greatest need. There is overwhelming evidence to support breastfeeding or breast milk feeding of LBW and preterm infants in developing countries. It is now recommended that mothers with HIV should breastfeed their infants when the infant or mother is on effective antiretroviral therapy. It is also important to underscore the need for further studies in these areas where there is limited evidence. The criteria used to identify and triage preterm (early and late) and SGA infants at birth should be made cost-effective and available to communities with minimal resources (eg, robust and economical weighing scales should be made more widely available). When breastfeeding is not possible, products that are nutritionally adequate for preterm infants (<35 weeks gestation or <1500 g birth weight) should be made available. The provision and promotion of these nutritional alternatives should be done in a way that does not impact current breastfeeding strategies and recommendations. Supplements developed for breastfed preterm infants should be designed with due consideration of the protein/energy and micronutrient needs, safety studies, and risk-benet analyses that are appropriate for the developing world. Improved reference standards for intrauterine and postnatal growth for infants that dene optimal growth should consider the global population of preterm infants. n
is an effective way to meet an infants needs for warmth, breastfeeding, protection from infection, stimulation, safety, and love. Its key features include early, continuous and prolonged skin-to-skin contact between the mother and the infant, exclusive breastfeeding, and support provided during the hospital stay and continued at home. Kangaroo mother care has been shown to reduce morbidity and mortality in preterm infants. A recent review for the Lives Saved Tool by Lawn et al82 has shown that kangaroo mother care in the rst week of life reduced neonatal mortality by 51% (RR 0.49; 95% CI 0.29-0.82) compared with standard care. A meta-analysis of 5 randomized controlled trials suggested signicant reductions in serious morbidity for infants <2000 g (RR 0.34; 95% CI 0.17-0.65).82 Kangaroo mother care can be practiced in facility as well as community settings. These benets may also be evident in facilities in developing countries. Mother-infant dyads that practice kangaroo mother care have reduced rates of mortality and lengths of stay.83 Skin Barrier Therapy for Preterm Infants An important determinant of the high morbidity and mortality rates for preterm infants is the integrity of the skin barrier.84 The immature skin barrier allows high rates of transepidermal water loss and concomitant loss of uid and heat and increases the susceptibility to invasive infections.85-87 Enhancement of the skin barrier through topical emollient therapy reduces morbidity and mortality in preterm infants.88-90 A randomized trial from Bangladesh has shown that applying sunower oil to the skin of preterm infants reduces sepsis by 41% and mortality by 26%.88 On the other hand, a multicenter study of extremely LBW preterm infants (birth weight <1000 g) indicates that application of a commercially available emollient ointment has no effect on neonatal mortality.90 Although the evidence is not conclusive, a Cochrane review has shown that emollient interventions improves daily weight gain by 5.1 g (95% CI 3.5-6.7), reduces length of stay by 4.5 days (95% CI 2.46.5) and has a slight, positive effect on postnatal complications and weight gain at 4-6 months.91 Another noteworthy intervention for preterm infants is swaddling; infants who are swaddled have improved neuromuscular development, less physiologic distress, better motor organization, and more self-regulatory ability than those who are not.92
Author Disclosures
All authors received an honorarium from Mead Johnson Nutrition for attendance, presentation, and manuscript preparation. Z. B. wrote the rst draft of this manuscript.
Reprint requests: Zulqar A. Bhutta, MBBS, FRCP, FRCPCH, FCPS, PhD, Noordin Noormahomed Sharief Endowed Professor & Founding Chair, Division of Women & Child Health, The Aga Khan University, Karachi 74800, Pakistan. E-mail: zulqar.bhutta@aku.edu.
Discussion
Despite a number of limitations and gaps in evidence, there is sufcient knowledge to recommend strategies to prevent and mitigate morbidity and mortality of the LBW and/or preterm infant in the developing world. Addressing maternal undernutrition and risk factors for IUGR through evidence-based interventions such as balanced energy protein supplements and strategies to address food insecurity. In addition, addressing maternal micronutrient deciencies and reducing the burden of morbidity and malaria are important. In the long term, reducing family size and increasing interpregS112
