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  • 1. Global and National Prevalence of Diabetes Worldwide Perspective on Diabetes An epidemic of diabetes and obesity is sweeping the globe, largely because of marked shifts in dietary practices and physical activity. In 2000, 171 million persons on the planet were known to have diabetes, and by 2030, this figure is expected to increase to 366 million. More than 80% of people with diabetes worldwide live in low- and middle- income countries. During the next 2 decades, the world population is expected to increase by 37%, but the prevalence of diabetes will increase by 114%. In India, sub-Saharan Africa, and Latin America, diabetes prevalence is projected to increase by 150% to 160%.1 In the United States and other developed economies, the rise in diabetes prevalence is projected to be higher than 50%. As shown in Figure 46-1, in 2005, 20.8 million people (7% of the population) have been diagnosed with some form of diabetes. Another 6.2 million with diabetes are undiagnosed. Of women 20 years or older, 8.8% have overt diabetes, but there is a strong predilection for this disease among ethnic groups. Higher-than-expected rates of pregestational diabetes in women of childbearing age have been reported for 13.3% of non- Hispanic blacks, 9.5% of Hispanic and Latino Americans, and 12.8% of Native Americans.2 Epidemiology of Diabetes in U.S. Women Studies suggest that the prevalence of diabetes among women of child- bearing age is increasing in the United States.3,4 Continued immigra- tion among populations with high rates of type 2 diabetes and the impact of changes in diet (i.e., increased calories and fat content) and lifestyle (i.e., sedentary) have brought marked increases in the percent- age of patients with preexisting diabetes who will become pregnant in the future. A virtual epidemic of childhood obesity is occurring in the United States, bringing with it a sharp rise in childhood and adolescent diabetes. This trend will have a profound impact on obstetrics and pediatrics in the next 2 decades and beyond.5 Increased outreach efforts to provide care to the populations experiencing rising rates of pregestational diabetes will be necessary if a significant increase in maternal and newborn morbidity is to be avoided. When offspring of diabetic mothers are compared with weight-matched controls, the risk of serious birth injury is doubled, the likelihood of cesarean section is tripled, and the incidence of newborn intensive care unit admission is quadrupled.6 Before the 20th century, pregnancy in the diabetic woman por- tended death of mother or child, or both. In the 21st century, centers providing meticulous metabolic and obstetric surveillance report peri- natal loss rates approaching but still higher than those seen in the nondiabetic population.7,8 Nevertheless, major problems with fetal and maternal management persist. Stillbirth rates have fallen dramatically but remain threefold or fourfold greater than rates for the normogly- cemic population. Congenital fetal anomalies, many of them life threatening and debilitating, remain three to four times more common in diabetic pregnancies than in nondiabetic pregnancies.9 Macrosomia and birth injury occur 10 times more frequently in diabetic fetuses. Studies indicate that the magnitude of such risks is proportional to the degree of maternal hyperglycemia.10,11 To a great extent, the excessive fetal and neonatal morbidity of diabetes in pregnancy is preventable or at least reducible by meticulous prenatal and intrapartum care. This chapter reviews the pathophysiology of this complex group of disorders and identifies the obstetric interventions that can improve outcome. Classification and Pathobiology of Diabetes Mellitus Diagnostic and classification criteria for diabetes were issued by the American Diabetes Association (ADA) in 1997.12 These criteria were further modified in 2003 regarding the diagnosis of impaired fasting glucose.13 This nomenclature is useful because it categorizes patients according to the underlying pathophysiology, although we recognize that the criteria are not as mutually exclusive as once thought. The classification includes four clinical types: 1. Type 1 diabetes, formerly referred to as insulin-dependent or juve- nile-onset diabetes. 2. Type 2 diabetes, formerly referred to as non–insulin-dependent or adult-onset diabetes 3. Other specific types of diabetes related to a variety of genetic-, drug-, or chemical-induced diabetes 4. Gestational diabetes mellitus An alternative classification that is commonly used in obstetrics was proposed by Priscilla White when she was at the Joslin Clinic in Boston Chapter 46 Diabetes in Pregnancy Thomas R. Moore, MD, and Patrick Catalano, MD
  • 2. 954 CHAPTER 46 Diabetes in Pregnancy in 1932.14 This classification (Table 46-1) was based on the duration of the disease and secondary vascular damage to retinal, renal, and car- diovascular structures. Because the White classification is primarily descriptive and because it does not reflect the increase in type 2 dia- betes in the population and the discovery of better-defined genetic causes, the ADA classification is preferred. The pathophysiology of the various types of diabetes is discussed subsequently. Type 1 Diabetes Type 1 diabetes accounts for approximately 5% to 10% of patients diagnosed with diabetes in the general population. However, type 1 diabetes may represent a slightly greater fraction of women in the reproductive age group because of the relatively earlier age of onset of type 1 diabetes compared with type 2 diabetes. Type 1 diabetes results from a cellular-mediated autoimmune destruction of the beta cells of the pancreas. Markers of the immune response include islet cell auto- antibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD2, formerly designated GAD65), and autoanti- bodies to the tyrosine phosphatase IA-2 and IA-2β. One and usually more of these autoantibodies are present in 85% to 90% of individuals with elevated fasting glucose and type 1 diabetes.15 Autoimmune destruction of beta cells has many genetic predisposi- tions and is related to environmental factors. Although viruses were initially implicated, the environmental conditions leading to auto destruction of the beta cells remain largely undefined. Most evidence indicates a genetic predisposition related to an individual’s human leukocyte antigen (HLA) associations with linkage to DQA and DQB genes. Type 1 diabetes is concordant in 33% to 50% of monozygotic twins, suggesting that environmental triggers are required to initiate the disease process in genetically predisposed individuals. Type 1 diabetes usually is characterized by an abrupt clinical onset after a period of immune destruction of the beta cells that might have been in progress for some time. The beta cell destruction continues after the clinical onset of diabetes, usually leading to an absolute insulinopenia with resultant life-long requirements for insulin replacement. Although type 1 diabetes was previously referred to as juvenile-onset diabetes, it can occur at virtually any age. The disease is particularly common in whites, especially those of Northern European ancestry, and Sardinians. Type 2 Diabetes Type 2 diabetes involves a loss of balance between insulin sensitivity and insulin (i.e., beta cell) response. The relationship between these two factors can be expressed as the disposition index (i.e., the normal inverse relationship between the two factors can be expressed as a constant).16 A decline in the disposition index is associated with the development of type 2 diabetes. Both insulin resistance and beta cell dysfunction exist in individuals who develop type 2 diabetes. There is little agreement about whether the beta cell function is an independent event or is coincident with decreased insulin sensitivity and whether the abnormalities are causally linked. The decreased insulin sensitivity and inadequate insulin response leads to an increase in circulating glucose concentrations, and the decreased insulin sensitivity in individuals with type 2 diabetes results in the inability of insulin to suppress lipolysis in adipose tissue. Many predisposing factors are related to decreased insulin sensitivity (i.e., increased insulin resistance). They include obesity, a sedentary lifestyle, family history and genetics, puberty, advancing age, and of particular concern to the obstetrician, the intrauterine environment. Although it Estimated Age-Adjusted Total Prevalence of Diabetes in People 20 Years or Older, by Race/Ethnicity—United States, 2005 Percent American Indians/ Alaska Natives Non-Hispanic blacks Hispanic/Latino Americans Non-Hispanic whites 0 2 4 6 8 10 12 14 16 18 20 FIGURE 46-1 Estimated prevalence of diabetes in the United States 2005. For American Indians/Alaska Natives, the estimate of total prevalence was calculated using the estimate of diagnosed diabetes from the 2003 outpatient database of the Indian Health Service and the estimate of undiagnosed diabetes from the 1999- 2002 National Health and Nutrition Examination Survey (NHANES). For the other groups, the 1999-2002 NHANES estimates of total prevalence (diagnosed and undiagnosed) were projected to the year 2005. (Printed with permission from pubs/statistics/index.htm#age.) TABLE 46-1 THE WHITE CLASSIFICATION OF DIABETES IN PREGNANCY White Class Age at Onset (Years) Duration (Years) Complications A Any Any Diagnosed before pregnancy; no vascular disease B у20 or <10 No vascular disease C 10-19 or 10-19 No vascular disease D <10 or у20 Background retinopathy only or hypertension E Calcification of pelvic arteries (no longer used) F Nephropathy (>500 mg of proteinuria per day) H Arteriosclerotic heart disease R Proliferative retinopathy or vitreous hemorrhage T After renal transplantation Adapted from Hare JW, White P: Gestational diabetes and the White classification. Diabetes Care 3:394, 1980. Copyright © 1980 by the American Diabetes Association.
  • 3. 955CHAPTER 46 Diabetes in Pregnancy was formerly believed that type 2 diabetes was primarily a disorder of older individuals (accounting for its being called adult-onset diabetes), there has been a significant increase in the prevalence of type 2 diabetes since 1990. At the turn of the 21st century, an estimated 13.8 million people had a diagnosis of diabetes, 5 million people had undiagnosed diabetes, and 41 million people had prediabetes.17 Although it is not in the scope of this chapter to review the spec- trum of possible causes of type 2 diabetes, the increase in obesity in the general population is a contributing factor; it is estimated that approximately two thirds of the population in the United States are overweight or obese.18 Obesity, particularly central obesity, which is estimated by waist circumference, is a well-described risk factor. This increase in visceral obesity affects hepatic metabolic function and is a rich source of cytokines and inflammatory factors, which are recog- nized as contributing to increasing insulin resistance. Criteria for the diagnosis of diabetes in nonpregnant adults are shown in Table 46-2. Although the 75-g, 2-hour oral glucose tolerance test (OGTT) is the most sensitive and specific diagnostic test for type 2 diabetes, because of the ease of administration and reproducibility, the fasting glucose test is often used as a first-line diagnostic test,19 particularly in the nongravid population. Because the onset of type 2 diabetes is usually insidious, hyperglycemia not sufficient to make the diagnostic criteria for type 2 diabetes is often categorized as impaired fasting glucose (IFG) (100 mg/dL to 125 mg/dL) or, if the 75-g OGTT is employed, as impaired glucose tolerance (IGT) (2-hour glucose level of 140 mg/dL to 199 mg/dL). The IFG and IGT have been officially designated prediabetes, and prediabetic individuals are at high risk for the development of type 2 diabetes.19 Gestational Diabetes Mellitus Gestational diabetes mellitus (GDM) as defined by the Fourth Inter- national Workshop-Conference on Gestational Diabetes as “carbohy- drate intolerance of various degrees of severity, with onset or first recognition during pregnancy.”20 This definition does not preclude the possibility that glucose intolerance might have predated the pregnancy or that medications might be needed for optimal glucose control. The underlying pathophysiology of GDM in most instances is similar to that observed for type 2 diabetes: an inability to maintain an adequate insulin response because of the significant decreases in insulin sensitiv- ity with advancing gestation. About 2% to 13% of women diagnosed as having GDM have detectable antibodies directed against specific beta cell antigens.21,22 Some of these deficiencies are population depen- dent. Other patients diagnosed with GDM have genetic variants that have been identified as causes of diabetes in the general population, including autosomal dominant (discussed later) and maternal or mito- chondrial inheritance patterns.23,24 It is estimated that as many as 3% to 9% of the population of pregnant women will be diagnosed with GDM.15 This translates into approximately 135,000 cases of GDM per year in the United States alone. This is not surprising, because in many respects, GDM is the harbinger of type 2 diabetes for many women, based on the underlying pathophysiology of GDM and the increase in obesity in women of reproductive age. Similarly, there is an increase in the incidence of GDM in women immigrating to the United States, presumably because of changes in diet and lifestyle. Clinical recognition of GDM is impor- tant because therapy can reduce pregnancy complications and poten- tially reduce long-term sequelae in the offspring. Genetic and Other Causes of Diabetes The ADA’s fourth classification of diabetes includes specific types of diabetes attributed to “other causes.” These causes include genetic defects in insulin action, diseases of the exocrine pancreas (e.g., cystic fibrosis), and drug- or chemical-induced diabetes, such as in the treat- ment of human immunodeficiency virus (HIV) infection or after organ transplantation.19 One of the well-characterized genetic defects is often included under the heading of maturity-onset diabetes of the young (MODY) (i.e., the glucokinase [GK] mutation). In 1998, Hattersley and colleagues25 described the various phenotypic per- mutations associated with the mutations of the glucokinase gene. Glucokinase phosphorylates glucose to glucose-6 phosphate in the pancreas and liver. A heterozygous glucokinase mutation results in hyperglycemia, usually with a mildly elevated fasting glucose and abnormal OGTT result. This occurs because of a defect in the sensing of glucose by the beta cell, resulting in decreased insulin release, and to a lesser degree because of reduced hepatic glycogen synthesis. In pregnancy, it is estimated that 3% of women with GDM and an ele- vated fasting glucose level greater than 110 mg/dL have this mutation. If the heterozygous mutation is present in the fetus, then the altered glucose sensing by the fetal pancreas will result in a decrease in insulin secretion. In the fetus, insulin is a primary stimulus for growth, and any defect in fetal insulin secretion results in decreased fetal growth and possible growth restriction. Depending on whether the mother or fetus, or both, have a defect in the glucokinase gene, the phenotype of the infant can vary from intrauterine growth restriction (IUGR) through normal fetal growth and to macrosomia. Maternal-Fetal Metabolism in Normal and Diabetic Pregnancy There are significant changes in maternal metabolism in normal preg- nancy. These include changes in maternal nutrient metabolism (i.e., carbohydrate, lipid, and protein metabolism) and changes in factors such as energy expenditure. The overall goal of these maternal meta- bolic adaptations is to prepare the pregnant woman to meet the increased energy needs of the mother and growth of the fetus in the TABLE 46-2 CRITERIA FOR THE DIAGNOSIS OF DIABETES Symptoms of diabetes and a casual plasma glucose level м200 mg/dL (11.1 mmol/L). Casual is defined as any time of day without regard to time since the last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. or Fasting plasma glucose level м126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours. or Two-hour plasma glucose м200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water. Adapted from American Diabetes Association: Clinical practice recommendations: Standards of medical care for diabetes—2007. Diabetes Care 30:S4-S41, 2007.
  • 4. 956 CHAPTER 46 Diabetes in Pregnancy latter third of pregnancy, when approximately 70% of fetal growth takes place.26 The alterations in maternal metabolism are relatively uniform during pregnancy unless there are major perturbations such as starvation conditions. The metabolic changes during pregnancy therefore take place on the background of a woman’s pregestational metabolic status. For example, if a woman is healthy and lean before conception, there is an increased need to store adipose tissue in early pregnancy to meet the increased energy demands of late gestation and to develop insulin resistance in late gestation to provide nutrients for the growing fetus. If a woman is obese before conception, there is little need to gain additional adipose tissue, but there is the requirement to provide nutrients for the fetus in late gestation. Normal Glucose-Tolerant Pregnancy Glucose homeostasis is primarily a balance between insulin resistance and insulin secretion. The alterations in insulin resistance affect endog- enous glucose production (primarily hepatic glucose metabolism) and peripheral glucose metabolism, which takes place in skeletal muscle. In the lean pregnant woman with normal glucose tolerance, there is a significant 30% increase in basal hepatic glucose production by the third trimester of pregnancy (Fig. 46-2). This is associated with a sig- nificant increase in basal or fasting insulin concentrations.27 The decrease in fasting glucose concentrations most likely is the result of increasing plasma volumes in early gestation and increased fetoplacen- tal use in late pregnancy. In the postprandial state, the increasing insulin concentrations enhance glucose uptake into skeletal muscle and adipose tissue, and they almost completely suppress hepatic glucose production. Although this is the case in lean women, obese women with normal glucose tolerance have a decreased ability for insulin to completely suppress hepatic glucose production in late preg- nancy.28 These data support the concept of decreased insulin sensitivity in late gestation that is more severe in obese women compared with non-obese counterparts. Peripheral insulin resistance is defined as the decreased ability of insulin to affect glucose uptake primarily in skeletal muscle and to a lesser degree in adipose tissue. Various methods are used to assess insulin sensitivity in vivo, including mathematical models of fasting glucose and insulin modeling (e.g., homeostasis model assessment [HOMA],29 OGTT30 ), the intravenous glucose tolerance test (i.e., Bergman minimal model),31 and what many consider to be the gold standard: the hyperinsulinemic-euglycemic clamp.32 Most of these measures have identified a significant 50% to 60% decrease in insulin sensitivity in late gestation.33 The changes in insulin sensitivity during gestation are a reflection of a woman’s pregravid insulin sensitivity status. Lean women usually have greater pregravid insulin sensitivity compared with overweight or obese women. These differences mani- fest before pregnancy, and when evaluated against the metabolic back- ground of pregnancy, the relationships are similar in late pregnancy, albeit reduced by approximately 50% to 60% (Fig. 46-3). The decreases in insulin sensitivity in late pregnancy are accompanied by an increase in insulin response. The increased insulin response to a glucose load increases approximately threefold compared with pregravid measures (Fig. 46-4). Diabetic Pregnancy Alterations in glucose metabolism in women with diabetes have been most extensively examined in women with GDM, although the altera- tions in glucose metabolism in women with type 2 diabetes are most likely very similar but with increased insulin resistance and further decompensation of beta cell function. In lean and obese women with GDM with mildly elevated fasting glucose levels, there is a similar increase in basal endogenous glucose production, as was observed in subjects with normal glucose tolerance, although fasting insulin con- centrations, particularly in late gestation, are greater than observed in normal glucose-tolerant women.28,34 However, during insulin infusion during euglycemic clamps, the ability of insulin to suppress endoge- nous glucose production is decreased (approximately 80% versus 95%) in GDM compared with a matched control group. There is also a sig- Pregravid 90 100 110 120 130 140 mg/min 150 160 170 180 190 Pϭ.0005 Early pregnancy Late pregnancy FIGURE 46-2 Alterations in glucose production. Longitudinal changes in total basal endogenous (primarily hepatic) glucose production (mean ± SD) from pregravid through early gestation (12 to 14 weeks) and late gestation (34 to 36 weeks). (Adapted from Catalano PM, Tyzbir ED, Wolfe RR, et al: Longitudinal changes in basal hepatic glucose production and suppression during insulin infusion in normal pregnant women. Am J Obstet Gynecol 167:913- 919, 1992.) Pregravid *Pϭ.0003 Pϭ.04 Pϭ.005 Glucoseinfusionrate(mg/kg.min) 2 4 6 8 10 12 14 Early pregnancy Late pregnancy FIGURE 46-3 Alterations in insulin resistance. Longitudinal changes in glucose infusion rate (i.e., insulin sensitivity) in lean women from pregravid through early (12 to 14 weeks) and late (34 to 36 weeks) pregnancy during hyperinsulinemic-euglycemic clamp (mean ± SD). The asterisk indicates change over time from pregravid status through late pregnancy (ANOVA). (Adapted from Catalano PM, Tyzbir ED, Roman NM, et al: Longitudinal changes in insulin release and insulin resistance in non-obese pregnant women. Am J Obstet Gynecol 165:1667-1672, 1991.)
  • 5. 957CHAPTER 46 Diabetes in Pregnancy nificant decrease in insulin sensitivity in women who go on to develop GDM, when estimated before conception or after delivery,35 compared with a matched control group. During pregnancy, the percent decrease in insulin sensitivity is approximately the same as the percent change in a matched control group (i.e., approximately 50% to 60%). The decreased insulin sensitivity observed during pregnancy in the woman who develops GDM is a function of her pregravid metabolic status, and clinically, the increased glucose concentrations represent the inability of pancreatic beta cells to normalize glucose levels (Fig. 46-5). The relationship between insulin sensitivity and insulin response has been characterized by Bergman and colleagues16 as a hyperbolic curve or, when multiplied, as the disposition index. A curve that is “shifted to the left” can be plotted for individuals who go on to develop GDM (Fig. 46-6). Whether the insulin resistance precedes the beta cell defect or they occur concomitantly is not known with certainty. However, Buchanan36 proposed that insulin resistance caused the beta cell dysfunction in susceptible individuals. The increased risk of type 2 diabetes in women who formerly had GDM may be a function of decreasing insulin sensitivity (i.e., worsening insulin resistance) exac- erbated by increasing age, adiposity, and the inability of the beta cells to fully compensate. The data on the changes on glucose metabolism in women with type 1 diabetes are not as well examined. Schmitz and coworkers37 evaluated the longitudinal changes in insulin sensitivity in women with type 1 diabetes in early and late pregnancy and after delivery. There was a 50% decrease in insulin sensitivity in late gestation. There was no significant difference in insulin sensitivity in these women in early pregnancy or within 1 week of delivery compared with nonpregnant women with type 1 diabetes. Based on the available data, women with Pregravid Pϭ.025 Pϭ.025 *Pϭ.0001 1stPhaseinsulinresponse(μU/mL)2ndPhaseinsulinresponse(μU/mL) 0 100 200 400 300 500 600 700 800 A B Early pregnancy Late pregnancy Pregravid Pϭ001 *Pϭ.0001 0 1000 2000 4000 3000 5000 Early pregnancy Late pregnancy FIGURE 46-4 Increased insulin response. Changes in first (A) and second (B) phase pregravid through early (12 to 14 weeks) and late (34 to 36 weeks) pregnancy insulin response during an intravenous glucose tolerance test (mean ± SD). The asterisk indicates change over time from pregravid status through late pregnancy (ANOVA). (Adapted from Catalano PM, Tyzbir ED, Roman NM, et al: Longitudinal changes in insulin release and insulin resistance in non- obese pregnant women. Am J Obstet Gynecol 165:1667-1672, 1991.) Control GDM Ptϭ0.0001 Pgϭ0.03 Pregravid 0 0.1 0.2 0.3 Early pregnancy Late pregnancy FIGURE 46-5 Alterations in insulin sensitivity. Longitudinal changes in insulin sensitivity during clamp 40 mU·m−2 ·min−1 insulin infusion in obese women (mean ± SD). GDM, gestational diabetes mellitus; Pg, difference between groups; Pt, individual longitudinal changes with time. (Adapted from Catalano PM, Huston L, Amini SB, Kalhan SC: Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes. Am J Obstet Gynecol 180:903-916, 1999.) 0.0 0 200 Insulin sensitivity index (ISI) GDM Normal 3rd Trimester Postpartum Insulinsecretionrate(ISR) 400 600 800 1000 0.1 0.2 0.3 0.4 FIGURE 46-6 Insulin sensitivity and secretion relationships in normal women and women with gestational diabetes mellitus. Prehepatic insulin secretion was assessed during steady-state hyperglycemia using plasma insulin and C-peptide concentrations and C-peptide kinetics in individual patients. (Printed with permission from Buchanan TA: Pancreatic β-cell defects in gestational diabetes: Implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab 86:989-993, 2001.)
