Definition of bleeding events in studies evaluating prophylactic antithrombotic therapy in pregnant women: A systematic review and a proposal from the ISTH SSC

Abstract

Bleeding has been reported to be the leading direct cause of maternal death worldwide, being implicated in 27.1% (19.9–36.2) of maternal deaths.1.Say L. Chou D. Gemmill A. et al.Global causes of maternal death: a WHO systematic analysis.Lancet Glob Health. 2014; 2: e323-e333Abstract Full Text Full Text PDF PubMed Scopus (2771) Google Scholar Many studies investigating the effects of heparin prophylaxis during pregnancy with the aim of preventing venous thromboembolism or pregnancy loss, placenta‐mediated pregnancy complications, and intrauterine growth restriction, have been recently reported while others are ongoing. Whether or not heparin prophylaxis during pregnancy increases bleeding risk is a crucial question. In the absence of such prophylaxis, antepartum bleeding due to placenta praevia and placenta abruptio is observed in 2% to 5% of all pregnancies2.Sinha P. Kuruba N. Ante‐partum haemorrhage: an update.J Obstet Gynaecol. 2008; 28: 377-381Crossref PubMed Scopus (37) Google Scholar and the reported incidence of postpartum bleeding is 5% to 15% of all births.3.Dahlke J.D. Mendez‐Figueroa H. Maggio L. et al.Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines.Am J Obstet Gynecol. 2015; 213: 76.e1-76.e10Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar However, the exact frequencies of bleeding events in pregnancy are unknown, as is their severity. Indeed, during the antepartum period, there is no consistent definition of bleeding including early vaginal bleeding, the most frequent antepartum bleeding event.4.Hackney D.N. Glantz J.C. Vaginal bleeding in early pregnancy and preterm birth: systemic review and analysis of heterogeneity.J Matern Fetal Neonatal Med. 2011; 24: 778-786Crossref PubMed Scopus (11) Google Scholar Some authors have defined early vaginal bleeding as at least one episode of spotting whereas others have defined it as bleeding greater than menses or involving a risk of abortion or sufficient to prompt an ultrasound examination.4.Hackney D.N. Glantz J.C. Vaginal bleeding in early pregnancy and preterm birth: systemic review and analysis of heterogeneity.J Matern Fetal Neonatal Med. 2011; 24: 778-786Crossref PubMed Scopus (11) Google Scholar Primary postpartum hemorrhage (PPH) occurs during the first 24 hours and is more likely to result in maternal morbidity and mortality while secondary PPH refers to hemorrhage 24 hours to 6 weeks after delivery.5.Walfish M. Neuman A. Wlody D. Maternal haemorrhage.Br J Anaesth. 2009; 103: i47-i56Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar The definition of primary PPH also varies widely between different national guidelines, including those of the Royal College of Obstetricians and Gynaecologists (RCOG), the American College of Obstetricians and Gynecologists (ACOG), the International Federation of Gynecology and Obstetrics (FIGO), the Society of Obstetricians and Gynecologists of Canada (SOGC), the Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG), the French College of Gynaecologists and Obstetricians (CNGOF), the Netherlands Society of Obstetrics and Gynecology (NVOG), and the German Society for Gynecology and Obstetrics (DGGG).3.Dahlke J.D. Mendez‐Figueroa H. Maggio L. et al.Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines.Am J Obstet Gynecol. 2015; 213: 76.e1-76.e10Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 6.Bohlmann M.K. Rath W. Medical prevention and treatment of postpartum hemorrhage: a comparison of different guidelines.Arch Gynecol Obstet. 