Oppler ultrasound plays a fundamental role in the diagnosis of intrauterine growth-restricted (IUGR) fetuses. There is still confusion on the definition and management of IUGR. IUGR is a major cause of perinatal morbidity and mortality in the u.s.
Oppler ultrasound plays a fundamental role in the diagnosis of intrauterine growth-restricted (IUGR) fetuses. There is still confusion on the definition and management of IUGR. IUGR is a major cause of perinatal morbidity and mortality in the u.s.
Oppler ultrasound plays a fundamental role in the diagnosis of intrauterine growth-restricted (IUGR) fetuses. There is still confusion on the definition and management of IUGR. IUGR is a major cause of perinatal morbidity and mortality in the u.s.
Giancarlo Mari, MD, and Jason Picconi, MD, PhD Intrauterine growth restriction (IUGR) secondary to placental insufciency is a major cause of perinatal morbidity and mortality in the United States. Historically, Doppler changes occurring in IUGR fetuses play an important role in the diagnosis and management of these fetuses, and now, based on these changes, we have proposed a staging system for IUGR fetuses that demonstrates prognostic value. This manuscript also summarizes a practical classication for IUGR fetuses. We believe that future studies should differentiate among the different types of IUGR fetuses. Semin Perinatol 32:182-189 2008 Elsevier Inc. All rights reserved. KEYWORDS IUGR, Doppler, IUGR stages, IUGR classication D oppler ultrasound plays a fundamental role in the diag- nosis of intrauterine growth-restricted (IUGR) fetuses and also has the potential to play an important role in timing the delivery of some IUGR fetuses. Doppler ultrasonography of the umbilical and middle cerebral artery, in combination with biometry, provides the best tool to identify small fetuses at risk for an adverse outcome. 1,2 In addition, Doppler studies of the fetal cardiovascular system allow assessment of the blood ow redistribution observed in IUGR. 1 This process is mainly characterized by an increased umbilical artery and a decreased middle cerebral artery pulsatility index (MCA-PI), which suggests increased vascular resistance of the umbilical artery and cerebral vasodilatation. Approximately 10,000 papers on IUGR fetuses have been published in the literature (http://www.pubmed. com). Despite this large number of studies, there is still confusion on the denition and management of IUGR fe- tuses, because of the failure to differentiate between con- stitutionally and pathologically small fetuses. Addition- ally, studies on the pathogenesis of IUGR have been limited by the concept that IUGR fetuses represent a ho- mogeneous group. This has created confusion and ham- pered our understanding of the mechanisms that consti- tute the basis of IUGR. The result of this is that an IUGR can be dened differently in New York, London, or Paris. Therefore, it would be important to establish an interna- tional classication of IUGR fetuses. Several studies have determined longitudinal Doppler changes occurring in IUGR fetuses and, based on these changes, the authors of these studies have provided recom- mendations regarding the timing of delivery for IUGR fe- tuses. Loss of the brain-sparing effect was initially con- sidered a parameter to guide timing for the delivery of a growth-restricted fetus. 3 Arduini and coworkers reported that there is a Doppler temporal sequence that precedes the onset of late decelerations. 4 Hecher and coworkers 5 evaluated 93 IUGR fetuses with at least 3 Doppler studies following the diagnosis of IUGR, the last measurements being taken within 24 hours of delivery or intrauterine death. The amniotic uid index and umbilical artery pul- satility index were the rst variables to become abnormal, followed by changes in short-term variability of the fetal heart rate, middle cerebral artery pulsatility index, aortic pulsatility index, and ductus venosus S/a ratio. In fetuses delivered before 32 weeks, the perinatal mortality was higher if both short-term variability and ductus venosus pulsatility index were abnormal (39%) compared with only 1 or neither being abnormal (7%). The median time interval between the occurrence of the rst persistently abnormal nding and delivery was 3 days (range, 0-19 days) if short-term variability was the rst abnormal sign and 7 days (range, 0-43 days) if the ductus venosus pul- satility index was the rst variable to become abnormal. The authors did not perform biophysical proles (BPPs) in their population. Baschat and coworkers 6 studied growth-restricted fe- tuses with an umbilical artery pulsatility index 2 SD above the mean for gestational age, and serially assessed Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI. Address reprint requests to Giancarlo Mari, MD, Department of Obstetrics