Use of insulin analogs in pregestational diabetes and risk of congenital anomalies

Background: The use of insulin analogs in pregnancy is increasing, but information on teratogenic risks is lacking. Available studies on insulin analogs during pregnancy are not sufficiently powered to evaluate the risk of specific major malformations. Objectives: The aim of this study was to evaluate the risk of major congenital anomalies associated with insulin analogs use in women with pregestational diabetes. Methods: A population-based cohort of pregestational diabetic pregnancies was established retrospectively from seven European regions covered by EUROCAT congenital anomaly registries. Major congenital malformations were defined according the EUROCAT classification. Results: A total of 1877 births to women with pregestational diabetes were enrolled in the study during 1996-2012. During the first trimester, 870 births (46.3%) were exposed to only human insulin, 397 births (21.2%) to only insulin analogs, and 394 births (20.1%) to both human insulin and insulin analogs. The proportion of still birth and spontaneous abortion (4.0%) is higher among only insulin analog group compared with only human insulin group (1.4%). Overall, 132 births (7.0%) with major congenital malformation were detected, of which seven were chromosomal. The prevalence of major congenital anomalies in births exposed to only insulin analogs (3.8%) during the first trimester was significantly lower than those exposed to only human insulin (8.6%); relative risk=0.42 (95%CI 0.24-0.73). This is largely due to the decreased prevalence of non-chromosomal congenital heart defects (CHD): relative risk=0.18 (95%CI 0.05-0.58). The decreased prevalence remained after adjusting for glycemic control, planned pregnancy, and region. The prevalence of non-CHD congenital anomalies among births exposed to only insulin analogs in the first trimester (3.0%) was lower than those exposed to only human insulin (4.0%), but not statistically significant. Conclusions: This study shows that first trimester exposure to insulin analogs did not increase the risk of congenital anomalies compared with exposure to human insulin. The decrease risk of congenital anomalies was driven by CHDs. The higher risk of fetal death in relation to insulin analogs warranted further investigation.