Embryonic Period

The embryonic period begins approximately 26 days after conception.1–4 During this period, the lung begins to emerge as an outpouching of the primitive foregut (see Figure 16-1). This outpouching elongates and separates into two bronchial buds and the trachea. The right lung bud parallels the esophagus and branches further into three additional buds. The left lung bud is directed more laterally and divides into two additional buds. Thus, the asymmetry of the main bronchi present in the adult is established. The right and left lung buds continue to grow and branch into segmental and subsegmental bronchi.

By the end of the embryonic period (near the sixth week of gestation), the major bronchi are formed, consisting of 10 right branches and 9 left branches (Figure 16-2).^1–4 During this time, the pulmonary arteries and veins emerge from the developing heart. The diaphragm also develops during this stage and is formed by about the seventh gestational week.^1–4 The diaphragm separates abdominal contents from the thorax. Failure of the diaphragm to form completely can result in congenital diaphragmatic hernia, allowing abdominal organs to enter the pleural cavity and compress the lungs and possibly lead to severe underdevelopment, or hypoplasia, of the lung.

The dorsal portion of the foregut evolves into the esophagus. The formation of the tracheoesophageal septum separates the esophagus from the trachea (Figure 16-3). Teratogens (agents that disturb fetal development, such as drugs, infection, or chemicals) can produce congenital anomalies and may cause injury to the embryo during this stage of development, such as tracheoesophageal fistula (an abnormal opening between the trachea and the esophagus), choanal atresia (occlusion of the passageway between the nose and the pharynx), and pulmonary hypoplasia (underdevelopment of the lung).

Pseudoglandular Period

The pseudoglandular period begins about the sixth week and continues into the sixteenth week of gestation.1–3 The lung resembles a gland at this stage, giving rise to the name pseudoglandular. Branching and division of the tracheobronchial tree continue to occur asymmetrically and dichotomously (branching into two parts) forming the conducting airways. By the end of this period, the formation of respiratory bronchioles is nearly complete. Cilia, mucous glands, and goblet cells begin to appear in the epithelial lining at approximately 10 weeks’ gestation.^1–4 Absence or dysfunction of cilia can impair mucous transport and lead to chronic respiratory infections (see Chapter 1). Smooth muscle, which originates from the mesoderm, also appears during this stage and is present in the large bronchi by the twelfth week. Any event that alters the development of smooth muscle, cartilage, or vascular structures during this stage can lead to pulmonary disorders in infancy. A fetus born prematurely during this period is unable to survive.

Canalicular Period

The third stage of development, or the canalicular period, begins at approximately 17 weeks and continues through 26 weeks’ gestation.1–4 During this stage, the terminal bronchioles subdivide further to form the basic structure of the acinus, or gas-exchanging unit.^1–4 Capillaries begin to establish a network around the alveoli allowing for limited gas exchange by 22 weeks.^1–4 At approximately 23 weeks’ gestation, type I and type II alveolar cells begin to differentiate. Type I cells are important in the development of the alveolar capillary membrane, whereas type II cells are involved in surfactant production. By the end of the canalicular stage, some thin-walled primitive alveoli have developed, and the lung tissue is well vascularized. A fetus born prematurely at the end of this stage (approximately 24 to 26 weeks’ gestation) is potentially capable of air breathing and may survive with intensive medical care. The immature respiratory system often requires mechanical ventilatory assistance or surfactant replacement therapy or both. (See Chapter 3 for further discussion of surfactant replacement therapy.)

Saccular Period

The saccular period begins around 26 weeks of gestation.1–4 During this stage of development, the terminal airways continue to widen and form cylindrical structures called saccules. These saccules subdivide to form subsaccules, which eventually develop into alveoli. By the end of this stage, the blood-air barrier is established allowing for adequate gas exchange for the fetus if it is born prematurely. Alveolar cells continue to differentiate into type I and type II cells, with type II cells synthesizing pulmonary surfactant. Surfactant is a complex mixture of phospholipids and proteins that lines the inner walls of the alveoli and offsets surface tension forces at the air-liquid interface of the alveoli (see Chapter 3). Surfactant production begins at approximately 20 weeks’ gestation and is present in only small amounts in infants born prematurely. The production of surfactant increases during gestation and reaches adequate levels to support air breathing during the last two weeks of pregnancy. Mature surfactant contains the phospholipid phosphatidylglycerol (PG), which is required for normal surfactant function. PG first appears at about 35 weeks of gestation and increases to peak levels at term.^1–3 Immature surfactant has insufficient PG and is easily inhibited by hypoxia, hypothermia, and acidosis. Thus, premature infants, especially infants born before 35 weeks’ gestation, are susceptible to developing respiratory distress syndrome (RDS) because of surfactant deficiency. Maternal administration of prenatal corticosteroids, which induce surfactant production, and the administration of exogenous surfactant directly into the newborn lungs after birth can decrease the severity of RDS and the need for mechanical ventilation.

