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Obstentrics_Williams. World Health Organization: Guideline: daily iron and folic acid supplementation in pregnant women. 2012. Available at: http://apps.who.int/iris/bitstr eam/1t0665/77770/1/9789241501996_eng.pd?ua = 1. Accessed November 9, 2016 Wyszynski DF, Carman W], Cantor AB, et al: Pregnancy and birth outcomes among women with idiopathic thrombocytopenic purpura. ) Pregnancy 2016:829740 ,2016 Xiong L, Barrett AN, Hua R, et al: Non-invasive prenatal diagnostic testing for 3-thalassaemia using cell-free fetal DNA and next generation sequencing. Prenat Diagn 35(3):258, 2015 Yawata Y, Kanzaki A, Yawata A, et al: Characteristic features of the genotype and phenotype of hereditary spherocytosis in the Japanese population. Int) Hematol 71:118, 2000 Yeomans E, Lowe W, Eigenbrodt EH, et al: Liver histopathologic indings in women with sickle cell disease given prophylactic transfusion during pregnancy. m)Obstet Gynecol 163:958, 1990


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Obstentrics_Williams. Yeomans E, Lowe W, Eigenbrodt EH, et al: Liver histopathologic indings in women with sickle cell disease given prophylactic transfusion during pregnancy. m)Obstet Gynecol 163:958, 1990 Young NS: Bone marrow failure syndromes including aplastic anemia and myelodysplasia. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015 Yu CK, Stasiowska E, Stephens A, et al: Outcome of pregnancy in sickle cell disease patients attending a combined obstetric and haematology clinic. ) Obstet Gynaecol 29(6):512, 2009 Zhen L, Pen M, Han), et al: Non-invasive prenatal detection of haemoglobin Bart's disease by cardiothoracic ratio during the irst trimester. Eurt) Obstet Gynecol Reprod Bioi 193:92, 2015 Ziaei S, Norrozi M, Faghihzadeh S, et al: A randomized placebo-controlled trial to determine the efect of iron supplementation on pregnancy outcome in pregnant women with haemoglobin : 13.2 g/dl. B)OG 114:684, 2007


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Obstentrics_Williams. TYPES OF DIABETES. . . . . . . . . . . . . . . . . . . . . . . . . . .. 1097 PREGESTATIONAL DIABETES .....i...i...i....i.....i....1098 DIAGNOSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1098 FETAL EFFECTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1099 MATERNAL EFFECTS.. . . . . . . . . . . . . . . . . . . . . . . . . .. 1103 MANAGEMENT OF DIABETES IN PREGNANCY . . . . .. 1104 GESTATIONAL DIABETES. . . . . . . . . . . . . . . . . . . . . . .. 1 107 SCREENING AND DIAGNOSIS .................... 1108 MATERNAL AND FETAL EFFECTS .....i............. 1110 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1 111 Diabetes may exist bore the inception ofpregnancy, or may not appear until labour. The prognosis is generaly believed to be ominous or mother and chil, but a review of the literature shows that less than 25 percent of the mothers died from diabetic coma, while premature labour occurred in ony one third of the cases.


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Obstentrics_Williams. -J. Whitridge Williams (1903) In the early 1900s, overt diabetes complicating pregnancy was associated with horriic morbidity and mortality for a mother and her fetus. Although tremendously mitigated by the discovery of insulin, overt and gestational diabetes still are formidable complications of pregnancy. According to the Centers for Disease Control and Prevention (2017), the number of adults diagnosed with diabetes in the United States is 23.r1 million. And, almost a quarter of people with diabetes in the United States remain undiagnosed. tion more likely to develop type 2 diabetes, population growth within minority group at particular risk for type 2 diabetes, and a dramatic rise in obesity rates-also referred to as diabesiy. he term reflects the strong relationship of diabetes and the current obesity epidemic in the United States and underlines the critical need for diet and lifestyle interventions to change the trajectory of both.


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Obstentrics_Williams. here is keen interest in events that precede diabetes, and this includes the intrauterine environment. Here, early imprinting is believed to have efects later in life (Saudek, 2002). For example, in utero exposure to maternal hyperglycemia leads to fetal hyperinsulinemia, causing an increase in fetal fat cells. his leads to obesity and insulin resistance in childhood (Feig, 2002). These factors in turn lead to impaired glucose tolerance and diabetes in adulthood. This cycle of fetal exposure to diabetes leading to childhood obesity and glucose intolerance is discussed further in Chapter 48 (p. 941).


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Obstentrics_Williams. In nonpregnant individuals, the type of diabetes is based on its presumed etiopathogenesis and its pathophysiological manifestations. Absolute insulin deficiency, generally autoimmune in etiology, characterizes ype 1 diabetes. In contrast, insulin resistance, relative insulin deiciency, or elevated glucose production characterizes ype 2 diabetes (Table 57-1). Both types are generally preceded by a period of abnormal glucose homeostasis oten referred to as prediabetes. The terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are now obsolete. Pancreatic �-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: �-Cell destruction, usually absolute insulin deficiency Immune-mediated


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Obstentrics_Williams. TABLE 57-1. Etiological Classification of Diabetes Mellitus Type 1: �-Cell destruction, usually absolute insulin deficiency Immune-mediated Type 2: Ranges from predominantly insulin resistance to predominantly an insulin secretory defect with insulin resistance Genetic mutations of �-cell function-MODY 1-6, others Genetic defects in insulin action Genetic syndromes-Down, Klinefelter, Tuner Diseases of the exocrine pancreas-pancreatitis, cystic fibrosis Endocrinopathies-Cushing syndrome, pheochromocytoma, others Drug or chemical induced-glucocorticosteroids, thiazides, �-adrenergic agonists, others Infections-congenital rubella, cytomegalovirus, coxsackievirus MODY = maturit I-onset diabetes of the young. Data from Powers, 21n2.


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Obstentrics_Williams. MODY = maturit I-onset diabetes of the young. Data from Powers, 21n2. Diabetes is the most common medical complication of pregnancy. Women can be separated into those who were known to have diabetes before pregnancy-pregestationalior overt, and those diagnosed during pregnancy-gestational diabetes. The proportion of pregnancies complicated by diabetes more than doubled between 1994 and 2008, after which rates seem to have stabilized Oovanovic, 2015). Almost 258,000-6.5 percent-of gravidas in the United States had pregnancies coexistent with some form of diabetes in 2015 (Martin, 2017). Prevalence of diabetes is highest among non-Hispanic blacks, Mexican-Americans, Puerto Rican-Americans, and Native Americans (Golden, 2012). he incidence of gestational diabetes during the past 20 years, shown in Figure 57-1, is reminiscent of similar statistics for obesity (Chap. 48, p. 936). I:u


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Obstentrics_Williams. I:u FIGURE 57-1 Increasing prevalence of type 2 diabetes in the United States from 1995 to 2015. (Reproduced with permission from Centers for Disease Control and Prevention, 201o7.) Until the mid-1990s, the classification by Priscilla White (1978) for diabetic pregnant women was the linchpin of management. Today, the White classiication is used less frequently but still provides simple and useful information on pregnancy risks and prognosis (Bennett, 2015). And, because most currently cited literature also 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.


