Janet Rowan

Metformin versus Insulin for the Treatment of Gestational Diabetes

BACKGROUND Metformin is a logical treatment for women with gestational diabetes mellitus, but randomized trials to assess the efficacy and safety of its use for this condition are lacking. METHODS We randomly assigned 751 women with gestational diabetes mellitus at 20 to 33 weeks of gestation to open treatment with metformin (with supplemental insulin if required) or insulin. The primary outcome was a composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score less than 7, or prematurity. The trial was designed to rule out a 33% increase (from 30% to 40%) in this composite outcome in infants of women treated with metformin as compared with those treated with insulin. Secondary outcomes included neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance, and acceptability of treatment. RESULTS Of the 363 women assigned to metformin, 92.6% continued to receive metformin until delivery and 46.3% received supplemental insulin. The rate of the primary composite outcome was 32.0% in the group assigned to metformin and 32.2% in the insulin group (relative risk, 0.99 [corrected]; 95% confidence interval, 0.80 [corrected] to 1.23 [corrected]). More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again (76.6% vs. 27.2%, P<0.001). The rates of other secondary outcomes did not differ significantly between the groups. There were no serious adverse events associated with the use of metformin. CONCLUSIONS In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin. The women preferred metformin to insulin treatment. (Australian New Zealand Clinical Trials Registry number, 12605000311651.).

Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU): Body composition at 2 years of age

OBJECTIVE In women with gestational diabetes mellitus, who were randomized to metformin or insulin treatment, pregnancy outcomes were similar (Metformin in Gestational diabetes [MiG] trial). Metformin crosses the placenta, so it is important to assess potential effects on growth of the children. RESEARCH DESIGN AND METHODS In Auckland, New Zealand, and Adelaide, Australia, women who had participated in the MiG trial were reviewed when their children were 2 years old. Body composition was measured in 154 and 164 children whose mothers had been randomized to metformin and insulin, respectively. Children were assessed with anthropometry, bioimpedance, and dual energy X-ray absorptiometry (DEXA), using standard methods. RESULTS The children were similar for baseline maternal characteristics and pregnancy outcomes. In the metformin group, compared with the insulin group, children had larger mid-upper arm circumferences (17.2 ± 1.5 vs. 16.7 ± 1.5 cm; P = 0.002) and subscapular (6.3 ± 1.9 vs. 6.0 ± 1.7 mm; P = 0.02) and biceps skinfolds (6.03 ± 1.9 vs. 5.6 ± 1.7 mm; P = 0.04). Total fat mass and percentage body fat assessed by bioimpedance (n = 221) and DEXA (n = 114) were not different. CONCLUSIONS Children exposed to metformin had larger measures of subcutaneous fat, but overall body fat was the same as in children whose mothers were treated with insulin alone. Further follow-up is required to examine whether these findings persist into later life and whether children exposed to metformin will develop less visceral fat and be more insulin sensitive. If so, this would have significant implications for the current pandemic of diabetes.

Glycemia and Its Relationship to Outcomes in the Metformin in Gestational Diabetes Trial

OBJECTIVE To determine how glucose control in women with GDM treated with metformin and/or insulin influenced pregnancy outcomes. RESEARCH DESIGN AND METHODS Women randomly assigned to metformin or insulin treatment in the Metformin in Gestational Diabetes (MiG) trial had baseline glucose tolerance test (OGTT) results and A1C documented, together with all capillary glucose measurements during treatment. In the 724 women who had glucose data for analysis, tertiles of baseline glucose values and A1C and of mean capillary glucose values during treatment were calculated. The relationships between maternal factors, glucose values, and outcomes (including a composite of neonatal complications, preeclampsia, and large-for-gestational-age [LGA] and small-for-gestational-age infants) were examined with bivariable and multivariate models. RESULTS Baseline OGTT did not predict outcomes, but A1C predicted LGA infants (P = 0.003). During treatment, fasting capillary glucose predicted neonatal complications (P < 0.001) and postprandial glucose predicted preeclampsia (P = 0.016) and LGA infants (P = 0.001). Obesity did not influence outcomes, and there was no interaction between glycemic control, randomized treatment, or maternal BMI in predicting outcomes. The lowest risk of complications was seen when fasting capillary glucose was <4.9 mmol/l (mean ± SD 4.6 ± 0.3 mmol/l) compared with 4.9–5.3 mmol/l or higher and when 2-h postprandial glucose was 5.9–6.4 mmol/l (6.2 ± 0.2 mmol/l) or lower. CONCLUSIONS Glucose control in women with gestational diabetes mellitus treated with metformin and/or insulin is strongly related to outcomes. Obesity is not related to outcomes in this group. Targets for fasting and postprandial capillary glucose may need to be lower than currently recommended.

