Download PDF
CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2020; 80(07): 679-685
DOI: 10.1055/a-1170-5145
GebFra Science
Review

Hydroxychloroquine as a Preventive and Therapeutic Option in Preeclampsia – a Literature Review

Hydroxychloroquin als präventive und therapeutische Option bei Präeklampsie – eine Literaturübersicht
Daniela Deharde
1   Department of Obstetrics and Gynecology, University Hospital Münster, Münster, Germany
,
Walter Klockenbusch
1   Department of Obstetrics and Gynecology, University Hospital Münster, Münster, Germany
,
Ralf Schmitz
1   Department of Obstetrics and Gynecology, University Hospital Münster, Münster, Germany
,
Marcus Brand
2   Department of Internal Medicine, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital Münster, Münster, Germany
,
Helen Ann Köster
1   Department of Obstetrics and Gynecology, University Hospital Münster, Münster, Germany
,
Kathrin Oelmeier de Murcia
1   Department of Obstetrics and Gynecology, University Hospital Münster, Münster, Germany
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Corrected by:

Correction: Hydroxychloroquine as a Preventive and Therapeutic Option in Preeclampsia – a Literature ReviewGeburtshilfe Frauenheilkd 2020; 80(07): e71-e71
DOI: 10.1055/a-1230-0002

Abstract

Preeclampsia is one of the most feared complications of pregnancy and puerperium and represents a serious threat to mother and child. In addition, a history of preeclampsia increases the risk of future cardiovascular events. New diagnostic and therapeutic approaches are needed. New therapeutic options are currently being discussed, one of which is the administration of hydroxychloroquine. It is an antimalarial drug which is also used to treat rheumatological disease and its use in pregnancy is considered safe. A reduced incidence of preeclampsia in patients with selected rheumatological disorders after administration of hydroxychloroquine has already been shown; however, the case numbers are very low. Neither the full pathogenesis of preeclampsia nor the exact modes of action of hydroxychloroquine have been completely elucidated, but there are several common features which make hydroxychloroquine a promising option for the prevention and treatment of preeclampsia. Further research, especially prospective, randomized controlled trials, is needed to prove its efficacy. This review discusses the pathogenesis of preeclampsia and gives an overview of new options for its prevention and treatment, including the administration of hydroxychloroquine in pregnancy.

Zusammenfassung

Die Präeklampsie zählt zu den am meisten gefürchteten Schwangerschafts- und Wochenbettkomplikationen und stellt eine ernste Gefahr für Mutter und Kind dar. Hinzu kommt noch, dass eine vorherige Präeklampsie das Risiko für künftige kardiovaskuläre Ereignisse erhöht. Neue diagnostische und therapeutische Konzepte werden benötigt. Einige neue therapeutische Optionen werden inzwischen diskutiert, darunter die Gabe von Hydroxychloroquin. Hydroxychloroquin ist ein Antimalariamittel, das auch zur Behandlung von rheumatologischen Erkrankungen eingesetzt wird, und der Einsatz dieses Medikaments während der Schwangerschaft gilt als sicher. Bei Patientinnen mit spezifischen rheumatologischen Erkrankungen, die mit Hydroxychloroquin behandelt wurden, reduzierte sich die Häufigkeit von Präeklampsie, aber die Fallzahlen waren sehr niedrig. Weder die komplette Pathogenese von Präeklampsie noch die präzise Wirkungsweise von Hydroxychloroquin sind bislang gänzlich geklärt, aber es gibt mehrere Gemeinsamkeiten, die darauf hindeuten, dass Hydroxychloroquin eine vielsprechende Möglichkeit zur Prävention und Behandlung von Präeklampsie darstellen könnte. Es werden weitere Untersuchungen, insbesondere prospektive, randomisierte kontrollierte Studien, benötigt, um die Wirksamkeit von Hydroxychloroquin zu belegen. In dieser Übersichtsarbeit wird die Pathogenese von Präeklampsie diskutiert, und es wird ein Überblick der neuesten Optionen bei der Prävention und Behandlung von Präeklampsie einschließlich der Hydroxychloroquin-Gabe während der Schwangerschaft vermittelt.