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Obstentrics_Williams. Beginning several years ago, the American College of Obstetricians and Gynecologists no longer recommended the White classification. Instead, the current focus is whether diabetes antedates pregnancy or is irst diagnosed during pregnancy. Many now recommend adoption of the classiication proposed by the American Diabetes Association (ADA), which is shown in Table 57-3.


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Obstentrics_Williams. he rising prevalence of type 2 diabetes, particularly in younger people, has led to an increasing number of afected pregnancies. For example, the CDC (2015) estimates that more than 5000 new cases of type 2 diabetes are diagnosed each year in youths before the age of 20 years. Feig and coworkers (2014) reported that the incidence of pregestational diabetes doubled from 7 per 1000 women in 1996 to 15 per 1000 in 2010. When considering the previously mentioned high percentage of diabetes that is undiagnosed, then many women identified to have gestational diabetes likely have type 2 diabetes previously unrecognized. In fact,rS 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 diagnostic challenge. Women with a TABLE 57-2. Classification Scheme Used from 1986 through 1994 for Diabetes


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Obstentrics_Williams. Women with high plasma glucose levels, glucosuria, and ketoacidosis present no diagnostic challenge. Women with a TABLE 57-2. Classification Scheme Used from 1986 through 1994 for Diabetes Age of Onset (yr) 10 to 19 10 to 19 aWhen diagnosed during pregnancy: proteinuria :500 mg/24 hr before 20 weeks' gestation.


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Obstentrics_Williams. 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 levelr> 125 mg/dL are considered by the ADA (2017 a) and the World Health Organization (2013) to have overt diabetes first detected in pregnancy. Women with only minimal metabolic derangement may be more diicult to identiY. To diagnose overt diabetes in pregnancy, he International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel (2010) recognizes the threshold values found in Table 57-4 for fasting or random plasma glucose and glycosylated hemoglobin (HbA1J levels at prenatal care initiation. The ADA (2017a) and the World Health Organization (2013) now also consider a plasma glucose level >200 mg/dL measured 2 hours after a 75 g oral glucose load to be diagnostic. No consensus has been reached as to whether such testing should be universal or limited to those women classiied as high risk.


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Obstentrics_Williams. mg/dL measured 2 hours after a 75 g oral glucose load to be diagnostic. No consensus has been reached as to whether such testing should be universal or limited to those women classiied as high risk. Regardless, the tentative diagnosis of overt diabetes during pregnancy based on these thresholds should be conirmed postpartum. isk 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.


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Obstentrics_Williams. With overt diabetes, the embryo, fetus, and mother frequently experience serious complications directly attributable to diabetes. Peterson and colleagues (2015) estimate that thousands of these complications might be prevented each year by preconceptional care for improved glycemic control. The likelihood of successful outcomes with overt diabetes, however, is not simply related to glucose control. The degree of underlying cardiovascular or renal disease may be more important. Thus, advancing stages of the White classification, seen in Table 57-2, are inversely related to favorable pregnancy outcomes. Shown in Table 57-5 are data that chronicle the deleterious pregnancy outcomes with overt diabetes. hese maternal and fetal complications are described in the following sections.


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Obstentrics_Williams. Spontaneous Abortion. Several studies have shown that early miscarriage is associated with poor glycemic control (Chap. 18, p. 347). Up to 25 percent of diabetic gravidas have an early pregnancy loss (Galindo, 2006; Rosenn, 1994). hose whose HbA1c concentrations were > 12 percent or whose preprandial glucose concentrations were persistently > 120 mg/dL had an elevated risk. Bacon and associates (2015) reviewed 89 pregnancies in women with maturity-onset diabetes of the young (MODy), which is a monogenic form of diabetes. hese investigators found that only women with the causative glucose kinase gene (GCK) mutation were more likely to have a miscarriage. These women are characterized by hyperglycemic variability that is diicult to control. TABLE 57-3. Proposed Classification System for Diabetes in Pregnancy Gestational diabetes: diabetes d during pregnancy that is not clearly overt (type 1 or type 2) diabetes Type 1 Diabetes: Type 2 Diabetes:


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Obstentrics_Williams. Gestational diabetes: diabetes d during pregnancy that is not clearly overt (type 1 or type 2) diabetes Type 1 Diabetes: Type 2 Diabetes: Diabetes resulting from �-cell destruction, usually leading to Diabetes from inadequate insulin secretion in the face of a. Without vascular complications a. Without vascular complications b. With vascular complications (speciy which) b. With vascular complications (speciy which) Other types of diabetes: genetic in origin, associated with pancreatic disease, drug-induced, or chemically induced Data from American Diabetes Association, 2017a. TABLE 57-4. Diagnosis of Overt Diabetes in Pregnancya Measure of Glycemia Threshold


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Obstentrics_Williams. Data from American Diabetes Association, 2017a. TABLE 57-4. Diagnosis of Overt Diabetes in Pregnancya Measure of Glycemia Threshold Fasting plasma glucose At least 7.0 mmollL (126 mg/dL) Hemoglobin Ale At least 6.5% Random plasma glucose At least 11.1 mmol/L (200 mg/dL) plus confirmation aApply to women without known diabetes antedating pregnancy. The decision to perform blood testing for evaluation of glycemia all pregnant women r only on women with characteristics indicating a high risk for diabetes is based on the background frequency of abnormal glucose metabolism in the population and on local circumstances. Data from International Association of Diabetes and Pregnancy Study Groups Consensus Panel, 201n0.


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Obstentrics_Williams. Data from International Association of Diabetes and Pregnancy Study Groups Consensus Panel, 201n0. Preterm Delivery. Overt diabetes is an undisputed risk factor for preterm birth. Eidem and associates (2011) analyzed 1307 births in women with type 1 diabetes from the Norwegian NIedical 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 one review of more than 500,000 California births, 19 percent of women with pregestational diabetes had a preterm birth compared with 9 percent in controls (Yanit, 2012). In the Canadian study shown in Table 57-5, the incidence of preterm birth was 28 percent.


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Obstentrics_Williams. Malformations. he incidence of major malformations in women with type 1 diabetes is at least doubled and approximates 11 percent Qovanovic, 2015). These account for almost half of perinatal deaths in diabetic pregnancies. As shown in Table 57-6, cardiovascular malformations accounted for more than half of the anomalies. In a cohort study of more than 2 million births in Canada, the risk of an isolated cardiac defect was ivefold higher in women with type 1 diabetes (Uu, 2013). he caudal regression sequence, described in Chapter 10 (p. 196), is a rare malformation frequently associated with maternal diabetes (Garne, 2012).


