Children born to women who take a commonly used diabetes medication during pregnancy may have an increased risk of being overweight or obese, according to new data from two Norwegian studies.
Women with polycystic ovary syndrome (PCOS), gestational diabetes, type 2 diabetes, and even obesity are increasingly prescribed metformin during pregnancy, with studies indicating that the drug reduces the risk of PCOS-related complications.
Although it metformin is known to cross the placenta, the long-term impact of such intrauterine exposure on the offspring remains unclear, with previous investigations yielding conflicting results.
Now a follow-up study of two randomized controlled trials suggests that, contrary to expectations, children exposed to metformin in utero may have a higher average weight at 4 years of age than children not exposed. The findings were published online February 27 in the Journal of Clinical Endocrinology & Metabolism.
Moreover, the data from 182 children reveal that those whose mothers took metformin during pregnancy were more than twice as likely to be overweight or obese than those who took placebo, with the effect appearing to occur from age 6 months.
“The results were surprising, since limited past research in this area had suggested metformin would have a protective effect on the children’s metabolic health,” said lead author Liv Guro Engen Hanem, PhD candidate, of the Norwegian University of Science and Technology in Trondheim, in a press release by the Endocrine Society.
“Few studies have examined the long-term health of children born to women with PCOS who took metformin. Our findings indicate more research is needed to determine its effects on children who were exposed in the womb,” she added.
Data Turn Hypothesis on Its Head
Hypothesizing that offspring exposed to metformin during pregnancy would be less likely to be overweight or obese than those who received control, researchers conducted a follow-up of two randomized, controlled, double-blind studies.
In one study, 40 women aged 18 to 40 years with PCOS were randomized to metformin 1700 mg/day or placebo. The other study involved 257 women with PCOS and 274 pregnancies randomized to metformin 2000 mg/day or placebo.
All women were counseled on diet and lifestyle at inclusion and advised to take folate 0.8 mg/day and one multivitamin tablet daily throughout pregnancy to counteract the possible impact of metformin on folate and vitamin B levels.
In the current analysis, 292 children from the two studies were invited to take part in the follow-up, of whom 182 children, with 170 mothers, agreed.
Primary endpoints were height, weight, body mass index (BMI), and overweight/obesity at 4 years of age, for which complete data were available for 161 children, and head circumference at 1 year, for which complete data were available for 154 children.
There were no significant differences in baseline characteristics between the metformin and placebo groups, including maternal characteristics at inclusion, mode of contraception, pregnancy complications, maternal weight gain during pregnancy, placenta weight, and duration of breast feeding.
There was no significant difference in birth weight between infants exposed vs not exposed to metformin, but between age 6 months to 4 years it became apparent that those exposed to metformin were significantly heavier (P = .015).
At 4 years of age, the metformin group had a signficantly higher weight z-score (difference in means, 0.38; P = .017) and BMI z-score (difference in means 0.45; P = .010) than the placebo group. The latter was apparent from age 6 months.
There were consequently more overweight/obese children aged 4 years in the metformin (26; 32%) than placebo group (14; 18%) (odds ratio, 2.17; P = .038).
Metformin had no significant impact on height z-score vs placebo at 4 years of age (difference in means, 0.07; P = .651).
Number Needed to Harm With Metformin Was 7.4
The researchers calculated that the number needed to harm with metformin to have an additional case of overweight or obesity at 4 years of age was 7.4.
There was no effect of metformin on head circumference at 1 year of age, and the results were not modified by taking into account gender or maternal prepregnancy BMI.
Although the authors note the current analysis is the largest follow-up study to date of metformin exposure in utero, they acknowledge the findings may not be applicable to mothers without PCOS and a potential limitation is the low participation rate.
They nevertheless hypothesize that metformin may increase offspring weight via two primary mechanisms: maternal metabolic alterations that affect the intrauterine environment, and the direct effect of metformin on the offspring, potentially by inhibition of the mitochondria respiratory chain.
The researchers acknowledge that the clinical implications of their findings “are not known, and the body composition and metabolic health of these children should therefore be subject to further investigation.”
“Until we have more robust data on the possible beneficial effects of metformin use during pregnancy, it should only be used in randomized controlled trials with long-term follow-up of the children,” they conclude.
The research was funded by the Research Council of Norway and Novo Nordisk. The authors have reported no relevant financial relationships.
J Clin Endocrinol Metab. Published online February 27, 2018. Abstract
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