Physiologic transition from intrauterine to extrauterine life

INTRODUCTION — The transition from intrauterine to extrauterine life depends upon multiple physiologic changes that occur at birth. In most newborns, these changes occur successfully at delivery without requiring any special assistance. However, approximately 10 percent of newborns require some intervention at delivery; <1 percent require extensive resuscitation in the delivery room [1].

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

FETUS — Prior to delivery, the 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".)

Fetal circulation — 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).

Right-to-left shunting occurs at two levels in the fetus:

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

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

Oxygenated blood returns to the fetus from the placenta through the umbilical vein. Most of it then flows into the inferior vena cava and then the right atrium (figure 1), though a small amount perfuses the liver. After returning to the right atrium, oxygenated blood is largely shunted to the left atrium through the foramen ovale because of a streaming effect. It then travels to the left ventricle and aorta. (See 'Fetal oxygenation' below.)

The right atrium also receives venous return from the superior vena cava and the distal inferior vena cava. There is minimal mixing of this deoxygenated blood with the oxygenated blood originating from the ductus venosus (figure 1). Most of this venous return then travels from the right atrium to the right ventricle and then out to the pulmonary artery. Most of the right ventricular output (approximately 90 percent) bypasses the lung and flows through the patent ductus arteriosus to the descending aorta. This deoxygenated then flows through the aorta to the lower body. Approximately 40 to 45 percent of the cardiac output flows through the umbilical arteries to the placenta, where gas exchange (oxygenation and release of carbon dioxide) and nutrient exchange occur. (See 'Fetal oxygenation' below.)

Studies using magnetic resonance imaging (MRI) and Doppler ultrasound to measure fetal blood flow suggest that the relative distribution of the combined cardiac output (ie, blood flow from both the right and left ventricles) is approximately as follows [2-4]:

●Placenta – 40 to 45 percent

●Brain – 25 to 30 percent

●Abdominal organs and lower body – 20 to 25 percent

●Lungs – 8 to 10 percent

●Heart – 3 to 5 percent

Fetal oxygenation — Blood in the fetal circulation has a lower oxygen level compared with oxygen levels seen in extrauterine life. In the fetus, the highest oxygen levels are found in the umbilical vein, which has a partial pressure of oxygen (PO₂) of 55 to 60 mmHg [5]. As blood travels through the fetal circulation, oxygen levels decrease due to mixing with venous return and oxygen consumption by tissues. Blood returning to the placenta has a PO₂ of 15 to 25 mmHg.

The low oxygen levels in fetal blood provide adequate tissue oxygenation because of the following factors [6]:

●Fetal hemoglobin – Fetal hemoglobin (Hgb F) has increased oxygen affinity compared with mature hemoglobin (Hgb A), which facilitates oxygen transport across the placenta. The high affinity of Hgb F 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.

●Differential blood flow – The fetal circulation preferentially delivers more oxygenated blood to vital organs (eg, brain, heart, liver) (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 oxygen level in the fetal circulation also contributes to maintaining high pulmonary vascular resistance (since hypoxemia causes pulmonary vasoconstriction), which further promotes right-to-left shunting.

TRANSITION AT DELIVERY — When the umbilical cord is clamped at birth, several rapid physiologic changes must occur for the neonate to successfully make the transition from intrauterine to extrauterine life. These include:

●Alveolar fluid clearance

●Lung expansion

●Decrease in pulmonary vascular resistance with corresponding increase in pulmonary blood flow

●Increase in systemic blood pressure

●Closure of the right-to-left shunts (foramen ovale and ductus arteriosus)

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 [7]. 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 [8-10]. 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 [9]. Failure of hormonal adaptation and lack of increase in gene expression of the epithelial sodium channel is associated with respiratory distress at birth [11].

●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 [12]. The initial negative hydrostatic pressure drives alveolar fluid from the air spaces into the interstitium and subsequently the pulmonary vasculature and lymphatics [13].

●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 [6].

In a study of infants (gestational age ≥35 weeks), lung aeration and partial liquid clearance were achieved in the first few minutes after birth [14]. 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) [12]. Lung expansion also stimulates surfactant release, which reduces alveolar surface tension, increases compliance, and stabilizes the FRC.

Circulatory changes — At delivery, the following circulatory changes occur simultaneously:

●Increase in systemic vascular resistance and systemic blood pressure – This occurs when the umbilical cord is clamped, which removes the low-resistance placenta from the neonatal circulation.

●Decrease in pulmonary vascular resistance and pulmonary artery pressure – This occurs as a result of lung expansion [15]. (See 'Lung expansion' above.)

These two changes result in reversal of the direction of blood flow across the ductus arteriosus (ie, it flows left-to-right), resulting in an increased pulmonary blood flow [15-17]. With increased lung perfusion and expansion, neonatal oxygenation levels increase, which stimulates constriction of the ductus arteriosus. Constriction of the ductus arteriosus usually results in functional hemodynamic closure within 10 to 15 hours after delivery. (See "Patent ductus arteriosus (PDA) in term infants, children, and adults: Clinical manifestations and diagnosis", section on 'Ductal constriction'.)

The shift to left-to-right shunting after delivery also results in increased left ventricular stroke volume and increased cerebral perfusion [15,18]. In addition, the increased pulmonary blood flow in turn increases pulmonary venous return to the left atrium, with a resulting rise in left atrial pressure. As the left atrial pressure increases and the right atrial pressure falls, right-to-left shunting across the foramen ovale decreases. The flap of the foramen ovale closes when the left atrial pressure exceeds the right atrial pressure. Intra-atrial shunting functionally ceases at this point, although permanent anatomic closure of the foramen ovale (ie, fusion of the flap) often is not complete until the age of two years. (See "Patent foramen ovale", section on 'Embryology'.)

