Fetal Lungs and Respiratory System

The lungs develop late in the embryo and are not involved in respiratory gas exchange during fetal life. They must be prepared, however, to assume the full burden of gas exchange as soon as the umbilical cord is cut.

The fetal lungs are filled with fluid, and the blood circulation to them is highly reduced. To perform normal postnatal breathing, the lungs must grow to an appropriate size, respiratory movements must occur continuously, and the air sacs (alveoli) must become appropriately configured for air exchange.

Normal growth of the fetal lungs depends on their containing an adequate amount of fluid. During the last trimester of pregnancy, fluid constitutes 90% to 95% of the total weight of the lung. The fluid filling the fetal lungs differs in composition from amniotic fluid, and it has been shown to be secreted by the pulmonary epithelial cells. Secretion begins with a net movement of chloride ions into the lumina of the pulmonary passages. Water movement follows the chloride ions. Studies have shown a relationship between total fluid volume in the lungs and fetal breathing movements, with dilation and constriction of the larynx serving a valvelike function. In vitro studies have shown that proliferation of lung epithelial cells is stimulated by mechanical stretching. In vivo, the internal pressure of the lung fluid serves as the stretching agent. A reduced volume of lung fluid is associated with pulmonary hypoplasia.

Ultrasound analysis has shown that the fetus begins to make gross breathing movements as early as 10 weeks. These movements are periodic rather than continuous, and they have two forms. One type of movement is rapid and irregular, with varying rate and amplitude. The other form is represented by isolated, slow movements, almost like gasps. The former type is more prominent and is associated with conditions of rapid eye movement (REM) sleep. Periods of rapid breathing (often for about 10 minutes) alternate with periods of apnea (cessation of breathing).

Breathing movements in the adult are controlled by two centers located in the medulla. One of these centers controls inspiration, and the other controls expiration. In rodent fetuses, the center that controls expiration becomes functional in the midfetal period, slightly before functional maturation of the inspiratory center. Breathing movements are known to be responsive to maternal factors, many of which remain to be identified. The amount of breathing (minutes of breathing per hour) is highest in the evening and lowest in the early morning. The fetal breathing rate increases after the mother has eaten. This increase is related to the concentration of glucose in the maternal blood. Maternal smoking causes a rapid decrease in the rate of fetal breathing for up to 1 hour and is linked to impaired lung development.

Fetal breathing movements are essential for postnatal survival. One function of fetal breathing is to condition the respiratory muscles so that they can perform regular postnatal contractions. Another important function is to stimulate the growth of the embryonic lungs. If intrauterine breathing movements are suppressed, lung growth is retarded. This is a result of a reduction in the production of platelet-derived growth factor, insulinlike growth factor, and thyroid transcription factor-1, which stimulate cell proliferation and reduce apoptosis in the peripheral parts of the fetal lungs.

An important developmental adaptation of the fetal respiratory system is growth of the upper airway. Although a newborn is about 4% the weight of an adult, the diameter of its trachea is one third that of the adult trachea. Other components of the airway are similarly proportioned. If the trachea were narrower, the physical resistance to airflow would be so great that movement of air would be almost impossible. Even with these adaptations, the resistance of a neonate’s airway is five to six times greater than that of an adult.

A functionally important aspect of fetal lung development is the secretion of pulmonary surfactant by the newly differentiating type II alveolar cells of the lung, starting around 24 weeks’ gestation. Surfactant is a mixture of phospholipids (about two thirds phosphatidylcholine [lecithin]) and protein that lines the surface of the alveoli and reduces the surface tension. This reduction in surface tension reduces the inspiratory force required to inflate the alveoli and prevents the collapse of the alveoli during expiration.

Despite the early initiation of surfactant synthesis, large amounts are not synthesized until a few weeks before birth. At this time, the production of surfactant by the type II alveolar cells is higher than at any other period in an individual’s life, an adaptation that is an important preparation for the newborn’s first breath. Certain hormones and growth factors are involved in the synthesis of surfactant, and the effects of thyroid hormone and glucocorticoids are particularly strong.

Premature infants often have respiratory distress syndrome, which is manifested by rapid, labored breathing shortly after birth. This condition is related to a deficiency in pulmonary surfactant and can be ameliorated by the administration of glucocorticoids, which stimulate the production of surfactant by the alveolar epithelium. The risk of respiratory distress syndrome in infants born at 29 weeks is greater than 60% and decreases to 20% at 34 weeks and less than 5% at 37 weeks.

