Antepartum period

Pregnancy is associated with major changes in metabolic processes and endocrine function. Pregnancy has been characterized as a metabolic “tug of war” between the competing needs of the mother and the fetus.⁴⁷ The fetus and placenta influence maternal metabolic alterations in that these tissues become an additional site for metabolism of maternal hormones as well as new sites for hormonal biosynthesis. Many of the metabolic changes during pregnancy are aimed at providing substances (especially glucose, lipids, and amino acids) for the growth and development of the fetus. As the fetus and placenta grow, maternal fuel economy is altered to support this growth.^38,109

Human placental lactogen (hPL), estrogen, progesterone, and possibly leptin influence metabolic processes during pregnancy, primarily by altering glucose utilization and insulin action. These changes contribute to the diabetogenic effects of pregnancy, stimulate alterations in lipid and protein metabolism, and increase the availability of glucose and amino acids for transfer to the fetus, while at the same time providing an alternative energy substrate (free fatty acids) to meet maternal needs and maintain homeostasis. The changes in carbohydrate and lipid metabolism parallel the energy needs of the mother and fetus, whereas the changes in maternal nitrogen and protein metabolism occur early in pregnancy, before fetal demand.

Basal metabolic rate

The basal metabolic rate (BMR) increases during pregnancy (Figure 16-2). The rate of change varies with maternal prepregnant nutritional status and fetal growth. Significant variations are seen among individual women with up to an eightfold increase reported. Similar variations are reported for fat accretion.^17,79,91 If a woman has low energy reserves at conception, there is less of an increase in the BMR and energy is conserved.

The total energy required for pregnancy can be divided into three parts: (1) obligatory energy needed for the fetus, placenta, uterus, and breasts (which is the smallest part); (2) energy for maternal fat storage; and (3) energy maintenance of these new tissues.⁷⁹ If a woman has lower energy stores, less of the maternal energy intake is needed to maintain new tissues and energy is conserved for maternal basic needs and the fetal-placental unit.^{79,80,107,109} For example, in undernourished women, fetal weight accounts for 60% of the pregnancy weight gain, versus 25% in a well-nourished woman.¹⁰⁹ This energy-sparing response may allow the woman to sustain the pregnancy but is often at the expense of fetal growth, with decreased birth weight and risk of fetal growth restriction.¹⁰⁹ Prentice and Goldberg suggest that leptin might monitor a woman’s prepregnancy energy stores and adjust or coordinate maternal metabolic resources.¹⁰⁹ Women with large-for-gestational-age (LGA) infants tend to have increased BMR with less maternal energy storage.^79,111 

The pregnant woman meets the energy demands of pregnancy by increasing her intake, decreasing her activity, or limiting fat storage.^80,107 King and colleagues propose three examples of how women in different situations might alter their energy to sustain pregnancy.⁷⁹ First, an underweight impoverished woman with limited food, poor fat stores, and need for physical work cannot increase food intake or limit physical activity during pregnancy. Her body responds by decreasing basal energy expenditures so that pregnant energy needs are similar to prepregnant needs. Second, a normal weight woman in a developed country with fat stores before pregnancy and adequate nutrition during pregnancy increases fat stores in pregnancy and increases her BMR slightly. Finally, an overweight woman in a developed country increases her BMR by 20% or more, perhaps to reduce additional fat deposition.⁷⁹

Lipid metabolism

Pregnancy results in marked alterations in lipid metabolism with a markedly different lipoprotein profile, with marked increases in triglycerides, as well as increases in phospholipids and cholesterol. Basal oxidation of fatty acids increases 70% in pregnancy leading to a relative hyperlipidemia.²⁷ Synthesis of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), which are contained in triglycerides, and LDL and HDL, which are found in cholesterol, also increase.⁵⁹

Lipid metabolism in pregnancy is characterized by two phases and is analogous to the patterns of change in carbohydrate and protein metabolism.^19,57 During the first two trimesters, triglyceride synthesis and fat storage increase. VLDL increases threefold in the second and third trimesters. LDL decreases slightly initially, followed by a progressive rise.¹⁰⁰ HDL increases progressively to 24 weeks, then decreases to 32 weeks and stabilizes for the remainder of pregnancy.¹⁰⁰ Triglycerides increase 40% by 18 weeks and 250% by term.⁸⁷ Phospholipids and cholesterol levels also increase; the triglyceride-to-cholesterol level remains stable since cholesterol also increases.^59,58 By late pregnancy, cholesterol levels are 50% higher than prior to pregnancy, regardless of maternal dietary intake.⁴² These changes enhance the availability of substrates for the fetus.⁵⁷

Maternal fat storage is most prominent from 10 to 30 weeks, before the peak of fetal energy demands.⁷⁹ Promotion of lipogenesis and suppression of lipolysis during this phase are mediated by progressive increases in insulin responsiveness and enhanced by progesterone, cortisol, leptin, and prolactin.^{6,16,30,42,59} Estrogens decrease lipoprotein lipase activity.¹⁸ During this period the pregnant woman experiences a physiologic ketosis with a twofold to threefold increase in baseline ketone body production, with an acute increase after fasting, suggesting enhanced fat utilization.^116,130

Lipid metabolism in late pregnancy is illustrated in Figure 16-3. The third trimester is characterized by both lipogenesis and lipolysis, with increased breakdown of fat deposits.^19,32,57,58 These changes are mediated by increased adipose tissue lipolytic activity and decreased lipoprotein lipase (LPL) activity (due to estrogens).^19,58 LPL, which is present in the capillary endothelium of extrahepatic tissues, hydrolyzes circulating triglycerides, including VLDL, producing free fatty acids and glycerol.⁵⁸ Adipose tissue is broken down into free fatty acids and glycerol, which circulate to the liver and are converted to active forms (acyl-CoA and glycerol-3-phosphate) and re-esterified into triglycerides (circulate as VLDL).^19,58 Glycerol can also be used for glucose synthesis (gluconeogenesis). The increased lipolysis is due to the rise of hPL levels with its antiinsulinogenic and lipolytic effects, as well as the effects of cortisol, glucagon, and prolactin, resulting in increased lipolytic activity in adipose tissue.^{16,19,57,58,78} Enhanced ketogenesis in the liver is a consequence of increased oxidation of free fatty acids for energy and release of ketone bodies.⁵⁸ The fat mobilization is associated with increased glucose and amino acid uptake by the fetus. Thus fats are used by the mother as an alternative energy substrate, allowing the mother to conserve glucose for the fetus and her central nervous system (CNS) during the second half of gestation.^6,16,59,58 Fetal glucose and ketone uptake increases. Ketones are used by the fetus for oxidative metabolism, lipogenesis, triglyceride production, and as substrate for brain lipid synthesis.^{58,78,116,130}

The changes in lipid metabolism during pregnancy are reflected in changes in maternal serum free fatty acid concentrations as well as plasma triglyceride, cholesterol, and phospholipid levels. These changes may be exaggerated in obese women.²⁷ The minimal change in free fatty acids during early pregnancy is probably due to increased fat storage and augmented fat utilization. As maternal fat stores are mobilized, serum levels of triglycerides, free fatty acids, glycerol, and triglyceride-rich lipoproteins (VLDL) increase to peak near term.^19,58,59 Because elevations in free fatty acids are due to catabolism of stored triglycerides (into free fatty acid and glycerol), changes in free fatty acids are mirrored by changes in glycerol.⁶ Hypertriglyceridemia during the third trimester is primarily due to increases in VLDLs and decreased peripheral clearance.^16,19,58,59 The increase is due to reduced VLDL clearance secondary to decreased activity of LPL in the liver and adipose tissue, enhanced activity of cholesterol ester transferase, increased gastrointestinal absorption of lipids, and increased hepatic triglyceride production.^16,32,58,59 The decrease in lipoprotein lipase is due to increases in estrogens in late pregnancy and the increasing insulin resistance.^58,78 Near term, lipoprotein lipase activity increases in the mammary glands. This enhances availability of triglycerides for milk production.⁵⁷

Changes in lipid metabolism are accompanied by functional and morphologic changes in the adipocytes. Hypertrophy of these cells accommodates the increased fat storage during the first two thirds of pregnancy. In the last trimester, maximal glucose transport, glucose oxidation, and lipogenesis within the adipocytes decrease.⁴² The number of insulin receptors on the adipocytes increases in the first part of pregnancy and returns to prepregnant levels by term.^6,42 Because responsiveness of adipose tissue to insulin is not diminished as much as that of other tissues, these changes in the adipocytes facilitate fat storage.⁴² After a meal, maternal fat stores are replenished by increased glucose uptake, incorporation of glucose into glycerol, and esterification of fatty acids by adipocytes.⁶

Absorptive state.

