Perinatal Physiology

(See also Perinatal Anemia.)

Fetal erythropoiesis occurs in the yolk sac between 2 weeks and 10 weeks of gestation; in the liver, which is the main site of erythropoiesis, until about 18 weeks; and in the bone marrow beginning at about 18 weeks and becoming the primary site by 30 weeks. Cutaneous extramedullary hematopoiesis, which includes erythropoiesis, may be seen in neonates who have conditions causing severe anemia (eg, congenital infection, hemolytic anemia) (1).

In utero, red blood cell production is controlled exclusively by fetal erythropoietin produced in the liver; maternal erythropoietin does not cross the placenta. Fetal erythrocytes contain approximately 55 to 90% fetal hemoglobin (hemoglobin F or HbF), which has higher oxygen affinity than adult hemoglobin. As a result, a high oxygen concentration gradient is maintained across the placenta, resulting in abundant oxygen transfer from the maternal to the fetal circulation.

After birth, this increased oxygen affinity becomes less useful; fetal hemoglobin delivers oxygen less readily to tissues, which may be deleterious in neonates with severe pulmonary or cardiac disease and hypoxemia. The transition from fetal to adult hemoglobin begins before birth; at delivery, the site of erythropoietin production changes from the liver to the more sensitive peritubular cells of the kidney by an unknown mechanism. The abrupt increase in PaO2 from approximately 25 to 30 mm Hg in the fetus to 90 to 95 mm Hg just after delivery causes serum erythropoietin to fall, and red blood cell production shuts down between birth and about 6 to 8 weeks of life, causing physiologic anemia and contributing to anemia of prematurity in that particular population. This physiologic decrease in circulating red blood cells stimulates marrow production of red blood cells, now regulated by erythropoietin from the kidney, and thus physiologic anemia does not usually require any treatment.

Aged or damaged fetal red blood cells are removed from the fetal and maternal circulations by reticuloendothelial cells, predominantly macrophages. These cells convert heme to bilirubin (1 g of hemoglobin yields 35 mg of bilirubin). This bilirubin binds to albumin and is transported to the liver, where it is transferred into hepatocytes. Uridine 5'-diphospho-glucuronosyltransferase (UGT) then conjugates the bilirubin with uridine diphosphoglucuronic acid to form conjugated bilirubin (bilirubin diglucuronide), which is secreted actively into the bile ducts (Aged or damaged fetal red blood cells are removed from the fetal and maternal circulations by reticuloendothelial cells, predominantly macrophages. These cells convert heme to bilirubin (1 g of hemoglobin yields 35 mg of bilirubin). This bilirubin binds to albumin and is transported to the liver, where it is transferred into hepatocytes. Uridine 5'-diphospho-glucuronosyltransferase (UGT) then conjugates the bilirubin with uridine diphosphoglucuronic acid to form conjugated bilirubin (bilirubin diglucuronide), which is secreted actively into the bile ducts (1).

Fetal bilirubin is primarily cleared from the circulation by placental transfer into the mother’s plasma via a concentration gradient. The maternal liver then conjugates and excretes the fetal bilirubin.

The fetal liver, however, has relatively low UGT levels (undetectable at 20 weeks of gestation, < 10% of adult levels at birth) (2, 3). Bilirubin that is conjugated in the fetus makes its way into meconium in the gastrointestinal tract but cannot be eliminated from the body in utero because the fetus does not normally pass stool. The enzyme beta-glucuronidase, present in the fetus’ small-bowel luminal brush border, is released into the intestinal lumen, where it deconjugates bilirubin glucuronide; free (unconjugated) bilirubin is then reabsorbed from the intestinal tract and re-enters the fetal circulation.

At birth, the placental connection is terminated, and the neonatal liver continues to take up, conjugate, and excrete bilirubin into bile so it can be eliminated in the stool. However, because neonates have low UGT levels and lack proper intestinal bacteria for oxidizing bilirubin to urobilinogen in the intestines, unaltered bilirubin remains in the stool, imparting a typical bright-yellow color. Additionally, the neonatal gastrointestinal tract (like that of the fetus) contains beta-glucuronidase, which deconjugates some of the bilirubin.

