Normal Glucose Tolerance

Significant alterations occur in maternal metabolism during pregnancy, which provide for adequate maternal nutritional stores in early gestation to meet the increased maternal and fetal metabolic demands of late gestation and lactation. Although we are apt to think of DM as a disorder exclusively of maternal glucose metabolism, in fact DM affects all aspects of nutrient metabolism. In this section we consider maternal glucose metabolism as it relates to pancreatic β-cell production of insulin and insulin clearance, endogenous (i.e., primarily hepatic) glucose production, and suppression with insulin and peripheral glucose insulin sensitivity. We also address maternal protein and lipid insulin metabolism. Lastly, the effects of these alternations on maternal metabolism are examined as they relate to maternal energy expenditure and fetal growth.

Glucose Metabolism

Normal pregnancy has been characterized as a “diabetogenic state” because of the progressive increase in postprandial glucose levels and increased insulin response in late gestation. However, early gestation can be viewed as an anabolic state because of the increases in maternal fat stores and decreases in free fatty acid (FFA) concentration, particularly in normal weight and obese women. Garcia-Patterson and colleagues have described significant decreases in maternal insulin requirements in early gestation in women with type 1 diabetes ( Fig. 40-2 ). The mechanism for the decrease in insulin requirements has been ascribed to various factors that include increased insulin sensitivity and decreased substrate availability secondary to factors such as nausea, the fetus acting as a glucose sink, and enhanced maternal insulin secretion; however, the exact mechanism is not known. Longitudinal studies in women with normal glucose tolerance have shown significant alterations in all aspects of glucose metabolism as early as the end of the first trimester.

Mean insulin requirements and self-monitored blood glucose in women with type 1 diabetes.

(Modified from Garcia-Patterson A, Gich I, Amini SB, et al. Insulin requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction. Diabetologia. 2010;53:446.)

Progressive increases are seen in insulin secretion in response to an intravenous (IV) glucose challenge with advancing gestation ( Fig. 40-3 ). The increases in insulin concentration are more pronounced in lean women, compared with obese women, most probably as a response to the greater decreases in insulin sensitivity in lean women, as will be described later. Data regarding insulin clearance in pregnancy are limited. In separate studies, Bellman, Lind, and colleagues and Burt and Davidson reported no difference in insulin disappearance rate when insulin was infused intravenously in late gestation compared with nongravid subjects. In contrast, using a radiolabeled insulin, Goodner and Freinkel described a 25% increase in insulin turnover in a pregnant compared with a nonpregnant rat model. Using the euglycemic clamp, Catalano and associates reported a 20% increase in insulin clearance in lean women and a 30% increase in insulin clearance in obese women by late pregnancy ( Fig. 40-4 ). Although the placenta is rich in insulinase, the exact mechanism for the increased insulin clearance in pregnancy remains speculative.

Longitudinal increase in insulin response to an intravenous glucose challenge in lean and obese women with normal glucose tolerance: pregravid and early and late pregnancy. A, First phase: area under the curve from 0 to 5 minutes. B, Second phase: area under the curve from 5 to 60 minutes.

Longitudinal increases in metabolic clearance rate of insulin (mL/m ² /min) in lean and obese women with normal glucose tolerance: pregravid and early and late pregnancy.

Although there is a progressive decrease in fasting glucose with advancing gestation, this decrease is most probably a result of the increase in plasma volume in early gestation and the increase in fetoplacental glucose utilization in late gestation. Using various stable isotope methodologies in cross-sectional study designs, Kalhan and Cowett were the first to describe increased fasting hepatic glucose production in late pregnancy. Additionally, using a stable isotope of glucose in a prospective longitudinal study design, Catalano and coworkers reported a 30% increase in maternal fasting hepatic glucose production with advancing gestation ( Fig. 40-5 ), which remained significant even after adjusting for maternal weight gain. Tissue sensitivity to insulin involves both liver and peripheral tissues, primarily skeletal muscle. The increase in fasting maternal hepatic glucose production occurs despite a significant increase in fasting insulin concentration, which indicates a decrease in maternal hepatic glucose sensitivity in women with normal glucose tolerance in late pregnancy. In obese women, a further decrease of insulin to suppress hepatic glucose production was seen in late gestation, thereby indicating a further decrease in hepatic insulin sensitivity in obese women.

Longitudinal increase in basal endogenous (primarily hepatic) glucose production (mg/min) in lean and obese women with normal glucose tolerance: pregravid and early and late pregnancy.

Estimates of peripheral insulin sensitivity in pregnancy have included measurements of insulin response to a fixed oral or IV glucose challenge or the ratio of insulin to glucose under a variety of experimental conditions. Methodologies such as the minimal model and the euglycemic-hyperinsulinemic clamp have improved our ability to quantify peripheral insulin sensitivity. In lean women in early gestation, Catalano and colleagues reported a 40% decrease in maternal peripheral insulin sensitivity using the euglycemic-hyperinsulinemic clamp. However, when adjusted for changes in insulin concentrations during the clamp and residual hepatic glucose production (i.e., the insulin sensitivity index), insulin sensitivity decreased only 10% ( Fig. 40-6 ). In contrast, a 15% increase was seen in the insulin sensitivity index in obese women in early pregnancy compared with pregravid estimates. Hence, the decrease in insulin requirements in early gestation observed in some women may be a consequence of an increase in insulin sensitivity, particularly in women with decreased insulin sensitivity before conception.

Longitudinal changes in the insulin sensitivity index (glucose infusion rate adjusted for residual endogenous glucose production and insulin concentrations achieved during the glucose clamp) in lean and obese women with normal glucose tolerance: pregravid and early and late gestation.

Compared with the varied metabolic alterations in early pregnancy, consensus has been reached regarding the decrease in peripheral insulin sensitivity in late gestation. Spellacy and Goetz were among the first investigators to report an increase in insulin response to a glucose challenge in late gestation. Additionally, Burt demonstrated that pregnant women experienced less hypoglycemia in response to exogenous insulin in comparison with nonpregnant subjects. Later research by Fisher and associates (using a high-dose glucose infusion test), by Buchanan and colleagues (using the Bergman minimal model), and by Ryan and coworkers and Catalano and associates (using the euglycemic-hyperinsulinemic clamp) all demonstrated a decrease in insulin sensitivity ranging from 33% to 78% in late gestation. However, all these quantitative estimates of insulin sensitivity are overestimates because of non–insulin-mediated glucose disposal by the fetus and placenta. Hay and colleagues reported that in the pregnant ewe model, about one third of maternal glucose use was accounted for by uterine, placental, and fetal tissue. Additionally, Marconi and coworkers reported that based on human fetal blood sampling, fetal glucose concentration was a function of fetal size and gestational age in addition to maternal glucose concentration.

The decrease in insulin sensitivity during pregnancy has been ascribed to an increased production of various placental and maternal hormones, such as human placental lactogen (hPL), progesterone, estrogen, cortisol, and prolactin. However, recent evidence has focused on the role of several new mediators of insulin resistance such as leptin, tumor necrosis factor alpha (TNF-α), and resistin. Kirwan and coworkers reported that TNF-α was inversely correlated with the changes in insulin sensitivity from the time before conception through late gestation. In combination with other placental hormones, multivariate stepwise regression analysis revealed that TNF-α was the strongest independent predictor of insulin sensitivity in pregnancy, accounting for about half of the variance in the decrease in insulin sensitivity during gestation.

Pregnancy has been characterized as a chronic low-grade inflammatory condition because of the increase in activation of circulating blood leukocytes. The inflammation of pregnancy is further enhanced by maternal prepregnancy obesity. This increase in low-grade inflammation, particularly observed in obese women, has been related to increases in macrophage infiltration in both maternal white adipose tissue and the placenta. The increase in inflammation has been associated with increased circulating C-reactive protein (CRP) and interleukin-6 (IL-6). Both of these factors may exacerbate the increased insulin resistance previously noted in obese women with normal glucose tolerance because of effects on the postreceptor insulin-signaling cascade. These inflammatory cytokines may then relate to increased substrate availability for the developing fetus and resultant macrosomia.

