Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials
Summary 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 countri...
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| creator | Rodger, Marc A, Prof Gris, Jean-Christophe, Prof de Vries, Johanna I P, Prof Martinelli, Ida, MD Rey, Évelyne, MD Schleussner, Ekkehard, Prof Middeldorp, Saskia, Prof Kaaja, Risto, Prof Langlois, Nicole J, MSc Ramsay, Timothy, PhD Mallick, Ranjeeta, PhD Bates, Shannon M, Prof Abheiden, Carolien N H, MD Perna, Annalisa, MSc Petroff, David, PhD de Jong, Paulien, MD van Hoorn, Marion E, MD Bezemer, P Dick, PhD Mayhew, Alain D, MSc |
| description | Summary 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 [ |
| doi_str_mv | 10.1016/S0140-6736(16)31139-4 |
| format | Article |
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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.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(16)31139-4</identifier><identifier>PMID: 27720497</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adult ; Anticoagulants ; Aspirin ; Clinical trials ; Delivery, Obstetric ; Drug therapy ; Female ; Heparin, Low-Molecular-Weight - therapeutic use ; Heterogeneity ; Human health and pathology ; Humans ; Infant, Newborn ; Infant, Small for Gestational Age ; Internal Medicine ; Life Sciences ; Meta-analysis ; Patients ; Placenta ; Placenta Diseases - prevention & control ; Pre-Eclampsia - etiology ; Preeclampsia ; Pregnancy ; Pregnancy complications ; Pregnancy Complications - drug therapy ; Pregnancy Complications - etiology ; Pregnancy Complications - prevention & control ; Preventive medicine ; Randomized Controlled Trials as Topic ; Risk assessment ; Risk reduction ; Systematic review ; Thrombophilia - complications</subject><ispartof>The Lancet (British edition), 2016-11, Vol.388 (10060), p.2629-2641</ispartof><rights>Elsevier Ltd</rights><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited Nov 26, 2016</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c482t-dcbe32f3e982a1342c008779e0c97631a5fa33f66975e6689fbedd78332838643</citedby><cites>FETCH-LOGICAL-c482t-dcbe32f3e982a1342c008779e0c97631a5fa33f66975e6689fbedd78332838643</cites><orcidid>0000-0002-9899-9910 ; 0000-0002-4953-6549 ; 0000-0002-1006-6420</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1846736386?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,776,780,881,3536,27903,27904,45974,64362,64364,64366,72216</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27720497$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-01900640$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Rodger, Marc A, Prof</creatorcontrib><creatorcontrib>Gris, Jean-Christophe, Prof</creatorcontrib><creatorcontrib>de Vries, Johanna I P, Prof</creatorcontrib><creatorcontrib>Martinelli, Ida, MD</creatorcontrib><creatorcontrib>Rey, Évelyne, MD</creatorcontrib><creatorcontrib>Schleussner, Ekkehard, Prof</creatorcontrib><creatorcontrib>Middeldorp, Saskia, Prof</creatorcontrib><creatorcontrib>Kaaja, Risto, Prof</creatorcontrib><creatorcontrib>Langlois, Nicole J, MSc</creatorcontrib><creatorcontrib>Ramsay, Timothy, PhD</creatorcontrib><creatorcontrib>Mallick, Ranjeeta, PhD</creatorcontrib><creatorcontrib>Bates, Shannon M, Prof</creatorcontrib><creatorcontrib>Abheiden, Carolien N H, MD</creatorcontrib><creatorcontrib>Perna, Annalisa, MSc</creatorcontrib><creatorcontrib>Petroff, David, PhD</creatorcontrib><creatorcontrib>de Jong, Paulien, MD</creatorcontrib><creatorcontrib>van Hoorn, Marion E, MD</creatorcontrib><creatorcontrib>Bezemer, P Dick, PhD</creatorcontrib><creatorcontrib>Mayhew, Alain D, MSc</creatorcontrib><creatorcontrib>Low-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications Study Group</creatorcontrib><title>Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Summary 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.