Alveolar Period

The final period of lung development, the alveolar period, begins at approximately 36 weeks’ gestation and extends through infancy and childhood.1–4 During this stage, alveoli continue to develop and mature at a rapid rate, and pulmonary surfactant production increases. The full-term fetus has developed numerous alveoli with mature surfactant, creating an efficient alveolar capillary gas-exchange membrane. Although the lungs are completely developed, they do not take on a respiratory function until the moment of birth.

The lung at birth is not a miniature adult lung; it continues to develop and grow well into childhood. During the first years of life, alveoli develop rapidly paralleled by the expansion of the pulmonary capillary bed. As body weight increases, alveolar development increases proportionally, matched by an increase in the lungs’ oxygen uptake. At birth, approximately 50 million alveoli are present; by age 8 years, this number has increased to about 300 million alveoli.1–3 This explains why children who sustain lung injury during the neonatal period (birth to 28 days) can seemingly “outgrow” their lung disease. Alveolar development is usually complete by age 8; from this time on, alveoli increase in size until thoracic growth is complete.^1–4 Collateral pathways such as the canals of Lambert and pores of Kohn are poorly developed in young children. Consequently, children less than 10 years of age are more likely to develop airway obstruction and atelectasis than older children.⁵

Maternal-Fetal Gas Exchange

The placenta is a highly vascular gas-exchange organ, providing a circulatory link between mother and embryo; it is required for survival of the fetus. The fetus relies on maternal blood flow through the placenta for the exchange of nutrients and wastes, including oxygen delivery and carbon dioxide removal. The placenta separates the fetus from the endometrium (mucous membrane lining) of the uterus and consists of two compartments: (1) the fetal compartment, arising from the embryonic sac, and (2) the maternal compartment, derived from the endometrium. The placenta transports nutrients and wastes between mother and fetus through the umbilical cord. Abruptio placentae, or premature detachment of the placenta from the uterine wall, is a medical emergency and may result in life-threatening maternal hemorrhage and fetal asphyxia.

Shortly after the fertilized egg implants in the uterine wall, the placenta begins to develop with small finger-like projections invading the endometrial lining of the uterus. These projections, called chorionic villi, continue to branch further into the endometrium, creating irregular pockets around the villi called intervillous spaces (Figure 16-4). Maternal blood fills these spaces supplying oxygen and nutrients to the fetus. As the fetus matures, villi increase in number, expanding the surface area for gas exchange.

Maternal blood enters the intervillous space through the spiral arteries (see Figure 16-4). At this point, the diffusion of oxygen, carbon dioxide, and metabolic products occurs between maternal and fetal blood. After this exchange, maternal blood exits the intervillous spaces through venous channels. Oxygenated fetal blood leaves the chorionic villi via capillaries that merge into a single umbilical vein.

The placenta is not a very efficient gas-exchange organ. The PO₂ of maternal blood in the intervillous spaces is about 50 mm Hg, but blood leaving the placenta through the umbilical vein to oxygenate the fetus has a PO₂ value of only about 30 mm Hg. Fetal blood returning through the umbilical arteries to the placenta for reoxygenation has a PO₂ of only about 19 mm Hg.² The maximum PO₂ experienced by the fetus is about 30 mm Hg. The primary factor limiting oxygen transport to the fetus is blood flow. Any factor diminishing uterine or fetal blood flow results in fetal hypoxia and intrauterine growth retardation (IUGR). Severe reduction in fetal blood flow may result in fetal asphyxia and death. Table 16-3 shows normal blood gas values of the umbilical arteries and veins in a full-term fetus.