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Obstentrics_Williams. Poorly controlled diabetes, both preconceptionally and early in pregnancy, is thought to underlie this elevated severemalformation risk. s shown in Figure 57-2, increased maternal HbA[c levels and major malformations clearly correlate. To explain this, at least three interrelated molecular chain reactions have been linked to maternal hyperglycemia (Reece, 2012). hese include alterations in cellular lipid metabolism, excess production of toxic superoxide radicals, and activation of programmed cell death. In their review of molecular mechanisms underlying diabetic embryopathy, Yang and colleagues (2015) suggest that these cellular responses to oxidative stress represent potential therapeutic targets to prevent diabetes-induced embryopathy.


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Obstentrics_Williams. Altered Fetal Growth. Diminished growth may result from congenitl malformations or from substrate deprivation due to advanced maternal vascular disease. That said, fetal overgrowth is more typical of pregestational diabetes. Maternal hyperglycemia prompts fetal hyperinsulinemia, and this in turn stimulates excessive somatic growth. Except for the brain, most fetal organs are afected by the macrosomia that characterizes the fetus of a diabetic woman. Newborns such as the one shown in Figure 57-3 are described as being anthropometrically diferent from other largefor-gestational age (LGA) neonates (Catalano, 2003; Durnwald, 2004). Speciically, those whose mothers are diabetic have excesyrsive fat deposition on the shoulders and trunk, which predisposes to shoulder dystocia or cesarean delivery. he incidence of macrosomia rises signiicantly when mean maternal blood glucose concentrations chronically exceed 130 mg/dL (Hay, 2012). Hammoud and coworkers (2013)


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Obstentrics_Williams. he incidence of macrosomia rises signiicantly when mean maternal blood glucose concentrations chronically exceed 130 mg/dL (Hay, 2012). Hammoud and coworkers (2013) TABLE 57-5. Pregnancy Outcomes of Births in Nova TABLE 57-6. Major Congenital Anomalies in 36,345 Scotia from 1988 to 2002 in Women with Neonates Born to Women with Diabetes and without Pregestational Diabetes between 2004 and 201e1 (n.=.S16) (n.=.lS0,.S98) Factor P value �pe1.DM Type.2DM GDM Organ System n = 482 n = 4166 n = 31,700 Gestational 28 9 <.001 Cardiac 38 272 1129 Preterm birth 28 5 <.001 Urinary 3 28 260 <.001 CNS 13 64 FIGURE 57-3 This 6050-g macrosomic infant was born to a woman with gestational diabetes.


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Obstentrics_Williams. 15.8 400.) 11.7 30 25 5 3/1e9 5 2/1e7 0 <6 6-6.9 7-7.9 �8 FIGURE 57-2 The frequency of major congenital malformations in newborns ofwomen with pregestational diabetes stratified by hemoglobin Ale levels at first prenatal visit. (Data from Galindo A, Burguillo AG, Azriel S, et al: Outcome offetuses in women with pregestational diabetes mellitus, J Perinat Med. 2006;34(4):323-331.) 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 57-4, the birthweight distribution of neonates of diabetic mothers is skewed toward consistently heavier birthweights. 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. he abdominal circumference grew disproportionately larger in the diabetic groups. Analysis of head circumference/abdominal circumference


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Obstentrics_Williams. were compared with 843 examinations in 145 control women. he abdominal circumference grew disproportionately larger in the diabetic groups. Analysis of head circumference/abdominal circumference (HC/AC) ratios shows that this disproportionate growth occurs mainly ..0


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Obstentrics_Williams. FIGURE 57-4 Distribution of birthweight standard deviations from the normal mean for gestational age in 280 newborns of diabetic mothers and in 3959 neonates of nondiabetic mothers. (Reproduced with permission from Bradley RJ, Nicolaides KH, Brudenell JM.: Are all infants ofdiabetic mothers "macrosomic"7 BMJ 1988 Dec 17;297(6663):1o583-1o584') in diabetic pregnancies that ultimately yield macrosomic newborns. hese findings comport with the observation that virtually all neonates of diabetic mothers are growth promoted, and accelerated fetal growth is particularly evident in women with poor glycemic control.


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Obstentrics_Williams. Unexplained Fetal Demise. Worldwide, the risk offetal death is three to four times higher in women with pregestational diabetes (Cardosi, 2013; Patel, 2015). Stillbirth without an identiiable cause is a phenomenon relatively limited to pregnancies complicated by overt diabetes. These stillbirths are "unexplained" because common factors such as obvious placental insuiciency, placental abruption, fetal-growth restriction, or oligohydramnios are not identified. hese fetuses are typically large for gestational age and die before labor, usually late in the third trimester.


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Obstentrics_Williams. These unexplained stillbirths are associated with poor glycemic control. Lauenborg and coworkers (2003) identiied suboptimal glycemic control in two thirds of unexplained stillbirths between 1990 and 2000. Also, fetuses ofdiabetic 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 signiicantly related to fetal insulin levels. Such indings support the hypothesis that hyperglycemia-mediated chronic aberrations in oxygen and fetal metabolite transport may underlie these unexplained fetal deaths (Pedersen, 1977).


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Obstentrics_Williams. Aside from hyperglycemia alone, maternal ketoacidosis can cause fetal death. Explicable stillbirths due to placental insufficiency also occur with increased frequency in women with overt diabetes, usually in association with severe preeclampsia. In the prior California study of nearly a halfmillion singleton deliveries, the fetal death risk was sevenfold higher in women with hypertension and pregestational diabetes compared with the threefold increased risk associated with diabetes alone (Yanit, 2012). Stillbirth rates are also greater in women with advanced diabetes and vascular complications.


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Obstentrics_Williams. Hydramnios. Diabetic pregnancies are oten complicated by excess amnionic fluid. According to Idris and coworkers (2010), 18 percent of 314 women with pregestational diabetes were identified to have hydramnios, deined as an amnionic fluid index (AFI) >24 cm in the third trimester. And, women with elevated HbA)c values in the third trimester were more likely to have hydramnios. A likely-albeit unproven-explanation is that fetal hyperglycemia causes polyuria (Chap. 11, p. 228). In a study from Parkland Hospital, Dashe and colleagues (2000) found that the API parallels the amnionic luid glucose level among women with diabetes. Further support for this association was provided by Vink and associates (2006), who linked poor maternal glucose control to macrosomia and hydramnios.


