Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is carbohydrate intolerance with onset or first recognition during pregnancy.^{1 - 2} This diagnosis is independent of insulin use or persistence of the condition after the pregnancy and does not apply to pregnant women with previously diagnosed diabetes. Gestational diabetes has been recognized for decades,³ but the potential significance of the condition, as well as criteria for screening and diagnosis, remain controversial. While there is also controversy as to the optimal monitoring and treatment strategy, it is apparent that even mild degrees of maternal hyperglycemia may result in fetal developmental defects.⁴

Gestational diabetes affects up to 14% of the pregnant population, approximately 135 000 women per year in the United States.⁵ Insulin resistance occurs to some degree in all pregnancies,⁶ but those women who are unable to compensate develop GDM. Women at greatest risk of developing GDM are those who are obese, older than 25 years, have a previous history of abnormal glucose metabolism or poor obstetric outcome, have first-degree relatives with diabetes, or are members of ethnic groups with high prevalences of diabetes. Fetal macrosomia, defined as a birth weight that is either greater than the 90th percentile for gestational age and sex or 2 SDs or more above the normal mean weight,⁴ may affect up to 40% of the offspring of pregnancies complicated by GDM.⁷ One study observed macrosomia in 17.9% of pregnancies complicated by GDM despite treatment compared with 5.6% of control subjects.⁸ Macrosomia is associated with increased risk of birth injuries,^{9 - 10} a direct result of the large size of the fetus.⁹ The risk of shoulder dystocia is increased by as much as 30-fold in diabetic pregnancies when the infants weigh more than 4500 g.¹⁰ When the obstetrician delivers the infant early to stop the accelerated in utero growth, complications related to prematurity, such as hyperbilirubinemia, hypocalcemia, and respiratory distress,¹¹ may result. The infant of a woman with GDM is at higher risk of developing obesity, impaired glucose tolerance (IGT), or diabetes at an early age.^{12 - 15} Infants whose fathers were diabetic are at a much lower risk for these complications, which appear to be the result of the hyperglycemic intrauterine environment superimposed on a genetic predisposition to diabetes.^{14 ,16}

To date there is no evidence-based study indicating that prevention and rigorous treatment of GDM minimize maternal or fetal complications.¹⁷ Given the current recommended standards of care,^{18 - 19} it is unlikely that such studies could ethically be done today. The risk of GDM recurring in subsequent pregnancies is reported to be 60% to 90%, depending on the woman's first trimester weight in those pregnancies.²⁰ In addition, after a pregnancy with GDM, the mother has an increased risk of developing type 2 diabetes. In 1 study, 7 to 10 years postpartum, 30% of women with GDM had developed diabetes or IGT.⁵

Table 1 shows the most commonly recommended screening and diagnostic criteria for GDM.^{1 - 2 ,21} Most of the world uses some modification of the criteria of the World Health Organization (WHO),² which is based on a glucose load of 75 g. This is the same test load and criteria for diagnosis of diabetes and IGT used in nonpregnant adults, with the recommendation that the diagnosis of gestational IGT should alert the physician to the high-risk nature of the pregnancy, and that gestational IGT should be treated in the same way as GDM.² These criteria make the diagnosis of GDM at the lowest glucose concentrations. Several studies have shown that the WHO criteria^{22 - 24} identify more adverse outcomes than other criteria.

In the United States, the criteria endorsed by the National Diabetes Data Group²¹ and the American Diabetes Association (ADA)¹ are in general use. At the 4th International Workshop Conference on Gestational Diabetes Mellitus, sponsored by the ADA, the glucose concentrations considered diagnostic of GDM were lowered.²⁵ This change was made more than a decade after these criteria were originally proposed. During the intervening years, data were generated suggesting that lower degrees of glucose intolerance were associated with increased risk of adverse perinatal outcome.¹ The recommendation to test all pregnant women was changed and women who appear to be at low risk for GDM will no longer be screened with a glucose load test. This recommendation includes women who are members of ethnic groups with a low prevalence of GDM who have no known diabetes in first-degree relatives, are younger than 25 years, were not obese before pregnancy, have no history of abnormal glucose metabolism, and no history of a poor obstetric outcome.¹ In an identified low-risk group, the risk of GDM is less than 2%.¹

There are 3 studies that suggest that the risk of fetal macrosomia increases as the maternal postprandial glucose increases.^{7 ,26 - 27} Keeping 1-hour postprandial blood glucose levels between 120 mg/dL (6.7 mmol/L) and 140 mg/dL (7.8 mmol/L) minimizes the risk of macrosomia.^{7 ,26} Although therapy begins with diet,²⁸ insulin therapy should be initiated when peak postprandial response exceeds this target.^{7 ,26 - 28}

Women with GDM have been known to deliver large newborns despite only modest elevations of glucose.²⁹ Continuous glucose monitoring system use has enabled the detection of previously missed postprandial blood glucose peaks in GDM.³⁰ We used the continuous glucose monitoring system in 10 women with GDM and discovered that, on average, the women spent 1.8 hours per day with glucose concentrations 120 mg/dL (6.7 mmol/L) or greater. In these women, the continuous glucose monitoring system has revealed high postprandial blood glucose levels, which were previously unrecognized by intermittent fingerstick evaluation.³⁰

