Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Saf

767 views

Published on

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

Saf

  1. 1. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) Kaandorp S, Di Nisio M, Goddijn M, Middeldorp SThis is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 1 http://www.thecochranelibrary.comAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review)Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  2. 2. TABLE OF CONTENTSHEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Analysis 1.1. Comparison 1 Aspirin versus placebo, Outcome 1 Live-birth rate. . . . . . . . . . . . . . 16 Analysis 2.1. Comparison 2 Enoxaparin versus aspirin, Outcome 1 Live-birth rate. . . . . . . . . . . . . 17 Analysis 2.2. Comparison 2 Enoxaparin versus aspirin, Outcome 2 Preterm delivery. . . . . . . . . . . . 17 Analysis 2.3. Comparison 2 Enoxaparin versus aspirin, Outcome 3 Obstetric complications; pre-eclampsia. . . . . 18 Analysis 2.4. Comparison 2 Enoxaparin versus aspirin, Outcome 4 Obstetric complications; intrauterine growth restriction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 22INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) iCopyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  3. 3. [Intervention Review]Aspirin or anticoagulants for treating recurrent miscarriage inwomen without antiphospholipid syndromeStef Kaandorp1 , Marcello Di Nisio2 , Mariette Goddijn3 , Saskia Middeldorp41 Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, Netherlands. 2 Department of Vascular Medicine, F4-138,Academic Medical Center, Amsterdam, Netherlands. 3 Center for Reproductive Medicine, Department of Obstetrics and Gynecology,Academic Medical Center (H4-205), Amsterdam, Netherlands. 4 Department of Clinical Epidemiology, Department of General InternalMedicine, Leiden University Medical Center (LUMC), Leiden, NetherlandsContact address: Stef Kaandorp, Obstetrics and Gynaecology, Academic Medical Center, Meibergdreef 9, P.O. Box 22660, Amsterdam,1100 DD, Netherlands. s.p.kaandorp@amc.uva.nl.Editorial group: Cochrane Pregnancy and Childbirth Group.Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 1, 2009.Review content assessed as up-to-date: 29 April 2008.Citation: Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage inwomen without antiphospholipid syndrome. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD004734. DOI:10.1002/14651858.CD004734.pub3.Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACTBackgroundSince hypercoagulability might result in recurrent miscarriage, anticoagulant agents could potentially increase the live-birth rate insubsequent pregnancies in women with either inherited thrombophilia or unexplained recurrent miscarriage.ObjectivesTo evaluate the efficacy and safety of anticoagulant agents, such as aspirin and heparin, in women with a history of at least twomiscarriages without apparent causes other than inherited thrombophilia.Search methodsWe searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (April 2008), the Cochrane Central Register of ControlledTrials (The Cochrane Library 2007, Issue 1), MEDLINE (January 1966 to March 2007), and EMBASE (1980 to March 2007). Wescanned bibliographies of all located articles for any unidentified articles.Selection criteriaRandomised and quasi-randomised controlled trials that assessed the effect of anticoagulant treatment on the live-birth rate in womenwith a history of at least two miscarriages (up to 20 weeks of amenorrhoea) without apparent causes other than inherited thrombophiliawere eligible. Interventions included aspirin, unfractionated heparin, and low molecular weight heparin for the prevention of miscarriage.One treatment could be compared with another or with placebo.Data collection and analysisTwo authors assessed the trials for inclusion in the review and extracted the data. We double checked the data.Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 1Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  4. 