During the absorptive (fed) state, ingested nutrients (amino acid, glucose, triglyceride) are entering the blood from the gastrointestinal tract (see Chapter 12) and must be oxidized for energy, used for protein synthesis, or stored. The average meal takes 4 to 6 hours for complete absorption. In this state anabolism exceeds catabolism and glucose is the major energy source. Small amounts of amino acid and fat are converted into energy or used to resynthesize body proteins or for structural fat. Most of the amino acid and fat and any extra carbohydrate are transformed into adipose tissue; carbohydrate is also stored as glycogen.

Insulin has an anabolic and anticatabolic role during this state.⁷⁸ Insulin secretion increases and plasma insulin levels rise. Insulin promotes glucose uptake by the hepatocytes and peripheral tissues, inhibits glycogen breakdown, and inhibits lipolysis in adipose tissue. Glucose is converted to glycogen for storage in the liver, cardiac muscle, and skeletal muscle. Muscle amino acid uptake is enhanced and proteolysis inhibited.⁷⁸

After a meal the pregnant woman has higher glucose, insulin, and triglyceride levels and suppression of glycogen compared to nonpregnant women. Thus the absorptive state during pregnancy (see Figure 16-4, A) is characterized by relative hyperinsulinemia (related to decreased insulin sensitivity), hyperglycemia (due to failure of liver glucose uptake), insulin resistance (especially in skeletal muscle), hypertriglyceridemia, and lipogenesis (more glucose is converted to triglyceride for storage).^{6,16,78,119,129} Pregnancy has been called a state of facilitated anabolism to describe these metabolic alterations that conserve energy, especially during early pregnancy.⁹⁴ These changes increase glucose availability for transport to the fetus; increase availability of an alternate energy source (triglycerides) for maternal needs; and provide fewer stimuli for maternal gluconeogenesis, glycogenolysis, and ketogenesis.^42,47

Maternal blood glucose levels may rise transiently to 130 to 140 mg/dL (7.2 to 7.8 mmol/L) (see Figure 16-5). Gluconeogenesis and circulating free fatty acids are decreased. Under the influence of placental hormones, resistance of the liver and peripheral tissues to insulin is increased by as much as 60% to 70%.^119,129 The hyperinsulinemic response is most marked during the third trimester because of hypertrophy and hyperplasia of islet β cells. These cells become more responsive to alterations in blood glucose and amino acid levels. The increased insulin levels after eating overcome the insulin resistance to allow glucose uptake by muscles for storage as glycogen.¹¹⁹ Even with increased production of insulin, however, overall glucose levels are maintained, although at a relatively lower level than in nonpregnant women because of the counterbalancing effects of estrogen, progesterone, and hPL.

Postabsorptive and fasting state.

In the postabsorptive state (i.e., when nutrients are not entering the blood from the intestines, beginning 4 to 6 hours after a meal) and fasting state (12 or more hours after the last meal), energy must be supplied by body stores. Insulin levels are low. Fat and protein synthesis are decreased and catabolism exceeds anabolism. Gluconeogenesis (production of new glucose from lactate, amino acids [especially alanine], and glycerol) and catabolism of fat are the main sources of energy.⁷⁸ Plasma glucose levels are maintained during the postabsorptive state by use of these alternate sources of glucose and glucose-sparing or fat-utilization reactions.^16,42 The CNS continues to use glucose, while other organs and tissues become glucose sparing, depending on fat as the primary energy source.

During the fasting state (e.g., overnight between the evening meal and breakfast), plasma glucose levels decline. The magnitude of the decline is greater in pregnant women than in nonpregnant women, due to the continuous transfer of glucose to the fetus, and is associated with a more rapid conversion to fat metabolism. Fatty acids are liberated by breakdown of triglycerides. Lipolysis yields glycerol (converted to glucose by the liver) and free fatty acids, which are catabolized to ketone bodies (oxidized for energy). Under homeostatic conditions ketones do not accumulate in the body to produce ketoacidosis because excess ketones not needed for energy are rapidly cleared by the kidneys.⁷⁸

This response is an exaggeration of the changes normally seen during the overnight fast in nonpregnant women. These changes would normally raise blood glucose levels, but in the pregnant woman the fasting glucose level tends to be lower because of the limited availability of substrate for gluconeogenesis. For example, as early as 15 weeks’ gestation, maternal glucose levels after a 12- to 14-hour overnight fast are 15 to 20 mg (0.8 to 1.1 mmol/L) lower than levels in nonpregnant women. The decrease in glucose during the overnight “fasting” period is especially prominent during the second and third trimesters.^6,78

The exaggerated maternal responses during the fasting state are influenced by (1) continuous placental uptake of glucose and amino acids from the maternal circulation; (2) decreased peripheral utilization of glucose as plasma concentrations of ketones and free fatty acids increase; (3) decreased renal absorption of glucose; and (4) decreased hepatic glucose production. This response, seen primarily in late pregnancy, is characterized by lower fasting glucose and amino acid levels, increased blood glucose levels after eating, and increased plasma free fatty acids, triglycerides, ketones, and insulin secretion in response to glucose.^12,42,78 Thus the postabsorptive fasting state in pregnancy is characterized by a relative hypoglycemia (due to the fetal siphon, increased renal losses, and decreased liver production), hyperketonuria (ketones used as an alternative energy source), hypoaminoacidemia (due to placental transfer for use in fetal glucose production), and hypoinsulinemia (see Figures 16-4, B, and 16-5).^{12,24,57,72,78,98} Hypoalaninemia also develops because maternal protein stores can provide only limited substrate, which is insufficient to meet both maternal and fetal amino acid needs.⁴⁷ Increased insulin during the postabsorptive state enhances uptake of glucose into the maternal skeletal muscle and adipose tissue. In lean women, this leads to suppression of hepatic glucose production in late pregnancy. Less suppression is seen in obese women, therefore the alteration in insulin sensitivity is greater in obese than nonobese women.⁹⁸

Levels of lipoprotein lipase are increased, enhancing triglyceride breakdown with release of free fatty acids and glycerol (which is broken down into glucose) and production of ketone bodies to provide energy when plasma glucose supply is low.¹⁶ Glycerol is a source for hepatic gluconeogenesis. The elevated free fatty acids prevent glucose uptake and oxidation by maternal cells, thus preserving glucose for the maternal CNS and the fetus.¹² In the nonpregnant woman this switch to fat oxidation occurs after 14 to 18 hours of fasting; during pregnancy the switch occurs after 2 to 3 hours and has been termed accelerated starvation.^12,19,42,96

Metabolic changes characteristic of this state are primarily due to hPL, which promotes lipolysis to increase free fatty acid levels and opposes insulin action, thus increasing glucose availability to the fetus. Other factors influencing this response include increased glucose utilization by the fetus (“the fetal siphon”) and mother, along with an increase in the volume of distribution for glucose (i.e., hemodilution).⁷⁸ During the second half of pregnancy, effectiveness of insulin in translocating glucose into cells is reduced.⁷⁸ Because insulin is the ultimate arbitrator of both the absorptive and postabsorptive states, alterations in insulin secretion alter substrate availability to the mother and fetus.⁴⁷ The insulin antagonism in pregnancy is progressive, paralleling the growth of the fetoplacental unit, and disappears immediately after delivery. Placental hormones and other substances are major factors in producing this insulin antagonism.

Drainage of glucose and amino acids by the fetus may lead to increased maternal appetite and a feeling of faintness sometimes experienced in pregnancy. Pregnant women may experience more rapid development of ketosis and fasting hypoglycemia after food deprivation. With greater maternal reliance on fat utilization during pregnancy, production of ketone bodies and risks of abnormalities such as acidosis are increased. Dieting and caloric restriction during pregnancy should be considered potentially dangerous to both the mother and fetus.³⁷

Effects of metabolic changes on glucose tolerance tests

The alterations in carbohydrate metabolism in the absorptive state during pregnancy result in an elevated blood glucose response to a carbohydrate load. The progressive decrease in glucose tolerance is reflected in the criteria for an abnormal GTT in pregnancy. These changes are most marked in the third trimester.

