Comparing the efficacy of metformin plus aspirin with aspirin alone in preventing preeclampsia in high risk pregnancies: a randomized controlled trial

Hypertensive disorders of pregnancy accounts for approximately 18.1% maternal mortality with preeclampsia syndrome, complicating 2% to 3% of pregnancies worldwide. Clinicians are often forced to deliver early on maternal indications to prevent major maternal morbidity but in doing so, inflict severe prematurity on the fetus and put them at significant risk of severe disability including cerebral palsy, stroke (intracerebral bleeding), retinopathy of prematurity, chronic lung disease and death. The use of metformin in pregnancy is gaining pace as it is shown possibly to be efficacious in the prevention of pre-eclampsia as it is shown to reduce soluble fms-like tyrosine kinase-1 levels, which correlate significantly with gestational age at onset of pre-eclampsia and severity and altering maternal endothelial function. It has also been suggested that metformin may prevent pre-eclampsia by improving cardiovascular function and limiting gestational weight gain which is instrumental in the pathogenesis of late onset preeclampsia. The MiG trial’s offspring 2year follow-up showed that infants exposed to metformin had higher total body fat without any adverse outcomes, suggesting a healthier fat distribution. There was also a possible trend towards lower LDL cholesterol levels.

Hence, with a sample size of 132, we have designed a randomized control trial comparing the efficacy of metformin 1gm/day plus aspirin 150mg/day versus Aspirin 150mg alone (standard of care) in prevention of early onset preeclampsia as the primary outcome and comparison of adverse feto-maternal outcomes and incidence of late onset preeclampsia between the two groups as a secondary outcomes in all women who are deemed high-risk following first trimester combined screening using FMF algorithm [combining Maternal charactericstics, Mean Arterial pressure, Uterine artery Pulsatility Index, PLGF levels] with singleton pregnancies who are attending for their routine hospital visit at 11-13 weeks’ gestation trial.

Candidates who meet the inclusion criteria, will be enrolled for the study and will be randomly allocated into the 2 intervention groups. Primary outcome will be measured as incidence of preeclampsia developing pre term, diagnosed by ISSHP guidelines. Incidence of adverse maternal outcomes like cardiorespiratory complications, renal complications, hepatological and haematological complications, placental abruption, neurological complications along with core offspring adverse events like stillbirth, neonatal mortality rates gestational age at delivery, small-for-gestational-age, admission to neonatal unit required and respiratory support will be measured secondarily. Student t test will be applied to compare between the 2 groups .Two sided p values will be considered as statistically significant at p<0.05