In 2010, 18.8 million people in the United States, or 8.35% of the nation’s population, had diabetes. It is estimated that another 7 million people have diabetes that has not yet been diagnosed (Centers for Disease Control and Prevention [CDC], 2011b). About 3.7% of people aged 20 to 44 years have diagnosed or undiagnosed diabetes. There were 465,000 new cases of diabetes in this age group in 2010. People of minority racial and ethnic groups, such as African Americans, Hispanics, American Indians, and Asian/Pacific Islanders, have an 18% to 77% higher risk of diabetes than Caucasians (CDC, 2011b). Approximately 7% of all pregnancies are complicated by gestational diabetes (also known as gestational diabetes mellitus [GDM]) (American Diabetes Association [ADA], 2012).

Although comprehensive obstetric care and intensive metabolic management have reduced perinatal risk in pregnancies complicated by type 1 and type 2 diabetes, morbidity and mortality still remain higher than in the general population. Pregnant women with type 1 and type 2 diabetes have a 2.5-fold increase in risk of fetal death (Silver, 2007). Congenital defects and unexplained fetal death account for the increased fetal and neonatal mortality in women with type 1 and type 2 diabetes (Reece & Homko, 2000) and are likely related to comorbid conditions such as hypertension and obesity (Silver, 2007). Maternal hyperglycemia and disorders of fetal growth, metabolism, and possibly acidosis contribute to risk of fetal mortality (Silver, 2007). Preconception and early pregnancy glycemic control as evidenced by a near-normal glycosylated hemoglobin (A1C) during the period of organogenesis greatly reduces the risk of birth defects (McElvy et al., 2000; Reece & Homko, 2000; Silver, 2007). Women with poorly controlled preexisting diabetes in the early weeks of pregnancy are three to four times more likely than nondiabetic women to have a baby with a serious malformation, such as a heart defect or neural tube defect. Defects in offspring of women with preexisting diabetes have been found to be more severe, usually multiple, and more often fatal. They also are at increased risk of miscarriage and stillbirth. Glycemic control in women with pregestational diabetes prior to conception reduces these risks as well as the risk of macrosomia (Persson, Norman, & Hanson, 2009; Yang, Cummings, O’Connell, & Jangaard, 2006).

The rate of perinatal mortality with gestational diabetes remains similar to that for nondiabetic women, but when GDM is detected in the first trimester with an elevated A1C and fasting hyperglycemia, the risk for congenital defects has been found to approach that of women with pregestational type 2 diabetes (Schaefer-Graf et al., 2000). It is possible that these data from early diagnosed cases may actually represent type 2 diabetes that was first recognized during pregnancy rather than true gestational diabetes. The ADA (2011) recommends that women who meet standard criteria for diagnosis of type 2 diabetes at the first prenatal visit be referred to as having “overt diabetes,” not GDM. According to data using early and appropriate screening criteria, GDM is not associated with an increased risk of fetal death when compared to outcomes of pregnancies of women without diabetes (Silver, 2007).

Women with GDM are at higher risk of perinatal morbidity, such as obesity, gestational hypertension, preeclampsia, and cesarean birth (American College of Obstetricians and Gynecologists [ACOG], 2011; Persson, Pasupathy, Hanson, Westgren, & Norman, 2012).
Babies of women with GDM are at higher risk of macrosomia, shoulder dystocia, birth trauma, respiratory distress syndrome, major malformations, hypoglycemia and other metabolic abnormalities, and childhood obesity (ACOG, 2011; Persson et al., 2012). Maintenance of euglycemia throughout pregnancy in GDM reduces the risk of these hyperglycemia-related fetal and neonatal abnormalities. A significant number of pregnant women in the United States are overweight or obese before starting their pregnancy (CDC, 2011c). It is estimated that approximately 30% of pregnant women are obese and 8% are morbidly obese (CDC, 2011c). Being overweight or obese further complicates pregnancies with diabetes. The higher the prepregnancy body mass index of the woman with diabetes, the more risks of adverse outcomes for the mother and fetus (Persson et al., 2012).