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Obstentrics_Williams. Neonatal Efects. Before tests of fetal health and maturity became available, delivery before term was deliberately selected for women with diabetes to avoid unexplained stillbirth. Although this practice has been abandoned, a higher frequency of preterm delivery in women with diabetes persists. Most are indicated deliveries due to advanced diabetes with superimposed preeclampsia. hat said, Little and associates (2015) in their analysis of early-term delivery (37°/7 to 386/7 weeks) found a 13-percent reduction in such deliveries in women with diabetes between 2005 and 2011.


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Obstentrics_Williams. Although modern neonatal care has reduced neonatal death rates due to immaturity, neonatal morbidiy due to preterm birth continues to be a serious consequence. In one Neonatal Research Network study of 10,781 extremely preterm neonates, those born to diabetic women treated with insulin prior to pregnancy were at greater risk for necrotizing enterocolitis and late-onset sepsis than neonates of mothers without diabetes (Boghossian, 2016). Respiratory Distress Syndrome. Gestational age rather than overt diabetes is likely the most significant factor associated with respiratory distress syndrome (Chap. 33, p. 619). Indeed, in one analysis of 19,399 very-Iow-birthweight neonates delivered between 24 and 33 weeks' gestation, rates of respiratory distress syndrome in newborns of diabetic mothers were not higher compared with rates in neonates of nondiabetic mothers (Bental, 2011).


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Obstentrics_Williams. Hypoglycemia. Newborns of a diabetic mother experience a rapid drop in plasma glucose concentration after delivery. This is attributed to hyperplasia of the fetal �-islet cells induced by chronic maternal hyperglycemia. Low glucose concentrationsdefined as <45 mg/dL-are particularly common in newborns of women with unstable glucose concentrations during labor (Persson, 2009). Frequent blood glucose measurements in the newborn and active early feeding practices can mitigate these complications.


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Obstentrics_Williams. Hypocalcemia. Deined as a total serum calcium concentration <8 mg/dL in term newborns, early onset 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, 137 pregnant women with type 1 diabetes were managed with strict versus customary glucose control (DeMarini, 1994). Almost a third of neonates in the customary control group developed hypocalcemia compared with only 18 percent of those in the strict-control group.


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Obstentrics_Williams. Hyperbilirubinemia and Polycythemia. he pathogenesis of hyperbilirubinemia in neonates of diabetic mothers is uncertain. A major contributing factor is newborn polycythemia, which raises the bilirubin load (Chap. 33, p. 626). Polycythemia is thought to be a fetal response to relative hypoxia. According to Hay (2012), the sources of this fetal hypoxia are hyperglycemia-mediated elevations in maternal ainity for oxygen and fetal oxygen consumption. Together with insulin-like growth factors, this hypoxia leads to elevated fetal erythropoietin levels and red cell production. Fetal renal vein thrombosis is reported to result from polycythemia.


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Obstentrics_Williams. Cardiomyopathy. Newborns of diabetic pregnancies may have hypertrophic cardiomyopathy that primarily afects the interventricular septum (Rolo, 2011). Huang and coworkers (2013) propose that pathological ventricular hypertrophy in neonates born to women with diabetes is due to insulin excess. In severe cases, this cardiomyopathy may lead to obstructive cardiac failure. Russell and coworkers (2008) performed serial echo cardiograms on fetuses of 26 women with pregestational diabetes. In the first trimester, fetal diastolic dysfunction was already evident in some. In the third trimester, the fetal interventricular septum and right ventricular wall were thicker in fetuses of diabetic mothers. Most afected newborns are asymptomatic following birth, and hypertrophy usually resolves in the months after delivery.


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Obstentrics_Williams. Long-Term Cognitive Development. Intrauterine metabolic conditions have long been linked to neurodevelopment in ofspring. 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. Results from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study indicated that autism spectrum disorders or developmental delay were also more common in children of diabetic women (Krakowiak, 2012). Adane and colleagues (2016) conirmed a consistent relationship between maternal diabetes and diminished cognitive and language development in studies of younger children but not older children. Because interpreting efects of the intrauterine environment on neurodevelopment is confounded by postnatal factors, the link between maternal diabetes, glycemic control,


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Obstentrics_Williams. but not older children. Because interpreting efects of the intrauterine environment on neurodevelopment is confounded by postnatal factors, the link between maternal diabetes, glycemic control, and long-term neurocognitive outcome remains unconfirmed.


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Obstentrics_Williams. Inheritance of Diabetes. The risk of developing type 1 diabetes if either parent is afected is 3 to 5 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. Both types of diabetes develop after a complex interplay between genetic predisposition and environmental factors. Type 1 diabetes is prompted by environmental triggers such as infection, diet, or toxins and heralded by the appearance of islet cell autoantibodies in genetically vulnerable individuals (Pociot, 2016; Rewers, 2016). Some but not all studies have shown a reduction in risk for type 1 or type 2 diabetes associated with breastfeeding (Owen, 2006; Rewers, 2016). Diabetes and pregnancy interact signiicantly such that maternal welfare can be seriously jeopardized. With the possible exception of diabetic retinopathy, however, the long-term course of diabetes is not afected by pregnancy.


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Obstentrics_Williams. In an analysis ofmore than 800,000 pregnancies, Jovanovic and colleagues (2015) found that 1125 mothers with type 1 diabetes were at increased risk for hypertension and respiratory complications compared with nondiabetic women. And, 10,126 mothers with type 2 diabetes had an elevated risk for depression, hypertension, infection, and cardiac or respiratory complications compared with pregnant controls. Maternal death is uncommon, but rates in women with diabetes are still higher than those in unafected gravidas. In one analysis of972 women with type 1 diabetes, the maternal mortality rate was 0.5 percent, and deaths resulted from diabetic ketoacidosis, hypoglycemia, hypertension, and infection (Leinonen, 2001).


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Obstentrics_Williams. Preeclampsia. Pregnancy-associated hypertension is the complication that most often forces preterm delivery in diabetic women. he incidence of chronic and gestational hypertension-and especially preeclampsia-is remarkably increased (Chap. 40, p. 713). In a systematic review and metaanalysis of 92 studies including more than 25 million pregnancies, Bartsch and associates (2016) calculated a pooled relative risk of 3.7 for preeclampsia in women with pregestational diabetes. 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 12 times more likely to develop preeclampsia. As shown in Figure 57-5, women with type 1 diabetes in more advanced White classes of overt diabetes, who typically exhibit vascular complications and have preexisting nephropathy, are more likely to develop preeclampsia. This .g:-. .E )


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Obstentrics_Williams. .E ) FIGURE 57-5 Incidence of preeclampsia in 491 type 1 diabetic women in Sweden and the United States. (Data from Hansona, 1993; Sibaib, 2000.) rising risk with duration ofdiabetes 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 irst half of pregnancy (McCance, 2010). Preeclampsia rates did not difer except in a few women with a low antioxidantstatus at baseline. Diabetic Nephropathy. Diabetes is the leading cause of end stage renal disease in the United States (Chap. 53, p. 1034).


