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890 Low Molecular Weight Heparin for Prevention of Placenta-Mediated Pregnancy Complications: An Individual Patient Data Meta-Analysis

Antithrombotic Therapy
Program: Oral and Poster Abstracts
Type: Oral
Session: 332. Antithrombotic Therapy II
Monday, December 7, 2015: 6:30 PM
W307, Level 3 (Orange County Convention Center)

Marc Rodger, MD, MSc1, Johanna IP de Vries, MD PhD2*, Evelyne Rey, MD3*, Jean-Christophe JCG Gris, MD PhD4*, Ida Martinelli, MD5*, Ekkehard Schleussner, MD6*, Saskia Middeldorp, MD, PhD7, Shannon M Bates, MD, MSc8, Paulien de Jong, MD PhD9*, Nicole Langlois10*, Ranjeeta Mallick11*, Ranjeeta Mallick11*, Timothy Ramsay11*, David Petroff12*, Dick Bezemer13*, Marion van Hoorn2*, Carolien Abheiden2*, Risto Kaaja, MD, PhD14*, Annalisa Perna15* and Alain Mayhew11*

1Ottawa Blood Disease Center, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada
2Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, Netherlands
3CHU Ste-Justine, Montreal, Canada
4CHU Nimes, Nimes, France
5A. Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
6Department of Obstetrics and Gynecology, Jena University Hospital, Jena, Germany
7Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
8Department of Medicine, McMaster University, Hamilton, ON, Canada
9Amsterdam Medical Center, Amsterdam, Netherlands
10Ottawa Blood Disease Center, Ottawa Health Research Institute, Ottawa, Canada
11Ottawa Health Research Institute, Ottawa, Canada
12University of Leipzig, Leipzig, Germany
13VU University Medical Center, Amsterdam, Netherlands
14Helsinki Univ. Hosp., Turku Univ., Pori, Finland
15Centro di Richerche Cliniche per le Malattie Rare, Ranica, Italy

Introduction

Placenta-mediated pregnancy complications (PMPC) include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age (SGA) newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality. Affected women are at an elevated risk of recurrence in subsequent pregnancies. We completed a pooled summary-based (i.e. study level) meta-analysis that strongly suggests that low-molecular-weight heparin (LMWH) reduces the risk of recurrent PMPCs. However, our study-level meta-analysis was limited by high clinical and statistical heterogeneity likely due to the inclusion of women with heterogeneous prior PMPCs and trial designs (e.g. single vs multi-center trials). To address these limitations, the trialists agreed to conduct an individual patient data meta-analysis to identify sources of heterogeneity including exploring which patients benefit from LMWH and which outcomes are prevented.

Methods

We conducted a systematic review to identify randomised controlled trials that were eligible to contribute individual patient data to a meta-analysis to evaluate the effectiveness of LMWH for reducing the risk of PMPC in women with prior PMPCs. The primary outcome was a composite of early-onset or severe pre-eclampsia, birth of an SGA newborn < 5th percentile, late pregnancy loss (> 20 weeks), or placental abruption leading to delivery. Individual patient data from eligible women were re-coded in a prescribed format and combined in a common dataset for analysis. All studies were assessed for risk of bias.

Results

Data from 1049 women in nine trials were analysed; Participants were mostly Caucasian (88%) with a mean age of 31. 518 had thrombophilia. 525 women were randomised to LMWH and 524 to no LMWH. In our primary outcome analysis, LMWH did not significantly reduce the risk of recurrent PMPCs (LMWH 60/459 (13.1%) vs. no LMWH 92/449 (20.5%) p=0.1). Significant heterogeneity was noted between single center and multi-center trials. In multi-center trials, LMWH reduced HELLP (p=0.03) but none of the other secondary outcomes, whereas in single center trials LMWH reduced all of the secondary outcomes. In sub-group analysis, in multi-center trials LMWH reduced the primary outcome in women with prior abruption (p<0.01) but none of the other sub-groups, whereas in single center trials LMWH was beneficial in all the sub-groups (prior pre-eclampsia, prior severe pre-eclampsia, prior early onset pre-eclampsia, prior SGA <10th, prior SGA < 5th and prior abruption).

Conclusions

In this individual patient data meta-analysis, LMWH does not appear to reduce the risk of recurrent PMPC in women with prior PMPC. Promising results suggest that women with prior abruption may benefit from LMWH but this should be replicated in future multi-center trials.