Macrosomia has been defined as a weight greater than the 90th percentile for gestational age and sex or a birth weight of 4,000 g (8 lb, 13 oz) to 4,500 g (9 lb, 15 oz) (ACOG, 2000; Hod & Yogev, 2007). Risk of fetal injury sharply increases with birth weights above 4,500 g (ACOG, 2000). Other factors such as morbid maternal obesity and postmaturity are also associated with fetal macrosomia and, when combined with insulin-controlled diabetes, lead to an even higher occurrence. Fetal macrosomia predisposes the mother to a higher risk of postpartum hemorrhage and vaginal lacerations and the newborn to a variety of traumatic injuries such as shoulder dystocia with associated risk for brachial plexus injury and clavicular fracture (ACOG, 2000; Conway, 2007). Shoulder dystocia is the most common injury related to fetal macrosomia but occurs only in approximately 1.4% of all vaginal births (ACOG, 2000). When birth weight exceeds 4,500 g, the risk of shoulder dystocia has been reported to range from 9.2% to 24% (ACOG, 2000). If the woman has diabetes, birth weights greater than 4,500 g are associated with much higher rates of shoulder dystocia: from 19.9% to 50% (ACOG, 2000). Fetal macrosomia contributes to an increased risk of cesarean birth, with resultant increased surgical morbidity in the mother (Conway, 2007).

The Fetal Basis of Adult Disease theory holds that events that occur during fetal development can permanently alter gene expression throughout the lifetime of the individual. A link has emerged between fetal nutrition, birth weight, and metabolic profile in adulthood. Abnormal “programming” of nutrient management increases risk for developing metabolic diseases such as obesity, hypertension, cardiovascular disease, and type 2 diabetes (Barker, 2001). Hyperglycemia in pregnancy is associated with a higher risk of childhood obesity (Hillier et al., 2007) as well as a higher risk of prediabetes and type 2 diabetes in adult offspring of women with diabetes (Clausen et al., 2008).

In addition to the risk of fetal macrosomia for all women with diabetes, the other extreme of weight, intrauterine growth restriction (IUGR), is a significant risk for infants born to women who have vascular complications of diabetes. Retinopathy and nephropathy associated with hypertension and poor renal function may contribute to uteroplacental insufficiency that leads to infants who are small for their gestational age. Gestational hypertension, to which women with diabetes (with or without vascular disease) are predisposed, also decreases uterine blood flow, compromising intrauterine fetal growth. Maintaining excellent control of blood glucose levels and blood pressure can help to avoid IUGR. Mean blood glucose <80 to 90 mg/dL and blood pressure <110/65 mm Hg in pregnancy may be associated with an increased risk of IUGR (Kitzmiller, Jovanovic, Brown, Coustan, & Reader, 2008).

Neonatal metabolic abnormalities occur with a higher frequency in offspring of women with diabetes. Hypoglycemia, whose precise definition may vary by institution, occurs frequently in babies of mothers with uncontrolled diabetes (Straussman & Levitsky, 2010). Preterm and large-for-gestational-age infants are at greatest risk for the development of hypoglycemia in the neonatal period. Chronic maternal hyperglycemia leads to excessive insulin production in the fetus (i.e., fetal hyperinsulinemia), which lowers fetal plasma glucose and inhibits glycogen release from the fetal liver as a normal physiologic response to hypoglycemia. This combination contributes to the risk for hypoglycemia development in the first 24 hours of life when cutting the umbilical cord interrupts transplacental glucose. Early detection and prompt treatment prevent the potential severe neurologic sequelae associated with profound hypoglycemia.

Infants of diabetic mothers may exhibit polycythemia, which is defined as a venous hematocrit of greater than 65%. Chronic hyperglycemia and hyperinsulinemia cause increased oxygen consumption and decreased fetal arterial oxygen content. Erythropoietin production increases, resulting in polycythemia. The elevated red blood cell mass can also result in hyperbilirubinemia (Hatfield, Schwoebel, & Lynyak, 2011). Hypocalcemia and hypomagnesemia are other metabolic abnormalities occasionally seen in infants of women with type 1 and type 2 diabetes, the exact causes of which are unknown.

Strict maternal glycemic control has decreased the incidence of respiratory distress syndrome significantly, but other factors, such as iatrogenic prematurity due to early birth as a result of maternal or fetal compromise, continue to contribute to the risk. Fetal surfactant production is inhibited by hyperinsulinemia, which occurs more frequently in women with poor metabolic control and is the underlying mechanism for respiratory distress syndrome in this group (Hatfield et al., 2011).

Risks during pregnancy for the woman with type 1 or type 2 diabetes include an increased incidence of hypoglycemia (blood glucose less than 60 mg/dL) as a result of stricter control (Kitzmiller, Jovanovic, et al., 2008; Rosenn & Miodovnik, 2000). Hypoglycemia is more common in early pregnancy (41% to 68%), as is nocturnal hypoglycemia (Kitzmiller, Jovanovic, et al., 2008). Hypoglycemia does not seem to cause problems for the fetus unless blood sugar levels are chronically low, but hypoglycemia does threaten the well-being of the mother. Educational efforts focusing on prevention and appropriate management of hypoglycemia can decrease this risk.

