Fetal lungs develop by repetitive branching of both bronchial and pulmonary arterial trees
Two critical factors make gas exchange in the infant lung as effective as that in the adult lung: (1) the structural growth and coincident branching of lung segments and blood vessels that creates an extensive alveolar-capillary interface for efficient diffusion of gases, and (2) the production of surfactant (see pp. 613–615), which permits lung expansion without excessive inspiratory effort. The fetal lung begins as an outpouching of the foregut at ~24 days' gestation. Several days later, this lung bud branches into two tubular structures, the precursors of the main bronchi. At 4 to 6 weeks' gestation, the bronchial tree begins to branch repetitively. The further maturation of the lungs occurs in four overlapping phases:
1. Pseudoglandular period (5 to 17 weeks). The lung “airways” resemble branching exocrine glands, with acinar buds forming in the peripheral lung.
2. Canalicular period (16 to 26 weeks). The creation of channels (canalization) within the airways is complete when ~17 generations of airways have formed, including the respiratory bronchioles. Each respiratory bronchiole gives rise to as many as six alveolar ducts, which give rise to the primitive alveoli during the second trimester. The branching of the pulmonary arterial tree, which begins during the pseudoglandular period, parallels both temporally and spatially the branching of the bronchial tree. However, at ~24 weeks' gestation, considerable interstitial tissue separates the capillaries from the respiratory epithelium. N57-3
3. Saccular period (24 to 38 weeks). The respiratory epithelium thins greatly, with loss of connective tissue, and the capillaries push into the alveolar sacs. The potential for gas exchange improves after ~24 weeks' gestation, when capillaries proliferate and come into closer proximity to the thin type I alveolar pneumocytes (see p. 599). During this period, surfactant synthesis and storage begin (although not extensively) in the differentiated type II cells.
4. Alveolar period (late fetal life through early childhood). Alveoli-like structures are present at ~32 weeks' gestation, and at 34 to 36 weeks' gestation, 10% to 15% of the adult number of alveoli are present. Alveolar number continues to increase until as late as 8 years of age.
Alveolar-Capillary Distances in the Fetus at 24 Weeks
Contributed by Henry Binder
If the fetus were born at 24 weeks of development, the premature infant would have a very low diffusing capacity (see pp. 663–664) owing to the great distance between the edge of the alveolar lumen and the edge of the capillary lumen.
An increase in cortisol, with other hormones, triggers surfactant production in the third trimester
Hormones play a major role in controlling fetal lung growth and development in preparation for ex utero function. A key target is surfactant (see pp. 613–615), which increases lung compliance (see pp. 615–616) and thereby reduces the effort of inspiration. Numerous hormones stimulate surfactant biosynthesis, including glucocorticoids, thyroid hormones, thyrotropin-releasing hormone, and prolactin, as well as growth factors such as EGF. Glucocorticoids, in particular, play an essential role in stimulating fetal lung maturation by increasing the number of both type II pneumocytes and lamellar bodies (see pp. 614–615) within these cells. Glucocorticoid receptors are probably present in lung tissue at midterm. Fetal cortisol levels rise steadily during the third trimester and surge just before birth. Two thirds of this cortisol is of fetal origin; the rest crosses the placenta from the mother.
The predominant phospholipid in surfactant is dipalmitoylphosphatidylcholine (DPPC; see pp. 613–614). At ~32 weeks' gestation, increases in cortisol and the other hormones mentioned previously stimulate several regulatory enzymes. N57-4 Thus, the net effect is vastly increased production of pulmonary surfactant late in gestation. Coincident with increased surfactant synthesis is a large increase in lung distensibility and stability on inflation. However, in infants born prematurely with insufficient surfactant and lungs that are not structurally mature, severe respiratory distress (Box 57-2) can result. Because of the surfactant deficiency, the infant must invest excessive work to create an adequate tidal volume with each breath and to maintain a normal functional residual capacity following expiration.