  • 6. 958 CHAPTER 46 Diabetes in Pregnancy type 1 diabetes have similar alterations in insulin sensitivity compared with women with normal glucose tolerance. Mechanism of Insulin Resistance The mechanisms related to the changes in insulin resistance during pregnancy are better characterized because of research in the past decade. The insulin resistance of pregnancy is almost completely reversed shortly after delivery,38 consistent with the clinically marked decrease in insulin requirements. The placenta has long been suspected of producing hormonal factors related to these alterations in metabo- lism. The placental mediators of insulin resistance in late pregnancy have been ascribed to alterations in maternal cortisol concentrations and placenta-derived hormones such as human placental lactogen (HPL), progesterone, and estrogen.39-41 Kirwan and associates42 re- ported that circulating tumor necrosis factor-α (TNF-α) concentra- tions had an inverse correlation with insulin sensitivity as estimated from clamp studies. Among leptin, HPL, cortisol, human chorionic gonadotropin, estradiol, progesterone, and prolactin, TNF-α was the only significant predictor of the changes in insulin sensitivity from the pregravid period through late gestation. TNF-α and other cytokines are produced by the placenta, and 95% of these molecules are trans- ported to maternal rather than fetal circulations.42 Other factors, such as circulating free fatty acids, may contribute to the insulin resistance of pregnancy.43 Studies in human skeletal muscle and adipose tissue have demon- strated defects in the post-receptor insulin-signaling cascade during pregnancy. Friedman and colleagues showed that women in late pregnancy have reduced insulin receptor substrate-1 (IRS-1) concen- trations compared with those of matched nonpregnant women.44 Downregulation of the IRS-1 protein closely parallels insulin’s decreased ability to induce additional steps in the insulin signaling cascade that result in the transporter (GLUT-4) arriving at the cell surface to allow glucose to enter the cell. Downregulation of IRS-1 closely parallels the decreased ability of insulin to stimulate 2- deoxyglucose uptake in vitro in pregnant skeletal muscle. During late pregnancy in women with GDM, in addition to decreased IRS-1 con- centrations, the insulin receptor-β (i.e., component of the insulin receptor within the cell rather than on the cell surface) has a decreased ability to undergo tyrosine phosphorylation.44 This is an important step in the action of insulin after it has bound to the insulin receptor on the cell surface. This additional defect in the insulin-signaling cascade is not found in pregnant or nonpregnant women with normal glucose tolerance and results in a 25% lower glucose transport activity. TNF-α also acts by means of a serine/threonine kinase, thereby inhibiting IRS-1 and tyrosine phosphorylation of the insulin receptor.45 These post-receptor defects may contribute in part to the pathogenesis of GDM and an increased risk for type 2 diabetes in later life. Complications of Diabetes during Pregnancy Maternal Morbidity Women with pregestational diabetes are at risk for a number of obstet- ric and medical complications. The relative risk of these problems is proportional to the duration and severity of disease. Evers and cowork- ers reported the maternal morbidity of a cohort of 323 type 1 diabetic pregnancies followed prospectively in the Netherlands.46 Glycemic control was excellent (Hb A1c ≤7.0% in 75%), but the rates of pre- eclampsia (12.7%), preterm delivery (32%), cesarean section (44%), and maternal mortality (60 deaths per 100,000 pregnancies) were con- siderably higher than in the nondiabetic population. Retinopathy Diabetic retinopathy is the leading cause of blindness between the ages of 24 and 64 years.47 Some form of retinopathy is present in virtually 100% of women who have had type 1 diabetes for 25 years or more; approximately 20% of these women are legally blind. The topic of diabetic retinopathy has been reviewed elsewhere.48 The pattern of progression of diabetic retinopathy is predictable, proceeding from mild nonproliferative abnormalities, which are asso- ciated with increased vascular permeability, to moderate and severe nonproliferative diabetic retinopathy, which is characterized by vascu- lar closure, to proliferative diabetic retinopathy, which is characterized by the growth of new blood vessels on the retina and posterior surface of the vitreous. It has been proposed that pregnancy accelerates these changes, although the mechanism is controversial.49 Trials have not shown any acceleration in microvascular complications when pregnant and nonpregnant diabetic subjects were closely followed and compared.50 Vision loss resulting from diabetic retinopathy results from several mechanisms. First, central vision may be impaired by macular edema or capillary nonperfusion. Second, the new blood vessels of prolifera- tive diabetic retinopathy and contraction of the accompanying fibrous tissue can distort the retina and lead to tractional retinal detachment, producing severe and often irreversible vision loss. Third, the new blood vessels may bleed, adding the further complication of preretinal or vitreous hemorrhage. FACTORS AFFECTING PROGRESSION OF RETINOPATHY DURING PREGNANCY Although past studies suggested that rapid induction of glycemic control in early pregnancy stimulated retinal vascular proliferation,51 later investigations indicate that the severity and duration of diabetes before pregnancy have a greater effect. Temple and colleagues52 studied 179 women with pregestational type 1 diabetes, performing dilated fundal examination at the first prenatal visit, 24 weeks, and 34 weeks. Progression to proliferative diabetic retinopathy occurred in only 2.2%, and moderate progression occurred in 2.8%. However, progres- sion was significantly greater in women who had had diabetes for more than 10 years (10% versus 0%; P = .007) and in women with moderate to severe background retinopathy before pregnancy (30% versus 3.7%; P = .01). In the European Diabetes (EURODIAB) Prospective Compli- cations Study, 793 potentially childbearing women at baseline com- pleted the follow-up, and 21% gave birth. Duration of diabetes and high HbA1c levels at recruitment were significant risk factors for reti- nopathy progression, whereas giving birth was not.50 OPHTHALMOLOGIC MANAGEMENT DURING PREGNANCY Screening for retinopathy by a qualified ophthalmologist is recom- mended before pregnancy and again during the first trimester for patients with pregestational diabetes because of the demonstrated effectiveness of laser photocoagulation therapy in arresting progres- sion. Patients with minimal disease should be re-examined once or twice during the pregnancy and at 3 and 6 months after delivery. Those with significant retinal pathology may require monthly follow-up.53
  • 7. 959CHAPTER 46 Diabetes in Pregnancy Nephropathy Diabetes is the most common cause of end-stage renal disease in the United States and Europe. In the United States, diabetic nephropathy accounts for about 45% of new cases of this condition. In 2003, the cost for treatment of diabetic patients with end-stage renal disease was in excess of $55,000 annually per person and more than $5 billion in aggregate.54 About 20% to 40% of patients with type 1 or type 2 dia- betes develop evidence of nephropathy over time, but the rate and extent of progression are highly individual.53 The pathophysiology of diabetic renal disease is incompletely understood, but several factors play a role, including genetic suscepti- bility, control of hyperglycemia, and the duration and severity of coex- isting hypertension. Additional insults, such as repeated urinary tract infections, excessive glycogen deposition, and papillary necrosis, all hasten deterioration of renal function. The kidney is normal at the onset of diabetes, but within a few years, glomerular basement mem- brane thickening can be identified. By 5 years, there is expansion of the glomerular mesangium, resulting in diffuse diabetic glomerulosclero- sis. All patients with marked mesangial expansion exhibit proteinuria exceeding 400 mg in 24 hours. The peak incidence of nephropathy occurs after about 16 years of diabetes. CATEGORIES OF DIABETIC NEPHROPATHY Categories of diabetic nephropathy are distinguished by the level of urinary protein excretion. Table 46-3 shows normal values and the current clinical criteria for microalbuminuria and nephropathy. Screening for microalbuminuria can be performed by three methods: measurement of the albumin-to-creatinine ratio in a random spot collection; 24-hour collection with creatinine, allowing the simultane- ous measurement of creatinine clearance; and timed (e.g., 4-hour or overnight) collection. The first method is preferred because it is the easiest to carry out in an ambulatory setting, and it provides adequately accurate information. The other methods are rarely used.55 EFFECT OF PREGNANCY ON PROGRESSION OF NEPHROPATHY Although some clinicians discourage pregnancy in women with diabetic renal disease because of concerns of permanent renal deterio- ration as a result of the pregnancy, recent data consistently indicate that pregnancy does not measurably alter the time course of diabetic renal disease. Progression of diabetic nephropathy is closely related to the degree of glycemic control. To the extent that most women have better glyce- mic control during pregnancy, delay or slowing of renal function dete- rioration can be expected. A study of renal function for 4 years before and 4 years after pregnancy in 11 patients with diabetic nephropathy56 showed that the gradual rise in serum creatinine over that period was unaffected by the intervening pregnancy. Imbasciati and co- workers57 performed a longitudinal study of 58 women with chronic renal disease, following each through pregnancy. The mean serum creatinine level was 6 mg/dL at the start of the study and 6 mg/dL after delivery. Although they found that women with glomerular filtration rates less than 40 mL/min and with proteinuria greater than 1 g/day had increased risk of delivering a child with a birth weight less than 2500 g (odds ratio [OR] = 5.1; 95% confidence interval [CI], 1.03 to 25.6), the association was not related to renal disease, hypertension, and maternal age. When the cohort was taken as a whole, even those with lower glomerular filtration rates and higher levels of proteinuria had similarly modest changes in renal function when after- and before- pregnancy indices were compared.57 Rossing and colleagues58 evaluated the effect of pregnancy on dete- rioration of renal function in 93 women older than 20 years. They compared groups of never-pregnant and ever-pregnant women who received similar medical therapy and who had similar degrees of renal function at the start of the study. The results are shown in Figure 46-7. Based on this excellent prospective study, it is evident that pregnancy neither alters the time course of renal disease nor increases the likeli- hood of transition to end-stage renal disease. COURSE OF DIABETIC NEPHROPATHY DURING PREGNANCY In general, patients with underlying renal disease before pregnancy can be expected to experience various degrees of deterioration during pregnancy. The physiologic changes associated with normal pregnancy increase renal blood flow and glomerular filtration by 30% to 50%. Most women with preexisting diabetic nephropathy experience this improvement in renal function, especially during the second trimes- ter.59 During the third trimester, however, when mean arterial pressure and peripheral vascular resistance typically increase, women with diabetic microvascular disease may experience marked diminution of renal function, an exacerbation in hypertension, and in many cases, preeclampsia. The third-trimester increase in maternal blood pressure and serum creatinine concentration are among the most common FIGURE 46-7 End-stage renal disease. Cumulative incidence of end-stage renal disease (ESRD) in ever-pregnant (triangles) and never- pregnant (circles) groups. (From Rossing K, Jacobsen P, Hommel E, et al: Pregnancy and progression of diabetic nephropathy. Diabetologia 45:36, 2002.) TABLE 46-3 CATEGORIES OF DIABETIC RENAL DISEASE Category* Albumin-to-Creatinine Ratio (mg/mg)† Normal <30 Microalbuminuria 30-299 Nephropathy ≥300 *Categories of diabetic nephropathy are distinguished by the level of urinary protein excretion. Two of three collections in a 3- to 6-month period should be abnormal for a diagnosis of microalbuminuria or nephropathy. † The ratio of albumin to creatinine was determined by random spot collection. Adapted from American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 28(Suppl 1):S4-S36, 2005.
  • 8. 960 CHAPTER 46 Diabetes in Pregnancy precipitating events leading to indicated preterm delivery in diabetic women. Although delivering the fetus to interrupt the precipitous rise in blood pressure may result in premature birth, this is usually preferable to the risk of maternal renal failure or stroke (discussed later). Reece and colleagues60 reviewed the outcomes of 315 pregnant women with preexisting diabetic nephropathy. Of these, 17% ulti- mately developed end-stage renal disease, and 5% died as a result of renal insufficiency. During pregnancy, proteinuria and mean arterial pressure significantly increased from the first to the third trimester (P < .05). Another study by Purdy and coworkers61 demonstrated a rise in the mean serum creatinine level from 1.8 mg/dL before pregnancy to 2.5 mg/dL in the third trimester. Renal function was stable in 27%, transiently worsened during pregnancy in 27%, and demonstrated a permanent decline in 45%. Proteinuria increased during pregnancy in 79%, and exacerbation of hypertension or preeclampsia occurred in 73%. Ekbom and colleagues62 compared the outcomes of pregnancies in women with microalbuminuria or overt nephropathy and those without. Their results (Fig. 46-8) indicate that the likelihood of preterm delivery is considerably increased for women with microalbuminuria, mainly because of preeclampsia. RENAL DIALYSIS IN DIABETIC PREGNANT WOMEN Although women receiving dialysis for end-stage renal disease are often amenorrheic or at least anovulatory, pregnancies have become increasingly common63 during therapy (3% to 7%).64 Unfortunately, the prognosis for pregnancy in diabetic women with end-stage renal disease continues to be exceedingly poor, with fetal loss rates remaining in the range of 30% to 50% over the past decade. Neonatal death rates are between 5% and 15%, and less than one half of pregnancies among women with end-stage renal disease result in viable children. About 60% of births are premature, often because of uncontrollable hyper- tension, renal failure, or fetal growth failure.65 Of the 20% to 25% of pregnancies ending in live births, 40% of babies are severely growth restricted. A major practical problem with achieving a successful pregnancy outcome while on hemodialysis is proper maintenance of maternal vascular volume. Dialysis teams are accustomed to removing signifi- cant vascular volume at each session. However, during a normal preg- nancy, there is a progressive expansion in vascular volume of at least 20% to 30% above nonpregnant values from 8 to 30 weeks’ gestation. This volume augmentation is required to maintain uteroplacental per- fusion and fetal growth. Pregnancies in which vascular volume does not increase appropriately have a high incidence of fetal growth restric- tion and stillbirths. Difficulties with vascular underfill (e.g., hyperten- sion, poor fetal growth, asphyxia) and overfill (e.g., hypertension) are common in pregnant patients on hemodialysis and often are difficult to rectify. The poor prognosis associated with hemodialysis combined with other considerations has prompted increased interest in continuous ambulatory peritoneal dialysis. Several successful pregnancy series have been reported.65-67 Although fluid and chemical balance is con- stant and heparinization is not necessary, intrauterine deaths, abrup- tion, prematurity, hypertension, and fetal distress still occur. The best strategy for most diabetic women on dialysis desiring pregnancy is to undergo kidney transplantation. RENAL TRANSPLANTATION Successful pregnancy after renal transplantation is now a reality. Davison’s67 review of 1569 pregnancies in women with renal allografts found that of the 60% of pregnancies that continued beyond the first trimester, 92% resulted in a viable infant. Preeclampsia occurred in 30%, preterm delivery in about 50%, and IUGR in 20%. Patients with the worst renal function had the poorest pregnancy outcomes. Similar results were reported by Yassaee and Moshiri.68 The most common maternal complications in 95 pregnancies were anemia in 65%, and preeclampsia in 47%. Three patients lost their graft, and six had impaired kidney allograft function 2 years after pregnancy.68 In a historical cohort study, 86 women who had at least one post- transplantation pregnancy were compared with 125 who had no preg- nancy after renal transplantation. Patients were matched for age, cause of end-stage renal disease, treatment protocol, and first serum creati- nine level. The 5-year patient and graft survival rates were not signifi- cantly different between the study groups. Among the women with at least one pregnancy, only 10% had serum creatinine levels above 1.5 mg/dL at the end of 46 months of follow-up, compared with 28% of the never-pregnant group.69 Based on these findings, it appears that perinatal outcomes are better in patients who have undergone renal 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Preterm birth IUGR Preeclampsia Normal Microalbuminuria Nephropathy FIGURE 46-8 Outcomes of pregnancies in women with microalbuminuria or overt nephropathy. Pregnancy outcomes are compared for diabetic women with underlying renal disease. IUGR, intrauterine growth restriction. (Adapted from Ekbom P, Damm P, Feldt-Rasmussen U, et al: Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 24:1739, 2001. Copyright © American Diabetes Association. Reprinted with permission from the American Diabetes Association.)
  • 9. 961CHAPTER 46 Diabetes in Pregnancy transplantation than in those with end-stage renal disease who are on dialysis. Cardiovascular Complications Cardiovascular complications experienced by pregnant women with diabetes include chronic hypertension, pregnancy-induced hyperten- sion, and rarely, atherosclerotic heart disease. In composite studies of all types of diabetic pregnancies, the incidence of hypertensive disorders during pregnancy varies from 15% to 30%,70,71 with the rate of hypertension increased fourfold over that for the nondiabetic population.72 CHRONIC HYPERTENSION Chronic hypertension (i.e., blood pressure at or above 140/90 mm Hg before 20 weeks’ gestation)73 complicates 10% to 20% of preg- nancies in diabetic women and up to 40% of those in diabetic women with preexisting renal or retinal vascular disease.74 The perinatal prob- lems encountered with chronic hypertension include IUGR, maternal stroke, preeclampsia, and abruptio placentae. In pregestational diabe- tes, the prevalence of chronic hypertension increases with duration of diabetes and is closely associated with nephropathy.72,75 The Diabetes in Early Pregnancy (DIEP) study reported that women with type 1 diabetes have higher mean blood pressures throughout pregnancy than do normal controls.76 In a significant proportion of patients, this difference is probably evidence of underlying renal compromise. Preexisting chronic hypertension should be suspected when the diabetic patient’s systolic blood pressure exceeds 130/80 mm Hg before the third trimester. The diagnosis is strength- ened by finding a failure of mean blood pressure to decline normally in the late second trimester, elevation in the blood urea nitrogen level above 10 mg/dL, serum creatinine concentration above 1 mg/dL, cre- atinine clearance less than 100 mL/min, or a combination of these factors. PREECLAMPSIA Preeclampsia is more common among women with diabetes, occur- ring four times as frequently in women with pregestational diabetes as in those without diabetes.72 The risk of developing preeclampsia is proportional to the duration of diabetes before pregnancy and the existence of nephropathy and hypertension; more than one third of pregnant women who have had diabetes for more than 20 years develop this condition. As is shown in Figure 46-9, patients with White class B diabetes have a risk profile similar to that of nondiabetic patients, but women with evidence of renal or retinal vasculopathy (classes D, F, or R) have a 50% excess risk of hypertensive complications over the rate observed for those with no hypertension. Women with diabetic nephropathy have similar rates of preeclampsia. Renal function assessments should be performed in each trimester in women with overt diabetic vascular disease and in those who have had diabetes for more than 10 years. Significant proteinuria, plasma uric acid levels above 6 mg/dL, or evidence of HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) should prompt a workup for preeclampsia. HEART DISEASE Although coronary heart disease is rarely encountered in preg- nant women with diabetes, a study by Airaksinen and colleagues77 suggests that such women may have preclinical cardiomyopathy and autonomic neuropathy. The diabetic women studied had less than the expected increase in left ventricular size and stroke volume in preg- nancy, lower heart rate increases, and smaller increments in cardiac output. Although uncommon, atherosclerotic heart disease (White class H) may afflict diabetic patients in the later reproductive years. Patients with this complication have a mean age of 34 years and exhibit other evidence of diabetic vascular involvement (White class D or R).78 For diabetic women with cardiac involvement, pregnancy outcome is 0% Percentpreeclampsia No hypertension HypertensionHypertension and proteinuria Class B Class C Class D Class F/R 5% 10% 15% 20% 25% 30% 35% 40% FIGURE 46-9 Likelihood of preeclampsia in diabetic pregnancy by White’s class and preexisting hypertension. The risk of developing preeclampsia is proportional to the duration of diabetes before pregnancy and the existence of nephropathy and hypertension. (From Sibai BM, Caritis S, Hauth J, et al: Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 182:364, 2000.)
