Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5-10 year follow-up of the PregMet randomised controlled trial.

BACKGROUND: Metformin is increasingly used to treat gestational diabetes and type 2 diabetes in pregnancy, and in attempts to improve pregnancy outcomes in polycystic ovary syndrome and obesity. It passes across the placenta with possible long-term consequences for the offspring. We previously explored the effect of metformin, given to women with polycystic ovary syndrome during pregnancy, on children's growth up to 4 years of age. In this 5-10 year follow-up, we examined the cardiometabolic risk factors in these children.

METHODS: This is a follow-up of children from the PregMet study, a double-blind, randomised controlled trial comparing metformin with placebo in polycystic ovary syndrome pregnancies. In the PregMet study, between Feb 4, 2005, and Jan 27, 2009, 257 pregnant women aged 18-45 years with polycystic ovary syndrome according to the Rotterdam criteria were included with 274 singleton pregnancies at 5-12 weeks of gestation at 11 study centres in Norway. 17 women participated twice. Pregnant women were randomised to metformin (2000 mg/day) or placebo from inclusion in the first trimester to birth. Randomisation was stratified according to metformin use at conception. In this follow-up, the primary endpoint was body-mass index (BMI) in the offspring at 5-10 years of age assessed by the standard deviation score (Z score). The primary endpoint was analysed with independent sample t tests. ClinicalTrials.gov number NCT00159536.

FINDINGS: Of the 255 invited children from the PregMet study, 141 (55%) consented to participate and were included between April 29, 2014, and July 12, 2016. Maternal baseline characteristics in the first trimester were similar between groups. Children in the metformin group had a higher BMI Z score than those in the placebo group (difference in means=0·41, 95% CI 0·03-0·78, p=0·03).

INTERPRETATION: The increased BMI in metformin-exposed children might indicate a potential risk of inferior cardiometabolic health. Implications for adult health cannot be excluded.

FUNDING: The Research Council of Norway, Novo Nordisk Foundation, St Olavs University Hospital, and the Norwegian University of Science and Technology.