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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 ourpeer review process is
complete.
Literature review current through:  Jan 2017. | This topic last updated: Dec 02, 2015.

INTRODUCTION — The successful transition from intrauterine to extrauterine life is dependent

upon significant physiologic changes that occur at birth. In almost all infants, these changesear
successfully completed at delivery without equiring
r any special assistance. However, about 10
percent of infants will need some intervention, and less than 1 per
cent will require extensive
resuscitative measures at birth [1].

The physiologic changes that occur in the transition om

fr intrauterine to extrauterine life are
reviewed here. The indications and principles of neonatal esuscitation
r are discussed separately.
(See "Neonatal resuscitation in the delivery o
r om".)

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 vascularesistancer 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 vascularesistance
r 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 esonance
r imaging (MRI) and Doppler ultrasound to measur e
fetal blood flow suggest pulmonary blood flow may be higher (11 to 15 per cent of combined
ventricular output) [2,3].

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

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

● Ductus arteriosus − Blood shunted fr
om 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 emaining
r 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

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oxygenated blood originating from the ductus venosus (figure 1). Almost all of the right ventricular
output (90 percent) bypasses the lung and is shunted thr ough the patent ductus arteriosus to the
descending aorta distal to the origin of the car
otid 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 PO
2 as high
as 55±7 mmHg [4]. Oxygen saturation decreases when mixed with venous return, so that blood
returning to the placenta will have aPO2 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 compar

ed with extrauterine life requires
less oxygen because fetal metabolism and o
xygen consumption are decreased:

• The fetus does not need to maintain ther

moregulation because the thermal environment
is maintained by the mother.

• In the fetus, many physiologic functions ar

e reduced, including respiratory effort,
gastrointestinal digestion and absorption, and enal
r tubular reabsorption (due to the low
glomerular filtration rate). These changes educe
r tissue oxygen consumption.

● 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 thr ough 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 thr ough
the foramen ovale to the left side of the heart and aorta. This shunting is achieved
through differential velocities of incoming venous blood str eams and directing of
oxygenated blood to the foramen ovale. This educes
r mixing of oxygenated blood with
deoxygenated blood entering the right atrium fr om the superior vena cava. The
deoxygenated blood is directed toward the right ventricle and shunted thr ough the ductus
arteriosus to the aorta, but distal to the origin of the car
otid and coronary arteries.

The low fetal oxygen tension maintains the architecture of the fetal circulation by causing
pulmonary vascular constriction, which maintains pulmonary vascularesistance
r 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 c
ord 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

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● Circulatory changes with increases in pulmonary perfusion and systemic pr

essure, and closure
of the right-to-left shunts of the fetal circulation

Alveolar fluid clearance — Several mechanisms contribute to the clearance of alveolar fluid,

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 hor mones, 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 incr eases gene expression of the epithelial sodium
channel, promoting further resorption of alveolar fluid [8].

● 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 HO 2 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 pr
obably is only a
minor contributor to alveolar fluid clearance 5].
[

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

Circulatory changes — With the clamping of the umbilical cor d, 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.

These two changes decrease the fetal right-to-left shunt at the ductus arteriosus, e r sulting in an
increasing left-to-right shunt at the ductus arteriosus [11]. These two changes also result in an
increased blood flow through the pulmonary arteries and lungs. This shif t 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]. 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 venouseturn r 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 e r quire
resuscitative efforts at birth. (See"Neonatal resuscitation in the delivery o
r om".)

The following risk factors are associated with a greater likelihood of having difficulty making a
successful transition and of er quiring resuscitation [13]:

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● 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 pr

evia), or either
oligohydramnios or polyhydramnios

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

or meconium-stained amniotic fluid, antenatal asphyxia with abnor mal 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 following13]:

[

● 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 cir
culation)
● 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, andeduction
r of pulmonary vascular
resistance. Poor or absent spontaneous e r spiratory effort suggests that the infant is neurologically
depressed (usually brain asphyxia) or has impair ed muscular function. Causes of impair ed
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 malfor mation
(eg, bilateral choanal atresia or Robin sequence syndrome); the presence of meconium or mucus
in the airway; or rarely, airway obstruction due to disor
ders 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 obin
'R
sequence' and "Clinical features and diagnosis of meconium aspiration syndr ome", section on
'Airway obstruction'.)

Impaired lung function — The following conditions can impair lung function,esulting

r in
respiratory distress of the neonate at delivery:

● External causes − Any collection between the lung and the chest wall will pr event 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 congenita l 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'.)
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● Intrinsic lung disease − In preterm infants, impaired lung function is due to deficient
pulmonary surfactant, leading to hyaline membrane disease, or antenatally acquir ed
pneumonia. In full-term infants, causes include transient tachypnea of the newbor n, which
results from delayed resorption and clearance of fetal lung fluid, and antenatally acquired
pneumonia. (See "Pathophysiology, clinical manifestations, and diagnosis ofespiratory
r
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 newbor n

(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 canesult r 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 af ter birth. (See "Persistent
pulmonary hypertension of the newbor n".)

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 ar e
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 impair ed left
ventricular function. (See"Identifying newborns with critical congenital heart disease", section on
'Clinical features'.)

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 equiring
r any special assistance.

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

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

● A more difficult transition at birth may be due to the lack ofespiratory

r 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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GRAPHICS

Fetal circulation

The degr ee of o xygen saturation is indicate d by shading, as e xplained in the figur e

key.

Graphic 66765 Version 4.0

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Fetal cardiac circulation: Distribution of right (RV

O) and left (LVO)
ventricular output

Diagrammatic r epresentation of the fetal cir culation. Shown is the distribution of right and
left ventricular output (R VO, LVO) and the c ombined car diac output (CCO) in the cir culation
of the fetal lamb. The lar gest pr oportion of the CCO is distributed to the placenta for
oxygenation. Thr ough pr eferential str eaming, well- oxygenated lef t ventricular blood
supplies the brain and heart while right ventricular blood with lower o xygen content is
predominantly distributed to the placenta.

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

Originally published in: Fetal cardiology . Yagel S, Silverman NH, Gembruch U (Eds), T aylor & Francis,
Oxford, UK 2003. p.125. Reproduced with permission from T aylor & Francis. Copyright © 2003.
Algorithm updated from: Baschat AA , Gembruc h 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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