Research Gaps in Gestational Diabetes Mellitus: Executive Summary of an National Institute of Diabetes and Digestive and Kidney Workshop

Abstract

The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on research gaps in gestational diabetes mellitus (GDM) with a focus on 1) early pregnancy diagnosis and treatment and 2) pharmacologic treatment strategies. This manuscript summarizes the proceedings of the workshop. In early pregnancy, the appropriate diagnostic criteria for the diagnosis of GDM remain poorly defined, and an effect of early diagnosis and treatment on the risk of adverse outcomes has not been demonstrated. Despite many small randomized controlled trials of glucose-lowering medication treatment in GDM, our understanding of medication management of GDM is incomplete, as evidenced by discrepancies among professional society treatment guidelines. The comparative effectiveness of insulin, metformin, and glyburide remains uncertain, particularly with respect to long-term outcomes. Additional topics in need of further research identified by workshop participants included phenotypic heterogeneity in GDM and novel and individualized treatment approaches. Further research on these topics is likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children.

Introduction

Gestational diabetes mellitus (GDM), hyperglycemia first recognized in pregnancy, is a public health issue of global import. Its prevalence is increasing with the obesity epidemic and advancing age of motherhood. There has also been greater awareness of the risk associated with mild degrees of hyperglycemia in pregnancy since the Hyperglycemia and Adverse Pregnancy Outcomes Study (HAPO) demonstrated a linear relationship between adverse perinatal outcomes and increasing glucose levels at 24–28 weeks gestational age, without a clear inflection point (1).

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) convened the workshop “Research Gaps in Gestational Diabetes” to identify the major questions in this field. The workshop was held at the National Institutes of Health (NIH) in Bethesda, MD, August 2–3, 2017. NIDDK conveners and workshop co-chairs identified 1) early pregnancy diagnosis of GDM and 2) pharmacologic management of GDM as the two main topic areas for discussion. Participants were invited to give presentations in their areas of expertise, followed by participant discussion and proposal of other high-priority topics. This manuscript summarizes the proceedings of the workshop (Box 1).

Box 1. Research Gaps in GDM.

I. Early pregnancy diagnosis and treatment

A. Diagnostic criteria and definitions

B. Alternative markers for diagnosis

C. Effect of early diagnosis and treatment on outcomes

II. Pharmacologic management

A. Pharmacokinetics and placental transfer of oral glucose-lowering medications

B. Effects of glucose-lowering medications on perinatal outcomes

C. Effects of glucose-lowering medications on long-term outcomes

III. Additional gaps

A. Phenotypic heterogeneity

B. Novel and individualized treatment

Session I: Research Gaps in Early Diagnosis of GDM

The question of early diagnosis of GDM is pressing because women diagnosed with diabetes earlier in gestation, as compared to typical diagnosis at 24–28 weeks, may be more likely to have adverse outcomes and a need for insulin or other glucose-lowering medications (2, 3). In fact, women with GDM diagnosis prior to 12 weeks gestation may have similar pregnancy outcomes to women with preexisting or “overt” type 1 or type 2 diabetes (4). Hyperglycemia early in pregnancy may also result in unfavorable fetal metabolic imprinting (5). However, data showing benefit of early treatment of GDM are lacking: a 2014 United States Preventive Services Task Force review concluded that there was insufficient evidence to recommend for or against screening for GDM prior to 24 weeks given lack of evidence for effect on maternal or infant health outcomes (6). During the workshop, three key areas regarding early diagnosis and treatment in GDM were identified as priorities for further investigation: A) Diagnostic criteria and definitions; B) Alternative markers for diagnosis; and C) Effects of early diagnosis and treatment on outcomes.

IA. Diagnostic criteria and definitions

The conference used the Fifth International Workshop Conference on Gestational Diabetes Mellitus definition: glucose intolerance with onset or first recognition during pregnancy (7). Based on the initial studies of O’Sullivan and Mahan, GDM has been diagnosed primarily in the second and third trimesters (8). The criteria for the 2-step method (50 g glucose challenge test followed by the 100 g 3-hour oral glucose tolerance test (OGTT)) derived from the work of Carpenter and Coustan (9) are currently accepted by both the American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA), though ACOG also accepts the National Diabetes Data Group (NDDG) Criteria (10) rather than the old O’Sullivan and Mahan criteria. The HAPO Study also assessed glucose tolerance in late second and early third trimester, using the single step (75 g 2-hour OGTT), leading to the adoption of this approach by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) and World Health Organization. There continues to be extensive debate regarding the criteria used to make the diagnosis of GDM and whether the criteria used, which have been derived in late pregnancy, apply to early pregnancy. Moreover, there is interest in establishing diagnostic criteria for GDM in early pregnancy and determining whether early pregnancy GDM diagnosis and treatment could improve outcomes.