4. Main resultsTwo studies (189 participants) were included in the review. In one study, 54 pregnant women with recurrent miscarriage (RM) but nodetectable anticardiolipin antibodies were randomised to low-dose aspirin or placebo. RM was defined as three or more consecutivemiscarriages (occurring before 22 weeks’ gestational age (based on last menstrual period)). Similar live-birth rates were observed withaspirin and placebo, both 81% (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.78 to 1.29). In the other study, 107 women withconsecutive recurrent miscarriage without any apparent cause and no hereditary thrombophilia were randomised between enoxaparinand aspirin. Here RM was stated as three or more consecutive first trimester miscarriages or at least two consecutive second trimestermiscarriages. Similar live birth rates were observed with enoxaparin and aspirin, respectively 82% and 84% (RR 0.97, 95% CI 0.81 to1.16).Authors’ conclusionsThere is a paucity in studies on the efficacy and safety of aspirin and heparin in women with a history of at least two miscarriageswithout apparent causes other than inherited thrombophilia. The two reviewed trials studied different treatments and only one studywas placebo-controlled. Neither of the studies showed a benefit of one treatment over the other. Therefore, the use of anticoagulantsin this setting is not recommended. However, large randomised placebo-controlled trials are still urgently needed.PLAIN LANGUAGE SUMMARYAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndromeTwo studies (189 women) were included in the review. There is Insufficient evidence to say if anticoagulants help women with recurrentmiscarriage without antiphospholipid syndrome.Recurrent miscarriage (RM) is associated with inherited blood clotting disorders that could interfere with the placental blood circulation.Anticoagulant drugs for women with RM and such an underlying blood clotting problem may help, although these drugs may alsocause excessive bleeding. Judgement if anticoagulants help women with RM in the absence of antiphospholipid syndrome is not possiblebecause of the lack of sufficient evidence from the reviewed trials on this subject.BACKGROUND an evaluation of etiologic causes ((American College of ObstetricsRecurrent miscarriage (RM) is devastating for women and their and Gynecology (ACOG 2001); Dutch Society of Obstetrics andfamilies, while up to 15% of all clinically recognised pregnancies Gynecology (NVOG 2007)). However, the risk of a miscarriageend in miscarriage (miscarriage before the 20th week of gesta- after two or three consecutive miscarriages is almost similar (Regantional age) (Everett 1997; Huisjes 1984). Approximately 5% of 1988). Adequate characterisation of miscarriages and patients inwomen experience two or more miscarriages, whereas RM, de- RM studies is most important and, favourably, would be the samefined as three or more first trimester miscarriages, may affect as to make studies mutually comparable (Christiansen 2006). In thismany as 1% to 2% of women of reproductive age (Clifford 1994; review we decided to use the broad definition of RM: two or moreCook 1995; Stirrat 1990). The definition of RM remains the sub- miscarriages (up to 20 weeks of amenorrhoea).ject of debate. The World Health Organization (WHO) definesmiscarriage as a pregnancy ending in the death or expulsion ofthe fetus or the embryo before the 20th week of gestational age Miscarriage is associated with relevant maternal morbidity like(WHO 1977). Often RM is defined as three or more consecutive bleeding and infection and, sometimes, maternal death (NHMRCmiscarriages. According to recent European Society for Human 2001), particularly in low-income countries (Goyaux 2001).Reproduction & Embryology (ESHRE) guidelines, RM is tradi- Moreover, miscarriage, especially if recurrent, might cause impor-tionally defined as three or more consecutive miscarriages occur- tant psychological and emotional distress that can be further com-ring before 20 weeks’ amenorrhoea (Jauniaux 2006). Some guide- plicated by feelings of anxiety and depression as well as social with-lines use the definition of two or more miscarriages for offering drawal (Lee 1996).Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 2Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  5. 5. Several factors may be involved in the aetiology of recurrent mis- nancy outcomes may result from placental infarctions and throm-carriage. Women experiencing recurrent miscarriage may have an botic changes in decidual microvessels with possible placental in-underlying medical condition such as carrier status of a struc- sufficiency and fetal death (Infante-Reviard 1991; Lockshin 1999).tural chromosome abnormality (Braekeleer 1990; Franssen 2005), Heparin and low-dose aspirin seem to be effective and safe in re-antiphospholipid syndrome, or other blood clotting disorders ducing miscarriage rates in women with antiphospholipid anti-generally referred to as thrombophilias (Preston 1996). Factors body syndrome with significantly better pregnancy outcome thanless strongly associated with RM are anatomic abnormalities