Fetal Movements and Sensations

Ultrasonography has revolutionized the analysis of fetal movements and behavior because the fetus can be examined virtually undisturbed (except for an increase in vascular activity induced by the ultrasound) for extended periods. Earlier studies of fetal movements were principally concerned with the development of reflex responses, and the information was obtained largely by the analysis of newly aborted fetuses (see Chapter 11). Although valuable information on maturation of reflex arcs was obtained in this manner, many of the movements elicited were not those normally made by the fetus in utero.

The undisturbed embryo does not show any indication of movement until about weeks. The first spontaneous movements consist of slow flexion and extension of the vertebral column, with the limbs being passively displaced. Within a short time, a large repertoire of fetal movements evolves. After study by numerous investigators, a classification of fetal movements has been suggested (Box 18.1). The first fetal movements are followed in a few days by startle and general movements. Shortly thereafter, isolated limb movements are added (Fig. 18.7). Movements associated with the head and jaw appear later. Toward the end of the fourth month, the fetus begins a pattern of periods of activity, followed by times of inactivity. Many women first become aware of fetal movements at this time. Between the fourth and fifth months, the fetus becomes capable of gripping firmly onto a glass rod. Although weak protorespiratory movements are possible, they cannot be sustained.

Continuous ultrasound monitoring for extended periods reveals patterns involving many types of movements (Fig. 18.8). At different weeks of pregnancy, some movements are predominant, whereas others are in decline or are just beginning to take shape. Analysis of anencephalic fetuses has shown that although many movements occur, they are poorly regulated. These movements start abruptly, are maintained at the same force, and then stop abruptly. These abnormal patterns of movements are considered evidence for strong supraspinal modulation of movement in the fetus.

Human fetal activities, as reflected in breathing or general activity level, show distinct diurnal rhythms beginning at about 20 to 22 weeks’ gestation. There is a strong negative correlation between maternal plasma glucocorticoid levels and fetal activity. Fetal activity is highest in the early evening, when maternal blood glucocorticoid levels are lowest, and lowest in the early morning, when the concentration of maternal hormone peaks. Studies of women who have been given additional glucocorticoids or inhibitors have shown increased fetal activity when maternal corticoid levels are low. Usually, when the overall fetal activity is low, the fetus is in a state of REM sleep, but definitions of sleep and wakefulness in the fetus need further clarification.

Several sensory systems also begin to function during the fetal period. Near-term fetuses are responsive to 2000-Hz stimuli when in a state of wakefulness, but they are unresponsive during periods of sleep. Loud vibroacoustic stimuli applied to the maternal abdomen produce a fetal response consisting of an eye blink, a startle reaction, and an increase in heart rate. Although the fetus is constantly in the dark, the pupillary light reflex can usually be elicited by 30 weeks.

The issue of fetal pain has remained controversial with respect to fetal surgery and abortion techniques. Key is whether fetal withdrawal reactions to noxious stimuli really represent an adultlike sensation of pain. Because of the late development of thalamocortical fibers, which are required for awareness of noxious stimuli, and the presence of other endogenous inhibitors, many fetal physiologists believe that functional perception of pain in utero is unlikely to exist before 29 or 30 weeks of gestation.

Fetal Digestive Tract

The fetal digestive tract is not functional in the standard sense because the fetus obtains its nutrition from the maternal blood via the placenta. The digestive tract must be prepared, however, to assume the full responsibility for nutritional intake after birth. When the basic digestive tube and glands have formed in the early embryo, the remainder of the intrauterine period is devoted to cellular differentiation of the epithelia of the gut and preparation of the numerous cells involved for their specific roles in the digestive process. Beneath the epithelium, the walls of the digestive tube must become capable of propelling ingested food and liquid. Analysis of development of the fetal digestive tract has concentrated on (1) the biochemical adaptations of the epithelium of the various regions for digestive function and (2) the development of motility of the digestive tube.

The development and differentiation of epithelia or specific regional characteristics of the gut lining typically follow gradients along the length of the segment of the gut specifically involved. In the esophagus and stomach, differentiation of the mucosal epithelium is well under way starting around 4 months. Although parietal cells (hydrochloric acid–producing cells) and chief cells (pepsinogen-producing cells) are first seen at 11 and 12 weeks, there is little evidence of their secretions during fetal life. The contents of the stomach have a nearly neutral pH until after birth, but then gastric acid production increases greatly within a few hours.

