In humans, the neonatal period is defined as the first 4 weeks after birth. The newborn's ability to survive during this period depends on the adequate development and maturation of various fetal organ systems, adaptations of these organ systems to extrauterine life, and nurturing by a mother or other caretaker because of the neonate's extreme dependence. As the newborn loses its nutritional link with the placenta, the infant must now rely on its own gastrointestinal tract. Moreover, other functions normally carried out by the placenta are now entrusted to the liver and kidneys. Finally, on exiting its uterine “incubator,” the newborn must stabilize body temperature.
Although the newborn is prone to hypothermia, nonshivering thermogenesis in brown fat helps to keep the neonate warm
The body loses heat to the environment by radiation, conduction, convection, and evaporation (see pp. 1196–1197). The relative importance of these processes depends on the circumstances. For instance, at birth the infant moves from a warm and liquid environment to cool and dry surroundings. Hence, evaporation is the main source of heat loss at delivery, and then when the newborn's skin is dry, body heat is lost primarily by other means. The newborn is particularly susceptible to thermal stress, owing to some important predisposing factors: (1) large skin surface area relative to small body mass (or volume), and particularly the large surface area and high blood flow of the head; (2) limited ability to generate heat via shivering thermogenesis; (3) poor thermal insulation from the environment by adipose tissue; and (4) lack of behavioral adjustments, such as changing clothing or moving to a more favorable environment (see pp. 1223–1225).
Despite these factors, the newborn has important mechanisms for resisting hypothermia, including vasomotor responses, which divert warmed blood to or from the skin surface, and nonshivering thermogenesis, a process that occurs primarily in liver, brain, and brown fat (Fig. 57-6). Cold stress triggers an increase in the levels of TSH and epinephrine. TSH stimulates the release of the thyroid hormones, predominantly T4 (see p. 1006). Working in parallel, epinephrine activates, particularly in brown fat, the 5′/3′-monodeiodinase responsible for the peripheral conversion of circulating T4 to the far more active triiodothyronine (T3; see pp. 1009–1010). T3 acts locally in brown fat to uncouple mitochondrial oxidation from phosphorylation and thereby to increase heat production.
FIGURE 57-6 Nonshivering thermogenesis in brown fat. AC, adenylyl cyclase; Pi, inorganic phosphate; PKA, protein kinase A; RXR, retinoid X receptor; THR, thyroid hormone receptor; TRE, thyroid response element.
Brown fat differs from white fat in having a high density of mitochondria; the cytochromes in these mitochondria give the brown fat cells their color. Newborns have particularly high levels of brown fat in the neck and midline of the upper back. In brown fat, the locally generated T3 upregulates a protein called uncoupling protein 1 (UCP1; originally known as thermogenin). This protein is an H+ channel located in the inner mitochondrial membrane. Normally, intracellular purine nucleotides (e.g., ATP, GDP) inhibit UCP1. However, epinephrine, acting via a cAMP pathway, activates the lipase that liberates FAs from triacylglycerols. These FAs relieve the inhibition of the H+ channel and increase its conduction of protons. Consequently, the protons generated by electron transport enter the mitochondrion via UCP1, which dissipates the H+ gradient needed by the H+-translocating ATP synthase (see p. 118). Thus, the mitochondria in brown fat can produce heat without producing useful energy in the form of ATP. The oxidation of FAs in brown fat generates ~27 kcal/kg of body weight each day, contributing a large fraction of the neonate's high metabolic rate per mass.
The neonate mobilizes glucose and FAs soon after delivery
Elimination of the placental circulation at birth means that the newborn now has to ingest and digest its own food. However, the newborn may not start suckling for ~6 hours. During late fetal life, glucocorticoids promote rapid accumulation of glycogen via their action on glycogen synthase. In its first few hours, the neonate uses glycogenolysis to mobilize hepatic glycogen stores and thereby release glucose into the bloodstream. The two enzymes needed for breaking down hepatic glycogen, phosphorylase and glucose 6-phosphatase (see p. 1182), are present in the fetus but do not become active until soon after birth.
The newborn depletes hepatic glycogen stores in the first 12 hours of life and is susceptible to hypoglycemia if feeding is delayed. Stores of glycogen in cardiac muscle are 10 times those in the adult, and those in the skeletal muscle are 3 to 5 times those in the adult, but the fetus mainly uses the glycogen stored in these tissues to provide glucose for local use. The net effect is that during the first day of life, blood glucose levels may decline to 40 to 50 mg/dL, although they soon rise to near adult values once nutrition becomes adequate.
Infants born to diabetic mothers run a very high risk of having severe hypoglycemia (i.e., <40 mg/dL). The high maternal blood glucose levels translate to high fetal blood glucose levels, causing hyperplasia of β cells in the fetal pancreatic islets and hyperinsulinism in the fetus. Insulin levels remain high after birth, which produces extreme symptomatic hypoglycemia. Blood glucose levels tend to reach their low point within a few hours after birth and begin to recover spontaneously within 6 hours.
