Metformin Use in PCOS Pregnancies Increases theRisk of Offspring Overweight at 4 Years of Age:Follow-Up of Two RCTs

Liv Guro Engen Hanem, Solhild Stridsklev, Petur B. Julıusson, Øyvind Salvesen, Mathieu Roelants, Sven M. Carlsen, Rønnaug Ødegard, and Eszter Vanky

Context: Metformin is used in pregnancy in women with gestational diabetes mellitus, polycystic ovary syndrome (PCOS), and obesity. Metformin passes the placenta.

Objective: To explore the effects of metformin use in PCOS pregnancies on offspring growth to 4 years of age.

Design: Follow-up study of two randomized, double-blind, placebo-controlled trials.

Setting: Secondary care centers. Eleven public hospitals in Norway.

Participants: One hundred eighty-two children of mothers with PCOS who participated in two randomized controlled trials.

Intervention: Metformin 1700 or 2000 mg/d or placebo from first trimester to delivery in the original studies. No intervention in the current study.

Main Outcome Measures: Height, weight, body mass index (BMI), and overweight/obesity at 4 years of age and head circumference at 1 year of age, converted to z scores.

Results: The difference in height z score means between the groups at 4 years of age was non- significant (0.07 [95% confidence interval (CI):–0.22 to 0.36]; P = 0.651). At 4 years of age, the metformin group had higher weight z score than the placebo group [difference in means: 0.38 (0.07 to 0.69); P = 0.017] and higher BMI z score [difference in means: 0.45 (0.11 to 0.78); P = 0.010]. There were more overweight/obese children in the metformin group [26 (32%)] than in the placebo group [14 (18%)] at 4 years of age [odds ratio: 2.17 (1.04 to 4.61); P = 0.038]. The difference in mean head circumference z score at 1 year of age was 0.27 (–0.04 to 0.58; P = 0.093).

Conclusion: Metformin-exposed children had higher BMI and increased prevalence of overweight/obesity at 4 years of age. (J Clin Endocrinol Metab 103: 1612–1621, 2018)