Diabetic ketoacidosis (DKA) is a rare complication for women with diabetes. However, the occurrence of DKA carries serious morbidity and mortality for the mother and the fetus and may occur at lower glucose levels (<250 mg/dL; Kitzmiller, Jovanovic, et al., 2008). Acidosis can cause decreased oxygenation of the placenta through decreased uterine blood flow and decreased tissue perfusion (Carroll & Yeomans, 2005; Parker & Conway, 2007). Fetal loss may occur through spontaneous abortion in the first and early second trimesters or as an intrauterine fetal death during an episode of DKA in late second and third trimesters. Improved perinatal management has decreased the fetal loss rate to about 9% (Parker & Conway, 2007), as well as decreased the rate of perinatal mortality.

Women with microvascular complications, poor glycemic control, and a longer duration of diabetes have poorer outcomes. Retinopathy is frequently encountered in women of reproductive age. It may progress during pregnancy, especially in women with elevated first-trimester A1C followed by rapid normalization of blood glucose values. Dilated eye examination should occur in the first trimester with continued surveillance throughout pregnancy. Laser photocoagulation therapy can be performed during pregnancy, if indicated (Kitzmiller, Jovanovic, et al., 2008). Nephropathy is a more serious microvascular complication that has been associated with adverse outcomes, including IUGR, preterm birth, and intrauterine fetal death (Landon, 2007; Rosenn & Miodovnik, 2000). Excellent control of blood glucose levels and hypertension can reduce perinatal complications and preserve kidney function (Kitzmiller, Jovanovic, et al., 2008; Nielsen, Damm, & Mathiesen, 2009).

Hypertensive disorders commonly develop if not present at conception and include chronic hypertension, gestational hypertension, and preeclampsia. Women with hypertensive disorders are at higher risk of preterm birth and cesarean birth, with resultant need for neonatal intensive care. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated during pregnancy and should be stopped prior to conception or as soon as possible after discovery of pregnancy. Renal failure is a potential complication without meticulous control of blood pressure. Hypertensive disorders of pregnancy also increase the risk of chronic hypertension and cardiovascular events (Kitzmiller, Block, et al., 2008; Sullivan, Umans, & Ratner, 2011). Women with type 1 or type 2 diabetes are at a higher risk of cardiovascular disease than nondiabetic women. Heart failure and ischemic stroke occur more frequently in pregnant women with diabetes. Cardiovascular autonomic neuropathy is associated with increased maternal mortality and poorer pregnancy outcomes (Kitzmiller, Block, et al., 2008).

Gastroparesis or gastropathy is a neuropathic complication that causes delayed gastric emptying and may exacerbate nausea and vomiting. This can result in irregular absorption of nutrients, inadequate nutrition, and poor glycemic control (Kitzmiller, Block, et al., 2008; Rosenn & Miodovnik, 2000). Women who continue pregnancy with gastroparesis may require total parenteral nutrition.

Women with diabetes during pregnancy can be divided into two groups. The first group consists of women who have pregestational diabetes (type 1 or type 2 diabetes), including women diagnosed with diabetes at the first prenatal visit, and the second group consists of women with gestational diabetes.

Profound metabolic changes occur in normal pregnancy to allow for a continuously feeding fetus in an intermittently feeding mother. These alterations must be understood to comprehend the effects that diabetes has on a progressively changing metabolic state. In early pregnancy, beta-cell hyperplasia results in increased insulin production as a result of progesterone and estrogen increases, which also contributes to increased tissue sensitivity to insulin. This hyperinsulinemic state allows increased lipogenesis and fat deposition in early pregnancy in preparation for the dramatic rise in energy needs of the growing fetus in the latter half of pregnancy. As a result of these changes, along with nausea and vomiting, the mother has an increased risk for episodes of hypoglycemia in the first trimester. In women with type 1 diabetes and insulin-controlled type 2 diabetes, exogenous insulin needs may decrease.