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49. Rusia U, Madan N, Agarwal N, Sikka M, Sood SK. Effect of maternal iron deciency anaemia on foetal outcome. Indian J Pathol Microbiol 1995; 38:273-9. 50. World Health Organization (WHO). Worldwide prevalence of anaemia 1993-2005. WHO Global Database on Anaemia. In: de Benoist B, McLean E, Egli I, Cogswell M, eds. Geneva: WHO and Centers for Disease Contraol and Prevention (CDC) Atlanta; 2008. p. 1-51. 51. Bhutta ZA, Ali S, Cousens S, Ali TM, Haider BA, Rizvi A, et al. Alma-Ata: Rebirth and Revision 6 Interventions to address maternal, newborn, and child survival: what difference can integrated primary health care strategies make? Lancet 2008;372:972-89. ~a-Rosas JP, Viteri FE. Effects and safety of preventive oral iron or 52. Pen iron+folic acid supplementation for women during pregnancy. Cochrane Database Syst Rev 2009 Oct 7;CD004736. 53. Fall CH, Fisher DJ, Osmond C, Margetts BM. Multiple micronutrient supplementation during pregnancy in low-income countries: a metaanalysis of effects on birth size and length of gestation. Food Nutr Bull 2009;30:S533-46. 54. Haider BA, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev; 2012 Nov 14. CD004905. 55. Batool AH, Yakoob MY, Bhutta ZA. Effect of multiple micronutrient supplementation during pregnancy on maternal and birth outcomes. BMC Public Health 2011;11(suppl 3):S19. 56. Huybregts L, Roberfroid D, Lanou H, Menten J, Meda N, Van Camp J, et al. Prenatal food supplementation fortied with multiple micronutrients increases birth length: a randomized controlled trial in rural Burkina Faso. Am J Clin Nutr 2009;90:1593-600. 57. Srinivas SK, Edlow AG, Neff PM, Sammel MD, Andrela CM, Elovitz MA. Rethinking IUGR in preeclampsia: dependent or independent of maternal hypertension? J Perinatol 2009;29:680-4. 58. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009;33:130-7. Duley L. Calcium supplementation 59. Hofmeyr GJ, Lawrie TA, Atallah AN during pregnancy for preventing hypertensive disorders and related problems [review]. Cochrane Database Syst Rev 2010 Aug 4;CD001059. 60. Imdad A, Jabeen A, Bhutta ZA. Role of calcium supplementation during pregnancy in reducing risk of developing gestational hypertensive disorders: a meta-analysis of studies from developing countries. BMC Public Health 2011;11(suppl 3):S18. 61. Duley L, Gu lmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia [review]. Cochrane Database Syst Rev 2010 Nov 10;CD000025. 62. Dewey KG, Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B. Growth of breast-fed and formula-fed infants from 0 to 18 months: the DARLING Study. Pediatrics 1992;89:1035-41. 63. Birch E, Birch D, Hoffman D, Hale L, Everett M, Uauy R. Breast-feeding and optimal visual development. J Pediatr Ophthalmol Strabismus 1993;30:33-8. 64. Dewey KG, Heinig MJ, Nommsen-Rivers LA. Differences in morbidity between breast-fed and formula-fed infants. J Pediatr 1995;126:696-702. 65. Bhutta ZA, Ahmed T, Black RE, Cousens S, Dewey K, Giugliani E, et al. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008;371:417-40. 66. American AoPWoB. Breastfeeding and the use of human milk. Pediatrics 1997;100:1035-9. 67. Edmond KM, Zandoh C, Quigley MA, Amenga-Etego S, Owusu-Agyei S, Kirkwood BR. Delayed breastfeeding initiation increases risk of neonatal mortality. Pediatrics 2006;117:e380-6. 68. Arifeen S, Black RE, Antelman G, Baqui A, Cauleld L, Becker S. Exclusive breastfeeding reduces acute respiratory infection and diarrhea deaths among infants in Dhaka slums. Pediatrics 2001;108:e67. 69. Dimond HJ, Ashworth A. Infant feeding practices in Kenya, Mexico and Malaysia. The rarity of the exclusively breast-fed infant. Hum Nutr Appl Nutr 1987;41:51-64. 70. Perez-Escamilla R. Breastfeeding in Africa and the Latin American and Caribbean region: the potential role of urbanization. J Trop Pediatr 1994;40:137-43.
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Symposium Summary: Looking Back and Looking Forward
urrent clinical practice is based on the application of the best-available knowledge. Nutritional guidelines for preterm infants were last updated in 2005. This symposium served to establish a global consensus and a rm scientic base for neonatal nutrition practices. We feel condent to present updated recommendations in the Table. In addition, small-for-gestational-age infants were identied to be a unique population. The following recommendations for this group are: (1) feed according to gestational age, with special consideration of supplements for iron and micronutrients; and (2) do not promote rapid weight gain and avoid excess fat gain because they increase the risk for metabolic syndrome in later life. As a group, we also agreed on the following statements: (1) There is no conclusive evidence to recommend the routine use of prebiotics, probiotics, and synbiotics in preterm infants. Although data supporting the use of specic probiotics in the case of necrotizing enterocolitis are encouraging, available trials to not permit a decision to be made on optimum strain, dose, or protocol of use; and (2) There are insufcient data to recommend the routine use of glutamine, arginine, nucleotides, omega-3 polyunsaturated fatty acids, and lactoferrin to improve host defenses in preterm infants. Although we know more than we did a decade ago, there is a great need for additional knowledge about what works best in practice and to explore new areas of interest. The following gaps in knowledge were identied.
Biomarkers of zinc, copper, and vitamin A stores must be dened.
Prebiotics, Probiotics, and Synbiotics

