Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: a meta-analysis.
OBJECTIVE
To estimate the impact of adding low-molecular-weight heparin (LMWH) or unfractionated heparin to low-dose aspirin started ≤ 16 weeks' gestation on the prevalence of pre-eclampsia (PE) and the delivery of a small-for-gestational-age (SGA) neonate.


METHODS
A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed by searching the medical databases PubMed, EMBASE, Web of Science and Cochrane Central. Pregnant women randomized to receive LMWH or unfractionated heparin in addition to low-dose aspirin were compared with those who received low-dose aspirin alone. Outcome measures were PE, severe PE, early-onset PE and SGA. Pooled relative risks (RRs) with 95% CI were calculated using a random-effects model.


RESULTS
Eight RCTs met the inclusion criteria; the indication for recruitment was previous recurrent miscarriage in five studies (three included women with thrombophilia) and a history of severe or early-onset PE in three studies (including women with thrombophilia in one). LMWH was administered in seven studies and unfractionated heparin in one. In women with a history of PE, treatment with LMWH and aspirin, compared with aspirin alone, was associated with a significant reduction in development of PE (three trials (n = 379); RR, 0.54 (95% CI, 0.31-0.92); P = 0.03) and in delivery of SGA neonates (two trials (n = 363); RR, 0.54 (95% CI, 0.32-0.91); P = 0.02). These outcomes were not significantly reduced in women with recurrent miscarriage who received LMWH and aspirin, compared with aspirin alone. The small number of studies precluded sensitivity analyses and the evaluation of publication biases. Blinding to the allocation treatment was absent in all RCTs.


CONCLUSIONS
Based on limited evidence, the addition of LMWH to low-dose aspirin could reduce the prevalence of PE and SGA in women with a history of PE. This observation should be the basis of a well-conducted future trial rather than a recommendation for immediate clinical application. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Department of Social and Preventive Medicine, Université Laval, Québec, Canada.
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Roberge
Department of Social and Preventive Medicine, Université Laval, Québec, Canada.|Department of Obstetrics and Gynecology, Université Laval, Québec, Canada.|Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.
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Demers
Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.
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Nicolaides
Department of Obstetrics and Gynecology, Université Laval, Québec, Canada.
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Bureau
Department of Medicine, Université Laval, Québec, Canada.
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Côté
Department of Social and Preventive Medicine, Université Laval, Québec, Canada.|Department of Obstetrics and Gynecology, Université Laval, Québec, Canada.
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Bujold
D001241:Aspirin / Q000008:administration & dosage* / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D011225:Pre-Eclampsia / Q000517:prevention & control*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D006495:Heparin, Low-Molecular-Weight; D001241:Aspirin
aspirin; heparin; meta-analysis; pre-eclampsia; small-for-gestational age