The physiologic changes in glucose metabolism across gestation have implications for early pregnancy diagnosis of GDM (7). In one of the few studies examining longitudinal changes in results of oral glucose tolerance tests (OGTTs) across trimesters of pregnancy, post-load glucose levels increased with each trimester (8). Continuous glucose monitoring (CGM) studies confirm the rise in mean glucose with advancing gestation: post-prandial glucose levels as well as duration of time per day spent above selected thresholds increase as pregnancy progresses (9). Some studies have shown that fasting glucose falls during the early first trimester of pregnancy, though this has not been a consistent finding, especially in women with pre-pregnancy BMI > 30 kg/m² (8, 10). These longitudinal changes in glucose metabolism complicate interpretation of glucose levels measured in early pregnancy for GDM diagnosis. Two crucial issues relevant to early vs. late diagnosis of GDM are whether glucose levels are already elevated in early pregnancy, which would allow early testing and diagnosis, and whether they rise more in women with GDM than in normal women, which would favor later testing and diagnosis.

The major professional organization guidelines differ on the definition of GDM in early pregnancy, with most applying the usual criteria regardless of the timing of detection of glucose intolerance. (11–17). Importantly, it is uncertain whether current diagnostic criteria are valid prior to 24 weeks. ACOG accepts either the 24-week Carpenter-Coustan or NDDG criteria applied to a 100 g oral glucose tolerance test (OGTT) in early pregnancy, but there are few data supporting this practice (13). The IADPSG recommends screening for “overt” diabetes in early pregnancy using American Diabetes Association (ADA) criteria for the diagnosis of type 1 or type 2 diabetes outside of pregnancy (11). When IADPSG criteria for GDM, rather than those for “overt” diabetes, are applied in early pregnancy, they may fail to detect metabolic abnormalities that can impact fetal development. In addition, early elevations in glucose levels may not portend persistent hyperglycemia (18). Indeed, studies have shown that diagnoses of GDM in early pregnancy were not always confirmed by 24–28 week testing (19, 20). In women with a diagnosis of GDM in early pregnancy, up to 60% may have a normal OGTT in later gestation because of several potential factors, including the glycemic physiology changes (7, 8, 10), the fetal glucose steal phenomenon (21), and the well-known poor reproducibility of oral glucose tolerance testing (22).

Finally, women may not present for prenatal care before 12 weeks gestation. Therefore, in practice, early diagnosis and treatment may include evaluation as late as 16 or 20 weeks gestation. This may be several weeks after the onset of maternal hyperglycemia which starts as early as 11 to 15 weeks.(23).

IB. Alternative Markers for Diagnosis

Given the poor reproducibility, cost, inconvenience, and diagnostic uncertainty of glucose tolerance testing in early pregnancy, there has been a search for alternate early pregnancy diagnostic markers of GDM. Hemoglobin A1c (HbA1c) is an obvious candidate, but this test would need to be validated against pregnancy outcomes, as would other glycemic measures. Many clinical centers perform an early pregnancy HbA1c to detect previously undiagnosed overt diabetes. When comparing HbA1c prior to 20 weeks with IADPSG criteria at 24 weeks, women with HbA1c in the 5.7–6.4% range have a 27–29% rate of GDM (24). There is also evidence that a HbA1c of >5.9% at >24 weeks is associated with 2.6–3.6-fold risks of large for gestational age (LGA), macrosomia, caesarean delivery and hypertensive disorders, but its predictive value is less earlier in gestation (25). Newer technologies that may be routine in several years, such as continuous glucose monitoring (CGM), could be tested for diagnostic use, perhaps with both degree and duration of hyperglycemia incorporated into the definition of GDM.