  • 10. 962 CHAPTER 46 Diabetes in Pregnancy dismal, with a maternal mortality rate of 50% or higher and perinatal loss rates approaching 30%.79 Recognition of cardiac compromise in pregnant women with diabetes may be difficult because of the decrease in exercise tolerance that occurs during normal pregnancy. Compro- mised cardiac function may also be difficult to detect in patients restricted to bed rest for hypertension or poor fetal growth. It is prudent to obtain a detailed cardiovascular history in all diabetic patients and to consider electrocardiography and maternal echocar- diography in patients who have type 1 diabetes and are older than 30 years or in patients who have had diabetes for 10 years or more. With intensive monitoring, successful pregnancy is possible, albeit hazard- ous for women with significant cardiac disease.80 Diabetic Ketoacidosis Diabetic ketoacidosis (DKA) during pregnancy is a medical emergency for the mother and fetus. Pregnant women with type 1 diabetes are at increased risk for DKA, although the incidence and morbidity of this complication have decreased from 20% or more in the older literature to approximately 2% in later reports.81 The rate of intrauterine fetal death, formerly as high as 35% with DKA during pregnancy, has dropped to 10% or less. Precipitating factors for ketoacidosis include pulmonary, urinary, or soft tissue infections; poor compliance; and unrecognized new onset of diabetes. Because severe DKA threatens the life of the mother and fetus, prompt treatment is essential. Fetal well-being in particular is in jeopardy until maternal metabolic homeostasis is reestablished. High levels of plasma glucose and ketones are readily transported to the fetus, which may be unable to secrete sufficient quantities of insulin to prevent DKA in utero. DKA evolves from inadequate insulin action and functional hypo- glycemia at the target tissue level. This leads to increased hepatic glucose release but decreased or absent tissue disposal of glucose. Glucose-lacking tissues release ketone bodies, and vascular hypergly- cemia promotes osmotic diuresis. Over time, the diuresis causes pro- found vascular volume depletion and loss of electrolytes. The release of stress hormones (i.e., catecholamines, glucagon, growth hormone, and cortisol) further impairs insulin action and contributes to insulin resistance. Left unchecked, this cycle of dehydration, tissue hypoglyce- mia, and electrolyte depletion can lead to multisystem collapse, coma, and death. Early in the illness, hyperglycemia and ketosis are moderate. If hyperglycemia is not corrected, diuresis, dehydration, and hyperosmo- lality follow. Pregnant women in the early stages of ketoacidosis respond quickly to appropriate treatment of the initiating cause (e.g., broad-spectrum antibiotics), additional doses of regular insulin, and volume replacement. Patients with advanced DKA usually present with typical findings, including hyperventilation, normal or obtunded mental state (depend- ing on severity of the acidosis), dehydration, hypotension, and a fruity odor to the breath. Abdominal pain and vomiting may be prominent symptoms. The diagnosis of DKA is confirmed by the presence of hyperglycemia (glucose >200 mg/100 mL) with positive test results for serum ketones at a level of 1:4 or greater. As many as one third of patients in the early or very late stages of DKA may have initial blood glucose levels less than 200 mg/dL.82 A pregnant diabetic patient with a history of poor food intake or vomit- ing for more than 12 to 16 hours should have a thorough workup for DKA, including a complete blood cell count and electrolyte determina- tions. A serum bicarbonate level below 18 mg/dL should prompt per- formance of an arterial blood gas analysis. In all cases of DKA, the diagnosis is confirmed by arterial blood gases demonstrating a meta- bolic acidemia (i.e., base excess of −4 or lower).83 Table 46-4 contains a protocol for treatment of DKA. The impor- tant steps in management should include the following: ᭿ Search for and treat the precipitating cause. Typical initiators include pyelonephritis and pulmonary or gastrointestinal viral infections. ᭿ Perform vigorous and sustained volume resuscitation. The patient will continue to generate vascular volume deficits TABLE 46-4 TREATMENT PROTOCOL FOR DIABETIC KETOACIDOSIS* Measures Initial Phase (6-24 hr) Recovery Phase General Search for initiating cause of ketoacidosis. Insert bladder catheter. If patient is unconscious, establish nasogastric tube. Continue treatment of initiating cause. Remove bladder catheter when vascular volume is replaced. Fluids Administer 0.9% NaCl at 1000 mL/hr × 2 hr and then 500 mL/hr until 5-8 L infused. Continue 0.9% NaCl at 100 mL/hr for at least 48 hours to avoid return of ketoacidosis. Insulin Administer 20 U of insulin by IV bolus and then 5-10 U/hr by IV infusion. When acidosis is resolved and plasma glucose <160 mg/dL, reduce insulin infusion to 0.7-2.0 U/hr. Return to patient’s prior SC insulin dosing after plasma glucose is stable for at least 12 hr. Glucose When plasma glucose is <250 mg/dL, add 5% dextrose to 0.9% NaCl. Potassium If serum K+ level is normal or low, infuse KCl at 20 mEq/hr. If serum K+ level is high, wait until K+ is normal, then KCl at 20 mEq/hr. Measure serum K+ level every 2-4 hr. Use oral potassium supplementation for 1 week. Bicarbonate If pH is <7.1, add one ampule of bicarbonate (50 mEq) to IV; repeat until pH >7.1. *These are general guidelines. Because there may be wide variation in individual patient needs, there is no substitute for careful monitoring of each patient, particularly in the initial phase of therapy. IM, intramuscular; IV, intravenous; KCl, potassium chloride; NaCl, sodium chloride; SC, subcutaneous. Adapted from American College of Obstetricians and Gynecologists (ACOG): Clinical management guidelines for obstetrician-gynecologists. ACOG practice bulletin no. 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol 105:675-685, 2005.
  • 11. 963CHAPTER 46 Diabetes in Pregnancy until her glucose levels and acidosis are largely resolved. A physiologic fluid such as 0.9% NaCl with 20 mEq/L of potassium should be used and continued until the acidosis is substantially corrected (base excess of −2 or less). This usually requires an infusion at 1 to 2 L/hr for the first 1 to 2 hours, followed by reduced rates (150 to 200 mL/hr) until the base deficit approaches a normal level. ᭿ Place a bladder catheter to monitor urine output. ᭿ Use insulin to correct hyperglycemia. Although intermittent injections can be used, a continuous infusion of regular or short-acting insulin (i.e., lispro or aspart) allows frequent adjustments. When giving insulin as a continuous infusion, 1 to 2 units/hr gradually corrects the patient’s glucose abnormality over 4 to 8 hours. Attempts to normalize plasma glucose levels rapidly (i.e., in less than 2 to 3 hours) may result in hypoglycemia and further physiologic counterregulatory responses. ᭿ Monitor serum bicarbonate levels and arterial blood gas base deficits every 1 to 3 hours to guide management. Even when the plasma glucose level is normalized, acidemia may persist, as evidenced by continuing abnormalities in the patient’s electrolyte concentrations. Unless volume therapy is continued until the patient’s electrolyte stores and plasma concentrations have substantially returned to normal, DKA may reappear, and the cycle of metabolic derangement will be renewed. When DKA occurs after 24 weeks’ gestation, fetal status should be continuously monitored by fetal heart rate monitoring or a biophysical profile, or both. However, even when fetal status is questionable during the phase of therapeutic volume and plasma glucose correction, emer- gency cesarean section should be avoided. Usually, correction of the maternal metabolic disorder is effective in normalizing fetal status. Nevertheless, if a reasonable effort has been expended in correcting the maternal metabolic disorder and the fetal status remains a concern, delivery should not be delayed. Fetal Morbidity and Mortality Perinatal mortality in diabetic pregnancy has decreased 30-fold since the discovery of insulin in 1922 and the institution of intensive obstetric and infant care in the 1970s. Improved techniques of main- taining maternal euglycemia have led to later timing of delivery and reduced iatrogenic respiratory distress syndrome. Nevertheless, the perinatal mortality rates reported for diabetic women remain appro- ximately twice those observed in the nondiabetic population (Table 46-5). Congenital malformations, respiratory distress syndrome, and extreme prematurity account for most perinatal deaths in diabetic pregnancies. Miscarriage Studies of miscarriage rates from a decade ago indicated an increased incidence of spontaneous abortion among women with pregestational diabetes, especially those with poor glucose control during the peri- conceptional period. Given the well-documented association between congenital anomalies and hyperglycemia, such a finding is not surpris- ing. Sutherland and Pritchard84 reported the outcomes of 164 diabetic pregnancies managed with relaxed glycemic control and found a spon- taneous abortion rate of almost double the expected rate. Miodovnik and coworkers85 studied spontaneous abortion in diabetic pregnancy prospectively and found an increasing rate among patients with more advanced classes of diabetes (rates for classes C, D, and F were 25%, 44%, and 22%, respectively). Later studies of populations with better glycemic control report miscarriage rates similar to those in the non- diabetic population,86,87 indicating that diabetic women with excellent glycemic control have a risk of miscarriage equivalent to those without diabetes. These studies can be used to encourage patients who have not yet conceived to achieve excellent glycemic control. Patients presenting in early pregnancy with normal glycohemoglobin values can be reassured that the overall elevation in risk of miscarriage is modest. However, for patients with glycohemoglobin values 2 to 3 standard deviations above the norm, intense early pregnancy surveillance is indicated. Congenital Anomalies Among women with overt diabetes before conception, the risk of a structural anomaly in the fetus is increased fourfold to eightfold,88 compared with the 1% to 2% risk for the general population. In a cohort study of 2359 pregnancies in women with pregestational dia- betes, the major congenital anomaly rate was 4.6% overall, with 4.8% for type 1 diabetes and 4.3% for type 2 diabetes, more than double the expected rate. Neural tube defects were increased 4.2-fold and congeni- tal heart disease by 3.4-fold. Of all anomalies confirmed in the neonate, only 65% were diagnosed antenatally.9 The typical congenital anoma- lies observed in diabetic pregnancies and their frequency of occurrence are listed in Table 46-6. There is no increase in birth defects among offspring of diabetic fathers and nondiabetic women and women who develop gestational diabetes after the first trimester, indicating that glycemic control during embryogenesis is the main factor in the genesis of diabetes-associated birth defects. A classic report by Miller and coauthors89 compared the frequency of congenital anomalies in patients with normal or high first-trimester maternal glycohemoglobin levels and found only a 3.4% rate of anomalies with an Hb A1c value less than 8.5%, whereas the rate TABLE 46-5 PERINATAL MORTALITY RATES IN DIABETIC PREGNANCY* Group Gestational Overt Normal† Fetal mortality rate (%)* 4.7 10.4 5.7 Neonatal mortality rate (%)* 3.3 12.2 4.7 Perinatal mortality rate (%)* 8.0 22.6 10.4 *Mortality rates = deaths per 1000 live births. † Normal was determined from California data from 1986; figures were corrected for birth weight, sex, and race. TABLE 46-6 CONGENITAL MALFORMATIONS IN INFANTS OF INSULIN- DEPENDENT DIABETIC MOTHERS Anomaly Approximate Relative Risk Percent Risk (%) All cardiac defects 18 8.5 All central nervous system anomalies 16 5.3 Anencephaly 13 Spina bifida 20 All congenital anomalies 8 18.4 Adapted from Becerra JE, Khoury MJ, Cordero JF, et al: Diabetes mellitus during pregnancy and the risks for specific birth defects: A population based case-control study. Pediatrics 85:1, 1990.
  • 12. 964 CHAPTER 46 Diabetes in Pregnancy of malformations in patients with poorer glycemic control in the peri- conceptional period (Hb A1c above 8.5) was 22.4%. Lucas and cowork- ers90 reported an overall malformation rate of 13.3% in 105 diabetic patients. However, the risk of delivering a malformed infant was zero with an Hb A1 value less than 7%, 14% with Hb A1 between 7.2% and 9.1%, 23% with Hb A1 between 9.2% and 11.1%, and 25% with Hb A1 greater than 11.2%. PATHOGENESIS The mechanism by which hyperglycemia disturbs embryonic devel- opment is multifactorial. The potential teratologic role of disturbances in the metabolism of inositol, prostaglandins, and reactive oxygen species has been established.91 Embryonic hyperglycemia may promote excessive formation of oxygen radicals in susceptible fetal tissues, which are inhibitors of prostacyclin.92 The resulting overabundance of thromboxanes and other prostaglandins may then disrupt the vascu- larization of developing tissues. In support of this theory, addition of prostaglandin inhibitors to mouse embryos in culture medium pre- vented glucose-induced embryopathy.93 The pathogenic role of free radical species in teratogenesis with diabetes has been underscored by demonstrating the effect of dietary antioxidants experimentally. High doses of vitamins C and E decreased fetal dysmorphogenesis to non- diabetic levels in rat pregnancy and rat embryo culture.94,95 PREVENTION Because the critical time for teratogenesis is during the period 3 to 6 weeks after conception, nutritional and metabolic intervention must be instituted preconceptionally to be effective. Several clinical trials of preconceptional metabolic care have demonstrated that malformation rates equivalent to those in the general population can be achieved with meticulous glycemic control.96 Although studies of dietary folate and vitamin C supplementation have demonstrated success in reduc- ing the incidence of congenital anomalies in experimental diabetes in rats,97 the efficacy of a high-antioxidant diet in preventing diabetes- induced structural anomalies in humans has not been adequately explored. Preconceptional management of pregestational diabetics is discussed in the following sections. Intrauterine Growth Restriction Although the weights of infants of diabetic mothers (IDMs) usually are skewed into the upper range, IUGR occurs with significant fre- quency in diabetic pregnancies, especially in women with underlying vascular disease. Additional factors that increase the risk for IUGR in a diabetic pregnancy include the higher incidence of structural anoma- lies and maternal hypertension. Asymmetrical IUGR is encountered most frequently in diabetic patients with vasculopathy (i.e., retinal, renal, or chronic hyperten- sion).88 This association suggests that uteroplacental vasculopathy may promote restricted fetal growth in these patients.98 Patients with poor glycemic control and frequent episodes of ketosis and hypoglycemia are also prone to preeclampsia and poor fetal growth. Whether fetal growth restriction results from poor maternal-placental blood flow or intrinsically poor placental function is unresolved.99 Fetal Obesity Macrosomia has been defined using various criteria, which include birth weight greater than the 90th percentile, birth weight greater than 4000 g, and estimates of neonatal adiposity based on body composi- tion measures. As early as 1923, research by Moulton100 described vari- ability in weight among various mammalian species that was attributed to the amount of adipose tissue or fat mass rather than lean body mass. Using autopsy data and chemical analysis of 169 stillbirths, Sparks101 described a relatively comparable rate of accretion of lean body mass in fetuses that were small for gestational age (SGA), average for gesta- tional age (AGA), and large for gestational age (LGA), but he found considerable variation in the accretion of fetal fat in utero. The human fetus at term has the greatest percent of body fat (approximately 10% to 12%) compared with other mammals.102 GROWTH DYNAMICS The increased growth of the mother is composed primarily of total body water and adipose tissue in early gestation.26 Relative to the feto- placental unit, the human placenta attains most of its growth by the middle of the second trimester. In contrast, approximately 70% of fetal growth occurs over the last third of gestation (1000 g at 28 weeks to 3500 g at term). Yang and associates6 reported that IDMs with diabetes still have an increased relative risk (RR) of being LGA (RR = 3.59; 95% confidence interval [CI], 1.55 to 5.84) compared with the infants of women with normal glucose tolerance.100 Ogata and colleagues,103 using serial ultrasound measures of the fetus of women with diabetes, described an increase in the rate of abdominal circumference growth after 24 weeks’ gestation. The increase in growth appears to affect pri- marily insulin-sensitive tissues such as the subcutaneous fat included in measures of abdominal circumference.104 Ninety-five percent of the variance in fetal abdominal circumference can be accounted for by subcutaneous fat rather than intra-abdominal measures such as liver size. This is consistent with the inability of the fetal liver to store much glycogen in early third trimester. Reece and coworkers105 showed that fetuses of diabetic mothers have normal growth of lean body mass such as head and skeletal growth, even when there is marked hyperglycemia. In longitudinal ultrasound studies, Bernstein and associates106 reported that fetal fat and lean body mass demonstrate unique growth profiles. These unique ultrasound profiles potentially provide a more sensitive marker of abnormal fetal growth, particularly in infants of women with diabetes based on the increased fat mass rather than lean mass of these neonates.106 At delivery, body composition studies by Catalano and colleagues107 have shown that birth weight alone, even when AGA, may not be a sensitive enough measure of fetal growth in the infant of the diabetic mother. They reported that although there were no sig- nificant differences in birth weight or lean body mass, the infants of women with GDM had increased fat mass and percent body fat com- pared with a normoglycemic control group (Table 46-7). PATHOPHYSIOLOGY OF FETAL OVERGROWTH Maternal Glucose Concentrations. Because glucose is the most easily measured nutrient and marker of diabetes, most studies evaluat- ing the effect of diabetes on fetal growth have used measures of glucose as a reference. Findings from the DIEP indicate that birth weight cor- related best with second- and third-trimester postprandial glucose measures. When 2-hour postmeal glucose measures averaged 120 mg/ dL or less, approximately 20% of infants were macrosomic. In contrast, when 2-hour postprandial glucose measures averaged up to 160 mg/ dL, the rate of macrosomia reached 35%.108 Similarly, Combs and coworkers109 reported that macrosomia was significantly associated with postprandial glucose levels between 29 and 32 weeks’ gestation.109 In contrast, Persson and associates110 showed that fasting glucose concentrations account for 12% of the variance in birth weight and correlated best with estimates of neonatal fat. Uvena and colleagues111 found the strongest correlation was between fasting glucose and neo- natal adiposity, rather than postprandial measures. Fetal Insulin Concentrations. Based on the early work of Ped- ersen,112 fetal insulin has long been considered a principal driving
  • 13. 965CHAPTER 46 Diabetes in Pregnancy factor of in utero fetal growth. Experimental data gathered from non- human primates by Susa and coworkers113 showed that in the rhesus monkey when implanted with an Alzet pump, which delivered con- tinuous, increasing insulin concentrations to the fetus independent of the mother’s metabolic condition, there was evidence of fetal over- growth.111 In contrast, when genetic mutations such as glucokinase deficiencies existed only in the fetus, the inability of the beta cell to respond to increasing glucose concentrations results in fetal growth restriction.25 Many studies have confirmed the correspondence of increased cord insulin concentrations with fetal macrosomia. Schwartz and associates114 found that umbilical cord insulin concentrations at delivery correlated with the degree of macrosomia. Cordocentesis studies in late third trimester showed that the ratio of fetal plasma insulin to glucose and the degree of macrosomia were strongly corre- lated.115 Krew and colleagues116 reported that amniotic fluid C-peptide measures at term had a strong correlation with fetal adiposity but not lean body mass. The relationship between elevated insulin concentrations and fetal macrosomia exists in late pregnancy, and there is evidence of altered metabolic function in early gestation. Carpenter and colleagues117 reported that elevated amniotic fluid insulin concentrations obtained from normoglycemic patients at 14 to 20 weeks’ gestation and adjusted for maternal age and weight correlated with the likelihood of subse- quently diagnosed GDM (OR = 1.9; CI, 1.3 to 2.4). Each increase in amniotic fluid insulin multiple of the median (MOM) was associated with a threefold increase in fetal macrosomia.117 These data support the concept that the underlying pathophysiology of GDM and fetal macrosomia may exist earlier in gestation than is routinely screened for and that it is consistent with subclinical pregravid maternal meta- bolic disturbances. Growth Factors. There has been considerable interest in the role of insulin-like growth factors (IGFs) and fetal growth. Members of the IGF family have been implicated in abnormalities of increased and decreased fetal growth in humans. IGF-1 and the ratio of IGF-2 to the IGF-2 soluble receptor have been positively correlated with the Ponderal index.118 However, there is also direct evidence using rodent knockout models. Baker and coworkers119 reported that null mutations for the IGF1 or IGF2 gene decreases neonatal weight by 40% in mice. The effect of both genes is additive.119 Liu and associates120 previously reported that IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP-3) were significantly elevated in women with type 1 and 2 diabetes com- pared with a control group. These data are consistent with the findings of other investigators, including data for women with type 1 and 2 diabetes.121,122 Roth and colleagues123 reported that cord levels of IGF-1 were significantly greater in macrosomic IDMs than in nonmacroso- mic infants of glucose-tolerant or diabetic mothers. Radaelli and coworkers124 showed that there was a strong negative correlation between maternal circulating IGFBP-1 and lean body mass in the infants. The study authors speculated that IGFBP-1 might influence fetal growth by affecting IGF mediated placental nutrient transport, particularly of glucose or amino acids rather than lipids. Decreased IGFBP-1 levels are in keeping with a potential negative transcriptional regulation of the IGFBP1 gene by insulin.124 Maternal Obesity. Obesity is an epidemic in developed countries and the developing world.125 In the United States, the prevalence of obesity, defined as a body mass index (BMI = weight/height2 ) greater than 30 rose to 30.5% in 2000, compared with 22.9% from 1994 through 1998. The proportion of the population meeting the defini- tion of overweight (BMI > 25) increased from 55.9% to 64.5% during the same period.18 The risk of obesity is disproportionate among the races, increasing most among African Americans and Hispanics, the same populations at risk for type 2 diabetes. Several studies suggest that maternal obesity before conception has an independent effect on fetal macrosomia. Vohr and associates126 analyzed various risk factors for neonatal macrosomia in women with overt and GDM compared with obese and normal weight controls.126 Multiple regression analyses revealed the pre-pregnancy weight and weight gain were significant predictors for infants of GDM and control mothers. In an effort to better understand the potential independent effect of maternal obesity on growth of infants of GDM and normoglycemic women, Catalano and colleagues127 performed a stepwise logistic regression analysis on data for 220 infants of mothers with normal glucose tolerance and 195 infants of GDM (Table 46-8). Gestational age at term had the strongest correlation with birth weight and lean body mass. In contrast, maternal pregravid BMI had the strongest correlation (approximately 7%) with fat mass and percent body fat. Although almost 50% of the subjects had GDM, only 2% fraction of the variance was correlated to fat mass.127 These data support an independent effect of maternal pre- gravid obesity on fetal growth, particularly fat mass, independent of GDM. Other Fuels. Many factors are related to fetal overgrowth of the infant of a woman with diabetes. The significant decreases in insulin sensitivity in late gestation affect glucose and lipid and amino acid metabolism. Although we clinically concentrate on glucose, other nutrients most probably contribute to fetal overgrowth. This concept is consistent with the hypothesis of fuel-mediated teratogenesis first proposed by Freinkel in 1980.128 Circulating amino acid concentrations reflect the balance between protein breakdown and synthesis. Dug- gleby and Jackson129 estimated that there is a 15% increase in protein synthesis during the second trimester and a further 25% increase in the third trimester compared with levels in nonpregnant women. These differences appear to have a strong relationship to fetal growth, particularly lean body mass. Butte and coworkers130 and Metzger and associates131 independently reported higher amino acid concentrations in women with GDM compared with a normoglycemic control group. Zimmer and colleagues132 reported no significant difference in amino acid turnover in women with GDM and a control group. However, the TABLE 46-7 NEONATAL ANTHROPOMETRICS OF NEWBORNS OF WOMEN WITH GESTATIONAL DIABETES MELLITUS AND NORMAL GLUCOSE TOLERANCE Feature Measured* GDM (n = 195) NGT (n = 220) P Value Weight (g) 3398 ± 550 3337 ± 549 .26 Fat free mass (g) 2962 ± 405 2975 ± 408 .74 Fat mass (g) 436 ± 206 362 ± 198 .0002 Body fat (%) 2.4 ± 4.6 10.4 ± 4.6 .0001 Skinfold Triceps 4.7 ± 1.1 4.2 ± 1.0 .0001 Subscapular 5.4 ± 1.4 4.6 ± 1.2 .0001 Flank 4.2 ± 1.2 3.8 ± 1.0 .0001 Thigh 6.0 ± 1.4 5.4 ± 1.5 .0001 Abdominal wall 3.5 ± 0.9 3.0 ± 0.8 .0001 *Data are presented as the mean ± SD. GDM, gestational diabetes mellitus; NGT, normal glucose tolerance. Adapted from Catalano PM, Thomas A, Huston-Presley L, Amini SB: Increased fetal adiposity: A very sensitive marker of abnormal in utero development. Am J Obstet Gynecol 189:1698-1704, 2003.
