Intensive glycaemic targets in overweight and obese individuals with gestational diabetes mellitus: clinical trial protocol for the iGDM study.

INTRODUCTION: The prevalence of both obesity and gestational diabetes mellitus (GDM) has increased, and each is associated with adverse perinatal outcomes including fetal overgrowth, neonatal morbidity, hypertensive disorders of pregnancy and caesarean delivery. Women with GDM who are also overweight or obese have higher rates of pregnancy complications when compared with normal-weight women with GDM, which may occur in part due to suboptimal glycaemic control. The current recommendations for glycaemic targets in pregnant women with diabetes are based on limited evidence and exceed the mean fasting (70.9±7.8 mg/dL) and 1-hour postprandial (108.9±12.9 mg/dL) glucose values in pregnant individuals without diabetes. Our prior work demonstrated that the use of intensive (fasting <90 mg/dL and 1-hour postprandial <120 mg/dL) compared with standard (fasting <95 mg/dL and 1-hour postprandial <140 mg/dL) glycaemic targets resulted in improved glycaemic control without increasing the risk for hypoglycaemia in pregnant individuals with GDM, but the impact of intensive glycaemic targets on perinatal outcomes is unknown. METHODS AND ANALYSIS: The Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus: A Multicenter Randomized Trial (iGDM Trial) is a large, pragmatic randomised clinical trial designed to investigate the impact of intensive versus standard glycaemic targets on perinatal outcomes in women with GDM who are overweight and obese. During the 5-year project period, a multidisciplinary team of investigators from five medical centres representing regions of the USA with high rates of obesity will randomise 828 overweight and obese women with GDM to either intensive or standard glycaemic targets. We will test the central hypothesis that intensive glycaemic targets will result in lower rates of neonatal composite morbidity including large for gestational age birth weight, neonatal hypoglycaemia, respiratory distress syndrome and need for phototherapy when compared with standard glycaemic targets using the intention-to-treat approach to analysis. ETHICS AND DISSEMINATION: The Institutional Review Board (IRB) at Indiana University School of Medicine approved this study (IRB# 11435; initial approval date 25 August 2021). We will submit the results of the trial for publication in peer-reviewed journals and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT05124808.

Drugs to Control Diabetes During Pregnancy.

Diabetes is a common complication of pregnancy associated with both short- and long-term adverse maternal and offspring effects. All types of diabetes in pregnancy are increasing in prevalence. Treatment of diabetes in pregnancy, targeting glycemic control, improves both maternal and offspring outcomes, albeit imperfectly for many women. Pharmacologic treatment recommendations differ between pregestational and gestational diabetes. Improved treatment of diabetes in pregnancy will need to consider maternal disease heterogeneity and comorbidities as well as long-term offspring outcomes. In this review, the authors summarize recent clinical studies to highlight established pharmacologic treatments for diabetes in pregnancy and provide suggestions for further research.

Timing of Gestational Weight Gain and Adverse Perinatal Outcomes in Overweight and Obese Women.

OBJECTIVE: To evaluate whether inadequate or excessive gestational weight gain before the third trimester is associated with adverse pregnancy outcomes, and to evaluate the association of weight gain in the third trimester with fetal growth. METHODS: This was a retrospective cohort study of all eligible overweight and obese women with singleton pregnancies delivered at an academic institution between 2012 and 2014. Our primary exposure was inadequate or excess gestational weight gain during the first and second trimesters. Outcomes included small- (SGA) or large- (LGA) for-gestational-age birth weight as well adverse maternal outcomes and composite neonatal morbidity. Multivariable logistic regression was used to assess the relationship between weight gain and perinatal outcomes, and stratified analyses evaluated the relationship between third trimester weight gain and birth weight category. RESULTS: Of the 5,814 women, 1,280 (22%) had adequate, 1,428 (24.6%) had inadequate, and 3,106 (53.4%) had excessive weight gain in the first and second trimesters. Women with inadequate early gestational weight gain were more likely to deliver an SGA neonate (adjusted odds ratio [aOR] 1.59, 95% CI 1.23-2.06) and less likely to deliver an LGA neonate (aOR 0.73, 95% CI 0.54-0.98), whereas those with excessive early gestational weight gain were less likely to deliver an SGA neonate (aOR 0.66, 95% CI 0.52-0.85) and more likely to deliver an LGA neonate (aOR 1.66, 95% CI 1.32-2.1). Higher weight gain in the third trimester was associated with increased risk for LGA birth weight, but third trimester weight gain was not related to SGA birth weight. CONCLUSION: Early gestational weight gain is associated with birth weight category. Modifying weight gain in the third trimester may limit the risk for LGA birth weight, but higher weight gain in late gestation does not alter the association between inadequate early weight gain and the risk for SGA.