of low-dose aspirin alone (rate of live births of 71% to 80% ver-the uterus, hyperhomocysteinemia and endocrine abnormalities sus 42% to 44% respectively, an absolute risk difference of 0.36)(Christiansen 2005). (Kutteh 1996; Rai 1997), though findings have not always been consistent (Farquharson 2002). Both the therapy for recurrentThrombophilia are a diverse group of coagulation disorders as- miscarriage associated with the antiphospholipid syndrome andsociated with a predisposition to thrombosis and thus increased other possible therapies currently considered for the prevention ofrisk for thrombotic events as deep vein thrombosis and pulmonary recurrent miscarriage (as progesterone and immunotherapy) areembolism. These hypercoagulable states can be either acquired, as the topics covered in other Cochrane reviews (Empson 2005; Haasfor instance the antiphospholipid syndrome, or inherited as the 2008; Porter 2006).factor V Leiden mutation (which results in a decreased capacity toinactivate activated factor V by the protein C system, also known The prognosis in subsequent pregnancies of women with recur-as activated protein C (APC) resistance), the deficiency of physio- rent miscarriage without antiphospholipid antibody syndrome islogical anticoagulants like protein C, protein S and antithrombin the live-birth rate of approximately 50% to 89% (Brigham 1999;and the prothrombin G20210A gene mutation (resulting in in- Lindqvist 2006; Rai 2000; Stirrat 1990). For women with recur-creased concentrations of prothrombin in plasma) or an elevated rent miscarriage and underlying thrombophilic disorders, theselevel of factor VIII-ac. figures range from 63% to 80% (Preston 1996; Rai 2000). The differences between studies can probably be explained by differ-A growing body of evidence has implicated thrombophilia in ences in the populations of women participating in the studies.adverse obstetrical events (such as intrauterine growth restric-tion, miscarriage, severe pre-eclampsia, and placental abruption) The use of anticoagulants in pregnancy needs to be carefully moni-(Kupferminc 1999; Middeldorp 2007) and there is also reason- tored and evaluated for safety since it can carry risks for the motherable evidence to suggest that some cases of recurrent miscarriage and the fetus. In contrast to coumarin derivatives, neither unfrac-are associated with thrombosis of placental vessels and infarction. tionated heparin nor low molecular weight heparin cross the pla-Firstly, microthrombi are a common finding in the placental vas- centa and therefore do not have the potential to cause fetal bleedingculature of women with recurrent miscarriage (Rushton 1988). and teratogenicity (Ginsberg 2001). The maternal risks associatedSecondly, placental thrombosis and infarction have been described with heparin administration are uncommon but potentially seri-in association with certain thrombophilic defects (Dizon 1997; ous and include bleeding, heparin-induced thrombocytopenia andRai 1996), but other pathophysiological pathways than thrombo- heparin-induced osteopenia with fractures. Moreover, heparin ad-sis could also be involved, since adverse pregnancy outcomes can ministration may cause pain and slight bruising at injection sites.occur in women with thrombophilia in the absence of placental There is accumulating evidence that low molecular weight heparinthrombosis (Mousa 2000). Thirdly, thrombophilic defects are sig- is at least as effective and safe as unfractionated heparin with po-nificantly more prevalent amongst women with such pregnancy tential advantages during pregnancy, since they cause less heparin-complications (Rai 1995; Rey 2003). A meta-analysis showed that induced thrombocytopenia, can be administered once daily, andthe magnitude of the association between thrombophilia and fe- are associated with a lower risk of heparin-induced osteoporosistal loss varies according to the timing of fetal loss (Rey 2003). (Ginsberg 2001; Sanson 1999). Based on current evidence, low-In particular, first trimester recurrent miscarriage was associated dose aspirin (less than 150 mg/d) during the second and thirdwith factor V Leiden, APC resistance, and prothrombin G20210A trimesters appears to be safe, while the safety of higher doses ofmutation, while late non-recurrent fetal loss was associated with aspirin and/or aspirin ingestion during the first trimester remainsfactor V Leiden, prothrombin G20210A mutation, and protein S uncertain (Ginsberg 2001). The use of heparin in pregnancy hasdeficiency. Also, family studies showed that women with heredi- been