TYPES OF DIABETES
MANAGEMENT OF DIABETES IN PREGNANCY
SCREENING AND DIAGNOSIS
MATERNAL AND FETAL EFFECTS
According to the National Center for Health Statistics (2013), the number of adults diagnosed with diabetes in the United States has tripled from 6.9 million in 1991 to 20.9 million in 2011. Astoundingly, the Centers for Disease Control and Prevention (2010) have estimated that the number of Americans with diabetes will range from 1 in 3 to 1 in 5 by 2050. Reasons for this rise include an aging population more likely to develop type 2 diabetes, increases in minority groups at particular risk for type 2 diabetes, and dramatic increases in obesity—also referred to as diabesity. This term reflects the strong relationship of diabetes with the current obesity epidemic in the United States and underlines the critical need for diet and lifestyle interventions to change the trajectory of both.
There is keen interest in events that precede diabetes, and this includes the uterine environment, where early imprinting is believed to have effects later in life (Saudek, 2002). For example, in utero exposure to maternal hyperglycemia leads to fetal hyperinsulinemia, causing an increase in fetal fat cells. This leads to obesity and insulin resistance in childhood (Feig, 2002). This in turn leads to impaired glucose tolerance and diabetes in adulthood. This cycle of fetal exposure to diabetes leading to childhood obesity and glucose intolerance has been reported in Pima Indians and a heterogeneous Chicago population (Silverman, 1995).
TYPES OF DIABETES
In nonpregnant individuals, the type of diabetes is based on its presumed etiopathogenesis and its pathophysiological manifestations. Absolute insulin deficiency characterizes type 1 diabetes. In contrast, defective insulin secretion, insulin resistance, or increased glucose production characterizes type 2 diabetes (Table 57-1). Both types are generally preceded by a period of abnormal glucose homeostasis. The terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are now obsolete. Pancreatic β-cell destruction can begin at any age, but type 1 diabetes is clinically apparent most often before age 30. Type 2 diabetes usually develops with advancing age but is increasingly identified in younger obese adolescents.
TABLE 57-1. Etiological Classification of Diabetes Mellitus
Type 1: β-Cell destruction, usually absolute insulin deficiency
Type 2: Ranges from predominantly insulin resistance to predominantly an insulin secretory defect with insulin resistance
Genetic mutations of β-cell function—MODY 1–6, others
Genetic defects in insulin action
Genetic syndromes—Down, Klinefelter, Turner
Diseases of the exocrine pancreas—pancreatitis, cystic fibrosis
Endocrinopathies—Cushing syndrome, pheochromocytoma, others
Drug or chemical induced—glucocorticosteroids, thiazides, β-adrenergic agonists, others
Infections—congenital rubella, cytomegalovirus, coxsackievirus
MODY = maturity-onset diabetes of the young.
Modified from Powers, 2012.
Classification During Pregnancy
Diabetes is the most common medical complication of pregnancy. Women can be separated into those who were known to have diabetes before pregnancy—pregestational or overt, and those diagnosed during pregnancy—gestational diabetes. The incidence of diabetes complicating pregnancy increased approximately 40 percent between 1989 and 2004 (Getahun, 2008). In 2006, slightly more than 179,000—4.2 percent—of American women had pregnancies coexistent with some form of diabetes (Martin, 2009). African American, Native American, Asian, and Hispanic women are at higher risk for gestational diabetes compared with white women (Ferrara, 2007). The increasing incidence of gestational diabetes during the past 15 years, shown in Figure 57-1, is reminiscent of similar statistics for obesity (Chap. 48, p. 961).
FIGURE 57-1 Age-specific incidence of gestational diabetes from National Hospital Discharge Survey Data of nearly 59 million births in the United States from 1989 to 2004. (Redrawn from Getahun, 2008.)
White Classification in Pregnancy
Until the mid-1990s, the classification by Priscilla White for diabetic pregnant women was the linchpin of management. Today, the White classification is used less frequently, but its role remains important. And because most currently cited literature contains data from these older classifications, the one previously recommended by the American College of Obstetricians and Gynecologists (1986) is provided in Table 57-2.
TABLE 57-2. Classification Scheme Used from 1986 through 1994 for Diabetes Complicating Pregnancy
Beginning several years ago, the American College of Obstetricians and Gynecologists (2012, 2013) no longer recommended the White classification. Instead, the current focus is whether diabetes antedates pregnancy or is first diagnosed during pregnancy. Many now recommend adoption of the classification proposed by the American Diabetes Association (ADA), as shown in Table 57-3.
TABLE 57-3. Proposed Classification System for Diabetes in Pregnancy
The increasing prevalence of type 2 diabetes in general, and in younger people in particular, has led to an increasing number of affected pregnancies (Ferrara, 2007). In Los Angeles County, Baraban and coworkers (2008) reported that the age-adjusted prevalence tripled from 14.5 cases per 1000 women in 1991 to 47.9 cases per 1000 in 2003. Thus, the number of pregnant women with diabetes that was undiagnosed before pregnancy is increasing. Many women found to have gestational diabetes are likely to have type 2 diabetes that has previously gone undiagnosed (Feig, 2002). In fact, 5 to 10 percent of women with gestational diabetes are found to have diabetes immediately after pregnancy.
Women with high plasma glucose levels, glucosuria, and ketoacidosis present no problem in diagnosis. Similarly, women with a random plasma glucose level > 200 mg/dL plus classic signs and symptoms such as polydipsia, polyuria, and unexplained weight loss or those with a fasting glucose level exceeding 125 mg/dL are considered by the ADA (2012) to have overt diabetes. Women with only minimal metabolic derangement may be more difficult to identify. To diagnose overt diabetes in pregnancy, The International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel (2010) recommends threshold values for fasting or random plasma glucose and glycosylated hemoglobin (A1c) levels at prenatal care initiation (Table 57-4). There was no consensus on whether such testing should be universal or limited to those women classified as high risk. Regardless, the tentative diagnosis of overt diabetes during pregnancy based on these thresholds should be confirmed postpartum. Risk factors for impaired carbohydrate metabolism in pregnant women include a strong familial history of diabetes, prior delivery of a large newborn, persistent glucosuria, or unexplained fetal losses.
TABLE 57-4. Diagnosis of Overt Diabetes in Pregnancya
Impact on Pregnancy
With pregestational—or overt—diabetes, the embryo, fetus, and mother frequently experience serious complications directly attributable to diabetes. The likelihood of successful outcomes with overt diabetes is related somewhat to the degree of glycemic control, but more importantly, to the degree of underlying cardiovascular or renal disease. Thus, advancing stages of the White classification, seen in Table 57-2, are inversely related to favorable pregnancy outcomes. As an example shown in Table 57-5, data from Yang and associates (2006) chronicles the deleterious pregnancy outcomes of overt diabetes. These maternal and fetal complications are described in the following sections.
TABLE 57-5. Pregnancy Outcomes of Births in Nova Scotia from 1988 to 2002 in Women with and without Pregestational Diabetes
Spontaneous Abortion. Several studies have shown that early miscarriage is associated with poor glycemic control. In 215 women with type 1 diabetes enrolled for prenatal care before 9 weeks’ gestation, 24 percent had an early pregnancy loss (Rosenn, 1994). Only those whose initial glycohemoglobin A1c concentrations were > 12 percent or whose preprandial glucose concentrations were persistently > 120 mg/dL were at increased risk. In another analysis of 127 Spanish women with pregestational diabetes, poor glycemic control, defined by glycohemoglobin A1c concentrations > 7 percent, was associated with a threefold increase in the spontaneous abortion rate (Galindo, 2006).
Preterm Delivery. Overt diabetes is an undisputed risk factor for preterm birth. Eidem and associates (2011) analyzed 1307 births in women with pregestational type 1 diabetes from the Norwegian Medical Birth Registry. More than 26 percent were delivered preterm compared with 6.8 percent in the general obstetrical population. Moreover, almost 60 percent were indicated preterm births, that is, due to obstetrical or medical complications. In the Canadian study shown in Table 57-5, the incidence of preterm birth was 28 percent—a fivefold increase compared with that of their normal population.
Malformations. The incidence of major malformations in women with type 1 diabetes is doubled and approximates 5 percent (Eidem, 2010; Sheffield, 2002). These account for almost half of perinatal deaths in diabetic pregnancies. A twofold increased risk of major congenital defects in Norwegian women with pregestational type 1 diabetes included cardiovascular malformations that accounted for more than half of the anomalies (Table 57-6). In the National Birth Defects Prevention Study, the risk of an isolated cardiac defect was fourfold higher in women with pregestational diabetes compared with the twofold increased risk of noncardiac defects (Correa, 2008). The caudal regression sequence is a rare malformation frequently associated with maternal diabetes (Garne, 2012).
TABLE 57-6. Congenital Anomalies in Fetuses of 91 Women with Type 1 Diabetes between 1999 and 2004 in Norway
Poorly controlled diabetes, both preconceptionally and early in pregnancy, is thought to underlie this increased severe-malformation risk. As shown in Figure 57-2, Galindo and colleagues (2006) demonstrated a clear correlation between increased maternal glycohemoglobin A1c at first prenatal visit and major malformations. Eriksson (2009) concluded that the etiology was multifactorial. At least three interrelated molecular chain reactions have been linked to maternal hyperglycemia and can potentially explain the mechanism behind poor glycemic control and increased risk for major malformations (Reece, 2012). These include alterations in cellular lipid metabolism, excess production of toxic superoxide radicals, and activation of programmed cell death. For example, Morgan and associates (2008) demonstrated that hyperglycemia-induced oxidative stress inhibited migration of cardiac neural-crest cells in embryos of diabetic mice.