2014; 289: 555-567Crossref PubMed Scopus (33) Google Scholar, 7.Sentilhes L. Goffinet F. Vayssière C. Deneux‐Tharaux C. Comparison of postpartum haemorrhage guidelines: discrepancies underline our lack of knowledge.BJOG. 2017; 124: 718-722Crossref PubMed Scopus (31) Google Scholar The ACOG, DGGG, FIGO, and NVOG guidelines define PPH as blood loss >500 mL for vaginal deliveries and >1000 mL for caesarean deliveries, whereas the RANZOG and CNGOF guidelines do not take into account the mode of delivery, and the RCOG guideline divides PPH into three categories: minor (500 mL to 1 L), moderate (>1 to 2 L) and major (>2 L). At the same time, most international guidelines consider the visual estimation of the amount of blood loss as unreliable but do not provide objective tools to measure this loss.7.Sentilhes L. Goffinet F. Vayssière C. Deneux‐Tharaux C. Comparison of postpartum haemorrhage guidelines: discrepancies underline our lack of knowledge.BJOG. 2017; 124: 718-722Crossref PubMed Scopus (31) Google Scholar Major differences between national guidelines have also been reported concerning the pharmacological treatment of PPH, which further confuses assessment of the severity of PPH. For example, some guidelines recommend a two‐step administration of uterotonics, starting with oxytocin, but do not specify a defined sequence of drug administration. Finally, recommendations regarding the use of red blood cells transfusion also vary, being based either on clinical signs of PPH severity or on hemoglobin level threshold. Pregnancy and postpartum are associated with an increased risk of thrombosis, which may be reduced by thromboprophylaxis.8.Rodger M. Pregnancy and venous thromboembolism: “TIPPS” for risk stratification.Hematology Am Soc Hematol Educ Program. 2014; 2014: 387-392Crossref PubMed Scopus (50) Google Scholar Many studies have assessed the efficacy of antithrombotic therapies during these periods. As the risk of bleeding is higher with antithrombotic therapies,9.Lepercq J. Conard J. Borel‐Derlon A. et al.Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies.BJOG. 2001; 108: 1134-1140Crossref PubMed Google Scholar, 10.Nelson‐Piercy C. Powrie R. Borg J.‐.Y. et al.Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile.Eur J Obstet Gynecol Reprod Biol. 2011; 159: 293-299Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar the definitions and reporting of bleeding events are crucial to assess the safety of these agents during pregnancy and postpartum, and to avoid underreporting of complications. We therefore performed a systematic review to assess the reporting of bleeding complications in studies evaluating antithrombotic therapies in pregnant women. A systematic search of English language literature was conducted in Medline (2010 to December 2017).11.Nussbaumer‐Streit B. Klerings I. Wagner G. et al.Abbreviated literature searches were viable alternatives to comprehensive searches: a meta‐epidemiological study.J Clin Epidemiol. 2018; 102: 1-11Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar The search strategy was based on the following keywords; “clinical trial,” “heparin,” and “pregnancy.” No restrictions with regard to geographic location were applied. Studies were selected if they reported data on any bleeding event that occurred during pregnancy or the postpartum period. A systematic search of studies recorded in the following registries: ClinicalTrials.gov, Australian New Zealand Clinical Trials Registry (ANZCTR), International Clinical Trials Registry Platform (ICTRP), University Hospital Medical Information Network Clinical Trials Registry (UMIN‐CTR), Nederland Trial Register (NTR), and the European Clinical Trials Database (EudraCT) was also conducted using the same keywords. Two investigators independently reviewed all abstracts and the full text of relevant published studies identified in Medline (B.T. and E.C.). Disagreements between reviewers were resolved by consensus and were reviewed by a third investigator (L.B.). Studies were included if they met the following eligibility criteria: (a) randomized controlled trial; (b) inclusion of