Fetal and Neonatal Physiology

Two distinct circulations—fetoplacental and uteroplacental—underlie the transfer of gases and nutrients

The fundamental difference between the circulatory system of the fetus and that of the infant/adult is the presence of the placenta, which produces essential hormones (e.g., progestins, estrogens, chorionic gonadotropins) and performs a number of vital functions (e.g., gas exchange, nutrient transport, fluid balance, and waste removal) that other systems provide in extrauterine life. The fetus accomplishes these tasks by directing a large fraction of fetal blood flow from the aorta via the two umbilical arteries to the fetoplacental circulation within chorionic villi (see p. 1137 ). There the umbilical arteries branch into small tufts of vessels (villus capillaries) that come into apposition with the maternal uteroplacental circulation, which has a high blood flow (see pp. 1136–1137 ). The placental membranes (the syncytiotrophoblast) that separate these two distinct circulations permit the efficient exchange of respiratory gases, fluid, and larger molecules that are critical to sustain growth and maintain homeostasis. Accordingly, disturbances in the placental circulation or delivery of nutritive substrates can have serious consequences for the growth and development of the fetus.

The transfer of respiratory gases occurs by diffusion, driven by the partial pressure differences of these gases in various compartments, as is the case in the lungs after birth (see pp. 660–661 ). The uterine arterial blood enters the placenta with a of 80 to 100 mm Hg, whereas umbilical arterial blood enters with a of ~20 mm Hg, so that O ₂ diffuses from the uterine to the umbilical circulation. The result is that the effluent umbilical venous blood has a of about 35 to 50 mm Hg, whereas the uterine venous is consistently higher by 4 to 15 mm Hg. This difference is analogous to the alveolar-arterial gradient (see p. 698 ). However, with some substances, such as creatinine, the concentration is the same in fetal and maternal blood. Amino acids are transported across the syncytiotrophoblast and then diffuse into the fetal circulation. Transfer of immunoglobin G, a protein that provides passive immunity from the mother, is by receptor-mediated endocytosis (see p. 42 ). Fluid movement obeys the principles of Starling forces (see pp. 467–468 ).

Growth occurs by hyperplasia and hypertrophy

The growth of an organ occurs as a result of an increase in cell number (hyperplasia), an increase in cell size (hypertrophy), or both. Growth follows three sequential phases that are organ specific: (1) pure hyperplasia, (2) hyperplasia and concomitant hypertrophy, and (3) hypertrophy alone. For example, the placenta goes through all three phases of growth, but these phases are compressed because the placental life span is relatively short. Moreover, simple hypertrophy is the primary form of placental growth. Thus, the weight, RNA content, and protein content of the human placenta increase linearly until term, but cell number does not increase during the third trimester. Disturbances of placental growth have secondary consequences for the fetus. Perhaps the most important factor that currently can be modified is maternal smoking, which contributes to a reduction of birth weight and raises the risk of chronic disease in the offspring, as both a child and an adult.

In contrast to placental growth and development, growth of the fetus occurs almost entirely by hyperplasia. Thus, DNA content increases linearly in all fetal organs beginning early in the second trimester. Stimuli that either increase or decrease cell number, cell size, or both may accelerate or retard the growth of the whole fetus or of individual organs. The phase of growth during which the stimulus acts determines the response of the organ. For example, chromosomal aneuploidy is likely to have an effect on growth throughout gestation, whereas malnutrition or substance abuse will impair growth only when the exposure is present. Although some effects—such as those of malnutrition on growth—are reversible, there may also be long-term consequences for health.

Growth depends primarily on genetic factors during the first half of gestation and on epigenetic factors thereafter

The fertilized egg contains the genetic material that directs cell multiplication and differentiation and guides development of the human phenotype. For specific developmental events to occur at precise times, a programmed sequence of gene activation and suppression is necessary. N57-1 Ignoring apoptosis, the fertilized egg must undergo an average of ~42 divisions before newborn size is reached. A fertilized ovum weighing less than 1 ng gives rise to a newborn weighing slightly more than 3 kg (an increase of >10 ¹² fold). Not only must the total cell number in a term fetus lie within relatively narrow limits, but also the developmental program must trigger cell differentiation after a specified number of cell divisions. After birth, only approximately five additional divisions are necessary for the net increase in mass that is necessary to achieve adult size. However, many tissues (e.g., gastrointestinal tract, skin, blood cells) must continually undergo cell division to replenish cells lost by apoptosis.

Although the genetic makeup of the fetus principally determines its growth and development, other influences—both stimulatory and inhibitory—are superimposed on the genetic program. During the first half of pregnancy, the fetus's own genetic program is the primary determinant of growth, and thus constrains patterns of growth. During the second half of pregnancy, the patterns of growth and development are more variable. The four primary epigenetic factors at work during the second half of pregnancy are placental, hormonal, environmental (e.g., maternal nutrition), and metabolic (e.g., diabetes). We discuss the first two factors (placental and hormonal) in the next two sections.

