Diabetes mellitus is associated with the significant risks of developmental defects and stillbirth for the fetus, organ dysfunction for the mother during pregnancy, and increased lifetime likelihood for developing hypertensive disease, dyslipidemias, and progressive glucose intolerance. Physicians who care for pregnant women must be aware of the interplay between the physiologic changes of pregnancy and diabetes in order to optimize outcomes for both parturient and neonate.
EPIDEMIOLOGY AND ETIOLOGY OF DIABETES
Diabetes mellitus is a heterogeneous group of endocrine disorders characterized by elevated glucose levels, caused by a deficiency of insulin secretion or insulin resistance in peripheral tissue. Diabetes occurs in approximately 11% of the US population, with an additional 35% exhibiting symptoms of prediabetes. The prevalence has increased by 128% from 1988 to 2008, largely due to soaring rates of obesity.1,2 The incidence of preexisting diabetes during pregnancy grew from 10% to 21% between 1999 and 2005.3
Insulin is a peptide hormone secreted by the β cells in the pancreatic islets of Langerhans that binds to insulin cell surface receptors in the liver, skeletal muscle, and adipose tissue. Insulin binding causes a conformational change in the α portion of the receptor, which activates kinase domains on its intracellular β subunits. Autophosphorylation of tyrosine residues initiates a series of signaling events that increases translocation of glucose transporter type 4 (GLUT4) from storage vesicles to the cell membrane. Insulin is critical in modulating maternal glucose, fat, and protein metabolism. Normal glucose metabolism represents a balance between insulin and the counteractive effects of glucagon, cortisol, epinephrine, and growth hormone.
PATHOPHYSIOLOGY AND RISK FACTORS FOR DIABETES IN PREGNANCY
Diabetes that is diagnosed before pregnancy is described by the standard classification as either type 1 or type 2. A third type, gestational diabetes, refers to a glycemic disorder discovered during pregnancy in the absence of preexisting metabolic disease. Individuals who have impaired fasting glucose (IFG) are referred to as having prediabetes, and they have a higher risk of developing future diabetes. As expected, IFG and impaired glucose tolerance (IGT) are associated with obesity, particularly abdominal obesity, dyslipidemia, and hypertension.
Type 1 Diabetes
Patients with type 1 diabetes (T1D) account for approximately 5% to 10% of those with the disease. This term includes patients previously referred to as insulin-dependent diabetes mellitus, or juvenile-onset diabetes mellitus. T1D is due to an absolute deficiency of insulin secretion following the cell-mediated autoimmune destruction of the β cells of the pancreas. Biomarkers of this immune destruction include autoantibodies to islet cells, insulin itself, glutamic acid decarboxylase, and tyrosine phosphatases IA-2 and IA-2β. One or more of these autoantibodies is present when fasting hyperglycemia is initially detected. There is also a strong association with human leukocyte antigen (HLA) types linked to DQA and DQB genes and influenced by DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective.4 Approximately 15% of those with autoimmune diabetes also have other autoimmune disorders such as Graves disease, Hashimoto thyroiditis, Addison disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.4
In infants and children, destruction of 85% of β cells can lead to hyperglycemia, whereas in adults as little as a 40% reduction by the age of 20 years is sufficient for development of the disease.5 Although autoimmune destruction of β cells is more common in childhood and adolescence, it can occur at any age. It is thought to have multiple genetic predispositions and is believed to be related to poorly understood environmental factors.6,7 T1D may initially present with ketoacidosis or with a long-standing fasting hyperglycemia that worsens in the presence of infection or other stressors. Some forms of T1D have no known etiology. In these cases, there are episodes of ketoacidosis and varying degrees of insulin deficiency but no immunologic evidence of β cell autoimmunity and the known HLA associations.8
Type 2 diabetes (T2D) is caused by a combination of a resistance to insulin action and an inadequate insulin secretion to compensate for surges in glucose levels. The prevalence of T2D in pregnant women has increased as global obesity rates have soared. In the United States, approximately two-thirds of people are overweight or obese. Among pregnant women, 40% are either overweight or obese.9–11 There are substantial perinatal risks associated with obesity including hypertensive disease, gestational diabetes, fetal macrosomia, induction of labor, cesarean section, and postpartum hemorrhage.12,13 The risks associated with obesity increase with each elevation in the body mass index.