Two methods commonly used to evaluate glucose tolerance in pregnancy are (1) a one-step 75-g, 2-hour test (recommended by the World Health Organization); and (2) a two-step test with a 1-hour 50-g glucose challenge (screening test) followed by a 100-g, 3-hour oral glucose tolerance test (OGTT) if challenge levels are either 135 mg/dL (7.5 mmol/L) or greater (more women meet criteria for the 3-hour test, but a greater proportion of women with gestational diabetes mellitus [GDM] are identified) or 140 mg/dL (7.8 mmol/L).^78,98 The one-step testing has a lower detection rate for GDM.⁹⁷ The two-step test has been used most commonly in the United States, whereas the one-step test is used most commonly in other countries.^95,98 The Fifth International Workshop Conference on Gestational Diabees Mellitus recommended the two-step test.⁹⁵ However, following the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommended use of a 75-g glucose load followed by fasting, 12-, and 2-hour plasma glucose concentrations.⁶⁴

During pregnancy, the initial fasting blood glucose value is lower than in nonpregnant individuals, because of decreased glucose utilization and increased fat utilization by the mother (making increased glucose available to the fetus) and the subsequent effects of the fetal siphon. Blood glucose levels tend to remain high after ingestion of carbohydrates for a longer period of time secondary to insulin antagonism and decreased insulin sensitivity. Normally the magnitude of the increase in blood glucose after a carbohydrate feeding is a reflection of failure in glucose uptake by the liver. During pregnancy the increased glucose response in the face of increased endogenous insulin confirms the relative insensitivity and resistance of the liver (as well as peripheral tissues such as muscle and adipose tissue) to insulin.^78,98

Maternal-fetal relationships

Growth and development of the fetus is dependent upon the availability of a constant supply of glucose, amino acids, and lipids from the mother for energy, protein synthesis, and production of new tissues. The fetus must also develop adequate stores of these substances to meet the demands of the intrapartum period and transition to extrauterine life. Placental transfer of selected nutrients and hormones is summarized in Figure 16-6. Fetal requirements for substrates involved in carbohydrate, fat, and protein metabolism are discussed in the next section.

Alterations in maternal metabolic processes or in placental transfer of essential nutrients that increase the availability of specific substrates are usually an advantage to the fetus but can be a disadvantage in altered maternal metabolic states. For example, because fetal energy requirements are met almost exclusively by glucose, the metabolic changes in pregnancy increase availability of glucose in maternal plasma for placental transfer by reducing the efficiency of maternal glucose storage. If the usual metabolic changes of pregnancy or placental function are altered, however, variations in fetal growth—such as occur in the infant of a diabetic mother or the an infant with fetal growth restriction—may develop.¹²² Maternal glucose infusions during the intrapartum period can lead to a fetal hyperglycemia that stimulates insulin and inhibits glucagon secretion. This may delay gluconeogenesis after birth and increase the risk of neonatal hypoglycemia.

The placenta is a highly metabolic organ with its own substrate needs. Placental metabolic activities include glycolysis, gluconeogenesis, glycogenesis, oxidation, protein synthesis, amino acid interconversion, triglyceride synthesis, and alterations in the length of fatty acid chains (see Chapter 3). The placenta can modify nutrient uptake to meet fetal growth demands.¹¹⁵ The degree of glucose uptake by the placenta is similar to that of the brain. Cholesterol from the mother is essential for placental synthesis of estrogens and progesterone. Fatty acids are needed by the placenta for oxidation and membrane formation.¹⁶ Leptin may have a role in coordinating placental metabolism.⁸¹

Glucose is the nutrient that crosses the placenta in highest concentrations. The increased maternal reliance on fats as an alternative energy source, especially during the maternal postabsorptive fasting state, conserves maternal glucose for transfer to the fetus. The fetal-placental unit uses approximately 50% of the total maternal glucose needed for pregnancy.⁵⁷ Glucose crosses via facilitated transport by insulin dependent glucose transporters.⁸¹ Amino acids are transferred via active transport because levels are higher in the fetus than in the mother. Amino acids are removed from maternal circulation and concentrated in the placental intercellular matrix. As fetal amino acid levels fall, these placental stores are transferred to the fetus. Mechanisms for amino acid transfer include direct transfer from mother to fetus without modification in the placenta, metabolism of maternally derived amino acids by the placenta to produce other amino acids (which are then transferred to the fetus), and production of new amino acids by the placenta for fetal transfer.^57,61 Maternal lipoproteins do not cross the placenta directly, but are taken up by the placenta where placental lipoprotein lipase along with other lipases, enzymes, receptors, and fatty acid binding proteins facilitate transfer of fatty acids to the fetus.^57,58,59,78 Essential fatty acids and long-chain polyunsaturated fatty acids needed for fetal growth and development cross the placenta.⁵⁹ Free fatty acids are transferred to the fetus according to maternal-fetal concentration gradients mediated by specific fatty acid carriers. The pattern of essential and other fatty acids in the fetus reflect maternal concentrations.^57,61 Ketones, especially acetoacetate and β-hydroxybutyrate, diffuse readily across the placenta; concentrations are similar in the mother and fetus.⁷⁸ Inadequate maternal dietary fatty acids such as docosahexaenoic acid (DHA) increase the risk of altered neurologic and vision development in offspring.^18,44

The pregnant diabetic woman

The classification system for diabetes proposed by the National Diabetes Data Group and adopted by the American Diabetic Association includes (1) type 1 diabetes (“β-cell destruction, usually leading to absolute insulin deficiency”), (2) type 2 diabetes (“ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance”), (3) other specific types of diabetes (including genetic defects, pancreas alterations, or endocrine, drug-induced, or infectious etiologies), and (4) gestational diabetes mellitus.³ Individuals with impaired fasting glucose and/or impaired glucose tolerance are referred to as having “pre-diabetes.”³

The metabolic changes during pregnancy contribute to alterations in insulin requirements in insulin-dependent pregnant diabetic women. Because the metabolic changes in pregnancy normally lead to increased insulin availability by the end of pregnancy, it is not surprising that pregnant diabetic women experience an increase in insulin requirements by this time.^47,78,98

Management of the pregnant diabetic woman and the woman who develops gestational diabetes is complex. There are many controversies regarding screening, diagnosis, treatment, and outcomes of women with gestational diabetes.^46,70,78,87 Guidelines for screening and diagnosis of gestational diabetes from various groups around the world were summarized by Leary et al. in a recent article.⁸⁷ Some of the current controversies relate to the findings and subsequent recommendations from the HAPO study.^41,45,46,87 The HAPO study was a prospective, randomized controlled multinational study of 25,000 pregnant women in 10 countries who did not have a diagnosis of diabetes on study entry.^45,46 This study examined the relationship between maternal glucose concentrations lower than those diagnostic of diabetes and adverse perinatal outcomes.^45,85 Findings demonstrated a linear association between findings on the 75-g OGTT and the following fetal/maternal outcomes: birth weight greater than 90th percentile, increased cord blood C-peptide level, and risks of neonatal hypoglycemia, fetal shoulder dystocia, neonatal hyperbilirubinemia, and maternal preeclampsia.^45,46 In the HAPO study, both fasting and post 75-g OGTT levels were correlated to maternal and neonatal outcomes.^26,41,45,85 In response to the HAPO study, an IADPSG consensus panel recently published new guidelines on screening and diagnosis of GDM at the first prenatal visit for all or high-risk women and screening all women at 24 to 28 weeks. With the IADPSG recommendations women would be diagnosed with GDM earlier on the basis of an initial fasting glucose of 92 to 126 mg/dL (5.1 to 7.0 mmol/L) or an abnormal fasting (92 mg/dL or 5.1 mmol/L), 1-hour (180 mg/dL or 10.0 mmol/L), or 2-hour (153 mg/dL or 8.5 mmol/L) 75-g OGTT with a single abnormal glucose considered adequate for the diagnosis.⁶⁴ Recommendations are controversial and their effect on current practice and policies is unclear.^41,87,132

GDM is defined as “carbohydrate intolerance of various degrees of severity with onset or first recognition during pregnancy.”⁹⁸ GDM occurs in 3% to 9% of pregnancies in the United States.⁹⁸ Women with GDM have a pronounced peripheral insulin resistance, decreased numbers of insulin receptors, and decreased binding of insulin to target cells, which results in a progressive alteration in glucose tolerance.¹⁶ Fasting, postprandial, and 24-hour glucose, and lipid and amino acid concentrations are altered.¹⁶ Possible etiologies include an autoimmune defect in the β cells, impaired β-cell function, increased insulin degradation, and decreased tissue sensitivity to insulin, either due to impaired insulin-receptor binding or intracellular insulin signaling.¹¹⁰ Two to 13% of women with GDM have specific antibodies against β-cell antigens.⁹⁸ Most women with GDM have impaired β-cell function and adaptation during pregnancy with chronic insulin resistance, which has an additive effect in pregnancy.⁹⁸ It is unclear if insulin resistance occurs prior to alterations in β-cell function or if these events occur together.⁹⁸ A decrease in IRS-1 concentration and decreased ability of insulin receptor-B (found inside skeletal muscle cells) to be phosphorylated by tyrosine have been reported.⁹⁸ These changes further alter insulin signaling and reduces glucose transport activity. In late pregnancy, the pregnant woman normally increases insulin secretion, but the woman with GDM, because of underlying chronic insulin resistance, has even greater insulin resistance, producing less insulin compared to the amount of resistance.⁹⁸