Infant Respiratory Distress Syndrome
Infant respiratory distress syndrome (IRDS), which affects ~30,000 newborns annually in the United States, is characterized by increased work of breathing (nasal flaring, the use of accessory musculature, intercostal and subcostal retractions, tachypnea, and grunting) and impaired gas exchange (cyanosis). Retractions occur because the lungs—with collapsed, fluid-filled, and poorly expanded alveoli—are less compliant than the chest wall, with nonossified ribs. The increased inspiratory effort to expand the noncompliant lungs creates a very negative intrapleural pressure. As a result, the chest wall becomes distorted, caving in between the ribs or beneath or above the rib cage, so that the increased inspiratory work does not much improve tidal volume. The more immature the infant, the more severe and life-threatening the lung disease and the more likely that signs of respiratory distress become apparent immediately after birth or within a few minutes. N57-10
In more mature preterm infants, the signs of IRDS may evolve over several hours. A chest radiograph reveals atelectasis with air bronchograms (i.e., air-filled bronchi standing out against the white background of collapsed lung tissue) and pulmonary edema. The edema and consolidation or collapse of alveoli can produce severe restrictive lung disease (see p. 611) and subsequent fatigue from the increased effort needed to breathe, contributing to respiratory failure that requires mechanical ventilation. Milder cases usually resolve spontaneously. IRDS occurs most commonly in premature infants, and the course is often confounded by the coexistence of a patent ductus arteriosus (see p. 1158), poor nutrition, and risk of infection. This combination of problems also raises the risk of short- and long-term complications, such as disruption of lung development (bronchopulmonary dysplasia), necrotizing enterocolitis, and intraventricular hemorrhage.
IRDS is usually caused by a deficiency of pulmonary surfactant owing to prematurity. Prematurity is by far the single most important risk factor for development of IRDS; others include male sex, delivery by cesarean section, perinatal asphyxia, second twin pregnancy, maternal diabetes, and deficiency of surfactant protein B or the ATP-binding cassette (ABC) protein ABCA3 (see p. 119). Surfactant insufficiency can result from abnormalities of surfactant synthesis, secretion, or recycling. Reduced surfactant lowers compliance directly (see pp. 615–616) and further lowers compliance indirectly because alveoli—with their propensity to collapse—tend to be on the lowest, flat part of the lung pressure-volume curve (stage 1 in Fig. 27-4B). Because of the tendency of alveoli to collapse, blood perfuses poorly ventilated or nonventilated alveoli, which results in hypoxemia (see pp. 692–693). In the extreme, when the alveoli are nonventilated, the result is venous admixture or shunt (see p. 693). In addition, capillary damage allows leakage into the alveolar space of plasma proteins, which may inactivate surfactant and thereby exacerbate the underlying condition.
The discovery that a deficiency of surfactant is the underlying problem in infants with IRDS prompted investigators to (1) develop means to assess fetal lung maturity and adequacy of surfactant production before delivery, (2) stimulate surfactant production in the fetus (by administration of corticosteroids to the mother prior to delivery), and (3) provide exogenous surfactant to the lungs until native synthesis occurs. As indicated in the following three paragraphs, each of these strategies has been a successful step in dramatically reducing the incidence and severity of IRDS.
Knowledge of lung maturity helps reduce complications in infants who are born prematurely or need to be delivered prematurely for specific medical indications related to the health of the mother or the infant. Clinical tests for assessing lung maturity exploit the knowledge that the major surfactant lipids are phosphatidylcholines (i.e., lecithins) and that phosphatidylglycerol (see pp. 613–614) is also overrepresented. A ratio of lecithin to sphingomyelin (L/S ratio) > 2.0 in the amniotic fluid is consistent with mature lungs, as is a positive result on phosphatidylglycerol assay.