Tools used to assess the microbiome at birth and subsequent changes need to be identied. The optimal microbiome needs to be dened, and efforts should be made to preserve it or restore it, as indicated by research evidence.
Community Support
The quality and quantity of education provided to pediatricians and parents who care for late preterm and post discharge infants need to be improved.
Human Milk
It is widely appreciated that human milk provides the best nutrition for normal healthy term infants, but human milk may not meet the needs of all preterm infants. Human milk fortiers for preterm infants at a variety of postnatal ages should be made available to infants who will benet from them, given their special needs. Extremely-low-birth-weight infants cared for in settings where exclusive human milk feeding is used may not receive all the required nutrients. Strategies to meet their needs must be developed while efforts to support and promote exclusive breastfeeding for healthy infants are preserved. Baby Friendly hospital environment practices should be compatible with the need to best serve the nutritional requirements of these high risk infants.
Growth
Improved reference standards for intrauterine and postnatal growth for each subpopulation of preterm infants that take short- and long-term outcomes into account need to be developed.
Protein and Energy

Currently, protein delivery to the preterm infant does not meet the infants need for protein, given the extraordinarily rapid growth required to match intrauterine rates. We know that more protein is needed early in life and less is needed later in life when growth rate decreases. Strategies need to be developed that enable health care providers to dene and deliver the appropriate amount of protein to each infant according to his/her individual need. The quality of protein required by preterm infants for optimal growth and development at various postnatal ages must be dened in more detail.
Small-for-Gestational-Age Infants
There is a need for improved algorithms to identify and triage preterm (early and late) and small-for-gestational-age infants at birth that require minimal resources and are adaptable to less-privileged community settings (eg, inexpensive and robust weighing scales). Bringing Science to the Bedside Extraordinary efforts are expended each year to make new scientic discoveries designed to improve nutrition for preterm infants. After validating new science as a basis for nutritional products, there is an equally important need to
Micronutrients
Please see the Author Disclosures at the end of this article.
The optimal amounts of iron and vitamin D relative to somatic weight and gestational age need to be dened.
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Table. Daily nutrient needs of groups of preterm infants

Micropreterm, 29 weeks Energy, kcal/kg Protein, g/kg Calcium, mg/kg 120-140 3.5-4.5 120-180 Preterm, $29 and 34.0 weeks 110-130 3.5-4.2 120-160 Late preterm, 34-38 weeks 110-130 3.0-3.6 70-140 Postdischarge 105-125 2.8-3.2 100-120 Term, $38 weeks 90-110 1.5-2.3 80-100
quickly deliver new and effective solutions to preterm infants globally. Efforts must be made to improve: (1) partnerships between the industry and academia to better support the needs of all infants and children; (2) regulatory approval processes by which new knowledge leads to better products to meet the specic needs of these infants; (3) mutual understanding of all concerned parties (academicians, industry, and regulators) involved in creating and implementing new advances in specialty nutritional support, for low-birth-weight and very-low-birth-weight infants in a manner that does not compromise the use of human milk as the preferred mode of feeding normal infants; (4) the ability of the health care community to provide the context, support, and dissemination of new scientic discoveries; and (5) the manner in which new improvements are analyzed for safety, risks, and benets. These tests must be conducted in settings that are representative of developing and developed countries. Key stakeholders, academia, health care professional associations, United Nations agencies, and industry representatives must be involved in these processes that consider the best interest of children as the rst priority. It is clear that understanding the science of neonatal nutrition is not the nal outcome; rather, it represents the beginning of a journey. If it is our expectation that our scientic knowledge will improve the well being of preterm infants, we must engage in activities that will facilitate translating it to practical application. We must consider that the overarching goal of the global neonatal community is reaching the great majority of low-birth-weight infants who presently have a high risk of death and disability from inadequate nutrition and care in the rst weeks of life. Most of these infants are born in developing countries and account for nearly 50% of the 4 million deaths that occur annually in infants and
young children. Most of these deaths are preventable; it is up to us to create the environment where we make neonatal careespecially good nutritionan essential component of health investments at the local, national, and international levels. We have to start by declaring that the present situation is unacceptable and that all concerned parties must join forces in securing better opportunities for health, growth and mental development of all infants, especially those most vulnerable.
Author Disclosures
Carol Lynn Berseth, MD, is the Medical Director for Global Innovation at Mead Johnson Nutrition. She organized and facilitated the Symposium on Nutrition of the Preterm Infant. Ricardo Uauy, MD, PhD, chaired the Symposium on Nutrition of the Preterm Infant. Mead Johnson Nutrition paid his travel expenses. He also received an honorarium to compensate his time for contributing to, organizing, and chairing the meeting and for his contribution to the nal editing of the Supplement. C. B. wrote the rst draft of this manuscript. n Carol Lynn Berseth, MD Mead Johnson Nutrition Evansville, IN Ricardo Uauy, MD, PhD INTA U of Chile and Neonatology Division Catholic University Santiago, Chile
Reprint requests: Carol Lynn Berseth, MD, Department of Medical Affairs: Mead Johnson Nutrition, 2500 W Lloyd Expressway, Evansville, IN 47721. E-mail: carol.berseth@mjn.com
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March 2013  Volume 162  Number 3  Supplement 1