Key words

hydroxychloroquine - rheumatological disease - preeclampsia

Schlüsselwörter

Hydroxychloroquin - rheumatologische Erkrankungen - Präeklampsie


Publication History

Received: 12 February 2020

Accepted after revision: 03 May 2020

Article published online:
14 July 2020

© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 WHO. WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. Geneva: WHO; 2011
    Google Scholar
  • 2 Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and maternal mortality. Curr Opin Obstet Gynecol 2013; 25: 124-132
    CrossrefPubMedGoogle Scholar
  • 3 Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V. (DGGG). Hypertensive Pregnancy Disorders: Diagnosis and Therapy. Guideline of the German Society of Gynecology and Obstetrics (S2k-Level, AWMF-Registry No. 015/018). 2019. Online (last access: 07.06.2020): https://www.awmf.org/leitlinien/detail/ll/015-018.html
    PubMedGoogle Scholar
  • 4 American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Report of the American College of Obstetricians and Gynecologistsʼ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122: 1122-1131
    CrossrefPubMedGoogle Scholar
  • 5 Zeisler H, Llurba E, Chantraine F. et al. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med 2016; 374: 13-22
    CrossrefPubMedGoogle Scholar
  • 6 Stepan H, Kuse-Fohl S, Klockenbusch W. et al. Diagnosis and Treatment of Hypertensive Pregnancy Disorders. Guideline of DGGG (S1-Level, AWMF Registry No. 015/018, December 2013). Geburtsh Frauenheilk 2015; 75: 900-914
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Armaly Z, Jadaon JE, Jabbour A. et al. Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches. Front Physiol 2018; 9: 973
    CrossrefPubMedGoogle Scholar
  • 8 Bartsch E, Medcalf KE, Park AL. et al. Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BMJ 2016; 353: i1753
    CrossrefPubMedGoogle Scholar
  • 9 Bujold E, Roberge S, Lacasse Y. et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116: 402-414
    CrossrefPubMedGoogle Scholar
  • 10 Roberge S, Villa P, Nicolaides K. et al. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther 2012; 31: 141-146
    CrossrefPubMedGoogle Scholar
  • 11 Rolnik DL, Wright D, Poon LC. et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med 2017; 377: 613-622
    CrossrefPubMedGoogle Scholar
  • 12 Li C, Raikwar NS, Santillan MK. et al. Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1. Placenta 2015; 36: 446-453
    CrossrefPubMedGoogle Scholar
  • 13 Raymond D, Peterson E. A critical review of early-onset and late-onset preeclampsia. Obstet Gynecol Surv 2011; 66: 497-506
    CrossrefPubMedGoogle Scholar
  • 14 Herzog EM, Eggink AJ, Willemsen SP. et al. Early- and late-onset preeclampsia and the tissue-specific epigenome of the placenta and newborn. Placenta 2017; 58: 122-132
    CrossrefPubMedGoogle Scholar
  • 15 Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330: 565
    CrossrefPubMedGoogle Scholar
  • 16 Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension 2008; 51: 970-975
    CrossrefPubMedGoogle Scholar
  • 17 Valencia-Ortega J, Zarate A, Saucedo R. et al. Placental Proinflammatory State and Maternal Endothelial Dysfunction in Preeclampsia. Gynecol Obstet Invest 2019; 84: 12-19
    CrossrefPubMedGoogle Scholar
  • 18 Yu CK, Smith GC, Papageorghiou AT. et al. An integrated model for the prediction of preeclampsia using maternal factors and uterine artery Doppler velocimetry in unselected low-risk women. Am J Obstet Gynecol 2005; 193: 429-436