FIGURE 57-2 The frequency of major congenital malformations in newborns of women with pregestational diabetes stratified by hemoglobin A1c levels at first prenatal visit. (Data from Galindo, 2006.)
Altered Fetal Growth. Diminished growth may result from congenital malformations or from substrate deprivation due to advanced maternal vascular disease. However, fetal overgrowth is more typical of pregestational diabetes. Maternal hyperglycemia prompts fetal hyperinsulinemia, particularly during the second half of gestation. This in turn stimulates excessive somatic growth or macrosomia. Except for the brain, most fetal organs are affected by the macrosomia that characterizes the fetus of a diabetic woman. Such infants are described as being anthropometrically different from other large-for-gestational age (LGA) infants (Durnwald, 2004; McFarland, 2000). Specifically, those whose mothers are diabetic have excessive fat deposition on the shoulders and trunk, which predisposes to shoulder dystocia or cesarean delivery (Fig. 57-3).
FIGURE 57-3 This 6050-g macrosomic infant was born to a woman with diabetes.
The incidence of macrosomia rises significantly when mean maternal blood glucose concentrations chronically exceed 130 mg/dL (Hay, 2012). Hammoud and coworkers (2013) reported that the macrosomia rates for Nordic women with type 1, type 2, or gestational diabetes were 35 percent, 28 percent, and 24 percent, respectively. As shown in Figure 57-4, the birthweight distribution of neonates of diabetic mothers is skewed toward consistently heavier birthweights compared with that of normal pregnancies.
FIGURE 57-4 Distribution of birthweight standard deviation from the normal mean for gestational age in 280 infants of diabetic mothers and in 3959 infants of nondiabetic mothers. (From Bradley, 1988, with permission.)
In the study by Hammoud and colleagues (2013), fetal growth profiles from 897 sonographic examinations in 244 women with diabetes were compared with 843 examinations in 145 control women. The abdominal circumference evolved differently in the diabetic groups. Analysis of head circumference/abdominal circumference (HC/AC) ratios shows that this disproportionate growth occurs mainly in diabetic pregnancies that ultimately yield macrosomic newborns (Fig. 57-5). These findings comport with the observation that virtually all neonates of diabetic mothers are growth promoted. Ben-Haroush and associates (2007) analyzed fetal sonographic measurements between 29 and 34 weeks’ gestation in 423 diabetic pregnancies and found that accelerated fetal growth was particularly evident in women with poor glycemic control.
FIGURE 57-5 Comparison of sonographic fetal anatomic measurements by gestational age and subdivided according to presence or absence of macrosomia among women with various types of diabetes types and controls. A.Abdominal circumference measurements. B. Head circumference (HC)/Abdominal circumference (AC) ratio. DM = diabetes mellitus; GDM = gestational diabetes mellitus. (Redrawn from Hammoud, 2013, with permission.)
Unexplained Fetal Demise. The risk of fetal death is three to four times higher in women with type 1 diabetes compared with that of the general obstetrical population (Eidem, 2011). Stillbirth without an identifiable cause is a phenomenon relatively limited to pregnancies complicated by overt diabetes. These stillbirths are “unexplained” because common factors such as obvious placental insufficiency, abruption, fetal-growth restriction, or oligohydramnios are not identified. These infants are typically LGA and die before labor, usually after 35 weeks’ gestation or later (Garner, 1995).
These unexplained stillbirths are associated with poor glycemic control. Lauenborg and coworkers (2003) identified suboptimal glycemic control in two thirds of unexplained stillbirths between 1990 and 2000. Also, fetuses of diabetic mothers often have elevated lactic acid levels. Salvesen and colleagues (1992, 1993) analyzed fetal blood samples and reported that mean umbilical venous blood pH was lower in diabetic pregnancies and was significantly related to fetal insulin levels. Such findings support the hypothesis that hyperglycemia-mediated chronic aberrations in oxygen and fetal metabolite transport may underlie these unexplained fetal deaths (Pedersen, 1977). However, the exact mechanisms by which uncontrolled hyperglycemia leads to elevated lactic acid levels and fetal acidosis remain unclear.
Explicable stillbirths due to placental insufficiency also occur with increased frequency in women with overt diabetes, usually in association with severe preeclampsia. In a retrospective analysis of more than 500,000 singleton deliveries, Yanit and associates (2012) found that the fetal death risk was sevenfold higher in women with hypertension and pregestational diabetes compared with the threefold increased risk associated with diabetes alone. Stillbirth is also increased in women with advanced diabetes and vascular complications. Maternal ketoacidosis can also cause fetal death.
Hydramnios. Diabetic pregnancies are often complicated by excess amnionic fluid. According to Idris and coworkers (2010), 18 percent of 314 women with pregestational diabetes were identified with hydramnios, defined as an amnionic fluid index (AFI) greater than 24 cm in the third trimester. A likely—albeit unproven—explanation is that fetal hyperglycemia causes polyuria (Chap. 11, p. 234). In a study from Parkland Hospital, Dashe and colleagues (2000) found that the AFI parallels the amnionic fluid glucose level among women with diabetes. This finding suggests that the hydramnios associated with diabetes is a result of increased amnionic fluid glucose concentration. Further support for this hypothesis was provided by Vink and associates (2006), who linked poor maternal glucose control to macrosomia and hydramnios. In their retrospective analysis of diabetic pregnancies, Idris and coworkers (2010) also found that women with elevated glycohemoglobin A1c values in the third trimester were more likely to have hydramnios.
Neonatal Effects. Before tests of fetal health and maturity became available, delivery before term was deliberately selected for women with diabetes to avoid unexplained fetal death. Although this practice has been abandoned, there is still an increased frequency of preterm delivery in women with diabetes. Most are due to advanced diabetes with superimposed preeclampsia. Thankfully, modern neonatal care has largely eliminated neonatal deaths due to immaturity. Conversely, neonatal morbidity due to preterm birth continues to be a serious consequence.
Respiratory Distress Syndrome. Historically, newborns of diabetic mothers were thought to be at increased risk for respiratory distress from delayed lung maturation. Subsequent observations challenged this concept, and gestational age rather than overt diabetes is likely the most significant factor associated with respiratory distress syndrome. Indeed, in their analysis of 19,399 very-low-birthweight neonates delivered between 24 and 33 weeks’ gestation, Bental and colleagues (2011) were unable to demonstrate an increased rate of respiratory distress syndrome in newborns of diabetic mothers. This is discussed further in Chapter 33 (p. 637).
Hypoglycemia. Newborns of a diabetic mother experience a rapid drop in plasma glucose concentration after delivery. This is attributed to hyperplasia of the fetal β-islet cells induced by chronic maternal hyperglycemia. Low glucose concentrations—defined as < 45 mg/dL—are particularly common in newborns of women with unstable glucose concentrations during labor (Persson, 2009). In a recent analysis of prenatal outcomes during a 20-year period in Finnish women with type 1 diabetes, the incidence of neonatal hypoglycemia declined significantly over time (Klemetti, 2012). The authors attributed this to frequent blood glucose measurements and active early feeding practices in such neonates. Prompt recognition and treatment of the hypoglycemic newborn minimizes adverse sequelae.
Hypocalcemia. Defined as a total serum calcium concentration < 8 mg/dL in term newborns, hypocalcemia is one of the potential metabolic derangements in neonates of diabetic mothers. Its cause has not been explained. Theories include aberrations in magnesium–calcium economy, asphyxia, and preterm birth. In a randomized study by DeMarini and associates (1994), 137 pregnant women with type 1 diabetes were managed with strict versus customary glucose control. Almost a third of neonates in the customary control group developed hypocalcemia compared with only 18 percent of those in the strict control group.
Hyperbilirubinemia and Polycythemia. The pathogenesis of hyperbilirubinemia in neonates of diabetic mothers is uncertain. A major contributing factor is newborn polycythemia, which increases the bilirubin load (Chap. 33, p. 643). Polycythemia is thought to be a fetal response to relative hypoxia. According to Hay (2012), the sources of this fetal hypoxia are hyperglycemia-mediated increases in maternal affinity for oxygen and fetal oxygen consumption. Together with insulin-like growth factors, this hypoxia leads to increased fetal erythropoietin levels and red cell production. Venous hematocrits of 65 to 70 volume percent have been observed in up to 40 percent of these newborns (Salvesen, 1992). Renal vein thrombosis is reported to result from polycythemia.
Cardiomyopathy. Infants of diabetic pregnancies may have hypertrophic cardiomyopathy that primarily affects the interventricular septum (Rolo, 2011). In severe cases, this cardiomyopathy may lead to obstructive cardiac failure. Russell and coworkers (2008) performed serial echocardiograms on fetuses of 26 women with pregestational diabetes. In the first trimester, fetal diastolic dysfunction was evident compared with that of nondiabetic controls. In the third trimester, the fetal interventricular septum and right ventricular wall were thicker in fetuses of diabetic mothers. The authors concluded that cardiac dysfunction precedes these structural changes. Fortunately, most affected newborns are asymptomatic following birth, and hypertrophy resolves in the months after delivery. Relief from maternal hyperglycemia is presumed to promote this resolution (Hornberger, 2006). Conversely, fetal cardiomyopathy may progress to adult cardiac disease.