  • 14. 966 CHAPTER 46 Diabetes in Pregnancy investigators found that hyperinsulinemia was required to maintain normal amino acid turnover in the GDM women.132 Kalhan and coworkers133 reported that leucine turnover and oxidation were greater in the obese woman with GDM compared with less obese control subjects. The increased insulin concentrations required to maintain appropriate amino acid levels in the woman with diabetes may be another manifestation of the increased insulin resistance in pregnant women with GDM. Knopp and associates134 found that there is a twofold to fourfold increase in triglyceride concentrations and a 25% to 50% increase in cholesterol during gestation. This group also reported a further increase in triglyceride and high-density lipoprotein cholesterol concentrations in type 2 and GDM patients.135 Similarly, Xiang and colleagues43 described increased basal free fatty acid concentrations in Hispanic women with GDM in the third trimester compared with a matched control group.136 Knopp and coworkers137 also reported that mid-tri- mester triglyceride concentrations were a better predictor of macroso- mia than glucose values during the glucose tolerance test. Similarly, Kitajima and colleagues138 examined lipid profiles in women with an abnormal glucose challenge test in pregnancy and reported that the triglycerides had a significant correlation with birth weight, even after adjusting for significant covariables. Although lipid transport from the mother to fetus is not well understood, maternal lipid metabolism may play a significant role in fetal growth, particularly in accrual of adipose tissue. Birth Injury Birth injury is more common among the offspring of diabetic mothers, and macrosomic fetuses are at the highest risk.139 The most common birth injuries associated with diabetes are brachial plexus palsy, facial nerve injury, humerus or clavicle fracture, and cephalhematoma. Athu- korala and associates140 studied women with gestational diabetes and found a positive relationship between the severity of maternal fasting hyperglycemia and the incidence of shoulder dystocia, with a doubling of risk with each 1-mmol increase in the fasting plasma glucose value on the OGTT. Shoulder dystocia occurred more often in diabetic deliv- eries requiring operative vaginal assistance (RR = 9.58; CI, 3.70 to 24.81: P < .001) and in fetuses above the 90th percentile of birth weight for age (RR = 4.57; CI, 1.74 to 12.01; P < .005) (Fig. 46-10). Most of the birth injuries occurring in infants of diabetic pregnancy are associated with difficult vaginal delivery and shoulder dystocia. Although shoulder dystocia occurs in 0.3% to 0.5% of vaginal deliver- ies among normal pregnant women, the incidence is twofold to four- fold higher for women with diabetes because the excessive fetal fat deposition associated with hyperglycemia in poorly controlled diabetic pregnancy causes the fetal shoulder and abdominal widths to become massive.140 Although one half of shoulder dystocias occur in infants of normal birth weight (2500 to 4000 g), the incidence of shoulder dys- TABLE 46-8 STEPWISE REGRESSION ANALYSIS OF FACTORS RELATING TO FETAL GROWTH AND BODY COMPOSITION IN INFANTS OF WOMEN WITH GESTATIONAL DIABETES MELLITUS (n = 195) AND NORMAL GLUCOSE TOLERANCE (n = 220) Factor r 2 Dr 2 P value Birth Weight Estimated gestational age 0.114 — Pregravid weight 0.162 0.048 Weight gain 0.210 0.048 Smoking (−) 0.227 0.017 Parity 0.239 0.012 .0001 Lean Body Mass Estimated gestational age 0.122 — Smoking (−) 0.153 0.031 Pregravid weight 0.179 0.026 Weight gain 0.212 0.033 Parity 0.225 0.013 Maternal height 0.241 0.016 Paternal weight 0.250 0.009 .0001 Fat Mass* Pregravid BMI 0.066 — Estimated gestational age 0.136 0.070 Weight gain 0.171 0.035 Group (GDM) 0.187 0.016 .0001 Percent Body Fat* Pregravid BMI 0.072 — Estimated gestational age 0.116 0.044 Weight gain 0.147 0.031 Group (GDM) 0.166 0.019 .0001 *Pregravid maternal obesity has the strongest correlation with neonatal measures of fat mass/% body fat in contrast to lean body mass. BMI, body mass index; GDM, gestational diabetes mellitus. Adapted from Catalano PM, Ehrenberg HM: The short and long term implications of maternal obesity on the mother and her offspring. BJOG 113:1126-1133, 2006. Assisted, DM Unassisted, DM Assisted, no DM Unassisted, no DM 3750–4000 3500–3750 4250–4500 Birth weight (grams) 0 50 100 150 200 250 Shoulderdystociaincidenceper1000 300 350 400 4000–4250 4750–5000 4500–4750 FIGURE 46-10 Risk of shoulder dystocia by diabetes status and instrumental delivery. Shoulder dystocia occurred more often in diabetic deliveries requiring operative vaginal assistance and in fetuses above the 90th percentile of birth weight for age. DM, diabetes mellitus. (From Nesbitt TS, Gilbert WM, Herrchen B: Shoulder dystocia and associated risk factors with macrosomic infants born in California. Am J Obstet Gynecol 179:476, 1998.)
  • 15. 967CHAPTER 46 Diabetes in Pregnancy tocia rises 10-fold to 5% to 7% among infants weighing 4000 g or more. However, if maternal diabetes is present, the risk at each birth- weight class is increased fivefold.141 These risks are further magnified if a forceps or vacuum delivery is performed.142 The level of glycemic control is strongly correlated with the risk of shoulder dystocia and birth injury, presumably because increasing levels of hyperglycemia are associated with greater fetal fat deposition. Athukorola and colleagues140 reported a positive correlation between the severity of maternal fasting hyperglycemia and the risk of shoulder dystocia, with each 1-mmol increase in the fasting value in the OGTT associated with an increasing relative risk of 2.09 (CI, 1.03 to 4.25). Although it would be desirable to predict shoulder dystocia on the basis of warning signs during labor such as labor protraction, a suspected macrosomic infant, or the need for midpelvic forceps delivery, less than 30% of these events can be predicted from clinical factors.143 Neonatal Morbidity and Mortality Polycythemia and Hyperviscosity Polycythemia (i.e., central venous hemoglobin concentration >20 g/dL or hematocrit >65%) occurs in 5% to 10% of IDMs and is apparently related to glycemic control. Hyperglycemia is a powerful stimulus for fetal erythropoietin production, which is probably mediated by decreased fetal oxygen tension.144 Untreated, neonatal polycythemia may promote vascular sludging, ischemia, and infarction of vital tissues, including the kidneys and central nervous system. Neonatal Hypoglycemia Approximately 15% to 25% of neonates delivered from women with diabetes during gestation develop hypoglycemia during the immediate newborn period.145 Neonatal hypoglycemia is less common when tight glycemic control is maintained during pregnancy146 and in labor. A detailed study by Taylor and associates147 found no correlation between the likelihood of neonatal hypoglycemia and Hb A1c, whereas mean maternal glucose levels during labor were strongly predictive. Because unrecognized postnatal hypoglycemia may lead to neonatal seizures, coma, and brain damage, it is imperative that the neonatal team caring for the neonate follow a protocol of frequent postnatal glucose monitoring until metabolic stability is ensured. Neonatal Hypocalcemia and Hyperbilirubinemia Low levels of serum calcium (<7 mg/100 mL) have been reported in up to 50% of IDMs during the first 3 days of life, although later series record an incidence of 5% or less with better-managed pregnancies.148 Neonatal hyperbilirubinemia occurs in approximately 25% of IDMs, a rate approximately double that for normal infants, with prematurity and polycythemia being the primary contributing factors. Close moni- toring of the newborn of diabetic pregnancy is necessary to avoid the further morbidity of kernicterus, seizures, and neurologic damage. Hypertrophic and Congestive Cardiomyopathy In some macrosomic, plethoric infants of mothers with poorly con- trolled diabetes, a thickened myocardium and significant asymmetrical septal hypertrophy has been described.149 The prevalence of clinical and subclinical asymmetrical septal hypertrophy in IDMs has been estimated to be as high as 30% at birth, with resolution by 1 year of age.150 Kjos and colleagues151 found that cardiac dysfunction associated with this entity often leads to respiratory distress, which may be mis- taken for hyaline membrane disease. IDMs who manifest cardiac dysfunction in the neonatal period may have congestive or hypertrophic cardiomyopathy. This condition is often asymptomatic and unrecognized. Echocardiograms show a hypercontractile, thickened myocardium, often with septal hypertro- phy disproportionate to the ventricular free walls.152 The ventricular chambers are often smaller than normal, and there may be anterior systolic motion of the mitral valve, producing left ventricular outflow tract obstruction. Neonatal septal hypertrophy may be a response to chronic hyper- glycemia. The maternal level of IGF-1, which is elevated in subopti- mallycontrolleddiabeticpregnancy,issignificantlyelevatedinneonates with asymmetrical septal hypertrophy. Because IGF-1 does not cross the placenta, it may exert its action through binding to the IGF-1 receptor on the placenta.153 Halse and coworkers154 found that the level of B-type natriuretic protein (BNP), a marker for congestive cardiac failure, is elevated in neonates whose mothers had poor glycemic control during the third trimester. Septal hypertrophy can be identified with sonography in the pre- natal period. Cooper and coworkers155 performed serial fetal echocar- diography on 61 pregnant, diabetic women, demonstrating excessive ventricular septal thickness in the fetuses that were diagnosed postna- tally with asymmetrical septal hypertrophy. When the newborns with asymmetrical septal hypertrophy were compared with normal infants, birth weights (4009 versus 3457 g; P < .01) and maternal glycosylated hemoglobin levels (6.7% versus 5.7%) were higher in infants with cardiomyopathy. Respiratory Distress Syndrome Until recently, respiratory distress syndrome was the most common and most serious disease in IDMs. In the 1970s, improved prenatal maternal management for diabetes and new techniques in obstetrics for timing and mode of delivery resulted in a dramatic decline in its incidence, from 31% to 3%.156 However, even when matched by gesta- tional week of pregnancy, IDMs are more than 20 times as likely as infants from normal pregnancies to develop respiratory distress syndrome.157 The increased susceptibility to respiratory distress may result from altered production of alveolar surfactant or abnormal pulmonary function. Kulovich and Gluck158 reported delayed timing of phospho- lipid production in diabetic pregnancy, as indicated by a delay in the appearance of phosphatidylglycerol in the amniotic fluid. In their study, maturational delay occurred only in gestational diabetes (White class A patients); fetuses of women with other forms of diabetes showed normal or accelerated maturation of pulmonary phospholipid profiles. Although some investigators have failed to demonstrate a delay in lung maturation in diabetic pregnancy,159,160 most reports in the litera- ture indicate a significant biochemical and physiologic delay in IDMs. Tyden and colleagues161 and Landon and coworkers162 reported that fetal lung maturity occurred later in pregnancies with poor glycemic control (mean plasma glucose level >110 mg/dL), regardless of class of diabetes, when the infants were stratified by maternal plasma glucose levels. These findings were confirmed by Moore,163 who demonstrated no differences in the rate of rise of the amniotic fluid lecithin-to- sphingomyelin ratio among types of diabetes or degree of glucose control but found that amniotic fluid phosphatidylglycerol was delayed approximately 1.5 weeks in women with pregestational or GDM dia- betes compared with controls (Fig. 46-11). The delay in phosphatidyl- glycerol was associated with an earlier and higher peak in the level of phosphatidyl inositol, suggesting that elevated maternal plasma levels of myoinositol in diabetic women may inhibit or delay the production of phosphatidylglycerol in the fetus.
  • 16. 968 CHAPTER 46 Diabetes in Pregnancy It is possible that poor neonatal respiratory performance in the IDM may have a histologic basis in addition to a biochemical cause. Kjos and coauthors151 identified respiratory distress in 3.4% of infants delivered of diabetic women, but surfactant-deficient airway disease accounted for less than one third of cases, with transient tachy- pnea, hypertrophic cardiomyopathy, and pneumonia responsible for most. The near-term infant of a mother with poorly controlled diabetes is more likely to have neonatal respiratory dysfunction than is the infant of a nondiabetic mother. The observations of Moore163 indicate that the average nondiabetic fetus achieves pulmonary maturity at 34 to 35 weeks’ gestation, with more than 99% of normal newborns having a mature phospholipid profile by 37 weeks. In diabetic preg- nancy, however, it cannot be assumed that lung maturity exists until approximately 10 days after the nondiabetic time (38.5 gestational weeks). Any delivery contemplated before 38.5 weeks’ gestation for other than the most urgent fetal and maternal indications should be preceded by documentation of pulmonary maturity by amniocentesis. The neonatal complications of the offspring of diabetic pregnancy is discussed further in Chapter 58. Long-Term Risks for the Fetus of the Obese Mother Although much has been written about the increased risk of the meta- bolic syndrome (i.e., obesity, hypertension, insulin resistance, and dys- lipidemia) in infants born SGA, evidence points toward an increase in adolescent and adult obesity in infants born LGA or macrosomic. There has been abundant evidence linking higher birth weights to increased obesity of adolescents and adults for at least 25 years.164 Large cohort studies such as the Nurses Health Study165 and the Health Pro- fessional Follow-up Study166 report a J-shaped curve (i.e., a slightly greater BMI among subjects born small but a much greater prevalence of overweight and obesity in those born large).167 The increased preva- lence of adolescent obesity is related to an increased risk of the meta- bolic syndrome. The increased incidence of obesity accounts for much of the 33% increase in type 2 diabetes, particularly among the young. Between 50% and 90% of adolescents with type 2 diabetes have a BMI greater than 27,168 and 25% of obese children between 4 and 10 years old have impaired glucose tolerance.169 The epidemic of obesity and subsequent risk for diabetes and components of the metabolic syn- drome may begin in utero with fetal overgrowth and adiposity, rather than undergrowth. A retrospective cohort study by Whitaker170 enrolling more than 8400 children in the United States in the early 1990s reported that children who were born to obese mothers (based on BMI in the first trimester) were twice as likely to be obese when they were 2 years old. If a woman had a BMI of 30 or more in the first trimester, the preva- lences of childhood obesity (BMI > 95th percentile based on criteria of the Centers for Disease Control and Prevention [CDC]) at ages 2, 3, and 4 years were 15.1%, 20.6%, and 24.1%, respectively. This was between 2.4 and 2.7 times the prevalence of obesity observed in children of mothers whose BMI values were in the normal range (18.5 to 24.9). This effect was only slightly modified by birth weight. There is an independent effect of maternal pregravid weight and diabetes on birth weight and on the adolescent risk of obesity. Langer and colleagues171 reported that in obese women with GDM whose glucose was well controlled on diet alone, the odds of fetal macrosomia (birth weight >4000 g) were significantly increased (OR = 2.12) com- pared with women with well-controlled (diet only) GDM and normal BMIs. Similar results were reported for women with GDM who were poorly controlled with diet or with insulin. In well-controlled, insulin- requiring women with GDM, there was no significant increased risk of macrosomia with increasing pregravid BMI. Dabelea and associ- ates172 reported that the mean adolescent BMI was 2.6 kg/m2 greater in sibling offspring of diabetic pregnancies compared with the index siblings born when the mothers previously had normal glucose toler- ance. Both maternal pregravid obesity and the presence of maternal diabetes may independently affect the risk of adolescent obesity in the offspring. This risk of developing the metabolic syndrome in adolescents was addressed by Boney and colleagues173 in longitudinal cohort study of AGA and LGA infants of women with normal glucose tolerance and GDM. The metabolic syndrome was defined as the presence of two or more of the following components: obesity, hypertension, glucose intolerance, and dyslipidemia. Maternal obesity was defined as a pre- gravid BMI higher than 27.3. Children who were LGA at birth had an increased hazard ratio (HR) for metabolic syndrome (HR = 2.19; CI, 1.25 to 3.82; P = .01) by age 11 years, as did children of obese women (HR = 1.81; CI, 1.03 to 3.19; P = .04). The presence of maternal GDM was not independently significant, but the risk for developing meta- bolic syndrome was significantly different between LGA and AGA off- spring of GDM by age 11 years (RR = 3.6). Childhood Neurologic Abnormalities Several reports have suggested childhood neurodevelopmental abnor- malities in offspring of diabetic mothers. Rizzo and colleagues174 com- pared the offspring of 201 mothers with diabetes with 83 children of normal mothers and correlated subsequent childhood obesity in the offspring of diabetic mothers with internalizing behavior problems, 29 0 Cumulative%PGՆ3% 20 40 60 80 100 31 33 35 Gestational week at amniocentesis 37 39 41 43 Controls Overt DM GDM FIGURE 46-11 Delay in fetal pulmonary phosphatidyl glycerol. The delay in fetal pulmonary phosphatidyl glycerol was associated with a sustained peak in phosphatidyl inositol in diabetic pregnancy, suggesting that elevated maternal plasma levels of myoinositol in a diabetic woman may inhibit or delay the production of phosphatidyl glycerol in the fetus. DM, diabetes mellitus; GDM, gestational diabetes mellitus; PG, phosphatidyl glycerol. (From Moore TR: A comparison of amniotic fluid fetal pulmonary phospholipids in normal and diabetic pregnancy. Am J Obstet Gynecol 186:641, 2002.)
  • 17. 969CHAPTER 46 Diabetes in Pregnancy somatic complaints, anxiety or depression, and social problems. Ornoy and associates175 assessed IQ scores on the Wechsler Intelligence Scale for Children–Revised (WISC-R) and Bender tests of the children born to diabetic mothers. No differences were found between the study groups in various sensorimotor functions compared with controls, but the children of diabetic mothers performed less well than controls in fine and gross motor functions, and they scored lower on the Pollack taper test, which is designed to detect inattention and hyperactivity. These investigators also found a negative correlation between the severity of maternal hyperglycemia, as assessed by glycosylated hemo- globin levels in the third trimester, and performance on neurodevel- opmental and behavioral tests. Preconceptional Management of Women with Pregestational Diabetes Although widely underused,176 preconceptional care programs have consistently been associated with decreased morbidity and mortality.177 Patients enrolled in preconceptional diabetes-management programs obtain earlier prenatal care and have lower Hb A1c values in the first trimester.178 A comparison of outcomes among women participating in a intensive preconceptional program with outcomes among women receiving standard care demonstrated lower perinatal mortality (0% versus 7%) and reduced congenital anomalies (2% versus 14%). When the preconceptional program was discontinued because of a lack of funds, the congenital anomaly rate increased by more than 50%.7 Risk Assessment Several factors should be considered in preconceptional diabetes risk assessment (Table 46-9): ᭿ Glycemic control should be assessed directly from glucose logs and by glycosylated hemoglobin levels. ᭿ For patients who have had diabetes for 10 years or longer, an electrocardiogram, an echocardiogram, and microalbuminuria and serum creatinine studies should be performed. ᭿ Because retinopathy can progress during pregnancy, the patient should establish a relationship with a qualified ophthalmologic provider. A baseline retinal evaluation should be completed within the year before conception, with laser photocoagulation performed if needed. Previous laser treatment is not a contraindication to pregnancy and may avoid significant hemorrhage during pregnancy. ᭿ Thyroid function (i.e., thyroid-stimulating hormone and free thyroxine) should be evaluated and corrected as necessary in all patients with pregestational diabetes because of the frequent coincidence of autoimmune thyroid disease and diabetes. ᭿ A daily prenatal vitamin that provides 1 mg of folic acid should be prescribed for a minimum of 3 months before conception, because folate supplementation significantly reduces the risk of congenital neural tube defects. ᭿ The patient’s occupational, financial, and personal situation should be reviewed, because job and family pressures can become barriers to achieving and maintaining excellent glycemic control. In patients with pre-pregnancy hypertension or proteinuria, particular emphasis should be given to defining support systems that permit extended bed rest in the third trimester, if it becomes necessary. ᭿ The patient’s preconception medications should be reviewed and altered to avoid teratogenicity and potential embryonic toxicity. Statins are pregnancy category X drugs and should be discontinued before conception. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) should be discontinued before conception because of first trimester teratogenicity and fetal renal toxicity in the second half of pregnancy. Among oral antidiabetic agents used by reproductive-aged women, metformin and acarbose are classified as pregnancy category B drugs, although systematic data on safety are lacking. All other agents are category C drugs, and unless the potential risks and benefits of oral antidiabetic agents in the preconception period have been TABLE 46-9 PRECONCEPTIONAL EVALUATION OF THE DIABETIC PATIENT Procedure Tests Recommendations Medical history, family history, review of symptoms Selected patients: fasting and postprandial C-peptide determinations to clarify type of diabetes Avoid pregnancy until Hb A1c value is in the normal, nonpregnant range Physical examination findings Hypertension ECG, cardiac, renal evaluation Antihypertensive medications Retinopathy Retinal evaluation Ophthalmology consultation Goiter T4, thyroid-stimulating hormones, antibodies Neuropathy Vascular, podiatric evaluations Obesity Exercise, weight loss Proteinuria 24-hr urine for protein, creatinine Nephrology consultation if renal function abnormal Diabetes assessment Hb A1c Glycemic control Home glucose monitoring Stable glycemic profile Nutrition Dietitian consultation Occupational and family life assessment Help prepare patient for lifestyle commitments necessary for tight glycemic control ECG, electrocardiogram; Hb, hemoglobin; T4, thyroxine.