pregnant women; (c) comparison of intravenous or subcutaneous heparin treatment versus either placebo or no treatment, or aspirin, or heparin treatment either at another dose or combined with a low dose of aspirin; (d) heparin administration up to at least 32 weeks of gestation; (e) follow‐up including the postpartum period. We excluded studies in which the number and/or the types of bleeding events observed in each group of treatment were not reported. Studies could be ongoing or still recruiting patients. The same two investigators included all relevant studies if they met the eligibility criteria. The methods used to document and classify bleeding complications, including their validation by an independent clinical events committee, were recorded whenever available. Two reviewers (B.T. and E.C.) independently extracted data using a standardized form. Disagreement was resolved by consensus and by the opinion of a third reviewer (L.B.), if necessary. The following data were extracted: aim of the study, number of patients included, number of patients taken into account in the safety analysis, heparin types and regimens used during pregnancy, aspirin dosage, duration of heparin therapy, definitions and types and rates of bleeding events occurring both antepartum and postpartum, and validation of bleeding events by an Independent Clinical Events Committee. Our objective was to provide a uniform definition of major bleeding, clinically relevant nonmajor bleeding, and minor bleeding for the evaluation of prophylactic antithrombotic therapy in pregnant women. In the first step, a unanimous proposal for classification was developed by a working group of experts in obstetrics and thrombosis (B. Tardy, P. Kamphuisen, M. N. Varlet, C. Chauleur, L. Bertoletti). All these experts, including two obstetricians, have been involved for many years in studies evaluating antithrombotic therapies in pregnant women either as principal investigator (C. Chauleur) or as investigators (M. N. Varlet, C. Chauleur) or as members of independent clinical events committees (B. Tardy, P. Kamphuisen, L. Bertoletti). In the second step, the classification was modified according to consensual propositions from a second working group including study principal investigators (S. Middeldorp, M. Rodger) or study investigators in this domain (A. Buchmuller, F. Ni Ainle, P. Verhamme, I. Bistervels, M. T. De Sancho). The final draft was then sent to the chairman of the subcommittee (M. Crowther) who requested the subcommittee members to review and comment on the text within 1 month. Responses were obtained from five cochairpersons and the text was revised to take their input into account. From January 2010 to December 2017, a total of 54 studies were identified. Among these, 38 were excluded owing to the absence or inadequacy of randomization (n = 17), the absence of evaluation of bleeding events (n = 1), heparin treatment withdrawal before the third trimester (n = 6), heparin treatment initiation after delivery (n = 3), study description alone (n = 4), study interview (n = 3), duplicate study (n = 1), and comparison of drugs not including intravenous or subcutaneous heparin (n = 3). Sixteen studies met the eligibility criteria, including a total of 2690 patients for whom data on bleeding events were reported in the safety outcome analysis (Table 1). Ten of these studies were performed to investigate the effect of antithrombotic prophylaxis on pregnancy complications such as preeclampsia, eclampsia, HELLP syndrome, intrauterine fetal death, placenta abruption, and fetal growth restriction,12.Groom K.M. McCowan L.M. Mackay L.K. et al.Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.Am J Obstet Gynecol. 2017; 216: 296.e1-296.e14Abstract Full Text Full Text PDF Scopus (55) Google Scholar, 13.Haddad B. Winer N. Chitrit Y. et al.Enoxaparin and aspirin compared with aspirin alone to prevent placenta‐mediated pregnancy complications: a randomized controlled trial.Obstet Gynecol. 