The second half of pregnancy is characterized by accelerated growth of the fetus and rapidly increasing levels of maternal and placental diabetogenic hormones, which include human placental lactogen, cortisol, estrogen, progesterone, and prolactin. Insulin resistance and increased insulin production result from increased circulating levels of insulin-antagonizing hormones (Lain & Catalano, 2007; Parker & Conway, 2007). Increased insulin needs in women with type 1 and type 2 diabetes and the appearance of glucose intolerance in women who have limited pancreatic reserve due to predisposing risk factors are the result of these normal metabolic changes of pregnancy. This constitutes the diabetogenic state of pregnancy—hyperglycemia in the presence of hyperinsulinemia—which allows a continuous supply of glucose to passively diffuse to the fetus transplacentally (Parker & Conway, 2007).

The anabolic phase (i.e., fat storage) of the first 20 weeks of pregnancy is followed by a catabolic phase (i.e., fat breakdown or lipolysis) in the latter half of pregnancy (Lain & Catalano, 2007). This state is referred to as “accelerated starvation” because of the rapid switch from carbohydrate to lipid metabolism during fasting as a fuel source for the mother. Fat breakdown increases circulating fatty acids, triglycerides, and ketones, predisposing the woman with type 1 diabetes to an increased risk for the earlier development of ketoacidosis and starvation ketosis than in women with GDM and type 2 diabetes (Kitzmiller, Jovanovic, et al., 2008).
Hepatic glucose production increases during the latter half of pregnancy to meet the fetal and placental demands during maternal fasting (Lain & Catalano, 2007).

In the absence of vascular disease, the pathologic manifestations of diabetes in pregnancy are usually the result of maternal hyperglycemia. Excessive hyperglycemia, as a result of insulin deficiency with a corresponding increase in counterregulatory hormones (e.g., glucagon, epinephrine, growth hormone, and cortisol), contributes to the development of DKA. Factors in pregnancy that trigger the release of these hormones and development of DKA are fasting hyperglycemia, infection, stress, emesis, dehydration, gastroparesis, and beta-cell-sympathomimetic and steroid administration for the treatment of preterm labor (Carroll & Yeomans, 2005; Kitzmiller, Block, et al., 2008). Continuous subcutaneous insulin infusion (CSII) pump failure and poor patient compliance have also led to the development of DKA during pregnancy. Excessive hyperglycemia results from increased hepatic glucose and ketone production and insulin deficiency. Urinary excretion of potassium, sodium, and water occurs as a result of osmotic diuresis due to excessive plasma glucose. Fat metabolism leads to increased circulating levels of free fatty acids and ketonemia, which quickly overwhelm the maternal buffering system, and metabolic acidosis results (Kitzmiller, Jovanovic, et al., 2008). Maternal hyperglycemia during the time of organogenesis may result in spontaneous abortion or congenital malformations (Correa et al., 2008; Persson et al., 2009). Sustained or intermittent maternal hyperglycemia later in pregnancy stimulates fetal hyperinsulinemia as a normal fetal physiologic response to elevated blood glucose with pathologic consequences. Fetal hyperinsulinemia mediates accelerated fuel use and conversion of glucose to fat. Central fat deposition results in excessive fetal growth (e g., macrosomia) (Moore, 2004; Sacks, 2007). Maternal hyperglycemia also contributes to fetal hypoxia. Hyperinsulinemia promotes catabolism of the extra fuel, using energy and depleting fetal oxygen stores (Hatfield et al., 2011; Moore, 2004). Fetal hyperinsulinemia also inhibits the release of surfactant that is necessary for pulmonary maturation resulting in respiratory distress syndrome. Maternal hyperglycemia is also associated with other neonatal metabolic abnormalities. Polyhydramnios, hypertension, urinary tract infections, pyelonephritis, and monilial vaginitis are other maternal complications of hyperglycemia.

Screening for GDM is recommended between 24 and 28 weeks’ gestation, when the diabetogenic hormones are exerting a significant influence on insulin performance. Women without risk factors for GDM do not require screening (ACOG, 2001; ADA, 2004a). Display 8-1 lists the characteristics of women who are at low risk for developing GDM. Women younger than 25 years old with any other risk factor for GDM should be tested. Risk factors identifying women who should undergo early screening for GDM at the first prenatal visit (as soon as risk is identified) are listed in Display 8-2. The ADA (2011) recommends testing for type 2 diabetes at the first prenatal visit in populations with a high prevalence of type 2 diabetes, such as Hispanics, African Americans, Native Americans, Southeast Asians, and Pacific Islanders with a fasting blood glucose value and an A1C. If the A1C is ≥6.5 and/or the fasting blood glucose is ≥126 mg/dL, overt diabetes is diagnosed. If the screening at the first prenatal visit is normal, screening is repeated between 24 and 28 weeks of gestation (ADA, 2011).

