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Physiologic transition from intrauterine to extrauterine life

Author: Caraciolo J Fernandes, MD
Section Editor: Leonard E Weisman, MD
Deputy Editor: Melanie S Kim, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2019. | This topic last updated: Sep 04, 2018.

INTRODUCTION

The successful transition from intrauterine to extrauterine life is dependent upon significant
physiologic changes that occur at birth. In almost all infants, these changes are successfully
completed at delivery without requiring any special assistance. However, about 10 percent of infants
will need some intervention, and less than 1 percent will require extensive resuscitative measures at
birth [1].

The physiologic changes that occur in the transition from intrauterine to extrauterine life are reviewed
here. The indications and principles of neonatal resuscitation are discussed separately. (See
"Neonatal resuscitation in the delivery room".)

FETUS

Prior to delivery, the human fetus depends upon the placenta for gas and nutrient exchange with the
maternal circulation. A discussion on the development of the placenta, which is essential for normal
fetal growth and development, is found separately. (See "Placental development and physiology".)

The low vascular resistance of the placenta and the high vascular resistance of the fluid-filled fetal
lungs result in right-to-left shunts characteristic of the fetal circulation (figure 1).

Fetal circulation — In the fetus, the placenta has the lowest vascular resistance and receives 40
percent of the fetal cardiac output, which results in a low systemic pressure (figure 1). In contrast, the
fetal lungs are filled with fluid, resulting in a high vascular resistance and less than 10 percent of the
cardiac output going to the lungs (algorithm 1). In contrast to earlier studies in lambs, subsequent
studies using magnetic resonance imaging (MRI) and Doppler ultrasound to measure fetal blood flow
suggest pulmonary blood flow may be higher (11 to 15 percent of combined ventricular output) [2,3].

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Two right-to-left shunts occur in the fetus because of the high pulmonary vascular resistance and low
systemic pressure:

● Foramen ovale − Blood shunted from the right to left atrium

● Ductus arteriosus − Blood shunted from the pulmonary artery to the aorta

From the placenta, oxygenated blood flows through the umbilical vein and splits upon entering the
abdomen of the fetus (figure 1). The majority flows through the ductus venosus into the inferior vena
cava, and then the right atrium; the remaining blood perfuses the liver. Blood originating from the
ductus venosus enters the right atrium and, because of a streaming effect, is largely shunted through
the foramen ovale into the left side of the heart and aorta. (See 'Fetal oxygenation' below.)

In contrast, less oxygenated blood from the superior vena cava and the inferior vena cava distal to the
ductus venous flows from the right atrium into the right ventricle with minimal mixing with the
oxygenated blood originating from the ductus venosus (figure 1). Almost all of the right ventricular
output (90 percent) bypasses the lung and is shunted through the patent ductus arteriosus to the
descending aorta distal to the origin of the carotid arteries. This deoxygenated blood is transported
through the aorta and the umbilical arteries to the placenta, where it releases carbon dioxide and
waste products and collects oxygen and nutrients.

Fetal oxygenation — The intrauterine oxygen tension is low compared with that seen in extrauterine
life. The highest oxygenated fetal blood is found in the umbilical vein with PO2 as high as 55±7 mmHg
[4]. Oxygen saturation decreases when mixed with venous return, so that blood returning to the
placenta will have a PO2 of 15 to 25 mmHg.

Despite the low oxygen tension in the fetus, there is adequate tissue oxygenation because of the
following factors [5]:

● Fetal hemoglobin − Fetal hemoglobin has increased oxygen affinity compared with adult
hemoglobin, which facilitates oxygen transport across the placenta. The high affinity of fetal
hemoglobin may result in up to 80 percent saturation, a level that promotes sufficient oxygen
transport across the placenta to meet the metabolic needs of the fetus.

● Decreased fetal oxygen consumption − Intrauterine compared with extrauterine life requires less
oxygen because fetal metabolism and oxygen consumption are decreased:

• The fetus does not need to maintain thermoregulation because the thermal environment is
maintained by the mother.

• In the fetus, many physiologic functions are reduced, including respiratory effort,
gastrointestinal digestion and absorption, and renal tubular reabsorption (due to the low
glomerular filtration rate). These changes reduce tissue oxygen consumption.