PROSPERO registration:CRD42013006249

 

Primary Analysis

All Studies

 

Multi-Center Studies

 

Single Center Studies

 

Composite outcome

     Risk difference

     (95% CI)

N=908

-0.07

(-0.16, 0.01)

p = 0.10

N=524

-0.01

(-0.11, 0.09)

p = 0.89

N=384

-0.17

(-0.21, -0.13)

p < .0001

Secondary Outcome Analyses

 

 

 

Severe or Early Preeclampsia

     Risk difference

     (95% CI)

 

N=946

-0.04

(-0.10, 0.02)

p = 0.20

N=562

0.01

(-0.06, 0.07)

p = 0.81

N=384

-0.11

(-0.16, -0.07)

p <.0001

HELLP

     Risk difference

     (95% CI)

 

N=813

-0.02

(-0.04, -0.004)

p = 0.01

N=429

-0.01

(-0.02, -0.001)

p = 0.03

N=384

-0.04

(-0.07, -0.01)

p = 0.02

SGA <10

     Risk difference

     (95% CI)

N=913

-0.08

(-0.14, -0.02)

p = 0.01

N=529         

-0.03

(-0.10, 0.03)

p = 0.32

N=384

-0.14

(-0.18, -0.10)

p <0.0001

Abruption leading to delivery

     Risk difference

     (95% CI)

N=945

-0.01

(-0.02, 0.003)

p = 0.14

N=561

-0.01

(-0.03, 0.01)

p = 0.53

N=384

-0.016

(-0.027, -0.005)

p = 0.005

Subgroup Analyses

 

 

 

Prior preeclampsia

              Risk difference

              (95% CI)

 

N=583

-0.12

(-0.19, -0.04)

p = 0.002

N=288

-0.06

(-0.19, 0.06)

p = 0.34

N=295

-0.17

(-0.24, -0.11)

p <.0001

Prior severe or early onset Preeclampsia

              Risk difference

              (95% CI)

N=487

-0.10    

(-0.19, -0.02)    

p = 0.02

N=236

-0.04    

(-0.19, 0.12)      

p = 0.65

N=251

-0.17    

(-0.23, -0.11)

p <.0001

Any prior late loss

(2 >12 weeks or 1 >16 weeks)

              Risk difference

              (95% CI)

 

N=245

0.001

(-0.11, 0.12)

p = 0.98

N=0

 

Prior SGA < 10

              Risk difference

              (95% CI)

N=305

-0.12    

(-0.25, 0.01)

p = 0.08

N=203

-0.03    

(-0.17, 0.10)

p = 0.64

N=102

-0.29    

(-0.38, -0.20)

p <.0001

Prior abruption

              Risk difference

              (95% CI)

N=281

-0.16    

(-0.22, -0.11)

p <.0001

N=95

-0.13    

(-0.22, -0.04)

p = 0.01

N=186

-0.18    

(-0.22, -0.14)

p <.0001

Disclosures: Rodger: Biomerieux: Honoraria , Research Funding . Off Label Use: Low Molecular Weight Heparin to prevent pregnancy complications. de Vries: Pfizer: Research Funding . Rey: Leo Pharma: Other: Travel Grant . Gris: Sanofi: Consultancy , Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Stago: Consultancy , Membership on an entity’s Board of Directors or advisory committees , Research Funding , Speakers Bureau ; Leo Pharma: Consultancy , Speakers Bureau ; LFB: Consultancy , Membership on an entity’s Board of Directors or advisory committees , Research Funding , Speakers Bureau ; Baxter: Research Funding ; BI: Speakers Bureau ; Bayer: Speakers Bureau ; BMS: Speakers Bureau . Schleussner: Bayer: Speakers Bureau ; Pfizer: Research Funding , Speakers Bureau ; Merck: Research Funding , Speakers Bureau . Middeldorp: GSK/Aspen: Research Funding ; Bayer: Consultancy , Speakers Bureau ; BI: Consultancy , Speakers Bureau ; BMS: Consultancy , Research Funding , Speakers Bureau ; Pfizer: Consultancy , Research Funding , Speakers Bureau ; Daiichi-Sankyo: Consultancy , Speakers Bureau . Bates: Eli Lilly Canada: Other: I hold the Eli Lilly Canada/May Cohen Chair in Women's Health. Eli Lilly Canada provides unrestricted funding for partial salary support through this Chair. Eli Lilly Canada does not manufacture/distribute drugs relevant to the topic to be discussed. .

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