Evaluation for GDM in the United States is currently performed in a two-step approach (ACOG, 2001). The screening test consists of ingestion of a 50 g glucose solution (glucola) without consideration of time of day or last meal and obtaining a plasma or serum glucose level 1 hour after ingestion. The positive thresholds of 130 and 140 mg/dL have been used for the screening glucola. A value of 130 mg/dL identifies approximately 80% of women with gestational diabetes, whereas a cutoff of 140 mg/dL identifies approximately 90% of women with gestational diabetes (ACOG, 2001). The decision for which cutoff to use should be based on cost-effectiveness and risk factors in the population to be tested. An extremely elevated result on the glucose challenge is considered diagnostic, alleviating the need for an oral glucose tolerance test (OGTT). Some healthcare centers use a value of 200 mg/dL, while others use 180 mg/dL as the diagnostic threshold (Russell, Carpenter, & Coustan, 2007).

If the test result is positive, a diagnostic 3-hour, 100 g oral OGTT is administered after an 8-hour fast preceded by 3 days of unrestricted diet and activity. Women should refrain from smoking or eating and should remain seated during testing. Plasma glucose determinations are made at fasting and at 1-, 2-, and 3-hour intervals after ingestion of the glucose solution. The diagnostic criteria are listed in Table 8-1. Two or more thresholds must be met or exceeded to diagnose GDM (ACOG, 2001).

One abnormal value has been associated with adverse outcomes with 30% of these women exhibiting two abnormal values 1 month later (Neiger & Coustan, 1991). Women with one abnormal value on the OGTT warrant closer surveillance with MNT and blood glucose monitoring or by repeat testing because of a much higher risk of adverse perinatal outcomes without treatment (Corrado et al., 2009; McLaughlin, Cheng, & Caughey, 2006). In the one-step approach, the screening 50 g test is omitted, and the 75 g, 2-hour OGTT is administered. The one-step approach for diagnosis has widespread use in Europe (Russell et al., 2007) and is endorsed for use in the United States by the ADA (2011) based on the results of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study and the recommendations of the International Association of the Diabetes and Pregnancy Study Groups.

The HAPO Study was an observational study of 23,325 pregnant women at 15 healthcare centers in 9 countries (HAPO Study Cooperative Research Group, 2008). All women had a 75-g, 2-hour OGTT at 28 weeks of gestation, and the results were blinded unless the fasting value exceeded 105 mg/dL and/or the 2-hour value exceeded 200 mg/dL. The goal of the study was to relate the blood glucose levels on the 75 g, 2-hour OGTT to pregnancy outcomes. The researchers found that the risk of adverse outcome was a continuum, even at levels that were previously considered normal. As blood glucose levels rose, so did the risk of macrosomia, cesarean birth, and neonatal hypoglycemia. The authors concluded that they could not determine what level of blood glucose is clinically important or what level should be considered abnormal (HAPO Study Cooperative Research Group, 2008).

The International Association of Diabetes and Pregnancy Study Groups (IADPSG), a collection of experts on diabetes and pregnancy and representatives from various organizations who have an interest in diabetes and pregnancy, came to a consensus about what criteria should be used to diagnose GDM based on the results of the HAPO Study (IADPSG, 2010). The IADPSG recommends using only the 2-hour, 75 g OGTT to diagnose GDM, thus eliminating the two-step process. They do not recommend using an OGTT before 24 weeks of gestation. The recommended threshold values for the diagnosis of GDM are listed in Table 8-1. These values are based on values in the HAPO Study where the odds ratios of birth weight, cord C-peptide, and percent neonatal body fat greater than the 90th percentile reached 1.75 times the odds of these outcomes at mean glucose values. GDM is diagnosed if only one value exceeds the threshold values. Using these threshold values, the rate of GDM in the HAPO Study was 17.8% (IADPSG, 2010). Adopting the IADPSG criteria for the diagnosis of gestational diabetes is expected to significantly increase the rate of GDM.

The clinical manifestations of diabetes occur as a result of hypoglycemia and hyperglycemia. Glycemic goals for pregnancy in women with diabetes reflect the plasma blood glucose values found in pregnant women who do not have diabetes; 60 to 95 mg/dL fasting, 60 to 105 mg/dL before a meal, 140 mg/dL 1 hour after a meal, and 120 mg/dL 2 hours after a meal (ACOG, 2001

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