Diabetes Mellitus
Aviva Lee-Parritz
John P. Cloherty
I. DIABETES AND PREGNANCY OUTCOME.
Improved management of diabetes mellitus and advances in obstetrics, such as ultrasonography and measurement of fetal lung maturity (FLM), have reduced the incidence of adverse perinatal outcome in infants of diabetic mothers (IDMs). With appropriate management, women with good glycemic control and minimal microvascular disease can expect pregnancy outcomes comparable to the general population. Women with advanced microvascular disease, such as hypertension, nephropathy, and retinopathy, have a 25% risk of preterm delivery because of worsening maternal condition or preeclampsia. Pregnancy does not have a significant impact on the progression of diabetes. In women who begin pregnancy with microvascular disease, diabetes often worsens, but in most, the disease return to baseline. Preconception glucose control may reduce the rate of complications to as low as that seen in the general population.
II. DIABETES IN PREGNANCY
General principles
Definition. Diabetes that antedates the pregnancy can be associated with adverse fetal and maternal outcomes. The most important complication is diabetic embryopathy resulting in congenital anomalies. Congenital anomalies are associated with 50% of perinatal deaths among women with diabetes compared to 25% among nondiabetic women. The risk of congenital anomalies is related to the glycemic profile at the time of conception. Women with type 1 and type 2 diabetes are at significantly increased risk for hypertensive disorders, such as preeclampsia, which is potentially deleterious to both maternal and fetal wellbeing. The White classification is a risk stratification profile based on length of disease and presence of vascular complications (see Table 2.1). Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance of variable severity first diagnosed during pregnancy, and it affects 3% to 5% of pregnancies.
Epidemiology. Approximately 3% to 5% of patients with GDM actually have underlying type 1 or type 2 diabetes, but pregnancy is the first opportunity for testing. Risk factors for GDM include advanced maternal age, multifetal gestation, increased body mass index, and strong family history of diabetes. Certain ethnic groups, such as Native Americans, Southeast Asians, and African Americans, have an increased risk of developing GDM.
Pathophysiology for diabetes antedating pregnancy. In the first half of pregnancy, as a result of nausea and vomiting, hypoglycemia can be as much of a problem as hyperglycemia. Hypoglycemia, followed by hyperglycemia from counter-regulatory hormones, may complicate glucose control. Maternal hyperglycemia leads to fetal hyperglycemia and fetal hyperinsulinemia, which results in fetal overgrowth. Gastroparesis from long-standing diabetes may be a factor as well. There does not appear to be a direct relation between hypoglycemia alone and adverse perinatal outcome. Throughout pregnancy, insulin requirements increase because of the increasing production of placental hormones that antagonize the action of insulin. This is most prominent in the mid—third trimester and requires intensive blood glucose monitoring and frequent adjustment of insulin dosage.
Table 2.1 White Classification of Maternal Diabetes (Revised)
Gestational diabetes (GD):
Diabetes not known to be present before pregnancy
Abnormal glucose tolerance test in pregnancy
GD diet
Euglycemia maintained by diet alone
GD insulin
Diet alone insufficient; insulin required
Class A:
Chemical diabetes; glucose intolerance before pregnancy; treated by diet alone; rarely seen
Prediabetes; history of large babies >4 kg or unexplained stillbirths after 28 weeks
Class B:
Insulin-dependent; onset after 20 years of age; duration <10 years
Class C:
C1: Onset at 10-19 years of age
C2: Duration 10-19 years
Class D:
D1: Onset before 10 years of age
D2: Duration 20 years
D3: Calcification of vessels of the leg (macrovascular disease)
D4: Benign retinopathy (microvascular disease)
D5: Hypertension (not preeclampsia)
Class F:
Nephropathy with >500 mg/day of proteinuria
Class R:
Proliferative retinopathy or vitreous hemorrhage
Class RF:
Criteria for both classes R and F coexist
Class G:
Many reproductive failures
Class H:
Clinical evidence of arteriosclerotic heart disease
Class T:
Prior renal transplantation
Note: All classes below A require insulin. Classes R, F, RF, H, and T have no criteria for age of onset or duration of disease but usually occur in long-term diabetes. Modified from Hare JW. Gestational diabetes. In: Diabetes complicating pregnancy: The Joslin Clinic Method. New York: Alan R. Liss; 1989.