Beyond glucose, other biomarkers may be useful in GDM diagnosis in early pregnancy. For example, potential biomarkers tested later in pregnancy include plasma glycated CD59 (pGCD59) which had high sensitivity and specificity for diagnosis of GDM when measured at 24–28 weeks and was associated with large for gestational age (LGA) birth weight (26). Another is 1,5-anhydroglucitol, which, when measured in the 3^rd trimester, also predicted macrosomia with similar predictive value as HbA1c in a study of 82 women with type 1 DM (27).

IC. Effect of Early Diagnosis and Treatment on Outcomes

Participants emphasized that more information is needed about the association of early pregnancy glycemia with pregnancy outcomes. In most GDM prevention trials, in which the intervention usually takes place in early pregnancy or prior to pregnancy, the primary outcome is the diagnosis of GDM by OGTT at 24–28 weeks; less emphasis has been placed on clinical outcomes such as fetal overgrowth (28–32). Since maternal and fetal adverse outcomes are directly related to the degree of hyperglycemia (1, 33, 34), capturing the richness of continuous data relating dysglycemia to adverse outcomes was felt to be of paramount importance.

ID. Research priorities in early diagnosis and treatment

There are many ongoing studies of early GDM diagnosis and treatment GDM; four of these studies were reviewed by the participants to frame the discussion of research priorities (Table 1). Among these studies, there is variation in the criteria by and gestational age at which “early” GDM is diagnosed. All of the studies are examining the effects of early GDM treatment on the risk of maternal or neonatal perinatal outcomes.

Table 1.

Select Ongoing Studies of Early Diagnosis and/or Treatment of GDM

Study Name	Principal Investigator/Institution	Target Sample Size	Key Inclusion Criteria	Intervention	Primary Outcome(s)
Early Screen and Treatment for Gestational Diabetes NCT02377531	Alejandro R. Rodriguez/University of South Florida	1020	BMI†>30 kg/m2, 12–18 weeks gestation	2-step screening* and diagnosis at 12–18 weeks gestation followed by treatment if diagnosed	Composite perinatal morbidity
Pre-diabetes: can early INTervention improve pregnancy Outcome (PINTO) ACTRN12615000904572	Ruth Hughes/University of Otago	150	HbA1c+ at <14 weeks gestation of 5.9–6.4%	Blood sugar monitoring beginning at <14 weeks gestation and medication as required	Preeclampsia; neonatal composite outcome
Early Gestational Diabetes Screening in the Gravid Obese Woman (EGGO) NCT01864564	Lori M. Harper/University of Alabama at Birmingham	960	BMI†≥30 kg/m2, 14–18 weeks gestation, no prior cesarean-section	2-step screening* at 14–18 weeks gestation followed by treatment if diagnosed	Composite perinatal outcome
Treatment of Booking GDM (TOBOGM) ACTRN12616000924459	David Simmons/Western Sydney University	800	GDM by IADPSG criteria at <20 weeks gestation	Delayed GDM treatment (24–28 weeks); blinded	Pregnancy-induced hypertension; neonatal composite outcome

^†BMI=body mass index.

⁺HbA1c=hemoglobin A1c *2-step screening: 50 gram non-fasting glucose load screening test followed by a 100 gram oral glucose tolerance test for diagnosis. (1)

Studying early (<20 weeks) versus late (24–28 week) diagnosis and treatment of GDM was of broad interest. Participants felt that emphasis should be placed on whether early screening, diagnosis, and treatment reduce short and long term adverse perinatal outcomes rather than just the subsequent diagnosis of GDM. There was some discussion of ethical concerns about not treating a diagnosis of GDM in early pregnancy in the context of a research study, as it was felt that the detrimental effects of hyperglycemia on fetal development are well known. However, given the lack of evidence supporting benefits of early treatment compared to the current standard of care (treatment later in pregnancy), participants felt that this issue should be addressed in a prospective manner rather than using retrospective analyses which could be subject to bias.

