April 2018, Dr Chee L Khoo
Another day, another study published on the good or bad about metformin use in pregnancy. There is a lot of confusion and unknowns about the benefit or safety of metformin to the mother-to-be or to the long-term outcome of the baby. When there is a lot of conflicting data coming our way, we need to sit back and look at the overall picture of hyperglycaemia in pregnancy and its management before we can make sense of these studies.
There is no question that women with pregestational diabetes (whether T1D or T2D) with suboptimal glycaemic control have poor pregnancy outcomes (much higher miscarriage rates), poor maternal and foetal outcomes and significantly higher rates of major foetal malformations. We have studies to tell us that improving pre-gestational HbA1c and tight glucose control during pregnancy makes giant differences to all outcomes.
The original concept of gestational diabetes was really about future diabetes risk to the mother. We know that women with GDM are at much higher risks of developing T2D down the track. It wasn’t really about pregnancy or foetal outcomes. But the Hyperglycaemia and Adverse pregnancy outcomes (HAPO), Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) and other trials suggests that any grade of hyperglycaemia is associated with adverse pregnancy outcomes. The tricky bit is drawing the line as to where GDM is defined. The experts are still arguing about those numbers.
If hyperglycaemia during pregnancy is associated with adverse pregnancy outcomes, surely bringing the glucose levels down will benefit, right? Well, another tricky question here. We don’t actually have lots of data supporting that approach. The problem comes back to where you draw the line in defining GDM. If you raise the bar higher in defining GDM, there will probably be more adverse outcomes. On the other hand, lowering the bar too low not only increase the number of women who will be deemed to have GDM and treatment is then necessary. This is where the issues with metformin in pregnancy comes in.
Metformin has been used in pregnancy for some time. Data from South Africa suggest that metformin and sulphonyureas are not teratogenic but perinatal mortality rates were higher than insulin (Ekspebegh 2007). A meta-analysis based on metformin exposure in 351 women with PCOS did not suggest an increase in congenital anomaly with metformin use in pregnancy (Cassina 2014) but the study was only very small. There are some studies which suggest that metformin might reduce miscarriage rates (Feng 2015).
The Metformin in Gestational Diabetes (MiG) randomised clinical trial looked at 751 women with GDM and found that metformin was comparable to insulin in maternal and foetal outcomes including respiratory distress, premature birth, birth weight and neonatal anthropometrics and LGA (Rowan 2008). A recent meta-analysis came to a similar conclusion (Balsell 2015).
Thus, metformin is probably safe to the mother and foetus but data is limited. However, the follow up of a Finnish randomised control trial (RCT) found that children exposed to metformin in pregnancy were significantly heavier at the age of 12 months, and taller and heavier at 18 months, although the study was small, with a total of 97 children. There were also no differences in motor, social and linguistic development evaluated at the age of 18 months.
The Finnish study we reviewed last month reported that that head circumference is increased in the metformin group only in mothers who were overweight (BMI>25). Similarly, birth weight was reduced in the metformin group but only in normal weight mothers. This suggests a growth restrictive effect of metformin in normal weight women with PCOS.
We know that metformin crosses the placenta and plasma levels are similar in both maternal and foetal circulation (Norris 2006). But embryonic susceptibility to metformin depends on the presence of metformin transporters which may be lacking in early embryos. Foetal and placenta cells are more differentiated than embryonic cells and metformin can inhibit the complex 1 in the respiratory chain (which is responsible for energy generation) leading to increase in AMPK activity which can affect various gene expressions in the foetus. This can have epigenetic effects.
Metformin have energy restrictive effect and this can lead to increased future cardiometabolic risks in the offspring. While metformin is probably safe for mothers with GDM and the newborn, there is limited evidence of safety in women with pre-gestational diabetes using metformin. There is no convincing evidence of increased malformations with metformin but the long term effects on the offspring is still unknown.
As you can see, the jury is still out in relation to not just the use of metformin in pregnant women but also the treatment of women with GDM. Calorie restricting a pregnant woman with borderline hyperglycaemia early in pregnancy may lead to calorie restriction in the early embryo and foetus with future cardiometabolic consequences (Hales 1992).
As part of an NHMRC multi-centred funded study, South west Sydney is undertaking a study to see if that treatment is really needed in women with mild hyperglycaemia in early pregnancy. If you have a woman who is at high risk of developing GDM during her pregnancy and she is < 20 weeks gestation, please don’t organise an oral glucose tolerance test (OGTT). They may qualify for the trial. Refer them immediately to Campbelltown Antenatal Clinic for booking and potential recruitment. Tell them that she may be eligible for the TREATMENT OF BOOKING GESTATIONAL DIABETES MELLITUS (TOBOGM) STUDY. For more information about the TOBOGM trial,
Email: ToBOGM@westernsydney.edu.au or Phone: 02 46344593
Reference
Ekpebegh CO, Coetzee EJ, van der Merwe L, Levitt NS (2007) A 10-year retrospective analysis of pregnancy outcome in pregestational type 2 diabetes: comparison of insulin and oral glucose-lowering agents. Diabet Med 24:253–258
Cassina M, Dona M, Di Gianantonio E, Litta P, ClementiM(2014) First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis. Hum Reprod Update 20:656– 669
Feng L, Lin XF, Wan ZH, Hu D, Du YK (2015) Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis. Gynecol Endocrinol 31:833–839
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP (2008). Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 358:2003–2015
Balsells M, Garcia-Patterson A, Sola I, RoqueM, Gich I, Corcoy R (2015) Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 350:h102
Hellmuth E, Damm P, Molsted-Pedersen L (2000) Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med 17:507–511
Hughes RC, Rowan JA (2006) Pregnancy in women with type 2 diabetes: who takes metformin and what is the outcome? Diabet Med 23:318–322
Charles B, Norris R, Xiao X, HagueW(2006) Population pharmacokinetics of metformin in late pregnancy. Ther DrugMonit 28:67– 72
Hales CN, Barker DJ (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35: 595–601