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

Abstract

Objective To determine if treatment with pravastatin prevents preeclampsia in pregnant patients at risk for preeclampsia. Material & Methods The study was performed in four major tertiary hospitals in Surabaya, Bandung, and Makassar between 2017-2021. Pregnant women at high risk of developing preeclampsia were recruited and randomized into an intervention group and control group. The control group received low dose aspirin (80 mg) and calcium (1 g) daily, while the intervention group received additional pravastatin (20 mg twice daily) started from 14-20 weeks’ gestation until delivery. The pregnancy was followed until delivery, and the clinical data was collected. The primary outcome was the occurrence of preeclampsia. Result A total of 173 people participated in this study, including 86 in the control group and 87 in the pravastatin group. The pravastatin group had a significantly lower rate of preterm preeclampsia (13.8% vs 26.7%; p=0.034; (OR=0.034, 95% CI: 0.202-0.905) and preterm birth (16.1 % vs. 36 %; p=0.003; OR= 0.340, 95% CI: 0.165-0.7), mostly indicated preterm birth. Preeclampsia occurs later in the pravastatin group than in the control group (36.39+2.32 vs 34.89+3.38 weeks, p=0.048). Overall the pravastatin group had better perinatal outcomes. Neonates with low Apgar scores (<7) at 1 minute (5.7% vs 25.6%, p=0.000) and 5 minutes (2.3% vs 25.6%, p=0.028) were significantly less common in the pravastatin group. Additionally, the rate of low birthweight babies (< 2500g) was lower in pravastatin group (27.6% vs 40.7%; p= 0.069). Conclusion Pravastatin (20 mg bid) significantly reduces the risk for preterm preeclampsia and preterm birth in women at a high risk of developing preeclampsia.

Pre-eclampsia

“…Pravastatin is an oral statin used to lower LDL cholesterol and triglycerides, which also has anti-inflammatory actions. A trial in 173 women at high risk of developing pre-eclampsia reported that daily pravastatin from the second trimester (14-20 weeks of gestation) until delivery significantly reduced the rate of preterm pre-eclampsia (13.8% versus 26.7% in the control group) and preterm birth 271 . Pravastatin may not be effective at preventing term pre-eclampsia: there was no reduction in the incidence of term pre-eclampsia in this 271 or another trial of 1,120 women at high risk of developing term pre-eclampsia given daily pravastatin from 35-37 weeks of gestation to delivery 272 .…”

Challenges in Conducting Therapeutic Trials in Pregnancy: Emphasizing Recent Lessons Learned

“…For example, 2 small randomized placebo‐controlled trials, conducted by the National Institute of Child Health and Human Development Obstetric‐Fetal Pharmacology Research Centers (NICHD‐OPRC) Network, in which pravastatin 10 and 20 mg were used daily starting at 12‐16 weeks, showed that compared to placebo, pravastatin use among those with a history of severe preeclampsia that required delivery at <34 weeks was associated with lower rates of preeclampsia, preeclampsia with severe features, and indicated preterm delivery before 37 weeks 52,53 . Similarly, the Indonesia Pravastatin to Prevent Preeclampsia Study (INOVASIA) showed that pravastatin (20 mg twice daily) added to standard of care was associated with lower rates of preterm preeclampsia (<37 weeks) and preterm birth, as well as better perinatal and neonatal outcomes (including lower rates of low and very low birth weight and higher Apgar scores) 54 . On the other hand, a large multicenter trial randomly assigned 1120 pregnant people at high risk (≥1 in 20 likelihood) for term preeclampsia to receive pravastatin 20 mg daily versus placebo from 35 to 37 weeks of pregnancy until delivery or 41 weeks 55 .…”

“…52,53 Similarly, the Indonesia Pravastatin to Prevent Preeclampsia Study (INOVASIA) showed that pravastatin (20 mg twice daily) added to standard of care was associated with lower rates of preterm preeclampsia (<37 weeks) and preterm birth, as well as better perinatal and neonatal outcomes (including lower rates of low and very low birth weight and higher Apgar scores). 54 On the other hand, a large multicenter trial randomly assigned 1120 pregnant people at high risk (≥1 in 20 likelihood) for term preeclampsia to receive pravastatin 20 mg daily versus placebo from 35 to 37 weeks of pregnancy until delivery or 41 weeks. 55 While pravastatin was not effective in preventing preeclampsia in this trial, 55 likely due to its being started too late in pregnancy, the study demonstrates the safety of pravastatin in pregnancy, especially in the late third trimester, a critical time of myelination for the developing fetus.…”

Strategies for Safeguarding High-Risk Pregnancies From Preterm Birth: A Narrative Review

“…Pravastatin (20 mg bid) can be used to prevent preeclampsia and preterm birth in high-risk women; compared to control, pravastatin reduced preterm birth (16.1 vs. 36%, p=0.003, OR=0.340), and was generally related to better perinatal outcomes [36].…”