Diagnosis of preexisting T2D occurs at the patient’s initial examination in the first trimester. A hemoglobin A1c (HbA1c) greater than 6.5%, fasting glucose greater than 126 mg/dL (6.99 mmol/L), a 2-hour plasma glucose greater than 200 mg/dL (11.1 mmol/L) after a 75-g glucose load, or a random plasma glucose greater than 200 mg/dL, indicate that the patient has T2D rather than gestational diabetes.4,8
The hyperglycemia of T2D may evolve in several ways, depending on the underlying disease process. IFG and/or IGT can exist without meeting the criteria for a diagnosis of diabetes. Some patients can achieve adequate glucose control with weight loss, exercise, nutritional management, and/or oral hypoglycemic agents. Others may require medications such as metformin or exogenous insulin for glucose control. Although the precise causes of T2D are not known, autoimmune destruction of β cells is not involved. Most of these patients are obese, and increased weight confers a degree of insulin resistance that cannot be compensated for by normal insulin secretion. Although insulin resistance may improve with pharmacologic management or weight loss and exercise, it seldom disappears or resolves completely.4,8
In addition to T1D and T2D, other rare types of diabetes can affect pregnant women. These include genetic defects of the β cell, abnormalities in insulin action (as is found in mature-onset diabetes of the young), diseases of the exocrine pancreas, endocrinopathies, drug-induced diabetes, and those caused by infections such as rubella. Other congenital syndromes, such as Down syndrome, can be associated with an elevated risk of diabetes. Finally, there are uncommon syndromes of immune-mediated diabetes, such as Stiff Person syndrome (SPS) syndrome and diabetes caused by anti-insulin receptor antibodies (known in the past as type B insulin resistance).4,8
Pregnancy exerts complex changes on maternal physiology and metabolism. During pregnancy, there is a progressive increase in peripheral resistance to insulin at the receptor and postreceptor level due to an increase in counterregulatory hormones, such as placental lactogen, placental growth hormone, cortisol, and progesterone.14 Gestational diabetes (GDM) occurs when the increase in insulin resistance is not met by augmented pancreatic β cell mass and insulin secretion.15,16 GDM is defined as hyperglycemia that is newly diagnosed during pregnancy. GDM is now found in 2% to 17.8% of pregnant women, depending on the diagnostic criteria used and the population studied.17 It is the most common medical complication of pregnancy and is increasing worldwide. Pregnant women with GDM or pre-GDM are at elevated risk of significant neonatal and obstetric complications, morbidity, and mortality.18,19
For many years, the criteria used to diagnose GDM included any degree of glucose intolerance, regardless of whether its onset occurred in pregnancy. These criteria did not take into account whether the hyperglycemia persisted after pregnancy and did not exclude the possibility that unrecognized glucose intolerance may have preceded or begun concomitantly with the pregnancy. In addition, the criteria varied among countries, making international comparisons of the incidence of diabetes in pregnancy and treatment protocols difficult.20
Although the association between a history of previous stillbirth, fetal macrosomia, and diabetes was recognized as early as in the 1950s, the precise nature of the relationship between maternal glucose levels and poor pregnancy outcomes remains obscure to this day.21 The Hyperglycemia and Adverse Pregnancy Outcome study was designed to evaluate the relationship between a 75-g glucose load in a 2-hour oral glucose tolerance test (OGTT) and poor pregnancy outcomes.22 This study demonstrated a continuous relationship between OGTT serum glucose values below those that are diagnostic for diabetes and several perinatal outcomes. The International Association of Diabetes in Pregnancy Study Groups (IADPSG) study was organized to identify OGTT plasma glucose levels that correspond to an increased risk of fetal macrosomia, neonatal adiposity, and fetal hyperinsulinemia (all greater than 90th percentile). The IADPSG recommended either testing all pregnant women or only those with risk factors (depending on background frequency of abnormal glucose metabolism in the population and local circumstances) using a single 75-g, 2-hour OGTT with cutoffs at an odds ratio of 1.75.23 The diagnosis of GDM is made when the fasting plasma glucose values are at least 92 mg/dL (5.1 mmol/L), a 1-hour value of at least 180 mg/dL (10.0 mmol/L), and a 2-hour value of at least 153 mg/dL (8.5 mmol/L). Please refer to Table 23-1.23