    CrossrefPubMedGoogle Scholar
  • 19 Eiland E, Nzerue C, Faulkner M. Preeclampsia 2012. J Pregnancy 2012; 2012: 586578
    CrossrefPubMedGoogle Scholar
  • 20 Burton GJ, Redman CW, Roberts JM. et al. Pre-eclampsia: pathophysiology and clinical implications. BMJ 2019; 366: l2381
    CrossrefPubMedGoogle Scholar
  • 21 Abd Rahman R, DeKoninck P, Murthi P. et al. Treatment of preeclampsia with hydroxychloroquine: a review. J Matern Fetal Neonatal Med 2018; 31: 525-529
    CrossrefPubMedGoogle Scholar
  • 22 Kim J, Lee KS, Kim JH. et al. Aspirin prevents TNF-alpha-induced endothelial cell dysfunction by regulating the NF-kappaB-dependent miR-155/eNOS pathway: Role of a miR-155/eNOS axis in preeclampsia. Free Radic Biol Med 2017; 104: 185-198
    CrossrefPubMedGoogle Scholar
  • 23 Matsubara K, Matsubara Y, Hyodo S. et al. Role of nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. J Obstet Gynaecol Res 2010; 36: 239-247
    CrossrefPubMedGoogle Scholar
  • 24 El-Sayed AAF. Preeclampsia: A review of the pathogenesis and possible management strategies based on its pathophysiological derangements. Taiwan J Obstet Gynecol 2017; 56: 593-598
    CrossrefPubMedGoogle Scholar
  • 25 Romero R, Erez O, Huttemann M. et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol 2017; 217: 282-302
    CrossrefPubMedGoogle Scholar
  • 26 Venkatesha S, Toporsian M, Lam C. et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006; 12: 642-649
    CrossrefPubMedGoogle Scholar
  • 27 Dunn L, Greer R, Flenady V. et al. Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes. Fetal Diagn Ther 2017; 41: 81-88
    CrossrefPubMedGoogle Scholar
  • 28 Paauw ND, Terstappen F, Ganzevoort W. et al. Sildenafil During Pregnancy: A Preclinical Meta-Analysis on Fetal Growth and Maternal Blood Pressure. Hypertension 2017; 70: 998-1006
    CrossrefPubMedGoogle Scholar
  • 29 Gillis EE, Mooney JN, Garrett MR. et al. Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt-Sensitive Rat. Hypertension 2016; 67: 647-653
    CrossrefPubMedGoogle Scholar
  • 30 Groom KM, Ganzevoort W, Alfirevic Z. et al. Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR): comment from the STRIDER Consortium. Ultrasound Obstet Gynecol 2018; 52: 295-296
    CrossrefPubMedGoogle Scholar
  • 31 Spradley FT, Tan AY, Joo WS. et al. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension. Hypertension 2016; 67: 740-747
    CrossrefPubMedGoogle Scholar
  • 32 Thadhani R, Hagmann H, Schaarschmidt W. et al. Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia. J Am Soc Nephrol 2016; 27: 903-913
    CrossrefPubMedGoogle Scholar
  • 33 Karumanchi SA, Granger JP. Preeclampsia and Pregnancy-Related Hypertensive Disorders. Hypertension 2016; 67: 238-242
    CrossrefPubMedGoogle Scholar
  • 34 Brownfoot FC, Hastie R, Hannan NJ. 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
    CrossrefPubMedGoogle Scholar
  • 35 Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017; 120: 229-243
    CrossrefPubMedGoogle Scholar
  • 36 Karalis DG, Hill AN, Clifton S. et al. The risks of statin use in pregnancy: A systematic review. J Clin Lipidol 2016; 10: 1081-1090
    CrossrefPubMedGoogle Scholar
  • 37 Ahmed A, Williams DJ, Cheed V. et al. Pravastatin for early-onset pre-eclampsia: a randomised, blinded, placebo-controlled trial. BJOG 2019; DOI: 10.1111/1471-0528.16013.
    CrossrefPubMedGoogle Scholar
  • 38 Brownfoot FC, Tong S, Hannan NJ. et al. 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
    CrossrefPubMedGoogle Scholar
