Preventing Recurrent Gestational Diabetes With Metformin (PRoDroME)

Imperial College Healthcare NHS Trust, London North West Healthcare NHS Trust, The Novo Nordisk UK Research Foundation

Study Hypothesis: Intervention with metformin therapy early in pregnancy will prevent gestational diabetes mellitus recurring in previously affected pregnancies.

Gestational diabetes mellitus (GDM) is a common medical complication of pregnancy and is associated with increased risks to mother and baby. The incidence is increasing reflecting changing pre-gravid female demographics. Once one pregnancy is complicated by GDM, subsequent pregnancies are more likely to be affected by the same condition. This reported risk of recurrence is estimated to range between 35 and 80%, with non-caucasian ethnicity being the strongest predictor of GDM recurrence. Evidence regarding further predictors of recurrent GDM is conflicting and measures that might prevent recurrence need exploring. Metformin is commonly used in the treatment of established GDM and has been shown to reduce the incidence of GDM in the context of polycystic ovarian syndrome.

Metformin (500mg tablets) to start at a dose of 500mg once daily with an increase of 500mg every five days until the maximum dose of 1000mg twice daily is reached.

Matched placebo tablets (500mg) to start at a dose of 500mg once daily with an increase of 500mg every five days until the maximum dose of 1000mg twice daily is reached.

Composite of neonatal outcomes (neonatal hypoglycaemia requiring treatment, respiratory distress syndrome requiring oxygen therapy/ continuous positive airway pressure, neonatal hyperbilirubinaemia requiring phototherapy).

Difference in requirement for medical services and unplanned hospital/ General Practitioner attendances between the two arms

Inclusion Criteria: Singleton pregnancy; 8-22 weeks gestation Previous pregnancy complicated by gestational diabetes Exclusion Criteria: Established pre-existing diabetes (including unrecognised diabetes defined as a fasting plasma glucose ≥ 7.0mmol/L and/ or HbA1c ≥ 48mmol/mol); Contraindications to metformin therapy (creatinine ≥ 130μmol/L/ alanine transaminase ≥ 2.0 x upper limit normal/ previous intolerance to metformin) Planned continued antenatal care/ delivery at centre not included in trial Planned fast for cultural/ religious reasons e.g. Ramadan

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