Male foetal sex is recognised as an independent risk factor for adverse pregnancy outcomes including preterm birth, neonatal care unit admission and lower Apgar scores. Male foetuses appear to increase the risk of maternal gestational diabetes in the mother due to impacts on beta cell function, and in pregnancies impacted by gestational diabetes, male offspring have higher rates of hypoglycaemia, respiratory distress and macrosomia. Metformin exposure in animal models has also demonstrated sex-specific effects with different patterns in adiposity and lipid levels observed between male and female offspring exposed to metformin in utero. The aim of this analysis is to determine whether foetal sex modifies maternal and neonatal outcomes in gestational diabetes, and evaluate the sex-specific response to metformin on insulin usage, fasting glucose at 32 and 38 weeks and foetal size. We conducted a secondary analysis of the Early Metformin in Gestational Diabetes (EMERGE) randomised controlled trial and analysed neonatal outcomes according to sex and metformin exposure. At randomisation, women carrying a male foetus had a higher plasma glucose at 60 min on oral glucose tolerance testing (9.69 vs. 9.37 mmol/L, p = 0.039). In exploratory analyses, metformin exposure in male pregnancies was associated with lower fasting glucose at 32 (4.88 vs. 5.01 mmol/L, p = 0.014) and 38 weeks (4.49 vs. 4.69 mmol/L, p = 0.002) and reduced insulin use (38% vs. 53%, p = 0.014), with smaller effects in female pregnancies. Metformin-exposed females had higher rates of birth weight 4000 g compared to female offspring regardless of metformin exposure. However, the sex-by-treatment interaction was not significant, so these findings should be regarded as hypothesis-generating. Glucometer data suggested a greater mean glucose reduction in males than females (0.29 mmol/L (95% CI 0.29–0.30) versus 0.21 mmol/L (95% CI 0.20–0.21)). Further follow-up is required to determine whether foetal sex influences long-term effects of metformin in pregnancy.
Newman et al. (2026) studied this question.