27th February 2019, Dr Chee L Khoo
Primum non nocere (first do no harm) is quite an appropriate term when is comes to managing pregnant women who either have dysglycaemia or are at risk of dysglycaemia. While there is no question that hyperglycaemia during pregnancy is associated with both poor maternal and foetal outcomes as well as epigenetic changes which can affect the next generation, who and how to treat is still debatable.
Metformin is increasingly being prescribed to pregnant women with PCOS, gestational diabetes and obesity. In fact, metformin is recommended in line with insulin in a number of international guidelines (Norwegian guidelines, the guidelines of the National Institute for Health and Care Excellence, and the American Society of Maternal-Fetal Medicine (SMFM),) However, the evidence on safety or benefit of intrauterine metformin use and long-term cardio-metabolic health of offspring born to women with polycystic ovary syndrome is inconclusive.
When 182 children were followed up over 4 years, kids who were exposed to metformin during pregnancy in the PregMet study were found to have higher BMI and higher prevalence of overweight or obesity (1). Similarly, kids born to mothers who had GDM and was exposed to metformin (+/- insulin) had increased weight and height at 18 months and altered fat distribution at 24 months (2,3). In another study, kids born to mothers who had taken metformin had a higher BMI, increased waist circumference, waist-to hip ratio, and abdominal fat when examined at 9 years old compared to children whose mothers were treated with insulin only (4).
141 kids in the original PregMed study were followed up to between 5-10 years old. 71 mothers were exposed to metformin during the pregnancy while 70 were not. Kids in the metformin group had higher BMI, higher abdominal adiposity and weigh more than kids in the placebo group. There was no difference between the groups in adiponectin, cholesterol, triglycerides, HDL-cholesterol, non-HDL cholesterol, alanine transaminase, glucose, HbA1c, insulin C-peptide, HOMA2-IR, blood pressure, or heart rate.
Maternal pre-pregnancy BMI had an effect on the metabolic effect of metformin: metformin-exposed children had higher measures of adiposity than placebo exposed children, higher triglycerides, and heart rate, and lower HDL-cholesterol only when maternal prepregnancy BMI was greater than 30 kg/m².
Among metformin-exposed children with overweight or obesity, 67% were overweight or obese already at 4 years of age. High BMI (obesity) in childhood often tracks into adulthood, and the risk of persistent high BMI increases with age. High BMI in childhood predicts cardiometabolic risk factors, and moderately increases the risk of morbidity. 13 Early onset and duration of obesity are related to subsequent metabolic abnormal obesity phenotype.
Metformin treatment in polycystic ovary syndrome pregnancies is not without potential harm. It resulted in a higher mean BMI accompanied by central adiposity and more children with obesity at 5–10 years of age compared with children born to mothers not exposed to metformin. These results can have implications for future health of the children.
- Engen Hanem LG, Stridsklev S, Júlíusson PB, et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age; follow-up of two RCTs. J Clin Endocrinol Metab 2018; 103: 1612–1621.
- Ijas H, Vaarasmaki M, Saarela T, Keravuo R, Raudaskoski T. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months. BJOG 2015; 122: 994–1000.
- Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 2011; 34: 2279–84.
- Rowan JA, Rush EC, Plank LD, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age. BMJ Open Diabetes Res Care 2018; 6: e000456.
- Liv Guro Engen Hanem, Øyvind Salvesen, Petur B Juliusson, et al. Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5–10 year follow-up of the PregMet randomised controlled trial. Lancet Child Adolesc Health 2019; 3: 166–74