Placental glucose transport is a process that takes place through facilitated diffusion. Glucose transport is dependent on a family of glucose transporters referred to as the GLUT glucose transporter family . The principal glucose transporter in the placenta is GLUT1, which is located in the syncytiotrophoblast. GLUT1 is located on both the microvillus and basal membranes . Basal membrane GLUT1 may be the rate-limiting step in placental glucose transport. A twofold to threefold increase is seen in the expression of syncytiotrophoblast glucose transporters with advancing gestation. Although GLUT3 and GLUT4 expression have been identified in placental endothelial cells and intervillous nontrophoblastic cells, respectively, the role they may play in placental glucose transport remains speculative.

Debate has been ongoing regarding the location and/or function of insulin receptors in the placenta. In early pregnancy, insulin receptors are abundant on the syncytiotrophoblast, the cellular layer in contact with maternal blood. In late gestation, insulin receptors are increased on the placental vascular endothelium (i.e., in contact with fetal blood). Maternal insulin response in early pregnancy, as is often seen in women who are obese or who have diabetes, was strongly related to placental weight at birth. Placental weight at birth has the strongest correlation with birthweight, that is, fat and lean body mass. The implication of these data is that early maternal pregnancy metabolism, insulin resistance and response, may affect placental growth and gene expression, which only becomes clinically manifest as fetal overgrowth in late gestation.

Type 1 Diabetes Mellitus

Type 1 diabetes mellitus is usually characterized by an abrupt onset at a young age and absolute insulinopenia with lifelong requirements for insulin replacement. Although depending on the population, the onset of type 1 diabetes may occur in individuals in their third or fourth decades of life. Although the phenotype of the individual with type 1 diabetes has often been conceptualized as being thin, in an 18-year follow-up study, the prevalence of overweight increased by 47%, and the prevalence of obesity increased sevenfold. Patients with DM may have a genetic predisposition for antibodies directed against their pancreatic islet cells. The degree of concordance for the development of type 1 diabetes in monozygotic twins is 33%, suggesting that the events subsequent to the development of autoantibodies and appearance of glucose intolerance are also related to environmental factors. Because of the complete dependence on exogenous insulin, pregnant women with type 1 diabetes are at increased risk for the development of diabetic ketoacidosis (DKA). Additionally, because intensive insulin therapy is used in women with type 1 diabetes to decrease the risk for spontaneous abortion and congenital anomalies in early gestation, these women are at increased risk for hypoglycemic reactions. Studies by Diamond and Rosenn have shown that women with type 1 diabetes are more likely to experience hypoglycemic reactions during pregnancy because of diminished counterregulatory epinephrine and glucagon response to hypoglycemia. The deficiency in this counterregulatory response may be in part due to an independent effect of pregnancy.

The alterations in glucose metabolism in women with type 1 diabetes are not well characterized. Because of maternal insulinopenia, insulin response during gestation can only be estimated relative to pregravid requirements. Estimates of the change in insulin requirements are complicated by the degree of preconceptional glucose control and potential presence of insulin antibodies. Garcia-Patterson reported on the change in insulin requirements in women with type 1 diabetes and strict glucose control prior to conception. In early pregnancy, both insulin requirements and total insulin peak at 9 weeks’ gestation and reach a nadir at 16 weeks to baseline prepregnancy levels. After 16 weeks, insulin requirements gradually increase through 37 weeks. This represents a total increase in insulin requirements of 5.19% per week and about a twofold increase relative to prepregnancy requirements. A 5% decrease in insulin requirements after 36 weeks’ gestation was also noted by McManus and Ryan. The decrease in insulin requirements was associated with a longer duration of DM but not with adverse perinatal outcome. The fall in insulin requirements in early pregnancy in women with type 1 diabetes may be a reflection of increased insulin sensitivity as was previously described.

Schmitz and associates have evaluated the longitudinal changes in insulin sensitivity in women with type 1 diabetes in early and late pregnancy, as well as postpartum, in comparison with nonpregnant women with type 1 diabetes. In the pregnant women with type 1 diabetes, a 50% decrease in insulin sensitivity was observed only in late gestation. No significant difference was found in insulin sensitivity in pregnant women with type 1 diabetes in early pregnancy or within 1 week of delivery compared with nonpregnant women with type 1 diabetes. Therefore based on the available data, women with type 1 diabetes appear to have a similar decrease in insulin sensitivity compared with women with normal glucose tolerance. Relative to the issue of placental transporters (GLUT1), a report by Jansson and Powell describes an increase in both basal GLUT1 expression and glucose transport activity from placental tissue in women with White class D pregnancies.

Type 2 Diabetes and Gestational Diabetes

The pathophysiology of type 2 diabetes involves abnormalities of both insulin-sensitive tissue (i.e., both a decrease in skeletal muscle and hepatic sensitivity to insulin) and β-cell response as manifested by an inadequate insulin response for a given degree of glycemia. Initially in the course of the development of type 2 diabetes, the insulin response to a glucose challenge may be increased relative to that of individuals with normal glucose tolerance but is inadequate to maintain normoglycemia. Whether decreased insulin sensitivity precedes β-cell dysfunction in the development of type 2 diabetes continues to be debated. Arguments and experimental data support both hypotheses.

Despite the limitations of any classification system, certain generalizations can be made regarding women with type 2 diabetes or GDM. These individuals are typically older and more often are heavier compared with individuals with normal glucose tolerance. The onset of the disorder is usually insidious, with few patients complaining of the classic triad of polydipsia, polyphagia, and polyuria. Individuals with type 2 diabetes are often initially recommended to lose weight, increase their activity (i.e., exercise), and follow a diet low in saturated fats and high in complex carbohydrates. Oral agents are often used to increase insulin response, enhance insulin sensitivity, or increase renal excretion of glucose. Individuals with type 2 diabetes may eventually require insulin therapy to maintain euglycemia but are at significantly less risk for DKA. Data from monozygotic twin studies have reported a lifetime risk for both twins developing type 2 diabetes that ranges between 58% and almost 100%, suggesting that the disorder has a strong genetic component.

Type 2 pregestational diabetes is usually classified as class B diabetes according to the White classification system. Women who develop GDM—that is, glucose intolerance first recognized during pregnancy—share many of the metabolic characteristics of women with type 2 diabetes. Although earlier studies reported a 10% to 35% incidence of islet cell antibodies in women with GDM as measured by immunofluorescence techniques, research using specific monoclonal antibodies has described a much lower incidence, on the order of 1% to 2%, which suggests a low risk for type 1 diabetes in women with GDM. Furthermore, postpartum studies of women with GDM have demonstrated defects in insulin secretory response and decreased insulin sensitivity, indicating that typical type 2 abnormalities in glucose metabolism are present in women with GDM. The alterations in insulin secretory response and insulin resistance in women with a previous history of GDM compared with a weight-matched control group may differ depending on whether the women with previous GDM are lean or obese. Thus in women with GDM, the hormonal events of pregnancy may represent an unmasking of a genetic susceptibility to type 2 diabetes.

Significant alterations in glucose metabolism are found in women who develop GDM relative to women with normal glucose tolerance. Decreased insulin response to a glucose challenge has been demonstrated by Yen, Fisher, and Buchanan and their colleagues in women with GDM in late gestation. In prospective longitudinal studies of both lean and obese women with GDM, Catalano and associates also showed a progressive decrease in first-phase insulin response in late gestation in lean women who develop GDM compared with a weight-matched control group ( Fig. 40-7 ). In contrast, in obese women who develop GDM, no difference in first-phase insulin response was reported, but rather a significant increase was seen in second-phase insulin response to an IV glucose challenge compared with that of a weight-matched control group (see Fig. 40-7 ). These differences in insulin response may be related to the ethnicity of the various study groups. Although the metabolic clearance rate of insulin is increased with advancing gestation, no evidence suggests that a significant difference exists between women with normal glucose tolerance and those with GDM.

Longitudinal increase in insulin response to an intravenous glucose challenge in lean and obese women with normal glucose tolerance and gestational diabetes mellitus (GDM): pregravid and early and late pregnancy. A, First phase: area under the curve from 0 to 5 minutes. B, Second phase: area under the curve from 5 to 60 minutes.

