Glycemic and Adiposity Benefits with Metformin Use in Pregnancy

A placebo-controlled trial was conducted to determine fetal, neonatal, and maternal outcomes associated with metformin use during pregnancy in women with T2DM.  

There is an unmet need to manage type 2 diabetes mellitus (T2DM) in women who are pregnant. Pregnant women with T2DM are at risk for adverse pregnancy outcomes, including pre-eclampsia and cesarean sections. Furthermore, T2DM increases the risk of pre-term birth, large neonate size for gestation age, and increased prevalence of neonatal intensive care unit admission (ICU) in infants. Previous studies showcased that the use of metformin during pregnancy in T2DM reduced maternal and neonatal hypoglycemia, neonatal ICU admission, pregnancy-induced hypertension, and gestational weight gain. However, these studies were limited by their methodologies, with small sample sizes and insufficient allocation assignment and masking. Due to limited data, metformin should not be used during pregnancy unless needed, and insulin is recommended to manage T2DM in pregnant patients. 

Since metformin crosses the placenta, potential safety concerns exist. The purpose of this prospective, multicenter, international, randomized, parallel, double-masked, placebo-controlled trial is to determine if the addition of metformin to insulin in pregnant women with T2DM will increase or decrease the risk of neonatal morbidity and mortality. The primary outcome included a composite of fetal and neonatal outcomes determined by either loss in pregnancy, pre-term birth at less than 37 weeks’ gestation, birth injury, moderate or severe respiratory distress syndrome, neonatal hypoglycemia, and NICU admission lasting over 24 hours. The secondary outcome of interest was associated with maternal outcomes, including glycemic and hypertension control, the prevalence of cesarean section, gestation weight gain, and insulin dose.  

This trial took place at 29 hospital centers, with 25 locations in Canada and four Australian locations. Women eligible for the trial had to be between 18-45 years of age, with a diagnosis of T2DM before pregnancy or before 20 weeks of gestation with a live singleton fetus between 6-22 weeks plus six days of gestation receiving insulin. Women were excluded from the study if they had T1DM, hypersensitivity, or contraindications to metformin or had previously participated in this trial. Women were randomized to receive either metformin titrated up to 1000 mg twice daily or placebo in addition to insulin, which was short-acting insulin before meals and long-acting insulin before bedtime. Patients in both groups had fasting blood glucose levels checked before breakfast, before the last meal of the day, and two hours postprandial. Insulin doses were adjusted based on glucose targets of fasting glucose and postprandial. Patients in both groups were monitored every 1-4 weeks for standard clinical care, in which blood pressure, body weight, medication tolerance, insulin doses, glucometer readings, and hypoglycemic events were noted.    

In this trial, 502 women were randomly assigned, with 253 women allocated to receive metformin and 249 allocated to receive the placebo. The average age was 34.7 years in the metformin group, the average pre-pregnancy weight of 94.4 kg upon randomization, and the average first HbA1c of 6.42%. The average age was 35.0 years in the placebo-allocated group, an average pre-pregnancy weight of 90.0 kg, and the average first HbA1c of 6.41%. By the end of the pregnancy, women in the metformin allocated group had better glycemic control with HbA1c of 5.90% and mean glucose of 6.05 mmol/L vs. HbA1c of 6.10% and 6.27 mmol/L in the placebo group (p=0.015). Women in the metformin-allocated group experienced more mild hypoglycemic events, but there was no difference in the number of severe hypoglycemic events amongst the two groups. Women in the metformin group had gained less weight, both overall and weekly, but had more women with weight below per the Institute of Medicine guideline recommendations. Although fewer women in the metformin group had cesarean sections, the infants’ birth weight in the metformin group was small for gestational age (13% vs. 7%, RR 1.96, 95% CI: 1.10-3.64).  

Compared to the placebo, pregnant women with T2DM treated with metformin in addition to insulin had achieved better glycemic control, lower insulin requirement, less gestational weight gain, and fewer cesarean births. Infants of women treated with metformin weighed less, had reduced adiposity, and had an earlier gestational age. This study utilized a large population size with patients of varying ethnicities and varying socioeconomic status. However, further studies should be done to find a difference in stillbirth and perinatal mortality amongst the two groups.  

Practice Pearls: 

• Metformin use in conjunction with insulin may increase the chances of mild to moderate hypoglycemic events.  
• Pregnant women with T2DM on metformin should be counseled on GI tolerability and adverse events.   
• If women are initiated on metformin during pregnancy, weight should be monitored and they should be counseled on the association of smaller infant birth weight for gestational age. 

Feig, Denice S, et al. “Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy): a Multicentre, International, Randomised, Placebo-Controlled Trial.” The Lancet Diabetes & Endocrinology, vol. 8, no. 10, 2020, pp. 834–844., doi:10.1016/s2213-8587(20)30310-7. 

Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017 

Tarry-Adkins, Jane L., et al. “Neonatal, Infant, and Childhood Growth Following Metformin versus Insulin Treatment for Gestational Diabetes: A Systematic Review and Meta-Analysis.” PLOS Medicine, vol. 16, no. 8, 2019, doi:10.1371/journal.pmed.1002848. 

Shana Indawala, PharmD Candidate, University of South Florida Health, Taneja College of Pharmacy