Diabetes Mellitus During Pregnancy

Isaac Blickstein, Sharon Perlman, Yenon Hazan, Chani Topf-Olivestone and Eric S. Shinwell

In the United States, depending on the diagnostic criteria used, 135,000 to 200,000 women develop gestational diabetes mellitus (GDM) annually, adding to the number of pregnant women already with either type 1 or type 2 diabetes.¹⁴ Of greater concern may be the need to address the fact that approximately 80% of these mothers develop type 2 diabetes and metabolic syndrome, both of which are associated with high mortality and morbidity. Furthermore, there is a threefold to fivefold higher risk for the development of metabolic syndrome and diabetes in the neonates of diabetic mothers (see Chapter 17). Diabetes mellitus (DM) that results from a relative or absolute lack of insulin is encountered frequently during pregnancy in two different situations: the first includes women who had diabetes mellitus before pregnancy, the so-called pre-gestational diabetes mellitus (pre-GDM) and the second comprises healthy pregnant women who develop glucose intolerance during pregnancy, the so-called gestational diabetes mellitus. The two entities are entirely distinct from both an obstetric and neonatal perspective. The former is a disease state and the pregnant woman might have complications that are associated with DM, such as nephropathy, neuropathy, or retinopathy. These manifestations represent the association of DM and small vessel injury, and as such may affect placental function and fetal growth. The latter, however, is frequently a transient pregnancy problem that might affect the growing fetus in the opposite way—by enhanced growth, macrosomia, difficult births (dystocia), and increased need for interventions during labor and delivery.

This chapter focuses mainly on GDM and its neonatal consequences.

Gestational Diabetes Mellitus

GDM is defined as glucose intolerance beginning or diagnosed for the first time during pregnancy.⁶ Gestational diabetes mellitus complicates approximately 7% of all pregnancies in the United States. Despite the great variations that exist among different populations and ethnicities, the prevalence of GDM is increasing in the United States, probably secondary to increasing rates of maternal overweight and overt obesity.

Screening and Diagnosis

Screening and diagnosing GDM have a long history of controversy, mainly because of significant questions regarding the implications on health care costs, the effect on obstetric interventions, and whether identification and treatment of GDM will improve maternal and perinatal outcomes. In 2001, the American College of Obstetricians and Gynecologists (ACOG) recommended that all pregnant women should be screened for GDM, whether by patient history, clinical risk factors, or with a glucose challenge test.⁶ The latter comprises a “two step” method consisting of a 50-g, 1-hour glucose challenge test (GCT), while relying on a 100-g, 3-hour oral glucose tolerance test (OGTT) for definitive diagnosis. However, in 2003, the US Preventive Services Task Force (USPSTF) and the Cochrane Collaboration found insufficient evidence to recommend for or against screening for GDM, similar to the conclusion reached in 2008, namely, that insufficient evidence exists to balance between the benefits and harms of screening for gestational diabetes.²¹ In the same year, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Cooperative Group published the results of a large, multicenter observational study designed to examine the relationship between maternal hyperglycemia less severe than overt GDM and adverse pregnancy outcome.^8,17 This study clearly demonstrated a relationship between increased maternal blood glucose and birth weight, cord blood C-peptide (a measure for intrauterine fetal hyperinsulinemia), neonatal hypoglycemia, and delivery by cesarean section.

Toward the end of the last decade, the International Association of Diabetes in Pregnancy Study Group recommended a simplified “one step” approach to the screening and diagnosis of GDM with a 75-g, 2-hour glucose tolerance test.¹⁵ Although implementation of these guidelines would presumably double the number of patients diagnosed with GDM, no evidence exists that this will lead to clinically significant improvement in maternal and neonatal outcomes. Regardless of these reservations, universal screening for GDM was adopted by more than 90% of practices.⁶

In the sequential “two step” testing, a 50-g GCT is performed in pregnant women between 24 and 28 weeks’ gestation unless a high risk for developing GDM exists (glycosuria, diabetes in first-degree relative, history of glucose intolerance, previous GDM, marked obesity, and previous infant with macrosomia). At-risk women should be screened by the 50-g GCT at their first prenatal visit. Screening cutoff values are 130 mg/dL (7.20 mmol/L; 90% sensitivity) or 140 mg/dL (7.75 mmol/L; 80% sensitivity). Random or fasting glucose measurement is not recommended for screening because of poor specificity.