During the postpartum period, women with GDM continue to show defects in insulin action and sensitivity, even after glucose tolerance tests have normalized.² Women with GDM have an increased risk for later development of diabetes, primarily type 2.¹⁶ Approximately 10% develop diabetes in the first months postpartum, 50% by 5 years postpartum, and 70% by 10 years postpartum.^2,16,17 The risk is greater with weight gain after pregnancy or GDM in a subsequent pregnancy.^2,16 Several studies suggest that infant outcomes, including macrosomia and shoulder dystocia, could be reduced by treating women with mild hyperglycemia who did not reach diagnostic criteria for GDM.^26,85

Pregnant women with type 1 diabetes may experience no change or decreased insulin requirements during the first trimester because of increased glucose siphoning by the fetus, which decreases maternal blood glucose levels. Maternal food intake may also decrease during this period because of the nausea and vomiting of pregnancy. Because circulating glucose levels are reduced, maternal insulin requirements are often lowered. As pregnancy progresses, the diabetogenic actions of increasing amounts of placental hormones and the increasing insulin insensitivity outweigh the effects of the fetal siphon. Women with type 1 diabetes appear to have similar alterations in insulin sensitivity during pregnancy to woman with normal glucose tolerance.⁹⁸ Thus maternal insulin requirements usually increase during the second half of gestation to levels two to three times higher than prepregnancy values.^47,78,98

The diabetic woman may have altered insulin requirements during labor, probably because of an increase in energy needs (and thus glucose utilization) and the presence of oxytocin, with its insulin-like effects. After delivery and removal of the placenta, levels of estrogens, progesterone, and hPL fall rapidly. This quickly reverses the insulin insensitivity of pregnancy. Maternal insulin requirements usually fall rapidly to prepregnancy levels or even below (due to a rebound phenomenon). Oxytocin may also contribute to these changes. As a result, the insulin-dependent diabetic woman may need little or no exogenous insulin the first few days after delivery. Insulin requirements generally return to prepregnancy levels by 4 to 6 weeks postpartum.³⁷

Levels of glycosylated hemoglobin and other glycosylated proteins are useful in monitoring glucose concentrations over time and in genetic counseling and have been used to evaluate fetal and maternal risks for complications in a pregnancy complicated by maternal diabetes. Glycosylated hemoglobin is formed slowly over the lifespan of the red blood cell and represents an overall measure of glycemia. The parameters used most frequently are hemoglobin A1c (the most abundant component of hemoglobin A) and total amounts of hemoglobin A. Levels of glycosylated hemoglobin A reflect ambient glucose concentrations over the previous 4 to 6 weeks and have been used to monitor maternal glycemic control on a monthly basis. Hemoglobin A1c is higher in pregnant diabetic women than in other pregnant women, but lower than in nonpregnant diabetic women. Maternal levels of hemoglobin A1c correlate with development of fetal anomalies, with the lowest levels having the least risk.^98,111 Hemoglobin A1c is not as useful as an independent measure of glycemic control in pregnancy, because these levels may not be a good predictor of capillary blood glucose levels in the woman.

Carbohydrate metabolism

The fetus has been described as a “glucose-dependent parasite” and uses glucose from the mother as the major substrate for energy production.⁸² Eighty percent of fetal energy comes from carbohydrate (glucose) oxidation.^71,114 Fetal glucose utilization rates (averaging 5 mg/kg/min) are higher than in adults (2 to 3 mg/kg/min).^51,71 Even with fetal growth restriction, maternal glucose is the major energy substrate for the fetus, although the placenta can produce alternate substrates such as lactate and ketone bodies for use as energy and for glycogen synthesis.⁷¹

Glucose is transported across the placenta via sodium-independent carrier-mediated facilitated diffusion.^68,116 The placenta has a high facility for glucose uptake and transport via a family of membrane transport proteins (GLUTs, which is the gene symbol for facilitated glucose transporter) on the microvillous membrane facing maternal blood and fetal-facing basal membrane of the placenta.^62,68,108 Various GLUT isoforms are expressed in the syncytiotrophoblast, including GLUT-1, -3, -4, and -12. GLUT-4 and -12 are sensitive to insulin.⁶⁸ GLUT-1 and GLUT-2 are expressed early in development and are found on both the trophoblast and blastocyst.¹⁰⁴ GLUT-1 is the major fetal glucose transporter; fetal GLUT-2 levels remain low.¹¹⁸ GLUT-1 is expressed on almost all fetal tissues, enhancing cellular glucose uptake.¹²¹ In animal models maternal hyperglycemia during early gestation down-regulates these receptors, increasing the risk of apoptosis and neural tube and limb defects. There is a fivefold greater increase in GLUT-1 on the microvillous membrane facing maternal blood than on the fetal-facing basal membrane during the first trimester.^62,68,108 This increases the movement of maternal glucose into the placenta, where approximately 30% to 40% is used by the placenta for oxidation or converted to glycogen and lactate to meet its energy needs.⁶⁸

Basal membrane glucose transport is the rate-limiting step in fetal glucose transfer.^8,68 In the second half of pregnancy, basal membrane GLUT-1 receptors increase at least twofold and their activity increases 50% to meet increasing demands with fetal growth in late pregnancy.^62,108 If the uteroplacental nutrient supply is diminished, the fetus consumes nutrients and oxidizes them at the usual rate, but the placenta reduces consumption of both nutrients and oxygen. Increased placental GLUT-1 receptors with increased glucose transport to the fetus have been found in diabetic women with hyperglycemia.¹²⁰ Placental glucose transport is summarized in Figure 16-7.

During the first few days after fertilization, the zygote has a limited ability to metabolize glucose. After the embryonic genome is activated, glucose metabolism increases.²⁹ Both glucose and pyruvate uptake increase initially; glucose uptake remains high throughout pregnancy, while pyruvate uptake falls.

The major regulators of fetal growth are IGF-I and IGF-II, which stimulate cell proliferation, differentiation, and metabolism.³⁸ IGFs act via cell membrane receptors and are modulated by a group of binding proteins. The liver is the main source of IGFs, which have autocrine, paracrine, and endocrine functions. IGF-I can be detected in fetal tissue by 9 weeks’ gestation and in fetal circulation by 15 weeks’ gestation.³⁴ Both IGF-I and IGF-II increase with gestational age. In early gestation, IGF-II activity, which is not significantly affected by nutritional factors, is predominant. In late pregnancy, IGF-I, which is regulated by nutrient availability, is predominant. Fetal growth in later gestation is regulated by the interaction of glucose, insulin, and IGF-I.³⁸ Glucose transfer across the placenta stimulates fetal insulin release. Insulin in turn stimulates lipogenesis and IGF, which increases fetal anabolism and placental uptake of glucose and other nutrients for fetal (versus placental) use.

Lower levels of IGF-I are seen in preterm and growth-restricted infants.⁸⁹ Levels are also reduced in infants of mothers who smoke.¹¹³ Even though glucose and insulin concentrations are lower with fetal growth restriction, the fetus maintains glucose uptake and utilization due to increased insulin sensitivity, enhancing movement of glucose into cells. This is mediated by increased expression of GLUT and insulin-responsive glucose transporters.¹¹⁶ With chronic substrate deprivation, the growth restricted fetus will develop systems for glucose production, initially by glycogenolysis (breakdown of glycogen to glucose) and later by gluconeogenesis (production of new glucose from lactate, amino acids [especially alanine], and glycerol) along with the reduction in fetal growth.¹¹⁶ Poor fetal nutrition may alter the ability to produce and respond to insulin in adulthood, increasing the risk of type 2 diabetes, or may alter fetal low-density lipoprotein metabolism, increasing the risk of later coronary artery disease.^{18,36,89,74,131}

Under basal, nonstressed conditions, the fetal glucose pool is in equilibrium with the maternal pool.¹³² Enzymes for fetal gluconeogenesis are present by 3 months’ gestation, but fetal glucose production is minimal and maternal glucose remains the source of fetal glucose.^52,71,116 Ambient fetal glucose levels are generally 20 to 40 mg/dL (1.1 to 2.2 mmol/L) less than maternal levels (or 70% to 80% of maternal values) and increase slightly toward the end of gestation.^71,78 This gradient is regulated by the placenta and favors transfer of glucose across the placenta from the mother through carrier-mediated facilitated diffusion (GLUTs) (Figure 16-7).

