title: Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials.
abstract: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis.
  
  
  
  We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249.
  
  
  
  We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications.
  
  
  
  Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore.
  
  
  
  Canadian Institutes of Health Research.
authors.affiliation: Ottawa Blood Disease Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada. Electronic address: mrodger@ohri.ca.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Rodger
authors.affiliation: Consultations et Laboratoire d'Hématologie et Délégation à la Recherche Clinique et à l'Innovation, Nîmes cédex 09, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Gris
authors.affiliation: Department of Obstetrics and Gynaecology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Johanna I P
authors.initials: JIP
authors.lastname: de Vries
authors.affiliation: A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Martinelli
authors.affiliation: CHU Ste-Justine, Montreal, QC, Canada.
authors.forename: Évelyne
authors.initials: É
authors.lastname: Rey
authors.affiliation: Jena University Hospital, Department of Obstetrics and Gynaecology, Jena, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schleussner
authors.affiliation: Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9, Amsterdam, the Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Middeldorp
authors.affiliation: Turku University, Turku University Hospital, Åbo, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Kaaja
authors.affiliation: Centre for Practice-Changing Research, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Langlois
authors.affiliation: Centre for Practice-Changing Research, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Ramsay
authors.affiliation: Centre for Practice-Changing Research, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Ranjeeta
authors.initials: R
authors.lastname: Mallick
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Bates
authors.affiliation: Department of Obstetrics and Gynaecology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Carolien N H
authors.initials: CNH
authors.lastname: Abheiden
authors.affiliation: Laboratorio di Biostatistica, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Ranica, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Perna
authors.affiliation: University of Leipzig, Clinical Trial Centre, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Petroff
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Paulien
authors.initials: P
authors.lastname: de Jong
authors.affiliation: Department of Obstetrics and Gynaecology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Marion E
authors.initials: ME
authors.lastname: van Hoorn
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: P Dick
authors.initials: PD
authors.lastname: Bezemer
authors.affiliation: Centre for Practice-Changing Research, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Alain D
authors.initials: AD
authors.lastname: Mayhew
mesh_terms: D000328:Adult; D036861:Delivery, Obstetric; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D010922:Placenta Diseases / Q000517:prevention & control*; D011225:Pre-Eclampsia / Q000209:etiology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D016032:Randomized Controlled Trials as Topic; D019851:Thrombophilia / Q000150:complications
chemical_list: D006495:Heparin, Low-Molecular-Weight