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Obstentrics_Williams. Diabetic Nephropathy. Diabetes is the leading cause of end stage renal disease in the United States (Chap. 53, p. 1034). Clinically detectable nephropathy begins with microalbumin uria-30 to 300 mg/24 hours. his 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 ofovert proteinuria is nearly 30 percent in individuals with type 1 diabetes and ranges from 4 to 20 per cent in those with type 2 diabetes (Reutens, 2013). Regression is common and, presumably from improved glucose control, the incidence ofnephropathy with type 1 diabetes has declined.


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Obstentrics_Williams. Approximately 5 percent of pregnant women with diabetes already have renal involvement. Approximately 40 percent of these will develop preeclampsia (Vidaef, 2008). In those with microproteinuria, this incidence may not be as high (How, 2004). However, mbia and associates (2018) reported that the rates ofpreterm delivery, birthweight <2500 g, and growth restriction were significantly higher in neonates of diabetic women with microproteinuria compared with those of diabetic gravidas without proteinuria.


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Obstentrics_Williams. In general, pregnancy does not appear to worsen diabetic nephropathy. In one prospective study of 43 women with diabetes, diabetic nephropathy did not progress through 12 months after delivery (Young, 2012). Most ofthese women had only mild renal impairment. Conversely, pregnancy in women with moderate-to-severe renal impairment may have accelerated progression of their disease (Vidaef, 2008). As in women with glomerulopathies, hypertension or substantial proteinuria before or during pregnancy is a major predictive factor for ultimate progression to renal failure in women with diabetic nephropathy (Chap. 53, p. 1033).


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Obstentrics_Williams. Diabetic Retinopathy. Retinal vasculopathy is a highly speciic complication ofboth type 1 and type 2 diabetes. In the United States, diabetic retinopathy is the most important cause ofvisual impairment in working-aged adults. he first and most common visible lesions are small microaneurysms followed by blot hemorrhages that form when erythrocytes escape from the aneurysms. hese areas leak serous fluid that creates hard exudates. Such features are termed backgroundor nonprolierative 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 exuates. hese are considered preprolerative retinopathy. In response to ischemia, neovascularization begins on the retinal surface and out into the vitreous cavity. Vision is obscured when these vessels bleed. Laser photocoagulation before hemorrhage reduces the rate of visual loss progression and blindness by half. The


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Obstentrics_Williams. surface and out into the vitreous cavity. Vision is obscured when these vessels bleed. Laser photocoagulation before hemorrhage reduces the rate of visual loss progression and blindness by half. The procedure may be performed during pregnancy when indicated.


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Obstentrics_Williams. 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 during pregnancy. The same group of investigators evaluated 80 type 2 diabetics and identified retinopathy, mostly mild, in 14 percent during early pregnancy. Progression was identiied in only 14 percent (Rasmussen, 2010). This complication is believed to be a rare example of a long-term adverse efect of pregnancy.


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Obstentrics_Williams. Other risk factors that have been associated with progression of retinopathy include hypertension, higher levels of insulin-like growth factor-I, placental growth factor, and macular edema identiied in early pregnancy (Bargiota, 2011; Huang, 2015; Mathiesen, 2012; Ringholm, 2011; Vestgaard, 2010). The American Academy of Ophthalmology (2016) recommends that pregnant women with preexisting diabetes should routinely be ofered retinal assessment after the first prenatal visit. Subsequent eye examinations depend on severity of retinopathy and level of diabetes control. Currently, most agree that laser photocoagulation and good glycemic control during pregnancy minimize the potential for deleterious efects of pregnancy.


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Obstentrics_Williams. Ironically, "acute" rigorous metabolic control during pregnancy has been linked to acute worsening of retinopathy. In a study of 201 women with retinopathy, almost 30 percent suffered eye disease progression during pregnancy despite intensive glucose control (11cElvy, 2001). That said, Wang and coworkers (1993) observed that although retinopathy worsened during the critical months of rigorous glucose control, long-term progression of eye disease actually slowed. Arun and Taylor (2008) found that only four women required laser photocoagulation during pregnancy, and none required laser in the next 5 years.


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Obstentrics_Williams. Diabetic Neuropathy. Peripheral symmetrical sensorimotor diabetic neuropathy is uncommon in pregnant women. But, a form of this, known as diabetic gastropathy, can be troublesome during pregnancy. It causes nausea and vomiting, nutritional problems, and diiculty with glucose control. Women with gastroparesis are advised that this complication is associated with a high risk of morbidity and poor perinatal outcome (Kitzmiller, 2008). Treatment with metoclopramide and D2-receptor antagonists is sometimes successful. Gastric neurostimulators have also been successfully used during pregnancy (Fuglsang, 2015). Treatment of hyperemesis gravidarum can be challenging, and we routinely provide insulin by continuous infusion for women who are admitted with this condition (Chap. 54, p. 1044).


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Obstentrics_Williams. Diabetic Ketoacidosis. his serious complication develops in approximately 1 percent of diabetic pregnancies and is most often encountered in women with type 1 diabetes (Hawthorne, 201r1). It is increasingly being reported in women with type 2 or even those with gestational diabetes (Bryant, 2017; Sibai, 2014). Diabetic ketoacidosis (DKA) may develop with hyperemesis gravidarum, infection, insulin noncompliance, 3-mimetic drugs given for tocolysis, and corticosteroids given to induce fetal lung maturation. DKA results from an insulin deiciency combined with an excess in counter-regulatory hormones such as glucagon. his leads to gluconeogenesis and ketone body formation. The ketone body 3-hydroxybutyrate is synthesized at a much greater rate than acetoacetate, which is preferentially detected by commonly used ketosis-detection methods. herefore, serum or plasma assays for 3-hydroxybutyrate more accurately reflect true ketone body levels.


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Obstentrics_Williams. Of gravidas with DA, fewer than 1 percent die, but perinatal mortality rates from a single episode of DKA may reach 35 percent (Guntupalli, 2015). Noncompliance is a prominent factor, and this and ketoacidosis were historically considered prognostically bad signs in pregnancy (Pedersen, 1974). Importantly, pregnant women usually develop ketoacidosis at lower blood glucose thresholds than when nonpregnant. In a study from Parkland Hospital, the mean glucose level for pregnant women with DKA was 380 mg/dL, and the mean HbA]c value was 10 percent (Bryant, 2017). Euglycemic ketoacidosis during pregnancy is possible but rare (Sibai, 2014). 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.