Fasting glucose concentrations decrease with advancing gestation in women who develop mild GDM. In late pregnancy, however, hepatic glucose production increases in women with GDM in comparison with a matched control group. In late gestation, women with GDM have increased fasting insulin concentrations ( Fig. 40-8 ) and less suppression of hepatic glucose production during insulin infusion, thereby indicating decreased hepatic glucose insulin sensitivity in women with GDM compared with a weight-matched control group. In the studies of Xiang and associates, a significant correlation was found between fasting FFA concentrations and hepatic glucose production, which suggests that increased FFA concentrations may contribute to hepatic insulin resistance.

Longitudinal increase in basal or fasting insulin (µg/mL) in lean and obese women with normal glucose tolerance and gestational diabetes mellitus (GDM): pregravid and early and late pregnancy.

Women with GDM have decreased insulin sensitivity in comparison with weight-matched control groups. Ryan and colleagues were the first to report a 40% decrease in insulin sensitivity in women with GDM compared with a pregnant control group in late pregnancy using a hyperinsulinemic-euglycemic clamp. Xiang and associates found that women with GDM who had normal glucose tolerance within 6 months of delivery had significantly decreased insulin sensitivity as estimated by the glucose clearance rate during a hyperinsulinemic-euglycemic clamp compared with that of a matched control group. Using similar techniques, Catalano and coworkers described the longitudinal changes in insulin sensitivity in both lean and obese women who developed GDM in comparison with a matched control group. Women who developed GDM had decreased insulin sensitivity compared with that of the matched control group ( Fig. 40-9 ). The differences in insulin sensitivity were greatest before and during early gestation; by late gestation, the differences in insulin sensitivity between the groups were less pronounced but still significant. Of interest, an increase in insulin sensitivity was noted from the time before conception through early pregnancy (12 to 14 weeks), particularly in those women with the greatest decreases in insulin sensitivity before conception. The changes in insulin sensitivity from the time before conception through early pregnancy were significantly correlated with changes in maternal weight gain and energy expenditure. The relationship between these alterations in maternal glucose insulin sensitivity and weight gain and energy expenditure may help explain the decrease in maternal weight gain and insulin requirements in women with diabetes in early gestation. In summary, the various degrees of decreased insulin sensitivity observed in late pregnancy in women with normal glucose tolerance or gestational diabetes are but a reflection of their individual prepregnancy insulin sensitivity. Unless unforeseen severe metabolic events occur during pregnancy, relatively uniform decreases are apparent in insulin sensitivity with advancing gestation in all women.

Longitudinal changes in the insulin sensitivity index (glucose infusion rate adjusted for residual endogenous glucose production and insulin concentrations achieved during the glucose clamp) in lean and obese women with normal glucose tolerance and gestational diabetes mellitus (GDM): pregravid and early and late pregnancy.

The interactions of β-cell response and insulin sensitivity are hallmarks of the metabolic adaptations of pregnancy. As described by Bergman, the relationship between insulin response and insulin resistance is fixed in nonpregnant individuals and follows a hyperbolic curve (i.e., the disposition index [DI]; Fig. 40-10 ). Buchanan described a similar relationship between insulin response and insulin action during pregnancy. Indeed, when the DI has been compared between women with normal glucose tolerance and GDM both during and after pregnancy, the failure of the β-cell to compensate for insulin resistance in GDM has been similar to the hyperbolic changes in the control group (see Fig. 40-10 ). This relationship between insulin sensitivity and insulin resistance, however, may not hold in early pregnancy, when both an increase in insulin sensitivity and insulin response may be evident.

Insulin sensitivity index. GDM, gestational diabetes mellitus.

Studies in human skeletal muscle and adipose tissue have demonstrated that postreceptor defects in the insulin-signaling cascade are related to decreased insulin sensitivity in pregnancy. Garvey and colleagues were the first to demonstrate that there were no significant differences in the glucose transporter (GLUT4) responsible for insulin action and skeletal muscle in pregnant compared with nonpregnant women. Based on the studies of Friedman and colleagues in pregnant women with normal glucose tolerance and GDM, as well as in weight-matched nonpregnant control subjects, defects were apparent in the insulin-signaling cascade relating to pregnancy and to what may be additional abnormalities in women with gestational diabetes. All pregnant women appeared to have a decrease in expression of insulin receptor substrate 1 (IRS1). The downregulation of the IRS1 protein closely parallels the decreased ability of insulin to induce additional steps in the insulin-signaling cascade, which results in movement of the GLUT4 to the cell surface membrane to facilitate glucose transport into the cell. The downregulation of IRS1 protein closely parallels the ability of insulin to stimulate 2-deoxyglucose uptake in vitro. In addition to the previous mechanisms, women with GDM demonstrate a distinct decrease in the ability of insulin receptor – β , that component of the insulin receptor not on the cell surface, to undergo tyrosine phosphorylation. The additional defect in the insulin-signaling cascade results in a 25% lower glucose transport activity ( Fig. 40-11 ).

Schematic model of insulin-signaling cascade in skeletal muscle. GLUT, glucose transporter; IR, insulin receptor; IRS, insulin receptor substrate.

Amino Acid Metabolism

Although glucose is the primary source of energy for the fetus and placenta, no appreciable amounts of glucose are stored as glycogen in the fetus or placenta. However, accretion of protein is essential for growth of fetoplacental tissue. Nitrogen retention is increased in pregnancy in both maternal and fetal compartments, and this increase results in about 0.9 kg of maternal fat-free mass by 27 weeks. A significant decrease is apparent in most basal maternal amino acid concentrations in early pregnancy before the accretion of significant maternal or fetal tissue. These anticipatory changes in amino acid metabolism occur after a shorter period of fasting in comparison with nonpregnant women and may be another example of the accelerated starvation of pregnancy described by Freinkel and coworkers. Furthermore, amino acid concentrations, such as of serine, correlate significantly with fetal growth in both early and late gestation. Maternal amino acid concentrations were significantly decreased in mothers of small-for-gestational-age (SGA) neonates in comparison with maternal amino acid concentrations in appropriately grown neonates.

Based on a review of various studies, Duggleby and Jackson have estimated that during pregnancy, protein synthesis is similar to that in nonpregnant women in the first trimester. However, a 15% increase in protein synthesis occurs during the second trimester, and a further increase is seen in the third trimester, by about 25%. Additionally, interindividual differences at each time point are marked, and these differences have a strong relationship with fetal growth: mothers who had increased protein turnover in midpregnancy had babies who had increased lean body mass after adjustment for important covariables.

Amino acids can be used for protein accrual or they can be oxidized as an energy source. Estimation of urea synthesis using stable isotopes has been performed in a number of studies. In general, a modest shift in oxidation occurs in early pregnancy with an accrual of amino acids for protein synthesis in late gestation. Kalhan and colleagues reported significant pregnancy-related adaptations in maternal protein metabolism early in gestation before any significant increase in fetal protein accretion. Catalano and associates have also reported decreased amino acid insulin sensitivity based on a decreased suppression of leucine turnover during insulin infusion in late gestation. Some evidence suggests an increase in basal leucine turnover in women with GDM compared with that of a matched control group. Whether these decreases in amino acid insulin sensitivity are related to decreased whole-body and liver protein synthesis or increased breakdown are not known at this time.

Cetin and associates reported that placental amino acid exchange is altered in pregnancies complicated by GDM. Ornithine concentrations were significantly increased in women with GDM compared with controls, and in the cord blood of infants of women with GDM, significant increases were observed in multiple amino acids, including phenylalanine and leucine, but decreases in glutamate were also found. The investigators speculate that in infants of women with GDM, the altered in utero fetal milieu affects fetal growth through multiple mechanisms that affect various nutrient compartments.

Amino acids are actively transported across the placenta from mother to fetus through energy-requiring amino acid transporters. These transporters are highly stereospecific, but they have low substrate specificity. Additionally, they may vary in location between the microvillus and basal membranes. Decreased amino acid concentrations have been reported in growth-restricted neonates in comparison with appropriately grown neonates, and decreased amino acid transporter activity has been implicated as a possible mechanism. However, the potential role, if any, of placental amino acid transporters in the development of fetal macrosomia in women with diabetes is currently unknown.

