INOVASIA Study: A Randomized Open Controlled Trial to Evaluate Pravastatin to Prevent Preeclampsia and Its Effects on sFlt1/PlGF Levels

Abstract

Objectives To evaluate the effect of pravastatin to prevent preeclampsia (PE) in pregnant women at a high risk of developing preeclampsia and the maternal and perinatal outcomes and the sFlt1/PLGF ratio. Study Design This is an open labelled RCT part of INOVASIA trial. Pregnant women at a high risk of developing PE were recruited and randomized into an intervention group (40) and a control group (40). The inclusion criteria consisted of pregnant women with positive clinical risk factor and abnormal uterine artery doppler examination at 10-20 weeks gestational age. The control group received low dose aspirin (80 mg/day) and calcium (1 g/day), while the intervention group received additional pravastatin (20 mg twice daily) starting from 14-20 weeks gestation until delivery. Research blood samples were collected before the first dose of pravastatin and before delivery. The main outcome was the rate of maternal preeclampsia, maternal-perinatal outcomes, and sFlt-1, PLGF, sFlt-1/PlGF ratio and sEng levels. Results The rate of preeclampsia was (non-significantly) lower in the pravastatin group compared with the control group (17.5% vs 35%). The pravastatin group also had a (non-significant) lower rate of severe preeclampsia, HELLP syndrome, acute kidney injury and severe hypertension. The rate of (iatrogenic) preterm delivery was significantly (p=0.048) lower in the pravastatin group (n=4) compared with the controls (n=12). Neonates in the pravastatin group had significantly higher birthweights (2931 + 537 vs 2625 + 872 g; p=0.006), lower Apgar scores < 7 (2.5 vs 27.5%, p=0.002), composite neonatal morbidity (0 vs 20%, p=0.005) and NICU admission rates (0 vs 15%, p=0.026). All biomarkers show a significant deterioration in the control group compared with non significant changes in the pravastatin group. Conclusions Pravastatin holds promise in the secondary prevention of preeclampsia and placenta-mediated adverse perinatal outcomes by improving the angiogenic imbalance.

INOVASIA Study: A Multicenter Randomized Clinical Trial of Pravastatin to Prevent Preeclampsia in High-Risk Patients

“…In the Surabaya arm of the INOVASIA study we were able to show that the serum sFlt-1 levels rose significantly during gestation in the control group, but only slightly in the pravastatin group. Serum PlGF levels went down significantly in the control group, but only slightly (non significant) in the pravastatin group 30 . Mendoza et al also reported that the ratio of sFlt1/PlGF was lowered in women with early onset fetal growth restriction treated with pravastatin compared to no therapy 63 .…”

“…24 We recently measured the serum levels of HO-1 and sFlt1 in early-onset preeclampsia, late-onset preeclampsia, and normal pregnancy. 25 There was no difference in serum HO-1 levels across the three groups, and no correlation between serum HO-1 and sFlt-1 levels. 25 Correcting the imbalance may eventually resolve the maternal endothelial cell dysfunction.…”

“…Another limitation is that we could not collect reliable data on prematurity-associated neonatal morbidities like respiratory distress syndrome and jaundice. In the Surabaya arm of INOVASIA trial, neonates in pravastatin group had a significantly lower composite morbidity (0 vs 20%) and NICU admission (0 vs 15%) in comparison to control group 30 .…”

“…PlGF, sEng, VEGF, NO, IL-6, and ET-1 substantially 30,31 . In the Surabaya arm of the INOVASIA study we were able to show that the serum sFlt-1 levels rose significantly during gestation in the control group, but only slightly in the pravastatin group.…”

“…We recently reported biomarker data from the Surabaya center, which was the only center in the INOVASIA study with ability to assay serum sFlt and PLGF [28]. In the Surabaya arm of the INOVASIA study, we demonstrated that pravastatin may more or less stabilize serum levels of sFlt1, PlGF, and sEng when compared with the marked deterioration in the control group 30 .…”