Metformin
It is well-known that increased insulin resistance and associated high
blood glucose levels have a great impact on menstrual cycle frequency
and reproductive outcomes. Furthermore high blood glucose levels can
lead to adverse pregnancy outcomes such as miscarriage, congenital
malformations, stillbirth and neonatal death however, pregnancy can
adversely affect maternal health leading to worsening control of
diabetes and associated consequences of cardiovascular disease, retinal
and renal pathology (27). As more women are delaying conception, seeking
fertility treatment and/or becoming pregnant at an older age, the
prevalence of type II diabetes in pregnancy is suspected to rise.
Metformin is an anti-hyperglycaemic biguanide drug used commonly in the
treatment of type II diabetes mellitus (28). Inhibition of hepatic
gluconeogenesis and reduction of glucagon action results in reduced
serum insulin and glucose concentrations, which in turn improves
ovulation, pregnancy and live birth rates (29). Women with diabetes are
often advised to use metformin pre-conceptually in addition to or
alternative to insulin as the benefits of improved glucose control are
likely to outweigh the potential risks (30).
Diabetes Mellitus is a very common condition in the UK, and its
prevalence is increasing. 1st line treatment according
to the NICE guidelines for Type 2 Diabetes Mellitus is Metformin. In
general, metformin is thought to be safe however there is insufficient
data on its use in the first trimester and risk of miscarriage (30). Few
studies have determined the effect of metformin on reproductive outcomes
when used to treat diabetes. One small study of 35 women found that
patients who are on metformin for diabetes had better embryo quality
than patient’s undergoing insulin therapy however this did not affect
the implantation, clinical pregnancy or miscarriage rate (31). Metformin
is also used as an ovulation induction agent in polycystic ovary
syndrome (PCOS), and a Cochrane review of 42 studies (evidence range
very low to moderate) concluded that metformin alone over placebo may be
beneficial for live birth rates however the evidence quality was low
(29). Another Cochrane review including 9 studies of moderate quality
evidence, found that metformin use compared to placebo, before and after
ART treatment in patients with PCOS, increased clinical pregnancy rates
and reduced the risk of complications such as ovarian hyperstimulation
syndrome, however there was no convincing evidence of an effect on live
birth rates (32). More information on the reproductive outcomes before
and during ART with use of metformin on both male and female partners is
required to help guide clinical decision-making.