Table 23-1. International Association of Diabetes and Pregnancy Study Groups (IADPSG) Recommendations for Gestational Diabetes Screeninga
These criteria have been shown to be cost-effective compared with current standard of care.24 The American Diabetes Association (ADA) has adopted these criteria, although the American College of Obstetricians and Gynecologists (ACOG) still advocates testing all pregnant women with a 50-g, 1-hour test at 24 to 28 weeks and relying on the result of a 100-g, 3-hour OGTT.8,25
Risk factors for developing GDM include advanced maternal age, obesity, polycystic ovary disease, a family history of T2D, and a previous history of gestational diabetes, stillbirth, fetal malformation or macrosomia. Obesity increases the overall risk of GDM by a factor of 3.76.26 Perinatal mortality and an increase in congenital malformations are also strongly correlated with maternal obesity in patients with T2D.27
Diabetes during pregnancy has historically been classified using the system proposed by Priscilla White in 1949 based on a case series of women with T1D at the New England Deaconess Hospital in Boston, Massachusetts.28 In this study, she found significant associations among the onset of diabetes, its duration, and the degree of vasculopathy, to adverse outcomes of pregnancy. These criteria were later modified to make clear that class A diabetes should include only those women with pre-GDM.29 The ongoing relevance of the White classification to assess pregnancies at risk for elevated perinatal morbidity and mortality has been eroded by the increasing prevalence of T2D.30,31 Currently, 90% of pregnant diabetic patients have GDM, and T1D and T2D account for the remaining 10% of cases.
ACUTE MATERNAL COMPLICATIONS OF DIABETES
During pregnancy, women with diabetes experience both acute and chronic diabetic complications related to glycemic control, as well as the risks associated with their higher prevalence of preeclampsia. Acute complications include diabetic ketoacidosis (DKA), hyperosmolar hyperglycemia state (HHS), and hypoglycemia. The underlying mechanism for both DKA and HHS is reduction in the effective action of insulin and the elevation of the counterregulatory hormones such as glucagon, cortisol, growth hormone, and catecholamines.
DKA can occur in patients with T1D and in those with T2D who develop further insulin resistance following trauma or severe infection.32,33 DKA is characterized by hyperglycemia, metabolic acidosis, and increased ketone formation.32 Although the incidence of DKA during pregnancy has declined significantly over the years, it remains a medical emergency; historically fetal mortality rates of 30% to 90% and maternal mortality rates of 5% to 15% have been reported.33–35
DKA occurs in approximately 1% to 2% of pregnancies complicated by diabetes, and it is rare in patients with gestational diabetes.32,34–36 Although improved glycemic control in pregnant diabetics has decreased the incidence of DKA in those with known diabetes, up to 30% of cases occur in those women who are unaware they have diabetes.34,36 DKA is also more common as further insulin resistance develops in the second and third trimesters.37,38
Several triggers have been reported to precipitate DKA in pregnancy. Cessation of insulin therapy and infection account for 40% and 20% of cases, respectively, and in 30% of cases acidosis has been the initial presentation of undiagnosed diabetes.39,40 Risk factors that predispose pregnant patients to DKA include infection, vomiting, diabetic gastroparesis, the use of corticosteroids (such as betamethasone given to accelerate fetal lung maturation) and β-sympathomimetic drugs used for uterine tocolysis. In one case series, vomiting and the use of β-mimetic drugs accounted for up to 57% of cases of DKA.41 During an episode of DKA, a patient may experience nausea, vomiting, abdominal pain, tachypnea, hypotension, tachycardia, and stupor, and he or she may have a sweet-scented breath from exhaled ketones.
DKA is a result of inadequate insulin action and the failure of glucose utilization at the cellular level. Hormones, such as glucagon, catecholamines, cortisol, and growth hormone, enable cellular metabolism of carbohydrates, proteins, and lipids. An increase in gluconeogenesis and glycogenolysis in the liver and decreased peripheral glucose utilization leads to hyperglycemia. Free fatty acids are released from adipose tissue and converted into ketones, acetoacetate, and β-hydroxybutyrate. Ketones dissociate at physiologic pH and are neutralized by bicarbonate. The compensated respiratory alkalosis of pregnancy, however, reduces patient’s buffering capacity and renders patients more susceptible to metabolic acidosis at lower glucose levels.