The usual lower limit for fetal glucose is 54 mg/dL (3 mmol/L), especially after 30 weeks.⁵¹ If fetal glucose supply decreases, then placental glucose uptake increases, and vice versa, as seen with the infant of a diabetic mother.^68,71 Extra glucose is stored by the fetus as glycogen and triglycerides.⁷³ The levels at which glucose carriers become saturated are significantly above the usual maternal blood glucose level, which promotes a constant supply of glucose to the fetus.⁸² There is no net transfer of insulin or glucagon to the fetus (see Figure 16-6). With adequate maternal nutrition, gluconeogenesis and ketogenesis are not seen in the fetus.^93,116 If the placental supply of glucose is inadequate, the fetus can use ketone bodies and other substrates as alternative energy sources.¹¹⁶ As noted above, with prolonged glucose deprivation, the fetus can produce some glucose initially by glycogenolysis and later by gluconeogenesis, probably mediated by cortisol.^51,116

Fetal glucose utilization is independent of maternal glucose availability. The linear relationship between maternal and fetal glucose levels is maintained during maternal euglycemia, hypoglycemia, and hyperglycemia.⁷³ The mother meets this demand by an increasing reliance on fat metabolism for her own fuel needs. If the maternal system is not able to meet the fetal demand for gluconeogenic precursors, hypoglycemia can result. Because fetal blood glucose levels are 70% to 80% of maternal values, maternal hypoglycemia leads to even lower fetal blood glucose levels.⁷⁸ Placental glucose transfer increases with increasing gestational age not only by increases in GLUT, but also by increases in insulin receptors on fetal tissues particularly adipose tissue and skeletal muscle. Glucose is also needed by the fetus for protein synthesis, as a precursor for fat synthesis, for conversion to glycogen for storage, and as the primary substrate for oxidative metabolism. Most of the transferred glucose is oxidized to carbon dioxide and water with release of energy by the tricarboxylic acid cycle and oxidative phosphorylation.

The fetus has an active capacity for anaerobic metabolism, which has a greater role in fetal metabolic processes than it does in adults. The fetus has increased amounts of glycolytic isoenzymes such as hexokinase, glucose-6-phosphate dehydrogenase (G6PD), and pyruvate dehydrogenase, which favor anaerobic glycolysis.⁷³ Fetal and especially placental tissues actively metabolize glucose to lactate. The lactate generated by the placenta serves as an important fuel for the fetus.⁵¹ Lactate is a major precursor of fetal hepatic glycogen and fatty acid synthesis.⁷³ Under aerobic conditions the fetus is a net consumer of lactate. The placenta produces large amounts of lactate and ammonia, which may help in regulating metabolic activities in the fetal hepatocytes.⁵¹ The fetus can also use ketone bodies produced from β-oxidation of fatty acids as another alternative fuel source.¹¹⁶

The fetal liver contains enzymes needed to both synthesize and catabolize glycogen to store and release glucose. The fetus can also synthesize glycogen from pyruvate, acetate, and alanine.⁷³ Glycogen synthesis is greater than glycogenolysis in the fetus. Glycogen synthetase and other gluconeogenic enzymes can be found in the liver from the eighth week and increase to term, with a rapid increase seen after 36 weeks’ gestation.^73,93 Deposition of hepatic glycogen during the perinatal period is regulated by glucocorticoids and insulin. Glucocorticoids may induce glycogen synthetase, which is then activated by insulin. Fetal cells have increased insulin receptors, greater receptor affinity for glucose, and delayed maturation of hepatic glucagon receptors. These changes promote storage of glucose as glycogen and fat. Glycogen can be synthesized from lactate, pyruvate, alanine, and glycerol as well as glucose.¹⁰⁸ 

Glycogen is stored in fetal tissues from 9 weeks’ gestation on and increases slowly from 15 to 20 weeks, then more rapidly during the third trimester.⁷¹ Until 20 to 24 weeks, the fetal liver is the main glycogen storehouse; after that time, glycogen is stored in cardiac and skeletal muscle, and to a lesser extent in the kidneys, intestines, and brain (primarily in the astrocytes).^107,108 Liver and skeletal muscle glycogen concentrations peak at term.¹⁰⁸ Compared with adults, the term fetus has significantly more liver, skeletal muscle, and cardiac muscle glycogen stores. Liver glycogen synthesis is regulated by fetal insulin, the hypothalamic-pituitary axis, and thyroid hormones.¹⁰⁸

Immunoreactive insulin is present in fetal plasma and islet tissue as early as 8 weeks’ gestation.^71,120 Insulin levels are dependent upon fetal glucose levels.⁵¹ Insulin production is stimulated by increasing glucose and amino acid concentrations, especially after 20 weeks.⁷¹ Fetal glucose metabolism is relatively independent of the insulin-glucagon regulatory mechanisms seen after birth, however. Acute changes in glucose concentrations leading to hypoglycemia or hyperglycemia do not significantly alter fetal insulin or glucagon secretion.¹¹⁸ However, secretion of these hormones is markedly altered by chronic changes such as long-term hyperglycemia in a diabetic woman, which augments insulin secretion by β-cell hyperplasia and suppresses glucagon, or by chronic maternal malnutrition, which depresses insulin and stimulates release of fetal glucagon.^71,132 Because insulin is a fetal growth hormone, fetal hyperinsulinemic states are associated with fetal and neonatal macrosomia.^57,71

Glucagon is found in fetal plasma by 15 weeks’ gestation and reaches peak concentrations at 24 to 26 weeks. In comparison with adults, the number of fetal hepatic glucagon receptors is decreased and insulin receptors are increased. Fetal liver cells, erythrocytes, monocytes, and lung cells have an increased affinity for insulin. These attributes promote insulin-mediated anabolic processes such as glycogen formation and decrease glucagon-mediated catabolism.¹³²

The fetal liver receives the highest net flux of maternal glucose because it is the first organ system encountered by blood returning from the placenta (see Chapter 9). Fetal hepatic enzymes for glycogenesis (carbohydrate to glycogen) are increased, whereas enzymes for glycolysis (carbohydrate to pyruvate and lactate) and gluconeogenesis (fat and protein to glucose) are present but decreased. For example, glucose-6-phosphatase, an enzyme involved in gluconeogenesis and inhibited by glucose and amino acids, is at 20% to 50% of adult levels at midgestation. These relationships are maintained until birth, when decreased glucose availability and onset of high-fat feedings stimulate decreases in glycogenolytic enzymes.

Lipid metabolism

Lipids are a critical component of brain development, of retinal development, and for structural and functional integrity of neuronal and glial membranes, and are the main component of the myelin sheath.^32,58,63,127 Fetal fat content increases during gestation from 0.5% of body weight in early gestation to approximately 3.5% by 28 weeks and 16% by term or by approximately 3.4 g/kg/day in the third trimester.¹²⁷ This increase is due to transfer of fatty acids from the mother and active lipogenesis in the fetal liver and other tissues. Lipogenesis is primarily through the fatty acid synthetase pathway, which is highly active in the fetus. The placenta modulates the fatty acid supply for its use and for fetal use.¹⁹ Placental leptin stimulates lipolysis and is excreted to both maternal and fetal circulations. As a result the placenta may have a role in modulating fatty acid supply based on fetal demands.⁴⁴

Long-chain polyunsaturated fatty acids in the mother are primarily found in the form of esterified fatty acids such as triglycerides, phospholipids, and esterified cholesterol. Maternal lipoproteins do not cross the placenta but are taken up by the placenta where they are broken down and their products used for energy or steroid hormone production or released to the fetus.⁵⁹ The placenta contains various tissue receptors, enzymes, and fatty acid binding proteins to upload these lipoproteins and to transport polyunsaturated fatty acids and nonesterified fatty acids to the fetus.^32,68 Free fatty acids cross by diffusion in limited amounts, with a net flux of unesterified fatty acids to the fetus.^58,59,125 These fatty acids are derived primarily from maternal circulating free fatty acids or cleavage of maternal triglycerides by lipoprotein lipase.⁵⁶ The maternal diet is reflected in the fatty acid content of fetal tissues.⁵⁹ Ketone bodies and glycerol also cross the placenta.⁵⁹ Placental lipid transport is illustrated in Figure 16-8. Because transport of fatty acids is partly controlled by maternal concentrations, increased maternal levels are associated with increased transfer and fetal storage.^{16,19,62,123,125} Other factors influencing free fatty acid transfer include serum albumin level, fatty acid chain length, lipid solubility, uteroplacental and umbilical blood flow, α-fetoprotein, placental proteins that bind fatty acids, and binding affinity.^58,71,125

