Periodic Reporting for period 2 - MIMICH (Metformin Impact on Maternal and Infant Cardiometabolic Health)
Reporting period: 2022-08-01 to 2024-01-31
The problem being addressed
MIMICH
Amongst women with poor cardiometabolic health embarking on pregnancy, hyperglycaemia is a very common feature. 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 fact that the majority of women with hyperglycaemia have 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 a combination of 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. There is some circumstantial evidence from the clinical trials, which have used metformin to limit fetal growth in women with hyperglycaemia, that metformin reduces the risk of gestational hypertension. However, the effect on the rate of pre-eclampsia, was not clear which may reflect different disease aetiologies between some types of pre-eclampsia and gestational hypertension. The effect of metformin on both maternal cardiometabolic health and placental function therefore warrants further investigation so that this therapy can be targeted to the women who will benefit most.
Given the uncertainty regarding the potential benefits (improvement in maternal metabolic health and reduction in hypertensive disease) but potential negative effects on placental function (reduction in fetal growth and antiproliferative cellular actions), 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. During the course of this trial, metformin will continue to be offered to women with type 2 diabetes and GDM who do not have risk factors for placental disease and/or where the baby is ≥50th centile after 24 weeks, where the overriding goal of therapy is the prevention of fetal macrosomia and its associated complications.
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:
To date there is only limited evidence regarding the impact of in utero metformin exposure on childhood metabolic health.
Postnatal catch-up or accelerated growth often defined as a delta weight SD score >0.5 or 0.67 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. Of note, infants exposed to metformin in the EMPOWaR study, a randomized study of obese pregnant women, were thinner (lower ponderal index) at birth, which if associated with accelerated postnatal weight gain (akin to the mouse studies), could confer an increased cardiometabolic risk to the offspring.
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
MIMICH
Amongst women with poor cardiometabolic health embarking on pregnancy, hyperglycaemia is a very common feature. 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 fact that the majority of women with hyperglycaemia have 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 a combination of 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. There is some circumstantial evidence from the clinical trials, which have used metformin to limit fetal growth in women with hyperglycaemia, that metformin reduces the risk of gestational hypertension. However, the effect on the rate of pre-eclampsia, was not clear which may reflect different disease aetiologies between some types of pre-eclampsia and gestational hypertension. The effect of metformin on both maternal cardiometabolic health and placental function therefore warrants further investigation so that this therapy can be targeted to the women who will benefit most.
Given the uncertainty regarding the potential benefits (improvement in maternal metabolic health and reduction in hypertensive disease) but potential negative effects on placental function (reduction in fetal growth and antiproliferative cellular actions), 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. During the course of this trial, metformin will continue to be offered to women with type 2 diabetes and GDM who do not have risk factors for placental disease and/or where the baby is ≥50th centile after 24 weeks, where the overriding goal of therapy is the prevention of fetal macrosomia and its associated complications.
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:
To date there is only limited evidence regarding the impact of in utero metformin exposure on childhood metabolic health.
Postnatal catch-up or accelerated growth often defined as a delta weight SD score >0.5 or 0.67 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. Of note, infants exposed to metformin in the EMPOWaR study, a randomized study of obese pregnant women, were thinner (lower ponderal index) at birth, which if associated with accelerated postnatal weight gain (akin to the mouse studies), could confer an increased cardiometabolic risk to the offspring.
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
Work performed since the beginning of the project has been:
• Obtaining sponsorship
• Recruitment of the Project Manager
• Writing and submitting the ethics application for MIMICH (including creating all applicable documentation for the trial)
• Database creation and testing
• Obtaining NHS approval and the notification of no objection to open the trial at site
• Creation of trial management group (TMG) and trial oversight committee (TOC)
• Obtaining relevant 3rd party contracts e.g. Sealed Envelope randomisation platform
• Participant recruitment
• Continuous trial monitoring (data cleaning) including data verification and query raising and resolution
• Recruitment of PhD students, lab techs and trial assistant
• Placental collection and experimentation (approx. 19 high resolution respirometry tests and protein assay, and approx. 20 RNA extractions for RNA-seek) – no results as yet due to early stage of experimentation (PhD student project commenced October 2022)
• Blood sample processing and storage for later experimentation (per participant)
• Obtaining sponsorship for MIMICH II
• Writing and submitting ethics application for MIMICH II
• Database creation and testing
• Amendment submissions and implementation
• Continuous report writing including monthly TMG reports, monitoring reports and TOC reports
• Regular recruitment and budget management meetings
• Obtaining sponsorship
• Recruitment of the Project Manager
• Writing and submitting the ethics application for MIMICH (including creating all applicable documentation for the trial)
• Database creation and testing
• Obtaining NHS approval and the notification of no objection to open the trial at site
• Creation of trial management group (TMG) and trial oversight committee (TOC)
• Obtaining relevant 3rd party contracts e.g. Sealed Envelope randomisation platform
• Participant recruitment
• Continuous trial monitoring (data cleaning) including data verification and query raising and resolution
• Recruitment of PhD students, lab techs and trial assistant
• Placental collection and experimentation (approx. 19 high resolution respirometry tests and protein assay, and approx. 20 RNA extractions for RNA-seek) – no results as yet due to early stage of experimentation (PhD student project commenced October 2022)
• Blood sample processing and storage for later experimentation (per participant)
• Obtaining sponsorship for MIMICH II
• Writing and submitting ethics application for MIMICH II
• Database creation and testing
• Amendment submissions and implementation
• Continuous report writing including monthly TMG reports, monitoring reports and TOC reports
• Regular recruitment and budget management meetings
By the end of the MIMICH project we are on track to deliver on the following state of the art objectives:
1. First trial to assess fetal growth using 3D ultrasound in the context of a treatment intervention in pregnancy for the management of diabetes
2. First study to correlate postnatal childhood growth to fetal adipose growth during pregnancy
3. First study to perform molecular phenotyping of the placenta in women with cardiometabolic disease in pregnancy
4. First study to describe the impact of in vivo exposure to metformin on placental function
1. First trial to assess fetal growth using 3D ultrasound in the context of a treatment intervention in pregnancy for the management of diabetes
2. First study to correlate postnatal childhood growth to fetal adipose growth during pregnancy
3. First study to perform molecular phenotyping of the placenta in women with cardiometabolic disease in pregnancy
4. First study to describe the impact of in vivo exposure to metformin on placental function