David P. Carlton
Birth involves changes in numerous organ systems in the infant, but only a few require relatively rapid postnatal adjustment. The most important of these birth-related changes involve transitional function in the respiratory, cardiovascular, thermoregulatory, and metabolic systems.
Within minutes after birth, regular breathing efforts are sustained, lung compliance improves, airway resistance diminishes, and a functional residual capacity is established. With these changes, gas tensions of both oxygen and carbon dioxide in the blood approach those expected in the mature postnatal infant. The physiological triggers for establishing regular breathing efforts are probably the loss of the umbilical circulation and the increase in systemic oxygen content.1-3
A critical element necessary for pulmonary adaptation after birth is surfactant. Surfactant derives its importance from its ability to lower the surface tension of the alveolar lining layer, the shallow pool of liquid that overlies the cells of the distal airspaces. Without a very low surface tension at end-expiration, the airspaces become atelectatic with exhalation. It is a deficiency of surfactant that underlies the patho-physiology of the respiratory distress observed after premature birth.4
Surfactant is synthesized in the type II cells that line the distal airspaces. It is composed primarily of lipids, including the disaturated phospholipids, which are responsible for the relevant biophysical properties. Associated with these lipids are a small but critical collection of proteins, the surfactant-associated proteins A, B, C, and D. Proteins B and C are water-insoluble, hydrophobic proteins that are closely associated with the lipid component of surfactant. The pivotal role of these latter 2 proteins is exemplified by respiratory distress syndromes that result from their genetic alteration. Specifically, the absence of surfactant protein B results in severe respiratory failure unresponsive to routine supportive care.5
During the latter stages of intrauterine development, the enzymes important in surfactant production increase and result in an increase in intracellular surfactant content. At the time of birth, much of this stored surfactant is released into the alveolar space. Surfactant release is stimulated by lung inflation and the increase in circulating catecholamine concentration that accompanies birth. The premature infant has less surfactant available for extrusion into the airspace at the time of birth than does a term infant.6
In addition to an adequate concentration of surfactant, postnatal lung adaptation also depends on clearance of fluid from the lumen of the lung. Before birth, the potential airspaces are filled with liquid, and failure to remove this liquid after birth results in respiratory difficulty and hypoxemia. Fetal lung liquid is produced by a process that is dependent on the secretion of Cl ions across the respiratory epithelium into the lung lumen. The importance of fetal lung liquid derives from its ability to act as a dynamic template around which the lung develops in utero. If the fetal airspaces are inadequately distended with liquid, lung growth is stunted and lung cell differentiation is disturbed.7
Clearance of fetal lung liquid at the time of birth does not occur primarily by egress of fluid from the lungs by way of the trachea. Rather, the liquid contained within the fetal airspaces at the time of birth is reabsorbed across the respiratory epithelium, a process that is driven by transcellular movement of Na ions from the lung liquid into the interstitium through channels on the apical surface of the distal lung cells. The complete characterization of events that initiate and maintain Na and liquid reabsorption from the lung is not clear but likely involve changes in oxygen tension and circulating catecholamines associated with delivery.8
See Chapter 50 for more information.
Profound changes in central circulatory patterns occur after birth and are necessary for the successful transition to extrauterine life. The extent to which this transition fails to take place influences not only the clinical condition of patients who have structural heart disease but also infants whose primary illness may appear to have little, if any, relationship to the circulation.
The blood flow pattern of the fetus can be considered to be composed of 2 parallel circuits, as contrasted with the circulation of the adult with 2 circulations linked in series. That is, in the mature adult circulation, venous blood enters the right atrium and is ejected from the right ventricle into the pulmonary circulation. This same blood then drains from the pulmonary venous system into the left atrium and is ejected from the left ventricle into the systemic circulation. The right and left ventricular outputs are essentially equivalent and either one accurately represents cardiac output. However, in the fetus, the output from the right and left ventricles each contribute, in parallel, to systemic blood flow because a portion of the right ventricular output traverses the ductus arteriosus and contributes to blood flow to the descending aorta. Because cardiac output to regional vascular beds in the fetus has to be considered with this arrangement in mind, both right and left ventricular outputs are important when considering fetal cardiac function.9-11
In some infants after birth, pulmonary vascular resistance fails to decrease as expected. In patients with the most severe form of this condition, called persistent pulmonary hypertension of the newborn or persistent fetal circulation, blood destined for the pulmonary circulation is diverted right to left into the descending aorta through a patent ductus arteriosus. The severe right-to-left shunting seen in this condition may result in life-threatening hypoxemia. Reducing pulmonary vascular resistance, for instance, by inhalation of nitric oxide, can effectively treat this condition.18
See Chapter 483 for more detailed information.