  • 18. 970 CHAPTER 46 Diabetes in Pregnancy carefully weighed, they usually should be discontinued in pregnancy. Metabolic Management The goal of preconceptional metabolic management is to achieve an Hb A1c level within the normal range before conception using a safe and reliable medication regimen that permits a smooth transition through the first trimester. The patient should be skilled in managing her glucose levels in a narrow range well before pregnancy begins, so that the inevitable insulin adjustments necessitated by the appetite, metabolic, and activity changes of early pregnancy can be accom- plished smoothly. A regimen of regular monitoring of preprandial and postprandial capillary glucose levels should be instituted. Although there are no data indicating that postprandial glucose monitoring is required before pregnancy to achieve adequate control, monitoring these levels increases the preconceptional woman’s awareness of the interaction of dietary content and quality with postprandial glycemic excursions.179 The insulin regimen should result in a smooth glucose profile through- out the day, with no hypoglycemic reactions between meals or at night. Oral Hypoglycemic Agents A longitudinal trial in the United Kingdom of intensified metabolic therapy in nonpregnant women with type 2 diabetes180 demonstrated that oral agents were more effective than insulin in lowering Hb A1c levels. This effect was attributed to improved compliance and fewer hypoglycemic reactions. For this and other reasons, most women with type 2 diabetes use one or more oral agents for glycemic control—typi- cally metformin and a sulfonylurea or thiazolidinediones. Details of the mechanism of action and pharmacology of these oral hypoglyce- mic agents are discussed later. Despite the absence of evidence of tera- togenicity for most of these compounds, none is recommended for use in pregnancy. Standard practice is to transition these patients to insulin management preconceptionally. A possible exception is the use of metformin in infertile patients with polycystic ovary syndrome who are otherwise oligo-ovulatory. These patients have higher conception and lower miscarriage rates with metformin treatment.181 Although two small series documenting the apparent safety of continuing metformin during pregnancy have been published,182,183 discontinuing metformin after pregnancy is established is recommended. Metformin readily crosses the placenta, exposing the fetus to con- centrationsapproachingthoseinthematernalcirculation.Thesequelae of such exposure (i.e., effects on neonatal obesity and insulin resis- tance) remain unknown. A study of perfused human placental lobules from gestational diabetic and normoglycemic women demonstrated that metformin was readily transferred from the maternal to the fetal circulation.184 A more direct assessment of maternal and fetal pharmacodynamics was performed by Charles and coworkers185 by obtaining maternal blood in the third trimester from metformin takers with gestational or type 2 diabetes. Cord blood also was obtained. Mean metformin concentrations in cord and maternal plasma were 0.81 and 1.2 mg/L, respectively. The maternal plasma half-life is 5.1 hours. Because these pharmacokinetics are similar to those in nonpregnant patients, no dosage adjustment is warranted.185 With regard to teratogenicity associated with metformin use in pregnancy, Gilbert and associates performed a meta-analysis of eight available studies. The malformation rate in the disease-matched control group was approximately 7.2%, statistically significantly higher than the rate found in the metformin group (1.7%). After adjustment for confounders, first-trimester metformin treatment was associated with a statistically significant 57% reduction in birth defects.186 In a study of women with type 2 diabetes mellitus, 93 of whom took metformin (61 in the first trimester and 32 throughout the pregnancy) and 121 of whom did not take metformin, there was no difference between the metformin and control groups in the rate of preeclampsia (13% versus 14%; P = .84), perinatal loss (3% versus 2%; P = .65), or neonatal morbidity, including rate of prematurity (23% versus 22%; P = .7), admission to the neonatal unit (40% versus 48%; P = .27), respiratory distress (9% versus 18%; P = .07), and neonatal hypoglycemia (20% versus 31%; P = .08).187 The concentrations of metformin in breast milk are generally low, and the mean infant exposure to metformin has been reported in the range of 0.28% to 1.08% of the weight-normalized maternal dose. No adverse effects on blood glucose of nursing infants have been reported.188 Antihypertensive Medications Hypertension is a common comorbidity of diabetes and is found in 20% to 30% of women who have had diabetes for longer than 10 years. Although treatment of modest degrees of hypertension (<160 mm Hg systolic) during pregnancy has not been shown to be beneficial in improving perinatal outcome,74 treatment in nonpregnant diabetic women is recommended when blood pressure is consistently higher than 130/80 mm Hg.19 The U.K. Prospective Diabetes Study and the Hypertension Optimal Treatment trial demonstrated improved out- comes, especially in preventing stroke, in patients assigned to lower blood pressure targets. Patients frequently enter the preconceptional period taking one or more antihypertensive medications.189 In precon- ceptional and pregnant patients with diabetes and chronic hyperten- sion, blood pressure target goals of 110/65 to 129/79 mm Hg are recommended in the interest of long-term maternal health and mini- mizing impaired fetal growth.19 None of the commonly used antihypertensive medications (e.g., calcium channel blockers, β-blockers, methyldopa) is teratogenic. ACE inhibitors deserve special mention because in nonpregnant subjects with diabetic nephropathy, they have been shown to ameliorate pro- teinuria and delay progression to end-stage renal disease. These medi- cations are therefore considered first-line agents for diabetic women with significant proteinuria.180 Many women with type 1 diabetes present for consultation preconceptionally or even in early pregnancy while taking these medications. It is not clear whether these medica- tions have teratogenic effects when used in the first trimester, but use in the second trimester and beyond can cause a marked reduction in fetal renal blood flow, resulting in oligohydramnios and even frank fetal renal failure.190 These medications should not be used during pregnancy, especially after the first trimester. Similar concerns exist for other agents in this family (i.e., ARBs and angiotensin receptor antagonists).191 Diagnosing Diabetes Overt Diabetes Patients with type 1 diabetes are typically diagnosed during an episode of hyperglycemia, ketosis, and dehydration. Type 1 diabetes is rarely
  • 19. 971CHAPTER 46 Diabetes in Pregnancy diagnosed during pregnancy. The diagnosis of type 2 diabetes cannot be accomplished during pregnancy because of the overlap with early- onset gestational diabetes. Although the finding of an elevated Hb A1c level in early pregnancy may be suggestive, definitive diagnosis of type 2 diabetes must be made after pregnancy. The diagnostic criteria rec- ommended by the ADA for diabetes are listed in Table 46-2. Hyperglycemia not sufficient to meet the diagnostic criteria for diabetes is categorized as IFG or IGT, depending on whether it is identified through a fasting plasma glucose level or a 75-g, 2-hour OGTT19 : IFG: fasting plasma glucose level of 100 to 125 mg/dL (5.5 to 6.9 mmol/L) IGT: 2-hour plasma glucose level of 140 to 199 mg/dL (7.8 to 11 mmol/L) Patients with IFG or IGT before pregnancy should be considered at extremely high risk for developing GDM. GDM patients whose postpartum testing results in the diagnosis of IFG or IGT are at sig- nificant risk for the disease evolving into frank diabetes within 5 to 10 years. Patients with IFG or IGT should be counseled regarding weight loss and provided instruction for increasing physical activity. Monitoring for the development of diabetes in those with prediabetes should be performed every 1 to 2 years. Screening for and appropriate treatment for other cardiovascular risk factors (e.g., tobacco use, hypertension, dyslipidemia) is important. There is insufficient evidence to support the use of drug therapy in women with IFG or IGT. Gestational Diabetes Risk Factor Screening Risk factor assessment for GDM should be performed at the first pre- natal visit. High-risk clinical characteristics include the following: ᭿ Age older than 35 to 40 years ᭿ Obesity (BMI > 30) ᭿ History of GDM ᭿ Delivery of a previous LGA infant ᭿ Polycystic ovary syndrome ᭿ A strong family history of diabetes Patients with these risk factors should receive plasma glucose screening without delay. High-risk women not found to have GDM at the initial screening should be tested again between 24 and 28 weeks’ gestation. Previously, screening of all pregnant women for GDM was recom- mended, but the ADA192 modified this recommendation such that screening can be omitted for low-risk women meeting all of the criteria listed in Table 46-10. This policy is based on the findings of Naylor and colleagues,193 who reported that women with one or no risk factors had a 0.9% risk of GDM, whereas 4% to 7% of those with two to five risk factors were diagnosed with GDM, resulting in a sensitivity of approxi- mately 80% with a false-positive rate of 13%. One- or Two-Step Screening The diagnosis of GDM is based on a positive OGTT result. Guidelines issued by the Fourth International Workshop-Conference on Gesta- tional Diabetes Mellitus194 and reaffirmed by the Fifth International Conference195 and the American College of Obstetricians and Gyne- cologists (ACOG)196 recommend the use of the Carpenter and Coustan diagnostic criteria for the 3-hour, 100-g glucose OGTT (Table 46-11). However, these expert bodies also acknowledge the alternative use of a single-step, 2-hour, 75-g glucose OGTT. ONE-STEP OPTION The one-step, 75-g glucose, 2-hour OGTT, which is commonly used outside the United States, is no longer recommended because of its inferior detection rate of GDM. Mello and colleagues197 compared the diagnostic efficiency of the 75-g, 2-hour OGTT with the 3-hour, 100 g- OGTT and found that the 2-hour test was less than one half as sensitive in diagnosing GDM (5% versus 12%). The current one-step option involves direct administration of the 3-hour, 100-g glucose OGTT. Two or more values must be met or exceeded for the diagnosis of GDM. The critical cutoff values for the 3-hour OGTT are listed in Table 46-11. Direct, one-step administra- tion of the 3-hour, 100-g OGTT test should be considered in women with prior GDM, especially those with additional risk factors such as obesity. TWO-STEP OPTION In the two-step approach, a screening glucose challenge test (GCT) is administered using 50 g of glucose in the fasting or nonfasting state. TABLE 46-10 LOW-RISK CRITERIA FOR GESTATIONAL DIABETES SCREENING American Diabetes Association: Gestational diabetes mellitus: A position statement. Diabetes Care 27(Suppl 1):S88, 2004. TABLE 46-11 THREE-HOUR 100-GRAM ORAL GLUCOSE TOLERANCE TEST FOR GESTATIONAL DIABETES Test Prerequisites 1-hr, 50-g glucose challenge result ≥135 mg/dL Overnight fast of 8-14 hr Carbohydrate loading for 3 days, including ≥150 g of carbohydrate Seated, not smoking during the test Two or more values must be met or exceeded for a diagnosis of GDM Assessment for Gestational Diabetes Mellitus Plasma Glucose Level after a 100-g Glucose Load mg/dL (mmol/L) Fasting 95 (5.3) 1 hr 180 (10.0) 2 hr 155 (8.6) 3 hr 140 (7.8)
  • 20. 972 CHAPTER 46 Diabetes in Pregnancy For those whose plasma glucose value obtained after 1 hour exceeds a critical threshold value, a 100-g, 3-hour OGTT is administered, using the diagnostic criteria listed in Table 46-11. THRESHOLD VALUE FOR THE GLUCOSE CHALLENGE TEST The sensitivity of the GDM testing regimen depends on the thresh- old value used for the 50-g GCT. Recommendations from the ADA19 and ACOG196 explain that using a threshold value of 140 mg/dL results in approximately 80% detection of GDM, whereas using a threshold of 130 mg/dL results in 90% detection. A potential disadvantage of using the lower value of 130 mg/dL is an approximate doubling in the number of OGTTs performed. The Canadian study,193 based on receiver-operator curve analysis, calculated that diagnostic efficiency was optimized when a GCT threshold of 130 mg/dL was used for intermediate-risk women (i.e., two to four risk factors) and 128 mg/dL for higher-risk women. These issues are summarized in Table 46-12. A threshold plasma glucose value of 130 mg/dL is recommended for use in practices with a significant proportion of higher-risk gravi- das (e.g., multiracial, obese). This approach provides excellent test sensitivity for GDM (>90%) with acceptable cost. Definitive random- ized trials regarding cost-effectiveness with respect to perinatal out- comes and neonatal costs have not yet been performed.198 MAXIMUM VALUE FOR THE GLUCOSE CHALLENGE TEST The risk of GDM is approximately proportional to the result of the 1-hour GCT. Dooley and coworkers199 found that among nonwhite women, the risk of GDM with a 1-hour glucose value of 200 mg/dL or more is greater than 90%. Bobrowski and colleagues200 reported that all patients with a screening result above 216 mg/dL had a positive 3- hour OGTT result. Most experts omit the 3-hour OGTT for patients with GCT results of 200 mg/dL or greater and manage the patient as a gestational diabetic. SINGLE ABNORMAL VALUE ON THE 3-HOUR ORAL GLUCOSE TOLERANCE TEST A fasting plasma glucose level exceeding 126 mg/dL should be con- sidered highly suspicious for diabetes in pregnant and nonpregnant patients. Individuals with fasting plasma glucose levels above 126 mg/ dL should have another fasting test; if the result of the second test is high, GDM is confirmed. Patients with a single abnormal OGTT value are at increased risk for infants with macrosomia and neonatal morbidity. Berkus and col- leagues201 followed 764 patients with GDM, stratified by the number of abnormal values on their OGTTs. Patients with one or more abnormal OGTT values had double the incidence of macrosomic infants (23% to 27% versus 13%; P < .01). When Langer and cowork- ers202 compared perinatal outcomes in patients with a single abnormal OGTT value with normal women and with aggressively managed GDM patients, they found the incidence of macrosomia to be more than threefold higher in the single abnormal value group than in the normal (34% versus 9%) and GDM (34% versus 12%) groups. Neo- natal morbidity was fivefold higher in the single abnormal OGTT value group (15%) compared with the control and GDM groups (3%). McLaughlin and colleagues203 reviewed the perinatal outcomes of 14,036 women who had normal 1-hour or 3-hour glucose levels using standard criteria (i.e., 1-hour GCT cutoff of 140 mg/dL and 3-hour OGTT [see Table 46-11]). Of these, 3% had a single elevated value on the 3-hour test. Comparing the single elevated value group to those with all normal values, higher rates of cesarean delivery, preeclampsia, chorioamnionitis, birth weights higher than 4000 g and 4500 g, and neonatal intensive care unit admission were recorded (adjusted OR = 1.6, 1.5, 1.5, 1.7, 2.2, and 1.5, respectively; P < .03).203 These results underscore the problems associated with the methods used to identify patients with GDM. The relationships among carbo- hydrate metabolism, macrosomia, and neonatal morbidity create a continuum that defies a single, clear-cut criterion for diagnosis in all populations. The recommended schemes identify at most 90% of preg- nancies susceptible to hyperglycemia and fetal macrosomia. The astute clinician should approach women with several GDM risk factors and a single abnormal OGTT value with caution. When in doubt, a trial of capillary glucose testing may help to clarify the patient’s metabolic status. Other Tests for Gestational Diabetes Several investigators have searched for a single, nonglucose blood test that can accurately predict the results of the OGTT. Because of the proportional relationship of glycated proteins and long-term plasma glucose concentrations, fructosamine and Hb A1c screening have been evaluated. Roberts and colleagues204 suggested that fructosamine screening for GDM could produce a sensitivity of 85% with a specific- ity of 95%. A positive relationship between fructosamine levels and macrosomia was demonstrated.205,206 However, subsequent studies have reported significantly lower sensitivities.207,208 Inferior sensitivity and predictive values have been reported for glycohemoglobin measurements (i.e., Hb A1 and Hb A1c) by Shah and colleagues,209 Baxi and associates,210 and Artal and coworkers211 (22%, 63%, and 74%, respectively). A study by Agarwal and associates212 assessed the use of lower cutoffs for fructosamine and Hb A1c to exclude subjects from further GDM screening and higher cutoffs for one-step diagnosis. The lower cutoffs achieved sensitivities of 90% and negative predictive values of more than 85%. However, the upper cutoff values did not achieve acceptable positive predictive values to be useful for diagnosing GDM. Thus the role of these tests would be to identify patients rather than to screen for GDM, but using them would impose TABLE 46-12 SENSITIVITY AND COST ASSOCIATED WITH UNIVERSAL AND SELECTIVE SCREENING WITH VARIOUS GLUCOSE CHALLENGE THRESHOLDS Factor Threshold Value for 1-hr, 50-g Glucose Challenge 130 mg/dL 140 mg/dL Sensitivity (%) 100 79 Percent of population (%) requiring OGTT 22 13 Threshold Value (mg/dL) Sensitivity (%) Universal 140 90 130 100 Risk factors + age ≥25 yr 140 85 130 95 OGTT, oral glucose tolerance test. Adapted from Coustan DR, Nelson C, Carpenter MW, et al: Maternal age and screening for gestational diabetes: A population based study. Obstet Gynecol 73:557, 1989.
  • 21. 973CHAPTER 46 Diabetes in Pregnancy an additional step and cost on the diagnostic regimen. Although screening with glycosylated proteins could theoretically reduce the number of two-step diagnostic procedures, their lack of sensitivity in diagnosis and the additional time and cost have left these studies of limited use in screening for GDM. Timing of Gestational Diabetes Screening FIRST-TRIMESTER SCREENING The timing of glucose tolerance testing during pregnancy is critical, because delayed diagnosis increases the duration of deranged maternal metabolism and accelerated fetal growth. However, because the preva- lence of GDM increases with advancing gestation due to rising insulin resistance mediated by placental hormones, testing too early can over- look some patients who will develop disease later. A surprising percentage of patients (6% to 20%) with GDM can be diagnosed in the first trimester. Most have significant risk factors for glucose intolerance. Moses and associates213 assessed the prevalence of GDM in patients with various risk factors. GDM was identified in 6.7% overall, in 8.5% of women 30 years old or older, in 12.3% of women with a BMI of 30 or more, and in 11.6% of women with a family history of diabetes. A combination of risk factors predicted GDM in 61% of cases compared with 4.8% of those without risk factors. The additional effect of ethnicity on the prevalence of GDM is summarized in Table 46-13. Risk factor assessment for GDM (i.e., maternal age, ethnicity, obstetric and family history, body habitus, prior GDM, prior IGT, prior macrosomic infant, or unexplained stillbirth) should be performed at the first prenatal visit of all pregnant women. Patients with any of these risk factors (Table 46-14) should undergo screening as soon as feasible, and if results are negative, tests should be repeated at 24 to 28 weeks’ gestation. THIRD-TRIMESTER SCREENING Because the insulin resistance that causes hyperglycemia increases as the third trimester progresses, early testing may miss some patients who later become glucose-intolerant. Performing the test too late in the third trimester limits the time in which metabolic intervention can take place. For this reason, it is recommended that glucose tolerance testing be performed in all patients at 24 to 28 weeks’ gestation.214 Whether administered at 12 or 26 weeks, the GCT can be per- formed without regard to recent food intake (i.e., nonfasting state). Coustan and coworkers215 have shown that tests performed in fasting subjects are more likely to yield falsely elevated results than are tests conducted between meals. This finding was confirmed by Sermer and colleagues.216 Metabolic Management of Women with Pregestational Diabetes The primary goals of metabolic management (i.e., glycemic monitor- ing, dietary regulation, and insulin therapy) in diabetic pregnancy are to prevent or minimize the postnatal sequelae of diabetes—macroso- mia, shoulder dystocia, birth injury, and postnatal metabolic instabil- ity—in the newborn. A secondary goal is to reduce the risk of pediatric and adult metabolic syndrome in the offspring. If this goal is to be achieved, glycemic control must be instituted early and aggressively. Principles of Medical Nutritional Therapy There is a surprising lack of well-controlled research on the optimal diet for lean or obese women with diabetes. Most recommendations regarding dietary therapy are based on common sense and experience. Because women with all types of diabetes experience inadequate insulin action after feeding, the goal of medical nutritional therapy is to avoid single, large meals containing foods with a high percentage of simple carbohydrates that release glucose rapidly from the maternal gut. Three major meals and three snacks are preferred, because this multiple-feeding regimen limits the amount of calories presented to the bloodstream during any given interval. The use of nonglycemic foods that release calories from the gut slowly also improves metabolic control. Examples include foods with complex carbohydrates and fiber, such as whole-grain breads and legumes. Carbohydrates should account for no more than 50% of the diet, with protein and fats equally accounting for the remainder.19 Medical nutritional therapy should be supervised by a trained professional—ideally, a registered dietitian. In many programs, die- TABLE 46-14 RISK FACTORS FOR GESTATIONAL DIABETES Patients with any of these factors should be screened for GDM at the first prenatal visit: Maternal age >25 yr Previous macrosomic infant Previous unexplained fetal demise Previous pregnancy with GDM Strong immediate family history of NIDDM or GDM Obesity (>90 kg) Fasting glucose >140 mg/dL (7.8 mM) or random glucose >200 mg/dL (11.1 mM) GDM, gestational diabetes mellitus; NIDDM, non–insulin-dependent diabetes mellitus. TABLE 46-13 PREVALENCE OF GESTATIONAL DIABETES IN VARIOUS NATIONAL AND ETHNIC GROUPS Study Population Prevalence (%) Harris et al, 1997 Native American (Cree) 8.3 Henry et al, 1993 Australian 7.8 Vietnamese 4.3 Nahum et al, 1993 African American 7.5 White 4.7 Asian 4.2 Lopez-de la Pena et al, 1997 Mexican 6.9 Yalcin et al, 1996 Turkish 6.6 Rith-Najarian et al, 1996 Native American (Chippewa) 5.8 Fraser et al, 1994 Israeli 5.7 Bedouin 2.4 Rizvi et al, 1992 Pakistani 3.5 Miselli et al, 1994 Italian 2.3 Serirat et al, 1992 Thai 2.2 Jang et al, 1995 Korean 2.2 Mazze et al, 1992 White, Minnesota 1.5