Essential fatty acids (EFA), such as linoleic and α-linolenic acids, cannot be synthesized by the fetus and must be transported across the placenta.^32,58,59,68 These substances can then be desaturated by the fetus to form other fatty acids.⁵⁸ Transfer of essential fatty acids increases in late pregnancy, when demand for brown and white adipose tissue development and for vascular and neural growth increases; however, some early transfer is needed for uteroplacental vascular development.¹²⁵ Long-chain polyunsaturated fatty acids (LCPUFA) from the mother are critical for development of the brain and retinal and brain growth.^44,58 The fetus has limited capacity to synthesize LCPUFA due to low levels of desaturating enzymes.^44,58 In the third trimester when fetal neuronal and vascular growth is high, selective transport of LCPUFA derivatives such as arachidonic acid and docosahexaenoic acid (DHA) increases.^58,59,126 The preterm infant thus needs a diet that includes these critical substances.⁴⁴ Linoleic acid is converted to arachidonic acid, the main precursor for prostaglandins, thromboxanes, and leukotrienes; α-linolenic acid is converted to DHA (needed for fetal growth and development) and eicosapentaenoic acid (precursor of prostaglandins that inhibit platelet aggregation).¹⁹

Increased fat deposition during the third trimester is associated with increasing fetal weight and decreased serum triglycerides because these are used in fat deposition.²³ Most (80%) of the fetal fat accretion during this period is due to de novo synthesis from acetyl coenzyme A (CoA) with formation of palmitic acid, especially in the brain and liver.^56,125

Fetal lipid metabolism is characterized by early development of mechanisms for cholesterol metabolism and lipogenesis with decreased lipolytic activity throughout gestation, except in the liver.¹⁰¹ Fetal fatty acid synthesis occurs through lipogenesis and desaturation of essential fatty acids. Lipogenesis is dependent upon substrate availability. Lipogenic precursors include glucose, lactate, and ketone bodies; the latter two are the most important.^56,109

The rate of synthesis is primarily controlled by the ratio of plasma insulin-to-glucagon levels. Insulin stimulates and glucagon inhibits fatty acid synthesis. The action of glucagon is mediated by cyclic adenosine monophosphate (cAMP), which inhibits acetyl-CoA enzymes.⁵⁶ The high insulin-to-glucagon ratio in the fetus promotes fatty acid synthesis. Lipogenesis is increased by glucose, fatty acids, and T4 (see Chapter 19) and reduced by catecholamines.¹²⁵ The fetal liver and brain contain enzymes for ketone oxidation as an alternative energy substrate; the fetal brain can use ketones for energy by 10 to 12 weeks’ gestation.^59,108 Lipolytic activity becomes active after delivery, when the infant can no longer rely on a constant glucose supply from the mother and must cope with a relatively high fat intake.

By 15 weeks the fetus has developed enzymes to convert acetate or citrate to fatty acid and thus the potential to use fat as an alternative source of energy. Blood lipid and free fatty acid levels are relatively stable after about 26 weeks but remain low until after delivery. The free fatty acids that cross the placenta are used by the fetus in organ development; synthesis of pulmonary surfactant, other phospholipids, bile, and serum lipoprotein; formation of cell membranes; precursors for prostaglandins; and as second messenger precursors. Fatty acids needed by developing neuronal and glial cells and in formation of the myelin sheath are synthesized within the brain.⁵⁶

The fetus needs cholesterol for cell membranes, bile acid synthesis, embryogenesis (cell proliferation and differentiation), synaptogenesis, production of steroid hormones, and cell-cycle regulation.⁵⁸ The fetus obtains cholesterol from endogenous biosynthesis and placental transport.⁵⁹ Fetal cholesterol levels are high in early pregnancy, decrease, then rise, peaking in the third trimester.^59,101 Fetal and maternal cholesterol levels are not correlated.⁵⁹ Activity of the pentose phosphate intermediary metabolic pathway is also high in the fetus. Activity of this pathway is associated with cell proliferation and an increased requirement for ribose phosphate precursors of nucleic acids and provision of nicotinamide-adenine dinucleotide (NADH) for synthesis of long-chain fatty acids.

Protein metabolism

At least 10 amino acids are essential for the fetus, including those essential for adults plus cysteine and histidine, with a dependency on arginine and tyrosine. Arginine and leucine are insulin secretogogues; arginine may also enhance vascular development. Taurine helps regulate metabolism and is needed in development of the heart, eye, and brain. Because of the relative inactivity of hepatic enzymes such as cystathionase and phenylalanine hydroxylase, the fetus cannot synthesize tyrosine and cysteine from phenylalanine and methionine. The fetus uses amino acids for protein synthesis or oxidation because organ development involves continuous remodeling (breakdown and resynthesis) of tissue. The availability of glucose and other substances influences fetal amino acid catabolism and protein accretion.⁵⁴

There is a net flux of most amino acids from the mother to the fetus.⁸² Because concentrations of most amino acids are higher in fetal than maternal blood, amino acids are actively transported from maternal blood across the placental microvillous membrane.⁶⁸ Amino acid levels in the syncytiotrophoblast are higher than in either maternal or fetal circulations. Facilitated diffusion moves substances across the syncytiotrophoblast basal membrane to fetal blood.⁶⁸ There are at least 15 different amino acid transporters, each mediating uptake of several different amino acids, and each amino acid may use multiple transport systems.⁶⁸

Placental amino acid transport is illustrated in Figure 16-9. Fetal-to-maternal amino acid nitrogen ratios average 1.03 to 3.0, with a net active transfer of nitrogen to the fetus of 54 nmol/day and a total accumulation of about 400 g of protein by term.^6,54,82 Amino acid transport is not significantly affected by fluctuations in uterine or placental blood flow.⁵⁴ Transport may be down-regulated in the growth restricted fetus.⁶⁸

Amino acids are supplied to the fetus in greater amounts than are needed for nitrogen accretion. The fetus uses the carbon from excess amino acids for oxidation and to make nonessential amino acids.⁵⁴ Some critical amino acids are not transferred across the placenta directly but are, instead, produced in the placenta. For example, glutamate, which is needed for neurotransmitters and brain development, is not transferred from mother to fetus. Instead glutamine is transferred from the mother to the placenta, where it is used to produce glutamate. Similarly asparagine is used by the placenta to produce aspartate, another neurotransmitter. Both glutamate and aspartate are toxic, so by transferring precursors, the placenta can produce only the amounts that are needed by the fetus. The placenta also produces ammonia, which is used by the fetal liver for additional protein synthesis.

Transitional events

Metabolic transition is characterized by a shift from the anabolic-dominant fetal state to the catabolic state of the neonate. This transition is influenced by genetic, environmental, and endocrine factors as well as by major alterations in energy metabolism within the mitochondria. Changes in metabolism with birth are regulated by the expression of specific genes and gene products that alter the activity of various enzymes.²³ Shortly prior to term birth, induction of hepatic glucose production begins and is enhanced postbirth by increased glucocorticoids and glucagon.¹¹⁶ The ability of the fetus to use glucose anaerobically and to readily metabolize lactate may be important in maintaining homeostasis during the stresses of labor and delivery. The fetus prepares for this transition during the last weeks of gestation by increasing fuel storage in the form of glycogen and lipids. Glycogen is critical in order to maintain glucose homeostasis immediately after birth, whereas the fat stores, through lipolysis of fatty acids and ketone bodies, serve as an alternate energy source. Postnatal changes in metabolism involve the transition from the almost exclusive reliance on glucose for energy production in the fetus to markedly increased use of fatty acid oxidation and ketone body use for energy production in the neonate. An increase in epinephrine, norepinephrine, and glucagon and a decrease in insulin at birth promote mobilization of fatty acids and glycogen metabolism.⁷³

Carbohydrate metabolism

Birth results in the loss of the maternal glucose source. As a result, neonatal blood glucose normally falls after birth, reaching a nadir at 30 to 90 (generally around 60) minutes after birth (Figure 16-10).⁷¹ This fall in glucose is thought to be necessary for activating postnatal glucose production processes.¹¹⁶ Glucose values then rise and stabilize by 2 to 3 hours after birth.^52,71 The glucose nadir and timing of the nadir are influenced by maternal glucose infusion during the intrapartum period.⁷¹ Steady-state hepatic release of glucose at 4 to 6 mg/kg/min is seen by 2 to 3 hours in term infants.^40,107 Mean glucose levels in term healthy infants in the first week average 80 mg/dL.⁷¹ The basis for the fall in blood glucose is summarized in Table 16-4.

