Management of sulfonylurea treated monogenic diabetes in pregnancy: implications of placental Glibenclamide transfer

Abstract

HNF1A/HNF4A maturity onset diabetes of the young (MODY) and KATP channel neonatal diabetes (NDM) are optimally treated with sulfonylureas outside pregnancy, but there is little evidence regarding the most appropriate treatment during pregnancy. Glibenclamide has been widely used in the treatment of gestational diabetes, however recent data establishes that glibenclamide crosses the placenta, and increases risk of macrosomia and neonatal hypoglycaemia. This raises questions about its use in pregnancy. We review the available evidence and make recommendations for the management of monogenic diabetes in pregnancy. Due to the risk of stimulating increased insulin secretion in utero, we recommend that in women with HNF1A/ HNF4A MODY, those with good glycaemic control on a sulfonylurea pre-conception either transfer to insulin before conception [at the risk of a short-term deterioration of glycaemic control] or continue with sulfonylurea (glibenclamide) treatment in the first trimester and transfer to insulin in the second trimester. Early delivery is needed if the fetus inherits an HNF4A mutation from either parent as increased insulin secretion results in ~800g weight gain in utero, and prolonged severe neonatal hypoglycaemia can occur post-delivery. If the fetus inherits a KATP neonatal diabetes mutation from their mother they have greatly reduced insulin secretion in utero that reduces fetal growth by approximately 900g. Treating the mother with glibenclamide in the third trimester treats the affected fetus in utero normalising fetal growth but is not desirable, especially in the high doses used in this condition, if the fetus is unaffected. Prospective studies of pregnancy in monogenic diabetes are needed.