Prevention of recurrent preeclampsia in high-risk pregnancies: Is it time for a paradigm shift?

Statins are the class of drugs traditionally used to treat hyperlipidemia. Owing to the association of preeclampsia and high maternal hyperlipidemia and its ability to reverse an angiogenic imbalance and correct endothelial dysfunction, pravastatin (hydrophilic statin) has been used to prevent or treat preeclampsia during pregnancy. Although pravastatin has been demonstrated to have preventative effects in preeclampsia model mice without negatively affecting offspring outcomes, and the Food and Drug Administration removed the “Pregnancy Category X” label for statins, their safety concerning the fetus is still of concern. Recently, Costantine et al1Costantine M.M. Clifton R.G. Boekhoudt T.M. et al.Long-term neurodevelopmental follow-up of children exposed to pravastatin in utero.Am J Obstet Gynecol. 2023; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (2) Google Scholar determined the long-term neuromotor, cognitive, and behavioral outcomes of children exposed to pravastatin in utero during the second and third trimesters of pregnancy. The study included 15 participants receiving treatment with pravastatin (8 assigned to the 10-mg group and 7 to the 20-mg group) and 15 participants receiving a placebo. No identifiable long-term neurodevelopmental safety signal was evident with the use of pravastatin during pregnancy at a follow-up median of 4.7 years (interquartile range, 2.5–6.9). However, there are some confusions in this study that need to be explained. The sample size is too small. This study was started in 2012 (Investigational New Drug number: 114205; ClinicalTrials.gov identifier: NCT01717586).2Costantine M.M. Cleary K. Hebert M.F. et al.Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.Am J Obstet Gynecol. 2016; 214: 720.e1-720.e17Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar Despite holding during the phase of the COVID-19 pandemic (March 16, 2020 to June 2, 2020), why had so few patients been recruited in this study during the study period at 5 sites? What was the total number of patients included in this clinical trial? The Child Behavior Checklist was used to assess the child’s behavioral problems and social competencies as reported by parents. It was given to individuals aged 1.5 to 5.0 years (n=22) and 6.0 to 18.0 years (n=7). Considering the start year of 2012, what was the age distribution of the 7 children, and why was there an 18-year-old child? There is a randomized, blinded, placebo-controlled trial that found that a pravastatin dosage of 40 mg daily had no detectable adverse effects on the short-term health of offspring with early-onset preeclampsia.3Ahmed A. Williams D.J. Cheed V. et al.Pravastatin for early-onset pre-eclampsia: a randomised, blinded, placebo-controlled trial.BJOG. 2020; 127: 478-488Crossref PubMed Scopus (72) Google Scholar Furthermore, there is a study that found that statins were associated with an increased risk of low birthweight and preterm labor.4Chang J.C. Chen Y.J. Chen I.C. Lin W.S. Chen Y.M. Lin C.H. Perinatal outcomes after statin exposure during pregnancy.JAMA Netw Open. 2021; 4e2141321Crossref Scopus (11) Google Scholar We agree with Costantine et al1Costantine M.M. Clifton R.G. Boekhoudt T.M. et al.Long-term neurodevelopmental follow-up of children exposed to pravastatin in utero.Am J Obstet Gynecol. 2023; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (2) Google Scholar that their study indicates a trend toward improved motor and cognitive functions in the children of women who have a history of preeclampsia and who were receiving antenatal pravastatin. This finding might warrant its earlier use to prevent preeclampsia in high-risk women and justify a larger clinical trial to confirm its effectiveness. Reply: Investigations of pravastatin for the prevention of preeclampsiaAmerican Journal of Obstetrics & GynecologyPreviewWe thank Lin and Li1 for their interest in our study and their letter, which highlights important considerations regarding investigations of pravastatin for the prevention of preeclampsia. Full-Text PDF