In the small intestine, villi begin to form in the upper duodenum at the end of the second month, and crypts appear 1 to 2 weeks later. The formation of villi and crypts spreads along the length of the intestine in a spatiotemporal gradient. By approximately 16 weeks of gestation, villi have formed along the entire length of the intestine, and crypts appear in the lower ileum by 19 weeks. Villi even form in the colon during the third and fourth months, but they then regress and are gone by the seventh or eighth month.

Individual epithelial cell types, including Brunner’s glands, which protect the duodenal lining from gastric acid, appear in the small intestine early in the second trimester. Although the presence of most enzymes or proenzymes characteristic of the intestinal lining can be shown histochemically during the midfetal period, the amounts of these substances are generally quite small. Activity of some of the enzymes secreted by the exocrine pancreatic tissue can also be shown between 16 and 22 weeks’ gestation. Meconium, a greenish mixture of desquamated intestinal cells, swallowed lanugo hair, and various secretions, begins to fill the lower ileum and colon late in the fourth month (Fig. 18.9).

Differentiation of the neuromuscular complex of the digestive tract also follows a gradient, with the circular layer of smooth muscle forming in the esophagus at 6 weeks. Myenteric plexuses (parasympathetic neurons) take shape after the inner circular muscle layer is present, but before the formation of the outer longitudinal layer of muscle a couple weeks later in any given region. Starting in the esophagus at 6 weeks, the final formation of myenteric plexuses throughout the length of the digestive tract is complete at 12 weeks. The first spontaneous rhythmical activity in the small intestine is seen in the seventh week, at approximately the time of formation of the inner circular muscular layer. Recognizable peristaltic movements do not begin until the fourth month, however. Fetuses older than 34 weeks are able to pass meconium in utero.

Another intrauterine preparation for feeding is the development of swallowing and the sucking reflex. Swallowing is first detected at 10 to 11 weeks of gestation, and then its incidence gradually increases. The function of fetal swallowing is unclear, but by term, fetuses swallow 200 to 750 mL or more of amniotic fluid per day. The amniotic fluid contains protein, and much of this is absorbed through the gut by a process of intracellular digestion, occurring by the uptake of macromolecules by fetal enterocytes. According to some estimates, 15% to 20% of total body protein deposition is derived from protein found in amniotic fluid. The swallowed amniotic fluid may contain growth factors that facilitate the differentiation of epithelial cells in the digestive tract. To a certain extent, taste seems to regulate fetal swallowing. Taste buds are seemingly mature by 12 weeks, and the amount of swallowing increases if saccharin is introduced into the amniotic fluid. Conversely, swallowing is reduced if noxious chemicals are added. Fetal swallowing is followed by gastric peristalsis and gastric emptying, which begin at 12 weeks. The gastric emptying cycles mature throughout the fetal period and are important in maintaining the overall balance of amniotic fluid.

Coordinated sucking movements do not appear until late in fetal development. Although noncoordinated precursors of sucking movements occur by 18 weeks, it is not until 32 to 36 weeks that the fetus undertakes short bursts of sucking. These short bursts are not associated with effective swallowing movements. Ineffective sucking is the main reason that premature infants of this age must be fed through a nasogastric tube. Mature sucking capability appears after 36 weeks.

Fetal Kidney Function

Although the placenta performs most excretory functions characteristic of the kidney during prenatal life, the developing kidneys also function by producing urine. As early as 5 weeks of gestation, the mesonephric kidneys produce small amounts of very dilute urine, but the mesonephros degenerates late in the third month, after the metanephric kidneys have taken shape. Tubules of the metanephric kidneys begin to function between 9 and 12 weeks of gestation, and resorptive functions involving the loop of Henle occur by 14 weeks, even though new nephrons continue to form until birth. The urine produced by the fetal kidney is hypotonic to plasma throughout most of pregnancy. This is a reflection of immature resorptive mechanisms, which are manifested morphologically by short loops of Henle. As the neural lobe of the hypophysis produces antidiuretic hormone beginning at 11 weeks, another mechanism for the concentration of urine begins to be established.