The umbilical cord connecting the placenta to the fetus contains one vein that delivers oxygenated blood to the fetus and two arteries that carry deoxygenated blood from the fetus back to the placenta. Placental circulation can be compared with the pulmonary circulation in postnatal life: The placenta functions similar to the lungs. The umbilical vein carries oxygenated blood from the placenta to the fetus just as the pulmonary veins carry oxygenated blood from the lungs to the left atrium. Umbilical arteries carry deoxygenated fetal blood back to the placenta for reoxygenation, just as the pulmonary artery carries deoxygenated blood from the body back to the lungs. See the section on fetal circulation later in this chapter for a complete description of fetal circulation.

A tough gelatinous material called Wharton’s jelly surrounds the umbilical vessels, which prevents the cord from kinking and occluding blood flow to the fetus (Figure 16-5). After birth, the umbilical vessels remain open for a short time, allowing vascular access for fluid infusion and blood sampling.

Fetal Hemoglobin

Fetal blood oxygen tension is low compared with values seen after birth. As stated previously, the most oxygenated fetal blood is found in the umbilical vein with a PO₂ of approximately 30 mm Hg. Nevertheless, fetal tissues are adequately oxygenated for the following reasons: (1) the unique blood flow through fetal circulation results in increased blood flow to vital organs (liver, heart, and brain); (2) the fetus has an increased number of red blood cells and hemoglobin compared with the adult; (3) and fetal hemoglobin (HbF) has an increased affinity for oxygen compared with adult hemoglobin.⁶

HbF is the predominant form of hemoglobin in the fetus at approximately eight weeks of gestation; HbF continues to increase until the third trimester when its concentration begins to decline gradually. At 24 weeks of gestation, HbF constitutes about 90% of the total hemoglobin, whereas at birth, HbF represents approximately 70% of the total hemoglobin.⁴ The production of HbF decreases rapidly after birth, and by 6 to 12 months of age, HbF has been replaced by adult hemoglobin (HbA).⁴

HbF has a greater affinity for oxygen than HbA. This increase in oxygen affinity is associated with a left shift of the fetal oxyhemoglobin dissociation curve (Figure 16-6), which means that oxygen binds more readily to HbF. The placental transfer of oxygen from maternal blood to fetal blood is thus facilitated, allowing the fetus to survive in a relatively hypoxic environment. Therefore, a PO₂ of 30 mm Hg in the fetus corresponds to a hemoglobin saturation of 75% to 80% (see Chapter 8 for further discussion of the oxyhemoglobin equilibrium curve). Maternal hypoxia or hyperventilation can have profound effects on fetal oxygenation; in the case of maternal hyperventilation, the resulting alkalosis shifts the maternal oxygen-hemoglobin equilibrium curve to the left (greater hemoglobin affinity for oxygen), decreasing oxygen availability to the fetus and potentially causing fetal distress.⁴

Amniotic Fluid

Amniotic fluid, a clear liquid produced by the fetal membranes and the fetus, appears early and surrounds the fetus throughout pregnancy. Amniotic fluid is composed mainly of water; however, its composition changes throughout gestation. During the first half of gestation, amniotic fluid is similar to maternal and fetal serum; in the second half, it is similar to dilute fetal urine with added phospholipids from the fetal lung.⁴ Amniotic fluid is continuously secreted and reabsorbed throughout gestation with a volume reaching approximately 1000 mL at full term. The fetus swallows this fluid, which is absorbed by the digestive tract and excreted as urine. Amniotic fluid serves many important functions. It protects the fetus from trauma by cushioning any blows or impacts to the maternal abdomen, and it allows the fetus to move freely, permitting fetal growth and development. In addition, amniotic fluid helps control the temperature of the fetus by maintaining a relatively constant thermal environment.

Polyhydramnios—an excessive amount of amniotic fluid—occurs when the fetus does not swallow and absorb the usual amount of amniotic fluid. The most common cause of polyhydramnios is a birth defect of the central nervous system or gastrointestinal tract resulting in a fetal swallowing dysfunction. A complication associated with polyhydramnios is premature rupture of amniotic membranes, which may lead to premature delivery.