2016; 128: 1053-1063Crossref PubMed Scopus (55) Google Scholar, 14.de Vries J.I.P. van Pampus M.G. Hague W.M. et al.Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT.J Thromb Haemost. 2012; 10: 64-72Crossref PubMed Scopus (139) Google Scholar, 15.Rodger M. Hague W.M. Kingdom J. et al.Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open‐label randomised trial.Lancet. 2014; 384: 1673-1683Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 16.Martinelli I. Ruggenenti P. Cetin I. et al.Heparin in pregnant women with previous placenta‐mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.Blood. 2012; 119: 3269-3275Crossref PubMed Scopus (95) Google Scholar, 17.Gris J.‐.C. Chauleur C. Faillie J.‐.L. et al.Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH‐AP trial.Thromb Haemost. 2010; 104: 771-779Crossref PubMed Scopus (75) Google Scholar, 18.Gris J.‐.C. Chauleur C. Molinari N. et al.Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre‐eclampsia. The pilot randomised controlled NOH‐PE trial.Thromb Haemost. 2011; 106: 1053-1061Crossref PubMed Scopus (85) Google Scholar, 19.Salim R. Nachum Z. Gavish I. Romano S. Braverman M. Garmi G. Adjusting enoxaparin dosage according to anti‐FXa levels and pregnancy outcome in thrombophilic women.Thromb Haemost. 2016; 116: 687-695Crossref PubMed Scopus (12) Google Scholar, 20.Kingdom J.C.P. Walker M. Proctor L.K. et al.Unfractionated heparin for second trimester placental insufficiency: a pilot randomized trial.J Thromb Haemost. 2011; 9: 1483-1492Crossref PubMed Scopus (27) Google Scholar, 21.van Hoorn M.E. Hague W.M. van Pampus M.G. et al.Low‐molecular‐weight heparin and aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with antiphospholipid antibodies: the FRUITRCT.Eur J Obstet Gynecol Reprod Biol. 2016; 197: 168-173Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar the aim of six studies being the prevention of spontaneous abortion22.Pasquier E. de Saint Martin L. Bohec C. et al.Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double‐blind placebo‐controlled trial.Blood. 2015; 125: 2200-2205Crossref PubMed Scopus (82) Google Scholar, 23.Fouda U.M. Sayed A.M. Ramadan D.I. Fouda I.M. Efficacy and safety of two doses of low molecular weight heparin (enoxaparin) in pregnant women with a history of recurrent abortion secondary to antiphospholipid syndrome.J Obstet Gynaecol. 2010; 30: 842-846Crossref Scopus (16) Google Scholar, 24.Fouda U.M. Sayed A.M. Abdou A.M.A. Ramadan D.I. Fouda I.M. Zaki M.M. et al.Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome.Int J Gynaecol Obstet. 2011; 112: 211-215Crossref PubMed Scopus (51) Google Scholar, 25.Visser J. Ulander V.‐.M. Helmerhorst F.M. et al.Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial.Thromb Haemost. 2011; 105: 295-301Crossref PubMed Scopus (152) Google Scholar, 26.Kaandorp S.P. Goddijn M. van der Post J.A.M. et al.Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.N Engl J Med. 2010; 362: 1586-1596Crossref PubMed Scopus (364) Google Scholar, 27.Clark P. Walker I.D. Langhorne P. et al.SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low‐molecular‐weight heparin and low‐dose aspirin in women with recurrent miscarriage.Blood. 2010; 115: 4162-4167Crossref PubMed Scopus (209) Google Scholar (Table 1). The prevention of venous thromboembolism during pregnancy (in addition to the prevention of placenta‐mediated complications) was explored in only one study.15.Rodger M. Hague W.M. Kingdom J. et al.Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open‐label randomised trial.Lancet. 2014; 384: 1673-1683Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar Fixed prophylactic doses of low molecular weight heparin (LMWH) were compared to standard care in seven studies12.Groom K.M. McCowan L.M. Mackay L.K. et al.Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.Am J Obstet Gynecol. 2017; 216: 296.e1-296.e14Abstract Full Text Full Text PDF Scopus (55) Google Scholar, 13.Haddad B. Winer N. Chitrit Y. et al.Enoxaparin and aspirin compared with aspirin alone to prevent placenta‐mediated pregnancy complications: a randomized controlled trial.Obstet Gynecol. 2016; 128: 1053-1063Crossref PubMed Scopus (55) Google Scholar, 15.Rodger M. Hague W.M. Kingdom J. et al.Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open‐label randomised trial.Lancet. 2014; 384: 1673-1683Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 16.Martinelli I. Ruggenenti P. Cetin I. et al.Heparin in pregnant women with previous placenta‐mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.Blood. 2012; 119: 3269-3275Crossref PubMed Scopus (95) Google Scholar, 17.Gris J.‐.C. Chauleur C. Faillie J.‐.L. et al.Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH‐AP trial.Thromb Haemost. 2010; 104: 771-779Crossref PubMed Scopus (75) Google Scholar, 18.Gris J.‐.C. Chauleur C. Molinari N. et al.Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre‐eclampsia. The pilot randomised controlled NOH‐PE trial.Thromb Haemost. 2011; 106: 1053-1061Crossref PubMed Scopus (85) Google Scholar, 22.Pasquier E. de Saint Martin L. Bohec C. et al.Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double‐blind placebo‐controlled trial.Blood. 2015; 125: 2200-2205Crossref PubMed Scopus (82) Google Scholar including one study that used a subcutaneous placebo.22.Pasquier E. de Saint Martin L. Bohec C. et al.Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double‐blind placebo‐controlled trial.Blood. 2015; 125: 2200-2205Crossref PubMed Scopus (82) Google Scholar Low‐dose aspirin (LDA) was administered in the LMWH and standard care groups in three of these studies.12.Groom K.M. McCowan L.M. Mackay L.K. et al.Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.Am J Obstet Gynecol. 2017; 216: 296.e1-296.e14Abstract Full Text Full Text PDF Scopus (55) Google Scholar, 13.Haddad B. Winer N. Chitrit Y. et al.Enoxaparin and aspirin compared with aspirin alone to prevent placenta‐mediated pregnancy complications: a randomized controlled trial.Obstet Gynecol. 2016; 128: 1053-1063Crossref PubMed Scopus (55) Google Scholar, 18.Gris J.‐.C. Chauleur C. Molinari N. et al.Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre‐eclampsia. The pilot randomised controlled NOH‐PE trial.Thromb Haemost. 2011; 106: 1053-1061Crossref PubMed Scopus (85) Google Scholar The weight‐adjusted dose of LMWH compared to standard care was reported in two studies, in which all patients also received LDA.14.de Vries J.I.P. van Pampus M.G. Hague W.M. et al.Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT.J Thromb Haemost. 2012; 10: 64-72Crossref PubMed Scopus (139) Google Scholar, 21.van Hoorn M.E. Hague W.M. van Pampus M.G. et al.Low‐molecular‐weight heparin and aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with antiphospholipid antibodies: the FRUITRCT.Eur J Obstet Gynecol Reprod Biol. 2016; 197: 168-173Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar A prophylactic dose of LMWH (enoxaparin, 40 mg/d) was compared with a fixed prophylactic dose of unfractionated heparin or a low dose of LMWH (enoxaparin, 20 mg/d) or an LMWH dose adjusted according to anti‐Xa levels in three other studies.19.Salim R. Nachum Z. Gavish I. Romano S. Braverman M. Garmi G. Adjusting enoxaparin dosage according to anti‐FXa levels and pregnancy outcome in thrombophilic women.Thromb Haemost. 2016; 116: 687-695Crossref PubMed Scopus (12) Google Scholar, 23.Fouda U.M. Sayed A.M. Ramadan D.I. Fouda I.M. Efficacy and safety of two doses of low molecular weight heparin (enoxaparin) in pregnant women with a history of recurrent abortion secondary to antiphospholipid syndrome.J Obstet Gynaecol. 