Long-Term Cognitive Development. Intrauterine metabolic conditions have long been linked to neurodevelopment in offspring. This may also be true in children of diabetic mothers. Despite rigorous antepartum management, Rizzo and colleagues (1995) found numerous correlations between maternal glycemia and intellectual performance in children up to age 11 years in 139 offspring of diabetic women. In a study of more than 700,000 Swedish-born men, the intelligence quotient of those whose mothers had diabetes during pregnancy averaged 1 to 2 points lower (Fraser, 2014). DeBoer and associates (2005) demonstrated impaired memory performance in infants of diabetic mothers at age 1 year. Finally, results from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study indicated that autism spectrum disorders or developmental delay were more common in children of diabetic women (Krakowiak, 2012). Although interpreting effects of the intrauterine environment on neurodevelopment is certainly confounded by postnatal events, emerging data at least support a link between maternal diabetes, glycemic control, and neurocognitive outcome.
Inheritance of Diabetes. The risk of developing type 1 diabetes if either parent is affected is 3 to 4 percent. Type 2 diabetes has a much stronger genetic component. If both parents have type 2 diabetes, the risk of developing it approaches 40 percent. McKinney and coworkers (1999) studied 196 children with type 1 diabetes and found that older maternal age and maternal type 1 diabetes are important risk factors. Plagemann and colleagues (2002) have implicated breast feeding by diabetic mothers in the genesis of childhood diabetes. Conversely, breast feeding has also been associated with a reduced risk of type 2 diabetes (Owen, 2006). The Trial to Reduce Insulin-dependent Diabetes Mellitus in the Genetically At Risk (TRIGR) was designed to analyze hydrolyzed formula use, rather than breast milk, to reduce rates of type 1 diabetes in at-risk children by age 10. This study will be complete in 2017 (Knip, 2011).
Diabetes and pregnancy interact significantly such that maternal welfare can be seriously jeopardized. With the possible exception of diabetic retinopathy, however, the long-term course of diabetes is not affected by pregnancy.
Maternal death is uncommon, but rates in women with diabetes are still increased. In an analysis of 972 women with type 1 diabetes, Leinonen and associates (2001) reported a maternal mortality rate of 0.5 percent. Deaths resulted from diabetic ketoacidosis, hypoglycemia, hypertension, and infection. Especially morbid is ischemic heart disease. Pombar and coworkers (1995) reviewed 17 women with coronary artery disease—class H diabetes—and reported that only half survived pregnancy.
Preeclampsia. Hypertension that is induced or exacerbated by pregnancy is the complication that most often forces preterm delivery in diabetic women. The incidence of chronic and gestational hypertension—and especially preeclampsia—is remarkably increased in diabetic mothers. In the study cited earlier by Yanit and colleagues (2012), preeclampsia developed three to four times more often in women with overt diabetes. Moreover, those diabetics with coexistent chronic hypertension were almost 12 times more likely to develop preeclampsia. Special risk factors for preeclampsia include any vascular complication and preexisting proteinuria, with or without chronic hypertension. As shown in Figure 57-6, women with type 1 diabetes who are in more advanced White classes of overt diabetes increasingly developed preeclampsia. This increasing risk with duration of diabetes may be related to oxidative stress, which plays a key role in the pathogenesis of diabetic complications and preeclampsia. With this in mind, the Diabetes and Preeclampsia Intervention Trial (DAPIT) randomly assigned 762 women with type 1 diabetes to antioxidant vitamin C and E supplementation or placebo in the first half of pregnancy (McCance, 2010). There were no differences in preeclampsia rates except in a few women with a low antioxidant status at baseline. Temple and coworkers (2006) prospectively studied hemoglobin A1c levels at 24 weeks’ gestation in 290 women with type 1 diabetes and found that preeclampsia was related to glucose control. Management of preeclampsia is discussed in Chapter 40 (p. 749).
FIGURE 57-6 Incidence of preeclampsia in 491 type 1 diabetic women in Sweden and the United States. (Data from Hansona, 1993; Sibaib, 2000.)
Diabetic Nephropathy. Diabetes is the leading cause of end-stage renal disease in the United States (Chap. 53, p. 1060). Clinically detectable nephropathy begins with microalbuminuria—30 to 300 mg/24 hours. This may manifest as early as 5 years after diabetes onset. Macroalbuminuria—more than 300 mg/24 hours—develops in patients destined to have end-stage renal disease. Hypertension almost invariably develops during this period, and renal failure ensues typically in the next 5 to 10 years. The incidence of overt proteinuria is nearly 30 percent in individuals with type 1 diabetes and ranges from 4 to 20 percent in those with type 2 diabetes (Reutens, 2013). Progression from microalbuminuria is not inexorable, and regression is common. Presumably from improved glucose control, the incidence of nephropathy in individuals with type 1 diabetes has declined in the past few decades. Investigators for the Diabetes Control and Complications Trial (2002) reported that there was a 25-percent decrease in the rate of nephropathy for each 10-percent decrease in hemoglobin A1c levels.
Approximately 5 percent of pregnant women with diabetes already have renal involvement. Approximately 40 percent of these will develop preeclampsia (Vidaeff, 2008). High rates are also illustrated in Figure 57-6. However, this may not be the case with microproteinuria. In one analysis of 460 women, How and colleagues (2004) found no association between preeclampsia and microproteinuria. Nevertheless, they found that chronic hypertension with overt diabetic nephropathy increased the risk of preeclampsia to 60 percent.
In general, pregnancy does not appear to worsen diabetic nephropathy. In their prospective study of 43 women with diabetes, Young and associates (2012) could not demonstrate diabetic nephropathy progression through 12 months after delivery. Most of these women had only mild renal impairment. Conversely, pregnancy in women with moderate to severe renal impairment may accelerate progression of their disease (Vidaeff, 2008). As in women with glomerulopathies, hypertension or substantial proteinuria before or during pregnancy is a major predictive factor for progression to renal failure in women with diabetic nephropathy (Chap. 53, p. 1062).
Diabetic Retinopathy. Retinal vasculopathy is a highly specific complication of both type 1 and type 2 diabetes. In the United States, diabetic retinopathy is the most important cause of visual impairment in persons younger than age 60 years (Frank, 2004). The first and most common visible lesions are small microaneurysms followed by blot hemorrhages that form when erythrocytes escape from the aneurysms. These areas leak serous fluid that creates hard exudates. Such features are termed benign or background or nonproliferative retinopathy. With increasingly severe retinopathy, the abnormal vessels of background eye disease become occluded, leading to retinal ischemia and infarctions that appear as cotton wool exudates. These are considered preproliferative retinopathy. In response to ischemia, there is neovascularization on the retinal surface and out into the vitreous cavity. Vision is obscured when there is hemorrhage. Laser photocoagulation before hemorrhage, as shown in Figure 57-7, reduces the rate of visual loss progression and blindness by half. The procedure is performed during pregnancy when indicated.
FIGURE 57-7 Retinal photographs from a 30-year-old diabetic woman. A. Optic nerve head showing severe proliferative retinopathy characterized by extensive networks of new vessels surrounding the optic disc. B. A portion of the acute photocoagulation full “scatter” pattern following argon laser treatment. (From Elman, 1990, with permission.)
Vestgaard and coworkers (2010) reported that almost two thirds of 102 pregnant women with type 1 diabetes examined by 8 weeks’ gestation had background retinal changes, proliferative retinopathy, or macular edema. A fourth of these women developed progression of retinopathy in at least one eye. The same group of investigators evaluated 80 type 2 diabetics and identified retinopathy, mostly mild, in 14 percent during early pregnancy. Progression was identified in only 14 percent (Rasmussen, 2010). This complication is believed to be a rare example of a long-term adverse effect of pregnancy. However, in a prospective postpartum 5-year surveillance of 59 type 1 diabetic women, Arun and Taylor (2008) found that baseline retinopathy was the only independent risk factor for progression.
Other risk factors that have been associated with progression of retinopathy include hypertension, higher levels of insulin-like growth factor-I, and macular edema identified in early pregnancy (Bargiota, 2011; Mathiesen, 2012; Ringholm, 2011; Vestgaard, 2010). The National Institute for Health and Clinical Excellence (2008) established guidelines recommending that pregnant women with preexisting diabetes should routinely be offered retinal assessment after the first prenatal visit. Currently, most agree that laser photocoagulation and good glycemic control during pregnancy minimize the potential for deleterious effects of pregnancy.
Ironically, “acute” rigorous metabolic control during pregnancy has been linked to acute worsening of retinopathy. In a study of 201 women with retinopathy, McElvy and associates (2001) found that almost 30 percent suffered eye disease progression during pregnancy despite intensive glucose control. That said, Wang and coworkers (1993) have observed that retinopathy worsened during the critical months of rigorous glucose control, but long term, deterioration of eye disease slowed. In their study mentioned above, Arun and Taylor (2008) found that only four women required laser photocoagulation during pregnancy, and none required laser in the next 5 years.