Even in the normal newborn, low levels of blood glucose in the immediately postnatal period lead to a decrease in blood levels of insulin (see pp. 1035–1050) and a reciprocal increase of glucagon (see pp. 1050–1053). This hormonal milieu promotes the net release of glucose by the liver. In the liver, glucagon acts via cAMP to stimulate glycogenolysis, inhibit glycogen synthesis, stimulate gluconeogenesis, and initiate synthesis of some gluconeogenic enzymes. All these actions promote formation of glucose for release into the bloodstream (see Fig. 51-12). In contrast to the adult, in whom phosphorylation is the main mechanism for regulating the enzymes involved in glycogen metabolism, in the fetus, the relative concentration of the enzymes may be more important.
Epinephrine also promotes glucose mobilization (see Fig. 58-9) in the immediately postnatal period, and it uses the same cAMP pathway as glucagon. Hypoxia, hypoglycemia, and hypothermia all stimulate the release of epinephrine from the adrenal medulla.
During the final 2 months of gestation, the fetus stores ~500 g of fat (i.e., ~15% of body weight), an important source of energy for the neonate. Decreased blood glucose just after birth raises levels of glucagon and epinephrine, which stimulate hormone-sensitive lipase in adipose tissue via cAMP (see p. 1182). This lipase breaks down triacylglycerols into glycerol and FAs, which enter the bloodstream. The liver can take up glycerol and ultimately synthesize glucose (i.e., gluconeogenesis). N57-7 The liver can also take up FAs and generate ketone bodies, which are important as the newborn deals with glycogen depletion.
Gluconeogenesis with Glycerol as the Starting Material
Contributed by Emile Boulpaep, Walter Boron
As noted in the text, hepatocytes can take up glycerol and use it in gluconeogenesis. As outlined in Fig. 58-6B, after taking up glycerol, hepatocytes can use a three-step process to convert glycerol (highlighted by a rose-colored background in the left limb of the figure) to glyceraldehyde-3-phosphate. The first step is to use glycerol kinase to convert glycerol and ATP to L-glycerol-3-phosphate and ADP. The second step is to use glycerol-3-phosphate dehydrogenase (plus oxidized nicotinamide adenine dinucleotide [NAD+]) to oxidize L-glycerol-3-phosphate to dihydroxyacetone phosphate (plus reduced NAD [NADH] + H+). The third step is to use triose phosphate isomerase to isomerize the dihydroxyacetone phosphate to glyceraldehyde-3-phosphate.
Hepatocytes can use the glyceraldehyde-3-phosphate to generate glucose. The first step is to use aldolase to combine glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (generated in the second step of glyceraldehyde-3-phosphate) to generate fructose-1,6-bisphosphate. The second step is to bypass the phosphofructokinase reaction of glycolysis by using fructose-1,6-bisphosphatase to generate fructose-6-phosphate. The third step is to use phosphoglucoisomerase to isomerize the fructose-6-phosphate to glucose-6-phosphate. Finally, glucose-6-phosphatase in the endoplasmic reticulum bypasses the glucokinase reaction of glycolysis by converting glucose-6-phosphate to glucose. Glucagon stimulates production of both fructose-1,6-bisphosphatase and glucose-6-phosphatase.
Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 3rd ed. Worth Publishers: New York; 2000.
The neonate's metabolic rate—expressed per kilogram of body weight—is much higher than that of the adult. Through the first year of life, the growing infant has a daily resting metabolic rate of ~55 kcal/kg, which is nearly double the value of ~30 kcal/kg for a healthy young adult. At birth, the growing infant has a daily caloric requirement of 100 to 120 kcal/kg, which will fall to 90 to 100 kcal/kg by the end of the first year. The difference between the caloric requirement and resting metabolic rate represents the calories expended in physical activity and growth.
Breast milk from a mother with a balanced diet satisfies all of the infant's nutritional requirements during the first several months of life
Provided the mother's diet is adequate during pregnancy, the newborn is in complete nutritional balance at birth. The newborn's natural nutrition for the first few days of life is colostrum (a milk-like substance secreted by the mammary glands), and thereafter it is breast milk (see Table 56-7 for the composition of these substances), both of which the newborn's gastrointestinal tract can readily digest. The American Academy of Pediatrics recommends exclusive breast-feeding for the first 6 months, and then breast-feeding complemented with consumption of other foods until at least 1 year of age. If the infant is breast-fed, and if the mother's nutritional status is good, colostrum and breast milk meet all of the newborn's nutritional needs. Moreover, colostrum and breast milk make important contributions to the newborn's immune status. Both contain high concentrations of immunoglobulin A (or secretory) antibodies directed against bacteria and viruses, and they also contain macrophages. Breast milk contains factors that promote the growth of lactobacilli, which colonize the colon and may protect the infant from some virulent strains of Escherichia coli.