Oligohydramnios—too little amniotic fluid—results from prematurely ruptured membranes, placental dysfunction, or fetal abnormalities such as renal agenesis (failure of the kidneys to form). The absence of fetal urine as a component of amniotic fluid is the most common cause of oligohydramnios. Complications for the fetus with oligohydramnios include asphyxia secondary to umbilical cord compression and skeletal deformities caused by uterine wall compression of the fetus.

As stated previously, the fetus periodically exhibits shallow respiratory chest movements or “fetal breathing.” This normal occurrence moves amniotic and fetal lung fluid into and out of the oropharynx. Vagal stimulation and hypoxic stress caused by cord compression may cause rectal sphincter muscles to relax, resulting in release of meconium (fetal bowel contents) into the amniotic fluid. Deep gasping movements of the distressed fetus may cause amniotic fluid and meconium to be aspirated into the infant’s lung. Meconium aspiration usually leads to respiratory distress after birth because of airway obstruction or chemical irritation; this is known as meconium aspiration syndrome. Meconium is found in amniotic fluid in approximately 12% of all births.⁴

Amniocentesis involves the withdrawal of a sample of amniotic fluid for laboratory analysis. It is performed to test for lung maturity and to aid in the diagnosis of fetal abnormalities. The proportions of lecithin and sphingomyelin (L/S ratio) and the amount of phosphatidylglycerol in amniotic fluid are predictors of lung maturation (see Chapter 3 for further discussion).

Respiratory Transition

As stated previously, the production of fetal lung fluid decreases shortly before term delivery, leaving approximately 35% of the original lung volume to be removed by the squeeze effect on the chest during vaginal delivery and by absorption via pulmonary capillaries and the lymphatic system after birth. Before delivery, the fetal lung contains 10 to 30 mL/kg of fluid, which is comparable to newborn functional residual capacity (FRC).⁴ Infants born by cesarean section and infants born after a precipitous (rapid) delivery do not benefit from vaginal chest compression and may experience retention of fetal lung fluid. Such fluid retention can result in short-term respiratory distress known as transient tachypnea of the newborn.⁴

After vaginal delivery, the thorax is decompressed and expands, creating a negative intrathoracic pressure that facilitates air entry into the lungs. With the first breaths, a newborn must generate pressures of −20 to −70 cm H₂O to overcome the surface tension of airless alveoli and the viscosity of residual lung fluid.¹⁵ As additional alveoli inflate with subsequent breaths, surface tension is reduced and transpulmonary pressures decrease, allowing the FRC to be established within a few hours of birth. A premature infant born with underdeveloped pulmonary surfactant has great difficulty establishing the FRC because of the continued need for high transpulmonary pressures to overcome the surface tension of collapsed alveoli; this predisposes the premature infant to the development of respiratory distress syndrome (see Clinical Focus 16-1).

A transient period of asphyxia occurs after the umbilical cord is clamped and placental blood flow ceases; this lack of oxygen helps activate chemoreceptors that stimulate breathing efforts. The sensory stimulation experienced by the neonate when transitioning from the warm, moist intrauterine environment to the cooler, drier delivery room, coupled with handling and drying further stimulate breathing. Approximately 10% of newborns require some assistance to begin breathing at birth, usually in the form of oxygen administration or positive pressure ventilation, or both.⁷ Box 16-1 summarizes conditions that may necessitate these interventions, known as neonatal resuscitation.

Circulatory Transition

The transition from fetal to neonatal circulation is characterized by a series of dramatic cardiovascular changes. The fetus prepares for this transition by increasing the expression of pulmonary vasodilators, nitric oxide synthase, and soluble guanylate cyclase (see Chapter 6, Humoral Agents and Nitric Oxide) late in gestational life.¹⁶ Figure 16-15 illustrates neonatal circulation. Shortly after delivery, the umbilical cord is clamped, eliminating the low-resistance placenta from the circulation; this decreases blood flow to the right atrium from the umbilical vein, resulting in a decrease in pressure on the right side of the heart. Clamping of the cord also stops blood flow from the descending aorta into the placenta, increasing left-sided pressures and systemic vascular resistance (SVR). As a result,

left-sided heart pressures become greater than right-sided heart pressures. This reversal in pressure gradients physically pushes and closes the flaplike valve between the atria, functionally closing the foramen ovale. Anatomical closure of the foramen ovale occurs as tissue grows around the opening; this process may not be complete for weeks to months. Occasionally, the foramen remains patent into adulthood.¹⁷

