Prevention of Pre-eclampsia Using Metformin: a Randomized Control Trial (PREMET)

This is an open label, randomized control trial (RCT) in which high risk for pre-eclampsia pregnant subjects will be randomly assigned to either an intervention group (metformin 1 gm twice daily plus aspirin 100 mg per day and standard of care) versus control group (aspirin 100 mg per day and standard of care) that will be administered between 11 to 13 weeks of gestation until delivery . Only women at high risk of pre-eclampsia as defined by the ACOG practice bulletin will be included (see inclusion criteria). Patient assignment will not be blinded as control group will not be given a placebo; the data will be analyzed on an intention to treat basis. Enrolled subjects will be followed throughout pregnancy and up to 30 days post-delivery (as per hospital practice).

Preeclampsia (PET) is one of the leading causes of maternal morbidity and mortality . Its pathophysiology is poorly understood. Consequently, there are no efficient preventive and treatment modality. PET is associated with significant perinatal morbidity and mortality including prolonged hospitalization and is a major contributor to a large proportion of iatrogenic preterm birth. Women who suffer from PET are at a greater risk of hypertensive and cardiovascular diseases in later life and more likely to suffer from premature death. Since the only treatment for PET is delivery, a logical approach to reducing the incidence and therefore consequences is prevention. For this to be effective those at risk have to be identified and any timely interventions introduced. Amongst the risk factors are maternal age, obesity, medical disorders such as antiphospholipid syndrome, hypertensive disorders, renal diseases diabetes mellitus and previous PET. A history of PET increases the risk of recurrence 7 fold and this is compounded by GA at delivery for the affected pregnancy . Moreover, both chronic hypertension and pre-existing diabetes increase the risk of PET which is further enhanced by the degree of glycemic control. Interestingly maternal and paternal history of diabetes and hypertension have been associated with increased risk of PET. Additionally, maternal age > 40 years and pregnancy interval > 10 years increases the risk of PET by two to three folds respectively .A BMI > 35 increases the risk of PET by 4 folds in both multiparous and nulliparous women. Moreover, assisted reproduction techniques and multiple gestation have also been associated with increased risk of PET. A combination of diabetes and obesity, which has a high prevalence in Qatar, significantly increases the risk of PET. Despite these risk factors only a fraction of those with at high risk eventually develop PET as the current criteria for prediction is not specific. Various measures to predict, prevent and treat pre-eclampsia have been investigated and tried by several groups/researchers. However, these have not been very successful, primarily because PET is a disease of theories with an unclear primary pathophysiology and thus no clear target for either these predictive tools or interventions. Evidence, however, does suggest that in patients at risk of developing PET there is inadequate trophoblastic invasion, placental hypo-perfusion, and endothelial cell activation . This the basis for the most widely noninvasive clinical tool of Doppler velocimetry of the uterine artery; but again, this has a poor sensitivity. An imbalance in pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) (decreased) and antiangiogenic factors such as soluble FMSlike tyrosine kinase -1 (sFlt-1) (increased) has been implicated for the inadequate remodeling of spiral arteries (which is essential for the maintenance of a normal placental perfusion) in women who develop PET. Vascular endothelial growth factor (VEGF) is an important signaling protein in health and diseases such as cancer, kidney diseases and PET . The VEGF family is composed of five members and three tyrosine kinase receptors. The signaling proteins are: VEGFA, VEGFB,VEGFC, VEGFD and placental growth factor (PlGF) (reviewed in (20)). The receptor tyrosine kinase consists of VEGFR1 (also known as Flt-1), VEGFR2 and VEGF3, with different binding capacity to VEGF proteins . A soluble Fms like tyrosine kinase-1 (sFlt-1) a truncated form of VEGFR1, has also been identified which lacks the VEGFR1 cytosolic domain. In addition to ligand binding, VEGFR has been shown to be activated through non-ligand binding and mechanical forces. VEGF proteins are upregulated under hypoxic conditions such as PET, growth factor signaling and by hormones such as estrogen .PET is characterized by a hypoxic environment, resulting in considerable changes in maternal leukocyte gene expression, altered expression of the VEGF signaling pathway and AMPactivated protein kinase (AMPK) and secretion of sFlt-1 into the maternal circulation.VEGF including PIGF has been identified as a crucial in the signaling pathway for angiogenesis and vasculogenesis during placental development .Indeed, deletion of a single VEGF allele in mice resulted in embryonic lethality due to immature angiogenesis. The invasion of maternal spiral arteries by cytotrophoblasts is vital for adequate oxygen and nutrient supply . This process is believed to be mediated by binding of VEGF and PIGF to Flt-1 . Further, fetal DNA variants at the Flt-1 region has been associated with PET and reported recently . However, the pathophysiology of PET is still unclear and understanding of its molecular mechanism is warranted. A decreased level of VEGF and PIGF free form has been observed that has been attributed to their blockade by the increased level of sFlt-1 in pre-eclamptic women . Indeed, the introduction of sFlt-1 to a pregnant rat led to hypertension and proteinuria similar to that seen in PET women . Furthermore, an altered ratio of serum PIGF/sFlt-1 has been found to be associated with PET diagnosis and disease severity . Indeed, there is now a drive to use this ratio in screening women at risk of PET but most of the data were generated in late pregnancy rather than in early pregnancy - a time when interventions have been shown to have maximum impact . It would seem from this greater understanding of the underlying physiological changes in women that develop PET that any interventions that have the potential to alter this milieu are more likely to be successful .Very recently a double-blind, placebo-controlled trial, that randomly assigned pregnant women without diabetes who had a body-mass index of more than 35 to receive metformin, at a dose of 3.0 g per day, or placebo (225 women in each group) from 12 to 18 weeks of gestation until delivery showed a significant reduction in the incidence of PET in those who received metformin . Since metformin is now frequently prescribed to obese type II diabetic women and gestational diabetics with poor glycemic control on diet, it is hypothesized in those at risk of PET, metformin will not only reduce the incidence of PET but will modify the PIGF/s-Flt-1 ratio in favor of normal pregnancies.

The control group will receive standard care treatment including aspirin according to ACOG guidelines. The control group estimated number of enrollment is 207 patients.

The intervention group will be give metformin 500 mg orally three times daily in addition to standard of care. The estimated number to be enrolled are 207 patients.

Metformin is a medication used for treatment of diabetes. In this study it will be used to explore is potential role in prevention of preeclampsia. The drug will start before 12 week of pregnancy and continue till delivery

To compare the incidence of PET between the metformin group (intervention group) versus control group

Comparing PIGF/sFlt-1 ratio in PET patients who received metformin versus PET patient in the standard care group

Comparing gestational age at PET onset, gestation age at delivery and PET severity between study groups

Inclusion Criteria: Confirmed pregnancy Gestational age < 12+0 weeks Live fetus at time of booking ultrasound scan (between 11+0 and 13+6 weeks of gestation) To be considered as high risk of preeclampsia Exclusion Criteria: Age under 18 years Hyperemesis gravidarum Unable to sign the consent form Type 1 or 2 diabetes mellitus Early gestational diabetes Auto-immune disease Fetal abnormality identified at time of scanning (between 11+0 and 13+6 weeks of gestation) Bleeding disorder Peptic ulcer Hypersensitivity to aspirin or metformin Long use of NSAIDS before initiation of intervention Contraindication to metformin or aspirin and participation in another concurrent trial.

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