  • 22. 974 CHAPTER 46 Diabetes in Pregnancy tary counseling is capably provided by a certified diabetes educator. In any case, formal dietary assessment and counseling should be provided at several points during the pregnancy to design a dietary prescription that can provide adequate quantity and distribution of calories and nutrients to meet the needs of the pregnancy and support achieving the plasma glucose targets that have been established. For obese women (BMI > 30 kg/m2 ), a 30% to 33% calorie restriction (to 25 kcal/kg of actual weight per day or less) has been shown to reduce hyperglycemia and plasma triglycerides with no increase in ketonuria. Moderate restriction of dietary carbohydrates to 35% to 40% of calories has been shown to decrease maternal glucose levels and improve maternal and fetal outcomes.217 In a nonrandomized study, subjects with low-carbohydrate intake (<42%) frequently required the addition of insulin for glucose control (RR = 0.14; P < .05), had a sig- nificantly lower rate of macrosomia (RR = 0.22; P < .04), and had a lower rate of cesarean deliveries for cephalopelvic disproportion and macrosomia (RR = 0.15; P < .04). Low-Glycemic Foods Manipulation of the type of carbohydrate in the diet can provide additional benefits in glycemic control. Crapo and coauthors218 com- pared the blood glucose excursions induced by the ingestion of 50 g of carbohydrate from dextrose, rice, potatoes, corn, and bread. They observed that the highest glucose response occurred with dextrose and potatoes, with much lower peaks occurring after intake of corn and rice. This led to the concept of classifying foods by their glycemic index related to their tendency to induce hyperglycemia. In general, low- glycemic foods, such as complex (rather than simple) carbohydrates and those with higher soluble fiber content, are associated with a more gradual release of glucose into the bloodstream. Formal dietary consultation at periodic intervals during the preg- nancy improves metabolic control. Timing and content of meals should be reviewed at each visit together with the patient’s individual food preferences. In all pregnant women, the continuing fetal con- sumption of glucose from the maternal bloodstream results in a steady downward drift in maternal glucose levels unless feeding occurs. In patients taking insulin or oral hypoglycemics, prolonged periods (>4 hours) without food intake increase the risk of hypoglycemic episodes. In these patients, a rather rigid schedule of three meals plus snacks at mid-morning, mid-afternoon, and bedtime is often necessary to achieve smooth control. Because insulin resistance changes dynami- cally during pregnancy, the dietary prescription must be continually adjusted according to the patient’s weight gain, insulin requirement, and pattern of exercise. Avoiding Nocturnal Hypoglycemia Unopposed intermediate-acting insulin action during the hours of sleep frequently results in severe nocturnal hypoglycemia at 3 to 4 AM in individuals with type 1 diabetes. Reducing the insulin dose to avoid this complication typically leads to unacceptably high glucose levels on rising at 6 to 7 AM, whereas adding a bedtime snack helps to moderate the effect of bedtime insulin and to sustain glucose levels during the night. The snack should contain a minimum of 25 g of complex car- bohydrate and enough protein or fat to help prolong release from the gut during the hours of sleep. Avoiding Ketosis The issue of maternal ketosis and its potential effect on childhood mental performance is a source of continuing controversy. Churchill and associates219 reported that ketonuria during pregnancy is associ- ated with impairment of neuropsychological development of offspring. This report has resulted in admonitions to avoid caloric reduction in any pregnant woman. The methodology in Churchill and associates’ study has been criticized, however, because the ketonuria data were obtained from many different hospitals by having a nurse obtain a single urine sample for ketone testing on the day of delivery. Coetzee and colleagues220 found morning ketonuria in 19% of women with insulin-independent diabetes on a 1000-calorie diet, 14% of those on a 1400- to 1800-calorie diet, and 7% of normal pregnant women on a free diet. There were no untoward neonatal events in infants of any of the ketonuric mothers. Rizzo and coworkers174 studied 223 pregnant women with diabetes and their offspring and 35 with normal glucose tolerance and found no relationship between maternal hypoglycemia and intellectual function of the offspring. There may be a difference between starvation ketosis and the ketosis that develops with poorly controlled diabetes. Ketonuria develops in 10% to 20% of normal pregnancies after an overnight fast and may protect the fetus from starvation in the nondiabetic mother. In the final analysis, significant maternal ketonemia resulting in maternal acid- emia is probably unfavorable for the mother and fetus. The small degrees of ketosis occurring in many pregnant women, including those with diabetes, are unlikely to lead to measurable deficits in the newborn. Principles of Glucose Monitoring Glycohemoglobin Measurements of glycosylated hemoglobin have proved to be a useful index of glycemic control over the long term (4 to 6 weeks), providing a numeric index of the patient’s overall compliance.221 Although assess- ing Hb A1c levels every 4 to 6 weeks during pregnancy rarely alters management significantly, it can provide the patient with a score by which she can rate the success of her hourly efforts to keep her blood glucose levels within a narrow range. Glycohemoglobin levels are too crude to guide the adjustments to insulin. Self-Monitoring of Blood Glucose The availability of capillary glucose chemical test strips has revolution- ized the management of diabetes, and they should be considered the standard of care for pregnancy monitoring. The discipline of measur- ing and recording blood glucose levels before and after meals has a positive effect on improving glycemic control.222 TIMING OF CAPILLARY GLUCOSE MONITORING The frequency and timing of self-monitoring of blood glucose should be individualized (Table 46-15). However, because postprandial values have the strongest correlation with fetal growth, checking after meals is essential. The DIEP study reported that when postprandial glucose values averaged 120 mg/dL, approximately 20% of infants were macrosomic, whereas a modest 30% rise in postprandial glucose levels to a mean level of 160 mg/dL resulted in a 35% rate of macrosomia.223 Similar results emphasizing postprandial blood glucose monitoring were reported by de Veciana and associates,224 who randomized dia- betic women to use of preprandial or postprandial blood glucose levels for dietary and insulin management. The women managed using post- prandial levels had markedly better results than did those managed using preprandial levels. In the postprandial group, with the mean (± standard deviation) change in the glycosylated hemoglobin value greater (−3 ± 2.2% versus 0.6 ± 1.6%; P < .001), the birth weights were lower (3469 ± 668 g versus 3848 ± 434 g; P = .01), and the rates of
  • 23. 975CHAPTER 46 Diabetes in Pregnancy neonatal hypoglycemia (3% versus 21%; P = .05) and macrosomia (12% versus 42%; P = .01) were lower. With these facts in mind, a typical glucose monitoring schedule involves capillary glucose checks on rising in the morning, 1 or 2 hours after breakfast, before and after lunch, before dinner, and at bedtime. For patients taking intermediate- or long-acting medication at bedtime, a capillary glucose level between 3 and 4 AM (the lowest glucose level of the day) two to three times per week is helpful in interpreting the glucose values in the morning. The clinician should be aware of the specific type of capillary glucose reflectance meter being used by the patient, because plasma glucose values are 10% to 15% less than those measured in whole blood from the same sample. Most of the newer reflectance meters are calibrated for plasma glucose readings. The target glucose values used in management depend on the type of meter used. TARGET CAPILLARY GLUCOSE LEVELS Controversy exists about whether the target glucose levels to be maintained during diabetic pregnancy should be designed to limit macrosomia or to closely mimic nondiabetic pregnancy profiles. The Fifth International Workshop-Conference on Gestational Diabetes195 recommends the following: Fasting plasma glucose level of 90 to 99 mg/dL (5.0 to 5.5 mmol/L) and 1-hour postprandial plasma glucose level less than 140 mg/dL (<7.8 mmol/L) or 2-hour postprandial plasma glucose level less than 120 to 127 mg/ dL (<6.7 to 7.1 mmol/L) Only recently have data been reported that describe normal glucose variations during pregnancy in nondiabetic gravidas. The profiles described by Cousins and colleagues225 (Fig. 46-12) are derived from highly controlled studies in which volunteer subjects were fed test meals with specific caloric content on a rigid schedule. Parretti and coworkers226 profiled normal pregnant women twice monthly prepran- dially and postprandially during the third trimester. Testing was done with capillary glucose meters, and the women followed an ad libitum diet. The results of the 95th percentile of the plasma glucose excursions are shown in Figure 46-13. Fasting and premeal plasma glucose levels are usually below 80 mg/dL and often below 70 mg/dL. Peak postpran- dial plasma glucose values rarely exceed 110 mg/dL. Yogev and colleagues227 obtained continuous glucose information from nondiabetic pregnant women using a sensor that monitored TABLE 46-15 TIMING OF HOME CAPILLARY GLUCOSE MONITORING Capillary Glucose Assessment Advantage Disadvantage Preprandial Permits prospective adjustment of food intake, supplementation of preprandial insulin Preprandial or fasting glucose levels correlate poorly with fetal morbidity. Significant postprandial hyperglycemia may go undetected. Postprandial Permits supplementation of insulin to reduce postprandial glucose overshoots; improved postprandial control correlates with improved fetal or neonatal outcome Results are obtained after food intake. Bedtime Permits adjustment of calories at bedtime snack, adjustment of bedtime insulin 3-4 AM Enables detection of nocturnal hypoglycemia Interrupts sleep, may increase stress Fasting ϭ 85.2 Ϯ 3.8 24 hr mean ϭ 93.4 Ϯ 1.9 Fasting ϭ 77.7 Ϯ 2.3 24 hr mean ϭ 85.6 Ϯ 2.9 3rd trimester 2nd trimester Postpartum SleepGlucose 0800 40 60 80 mg/100mLmg/100mLmg/100mL 100 120 40 60 80 100 120 40 60 80 100 120 1200 1600 Clock hours 2000 2400 0400 0800 Fasting ϭ 74 Ϯ 2.7 24 hr mean ϭ 87.3 Ϯ 1.7 FIGURE 46-12 Glucose variations during pregnancy. Profile of blood glucose over 24 hours in the second and third trimesters of pregnancy, with postpartum observations used as a control. Error bars represent standard error. Arrows indicate time of test meal administration. (From Cousins L, Rigg L, Hollingsworth D, et al: The 24-hour excursion and diurnal rhythm of glucose, insulin and C peptide in normal pregnancy. Am J Obstet Gynecol 136:483, 1980.)
  • 24. 976 CHAPTER 46 Diabetes in Pregnancy interstitial fluid glucose levels, and they found results similar to those of Parretti and coworkers.226 The range of normal glucose levels occur- ring in nondiabetic pregnancy is summarized in Table 46-16. In consideration of these facts, the target plasma glucose values to be used during pregnancy management of women with diabetes should range from 65 to 95 mg/dL preprandially and never exceed 130 to 140 mg/dLpostprandiallyat1hour.226 Superbglycemiccontrolrequires attention to preprandial and postprandial glucose levels. Principles of Insulin Therapy Despite the fact that no available insulin delivery method approaches the precise secretion of the hormone from the human pancreas, the judicious use of modern insulins can mimic these patterns remarkably well. The goal of exogenous insulin therapy during pregnancy must be to achieve diurnal glucose excursions similar to those of nondiabetic pregnant women. Given that in normal pregnant women, postprandial blood glucose excursions are maintained within a relatively narrow range (70 to 120 mg/dL), the task of reproducing this profile is daunting and requires meticulous daily attention by both patient and physician. As pregnancy progresses, the increasing fetal demand for glucose results in lower fasting and between-meal blood glucose levels, increas- ing the risk of symptomatic hypoglycemia. Upward adjustment of short-acting insulins to control postprandial glucose surges within the target range only exacerbates the tendency to interprandial hypoglyce- mia. Any insulin regimen for pregnant women requires combinations and timing of insulin injections different from those that would be effective in the nonpregnant state. The regimens must be modified continually as the patient progresses from the first to the third trimes- ter and as insulin resistance rises. The regimen should always be matched to the patient’s unique physiology, work, rest, and food intake schedule. Types of Insulin The types of insulin frequently used in diabetes control are listed in Table 46-17. Several newer insulins are available for use, but most have not been extensively evaluated in pregnancy. They include the short- acting insulins lispro (Humalog) and aspart (Novolog) and the newer, very-long-acting, molecularly modified insulins detemir (Levemir) and glargine (Lantus). The activity profiles of the intermediate- and long-acting insulins are shown in Figure 46-14.228 Typical Insulin Regimens Flexibility is important in dosing and adjusting insulin during preg- nancy. Although most patients find it necessary to organize their meal- times and physical activity around their insulin regimen, changing the timing of insulin injections and types of insulin is frequently necessary TABLE 46-16 AMBULATORY GLUCOSE VALUES IN PREGNANT WOMEN WITH NORMAL GLUCOSE TOLERANCE Study Subjects (N) Fasting (mg/dL) Postprandial Level at 60 min (mg/dL) Postprandial Peak (mg/dL) Parretti et al, 2001 51 69 (57-81) 108 (96-120) Yogev et al, 2004 57 75 (51-99) 105 (79-131) 110 (68-142)* *The time of the peak postprandial glucose concentration was 70 minutes (range, 44 to 96). Adapted from Metzger BE, Buchanan TA, Coustan DR, et al: Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 30:S251-S260, 2007. 28 Weeks 8:00 AM 50 60 70 Plasmaglucosemg/dL 80 90 100 110 120 67 62 65 106 103 111 89 95 99 78 73 81 106 109 108 95 100 102 81 79 80 75 70 75 70 69 73 106 104 108 91 92 103 74 73 76 68 74 75 66 72 73 70 68 68 9:00 AM 10:00 AM 12:00 AM 1:00 PM 2:00 PM 4:00 PM 6:00 PM 8:00 PM 9:00 PM 10:00 PM 12:00 AM 2:00 AM 4:00 AM 6:00 AM 32 Weeks 36 Weeks FIGURE 46-13 Diurnal plasma glucose profile in normoglycemic third-trimester gravidas. The numbers represent the 95th percentile values. (Adapted from Parretti E, Mecacci F, Papini M, et al: Third-trimester maternal glucose levels from diurnal profiles in nondiabetic pregnancies: Correlation with sonographic parameters of fetal growth. Diabetes Care 24:1317, 2001. Copyright © American Diabetes Association. Reprinted with permission from the American Diabetes Association.)
  • 25. 977CHAPTER 46 Diabetes in Pregnancy to match lifestyle and occupational needs and to optimize glycemic control. The following guidelines and examples can help in managing and adjusting insulin during pregnancy: 1. In the first trimester, reduce the insulin dose by 10% to 25% to avoid hypoglycemia. Reduced physical activity and caloric intake associ- ated with the appetite changes and fatigue of early pregnancy lead to increased insulin effectiveness and interprandial hypoglycemia. It is typical to reduce insulin progressively from the 6th to the 14th week and then to begin restoring it as the insulin resistance mediated by rising placental hormones returns in the second trimester. Jovanovic and colleagues108 reported from the DIEP study that a significant 18% increase in mean weekly dosage was observed between weeks 3 and 7 (P < .0001), followed by a signifi- cant 9% decline from week 7 through week 15 (P < .0001). In women with pregestational diabetes, continual downward adjust- ment in insulin is typically required from the first prenatal visit until approximately 14 to 16 weeks, after which requirements begin to rise steadily. 2. A typical total insulin dose is 0.7 units/kg in the first trimester, but this must be increased progressively with pregnancy duration from the second trimester onward. In women with type 1 diabetes, insulin increases are usually 20% to 30% over nonpregnant baseline by the end of pregnancy (Figure 46-15).229 In insulin-resistant type 2 patients, 30% to 150% increases are not unusual. Insulin require- ments normally plateau after 35 weeks’ gestation and often drop significantly after 38 weeks. TABLE 46-17 INSULIN PREPARATIONS AND PHARMACOKINETICS Insulin Preparation Time to Peak Action (hr)* Total Duration of Action (hr)* Comment Insulin lispro (Humalog) 1 2 Onset within 10 min of injection; no need to delay meal onset after injection Insulin aspart (Novolog) 1 2 Onset within 10 min of injection; no need to delay meal onset after injection Regular insulin 2 4 Good coverage of individual meals if injected 20 min before eating; increased risk of postprandial hypoglycemia with unopposed action 2-3 hr after eating. NPH insulin 4 8 Provides intermediate-acting control; give on rising and at bedtime; risk of 3 AM hypoglycemia Insulin glargine (Lantus) 5 <24 Prolonged flat action profile; limited pregnancy experience; increased risk of nocturnal hypoglycemia or undertreatment during the day *Times are approximate in typical pregnant women with diabetes. 0 0 mg/Kg/min μmol/Kg/min 0 4 8 12 16 20 24 1.0 2.0 3.0 4.0 4 8 Time (hours) SC insulin n ϭ 20 type 1 diabetic patients Mean Ϯ SE 12 16 20 24 Ultralente NPH CSII Glargine FIGURE 46-14 Activity profiles of intermediate- and long-acting insulins. The kinetics of NPH, Ultralente, glargine (Lantus), and continuous subcutaneous insulin infusion with lispro insulin are graphed. The curves show the glucose infusion rate necessary to maintain plasma glucose at 130 mg/dL. CSII, continuous subcutaneous insulin infusion; SC, subcutaneous; SE, standard error. (From Lepore M, Pampanelli S, Fanelli C, et al: Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and Ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 49:2142, 2000. Copyright © American Diabetes Association. Reprinted with permission from the American Diabetes Association.) FIGURE 46-15 Progressive insulin requirements. The insulin requirements of women with gestational diabetes change throughout pregnancy. (From Langer O: Maternal glycemic criteria for insulin therapy in gestational diabetes mellitus. Diabetes Care 21[Suppl 2]: B91, 1998.)
  • 26. 978 CHAPTER 46 Diabetes in Pregnancy 3. The kinetics of NPH insulin are such that care must be taken to time peak action at 5 to 7 AM and avoid peaking at 4 AM, when maternal glucose levels are lowest. For many women, whose bedtime may be at 8 or 9 PM, NPH peaks early and exposes the mother and fetus to nocturnal hypoglycemia. It is often better to administer NPH at a set time between 10 and 11 PM, not the less accurate timing of “bedtime,” to optimize needed insulin action during the hours of 5 to 7 AM. 4. A combination of short- and intermediate-acting insulins is employed to maintain glucose levels in an acceptable range. A typical regimen involves intermediate-acting insulin (NPH) before breakfast and at bedtime, with injections of regular or short-acting insulin before breakfast and before dinner. Two thirds of insulin is given in the morning and one third in the afternoon and at bedtime. For example, the regimen may be 20 units of NPH and 10 units of regular insulin in the morning, 8 units of regular insulin with dinner, and 8 units of NPH at 10 PM. The AM dose of NPH covers the periods before and after lunch. Avoid NPH injections at din- nertime because the peak occurs at 2 to 3 AM, creating symptomatic hypoglycemia. 5. Preprandial doses of regular insulin sufficient to keep 1-hour post- prandial plasma glucose levels below 130 mg/dL may result in hypo- glycemia 2 to 4 hours later (e.g., regular insulin before breakfast often causes hypoglycemia at 10 AM). When regular insulin is used to cover the major meals, snacks are essential in the late morning, the late afternoon, and before bedtime to avoid interprandial hypo- glycemia. This interprandial hypoglycemia effect is intensified if the regular insulin injection is not given at least 20 to 30 minutes before the meal. This precaution is particularly relevant for hospitalized patients (because meals do not always arrive on schedule) and when taking meals in restaurants. 6. The short-acting insulins lispro or aspart are preferred during dia- betic pregnancy. Lispro is manufactured by inverting a short amino acid sequence within the insulin molecule, resulting in a signifi- cantly faster onset of action. Lispro injections immediately before meals reduce the risk of hangover hypoglycemia because of the short duration of action. Using an in vitro perfusion model, Holcberg and colleagues230 reported that lispro does not cross the human placenta. Compared with regular human insulin, the peak serum lispro concentration is three times higher, time to peak is 4.2 times faster, the absorption rate constant is double, and the dura- tion of action is one half as long.228 These kinetics allow the patient to inject insulin just before eating, rather than having to delay 20 to 30 minutes to allow regular insulin to begin its effect. Compared with regular insulin, lispro reduced postprandial hyperglycemia and decreased the rate of mild hypoglycemic episodes; it was also associ- ated with lower predelivery Hb A1c values and received higher patient satisfaction scores.231 Similar findings have been reported when insulin aspart was compared with regular insulin.232 In summary, lispro or aspart can be substituted 1:1 for regular insulin, and each is highly effective when given before meals in reducing postprandial glycemia while avoiding insulin hangover, which increases patient compliance. Short-acting insulins are effective when used in the insulin pump (discussed later).233 With regard to safety and effectiveness, small studies have indicated equivalent perinatal outcomes.234,235 Mathieson and coworkers236 reported similar perinatal outcomes but improved maternal glycemic control in pregnant women randomized to aspart or regular insulin, dem- onstrating significantly lower mean postprandial plasma glucose levels with aspart (P = .003). A more detailed study of glucose dynamics after administration of aspart or regular insulin to women with gestational diabetes by Pettitt and associates237 found that glucose areas under the curve were significantly lower with insulin aspart (180-min area, 7.1 mg·h·dL−1 ; P = .018) but not with regular insulin (30.2 mg·h·dL−1 ; P = .997) or with no insulin (29.4 mg·h·dL− 1 ), indicating the potential for improved glycemic control with short-acting insulins compared with regular insulin. 7. The use of insulin glargine during pregnancy is problematic because of its 20- to 26-hour duration. In three large comparative trials of nonpregnant subjects, glargine decreased glycosylated hemoglobin or fasting blood glucose levels, or both, to an extent similar to that seen with NPH insulin. A lower incidence of hypoglycemia, espe- cially at night, was reported in most trials with insulin glargine compared with NPH insulin.238 Experience is limited in pregnancy, but the few studies existing demonstrate satisfactory results.239,240 Although the relatively flat activity profile of glargine is attractive, the dose must be regulated to keep basal insulin action during the night from causing hypoglycemia. During the day, when insulin resistance and insulin requirements are higher, the nocturnal basal rate is usually inadequate, and NPH must be added. As shown in Figure 46-14, the nocturnal low glucose level (typically at 4 AM) decreases as the third trimester progresses. Great care must be exer- cised in using glargine to avoid severe nocturnal hypoglycemia. Glargine appears to be safe for use during embryogenesis if glucose control is adequate.241 Adjusting Insulin Dosage Using Carbohydrate Counting, Preprandial Glucose Levels, and Insulin Corrections Intermediate- and long-acting insulins should be adjusted no more frequently than weekly or biweekly to maintain preprandial plasma glucose levels in the target range (70 to 105 mg/dL). However, with short-acting insulins, glycemic control is better when the patient is able to vary, within a reasonable range, the insulin dose she uses to cover a meal, depending on its calorie content (or grams of carbohydrate) and the plasma glucose level existing at the time she begins eating. This often means varying short-acting insulin dosage with every injection. CARBOHYDRATE COUNTING Patients with pregestational diabetes are usually taught to count the grams of carbohydrate in their meals and adjust the short-acting insulin dosage accordingly. A typical meal containing 60 grams of carbohydrate may require 4 to 6 units of lispro (ratio of 1 unit of insulin to grams of carbohydrate of 1:15) in the nonpregnant indi- vidual. In the first trimester, a typical ratio is approximately 1:12. However, by the second trimester, more insulin is required (1:10 to 1:6), and in the third trimester, especially in patients with some degree of insulin resistance, ratios fall to 1:6 or even 1:2. The clinician should anticipate these increases in insulin as pregnancy progresses, because the patient often interprets these changes as errors or failure. Carbohydrate counting has limits in accuracy (e.g., miscalculation of carbohydrate content, individual differences in glucose uptake dynamics), which may result in erratic control. During pregnancy, women who relatively strictly regiment their food quantity, content, and timing, so that carbohydrate calculations are within a reasonably narrow range, have better control. PREPRANDIAL GLUCOSE LEVELS Given the same calorie content of a meal, achieving target post- prandial plasma glucose levels requires more insulin if the preprandial glucose level is higher. Allowing patients to add 2 units of lispro when
  • 27. 979CHAPTER 46 Diabetes in Pregnancy the preprandial glucose level exceeds 120 mg/dL and to reduce lispro dosage by 2 units when the preprandial glucose level is below 80 mg/dL provides smoother control and avoids undesired postprandial glyce- mic excursions when the preprandial glucose is outside the target range. INSULIN CORRECTIONS Women with pregestational diabetes are frequently taught how to perform preprandial and postprandial insulin corrections. A typical regimen is to add 1 to 2 units of lispro for every 50 mg/dL that the glucose level is out of target range. A preprandial glucose level of 130 mg/dL would require 1 unit of lispro over the prescribed dose for that meal. As pregnancy progresses, corrections increase from 1 per 50 mg/dL to 1 per 20 mg/dL. However, the patient must be instructed not to take more than 4 to 6 correction units in a single bolus during pregnancy and instead retest glucose in 1 to 2 hours and apply an additional correction at that time. Use of the Insulin Pump Most of the principles described to enhance and smooth glycemic control by manipulating timing, quantity, and type of insulin can be used with greater facility with continuous, subcutaneous insulin infu- sion delivered by a programmable pump. These devices, which infuse insulin by means of a convenient catheter placed into the subcutaneous tissue near the abdomen, can be programmed to provide varying basal and bolus levels of insulin, which change smoothly even while the patient sleeps or exercises. The effectiveness of continuous, subcutaneous insulin infusion in pregnancy is well established.242-244 Hieronimus and colleagues245 com- pared outcomes of 33 pregnant women managed with insulin pumps with 23 receiving multiple injections and reported similar Hb A1c levels and rates of macrosomia and cesarean deliveries. Lapolla and cowork- ers246 reported a small cohort of 25 women treated with insulin pumps in pregnancy compared with conventional insulin treatment (n = 68) and found no differences in glycemic control or perinatal outcome. Use of continuous, subcutaneous, programmable insulin infusion has several advantages over conventional intermittent insulin admin- istration, including the convenience of changing basal rates automati- cally when the patient is asleep or otherwise occupied and providing adjustable boluses discreetly from a pump worn under the clothing without the need for needles, syringes, and medication vials. Because pump malfunctions, precipitation of insulin inside the pump mecha- nism, abscess formation, and poor uptake from the infusion site can occur unexpectedly, successful insulin pump use requires a meticulous patient, a knowledgeable diabetologist or perinatologist, and prompt availability of emergency counseling and assistance on a 24-hour basis.247 A properly designed insulin pump infusion scheme allows conve- nient tailoring of the insulin administration profile to the patient’s individual metabolic and lifestyle rhythms. A sample regimen is shown in Table 46-18. The lowest infusion rate of the day is between 11 PM and 4 AM, when it is set at about 70% of the mean rate needed during the day. The basal rate must be increased to 1.3 to 1.5 times the mean daily rate between 5 AM and 10 AM to provide extra insulin coverage for the high insulin-resistance period as the day begins (i.e., dawn effect). For the remainder of the day (10 AM to 11 PM), a steady mean infusion rate is usually sufficient. Insulin boluses, programmed to limit the postprandial excursion to 130 mg/dL or less at 1 hour, are given as often as needed. The enhanced ability for the patient to administer extra insulin doses without syringes and insulin vials is of great value in improving the smoothness of glycemic control. Starting Insulin with Gestational Diabetes Clinicians and patients are reluctant to start insulin in patients with gestational diabetes, but this intervention may be essential if macroso- mia is to be reduced or avoided. Because the period of maximum fetal growth velocity (200 g/wk) and fat accretion occurs at approximately 33.5weeks’gestation,delayingdefinitivetherapywithrepeatedattempts to correct a suboptimal glucose profile with dietary adjustments may, by 33 to 34 weeks, have missed the time when glycemic intervention is most effective in modulating fetal growth. It is reasonable to allow a 1- to 2-week trial of dietary management before resorting to other measures, but waiting longer does not significantly increase the likeli- hood of good control. McFarland and colleagues248 have shown that approximately 50% of patients achieve good glycemic control during the first 2 weeks of dietary therapy, but by the 4th week, only an addi- tional 10% attain acceptable blood glucose levels. The value of insulin administration in gestational diabetes was assessed by Crowther and associates,249 who randomized 1000 women with gestational diabetes to insulin treatment or no medical therapy in the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS trial). Controls with normal OGTT results were included in the trial. In the insulin group, glucose levels were maintained at less than 99 mg/dL before meals and less than 126 mg/dL 2 hours postprandially. The rate of serious perinatal complications was signifi- cantly lower among the infants of 490 women in the intervention group than among the infants of 510 women in the routine-care group (1% versus 4%; RR adjusted for maternal age, race or ethnic group, and parity = 0.33; CI, 0.14 to 0.75; P = .01). The intervention group had a significantly higher rate of labor induction than the routine-care group (39% versus 29%), but the rates of cesarean delivery were similar. Cord plasma glucose levels were higher in women receiving routine care compared with controls, but it was normalized by treatment for mild GDM (P = .01). At 3 months after delivery, the TABLE 46-18 TYPICAL SECOND-TRIMESTER CONTINUOUS ADMINISTRATION PROFILE USING A SUBCUTANEOUS INSULIN INFUSION PUMP Time Basal Rate Bolus (U) Comment 12 midnight 0.6 U/hr Lower basal rate for sleep 5 AM 1.5 U/hr Higher basal rate opposes the “dawn effect” of rising serum glucose from 4 to 6 AM 7 AM 8 Prebreakfast bolus 9 AM 1.0 U/hr Lower basal rate to match increased physical activity, decreased insulin needs 12 noon 4 Prelunch bolus 6 PM 4 Predinner bolus 10 PM 0.6 U/hr Lower basal rate for sleep
