Neonatal bilirubin metabolism
(See also Liver Structure and Function Liver Structure and Function The liver is a metabolically complex organ. Hepatocytes (liver parenchymal cells) perform the liver’s metabolic functions: Formation and excretion of bile as a component of bilirubin metabolism... read more and Neonatal Hyperbilirubinemia Neonatal Hyperbilirubinemia Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). The serum bilirubin level required to cause jaundice varies with... read more .)
Aged or damaged fetal red blood cells are removed from the circulation by reticuloendothelial cells, which convert heme to bilirubin (1 g of hemoglobin 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 gastrointestinal 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 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.
Neonatal cardiovascular function
Fetal circulation is marked by right-to-left shunting of blood around the unventilated lungs through a patent ductus arteriosus Patent Ductus Arteriosus (PDA) Patent ductus arteriosus (PDA) is a persistence of the fetal connection (ductus arteriosus) between the aorta and pulmonary artery after birth. In the absence of other structural heart abnormalities... read more (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
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
Normally, these two structures close shortly after birth.
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 hours 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 Patent Ductus Arteriosus (PDA) Patent ductus arteriosus (PDA) is a persistence of the fetal connection (ductus arteriosus) between the aorta and pulmonary artery after birth. In the absence of other structural heart abnormalities... read more , the reopened foramen ovale, or both. Consequently, the neonate becomes severely hypoxemic, a condition called persistent pulmonary hypertension Persistent Pulmonary Hypertension of the Newborn Persistent pulmonary hypertension of the newborn is the persistence of or reversion to pulmonary arteriolar constriction, causing a severe reduction in pulmonary blood flow and right-to-left... read more or persistent fetal circulation (although there is no umbilical circulation). The goal of treatment is to reverse the conditions that caused pulmonary vasoconstriction.
Neonatal endocrine function
(See also Overview of the Endocrine System Overview of the Endocrine System The endocrine system coordinates functioning between different organs through hormones, which are chemicals released into the bloodstream from specific types of cells within endocrine (ductless)... read more .)
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 minutes after birth, after which neonates are typically able to maintain normal glucose homeostasis. Infants at highest risk of neonatal hypoglycemia Neonatal Hypoglycemia Hypoglycemia is difficult to define in neonates but is generally considered a serum glucose concentration 40 mg/dL ( 2.2 mmol/L) in symptomatic term neonates, 45 mg/dL ( 2.5 mmol/L) in asymptomatic... read more include those with reduced glycogen stores (small-for-gestational-age infants Small-for-Gestational-Age (SGA) Infant Infants whose weight is the 10th percentile for gestational age are classified as small for gestational age. Complications include perinatal asphyxia, meconium aspiration, polycythemia, and... read more and premature infants Premature Infants An infant born before 37 weeks gestation is considered premature. Prematurity is defined by the gestational age at which infants are born. Previously, any infant weighing read more ), critically ill infants with increased glucose catabolism, and infants of diabetic mothers (secondary to temporary fetal hyperinsulinemia).
Neonatal hematopoietic function
(See also Perinatal Anemia Perinatal Anemia Anemia is a reduction in red cell mass or hemoglobin and is usually defined as hemoglobin or hematocrit > 2 standard deviations below the mean for age. Some authorities also consider a relative... read more .)
In utero, red blood cell 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 hemoglobin (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 hemoglobin 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 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 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 red blood cell production shuts down between birth and about 6 to 8 weeks, causing physiologic anemia Physiologic anemia Anemia is a reduction in red cell mass or hemoglobin and is usually defined as hemoglobin or hematocrit > 2 standard deviations below the mean for age. Some authorities also consider a relative... read more and contributing to anemia of prematurity. This physiologic decrease in circulating red blood cells stimulates marrow production of red blood cells and does not usually require any treatment.
Neonatal immunologic function
(See also Cellular Components of the Immune System Cellular Components of the Immune System The immune system consists of cellular components and molecular components that work together to destroy antigens. (See also Overview of the Immune System.) Although some antigens (Ags) can... read more and Molecular Components of the Immune System Molecular Components of the Immune System The immune system consists of cellular components and molecular components that work together to destroy antigens (Ags). (See also Overview of the Immune System.) Acute phase reactants are plasma... read more .)
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, antiseizure drugs). 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 month of gestation and monocytes can be identified in the 4th month of gestation. Their level of function increases with gestational age Gestational Age Gestational age and growth parameters help identify the risk of neonatal pathology. Gestational age is the primary determinant of organ maturity. Gestational age is loosely defined as the number... read more 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 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 x-ray 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 2nd trimester and reaches nearly normal levels by 30 to 32 weeks 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 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, 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 breast 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. Premature infants, in particular, may become profoundly hypogammaglobulinemic during the first 6 months of life. By age 1 year, 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 years.
Although the antibody response to initial doses of vaccines may be lower in premature infants than in term infants, premature infants are still able to mount a protective response to most vaccines and should be immunized on the same schedule Childhood Vaccination Schedule Vaccination follows a schedule recommended by the Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics, the American Academy of Family Physicians, and the American... read more as term infants. However, infants who weigh < 2 kg when they receive their first dose of hepatitis B vaccine Hepatitis B (HepB) Vaccine The hepatitis B vaccine is 80 to 100% effective in preventing infection or clinical hepatitis B in people who complete the vaccine series. For more information, see Hepatitis B Advisory Committee... read more should receive 3 additional doses if the first dose is given when they are < 1 month of age (because they have a decreased antibody response; 1 Neonatal pulmonary function The transition from life in utero to life outside the womb involves multiple changes in physiology and function. Also see Perinatal Problems. (See also Liver Structure and Function and Neonatal... read more ).
Neonatal immunologic function reference
Neonatal pulmonary function
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 delivery contributes little to pulmonary fluid clearance (1 Neonatal pulmonary function reference The transition from life in utero to life outside the womb involves multiple changes in physiology and function. Also see Perinatal Problems. (See also Liver Structure and Function and Neonatal... read more ). Transient tachypnea of the newborn Transient Tachypnea of the Newborn Transient tachypnea of the newborn is transient respiratory distress caused by delayed resorption of fetal lung fluid. Symptoms and signs include tachypnea, retractions, grunting, and nasal... read more 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 Respiratory Distress Syndrome in Neonates Respiratory distress syndrome is caused by pulmonary surfactant deficiency in the lungs of neonates, most commonly in those born at 37 weeks gestation. Risk increases with degree of prematurity... read more develops. The production and function of surfactant may be decreased by maternal diabetes Diabetes Mellitus in Pregnancy Pregnancy aggravates preexisting type 1 (insulin-dependent) and type 2 (non–insulin-dependent) diabetes but does not appear to exacerbate diabetic retinopathy, nephropathy, or neuropathy (1)... read more , neonatal meconium aspiration Meconium Aspiration Syndrome Intrapartum meconium aspiration can cause inflammatory pneumonitis and mechanical bronchial obstruction, causing a syndrome of respiratory distress. Findings include tachypnea, rales and rhonchi... read more , and neonatal sepsis Neonatal Sepsis Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more . Neonatal surfactant production in the preterm infant can be increased by giving corticosteroids to the mother for 24 to 48 hours before delivery. Intratracheal surfactant also can be given to the neonate after delivery.
Neonatal pulmonary function reference
Neonatal renal function
At birth, renal function is generally reduced, particularly in premature infants. Glomerular filtration rate (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 years.
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