Lipid Metabolism

Although ample literature supports the changes in glucose metabolism during gestation, the data regarding the alterations in lipid metabolism are meager by comparison. Darmady and Postle measured serum cholesterol and triglyceride before, during, and after pregnancy in 34 normal women and observed a decrease in both cholesterol and triglyceride at about 7 weeks’ gestation. Both of the levels increased progressively until term, and then a decrease was seen in serum triglyceride postpartum. The decrease was more rapid in women who breastfed compared with those women who bottle-fed their infants. Additionally, Knopp and coworkers have reported that a twofold to fourfold increase occurs in total triglyceride concentration and a 25% to 50% increase is seen in total cholesterol concentration during gestation. A 50% increase in low-density lipoprotein (LDL) cholesterol and a 30% increase in high-density lipoprotein (HDL) cholesterol is seen by midgestation, but these decrease slightly in the third trimester. Maternal triglyceride and very-low-density lipoprotein (VLDL) triglyceride levels in late gestation are positively correlated with maternal estriol and insulin concentrations.

A study by Vahratian and associates examined the changes in lipid levels during pregnancy in normal-weight compared with overweight and obese women from 6 to 10 through 32 to 36 weeks’ gestation. The levels of total cholesterol, triglycerides, and LDL and HDL cholesterol increased throughout gestation. Although the concentrations in the overweight and obese women were generally higher in early pregnancy, the rate of change of LDL cholesterol and total cholesterol was lower in later gestation.

FFAs have been associated with fetal overgrowth, particularly of fetal adipose tissue. A significant difference in the arteriovenous FFA concentration is seen at birth, much the same as with arteriovenous glucose concentration. Multiple clinical studies suggest the contribution of maternal lipids to fetal growth and in particular to adiposity. Knopp and coworkers reported that neonatal birthweight was positively correlated with triglyceride and FFA concentrations in late pregnancy. Similar conclusions were reached by Ogburn and colleagues, who showed that insulin concentrations decrease FFA concentrations, inhibit lipolysis, and result in increased fat deposition. Kleigman reported that infants of obese women had an increased birthweight and skinfold thickness and higher FFA levels compared with infants of lean women. DiCianni and associates reported that in women with a positive glucose screen but normal glucose tolerance, their serum triglycerides and prepregnancy body mass index (BMI) had a significant correlation with birthweight at term. In Australia, Nolan and coworkers showed that nonfasting maternal triglycerides measured at 9 to 12 weeks’ gestation were significantly correlated with neonatal birthweight ratio at term. Finally, in a well-controlled German GDM population, Schaeffer-Graf and colleagues reported that maternal FFA concentrations correlated with ultrasound estimates of neonatal abdominal circumference and anthropometric estimates of neonatal fat mass at delivery. Maternal FFA concentrations were positively correlated with cord FFA. Although FFA concentrations were higher in cord blood of large-for-gestational-age (LGA) neonates compared with either appropriately grown or SGA neonates, a paradoxic negative correlation of cord triglycerides and birthweight was reported. The authors speculated that SGA newborns have a lower lipoprotein lipase activity and hence were unable to hydrolyze triglycerides. In contrast, the LGA neonates have lower cord triglyceride con­centrations because of enhanced lipoprotein lipase activity resulting from their increased number of fat cells. Similar findings were noted by Merzouk and coworkers in growth-restricted infants. Lastly, the placentae of women with GDM have increased expression of genes related to inflammation and lipid metabolism in comparison with those of a BMI-matched control group.

In summary, in women with evidence of decreased insulin sensitivity (obesity and/or GDM) in addition to glucose, maternal lipid metabolism accounts for a significant proportion of fetal growth, particularly adiposity. These data support the original work by Freinkel, which proposed that fetal growth or overgrowth is a function of multiple nutritional factors in addition to glucose.

Lipid metabolism in women with diabetes mellitus is influenced by whether the woman has type 1 or type 2 diabetes. This also applies when these women become pregnant. In women with type 2 diabetes and gestational diabetes, Knopp and coworkers reported an increase in triglyceride and a decrease in HDL concentration. However, Montelongo and colleagues observed little change in FFA concentrations through all three trimesters after a 12-hour fast. Koukkou and coworkers noted an increase in total triglyceride but lower LDL cholesterol in women with GDM. Increased triglyceride concentrations during pregnancy have also been reported to be related to the development of GDM and preeclampsia in women with normal pregravid glucose tolerance, both of which are related to increased insulin resistance. In women with type 1 diabetes, no change was observed in total triglycerides, but a lower cholesterol concentration was reported secondary to a decrease in HDL. This is of interest because HDL acts as a plasma antioxidant, and thus a lower HDL level may be related to the increase in congenital malformations in women with type 1 diabetes. Oxidative stress has been implicated as a potential factor in the incidence of anomalies in women with type 1 diabetes.

Hyperinsulinemic-euglycemic clamp studies in pregnant women with normal glucose tolerance and GDM revealed a decreased ability of insulin to suppress plasma FFAs with advancing gestation. Insulin’s ability to suppress plasma FFAs was lower in women with GDM compared with women with normal glucose tolerance.

Taken together, these studies demonstrate decreased nutrient insulin sensitivity in all women with advancing gestation. These decreases in insulin sensitivity are further exacerbated by the presence of decreased pregravid maternal insulin sensitivity, which manifests in later pregnancy as GDM and results in greater nutrient availability and higher ambient insulin concentrations for the developing fetoplacental unit, which may eventually result in fetal overgrowth.

Maternal Weight Gain and Energy Expenditure

Estimates of the energy cost of pregnancy range from a cost of 80,000 kcal to a net savings of up to 10,000 kcal. As a result, the recommendations for nutritional intake in pregnancy differ and depend on the population being evaluated. Furthermore, recommendations for individuals within a population may be more diverse than previously believed, making general guidelines for nutritional intake difficult.

The theoretic energy cost of pregnancy was originally estimated by Hytten and Leitch using a factorial method. The additional cost of pregnancy consisted of (1) the additional maternal and fetoplacental tissue accrued during pregnancy and (2) the additional “running cost” of pregnancy (e.g., the work of increased cardiac output). In Hytten’s model, the greatest increases in maternal energy expenditure occur between 10 and 30 weeks’ gestation, primarily because of maternal accretion of adipose tissue. However, the mean increases in maternal adipose tissue vary considerably among various ethnic groups. Forsum and associates reported a mean increase of more than 5 kg of adipose tissue in Swedish women, whereas Lawrence and colleagues found no increase in adipose tissue stores in women from the Gambia.

Basal metabolic rate accounts for 60% to 70% of total energy expenditure in individuals not engaged in competitive physical activity, and this correlates well with total energy expenditure. As with the changes in maternal accretion of adipose tissue, wide variations are seen in the change in maternal basal metabolic rate during gestation, not only in different populations but again within relatively homogeneous groups. The cumulative energy changes in basal metabolic rate range from a high of 52,000 kcal in Swedish women to a net savings of 10,700 kcal in women from the Gambia without nutritional supplementation. The mean increase in basal metabolic rate in Western women relative to a nonpregnant, nonlactating control group averages about 20% to 25%. However, the coefficient of variation of basal metabolic rate ranges from 93% in women in the United Kingdom to more than 200% in Swedish women. When assessing energy intake in relation to energy expenditure, however, estimated energy intake remains lower than the estimates of total energy expenditure. These discrepancies have usually been explained by factors such as increased metabolic efficiency during gestation, decreased maternal activity, and unreliable assessment of food intake.

Data in nonpregnant subjects may help explain some of the wide variations in metabolic parameters during human gestation, even with homogeneous populations. Swinburn and colleagues reported that in the Pima Indian population, subjects with decreased insulin sensitivity gained less weight compared with more insulin-sensitive subjects (3.1 vs. 7.6 kg) over a period of 4 years. Furthermore, the percentage weight change per year was highly correlated with glucose disposal as estimated from clamp studies. Catalano and coworkers evaluated the changes in maternal accretion of body fat and basal metabolic rate in lean and obese women with normal GDM. Women who developed GDM had decreased insulin sensitivity in early gestation compared with a matched control group and had significantly smaller increases in body fat than women with normal glucose tolerance. A significant inverse correlation was found between the changes in fat accretion and insulin sensitivity (i.e., women with decreased pregravid insulin sensitivity had less accretion of body fat compared with women with increased pregravid insulin sensitivity).

