Physiologic transition from intrauterine to extrauterine life Author Caraciolo J Fernandes, MD Section Editor Leonard E Weisman, MD Deputy Editor

Melanie S Kim, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2013. | This topic last updated: Dec 19, 2012. 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 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 (figure 2). 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 to that seen in extrauterine life. The highest oxygenated fetal blood is found in the umbilical vein with PO2 as high as 55 7 mmHg [2].

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 [3]: Fetal hemoglobin Fetal hemoglobin has increased oxygen affinity compared to maternal 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 to 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 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, including labor, initial breaths, and thoracic squeeze.

Labor Studies in lamb models have helped elucidate a better understanding of the regulation of alveolar fluid [4]. 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 [5-7]. 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 [6]. Initial breaths The initial effective breaths of the neonate generate high transpulmonary pressures: mean esophageal pressures of -52 cm H2O during inspiration and 71 cmH2O during expiration have been measured in term infants [8]. 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 [3].

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) [8]. 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. These two changes decrease the right-to-left shunt at the ductus arteriosus, resulting in an increased blood flow through the pulmonary arteries and lungs. 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 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 [9]: 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 [9]: 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 [3]. (See "Congenital anomalies of the nose", section on 'Choanal atresia' and "Congenital anomalies of the jaw, mouth, oral cavity, and pharynx", section on 'Robin sequence' 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 fullterm 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 and clinical manifestations 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 If adequate ventilation does not occur immediately after birth because of apnea, airway blockage, or impaired lung function, hypoxia and acidosis develop, leading to persistence of pulmonary vasoconstriction and pulmonary hypertension. Persistent pulmonary hypertension causes persistent right-to-left shunting through the ductus arteriosus and foramen ovale, resulting in decreased pulmonary arterial flow and continued hypoxemia and hypercapnia. (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 "Congenital heart disease (CHD) in the newborn: Presentation and screening for critical CHD", section on 'Critical CHD'.) 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 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.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Kattwinkel J, Perlman JM, Aziz K, et al. Part 15: neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S909. 2. 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. 3. Goldsmith JP. Delivery room resuscitation of the newborn. In: Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 9th, Martin RJ, Fanaroff AA, Walsh MC (Eds), Elsevier Mosby, St. Louis 2011. Vol 1, p.449. 4. Olver RE, Walters DV, M Wilson S. Developmental regulation of lung liquid transport. Annu Rev Physiol 2004; 66:77. 5. Bland RD, Nielson DW. Developmental changes in lung epithelial ion transport and liquid movement. Annu Rev Physiol 1992; 54:373. 6. 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.

7. Wilson SM, Olver RE, Walters DV. Developmental regulation of lumenal lung fluid and electrolyte transport. Respir Physiol Neurobiol 2007; 159:247. 8. 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. 9. American Academy of Pediatrics. Overview and principles of resuscitation. In: Textbook of Neonatal Resuscitation, 5th ed, Kattwinkel, J (Ed), American Academy of Pediatrics 2006. Topic 4970 Version 7.0