Complications of type 1 and type 2 diabetes during pregnancy
Differential diagnosis
Ketoacidosis is an uncommon complication during pregnancy. However, ketoacidosis carries a 50% risk of fetal death, especially if it occurs before the third trimester. Ketoacidosis can be present in the setting of even mild hyperglycemia (200 mg/dL) and should be excluded in every patient with type 1 diabetes who presents with hyperglycemia and symptoms such as nausea, vomiting, or abdominal pain.
Stillbirth remains an uncommon complication of diabetes in pregnancy. It is most often associated with poor glycemic control, fetal anomalies, severe vasculopathy, and intrauterine growth restriction (IUGR), as well as severe preeclampsia. Shoulder dystocia that cannot be resolved can also result in fetal death.
Polyhydramnios is not an uncommon finding in pregnancies complicated by diabetes. It may be secondary to osmotic diuresis from fetal hyperglycemia. Careful ultrasonographic examination is required to rule out structural anomalies, such as esophageal atresia, as an etiology, when polyhydramnios is present.
Severe maternal vasculopathy, especially nephropathy and hypertension, is associated with uteroplacental insufficiency, which can result in IUGR, fetal intolerance of labor, and neonatal complications.
III. MANAGEMENT OF DIABETES DURING PREGNANCY
General principles for type 1 or type 2 diabetes. Management of type 1 or type 2 diabetes during pregnancy begins before conception. Tight glucose control is paramount during the periconceptional period and throughout pregnancy. Optimal glucose control requires coordinated care between endocrinologists, maternal—fetal medicine specialists, diabetes nurse educators, and nutritionists. Preconception glycemic control has been shown to decrease the risk of congenital anomalies to close to that of the general population. However, <30% of pregnancies are planned. Physicians should discuss pregnancy planning or recommend contraception for all diabetic women of childbearing age until glycemic control is optimized.
General principles for gestational diabetes. In the United States, most women are screened for GDM between 24 and 28 weeks’ gestation by a 50-g, 1-hour glucose challenge. A positive result of a blood glucose equal to or greater than 140 mg/dL is followed by a diagnostic 100-g, 3-hour oral glucose tolerance test (GTT). A positive test is defined as two or more elevated values on the GTT. There is a current movement to move to a single diagnostic test, consisting of a 75-g, 2-hour GTT, a method that is used uniformly outside of the United States. Uncontrolled GDM can lead to fetal macrosomia and concomitant risk of fetal injury at delivery. GDM shares many features with type 2 diabetes. Women diagnosed with GDM have a 60% lifetime risk of developing overt type 2 diabetes.
Testing (first trimester) for type 1 and type 2 diabetes
Measurement of glycosylated hemoglobin in the first trimester can give a risk assessment for congenital anomalies by reflecting ambient glucose concentrations during the period of organogenesis.
Accurate dating of the pregnancy is obtained by ultrasonography.
Ophthalmologic examination is mandatory, because retinopathy may progress because of the rapid normalization of glucose concentration in the first trimester. Women with retinopathy need periodic examinations throughout pregnancy, and they are candidates for laser photocoagulation as indicated.
Renal function is assessed by 24-hour urine collection for protein excretion and creatinine clearance. Patients with recent diagnosis of diabetes can have screening of renal function with urine microalbumin, followed by a 24-hour collection if abnormal.
Thyroid function should be evaluated.