Regarding surfactant production, the 2000 National Institutes of Health Consensus Development Conference Antenatal Corticosteroids Revisited recommended antenatal steroid therapy for pregnant women with fetuses between 24 and 34 weeks' gestational age who are at risk of preterm delivery within 7 days. This treatment accelerates lung maturation and surfactant production and diminishes the incidence of IRDS.
Finally, the postnatal administration of surfactant has dramatically reduced the mortality and improved the clinical course of IRDS, as illustrated for an experimental animal in Figure 57-2.
FIGURE 57-2 Effects of surfactant on the deflation limb of a static pulmonary pressure-volume diagram. These results are from experiments on normal rat lungs, lungs made surfactant deficient by saline lavage, and lavaged lungs subsequently treated with either DPPC or an extract from a calf-lung lavage (which also contains surfactant apoproteins SP-B and SP-C). TLC, total lung capacity. (Data from Hall SB, Venkitaraman AR, Whitsett JA, et al: Importance of hydrophobic apoproteins as constituents of clinical exogenous surfactants. Am Rev Resp Dis 145:24–30, 1995.)
Fetal Synthesis of Dipalmitoylphosphatidylcholine
Contributed by Ervin Jones
The predominant phospholipid in surfactant is DPPC (see pp. 613–614), which is synthesized as outlined in eFigure 57-1. Abundant glycogen stores in fetal type II pneumocytes serve as a primary energy and carbon source for the FAs involved in phospholipid synthesis. The condensation of diacylglycerol with cytosine diphosphate choline ultimately leads to the production of DPPC. At ~32 weeks' gestation, increases in cortisol and other hormones stimulate several regulatory enzymes, including acetyl coenzyme A carboxylase, FA synthase, and CTP: phosphocholine cytidylyl transferase. The net effect is vastly increased production of pulmonary surfactant late in gestation. Coincident with increased surfactant synthesis is a large increase in lung distensibility and stability on inflation.
EFIGURE 57-1 Synthesis of DPPC. Before birth, cortisol upregulates several enzymes (highlighted in yellow) that are important for the synthesis of surfactant. CoA, coenzyme A; CDP, cytidine diphosphate; CMP, cytidine monophosphate; CTP, cytidine triphosphate; Pi, inorganic phosphate; PPi, inorganic pyrophosphate.
Respiratory Distress Syndrome of the Newborn
Contributed by Emile Boulpaep, Walter Boron
Two of the signs of infant respiratory distress described in Box 57-2—cyanosis and tachypnea—reflect central hypoxemia, that is, reduced oxygen content of the arterial blood. In this case, the hypoxemia is the result of poor alveolar ventilation. As described on page 652, cyanosis is the purplish color of poorly saturated Hb. As described in Box 32-2, tachypnea is an increase in respiratory rate, in this case probably caused by stimulation of both the central and peripheral chemoreceptors due to respiratory acidosis and hypoxia.
Several of the other signs described in Box 57-2—nasal flaring, intercostal and subcostal retractions, the use of accessory musculature, and grunting—are indications of low lung compliance. Nasal flaring (produced by cranial nerve VII; see Fig. 32-4) is a reflection of the increased inspiratory drive and is produced by one of the secondary muscles of inspiration (see point 4—upper respiratory tract muscles—on page 607). Other accessory or secondary muscles of inspiration also come into play. The intercostal and subcostal retractions are the result of the very negative intrapleural pressure (PIP) generated by the young patient in an attempt to inflate its poorly compliant alveoli. Grunting is the sound made by closure of the glottis as the infant halts expiration at a lung volume (VL) that is considerably higher than the true functional residual capacity (FRC) to which the lungs would deflate without grunting. This true FRC would be quite low, owing to the extremely high elastic recoil of these low-surfactant lungs. One might think of the relatively high VL at the point of grunting as a “pseudo-FRC” from which the infant can begin the next inspiration with much less effort than if VL had been allowed to fall all the way to the true FRC. The reason that the effort is so much less at the VL of grunting is that the PTP-VL relationship (see Fig. 27-4B) is highly nonlinear, such that the compliance (i.e., the slope of the PTP-VL curve) is much higher at the VL of grunting than at the VL of the true FRC.