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● Differential blood flow − In the fetus, the blood flow is structured so that vital organs (eg, liver,
heart, and brain) receive blood with a relatively high degree of oxygen saturation (figure 1).

• Liver − The liver receives blood directly from the umbilical vein without mixing with
deoxygenated fetal blood.

• Brain and heart − Blood flowing through the coronary and carotid arteries has a high degree
of oxygen saturation because oxygenated blood from the umbilical vein flows to the right
atrium (via the ductus venosus and inferior vena cava) and is shunted through the foramen
ovale to the left side of the heart and aorta. This shunting is achieved through differential
velocities of incoming venous blood streams and directing of oxygenated blood to the
foramen ovale. This reduces mixing of oxygenated blood with deoxygenated blood entering
the right atrium from the superior vena cava. The deoxygenated blood is directed toward the
right ventricle and shunted through the ductus arteriosus to the aorta, but distal to the origin
of the carotid and coronary arteries.

The low fetal oxygen tension maintains the architecture of the fetal circulation by causing pulmonary
vascular constriction, which maintains pulmonary vascular resistance at a high level, thereby
promoting right-to-left shunting through the foramen ovale and ductus arteriosus.

TRANSITION AT DELIVERY

To successfully make the transition from intrauterine to extrauterine life when the umbilical cord is
clamped at birth, the neonate must rapidly make physiologic changes in cardiopulmonary function. A
successful transition is characterized by the following features:

● Alveolar fluid clearance

● Lung expansion
● Circulatory changes with increases in pulmonary perfusion and systemic pressure, and closure of
the right-to-left shunts of the fetal circulation

Alveolar fluid clearance — Several mechanisms contribute to the clearance of alveolar fluid and
lung aeration, including labor, initial breaths, and thoracic squeeze.

● Labor − Studies in lamb models have helped elucidate a better understanding of the regulation of
alveolar fluid [6]. Chloride-driven liquid secretion predominates during gestation, which stretches
the lung and promotes lung growth and development. During late gestation, in response to
increased concentrations of catecholamines and other hormones, the lung epithelium switches
from active secretion of chloride and liquid into the air spaces to active resorption of sodium and
liquid [7-9]. Increased oxygen tension at birth enhances the capacity of the epithelium to transport
sodium and increases gene expression of the epithelial sodium channel, promoting further
resorption of alveolar fluid [8].

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● Initial breaths − The initial effective breaths of the neonate generate high transpulmonary
pressures: mean esophageal pressures of -52 cm H2O during inspiration and 71 cm H2O during
expiration have been measured in term infants [10]. The initial negative hydrostatic pressure
drives alveolar fluid from the air spaces into the interstitium and subsequently the pulmonary
vasculature.

● Thoracic squeeze − Although once thought to be the primary mechanism for alveolar clearance,
the pressure upon the chest wall of the infant during delivery probably is only a minor contributor
to alveolar fluid clearance [5].

In a study of infants (gestational age ≥35 weeks), lung aeration and partial liquid clearance were
achieved in the first few minutes after birth [11]. Complete airway clearance was observed in 49, 78,
and 100 percent of infants at 2, 4, and 24 hours after delivery. However, no clinical or radiographic
information was provided.

Lung expansion — With the first effective breath, air movement begins as intrathoracic pressure
falls, starting at pressures of less than -5 cm H2O. Increasing inspiratory pressure expands the
alveolar air spaces and establishes functional residual capacity (FRC) [10]. Lung expansion also
stimulates surfactant release, which reduces alveolar surface tension, increases compliance, and
stabilizes the FRC.

Circulatory changes — With the clamping of the umbilical cord, the placenta with its low vascular
resistance is removed from the neonatal circulation, resulting in a rise in neonatal systemic blood
pressure. At the same time, lung expansion reduces both pulmonary vascular resistance and the
pulmonary artery pressure [12].

These two changes decrease the fetal right-to-left shunt at the ductus arteriosus, resulting in an
increasing left-to-right shunt at the ductus arteriosus [12,13]. These two changes also result in an
increased blood flow through the pulmonary arteries and lungs. This shift to left-to-right shunting after
delivery results in an increase in ventricular stroke volume, which is associated with an increase in
cerebral oxygen saturation [12,14]. With increased lung perfusion and expansion, neonatal
oxygenation saturation is increased, which stimulates closure of the ductus arteriosus.

