Metformin Exposure in the First Trimester of Pregnancy and Risk of All or Specific Congenital Anomalies: Exploratory Case-Control Study

Metformin affects stem cell function and has been shown to cross the human placenta at term, exposing the fetus to concentrations approaching those in the maternal circulation. Limited evidence from3 meta-analyses and a cohort study suggests that the rate of all major congenital anomalies combined is not significantly increased after exposure to metformin. As teratogens tend to increase the risk of specific, rather than all, congenital anomalies, an increased risk of specific congenital anomalies after first trimester metformin exposure cannot be ruled out. The researchers designed a population-based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of nongenetic anomalies, and all nongenetic anomalies combined, were compared with controls (all other nongenetic anomalies or genetic syndromes). Eleven EUROmediCAT European congenital anomaly registries surveying 1,892,482 births in Europe between 2006 and 2013 were used. There were 50,167 babies affected by congenital anomaly (41,242 nongenetic and 8925 genetic) including live births, fetal deaths from 20 weeks' gestation, and terminations of pregnancy for fetal anomaly. EUROCAT population-based registries record all major congenital anomalies among live births, fetal deaths at 20 weeks' gestation or later, and terminations of pregnancy for fetal anomaly, using ICD-10 (International Classification of Diseases, 10th Revision) codes. Detailed descriptions of registries and the methods used have been published previously. The EUROmediCAT database includes data, since 1995, from those EUROCAT registries that record first trimester drug exposure either directly or through linkage with healthcare databases with information on prescribing and dispensing of drugs. Exposure to metformin in the first trimester was rare before 2006, so this study was based on data from 2006 onwards. Registries with less than 3 exposures were excluded. The researchers recorded 53,689 babies affected by congenital anomaly in the EUROmediCAT database (2006-2013), of 1,892,482 births surveyed, across the 11 registries that were eligible to take part in this study. After exclusions, 50,167 babies with congenital anomaly were left for analysis, consisting of 41,242 with a nongenetic anomaly and 8925 with a genetic syndrome. In all, 168 babies affected by congenital anomaly (141 nongenetic and 27 genetic)were exposed to metformin (3.3 per 1000 babies affected by congenital anomaly), of which 2 had a combined preparation (A10BD02 metformin and sulfonylureas). Overall, metformin exposure among fetuses with all nongenetic anomalies combined compared with controls was not statistically significantly different (adjusted odds ratio, 0.84; 95% confidence interval, 0.55-1.30). The only significant result was for pulmonary valve atresia (adjusted odds ratio, 3.54; 1.05-12.00, compared with nongenetic controls; 2.86, 0.79-10.30, compared with genetic controls). This one significant association was no more than would be expected by chance given the number of comparisons that were made. Further surveillance is needed to increase the sample size and follow up the signal related to the cardiac anomaly seen, but these findings are reassuring given the increasing use of metformin in pregnancy.