In the basal state, lean women increase the use of carbohydrate as a metabolic fuel, whereas in obese women, there is an increased use of lipids for oxidative needs. However, with the decrease in insulin sensitivity in late gestation, all women have an increase in fat oxidation and decrease in nonoxidative glucose metabolism (storage). These increases in lipid oxidation are positively correlated with the increases in maternal leptin concentrations, possibly accounting for a role of leptin in human pregnancy. The result of these studies emphasize that an inverse relationship exists between the changes in maternal insulin sensitivity and accretion of adipose tissue in early gestation. The ability of women with decreased pregravid glucose insulin sensitivity (obese women and women with GDM) to conserve energy, not significantly increase body fat, and make sufficient nutrients available to produce a healthy fetus supports the hypothesis that decreased maternal insulin sensitivity may have a reproductive metabolic advantage in women when food availability is marginal (i.e., the thrifty gene hypothesis). In contrast, decreased maternal insulin sensitivity before conception in areas where food is plentiful and a sedentary lifestyle is more common and may manifest as GDM, and this increases the long-term risk for both diabetes and obesity in the woman and her offspring.

Fetal Death

In the past, sudden and unexplained stillbirth occurred in 10% to 30% of pregnancies complicated by type 1 DM, also called insulin-dependent diabetes mellitus (IDDM). Although relatively uncommon today, such losses still plague the pregnancies of patients who do not receive optimal care. Mathiesen and colleagues reported 25 stillbirths among 1361 singleton births of women with type 1 diabetes. In this series, the offspring of women with type 1 or type 2 diabetes were five times more likely to be stillborn compared with those of mothers without diabetes. Stillbirths have been observed most often after the 36th week of pregnancy in patients with poor glycemic control, hydramnios, fetal macrosomia, vascular disease, or preeclampsia. Women with vascular complications may develop fetal growth restriction (FGR) and intrauterine fetal demise (IUFD) as early as the second trimester.

Excessive stillbirth rates in pregnancies complicated by diabetes have been linked to chronic intrauterine hypoxia. Extramedullary hematopoiesis, frequently observed in stillborn infants of diabetic mothers (IDMs), supports chronic intrauterine hypoxia as a likely cause of these intrauterine fetal deaths. Studies of fetal umbilical cord blood samples in pregnant women with type 1 diabetes have demonstrated relative fetal erythremia and lactic acidemia. Maternal diabetes may also produce alterations in red blood cell (RBC) oxygen release and placental blood flow. Reduced uterine blood flow is thought to contribute to the increased incidence of intrauterine growth restriction (IUGR) observed in pregnancies complicated by diabetic vasculopathy. Ketoacidosis and preeclampsia, two factors known to be associated with an increased incidence of intrauterine deaths, may further decrease uterine blood flow.

Alterations in fetal carbohydrate metabolism also may contribute to intrauterine asphyxia. Considerable evidence links hyperinsulinemia and fetal hypoxia. Hyperinsulinemia induced in fetal lambs by an infusion of exogenous insulin produces an increase in oxygen consumption and a decrease in arterial oxygen content. Persistent maternal-fetal hyperglycemia occurs independent of maternal uterine blood flow, which may not be increased enough to allow for enhanced oxygen delivery in the face of increased metabolic demands. Thus hyperinsulinemia in the fetus of the diabetic mother appears to increase the metabolic rate and oxygen requirement in the fetus. Other factors such as hyperglycemia, ketoacidosis, preeclampsia, and maternal vasculopathy can also reduce placental blood flow and fetal oxygenation.

Congenital Malformations

Congenital malformations are the most important cause of perinatal loss in pregnancies complicated by type 1 and type 2 DM. In the past, these anomalies were responsible for only 10% of all perinatal deaths. Malformations now account for 30% to 50% of perinatal mortality. Neonatal deaths exceed stillbirths in pregnancies complicated by pregestational DM, and fatal congenital malformations are responsible for this pattern.

Most studies have documented a two to sixfold increase in major malformations in infants of type 1 and type 2 diabetic mothers. A large population-based cohort study of Canadian women revealed a 23% decline in congenital malformations in diabetic pregnancies from 1996 through 2010; however, the relative risk (RR) for malformations remained elevated in women with preexisting diabetes (RR, 2.33; 95% confidence interval [CI], 1.59 to 3.43). In a prospective analysis, Simpson and associates observed an 8.5% incidence of major anomalies in the diabetic population, whereas the malformation rate in a small group of concurrently gathered control subjects was 2.4%. Similar figures were obtained in the Diabetes in Early Pregnancy Study in the United States. The incidence of major anomalies was 2.1% in 389 control patients and 9% in 279 diabetic women. A recent case-control study of 13,030 infants with congenital anomalies and 4895 controls revealed a prevalence in type 1 diabetes of 2.2% versus 0.5% and in type 2 diabetes of 5.1% versus 3.7% in controls. In general, the incidence of major malformations in worldwide studies of offspring of diabetic women has ranged from 7.5% to 10% ( Table 40-2 ).

The insult that causes malformations in IDMs affects most organ systems and must act before the seventh week of gestation. Central nervous system malformations—particularly anencephaly, open spina bifida, and holoprosencephaly—are increased tenfold. Cardiac anomalies are the most common malformations seen in IDMs, with ventricular septal defects and complex lesions such as transposition of the great vessels increased fivefold. The congenital defect thought to be most characteristic of diabetic embryopathy is sacral agenesis or caudal dysplasia, an anomaly found 200 to 400 times more often in offspring of diabetic women ( Fig. 40-12 ). However, this defect is not pathognomonic for diabetes because it also occurs in nondiabetic pregnancies.

Infant of a diabetic mother with sacral agenesis and hypoplastic lower extremities.

Impaired glycemic control and associated derangements in maternal metabolism appear to contribute to abnormal embryogenesis. Maternal hyperglycemia has been proposed by most investigators as the primary teratogenic factor, but hyperketonemia, hypoglycemia, somatomedin inhibitor excess, and excess free oxygen radicals have also been suggested ( Box 40-1 ). The profile of a woman most likely to produce an anomalous infant would include a patient with poor periconceptional glucose control, long-standing diabetes, and vascular disease. Genetic susceptibility to the teratogenic influence of diabetes may also be a factor.

Several mechanisms have been proposed by which the previously mentioned teratogenic factors produce malformations. Freinkel and colleagues first suggested that anomalies might arise from inhibition of glycolysis, the key energy-producing process during embryogenesis. They found that the addition of D-mannose to the culture medium of rat embryos inhibited glycolysis and produced growth restriction and derangement of neural tube closure. Freinkel and colleagues stressed the sensitivity of normal embryogenesis to alterations in these key energy-producing pathways, a process he labeled “fuel-mediated” teratogenesis. Goldman and Baker suggested that the mechanism responsible for the increased incidence of neural tube defects (NTDs) in embryos cultured in a hyperglycemic medium may involve a functional deficiency of arachidonic acid, because supplementation with arachidonic acid or myoinositol will reduce the frequency of NTDs in this experimental model. Pinter and Reece, along with Pinter and associates, confirmed these studies and demonstrated that hyperglycemia-induced alterations in neural tube closure include disordered cells, decreased mitoses, and changes indicative of premature maturation. Pinter and colleagues further demonstrated that hyperglycemia during organogenesis has a primary deleterious effect on yolk sac function with resultant embryopathy.

Altered oxidative metabolism from maternal diabetes may cause increased production of free oxygen radicals in the developing embryo, which are likely teratogenic. Supplementation of oxygen radical–scavenging enzymes, such as superoxide dismutase, to the culture medium of rat embryos protects against growth delay and excess malformations. It has been suggested that excess free oxygen radicals may have a direct effect on embryonic prostaglandin biosynthesis. Free oxygen radical excess may enhance lipid peroxidation, and in turn, generated hydroperoxides might stimulate thromboxane biosynthesis and might inhibit prostacyclin production, an imbalance that could have profound effects on embryonic development. Finally, oxidative stress in diabetic rats is associated with the accumulation of glycation products and altered vascular endothelial growth factor (VEGF) expression in cardiovascular regions of the developing heart associated with endocardial cushion defects.