Glucose resorption in the renal tubules reaches a maximum threshold of about 240 mg/dL (13.3 mmol/L), beyond which glucosuria develops. With increasing hyperglycemia, an osmotic diuresis occurs leading to total body water depletion, hypovolemia, hyperosmolarity, and electrolyte depletion.42 Maternal acidosis, hyperglycemia, severe volume depletion, and electrolyte abnormalities contribute to the high rates of fetal loss. The consequences of maternal DKA for the fetus are discussed below.
The greater susceptibility to develop ketosis during pregnancy is reflected in the likelihood that overt DKA can occur at lower blood glucose levels.43,44 While euglycemic ketoacidosis is rare, it has been reported in pregnancies complicated by gestational diabetes.45,46 In euglycemic (or normoglycemic) ketoacidosis, the patient has a metabolic acidosis in the absence of elevated serum glucose, a process that is thought to be due to accelerated starvation and near total depletion of hepatic glycogen stores.45–48
Hyperosmolar Hyperglycemic State
Previously known as hyperosmolar nonketotic coma or hyperosmolar hyperglycemic nonketotic syndrome, HHS is a severe complication of uncontrolled hyperglycemia. It develops predominantly in patients with T2D.49 In one study of HHS patients diagnosed in an emergency department, 30% to 40% were unaware of their underlying diabetes.50 Typically, patients become increasingly hyperglycemic without increasing their fluid intake to compensate for their polyuria. As a result, they develop severe osmotic dehydration, increasing hyperosmolarity, and moderate azotemia without ketosis or significant acidosis. Mental status changes may be followed by somnolence, coma, and seizures.51
Initial laboratory evaluation for suspected hyperglycemic associated DKA and HHS should include determination of plasma glucose, blood urea nitrogen, creatinine, serum ketones, electrolytes (with calculation of the anion gap), chemistry profile, osmolality, urinalysis, urine ketones, arterial blood gas, complete blood count and differential.37 Diagnostic criteria for DKA include a serum glucose greater than 250 mg/dL (13.9 mmol/L), arterial pH less than 7.3, serum bicarbonate less than 18 mEq/L, and moderate ketonuria or ketonemia.52 For HHS, the diagnostic criteria include a serum glucose greater than 600 mg/dL (33.3 mmol/L), arterial pH greater than 7.3, serum bicarbonate greater than 15 mEq/mL, and minimal ketonuria or keturia. HHS develops over several days to weeks, but the time course for acute DKA in T1D and T2D is shorter. Although both DKA and HHS are often precipitated by infection, altered mental status is more common with HHS due to the hyperosmolality, and vomiting, dehydration, and abdominal pain are more characteristic of DKA.
Successful management of DKA and HHS requires resolution of dehydration, hyperglycemia, electrolyte abnormalities, precipitating factors, and close monitoring. The goal of fluid resuscitation is to expand the intravascular and extravascular volume and restore renal perfusion. Typically, 1 to 1.5 L isotonic saline (0.9% NaCl) should be infused over the first hour. Additional fluid replacement is guided by volume status, glucose-corrected serum sodium levels, and urine output. Fluid replacement should aim to correct deficits within the first 24 hours.
The average fluid deficit in a nonpregnant patient with HHS may be up to 9 L.50 A general guideline is to replace half of the fluid deficit in the first 12 hours and the remaining deficit in the next 12 to 24 hours, with frequent monitoring of the serum sodium. Serum osmolality should not be decreased by more than 3 mOsm/kg per hour to reduce the risk of developing cerebral edema.32
Regular insulin has usually been the insulin treatment of choice. In the absence of hypokalemia, an intravenous bolus of 0.1 U/kg is initiated followed by a continuous infusion of 0.1 U/kg per hour. If the blood glucose does not decrease at a rate of 50 to 75 mg/dL per hour (2.7-4.2 mmol/L per hour), the insulin rate should be increased. When the plasma glucose decreases to 200 mg/dL (11.1 mmol/L) in DKA or 300 mg/dL (16.6 mmol/L) in HHS, the rate of insulin infusion can be decreased to 0.05 to 0.1 U/kg per hour and a 5% dextrose drip initiated to maintain blood glucose levels.52 Subsequent management involves adjusting of the rate of insulin and dextrose infusions to maintain glucose levels until the acidosis in DKA resolves or the hyperosmolality in HHS clears.
