Metformin in gestational diabetes mellitus

Gestational diabetes mellitus (GDM) can affect up to 1 in 5 of pregnancies and is associated with adverse pregnancy outcomes including pre-eclampsia, neonatal hypoglycaemia, large for gestational age, increased adiposity and birth trauma. Good glycaemic control is the key to reduce these outcomes. Diet and lifestyle modification followed by insulin as necessary is the conventional type of management. Metformin is increasingly used in pregancy but with limited evidence, its role in GDM has not been well-established. A systematic review including both randomized and non-randomized controlled studies have been conducted to evaluate the contemporary evidence of metformin in GDM. It is suggested that metformin in GDM could be a useful alternative to insulin and is regarded as the best oral anti-hyperglycaemic agent in GDM management currently. However, almost half of metformin-treated GDM patients required supplementary insulin to achieve target glucose levels (metformin failure). Women with higher metabolic risk factors are likely to develop metformin failure. A clinical cohort of metformin-treated GDM is used to develop the predictive model to identify GDM women who are at risk of metformin failure. It has been found that women identified by new IADPSG and NICE 2015 fasting criteria are highly likely to develop metformin failure. It has also been established a number of algorithm based on various baseline characters of GDM women which will help primary healthcare physicians choose the best medication for GDM management. One of the possible side-effects of metformin includes lowering of serum vitamin B12 levels whereas serum vitamin B12 deficiency during pregnancy which is associated with increased insulin resistance. It is reported that in low vitamin B12 state, offspring’s insulin resistance is found to be higher among women with high folate low B12 state. Hence, in order to fully appreciate the role of vitamin B12 deficiency in metformin failure, it is first necessary to understand the effects of folate in low vitamin B12 condition on pregnancy outcomes in GDM. It has also been found that in normal vitamin B12 GDM women, serum folate levels are negatively associated with plasma glucose levels but not low B12 state. This underlines the fact that in order for folate to have its role, it is important to have normal vitamin B12 levels. Despite increasing use of metformin, it is not yet routine to check vitamin B12 levels before it is given. It is important to understand whether vitamin B12 has a role in metformin action. Thus, the mechanism by which vitamin B12 deficiency might interfere with metformin action was studied. In vitamin B12 deficient hepatocytes, metformin stimulation of AMPK was reduced which was followed by reduced downstream signalling in lipid metabolism. This effects were reversed by vitamin B12 supplementation. Thus, it is concluded that vitamin B12 deficiency could interfere with metformin action and before metformin is given, every GDM woman should be checked for serum vitamin B12 levels and should be supplemented if deficient. Overall, vitamin B12 could play a critical role in GDM management and it is important for every GDM woman to have normal vitamin B12 levels