and Gynecology, Wayne State University, 3990 John R. Box 163, Detroit, MI 48201. E-mail: gmari@med.wayne.edu 182 0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.02.011 fetal well-being using BPP scoring and additional Doppler studies. In 34 fetuses, Doppler studies revealed deteriora- tion of the umbilical artery and ductus venosus parameters at a median of 4 days before delivery, whereas 2 to 3 days before delivery, fetal breathing movement began to de- cline, followed by a drop in amniotic uid volume the next day. Delivery occurred between 24 and 37 weeks gesta- tion and was prompted by an abnormal BPP and abnormal Doppler. Computerized cardiotocography was not em- ployed in this study. Ferrazzi and coworkers 7 conducted a longitudinal study of 26 growth-restricted fetuses that had abnormal uterine and umbilical artery Doppler velocimetry, and based the decision to deliver the fetus on a nonreactive nonstress test (NST) dened as the absence of accelerations of at least 10 beats per min for 10 seconds, with a short-termvariation 2.2 seconds for a period of greater than 120 minute. The authors reported that an abnormal ductus venosus as well as decreased aortic and pulmonary outow tract velocities were associated with perinatal death and occurred in 50% of patients 4 to 5 days before delivery. Interestingly, the authors observed that more than 50% of fetuses that were delivered because of an abnormal fetal heart rate did not have venous Doppler abnormalities. The authors likewise did not perform BPPs in their population. Cosmi and coworkers were the rst to perform a longitu- dinal study on IUGR fetuses in which no cause for the IUGR with placental insufciency was detected (idiopathic IUGR). 8 The authors reported that 54% of the fetuses had a normal venous Doppler at the time of delivery. We reported a longitudinal study in 10 IUGR fetuses fol- lowed from the time the diagnosis of IUGR was made up to delivery of IUGR fetuses. 9 The data are summarized in Figure 1. The data suggest that the last changes occurring in the cardiovascular system of severe IUGR fetuses are right cardiac failure followed by left cardiac failure. Limitations of Previous Longitudinal Studies on IUGR Fetuses Although previously cited studies suggest that there might be a common sequence of biophysical changes that indicate pro- gressive fetal compromise in IUGR, a careful review reveals that there are some differences among the studies. For exam- ple, the involvement of the fetal brain and heart, as detected by an abnormal fetal heart rate/BPP, or DVDoppler indices, is highly variable among fetuses and does not follow a predict- able pattern. Amniotic uid volume was among the rst pa- rameters to become abnormal in the study of Hecher and coworkers, 5 but was among the last in the study of Baschat and coworkers. 6 Whereas Ferrazzi and coworkers 7 and Hecher and coworkers 5 based their interventions on comput- erized cardiotocography, which is not used in the US, Bas- chat and coworkers 6 used Doppler abnormality and the ab- normal BPP, which is not used in Europe. Moreover, our study on the longitudinal cardiovascular changes, as well as the above-cited studies, considered IUGR fetuses as a homo- geneous group and did not distinguish between IUGR with and without maternal disease. It is likely that the differences found among the above studies can be attributed to differences in the growth-restricted fetuses studied. We believe that more useful information could be provided if authors differentiated between idiopathic IUGR and IUGR secondary to maternal diseases. A recent preliminary study has reported that IUGR fetuses undergo a series of cardiovascular changes which are differ- ent between idiopathic IUGR fetuses and IUGR diagnosed in patients with preeclampsia. 10 In idiopathic IUGR fetuses, Doppler changes can be predicted on almost a day-by-day basis, and if no abrupt adverse event occurs, such as a pla- cental abruption, these fetuses can be followed until fetal cardiac failure occurs. This is not the case in patients with preeclampsia or other maternal pathology in which the changes occurring in IUGR fetuses are unpredictable. 10 Therefore, IUGR fetuses should be differentiated on the basis of associated maternal or fetal pathology. We have reported that if IUGR fetuses are delivered before 25 weeks, they invariably die, whereas if they are delivered after 29 weeks, such fetuses usually survive. 11 Based on ges- tational age at diagnosis, we have divided IUGR fetuses into (1) very early IUGR (25 weeks), (2) early IUGR (between 25 and 30 weeks), and (3) late IUGR fetuses (30 weeks). MCA-PSV: A New Parameter in the Assessment of IUGR Fetuses Recently, we have performed a cross-sectional and a longitu- dinal assessment of the MCA-PI and MCA-PSV in growth- restricted fetuses. 