Response to Medical Nutritional Therapy and Need for Pharmacological Therapy in Women with Gestational Diabetes.

OBJECTIVE: We assessed if the initial response to medical nutritional therapy (MNT) can help predict the need for pharmacological therapy in women with gestational diabetes mellitus (GDM). STUDY DESIGN: We identified 1,174 women with GDM who underwent standardized dietary counseling and reported glucose values from the first week of MNT. We compared women who required pharmacological therapy with those who did not use bivariate statistics, and used multivariable logistic regression modeling to assess for factors predicting the need for pharmacological therapy. RESULTS: We identified 819 women (69.8%) who needed pharmacological therapy. They had higher prepregnancy body mass index, higher rates of GDM diagnosis before 24 weeks, and higher oral glucose tolerance test values. After adjustment for covariates, age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.01-1.08), obesity (OR: 2.49; 95% CI: 1.70-3.66), and ≥33% of abnormal glucose values from the first week of MNT (OR: 13.84; 95% CI: 9.4-20.20) were associated with the need for pharmacological therapy. Area under the curve of the regression model was 0.83, with a sensitivity of 72.2%, a specificity of 86.8%, and a positive predictive value of 92.5%. CONCLUSION: Glucose values from the first week of MNT were the strongest predictor of needing pharmacological therapy. Further studies are needed to define metabolic predictors of response to MNT in women with GDM.

Novel therapies for diabetes mellitus in pregnancy.

Diabetes is a common complication of pregnancy, and the prevalence of all types of the disease is increasing worldwide. Diabetes in pregnancy is associated with short term and long term adverse effects for mother and child. The goal of treatment of diabetes in pregnancy is to minimize maternal and fetal adverse events related to hyperglycemia. Treatment options vary by type of diabetes, from a focus on lifestyle modifications in gestational diabetes to continuous glucose monitoring and insulin pumps in pregestational diabetes. Nevertheless, given the commonality of hyperglycemia, considerable overlap exists in the treatment of different types of diabetes in pregnancy. Also, despite ongoing research on treatment of diabetes in pregnancy for decades, changes in the characteristics of the patient population have highlighted the limited effectiveness of different therapies. Specifically, despite the co-occurrence of obesity and diabetes, treatment recommendations including glycemic targets are not altered in such cases and a single optimal treatment strategy for each type of diabetes in pregnancy does not seem to exist. Rather, the approach to treating pregnant women with diabetes likely needs to be individualized to maximize the short term and long term health of mother and child. This article will review recent clinical studies to summarize established treatment strategies and introduce novel therapies for diabetes in pregnancy.

Pregnancy outcomes in women with an early diagnosis of gestational diabetes mellitus.

AIM: To examine pregnancy outcomes in women with gestational diabetes mellitus (GDM) based on the timing of diagnosis. METHOD: We compared demographics, blood sugars and outcomes between women diagnosed before (n = 167) or after 24 weeks' gestation (n = 1202) in a single hospital between 2009 and 2012. Because early screening is risk-based we used propensity score modelling and conditional logistic regression to account for systematic differences. RESULTS: Women diagnosed with GDM before 24 weeks were more likely to be obese and they were less likely to have excess gestational weight gain (35 vs. 45%, p = 0.04). Early diagnosis was associated with more frequent therapy including glyburide (65 vs. 56%, p < 0.001) and insulin (19 vs 6%, p < 0.001). After propensity score modelling and accounting for covariates, early diagnosis was associated with an increased risk for macrosomia (OR 2, 95% 1-4.15, p = 0.0498). Early diagnosis was not associated with other adverse outcomes. In a subgroup analysis comparing women treated with glyburide prior to 24 weeks compared to those diagnosed after 24 weeks, early diagnosis in women treated with glyburide was associated with an increased risk for macrosomia (OR 2.3, 95% CI 1.1-5.4, P = 0.04). CONCLUSION: Women diagnosed with GDM before 24 weeks have unique features, are at risk for adverse outcomes, and require targeted approaches to therapy.