In utero, the fetus consumes oxygen to maintain normal cellular respiration and produce energy. Heat is generated as an expected byproduct of these reactions. When values are normalized to body weight, the fetus generates about twice as much heat as an adult of the same species. Most of the heat generated by the fetus is dissipated in the placenta as fetal blood is cooled by the maternal circulation. The balance, perhaps 10% to 20% of the total fetal heat production, is dissipated through the fetal skin, amniotic fluid, and uterine wall. Under conditions in which the efficiency of heat transfer in the placental circulation is diminished, the fetal skin and amniotic fluid can assume a greater role in heat removal. The uterus and placenta are metabolically active, but most of the heat generated in the uterus is a result of fetal metabolism.19
At equilibrium, the sum of fetal heat generation and dissipation results in a fetal temperature that is about 0.5 °C greater than maternal temperature. An increase in maternal temperature will result in an increase in fetal temperature, and this observation highlights the disadvantage the fetus has to overcome in regulating body temperature. This disadvantage extends to hypothermic situations as well, although this condition is encountered much less frequently than maternal fever.20
Unlike the newborn, the fetus has a limited capacity for thermogenesis. The biological basis for this limitation is unclear but is likely the result of substances from the placenta that circulate in the fetus and diminish after birth with removal of the umbilical circulation. Replicating in utero those events that occur after birth, including inflating the lungs, exposure to oxygen, body cooling, and thyroid hormone infusion, do not induce a substantial thermogenic response, whereas cord occlusion does so.21
After delivery, the relatively low ambient environmental temperature and evaporation of the residual amniotic fluid from the skin combine to increase heat loss from the newborn infant. In addition to these environmental challenges, the newborn is intrinsically disadvantaged compared to the adult by virtue of the increased surface area of the newborn relative to body weight. Thus, heat production, relative to body weight, must be greater in the newborn to maintain a normal body temperature. Measurements of perinatal thermal balance suggest that heat production increases by about twofold shortly after birth to overcome the relative disadvantage of a greater surface area.22
Heat production postnatally is the result of shivering and nonshivering thermogenesis. In adults, heat production from shivering thermogenesis contributes significantly to maintenance of body temperature under conditions of cold stress. An increase in metabolic rate and heat production occurs as a result of shivering thermogenesis, which is characterized by involuntary muscle contractions that may be initially undetectable except with electromyography. The increase in heat production from shivering is substantial but limited in its long-term ability to maintain heat production.23
The proportion of heat generated from shivering and nonshivering thermogenesis after birth depends on the species studied. In general, nonshivering thermogenesis is thought to be more important than shivering thermogenesis in the newborn, but there are species in which shivering thermogenesis supplies most, if not all, of the heat production even within hours after delivery. Interestingly, in some species that rely entirely on nonshivering thermogenesis after birth, shivering thermogenesis can be induced if nonshivering thermogenesis is inhibited. This observation suggests that although under usual circumstances nonshivering thermogenesis may be the primary means by which heat is generated in the newborn, at least some capacity for shivering may exist.
The immediate control of thermogenesis, both shivering and nonshivering, is by way of the central nervous system. Cutaneous receptors responsive to thermal stimuli are present on the skin, and such receptors respond independently to cold and warm stimuli. Nearly all skin surfaces have receptors for both cold and warm stimuli, but receptors responsive to cold are more abundant than are receptors responsive to heat. The thermoreceptive afferent signals are ultimately processed in several areas of the brain, including the midbrain and hypothalamus. Efferent signaling responsible for initiating shivering thermogenesis is by way of the motor neurons. Nonshivering thermogenesis is also mediated by efferents from the central nervous system.24
Brown adipose tissue is responsible for the generation of heat associated with nonshivering thermogenesis. Although brown adipose tissue can be found in a variety of locations within the body, the upper back and neck, mediastinum, and perinephric areas are major sites of brown fat storage in the newborn. Brown fat is relatively more abundant in the newborn than in the adult. Brown fat increases in abundance postnatally, at least for some period of time. The degree to which brown fat supplies significant amounts of heat in the premature infant is less clear than it is in the term newborn.25
The thermogenic response attributed to brown adipose tissue is the result of both neurogenic and biochemical responses. Sites within the hypothalamus coordinate input from thermoreceptive afferents and also regulate sympathetic output to the brown fat stores in the body. Sympathetic stimulation of nerves in the brown adipose tissue results in the release of norepinephrine. Subsequent binding of norepinephrine to β-adrenergic receptors on the fat cell triggers an increase in cyclic adenosine monophosphate through the action of adenylate cyclase. An intracellular lipase then liberates fatty acids from cytoplasmic stores of triglycerides, making them available for mitochondrial processing, oxidation, and heat generation.