Session II: Research Gaps in Pharmacologic Management of Gestational Diabetes

One clear sign that there are research gaps in the appropriate pharmacologic management of GDM is the variation among professional organization guidelines (Table 2). The 2018 ACOG Practice Bulletin recommends insulin as first-line treatment in women with GDM who require a glucose-lowering medication; ACOG considers metformin to be second-line in those who decline insulin, and both metformin and insulin are preferred to glyburide (12, 35). The 2018 Society for Maternal-Fetal Medicine statement on treatment of GDM states that both metformin and insulin are reasonable first line treatments for GDM when diet and physical activity are not sufficient to achieve adequate glucose control (36). The 2018 American Diabetes Association (ADA) Standards of Care consider insulin to be first-line, but based on trans-placental fetal exposure to metformin being greater than glyburide, the ADA does not suggest a preference of one oral agent over the other (37). These conflicting recent guidelines highlight the need for further research comparing the effectiveness of insulin and oral agents in GDM.

Table 2.

2018 Pharmacologic Treatment Guidelines for Gestational Diabetes Mellitus Not Responding to Nutrition Therapy

	Preferred and/or first choice	Alternative
American College of Obstetricians and Gynecologists (10)	Insulin	Metformin
American Diabetes Association (40)	Insulin	Metformin or Glyburide
The Society for Maternal Fetal Medicine (39)	Insulin or Metformin	Glyburide

As reflected in the guidelines, insulin is well accepted as a pharmacotherapy for GDM; most of the controversy regarding pharmacologic management relates to the use of oral glucose-lowering medications. Cochrane Reviews on this subject suggest that due to imprecision, risk of bias, and inconsistencies among studies, it is difficult to determine the relative benefits and risks of insulin versus glyburide versus metformin (38, 39). At the same time, use of oral glucose-lowering medications has become widespread (40, 41). For example, glyburide use in the treatment of GDM increased dramatically between 2000 and 2011 in the US, with glyburide use becoming more prevalent than insulin use in 2007 (41, 42).

Workshop participants identified three key areas of uncertainty with respect to pharmacologic treatment of GDM: A) Pharmacokinetics and placental transfer of oral glucose-lowering medications, B) Effects of glucose-lowering medications on perinatal outcomes, and C) Effects of glucose-lowering medications on long-term outcomes.

IIA. Pharmacokinetics and placental transfer of oral glucose-lowering medications

The pharmacokinetics of commonly used oral glucose-lowering medications in pregnancy were reviewed. Glyburide, a drug commonly used in the U.S. for treatment of hyperglycemia in GDM, has different pharmacokinetics in pregnancy than in the non-pregnant state. The dose-response relationship in pregnancy is not clear, with small studies suggesting the possibility of a ceiling effect on insulin secretion. Further, glyburide is often taken before bedtime or immediately before a meal; neither approach is rational since its peak effect on insulin secretion occurs 2–4 hours after dosing (43, 44). Though an older literature using insensitive assays of plasma glyburide suggested trivial placental transfer, more recent studies using sensitive assays reveal significant maternal-to-fetal transfer, which may at times be limited by the combined effects of placental metabolism of glyburide and fetal-to-maternal efflux transporters (45, 46). Recent data suggest that glyburide may also increase the expression of the primary placental glucose transporter, GLUT-1 (47), perhaps contributing to fetal overgrowth by increased nutrient transport.

The National Institute of Child Health and Human Development (NICHD) Obstetric-Fetal Pharmacology Research Unit (OPRU) Network performed a pharmacokinetic-pharmacodynamic (PK-PD) study of glyburide and found that glyburide concentrations were approximately 50% lower in women with GDM compared to non-pregnant women with T2DM for any given dose of glyburide (48). Although higher doses have neither been tested nor recommended in pregnancy, this reduction in glyburide levels during pregnancy suggests the need to explore different glyburide administration and dosing strategies. One possibility is that dosing of glyburide, as well as that of other medications, could be individualized, a strategy that is currently being tested (NCT03029702).

Metformin has dose-dependent absorption and bioavailability. The extended release formulation has not been studied in pregnancy. Metformin is transferred to the fetus with high fetal-to-maternal ratios; there are likely effects of a slowly equilibrating fetal compartment. The OPRU real-world PK study of serum levels in women taking metformin found that metformin clearance increased in mid-to late-pregnancy with increasing GFR, with a wide range of metformin concentrations in umbilical cord plasma and in breast milk post-partum (49). Results have not yet been reported for a completed PK-PD study comparing metformin, glyburide, and their combination in GDM (NCT01329016). Metformin has a wide array of cellular effects including growth inhibition, suppression of mitochondrial respiration, epigenetic modifications on gene expression, potential fetal nutrient restriction, and possibly alteration of postnatal gluconeogenic responses. The fetus (but not the embryo) expresses metformin transporters. These properties raise important questions about developmental programming of metabolic disease in offspring (50).