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Obstentrics_Williams. Infections. The rates of many infections are higher in diabetic pregnancies. Common ones include candidal vulvovaginitis, urinary and respiratory tract infections, and puerperal pelvic sepsis. However, in one study of more than 1250 diabetic gravidas screened before 16 weeks' gestation, rates of bacterial vaginosis or vaginal colonization with Candida or Tricho monas species were not increased (Marschalek, 2016). But, in their population-based study of almost 200,000 pregnancies, Sheiner and coworkers (2009) found a twofold greater risk of asymptomatic bacteruria in women with diabetes. Similarly, Alvarez and associates (2010) reported positive urine culture results in 25 percent of diabetic 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


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Obstentrics_Williams. 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. 1027). Finally, Johnston and colleagues (2017) reported that 16.5 percent of women with pregestational diabetes had postoperative wound complications following cesarean delivery.


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Obstentrics_Williams. • Management of Diabetes in Pregnancy Because of the close relationship between pregnancy complications and maternal glycemic control, eforts to achieve glucose targets are typically more aggressive during pregnancy. Management preferably should begin before pregnancy and include speciic goals during each trimester. To minimize early pregnancy loss and congenital malformations in ofspring of diabetic mothers, optimal medical care and education are recommended before conception (Chap. 8, p. 147). he National Preconception Health and Healthcare Initiative Clinical Workgroup for the CDC established values TABLE 57-7. 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 Low-dose, intravenous Loading dose: 0.2-0.4 U/kg Maintenance: 2-10 U/hr Total replacement in first 12 hours of 4-6 L 1 L in first hour


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Obstentrics_Williams. Low-dose, intravenous Loading dose: 0.2-0.4 U/kg Maintenance: 2-10 U/hr Total replacement in first 12 hours of 4-6 L 1 L in first hour 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 Data from Bryant, 20017; Landon, 2002; Sibai, 2014. for optimal glycemic control (Frayne, 2016). This was defined Insulin Treatment as HbA}c <6.5 percent in women with pregestational diabetes. The overtly diabetic gravida is best treated with insulin. While Unfortunately, nearly half of pregnancies in the United States oral hypoglycemic agents have been used successfully for gesare unplanned, and diabetic women frequently begin pregnancy tational diabetes (p. 11r12), these agents are not currently recwith suboptimal glucose control (Finer, 2016; Kim, 2005).


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Obstentrics_Williams. ommended for overt diabetes, although this is controversial The ADA (20 17b) has also deined optimal preconcep(American College of 0bstetricians and Gynecologists, 20 16b). tional glucose control using insulin. Relective values are selfMaternal glycemic control can usually be achieved with mulmonitored preprandial glucose levels of70 to 100 mg/dL, peak tiple daily insulin injections and adjustment of dietary intake. 2-hour postprandial values of 100 to 120 mg/dL, and mean he action proiles of commonly used short-and long-termdaily glucose concentrations < 110 mg/dL. In one prospective insulins are shown in Table 57-8. population-based study of 933 pregnant women with type 1 diabetes, the risk of congenital malformations was not demonstrably higher with HbA}c levels <6.9 percent compared with the risk in more than 70,000 nondiabetic controls Qensen, 2010). These investigators also found a substantial fourfold greater risk for malformations at levels > 10 percent.


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Obstentrics_Williams. If indicated, evaluation and treatment for diabetic complica TABLE 57-8. Action Profiles of Commonly Used Insulins Insulin Type Onset Peak (hr) Duration (hr) Lispro <15nmin 0.5-1n.5 Glulisine <15 min 0.5-1.5 3-4 tuted before pregnancy. Finally, folate, 400 jLg/d orally, is given periconceptionally and during early pregnancy to decrease the risk of neural-tube defects. Aspart <15 min 0.5-1n.5 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 provide education. This also provides an opportunity to assess the extent of diabetic vascular complications and precisely establish gestational age. aMinimal peak activity. NPH = neutral protamine Hagedorn; SC = subcutaneous. Data from Powers, 201 2.


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Obstentrics_Williams. Subcutaneous insulin infusion by a calibrated pump does not yield better pregnancy outcomes compared with multiple daily injections. But, an infusion pump is a safe alternative in appropriately selected patients (Farrar, 2016; Sibai, 2014). With the advent of sensor-augmented insulin pumps and closed-loop insulin delivery systems, improved glycemic control with either manual or computer-generated insulin adjustments based on continuous glucose monitoring is now possible. One small randomized, crossover study of 16 pregnant women compared these two technologies (Stewart, 2016). Those with automatic closed-loop systems had glucose values within target range for a higher percentage of time and had lower daily median glucose values. Moreover, their rates of hypoglycemic episodes were not increased. Roeder and colleagues (2012) noted with insulin pump use in women with type 1 diabetes that total daily insulin doses declined in the first trimester but later rose more than threefold.


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Obstentrics_Williams. increased. Roeder and colleagues (2012) noted with insulin pump use in women with type 1 diabetes that total daily insulin doses declined in the first trimester but later rose more than threefold. Postprandial glucose elevations prompted most of the required daily-dose increases. If a continuous-infusion insulin pump is elected, it is best started before pregnancy to avoid the hypoglycemia and ketoacidosis risk associated with the learning curve (Sibai, 2014).


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Obstentrics_Williams. Monitoring. Self-monitoring of capillary glucose levels using a glucometer is recommended because this involves the woman in her own care. he ADA (2017b) recommends fasting and postprandial glucose monitoring. 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 have shown that pregnant women with diabetes experience signiicant periods of daytime hyperglycemia and nocturnal hypoglycemia that are undetected by traditional monitoring (Combs, 2012). Such glucose monitoring systems, coupled with a continuous insulin pump, ofer the potential of an "artificial pancreas" to avoid undetected hypo-or hyperglycemia during pregnancy.


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Obstentrics_Williams. Diet. Nutritional planning includes appropriate weight gain through carbohydrate and caloric modiications based on height, weight, and degree of glucose intolerance (merican Diabetes Association, 2017b; Bantle, 2008). he mix of carbohydrate, protein, and fat is adjusted to meet the metabolic goals and individual patient preferences. A minimum of 175 g/d of carbohydrates ideally is provided. In one analysis of more than 200 obese pregnant women with glucose intolerance, a lower carbohydrate intake, particularly late in pregnancy, was TABLE 57-9. Self-Monitored Capillary Blood Glucose Goals Fasting :;95 Premeal :;100 1-hr postprandial :;140 2-hr postprandial :;120


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Obstentrics_Williams. TABLE 57-9. Self-Monitored Capillary Blood Glucose Goals Fasting :;95 Premeal :;100 1-hr postprandial :;140 2-hr postprandial :;120 Hemoglobin Ale :;6% associated with lower fat mass in ofspring at birth (Renault, 2015). Allotted carbohydrates are distributed throughout the day in three small-to moderate-sized meals and two to four snacks. 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.


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Obstentrics_Williams. Hypoglycemia. Diabetes tends to be unstable in the first half of pregnancy, and the incidence of hypoglycemia peaks during the irst trimester. Chen and coworkers (2007) identified hypoglycemic events-blood glucose values <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 and required assistance from another person. Caution is recommended when attempting euglycemia in women with recurrent episodes of hypoglycemia.