DIFFICULTIES IN TRANSITION — Although most newborns successfully transition from intrauterine to extrauterine life without incident, approximately 10 percent have some difficulty and require resuscitative measures at birth [1].

The following sections review some of the more common reasons for difficulties in transitioning from the intrauterine to extrauterine life. Details of neonatal resuscitation are provided separately. (See "Neonatal resuscitation in the delivery room".)

Preterm birth — Preterm neonates are inherently more likely to experience difficulties in transitioning from the intrauterine to extrauterine environment given their smaller size and immature development. Preterm neonates can have respiratory difficulties due to surfactant deficiency (ie, respiratory distress syndrome [RDS]). RDS and other short-term complications of preterm birth are discussed in detail separately. (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis" and "Overview of short-term complications in preterm infants".)

Neurologic impairment — Newborns with neurologic impairment (eg, from perinatal asphyxia or exposure to maternally administered opioids) may present with poor respiratory effort at birth. The lack of vigorous, regular spontaneous respirations interferes with alveolar fluid clearance, lung inflation, and reduction of pulmonary vascular resistance. A rare cause of poor respiratory effort at birth is spinal muscular atrophy. (See "Perinatal asphyxia in term and late preterm infants" 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 (PVR). Causes of blockage include:

●Congenital upper airway malformation (eg, bilateral choanal atresia, laryngeal web, Pierre Robin sequence) (see "Congenital anomalies of the nose" and "Congenital anomalies of the larynx" and "Syndromes with craniofacial abnormalities", section on 'Pierre Robin sequence')

●Meconium or mucus in the airway (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")

●External compression of the airway (eg, cystic hygroma, congenital goiter) (see "Vascular lesions in the newborn", section on 'Lymphatic malformations' and "Approach to congenital goiter in newborns and infants")

Pulmonary disorders — Neonatal pulmonary disorders that can present with respiratory distress at delivery include (see "Overview of neonatal respiratory distress and disorders of transition"):

●Transient tachypnea of the newborn (see "Transient tachypnea of the newborn")

●RDS (see "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis")

●Pneumothorax (see "Pulmonary air leak in the newborn")

●Pleural effusions (eg, hydrops fetalis) (see "Approach to the neonate with pleural effusions" and "Nonimmune hydrops fetalis in the neonate: Causes, presentation, and overview of neonatal management")

●Pulmonary hypoplasia (eg, due to congenital diaphragmatic hernia or severe congenital anomalies of the kidney and urinary tract) (see "Evaluation of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Amniotic fluid' and "Congenital diaphragmatic hernia (CDH) in the neonate: Clinical features and diagnosis")

Persistent pulmonary hypertension — In persistent pulmonary hypertension of the newborn (PPHN), PVR remains abnormally elevated after birth, resulting in right-to -eft shunting through the ductus arteriosus and foramen ovale. This can result in severe life-threatening hypoxemia and hypercapnia that may not respond to conventional respiratory support. PPHN is usually associated with an underlying respiratory or systemic condition (eg, sepsis, meconium aspiration syndrome), though some cases are idiopathic. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Congenital heart disease — Newborns with severe congenital heart disease may have difficulty transitioning to extrauterine life, especially those with cyanotic and/or ductal-dependent lesions (table 1). (See "Identifying newborns with critical congenital heart disease", section on 'Clinical features'.)

SUMMARY

●Fetal circulation – The low vascular resistance of the placenta and the high vascular resistance of the fluid-filled fetal lungs result in right-to-left shunting characteristic of the fetal circulation (figure 1). (See 'Fetal circulation' above.)

●Oxygen delivery in the fetus – Blood in the fetal circulation has a low oxygen level (eg, partial pressure of oxygen [PO₂] 25 to 60 mmHg). This provides adequate oxygenation for the developing fetus because:

•Fetal hemoglobin has a high oxygen affinity

•Fetal metabolism and oxygen consumption are much lower than that of extrauterine life

•The fetal circulation preferentially delivers more oxygenated blood to vital organs (eg, brain, heart, liver)

●Transition at birth ‒ When the umbilical cord is clamped at birth, several rapid physiologic changes must occur for the neonate to successfully make the transition from intrauterine to extrauterine life. These include (see 'Transition at delivery' above):

•Alveolar fluid clearance (see 'Alveolar fluid clearance' above)

•Lung expansion (see 'Lung expansion' above)

•Decrease in pulmonary vascular resistance with corresponding increase in pulmonary blood flow (see 'Circulatory changes' above)

•Increase in systemic blood pressure (see 'Circulatory changes' above)

•Closure of the right-to-left shunts (foramen ovale and ductus arteriosus) (see 'Circulatory changes' above)

●Difficulties in transitioning ‒ Although most newborns successfully transition from intrauterine to extrauterine life, approximately 10 percent have some difficulty and require resuscitative measures at birth. (See "Neonatal resuscitation in the delivery room".)

Some of the more common reasons for difficulties in transitioning from the intrauterine to extrauterine life:

•Preterm birth (see 'Preterm birth' above)

•Neurologic impairment (eg, perinatal asphyxia or exposure to maternally administered opioids) (see 'Neurologic impairment' above)

•Blockage of the airways (see 'Blockage of the airways' above)

•Pulmonary disorders (eg, transient tachypnea of the newborn, pneumothorax) (see 'Pulmonary disorders' above)

•Persistent pulmonary hypertension (see 'Persistent pulmonary hypertension' above)

•Congenital heart disease (see 'Congenital heart disease' above)