An Early Pregnancy HbA1c ≥5.9% (41 mmol/mol) Is Optimal for Detecting Diabetes and Identifies Women at Increased Risk of Adverse Pregnancy Outcomes

OBJECTIVE Pregnant women with undiagnosed diabetes are a high-risk group that may benefit from early intervention. Extrapolating from nonpregnancy data, HbA1c ≥6.5% (48 mmol/mol) is recommended to define diabetes in pregnancy. Our aims were to determine the optimal HbA1c threshold for detecting diabetes in early pregnancy as defined by an early oral glucose tolerance test (OGTT) at <20 weeks’ gestation and to examine pregnancy outcomes relating to this threshold. RESEARCH DESIGN AND METHODS During 2008–2010 in Christchurch, New Zealand, women were offered an HbA1c measurement with their first antenatal bloods. Pregnancy outcome data were collected. A subset completed an early OGTT, and HbA1c performance was assessed using World Health Organization criteria. RESULTS HbA1c was measured at a median 47 days’ gestation in 16,122 women. Of those invited, 974/4,201 (23%) undertook an early OGTT. In this subset, HbA1c ≥5.9% (41 mmol/mol) captured all 15 cases of diabetes, 7 with HbA1c <6.5% (<48 mmol/mol). This HbA1c threshold was also 98.4% (95% CI 97–99.9%) specific for gestational diabetes mellitus (GDM) before 20 weeks (positive predictive value = 52.9%). In the total cohort, excluding women referred for GDM management, women with HbA1c of 5.9–6.4% (41–46 mmol/mol; n = 200) had poorer pregnancy outcomes than those with HbA1c <5.9% (<41 mmol/mol; n = 8,174): relative risk (95% CI) of major congenital anomaly was 2.67 (1.28–5.53), preeclampsia was 2.42 (1.34–4.38), shoulder dystocia was 2.47 (1.05–5.85), and perinatal death was 3.96 (1.54–10.16). CONCLUSIONS HbA1c measurements were readily performed in contrast to the low uptake of early OGTTs. HbA1c ≥5.9% (≥41 mmol/mol) identified all women with diabetes and a group at significantly increased risk of adverse pregnancy outcomes.

Prophylactic and therapeutic enoxaparin during pregnancy: Indications, outcomes and monitoring

Objectives: To evaluate the efficacy and safety of prophylactic and therapeutic enoxaparin in pregnancy.

Admissions to neonatal intensive care unit following pregnancies complicated by gestational or type 2 diabetes

Background:  When gestational diabetes mellitus (GDM) is diagnosed in a population with a high prevalence of unrecognised type 2 diabetes mellitus (type 2 DM), the rate of neonatal morbidity is not clear. There is also a paucity of data reporting neonatal outcome in women with recognised type 2 DM.

A Trial in Progress: Gestational Diabetes: Treatment with metformin compared with insulin (the Metformin in Gestational Diabetes [MiG] trial)

The Metformin in Gestational Diabetes (MiG) trial is a prospective randomized multicenter trial in women with gestational diabetes mellitus (GDM) that is testing the hypothesis that metformin treatment, compared with insulin, is associated with similar perinatal outcomes, improved markers of insulin sensitivity in the mother and baby, and improved treatment acceptability. Women with GDM who are at 20–33 weeks’ gestation in a singleton pregnancy and meet entry criteria are randomized to insulin or metformin treatment. The primary outcome is a composite of neonatal morbidity, with 750 recruits required. The trial finished recruiting in October 2006. Interim data on 200 women (and subsequently 550 women) have been reviewed by the data safety monitoring committee, which has reported that the trial should answer the hypotheses and no protocol changes are required. Data from 457 women show recruits are a mean age of 33.3 ± 5.3 years; BMI of 32.1 ± 7.8 kg/m2; and ethnicity 47.2% European/Caucasian, 25.7% Polynesian, and 24.3% Indian/Asian. The mean fasting glucose at recruitment is 5.3 ± 1.1 mmol/l and A1C is 5.7 ± 0.8%. Long-term follow-up of children started at age 2 years, with assessments of body composition, neurodevelopment, diet, and activity levels. The MiG trial will address the efficacy and detailed safety of metformin compared with insulin in women with GDM. Long-term follow-up of offspring will examine whether treatment influences later health (Australasian Clinical Trials Registry number 12605000311651). GDM is diagnosed in over 4% of pregnant women (1,2). The prevalence is increasing as the pregnancy population becomes older and fatter. Women with GDM have increased rates of pregnancy complications and risks of later type 2 diabetes (1,2). The offspring of women with GDM also have increased risks of perinatal complications and long-term risks of obesity and type 2 diabetes (1– …