Intrauterine renal function is unnecessary for fetal life because embryos with bilateral renal agenesis survive in utero. Bilateral renal agenesis, however, is commonly associated with oligohydramnios (see Chapter 7), thus indicating that the overall balance of amniotic fluid requires a certain amount of fetal renal function.

Endocrine Function in the Fetus

The development of prenatal endocrine function occurs in several phases. Most endocrine glands (e.g., thyroid, pancreatic islets, adrenals, gonads) form early in the second month as the result of epithelial-mesenchymal interactions. As these glands differentiate late in the second month or early in the third, they develop the intrinsic capacity to synthesize their specific hormonal products. In most cases, the amount of hormone secreted is initially very small; increased secretion often depends on the stimulation of the gland by a higher-order hormone produced in another gland.

The anterior pituitary gland develops similarly to many other endocrine glands. Its hormonal products generally stimulate more peripheral endocrine glands, such as the thyroid, adrenals, and gonads, to produce or release their specific hormonal products. Pituitary hormones can be shown immunocytochemically within individual pituitary epithelial cells as early as 8 weeks (adrenocorticotropic hormone [ACTH]) or 10 weeks (luteinizing hormone and follicle-stimulating hormone). Most pituitary hormones are typically not present in the blood in detectable quantities, however, until a couple of months after they can be shown in the cells that produce them. An exception is growth hormone, which can be detected in plasma by 10 weeks of gestation.

While the anterior pituitary is developing its intrinsic synthetic capacities, the hypothalamus also takes shape and develops its capacity to produce the various releasing and inhibitory factors that modulate the function of the pituitary gland. Regardless of its intrinsic capacities, the hypothalamus is limited in its influence on the embryonic pituitary gland until about 12 weeks of gestation, when the neurovascular links between the hypothalamus and pituitary become established.

At each level in the control hierarchy, a generally low intrinsic level of hormone production can be stimulated by the actions of hormones produced by the next higher-order gland. The amount of thyroid hormone released is considerably increased when thyroid-stimulating hormone, released by the anterior pituitary, acts on the thyroid gland. The release of this hormone by the pituitary is regulated by thyrotropin-releasing hormone, which is produced in the hypothalamus. Regardless of the nature of the upstream stimulation of the thyroid, the forms of thyroid hormone released by the fetal thyroid are largely biologically inactive because of enzymatic modifications or through sulfation. Late in gestation, thyroid hormone accelerates the development of brown fat in the fetus. Brown fat, much of which is stored in depots in the upper back, maintains body temperature in the neonate through a process of nonshivering thermogenesis. Studies on anencephalic fetuses have shown that the anterior pituitary can produce and release most of its hormones in the absence of hypothalamic input, although plasma concentrations of some are reduced.

Among the fetal endocrine glands, the adrenal remains the most enigmatic. By 6 to 8 weeks of development, the inner cortex enlarges greatly to form a distinct fetal zone, which later in pregnancy occupies about 80% of the gland. By the end of pregnancy, the adrenal glands weigh 4 g each, the same mass as that of the adult glands (Fig. 18.10). The fetal adrenal cortex produces 100 to 200 mg of steroids each day, an amount several times higher than that of the adult adrenal glands. The main hormonal products of the fetal adrenal are Δ⁵-3β-hydroxysteroids, such as dehydroepiandrosterone, which are inactive alone, but are converted to biologically active steroids (e.g., estrogens, especially estrone) by the placenta and liver. The fetal adrenal cortex depends on the presence of pituitary ACTH; in its absence, the fetal adrenal cortex is small. If exogenous ACTH is administered, the fetal adrenal cortex persists after birth.

There is a parallel between the presence of the fetal adrenal cortex and functions of the embryonic testis. In the testis, a population of Leydig cells produces testosterone, which is necessary for the morphogenesis of many components of the male reproductive system. Then these cells regress until after birth, when a new population of Leydig cells takes over the production of testosterone to fulfill the needs of postnatal life.

Despite the prominence of the fetal adrenal cortex, its specific functions during pregnancy are still unclear. The large fetal zone of the adrenal cortex produces a steroid precursor for estrogen biosynthesis by the placenta. Fetal adrenal hormones influence maturation of the lungs (as prolactin has also been postulated to do), liver, and epithelium of the digestive tract (Box 18.2). In sheep, products of the adrenal cortex prepare the fetus for independent postnatal life and influence the initiation of parturition, but the situation in primates is considerably less clear. Shortly after birth, the fetal adrenal cortex rapidly involutes (see Fig. 18.10). Within 1 month after birth, the weight of each gland is reduced by 50%, and the volume of the fetal cortex decreases from 70% of total adrenal volume to approximately 3%. By 1 year of age, each gland weighs only 1 g. The mass of the adrenal glands does not return to that of the late fetus until adulthood.