Fetal respiratory movements begin near the end of the first trimester but wane just before birth
Fetal breathing movements commence near the end of the first trimester, as confirmed in humans by studies using both Doppler ultrasonography and tocodynamometer (an external device that records uterine movements). It appears that hypoxia and tactile stimulation of the fetus promote these breathing movements, which occupy less than half of any 24-hour period. Near term, breathing movements are regular, similar to those found after birth. However, just before labor, fetal breathing decreases. In experimental animals, reducing breathing limits growth and expansion of the lungs.
The fetal lung undergoes many changes in preparation for birth. In utero, the alveoli and airways of the fetal lung are filled with a volume of fluid approximating the functional residual capacity (see p. 602) of the neonatal lung. The onset of labor is accompanied by increases in catecholamines and arginine vasopressin, which decrease fluid production by the fetal lung and initiate active fluid reabsorption via epithelial Na+ channels (ENaCs). The reabsorbed fluid moves out of the lung mainly via the pulmonary circulation and to a lesser extent via the pulmonary lymphatics. The small portion of remaining lung fluid is forced out of the trachea as the fetus passes through the birth canal (Box 57-3).
Any disturbance that abruptly interferes with the ability of the placenta to exchange O2 and CO2 between the maternal and fetal circulations can lead to fetal asphyxia—low , high , and acidosis. Common causes include maternal hypotension, abruptio placentae (i.e., breaking away of a portion of the placenta from the uterine wall), a prolapsed umbilical cord (i.e., descent of the umbilical cord into the birth canal in front of the head or other part of the fetus so that it becomes compressed), and severe anemia or polycythemia (which can occur with twin-twin transfusion). A major consequence of the asphyxia is depressed myocardial function and reduced cardiac output, which further exacerbates the reduced O2 delivery to the tissues.
In the brain, asphyxia produces substantial alterations in cerebral intracellular metabolism. As the brain is forced to shift from aerobic to anaerobic metabolism, high-energy phosphate compounds (e.g., ATP) decrease in concentration, and their breakdown products (e.g., ADP and inorganic phosphate) increase. The changes in metabolism disrupt the integrity of neurons and glia. Damage to the endothelium can cause hemorrhage with the brain parenchyma, ventricles, or choroid plexus.
Fetuses experiencing chronic O2 deficiency in utero for a prolonged period are at increased risk after birth of metabolic derangements as well as cerebral and intraventricular hemorrhage.
The fetal circulation has four unique pathways—placenta, ductus venosus, foramen ovale, and ductus arteriosus—to facilitate gas and nutrient exchange
The circulatory system differentiates from the embryonic mesoderm, and the fetal heart begins to beat and circulate blood in the fourth week of gestation. The fundamental difference between the fetal and postnatal circulations is that the placenta performs for the fetus functions that—at least in part—are performed by four organ systems in extrauterine life: (1) the lungs (gas exchange), (2) the gastrointestinal tract (nutrition), (3) the liver (nutrition, waste removal), and (4) the kidneys (fluid and electrolyte balance, waste removal).
Just as in the mature circulation, the fetal right ventricle pumps most of its output to the gas-exchange organ (i.e., the placenta). The fetal left ventricle pumps most of its output to systemic tissues. The key principle governing the unique pattern of fetal blood flow is the presence of three shunts that allow blood to bypass future postnatal routes and instead direct a large fraction of deoxygenated blood to the placenta. Just as in the postnatal circulation, the relative vascular resistance of an organ determines the fraction of cardiac output distributed to that organ. Thus, the fetal heart pumps a large fraction of its output to the low-resistance placenta and smaller fractions to other organs that, in utero, have relatively high vascular resistance.