An important finding in the study of thermogenesis was the discovery of uncoupling protein 1 (UCP1). UCP1 represents a critical factor in the mechanism of heat generation in nonshivering thermogenesis, exemplified by the observation that genetically altered mice that lack UCP1 are unable to produce heat efficiently when exposed to cold and therefore become hypothermic. During mitochondrial respiration, protons are generated outside the inner mitochondrial membrane and contribute to the electrochemical gradient for protons across this barrier. Under conditions in which adenosine 5′-diphosphate is plentiful, the adenosine 5′-triphosphate (ATP) synthase present on the inner mitochondrial membrane uses protons as the driving force for ATP synthesis. In the absence of this pathway for proton entry, mitochondrial respiration slows. UCP1 acts as an ion transport protein, allowing the entry of protons so that respiration can continue, albeit generating heat instead of ATP, a process called uncoupling. UCP1 is activated by free fatty acids and inhibited by purine nucleotides. Long-term regulation of UCP1 is not well characterized.26
An important intracellular source of energy for thermogenesis is the generation of free fatty acids from triglycerides. The glycerol produced as part of this reaction is released into the circulation and is one means by which thermogenesis is measured indirectly in experimental studies. Lipoprotein lipase is developmentally regulated, and its activity is increased after birth. Free fatty acids generated by lipoprotein lipase may contribute to intracellular sources of energy for heat production. Circulating free fatty acids probably do not serve as an acute source of energy during periods of cold stress but rather replenish depleted intracellular fat stores.25
There exists an ambient temperature range in which the infant’s body temperature is normal and its metabolic rate at a minimum. The ambient temperature around this point is designated the neutral thermal environment. In this temperature range, no extra metabolic energy is used to produce heat, and the infant has no need to dissipate any extra heat. If heat loss occurs (commonly by exposure to a lower ambient temperature or by evaporative heat loss), then the infant must use thermogenesis to maintain body temperature. This results in an increase in energy consumption and oxygen demand.27
As heat loss continues, body temperature will begin to decrease if the increase in metabolic rate cannot keep pace with heat loss. Although the newborn infant has the capacity to respond to a cold stress by increasing heat production, the absolute extent to which the newborn can sustain a cold stress and maintain a normal temperature is limited when compared to the adult. In a term infant with little or no clothing, this temperature is near 25 °C as contrasted with adults under similar conditions in whom 5 °C might represent an equivalent stress. In infants and adults, the length of time that such a stress may be tolerated without hypothermia is short. Thermal insulation with clothing can lower these temperatures, as will maneuvers that reduce radiative, conductive, and convective heat losses.
As the ambient temperature increases above the neutral thermal environment, body temperature will increase unless heat loss can be enhanced by sweating or changes in the environment. Vasomotor responses will have already been recruited maximally by the time an increase in ambient temperature causes the infant’s body temperature to increase. Thus, if sweating is limited, neutral thermal environment is likely near that ambient temperature at which the infant’s body temperature begins to increase.
The endocrinologic regulation of the fetus is determined to a great extent by the fetus itself, although placental and maternal hormones are important. The capacity for self-regulation occurs early in development. The fetal hypothalamus has demonstrable concentrations of releasing hormones by the late first or early second trimester, and hormone appearance in the pituitary occurs during a similar time frame. Placentally derived hormones include estrogens, progesterone, human chorionic gonadotropin, and human placental lactogen, but the importance to the fetus of many of the placental hormones is uncertain. Although the placenta restricts the movement of many maternal hormones into the fetus, important maternal hormones that cross the placenta directly or do so after modification in the placenta include steroid hormones and thyrotropin-releasing hormone. Cortisol and thyroid hormone are both involved indirectly in postnatal adaptation.28
The fetal adrenal gland develops early in the first trimester and contains the full spectrum of enzymes important in steroidogenesis in the mature adrenal gland. Corticotropin-releasing factor is present in the fetal hypothalamus during early development, and adrenocorticotropin is present at the same time in the pituitary. Adrenocorticotropin has the dual effect of not only increasing steroid synthesis but also promoting growth and maturation of the adrenal gland. Most of the circulating fetal cortisol derives from the fetal adrenal gland with the remainder being transplacental. The synthetic capability of the fetal adrenal gland, at least for cortisol, is at least as great as that in the adult.