Fetal endocrinology is complicated by the presence of the placenta, which can synthesize and release many hormones, convert hormones released from other glands to active forms, and potentially exchange other hormones with the maternal circulation. By 6 to 7 weeks, hormone production (e.g., progesterone) by the placenta is enough to maintain pregnancy even if the ovaries are removed.

One of the earliest placental hormones produced is human chorionic gonadotropin (HCG) (see Chapter 7). One later function of HCG is to stimulate steroidogenesis by the placenta. The synthesis of HCG by the syncytiotrophoblast of the placenta is regulated by the production of gonadotropin-releasing hormone by cells of the cytotrophoblast. Synthesis of this hormone by the placenta supplants its normal production by the hypothalamus and is probably an adaptation that allows earlier and more local control of HCG than could be accomplished by the hypothalamus.

Clinical Correlation 18.1 discusses the clinical study and manipulation of the fetus.

Clinical Correlation 18.1   Clinical Study and Manipulation of the Fetus

New imaging and diagnostic techniques have revolutionized the study of living fetuses. Many congenital malformations can be diagnosed in utero with accuracy. On the basis of this information, the surgeon can treat some congenital malformations through fetal surgery much more efficiently than by traditional surgery on infants or older children.

Fetal Diagnostic Procedures

Imaging Techniques

Because of its safety, cost, and ability to look at the fetus in real time, ultrasonography is currently the most widely used obstetrical imaging technique (Figs. 18.11 and 18.12). It is useful for the simple diagnosis of structural anomalies and can be used in real time to guide fetal invasive procedures, such as chorionic villus sampling and intrauterine transfusions. The major uses of ultrasonography are summarized in Box 18.3.

Box 18.3   Uses for Ultrasonography During Pregnancy

1. Estimation of fetal age

2. Confirmation of multiple fetuses

3. Diagnosis of placental abnormalities, including hydatidiform mole

4. Localization of placenta in suspected placenta previa

5. Diagnosis of ectopic pregnancy

6. Documentation of follicular development

7. Adjunct to clinical procedures (e.g., amniocentesis, chorionic villus sampling, intrauterine transfusion, intrauterine surgical procedures)

8. Detection of fetal congenital malformations

9. Detection of maternal uterine anomalies

10. Detection of oligohydramnios or polyhydramnios

11. Confirmation of fetal death

12. Confirmation of fetal position

Conventional radiographs continue to be used in certain circumstances, but because of the potential for radiation damage to the fetal and maternal gonads, their use is less common than previously. The use of radiographs is limited by their inability to discriminate the details of soft tissues, including cartilaginous components of the skeleton. By injecting radiopaque substances into the amniotic cavity (amniography, fetography), clinicians can obtain outlines of the fetus and amniotic cavity. Other imaging techniques, such as magnetic resonance imaging, computed tomography, and xeroradiography, produce useful images of the fetus, but their use is limited because of factors such as cost and availability (Figs. 18.13 and 18.14).

Fetoscopy is the direct visualization of the fetus through a tube inserted into the amniotic cavity. This technique is accomplished principally through the use of fiberoptic technology. Because of the risk of spontaneous abortion and infection, this technique is not normally used for purely diagnostic purposes, but rather as an aid to intrauterine sampling procedures. Its use has been largely supplanted by other techniques that rely on ultrasound guidance.

Sampling Techniques

The classic sampling technique is amniocentesis, which involves the insertion of a needle into the amniotic sac and removal of a small amount of amniotic fluid for analysis. Amniocentesis is normally not done before 13 weeks of gestation because of the relatively small amount of amniotic fluid.

Amniocentesis was originally used for detecting chromosomal anomalies (e.g., Down syndrome) in fetal cells found in the amniotic fluid and for the determination of levels of α-fetoprotein, a marker for closure defects of the neural tube and certain other malformations. Analysis of the fetal cells in amniotic fluid is also the basis for determining the gender of embryos. This is typically accomplished by the use of a fluorescent dye that intensely stains the Y chromosome. At present, various analytic procedures on amniotic fluid and cells cultured from the fluid are used to detect many enzymatic and biochemical defects in embryos and to monitor the condition of the fetus.

