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

Abstract

The optimum treatment for HNF1A/HNF4A maturity‐onset diabetes of the young and ATP‐sensitive potassium (KATP) channel neonatal diabetes, outside pregnancy, is sulfonylureas, but there is little evidence regarding the most appropriate treatment during pregnancy. Glibenclamide has been widely used in the treatment of gestational diabetes, but recent data have established 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 maturity‐onset diabetes of the young, those with good glycaemic control who are on a sulfonylurea per 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 because increased insulin secretion results in ~800‐g 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 ~900 g. 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.

Transient Neonatal Diabetes: An Etiologic Clue for the Adult Diabetologist

“…Finally, K ATP channel mutations have important implications for clinical management during pregnancy, particularly regarding glyburide therapy (18). Treatment recommendations in mothers with K ATP channel mutations are dependent on the fetal genotype because of differing effects of treatment on fetuses with or without the mutation (18).…”

Use of oral antidiabetic drugs in the treatment of maturity‐onset diabetes of the young: A mini review

“…Thus, most pregnant HNF1‐α/HNF4‐α MODY patients prefer remaining on this therapy rather than being switched to insulin . However, recent data show that glibenclamide crosses the placenta and may increase the risk of foetal macrosomia and neonatal hypoglycaemia that questions its use during pregnancy . Thus, the expert panel recommends that pregnant women with HNF1‐α/HNF4‐α MODY with good glycaemic control on sulphonylurea transfer to insulin already either before the conception (although with the risk of a short‐term deterioration of glycaemic control) or no later than after the first trimester to minimize the risk of increased insulin secretion in utero.…”

“…In case the foetus inherits an HNF4A mutation, early delivery is recommended as a prevention of macrosomia and prolonged postdelivery neonatal hypoglycaemia due to increased insulin secretion. Also, the authors call for prospective studies in monogenic diabetes in pregnancy to evaluate the optimal treatment options for those patients …”

“…14 However, recent data show that glibenclamide crosses the placenta and may increase the risk of foetal macrosomia and neonatal hypoglycaemia that questions its use during pregnancy. 51 Thus, the expert panel recommends that pregnant women with HNF1-α/ HNF4-α MODY with good glycaemic control on sulphonylurea transfer to insulin already either before the conception (although with the risk of a short-term deterioration of glycaemic control) or no later than after the first trimester to minimize the risk of increased insulin secretion in utero. In case the foetus inherits an HNF4A mutation, early delivery is recommended as a prevention of macrosomia and prolonged postdelivery neonatal hypoglycaemia due to increased insulin secretion.…”

“…Also, the authors call for prospective studies in monogenic diabetes in pregnancy to evaluate the optimal treatment options for those patients. 51…”