Response to Comment on Hughes et al. An Early Pregnancy HbA1c ≥5.9% (41 mmol/mol) Is Optimal for Detecting Diabetes and Identifies Women at Increased Risk of Adverse Pregnancy Outcomes. Diabetes Care 2014;37:2953–2959

We appreciate the opportunity to respond to the comments made by Anderson et al. (1) on our recent article (2). We agree, as highlighted under our study limitations, that the low participation rate in the oral glucose tolerance test (OGTT) could affect the validity of the HbA1c sensitivity and specificity calculations. As women with lower HbA1c (particularly <5.6% [38 mmol/mol]) were least likely to consent to an early OGTT, it is possible that the optimal HbA1c threshold for identifying women with undiagnosed preexisting diabetes (not gestational diabetes mellitus [GDM]) is in fact lower than 5.9% (41 mmol/mol) and we invite others …

Is There a Role for HbA1c in Pregnancy

Outside pregnancy, HbA1c analysis is used for monitoring, screening for and diagnosing diabetes and prediabetes. During pregnancy, the role for HbA1c analysis is not yet established. Physiological changes lower HbA1c levels, and pregnancy-specific reference ranges may need to be recognised. Other factors that influence HbA1c are also important to consider, particularly since emerging data suggest that, in early pregnancy, HbA1c elevations close to the reference range may both identify women with underlying hyperglycaemia and be associated with adverse pregnancy outcomes. In later pregnancy, HbA1c analysis is less useful than an oral glucose tolerance test (OGTT) at detecting gestational diabetes. Postpartum, HbA1c analysis detects fewer women with abnormal glucose tolerance than an OGTT, but the ease of testing may improve follow-up rates and combining HbA1c analysis with fasting plasma glucose or waist circumference may improve detection rates. This article discusses the relevance of HbA1c testing at different stages of pregnancy.

Maternal and Neonatal Circulating Markers of Metabolic and Cardiovascular Risk in the Metformin in Gestational Diabetes (MiG) Trial: Responses to maternal metformin versus insulin treatment

OBJECTIVE This study was designed to compare glucose, lipids, and C-reactive protein (CRP) in women with gestational diabetes mellitus treated with metformin or insulin and in cord plasma of their offspring and to examine how these markers relate to infant size at birth. RESEARCH DESIGN AND METHODS Women with gestational diabetes mellitus were randomly assigned to metformin or insulin in the Metformin in Gestational Diabetes trial. Fasting maternal plasma glucose, lipids, and CRP were measured at randomization, 36 weeks’ gestation, and 6–8 weeks postpartum as well as in cord plasma. Women with available cord blood samples (metformin n = 236, insulin n = 242) were included. RESULTS Maternal plasma triglycerides increased more from randomization to 36 weeks’ gestation in women treated with metformin (21.93%) versus insulin (9.69%, P < 0.001). Maternal and cord plasma lipids, CRP, and neonatal anthropometry did not differ between treatments. In logistic regression analyses adjusted for confounders, the strongest associations with birth weight >90th centile were maternal triglycerides and measures of glucose control at 36 weeks. CONCLUSIONS There were few differences in circulating maternal and neonatal markers of metabolic status and no differences in measures of anthropometry between the offspring of women treated with metformin and the offspring of women treated with insulin. There may be subtle effects of metformin on maternal lipid function, but the findings suggest that treating gestational diabetes mellitus with metformin does not adversely affect lipids or CRP in cord plasma or neonatal anthropometric measures.