Feedings invoke the gastrocolic reflex, and bilirubin is excreted in stool before most of it can be deconjugated and reabsorbed. However, in many neonates, the unconjugated bilirubin is reabsorbed and returned to the circulation from the intestinal lumen (enterohepatic circulation of bilirubin), contributing to physiologic hyperbilirubinemia and jaundice. Increased hematocrit and shorter life span of red blood cells in the neonate result in increased bilirubin production and also contribute to physiologic hyperbilirubinemia.

(See also Liver Structure and Function and Neonatal Hyperbilirubinemia.)

Fetal immune function develops throughout gestation. Most immune mechanisms are not fully functional even in full-term infants. Thus, all neonates and young infants are immunodeficient relative to adults and are at increased risk of overwhelming infection. In preterm infants, earlier gestational age correlates with poorer immune function. Risk of neonatal infection is increased by maternal illness, neonatal stress, and medications (eg, immunosuppressants, antiseizure medications). Neonates’ decreased immune response may also result in an absence of fever or localized clinical signs (eg, meningismus) with some infections.

In the fetus, phagocytic cells present at the yolk sac stage of development are critical for the inflammatory response that combats bacterial and fungal infection. Granulocytes can be identified in the second month of gestation, and monocytes can be identified in the fourth month of gestation. Their level of function increases with gestational age but is still low at term.

At birth, the ultrastructure of neutrophils is normal, but in most neonates, chemotaxis of neutrophils and monocytes is decreased because of an intrinsic abnormality of cellular locomotion and adherence to surfaces. These functional deficits are more pronounced in preterm infants.

By about the 14th week of gestation, the thymus is functioning, and hematopoietic stem cell–produced lymphocytes accumulate in the thymus for development. Also by 14 weeks, T cells are present in the fetal liver and spleen, indicating that mature T cells are established in the secondary peripheral lymphoid organs by this age. The thymus is most active during fetal development and in early postnatal life. It grows rapidly in utero and is readily noted on chest radiograph in a healthy neonate, reaching a peak size at age 10 years then involuting gradually over many years.

The number of T cells in the fetal circulation gradually increases during the second trimester and reaches nearly normal levels by 30 to 32 weeks of gestation. At birth, neonates have a relative T lymphocytosis compared to adults. However, neonatal T cells do not function as effectively as adult T cells. For example, neonatal T cells may not respond adequately to antigens and may not produce cytokines.

B cells are present in fetal bone marrow, blood, liver, and spleen by the 12th week of gestation. Trace amounts of IgM and IgG can be detected by the 20th week, and trace amounts of IgA can be detected by the 30th week. Because the fetus is normally in an antigen-free environment, only small amounts of immunoglobulin (predominantly IgM) are produced in utero. Elevated levels of cord serum IgM indicate in utero antigen challenge, usually caused by congenital infection. Almost all IgG is acquired maternally from the placenta. After 22 weeks of gestation, placental transfer of IgG increases, reaching maternal levels or greater at term. Thus, IgG levels at birth in preterm infants are decreased relative to levels in term infants (1).

The passive transfer of maternal immunity from transplacental IgG and secretory IgA and antimicrobial factors in human milk (eg, IgG, secretory IgA, white blood cells, complement proteins, lysozyme, lactoferrin) compensate for the neonate’s immature immune system and confer immunity to many bacteria and viruses. Protective immune factors in human milk coat the gastrointestinal and upper respiratory tracts via mucosa-associated lymphoid tissue and decrease the likelihood of invasion of mucous membranes by respiratory and enteric pathogens.

Over time, passive immunity begins to wane, reaching a nadir when the infant is 3 to 6 months old. Preterm infants, in particular, may become profoundly hypogammaglobulinemic during the first 6 months of life. By age 1 year, the IgG level rises to about half of average adult levels. IgA, IgM, IgD, and IgE, which do not cross the placenta and therefore are detectable only in trace amounts at birth, increase slowly during childhood. IgG, IgM, and IgA reach adult levels by approximately 5 to 10 years of age (2).

