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Statins to prevent or treat preeclampsia: sometimes it is too late

Published:October 17, 2021DOI:https://doi.org/10.1016/j.ajog.2021.10.014
      The use of pravastatin in obstetrics has become an important subject addressed in several publications in the American Journal of Obstetrics & Gynecology.
      • Smith D.D.
      • Costantine M.M.
      The role of statins in the prevention of preeclampsia.
      ,
      • Costantine M.M.
      • West H.
      • Wisner K.L.
      • et al.
      A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia.
      Two randomized placebo-controlled clinical trials on the efficacy of pravastatin to treat women with early-onset preeclampsia or prevent term preeclampsia did not show evidence of benefit.
      • Smith D.D.
      • Costantine M.M.
      The role of statins in the prevention of preeclampsia.
      ,
      • Döbert M.
      • Varouxaki A.N.
      • Mu A.C.
      • et al.
      Pravastatin versus placebo in pregnancies at high risk of term preeclampsia.
      This is in contrast with the results of preclinical studies, including case reports where pravastatin—either as a treatment or as a prophylaxis—seemed to be effective.
      • Smith D.D.
      • Costantine M.M.
      The role of statins in the prevention of preeclampsia.
      What positive pravastatin reports have in common is that the medication was administered in the first trimester of pregnancy or at the beginning of the second trimester of pregnancy.
      • Smith D.D.
      • Costantine M.M.
      The role of statins in the prevention of preeclampsia.
      The rationale for statin administration is to reverse the angiogenic or antiangiogenic imbalance that is detected before the clinical recognition of preeclampsia
      • Romero R.
      • Nien J.K.
      • Espinoza J.
      • et al.
      A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.
      and other great obstetrical syndromes, such as fetal death
      • Whitten A.E.
      • Romero R.
      • Korzeniewski S.J.
      • et al.
      Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death.
      and massive perivillous fibrin deposition.
      • Soto E.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion.
      Pravastatin can improve the angiogenic or antiangiogenic profile when administered early. Thus, we believe that the appropriate approach to test the efficacy of pravastatin is to administer it as soon as an abnormal angiogenic or antiangiogenic profile is detected. Longitudinal studies show that abnormalities in placental growth factor, soluble fms-like tyrosine kinase-1, and endoglin are detectable at different times in pregnancy according to the specific obstetrical syndrome.
      • Romero R.
      • Nien J.K.
      • Espinoza J.
      • et al.
      A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.
      For example, the abnormalities are detected earlier in patients with massive perivillous fibrin deposition than in patients destined to develop preeclampsia.
      • Soto E.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion.
      We believe that the lack of efficacy of pravastatin to prevent late-onset preeclampsia when started at 36 weeks of gestation
      • Döbert M.
      • Varouxaki A.N.
      • Mu A.C.
      • et al.
      Pravastatin versus placebo in pregnancies at high risk of term preeclampsia.
      may reflect that the medication has been administered too late in pregnancy and that some patients with late-onset preeclampsia do not have an abnormal angiogenic or antiangiogenic profile.
      • Soto E.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion.
      We believe that future trials on the efficacy of pravastatin to prevent preeclampsia or other adverse pregnancy outcomes should select patients based on the abnormality in the angiogenic or antiangiogenic profile and the medication be started early in the midtrimester of pregnancy to increase the likelihood of a therapeutic effect, which is unlikely to be realized when the drug is started at 36 weeks of gestation. The initiation of pravastatin in the second trimester of pregnancy would decrease the potential teratogenic risk of pravastatin when administered in the first trimester of pregnancy.
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      References

        • Smith D.D.
        • Costantine M.M.
        The role of statins in the prevention of preeclampsia.
        Am J Obstet Gynecol. 2020; ([Epub ahead of print])
        • Costantine M.M.
        • West H.
        • Wisner K.L.
        • et al.
        A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia.
        Am J Obstet Gynecol. 2021; ([Epub ahead of print])
        • Döbert M.
        • Varouxaki A.N.
        • Mu A.C.
        • et al.
        Pravastatin versus placebo in pregnancies at high risk of term preeclampsia.
        Circulation. 2021; 144: 670-679
        • Romero R.
        • Nien J.K.
        • Espinoza J.
        • et al.
        A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.
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        • Romero R.
        • Korzeniewski S.J.
        • et al.
        Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death.
        Am J Obstet Gynecol. 2013; 208: 310.e1-310.e11
        • Soto E.
        • Romero R.
        • Kusanovic J.P.
        • et al.
        Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion.
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      Linked Article

      • Reply: Timing of pravastatin initiation for preeclampsia prevention
        American Journal of Obstetrics & Gynecology
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          We read with interest the letter by Voto and Zeitune that highlighted important considerations regarding the investigation of pravastatin in the prevention of preeclampsia.1 As reported by the authors, 2 randomized placebo-controlled clinical trials of pravastatin evaluating the treatment of early-onset preeclampsia2 and prevention of term preeclampsia3 did not show evidence of benefit or reduction in antiangiogenic biomarkers. This is in contrast to preclinical murine studies,4,5 randomized placebo-controlled pilot clinical trials in the United States,6,7 and a recent trial in Indonesia, all of which showed the use of pravastatin in improving angiogenic and antiangiogenic profiles and preventing preeclampsia.
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