12 Our data show that, although the MCA waveforms change in growth-restricted fetuses, the MCA- Figure 1 The bars indicate the time interval (median time in days) between occurrence of pathologic ndings and delivery IUGR fetuses. MV, mitral valve; TV, tricuspid valve; AoA, aortic arch; RF, reversed ow; UV umbilical vein; P, pulsation; DV, ductus venosus reversed ow; AoI, aortic isthmus; PI, pulsatility index; UA, umbil- ical artery; MCA, middle cerebral artery; PSV, peak systolic velocity, HA, hepatic artery; SA, splenic artery, IVC, inferior vena cava. (Color version of gure is available online.) Doppler changes in IUGR fetuses 183 PSV predicts perinatal mortality more accurately than the MCA-PI. This nding can be explained in the following way: initially, the MCA-PI is abnormal in most of the fetuses, but subsequently the MCA-PI increases and a tendency toward normalization occurred before delivery or fetal death. The MCA-PSV, conversely, progressively increased with advanc- ing gestation in all fetuses, with a tendency to slightly de- crease just before fetal biophysical deterioration or the occur- rence of fetal demise. However, despite this decrease, the MCA-PSV value remains above the upper limit of normal (ie, Figure 2 Individual longitudinal values for the middle cerebral artery peak systolic velocity in 10 IUGR fetuses plotted over the reference range. IUFD, intrauterine-fetal demise; ND, neonatal death; g, grams. (Reprinted with permission. 12 ) 184 G. Mari and J. Picconi Figure 3 Linear regressions with the 95% condence interval of the middle cerebral artery peak systolic velocity (MCA-PSV) multiples of the mean (MoM), with: (A) the hemoglobin MoM values, (B) the pO 2 MoM values, (C) the pCO 2 MoM values, and (D) the pH MoM values in fetuses at risk of anemia. (Reprinted with permission. 13 ) Figure 4 Linear regressions with the 95% condence interval of the of the middle cerebral artery peak systolic velocity (MCA-PSV) multiples of the mean (MoM) with: (A) the hemoglobin MoM values, (B) the pO 2 MoM values, (C) the pCO 2 MoMvalues, and (D) the pHMoMvalues in fetuses with intrauterine growth restriction (IUGR). (Reprinted with permission. 13 ) Doppler changes in IUGR fetuses 185 abnormal) until a few hours before delivery or fetal demise (Fig. 2). Why Is the MCA-PSV Increased in IUGR Fetuses? Although the MCA-PSV is increased in anemic fetuses, IUGR fetuses are not anemic. Therefore the question that arises is: What is the mechanismof increased MCA-PSVin anemic and nonanemic fetuses? To answer this question, Hanif and co- workers performed a new study which demonstrated the mechanisms that determine increased MCA-PSVare different in anemic appropriate- for-gestational-age (AGA) compared with nonanemic IUGR fetuses. 13 In anemic fetuses, the high MCA-PSV is related to a decreased fetal hemoglobin that might decrease blood viscosity, and consequently there is an increased cardiac output. On the other hand, in IUGR fe- tuses, the MCA-PSVincrease is signicantly related to hypox- emia and hypercapnia, and thus to brain auto-regulation. Figures 3 and 4 report the correlation between MCA PSV and fetal blood gas analysis. Staging and Classication of IUGR Fetuses Categorization of IUGR fetuses into three stages of severity using nonstress testing and umbilical artery Doppler ve- locimetry has previously been performed by Pardi and coworkers. 14 This study showed that, if the nonstress test and umbilical artery Doppler studies were normal (group I fetuses), there was no fetal acidosis or hypoxemia. In contrast, group II fetuses with a normal nonstress test and abnormal umbilical artery Doppler study (pulsatility in- dex 2 SD below the mean) showed a 5% rate of hypoxia/ acidemia, and group III fetuses with an abnormal non- stress test and umbilical artery Doppler studies showed a 60% rate of hypoxia/acidemia. Although the study by Pardi and coworkers is informative, greater clinical utility may be achieved by the use of fetal Doppler in additional vessels. We have recently proposed a staging for IUGR fetuses based on fetal biometry, Doppler cardiovascular changes, amniotic uid, and clinical parameters. 15 A summary of this staging system is reported in Table 1. Figure 5 (A) An abnormal umbilical artery Doppler (the arrows point to the low diastole indicating a high placental resistance). (B) Abnormal middle cerebral artery Doppler at 27 weeks gestation (the vertical arrows point to the diastole that is increased, indicating brain sparing effect; the horizontal arrows indicate the peak systolic velocity that appears normal). An abnormal pulsatility index of either the umbilical or middle cerebral artery characterizes stage I. (Reprinted with permission. 