Metformin exposure may affect fetal growth differently in normal-weight and overweight women with polycystic ovary syndrome (PCOS), according to a post-hoc analysis of data from a randomized clinical trial (RCT).

While infants born to overweight mothers on metformin had a significantly larger mean head circumference than those born to overweight women on placebo, normal-weight women who took metformin during pregnancy delivered shorter, thinner infants than those on placebo, Dr. Anna Hjorth-Hansen of Levanger Hospital in Norway et al. found.

“Metformin can result in larger head size in children born to overweight mothers, and metformin can possibly restrict fetal growth in offspring born to normal-weight mothers,” Dr. Hjorth-Hansen reported.

Metformin may be used as first-line therapy after diet and lifestyle changes, or as an insulin supplement, in women with PCOS and gestational diabetes mellitus (GDM), the researchers note in their report in the Journal of Clinical Endocrinology and Metabolism.

However, there is little evidence to support this practice, “and little knowledge about possible effects of metformin on growth, metabolism, endocrine and nervous system development in the fetus, and cognitive and psychologic effects later in life.”

Dr. Hjorth-Hansen et al. analyzed data on 258 pregnancies in women with PCOS from the randomized PregMet study, conducted at 11 healthcare centers in Norway. Participants took either 2,000 mg/day of metformin or placebo, starting in their first trimester. Women with diabetes mellitus or fasting serum glucose higher than 126 mg/dL were excluded.

At week 19, bi-parietal diameter (BPD) was similar between the metformin and placebo groups. But at 32 weeks, BPD was 0.9 mm larger in the metformin group (mean, 86.1 vs. 85.2 mm; P=0.027).

At birth, mean head circumference (HC) was 0.5 cm larger in the infants who had been exposed to metformin than in the placebo group (P=0.007). Fetal metformin exposure was associated with larger HC (but still within the normal range) in women who were obese or overweight before pregnancy, but not in normal-weight women.

Among normal-weight mothers, metformin use was associated with shorter infant length and birthweight.

Head circumference was in the normal range for all of the metformin-exposed children, Dr. Hjorth-Hansen noted. “Generally, large head circumference is associated with larger brain volume and good cognitive function. It is difficult to say at this time what effect, if any, it might have on the children.

We think larger head size is probably beneficial. However, our research group is currently conducting a follow-up study on these children with cognitive function tests as well as a follow-up on their general physical health, he added. 

“Metformin is an old, cheap, well-tolerated and non-toxic drug, with no teratogenicity reported,” Dr. Hjorth-Hansen concluded. “We think it is important to keep in mind that even a well-tested, well-known drug such as metformin may affect the development of the fetus.”