Fetal Macrosomia

Macrosomia has been variously defined as birthweight greater than 4000 to 4500 g, as well as LGA, in which birthweight is above the 90th percentile for population and sex-specific growth curves. Fetal macrosomia complicates as many as 50% of pregnancies in women with GDM and 40% of pregnancies complicated by type 1 and type 2 diabetes, which includes some women treated with intensive glycemic control ( Fig. 40-13 ). Delivery of an infant weighing greater than 4500 g occurs 10 times more often in women with diabetes compared with a population of women with normal glucose tolerance.

Two extremes of growth abnormalities in pregnancies complicated by diabetes mellitus. On the left is a severely growth-restricted infant, and on the right is a macrosomic infant.

According to the Pedersen hypothesis, maternal hyperglycemia results in fetal hyperglycemia and hyperinsulinemia, which results in excessive fetal growth. Increased fetal β-cell mass may be identified as early as the second trimester. Evidence in support of the Pedersen hypothesis has come from the studies of amniotic fluid and cord blood insulin and C-peptide concentrations. Both are increased in the amniotic fluid of insulin-treated women with diabetes at term and correlate with neonatal fat mass. Lipids and amino acids, which are elevated in pregnancies complicated by GDM, may also play a role in excessive fetal growth by either stimulating the release of insulin and other growth factors from the fetal pancreatic β-cells and placenta or by providing the necessary nutrients for excessive fetal growth. Infants of mothers with GDM have an increase in fat mass, compared with fat-free mass, in comparison with infants of women with normal glucose tolerance. Additionally, the growth is disproportionate, with chest-to-head and shoulder-to-head ratios larger than those of infants of women with normal glucose tolerance. These anthropometric differences may contribute to the higher rate of shoulder dystocia and birth trauma observed in these infants.

The results of several clinical series have validated the Pedersen hypothesis inasmuch as tight maternal glycemic control has been associated with a reduction in macrosomia and, in particular, with a reduction in fat mass. Using daily capillary glucose values obtained during the second and third trimesters in women who required insulin, Landon and colleagues reported a rate of 9% for macrosomia when mean values were below 110 mg/dL compared with 34% when less optimal control was achieved. Jovanovic and associates have suggested that 1-hour postprandial glucose measurements correlate best with the frequency of macrosomia. After controlling for other factors, these authors noted that the strongest prediction for birthweight was third-trimester nonfasting glucose measurements.

In a series of metabolic studies, Catalano and associates estimated body composition in 186 neonates using anthropometry. Fat-free mass, which represented 86% of mean birthweight, accounted for 83% of the variance in birthweight; and fat mass, which made up only 14% of birthweight, accounted for 46% of the variance in birthweight. In addition, significantly greater fat-free mass was observed in male compared with female infants. Using independent variables such as maternal height, pregravid weight, weight gain during pregnancy, parity, paternal height and weight, neonatal sex, and gestational age, the authors accounted for 29% of the variance in birthweight, 30% of the variance in fat-free mass, and 17% of the variance in fat mass. Including estimates of maternal insulin sensitivity in 16 additional subjects, they were able to explain 48% of the variance in birthweight, 53% of the variance in fat-free mass, and 46% of the variance in fat mass. Studies by Caruso and colleagues have corroborated these findings, reporting that women with unexplained FGR had greater insulin sensitivity compared with a control group of women whose infants were an appropriate weight for their gestational age. The potential mechanisms for this relate to the possibility that maternal circulating nutrients for glucose, FFAs, and amino acids available for placental transport to the fetus are decreased because of the relative increase in maternal insulin sensitivity. A positive correlation between birthweight and weight gain has been observed in women with normal glucose tolerance. The correlation was strongest in women who were lean before conception, and it became progressively weaker as pregravid weight for height increased. In women with GDM, no significant correlations were found between maternal weight gain and birthweight irrespective of pregravid weight for height. Although these studies emphasize the role of the maternal metabolic environment and fetal growth, Kim and colleagues have reported that GDM actually contributed the least (2.0% to 8.0%) to the development of LGA infants in a general obstetric population, whereas excessive gestational weight gain contributed the most (33.3% to 37.7%).

Normalization of birthweight in infants of women with GDM, however, may in itself not help those infants achieve optimal growth. In a study of approximately 400 infants of women with normal glucose tolerance and GDM, Catalano and coworkers showed that the infants of women with GDM had increased fat mass, but not lean body mass or weight, compared with a control group even after adjustment for potential confounding variables ( Table 40-3 ). Similarly, when only infants who were an appropriate size for their gestational age (i.e., between the 10th and 90th percentiles) were examined, the infants of the women with GDM had significantly greater fat mass and percentage of body fat but had less lean mass compared with the control group, and no difference was observed in birthweight. Of note, in the infants of the women with GDM, the strongest correlations with fat mass were fasting glucose and gestational age; this accounted for 17% of the variance in infant fat mass.

Hypoglycemia

Neonatal hypoglycemia, a blood glucose level less than 35 to 40 mg/dL during the first 12 hours of life, results from a rapid drop in plasma glucose concentrations following clamping of the umbilical cord. Hypoglycemia, a byproduct of hyperinsulinemia, is particularly common in macrosomic newborns, in whom rates exceed 50%. We have observed an overall rate of 27% in offspring of diabetic women delivered at our institution. The degree of hypoglycemia may be influenced by at least two factors: maternal glucose control during the latter half of pregnancy during labor and delivery. Prior poor maternal glucose control can result in fetal β-cell hyperplasia, which leads to exaggerated insulin release following delivery. IDMs who exhibit hypoglycemia have elevated cord C-peptide and free insulin levels at birth and show an exaggerated pancreatic response to glucose loading. The hyperinsulinemia and resultant hypoglycemia typically lasts for several days following birth.

Respiratory Distress Syndrome

Experimental animal studies have provided evidence that hyperglycemia and hyperinsulinemia can affect pulmonary surfactant biosynthesis, and in vitro studies have documented that insulin can interfere with substrate availability for surfactant biosynthesis. Insulin excess may interfere with the normal timing of glucocorticoid-induced pulmonary maturation in the fetus. Cortisol apparently acts on pulmonary fibroblasts to induce synthesis of fibroblast-pneumocyte factor, which then acts on type II cells to stimulate phospholipid synthesis. Carlson and coworkers demonstrated that insulin blocks cortisol action at the level of the fibroblast by reducing the production of fibroblast-pneumocyte factor.

Clinical studies to investigate the effect of maternal diabetes on fetal lung maturation have produced conflicting data. The role of amniocentesis in determining fetal lung maturity is discussed with timing and mode of delivery. Several studies suggest that in women with well-controlled diabetes whose fetus is delivered at 38 to 39 weeks’ gestation, the risk for respiratory distress syndrome (RDS) is no higher than that observed in the general population . Kjos and Walther studied the outcome of 526 diabetic gestations delivered within 5 days of amniotic fluid fetal lung maturation testing and reported hyaline membrane disease (HMD) in five neonates (0.95%), all of whom were delivered before 34 weeks’ gestation. Mimouni and associates compared outcomes of 127 IDMs with matched controls and concluded that well-controlled diabetes in pregnancy is not a direct risk factor for the development of RDS. Yet cesarean delivery not preceded by labor and prematurity, both of which are increased in diabetic pregnancies, clearly increases the likelihood of neonatal respiratory disease. With cesarean delivery, many of these cases represent retained lung fluid or transient tachypnea of the newborn, which usually resolves within the first days of life.

Calcium and Magnesium Metabolism

Neonatal hypocalcemia, with serum levels below 7 mg/dL or an ionized level less than 4 mg/dL, occurs at an increased rate in IDMs when controlling for predisposing factors such as prematurity and birth asphyxia. With modern management, the frequency of neonatal hypocalcemia is less than 5% in IDMs. Hypocalcemia in IDMs has been associated with a failure to increase parathyroid hormone synthesis following birth. Decreased serum magnesium levels have also been documented in pregnant diabetic women as well as in their infants. Mimouni and associates described reduced amniotic fluid magnesium concentrations in women with type 1 DM. These findings may be explained by a drop in fetal urinary magnesium excretion, which would accompany a relative magnesium-deficient state. Paradoxically, magnesium deficiency may then inhibit fetal parathyroid hormone secretion.

Hyperbilirubinemia and Polycythemia

Hyperbilirubinemia is frequently observed in the IDM. Neonatal jaundice has been reported in as many as 25% to 53% of pregnancies complicated by pregestational DM and 38% of pregnancies in women with GDM. Jaundice observed in IDMs can be attributed largely to prematurity. However, jaundice is also increased in macrosomic IDMs.