Administering bicarbonate to treat the metabolic acidosis in DKA is controversial. Bicarbonate use may be associated with paradoxical central nervous system acidosis, hypokalemia, hypertonicity, and cerebral edema.41,53 Electrolyte abnormalities necessitate continuous electrocardiographic (ECG) monitoring, and patients should be treated in an intensive care unit setting with continuous fetal monitoring and assessment of fetal well-being with a biophysical profile.
Studies have evaluated the efficacy of the rapid-acting insulin analogs, such as Lispro, given subcutaneously for patients in diabetic ketosis.54,55 Although these regimens permit treatment of noncomplicated DKA in general wards or in the emergency department, their use in pregnancy has not been evaluated.
Hypoglycemia is the greatest limitation to insulin therapy in T1D and to tight glucose control in T2D.56,57 It occurs in 33% to 71% of those with T1D, and in these patients, severe hypoglycemia is three to five times more frequent than T2D during early pregnancy.58 Severe hypoglycemia is the most common adverse event in pregnant women who use insulin. There are no data, however, which suggest that treated episodes of hypoglycemia contribute to poor pregnancy outcomes.59
Hypoglycemia is most common in the first trimester, although it can occur in subsequent trimesters and can be asymptomatic at night. Insulin requirements increase during pregnancy because of a progressive insulin resistance in periphery. At term, insulin needs are 1.0 U/kg per day compared with 0.7 U/kg per day prior to pregnancy.60 The risk of hypoglycemia in diabetic pregnancy also may be related to fetal use of maternal glucose during periods of maternal fasting. As blood glucose levels drop, patients initially experience adrenergic symptoms of palpitations, perspiration, and hunger, which signify physiologic efforts to restore carbohydrate levels. With further decreases in blood glucose levels, patients experience neurologic symptoms of altered behavior, mood swings, and finally diminished consciousness and convulsions.61
Severe hypoglycemia in pregnant diabetics has been implicated as a cause for maternal traffic accidents and even death.61–63 In a patient who has severe low blood sugar and is able to swallow, oral carbohydrates must be given promptly. In those who are obtunded and who do not have intravenous access, 1 mg of glucagon can be given intramuscularly.52,64
Pregnant women with diabetes are at higher risk for developing preeclampsia, which is characterized by hypertension and proteinuria after 20 weeks of pregnancy. Those with severe disease may develop the syndrome known as HELLP (hemolysis, elevated liver enzymes, low platelets) or eclampsia.65–67 Although the topic of hypertensive disease of pregnancy is discussed in detail elsewhere, it is important to note that preeclampsia and cesarean delivery are both more common in undiagnosed GDM and may be prevented with treatment of even mild hyperglycemia.68
NONACUTE AND LONG-TERM MATERNAL COMPLICATIONS OF DIABETES
Hyperglycemia causes changes at the cellular level that result in accelerated microvascular and macrovascular disease. Elevated glucose levels are associated with oxidative stress, decreased nitric oxide availability, oxidation of low-density lipoproteins, and activation of procoagulants.60,69 In general, the occurrence of chronic complications is related to the duration of diabetes and degree of glycemic control (see Table 23-2). Whereas the long-term complications of T1D are typically microvascular angiopathies, affecting the retina, kidneys, and the autonomic nervous system, those for T2D are macrovascular and affect the heart, central nervous system, and peripheral vascular system. Tight glucose control can lessen the severity and/or progression of these microvascular complications.70–72
Table 23-2. Complications of Chronic Diabetes
Patients with diabetes have greater susceptibility to infection through increased inflammation and decreased cell-mediated immunity. During pregnancy women are at elevated risk for urinary tract infections that can develop into pyelonephritis and septicemia. Candidal infections, such as oral thrush and vulvovaginal yeast infections, are also more prevalent. Gingival inflammation is common in pregnancy and can lead to oral infections in diabetics. Among pregnant patients, obesity and diabetes are independent risk factors for infection following cesarean section.73
