Prenatal Metformin Exposure Linked to Adiposity, Obesity in Children

February 14, 2019

By Anne Harding

NEW YORK (Reuters Health) - In utero metformin exposure is associated with a higher BMI, more central adiposity and greater obesity risk in children born to mothers with polycystic ovary syndrome (PCOS), new findings show.

"This is the first follow-up study on children who were metformin-exposed in utero, compared to placebo. Our study indicates that metformin increases the risk of higher BMI, abdominal fat deposition and obesity in childhood. These findings might be markers of future increased risk of inferior cardio-metabolic health," Dr. Liv Guro Engen Hanem and Dr. Eszter Vanky of the Norwegian University of Science and Technology in Trondheim told Reuters Health in a joint email.

"It is uncertain whether the results of this paper describing the effect of metformin on offspring health are applicable to non-PCOS pregnancies," they added. "This can, however, not be excluded."

Metformin is increasingly being prescribed to pregnant women with PCOS, gestational diabetes and obesity, the two researchers and their colleagues note in The Lancet Child & Adolescent Health, online January 28. But evidence for the drug's efficacy and safety in pregnancy is lacking.

"Metformin is now recommended in line with insulin as medical treatment of GDM in both Norwegian guidelines, the guidelines of the National Institute for Health and Care Excellence, and the American Society of Maternal-Fetal Medicine (SMFM), but not in the guidelines of the American Diabetes Association," Dr. Hanem and Dr. Vanky noted.

The current report is a follow-up from the PregMet study, in which the researchers randomly assigned 257 pregnant women with PCOS to metformin or placebo. Previously, the authors found that the children exposed in utero had higher BMI Z scores than unexposed children from six months of age to four years.

In the new study, the authors looked at body composition in 141 PregMet study offspring when they were 5 to 10 years old. Twelve (17%) of the metformin-exposed children were obese, compared to one (1%) of the non-exposed children.

Five (8%) exposed children had metabolically abnormal overweight or obesity, versus none of the non-exposed group.

The metformin-exposed children had a significantly higher BMI Z score (difference in means, 0.41), and their waist-to-height-ratio Z score and waist-circumference Z scores were also higher. Height and head circumference were similar in the metformin and placebo groups.

"The consideration of metformin treatment in PCOS pregnancies should include assessment of individual patient risk, and the beneficial effects of metformin for pregnancy outcome should be weighed against potential effects on cardiometabolic health of the children," Dr. Hanem and Dr. Vanky said.

They concluded, "Randomized controlled studies are necessary for clinical evidence and good patient care. We, doctors and other caregivers have to continue performing them, even if they are laborious, challenging and expensive."

Dr. David H. Abbott of the University of Wisconsin-Madison, who wrote an accompanying comment, told Reuters Health by phone, "I applaud (the authors) for the study they are doing and following up, because it takes decades to do this, which is why other people haven't done it."

"I was appalled that we hadn't learned the lessons of DES and thalidomide and we still have this casualness about a drug that appears safe but really hasn't been studied in appropriate animal models to just check on its safety in offspring," he added.

Metformin has widespread effects beyond glucose metabolism, for example on gut function and how cells release hormones and replicate, Dr. Abbott added. "Don't let that anywhere near a developing fetus."

The study was funded by The Research Council of Norway, Novo Nordisk Foundation, St. Olavs University Hospital and the Norwegian University of Science and Technology.


Lancet Child Adolesc Health 2019.