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Obstentrics_Williams. In a Cochrane database review, Middleton and colleagues (2016) determined that loose glycemic control, defined as fasting glucose valuesr> 120 mg/dL, was associated with greater risks for preeclampsia, cesarean delivery, and birthweight above the 90th percentile compared with women with tight or moderate control. Importantly, no obvious benefit were gained from very tight control, defined by fasting values <90 mg/dL, and there were more cases of hypoglycemia. hus, women with overt diabetes who have glucose values that are viewed by some as "considerably above" this 90 mg/dL threshold can expect good pregnancy outcomes.


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Obstentrics_Williams. Maternal serum alpha-fetoprotein determination at 16 to 20 weeks' gestation is used in association with targeted sonographic examination to detect neural-tube defects and other anomalies (Chap. 14, p. 283). hese levels may be lower in diabetic pregnancies, and interpretation is altered accordingly. Because the incidence of congenital cardiac anomalies is fivefold 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 diicult than in similarly sized women without diabetes.


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Obstentrics_Williams. 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. his is followed by a greater insulin requirement due to the elevated peripheral resistance to insulin described in Chapter 4 (p. 56). During the past several decades, the threat of late-pregnancy stillbirth 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. 331). 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 (2016b) suggests initiating such testing at 32 to 34 weeks' gestation.


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Obstentrics_Williams. College of Obstetricians and Gynecologists (2016b) suggests initiating such testing at 32 to 34 weeks' gestation. At Parkland Hospital, women with diabetes are seen in a specialized obstetrical clinic every 2 weeks. During these visits, glycemic control records are evaluated and insulin adjusted. Women are routinely instructed to perform fetal kick counts beginning early in the third trimester. At 34 weeks, admission is ofered 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.


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Obstentrics_Williams. Labor induction may be attempted when the fetus is not excessively large and the cervix is considered favorable (Chap. 26, p. 503). Little and colleagues (2015) analyzed term singleton births from 2005 to 201r1 and showed a higher percentage of diabetic women were delivered each year before 39 weeks compared with the entire cohort-37 versus 29 percent. Cesarean delivery at or near term has frequently been used to avoid traumatic birth of a large fetus 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 incre�sed cesarean delivery rate. In an analysis of pregnancy outcomes of diabetic women from University of labama at Birmingham according to the White classiication, the rate of cesarean delivery and preeclampsia escalated with White class (Bennett, 2015). In another study, a HbA,c level >6.4 percent at delivery was independently


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Obstentrics_Williams. to the White classiication, the rate of cesarean delivery and preeclampsia escalated with White class (Bennett, 2015). In another study, a HbA,c 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 40 years at Parkland Hospital.


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Obstentrics_Williams. Reducing or withholding the dose of long-acting insulin to be 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 suicient amounts to maintain normoglycemia. Capillary or plasma glucose levels are checked frequently, especially during active labor, and regular insulin is administered accordingly. Often, women may require virtually no insulin for the irst 24 hours or so postpartum. Subsequently, insulin requirements may luctuate markedly during the next few days. Infection must be promptly detected and treated. When appropriate, oral agents can be restarted.


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Obstentrics_Williams. Counseling in the puerperium should include a discussion of birth control. Efective contraception is especially important in women with overt diabetes to allow optimal glucose control before subsequent conception. In the United States in 2010, almost 5 percent of gravidas were afected by gestational diabetes (DeSisto, 2014). W orldwide, its prevalence difers 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. A National Institutes of Health (NIH) Consensus Development Conference (2013) was convened to study this. he American College of Obstetricians and Gynecologists (2017a) has also updated its recommendations. These two authoritative sources provide an analysis of the issues surrounding the diagnosis and bolster the approach to identiying and treating women with gestational diabetes.


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Obstentrics_Williams. The word gestational implies that diabetes is induced by pregnancy-ostensibly because of exaggerated physiological changes in glucose metabolism (Chap. 4, p. 56). Gestational diabetes is deined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy (American College of Obstetricians and Gynecologists, 2017a). This deinition applies whether or not insulin is used for treatment and undoubtedly includes some women with previously unrecognized overt diabetes. Use of the term gestational diabetes has been encouraged to communicate the need for enhanced surveillance and to TABLE 57-1 0. 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.


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Obstentrics_Williams. 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 less than 70 mg/dL, the infusion is changed from saline to 5% dextrose and delivered at a rate of 100-150 cc/h (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 1n.25 U/h 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.


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Obstentrics_Williams. 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. he likelihood of fetal death with appropriately treated gestational diabetes is not diferent 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 1097, evidence is mounting for long-range complications that include obesity and diabetes in their ofspring.


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Obstentrics_Williams. Despite almost 50 years of research, there is still no agreement regarding optimal gestational diabetes screening. The diiculty in achieving consensus is underscored by the controversy following publication of the single-step approach espoused by the International Association of Diabetes and Pregnancy Study Groups Consensus Panel (2010) and shown in Table 57-11. his strategy was greatly influenced by results of the Hypoglycemia and Pregnancy Outcomes (HAPO) Study, described later. Although the ADA (2017 a) supports this new scheme, the American College of Obstetricians and Gynecologists (2017a) 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 insuicient to adopt a one-step approach.


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Obstentrics_Williams. he recommended two-step approach begins with either universal or risk-based selective screening using a 50-g, I-hour oral glucose challenge test. Participants in the Fifth International TABLE 57-1 1. Threshold Values for Diagnosis of Gestational Diabetes be equaled or exceeded for the diagnosis of gestational diabetes. bin addition, 1.7% of participants in the initial cohort were unblinded because of fasting plasma glucose levels >5.8 mmol/L (105 mg/dL) or 2-hr OGTI values > 11n.1 mmollL (200 mg/dL), bringing the total to 17.8%. OGI = oral glucose tolerance test. Data from International Association of Diabetes and Pregnancy Study Groups, 2010.


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Obstentrics_Williams. OGI = oral glucose tolerance test. Data from International Association of Diabetes and Pregnancy Study Groups, 2010. Workshop Conferences on Gestational Diabetes endorsed use ofselective screening criteria shown in Table 57-12. Conversely, the American College of Obstetricians and Gynecologists (2017a) recommends universal screening of pregnant women using a laboratory-based blood glucose test. It is suggested that attempts to identiy the 10 percent of women who should not be screened would add unnecessary complexity. Screening should TABLE 57-12. Risk-Based Recommended Screening Strategy for Detecting GDMa 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 No history of abnormal glucose metabolism No history of poor obstetrical outcome


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Obstentrics_Williams. Member of an ethnic group with a low prevalence of GDM No known diabetes in first-degree relatives 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 OGI for those meeting the threshold value in the GCT One-step procedure: diagnostic 100-g OGTI 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 aCriteria of the Fifth Intenational Workshop-Conference on Diabetes. GDM = gestational diabetes mellitus; OGTI = oral glucose tolerance test.