Figure 57-3 shows the placenta and the three shunts. Because the right and left fetal hearts largely pump in parallel rather than in series, and because the inputs and outputs of these two sides mix, we define the combined cardiac output (CCO) as the sum of the outputs of the right and left ventricles. Figure 57-3A shows the fraction of the CCO that flows through the fetal circulatory system at important checkpoints. Figure 57-3B shows representative values for the O2 saturation () of HbF and the at these same checkpoints.
FIGURE 57-3 Fetal circulation. A, This schematic drawing is based on data that show the major elements of the fetal circulation obtained from studies on intact fetal lambs, with catheters inserted to measure blood flow, pressure, and O2 content. The data serve as approximations for near-term human fetuses, for which comparable data are not obtainable. Note that, in the main drawing, the heart is upside down for the sake of presenting the blood flow as simply as possible. The heart is right side up in the inset. Because the inputs and outputs of the right and left hearts mix, we define the CCO as the sum of the outputs of the right and left ventricles. The percent of the CCO that passes various checkpoints is represented as a number in a dark gray box. Note that the CCOs of the right ventricle (66%) and the left ventricle (34%) add up to 100%. The fetal circulation has four unique pathways: placenta, ductus venosus, foramen ovale, and ductus arteriosus. GI, gastrointestinal. B, This schematic drawing is the same as in A except that, at each checkpoint, we show the O2 saturation () of HbF against a black background and the (in mm Hg) against a white background. The relationship between the and values is based on the O2 saturation curve for HbF (similar to the curve labeled “Hb + CO2” in Fig. 29-7). The of blood at any point where two streams of blood merge is derived from the flow-weighted mixture of oxygen flows as follows: ()Merged = [(flow × )Stream-A + (flow × )Stream-B]/[flowStream-A + flowStream-B]. The resultant of that mixture is dictated by the HbF-O2 dissociation curve, which shows the for any . The numerical values in this figure are reasonable estimates for a healthy near-term fetus.
Of the CCO late in gestation, ~69% reaches the thoracic aorta (see Fig. 57-3A). About 50% of the CCO enters the placenta as deoxygenated blood through the paired umbilical arteries, which arise from the two common iliac arteries. This massive blood flow to the placenta not only shunts blood away from the lower trunk, but also lowers effective blood flow to all abdominal viscera, including the kidneys. The umbilical arteries branch repeatedly to form dense capillary networks within the villi (see p. 1136). As fetal blood enters the placenta, it has a lower than maternal blood, so that O2 passively diffuses from maternal to fetal blood. After O2 equilibration across the placental membranes, the fetal blood has a higher O2 content (see p. 650) than maternal blood because (1) HbF has a higher O2 affinity than does HbA, and (2) fetal blood has a higher Hb content than maternal blood. The single umbilical vein returns well-oxygenated blood ( of 85%) from the placenta to the fetus.
The relatively large volume of well-oxygenated umbilical venous blood (~50% of CCO) returns to the lower body from the placenta but bypasses the largely nonfunctional liver by shunting through the ductus venosus—the fetal first shunt. In addition, some blood from the portal circulation enters the ductus venosus. Blood from the ductus venosus then merges with blood from the inferior vena cava (~19% of CCO) that drains the lower limbs, kidneys, and splanchnic organs. Thus, ~69% of the CCO ( of 70%) enters the right atrium.
The second major shunt is blood entering the right atrium and then crossing the foramen ovale—an oval hole between two flaps of tissue in the septum that divides the atria N57-5—to enter the left atrium. Of the 69% of the CCO that enters the right atrium via the inferior vena cava, ~27% of the CCO shunts through the foramen ovale directly into the left atrium. This movement represents a right-to-left shunt. Therefore, the left heart receives relatively well-oxygenated blood ( ≅ 70%) derived from the mixing of blood from the placenta and the caudal portion of the inferior vena cava. In addition, the left atrium receives 7% of the CCO as poorly oxygenated blood ( ≅ 46%) from the nonfunctional lungs. Thus, the left ventricle pumps a total of 27% + 7% = 34% of the CCO ( ≅ 65%). Because this blood enters the aorta upstream from the ductus arteriosus, it primarily flows to the coronary circulation, head, and forelimbs.