In addition, the increased pulmonary arterial blood flow raises pulmonary venous return to the left
atrium and left atrial pressure. As the left atrial pressure increases and the right atrial pressure falls,
right-to-left shunting across the foramen ovale decreases. Closure of the foramen ovale occurs when
the left atrial pressure exceeds the right atrial pressure.

DIFFICULTIES IN TRANSITION

Although most neonates successfully transition between intrauterine and extrauterine life, about 10
percent will have some difficulty and require resuscitative efforts at birth. (See "Neonatal resuscitation

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in the delivery room".)

The following risk factors are associated with a greater likelihood of having difficulty making a
successful transition and of requiring resuscitation [15]:

● Maternal conditions − Advanced maternal age, maternal diabetes mellitus or hypertension,

maternal substance abuse, or previous history of stillbirth, fetal loss, or early neonatal death

● Fetal conditions − Prematurity, postmaturity, congenital anomalies, or multiple gestation

● Antepartum complications − Placental anomalies (eg, placenta previa), or either

oligohydramnios or polyhydramnios

● Delivery complications − Transverse lie or breech presentation, chorioamnionitis, foul-smelling or

meconium-stained amniotic fluid, antenatal asphyxia with abnormal fetal heart rate pattern,
maternal administration of a narcotic within four hours of birth, or delivery that requires
instrumentation (eg, forceps, vacuum, or cesarean delivery)

Neonatal difficulties at birth include the following [15]:

● Lack of respiratory effort

● Blockage of the airways
● Impaired lung function
● Persistent increased pulmonary vascular resistance (also referred to as persistent pulmonary
hypertension or persistent fetal circulation)
● Abnormal cardiac structure and/or function

Lack of respiratory effort — The lack of vigorous, regular spontaneous respirations at birth
interferes with alveolar fluid clearance, lung inflation, and reduction of pulmonary vascular resistance.
Poor or absent spontaneous respiratory effort suggests that the infant is neurologically depressed
(usually brain asphyxia) or has impaired muscular function. Causes of impaired respiratory effort vary
from benign and readily reversible problems (eg, exposure to maternally administered opioids) to
more severe and refractory problems (eg, severe and prolonged hypoxia or congenital neuromuscular
disorder). (See "Etiology and pathogenesis of neonatal encephalopathy", section on 'Risk factors'
and "Spinal muscular atrophy".)

Blockage of the airways — Mechanical blockage of the airway prevents the infant from making
adequate initial breaths, thereby interfering with alveolar fluid clearance, lung inflation, and the fall in
pulmonary vascular resistance. Causes of blockage include congenital airway malformation (eg,
bilateral choanal atresia or Robin sequence syndrome); the presence of meconium or mucus in the
airway; or rarely, airway obstruction due to disorders such as laryngeal webs, cystic hygroma, or
congenital goiter [5]. (See "Congenital anomalies of the nose", section on 'Choanal atresia' and
"Congenital anomalies of the jaw, mouth, oral cavity, and pharynx", section on 'Pierre Robin sequence'

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and "Clinical features and diagnosis of meconium aspiration syndrome", section on 'Airway
obstruction'.)

Impaired lung function — The following conditions can impair lung function, resulting in respiratory
distress of the neonate at delivery:

● External causes − Any collection between the lung and the chest wall will prevent the lung from
expanding. This includes pneumothorax and pleural effusions, which may occur in an infant with
hydrops fetalis. (See "Pulmonary air leak in the newborn", section on 'Pneumothorax' and
"Nonimmune hydrops fetalis".)

● Pulmonary hypoplasia − In congenital diaphragmatic hernia, pulmonary hypoplasia occurs

because of external compression of the fetal lung by the herniated abdominal contents.
Pulmonary hypoplasia also is associated with oligohydramnios and is seen in infants with severe
congenital anomalies of the kidney and urinary tract. (See "Congenital diaphragmatic hernia in
the neonate" and "Evaluation of congenital anomalies of the kidney and urinary tract (CAKUT)",
section on 'Amniotic fluid'.)

