Intrauterine Metformin Exposure and Offspring Cardiometabolic Risk Factors at 5-10 Year Follow-Up: The PedMet Study

Abstract

Background: Metformin is increasingly used in pregnancy. It passes the placenta with possible long-term consequences for the offspring. We explored potential effects of intrauterine metformin exposure on cardiometabolic risk factors, in 5-10 year old children of women with polycystic ovary syndrome (PCOS). Methods: Follow-up of children from the PregMet-study - a randomized controlled trial comparing metformin (2000 mg) to placebo in PCOS pregnancies. The primary endpoint was Body Mass Index (BMI) standard deviation score (z-score). Secondary endpoints included weight-related anthropometric measurement z-scores, bioelectrical impedance measurements, biochemical analyses (adiponectin, alanine transaminase (ALT), lipids, fasting glucose, insulin C-peptide, HbA1c), HOMA2-IR, blood pressure, and heart rate. Findings: From 2014 to 2016, we included 141 (55%) of 255 invited children. Maternal baseline characteristics in first trimester were comparable between groups. The BMI z-score was higher in the metformin group than in the placebo group (difference in means (d)=0·41, 95% CI 0·03-0·78, p=0·03). Metformin-exposed children had higher waist-to-height ratio z-score (d=0·36, 95% CI 0·06-0·67, p=0·02), waist circumference zscore (d=0·40, 95% CI 0·08-0·71, p=0·01), weight z-score (d=0·43, 95% CI 0·04-0·82, p=0·03), and borderline significantly higher body-fat (kg) (d= 1·8, 95% CI 0·0-3·6, p=0·05). Height z-score, head circumference z-score, muscle-mass (kg), biochemical analyses, blood pressure, and heart rate were comparable between groups. Interpretation: The increased BMI, waist circumference, and waist-to-height ratio in metformin-exposed children may indicate potential risk of inferior cardiometabolic health. Implications for adult health cannot be excluded. Clinical Trial Number: ClinicalTrials.gov-number:NCT00159536 Funding Statement: The Research Council of Norway, Novo Nordisk Foundation, St. Olavs University Hospital and the Norwegian University of Science and Technology. Declaration of Interests: The authors report no financial or personal conflicts of interest in this work. Ethics Approval Statement: The PregMet-study (project number 145.04) and the PedMet-study (project number 2014/96) were approved by the Committee for Medical Research Ethics of Health Region IV, Norway. Written, informed consent was obtained from each child’s parent or guardian before inclusion in the PedMet-study. The declaration of Helsinki and the Good Clinical Practice guidelines were followed throughout the studies.