Endocrine Disorders of Pregnancy
Clark T. Johnson
Lorraine A. Milio
DIABETES MELLITUS
Diabetes mellitus (DM) is the most common medical complication of pregnancy in the United States, affecting nearly 7% of all pregnancies. As the incidence of type 2 DM increases nationwide, cases of gestational diabetes mellitus (GDM) have grown also. In 90% of diabetic pregnancies, the cause is GDM.
Diabetes in pregnancy is categorized as pregestational diabetes (diagnosed prior to pregnancy) or GDM (diagnosed during pregnancy). Pregestational diabetes is further classified as type 1 or type 2 (Table 13-1). One half percent to 1% of pregnancies are complicated by pregestational DM.
Carbohydrate metabolism changes during pregnancy to provide adequate nutrition for both the mother and the fetus.
In the fasting state, maternal serum glucose is lower in pregnancy than in the nonpregnant state (55 to 65 mg/dL), whereas free fatty acid, triglyceride, and plasma ketone concentrations are increased. A state of relative maternal starvation exists in pregnancy, during which glucose is spared for fetal consumption and alternate fuels are used by the mother.
GDM is similar to type 2 DM, in which increased pancreatic secretion cannot overcome decreased insulin sensitivity of maternal target tissues. Increased metabolism in pregnancy also increases insulin clearance. These changes are due to the effects of estrogen, progesterone, cortisol, prolactin, and human placental lactogen. The net result is hyperglycemia.
Diagnosis and Screening
Diagnosis of type 1 and 2 DM before pregnancy is by standard criteria: two abnormal fasting glucose levels ≥126 mg/dL or a random glucose level of ≥200 mg/dL (Table 13-2). Classic symptoms are polydipsia, polyuria, and polyphagia. Clinical signs include weight loss, hyperglycemia, persistent glucosuria, and ketoacidosis.
Universal screening for GDM is standard in the United States, whether by patient history, clinical risk factors, or laboratory testing. Testing is typically performed at 24 to 28 weeks, but if strong risk factors such as obesity, family history, or a personal history of GDM are present, blood glucose screening may be performed at the first prenatal visit. Not all patients require screening via blood glucose testing (Table 13-3).
Screening for GDM has undergone much scrutiny in recent years as a result of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study in which progressive hyperglycemia was linked to adverse perinatal outcomes. For many years, a two-step screening/diagnostic protocol has been widely used. In this screening, a 50-g oral glucose challenge is consumed, followed by serum glucose measurement at
1 hour. No fasting or dietary preparation is required. A serum glucose ≥140 mg/dL identifies 80% of GDM, whereas decreasing the cutoff to ≥130 mg/dL identifies over 90% of GDM but with more “false positives.” A serum glucose ≥200 mg/dL diagnoses GDM without additional testing.
If the screening test is positive, then a diagnostic 3-hour glucose tolerance test (GTT) should be performed with 100-g oral glucose after at least 8 hours of fasting (Table 13-4). With abnormal fasting or any other two abnormal values, the diagnosis of DM is confirmed. In patients at high risk for GDM with a normal GTT, a follow-up GTT can be performed at 32 to 34 weeks to identify late-onset diabetes.
Based on the HAPO study, the International Association of Diabetes and Pregnancy Study group, in 2010, recommended that a universal 75-g, 2-hour GTT be used in a single-step screening/diagnosis of GDM. In this schemata, the diagnosis of GDM would be made when any single threshold value was reached or exceeded (fasting value = 92 mg/dL, 1-hour value = 180 mg/dL, and 2-hour value = 153 mg/dL).
This protocol was endorsed by the American Diabetes Association. However, there has been concern that using this criterion for diagnosis of GDM would result in 17% to 18% of pregnancies diagnosed with GDM and would improved
perinatal outcomes justify the increased burden of managing such a surge in diagnosed patients. In 2013, a National Institute of Child Health and Human Development consensus panel concluded that there was not enough evidence to date to warrant recommendation of this protocol for universal diagnosis of GDM.
Classification of GDM depends on the management required to control blood glucose levels. Type A1 achieves euglycemia by dietary changes alone. Type A2 requires additional (i.e., medical) therapy.
TABLE 13-1 Comparison of Type 1 and Type 2 Diabetes Mellitus | ||||||||||||
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TABLE 13-2 Diabetic Screening in the Nonpregnant Patient | ||||||||||||||||
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TABLE 13-3 Gestational Diabetes Risk Assessment | ||||||||||||
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TABLE 13-4 Criteria for Diagnosis of Gestational Diabetes from Oral Glucose Tolerance Testing | ||||||||||||||||||
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Fetal Complications of Diabetes Mellitus
Fetal and neonatal complications of DM in pregnancy are increased with both gestational and pregestational DM, but the incidence is much higher in pregestational DM and with poor glycemic control. Fetal glucose levels are similar to maternal blood glucose levels, and both fetal hyperglycemia and hypoglycemia have important effects.