Diabetic Neuropathy. Peripheral symmetrical sensorimotor diabetic neuropathy is uncommon in pregnant women. But a form of this, known as diabetic gastropathy, is troublesome during pregnancy. It causes nausea and vomiting, nutritional problems, and difficulty with glucose control. Women with gastroparesis should be advised that this complication is associated with a high risk of morbidity and poor perinatal outcome (Kitzmiller, 2008). Treatment with metoclopramide and H2-receptor antagonists is sometimes successful. Hyperemesis gravidarum is further discussed in Chapter 54 (p. 1070).
Diabetic Ketoacidosis. This serious complication develops in approximately 1 percent of diabetic pregnancies (Hawthorne, 2011). It is most often encountered in women with type 1 diabetes. It is increasingly being reported in women with type 2 or even those with gestational diabetes (Sibai, 2014). Diabetic ketoacidosis (DKA) may develop with hyperemesis gravidarum, β-mimetic drugs given for tocolysis, infection, and corticosteroids given to induce fetal lung maturation. DKA results from an insulin deficiency combined with an excess in counter-regulatory hormones such as glucagon. This leads to gluconeogenesis and ketone body formation. The ketone body β-hydroxybutyrate is synthesized at a much greater rate than acetoacetate, which is preferentially detected by commonly used ketosis detection methodologies. Therefore, serum or plasma assays for β-hydroxybutyrate more accurately reflect true ketone body levels.
The incidence of fetal loss can be as high as 20 percent with DKA. Noncompliance is a prominent factor, and this and ketoacidosis were historically considered prognostically bad signs in pregnancy (Pedersen, 1974). Pregnant women usually develop ketoacidosis at lower blood glucose thresholds than when nonpregnant. In a study from China, the mean glucose level for pregnant women with DKA was 293 mg/dL compared with 495 mg/dL for nonpregnant women (Guo, 2008). Chico and associates (2008) reported ketoacidosis in a pregnant woman whose plasma glucose was only 87 mg/dL.
One management protocol for diabetic ketoacidosis is shown in Table 57-7. An important cornerstone of management is vigorous rehydration with crystalloid solutions of normal saline or Ringer lactate.
TABLE 57-7. Protocol Recommended by the American College of Obstetricians and Gynecologists (2012) for Management of Diabetic Ketoacidosis During Pregnancy
Obtain arterial blood gases to document degree of acidosis present; measure glucose, ketones, and electrolyte levels at 1- to 2-hour intervals
Loading dose: 0.2–0.4 U/kg
Maintenance: 2–10 U/hr
Isotonic sodium chloride
Total replacement in first 12 hours of 4–6 L
1 L in first hour
500–1000 mL/hr for 2–4 hours
250 mL/hr until 80 percent replaced
Begin 5-percent dextrose in normal saline when glucose plasma level reaches 250 mg/dL (14 mmol/L)
If initially normal or reduced, an infusion rate up to 15–20 mEq/hr may be required; if elevated, wait until levels decrease into the normal range, then add to intravenous solution in a concentration of 20–30 mEq/L
Add one ampule (44 mEq) to 1 L of 0.45 normal saline if pH is < 7.1
From Landon, 2007, with permission.
Infections. Almost all types of infections are increased in diabetic pregnancies. Stamler and coworkers (1990) reported that almost 80 percent of women with type 1 diabetes develop at least one infection during pregnancy compared with only 25 percent in those without diabetes. Common infections include Candida vulvovaginitis, urinary and respiratory tract infections, and puerperal pelvic sepsis. In their population-based study of almost 200,000 pregnancies, Sheiner and colleagues (2009) found a twofold increased risk of asymptomatic bacteruria in women with diabetes. Similarly, Alvarez and associates (2010) reported positive urine cultures in a fourth of diabetic women compared with 10 percent of nondiabetic pregnant women. In a 2-year analysis of pyelonephritis at Parkland Hospital, 5 percent of women with diabetes developed pyelonephritis compared with 1.3 percent of the nondiabetic population (Hill, 2005). Fortunately, these latter infections can be minimized by screening and eradication of asymptomatic bacteriuria (Chap. 53, p. 1053). Takoudes and colleagues (2004) found that pregestational diabetes is associated with a two- to threefold increase in wound complications after cesarean delivery.
Management of Diabetes in Pregnancy
Because of the relationship between pregnancy complications and maternal glycemic control, efforts to achieve glucose targets are typically more aggressive during pregnancy. Management preferably should begin before pregnancy and include specific goals during each trimester.
To minimize early pregnancy loss and congenital malformations in offspring of diabetic mothers, optimal medical care and education are recommended before conception (Chap. 8, p. 157). Unfortunately, nearly half of pregnancies in the United States are unplanned, and many diabetic women frequently begin pregnancy with suboptimal glucose control (Finer, 2011; Kim, 2005).
The ADA has defined optimal preconceptional glucose control using insulin to include self-monitored preprandial glucose levels of 70 to 100 mg/dL, peak postprandial values of 100 to 129 mg/dL, and mean daily glucose concentrations < 110 mg/dL (Kitzmiller, 2008). Glycosylated hemoglobin measurement, which reflects an average of circulating glucose for the past 4 to 8 weeks, is useful to assess early metabolic control. The ADA (2012) defines optimal values to be < 7 percent. In their prospective population-based study of 933 pregnant women with type 1 diabetes, Jensen and colleagues (2010) found the risk of congenital malformations was not demonstrably higher with glycosylated hemoglobin levels < 6.9 percent compared with that in more than 70,000 nondiabetic controls. They also identified a substantial fourfold increased risk for malformations at levels > 10 percent.
If indicated, evaluation and treatment for diabetic complications such as retinopathy or nephropathy should also be instituted before pregnancy. Finally, folate, 400 μg/day orally is given periconceptionally and during early pregnancy to decrease the risk of neural-tube defects.
Careful monitoring of glucose control is essential. For this reason, many clinicians hospitalize overtly diabetic women during early pregnancy to initiate an individualized glucose control program and offer education. It also provides an opportunity to assess the extent of diabetic vascular complications and precisely establish gestational age.
The overtly diabetic pregnant woman is best treated with insulin. Although oral hypoglycemic agents have been used successfully for gestational diabetes (p. 1141), these agents are not currently recommended for overt diabetes except for limited and individualized use (American College of Obstetricians and Gynecologists, 2012). Maternal glycemic control can usually be achieved with multiple daily insulin injections and adjustment of dietary intake. The action profiles of commonly used short- and long-term insulins are shown in Table 57-8.
TABLE 57-8. Action Profiles of Commonly Used Insulins
Subcutaneous insulin infusion by a calibrated pump may be used during pregnancy. However, as demonstrated in a Cochrane Database review by Farrar and associates (2007), there is scarce robust evidence for specific salutary pregnancy effects. In a metaanalysis of six small randomized trials comparing insulin pumps to multiple daily injections of insulin, there were no significant differences in LGA birthweight, maternal hypoglycemia, or retinopathy progression (Mukhopadhyay, 2007). Notably, more women using insulin pumps developed ketoacidosis. Roeder and colleagues (2012) noted with insulin pump use in women with type 1 diabetes that total daily doses declined in the first trimester but later increased by more than threefold. Postprandial glucose excursions accounted for most increases. Women who use an insulin pump must be highly motivated and compliant to minimize the risk of nocturnal hypoglycemia (Gabbe, 2003).
Monitoring. Self-monitoring of capillary glucose levels using a glucometer is recommended because this involves the woman in her own care. Glucose goals recommended during pregnancy are shown in Table 57-9. Advances in noninvasive glucose monitoring will undoubtedly render intermittent capillary glucose monitoring obsolete. Subcutaneous continuous glucose monitoring devices reveal that pregnant women with diabetes experience significant periods of daytime hyperglycemia and nocturnal hypoglycemia that are undetected by traditional monitoring (Combs, 2012). In one randomized trial of 71 women, those with periodic supplemental access to continuous glucose data had lower glycosylated hemoglobin levels—5.8 versus 6.4 percent—and delivered fewer overgrown newborns (Murphy, 2008). To date however, there have been no trials evaluating the impact of personal continuous monitoring devices that give immediate feedback to pregnant women. Such glucose monitoring systems, coupled with a continuous insulin pump, offer the potential of an “artificial pancreas” to avoid undetected hypo- or hyperglycemia during pregnancy.
TABLE 57-9. Self-Monitored Capillary Blood Glucose Goals
Diet. Nutritional planning includes appropriate weight gain through carbohydrate and caloric modifications based on height, weight, and degree of glucose intolerance (American Diabetes Association, 2012; Bantle, 2008). The mix of carbohydrate, protein, and fat is adjusted to meet the metabolic goals and individual patient preferences, but a 175-g minimum of carbohydrate per day should be provided. Carbohydrate should be distributed throughout the day in three small- to moderate-sized meals and two to four snacks (Bantle, 2008). Weight loss is not recommended, but modest caloric restriction may be appropriate for overweight or obese women. An ideal dietary composition is 55 percent carbohydrate, 20 percent protein, and 25 percent fat, of which < 10 percent is saturated fat.
Hypoglycemia. Diabetes tends to be unstable in the first trimester. Hellmuth and associates (2000) reported that 37 percent of 43 women with type 1 diabetes had maternal hypoglycemia during the first trimester, and the average duration was more than 2 hours. Similarly, Chen and coworkers (2007) identified hypoglycemic events—blood glucose < 40 mg/dL—in 37 of 60 women with type 1 diabetes. A fourth of these were considered severe because the women were unable to treat their own symptoms. Rosenn and colleagues (1994) noted that maternal hypoglycemia had a peak incidence between 10 and 15 weeks’ gestation. Caution is recommended when attempting euglycemia in women with recurrent episodes of hypoglycemia.