2010; 30: 842-846Crossref Scopus (16) Google Scholar, 24.Fouda U.M. Sayed A.M. Abdou A.M.A. Ramadan D.I. Fouda I.M. Zaki M.M. et al.Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome.Int J Gynaecol Obstet. 2011; 112: 211-215Crossref PubMed Scopus (51) Google Scholar Fixed prophylactic doses of unfractionated heparin compared to standard care were evaluated in one study.20.Kingdom J.C.P. Walker M. Proctor L.K. et al.Unfractionated heparin for second trimester placental insufficiency: a pilot randomized trial.J Thromb Haemost. 2011; 9: 1483-1492Crossref PubMed Scopus (27) Google Scholar Prophylactic doses of LMWH combined with LDA, compared to LDA alone, or to LMWH alone, or to standard care were assessed in three studies.25.Visser J. Ulander V.‐.M. Helmerhorst F.M. et al.Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial.Thromb Haemost. 2011; 105: 295-301Crossref PubMed Scopus (152) Google Scholar, 26.Kaandorp S.P. Goddijn M. van der Post J.A.M. et al.Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.N Engl J Med. 2010; 362: 1586-1596Crossref PubMed Scopus (364) Google Scholar, 27.Clark P. Walker I.D. Langhorne P. et al.SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low‐molecular‐weight heparin and low‐dose aspirin in women with recurrent miscarriage.Blood. 2010; 115: 4162-4167Crossref PubMed Scopus (209) Google Scholar Among these 16 studies retained for analysis, only one was a double‐blind, placebo‐controlled trial (evaluating enoxaparin vs placebo).22.Pasquier E. de Saint Martin L. Bohec C. et al.Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double‐blind placebo‐controlled trial.Blood. 2015; 125: 2200-2205Crossref PubMed Scopus (82) Google ScholarTable 1Study characteristicsAuthor/year(ACRONYM)Trial registration no.AimPrevention of: (Study duration)No of patients (outcome analysis)Treatment (type, dose)Duration of heparin treatmentPostpartum: % of cesarean deliveriesProphylaxisDefinitions of bleeding types (outcome)Types of bleeding recorded% of reported bleedsIACGroom12.Groom K.M. McCowan L.M. Mackay L.K. et al.Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.Am J Obstet Gynecol. 2017; 216: 296.e1-296.e14Abstract Full Text Full Text PDF Scopus (55) Google Scholar(EPPI) ACTRN12609000699268Preeclampsia and IGR(2010‐2015)149Standard care vs enoxaparin 40 mg/d>6 and <16 WG to 36 WG or delivery53%NRPostpartum hemorrhagePlacenta abruption/Antepartum hemorrhage9.1 vs 9.7NoMajor PPHdReported in the Results section as major when >1000 mL and minor when ≥500 mL.9.1 vs 5.6NoMinor PPHdReported in the Results section as major when >1000 mL and minor when ≥500 mL.39 vs 37.5NoHaddad13.Haddad B. Winer N. Chitrit Y. et al.Enoxaparin and aspirin compared with aspirin alone to prevent placenta‐mediated pregnancy complications: a randomized controlled trial.Obstet Gynecol. 2016; 128: 1053-1063Crossref PubMed Scopus (55) Google Scholar(HEPEPE) NCT00986765Placental vascular complications(2009‐2015)244Standard care vs enoxaparin 40 mg/d<14 wk until delivery (ASA until 35 WG)52.50%LMWH (in 83 women)Placenta abruptionHemorrhagePlacenta abruption2.5 vs 2.5YeslIt is not specified whether this committee was independent.Major bleed,1.6 vs 1.6NoPPH4.9 vs 6.6NoAny bleeding5.7 vs 10.7Novan Hoorn21.van Hoorn M.E. Hague W.M. van Pampus M.G. et al.Low‐molecular‐weight heparin and aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with antiphospholipid antibodies: the FRUITRCT.Eur J Obstet Gynecol Reprod Biol. 2016; 197: 168-173Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar(Fruit‐RCT)Preeclampsiaa) in women with APS (2000‐2009)32Standard care vs W‐A dalteparin/d,>6 and <12 WG until onset of labour or cesarean or 36 WGNR (a)39% (b)W‐A dalteparine(6 wk) (a,b)NonePlacenta abruption6.3 vs 0Node Vries14.de Vries J.I.P. van Pampus M.G. Hague W.M. et al.Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT.J Thromb Haemost. 