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Obstentrics_Williams. Reproduced with permission from Metzger BE, Coustan DR, the Organizing Committee: Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus, Diabetes Care. 1998 Aug; 21 SuppIn2:B161n-B167. TABLE 57-13. Diagnosis of GDM Using Threshold women not known to have glucose intolerance earlier in preg nancy. This 50-g screening test is followed by a dianostic 100-g, Tolerance Testa,b 3-hour oral glucose tolerance test (OGT) if screening results meet or exceed a predetermined plasma glucose concentration. For the 50-g screen, the plasma glucose level is measured 1 hour ater a 50-g oral glucose load without regard to the time


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Obstentrics_Williams. Fasting 105 5.8 95 5.3 of day or time oflast meal. In a recent review, the pooled sensitiv1-hr 190 10.6 180 2-hr 165 9.2 155 8.6 ity for a threshold of 140 mg/dL ranged from 74 to 83 percent depending on 100-g thresholds used for diagnosis (van Leeuwen, 3-hr 145 8.0 140 2012). Sensitivity estimates for a 50-g screen threshold of 135 aThe test should be performed when the patient is fasting. bTwo or more of the venous plasma glucose concentra mg/dL improved only slightly to 78 to 85 percent. Importantly, speciicity 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. Using a threshold of 130 mg/dL marginally improves sensitivity with a further decline in speciicity (Donovan, 2013). That said, in the absence of clear evidence supporting one cutof value over another, the American College of Obstetricians and Gynecolo gists (2017a) sanctions using anyrone of the three 50-g screen thresholds. At Parkland Hospital, we continue to use 140


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Obstentrics_Williams. cutof value over another, the American College of Obstetricians and Gynecolo gists (2017a) sanctions using anyrone of the three 50-g screen thresholds. At Parkland Hospital, we continue to use 140 mg/dL as the screening threshold to prompt the 100-g test.


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Obstentrics_Williams. Justiication 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 ater an overnight fast and was between 140 and 198 mg/dL 2 hours ater ingesting a 75-g glucose solution. Women in the intervention group had a signiicantly lower risk of a composite adverse outcome that included perinatal death, shoulder dystocia, fetal bone fracture, and fetal nerve palsy. Macrosomia deined 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.


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Obstentrics_Williams. Slightly diferent results were reported by the MaternalFetal Medicine Units Network randomized trial of958 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 identiied in women with fasting glucose levels <95 mg/dL. hey reported no diferences 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 signiicant decrease in shoulder dystocia rate-1.5 versus 4 percent-in treated versus control women.


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Obstentrics_Williams. Based largely on these two landmark studies, the U.S. Preventive Sevices Task Force (2014) now recommends universal screening in low-risk women after 24 weeks' gestation. However, the Task Force concluded that evidence is insuicient to assess the balance of benefits versus harms of screening before 24 weeks. For screening, the optimal OGTT ro identiy gestational diabetes has not been agreed upon. The World Health Organization (2013) and the ADA (2017a) recommend the tions listed are met or exceeded for a positive diagnosis. (Serum glucose level. dSerum or plasma glucose level. NDDG = National Diabetes Data Group. Data from American Diabetes Association, 201n7a; Ferrara, 2002.


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Obstentrics_Williams. NDDG = National Diabetes Data Group. Data from American Diabetes Association, 201n7a; Ferrara, 2002. 75-g, 2-hour OGTT, but acknowledge that the diagnosis can be accomplished using the two-step strategy. In the United States, however, the 1 OO-g, 3-hour OGTT performed after an overnight fast is recommended by the American College of Obstetricians and Gynecologists (2017a). Proposed criteria for interpretation of the diagnostic 100-g OGTT are shown in Table 57-13. In a secondary analysis of the Maternal-Fetal Medicine Units Network treatment trial, Harper and colleagues (2016) showed that women diagnosed with either the National Diabetes Data Group (NDDG) or the Carpenter-Co us tan criteria beneited from treatment. However, the number needed to treat to prevent a shoulder dystocia was higher for the Carpenter-Co us tan criteria. At Parkland Hospital we continue to use the NDDG criteria for diagnosis. Criteria for the 75-g OGTT recommended are shown in Table 57-11.


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Obstentrics_Williams. The Hyperglycemia and Adverse Pregnancy Outcome Study


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Obstentrics_Williams. 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 a 75-g OGTT after an 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 stratiied into seven categories (Fig. 57-6). hese values were then correlated with rates for birthweight >90th percentile (LGA) , primary cesarean delivery, neonatal hypoglycemia, and cord-serum C-peptide levels >90th percentile. Odds of each outcome


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Obstentrics_Williams. were then correlated with rates for birthweight >90th percentile (LGA) , primary cesarean delivery, neonatal hypoglycemia, and cord-serum C-peptide levels >90th percentile. Odds of each outcome were calculated using the lowest category-for example, fasting plasma glucose :;75 mg/dL-as the referent group. Their indings in general supported the supposition that increasing plasma glucose levels were associated with increasing adverse outcomes. Ecker and diagnosis rates but not with reduced macrosomia rates compared with a twostep approach. Remarkably, they identi � rate associated with adoption of the : IADPSG recommendations. he ADA ) (2013, 2017a) initially recommended ) adopting this new approach, however, ..J,approach described on page 1108, they now concede that data support a twostep strategy as well.


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Obstentrics_Williams. -1hour ; 105 106-132 133-155 156-171 172-193 194-211 ::212 Prompted by the disparate recommen -2hour ; 9091-108 109-125 126-139 140-157 158-177 ::178 dations, the NIH Consensus Development Conference on Diagnosing FIGURE 57-6 Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. The fre quency of newborn birthweight ::90th percentile for gestational age plotted against glucose was convened. his conference included levels fasting and at 1-and 2-hr intervals following a 75-g oral glucose load. LGA = large for gestational age. (Reproduced with permission from HAPO Study Cooperative Research input from a multidisciplinary planning Group, Metzger BE, Lowe LP, et al: Hyperglycemia and adverse pregnancy outcomes, N Engl committee, a systematic evidence review J Med. 2008 May 8;358(19):1991-2002.)


Obstentrics_Williams

Obstentrics_Williams. J Med. 2008 May 8;358(19):1991-2002.) Greene (2008) concluded that it would be diicult to show that treating lesser degrees of carbohydrate intolerance would provide any meaningful improvements in clinical outcomes. We agree that changes in criteria are not justiied until clinical trials prove benefits. his position was also endorsed by the 2013 NIH Consensus Development Conference.