If the mother's dietary intake of iron is adequate during pregnancy, the infant's hepatic stores of iron will be adequate for hematopoiesis for 6 to 9 months following delivery.
The calcium in breast milk can meet the infant's needs for the rapid calcification of bones and teeth. Although the supply of calcium per se is unlikely to be a problem, vitamin D is necessary for the proper absorption of calcium by the intestines (see pp. 1065–1067). Vitamin D supplementation may be necessary if the newborn or the mother is not exposed to sufficient sunlight to generate vitamin D in the skin (see p. 1064). Supplementation may also be required in formula-fed infants and in infants born prematurely. Rickets (see Box 52-2) can develop rapidly in a vitamin D–deficient infant. N57-8
Scurvy in Infants
Contributed by Ervin Jones
Vitamin C (ascorbic acid; see Table 45-3) is necessary for the synthesis of hydroxyproline in collagen and chondroitin sulfate in cartilage, bone, and other connective tissues. The neonate is normally born with sufficient stores of vitamin C and receives adequate amounts of this vitamin in breast milk. If the breast milk or formula is vitamin C deficient, the infant may develop scurvy, which can be prevented by administering vitamin C supplements to the mother or infant. Scurvy is a disease manifest by lesions on the skin and mucous membranes.
The neonate is at special risk of developing fluid and acid-base imbalances
The newborn normally loses 6% to 10% of body weight during the first week of life, which reflects a decrease in interstitial and intravascular volume. After ~1 week, the rate of fluid intake begins to exceed that rate of loss, and term infants return close to birth weight by weeks.
The newborn's total-body water is ~75% of body weight compared with 60% for men and 50% for women (see Table 5-1). Once the newborn is in a steady state, daily turnover of body water is 100 to 120 mL/kg (i.e., 3- to 4-fold higher than in adults). About one third of this fluid loss occurs via skin and respiration, whereas the other two thirds occurs via urine and stool. Large variations in newborn fluid loss may go undetected because of the environment, the neonate's large ratio of surface area to mass, and the inability to seek access to water. Thus, small changes in the balance between fluid intake and loss can lead to rapid and profound disturbances in body fluid compartments, which requires very careful management.
The immaturity of the neonate's kidneys further complicates matters. For example, the glomerular filtration rate (GFR; see p. 739), which is extremely low at birth, increases rapidly during the first 2 weeks of life. However, even when normalized for body surface area, GFR does not reach adult levels until ~1 year of age, in part because renal blood flow during that time increases from ~5% to 20% of cardiac output. Moreover, the dehydrated newborn has limited capacity to conserve fluid because the concentrating ability of the kidney (i.e., a maximal urine osmolality of ~450 mOsm) is substantially less than that of an adult (~1200 mOsm). This difference reflects shorter loops of Henle and low urea concentrations in the medullary interstitium until the newborn ingests protein.
Because of the newborn's relatively high metabolic rate, the neonate generates a greater load of nonvolatile acids (see p. 821) than the adult. Moreover, the immature state of neonatal kidneys with respect to acid excretion puts the neonate at risk of developing metabolic acidosis (see p. 635).
Humoral and cellular immune responses begin at early stages of development in the fetus
Maternal antibodies play a key role in protecting the infant from infection both in utero and during the first several months after birth.
The placenta actively transports the small immunoglobulin G (IgG) antibodies from mother to fetus, so that fetal IgG levels are even higher than those in the mother. These maternal IgG antibodies ward off infection by viruses and some bacteria. However, maternal IgA (which is primarily present in secretions), IgE, and IgM antibodies generally do not cross the placenta in appreciable amounts, and the baby is generally born with very low levels of these other immunoglobulins.
The fetus begins to develop its own immune capabilities at very early stages of development. However, because the fetus is isolated from antigens, the fetal immune system normally does not make large amounts of antibodies. Nevertheless, the fetus can respond to intrauterine infections by generating IgM antibodies. In addition, the fetus also begins to produce other proteins that help to protect against bacterial and viral infections. Among these are the following: (1) the components of the complement pathway; (2) lysozyme, an enzyme found in secretions such as tears and mucus, which digests the cell walls of bacteria and fungi; and (3) interferon-γ, which is produced by T lymphocytes and which activates B lymphocytes, macrophages, and endothelial cells.
Not only does the fetus have high prenatal levels of maternal IgG, but the newborn receives copious amounts of secretory IgA antibodies in colostrum and breast milk. However, the blood levels of maternal IgG antibodies progressively fall, and IgG levels in the infant's blood reach a nadir at ~3 months of age. After that time, the infant's own production of IgG antibodies causes total IgG levels to increase gradually. However, even at 1 year of age, IgG levels—as well as the levels of IgA, IgM, and IgE—are only half of adult levels.
