The transition from life in utero to life outside the womb involves multiple changes in physiology and function. Also see Perinatal Problems.
Aged or damaged fetal RBCs are removed from the circulation by reticuloendothelial cells, which convert heme to bilirubin (1 g of Hb yields 35 mg of bilirubin). This bilirubin is transported to the liver, where it is transferred into hepatocytes. Glucuronyl transferase then conjugates the bilirubin with uridine diphosphoglucuronic acid (UDPGA) to form bilirubin diglucuronide (conjugated bilirubin), which is secreted actively into the bile ducts. Bilirubin diglucuronide makes its way into meconium in the GI tract but cannot be eliminated from the body, 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 reenters the fetal circulation. Fetal bilirubin is cleared from the circulation by placental transfer into the mother’s plasma following a concentration gradient. The maternal liver then conjugates and excretes the fetal bilirubin.
At birth, the placental connection is terminated, and although the neonatal liver continues to take up, conjugate, and excrete bilirubin into bile so it can be eliminated in the stool, neonates lack proper intestinal bacteria for oxidizing bilirubin to urobilinogen in the gut; consequently, unaltered bilirubin remains in the stool, imparting a typical bright-yellow color. Additionally, the neonatal GI 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.
Fetal circulation is marked by right-to-left shunting of blood around the unventilated lungs through a 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 (including placental) circulation. About 90 to 95% of the right heart output bypasses the lungs and goes directly to the systemic circulation. The fetal ductus arteriosus is kept open by low fetal systemic Pao2 (about 25 mm Hg) along with locally produced prostaglandins. The foramen ovale is kept open by differences in atrial pressures: left atrial pressure is relatively low because little blood is returned from the lungs, but right atrial pressure is relatively high because large volumes of blood return from the placenta.
Normal Circulation in a Fetus
Profound changes to this system occur after the first few 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. 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, thus reducing the pressure differential between left and right atria; this effect contributes to the functional closure of the foramen ovale.
As pulmonary blood flow is established, venous return from the lungs increases, raising left atrial pressure. Air breathing increases the Pao2, which constricts the umbilical arteries. 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 two fetal components of the interatrial septum (septum primum and septum secundum) are pushed together, stopping flow through the foramen ovale. In most people, the two septa eventually fuse and the foramen ovale ceases to exist.
Soon after birth, systemic resistance becomes higher than pulmonary resistance, a reversal from the fetal state. Therefore, the direction of blood flow through the patent ductus arteriosus reverses, creating left-to-right shunting of blood (called transitional circulation). This state lasts from moments after birth (when the pulmonary blood flow increases and functional closure of the foramen ovale occurs) until about 24 to 72 h of age, when the ductus arteriosus constricts. Blood entering the ductus and its vasa vasorum from the aorta has a high Po2, which, along with alterations in prostaglandin metabolism, leads to constriction and closure of the ductus arteriosus. Once the ductus arteriosus closes, an adult-type circulation exists. The 2 ventricles now pump in series, and there are no major shunts between the pulmonary and systemic circulations.
During the days immediately after birth, a stressed neonate may revert to a fetal-type circulation. Asphyxia with hypoxia and hypercarbia causes the pulmonary arterioles to constrict and the ductus arteriosus to dilate, reversing the processes described previously and resulting in right-to-left shunting through the now-patent ductus arteriosus, the reopened foramen ovale, or both. Consequently, the neonate becomes severely hypoxemic, a condition called persistent pulmonary hypertension or persistent fetal circulation (although there is no umbilical circulation). The goal of treatment is to reverse the conditions that caused pulmonary vasoconstriction.
(See also Overview of the Endocrine System.)
The fetus depends completely on the maternal supply of glucose via the placenta and does not contribute to glucose production. The fetus begins to build a hepatic glycogen supply early in gestation, accumulating most glycogen stores during the 2nd half of the 3rd trimester. The neonate’s glucose supply terminates when the umbilical cord is cut; concurrently, levels of circulating epinephrine, norepinephrine, and glucagon surge, while insulin levels decline. These changes stimulate gluconeogenesis and mobilization of hepatic glycogen stores.
In healthy, term neonates, glucose levels reach a nadir 30 to 90 min after birth, after which neonates are typically able to maintain normal glucose homeostasis. Infants at highest risk of neonatal hypoglycemia include those with reduced glycogen stores (small-for-gestational-age infants and premature infants), critically ill infants with increased glucose catabolism, and infants of diabetic mothers (secondary to temporary fetal hyperinsulinemia).
(See also Perinatal Anemia.)
In utero, RBC production is controlled exclusively by fetal erythropoietin produced in the liver; maternal erythropoietin does not cross the placenta. Fetal cells contain about 55 to 90% of fetal Hb (hemoglobin F or HbF), which has high oxygen affinity. 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. This increased oxygen affinity is less useful after birth, because fetal Hb gives up oxygen to tissues less readily, and it may be deleterious if severe pulmonary or cardiac disease with hypoxemia exists.
The transition from fetal to adult Hb 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 about 25 to 30 mm Hg in the fetus to 90 to 95 mm Hg in the neonate just after delivery causes serum erythropoietin to fall, and RBC production shuts down between birth and about 6 to 8 wk, causing physiologic anemia and contributing to anemia of prematurity.
At term, most immune mechanisms are not fully functional, more so with increasing prematurity. Thus, all neonates and young infants are immunodeficient relative to adults and are at increased risk of overwhelming infection. This risk is enhanced by prematurity, maternal illness, neonatal stress, and drugs (eg, immunosuppressants, anticonvulsants). Neonates’ decreased immune response may explain the absence of fever or localized clinical signs (eg, meningismus) with infection.
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 2nd mo of gestation and monocytes can be identified in the 4th mo 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 premature infants.
By about the 14th wk of gestation, the thymus is functioning, and hematopoietic stem cell–produced lymphocytes accumulate in the thymus for development. Also by 14 wk, 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 x-ray in a healthy neonate, reaching a peak size at age 10 yr then involuting gradually over many years.
The number of T cells in the fetal circulation gradually increases during the 2nd trimester and reaches nearly normal levels by 30 to 32 wk 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 wk of gestation. Trace amounts of IgM and IgG can be detected by the 20th wk and trace amounts of IgA can be detected by the 30th wk; 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 wk gestation, placental transfer of IgG increases to reach maternal levels or greater at term. IgG levels at birth in premature infants are decreased relative to gestational age.
The passive transfer of maternal immunity from transplacental IgG and secretory IgA and antimicrobial factors in breast milk (eg, IgG, secretory IgA, WBCs, complement proteins, lysozyme, lactoferrin) compensate for the neonate’s immature immune system and confer immunity to many bacteria and viruses. Protective immune factors in breast milk coat the GI 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 mo old. Premature infants, in particular, may become profoundly hypogammaglobulinemic during the first 6 mo of life. By 1 yr, the IgG level rises to about 60% 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 about age 10 yr.
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 wk 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 by compression of the fetal thorax during delivery and by absorption of fluid into cells in the lung via epithelial sodium channel activation. Transient tachypnea of the newborn is probably caused by delay in this clearance process.
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, which would otherwise cause atelectasis and increase the work of breathing. 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 by maternal diabetes, neonatal meconium aspiration, and neonatal sepsis. Neonatal surfactant production in the preterm infant can be increased by giving corticosteroids to the mother for 24 to 48 h before delivery. Intratracheal surfactant also can be given.
At birth, renal function is generally reduced, particularly in premature infants. GFR increases progressively during gestation, particularly during the 3rd trimester. 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 yr.