The newborn responds to the decrease in blood glucose in several ways. The rapid glycogenolysis (liberation of glucose from glycogen) after birth is stimulated by a fall in the insulin-to-glucagon ratio and sluggish insulin secretion (because of the decreased blood glucose with removal of the placenta), increased serum glucagon, stimulation of the sympathetic nervous system with catecholamine release, increased thyroid stimulating hormone, and increases in hepatic cAMP.^23,107,118 Because insulin promotes transfer of glucose out of the blood into cells, the lowered levels decrease transfer and elevate blood glucose levels. Glucagon stimulates conversion of glycogen into glucose, also raising blood glucose levels.

Hepatic glycogen stores decrease markedly during this period. In the term infant, glycogen stores only last an estimated 10 hours after birth before glucose must be produced by gluconeogenesis (production of new glucose from lactate, amino acids [especially alanine], and glycerol).⁴⁰ As glycogen falls, the newborn responds by mobilizing fat stores with release of free fatty acids. This response is stimulated by the catecholamine release associated with cooling at birth (see Chapter 20), which rapidly increases free fatty acids.¹²¹ Increased secretion of catecholamines at birth increases glucagon secretion (together these activate hepatic glycogen phosphorylase and glycogenolysis), suppresses insulin, reverses the fetal insulin-to-glucagon ratio, increases lipolysis to provide an alternate energy source, activates enzymes needed for gluconeogenesis, and augments growth hormone secretion.^116,121,132 Healthy infants are able to readily mobilize free fatty acids and oxidize ketones to maintain their blood glucose levels.

Breastfed infants have lower blood glucose levels and higher ketone bodies than bottle-fed infants.^52,116 The elevated ketone bodies may provide an alternate fuel during the period of lower nutrient intake as breastfeeding is being established. This may be especially important for the brain, which can readily use ketones as an alternate energy source.^{23,52,116,121} Production of glucose from amino acids, especially alanine, increases and accounts for 4% to 10% of the glucose used for energy in term infants.

Gluconeogenesis also contributes to systemic glucose production after birth. Substrates metabolized by the liver to produce glucose include glycerol, lactate, alanine, and pyruvate.^40,71,73,121 Lactate may account for up to 30% of hepatic glucose production, with 5% to 10% from alanine and glycerol via gluconeogenesis.⁹⁴ Gluconeogenic enzyme activity increases after birth. Both glycogenolysis and gluconeogenesis pathways are dependent on the hepatic microsomal glucose-6-phosphatase (G6PD) enzyme system, which has only about 10% of adult activity at birth.⁶⁰ The cortisol surge with birth stimulates G6PD activity in the liver and hepatic glucose release.¹¹⁶ Adult values are reached by about 3 days in term infants, but take longer in preterm infants.⁶⁰ By 12 to 24 hours after birth, both gluconeogenesis and ketogenesis are active.^93,121 From late fetal life to 3 days after birth, blood glucose regulation is glucose dominant. As a result, gluconeogenesis is diminished during this period. After this period, blood glucose regulation becomes insulin dominant (the adult pattern). The increased gluconeogenesis after birth is regulated by changes in the serum insulin-to-glucagon ratio, catecholamine secretion, fatty acid oxidation, and activation of hepatic enzyme systems.¹²¹ The very low–birth weight (VLBW) infant is able to produce glucose to meet basal metabolic needs with appropriate responses to exogenous glucose and amino acid infusions, although hepatic glucose production may be sluggish or incomplete. In the first day after birth in term infants, about 50% of glucose is produced via glucogenolysis and 30% to 40% by gluconeogenesis (primarily from glycerol, but also from alanine and lactate).⁵²

After birth, GLUT-1 glucose transporters decrease, whereas GLUT-2 (involved in uptake of glucose by liver, pancreatic β cells, and intestinal and renal epithelium) and GLUT-3 (involved in uptake by neurons, especially in the cerebellum, skeletal muscle, and other tissues) increase rapidly.^{35,52,120,122} Activity of GLUT-4 (involved in uptake by muscle and adipose tissue) and other GLUTs increases more slowly.^120,122 GLUT-1, although lower in the neonate than in the fetus, remains active and needed for transfer of glucose into red blood cells and across the blood-brain barrier.¹²⁶ Both GLUT-1 and GLUT-3 are important in regulating brain glucose supply and are prominent in the blood-brain barrier epithelial cells, astrocytes, oligodendrocytes, choroid plexus, and cerebral cortex.⁵² Major alternative fuels for the brain are pyruvate, lactate, and ketones. These are transported across the blood-brain barrier by monocarboxylate transporters.⁵²

Increased glucagon concentrations and norepinephrine are important in subsequent activation of the hepatic gluconeogenic enzymes.^71,73,77,122 The predominant enzymes activated during this period are hepatic glycogen phosphorylase, glucose-6-phosphate dehydrogenase (G6PD), and phosphoenolpyruvate carboxykinase (PEP-CK). Hepatic glycogen phosphorylase is activated by norepinephrine and glucagon and stimulates glycogenolysis.^40,116 G6PD activity increases markedly after birth, increasing hepatic release of glucose.¹¹⁶ This is probably due to surges of glucagon and cAMP, which help shift the activity of the liver from glycogen storage to glucose production. PEP-CK, which is inhibited by insulin, is the rate-limiting enzyme for gluconeogenesis.^40,116 With changes in the insulin-to-glucagon ratio after birth, this enzyme increases about 20-fold, reaching adult levels by 24 hours after birth and thus increasing gluconeogenesis.^40,121

The resumption of a carbohydrate source (i.e., feeding) generally stabilizes the infant’s glucose concentration, and most neonates achieve a steady-state in their glucose concentrations by about 5 days. The first enteral feeding immediately increases blood glucose levels. This increase is accompanied by an increase in plasma insulin levels in term infants and development of cyclic changes in insulin and blood glucose levels. In preterm infants the initial feeding is not accompanied by similar hormonal changes and the cyclic responses in insulin and blood glucose take 2 to 3 days to develop (and longer in VLBW infants or infants who are not fed). Enteral feeding stimulates production of digestive hormones and secretion of peptides critical for induction of gastrointestinal tract maturation and development of the enteroinsular axis (see Chapter 12). These changes lead to additional modifications of hepatic metabolism.

Basal glucose production in newborns is 4 to 6 mg/kg/min versus 2 to 3 mg/kg/min in adults and approximately 6 to 8 mg/kg/min in preterm infants and infants with symmetric growth restriction.^40,51,52,116 The high glucose needs in neonates reflect the increased brain-to-body mass, in that the brain has a high obligatory glucose use.^62,73 For infants weighing less than 1000 g, glucose is the major energy source for most of the neonatal period.³⁵ Newborns are able to use ketone bodies and lactate for brain energy metabolism if inadequate glucose is available, although excess levels can be damaging. This mechanism is present in term, large preterm, and term small-for-gestational-age (SGA) infants but is absent in VLBW infants and other intrauterine growth–restricted infants who are at risk for hypoglycemia.⁵⁰ Glycogen stores in astrocytes may provide another alternative source of glucose for the neurons during periods of low glucose.⁵⁰

Lipid metabolism

The inability of the fetus to readily oxidize fatty acids is rapidly reversed at birth because of changes in the functional ability of enzymes such as carnitine palmitoyltransferase. During this period the levels of glucose and free fatty acids are mirror images of each other. Lipolysis, with enhanced oxidation of free fatty acids and ketogenesis, increases quickly after birth, reaching a maximum within a few hours.^36,56,76,107 This increase is reflected in changes in plasma free fatty acid levels, which rise rapidly beginning 4 to 6 hours after birth and reach adult levels by 24 hours. By this time, 60% to 70% of the infant’s energy is produced from oxidation of fat.¹¹⁴

Fat is the major form of stored calories in the newborn, and the preferred energy source for tissues such as the heart and adrenal cortex, which have high energy demands. Fat stores are significantly reduced in low–birth weight infants. After birth, mobilization of fatty acids from these stores is reflected in the rise in serum levels over the first few hours. This process is initiated by the increase in catecholamines and glucagon, resulting in increased cAMP followed by an increase in protein kinases, phosphorylation, and activation of adipose tissue lipase with release of fatty acids.^36,56

The transition from glucose to fatty acid oxidation after birth is reflected in the fall of the respiratory quotient from 0.9 to less than 0.8 by 2 hours.^76,114 This indicates that the infant has moved from obtaining nearly two thirds of its energy from oxidation of glycogen immediately after birth, to deriving most of its energy from fat metabolism, conserving glucose to ensure an adequate glucose supply for the central nervous system.^40,71,107 This transition reflects increasing dependence on oxidative metabolism and is associated with an increase in the number of mitochondria and enzymes of the Krebs cycle and changes in serum free fatty acid levels. This shift to fat metabolism is delayed in infants of diabetic mothers with hyperinsulinemia.^71,73 The neonate’s brain may use free fatty acids, along with branched-chain amino acids and ketones, as additional energy sources.⁴⁰

The increase in fatty acid oxidation and ketogenesis after birth, stimulated by the thyroid stimulating hormone surge and increased thyroid hormones with birth, is related to increased enzyme activity, especially of carnitine palmitoyltransferase. Carnitine activity enhances fatty acid oxidation. Concentrations of carnitine are high in human milk for 2 to 3 days after delivery. Another factor influencing this change is alteration in the insulin-to-glucagon ratio with increased glucagon. This increases the availability of substrates such as acetyl-CoA and carnitine for fatty acid oxidation in the mitochondria.