IIB. Effects of glucose-lowering medications on perinatal outcomes

A meta-analysis of 15 randomized controlled trials of drug treatment in GDM considered 14 primary and 16 secondary outcomes in 2,509 subjects (51). Compared to insulin, treatment with glyburide resulted in higher birthweight and more macrosomia and neonatal hypoglycemia. Compared to insulin, treatment with metformin resulted in less maternal weight gain, lower gestational age at delivery, and a reduction in neonatal hypoglycemia that approached statistical significance. In comparison with glyburide, treatment with metformin was associated with less maternal weight gain, macrosomia, LGA, and lower birth weight, but preterm birth was increased. However, treatment failure was higher for metformin than glyburide. A recent study (N=104) of glyburide vs. metformin and their combination, not included in the meta-analyses, showed relatively high rates of metformin intolerance, but the combination of these two oral medications reduced the need for insulin to 11% (52). One study has tested acarbose, but 42% of acarbose-treated participants ultimately required insulin; furthermore, use of acarbose is limited by gastrointestinal side effects (53–55).

In summary, glyburide appears to have comparable glycemic efficacy to insulin, but there is concern for higher rates of adverse perinatal outcomes and uncertainty regarding the optimal dosing strategy in pregnancy (56). Metformin may improve some perinatal outcomes compared to insulin, while possibly increasing the risk of prematurity, but this has not been consistent in all studies (51, 57, 58). Meta-analyses comparing oral agents with insulin for the treatment of GDM are limited by the methodology of the source trials. Specifically, the diagnostic criteria for GDM and the target glucose levels are often unclear and not uniform. The severity of hyperglycemia is variable and influences the effectiveness of a given glucose-lowering medication. Most of the trials have been small, with wide confidence intervals around the effect estimates; workshop participants also questioned whether sample sizes from previous studies were large enough to assess short or long-term safety.

IIC. Effects of glucose-lowering medications on long-term outcomes

The relationship between pharmacologic treatment of GDM and long-term outcomes merits further study. Women with GDM have an increased risk of subsequent metabolic syndrome, dysglycemia, type 2 diabetes, and cardiovascular disease. Offspring have risks of obesity, metabolic syndrome, diabetes, and behavioral and neurodevelopmental conditions, potentially related to fetal programming in the intrauterine environment (59). In an observational analysis, hyperglycemia in pregnancy was associated with an increased risk of childhood obesity at 5–7 years, but there was no adjustment for maternal weight (5). By contrast, long-term follow up of a randomized trial of treatment of mild GDM, where insulin was used as pharmacologic treatment if needed, showed no effect on offspring BMI at 7 years, but girls had lower fasting glucose levels (60), suggesting no harm and possible benefit of insulin treatment.

There are some long-term follow-up data for metformin. In studies of metformin use in pregnant women with PCOS, offspring of mothers exposed to metformin weighed 0.5 kg more at 1 year, but their mothers were also heavier in the first trimester (61). In the Metformin in Gestational Diabetes (MiG) trial (62), children of mothers initially assigned to metformin during pregnancy had higher skinfold measurements but no difference in body fat percent by body composition measures or in neurodevelopmental outcomes at age 2 compared to offspring of women randomized to insulin (63). Of note, 46% of the women randomized to metformin also received insulin treatment during the pregnancy. Small subgroups of these children were followed for up to 7 or 9 years. There was no difference in total or abdominal body fat percent or metabolic measures between offspring exposed to metformin compared with those whose mothers were treated with insulin, but metformin offspring were larger by several measures at 9 years, including weight, waist and arm circumference, triceps skin fold, and waist-to-height ratio, with a trend to increased BMI and fat mass and fat-free mass by DXA (64).

There are no long-term maternal or child outcome data for glyburide.

IID. Research priorities in pharmacologic management of GDM

Participants extensively debated inclusion of glyburide in future interventional studies on the treatment of GDM. Some participants voiced concern about continued use of glyburide for GDM based on the current state of knowledge, which suggests potential inferiority. Others felt that strong consideration should be given to further research on glyburide since it is currently the most commonly used glucose-lowering medication for GDM in the United States and has lower placental transfer than metformin (45). Thus, after discussion, consensus emerged that future research of pharmacologic management of GDM should include all three commonly used agents: insulin, glyburide and metformin. Moreover, optimal dosing of oral medications, with evaluation of pharmacokinetics, maternal blood levels, and cord blood levels, should be evaluated.