Elimination of blood flow through the umbilical circulation also results in closure of the ductus venosus within one week of delivery. The ductus venosus becomes the ligamentum venosum. As shown in Figure 16-16, PVR decreases after birth because of pulmonary vessel dilation associated with the ever increasing PO₂ and decreasing PCO₂ caused by ventilation—that is, ventilation removes the stimulus for hypoxic pulmonary vasoconstriction. Consequently, more blood flows to the lungs from the right ventricle, decreasing blood flow through the ductus arteriosus. Anatomical closure of the ductus arteriosus begins before birth, when endothelial tissue (known as intimal mounds) forms in the ductal lumen.¹³ At birth, smooth muscle surrounding the ductus arteriosus begins to constrict because ventilation elevates blood oxygen levels, which in turn inhibits the synthesis of prostaglandins responsible for ductal patency during fetal life. Normally, the ductus arteriosus anatomically closes two to four weeks after delivery and becomes the ligamentum arteriosum by the twelfth week of postnatal life.^3,13 Hypoxia and acidosis may delay closure of the ductus arteriosus, maintaining a pathway that allows blood to flow between the pulmonary artery and aorta. This condition is known as patent ductus arteriosus (PDA) and is discussed later in this chapter.

Infants born prematurely with underdeveloped surfactant (RDS) or with cardiopulmonary compromise (e.g., infection, meconium aspiration) may be unable to generate the high pressures required to expand collapsed alveoli at birth; this results in low PaO₂ and persistent pulmonary vasoconstriction, sometimes referred to as persistent fetal circulation. PVR remains elevated in these infants, causing continued right-to-left shunting through the foramen ovale and ductus arteriosus, similar to conditions in fetal life. Unoxygenated venous blood bypasses the lungs through the fetal anatomical shunts and flows directly into the systemic circulation, causing significant arterial hypoxemia. This condition, commonly known as persistent pulmonary hypertension of the newborn (PPHN), manifests in the first 12 hours after birth, causing respiratory distress and arterial hypoxemia that is often unresponsive to oxygen therapy (refractory hypoxemia) because the blood supply does not come in contact with the lungs. Nevertheless, oxygen therapy is used in an attempt to reduce PVR. Some infants require more aggressive therapy, such as extracorporeal life support (ECLS), also known as extracorporeal membrane oxygenation (ECMO), which is a process whereby the blood is oxygenated outside of the body via a mechanical membrane oxygenator. Nitric oxide therapy may also be used to reduce PVR (see Clinical Focus 16-5). Table 16-5

summarizes the major cardiovascular changes that occur during transition to extrauterine life. Many congenital cardiac defects require a PDA for survival, in which case prostaglandin therapy may be initiated to keep the ductus open. These conditions are described in the next section.

Ventricular Septal Defect

Failure of the septum between the right and left ventricles to close is known as a ventricular septal defect (VSD) and is the most common type of congenital heart defect (Figure 16-18).¹⁸ VSD may occur as an isolated defect or in association with other defects, such as tetralogy of Fallot. Symptoms depend on the size of the defect, which shunts blood from the left ventricle (higher pressure) to the right ventricle (lower pressure), causing right ventricular hypertrophy and pulmonary hypertension. Left untreated, a VSD may result in right-sided heart pressures exceeding left-sided heart pressures, reversing the direction of the shunt and causing cyanosis. Small VSDs may close on their own, whereas larger defects require surgical or catheter-based closure.