Diabetic fetopathy, which is a result of maternal postprandial hyperglycemia, can be minimized when the peak postprandial response is blunted.^{7 ,26 - 27} This is best accomplished by carbohydrate restriction.³¹ The optimal dietary prescription provides the caloric and nutrient needs to sustain pregnancy but does not cause postprandial hyperglycemia. To date, there are no randomized controlled trials specifically focused on the development of an optimal diet for women with GDM; therefore, the standard ADA recommendations were adopted. The ADA's diet for nonpregnant persons suggests that meal plans could have up to 60% carbohydrate composition. Instituting this high-carbohydrate diet for GDM results in the need for insulin therapy in greater than 50% of women.²⁸ The National Academy of Sciences concluded that healthy obese pregnant women (>150% of ideal body weight) should only gain 6.75 kg; the subsequent infant birth weight was optimized if the maternal weight gain was minimized to less than 3 kg or if no weight was gained.³² No dietary recommendations were made in that report to either obese or lean pregnant women with diabetes. In animal studies of calorie-restricted diets, there is a decreased pancreatic β-cell mass and a tendency to develop diabetes in the offspring.³³ These observations are now being confirmed in humans as intrauterine growth retardation is associated with subsequent diabetes in populations with a high prevalence of malnutrition.³⁴

The only randomized trial that studied the impact of a calorie-restricted diet in GDM reported a comparison of 2400 vs 1200 kcal per day.³⁵ The 2 groups, after more than 6 weeks of assigned diet, differed significantly in mean glucose levels; ketonemia developed in the calorie-restricted group after 1 week on the 1200 kcal per day diet. A 33% carbohydrate-restricted diet was studied, resulting in normal range birth-weight infants and no maternal ketonemia.³⁶ The role of ketones in pregnancies complicated by diabetes has also remained controversial.^{37 - 38} Ketonuria develops in 10% to 20% of all pregnancies after an overnight fast and may protect the fetus from starvation. In addition, there may be a difference between the ketonemia produced from starvation and the ketonemia produced from poorly controlled diabetes. Two studies related neonatal complications to maternal ketones only in those mothers with ketonemia from hyperglycemia—not from starvation.^{39 - 40}

When dietary strategies fail to achieve the glucose goals for women with GDM, insulin therapy needs to be initiated.¹ There is only 1 report in the United States in which glyburide was used during pregnancies complicated by GDM.⁴¹ Until there is a multicenter clinical trial with more data, both the American College of Obstetricians and Gynecologists¹⁹ and the ADA do not recommend the use of oral hypoglycemic agents during pregnancy.¹⁸ The type of insulin chosen should be based on the specific glucose abnormalities; the frequency of monitoring and the criteria for initiation of insulin are controversial. A report shows that insulin does decrease the incidence of macrosomia, but does not decrease the cesarean delivery rate.⁴² Some obstetricians believe that women who require insulin therapy are at a higher risk for difficulties during delivery and liberalize criteria for cesarean delivery.⁴³ Others have shown that decreased incidence of macrosomia decreases the cesarean delivery rate if the indications for operative delivery are not changed for the woman with GDM who requires insulin.⁴²

The type of insulin and its dosage schedule should be prescribed to lower the baseline and postprandial glucose levels. The basal need may be given by using an insulin pump or multiple doses of isophane insulin (neutral protamine Hagedorn) (NPH).⁴² The meal–related hyperglycemia peaks should be treated with rapid-acting insulin. Insulin lispro, an analog of human insulin, possesses unique properties that facilitate lowering the postprandial glucose concentration and is a valuable therapeutic option in the treatment of GDM.⁴⁴ The rapid absorption of insulin lispro allows for a faster peak insulin concentration vs regular human insulin. This effect more closely mimics the physiological first-phase insulin release and results in lower postprandial glucose concentrations. In a study designed to assess the safety and efficacy of insulin lispro for the treatment of GDM, 42 women with GDM were randomized to either NPH and regular insulin or NPH and insulin lispro.⁴⁴ After 6 weeks of therapy, the lispro group had significantly lower postprandial glucose levels without an increase in hypoglycemic events. In addition, no increase in lispro-specific or insulin-specific antibodies was demonstrated in the lispro group. The studies of the safety and efficacy of insulin analogs for the treatment of women with type 1 and type 2 diabetes are still in progress.

Pregnancy is a time when metabolic changes are carefully regulated to provide optimum substrate to both mother and fetus. Subtle perturbations in metabolism during pregnancy can have implications not only for the mother and fetus but also for future generations. The challenge for the 21st century is to develop management strategies establishing a maternal-fetal environment that does not place the mother, infant, or subsequent generations at risk. Ideally, there will be resolution of the controversy over the best screening and treatment methods and triggers for initiation of treatment.