2012; 10: 64-72Crossref PubMed Scopus (139) Google Scholar(Fruit‐RCT)ISRCTN 87325378b) in woman with thrombophilia(2000‐2009)139NonePlacenta abruption1.4 vs 1.4NoHematomajThere was no definition of bleeding including the postpartum period.0 vs 1.4NoPasquier22.Pasquier E. de Saint Martin L. Bohec C. et al.Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double‐blind placebo‐controlled trial.Blood. 2015; 125: 2200-2205Crossref PubMed Scopus (82) Google Scholar(PREFIX)NCT00740545Unexplained recurrent miscarriage(2007‐2012)256Placebo vs enoxaparin 40 mg/d<5 WG until 35 WGNRNRBleeding episodesPlacenta abruption0 vs 0NoMajor bleedingoDefined as bleeding from gums or nose and the amount of vaginal blood loss at delivery.1.7 vs 1.4NoMinor bleeding14.4 vs 23.9NoRodger15.Rodger M. Hague W.M. Kingdom J. et al.Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open‐label randomised trial.Lancet. 2014; 384: 1673-1683Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar(TIPPS)NCT00967382Complications in pregnant women with thrombophilia(2000‐2012)284Standard care vs dalteparin17The recruitment rate per center per month is the aim of this study. 5000 IU/d<21 WG until 37 WG39%Dalteparine 5000 UI/d (6 wk)Major bleedingPlacenta abruption2.1 vs 2.7YesMajor bleeding1.4 vs 2.1YesMinor bleeding9.2 vs 19.6YesMajor PPH1 vs 1YesMartinelli16.Martinelli I. Ruggenenti P. Cetin I. et al.Heparin in pregnant women with previous placenta‐mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.Blood. 2012; 119: 3269-3275Crossref PubMed Scopus (95) Google Scholar(HAPPY)EudraCT2006‐004205‐26Placental vascular complications(2007‐2010)128Standard care vs nadroparin 3800 IU/d<12 WG until delivery44%NRNonePlacenta abruption1.5 vs 0YesMajor bleedingjThere was no definition of bleeding including the postpartum period.1.5 vs 0NoMinor bleedingjThere was no definition of bleeding including the postpartum period.12 vs 5NoGris18.Gris J.‐.C. Chauleur C. Molinari N. et al.Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre‐eclampsia. The pilot randomised controlled NOH‐PE trial.Thromb Haemost. 2011; 106: 1053-1061Crossref PubMed Scopus (85) Google Scholar(NOH‐PE)Placental vascular complications in previous preeclampsia(2000‐2010)224Standard care vs enoxaparin 40 mg/dFrom positive pregnancy test until onset of labor34%Enoxaparine 40 mg/d (6 wk)Placenta abruptionMajor bleedingPPHmEnoxaparin 40 mg/d was given in all cases 1 d after delivery for 6 wk.Placenta abruption1.8 vs 0.9YesMajor bleeding0 vs 0YesPPH4.5 vs 3.6YesGris17.Gris J.‐.C. Chauleur C. Faillie J.‐.L. et al.Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH‐AP trial.Thromb Haemost. 2010; 104: 771-779Crossref PubMed Scopus (75) Google Scholar(NOH‐AP)Placental vascular complications in previous placenta abruption(2000‐2009)160Standard care vs enoxaparin 40 mg/dFrom positive pregnancy test to 36 WG or delivery62%NRPlacenta abruption3.8 vs 1.3YesMajor bleeding0 vs 0YesPPH7.5 vs 2.5YesFouda23.Fouda U.M. Sayed A.M. Ramadan D.I. Fouda I.M. Efficacy and safety of two doses of low molecular weight heparin (enoxaparin) in pregnant women with a history of recurrent abortion secondary to antiphospholipid syndrome.J Obstet Gynaecol. 2010; 30: 842-846Crossref Scopus (16) Google ScholarNCT 01051778Recurrent abortion due to APS(2006‐2008)60UFH 5000 IU bid vs enoxaparin 40 mg/dFrom positive pregnancy to delivery13Enoxaparin 40 mg/d was given in all cases 1 d after delivery for 6 wk.17%Enoxaparin 40 mg/d (6 wk)Excessive hemorrhage0 vs 0NoFouda24.Fouda U.M. Sayed A.M. Abdou A.M.A. Ramadan D.I. Fouda I.M. Zaki M.M. et al.Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome.Int J Gynaecol Obstet. 2011; 112: 211-215Crossref PubMed Scopus (51) Google ScholarRecurrent abortion due to APS(2008‐2010)60Enoxaparin 20 mg/d vs enoxaparin 40 mg/dFrom positive pregnancy test to delivery20%NRExcessive hemorrhagePlacenta abruption0 vs 0NoPPH0 vs 0Visser25.Visser J. Ulander V.‐.M. Helmerhorst F.M. et al.Thromboprophylaxis f