We have reported that good pregnancy outcomes can be achieved in women with mean preprandial plasma glucose values up to 143 mg/dL (Leveno, 1979). In women with diabetes who are not pregnant, the Diabetes Control and Complications Trial Research Group (1993) found that similar glucose values delayed and slowed diabetic retinopathy, nephropathy, and neuropathy. Thus, women with overt diabetes who have glucose values considerably above those defined as normal both during and after pregnancy can expect good outcomes.
Maternal serum alpha-fetoprotein determination at 16 to 20 weeks’ gestation is used in association with targeted sonographic examination at 18 to 20 weeks to detect neural-tube defects and other anomalies (Chap. 14, p. 284). Maternal alpha-fetoprotein levels may be lower in diabetic pregnancies, and interpretation is altered accordingly. Because the incidence of congenital cardiac anomalies is five times greater in mothers with diabetes, fetal echocardiography is an important part of second-trimester sonographic evaluation (Fouda, 2013). Despite advances in ultrasound technology, however, Dashe and associates (2009) cautioned that detection of fetal anomalies in obese diabetic women is more difficult than in similarly sized women without diabetes.
Regarding second-trimester glucose control, euglycemia with self-monitoring continues to be the goal in management. After the first-trimester instability, a stable period ensues. This is followed by an increased insulin requirement. Recall that Roeder and coworkers (2012) identified a threefold increase in total daily insulin after the first trimester in women using an insulin pump. This is due to the increased peripheral resistance to insulin described in Chapter 4 (p. 53).
Third Trimester and Delivery
During the last several decades, the threat of late-pregnancy fetal death in women with diabetes has prompted recommendations for various fetal surveillance programs beginning in the third trimester. Such protocols include fetal movement counting, periodic fetal heart rate monitoring, intermittent biophysical profile evaluation, and contraction stress testing (Chap. 17, p. 335). None of these techniques has been subjected to prospective randomized clinical trials, and their primary value seems related to their low false-negative rates. The American College of Obstetricians and Gynecologists (2012) suggests initiating such testing at 32 to 34 weeks’ gestation.
At Parkland Hospital, women with diabetes are seen in a specialized obstetrical complications clinic every 2 weeks. During these visits, glycemic control is evaluated and insulin adjusted. They are routinely instructed to perform fetal kick counts beginning early in the third trimester. At 34 weeks, admission is offered to all insulin-treated women. While in the hospital, they continue daily fetal movement counts and undergo fetal heart rate monitoring three times a week. Delivery is planned for 38 weeks.
Labor induction may be attempted when the fetus is not excessively large and the cervix is considered favorable (Chap. 26, p. 523). Cesarean delivery at or near term has frequently been used to avoid traumatic birth of a large infant in a woman with diabetes. In women with more advanced diabetes, especially those with vascular disease, the reduced likelihood of successful labor induction remote from term has also contributed to an increased cesarean delivery rate. In a nested case-control study of 209 women with type 1 diabetes, Lepercq and colleagues (2010) reported a 70-percent cesarean delivery rate overall. Two thirds of these were delivered without labor. Both maternal body mass index (BMI) > 25 kg/m2 and low Bishop score were independently associated with cesarean delivery for those in labor. In another study, a glycohemoglobin level > 6.4 percent at delivery was independently associated with urgent cesarean delivery. This suggests that tighter glycemic control during the third trimester might reduce late fetal compromise and cesarean delivery for fetal indications (Miailhe, 2013). The cesarean delivery rate for women with overt diabetes has remained at approximately 80 percent for the past 35 years at Parkland Hospital.
Reducing or withholding the dose of long-acting insulin given on the day of delivery is recommended. Regular insulin should be used to meet most or all of the insulin needs of the mother during this time, because insulin requirements typically drop markedly after delivery. We have found that continuous insulin infusion by calibrated intravenous pump is most satisfactory (Table 57-10). Throughout labor and after delivery, the woman should be adequately hydrated intravenously and given glucose in sufficient amounts to maintain normoglycemia. Capillary or plasma glucose levels should be checked frequently, especially during active labor, and regular insulin should be administered accordingly.
TABLE 57-10. Insulin Management During Labor and Delivery
• Usual dose of intermediate-acting insulin is given at bedtime.
• Morning dose of insulin is withheld.
• Intravenous infusion of normal saline is begun.
• Once active labor begins or glucose levels decrease to < 70 mg/dL, the infusion is changed from saline to 5-percent dextrose and delivered at a rate of 100–150 mL/hr (2.5 mg/kg/min) to achieve a glucose level of approximately 100 mg/dL.
• Glucose levels are checked hourly using a bedside meter allowing for adjustment in the insulin or glucose infusion rate.
• Regular (short-acting) insulin is administered by intravenous infusion at a rate of 1.25 U/hr if glucose levels exceed 100 mg/dL.
Data from Coustan DR. Delivery: timing, mode, and management. In: Reece EA, Coustan DR, Gabbe SG, editors. Diabetes in women: adolescence, pregnancy, and menopause. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2004; and Jovanovic L, Peterson CM. Management of the pregnant, insulin-dependent diabetic woman. Diabetes Care 1980;3:63–8. From Pregestational diabetes mellitus. ACOG Practice Bulletin No. 60. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005;105:675–85; reaffirmed 2012.
Often, women may require virtually no insulin for the first 24 hours or so postpartum. Subsequently, insulin requirements may fluctuate markedly during the next few days. Infection must be promptly detected and treated.
Counseling in the puerperium should include a discussion of birth control. Available options are discussed in Chapter 38 (p. 695). Effective contraception is especially important in women with overt diabetes to allow optimal glucose control before subsequent conceptions.
In the United States, 5 to 6 percent of pregnancies—almost 250,000 women—are affected annually by various forms of gestational diabetes. Worldwide, its prevalence differs according to race, ethnicity, age, and body composition and by screening and diagnostic criteria. There continue to be several controversies pertaining to the diagnosis and treatment of gestational diabetes. Accordingly, a National Institutes of Health (NIH) Consensus Development Conference (2013) was convened. Coincidental with publication of the Conference findings, the American College of Obstetricians and Gynecologists (2013) also updated its recommendations. These two authoritative sources provide an up-to-date analysis of the issues surrounding this diagnosis and bolster the approach to identifying and treating women with gestational diabetes, as described subsequently.
The word gestational implies that diabetes is induced by pregnancy—ostensibly because of exaggerated physiological changes in glucose metabolism (Chap. 4, p. 53). Gestational diabetes is defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy (American College of Obstetricians and Gynecologists, 2013). This definition applies whether or not insulin is used for treatment and undoubtedly includes some women with previously unrecognized overt diabetes. In their analysis of more than 1500 nonpregnant adults as part of National Health and Nutrition Examinations Survey (NHANES) IV, Karve and Hayward (2010) estimated that only 4.8 percent of individuals with impaired fasting glucose or glucose intolerance were aware of their diagnosis.
Use of the term gestational diabetes has been encouraged to communicate the need for increased surveillance and to stimulate women to seek further testing postpartum. The most important perinatal correlate is excessive fetal growth, which may result in both maternal and fetal birth trauma. The likelihood of fetal death with appropriately treated gestational diabetes is not different from that in the general population. Importantly, more than half of women with gestational diabetes ultimately develop overt diabetes in the ensuing 20 years. And, as discussed on page 1125, evidence is mounting for long-range complications that include obesity and diabetes in their offspring.
Screening and Diagnosis
Despite more than 40 years of research, there is still no agreement regarding optimal gestational diabetes screening. The difficulty in achieving consensus is underscored by the controversy following publication of the single-step approach espoused by the IADPSG Consensus Panel (2010) (Table 57-11). This strategy was greatly influenced by results of the Hypoglycemia and Pregnancy Outcomes (HAPO) Study described later. Although the ADA adopted this new scheme, the American College of Obstetricians and Gynecologists (2013) declined to endorse the single 75-gram oral glucose tolerance test. Instead, the College continues to recommend a two-step approach to screen and diagnose gestational diabetes. Similarly, the NIH Consensus Development Conference in 2013 concluded that evidence is insufficient to adopt a one-step approach.
TABLE 57-11. Threshold Values for Diagnosis of Gestational Diabetes
The recommended two-step approach begins with either universal or risk-based selective screening using a 50-g, 1-hour oral glucose challenge test. Participants in the Fifth International Workshop Conferences on Gestational Diabetes endorsed use of selective screening criteria shown in Table 57-12. Universal screening is also acceptable. Gabbe and associates (2004) surveyed practicing obstetricians and reported that 96 percent used universal screening. Screening should be performed between 24 and 28 weeks’ gestation in those women not known to have glucose intolerance earlier in pregnancy. This 50-g screening test is followed by a diagnostic 100-g, 3-hour oral glucose tolerance test (OGTT) if screening results meet or exceed a predetermined plasma glucose concentration.