Serum cholesterol levels in cord blood are 50 to 75 mg/dL (1.3 to 1.9 mmol/L), about one-half adult values, and serum triglycerides average 30 to 50 mg/dL (0.3 to 0.6 mmol/L).¹⁰¹ Cholesterol in preterm infants may be as high as 100 mg/dL (2.6 mmol/L) if they are born during the time of the normal fetal cholesterol peak in the third trimester.¹⁰¹ Low-density lipoprotein cholesterol concentrations decrease with increasing gestational age and are 25 to 30 mg/dL (0.5 to 0.8 mmol/L, about one fifth adult values) at term; high-density lipoprotein cholesterol is 25 mg/dL (0.6 mmol/L) at term (about one-half adult values).¹⁰¹ Very-low-density lipoprotein (VLDL) transports less than one third of the total serum triglycerides in the term infant, versus that in the adult in whom VLDL is the major transporter of triglycerides.¹⁰¹ Serum cholesterol and lipoprotein increase rapidly after birth, especially in breastfed infants.¹⁰¹

Protein metabolism

Serum amino acid levels are higher during the first few weeks of life.⁹² Urinary amino acids are elevated immediately after birth, with excretion of 8.8 mg/day in preterm and 7.6 mg/day in term infants versus 2.5 mg/day in older children. The average body nitrogen content at birth is 2%.⁹²

The newborn has a limited capacity to synthesize protein, primarily because of the relative inactivity of several hepatic enzymes. This limitation is especially marked in preterm infants, whose capacity to use excess amino acid is reduced. Preterm infants who receive excess protein or an unbalanced amino acid intake are at risk for hyperammonemia, azotemia, metabolic acidosis, and altered plasma amino acid profiles. The latter changes are associated with altered protein synthesis, growth, central nervous system (CNS) function, and bile acid uptake. The ability to metabolize excess amino acids may also be altered in the newborn depending on maturity of enzyme systems in the liver and skeletal muscle and activity of the urea cycle to eliminate nitrogen.

Neonatal hypoglycemia

The neonate may develop hypoglycemia if glycogen stores are insufficient to provide fuel during transition until production of energy by fat oxidation is adequate, or if the infant fails to adequately mobilize available glycogen stores. The physiologically optimal range for plasma glucose is given as 70 to 100 mg/dL (3.9 to 5.6 mmol/L).^77,122 Plasma glucose levels (whole blood glucose levels are 10% to 15% lower than plasma levels) below 40 mg/dL (2.2 mmol/L) are uncommon in the first few hours after birth in healthy infants with early feeding, and the lowest optimal level of glucose is probably around 60 mg/dL (3.3 mmol/L).^24,71,77,122 Arterial samples are slightly higher than venous samples (by 10% to 15%) with capillary samples intermediate.¹⁰ Elevated hematocrits can lead to lower glucose levels due to the high glucose utilization by the red blood cells. Newer technologies for continuous interstitial glucose monitoring, currently being investigated for use in the neonate, have identified more episodes of intermittent blood glucose levels than previously recognized, however the physiologic significance and long-term significance of these episodes are unknown.^48,53

Four approaches have been used to define hypoglycemia.^23,25 These include approaches based on appearance of clinical manifestations, measured glucose value ranges, acute metabolic changes and endocrine responses, and long-term neurologic outcomes.²³ None have been satisfactory. Aynsley-Green and Hawdon note that “hypoglycemia is a continuum, no single blood glucose concentration reflecting functional changes in every infant at that level.”⁵ Similarly, an expert panel concluded that the “rational definition of hypoglycemia is clearly not a specific value but a continuum of falling blood glucose values, creating thresholds for neurologic dysfunction, which may vary from one cause of hypoglycemia or clinical circumstance to another.”²²

Focus should be on promoting normoglycemia with prompt intervention for less optimal values.^22,104 The optimal glucose value and risk for neurologic sequelae probably varies from infant to infant depending on their brain maturity, glycogen stores, presence of hypoxia or ischemia, activity of gluconeogenic pathways, glucose transport status, and brain glucose demand.²⁴ Most sources cite levels below 40 to 45 mg/dL (2.2 to 2.5 mmol/L) as cutoff values for neonatal hypoglycemia.^{48,52,71,77,116} There is no evidence that the preterm infant is able to tolerate low glucose better than term infants.^5,122 Infants who are very immature or ill (hypoxia, ischemia, sepsis) may have greater glucose needs and be more vulnerable to the effects of hypoglycemia.²⁴ The American Academy of Pediatrics Committee on Fetus and Newborn recently published a practice guideline and algorithm for screening and management of hypoglycemia in late preterm and term newborns.²¹ This guideline suggests that for these infants, a “reasonable (although arbitrary) cutoff for treating symptomatic infants is 40 mg/dL. This value is higher than the physiologic nadir and higher than concentrations usually associated with clinical signs . . . . A reasonable goal is to maintain plasma glucose concentrations in symptomatic infants between 40 and 50 mg/dL.”^21,p.678

Clinical signs of hypoglycemia include tremors, jitteriness, irregular respiration, hypotonia, apnea, cyanosis, poor feeding, high-pitched cry, lethargy, irritability, hypothermia, and seizures. Because hypoglycemic infants may be symptomatic or asymptomatic and signs of hypoglycemia are often nonspecific, careful monitoring of infants at risk for development of hypoglycemia is critical. Multiple factors influence the outcome of infants with hypoglycemia, including severity and duration of the episode, cerebral blood flow and central nervous system (CNS) glucose levels, rates of glucose uptake, maturity, availability of alternative substrates, response to intervention, and type of clinical manifestation.^{22,24,50,93,116}

Glucose is critical for the brain and hypoglycemia increases the risk of brain injury. Decreased glucose availability increases release of glutamate, free radicals, and other toxic metabolites that can lead to mitochondrial damage, altered ATP-dependent ion transport across neuronal membranes, changes in cell membranes, cellular edema, and neuronal necrosis (see Chapter 15). Unfortunately many studies on the outcome of infants with hypoglycemia have significant methodologic limitations and there have been no controlled prospective studies.^13,107,116 Infants with persistent and recurrent hypoglycemia have the poorest neurologic outcomes.¹¹⁶ Hypoglycemia and hypoxic ischemic events may have an additive effect on neuronal injury.¹¹⁶ Brain neuroprotective responses to hypoglycemia include increased epinephrine, increased cerebral blood flow, use of alternative fuels such as ketone bodies and lactate, and degradation of glycogen stored in astrocytes.^107,115 This may contribute to the lack of clinical signs even with low blood glucose levels.⁴⁰ Kalahan and Devaskar concluded that “transient asymptomatic hypoglycemia in an otherwise healthy neonate has been associated with a good prognosis. Several studies of small groups of subjects have suggested that symptomatic hypoglycemia in the infant results in long-term neurologic damage. However, these data should be interpreted with caution because of a number of confounding variables.”⁷¹

Neonatal hypoglycemia can arise from an inadequate supply of glucose, alterations in endocrine regulation, or increased glucose regulation.^24,25,71,77 Preterm and SGA infants tend to develop hypoglycemia because of insufficient glycogen and fat stores and a decreased rate of gluconeogenesis. Normally with hypoglycemia, brain glucose utilization decreases by up to 50%, with increased reliance on ketones and lactate for energy. Preterm infants may be limited in their ability to mobilize these responses and thus more vulnerable to the effects of hypoglycemia.³⁵ Infants of diabetic mothers usually have sufficient stores; however, glycogenolysis is prevented by their high insulin levels and inability to secrete glucagon despite falling blood glucose levels. Infants at risk for neonatal hypoglycemia and associated mechanisms are summarized in Table 16-5.

Large-for-gestational-age (LGA) infants.

LGA infants (weight greater than 90th percentile or greater than 2 standard deviations for their gestational age) who are not offspring of diabetic women are also at higher risk for developing hypoglycemia and hyperinsulinemia.^107,116 The exact mechanism is unclear but may be related to increased insulin sensitivity or due to borderline maternal glucose tolerance.^71,107,116