Metformin Use in Pregnancy

Is current evidence supportive of metformin as an adjunct therapy for pregnant women with diabetes?

The prevalence of type 2 diabetes has increased drastically over the last several years. Pregnant women who have type 2 diabetes have risen by 90% over the previous 15 years. This rise can be attributed to several factors, such as a rise in obesity and metabolic syndromes. Women who get pregnant and have type 2 diabetes are at a greater risk for complications. “A recent cohort including over 17,000 pregnancies with diabetes found that neonatal death was more common in mothers with type 2 diabetes than type 1 diabetes” (Benham et al.). First-line therapy for type 2 diabetes in any patient is metformin. However, its efficacy in pregnant women with type 2 diabetes is not well defined.

The mechanism of action for metformin is increased sensitivity to insulin in the liver and the periphery tissues. Metformin does cross the placenta, which is why its use in pregnant women is done with caution. However, it indicates polycystic ovarian syndrome (PCOS) and can help reduce insulin resistance resulting in conception. A study was conducted that reviewed women exposed to metformin during their first trimester with those who were not and found that the incidence of congenital disabilities was approximately the same in both groups. The same research was done on pregnant women with type 2 diabetes, and the results were the same. There was no increase in the risk of congenital disabilities with the group of women taking metformin during their pregnancy. Some women develop diabetes only when they are pregnant. Metformin is also a viable treatment option for women with gestational diabetes. “Glycemic control was found to be significantly better for participants randomly assigned to metformin compared with insulin alone in some, but not all, meta-analyses that looked at this outcome” (Benham et al.). However, for women with gestational diabetes, neonatal outcomes were shown to be mixed. Some reduction in neonatal hypoglycemia was reported as well as less intensive care unit admissions. Ibrahim et al. reported that the neonates of mothers randomized to metformin (n = 43) and insulin (n= 39) had a lower incidence of neonatal intensive care unit admission (19% vs 41%, respectively; p = 0.026) and neonatal hypoglycemia (7% vs 39%, respectively; p = 0.001) in a trial of 90 women with gestational or type 2 diabetes.

Trials that have been conducted provide preliminary support for using metformin as an adjunct treatment, specifically to insulin therapy, for pregnant women with type 2 diabetes. As of right now, metformin use in pregnant women remains off-label. Clinical practice guidelines have referenced insufficient evidence as to the reason for not recommending metformin use in pregnant women. Therefore, health care practitioners can still prescribe metformin for off-label use. The benefit to using metformin, especially in women with gestational diabetes, is the ease of use. There are no needles involved, and no teaching must be done for its administration. Metformin is also relatively inexpensive, which can be a significant motivating factor for patients. Further research needs to be conducted to collect more evidence to influence a change in clinical practice guidelines. A key piece of research that is anticipated is to follow up with the offspring of study participants to determine the long-term effects of metformin as an adjunct therapy.

Practice Pearls:

• Metformin use as an adjunct therapy in women with diabetes (type 2 or gestational) is off-label. However, studies have collected evidence to support its efficacy with an increase in desirable outcomes.
• Desirable outcomes include increased glycemic control, reduced infant hypoglycemic events, and shorter intensive care unit admissions.
• Further studies will be conducted to follow up with the offspring of the participants in these studies to determine the long-term impact of metformin use as an adjunct therapy.

Benham, J.L., Donovan, L.E. & Yamamoto, J.M. Metformin in Pregnancy for Women with Type 2 Diabetes: a Review. Curr Diab Rep 21, 36 (2021).

Ibrahim MI, Hamdy A,  The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial. Arch Gynecol Obstet. 2014;289(5):959–65. 

Grace Behr, PharmD/MBA Candidate, Creighton University