Metformin use in pregnancy: promises and uncertainties

Abstract

Metformin has been prescribed in pregnancy for over 40 years; for much of this time, use has been limited both in numbers and geographically, and the evidence base has been confined to observational studies. In early years, perceived safety concerns and lack of availability of the drug in many countries acted as a barrier to use. More recently, RCTs have begun to examine the role of metformin in pregnancy in much-needed detail. However, this evidence base has been interpreted differently in different countries, leading to very wide variation in its current application in pregnancy. In this short review, we will discuss the history of metformin in pregnancy and highlight some of the key clinical trials. We will then consider some of the remaining controversies associated with metformin use in pregnancy, most important of these being the potential for long-term ‘programming’ effects on the fetus as a result of metformin being able to cross the placenta. We will also consider clinical situations where metformin might be avoided. Finally, we will discuss some future directions for this drug as it reaches its sixtieth anniversary.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4351-y) contains a slide of the figure for download, which is available to authorised users.

60 years of metformin use: a glance at the past and a look to the future

“…However, studies in PCOS suggested that metformin does not increase congenital malformations or miscarriage. In their review, Lindsay and Loeken [28] discuss the use of metformin in gestational diabetes, presenting evidence that metformin has a good safety profile and is effective at reducing rates of severe hypoglycaemia and weight gain in pregnant women. In contrast, however, in pregestational type 2 diabetes the evidence base for metformin use is not strong, but observational evidence suggests increased risk of preeclampsia and perinatal mortality.…”

The diversity of gestational diabetes: a therapeutic challenge

“…The main mechanism of action is reduction of hepatic glucose production, however several other antidiabetic effects may contribute, including modulation of appetite, modulation of steroidogenesis and AMP kinase activation and effects on the gut microbiota as reviewed in 17,18,20 . Also, metformin influences vitamin B12 absorption 21 , resulting in a 10-30 % reduction of cyanocobalamine levels in general diabetic therapy.…”

“…The compound does cross the placenta, and has been measured in cord blood at a concentration range similar to that in maternal blood 23 . There has also been some concern that a reduction of placental insulin resistance during metformin treatment could influence nutrient transport to the fetus negatively during maternal fast, and result in deficient fetal growth 18 .…”

“…Both these pathways have potential to influence the growing fetus, as they are highly used by proliferating tissues and hormone producing cells 17,18 . AMP kinase is involved in meiotic processes and the regulation of transcription in environmental stresses via histone phosphorylation or acetylation.…”

“…The unanswered questions now are mainly related to late offspring development, growth and fertility, as well as fat mass distribution and hypothetical effects on fetal programming 17,18 .…”