Metformin use in pregnancy: promises and uncertainties

Diabetologia, Aug 2017

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.

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Metformin use in pregnancy: promises and uncertainties

Metformin use in pregnancy: promises and uncertainties Robert S. Lindsay 0 1 2 Mary R. Loeken 0 1 2 0 Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center , Boston, MA , USA 1 Institute of Cardiovascular and Medical Sciences, British Heart Foundation (BHF) Glasgow Cardiovascular Research Centre, University of Glasgow , 126 University Place, Glasgow G12 8TA , UK 2 Robert S. Lindsay 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. Metformin; Pregnancy; Review; Teratogenesis - The initial development and use of metformin (outside of pregnancy) are reviewed elsewhere in this issue of Diabetologia [ 1 ]. With regard to pregnancy, it is important to note that it was acknowledged very early on that metformin crossed the placenta. More recent studies show similar plasma concentrations in the maternal and fetal circulation [ 2 ]. Further, the combination of increased lactic acidosis risk (mainly observed with the metformin-related biguanide, phenformin) and the relatively hypoxic fetal environment led to important concerns regarding potential adverse effects of metformin use in pregnancy, for both mother and child. In fact, the safety concerns related to phenformin use resulted in the withdrawal of metformin in many, although not all, countries [ 3 ]. These early concerns are charted in influential reports of the Aberdeen International Colloquia on Carbohydrate Metabolism in Pregnancy and the Newborn. The first colloquium, reported in 1975, included an entire chapter on ‘the use of sulphonylureas, biguanides and insulin in pregnancy’ [ 4 ]. By the time of the fourth report in 1988, the topic of use of metformin was given only a few lines and it was noted that use was not widespread [ 5 ]. Metformin use did, however, continue in other parts of the world. In developing countries, the relatively low cost of metformin compared with insulin made it an attractive option. Coetzee and colleagues published a series of important observational papers, commencing in the late 1970s, examining the use of metformin in South Africa [ 6–8 ]. In South Africa and other countries, where metformin was routinely used to treat type 2 diabetes, exposure inevitably began to occur in early pregnancy leading to the separate analysis of safety in early pregnancy, particularly regarding miscarriage and congenital anomaly. However, it was as metformin use became more popular in polycystic ovarian syndrome (PCOS) that a more robust literature developed, investigating exposure of the fetus to metformin in early pregnancy and, therefore, safety of its use. Safety and efficacy of metformin during pregnancy Safety in early pregnancy The early literature regarding metformin use in early pregnancy in humans was based on observational findings and of variable quality. Studies were usually small and it was often difficult to tease out the potential teratogenic effects of metformin, particularly as opposed to the well-established effects of maternal hyperglycaemia to increase risk of congenital malformation [ 9 ]. Similarly, animal studies have not been completely conclusive, and while increases in embryonic AMP-activated protein kinase (AMPK; AMPK activation being one potential effect of metformin) may be key in diabetic embryopathy, animal studies have not suggested an increase in embryopathy with early metformin exposure in vivo [ 10 ]. More recently, a meta-analysis based on metformin exposure in 351 women with PCOS has been carried out. Interestingly, the findings of this study do not suggest an increase in congenital anomaly with metformin use in pregnancy (OR of major birth defect 0.86 [95% CI 0.18, 4.08]) [ 11 ]. However, this estimate is based on a small sample size and, therefore, the confidence intervals remain wide. Metformin has also been extensively analysed in the context of PCOS-associated miscarriage and pregnancy indu (...truncated)


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Robert S. Lindsay, Mary R. Loeken. Metformin use in pregnancy: promises and uncertainties, Diabetologia, 2017, pp. 1-8, DOI: 10.1007/s00125-017-4351-y