Nuchal translucency and first-trimester serum screening. This is part of routine pregnancy care. It is especially important, as an abnormal nuchal translucency is also associated with structural abnormities, the risk of which is increased in this group of patients.
Testing (second trimester) for type 1 and type 2 diabetes
Maternal serum screening for neural tube defects is performed between 15 and 19 weeks’ gestation. Women with diabetes have a 10-fold increased risk of neural tube defects compared to the general population.
All patients undergo a thorough ultrasonographic survey, including fetal echocardiography for structural anomalies.
Women older than 35 years of age or with other risk factors for fetal aneuploidy are offered chorionic villus sampling or amniocentesis for karyotyping.
Testing (third trimester) for type 1 and type 2 diabetes, GDM
Ultrasonographic examinations are performed monthly through the third trimester for fetal growth measurement.
Weekly fetal surveillance using nonstress testing or biophysical profiles is implemented between 28 and 32 weeks’ gestation, depending on glycemic control and other complications (see Chap. 1).
Treatment for all types of glucose intolerance
Strict diabetic control is achieved with nutritional modification, exercise, and medications, with the traditional goals of fasting glucose concentration <95 mg/dL and postprandial values <140 mg/dL for 1 hour and 120 mg/dL for 2 hours. Recent data have suggested that in pregnant women, euglycemia may be even lower, with fasting glucose levels in the 60 mg/dL range and postmeal glucose levels <105 mg/dL. Insulin therapy has the longest record of accomplishment of perinatal safety. It has been demonstrated that human insulin analogs do not cross the placenta. More recently, the oral hypoglycemic agent glyburide has been shown to be effective in the management of GDM. Data are emerging that metformin may also be an alternative to achieve glycemic goals during pregnancy.
IV. MANAGEMENT OF LABOR AND DELIVERY FOR WOMEN WITH DIABETES
General principles. The risk of spontaneous preterm labor is not increased in patients with diabetes, although the risk of iatrogenic preterm delivery is increased for patients with microvascular disease as a result of IUGR, nonreassuring fetal testing, and maternal hypertension. Antenatal corticosteroids for induction of FLM should be employed for the usual obstetric indications. Corticosteroids can cause temporary hyperglycemia; therefore, patients may need to be managed
with continuous intravenous (IV) insulin infusions until the effect of the steroids wears off. Delivery is planned for 39 to 40 weeks, unless other pregnancy complications dictate earlier delivery. Elective delivery after 39 weeks does not require FLM testing. Nonemergent delivery before 39 weeks requires documentation of FLM testing using the lecithin-sphingomyelin (L/S) ratio greater than 3.5:1, positive Amniostat (phosphatidyglycerol present), saturated phosphatidylcholine (SPC) greater than 1,000 µg/dL, or mature FLM (see Table 2.2 and Fig. 2.1). Emergent delivery should be carried out without FLM testing. Route of delivery is determined by ultrasonography-estimated fetal weight, maternal and fetal conditions, and previous obstetric history. The ultrasonography-estimated weight at which an elective cesarean delivery is recommended is a controversial issue, with the American College of Obstetricians and Gynecologists recommending discussion of cesarean delivery at an estimated fetal weight of greater than 4,500 g due to the increased risk of shoulder dystocia.
Treatment. Blood glucose concentration is tightly controlled during labor and delivery. If an induction of labor is planned, patients are instructed to take onehalf of their usual basal insulin on the morning of induction. During spontaneous or induced labor, blood glucose concentration is measured every 1 to 2 hours. Blood glucose concentration higher than 120 to 140 mg/dL is treated with an infusion of IV short-acting insulin. IV insulin is very short acting, allowing for quick response to changes in glucose concentration. Active labor may also be associated with hypoglycemia, because the contracting uterus uses circulating metabolic fuels. Continuous fetal monitoring is mandatory during labor. Cesarean delivery is performed for obstetric indications. The risk of cesarean section for obstetric complications is approximately 50%. Patients with advanced microvascular disease
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