● Intrinsic lung disease − In preterm infants, impaired lung function is due to deficient pulmonary
surfactant, leading to hyaline membrane disease, or antenatally acquired pneumonia. In full-term
infants, causes include transient tachypnea of the newborn, which results from delayed resorption
and clearance of fetal lung fluid, and antenatally acquired pneumonia. (See "Pathophysiology,
clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn" and
"Transient tachypnea of the newborn" and "Neonatal pneumonia".)

The causes of respiratory distress at birth are discussed in detail separately. (See "Overview of
neonatal respiratory distress: Disorders of transition".)

Persistent pulmonary hypertension — Persistent pulmonary hypertension of the newborn (PPHN)

is the term used when the pulmonary vascular resistance (PVR) remains abnormally elevated after
birth. It results from blood shunting right to left through fetal circulatory pathways via the ductus
arteriosus and foramen ovale, and can result in severe life-threatening hypoxemia and hypercapnia
that may not respond to conventional respiratory support. It may be seen when adequate lung
expansion and ventilation does not occur immediately after birth. (See "Persistent pulmonary
hypertension of the newborn".)

Cardiac disease — Infants with severe congenital heart disease may have difficulty with the
transition to extrauterine life, especially those infants with cyanotic heart disease who are dependent
upon a patent ductus arteriosus for pulmonary or systemic blood flow, or those with severe pulmonary
edema due to increased pulmonary arterial blood flow or impaired left ventricular function. (See
"Identifying newborns with critical congenital heart disease", section on 'Clinical features'.)

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Preterm infants — Given their smaller size and incomplete development, preterm infants are
inherently more likely to experience difficulties in transition from the intrauterine to extrauterine
environment. Pre-delivery and delivery room practices, such as the administration of maternal
antenatal corticosteroid steroids, delayed cord clamping, and milking of the cord can facilitate the
transition [16,17]. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory
morbidity and mortality from preterm delivery".)

SUMMARY

● The successful transition from intrauterine to extrauterine life is dependent upon significant
physiologic changes that occur at birth. In almost all infants (90 percent), these changes are
successfully completed at delivery without requiring any special assistance.

● When the umbilical cord is clamped, an uneventful transition to extrauterine life includes
successful alveolar fluid clearance, lung expansion, and conversion from fetal to newborn
circulation with increased pulmonary arterial blood flow, increased systemic pressure, and
closure of the right-to-left shunts (foramen ovale and ductus arteriosus) of the fetal circulation.
(See 'Transition at delivery' above.)

● Approximately 10 percent of neonates have some difficulty and require resuscitative efforts at
birth. Infants who are more likely to require resuscitation can be identified by maternal and
neonatal risk factors, and the presence of antepartum and delivery room complications. (See
'Difficulties in transition' above.)

● A more difficult transition at birth may be due to the lack of respiratory effort of the infant,
blockage of his/her airway, impaired neonatal lung function, persistent increased pulmonary
vascular resistance, or the presence of cardiac disease. (See 'Difficulties in transition' above.)

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REFERENCES

1. Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: Neonatal Resuscitation: 2015 American
Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care. Circulation 2015; 132:S543.

2. Mielke G, Benda N. Cardiac output and central distribution of blood flow in the human fetus.
Circulation 2001; 103:1662.

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3. Prsa M, Sun L, van Amerom J, et al. Reference ranges of blood flow in the major vessels of the
normal human fetal circulation at term by phase-contrast magnetic resonance imaging. Circ
Cardiovasc Imaging 2014; 7:663.

4. Soothill PW, Nicolaides KH, Rodeck CH, Gamsu H. Blood gases and acid-base status of the
human second-trimester fetus. Obstet Gynecol 1986; 68:173.

5. Goldsmith JP. Delivery room resuscitation of the newborn. In: Neonatal-Perinatal Medicine: Dise
ases of the Fetus and Infant, 9th ed, Martin RJ, Fanaroff AA, Walsh MC (Eds), Elsevier Mosby,
St. Louis 2011. Vol 1, p.449.