Copyright 2013 by Mosby, Inc.

Global Neonatal Consensus Symposium: Feeding the Preterm Infant

The Journal of Pediatrics

March 2013  Volume 162  Number 3  Supplement 1

Copyright 2013 by Mosby, Inc.

Ricardo Uauy, MD, PhD and Carol Lynn Berseth, MD .....................................................................................................................................

Growth Curves: How to Best Measure Growth of the Preterm Infant

Human Milk and the Nutritional Needs of Preterm Infants

David I. Tudehope, AM, MBBS, FRACP ............................................................................................................................................................. S17

Lipid Needs of Preterm Infants: Updated Recommendations

Selected Macro/Micronutrient Needs of the Routine Preterm Infant

Intestinal Mucosal Defense System, Part 1. Consensus Recommendations for Immunonutrients

Intestinal Mucosal Defense System, Part 2. Probiotics and Prebiotics

Nutritional Needs of the Micropreterm Infant

Vol. 162, No. 3, Supp. 1

Global Neonatal Consensus Symposium: Feeding the Preterm Infant

Vol. 162, No. 3, Suppl. 1

Vol. 162, No. 3, Suppl. 1

Introduction to the Symposium on Nutrition of the Preterm Infant

Please see the Author Disclosures at the end of this article.

Growth Curves: How to Best Measure Growth of the Preterm Infant

Growth Assessment of the Preterm Infant

Estimated fetal weight World Health Organization

Limitations of Currently Available Growth Estimates

N 5635 1 164 871

Arbuckle et al 199316 Alexander et al 199618

1 087 629 3 134 879

Growth Curves: How to Best Measure Growth of the Preterm Infant

THE JOURNAL OF PEDIATRICS

Using Growth Curves to Manage Preterm Infants

Growth Curves: How to Best Measure Growth of the Preterm Infant

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Effects of Prematurity, IUGR, Postnatal Growth, and Early Nutrition on Neurodevelopment

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Lipid prole No No No No Lipid prole No Lipid prole No study available

Effects of IUGR. The effect of fetal growth on childhood or

Effects of Prematurity. Insulin resistance or glucose

THE JOURNAL OF PEDIATRICS

Effects of Early Nutrition. Very few studies have assessed

Early Growth Is Not a Perfect Surrogate of Nutritional Status in Preterm Infants

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Lapillonne and Grifn

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59. 60. 61.

Lapillonne and Grifn

Human Milk and the Nutritional Needs of Preterm Infants

CMV DBM EBM HM ICU IQ NEC

MM LBW NICU RCT TPN VLBW WHO

THE JOURNAL OF PEDIATRICS

Methods Used to Meet the Nutritional Needs of the Preterm Infant

Benets of HM and Breastfeeding for Preterm Infants

THE JOURNAL OF PEDIATRICS

Potential Disadvantages of HM for Preterm Infants

Nutritional Gaps with Feeding Mothers Unfortied Preterm Breast Milk

Feeding Plan for Preterm Infants

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Vol. 162, No. 3, Suppl. 1

March 2013 Volume 162 Number 3 Supplement 1

March 2013 Volume 162 Number 3 Supplement 1