Glycemic Control and Pregnancy Outcomes in Women with Type 2 Diabetes Treated with Oral Hypoglycemic Agents.

Objective There is limited data regarding the use of oral hypoglycemic agents (OHAs) in pregnant women with type 2 diabetes mellitus (T2DM). Study Design This was a retrospective cohort study of women with T2DM who were treated with OHA or insulin from the first trimester onward. Bivariate and multivariate logistic regression analyses were used to compare pregnancy outcomes in women treated with OHA to those treated with insulin. Results One-third (67/198) of women were treated with OHA. Women treated with OHA had a shorter disease duration (4.4 vs. 6.8 years; p = 0.001), were more likely to have a normal prepregnancy body mass index, and had less gestational weight gain (GWG; 22.4 vs. 30.4 lbs; p = 0.005). A lower GWG was noted in obese women treated with OHA (19.9 ± 18.6 vs. 28.3 ± 17.7 pounds; p = 0.008). First-trimester hemoglobin A1c values were lower with OHAs, but second- and third-trimester values were similar. Among women who started pregnancy using OHA, 37/67 (55.2%) remained on OHA at delivery. Pregnancy outcomes did not differ between women who received OHA and those treated with insulin. Conclusion OHA treatment is more likely in women with T2DM who begin pregnancy with less severe disease, and use of OHA may be associated with decreased GWG.

What we have learned about the role of 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth.

Despite major advances in neonatal care, the burden of preterm birth remains high. This is not unexpected since strategies to identify and treat risk factors in early pregnancy have not been very effective in reducing the preterm birth rate. Initial studies suggested a potential benefit for 17-alpha-hydroxyprogesterone caproate (17-OHPC) in decreasing the risk of recurrent preterm birth women with a singleton gestation. However, the use of 17-OHPC has not conferred benefit for other categories of women at high risk for preterm delivery (twins, triplets, and short cervical length). The increasing body of evidence suggests that preterm birth is a complex condition with variable mechanisms of disease and significant individual heterogeneity. This review will examine the plausibility of 17-OHPC in preventing preterm birth and the investigation of its clinical efficacy. We will also highlight factors to explain variations in clinical trial outcomes and outline the trajectory needed for future investigations.

Timing of delivery and pregnancy outcomes in women with gestational diabetes.

BACKGROUND: Women with gestational diabetes mellitus (GDM) commonly undergo induction of labor (IOL) at term, but the risks and benefits of IOL are incompletely understood. OBJECTIVE: We examined the relationship among gestational age, IOL, and the rate of cesarean delivery (CD) in women with GDM. STUDY DESIGN: We identified 863 women with GDM who underwent either IOL or spontaneous labor ≥37 0/7 weeks. Demographic, cervical favorability, and outcome data were abstracted from the medical record. We compared the CD rate in women undergoing IOL at each week of gestation with expectant management to a later gestational age. RESULTS: When compared to women who were expectantly managed, IOL at 37 weeks (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 0.76-3.06; P = .23), 38 weeks (aOR, 2.07; 95% CI, 0.89-4.80; P = .09), and 39 weeks (aOR, 0.79; 95% CI, 0.44-1.42; P = .43)) was associated with similar risk for CD as expectant management after adjustment for nulliparity, body mass index, baseline simplified Bishop score, and maternal age. CD rates were higher in nulliparous women, but did not differ significantly in those undergoing IOL or expectant management. In multiparous women, IOL was significantly associated with an increased risk for CD at 38 weeks (aOR, 7.47; 95% CI, 1.6-34.8; P = .01) and rates of CD (17.39% vs 2.2%, P = .001) were significantly higher in multiparous women with an unfavorable Bishop score induced <39 weeks. Neonatal morbidity was similar across gestational ages after adjustment for maternal body mass index and maternal glycemic control. CONCLUSION: IOL results in similar risk for CD as expectant management between 37-40 weeks of gestation. Rates of CD differed based on cervical exam and parity. These findings suggest that gestational age alone does not significantly impact maternal and neonatal outcomes, but that decisions regarding delivery in women with GDM should take into account cervical exam and parity.