Another widely used diagnostic technique is chorionic villus sampling. In this technique, ultrasonography is used as a guide to insert a biopsy needle into the placenta, from which a small sample of the villi is removed for diagnostic purposes. This technique is typically used at earlier periods of pregnancy (6 to 9 weeks) than amniocentesis.

With increasing sophistication of fetal imaging techniques, especially ultrasonography, direct sampling of fetal tissues is possible. Ultrasonography-guided sampling of fetal blood, mainly from umbilical vessels, is now common for the diagnosis of hereditary and pathological conditions, such as immunodeficiencies, coagulation defects, hemoglobin abnormalities, and fetal infections. It is also possible to obtain biopsy specimens of fetal skin and even the fetal liver for organ-specific abnormalities.

Therapeutic Manipulations on the Fetus

Some conditions are better treated in the fetal period than after birth (Box 18.4). In some cases involving blockage, severe structural damage to the fetus can be prevented. In other cases, the buildup of toxic waste products can be reduced. The recognition that fetal surgery produces essentially scarless results has stimulated some surgeons to consider corrective surgery in utero rather than waiting until after birth.

Box 18.4   Fetal Conditions Treatable in Utero

Surgical Treatment

1. Urinary obstruction (urethral valves)

2. Diaphragmatic hernia

3. Sacrococcygeal teratoma

4. Chylothorax

5. Cystic adenomatoid malformation of lung

6. Twin-twin transfusion syndrome

7. Hydrocephalus caused by aqueductal stenosis

8. Complete heart block

9. Spina bifida

Medical Treatment

1. Erythroblastosis fetalis

2. Adrenal hyperplasia

3. Hyperthyroidism and hypothyroidism

4. Fetal dysrhythmias

5. Diabetes

6. Agammaglobulinemia

7. Vitamin-responsive metabolic disorders

8. Idiopathic thrombocytic purpura

Fetal shunts can be applied to correct specific conditions in which major permanent damage would result before the time of birth. One such situation is a shunt into the urinary bladder to relieve the pressure and subsequent kidney damage caused by anatomical obstructions of the lower urinary tract. Figure 18.15 shows the consequence of nontreatment of a persistent cloacal plate, which results in megacystitis (enlarged bladder). Fetal shunts have also been used in attempts to relieve the cerebrospinal pressures that result in hydrocephaly (see Fig. 11.38), but the results of these procedures have been equivocal.

Fetal blood transfusions are used for the treatment of fetal anemia and severe erythroblastosis fetalis (see Chapter 7). Earlier, the blood was introduced intraperitoneally. With the increasing sophistication of umbilical cord blood sampling techniques, direct intravascular transfusions are now possible.

Open fetal surgery can now be performed because of the diagnostic procedures that allow an accurate assessment of the condition of the fetus. This is still a new and highly experimental procedure, and its application has been confined to cases of fetal anomalies that would cause grave damage to the fetus if left uncorrected before birth. Currently, the principal indications for open fetal surgery are blockage of the urinary tract, severe diaphragmatic hernia, and some cases of hydrocephalus. Open fetal surgery entails a risk to the mother as well, and the advisability of such a procedure must be carefully considered. With future improvements in procedures, correcting other malformations, such as cleft lip and palate or limb deformities in utero, may be possible.

Circulatory Changes at Birth

Two major events drive the functional adaptations of the circulatory system immediately at birth. The first is the cutting of the umbilical cord, and the second comprises the changes in the lungs after the first breaths of the newborn. These events stimulate a series of sweeping changes that not only alter the circulatory balance, but also result in major structural alterations in the circulatory system of the infant.

Cutting the umbilical cord results in an immediate cessation of blood entering the body via the umbilical vein. The major blood flow through the ductus venosus is eliminated, and the amount of blood that enters the right atrium via the inferior vena cava is greatly reduced. A consequence of this activity is a reduction of the stream of blood that was directly shunted from the right to the left atrium via the foramen ovale during fetal life.