Embryology of the Atrial Septum
Contributed by George Lister
Our understanding of atrial embryology informs us about fetal cardiac physiology. The atrial septum primum grows from superior to inferior to partition the atria into right and left. Before this septation is complete, small holes (foramina) develop in the midportion of the septum primum and begin to coalesce, creating an oval hole known as the foramen ovale. As this occurs, the atrial septum secundum begins to grow from superior to inferior and just to the right of the septum primum. Like a window shade, it grows down to cover the foramen ovale, but it does not grow completely to the center crux of the heart. As a result, and because the pressure in the right atrium minimally exceeds that in the left atrium in utero, the septum primum (the inferior portion of the atrial septum) is pushed away from the septum secundum and toward the left atrium, creating a “defect” in the atrial tissue that allows blood in the right atrium to move into the left atrium through the open foramen.
In the right atrium, 69% − 27% = 42% of the CCO entering the right atrium from the inferior vena cava does not shunt through the foramen ovale. This relatively well-oxygenated blood ( ≅ 70%) joins the relatively poorly oxygenated 21% of the CCO ( ≅ 29%) that enters the right atrium from the superior vena cava and another 3% from the coronary vessels—a total of 24% of CCO. Because of the valve-like nature of the septum surrounding the foramen ovale, none of the incoming blood from the superior vena cava or coronary vessels shunts through the foramen ovale. Rather, it goes through the tricuspid valve to the right ventricle. Thus, the right ventricle receives 42% + 21% + 3% = 66% of the CCO ( ≅ 55%). The in the fetal right ventricle is somewhat lower than that in the left ventricle. The blood from the right ventricle then enters the trunk of the pulmonary artery.
The right ventricle has a much larger stroke volume and pumps far more blood (66% of CCO) than the left (34% of CCO). Thus, the right ventricle has a relatively thick wall compared to its postnatal state and larger chamber volume in utero than the left ventricle. This difference is revealed in the electrocardiogram (ECG) of the newborn, which shows large right ventricular vectors and right-axis deviation compared with that of the older infant or adult. Despite the disparity in stroke volume, the two ventricles in utero pump at the same pressures because the low-resistance ductus arteriosus accepts nearly 90% of the output of the right ventricle.
The third major shunt, also a right-to-left shunt, directs blood from the pulmonary artery to the aorta via the ductus arteriosus. The ductus arteriosus is a large vessel with substantial smooth muscle in its wall. The patency of this vessel is due to active relaxation of this smooth muscle, mediated by the low of the perfusing blood and prostaglandins, particularly prostaglandin E2 (PGE2). Note that the ductus arteriosus exhibits hypoxic vasodilation, as do most systemic vessels (see p. 478). Fetal PGE2 levels are much higher than adult levels. Administering prostaglandin inhibitors to an experimental fetal animal causes the ductus arteriosus to vasoconstrict.
Although 66% of the CCO enters the pulmonary artery, only 7% of the CCO perfuses the unventilated fetal lungs. This dichotomy reflects the high resistance of the fetal pulmonary, which is the result of hypoxic vasoconstriction (see p. 687) and acidosis, the collapsed state of the airways, and perhaps leukotrienes (particularly leukotriene D4 [LTD4]). The rest of the blood entering the pulmonary artery, 66% − 7% = 59% of the CCO ( ≅ 55%), enters the descending aorta through the ductus arteriosus and mixes with the blood from the aortic arch, 10% of CCO, that did not perfuse the head and upper body ( ≅ 65%). Thus, the descending aorta receives 59% + 10% = 69% of the CCO ( ≅ 60%), the overwhelming majority of which (50% of CCO) perfuses the placenta. While the blood is in the placenta, rises from 60% to 85%.