15 ) (Color version of gure is available online.) Table 1 IUGR Staging Stage Umbilical a. Middle Cerebral a. Ductus v. Umbilical v. TV TR aPI ARF aPI aPSV aPI RF P RF E/A I* II III The presence of any one abnormal parameter in a stage would place the fetus in that stage. *Stage I: Abnormal (a) umbilical artery pulsatility index (PI) or middle cerebral artery PI. Stage II: Umbilical artery absent/reversed ow (ARF), elevated middle cerebral artery peak systolic velocity, abnormal ductus venosus pulsatility index (absent ductus venosus is included in this stage), and pulsation (P) of the umbilical vein. Stage III: Ductus venosus reversed ow, umbilical vein reversed ow, tricuspid valve (TV) E/A ratio >1, tricuspid valve regurgitation (TR). Reprinted with permission. 15 186 G. Mari and J. Picconi The Doppler waveforms used for staging are shown in Figures 5-7. Stage I IUGR fetuses are considered mild IUGR, and such patients are usually managed as outpatients, whereas stage II and III patients need to be admitted to the hospital when the fetuses are considered viable. Stage II patients are admitted for observation, whereas stage III patients are at high risk for fetal demise. The major advantage for selecting the parame- ters included in this staging system is the ability to clearly track the progression of abnormal parameters that start at the umbilical and middle cerebral arteries, and later progres- sively extend to the other parameters, up to the time of fetal demise if the fetuses remain undelivered. 9,10 Another advan- tage is the simplicity of the system. Only four fetal vessels and one cardiac valve needto be investigatedwithDoppler. Further- more, it is not necessary todetermine the parameters reportedin Figure 6 (A) Flow velocity waveforms of the middle cerebral artery. These waveforms were obtained in an IUGR fetus at 27 weeks gestation. The transverse arrows point to the MCA peak systolic velocity that is abnormal (76 cm/s). (B, C) Two sets of umbilical artery absent and reversed ow, respectively. (D) An abnormal ductus venosus Doppler (the arrows point to the a wave recorded at the atrial contraction; when there is a low a wave, the pulsatility index is abnormal). The presence of one of these ndings characterizes stage II. (Reprinted with permission. 15 ) (Color version of gure is available online.) Figure 7 The presence of one of the following ndings characterizes stage III ductus venosus reversed ow (A), umbilical vein reversed ow(B), abnormal tricuspid valve waveform(E/A 1) (C). (Reprinted with permission. 15 ) (Color version of gure is available online.) Doppler changes in IUGR fetuses 187 a certainstage if the parameters of the previous stage are normal. For example, if the UA PI and the MCA PI are normal, it is not necessary to determine the parameters of the next stage. This makes the staging system more easily applicable. The staging system is applicable both in pregnancies at a gestational age 30 weeks and 30 weeks, which makes the staging system applicable across all gestational. ages. The data also indicate that stage III fetuses have a lower birth weight than both stage II and stage I fetuses at similar gesta- tional ages (Fig. 8). Moreover, the data suggest that stage II and III IUGR fetuses are delivered earlier than fetuses of stage I (Fig. 9). No deaths occurred in stage I fetuses. At the other extreme, the mortality for stage III fetuses was high (50% if there was DVRF; 85% when DVRF was present in combina- tion with one of the other parameters that characterize stage III), whereas the mortality in stage II IUGR fetuses was inter- mediate between the two other stages (Fig. 10). In this study, we also noticed that fetuses could survive for days or weeks when ductus venosus reversed ow (RF) was present. It has been suggested that, when DVRF is present, the fetus may be acidemic. A recent preliminary study has reported that fetuses with DVRF are not necessarily acidemic at birth. 16 Based on the information obtained from our stag- ing system, we have proposed the following steps to classify IUGR fetuses: (1) In the presence of a fetus with an estimated weight below the 10th percentile, the rst step would be to determine the stage and amount of amniotic uid; (2) Mater- nal or fetal pathology/anomalies should be identied, if any; and (3) the gestational age should be reported. For example, if a fetus with an estimated weight below the 10th percentile has an abnormal umbilical and/or middle cerebral artery pul- satility index, the amniotic uid index (AFI) is 5.0 cm, there is no maternal or fetal pathology, and the gestational age is 28 weeks, the IUGR fetus should be classied as IUGR stage IA, 28 weeks, idiopathic. We use the term idiopathic for those IUGR fetuses in which no cause for placental insuf- ciency is found. 