Spontaneous abortion ranges between 6% and 29% with pregestational DM and correlates with poor glucose control and an elevated hemoglobin A1C (HbA1C) around the time of conception. Type 1 and type 2 DM carry the same risk of pregnancy loss, but the main causes of fetal loss for type 1 DM are congenital anomalies and complications of prematurity, whereas for type 2 DM, they are in utero fetal demise, fetal hypoxia, and chorioamnionitis. There is no increased incidence of spontaneous abortion in diabetics with excellent preconception glucose control (i.e., HbA1C <6%).
Congenital malformations are the most common cause of perinatal mortality in pregestational diabetic pregnancies and correlate with elevated HbA1C. Congenital anomalies account for 30% to 50% of perinatal mortality from diabetes. Maternal hyperglycemia is considered to be the principal factor causing congenital malformations. Six percent to 10% of infants of diabetic mothers have a major congenital anomaly (see Chapter 12). Again, there is no increase in congenital malformations when euglycemia and a normal HbA1C is present from conception through the first trimester.
The most common congenital malformations in diabetic pregnancies are in the cardiovascular system. Defects include transposition of the great vessels, ventricular and atrial septal defects, hypoplastic left ventricle, situs inversus, aortic anomalies, and complex cardiac anomalies. The rate of cardiac malformations is fivefold higher in diabetics.
Sacral agenesis/caudal regression is highly suggestive of diabetic fetopathy. It is a rare malformation but diagnosed up to 400 times more frequently in diabetic pregnancies and is nearly pathognomonic.
There is a 10-fold increase in the incidence of central nervous system malformations in infants of diabetic mothers, including anencephaly, holoprosencephaly, open spina bifida, microcephaly, encephalocele, and meningomyelocele.
Gastrointestinal (GI) system malformations, including tracheoesophageal fistula, bowel atresia, and imperforate anus, are also increased in diabetic gestations.
Genitourinary system anomalies including absent kidneys (leading to Potter syndrome), polycystic kidneys, and double ureter are more common in pregnancies complicated by diabetes.
Polyhydramnios occurs in 3% to 32% of diabetic pregnancies, 30 times the rate for nondiabetic gestations. Diabetes alone is the leading known cause of polyhydramnios. Furthermore, diabetes-associated congenital anomalies of the central nervous and GI systems can also lead to polyhydramnios. Mechanisms of polyhydramnios include increased fetal glycemic load resulting in polyuria, decreased fetal swallowing, and fetal GI obstructions. Higher perinatal morbidity and mortality rates are
associated with polyhydramnios, attributed in part to the higher incidence of both congenital anomalies and preterm delivery.
Macrosomia is defined as an estimated fetal weight more than 4,000 to 4,500 g or more than the 90th percentile at any gestational age, depending on the authority. It occurs in 25% to 42% of hyperglycemic versus 8% to 14% of euglycemic pregnancies, and maternal diabetes is the most significant single risk factor. Diabetic macrosomia is characterized specifically by a large fetal abdominal circumference and decreased head to abdominal circumference ratio because fetal hyperinsulinemia leads to abnormal fat distribution. Macrosomic fetuses have an increased mortality rate and higher risk for hypertrophic cardiomyopathy, vascular thrombosis, neonatal hypoglycemia, and birth trauma. They are more likely to be delivered by cesarean section and are at increased risk for shoulder dystocia during birth, which may result in fractured clavicles, facial paralysis, Erb palsy, Klumpke palsy, phrenic nerve injury, and intracranial hemorrhage.
Intrauterine growth restriction (IUGR) may complicate pregnancy for pregestational diabetic women with microvascular disease. Placentae of diabetic pregnancies can be compromised and may exhibit pathohistologic changes, including fibrinoid necrosis, abnormal villus maturation, and proliferative endarteritis of fetal stem arteries. There is wide variation, but these observations occur even with good glucose control, suggesting that irreversible placental abnormalities occur very early in gestation.
Poorly controlled diabetes increases risk for fetal demise in utero during the third trimester. Cord thrombosis and accelerated placental aging may be the cause.
Shoulder dystocia is increased threefold in diabetic gestations at any estimated fetal weight and is of even greater concern when macrosomia is also present. If shoulder dystocia occurs, infants of diabetic mothers are more likely to have brachial plexus injury than infants of women without DM. In macrosomic infants of diabetic mothers, vaginal delivery carries a 2% to 5% risk of brachial plexus injury.
