MIMICH
Amongst women with poor cardiometabolic health embarking on pregnancy, hyperglycaemia is very common. The prevalence of hyperglycaemia is increasing across Europe, alongside increasing rates of older maternal age, obesity and hypertension. Gestational diabetes (GDM) rates have recently been estimated at 5.4% (3.8-7.8) and the prevalence of type 2 diabetes has doubled (0.5-1.1% between 2008 & 2012). As a result of the majority of women with hyperglycaemia having other cardiometabolic risk factors (family history, obesity, dyslipidaemia, hypertension), compared to healthy subjects, these women have a 3-4 fold increased risk of pregnancy hypertension (7.4%). Rates of pre-eclampsia in women with type 2 diabetes have been reported to be as high as 31% and women with both diabetes and vascular disease are six times more likely to develop fetal growth restriction (FGR).
The effect of metformin on cellular metabolism has not been fully explained and remains controversial; metformin has been shown to disrupt mitochondrial respiration, alter redox status, impair tumour growth and cellular proliferation under hypoxic and nutrient deficient conditions. All of these actions suggest that metformin could negatively affect placental function particularly in the context of oxidative stress and hypoxia, although this has not been tested directly. Conversely, metformin has been demonstrated to have significant, anti-inflammatory properties in the systemic vasculature and in trophoblast cell lines.
Given the uncertainty regarding the potential benefits and potential negative effects on placental function highlighted above and by a recent expert review, a trial of metformin in women with hyperglycaemia and risk factors for placental disease is urgently needed.
No previous studies have investigated the effect of metformin on placental function, fetal growth and maternal cardiometabolic health in women with hyperglycaemia and concurrent risk factors for placental disease. Our group has pioneered the use of volumetric ultrasound techniques to improve the detection of fetal growth abnormalities. Previous studies investigating hypoglycaemic agents in pregnancy have used birthweight as the primary outcome, which provides only a crude estimate of fetal growth. In pregnancies where there are conflicting exposures influencing fetal growth and placental function absolute birthweight is not sufficient to detect subtle, but clinically significant changes in fetal growth and placental function. To address this limitation, in this study longitudinal measures of fetal growth will be used to quantify the deviation in fetal growth in the third trimester using fetal growth trajectory predictions based on second trimester fetal growth measurements from the same fetus. This will provide a much more sensitive assessment of the effect of metformin on fetal growth; the use of a continuous measure as a primary outcome also makes the study much more efficient as it requires a smaller sample size. Furthermore, longitudinal angiogenic markers will be measured to determine whether metformin has a measurable effect on placental function.
As it is routine clinical practice to offer metformin to women with hyperglycaemia, the intervention in this study will be to withhold metformin and manage hyperglycaemia with diet/insulin alone. A randomised study is essential to avoid treatment-selection bias and the study is necessarily open-label to aid the ongoing management of hyperglycaemia.
Objectives
Primary: To evaluate if withholding treatment with metformin in women, with type 2 diabetes or gestational diabetes (GDM) pregnancy AND risk factors for placental disease, affects fetal growth
Secondary: To evaluate the effect of the treatment on pregnancy outcome
Exploratory: To investigate the effect of metformin treatment on placental function and measures of maternal cardiometabolic health
MIMICH II:
There is only limited evidence regarding the impact of in utero metformin exposure on childhood metabolic health.
Postnatal catch-up or accelerated growth has been consistently associated with insulin resistance and metabolic syndrome-related disorders (e.g. type 2 diabetes) in later life. Accelerated growth during early postnatal life, irrespective of birth weight, has been shown to associate with changes in -cell function at 12 months and appears to be particularly important for metabolic health in later life. It is unclear from existing studies whether metformin exposure in utero affects postnatal catch up and therefore impacts future cardiometabolic health in later life.
Maternal cardiometabolic health after pregnancy
In women with cardiometabolic risk factors before pregnancy and who have an increased risk of adult cardiovascular mortality, immediate postnatal cardiometabolic health is especially important. It is not expected that metformin will have a significant long-term impact on cardiometabolic health in the mothers, but the absence of beneficial or deleterious effects are very important to guide future therapy guidelines.
Objectives
Primary: To determine what impact metformin has on early postnatal growth and metabolic function, in infants born to women with poor cardiometabolic health
Secondary: To determine if maternal exposure to metformin during pregnancy improves maternal cardiometabolic health status 1 year after pregnancy
