MICA: A pragmatic approach to the prevention of gestational diabetes and pre-eclampsia in obese pregnant women in resource poor settings

Gestational diabetes (too much sugar in the blood in pregnancy) and pregnancy hypertensive disorders (high blood pressure that occurs in pregnancy, and which can lead to fits in the mother and death in the baby) cause significant maternal and neonatal mortality and morbidity in low and middle income countries and there is no systematic approach to prevention. The estimated global prevalence of gestational diabetes is 16%, with higher rates in in South Asia and Africa [1]. Gestational diabetes increases the incidence of the adverse outcomes of caesarean section, pregnancy induced hypertensive disease, excessive birthweight, birth injury, future obesity and future diabetes: untreated, it contributes to a cycle which promotes obesity and diabetes in future generations[2]. Pregnancy hypertensive disorders account for 17.3% of maternal deaths in low socio-economic countries, and are the second commonest cause of maternal death after haemorrhage[3].

In resource rich countries, testing for gestational diabetes is undertaken in women at high risk, together with treatment of those affected and regular self-monitoring of blood sugar levels. Such an approach is inappropriate in resource poor settings due to the high cost of testing and blood sugar monitoring, and the lack of availability of blood sugar monitoring kits. However, measurement of maternal body mass index (weight and height) cheaply and effectively identifies a high-risk group for both gestational diabetes and pregnancy hypertensive disorders. Additionally, one of the treatments (metformin) for gestational diabetes is relatively cheap, widely available, and safe, regardless of blood sugar levels [4-6]. Recent in vitro and clinical data suggest that metformin might reduce the incidence and severity of pregnancy hypertensive disorders [6-8]. We propose that metformin could be a pragmatic approach to preventing gestational diabetes and pregnancy hypertensive disorders in obese pregnant women in resource poor settings.

This is a feasibility study of a clinical trial to determine whether metformin is effective in preventing gestational diabetes and pregnancy hypertensive disorders in women at high risk of both conditions. In this feasibility study, we will find out if it is possible for us to do a full trial, how big such a trial would be, and how expensive it would be. We will ask obese pregnant women in participating sites in Malawi and Zambia to take either metformin or matching placebo tablets. We will see how many women wish to participate, how many take the treatment, and what effect the treatment has. We will also be able to see how common gestational diabetes and pregnancy hypertensive disorders are in this population. Although this feasibility study is too small to answer the question "Is routine administration of metformin a pragmatic approach to preventing gestational diabetes and pregnancy hypertensive disorders in obese pregnant women in resource poor settings" it will facilitate a larger (and likely more expensive study) to be able to do so. Our group of clinicians, researchers and policy makers in Malawi, Zambia and the UK has the necessary expertise to carry out both the feasibility study and a further substantive study, and we are well placed to be able to translate the results of the research into clinical practice.

References
1. International Diabetes Federation (IDF) IDF Diabetes Atlas, 7th Edition, 2015.
2. NICE, Diabetes in pregnancy. NICE guideline 2015.
3. Global Burden of Disease Maternal Mortality and Morbidity Collaborators, Lancet, 2016. 388: p. 1775-1812.
4. Balsells, M., et al., BMJ, 2015. 350: p. h102.
5. Chiswick, C., et al., Lancet Diabetes Endocrinol, 2015. 3: p. 778-86.
6. Syngelaki, A., et al., N Engl J Med, 2016. 374: p. 434-43.
7. Brownfoot, F.C., et al., Am J Obstet Gynecol, 2016. 214: p. 356 e1-356 e15.
8. Romero, R., et al., Am J Obstet Gynecol, 2017. 217: p. 282-302

This is a feasibility study of a double masked randomised clinical trial of metformin (compared with matched placebo) for the prevention of gestational diabetes and pregnancy hypertensive disorders in women at high risk of both conditions. In PICO terms, the feasibility study is as follows:

Population: Obese pregnant women (BMI 26 kg/m2) in Malawi and Zambia.
Intervention: Metformin oral tablets (750mg slow release), up to 2.25mg daily from first visit (and certainly before 20 weeks gestation) until delivery, taken in addition to the current standard of care.
Comparator. Matched placebo taken with same frequency over similar duration of pregnancy again taken in addition to the current standard of care
Outcomes. Primary outcome: recruitment rate, incidence of gestational diabetes mellitus (ascertained by fasting 75g oral glucose tolerance test at 24-28 weeks gestation, results of which will be concealed until the end of pregnancy).

Sample size. In line with NIHR recommendations, we have not performed a formal sample size calculation for this feasibility study, we aim to recruit 100 women in each of the two sites: 200 in total.

In this feasibility study (trial development grant) we aim to determine
1. Whether a double blind randomised placebo controlled trial of metformin versus placebo, both given to obese pregnant women for the prevention of gestational diabetes and pre-eclampsia is feasible?
2. The prevalences of gestational diabetes and pregnancy hypertensive disorders in obese pregnant women in Malawi and Zambia?

We anticipate that the results of this feasibility study should facilitate a funding application for a definitive randomised trial of metformin in this scenario. Ultimately, we hope to show that universal treatment of overweight/obese pregnant women with metformin in low and middle income settings is effective in reducing GDM and pregnancy hypertensive disorders, safe, easy to implement and affordable.

This is a feasibility study to determine whether a substantive trial of a pragmatic approach to preventing and treating gestational diabetes and pregnancy hypertensive disorders in pregnant women in resource poor settings is feasible. We are guided by a Theory of Change model with "inputs" of MRC funding and the expertise of the co-applicants, and "outputs" as the activities of the applicants and the findings of the PAPAGENO study.

We anticipate the following impacts:
Academic
Open access publications and presentations at appropriate regional/international meetings
Training and capacity building of early career/senior researchers/research support staff
Project specific meetings to foster future multi-disciplinary collaborations and grant applications
Data sharing partners, academic community and local study populations.
Economic/societal
New knowledge targeted to local needs leading to increased effectiveness of public services
Improved health and quality of life for mothers and newborns
economic productivity through improved health of mothers
Improvements in research quality and impact
Higher profile of partner organisations from skills development and publications
Public engagement leading to greater health knowledge and empowerment of populations.

We plan for impact to be achieved via multiple channels:
Knowledge exchange (publications and presentations; direct communication with policymakers, practitioners and public) via range of appropriate communications channels
Development of effective new health processes
Development of relevant new skills
Improvement in effectiveness of local health services and health policy (through implementation of new knowledge