TABLE 57-12. Fifth International Workshop-Conference on Gestational Diabetes: Recommended Screening Strategy Based on Risk Assessment for Detecting Gestational Diabetes (GDM)
GDM risk assessment: should be ascertained at the first prenatal visit
Low Risk: Blood glucose testing not routinely required if all the following are present:
Member of an ethnic group with a low prevalence of GDM
No known diabetes in first-degree relatives
Age < 25 years
Weight normal before pregnancy
Weight normal at birth
No history of abnormal glucose metabolism
No history of poor obstetrical outcome
Average Risk: Perform blood glucose testing at 24 to 28 weeks using either:
Two-step procedure: 50-g oral glucose challenge test (GCT), followed by a diagnostic 100-g OGTT for those meeting the threshold value in the GCT
One-step procedure: diagnostic 100-g OGTT performed on all subjects
High Risk: Perform blood glucose testing as soon as feasible, using the procedures described above, if one or more of these are present:
Strong family history of type 2 diabetes
Previous history of GDM, impaired glucose metabolism, or glucosuria
If GDM is not diagnosed, blood glucose testing should be repeated at 24 to 28 weeks’ gestation or at any time symptoms or signs suggest hyperglycemia
OGTT = oral glucose tolerance test.
Modified from Metzger, 2007.
For the 50-g screen, the plasma glucose level is measured 1 hour after a 50-g oral glucose load without regard to the time of day or time of last meal. In a recent review, the pooled sensitivity for a threshold of 140 mg/dL ranged from 74 to 83 percent depending on 100-g thresholds used for diagnosis (van Leeuwen, 2012). Sensitivity estimates for a 50-g screen threshold of 135 mg/dL improved only slightly to 78 to 85 percent. Importantly, specificity dropped from a range of 72 to 85 percent for 140 mg/dL to 65 to 81 percent for a threshold of 135 mg/dL. That said, the American College of Obstetricians and Gynecologists (2013) recommends using either 135 or 140 mg/dL as the 50-g screen threshold. At Parkland Hospital, we continue to use 140 mg/dL.
Justification for screening and treatment of women with gestational diabetes was strengthened by the study by Crowther and coworkers (2005). They assigned 1000 women with gestational diabetes between 24 and 34 weeks’ gestation to receive dietary advice with blood glucose monitoring plus insulin therapy—the intervention group—or to undergo routine prenatal care. Women were diagnosed as having gestational diabetes if their blood glucose was < 100 mg/dL after an overnight fast and was between 140 and 198 mg/dL 2 hours after ingesting a 75-g glucose solution. Women in the intervention group had a significantly reduced risk of a composite adverse outcome that included perinatal death, shoulder dystocia, fetal bone fracture, and fetal nerve palsy. Macrosomia defined by birthweight ≥ 4000 g complicated 10 percent of deliveries in the intervention group compared with 21 percent in the routine prenatal care group. Cesarean delivery rates were almost identical in the two study groups.
Slightly different results were reported by the Maternal-Fetal Medicine Units Network randomized trial of 958 women (Landon, 2009). Dietary counseling plus glucose monitoring was compared with standard obstetrical care in women with mild gestational diabetes to reduce perinatal morbidity rates. Mild gestational diabetes was identified in women with fasting glucose levels < 95 mg/dL. They reported no differences in rates of composite morbidity that included stillbirth; neonatal hypoglycemia, hyperinsulinemia, and hyperbilirubinemia; and birth trauma. Importantly, secondary analyses demonstrated a 50-percent reduction in macrosomia, fewer cesarean deliveries, and a significant decrease in shoulder dystocia rates—1.5 versus 4 percent—in treated versus control women.
Based largely on these two studies, the U.S. Preventive Services Task Force (2013) now recommends universal screening in low-risk women after 24 weeks’ gestation. However, the Task Force concluded that evidence is insufficient to assess the balance of benefits versus harms of screening before 24 weeks. From the foregoing, there obviously is not international agreement as to the optimal glucose tolerance test to identify gestational diabetes. The World Health Organization (1998) and now the American Diabetes Association (2013) recommend the 75-g 2-hour oral glucose tolerance test. In the United States, however, the 100-g, 3-hour OGTT test performed after an overnight fast is recommended by the American College of Obstetricians and Gynecologists (2013). Criteria for interpretation of the 100-g diagnostic glucose tolerance test are shown in Table 57-13. Also shown are the criteria for the 75-g test most often used outside the United States.
TABLE 57-13.Fifth International Workshop Conference on Gestational Diabetes: Diagnostic Criteria of Gestational Diabetes by Oral Glucose Tolerance Testing
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study
This was a 7-year international epidemiological study of 23,325 pregnant women at 15 centers in nine countries (HAPO Study Cooperative Research Group, 2008). The investigation analyzed the association of various levels of glucose intolerance during the third trimester with adverse infant outcomes in women with gestational diabetes. Between 24 and 32 weeks’ gestation, the general population of pregnant women underwent 75-g oral glucose tolerance testing after overnight fasting. Blood glucose levels were measured fasting and then 1 and 2 hours after glucose ingestion. Caregivers were blinded to results except for women whose glucose levels exceeded values that required treatment and removal from the study. Glucose values at each of these three time posts were stratified into seven categories (Fig. 57-8). Values were then correlated with rates for birthweight > 90th percentile (LGA), primary cesarean delivery, clinical neonatal hypoglycemia, and cord-serum C-peptide levels > 90th percentile. C-peptide is a measurable by-product created during insulin production. Odds of each outcome were calculated using the lowest category—for example, fasting plasma glucose < 75 mg/dL—as the referent group. Their findings in general supported the supposition that increasing plasma glucose levels at each epoch were associated with increasing adverse outcomes.
FIGURE 57-8 Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. The frequency of newborn birthweight ≥ 90th percentile for gestational age plotted against glucose levels (mg/dL) fasting and at 1- and 2-hr intervals following a 75-g oral glucose load. LGA = large for gestational age. (Adapted from The HAPO Study Cooperative Research Group, 2008.)
In an editorial accompanying publication of the HAPO trial, Ecker and Greene (2008) posed the question: “Given the results of the HAPO study, should we lower our threshold for the diagnosis and treatment of gestational diabetes?” It was adjudged that it will be difficult to show that treating lesser degrees of carbohydrate intolerance—as suggested in the HAPO study—would provide any meaningful improvements in clinical outcomes. Thus Ecker and Greene (2008) concluded, and we agree, that changes in criteria are not justified until clinical trials prove benefits. Most recently, this position was endorsed by the 2013 NIH Consensus Development Conference.
International Association of Diabetes and Pregnancy Study Group
The IADPSG sponsored a workshop conference on the diagnosis and classification of gestational diabetes in 2008. After reviewing the results of the HAPO study, a panel was appointed to develop recommendations for the diagnosis and classification of hyperglycemia during pregnancy. This panel allowed for the diagnosis of overt diabetes during pregnancy as shown in Table 57-4. It also recommended a single-step approach to the diagnosis of gestational diabetes using the 75-g, 2-hour OGTT. Thresholds for fasting, 1-, and 2-hour values based on mean glucose concentrations from the entire HAPO study cohort were considered. These thresholds were derived using an arbitrary 1.75 odds ratio of outcomes such as LGA birthweight and cord serum C-peptide levels > 90th percentile. Only one of these thresholds would need to be met or exceeded to make the diagnosis of gestational diabetes (see Table 57-11).
It is estimated that implementation of these recommendations would increase the prevalence of gestational diabetes in the United States to 17.8 percent! Said another way, the number of women with mild gestational diabetes would increase almost threefold with no evidence of treatment benefit (Cundy, 2012). Despite these significant drawbacks, the ADA (2013) recommended adopting this new approach based on benefits inferred from trials in women identified using a two-step approach described on page 1138 (Crowther, 2005; Landon, 2009).
National Institutes of Health Consensus Development Conference on Diagnosing Gestational Diabetes Mellitus
Prompted by the IADPSG recommendations (2010) and their adoption by the ADA (2013), an NIH Consensus Development Conference (2013) was convened. This conference included input from a multidisciplinary planning committee, a systematic evidence review by the Agency for Healthcare Research and Quality (AHRQ) Evidence-Based Practice Center, expert testimony, and a nonbiased panel to produce the overall report. The panel concluded that there were potential benefits to worldwide standardization. However, it found insufficient evidence to adopt a one-step diagnostic process such as the one proposed by the IADPSG. Moreover, as mentioned previously, after consideration of these findings, the American College of Obstetricians and Gynecologists (2013) continues to recommend a two-step screening and diagnostic approach to gestational diabetes diagnosis. It noted no significant improvements in maternal or perinatal outcomes that would offset the tripling of gestational diabetes incidence that would derive from the one-step approach. We applaud this decision.
Maternal and Fetal Effects
Adverse consequences of gestational diabetes differ from those of pregestational diabetes. Unlike in women with overt diabetes, rates of fetal anomalies do not appear to be substantially increased (Sheffield, 2002). In a study of more than 1 million women from the Swedish Medical Birth Registry, major malformation rates were marginally increased—2.3 versus 1.8 percent (Fadl, 2010). The stillbirth rate was not increased in this study or in an analysis of 130 perinatal deaths in the HAPO study (2008). In contrast, and not unexpectedly, women with elevated fasting glucose levels have increased rates of unexplained stillbirths similar to women with overt diabetes. The ADA (2003) concluded that fasting hyperglycemia > 105 mg/dL may be associated with an increased risk of fetal death during the final 4 to 8 weeks. This increasing risk with progressive maternal hyperglycemia prompted the IADPSG (2010) to emphasize the importance of identifying women with evidence of preexisting diabetes early in pregnancy (see Table 57-4). Similar to women with overt diabetes, adverse maternal effects associated with gestational diabetes include an increased frequency of hypertension and cesarean delivery.