</description><subject>Adult</subject><subject>Anticoagulants</subject><subject>Aspirin</subject><subject>Clinical trials</subject><subject>Delivery, Obstetric</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Heparin, Low-Molecular-Weight - therapeutic use</subject><subject>Heterogeneity</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Infant, Newborn</subject><subject>Infant, Small for Gestational Age</subject><subject>Internal Medicine</subject><subject>Life Sciences</subject><subject>Meta-analysis</subject><subject>Patients</subject><subject>Placenta</subject><subject>Placenta Diseases - prevention & control</subject><subject>Pre-Eclampsia - etiology</subject><subject>Preeclampsia</subject><subject>Pregnancy</subject><subject>Pregnancy complications</subject><subject>Pregnancy Complications - drug therapy</subject><subject>Pregnancy Complications - etiology</subject><subject>Pregnancy Complications - prevention & control</subject><subject>Preventive medicine</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Risk assessment</subject><subject>Risk reduction</subject><subject>Systematic review</subject><subject>Thrombophilia - 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heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials</title><author>Rodger, Marc A, Prof ; Gris, Jean-Christophe, Prof ; de Vries, Johanna I P, Prof ; Martinelli, Ida, MD ; Rey, Évelyne, MD ; Schleussner, Ekkehard, Prof ; Middeldorp, Saskia, Prof ; Kaaja, Risto, Prof ; Langlois, Nicole J, MSc ; Ramsay, Timothy, PhD ; Mallick, Ranjeeta, PhD ; Bates, Shannon M, Prof ; Abheiden, Carolien N H, MD ; Perna, Annalisa, MSc ; Petroff, David, PhD ; de Jong, Paulien, MD ; van Hoorn, Marion E, MD ; Bezemer, P Dick, PhD ; Mayhew, Alain D, MSc</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c482t-dcbe32f3e982a1342c008779e0c97631a5fa33f66975e6689fbedd78332838643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adult</topic><topic>Anticoagulants</topic><topic>Aspirin</topic><topic>Clinical 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Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>British Nursing Index</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Newsstand Professional</collection><collection>Biological Sciences</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>ProQuest Healthcare Administration Database</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Psychology</collection><collection>Research Library (ProQuest Database)</collection><collection>ProQuest Science Journals</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>The Lancet (British edition)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rodger, Marc A, Prof</au><au>Gris, Jean-Christophe, Prof</au><au>de Vries, Johanna I P, Prof</au><au>Martinelli, Ida, MD</au><au>Rey, Évelyne, MD</au><au>Schleussner, Ekkehard, Prof</au><au>Middeldorp, Saskia, Prof</au><au>Kaaja, Risto, Prof</au><au>Langlois, Nicole J, MSc</au><au>Ramsay, Timothy, PhD</au><au>Mallick, Ranjeeta, PhD</au><au>Bates, Shannon M, Prof</au><au>Abheiden, Carolien N H, MD</au><au>Perna, Annalisa, MSc</au><au>Petroff, David, PhD</au><au>de Jong, Paulien, MD</au><au>van Hoorn, Marion E, MD</au><au>Bezemer, P Dick, PhD</au><au>Mayhew, Alain D, MSc</au><aucorp>Low-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>2016-11-26</date><risdate>2016</risdate><volume>388</volume><issue>10060</issue><spage>2629</spage><epage>2641</epage><pages>2629-2641</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><coden>LANCAO</coden><abstract>Summary 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.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27720497</pmid><doi>10.1016/S0140-6736(16)31139-4</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-9899-9910</orcidid><orcidid>https://orcid.org/0000-0002-4953-6549</orcidid><orcidid>https://orcid.org/0000-0002-1006-6420</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0140-6736 |
| ispartof | The Lancet (British edition), 2016-11, Vol.388 (10060), p.2629-2641 |
| issn | 0140-6736 1474-547X |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_01900640v1 |
| source | MEDLINE; Elsevier ScienceDirect Journals; ProQuest Central UK/Ireland |
| subjects | Adult Anticoagulants Aspirin Clinical trials Delivery, Obstetric Drug therapy Female Heparin, Low-Molecular-Weight - therapeutic use Heterogeneity Human health and pathology Humans Infant, Newborn Infant, Small for Gestational Age Internal Medicine Life Sciences Meta-analysis Patients Placenta Placenta Diseases - prevention & control Pre-Eclampsia - etiology Preeclampsia Pregnancy Pregnancy complications Pregnancy Complications - drug therapy Pregnancy Complications - etiology Pregnancy Complications - prevention & control Preventive medicine Randomized Controlled Trials as Topic Risk assessment Risk reduction Systematic review Thrombophilia - complications |
| title | Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials |
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