Studies in both healthy and growth-restricted infants have identified the important determinants of newborn body mass ( Fig. 57-1 ). The use of fetal ultrasonography now permits repetitive determination of measures of fetal growth, such as femur length, distance between the two parietal eminences of the head (biparietal diameter), head circumference, and abdominal circumference. For example, a healthy male infant gains 25 to 30 g/day during the last trimester of pregnancy. The ultrasound measurements provide valuable information about growth during gestation, whereas previously we made assumptions based solely on birth weight.

The mother's contribution to the fetal environment includes maternal health and nutritional status, age (e.g., adolescents and older women have infants with lower birth weight), parity, prepregnancy weight and prenatal weight gain, height, and cigarette smoking, although factors vary in importance depending on the environment (e.g., maternal infection with malaria is a significant factor in endemic areas). The father contributes to birth weight only via the genes that he passes on to his child, with the correlation between father and infant being ~12%. The correlation with maternal weight is ~22%. From observations in cases of oocyte donation, it is apparent that newborn weight is related more to anthropometric measures of the mother than of the father. The paternal body size has a small influence on fetal lean mass, and fetal sex also has a small effect (males have somewhat higher lean body mass). Multiparity and premature birth both correlate with low birth weight, and both have become more common with artificial fertilization techniques.

Increases in placental mass parallel periods of rapid fetal growth

The placenta plays several important roles in fetal growth and development. In addition to serving transport and storage functions, the placenta is involved in numerous biosynthetic activities. These include the synthesis of steroids, such as estrogen and progesterone, and of protein hormones, such as human chorionic gonadotropin (hCG) and the human chorionic somatomammotropins (hCSs; see p. 1139 ).

Fetal growth closely correlates with placental weight and trophoblast surface area. During periods of rapid fetal growth, placental weight increases. As the placental mass increases, the total surface area of the placental villi (see p. 1136 ) increases to sustain gas transport and fetal nutrition. Moreover, maternal blood flow to the uterus and fetal blood flow to the placenta also increase in parallel with the increase in placental mass. Placental growth increases linearly until ~4 weeks before birth, and adequate placental reserve is particularly important during the third trimester, when fetal growth is very rapid. Fetal growth restriction ( Box 57-1 ) can occur as a result of decreased placental reserve caused by any insult. For example, mothers who smoke during pregnancy tend to have small placentas and are at high risk of delivering a low-birth-weight baby.

Insulin, the insulin-like growth factors, and thyroxine stimulate fetal growth

In Chapter 48 , we discussed several hormones—including glucocorticoids, insulin, growth hormone (GH), the insulin-like growth factors (IGFs), and thyroid hormones—that are important for achieving final adult mass.

Many fetal tissues produce red blood cells early in gestation

During early gestation, islands of cells form within the yolk sac, some of which become primitive blood cells or hemocytoblasts. This phase of hematopoiesis ends by 6 weeks' gestation. Later, red blood cell (RBC) production (erythropoiesis; see pp. 431–433 ) occurs in many tissues not normally thought of as erythropoietic in the adult. At about the fourth week of gestation, the endothelium of blood vessels and the mesenchyme also begin to contribute to the pool of RBCs, followed shortly by the liver. The bone marrow, spleen, and other lymphoid tissues begin to produce RBCs only near the end of the first trimester. All these organ systems except bone marrow gradually lose their ability to manufacture blood cells, and by the third trimester, the bone marrow becomes the dominant source of blood cells.

RBCs formed early in gestation are nucleated, but as fetal development progresses, more and more of the circulatory RBCs are non-nucleated. The blood volume in the common circulation of the fetoplacental unit increases as the fetus grows. The fraction of total RBCs that are reticulocytes N57-2 (immature, non-nucleated erythrocytes with residual polyribosomes) is high in the young fetus, but it decreases to only ~5% at term. In the adult, the reticulocyte count is normally <1%. The life span of fetal RBCs depends on the age of the fetus; in a term fetus, it is ~80 days, or two thirds that in an adult (see pp. 431–433 ); it is shorter in the less mature fetus.

Embryonic hemoglobin (Hb) with different combinations of α-type chains (α and ζ) and β-type chains (ε and γ; see Table 29-1 ) is present very early in gestation. Production of ζ and ε chains ceases by 8 weeks, and programmed development N4-5 governs increased synthesis of fetal Hb (HbF, α ₂ γ ₂ ), which predominates at birth. Adult Hb (HbA, α ₂ β ₂ ) and a small amount of HbA ₂ (α ₂ δ ₂ ) gradually replace HbF during the first 12 months of life until eventually the adult pattern of Hb expression is established (see Table 29-2 ). An exception is in certain genetic abnormalities of α- or β-chain production (e.g., thalassemia), in which HbF persists.