Renal disorders complicate approximately 5% of pregnancies in women with preexisting diabetes, especially those with T1D, and may progress in those with poorly controlled hypertension and worsening glomerular filtration rates. Intensive glycemic control and aggressive treatment of hypertension can attenuate progression of nephropathy.74 Women with diabetes often have progressive proteinuria during pregnancy (protein excretion can double or triple in the third trimester), and this can cause confusion with the diagnosis of preeclampsia. Those with normal serum creatinine levels may have no further decline in kidney function or impairment of long-term survival.74 Women with creatinine levels higher than 1.5 mg/dL have the greatest risk of perinatal complications. Approximately 50% will deliver before term, 50% will develop preeclampsia, and 15% will have fetuses with intrauterine growth restriction (IUGR).75 Strict glycemic control and intensive antihypertensive treatment are essential in these patients.76
The prevalence of retinopathy in women with pre-GDM of both types is 10% to 36%. These rates increase in patients with T1D, and 57% to 62% are diagnosed with retinopathy during their initial eye examination during pregnancy. In patients with T2D, retinopathy is found in 17% to 28%. In T1D retinopathy often worsens during pregnancy, but this occurs less frequently in T2D.77 Neither the long-term risk of retinopathy nor its progression appears to worsen with pregnancy itself.78 Although rare, diabetic retinopathy has also been reported in GDM.79
Microvascular changes in the eye may be caused by diabetes, by pregnancy itself, or by rapid improvement in glycemic control when diabetes is discovered in pregnancy. Fluid retention, vasodilation, and augmented blood flow during pregnancy are thought to accelerate the loss of autoregulation in the retinal capillary bed. All patients with retinopathy should have their baseline level of ophthalmologic disease level established by a specialist after their first visit to the obstetrician. Laser photocoagulation treatment of retinopathy is effective in pregnancy and should not be delayed until after delivery.
Factors associated with the progression of retinopathy include the duration of T1D, degree of hyperglycemia, level of glycemic control at conception, stage of disease at the onset of pregnancy, and presence of chronic hypertension or preeclampsia.80–82 Rapid reduction in HbA1c has been associated with worsening of diabetic retinopathy.78 Although there are no controlled studies of whether the Valsalva maneuver during the second stage of labor can induce vitreous hemorrhages in patients with diabetic retinopathy, the ADA still recommends use of epidural anesthesia with an assisted second stage or cesarean delivery in these patients.82
Pregnant diabetics may experience several forms of diabetic neuropathy, but they have not been well studied. In patients with evidence of diabetes-induced cardiovascular autonomic dysfunction, hypotension must be avoided. In nonpregnant patients, the corrected QT interval (QTc) has been noted to correspond to the severity of autonomic neuropathy.83 It is not known whether the same association is seen in pregnant diabetics. Cardiovascular autonomic neuropathy can be evaluated by looking for diminished heart rate variability (such as with time domain analysis of R-R interval to paced breathing and Valsalva maneuvers) and decreased blood pressure on standing.84–86 Lack of heart rate variability in nonpregnant patients with a history of GDM is indicative of cardiac autonomic neuropathy and is related to glycemic control, not insulin sensitivity.86
A short-term increase in sensorimotor distal symmetric polyneuropathy (DPN) may develop during pregnancy and later resolve. Acute sensory neuropathy is rare, tends to result from poor glycemic control, and can follow acute changes in metabolic management. The neuropathy is typically worse at night, with few neurologic findings on physical examination. DPN is more common in T1D and in patients with long-standing T2D; it is rare in GDM.
Gastroparesis occurs when damage to the ganglia in the gastrointestinal tract inhibits gastric motility and delays intestinal transit time. Recent work indicates that gastric motility is directly influenced by glucose levels and that diminished autonomic nervous function is not the sole cause of gastroparesis diabeticorum.