Circulating cortisol concentrations increase through development, beginning near the end of the first trimester and increasing more rapidly during the final weeks of gestation. The increase in cortisol during the third trimester appears to have at least a permissive effect on the development of several major organ systems, including the lung, in which the molecular processes important in surfactant homeostasis and in lung water removal are induced circulating cortisol. Although the fetal adrenal gland provides the cortisol needed by the fetus for normal development, under conditions in which sufficient fetal cortisol is unavailable, placental or maternal steroids appear adequate for normal development. At the time of birth, both adrenocorticotropin and cortisol concentrations are increased, at least as compared to their values several days after delivery.
Similar to cortisol, thyroid hormone also plays a permissive role in postnatal adaptation. In utero, thyroid hormone concentrations begin to increase near midgestation, increasing more rapidly during the last few weeks before birth and then decreasing during the days to weeks after delivery. At the time of birth there is an increase in thyroid-stimulating hormone and a several-fold increase in circulating thyroid hormone concentration. The increase in thyroid-stimulating hormone at birth appears to be a result of the thermal stress associated with delivery.
Transplacental passage of maternal thyrotropin-releasing hormone occurs readily, but maternal thyroid-stimulating hormone and thyroid hormone transfer less well. Despite this inefficiency, adequate maternal thyroid hormone is now known to be important for optimal childhood neurologic development. This observation provides an important impetus for treatment of maternal hypothyroidism during pregnancy.
Thyroid hormone appears to play a role in regulating nonshivering thermogenesis and postnatal cardiovascular function, but the necessity of thyroid hormone to the successful extrauterine transition of the newborn infant is unclear. Patients who are diagnosed with congenital hypothyroidism rarely have clinical abnormalities that bring them to medical attention immediately after birth. This empiric observation highlights the importance of newborn screening programs in the detection of these infants.
See Chapter 526 for further information.
Glucose concentration in the fetal blood during the third trimester of pregnancy is approximately 80% that of the maternal concentration. In the fetus, glucose is supplied transplacentally, and most of this glucose is metabolized by the fetus for energy. There is little, if any, glucose synthesized by the fetus under normal conditions. The small portion of transplacental glucose that is not used immediately as energy is stored as glycogen in the fetal liver, but little glycogen is stored prior to the third trimester. Energy sources other than glucose are available to the fetus, including lactate, free fatty acids, ketones, and amino acids, but glucose is the major metabolic fuel during intrauterine development.
At the time of birth, the maternal glucose delivery to the fetus ceases with clamping of the umbilical cord. Circulating glucose concentrations in the infant must then be maintained by a combination of glycogenolysis and gluconeogenesis until enteral or intravenous glucose is supplied. During the initial 1 to 2 hours after birth, glucose concentration in the newborn decreases substantially and then increases over the next several hours to days to a value of 70 mg/dL. The production of glucose in the newborn averages 4 to 6 mg/kg body weight per minute and exceeds by twofold to threefold the basal synthetic rate in adults. The brain consumes a significant amount of the circulating glucose in the newborn because of the disproportionate size of the brain in relation to body weight compared to the adult. The usual postnatal increase in circulating catecholamine and glucagon concentrations, and the simultaneous decrease in insulin concentration, are important factors in the modulation of glucose concentrations in the newborn shortly after birth.
Hepatic glycogen content begins to decrease after delivery and is nearly exhausted by 12 hours after birth in the absence of exogenous glucose. After this time, gluconeogenesis and enteral or intravenous sources of glucose are necessary to assure glucose concentrations remain in an acceptable range. Glycogen stores in the liver release glucose in response to increases in glucagon and circulating catecholamines, changes that are associated with the mechanical event of cord clamping. The normal decrease in insulin concentration after birth also participates in the maintenance of normal circulating concentrations of glucose, although the decline in insulin concentration is not a result of the decrease in glucose concentrations after delivery. The relative contribution of epinephrine, norepinephrine, and glucagon in the regulation of hepatic glycogenolysis postna-tally in human infants is incompletely understood because the circulating concentrations of each of these are interdependent. Receptor-mediated stimulation of glycogenolysis occurs with both glucagon and catecholamines. Because hepatic glycogen stores increase significantly only during the latter part of gestation, premature birth increases the risk for hypoglycemia because of the relatively limited supply of glucose from glycogenolysis.