Antibodies obtained in utero from the mother protect the fetus against most childhood diseases, including diphtheria, measles, and poliomyelitis. The persistence of antibodies at levels high enough for protection varies considerably from one disease to another. For example, maternal measles antibodies are so persistent that vaccinations against measles often fail if attempted before the infant is 15 months of age. In contrast, maternal antibodies against whooping cough (pertussis) are generally inadequate to protect the infant beyond 1 to 2 months. The infant normally receives a first DTaP immunization (diphtheria, tetanus, and acellular pertussis), as well as a first poliomyelitis immunization, at 2 months of age.
In premature newborns, immaturity of organ systems and fragility of homeostatic mechanisms exacerbate postnatal risks
The World Health Organization defines a premature infant as one born sooner than 37 weeks after the mother's last menstrual period, compared with the normal 40 weeks (see p. 1142). Virtually all the challenges to the health of the neonate are made more severe by prematurity or intrauterine growth restriction (see Box 57-1), conditions that are therefore associated with reduced chances of survival. These problems generally reflect immaturity either of certain organ systems (e.g., lungs, intestines, liver, kidneys) or of homeostatic mechanisms (e.g., thermoregulation). N57-9
Problems of Prematurity
Contributed by Ervin Jones
Blood Plasma Parameters
Because both the respiratory and the renal systems regulate blood pH (see Equation 28-27), variations in one or both of these systems can lead to substantial fluctuations in blood pH in the premature infant. In addition, prematurity is often associated with hypoglycemia, hypocalcemia, hyperbilirubinemia, and hypoproteinemia (reflecting an immature liver).
Large numbers of mature alveoli begin to appear only relatively late in gestation (see p. 1156). Similarly, the type II alveolar pneumocytes begin to produce substantial amounts of surfactant only just before the normal term of gestation. As a result, premature infants have a reduced vital capacity and functional residual capacity. The greater the degree of prematurity, the greater the incidence of—and mortality from—infant respiratory distress syndrome (see Box 57-2). In addition to having these problems with pulmonary mechanics, premature newborns are also prone to difficulties with ventilatory control. For example, infants with a birth weight of <1500 g have a high incidence of recurrent apnea (i.e., cessation of breathing for >20 seconds, or long enough to produce either cyanosis or bradycardia; see Fig. 23-6A for the mechanism by which hypoxia can produce bradycardia).
Prematurity predisposes the newborn to necrotizing enterocolitis, in which intestinal ischemia leads to the inflammation and death of the mucosa or even the entire intestinal wall. Stresses such as asphyxia or hypothermia may trigger this condition. In addition, the digestive and absorptive systems—especially for lipids—may be inadequate in the premature infant. Because vitamin D is a fat-soluble vitamin required for the absorption of Ca2+ (see discussion beginning on page 1065), premature infants are at special risk of developing rickets.
The immature infant is born with inadequate stores of hepatic glycogen, stores that are essential for maintaining adequate plasma glucose levels in the first hours of extrauterine life. Inadequate hepatic synthesis of coagulation factors (see Table 18-4) can increase the risk of hemorrhage.
Immaturity leads to across-the-board impairment of renal function. Renal blood flow, GFR, and tubular function are all affected. Impaired concentrating ability leads to high urinary water losses. In addition, low gestational age is associated with high levels of insensible water loss because the skin is thin, the subcutaneous tissue is inadequate, and the surface-to-volume ratio is so large. Thus, fluid balance is a major problem for the premature infant. The premature infant is also at a greater risk than the term infant for developing acidosis.
The premature infant is at increased risk of anemia. The baby born at term has a relatively high Hb concentration (14 to 20 g/dL) and hematocrit (43% to 63%). The Hb level normally falls slowly during the first few months of life due to a decreased rate of hematopoiesis and then rises gradually during childhood. The nadir in Hb concentration is more marked in the premature infant for two reasons. First, the premature infant is born with approximately 2 g/dL less Hb than its term counterpart. Second, it has a reduced hematopoietic capacity, due at least in part to decreased iron stores.
Premature newborns have difficulty maintaining an adequate temperature, so that body temperature tends to approach the ambient temperature. In a relatively cool room, the body temperature of a premature infant can fall to 30°C. For this reason, a pediatrician treating a premature newborn places it in an incubator, which provides a neutral thermal environment (see p. 1196) and keeps the infant's body core temperature (see pp. 1193–1194) near 37°C. The more immature the newborn (i.e., the smaller the body and the higher the surface-to-volume ratio), the higher must be the temperature of the incubator to maintain the proper body core temperature in the infant.