In women who screen positive, a 100-g 3-hour OGTT is used to diagnose GDM. Gestational diabetes is diagnosed if two or more plasma glucose measurements are abnormal. The World Health Organization and the American Diabetes Association recommend simultaneous screening and diagnosis using a 75-g OGTT (Table 19-1).

TABLE 19-1

Diagnostic Glucose Values for Gestational Diabetes

Diagnostic Test	Fasting mg/L (mmol/L)	First Hour mg/L (mmol/L)	Second Hour mg/L (mmol/L)	Third Hour mg/L (mmol/L)
100-g OGTT Carpenter and Coustan*³	95 (5.25)	180 (10.0)	155 (8.6)	140 (7.75)
75-g OGTT World Health Organization^†	126 (7.0)	—	140 (7.75)	—
75-g OGTT American Diabetes Association*	95 (5.25)	180 (10.0)	155 (8.6)	—

^*Two or more abnormal values.

^†One or more abnormal value.

From American College of Obstetricians and Gynecologists. Gestational Diabetes: ACOG practice bulletin No. 30. Obstet Gynecol. 2001;98:525-538.

The interested reader will find more information about the controversial diagnosis of GDM elsewhere.¹⁶

Antenatal Management

Despite uncertainty regarding the clinical value of treating GDM, recent data strongly suggest that treatment may reduce adverse maternal and neonatal outcomes. The Australian Carbohydrate Intolerance Study in Pregnant Women randomized women to receive either routine care or treatment for GDM.⁴ Primary fetal outcomes included death, shoulder dystocia and its consequences such as bone fracture, and nerve palsy. Primary maternal outcomes were induction of labor and cesarean delivery. Infants of women in the treatment group had significantly fewer perinatal complications (RR 0.33; 95% CI 0.14, 0.75). There were more labor inductions in the treatment group (RR 1.36; 95% CI 1.15, 1.62), but the number of cesarean deliveries was similar in both groups. Further evidence of possible adverse effects associated with even mild maternal hyperglycemia comes from the HAPO trial.^8,15 The results of this trial point to a linear correlation between increasing maternal glucose levels and increasing birth weight, primary cesarean delivery, fetal C peptide levels, and neonatal hypoglycemia.

Most clinicians use glucose targets as defined by the Fifth International Workshop-Conference on Gestational Diabetes Mellitus (Table 19-2). Most authorities recommend measurement of fasting glucose combined with 1- or 2-hour postprandial testing.

TABLE 19-2

Treatment Targets for Gestational Diabetes Mellitus

	Fasting mg/L (mmol/L)	First Hour Postprandial mg/L (mmol/L)	Second Hour Postprandial mg/L (mmol/L)
Glucose levels	<96 (5.35)	<140 (7.75)	120-127 (6.65-7.05)

First-line therapy for women with gestational diabetes is nutritional and lifestyle modification (the so-called GDM-A1). Although medical nutritional therapy and exercise are safe, practical, and inexpensive interventions, their impact on patient outcomes has not been conclusively demonstrated in large randomized controlled trials.

In women with diabetes receiving preconception care and achieving established levels of glycemic control, the anomaly rate is similar to that of the general population. Jensen ¹² compared the risk of serious adverse pregnancy outcome at different glycosylated hemoglobin (HbA1C) levels with the background population. The risk was significantly higher when periconceptional HbA1C exceeded 6.9%, and the risk tended to increase gradually with increasing HbA1C, so that women with HbA1C exceeding 10.4% had a very high risk (16%). Perinatal mortality was increased even at HbA1C less than 6.9%.¹²

It is believed that GDM does not carry an increased risk of congenital anomalies because the hyperglycemia develops after embryonal organogenesis and the fetus is not exposed to high levels of glucose, ketones, and other metabolites involved in the pathophysiology of malformations in pre-GDM. Women presenting with presumable pre-GDM (glycosylated hemoglobin [HbA1C] levels greater than 9%, fasting glucose levels greater than 120 mg/dL; GDM diagnosed during the first trimester) should be offered a detailed sonographic anomaly scan for detection of fetal anatomical malformations.²⁵ Special attention should be focused on the cardiovascular, neural tube, gastrointestinal, urinary, and skeletal systems. Caudal agenesis is a specific malformation, seen predominantly (300- to 400-fold greater) in insulin-dependent diabetic pregnancies. Although the detection rate of fetal malformations has its own limitations, the benefits of ultrasonography should be discussed with all patients with GDM. Box 19-1 lists the major malformations encountered in pre-GDM pregnancies.

Box 19-1 Major Congenital Malformations in Infants of Diabetic Mothers