The Hb content ([Hb]) of fetal blood rises to ~15 g/dL by midgestation, equivalent to the level in normal men (see p. 434 ) and higher than [Hb] in maternal blood, which may be only ~12 g/dL. Fetal [Hb] increases near term and is ~17 g/dL in full-term infants and slightly less in premature infants. Postnatally, a substantial decrease in [Hb], with a nadir of ~11 g/dL near 2 months of age, is termed the physiological anemia of infancy because it does not respond to administration of iron or other hematinic agents. This level of anemia does not affect the well-being of an otherwise healthy infant. However, infants who are born prematurely (and therefore with a lower nadir) or who have other disturbances in O ₂ transport (e.g., hypoxemia, impaired cardiac output) can exhibit irritability, failure to grow normally, or tissue hypoxia.

The fetal gastrointestinal and urinary systems excrete products into the amniotic fluid by midpregnancy

The fetus imbibes considerable quantities of amniotic fluid by 20 weeks' gestation. However, not until the final 12 weeks of gestation is fetal gastrointestinal function similar to that of the normal infant at term. The fetal gastrointestinal tract continuously excretes small amounts of meconium into the amniotic fluid. Meconium consists of excretory products from the gastrointestinal mucosa and glands, along with unabsorbed residua from the imbibed amniotic fluid.

By the beginning of the second trimester, the fetus also begins to urinate. Fetal urine constitutes ~75% of amniotic-fluid production (see p. 1137 ). The fetal renal system does not acquire the capacity to regulate fluid, electrolyte, and acid-base balance until the beginning of the third trimester. Although the fetus has its final number of nephrons by 34 to 36 weeks' gestation, full development of renal function does not occur until several months following delivery, owing primarily to continued development of renal tubules and increased renal blood flow.

A surge in protein synthesis, with an increase in muscle mass, is a major factor in the rapid fetal weight gain during the third trimester

Fetal tissues constantly synthesize and break down proteins. Protein synthesis predominates throughout gestation, especially during the third trimester, when fetal protein synthesis—primarily in muscle and liver—increases 3- to 4-fold. The number of ribosomes per cell increases throughout gestation and early postnatal life. The efficiency of ribosomes at translating mRNA may also improve during gestation. Substrate availability (i.e., amino acids) and modulation of the synthetic apparatus by endocrine and other factors play important roles in regulating protein synthesis during gestation.

The formation of each peptide bond requires four molecules of ATP, so the energy cost of protein synthesis is 0.86 kcal/g. Protein synthesis comprises 15% to 20% of fetal metabolic expenditure in the third trimester. At equivalent phases of development, fetuses across several species invest similar fractions of total energy in protein synthesis. Because glucose is the major metabolic fuel, a shortfall of oxidized metabolic substrates (e.g., glucose and lactate) directly limits protein synthesis.

Increases in skeletal muscle mass account for 25% to 50% of fetal weight gain during the second half of gestation, when the number of muscle cells increases 8-fold and cell volume increases ~2.6-fold. Although skeletal muscle fibers are not differentiated in the first half of gestation, distinct type I and type II muscle fibers (see pp. 249–250 ) appear in equal amounts between 20 and 26 weeks of gestation.

Fetal lipid stores increase rapidly during the third trimester

Fetal fat stores account for only 1% of fetal body weight during the first trimester. By the third trimester, as much as 15% of fetal body weight is fat. At birth, humans have more fat than other warm-blooded animals (e.g., the newborn cat has 2%; the guinea pig, 9.5%; the rat, 11%), with the exception of hibernating mammals and migratory birds.

Approximately half the increase in body fat reflects increased lipid transport across the placenta, and the other half reflects increased fatty acid (FA) synthesis in the fetal liver. Blood levels of fetal lipids (i.e., triacylglycerols, FAs, and ketone bodies) remain low before 32 weeks' gestation. In the last 2 months, the fetus increases its lipid storage as triacylglycerols in white and brown adipose tissue as well as in liver. During this period, both subcutaneous fat (i.e., white fat) and deep fat (i.e., white and brown fat) increase exponentially. The stored fat ensures adequate fuel stores for postnatal survival, and it also provides thermal insulation to the newborn. In addition, brown fat is important for thermogenesis in the postnatal period.

Several factors are responsible for increased lipid stores in the near-term fetus. Increases in fetal albumin facilitate FA transfer across the placenta. Insulin acts on fetal hepatocytes to stimulate lipogenesis. Insulin also promotes the availability of substrates, including glucose and lactate, which in turn increase the synthesis of fat (see pp. 1047–1050 ).

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.

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.

Box 57-2

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. 27-4 B ). 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 .

N57-4

Fetal Synthesis of Dipalmitoylphosphatidylcholine

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.