17 If a fetus with an estimated weight below the 10th percentile has reversed umbilical artery Doppler, the AFI is 7 cm, the mother has diabetes and chronic hyperten- sion, and the gestational age is 26 weeks, then the IUGR should be classied as IUGR stage IIB, 26 weeks, diabetes chronic hypertension. If, in the previous case, instead of di- abetes and chronic hypertension, a diagnosis is made of cy- tomegalovirus (CMV) infection, the IUGR would be classied as IUGR stage IIB, 26 weeks, CMV infection. If, instead of CMV infection, a diagnosis of Down syndrome is made, the IUGR would be classied as IUGR stage IIB, 26 weeks, Down syndrome. Conclusion In conclusion, we believe that IUGR fetuses with and with- out placenta insufciency should be differentiated. In ad- dition, we should also divide the different types of IUGR with placenta insufciency based on the fetal and maternal pathology. The above-mentioned concepts are important and might have great implications for the future of IUGR studies. From information presented in this chapter, it is clear that not all IUGR fetuses are the same and they must be categorized into appropriate groups of severity and etiology, which has not been uniformly done in the past publications. This is useful, not just for management purposes, but also for the conduct of Figure 10 The bars represent the median mortality values (mortality occurring between 20 weeks gestation and 28 days after birth) for the fetuses in the three stages. The number in parentheses indicates the number of total deaths/total number of fetuses. The mortality was 50% when there was DVRF only; it was 85% when DVRF was present in combination with one of the other parameters. (Re- printed with permission. 15 ) Figure 8 The bars represent the median gestational age values at delivery for the fetuses in the three stages. The numbers in paren- theses indicate the number of fetuses. (Reprinted with permis- sion. 15 ) Figure 9 The bars represent the median birth weight values for the fetuses in the three stages. The numbers in parentheses indicate the number of fetuses. (Reprinted with permission. 15 ) 188 G. Mari and J. Picconi any clinical trials that aim to test the hypothesis that IUGR fetuses behave in different ways. References 1. Mari G, Deter RL: Middle cerebral artery ow velocity waveforms in normal and small-for-gestational-age fetuses. Am J Obstet Gynecol 166:1262-1270, 1992 2. Trudinger BJ, Giles WB, Cook CM, et al: Fetal umbilical artery ow velocity waveforms and placental resistance: clinical signicance. Br J Obstet Gynaecol 92:23-30, 1985 3. Mari G, Wasserstrum N: Flow velocity waveforms of the fetal circula- tion preceding fetal death in a case of lupus anticoagulant. Am J Obstet Gynecol 164:776-778, 1991 4. Arduini D, Rizzo G, Romanini C: Changes of pulsatility index fromfetal vessels preceding the onset of late decelerations in growth-retarded fetuses. Obstet Gynecol 79:605-610, 1992 5. Hecher K, Bilardo CM, Stigter RH, et al: Monitoring of fetuses with intrauterine growth restriction: a longitudinal study. Ultrasound Ob- stet Gynecol 18:564-570, 2001 6. Baschat AA, Gembruch U, Harman CR: The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol 18:571-577, 2001 7. Ferrazzi E, Bozzo M, Rigano S, et al: Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 19: 140-146, 2002 8. Cosmi E, Ambrosini G, DAntona D, et al: Doppler, cardiotocography, and biopgysical prole changes in growth restricted fetuses. Obstet Gynecol 106:1240-1245, 2005 9. Mari G, Deter RL, Hanif F, et al: Sequence of cardiovascular changes occurring in severe IUGR fetuses: part II. Ultrasound Obstet Gynecol 28:390, 2006 10. Mari G, Hanif F, Kruger M: Sequence of cardiovascular changes in IUGR in pregnancies with and without preeclampsia. Prenatal Diagno- sis 28:377-383, 2008 11. Mari G, Hanif F, Treadwell MC, et al: Gestational age at delivery and Doppler waveforms in very preterm IUGR fetuses as predictors of peri- natal mortality. J Ultrasound Med 26:555-559, 2007 12. Mari G, Hanif F, Kruger M, et al: Middle cerebral artery peak systolic velocity: a new Doppler parameter in the assessment of growth- restricted fetuses. Ultrasound Obstet Gynecol 29:310-316, 2007 13. Hanif F, Drennan K, Mari G: Variables affecting the middle cerebral artery peak systolic velocity in anemic and IUGR fetuses. AmJ Perinatol 24:501-505, 2007 14. Pardi G, Cetin I, Marconi AM, et al: Diagnostic value of blood sampling in fetuses with growth retardation. N Engl J Med 238:692-696, 1993 15. Mari G, Hanif F, Drennan F, et al: Staging of intrauterine growth- restricted fetuses. J Ultrasound Med 26:1469-1477, 2007 16. Picconi J, Hanif F, Mari G: Ductus venosus reversed ow in IUGR fetuses: Is it an indication for delivery? Am J Perinatol 25:199-204, 2008 17. Mari G, Hanif F: Intrauterine growth restriction: how to manage and when to deliver. Clin Obstet Gynecol 50:497-509, 2007 Doppler changes in IUGR fetuses 189