Esomeprazole to treat women with preterm preeclampsia: a randomized placebo controlled trial


      Preterm preeclampsia has a high rate of fetal death or disability. There is no treatment to slow the disease, except delivery. Preclinical studies have identified proton pump inhibitors as a possible treatment.


      The purpose of this study was to examine whether esomeprazole could prolong pregnancy in women who have received a diagnosis of preterm preeclampsia.

      Study Design

      We performed a double-blind, randomized controlled trial at Tygerberg Hospital in South Africa. Women with preterm preeclampsia (gestational age 26 weeks+0 days to 31 weeks+6 days) were assigned randomly to 40-mg daily esomeprazole or placebo. The primary outcome was a prolongation of gestation of 5 days. Secondary outcomes were maternal and neonatal outcomes. We compared circulating markers of endothelial dysfunction that was associated with preeclampsia and performed pharmacokinetic studies.


      Between January 2016 and April 2017, we recruited 120 participants. One participant was excluded because of incorrect randomization, which left 59 participants in the esomeprazole and 60 participants in the placebo group. Median gestational age at enrolment was 29+4 weeks gestation. There were no between-group differences in median time from randomization to delivery: 11.4 days (interquartile range, 3.6–19.7 days) in the esomeprazole group and 8.3 days (interquartile range, 3.8–19.6 days) in the placebo group (3 days longer in the esomeprazole arm; 95% confidence interval, –2.9–8.8; P=.31). There were no placental abruptions in the esomeprazole group and 6 (10%) in the placebo group (P=.01, P=.14 adjusted). There were no differences in other maternal or neonatal outcomes or markers of endothelial dysfunction. Esomeprazole and its metabolites were detected in maternal blood among those treated with esomeprazole, but only trace amounts in the umbilical cord blood.


      Daily esomeprazole (40 mg) did not prolong gestation in pregnancies with preterm preeclampsia or decrease circulating soluble fms-like tyrosine kinase 1 concentrations. Higher levels in the maternal circulation may be needed for clinical effect.