After just a few breaths, the pulmonary circulatory bed expands and can accommodate much greater blood flow than during the fetal period. Consequences of this change are a reduced flow of blood through the ductus arteriosus and a correspondingly greater return of blood into the left atrium via the pulmonary veins. Within minutes after birth, the ductus arteriosus undergoes a reflex closure. This shunt, which in prenatal life is actively kept open in great part through the actions of prostaglandin E₂, rapidly constricts after the oxygen concentration in the blood increases. The mechanism for constriction seems to involve the action of cytochrome P450, but the way it is translated into contraction of the smooth musculature of the ductus is unclear. Shortly after birth, platelets form a plug that seals the lumen of the constricted ductus arteriosus. The principal tissue involved in closure of the ductus is smooth muscle; the shunt also experiences a breakdown of elastic fibers and a thickening of the inner intimal layer. Although initial closure of the ductus arteriosus is based on a reflex mechanism, over the next few weeks it is followed by a phase of anatomical closure, during which cell death and proliferation of connective tissue combine to reduce the ductus into a fibrous cord.

Because of closure of the ductus arteriosus, increased pulmonary venous flow, and loss of 25% to 50% of the peripheral vasculature (placental circulation) when the umbilical cord is cut, the blood pressure in the left atrium becomes slightly increased over that in the right atrium. This increase leads to physiological closure of the interatrial shunt, with the result that all the blood entering the right atrium empties into the right ventricle (Fig. 18.18). Structural closure of the valve at the foramen ovale is prolonged, occurring over several months after birth. Before complete structural obliteration of the interatrial valve, it possesses the property of “probe patency,” which allows a catheter inserted into the right atrium to pass freely through the foramen ovale into the left atrium. As structural fusion of the valve to the interatrial septum progresses, the property of probe patency is gradually reduced and ultimately disappears. In approximately 20% of individuals, structural closure of the interatrial valve is not completed, thus leading to the normally asymptomatic condition of probe patent foramen ovale.

Although the ductus venosus also loses its patency after birth, its closure is more prolonged than that of the ductus arteriosus. The tissue of the wall of the ductus venosus is not as responsive to increased oxygen saturation of the blood as that of the ductus arteriosus.

After the postnatal pattern of the circulation is fully established, obliterated vessels or shunts that were important circulatory channels in the fetus either are replaced by connective tissue strands, forming ligaments, or are represented by relatively smaller vessels (see Fig. 18.18; Fig. 18.19). These changes are summarized in Table 18.1. In early postnatal life, the umbilical vein can still be used for exchange transfusions (in cases of hemolytic disease resulting from erythroblastosis fetalis) before its lumen becomes obliterated.

Lung Breathing in the Perinatal Period

Immediately after birth, the infant must begin to breathe regularly and effectively with the lungs to survive. The initial breaths are difficult because the lungs are filled with fluid and the alveoli are collapsed at birth. On a purely mechanical basis, air breathing is facilitated by a proportionally large diameter of the trachea and major airways. The large diameter reduces resistance to airflow, which would be insurmountable if these passageways were proportionally as small as the lungs.

Just before birth, increased levels of arginine vasopressin and adrenaline suppress the secretion of fetal lung fluid and stimulate its resorption by the pulmonary epithelial cells. At birth, the lungs contain about 50 mL of alveolar fluid, which must be removed for adequate air breathing. Approximately half of that volume enters the lymphatic system. Of the remainder, perhaps half may be expelled during birth. The remainder enters the bloodstream.

The alveolar sacs in the lungs begin to inflate on the first inspiration. The pulmonary surfactant, which was secreted in increasing amounts during the last few weeks of a term pregnancy, reduces the surface tension that would otherwise be present at the air-fluid interface on the alveolar surfaces and facilitates inflation of the lungs. With the rush of air into the lungs, the pulmonary vasculature opens and allows a greatly increased flow of blood through the lungs. This increased flow results in an increased oxygen saturation of the blood; the color of the caucasian newborn changes from a dusky purple to pink.

Breathing movements in the fetus are intermittent and irregular even after birth. Many factors can affect the frequency of breathing, but the factors responsible for the transition from intermittent to regular breathing remain poorly understood. Factors such as cold, touch, chemical stimuli, sleep patterns, and signals emanating from the carotid and aortic bodies have been implicated. During periods of wakefulness, breathing of the neonate soon stabilizes, but for several weeks after birth, short periods of apnea (5 to 10 seconds) are common during REM sleep.