The fetal and maternal consequences of GDM

The United States has the highest known incidence of GDM in the world, with as many as 7%, or 200,000, of pregnancies diagnosed with GDM each year. There is an accompanying high incidence of maternal and fetal morbidity associated with GDM, which is discussed below.

Fetal consequences

Uncontrolled maternal GDM exposes the fetus to an abnormal glucose load, leading to a compensatory increase in fetal insulin secretion. The resulting hyperinsulinemia often leads to excess fetal growth, and these large-for-gestational-age (LGA) fetuses face a significantly increased risk for morbidity at the time of vaginal birth, such as shoulder dystocia, brachial plexus injury, and newborn asphyxia. Consequently, most obstetricians prefer to deliver LGA infants via cesarean section. Fetuses exposed to a high intrauterine glucose environment also have elevated risks for a number of other complications upon delivery, including neonatal respiratory distress syndrome, cardiomyopathy, hypoglycemia, hypocalcemia, hypomagnesemia, polycythemia, and hyperviscosity.

In 2008, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, which followed the birth outcomes of approximately 25,000 pregnant women at 15 centers, reported that subclinical hyperglycemia was independently associated with LGA births and increased cord plasma serum C-peptide levels. The HAPO study also found weaker, but still significant, associations with neonatal hypoglycemia and primary cesarean delivery. Other investigators have reported that children born to mothers with GDM have nearly double the risk of developing childhood obesity and/or metabolic syndrome compared children born to nondiabetic mothers.

Fetal consequences

Uncontrolled maternal GDM exposes the fetus to an abnormal glucose load, leading to a compensatory increase in fetal insulin secretion. The resulting hyperinsulinemia often leads to excess fetal growth, and these large-for-gestational-age (LGA) fetuses face a significantly increased risk for morbidity at the time of vaginal birth, such as shoulder dystocia, brachial plexus injury, and newborn asphyxia. Consequently, most obstetricians prefer to deliver LGA infants via cesarean section. Fetuses exposed to a high intrauterine glucose environment also have elevated risks for a number of other complications upon delivery, including neonatal respiratory distress syndrome, cardiomyopathy, hypoglycemia, hypocalcemia, hypomagnesemia, polycythemia, and hyperviscosity.

In 2008, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, which followed the birth outcomes of approximately 25,000 pregnant women at 15 centers, reported that subclinical hyperglycemia was independently associated with LGA births and increased cord plasma serum C-peptide levels. The HAPO study also found weaker, but still significant, associations with neonatal hypoglycemia and primary cesarean delivery. Other investigators have reported that children born to mothers with GDM have nearly double the risk of developing childhood obesity and/or metabolic syndrome compared children born to nondiabetic mothers.

Maternal consequences

A number of studies also have shown that GDM can have adverse health consequences for the mother. Indeed, women with a history of GDM and obesity have a greater risk of developing metabolic syndrome than mothers with no such history. GDM also has been found to be a leading risk factor for women who subsequently develop hypertension, type 2 diabetes, and obesity.

Mechanisms

How GDM causes maternal and fetal morbidities is still unclear. Research suggests, however, that maternal gestational hyperglycemia and subsequent fetal hyperinsulinemia may predispose offspring to increased adiposity, impaired glucose tolerance, hyperinsulinemia, and insulin resistance. Women with GDM also have been shown to have fewer circulating progenitor cells at 24-32 weeks’ gestation and 1-2 days postpartum compared to controls. Because the normal physiologic increase in circulating progenitor cells during pregnancy is impaired in women with GDM, it is believe that this impairment may contribute to endothelial dysfunction and GDM-associated morbidities in mothers and infants. Ethnicity and vitamin D deficiency also have been shown to be associated with an increased risk for GDM-related morbidities. In addition, several recent studies have suggested that maternal pregravid body mass index is associated with adverse maternal and fetal outcomes independent of diabetes or elevated plasma glucose concentrations.

The evolution of a diagnostic controversy

Since the 1970s, the standard test for diagnosing GDM in the United States has been a 2-step screening approach, which uses a 50-g glucose challenge test (GCT) followed by a 100-g, 3-hour oral glucose tolerance test (OGTT). The current screening threshold for GDM in the United States is ≥140 mg/dL on the 50-g, 1-hour oral GCT. Those who screen positive are given a 100-g oral glucose load, and their plasma glucose concentration typically is measured 2 or 3 hours later. GDM is officially diagnosed with a positive result on ≥2 OGTTs. The current diagnostic thresholds for the OGTT are: ≥180 mg/dL (1 hour); ≥155 mg/dL (2 hour); and ≥140 mg/dL (3 hour).

These thresholds are based on landmark work by O’Sullivan and Mahan and O’Sullivan et al in the late 1960s and early 1970s and, subsequently, Carpenter and Coustan and Coustan et al. Outside the United States, however, the most common strategy for diagnosing GDM for many years has utilized a 1-step, 75-g OGTT. This approach, which holds that a single positive OGTT is diagnostic of GDM, was endorsed by the World Health Organization in 1999.

As early as the 1980s, based on their observations of adverse birth outcomes among women with subclinical hyperglycemia during pregnancy, Carpenter and Coustan and Coustan et al began suggesting that thresholds for GDM diagnosis should be set below the O’Sullivan and Mahan and O’Sullivan et al thresholds. More recently, others have proposed that the glucose tolerance test (step 1) be eliminated and that GDM diagnosis should be universally based on a single abnormal value on the 1-step, 75-g OGTT.