One of the enzymes important in liberating glucose from glycogen is glycogen phosphorylase, an enzyme regulated in part by catecholamines, glucagon, and thermal stress. As a result of the action of this enzyme, glucose-1-phosphate is generated and is itself converted to glucose-6-phosphate. Tissues containing glucose-6-phosphatase can then use glucose-6-phosphate to synthesize glucose and subsequently release it into the circulation. There are, however, a number of tissues that lack glucose-6-phosphatase, and in these tissues, glucose cannot be produced, necessitating that glucose-6-phosphate be metabolized intracellularly.
Because glycogen stores are limited, gluconeogenesis plays a critical role in regulating glucose concentration in the newborn. In animal studies, inhibition of gluconeogenesis after birth results in a profound decrease in circulating glucose concentrations. Lactate, pyruvate, and selected amino acids are substrates from which glucose can be synthesized. The enzymes responsible for the conversion of these compounds include glucose-6-phosphatase, fructose 1-6 diphosphatase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase. The cytosolic form of phosphoenolpyruvate carboxykinase is the rate-limiting enzyme in gluconeogenesis during development. It increases in concentration rapidly after birth as a result of an increase in transcription. Events associated with birth are considered the physiologic trigger for the increase in cytosolic activity of phosphoenolpyruvate carboxykinase, but the specific downstream effector molecules associated with birth that increase enzyme activity are unknown.
Although gluconeogenic precursors are essential to hepatic glucose production postna-tally, fatty acid oxidation also influences gluconeogenesis. Energy stored as fat exceeds the energy stored as glycogen by 5 to 10 times in the term infant at birth. Medium-chain triglycerides increase gluconeogenesis and circulating glucose concentrations even in the absence of exogenous gluconeogenic precursors. Conversely, inhibition of long-chain fatty acid oxidation results in a significant decrease in circulating glucose concentration.
Disturbances of glucose homeostasis are common in patients with problems specific to the neonatal period. Prominent in this group of patients are premature infants, infants who are small for gestational age, and infants born to mothers with diabetes mellitus. Hypoglycemia is associated with premature birth as a result of diminished activity of gluconeogenic enzymes and reduced hepatic glycogen stores. Similar explanations are relevant for the small-for-gestational-age infant, whether term or preterm.
See Chapters 47, 48, and 51 for further information.
During fetal development, the proportion of body weight composed of water decreases from 80% to 85% at 24 weeks’ gestation to 75% to 80% at term. In term infants at birth, intracellular water accounts for two thirds of total body water, and extracellular water accounts for the remaining one third. During the first week after birth, body weight decreases, an effect that is the result of water loss. The changes in water balance associated with birth appear to begin shortly before delivery. The biological basis of these changes are not completely understood but likely arise from perinatal changes in circulating hormone concentrations, which result in a loss of fluid from the circulation into the interstitial space and a simultaneous increase in hematocrit. Longer-term changes in body water balance occur after birth as well. During the first week after delivery, infants born at term tend to lose about 5% of their birth weight as a result of a decrease in both intracellular and interstitial fluid.
In the preterm infant, body weight decreases after birth in a fashion similar to that seen in term infants, but in an exaggerated fashion. Infants born modestly preterm may lose 5% to 10% of their birth weight, whereas the youngest of premature infants may lose 15% to 20% of their birth weight with no apparent ill effects. Their weight loss is a result of salt and water loss over the first week after birth, and the fluid is lost primarily from the interstitial space. Whether this weight loss is “normal” is a matter of definition. The spontaneous feeding and apparent health of term newborns lends itself well to describing the observed weight loss in term infants as normal. However, because fluid intake in small premature infants is often determined by rates of intravenous fluid infusions, these smallest of preterm infants cannot be considered to regulate fluid intake in the same manner as term infants. Thus, the range of “normal” for variables such as weight loss in this population is somewhat arbitrary and probably should be abandoned in favor of what is most desirable for optimal health. In this regard, the interpretation of epidemiological and prospective intervention studies suggest that there is a direct relationship between morbidity and the abundance of salt and water intake, at least in the early newborn period. Thus, the most prudent extrapolation of this information would lead to a strategy in which fluid intake is adjusted to allow a gradual loss of body weight over the first postnatal week, with restriction of sodium intake until near the time when the target weight loss has occurred. Frequent measurement of body weight, urine output, and serum concentrations of electrolytes help to assure this gradual transition.