Twenty-five percent to 40% of infants of diabetic mothers develop neonatal hypoglycemia. The serum glucose nadirs at about 24 hours of life. Poor maternal glycemic control during late pregnancy and at delivery increases the risk. The pathogenesis is in utero stimulation of the fetal pancreas by maternal hyperglycemia leading to fetal islet cell hypertrophy and beta cell hyperplasia. When the maternal glucose source is eliminated, the continued overproduction of insulin leads to newborn hypoglycemia with cyanosis, convulsions, tremor, apathy, diaphoresis, and a weak or high-pitched cry, if untreated. Severe or prolonged hypoglycemia is associated with neurologic sequelae and death. Standard of care includes testing neonatal blood glucose value within 1 hour of birth. Treatment should be instituted when the infant’s blood glucose drops below 40 mg/dL.
Neonatal hypocalcemia and hypomagnesemia are common in infants of diabetic mothers and correlate with the degree of glycemic control.
Thirty-three percent of infants born to diabetic mothers have polycythemia (hematocrit higher than 65%). Chronic intrauterine hypoxia increases erythropoietin production, resulting in vigorous hematopoiesis. Alternatively, elevated glucose may lead to early increased red blood cell destruction, followed by increased erythrocyte production.
Neonatal hyperbilirubinemia and neonatal jaundice occur more commonly in infants of diabetic mothers than in infants of nondiabetic patients of comparable gestational age because poor glycemic control delays fetal liver maturation.
Neonatal respiratory distress syndrome (RDS) may occur more frequently in diabetic pregnancies as a result of delayed fetal lung maturation. Fetal hyperinsulinemia
may suppress production and secretion of surfactant required for normal lung function at birth.
The risk of fetal cardiac septal hypertrophy and hypertrophic cardiomyopathy is increased in diabetic pregnancies (up to 10% have hypertrophic changes). There is a strong correlation between cardiomyopathy and poor maternal glycemic control. As an isolated finding, cardiac septal hypertrophy is a benign neonatal condition. However, it increases the risk of morbidity and mortality in neonates with sepsis or congenital structural heart disease.
Maternal Complications of Diabetes Mellitus
Maternal complications are increased with diabetes.
Diabetic ketoacidosis (DKA) is a potentially life-threatening metabolic emergency for both mother and fetus. In pregnant patients, DKA can occur at lower blood glucose levels (i.e., <200 mg/dL) and more rapidly than in nonpregnant diabetics. Although maternal death is rare with proper treatment, fetal mortality rates from 10% to 30% are reported. About half of DKA cases are due to medical illness, usually infection; another 20% result from dietary or insulin noncompliance. In 30% of cases, no precipitating cause is identified. Antenatal steroids for fetal lung maturity and beta-adrenergic tocolytics can precipitate or exacerbate hyperglycemia and DKA in pregestational diabetics.
The pathophysiology of DKA is relative or absolute insulin deficiency. The resulting hyperglycemia and glucosuria lead to osmotic diuresis, promoting urinary potassium, sodium, and fluid loss. Insulin deficiency also increases lipolysis and hepatic oxidation of fatty acids, producing ketones and eventually causing metabolic acidosis.
Diagnosis is by objective documentation of maternal hyperglycemia, acidemia, and serum ketosis. Signs and symptoms include abdominal pain, nausea and vomiting, polydipsia, polyuria, hypotension, rapid deep respiration, and impaired mental status (ranging from mild drowsiness to profound lethargy). Acidosis can be defined as a plasma bicarbonate level <15 mEq/L or arterial pH <7.3. In the presence of hyperglycemia, ketosis is presumed and can be verified by serum testing. Because pregnancy is a state of physiologic respiratory alkalosis, profound DKA may occur at a higher pH.
Initial management consists of vigorous intravenous (IV) hydration followed by IV insulin drip and frequent blood sugar checks to titrate dosing. Potassium and bicarbonate supplementation may be necessary. Insulin cannot be given if potassium is less than 3.0 mEq/L because insulin drives potassium into the cells and can cause profound hypokalemia with resultant cardiac arrhythmias. Check electrolytes every 4 hours and blood sugar hourly until DKA is resolved (Fig. 13-1). Evaluating for the underlying cause and pursuing treatment (e.g., antibiotics for a urinary tract infection) is part of the management.
Severe hypoglycemia, requiring hospitalization, may occur in up to 45% of mothers with type 1 DM. Patients with poorer glycemic control can have blunted autonomic responses and milder symptoms so they may present with more severe or prolonged episodes. Vomiting in early pregnancy also predisposes diabetics to low blood sugars. Severe hypoglycemia may be teratogenic in early gestation, but the effects on the developing fetus are not fully understood.