6. Olver RE, Walters DV, M Wilson S. Developmental regulation of lung liquid transport. Annu Rev
Physiol 2004; 66:77.

7. Bland RD, Nielson DW. Developmental changes in lung epithelial ion transport and liquid
movement. Annu Rev Physiol 1992; 54:373.

8. O'Brodovich HM. Immature epithelial Na+ channel expression is one of the pathogenetic
mechanisms leading to human neonatal respiratory distress syndrome. Proc Assoc Am
Physicians 1996; 108:345.

9. Wilson SM, Olver RE, Walters DV. Developmental regulation of lumenal lung fluid and electrolyte
transport. Respir Physiol Neurobiol 2007; 159:247.

10. Vyas H, Field D, Milner AD, Hopkin IE. Determinants of the first inspiratory volume and
functional residual capacity at birth. Pediatr Pulmonol 1986; 2:189.

11. Blank DA, Kamlin COF, Rogerson SR, et al. Lung ultrasound immediately after birth to describe
normal neonatal transition: an observational study. Arch Dis Child Fetal Neonatal Ed 2018;
103:F157.

12. Jain A, Mohamed A, Kavanagh B, et al. Cardiopulmonary Adaptation During First Day of Life in
Human Neonates. J Pediatr 2018; 200:50.

13. van Vonderen JJ, te Pas AB, Kolster-Bijdevaate C, et al. Non-invasive measurements of ductus
arteriosus flow directly after birth. Arch Dis Child Fetal Neonatal Ed 2014; 99:F408.

14. Noori S, Wlodaver A, Gottipati V, et al. Transitional changes in cardiac and cerebral
hemodynamics in term neonates at birth. J Pediatr 2012; 160:943.

15. American Academy of Pediatrics. Overview and principles of resuscitation. In: Textbook of Neo
natal Resuscitation, 5th ed, Kattwinkel J (Ed), American Academy of Pediatrics, 2006.

16. Katheria A, Blank D, Rich W, Finer N. Umbilical cord milking improves transition in premature
infants at birth. PLoS One 2014; 9:e94085.
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17. Niermeyer S, Velaphi S. Promoting physiologic transition at birth: re-examining resuscitation

and the timing of cord clamping. Semin Fetal Neonatal Med 2013; 18:385.

Topic 4970 Version 15.0

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GRAPHICS

Fetal circulation

The degree of oxygen saturation is indicated by shading, as explained in the

figure key.

Graphic 66765 Version 4.0

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Fetal cardiac circulation: Distribution of right (RVO) and left (LVO)

ventricular output

Diagrammatic representation of the fetal circulation. Show n is the distribution of right

and left ventricular output (RVO, LVO) and the combined cardiac output (CCO) in the
circulation of the fetal lamb. The largest proportion of the CCO is distributed to the
placenta for oxygenation. Through preferential streaming, w ell-oxygenated left
ventricular blood supplies the brain and heart w hile right ventricular blood w ith low er
oxygen content is predominantly distributed to the placenta.

DV: ductus venosus; IVC : inferior vena cava; SVC : superior vena cava; AAO: ascending aorta.

Originally published in: Fetal cardiology. Yagel S, Silverman NH, Gembruch U (Eds), Taylor &
Francis, Oxford, UK 2003. p.125. Reproduced with permission from Taylor & Francis. Copyright ©
2003. Algorithm updated from: Baschat AA, Gembruch U. Development of fetal cardiac and
extracardiac Doppler flows in early gestation. In: Fetal Cardiology, 2nd ed, Yagel S, Silverman
NH, Gembruch U (Eds), Informa Healthcare USA, Inc, New York 2009. p.157.

Graphic 70458 Version 5.0

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Contributor Disclosures
Caraciolo J Fernandes, MD Nothing to disclose Leonard E Weisman, MD Grant/Research/Clinical Trial
Support: Vax-Immune [Ureaplasma diagnosis, vaccines, antibodies, other medical diagnostics and pre-
analytical devices]. Patent Holder: Baylor College of Medicine [Ureaplasma diagnosis, vaccines, antibodies,
process for preparing biological samples]. Equity Ownership/Stock Options: Vax-Immune [Ureaplasma
diagnosis, vaccines, antibodies, other medical diagnostics and pre-analytical devices]. Melanie S Kim,
MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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