  • 28. 980 CHAPTER 46 Diabetes in Pregnancy intervention group had lower rates of depression and higher quality- of-life scores. With regard to newborn outcomes in the ACHOIS trial, umbilical cord serum insulin and insulin to glucose ratio were similar between the three groups, but leptin concentration, an indicator of fat mass, was lower in treated women with GDM compared with routine care (P = .02), suggesting that treatment of GDM using diet, blood glucose monitoring, and insulin, if necessary, influences the fetal adipoinsular axis, which may reduce the risk of childhood and adult obesity late in life.250 Jovanovic-Peterson and colleagues251 reported a protocol in which GDM patients were treated with insulin if any fasting glucose level exceeded 90 mg/dL or postprandial glucose level exceeded 120 mg/dL. Over a period of 6 years, this protocol resulted in a decrease in the rate of macrosomic infants from 18% to 7% and a drop in the cesarean rate from 30% to 20%. Buchanan and associates252 used ultrasound screen- ing of fetal abdominal circumference in 303 diet-controlled GDM patients at 28 weeks to identify early macrosomia that might benefit from insulin treatment. When pregnancies with a fetal abdominal cir- cumference above the 75th percentile were randomized to continued diet or twice-daily insulin therapy, birth weights and percentage of macrosomic infants were reduced in the insulin group (3647 ± 67 g versus 3878 ± 84 g; P < .02 and 13% versus 45%; P < .02). Neonatal obesity, as reflected by skinfold measurements at three sites (P < .005), also was lower. The insulin regimen used in managing women with gestational diabetes should be designed to address the patient’s individual glucose profile, because some women require insulin to prevent only fasting AM hyperglycemia and others only for postprandial excursions. Typi- cally, one to several postprandial glucose levels become consistently above target as the patient’s ability to compensate for rising insulin resistance becomes inadequate with diet alone. In such cases, giving short-acting insulin such as lispro or aspart (4 to 8 units to start) before meals is helpful. If more than 10 units of short-acting insulin is needed before the noon meal, adding a 6- to 8-unit dose of NPH before break- fast helps to achieve smoother control. If the fasting glucose levels rise above 90 to 95 mg/dL, 4 to 6 units of NPH insulin should be admin- istered between 10 to 11 PM. The doses are scaled up as necessary, twice weekly or more often, to keep glucose levels within the target range. Use of Oral Hypoglycemic Agents Maintaining glucose levels within the target range requires meticulous attention to diet and physical activity. For many patients, injecting insulin frequently is impossible, and there are many initiatives to augment glucose control with oral agents, particularly in patients with insulin-resistant type 2 diabetes. An ideal treatment would reduce insulin resistance, improve insulin secretion or action, and delay the uptake of glucose from the gut. Current strategies are aimed at aug- mentation of insulin supply (i.e., sulfonylurea and insulin therapy), amelioration of insulin resistance (i.e., exercise, weight loss, and met- formin and troglitazone therapy), and limitation of postprandial hyperglycemia (i.e., acarbose therapy). Pharmacology and Safety Sulfonylurea compounds, commonly prescribed in the past for patients with type 2 diabetes, have been considered contraindicated during pregnancy because of the high degree of transplacental penetration of most of these agents and the clinical reports of drug concentrations in the neonate higher than maternal levels associated with prolonged and severe neonatal hypoglycemia.253 However, rigorously designed trials have not been performed to assess these agents during pregnancy. Reports of fetal anomalies have been largely anecdotal. An increased rate of congenital malformations, particularly ear anomalies, has been reportedfromasmallcase-controlstudy.254 WhenTownerandcowork- ers255 evaluated the frequency of birth defects in fetuses of patients who took oral hypoglycemics during the periconceptional period, they found that the first-trimester glycohemoglobin level and duration of diabetes were strongly associated with fetal congenital anomalies but that use of oral hypoglycemic medications was not. Interest in glyburide, a second-generation oral sulfonylurea avail- able in the United States since 1984, has recently been rekindled. When glyburide was compared with first-generation sulfonylureas, it was equally effective, had a lower incidence of side effects, and reduced fasting blood glucose and glycohemoglobin levels, without the incon- venience of the additional training required to administer insulin. Because of its ability to enhance target tissue insulin sensitivity, glybu- ride has been shown to improve glycemic control in many type 2 dia- beticpatientswhohavepreviouslyfailedtherapy.Asadjunctivetherapy, glyburide can reduce the daily dosage for those who require large amounts of insulin.256 Glyburide A unique characteristic of glyburide that allows its use in pregnancy is its minimal transport across the human placenta.257 A study by Elliott and colleagues258 evaluated glyburide transport in 10 term human placentas with the single-cotyledon placental model and found virtu- ally no transfer of glyburide even at concentrations 100 times the typical therapeutic levels. This surprisingly low placental transfer may result from the very high plasma-protein binding of glyburide coupled with a short elimination half-life of 4 to 8 hours.257,259 Based on findings consistently showing minimal transfer of glybu- ride across the placenta, Langer and colleagues260 designed a random- ized trial to compare this oral agent with insulin in patients with gestational diabetes. They randomized 404 women with second- and third-trimester singleton pregnancies who had gestational diabetes requiring treatment to receive glyburide or insulin in an intensified treatment protocol. At the conclusion of the trial, there was no differ- ence between the groups in mean maternal blood glucose, percentage of infants who were LGA (12% and 13%, respectively), birth weight at or above 4000 g (7% and 4%), or neonatal complications (pulmonary, 8% and 6%; hypoglycemia, 9% and 6%; admission to neonatal inten- sive care unit, 6% and 7%; fetal anomalies, 2% and 2%). Only 4% of the glyburide group required insulin therapy. Glyburide was not detected in the cord serum of any infant in the glyburide group. However, only 82% of the glyburide and 88% of the insulin-treated patients achieved the target level of glycemic control, representing a glyburide “failure rate” of 18%. With regard to glyburide dosing during the trial, 31% of patients were treated with 2.5 mg, 21% with 5 mg, 19% with 10 mg, 9% with 15 mg, and 20% with 20 mg. The mean glyburide dose was 9.2 mg. Of the maternal outcome variables assessed, none was significantly different between groups except the dramatic (P = .03) reduction in maternal hypoglycemic episodes in the glybu- ride-treated group (2%) compared with the 20% rate for insulin. Beyond this single encouraging study, further nonrandomized experience with glyburide during pregnancy is accumulating.261,262 Chmait and coworkers,263 describing their experience with 69 patients with gestational diabetes managed on glyburide, reported that 19% of patients required adjunctive insulin therapy to keep glucose values in the target range. The adjunctive insulin rate was higher for women diagnosed earlier in pregnancy (20 versus 27 weeks; P < .003) and those whose average fasting glucose in the week before starting glyburide was
  • 29. 981CHAPTER 46 Diabetes in Pregnancy higher (126 versus 101 mg/dL). No cases of neonatal hypoglycemia occurred in the glyburide group. Langer and colleagues264 reanalyzed the previously cited random- ized, controlled trial, addressing the issues of glyburide dose, GDM severity, and pregnancy outcome and grouping trial participants into low (≤10 mg) and high (>10 mg) daily glyburide dose groups and low (≤95 mg/dL) or high (>95 mg/dL) GDM severity groups based on fasting OGTT values. The rates of macrosomia were 16% versus 5%, and the rates of infants who were LGA were 22% versus 8%, (P = .01), respectively, in the high-dose and low-dose glyburide groups. Stratifi- cation by disease severity (using the level of fasting glucose on glucose tolerance testing) revealed equally lower rates of LGA for the glybu- ride- and insulin-treated subjects in the low-severity group. In the higher-severity group, the rates of macrosomia and LGA were similar in the glyburide and insulin arms. The study authors suggested that achieving an excellent level of glycemic control, rather than the mode of pharmacologic therapy, is the key to improving outcomes in cases of GDM. There is a growing acceptance of glyburide use as a primary therapy for GDM.265 Although no new randomized trials have been completed, several retrospective series have been published comprising 504 glyburide-treated patients, and these studies have been summarized by Moore.266 Jacobson and coworkers267 performed a retrospective cohort com- parison of glyburide and insulin treatment of gestational diabetes. Patients with fasting plasma glucose levels greater than 140 mg/dL on glucose tolerance testing were excluded. The insulin group (n = 268) consisted of those diagnosed in 1999 through 2000, and the glyburide group (n = 236) was diagnosed in 2001 through 2002. Glyburide dosing was begun with 2.5 mg in the morning and increased by 2.5 to 5.0 mg weekly. If the dose exceeded 10 mg daily, twice-daily dosing was considered. If glycemic goals were not met on a maximum daily dose of 20 mg, patients were changed to insulin. The study size was insuffi- cient to detect less than a doubling of the rate of macrosomia or LGA and a 44% increase in neonatal hypoglycemia, but there were no sta- tistically significant differences in gestational age at delivery, mode of delivery, birth weight, LGA, or percent of macrosomic infants. The rate of preeclampsia doubled in the glyburide group (12% versus 6%; P < .02). Women in the glyburide group also had significantly lower post- treatment fasting and postprandial blood glucose levels. The glyburide group was superior in achieving target glycemic levels (86% versus 63%; P < .001). The failure rate (i.e., transfer to insulin) was 12%. Conway and associates268 reported a retrospective cohort of 75 glyburide-treated GDM patients. Good glycemic control was achieved by 84% of the subjects with glyburide, and 16% were switched to insulin. The rate of fetal macrosomia was similar between women suc- cessfully treated with glyburide and those who converted to insulin (11.1% versus 8.3%; P = 1.0), and the mean birth weight was also similar. A not significantly higher proportion of infants in the gly- buride group required intravenous glucose infusions because of hypoglycemia (25.0% versus 12.7%; P = .37). Small cohorts reported by Kremer and colleagues269 and Chmait and coworkers270 demonstrated glyburide failure requiring adjunctive or substitutive insulin rates in the range of 15% to 20%. In these studies, higher GCT results (>160 to 200 mg/dL) were predictive of an approximate 50% failure rate.271 The recommended glyburide dosing regimen, based largely on animal studies and a few human studies of nonpregnant subjects, is to administer the agent once daily, with twice-daily doses reserved for refractory cases. Later studies of glyburide pharmacodynamics suggest that the previously recommended dosing protocols may not be optimal in pregnancy. During development of the drug in the late 1960s, single- dose studies in nondiabetic subjects demonstrated glyburide absorp- tion within 1 hour, peak levels at about 4 hours, and low but detectable levels at 24 hours. The decrease of glyburide in the serum yielded a terminal half-life of about 10 hours, and the glucose-lowering effect could be expected to persist for 24 hours after a single morning dose. Later data have shown that glyburide peaks earlier in the serum and has a significantly shorter half-life than previously believed. These effects reflect the fact that glyburide has two major hydroxyl metabo- lites, both of which are biologically active and excreted equally in the bile and urine. Although advice in the Physician’s Desk Reference indi- cates that the glyburide metabolites provide no significant contribu- tion to glyburide’s hypoglycemic action (1 /400 and 1 /40, respectively, of glyburide’s potency), these data were obtained in rabbits. Yin and associates272 studied the glucose and insulin responses to glyburide in a group of nonpregnant, nondiabetic subjects. After a 5- mg oral dose, serum glyburide levels peaked at 2.75 hours and had sustained levels with a half-life ranging from 2 to 4 hours, considerably shorter than the quoted half-life of 10 hours. To clarify the potential difference in drug action when given as a single dose or chronically over weeks, Jaber and colleagues273 studied glyburide pharmacodynamics during multiple-dose administration. A significant prolongation in the half-life (week 0 = 4.0 ± 1.9 hr; week 6 = 13.7 ± 10.5 hr; and week 12 = 12.1 ± 8.2 hr) was observed during chronic dosing. These results suggest possible drug accumulation or tissue sensitization by glyburide. Yogev and coworkers274 examined the prevalence of undiagnosed, asymptomatic hypoglycemic events in diabetic patients using a con- tinuous glucose monitoring system for 72 consecutive hours. Hypo- glycemia was defined as more than 30 consecutive minutes of a glucose value below 50 mg/dL. Asymptomatic hypoglycemic events were recorded in 63% of insulin-treated patients but in only 28% of glybu- ride-treated patients. The mean number of hypoglycemic episodes per day was significantly higher in insulin-treated patients (4.2 ± 2.1) than in glyburide-treated patients (2.1 ± 1.1; P = .03). In insulin-treated patients, most hypoglycemic events were nocturnal (84%), whereas in glyburide-treated patients, episodes occurred equally during the day and night, suggesting a potential benefit of glyburide over insulin therapy in clinical use. Based on these data, glyburide should be taken at least 30 minutes— and preferably 60 minutes—before meals so that the peak action (2.5 hours after dosing) covers the postprandial glucose surge. Because of its extended duration of action, glyburide taken at 10 to 11 PM is effec- tive in lowering fasting plasma glucose levels in the morning. Signifi- cant interprandial hypoglycemia can occur with glyburide, and patients should carry glucose tablets with them at all times as a precaution. The maximum dose is 20 mg per day, and no more than 7.5 mg should be taken at a single time. Other Agents Metformin is frequently employed in patients with polycystic ovary syndrome and type 2 diabetes to improve insulin resistance and fertility.275 Although it has been documented that metformin therapy improves the success of ovulation induction276 and probably reduces first-trimester pregnancy loss in women with polycystic ovary syndrome,181 the effects of continuing metformin during pregnancy are not clear. Coetzee and Jackson277 treated pregestational and gestational diabetics with metformin, but the treatment failed in 54% and 29%, respectively. The perinatal mortality rate among the metformin patients was 61 per 1000, and the rate of neonatal jaundice was increased. Hellmuth and colleagues278 reported a series of
  • 30. 982 CHAPTER 46 Diabetes in Pregnancy women with gestational diabetes treated with metformin or tolbuta- mide before 1984. Women treated with metformin had a fourfold increase in preeclampsia and a higher perinatal mortality rate compared with those who were receiving tolbutamide. However, metformin-treated women were older, more obese, and treated later in pregnancy. A cohort study of metformin in pregnancy reported by Hughes and associates187 in 2006 included 93 women with metformin treatment (only 32 continued until delivery) and 121 controls. There was no dif- ference in perinatal outcomes between the groups. Glueck and cowork- ers183 compared nondiabetic women with polycystic ovary syndrome (n = 28) who conceived while taking metformin and continued the agent through delivery with matched women without metformin therapy (n = 39). Gestational diabetes developed in 31% of women who did not take metformin and in 3% of those who did (OR = 0.115; CI, 0.014 to 0.938). Because of the beneficial effect of metformin on first-trimester miscarriage, many patients with polycystic ovary syndrome enter pre- natal care taking this medication. Because metformin readily crosses the placenta,184 greater experience with this agent is necessary before it can be recommended for use throughout pregnancy.279 A large, properly powered, randomized, controlled trial is in progress to explore these issues.280 The α-glucosidase inhibitors, another class of oral agents, reversibly inhibit pancreatic amylase and α-glucosidase enzymes in the small intestine, delaying cleavage of complex sugars to monosaccharides and reducing the increase of blood glucose levels after a meal. Although these agents offer particular promise in pregnant women because of limited uptake from the gut, only a few studies of the drugs in preg- nancy are available. Bertini and colleagues281 compared insulin treat- ment (n = 27), glyburide (n = 24), and acarbose (n = 19) in gestational diabetes. No difference was observed in maternal glucose levels or in mean birth weight, although the rates of LGA fetuses were 3.7%, 25%, and 10.5% for the groups, respectively. Neonatal hypoglycemia was observed in eight newborns, six of whom were from the glyburide group. Glucose control was not achieved in five (20.8%) of the patients using glyburide and in eight (42.1%) of the patients using acarbose. Acarbose is given before meals, initially in a dose of 25 mg taken orally three times daily up to a maximum of 100 mg taken orally three times daily. Pregnancy Management of the Diabetic Patient and Fetus Fetal Surveillance The goals of third-trimester management of diabetic pregnancy are to prevent stillbirth and asphyxia while optimizing the opportunity for a safe vaginal delivery. This involves monitoring fetal growth to deter- mine the proper timing and route of delivery and testing for fetal well-being at frequent intervals. A regimen for fetal surveillance throughout pregnancy is provided in Table 46-19. The goals are to ᭿ Verify fetal viability in the first trimester ᭿ Validate fetal structural integrity in the second trimester ᭿ Monitor fetal growth during most of the third trimester ᭿ Ensure fetal well-being in the late third trimester A variety of fetal biophysical tests are available, including fetal heart rate testing, fetal movement counting, ultrasound biophysical scoring, and fetal Doppler studies. These tests, which are described in Chapter 21, are summarized in Table 46-20. Testing should be initiated early enough to avoid the risk of still- birth but not so early that a high rate of false-positive results is encoun- tered. Because the risk of fetal death is roughly proportional to the degree of hyperglycemia, testing should begin as early as 28 weeks’ gestation in patients with poor glycemic control or significant hyper- tension. In lower-risk patients, testing should begin at 34 to 36 weeks. Fetal movement counting should be performed in all pregnancies from 28 weeks onward. A fetal movement card for monitoring fetal move- ment is shown in Figure 46-16. Timing and Route of Delivery Assessing Fetal Size Monitoring fetal growth and predicting birth weight continue to be challenging and highly inexact processes. The purpose of such moni- toring is to identify the obese fetus and, if possible, avoid birth injury. Newborns weighing more than 4000 g are responsible for 42% to 74% of shoulder dystocias and 56% to 76% of all brachial plexus injuries, even though they account for only 6% of births.282 To identify the highest-risk fetuses, use of third-trimester ultrasound has been pro- posed, including serial plotting of biometric parameters, using a cutoff value for estimated fetal weight and applying a cutoff to a specific parameter (e.g., abdominal circumference).283 Because the risk of birth injury is proportional to birth weight,142 much effort has been focused on sonographic estimation of fetal weight (EFW). Several polynomial formulas using combinations of head, abdomen, and limb measurements have been developed.284,285 Unfortunately, even small errors in measurements of the head, abdomen, and femur are multiplied together in such formulas, result- ing in accuracies of no better than ± 15%. In the obese fetus, the inac- TABLE 46-19 FETAL SURVEILLANCE IN TYPES I AND II DIABETIC PREGNANCIES Time Test Preconception Maternal glycemic control 8-10 wk Sonographic crown-rump measurement 16 wk Maternal serum α-fetoprotein level 20-22 wk High-resolution sonography, fetal cardiac echography in women in suboptimal diabetic control (abnormal Hb A1c value) at first prenatal visit 24 wk Baseline sonographic growth assessment of the fetus 28 wk Daily fetal movement counting by the mother 32 wk Repeat sonography for fetal growth 34 wk Biophysical testing: Two times weekly nonstress test or Weekly contraction stress test or Weekly biophysical profile 36 wk Estimation of fetal weight by sonography 37-38.5 wk Amniocentesis and delivery for patients in poor control (persistent daily hyperglycemia) 38.5-40 wk Delivery without amniocentesis for patients in good control who have excellent dating criteria
  • 31. 983CHAPTER 46 Diabetes in Pregnancy curacies are further magnified. Perhaps this is why no single formula has proved adequate for identifying the macrosomic fetus.286 In the study by Combs and colleagues,287 an EFW of 4000 g had a sensitivity of 45% and a positive predictive value of 81%. To achieve 90% sensitiv- ity would have required using an EFW cutoff of 3535 g, which would have included 46% of the population and produced a 42% false-posi- tive rate. In an attempt to improve detection of macrosomia, Hackmon and coworkers288 performed a retrospective comparison of sonographic imaging results (i.e., EFW and amniotic fluid index [AFI]) for 50 newborns with severe macrosomia (birth weight ≥ 97th percentile) and 100 infants of normal weight. The mean middle-third-trimester AFI percentile and EFW percentiles for severe macrosomic infants were significantly higher than for controls (P < .0001). Significant correla- TABLE 46-20 TESTS OF FETAL WELL-BEING Test Frequency Reassuring Result Comment Fetal movement counting Every night from 28 wk 10 movements in <60 min Performed in all patients Nonstress test Twice weekly 2 heart-rate accelerations in 20 min Begin at 28-34 wk with insulin- dependent diabetes; start at 36 wk in diet-controlled gestational diabetes Contraction stress test Weekly No heart-rate decelerations in response to ≥3 contractions in 10 min Same as for nonstress test Ultrasound biophysical profile Weekly Score of 8 in 30 min 3 movements = 2 1 flexion = 2 30-sec breathing = 2 2-cm amniotic fluid = 2 Name: FETAL MOVEMENT RECORD Due Date: Start Date Number of weeks pregnant Date EXAMPLE 11/4/91 6:50 p.m. 7:28 p.m. 38 minutes Time First Movement Felt Time 10th Movement Felt Total Time Count the baby’s movements EVERY NIGHT. A movement may be a kick, swish or roll. Do not count hiccups or small flutters. You can start counting any time in the evening when the baby is active. BUT: COUNT EVERY NIGHT. Count baby’s movement while lying down, preferably on your left side. Mark down the time you feel the baby move for the first time. Mark down the time you feel the 10th fetal movement. You should feel at least 10 fetal movements within one hour. Call Labor and Delivery immediately if 1. 2. 3. 4. 5. 6. 7. INSTRUCTIONS you do not feel 10 movements with 1 hour; it takes longer and longer for your baby to move 10 times; you have not felt the baby move all day a) c) DO NOT WAIT UNTIL TOMORROW. b) FIGURE 46-16 Fetal movement card. The patient is instructed to note the time at which she begins monitoring fetal movements and then note the time at which the 10th movement is felt. If she has not recorded 10 movements in 1 hour, she is to call her physician.