Patent Ductus Arteriosus

Patent ductus arteriosus (PDA) occurs when the ductus arteriosus, the fetal shunt between the pulmonary artery and the aorta, does not close after birth (Figure 16-19). The size of the PDA determines how much blood is shunted from the aorta into the pulmonary artery or, in reverse, from the pulmonary artery into the aorta. The latter occurs when PVR exceeds SVR (often seen in hypoxic premature infants), creating a cyanosis-producing defect. A large PDA shunts significant volumes of blood into the pulmonary circulation, causing pulmonary hypertension. Infants requiring treatment have two options: (1) administration of indomethacin (Indocin) or ibuprofen lysine (NeoProfen) to block the production of ductal prostaglandin (allowing ductal smooth muscle constriction) or (2) surgical intervention, either with a percutaneous transcatheter ductal closure (PTDC) device or by surgical closure.^19,20

Atrioventricular Septal Defect

Atrioventricular septal defect (AVSD), also called atrioventricular canal (AV canal) defect, results from failure of the septa between the atria and ventricles to develop (Figure 16-20). Varying degrees of tricuspid and mitral valve malformation are also present, resulting in one large chamber or “hole” that allows blood to mix freely between all four chambers. The resultant left-to-right shunt increases pulmonary blood flow and causes volume hypertrophy of all chambers. The scooped-out appearance of the heart gives rise to the term AV canal defect, which is one of the most common types of heart defect present in patients with Down syndrome. Surgical repair is possible.²¹

Transposition of the Great Arteries

Transposition of the great arteries (TGA) causes severe cyanosis that is usually evident shortly after birth. In TGA, the aorta arises from the right ventricle, and the pulmonary artery arises from the left ventricle, creating two parallel circulations (Figure 16-22). Deoxygenated blood flows from the right atrium, through the right ventricle to the aorta, out into the systemic circulation and then back to the right atrium. Oxygenated blood returning to the left atrium through the pulmonary veins travels through the left ventricle, into the pulmonary circulation, and back to the left atrium.

Some form of communication (e.g., PDA, VSD, ASD) must exist between the two circulations for mixing of blood to occur and to allow some oxygenated blood to be delivered to the tissues. Prostaglandin therapy may be initiated to ensure patency of the ductus arteriosus while the infant awaits corrective surgery.

Anomalous Venous Return

In anomalous venous return, oxygenated blood returning from the lungs is carried by the pulmonary veins abnormally to the right atrium instead of the left atrium (Figure 16-23). The result is mixing of pulmonary and systemic blood in the right atrium, increasing pressures on the right side of the heart. An ASD must be present for oxygenated blood to move across to the left side of the heart and into systemic circulation. These infants are usually cyanotic and must have early surgical intervention.

Tricuspid Atresia

Complete occlusion of the tricuspid valve and hypoplastic (underdeveloped) right ventricle characterizes tricuspid atresia (Figure 16-24). Blood cannot flow from the right atrium into the right ventricle, so circulation is maintained by a right-to-left shunt through either an ASD or patent foramen ovale. A VSD is also present, allowing small amounts of blood to be directed to the right ventricle and pulmonary circulation. With this disorder, cyanosis is usually present at birth. Numerous surgical options are available for treatment. Preoperative management includes prostaglandin administration to maintain ductal patency and enhance pulmonary blood flow.

Truncus Arteriosus

Truncus arteriosus is a defect resulting from failure of the embryonic truncus arteriosus to separate into the aorta and pulmonary artery (Figure 16-25). A single great artery overlies the left and right ventricles, receiving blood through a large VSD. Pulmonary and systemic blood mix and circulate throughout the body, resulting in cyanosis. Surgical treatment involves separating the common vessel into two separate vessels and closing the VSD.

Aortic Stenosis

Narrowing found above, below, or at the level of the aortic valve obstructs flow out of the left ventricle and is the cause of the congenital heart defect known as aortic stenosis (Figure 16-27). Clinical manifestations depend on the degree of stenosis. Resistance to blood flow through the aorta results in increased left ventricular work and eventual hypertrophy. Left ventricular pressures may become high enough to cause elevation of pulmonary venous and pulmonary capillary pressures, causing pulmonary edema and congestive heart failure. Numerous options exist for surgical repair, including balloon dilation of the stenotic aortic valve, removal of the stenotic area of the aortic valve, and repair of the area above the valve with a patch to widen the narrowed area.

Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome includes (1) hypoplastic left ventricle, (2) aortic and mitral valve stenosis or atresia, and often (3) hypoplasia of the ascending aorta (Figure 16-28). Blood flow through the left ventricle is severely compromised, necessitating a PDA to supply the systemic circulation and an ASD to allow pulmonary venous blood to flow into the right atrium. Infants born with hypoplastic left heart syndrome appear gray and hypotensive shortly after birth and die without surgical intervention or heart transplantation.