Although severe hyperbilirubinemia may be observed independent of polycythemia, a common pathway for these complications most likely involves increased RBC production, which is stimulated by increased erythropoietin (EPO) in the IDM. Presumably, the major stimulus for red cell production is a state of relative hypoxia in utero. Cord EPO levels generally are normal in IDMs whose mothers demonstrate good glycemic control during gestation; however, hemoglobin A1c (HbA1c) values in late pregnancy are significantly elevated in mothers of hyperbilirubinemic infants.

Cardiomyopathy

A transient form of cardiomyopathy may occur in IDMs. Among symptomatic infants, septal hypertrophy may cause left ventricular outflow obstruction. Although most infants are asymptomatic, respiratory distress or signs of cardiac failure may arise. Cardiac hypertrophy likely results from fetal hyperinsulinemia, which leads to fat and glycogen deposition in the myocardium. Thus cardiomyopathy generally occurs in pregnancies com­plicated by macrosomia in which glucose levels are poorly controlled. Elevated levels of B-type natriuretic peptide (BNP) produced during cardiac stress have been reported in umbilical blood of IDMs and have been correlated with maternal glycemic control. In most cases, symptoms of cardiomyopathy improve over several weeks with supportive care, and echocardiographic changes resolve as well.

Nephropathy

Renal disease develops in 25% to 30% of women with IDDM, with a peak incidence after 16 years of diabetes. Overt diabetic nephropathy is diagnosed in women with type 1 or type 2 DM when persistent proteinuria exists in the absence of infection or other urinary tract disease. Damm and colleagues have reported the prevalence of diabetic nephropathy during pregnancy to be 2.3% (5/220) in women with type 2 diabetes and 2.5% (11/445) in women with type 1 diabetes. The criteria for diagnosis in the nonpregnant state includes a total urinary protein excretion (TPE) of greater than 500 mg in 24 hours or greater than 300 mg in 24 hours of urinary albumin excretion (UAE).

Before the development of overt diabetic nephropathy, some individuals develop incipient diabetic nephropathy defined by repetitive increases in UAE known as microalbuminuria . The diagnosis is established from a 24-hour urine collection exhibiting UAE of 20 to 199 µg/min or 30 to 299 mg in 24 hours. It is important to note that women who exhibit microalbuminuria in early pregnancy have a 35% to 60% risk for superimposed preeclampsia. Without specific interventions, about 80% of individuals with type 1 diabetes who develop sustained microalbuminuria experience an increase in UAE of 10% to 20% per year, leading to overt nephropathy. In the nonpregnant individual, improvement of glycemic and blood pressure control has been demonstrated to reduce the risk for, or slow the progression of, diabetic nephropathy. Renoprotective or antihypertensive therapy consisting of either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) is indicated in nonpregnant women with diabetes who exhibit microalbuminuria or overt nephropathy. In contrast, both ACE inhibitors and ARBs are contraindicated during pregnancy because they may result in fetal proximal tubal dysgenesis and oligohydramnios. A population-based study by Cooper and colleagues has indicated potential teratogenesis in women who received ACE inhibitors in early pregnancy and thus calls into question whether such agents are advised in women attempting conception. These researchers studied a cohort of 29,507 infants enrolled in Tennessee Medicaid born between 1985 and 2000 for whom there was no evidence of maternal diabetes. A total of 209 infants with exposure to ACE inhibitors during the first trimester alone were compared with 202 infants exposed to other antihypertensives during the first trimester and with 29,096 infants with no exposure to any antihypertensive agents during pregnancy. Major congenital malformations were identified from linked vital records and hospitalization claims during the first year of life. Infants with only first-trimester exposure to ACE inhibitors had an increased risk for major congenital malformations (RR, 2.71; 95% CI, 1.72 to 4.27) compared with infants who had no fetal exposure to other antihypertensive medications during only the first trimester. The increased risk conferred by ACE inhibitor exposure manifested as primarily anomalies of the cardiovascular and central nervous systems. Clearly, given this information, the risk and benefits of use of ACE inhibitors in diabetic women planning pregnancy must be considered.

Women with diabetic nephropathy have a significantly reduced life expectancy. Disease progression is characterized by hypertension, declining glomerular filtration rate (GFR), and eventual end-stage renal disease (ESRD) that requires dialysis or transplantation. In women with overt nephropathy, ESRD occurs in 50% by 10 years and in greater than 75% by 20 years.

Class F describes pregnant women with underlying renal disease. This includes those with reduced creatinine clearance or proteinuria of at least 500 mg in 24 hours measured during the first 20 weeks of gestation. Two factors present before 20 weeks’ gestation appear to be predictive of adverse perinatal outcome in these women (e.g., preterm delivery, low birthweight, or preeclampsia): proteinuria greater than 3 g per 24 hours and serum creatinine greater than 1.5 mg/dL.

In a series of 45 class F women, 12 women had such risk factors. Preeclampsia developed in 92%, with a mean gestational age at delivery of 34 weeks, compared with an incidence of preeclampsia of 36% in 33 women without these risk factors who reached an average gestational age of 36 weeks. Remarkably, perinatal survival was 100% in this series, and no deliveries occurred before 30 weeks’ gestation. Comparable series’ detailing perinatal outcomes in class F patients are presented in Table 40-4 .

The management of the diabetic woman with nephropathy requires great expertise. Limitation of dietary protein, which may reduce protein excretion in nonpregnant patients, has not been adequately studied during pregnancy. Although controversial, some nephrologists recommend a modified reduction in protein intake for pregnant women with nephropathy. Control of hypertension in pregnant women with diabetic nephropathy is crucial to prevent further deterioration of kidney function and to optimize pregnancy outcome. Suboptimal control of blood pressure has been associated with a significantly increased risk for preterm delivery in this population. Thus in contrast to higher suggested thresholds for treatment in nondiabetic individuals, some have recommended instituting antihypertensive therapy to maintain blood pressure less than 135/85 mm Hg in pregnant women with nephropathy. Prospective studies to evaluate blood pressure targets in pregnant women with diabetic nephropathy have not been conducted. Because calcium channel blockers have renoprotective effects similar to those of ACE inhibitors and do not appear to be teratogenic, these agents are our first choice for treatment of hypertension in pregnant women with diabetic nephropathy. Whether such agents benefit normotensive pregnant women with microalbuminuria or nephropathy has not been determined. Other options for treatment include labetalol or hydralazine.

Studies are limited and conflict as to whether a permanent worsening of diabetic renal disease in women with mild to moderate renal insufficiency occurs as a result of pregnancy. Several small studies of women with serum creatinine greater than 1.5 mg/dL suggest that pregnancy may be associated with a more rapid decline in postpartum renal function. The increased risk of ESRD in nondiabetic women with previous preeclampsia also raises the question as to whether preeclampsia has an independent effect on the incidence and progression of diabetic nephropathy. In summary, no deleterious effect on the progression of diabetic nephropathy is apparent provided that serum creatinine is in the normal range and significant proteinuria is absent in early pregnancy. In a review of 35 pregnancies complicated by diabetic nephropathy, proteinuria increased in 69%, and hypertension developed in 73%. After delivery, proteinuria declined in 65% of cases. In only two patients did protein excretion increase after gestation. In Gordon’s series, 26 women (58%) had more than a 1-g increase in proteinuria, and by the third trimester, 25 (56%) excreted more than 3 g in 24 hours. In most cases, protein excretion returned to baseline levels after gestation.

Normal pregnancy is marked by an approximate 50% increase in GFR, and thus a rise in creatinine clearance, accompanied by a modest decline in serum creatinine. Most women with diabetic nephropathy, however, do not exhibit a rise in creatinine clearance during gestation. In a study of 46 class F pregnancies, Gordon and colleagues reported a mean decrease in creatinine clearance of 7.9%. When evaluated according to initial creatinine clearance, no difference in the degree of change was noted when subjects were classified according to first-trimester renal function. Whereas few patients exhibited a rise in creatinine clearance, other smaller studies have demonstrated an increase in creatinine clearance in about one third of women. Given the importance of blood pressure control in reducing cardiovascular and renal complications in the nonpregnant state, Carr and colleagues studied the effect of poorly controlled hypertension in early pregnancy on renal function in 43 women with type 1 diabetes with nephropathy. Those women with mean arterial pressure in excess of 100 mm Hg demonstrated higher serum creatinine levels (1.23 vs. 0.895 mg/dL) compared with women with controlled hypertension.