      Key words

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        • Abalos E.
        • Cuesta C.
        • Grosso A.L.
        • Chou D.
        • Say L.
        Global and regional estimates of preeclampsia and eclampsia: a systematic review.
        Eur J Obstet Gynecol Reprod Biol. 2013; 170: 1-7
        • Duley L.M.
        The global impact of pre-eclampsia and eclampsia.
        Semin Perinatol. 2009; 33: 130-137
        • Baschat A.A.
        • Cosmi E.
        • Bilardo C.M.
        • et al.
        Predictors of neonatal outcome in early- onset placental dysfunction.
        Obstet Gynecol. 2007; 109: 253-261
        • Levine R.J.
        • Maynard S.E.
        • Qian C.
        • et al.
        Circulating angiogenic factors and the risk of preeclampsia.
        N Engl J Med. 2004; 350: 672-683
        • Powe C.E.
        • Levine R.J.
        • Karumanchi S.A.
        Preeclampsia, a disease of the maternal endothelium the role of antiangiogenic factors and implications for later cardiovascular disease.
        Circulation. 2011; 123: 2856-2869
        • Onda K.
        • Tong S.
        • Beard S.
        • et al.
        Proton pump inhibitors decrease soluble fms-like tyrosine kinase-1 and soluble endoglin secretion, decrease hypertension, and rescue endothelial dysfunction.
        Hypertension. 2017; 69: 457-468
        • Saleh L.
        • Samantar R.
        • Garrelds I.M.
        • van den Meiracker A.H.
        • Visser W.
        • Danser A.H.J.
        Low soluble fms-like tyrosine kinase-1, endoglin, and endothelin-1 levels in women with confirmed or suspected preeclampsia using proton pump inhibitors.
        Hypertension. 2017; 70: 594-600
        • Andersson T.
        • Röhss K.
        • Bredberg E.
        • Hassan-Alin M.
        Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole.
        Aliment Pharmacol Ther. 2001; 15: 1563-1569
        • Matok I.
        • Levy A.
        • Wiznitzer A.
        • Uziel E.
        • Koren G.
        • Gorodischer R.
        The safety of fetal exposure to proton-pump inhibitors during pregnancy.
        Dig Dis Sci. 2012; 57: 699-705
        • Gill S.K.
        • O’Brien L.
        • Einarson T.R.
        • Koren G.
        The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis.
        Am J Gastroenterol. 2009; 104: 1541-1545
        • Pasternak B.
        • Hviid A.
        Use of proton-pump inhibitors in early pregnancy and the risk of birth defects.
        N Engl J Med. 2010; 363: 2114-2123
        • Cluver C.A.
        • Walker S.P.
        • Mol B.W.
        • et al.
        Double blind, randomised, placebo-controlled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): a study protocol.
        BMJ Open. 2015; 5: e008211
        • Hall D.R.
        Understanding expectant management of pre-eclampsia.
        Obstet Gynaecol Forum. 2016; 26: 22-27
        • Harris P.A.
        • Taylor R.
        • Thielke R.
        • Payne J.
        • Gonzalez N.
        • Conde J.G.
        Research electronic data capture (REDCap): a metadata-driven methodology and workflow process for providing translational research informatics support.
        J Biomed Inform. 2009; 42: 377-381
        • Hall D.R.
        • Odendaal H.J.
        • Steyn D.W.
        • Grove D.
        Expectant management of early onset, severe pre-eclampsia: maternal outcome.
        BJOG. 2000; 107: 1252-1257
        • Hassan-Alin M.
        • Andersson T.
        • Bredberg E.
        • Röhss K.
        Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects.
        Eur J Clin Pharmacol. 2000; 56: 665-670
        • Chunduri R.H.B.
        • Dannana G.S.
        Development and validation of a high throughput UPLC–MS/MS method for simultaneous quantification of esomeprazole, rabeprazole and levosulpiride in human plasma.
        J Pharm Anal. 2016; 6: 190-198
        • Röhss K.
        • Hasselgren G.
        • Hedenström H.
        Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric ph in patients with symptoms of gastroesophageal reflux disease.
        Dig Dis Sci. 2002; 47: 954-958
        • Maynard S.E.
        • Min J.Y.
        • Merchan J.
        • et al.
        Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
        J Clin Invest. 2003; 111: 649-658
        • Brownfoot F.C.
        • Tong S.
        • Hannan N.J.
        • Hastie R.
        • Cannon P.
        • Kaitu’u-Lino T.J.
        Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta.
        BMC Pregnancy Childbirth. 2016; 16: 117
        • Brownfoot F.C.
        • Hastie R.
        • Hannan N.J.
        • et al.
        Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction.
        Am J Obstet Gynecol. 2016; 214: 356.e1-356.e15
        • Brownfoot F.C.
        • Tong S.
        • Hannan N.J.
        • et al.
        Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia.
        Hypertension. 2015; 66 (discussion 445): 687-697
        • Hannan N.J.
        • Brownfoot F.C.
        • Cannon P.
        • et al.
        Resveratrol inhibits release of soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin and improves vascular dysfunction - implications as a preeclampsia treatment.
        Sci Rep. 2017; 7: 1819
        • Thadhani R.
        • Kisner T.
        • Hagmann H.
        • et al.
        Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.
        Circulation. 2011; 124: 940-950
        • Vigil-De Gracia P.
        • Ludmir J.
        Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment.
        Obstet Gynecol. 2016; 128: 1181-1182
        • Paidas M.J.
        • Sibai B.M.
        • Triche E.W.
        • Frieling J.
        • Lowry S.
        • PRESERVE-1 Study Group
        Exploring the role of antithrombin replacement for the treatment of preeclampsia: a prospective randomized evaluation of the safety and efficacy of recombinant antithrombin in very preterm preeclampsia (PRESERVE-1).
        Am J Reprod Immunol. 2013; 69: 539-544
        • Sibai B.
        • Paidas M.J.
        LB02: randomized double-blind placebo controlled evaluation of the safety and efficacy of recombinant antithrombin vs placebo in preterm preeclampsia.
        Am J Obstet Gynecol. 2017; 216: S559-S560
        • D’Angelo A.
        • Valsecchi L.
        High dose antithrombin supplementation in early preeclampsia: a randomized, double blind, placebo-controlled study.
        Thromb Res. 2016; 140: 7-13

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        American Journal of Obstetrics & GynecologyVol. 220Issue 2
        • Preview
          Sandrim et al advises caution in evaluating proton pump inhibitors (PPI) to treat preeclampsia, in light of their prior work, suggesting PPI may have actions that could increase blood pressure, by interfering with nitric oxide (NO) homeostasis.
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      • Esomeprazole to treat women with preeclampsia: possible implications in the nitric oxide homeostasis
        American Journal of Obstetrics & GynecologyVol. 220Issue 2
        • Preview
          We read with interest the article by Cluver et al1 evaluating the use of proton pump inhibitor (PPI) esomeprazole to treat women with preterm preeclampsia.1 While the 40 mg of daily oral esomeprazole tested in their study did not prolong gestation in pregnancies with preterm preeclampsia or decrease circulating soluble fms-like tyrosine kinase-1 concentrations, the authors discuss that this dosage of esomeprazole may be too low to treat preterm preeclampsia and suggest that higher doses may still be effective.
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