The previously mentioned HAPO study followed up on these and other observations by utilizing the 1-step, 75-g OGTT to diagnose GDM in a large cohort of pregnant women. The HAPO study identified a strong, continuous association between adverse birth outcomes and maternal glucose concentrations below those typically diagnostic of diabetes. Based on these findings, in 2010, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommended changing the current GDM screening method used in the United States to the 1-step, 75-g OGTT and lowering plasma glucose thresholds for the diagnosis of GDM: fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose ≥180 mg/dL; and 2-hour plasma glucose ≥152 mg/dL. The IADPSG recommendations recently were endorsed by the American Diabetes Association (ADA) and are currently under review by other organizations in the United States.

A key argument for changing the current diagnostic guidelines for GDM in the United States is that a single diagnostic test–by eliminating the screening phase–will be more convenient for the provider and the patient. Furthermore, because it is more user-friendly, it is argued that the 1-step diagnostic test also will be much easier to administer and, thus, the earlier diagnosis and treatment of GDM will lead to more consistent care, better organized GDM research, and, ultimately, better outcomes for mothers and their babies.

Several recent studies suggest that the lower diagnostic threshold will result in medical costs savings. For example, Ohno et al investigated the cost-effectiveness of treating mild GDM and found, overall, that it is cost-effective in terms of improving maternal and neonatal outcomes including decreased rates of preeclampsia, cesarean sections, macrosomia, shoulder dystocia, permanent and transient brachial plexus injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admissions. A follow-up study by the same group found that screening pregnant women at 24-28 weeks’ gestational age under the new IADPSG guidelines with the 2-hour OGTT is cost-effective in improving maternal and neonatal outcomes but noted that questions about how the health care system will provide expanded care to this group of women will need to be examined.

Indeed, there are those who argue that implementing the IADPSG recommendations will have major adverse consequences for an already strained US health care workforce. It has been estimated that lowering the diagnostic plasma glucose thresholds, as recommended by the IADPSG, will increase the number of women diagnosed with GDM each year by almost 3-fold vs the previous ADA recommended criteria (37.7% vs 12.9%). Consequently, the US health care system will be challenged with the addition of potentially tens of thousands of women newly diagnosed with GDM at a time when recent health care reforms already are increasing the demand for physician and nursing services.

Already, the critical shortage of primary care clinicians in this country is being called a “national disaster” by some in the public health community. Demand for physician services will increase by an estimated 25% during the next decade, and there will be a national shortage of >400,000 nurses over that same period.

Research suggests that adopting IADPSG recommendations will entail not only a significant increase in the number of primary health care providers but also in their workload, as they may have to provide more intensive preconception and follow-up postnatal care for this group of patients. Werner et al, for example, analyzed the cost-effectiveness of 3 GDM diagnostic strategies: (1) no screening; (2) current screening practice (1-hour, 50-g GCT between 24-28 weeks, followed by 3-hour, 100-g glucose tolerance test when indicated); or (3) the screening practice proposed by the IADPSG. They found that IADPSG recommendations are cost-effective, but only when women diagnosed with GDM received additional prenatal monitoring to mitigate the risks of preeclampsia, shoulder dystocia, and birth injury. Postdelivery counseling and behavior modification to reduce patients’ future diabetes risks also were key to the cost-effectiveness of the lower diagnostic threshold in this study.

Others have expressed concerns that adopting the new diagnostic criteria for GDM will unnecessarily label many women with mild levels of hyperglycemia as being diabetic and at high risk for adverse consequences, especially if diagnosis is based on a single test. Kalter-Leibovici et al analyzed data from the Israeli HAPO study participants (n = 3345) to study the implications of implementing the IADPSG recommendations for screening and diagnosing GDM in Israel. They calculated adverse outcome rates and compared them for women who were positive according to: (1) IADPSG criteria; (2) IADPSG criteria with risk stratification; or (3) screening with body mass index or fasting plasma glucose. They found that one third of IADPSG-positive women were at low risk for adverse outcomes and could be managed less intensively. They concluded that implementing IADPSG recommendations will “substantially increase GDM diagnosis” and that risk stratification in IADPSG-positive women may be needed to reduce overtreatment.

Furthermore, there are medicolegal issues that would be created by the new diagnostic threshold. For example, it may result in an excessive rate of cesarean deliveries, because patients with an estimated fetal weight of 4000 g and GDM are currently offered an elective cesarean delivery, and such deliveries are associated with a number of maternal and fetal complications, including infection, excess bleeding, bowel problems, more neonatal intensive care admissions, and even death. Thus, if the cesarean delivery rate increases due to a GDM diagnostic change, there may be significantly more maternal and fetal complications, which may offset the gains made by the increased diagnosis of this condition. There also is the economic issue of the medical expenditures, monitoring, and treatment expected from obstetricians when new diagnoses are made.

Cundy has further argued that, “the concentration on mild degrees of hyperglycaemia may well be misplaced, as most of the outcomes usually attributed to gestational diabetes are more strongly associated with maternal obesity and weight gain in pregnancy. The new testing procedure (with a GDM diagnosis based on a single plasma glucose measurement) will inevitably be imprecise. Given the many reservations about the new criteria, an urgent but dispassionate debate is required on the risks, costs, and benefits of their introduction.”