Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: A meta-analysis of individual patient data from randomised controlled trials

M. Rodger, J. C. Gris, J. I P De Vries, Ida Marianna Martinelli, Evelyne Rey, Ekkehard Schleussner, Saskia Middeldorp, Risto Kaaja, Nicole J. Langlois, Timothy Ramsay, Ranjeeta Mallick, Shannon M. Bates, Carolien N H Abheiden, Annalisa Perna, David Petroff, Paulien de Jong, Marion E. van Hoorn, P. D. Bezemer, Alain D. Mayhew

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Canadian Institutes of Health Research.

Original languageEnglish
JournalThe Lancet
DOIs
Publication statusAccepted/In press - 2016

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Pregnancy Complications
Low Molecular Weight Heparin
Placenta
Meta-Analysis
Randomized Controlled Trials
Pregnancy
Abruptio Placentae
Pre-Eclampsia
Gestational Age
Parturition
Newborn Infant
Multicenter Studies
Recurrence
Reproductive History
Time and Motion Studies
Thrombophilia
Infant Mortality
Pregnant Women
Mothers
Research Personnel

ASJC Scopus subject areas

  • Medicine(all)

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Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications : A meta-analysis of individual patient data from randomised controlled trials. / Rodger, M.; Gris, J. C.; De Vries, J. I P; Martinelli, Ida Marianna; Rey, Evelyne; Schleussner, Ekkehard; Middeldorp, Saskia; Kaaja, Risto; Langlois, Nicole J.; Ramsay, Timothy; Mallick, Ranjeeta; Bates, Shannon M.; Abheiden, Carolien N H; Perna, Annalisa; Petroff, David; de Jong, Paulien; van Hoorn, Marion E.; Bezemer, P. D.; Mayhew, Alain D.

In: The Lancet, 2016.

Research output: Contribution to journalArticle

Rodger, M, Gris, JC, De Vries, JIP, Martinelli, IM, Rey, E, Schleussner, E, Middeldorp, S, Kaaja, R, Langlois, NJ, Ramsay, T, Mallick, R, Bates, SM, Abheiden, CNH, Perna, A, Petroff, D, de Jong, P, van Hoorn, ME, Bezemer, PD & Mayhew, AD 2016, 'Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: A meta-analysis of individual patient data from randomised controlled trials', The Lancet. https://doi.org/10.1016/S0140-6736(16)31139-4
Rodger, M. ; Gris, J. C. ; De Vries, J. I P ; Martinelli, Ida Marianna ; Rey, Evelyne ; Schleussner, Ekkehard ; Middeldorp, Saskia ; Kaaja, Risto ; Langlois, Nicole J. ; Ramsay, Timothy ; Mallick, Ranjeeta ; Bates, Shannon M. ; Abheiden, Carolien N H ; Perna, Annalisa ; Petroff, David ; de Jong, Paulien ; van Hoorn, Marion E. ; Bezemer, P. D. ; Mayhew, Alain D. / Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications : A meta-analysis of individual patient data from randomised controlled trials. In: The Lancet. 2016.
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abstract = "Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Canadian Institutes of Health Research.",
author = "M. Rodger and Gris, {J. C.} and {De Vries}, {J. I P} and Martinelli, {Ida Marianna} and Evelyne Rey and Ekkehard Schleussner and Saskia Middeldorp and Risto Kaaja and Langlois, {Nicole J.} and Timothy Ramsay and Ranjeeta Mallick and Bates, {Shannon M.} and Abheiden, {Carolien N H} and Annalisa Perna and David Petroff and {de Jong}, Paulien and {van Hoorn}, {Marion E.} and Bezemer, {P. D.} and Mayhew, {Alain D.}",
year = "2016",
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language = "English",
journal = "The Lancet",
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TY - JOUR

T1 - Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications

T2 - A meta-analysis of individual patient data from randomised controlled trials

AU - Rodger, M.

AU - Gris, J. C.

AU - De Vries, J. I P

AU - Martinelli, Ida Marianna

AU - Rey, Evelyne

AU - Schleussner, Ekkehard

AU - Middeldorp, Saskia

AU - Kaaja, Risto

AU - Langlois, Nicole J.

AU - Ramsay, Timothy

AU - Mallick, Ranjeeta

AU - Bates, Shannon M.

AU - Abheiden, Carolien N H

AU - Perna, Annalisa

AU - Petroff, David

AU - de Jong, Paulien

AU - van Hoorn, Marion E.

AU - Bezemer, P. D.

AU - Mayhew, Alain D.

PY - 2016

Y1 - 2016

N2 - Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Canadian Institutes of Health Research.

AB - Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Canadian Institutes of Health Research.

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