Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study

Abstract

ObjectiveTo investigate whether exposure to metformin during the first trimester of pregnancy, for diabetes or other indications, increases the risk of all or specific congenital anomalies.DesignPopulation based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of non-genetic anomalies, and all non-genetic anomalies combined, were compared with controls (all other non-genetic anomalies or genetic syndromes).Setting11 EUROmediCAT European congenital anomaly registries surveying 1 892 482 births in Europe between 2006 and 2013.Participants50 167 babies affected by congenital anomaly (41 242 non-genetic and 8925 genetic) including live births, fetal deaths from 20 weeks’ gestation, and terminations of pregnancy for fetal anomaly.Main outcome measureOdds ratios adjusted for maternal age, registry, multiple birth, and maternal diabetes status.Results168 babies affected by congenital anomaly (141 non-genetic and 27 genetic) were exposed to metformin, 3.3 per 1000 births. No evidence was found for a higher proportion of exposure to metformin during the first trimester among babies with all non-genetic anomalies combined compared with genetic controls (adjusted odds ratio 0.84, 95% confidence interval 0.55 to 1.30). The only significant result was for pulmonary valve atresia (adjusted odds ratio 3.54, 1.05 to 12.00, compared with non-genetic controls; 2.86, 0.79 to 10.30, compared with genetic controls).ConclusionsNo evidence was found for an increased risk of all non-genetic congenital anomalies combined following exposure to metformin during the first trimester, and the one significant association was no more than would be expected by chance. Further surveillance is needed to increase sample size and follow up the cardiac signal, but these findings are reassuring given the increasing use of metformin in pregnancy.

Pregestational diabetes in pregnancy: Complications, management, surveillance, and mechanisms of disease—A review

“…Large population-based studies and meta-analysis have found no increase in congenital anomalies when metformin was used in a mixed group of women with or without diabetes, or when used for subfertility. [37][38][39] A small study compared the outcomes for women taking gliclazide compared with those of women taking metformin in pregnancy and was not able to determine any differences in congenital anomalies, birth weight, or neonatal hypoglycaemia. 40 There are very few safety data on many of the newer oral or long acting parenteral agents, and it is likely that these data will only emerge very slowly, as case reports of inadvertent exposure occur.…”

Guidelines on prescribing psychotropic medication during the perinatal period

“…Therefore it is recommended that prescribers keep up to date with new information. An example is that since this guideline was finalised there has been a further observational study published on the rates of major congenital malformations associated with anticonvulsants (Weston et al 2016) and a case-controlled study of the risk of malformations with in utero exposure to metformin was generally reassuring (Given et al 2018) -an important observation given the recommended use of metformin for antipsychotic induced weight gain (Cooper et al 2016). UKTIS (http://www.uktis.org) provides information on fetal risk.…”

Obesity, fertility and pregnancy: can we intervene to improve outcomes?

“…Whether metformin is safe in pregnancy is also under debate (Barbour et al 2018). It is known that metformin freely crosses the placenta, and though a survey of 1.9 million births from 11 European population-based registries found no evidence of an association between metformin exposure in the first trimester and congenital anomalies (Given et al 2018), there is currently uncertainty as to whether metformin may affect long-term health of the offspring. The longest follow-up of children exposed to metformin in utero as part of a randomised controlled trial of gestational diabetes treatment extends to 9 years.…”