  • 32. 984 CHAPTER 46 Diabetes in Pregnancy tions were detected for birth weight and the AFI and EFW percentiles (r = 0.44 and r = 0.72, respectively; P < .0001). The best predictors of macrosomia were an AFI equal to the 60th percentile or higher and an EFW equal to the 71st percentile or higher, with a positive predictive value of 85%. However, even this enhanced protocol had a high-false positive rate. Considering the inaccuracy of weight prediction from a single set of sonographic measurements, serial analysis of parameters every 1.5 to 3 weeks is commonly used. However, trended serial EFW calcula- tions compared with a single measurement appear to be no better than a single estimate performed near term. Predictions based on the average of serial EFWs, linear extrapolation from two estimates, or extrapolation by second-order equations fitted to four estimates were no better than the prediction from the last estimate before delivery.289 In view of the inadequate methods used to diagnose macrosomia antenatally, the widespread practice of estimating fetal weight using ultrasound near term in diabetic pregnancy must be questioned. Parry and colleagues290 compared the cesarean rate for neonates falsely diag- nosed on ultrasound as macrosomic (i.e., false positives) with the rate for those correctly diagnosed as nonmacrosomic (i.e., true negatives). They found that the cesarean rate was significantly higher among the false-positive macrosomics than among the true negatives (42.3% versus 24.3%; RR = 1.74; P < .05). Even with nonmacrosomic fetuses, the availability to the clinician of a sonographic estimate of fetal weight significantly increases the risk of cesarean delivery. Predicting Shoulder Dystocia Because of the asymmetrical adipose deposition around the fetal chest and trunk, deliveries of macrosomic infants from women with diabetes are at high risk for shoulder dystocia and injury. However, prediction of this risk is not possible with adequate precision to avoid excessive unnecessary interventions.291 In a subanalysis of the ACHOIS trial, Athukorala and associates138 identified a linear increase in the risk of shoulder dystocia and the fasting glucose level on the glucose tolerance test, with an 18-mg/dL (1-mmol) increase in the fasting oral glucose tolerance test result leading to a relative risk of 2.09 (CI, 1.03 to 4.25). As reported by others, shoulder dystocia was 10-fold more common with operative vaginal delivery of GDM infants. However, there was no clear cutoff for the glucose tolerance test fasting value that was adequately predic- tive of shoulder dystocia. In an effort to minimize the incidence of shoulder dystocia and associated birth injury associated with suspected macrosomia, a number of management schemes have been proposed. Weeks and col- leagues292 assessed the management of 500 pregnancies with suspected macrosomia and found a high bias toward cesarean section and failed induction. Patients with a sonographic EFW greater than 4200 g underwent induction more often (42.5% versus 26.6%), failed to achieve active labor more frequently (49% versus 16.5%), and under- went cesarean section more frequently (52% versus 30%), regardless of actual birth weight. Despite these changes in labor management, the incidence of shoulder dystocia in the predicted and nonpredicted groups was the same (11.8% and 11.7%, respectively). There is no clinical method of reliably identifying the fetus likely to experience shoulder dystocia and injury during birth without an unacceptably high false-positive rate. Because 8% to 20% of fetuses from diabetic pregnancy weighing 4500 g or more will have shoulder dystocia, 15% to 30% of these will have recognizable brachial plexus injury, and 5% to 15% of these injuries will result in permanent deficit, approximately 443 to 489 cesarean sections would have to be per- formed for suspected macrosomia to prevent one case of permanent injury from shoulder dystocia.293 Delivery Timing Timing of delivery should minimize neonatal morbidity and mortality while maximizing the likelihood of vaginal delivery. Delaying delivery to as near the estimated due date as possible increases cervical ripeness and improves the chances of vaginal birth. However, the risks of fetal macrosomia, birth injury, and fetal death increase as the due date approaches. Earlier delivery may reduce the risk of shoulder dystocia, but the increase in failed labor inductions and neonatal respiratory distress is appreciable. Rayburn and colleagues294 reported a case-control study of out- comes of women with GDM requiring insulin who delivered at 38 weeks compared with normoglycemic controls. The study group was more likely to have an unfavorable cervix, but cesarean rates were not different between the study and control groups (12.7% versus 11.7%; P < .8). Mean birth weights and the frequency of birth weights greater than 4000 g were not different between the groups, suggesting that delivery at 38 to 39 weeks does not compromise maternal and infant outcomes significantly. When all these factors are considered, the optimal time for delivery of most diabetic pregnancies is between 38.5 and 40 weeks. Indications for delivery of the diabetic pregnancy are summarized in Table 46-21. Because of the apparent delay in fetal lung maturity in diabetic preg- nancies, delivery before 38.5 weeks’ gestation should be performed only for compelling maternal or fetal reasons. It may be tempting to consider early delivery in a diabetic preg- nancy with evolving macrosomia identified on ultrasonography. Because fetal growth between 37 and 40 weeks’ gestation in a 90th- percentile fetus is approximately 100 to 150 g per week, inducing labor 2 weeks early may reduce the risk of shoulder dystocia in some cases. Kjos and coauthors295 compared the outcomes associated with labor induction at 38 weeks with expectant management of women with gestational diabetes. They found that expectant management increased the gestational age at delivery by 1 week, but the cesarean delivery rate was not significantly different. Macrosomia was present in 23% of the expectantly managed group versus 10% in those induced at 38 weeks. Fetal lung maturity should be verified in all patients delivered before 38.5 weeks by the presence of greater than 3% phosphatidyl- glycerol or the equivalent on an amniocentesis specimen (Table 46-22). If obstetric dating is suboptimal, amniocentesis should be performed. TABLE 46-21 INDICATIONS FOR DELIVERY IN DIABETIC PREGNANCY Type Indications for Delivery Fetal Nonreactive, positive contraction stress test Reactive positive contraction stress test, mature fetus Sonographic evidence of fetal growth arrest Decline in fetal growth rate with decreased amniotic fluid 40-41 weeks’ gestation Maternal Severe preeclampsia Mild preeclampsia, mature fetus Markedly falling renal function (creatinine clearance <40 mL/min) Obstetric Preterm labor with failure of tocolysis Mature fetus, inducible cervix
  • 33. 985CHAPTER 46 Diabetes in Pregnancy After more than 40 weeks, the benefits of continued conservative man- agement are less than the danger of fetal compromise. Induction of labor before 42 weeks in diabetic pregnancy—regardless of the readi- ness of the cervix—is prudent. Labor or Cesarean The ACOG296 has recommended that primary cesarean delivery be discussed with diabetic gravidas with an EFW greater than 4500 g. This may reduce the risk of shoulder dystocia to some degree for an indi- vidual patient, but the effect on the larger obstetric population is less clear. Gonen and associates297 retrospectively assessed the impact of a policy of elective cesarean in cases with an EFW above 4500 g. During the 4 years of the study with more than 16,000 deliveries, macrosomia was correctly predicted in only 18% of cases. Of the 115 undiagnosed macrosomic cases, 13 infants were delivered by emergency cesarean, and 99 were delivered vaginally. Three infants (3%) with macrosomia and 14 infants (0.1%) without macrosomia sustained brachial plexus injury. The policy of preemptive cesarean for an EFW greater than 4500 g prevented at most a single case of brachial palsy. Conway and Langer298 performed a prospective trial enrolling dia- betic women among whom those with an EFW of 4250 g or more underwent elective cesarean section. Ultrasonography correctly identi- fied the presence or absence of macrosomia in 87% of patients. The cesarean section rate increased slightly after the protocol was initiated (22% versus 25%), but overall, shoulder dystocia was less common (2.4% versus 1.1%). Herbst299 conducted a cost-effectiveness analysis of “prophylactic” delivery (i.e., induction or cesarean) of the fetus with an EFW greater than 4500 g using risk and benefit rates estimated from the existing medical literature.299 For an infant of a normoglycemic pregnancy weighing 4500 g or more, routine obstetric management was the least expensive ($4014 per injury-free child) compared with elective cesar- ean cost of $5212 and induction cost of $5165. However, a sensitivity analysis suggested that with a shoulder dystocia risk higher than 10% (as is the case with a fetus weighing more than 4500 g in a diabetic pregnancy), primary cesarean or early induction is somewhat more financially advantageous. The current recommendation that cesarean section be considered when fetal weight is suspected to exceed 4500 g appears to confer a modest improvement in neonatal outcome. The decision to attempt vaginal delivery or perform a cesarean delivery is inevitably based on limited data. The patient’s obstetric history, the best EFW, a fetal adipose profile (i.e., abdomen larger than head), and clinical pelvimetry should all be considered. Midpelvic operative deliveries should be avoided when macrosomia is suspected, and low pelvic or even outlet operative deliveries must be approached with extreme caution if labor is protracted. With an EFW greater than 4500 g, a prolonged second stage of labor or arrest of descent in the second stage is an indication for cesarean delivery.296 Most large series of diabetic pregnancies report a cesarean section rate of 30% to 50%. The best means by which this rate can be lowered is by early and strict glycemic control in pregnancy. Conducting long labor inductions in patients with a large fetus and a marginal pelvis may increase, rather than lower, morbidity and costs. Intrapartum Glycemic Management Perinatal asphyxia and neonatal hypoglycemia correlate with maternal hyperglycemia during labor.300 Unfortunately, strict maternal euglyce- mia during labor does not guarantee newborn metabolic stability in infants with macrosomia and islet cell hypertrophy. The use of a combined insulin and glucose infusion during labor maintains the maternal plasma glucose level in a narrow range (80 to 110 mg/dL) and reduces the incidence of neonatal hypoglycemia.301 A protocol for administration of a continuous insulin infusion in labor is outlined in Table 46-23. Typical infusion rates are 5% dextrose in Ringer’s lactate at 100 mL per hour and lispro or aspart insulin at 0.5 to 1 units per hour. Capillary blood glucose is monitored hourly in these patients. For patients with diet-controlled GDM or mild type 2 diabetes, avoid- ing dextrose in all intravenous fluids during labor usually maintains excellent glucose control. When cesarean section is planned in a woman with diabetes, the procedure should be performed early in the day to avoid prolonged TABLE 46-22 CONFIRMATION OF FETAL MATURITY BEFORE INDUCTION OF LABOR OR PLANNED CESAREAN DELIVERY IN DIABETIC PREGNANCIES Phosphatidylglycerol >3% in amniotic fluid collected from vaginal pool or by amniocentesis Completion of 38.5 weeks’ gestation Normal last menstrual period First pelvic examination before 12 wk confirms dates Sonogram before 24 wk confirms dates Documentation of more than 18 wk of unamplified (fetoscope) fetal heart tones TABLE 46-23 INTRAPARTUM MATERNAL GLYCEMIC CONTROL Insulin Infusion Method 1. Withhold AM insulin injection. 2. Begin and continue glucose infusion (5% dextrose in water) at 100 mL/hr throughout labor. 3. Begin infusion of regular insulin at 0.5 U/hr. 4. Begin oxytocin as needed. 5. Monitor maternal glucose levels hourly using a capillary reflectance meter at bedside or laboratory determinations, or both. 6. Adjust insulin infusion. Plasma/Capillary Glucose (mg/dL) Infusion Rate (U/hr) <80 Insulin off 80-100 0.5* 101-140 1.0 141-180 1.5 181-220 2.0* >220 2.5* Intermittent Subcutaneous Injection Method 1. Give one half of the usual insulin dose in AM. 2. Begin and continue glucose infusion (5% dextrose in water) at 100 mL/hr throughout labor. 3. Begin oxytocin as needed. 4. Monitor maternal glucose levels hourly using a capillary reflectance meter at bedside or laboratory determinations, or both. 5. Administer regular insulin in small doses (2 to 5 U) to maintain glucose levels of 80 to 120 mg/dL. *Intravenous bolus of 2 to 5 units when the rate increases.
  • 34. 986 CHAPTER 46 Diabetes in Pregnancy periods of fasting. On the night before surgery, patients should be instructed to take their full dose of NPH or glyburide. No morning insulin or glyburide should be taken. A glucose-containing intravenous line should be established promptly on arrival at the hospital, with insulin given as intravenous boluses on a sliding scale as needed every 1 to 4 hours to maintain maternal plasma glucose in the range of 80 to 160 mg/dL. Postpartum Metabolic Management In the recovery room and after delivery, insulin can be given subcuta- neously to women with type 2 diabetes using a sliding scale until a regular diet is established. The insulin doses required after delivery are typically 30% to 50% of the preprandial doses required during preg- nancy just before delivery. Type 1 diabetes patients require more inten- sive glucose monitoring after delivery, because many experience a honeymoon phase, in which insulin requirements fall dramatically. The glucose-insulin intravenous infusion should be continued in type 1 diabetes patients, especially those who have had a cesarean delivery, until the diet has normalized. Management of the Neonate Neonatal Transitional Management Unmonitored and uncorrected neonatal hypoglycemia can lead to neonatal seizures, brain damage, and death. The degree of hypoglyce- mia correlates roughly with the degree of maternal glycemic control during the 6 weeks before birth. Pancreatic hypertrophy and chronic fetal hyperinsulinemia—holdovers from the chronically glucose-rich intrauterine environment—can lead to significant hypoglycemia after the umbilical supply of nutrients is interrupted by delivery. IDMs also appear to have disorders of catecholamine and glucagon metabolism and have diminished capability to mount normal compensatory responses to hypoglycemia. The current recommendations specify fre- quent blood glucose checks and early oral feeding when possible (ideally from the breast), with infusion of intravenous glucose if oral measures prove insufficient. Ordinarily, blood glucose levels can be controlled satisfactorily with an infusion of 10% glucose. If greater amounts of glucose are required, bolus administration of 5 mL/kg of 10% glucose is recommended, with gradually increasing concentrations of glucose administered every 30 to 60 minutes, if necessary. Breastfeeding Considering the number of perinatal complications experienced by many women with diabetes (e.g., preeclampsia, macrosomia-induced cesarean section, neonatal hypoglycemia), achieving a high rate of breastfeeding may seem to be a superfluous goal. However, mounting evidence indicates that breastfed infants have a much lower risk of developing diabetes than do those exposed to the proteins in cow’s milk.302,303 Pettitt and associates304 found that children who were exclu- sively breastfed had significantly lower rates of non–insulin-dependent diabetes mellitus than did those who were exclusively bottle-fed in all age groups. The odds ratio for non–insulin-dependent diabetes melli- tus in exclusively breastfed persons, compared with exclusively bottle- fed individuals, was 0.41 (CI, 0.18 to 0.93), adjusted for age, sex, birth date, parental diabetes, and birth weight. A study by Gimeno and de Souza305 found that a shorter duration of exclusive breastfeeding was a risk factor for childhood diabetes (OR = 2.13; CI, 1.8 to 3.55) and that the introduction to cow’s milk products before age 8 days was an important risk factor for the disease. Given the increased risk of dia- betes in offspring of women with diabetes, these data underscore the importance of encouraging breastfeeding in all postpartum women with diabetes. Most neonatologists maintain strict monitoring of glucose levels in newborn IDMs for at least 4 to 6 hours (frequently 24 hours), often necessitating admission to a newborn special care unit. This early sepa- ration of mother and neonate impedes breastfeeding and infant attach- ment, and it may delay the onset of lactogenesis in the diabetic mother. Neubauer and colleagues306 observed that milk of women with insulin- dependent diabetes came in later than it did in controls and had sig- nificantly lower lactose and higher total nitrogen at 2 to 3 days after delivery. The infants of these diabetic mothers had significantly less milk intake 7 to 14 days after delivery than did those of the control women. Delayed lactogenesis in the women with insulin-dependent diabetes most likely occurred in those with poor metabolic control. A study by van Beusekom and coauthors307 analyzed concentrations of micronutrients and macronutrients in milk and capillary blood and found that tight glycemic control was associated with normal propor- tions of milk nutrients, compared with the multitude of milk abnor- malities seen with moderate and poor control. Evidence indicates that with proper encouragement, sustained breastfeeding is possible for a significant proportion of patients with overt diabetes. Webster and coworkers308 longitudinally compared breastfeeding habits between women with diabetes and normal women. At discharge, 63% of mothers with insulin-dependent diabetes and 78% of mothers without diabetes were breastfeeding. At 8 weeks, the proportions of each were nearly identical (58% and 56%, respectively), and when the infants were 3 months old, 47% of mothers with insulin- dependent diabetes and 33% of women without diabetes continued to breastfeed. The study showed that IDMs were delivered atraumatically, and infants who are well oxygenated with mature lungs and who have excellent antecedent glucose control can be kept with their mothers under close glycemic monitoring for the first 1 to 2 hours of life. This permits early breastfeeding, which may reduce the need for intrave- nous glucose therapy. The actual techniques of infant nursing require some modification in women with overt diabetes, especially insulinopenic patients with type 1 diabetes. Increased maternal calorie and fluid intake is necessary to maintain milk supply in all women. The calorie expenditure during nursing and for the 30 to 45 minutes thereafter (probably during post-nursing lactogenesis) may precipitate severe hypoglycemia if compensatory calories are not ingested. This is espe- cially common during nursing late at night. Breastfeeding women with type 1 diabetes should be encouraged to take in fluids and food (100 to 300 calories per feeding episode) while nursing to avoid reactive hypoglycemia. Fortunately, studies of breastfeeding women with diabetes indicate that lactation, even for a short duration, has a beneficial effect on overall maternal glucose and lipid metabolism. For postpartum women who have GDM during their pregnancies, breastfeeding may offer a practical, low-cost intervention that helps to reduce or delay the risk of subsequent diabetes. References 1. Wild S, Roglic G, Green A, et al: Global prevalence of diabetes. Estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047-1053, 2004.
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