Although the antibody response to initial doses of vaccines may be lower in preterm infants than in term infants, preterm infants are still able to mount a protective response to most vaccines and should be immunized on the same schedule as term infants. However, for infants who weigh < 2 kg at birth, a different vaccination schedule is recommended for hepatitis B (see Hepatitis B (HepB) Vaccine and Neonatal Hepatitis B Virus (HBV) Infection) (3, 4).

(See also Cellular Components of the Immune System and Molecular Components of the Immune System.)

Fetal circulation is marked by right-to-left shunting of blood around the unventilated and minimally perfused lungs through the patent ductus arteriosus (connecting the pulmonary artery to the aorta) and foramen ovale (connecting the right and left atria). Shunting is encouraged by high pulmonary arteriolar resistance and relatively low resistance to blood flow in the systemic and placental circulation. Approximately 11% of the combined fetal cardiac output goes to the lungs throughout gestation, with the remainder reaching the systemic circulation directly (1).

The fetal ductus arteriosus is kept open by low fetal systemic PaO2 (approximately 25 mm Hg) along with locally produced prostaglandins. The foramen ovale is kept open by the difference in atrial pressures: left atrial pressure is relatively low because little blood is returned from the lungs, and right atrial pressure is relatively high because large volumes of blood return from the placenta.

Normal Circulation in a Fetus

In the fetus, blood entering the right side of the heart has already been oxygenated via the placenta. Because the lungs are not ventilated, only a small amount of blood needs to go through the pulmonary artery. Most of the blood from the right side of the heart bypasses the lungs through the  Foramen ovale Ductus arteriosus Normally, these 2 structures close shortly after birth. Red arrows represent the most highly oxygenated fetal blood (oxygen saturation ≥ 65%). Blue arrows represent the least highly oxygenated blood (oxygen saturation ≤ 45%). Purple arrows represent intermediate oxygen saturation (oxygen saturation 50–60%). Note that oxygen saturation throughout is significantly lower than in postnatal life.

Profound changes to this system occur after birth and the first few neonatal breaths, resulting in increased pulmonary blood flow and functional closure of the foramen ovale. Pulmonary arteriolar resistance drops acutely as a result of vasodilation caused by lung expansion, increased PaO2 and reduced PaCO2, and the release of vasodilators, particularly endothelium-derived nitric oxide. The elastic forces of the ribs and chest wall decrease pulmonary interstitial pressure, further enhancing blood flow through pulmonary capillaries. Increased venous return from the lungs raises left atrial pressure. Profound changes to this system occur after birth and the first few neonatal breaths, resulting in increased pulmonary blood flow and functional closure of the foramen ovale. Pulmonary arteriolar resistance drops acutely as a result of vasodilation caused by lung expansion, increased PaO2 and reduced PaCO2, and the release of vasodilators, particularly endothelium-derived nitric oxide. The elastic forces of the ribs and chest wall decrease pulmonary interstitial pressure, further enhancing blood flow through pulmonary capillaries. Increased venous return from the lungs raises left atrial pressure.

As pulmonary blood flow is established, venous return from the lungs continues to increase, raising left atrial pressure further. Increasing PaO2 constricts the umbilical arteries, and placental blood flow is reduced or stops, reducing blood return to the right atrium. Thus, right atrial pressure decreases while left atrial pressure increases; as a result, the septum primum is pushed against the septum secundum, causing functional closure of the foramen ovale. In approximately 75% of people, the 2 septa eventually fuse and the foramen ovale ceases to exist; the remaining 25% have a patent foramen ovale (2).

Within minutes after birth, systemic vascular resistance is higher than pulmonary vascular resistance, and pulmonary artery pressure decreases relative to systemic blood pressure. The direction of blood flow through the ductus arteriosus reverses, creating left-to-right shunting of blood (called transitional circulation). This state lasts from moments after birth until approximately 24 to 72 hours of age, when the ductus arteriosus constricts and closes. The mechanism of ductal closure is complex and begins well before delivery; after birth it depends in part on the high PO2 of blood entering the ductus and its vasa vasorum from the aorta as well as alterations in prostaglandin metabolism. Once the ductus arteriosus closes, an adult-type circulation exists. The 2 ventricles now pump in series, and there are normally no major shunts between the pulmonary and systemic circulations.