Women with gastroparesis may experience more protracted nausea and vomiting during pregnancy, and those with severe gastroparesis may require inpatient nutritional therapy and antiemetic therapy to prevent fetal losses.87–89 Gastroparesis is a diabetic complication that carries with it a significant risk of morbidity and poor pregnancy outcome, which is second only to coronary heart disease.90–92 Autonomic neuropathy is a complication of long-standing T1D, but it does not appear that pregnancy itself is a risk factor for the deterioration of autonomic nervous function.93–95
Although macrovascular diseases are more often found in T2D patients, coronary artery disease is not commonly seen in women of childbearing age, and only case reports have been published. Nonetheless, pre-GDM was associated with the risk of an acute coronary event with an odds ratio of 4.3 (2.3-7.9).90–92 Atypical and “silent” manifestation of coronary ischemia remain a concern, although improvements in care have reduced maternal mortality rates to 7.3% to 11%.90–92
A pregnancy with diabetes has significant health consequences for women in later life. Postpartum metabolic syndrome in patients with GDM is well described.96–101 Elevated plasma total cholesterol, low-density lipoprotein, and triglyceride concentrations are also found in women with GDM.102 In these patients, the increased lifetime risk of developing T2D may be as high as sevenfold.103 Women with GDM also exhibit higher elevations in plasma fibrinogen, thrombin-antithrombin complexes, and lower levels of coagulation inhibitors than those with normal pregnancies.69,104
Although the occurrence of hypertensive disease in pregnancy increases in the presence of diabetes, the relationship between the two is not well understood. Transient hypertension of pregnancy, which is diagnosed after 20 weeks’ gestation and not accompanied by proteinuria, is known to be associated with a higher risk of essential hypertension and glucose intolerance in later life. Interestingly, an abnormal glucose-loading test during pregnancy is a predictor of the development of preeclampsia in a subsequent pregnancy and future hypertension.97 Pregnant women with diabetes and those with gestational hypertension also have an elevated risk of cardiovascular disease, particularly those with a family history of T2D.98,99
Maternal DKA has substantial effects on the fetus as a result of its effects on oxygen transport. Hyperglycemia results in covalently bound glycosylated hemoglobin, which in turn alters the interaction between the β chains of the hemoglobin molecule. As a result of elevations in glycosylated hemoglobin, maternal red blood cells transfer less oxygen to the fetal hemoglobin molecules and may contribute to fetal hypoxia.105,106 Additionally, as maternal ketone bodies dissociate, the hydrogen ions and organic anions cross the placenta and cause fetal acidosis. A leftward shift of the oxyhemoglobin dissociation curve, with decreased 2,3-diphosphoglycerate levels, increases maternal hemoglobin affinity for oxygen, thus decreasing overall oxygen delivery to the fetus.
Fetal blood flow has been observed to redistribute during episodes of DKA, and treatment of maternal acidosis reverses abnormal blood flow.107,108 A fetal heart rate tracing that lacks variability, or has variable or late decelerations, such as an indeterminate category II tracing, is not an indication for immediate delivery until the metabolic condition is corrected.109 Emergency cesarean section in the setting of decompensated DKA could worsen maternal outcomes. β-Hydroxybutyrate is known to cross the placenta, and fetuses can thus acquire ketoacidosis. Bilateral basal ganglia infarctions have been noted in a case report of a neonate born during an episode of DKA.110
Perinatal hypoxia and birth asphyxia also occur in infants whose mothers have poorly controlled diabetes (primarily T1D), vascular disease, and nephropathy. In these cases, extreme hyperglycemia and ketosis reduce uterine and placental blood flow, which increases the risk of fetal hypoxia. Elevated fetal glucose concentrations also lead to increased placental glucose consumption, contributing to further lactate production and glycogen deposition.
Transient hypoglycemia in the immediate postnatal period is normal for all infants but occurs more quickly and to lower levels in infants of diabetic mothers, particularly in the setting of unstable maternal glucose levels. Neonatal hypoglycemia occurs in 5% to 12% of infants born of pre-GDM or GDM mothers.111 Early feeding or a glucose infusion started at 4 to 6 mg/min per kilogram body weight can be used to stabilize plasma glucose levels until the infant can take adequate oral nutrition.
Other acute physiologic abnormalities occur in infants of diabetic mothers (IDMs). Neonatal hypocalcemia and hypomagnesemia occurs in one-half of IDMs within 72 hours of birth. Hypocalcemia is likely to be a result of slow transition from fetal parathyroid to neonatal parathyroid control. Neonatal hypomagnesemia may be related to the same parathyroid issues but may also be worsened in cases of maternal hypomagnesemia with severe renal disease.112
Respiratory distress is often found in premature infants but occurs with even greater frequency in term infants born to women with GDM because hyperglycemia is thought to delay fetal lung maturation.112,113 In addition, the elevated risk of cesarean delivery leads to increased rates of transient tachypnea of the newborn and neonatal persistent pulmonary hypertension.114,115 See Table 23-3.
Table 23-3. Fetal Complications of Maternal Diabetes