  • 39 Tieu J, Coat S, Hague W. et al. Oral anti-diabetic agents for women with established diabetes/impaired glucose tolerance or previous gestational diabetes planning pregnancy, or pregnant women with pre-existing diabetes. Cochrane Database Syst Rev 2017; (10) CD007724
    PubMedGoogle Scholar
  • 40 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
    CrossrefPubMedGoogle Scholar
  • 41 Cluver CA, Hannan NJ, van Papendorp E. et al. Esomeprazole to treat women with preterm preeclampsia: a randomized placebo controlled trial. Am J Obstet Gynecol 2018; 219: 388.e1-388.e17
    CrossrefPubMedGoogle Scholar
  • 42 Shippey EA, Wagler VD, Collamer AN. Hydroxychloroquine: An old drug with new relevance. Cleve Clin J Med 2018; 85: 459-467
    CrossrefPubMedGoogle Scholar
  • 43 Rainsford KD, Parke AL, Clifford-Rashotte M. et al. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 2015; 23: 231-269
    CrossrefPubMedGoogle Scholar
  • 44 Hazes JM, Coulie PG, Geenen V. et al. Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use. Rheumatology 2011; 50: 1955-1968
    CrossrefPubMedGoogle Scholar
  • 45 Embryotox, online database. Online (last access: 19.04.2020): https://www.embryotox.de/arzneimittel/details/hydroxychloroquin/
    PubMedGoogle Scholar
  • 46 Costedoat-Chalumeau N, Amoura Z, Duhaut P. et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 2003; 48: 3207-3211
    CrossrefPubMedGoogle Scholar
  • 47 Abarientos C, Sperber K, Shapiro DL. et al. Hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis and its safety in pregnancy. Expert Opin Drug Saf 2011; 10: 705-714
    CrossrefPubMedGoogle Scholar
  • 48 Levy RA, de Jesus GR, de Jesus NR. et al. Critical review of the current recommendations for the treatment of systemic inflammatory rheumatic diseases during pregnancy and lactation. Autoimmun Rev 2016; 15: 955-963
    CrossrefPubMedGoogle Scholar
  • 49 Leroux M, Desveaux C, Parcevaux M. et al. Impact of hydroxychloroquine on preterm delivery and intrauterine growth restriction in pregnant women with systemic lupus erythematosus: a descriptive cohort study. Lupus 2015; 24: 1384-1391
    CrossrefPubMedGoogle Scholar
  • 50 Browning DJ. Pharmacology of Chloroquine and Hydroxychloroquine. In: Hydroxychloroquine and Chloroquine Retinopathy. New York: Springer Science + Business Media; 2014: 35-63
    CrossrefGoogle Scholar
  • 51 Schreiber K, Breen K, Cohen H. et al. HYdroxychloroquine to Improve Pregnancy Outcome in Women with AnTIphospholipid Antibodies (HYPATIA) Protocol: A Multinational Randomized Controlled Trial of Hydroxychloroquine versus Placebo in Addition to Standard Treatment in Pregnant Women with Antiphospholipid Syndrome or Antibodies. Semin Thromb Hemost 2017; 43: 562-571
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Muller-Calleja N, Manukyan D, Canisius A. et al. Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase. Ann Rheum Dis 2017; 76: 891-897
    CrossrefPubMedGoogle Scholar
  • 53 Browning DJ. The Prevalence of Hydroxychloroquine Retinopathy and Toxic Dosing, and the Role of the Ophthalmologist in Reducing Both. Am J Ophthalmol 2016; 166: ix-xi
    CrossrefPubMedGoogle Scholar
  • 54 Sciascia S, Hunt BJ, Talavera-Garcia E. et al. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am J Obstet Gynecol 2016; 214: 273.e1-273.e8
    CrossrefPubMedGoogle Scholar
  • 55 Mekinian A, Lazzaroni MG, Kuzenko A. et al. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study. Autoimmun Rev 2015; 14: 498-502
    CrossrefPubMedGoogle Scholar