The primary effect attributed to gestational diabetes is excessive fetal size or macrosomia that is variably defined and discussed further in Chapter 44 (p. 884). Maternal hyperglycemia prompts fetal hyperinsulinemia, particularly during the second half of pregnancy. This in turn stimulates excessive somatic growth. The perinatal goal is to avoid difficult delivery from macrosomia and concomitant birth trauma associated with shoulder dystocia. In a retrospective analysis of more than 80,000 vaginal deliveries in Chinese women, Cheng and associates (2013) calculated a 76-fold increased risk for shoulder dystocia in newborns weighing ≥ 4200 g compared with the risk in those weighing < 3500 g. Importantly, however, the odds ratio for shoulder dystocia in women with diabetes was less than 2. Although gestational diabetes is certainly a risk factor, it accounts for only a small number of pregnancies complicated by shoulder dystocia.
The excessive shoulder and trunk fat that commonly characterizes the macrosomic infant of a diabetic mother theoretically predisposes such infants to shoulder dystocia or cesarean delivery (Durnwald, 2004; McFarland, 2000). Landon and colleagues (2011) identified shoulder dystocia in approximately 4 percent of women with mild gestational diabetes compared with < 1 percent of women with a 50-g glucose screen result < 120 mg/dL. In a prospective study of fetal adipose measurements, however, Buhling and coworkers (2012) demonstrated no differences between measurements in 630 offspring of women with gestational diabetes and 142 without diabetes. The authors attributed this negative finding to successful treatment of gestational diabetes.
There is extensive evidence that insulin-like growth factors also play a role fetal-growth regulation (Chap. 44, p. 872). These proinsulin-like polypeptides are produced by virtually all fetal organs and are potent stimulators of cell differentiation and division. Luo and coworkers (2012) reported that insulin-like growth factor-I strongly correlated with birthweight. The HAPO study investigators also reported dramatic increases of cord-serum C-peptide levels with increasing maternal glucose levels following a 75-g OGTT. C-peptide levels > 90th percentile were found in almost a third of newborns in the highest glucose categories. Other factors implicated in macrosomia include epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, leptin, and adiponectin (Grissa, 2011; Loukovaara, 2004; Mazaki-Tovi, 2005).
Neonatal hyperinsulinemia may provoke hypoglycemia within minutes of birth. The incidence varies depending on the threshold definition. Cornblath and associates (2000) established a threshold of 35 mg/dL in term newborns. An NIH workshop conference on neonatal hypoglycemia supported use of such operational thresholds but cautioned that these are not strictly evidence-based (Hay, 2009). Newborns described by the HAPO study (2008) had an incidence of clinical neonatal hypoglycemia that increased with increasing maternal OGTT values defined in Figure 57-8. The frequency varied from 1 to 2 percent, but it was as high as 4.6 percent in women with fasting glucose levels ≥ 100 mg/dL. Likewise, cord-blood insulin levels are related to maternal glucose control (Leipold, 2004).
In women with gestational diabetes, maternal BMI is an independent and more substantial risk factor for fetal macrosomia than is glucose intolerance (Ehrenberg, 2004; Mission, 2013). Stuebe and colleagues (2012) completed a secondary analysis of women with either untreated mild gestational diabetes or normal glucose tolerance testing results. They found that higher BMI levels were associated with increasing birthweight, regardless of glucose levels. Also, maternal obesity is an important confounding factor in the diagnosis of gestational diabetes. In their metaanalysis, Torloni and coworkers (2009) estimated that the gestational diabetes prevalence increases by approximately 1 percent for every 1 kg/m2 increase in BMI. Weight distribution also seems to play a role because the risk of gestational diabetes is increased with truncal obesity. Suresh and colleagues (2012) verified that increased maternal abdominal subcutaneous fat thickness as measured by sonography at 18 to 22 weeks’ gestation correlated with BMI and was a better predictor of gestational diabetes. Martin and associates (2009) reported similar findings for sonographically measured maternal visceral adipose depth. Importantly, excessive gestational weight gain is commonly identified in women with gestational diabetes and also confers an additive risk for fetal macrosomia (Egan, 2014).
Women with gestational diabetes can be divided into two functional classes using fasting glucose levels. Pharmacological methods are usually recommended if diet modification does not consistently maintain the fasting plasma glucose levels < 95 mg/dL or the 2-hour postprandial plasma glucose < 120 mg/dL (American College of Obstetricians and Gynecologists, 2013). Whether pharmacological treatment should be used in women with lesser degrees of fasting hyperglycemia—105 mg/dL or less before dietary intervention—is unclear. There have been no controlled trials to identify ideal glucose targets for fetal risk prevention. On the other hand, the HAPO study (2008) did demonstrate increased fetal risk at glucose levels below the threshold used for diagnosis of diabetes. The Fifth International Workshop Conference recommended that fasting capillary glucose levels be kept ≤ 95 mg/dL (Metzger, 2007).
In a systematic review, Hartling and colleagues (2013) concluded that treating gestational diabetes resulted in a significantly lower incidence of preeclampsia, shoulder dystocia, and macrosomia. For example, the calculated risk ratio for delivering an infant > 4000 g after treatment was 0.50. These investigators caution that the attributed risk for these outcomes is low, especially when glucose values are only moderately elevated. Importantly, they were unable to demonstrate an effect on neonatal hypoglycemia or future metabolic outcomes in the offspring.
As discussed previously, reports by Crowther (2005) and Landon (2009) and their colleagues describe the benefits of dietary counseling and monitoring in women with gestational diabetes. The ADA recommends individualized nutritional counseling based on height and weight (Bantle, 2008). Nutritional instructions generally include a carbohydrate-controlled diet sufficient to maintain normoglycemia and avoid ketosis. On average, this includes a daily caloric intake of 30 to 35 kcal/kg. Moreno-Castilla and associates (2013) randomly assigned 152 women with gestational diabetes to either a 40- or a 55-percent daily carbohydrate diet and found no difference in insulin levels and pregnancy outcomes. The American College of Obstetricians and Gynecologists (2013) suggests that carbohydrate intake be limited to 40 percent of total calories. The remaining calories are apportioned to give 20 percent as protein and 40 percent as fat.
Although the most appropriate diet for women with gestational diabetes has not been established, the ADA (2003) has suggested that obese women with a BMI > 30 kg/m2 may benefit from a 30-percent caloric restriction, which approximates 25 kcal/kg/d. This should be monitored with weekly assessment for ketonuria, which has been linked with impaired psychomotor development in offspring (Rizzo, 1995; Scholte, 2012). That said, Most and Langer (2012) found that insulin was necessary to reduce excess birthweight in offspring of obese women with gestational diabetes.
The American College of Obstetricians and Gynecologists (2009) reviewed three randomized trials of exercise in women with gestational diabetes (Avery, 1997; Bung, 1993; Jovanovic-Peterson, 1989). The results suggest that exercise improved cardiorespiratory fitness without improving pregnancy outcome. Importantly, these trials were small and had limited power to show improvement in outcomes. Dempsey and coworkers (2004) found that physical activity during pregnancy reduced the risk of gestational diabetes. Brankston and associates (2004) reported that resistance exercise diminished the need for insulin therapy in overweight women with gestational diabetes. Conversely, Stafne and colleagues (2012), in a randomized controlled trial in 855 women, observed that a 1-week exercise program during the second half of pregnancy did not prevent gestational diabetes or improve insulin resistance. Importantly, the average BMI at enrollment was 24.8 ± 3.2. The American College of Obstetricians and Gynecologists (2013) recommends a moderate exercise program as part of the treatment plan for women with gestational diabetes.
Hawkins and colleagues (2008) compared outcomes in 315 women with diet-treated gestational diabetes who used personal glucose monitors with those of 615 gestational diabetics who were also diet-treated but who underwent intermittent fasting glucose evaluation during semi-weekly obstetrical visits. Women using daily blood-glucose self-monitoring had significantly fewer macrosomic infants and gained less weight after diagnosis than women evaluated during clinic visits only. These findings support the common practice of blood-glucose self-monitors for women with diet-treated gestational diabetes.
Postprandial surveillance for gestational diabetes has been shown to be superior to preprandial surveillance. DeVeciana and coworkers (1995) studied 66 pregnant women with gestational diabetes in whom insulin was initiated for fasting hyperglycemia. The women were randomly assigned to glucose surveillance using either preprandial or 1-hour postprandial capillary blood-glucose concentrations. Postprandial surveillance was shown to be superior in that blood-glucose control was significantly improved and was associated with fewer cases of neonatal hypoglycemia—3 versus 21 percent; less macrosomia—12 versus 42 percent; and fewer cesarean deliveries for dystocia—24 versus 39 percent. At Parkland Hospital, we were unable to demonstrate similar findings when we reviewed the impact of changing to postprandial monitoring in women with diet-treated gestational diabetes. We did, however, demonstrate a significant reduction in maternal weight gain per week—0.63 lb/week to 0.45 lb/week—in women managed with a postprandial monitoring schema. The American College of Obstetricians and Gynecologists (2013) recommends four-times daily glucose monitoring performed fasting and either 1 or 2 hours after each meal.