Symptoms include nausea, headache, diaphoresis, tremors, blurred or double vision, weakness, hunger, confusion, paresthesia, and stupor. Diagnosis is by careful history and review of symptoms and confirmed with a blood glucose measurement <60 mg/dL.
Treatment starts with 4 oz of juice or a glucose tablet. Assess serum glucose after 15 to 20 minutes, and repeat feeding until blood sugar is >70 mg/dL, followed with complex carbohydrates or a scheduled meal or snack. If the patient is unable to tolerate food and drink, a subcutaneous injection of glucagon is appropriate or an ampule of dextrose 10% can be given IV push followed by IV fluids containing 5% dextrose.
The Somogyi effect is rebound hyperglycemia after hypoglycemia secondary to counterregulatory hormone release. It usually occurs in the middle of the night but can happen after any hypoglycemic episode, manifesting as wide variations in blood glucose levels over a short period of time (e.g., between 2:00 and 6:00 A.M.). Diagnosis is by checking additional blood sugars (i.e., 3:00 A.M.) to identify unrecognized hypoglycemia. Treatment involves adding or modifying a nighttime snack or decreasing the overnight insulin dose in order to better match insulin needs with dietary intake.
The dawn phenomenon is also an early morning increase in plasma glucose, possibly due to normal nighttime production of growth hormone (GH), catecholamines, and cortisol. It is also diagnosed by checking early morning (i.e., 3:00 A.M.) blood sugar level. If the patient is euglycemic overnight, she may require increased bedtime insulin dosing to cover the effect of normal morning hormones. Differentiating between the Somogyi effect and the dawn phenomenon helps tailor the insulin regimen and achieve optimal glucose control.
Rapid progression of microvascular and atherosclerotic disease can occur in pregnant diabetics. Any evidence of ischemic heart disease, heart failure, peripheral vascular disease, or cerebral ischemia should be evaluated carefully. A pregestational diabetic older than age 30 years should have a baseline electrocardiogram (ECG). Maternal echocardiogram and cardiology consultation may be warranted. Preconception counseling is useful for these patients. For the most severe maternal disease, termination in early pregnancy may be considered and offered.
Nephropathy complicates 5% to 10% of diabetic pregnancies. In renal failure, with creatinine >1.5 mg/dL, there may be worsening failure with advancing pregnancy, but it is unclear if pregnancy actually hastens progression to end-stage disease. Diabetic nephropathy increases the risk for maternal hypertensive complications, preeclampsia, preterm birth, fetal growth restriction, and perinatal death. A new diagnosis of diabetic nephropathy is made in pregnancy if persistent proteinuria >300 mg/day in the absence of urinary tract infection is detected prior to 20 weeks’ gestation. Creatinine clearance <50 mL/min is associated with increased incidence of severe preeclampsia and fetal loss. Treatment with an angiotensin-converting enzyme inhibitor (ACE-I) before pregnancy has a prolonged maternal renal protective effect and improves outcomes; however, ACE-I is teratogenic especially in the second half of pregnancy. Intensive maternal and fetal surveillance throughout gestation is required with renal disease but can result in fetal survival rates >90% (see Chapter 16).
Diabetic retinopathy is the most common vascular manifestation of diabetes and a principal cause of adult-onset blindness in the United States. Proliferative retinopathy is believed to be a consequence of persistent hyperglycemia and is directly related to the duration of disease. Pregnancy does not change the long-term prognosis, but an ophthalmologic evaluation is recommended in preconception counseling or at the time of the pregnancy diagnosis. Progressive disease may be treated with laser treatment during pregnancy.
The incidence of chronic hypertension is increased in patients with pregestational DM, especially those with nephropathy (see Chapter 14).
Preeclampsia is two to four times more common in pregestational diabetics. The risk is increased with longer duration of disease, nephropathy or retinopathy, and chronic
hypertension. Up to a third of women with long-standing diabetes (>20 years) will develop preeclampsia. Even in GDM, the risk of preeclampsia is 13% to 18%. The threshold for preeclampsia workup in these women should be very low (see Chapter 14).
Preterm labor and delivery may be three to four times higher in patients with DM. Worsening maternal medical status, poor glycemic control, noncompliance with diabetic management, and nonreassuring fetal status result in many iatrogenic preterm deliveries.
Corticosteroids should be administered as indicated when there is an increased risk for preterm delivery before 34 weeks. Additional insulin or oral agents may be required for 5 to 7 days after steroid administration.
Diabetics also have increased maternal risk for adverse obstetric outcomes including third- and fourth-degree perineal lacerations and wound infection. Additionally, they are at increased risk for intrauterine fetal demise, particularly after 40 weeks’ gestation.
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