Since there are inadequate comparative data on perinatal outcomes associated with the use of each medication and scant data on long-term maternal and offspring outcomes related to oral medications, further study is warranted to evaluate the effect of pharmacologic interventions for GDM on both perinatal and long-term outcomes. Perinatal outcomes of interest include birth weight, preterm delivery, preeclampsia, gestational hypertension, neonatal adiposity, birth injury, C-peptide, hyperbilirubinemia, and hypoglycemia. Childhood long-term outcomes of interest include measures of childhood adiposity, metabolic dysfunction and cardiometabolic physiology. Maternal long-term outcomes of interest include post-partum development of T2DM, deterioration of beta cell function and postpartum weight retention and insulin resistance.

To accomplish these research goals, sample sizes in future research should to be large enough to examine safety endpoints, and study durations should ideally be long enough to evaluate long-term maternal and offspring outcomes.

Session III: Additional Research Gaps

The last session focused on topics in need of further research raised by workshop participants. Two areas emerged: A) Phenotypic heterogeneity and B) Novel and individualized treatment targets.

IIIA. Phenotypic heterogeneity

There is substantial metabolic heterogeneity in GDM. Although insulin secretion and sensitivity must be interpreted in tandem, some women with GDM may have a predominant defect in insulin resistance associated with inadequate beta-cell compensation, while others have a predominant defect in insulin secretion without excessive insulin resistance (65). The variable contribution of maternal obesity to GDM is another, related, source of heterogeneity (66, 67). Finally, many prior studies of GDM treatment have not been conducted in multi-ethnic U.S. populations, which may be especially heterogeneous in underlying pathophysiology and response to treatment. An understanding of sources of maternal and fetal heterogeneity could inform risk stratification of women with GDM, allowing for treatment intensification in high-risk GDM and while minimizing overtreatment of low-risk GDM.

IIIB. Novel and individualized treatment

Participants questioned whether we know the optimal glycemic targets for GDM treatment among various phenotypes of GDM and whether there are alternative non-glycemic targets. Recognition of the role of phenotypic heterogeneity in GDM suggests that treatment targets may need to be individualized. For example, glucose targets may need to be lower in pregnancies at higher risk for LGA. In line with this, glycemic risk thresholds might vary across different BMI categories and in different racial and ethnic populations. Alternative treatment targets may also be useful. Recent data suggest that maternal hyperlipidemia in GDM and obesity may contribute to fetal fat accretion (68). In a study of both obese and normal weight women in whom diet was controlled, early fasting triglycerides and free fatty acids were a stronger predictor of neonatal adiposity than 24-hour glycemic measures (67, 69, 70).

Fetal growth, as estimated by ultrasound measurements, was also considered as a potential treatment target to be used clinically. A GDM treatment strategy based on fetal abdominal circumference at 28 weeks has been successful in several previous interventional studies but has not been recommended in ACOG or ADA guidelines (71–77).

Conclusion

Currently, it remains unclear whether diagnosis and treatment of GDM before 20 weeks gestation improves perinatal outcomes. The workshop participants concluded that potential diagnostic criteria using glycemic or other measures before 20 weeks but ideally at 12–14 weeks should be evaluated for association with GDM-associated adverse perinatal outcomes. In addition, prior to recommending widespread screening and or treatment of GDM prior to 24 weeks, such a practice should be demonstrated to improve clinical outcomes. Further, there is uncertainty regarding criteria that should be used to diagnose GDM early in gestation.

The relative effectiveness, safety, acceptability, and long-term outcomes associated with use of insulin versus metformin versus glyburide remain unclear. Future research should compare all three medications and focus on both perinatal and long-term maternal and child outcomes. Optimal dosing strategies should also be evaluated for each of these agents.

Further research on the topics outlined herein are likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children. Research in this area would be facilitated by collaboration between maternal-fetal medicine specialists, endocrinologists, and pediatricians given the unpredictable timing of early pregnancy care and life course implications of GDM.