Prenatal stress, postnatal stress, and anatomical differences that result in the persistence of elevated pulmonary vascular resistance after birth may result in persistent pulmonary hypertension of the newborn. Hypoxemia and acidosis cause the pulmonary arterioles to constrict (or fail to relax) and the ductus arteriosus remains open or even dilates, preventing the processes described previously and resulting in reduced pulmonary blood flow with persistent right-to-left shunting through the ductus arteriosus, foramen ovale, or both.

(See also Congenital Cardiovascular Anomalies.)

Fetal lung development progresses through phases of organogenesis and differentiation. Fairly well-developed alveoli and type II surfactant–producing pneumocytes are present around the 25th week and continue to mature throughout gestation.

The lungs continually produce fluid—a transudate from pulmonary capillaries plus surfactant secreted by type II pneumocytes. For normal gas exchange to occur at birth, pulmonary alveolar fluid and interstitial fluid must be cleared promptly. This clearance process occurs primarily by absorption of fluid into cells in the lung via epithelial sodium channel activation. Compression of the fetal thorax during vaginal delivery contributes little to pulmonary fluid clearance (1). Transient tachypnea of the newborn is likely caused by delay in this clearance process (2).

On delivery, when elastic recoil of ribs and strong inspiratory efforts draw air into the pulmonary tree, air-fluid interfaces are formed in alveoli. At the first breath, surfactant is released into the air-fluid interfaces. Surfactant, a mixture of phospholipids (phosphatidylcholine, phosphatidyl glycerol, phosphatidylinositol), neutral lipids, and 4 surface-active proteins all stored in lamellar inclusions in type II pneumocytes, reduces high surface tension to allow alveolar expansion and maintenance of functional residual capacity. Surfactant works more effectively in small alveoli than in large alveoli, thus opposing the normal tendency of small alveoli to collapse into large alveoli (per Laplace’s law, which states that in an elastic cavity, pressure decreases as volume increases).

In some neonates surfactant may not be produced in sufficient quantities to prevent diffuse atelectasis, and respiratory distress syndrome develops. The production and function of surfactant may be decreased with prematurity, maternal diabetes, neonatal meconium aspiration, and neonatal sepsis. Neonatal surfactant production in the preterm infant can be increased by giving corticosteroids to the mother at 24 to 48 hours before delivery. Intratracheal surfactant also can be given to the neonate after delivery.

(See also Respiratory Problems in Neonates.)

The fetal kidney begins producing urine at approximately 10 weeks of gestation. Nephrogenesis continues until about 34 to 36 weeks. In infants born before 34 weeks, new nephrons continue to be produced but only for 40 days after delivery. The consequences of reduced numbers of nephrons may be seen into adulthood, and some studies have shown an association with obesity, hypertension, and other diseases (1).

Glomerular filtration rate (GFR) increases progressively during gestation, particularly during the third trimester. At birth, however, renal function is still generally reduced compared to normal childhood and adult renal function, particularly in preterm infants. GFR rapidly increases in the first months of life; however, GFR, urea clearance, and maximum tubular clearances do not reach adult levels until age 1 to 2 years.

Renal function assessment can be difficult in neonates, particularly in those born prematurely or for whom there is concern of perinatal hypoxic-ischemic kidney injury, because many factors affect neonatal creatinine levels. Because of the transplacental transfer of creatinine during a pregnancy, a neonate's creatinine level reflects maternal renal function. Premature infants have higher tubular reabsorption of creatinine than term infants. Creatinine is produced in muscle, and neonates have relatively lower muscle mass and thus lower creatinine production compared to adults, so even with a perinatal kidney injury, creatinine levels may not increase (2).

(See also Overview of the Endocrine System.)