With overt diabetic nephropathy, both albumin and total protein excretion may rise significantly during gestation. Importantly, a rise in total protein excretion to levels exceeding 300 mg in 24 hours may also be observed in women both with and without microalbuminuria in early pregnancy. Biesenbach and Zazgornik reported an average increase by the third trimester in total protein excretion to 478 mg in 24 hours in seven women with microalbuminuria in early pregnancy. This observation underscores the importance of obtaining baseline 24-hour urine measurements for total protein in all diabetic women because confusion arises as to the significance when new-onset macroalbuminuria or proteinuria is detected during the third trimester. Despite this recommendation, it may be challenging to distinguish preeclampsia from the natural progression of diabetic nephropathy, which often manifests as progressive proteinuria during pregnancy.

Gordon and colleagues have detailed the progressive rise in proteinuria during pregnancy in 46 class F pregnancies. The mean increase in proteinuria between initial values and third-trimester values was 3.08 (± 4 g) in 24 hours. Twenty-six women (58%) had more than a 1-g increase in proteinuria, and by the third trimester, 25 (56%) excreted more than 3 g in 24 hours, including three women who exceeded 10 g in 24 hours. The mean change in proteinuria was not correlated with alterations in creatinine clearance, and a similar increase in proteinuria was observed during pregnancy regardless of the initial level present.

In summary, changes in creatinine clearance are variable during pregnancy in women with diabetic nephropathy. Most women with nephropathy will not exhibit a normal rise in creatinine clearance. Protein excretion will frequently rise during gestation to levels that can reach the nephrotic range.

With improved survival of diabetic patients after renal transplantation, a growing number of kidney recipients have now achieved pregnancy (class T). Attempting pregnancy is not advised until 2 years after transplantation. Mycophenolate is contraindicated during pregnancy, and a decision as to whether to discontinue this drug prior to conception should be individualized. Most diabetic renal transplant patients have underlying hypertension, although in one series of 28 women, preeclampsia was diagnosed in only 17% of cases. Allograft rejection occurred in one case. Overall, despite an increase in deliveries before 37 weeks, perinatal survival was 100%. These excellent results have come from improvements in both perinatal management and newer immunosuppressive regimens.

Many transplantation centers strive to perform combined kidney-pancreas transplantations in diabetic individuals with ESRD. Gilbert-Hayn and McGrory reviewed pregnancy outcomes in 43 pancreas-kidney recipients, of whom 66% developed hypertension and 77% had pregnancies that resulted in preterm birth. In this series, 6% of women experienced a rejection episode during pregnancy.

Retinopathy

Class R diabetes designates women with proliferative retinopathy, which represents neovascularization or growth of new retinal capillaries. These vessels may cause vitreous hemorrhage with scarring and retinal detachment, which results in vision loss. As with nephropathy, prevalence of retinal disease is highly related to the duration of diabetes. At 20 years, nearly 80% of diabetic individuals have some element of diabetic retinopathy. Background changes are generally apparent, whereas proliferative diabetic retinopathy fortunately complicates only 3% of pregnancies. Excellent glycemic control prevents retinopathy and may slow its progression. Parity is not associated with a risk for subsequent retinopathy; however, pregnancy does convey more than a twofold independent risk for progression of existing retinopathy. Progression of diabetic retinopathy during pregnancy is associated with (1) retinal status at inception, (2) duration and early onset of diabetes, (3) elevated first-trimester HbA1c and persistent poor glycemic control or rapid normalization of blood glucose, and (4) hypertension. Retinopathy may worsen significantly during pregnancy despite the major advances that have been made in diagnosis and treatment of existing retinopathy. Ideally, women planning a pregnancy should have a comprehensive eye examination and treatment before conception. For those discovered to have proliferative changes during pregnancy, laser photocoagulation therapy with careful follow-up has helped maintain many pregnancies to a gestational age at which neonatal survival is likely.

In a large series of 172 patients, including 40 cases with background retinopathy and 11 with proliferative changes, only one patient developed new-onset proliferative retinopathy during pregnancy. A review of the literature by Kitzmiller and colleagues confirms the observation that progression to proliferative retinopathy during pregnancy rarely occurs in women with background retinopathy or in those without any eye-ground changes. Of the 561 women in these two categories, only 17 (3%) developed neovascularization during gestation. In contrast, 23 of 26 (88.5%) with untreated proliferative disease experienced worsening retinopathy during pregnancy.

Pregnancy may increase the prevalence of some background retinal changes. Characteristic streak-blob hemorrhages and soft exudates have been noted, and such retinopathy may progress despite strict metabolic control. At least two studies have related worsening retinal disease to plasma glucose at the first prenatal visit as well as the magnitude of improvement in glycemia during early pregnancy. In a subset of 140 women without proliferative retinopathy at baseline followed in the Diabetes in Early Pregnancy Study, progression of retinopathy was seen in 10.3%, 21.1%, 18.8%, and 54.8% of patients with no retinopathy, microaneurysms only, mild nonproliferative retinopathy, and moderate to severe nonproliferative retinopathy at baseline, respectively. Elevated glycosylated hemoglobin at baseline and the magnitude of improvement of glucose control through week 14 were associated with a higher risk for progression of retinopathy. Women with an initial glycohemoglobin greater than 6 standard deviations (SDs) above the control mean were nearly three times as likely to experience worsening retinopathy compared with those within 2 SDs of the mean. Whether improving control or simply suboptimal control contributes to a deterioration of background retinopathy remains uncertain. Hypertension may also be a significant risk factor for the progression of retinopathy during pregnancy. For women with proliferative changes, laser photocoagulation is indicated, and most will respond to this therapy. However, women who demonstrate severe florid disc neovascularization that is unresponsive to laser therapy during early pregnancy may be at great risk for deterioration of their vision. Termination of pregnancy may need to be considered in this group of patients.

In labor, women with proliferative retinopathy are generally advised to avoid the Valsalva maneuver to reduce the risk for retinal hemorrhage. Shortening of the second stage of labor or cesarean delivery has been advocated; however, studies are lacking that address this issue.

In addition to background and proliferative eye disease, vasoocclusive lesions associated with the development of macular edema have been described during pregnancy. Cystic macular edema is most often found in patients with proteinuric nephropathy and hypertensive disease, leading to retinal edema; macular capillary permeability is a feature of this process, and the degree of macular edema is directly related to the fall in plasma oncotic pressure present in these women. In one series, seven women with minimal or no retinopathy before becoming pregnant developed severe macular edema associated with preproliferative or proliferative retinopathy during the course of their pregnancies. Although proliferation was controlled with photocoagulation, the macular edema worsened until delivery in all cases and was often aggravated by photocoagulation. Although both macular edema and retinopathy regressed after delivery in some patients, in others, these pathologic processes persisted and resulted in significant visual loss.

Coronary Artery Disease

Class H diabetes refers to the presence of diabetes of any duration associated with ischemic myocardial disease. Symptomatic coronary artery disease is rare in type 1 diabetic women who are younger than 35 years. It is unknown whether the small number of women who have coronary artery disease are at an increased risk for infarction during gestation. The maternal mortality rate exceeded 50% for cases of infarction during pregnancy reported before 1980; however, all but 1 of 23 cases reported from 1980 to 2005 survived. A high index of suspicion for ischemic heart disease should be maintained in women with long-standing diabetes because anginal symptoms may be minimal in women, and infarction may present as congestive heart failure. Although more than a dozen reports have described successful pregnancies following myocardial infarction (MI) in diabetic women, cardiac status should be carefully assessed early in gestation or, preferably, before pregnancy. If electrocardiographic (ECG) abnormalities are encountered, echocardiography may be used to assess ventricular function, or modified stress testing may be performed. The decision to undertake a pregnancy in a woman with type 1 or type 2 DM and coronary artery disease needs to be made only after serious consideration. The potential for morbidity and mortality must be thoroughly reviewed with the patient and her family. The management of MI during pregnancy is discussed in Chapter 37 .