Historically, insulin has been considered standard therapy in women with gestational diabetes when target glucose levels cannot be consistently achieved through nutrition and exercise. It does not cross the placenta, and tight glycemic control can typically be achieved. In a report prepared for the AHRQ, Nicholson and associates (2009) were unable to determine a threshold above which insulin should be initiated. Pharmacological therapy—in this case insulin—is typically added if fasting levels persistently exceed 95 mg/dL in women with gestational diabetes. The American College of Obstetricians and Gynecologists (2013) also recommends that insulin be considered in women with 1-hour postprandial levels that persistently exceed 140 mg/dL or those with 2-hour levels above 120 mg/dL. Importantly, all of these thresholds are extrapolated from recommendations for managing women with overt diabetes.
If insulin is initiated, the starting dose is typically 0.7–1.0 units/kg/day given in divided doses (American College of Obstetricians and Gynecologists, 2013). A combination of intermediate-acting and short-acting insulin may be used, and dose adjustments are based on glucose levels at particular times of the day. At Parkland Hospital, insulin instruction for these women is accomplished either in a specialized outpatient clinic or during a short hospital stay. As shown in Table 57-8, insulin analogues such as insulin aspart and insulin lispro have a more rapid onset of action than regular insulin and theoretically could be helpful in postprandial glucose management. Experience with these analogues with gestational diabetes is limited, and Singh and coworkers (2008) were unable to demonstrate a benefit compared with conventional insulins.
Oral Hypoglycemic Agents
Several studies have attested to the safety and efficacy of gestational diabetes treatment with either glyburide (Micronase) or metformin (Glucophage) (Langer, 2000; Nicholson, 2009; Rowan, 2008). In one study, Langer and colleagues (2000, 2005) randomly assigned 404 women to insulin or glyburide therapy. Near normoglycemic levels were achieved with either regimen, and there were no apparent neonatal complications attributable to glyburide. In a follow-up study, Conway and coworkers (2004) reported that women with fasting glucose levels > 110 mg/dL did not adequately respond to glyburide therapy. Similar results were reported by Chmait (2004) and Kahn (2006) and their associates. At one time, glyburide was thought not to cross the placenta. However, Hebert and colleagues (2008, 2009) sampled 20 paired maternal-cord specimens and found the latter to have glyburide concentrations approximately half that of maternal levels.
Metformin treatment for polycystic ovarian disease throughout pregnancy reduced the incidence of gestational diabetes (Glueck, 2004). Because metformin crosses to the fetus, there was reticence to use it in pregnant women (Harborne, 2003). Subsequent studies have helped allay these concerns. Rowan and associates (2008) randomly assigned 751 women with gestational diabetes to metformin or insulin treatment. The primary outcome was a composite of neonatal hypoglycemia, respiratory distress syndrome, phototherapy, birth trauma, 5-minute Apgar score ≤ 7, and preterm birth. Similarities in the composite outcome between metformin and insulin led investigators to conclude that metformin was not associated with adverse perinatal outcomes. It is noteworthy that 46 percent of women in the metformin trial required supplemental insulin compared with only 4 percent of women treated with glyburide (Langer, 2000).
In their systematic review and metaanalysis of oral hypoglycemic agents for gestational diabetes, Nicholson and coworkers (2009) found no evidence of increased adverse maternal or neonatal outcomes with glyburide or metformin compared with insulin. Moore and associates (2010) randomly assigned 149 women with gestational diabetes who did not achieve glycemic control on diet therapy to either glyburide or metformin treatment. More than a third of women in the metformin group required supplemental insulin compared with 16 percent of those treated with glyburide.
Oral hypoglycemic agents are being increasingly used for gestational diabetes, although they have not been approved by the Food and Drug Administration for this indication. A survey of almost 1400 fellows of the American College of Obstetricians and Gynecologists found that 13 percent of respondents were using glyburide as first-line therapy for diet failure in women with gestational diabetes (Gabbe, 2004). The American College of Obstetricians and Gynecologists (2013) acknowledges that both glyburide and metformin are appropriate, as is insulin, for first-line glycemic control in women with gestational diabetes. Because long-term outcomes have not been studied, the committee recommends appropriate counseling when hypoglycemic agents are used.
In general, for women with gestational diabetes who do not require insulin, early delivery or other interventions are seldom required. There is no consensus regarding the value or timing of antepartum fetal testing. It is typically reserved for women with pregestational diabetes because of the increased stillbirth risk. The American College of Obstetricians and Gynecologists (2013) endorses fetal surveillance in women with gestational diabetes and poor glycemic control. At Parkland Hospital, women with gestational diabetes are routinely instructed to perform daily fetal kick counts in the third trimester (Chap. 17, p. 335). Insulin-treated women are offered inpatient admission after 34 weeks’ gestation, and fetal heart rate monitoring is performed three times each week.
Women with gestational diabetes and adequate glycemic control are managed expectantly. Elective labor induction to prevent shoulder dystocia compared with spontaneous labor remains controversial. One randomized trial evaluated induction at 38 weeks in 200 women with insulin-treated diabetes—187 of whom had gestational diabetes. Investigators reported a significantly lower proportion of newborns with a birthweight > 90th percentile in the active induction group—10 versus 23 percent (Kjos, 1993). However, there were no differences in rates of cesarean delivery or shoulder dystocia or in neonatal outcomes. Witkop and colleagues (2009) performed a systematic review and concluded that, in the aggregate, a reduction in fetal macrosomia is likely in women with gestational diabetes who undergo an elective labor induction at term. They also found a limited ability to draw definite conclusions based on available evidence. The American College of Obstetricians and Gynecologists (2013) also has concluded that no evidence-based recommendation can be made regarding delivery timing in women with gestational diabetes. To study this, a large multicenter trial (NCT01058772) expected to enroll 1760 women with gestational diabetes is currently recruiting participants (Maso, 2011).
Elective cesarean delivery to avoid brachial plexus injuries in overgrown fetuses is also an important issue. The American College of Obstetricians and Gynecologists (2013) has suggested that cesarean delivery should be considered in women with gestational diabetes whose fetuses have a sonographically estimated weight ≥ 4500 g. From their systematic review, Garabedian and coworkers (2010) estimated that as many as 588 cesarean deliveries in women with gestational diabetes and an estimated fetal weight of ≥ 4500 g would be necessary to avoid one case of permanent brachial plexus palsy. Effects of such a policy were retrospectively analyzed by Gonen and associates (2000) in a general obstetrical population of more than 16,000 women. Elective cesarean delivery had no significant effect on the incidence of brachial plexus injury.
Recommendations for postpartum evaluation are based on the 50-percent likelihood of women with gestational diabetes developing overt diabetes within 20 years (O’Sullivan, 1982). The Fifth International Workshop Conference on Gestational Diabetes recommended that women diagnosed with gestational diabetes undergo evaluation with a 75-g oral glucose tolerance test at 6 to 12 weeks postpartum and other intervals thereafter (Metzger, 2007). These recommendations are shown in Table 57-14 along with the classification scheme of the ADA (2013). Hunt and colleagues (2010) reviewed performance rates of postpartum glucose screening and found that anywhere between 23 and 58 percent of women actually undergo 75-g glucose testing. The American College of Obstetricians and Gynecologists (2013) recommends either a fasting glucose or the 75-g, 2-hour OGTT for the diagnosis of overt diabetes. The ADA (2011) recommends testing at least every 3 years in women with a history of gestational diabetes but normal postpartum glucose screening.
TABLE 57-14. Fifth International Workshop-Conference: Metabolic Assessments Recommended after Pregnancy with Gestational Diabetes
Women with a history of gestational diabetes are also at risk for cardiovascular complications associated with dyslipidemia, hypertension, and abdominal obesity—the metabolic syndrome (Chap. 48, p. 962). In a study of 47,909 parous women, Kessous and coworkers (2013) evaluated subsequent hospitalizations due to cardiovascular morbidity. They found that almost 5000 women with gestational diabetes were 2.6 times more likely to be hospitalized for cardiovascular morbidity. Shah and coworkers (2008) also documented excessive cardiovascular disease by 10 years in women with gestational diabetes. Akinci and associates (2009) reported that a fasting glucose level ≥ 100 mg/dL in the index OGTT was an independent predictor of the metabolic syndrome.
Recurrent Gestational Diabetes
In subsequent pregnancies, recurrence was documented in 40 percent of 344 primiparous women with gestational diabetes (Holmes, 2010). Obese women were more likely to have impaired glucose tolerance in subsequent pregnancies. Thus, lifestyle behavioral changes, including weight control and exercise between pregnancies, likely would prevent gestational diabetes recurrence (Kim, 2008). Ehrlich and colleagues (2011) found that the loss of at least two BMI units was associated with a lower risk of gestational diabetes in women who were overweight or obese in the first pregnancy. Getahun and coworkers (2010) found that only 4.2 percent of women without gestational diabetes in their first pregnancy were diagnosed with gestational diabetes when screened in a second pregnancy. This compared with 41.3 percent in women with a history of gestational diabetes.
Low-dose hormonal contraceptives may be used safely by women with recent gestational diabetes (Chap. 38, p. 709). The rate of subsequent diabetes in oral contraceptive users is not significantly different from that in those who did not use hormonal contraception (Kerlan, 2010). Importantly, comorbid obesity, hypertension, or dyslipidemia should direct the choice for contraception toward a method without potential cardiovascular consequences. In these instances, the intrauterine device is a good alternative.
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