Effect of excess gestational weight gain on pregnancy outcomes in women with type 1 diabetes.

OBJECTIVE: To evaluate the prevalence and clinical effects of excess gestational weight gain on birth weight and other pregnancy outcomes in women with type 1 diabetes. METHODS: We performed a retrospective cohort study of women with type 1 diabetes delivered between 2009 and 2012. Patients with excess weight gain were identified using the 2009 Institute of Medicine weight gain recommendations adjusted for gestational age at delivery and prepregnancy body mass index (BMI) category. Demographic and outcome data were abstracted from the medical record, and pregnancy outcomes were compared between women with and without excess gestational weight gain. RESULTS: Excess gestational weight gain occurred in 114 of 175 women (65.1%). Large-for-gestational-age (LGA) birth weight occurred in 48 of 114 (42.1%) of women with excess gestational weight gain and 5 of 61 (8.2%) of women with recommended weight gain (P<.001). The association between excess maternal weight gain and LGA birth weight remained significant after adjustment for prepregnancy BMI, gestational age at delivery, nulliparity, vascular complications, and hemoglobin A1c measurements (adjusted odds ratio 8.9, 95% confidence interval 3.1-26.2, P<.001). Stratified analyses demonstrated that excess maternal weight gain is associated with LGA neonates in both normal-weight and overweight or obese women. CONCLUSIONS: Excess maternal weight gain is common and leads to higher rates of LGA neonates in both normal-weight and overweight or obese women with type 1 diabetes. Interventions designed to limit excess gestational weight gain may reduce the risk for fetal overgrowth in women with type 1 diabetes. LEVEL OF EVIDENCE: II.

Asymmetric large for gestational age newborns in pregnancies complicated by diabetes mellitus: is maternal obesity a culprit?

OBJECTIVE: Evaluate the association between body mass index (BMI) and the delivery of an asymmetrically large for gestational age (A-LGA) newborn in women with diabetes. METHODS: Retrospective analysis of 306 pregnancies complicated by Type 1 and 55 by Type 2 diabetes. RESULTS: The prevalence of Type 1 and Type 2 diabetics delivering large for gestational age (LGA) infants was 42% and 49%, respectively. Of these 49% and 55% were A-LGA, respectively. Pre-pregnancy BMI was not associated with increased odds of delivering an A-LGA newborn in women with Type 1 or 2 diabetes. However, in Type 1 diabetics, each one-pound increase in maternal weight during pregnancy resulted in 4% increased odds of delivering an A-LGA newborn. For Type 2 diabetics, the odds of delivering an A-LGA infant was decreased by 10% for each 0.1 unit/kg increase in insulin dose. CONCLUSION: Although there is a known association between obesity and LGA in women with diabetes, we found that overweight and obese women with Type 1 or Type 2 diabetes do not have increased odds of delivering an A-LGA newborn. However, insulin dose in Type 2 diabetes and maternal weight gain in Type 1 diabetes were significantly associated with the odds of delivering an A-LGA neonate.

Clinical therapeutics in pregnancy.

Most drugs are not tested for use during pregnancy, consequently, labeling, which may include information about fetal safety, includes nothing about dosing, efficacy, or maternal safety. Yet these are concerns of health care providers considering treatment of disease during pregnancy. Therefore, the practitioner treats the pregnant woman with the same dose recommended for use in adults (typically men) or may decide not to treat the disease at all. However, is the choice of not treating a woman during pregnancy better than dealing with the challenges which accompany treatment? This paper, which summarizes metabolic and physiologic changes induced by pregnancy, illustrates that standard adult dosing is likely to be incorrect during pregnancy.