covered in another Cochrane review (Walker 2003).tary thrombophilia, especially those with combined defects or an- In clinical practice, women with recurrent miscarriage associatedtithrombin deficiency, have an increased risk of miscarriage and with inherited thrombophilia or recurrent miscarriage without anyintrauterine fetal death compared to women without these defects other apparent predisposing disorder are frequently seeking advice(Meinardi 1999; Preston 1996; Sanson 1996). about the indication for anticoagulant treatment. Some cliniciansThe antiphospholipid syndrome is associated both with vascu- tend to extrapolate the beneficial effect of anticoagulant therapylar thrombosis and pregnancy complications (including recurrent in women with antiphospholipid antibody syndrome and recur-miscarriage and premature delivery) (Levine 2002). Adverse preg- rent miscarriage to all women with recurrent miscarriage withoutAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 3Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  6. 6. apparent cause or with inherited thrombophilia; whether there is Types of outcome measuresevidence for this is the objective of this review. Primary outcomesOBJECTIVES Live-birth rateThe objective of this review was to determine whether anticoag-ulant treatment improves pregnancy outcome in women with a Secondary outcomeshistory of at least two miscarriages without apparent causes otherthan inherited thrombophilia. 1. Preterm delivery of a live infant between 24 and 28 weeks’ gestational age 2. Preterm delivery of a live infant between 28 and 32 weeks’ gestational ageMETHODS 3. Preterm delivery of a live infant between 32 and 37 weeks’ gestational age 4. Obstetric complications (pregnancy associatedCriteria for considering studies for this review hypertension, pre-eclampsia, intrauterine growth retardation) 5. Congenital malformations 6. Admission to special careTypes of studies 7. Side effects of the drug used, both for the mother and theRandomised controlled trials and quasi-randomised controlled tri- baby (maternal and/or neonatal bleeding, heparin-inducedals that assessed the effect of anticoagulant treatment on improv- thrombocytopenia, heparin-induced osteopenia, pain anding the live-birth rate in women with a history of at least two bruising at injection sites, allergic reactions to heparin, andmiscarriages without apparent causes other than inherited throm- teratogenicity)bophilia. 8. Thromboembolic complicationsTypes of participants Search methods for identification of studiesParticipants were pregnant women or women who were activelytrying to become pregnant with a history of at least two mis-carriages without apparent causes other than inherited throm-bophilia. Studies that included women with apparent causes (other Electronic searchesthan familial thrombophilia) of recurrent miscarriage (antiphos- We searched the Cochrane Pregnancy and Childbirth Group’s Tri-pholipid syndrome; uterine abnormalities; patients’ or their part- als Register by contacting the Trials Search Co-ordinator (Aprilners’ karyotype abnormalities; endocrine and toxic factors (dia- 2008).betes mellitus); miscarriage due to documented fetal malforma- The Cochrane Pregnancy and Childbirth Group’s Trials Registertion or the result of an infectious complication) have been in- is maintained by the Trials Search Co-ordinator and contains trialscluded only if the results from women with a history of at least two identified from:miscarriages without apparent causes other than inherited throm- 1. quarterly searches of the Cochrane Central Register ofbophilia could be extracted to be analysed separately. According Controlled Trials (CENTRAL);to the WHO definitions and ESHRE guidelines, the term miscar- 2. weekly searches of MEDLINE;riage referred to a miscarriage occurring before the 20th week of 3. handsearches of 30 journals and the proceedings of majoramenorrhoea. For the studies included in the review, the respective conferences;definition for recurrent miscarriage is reflected. The study popu- 4. weekly current awareness alerts for a further 44 journalslations are described whenever possible with regard to number of plus monthly BioMed Central email alerts.miscarriages, gestational age of the miscarriages, and maternal age. Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service canTypes of interventions be found in the ‘Specialized Register’ section within the edito-The interventions included were aspirin, unfractionated heparin, rial information about the Cochrane Pregnancy and Childbirthand low molecular weight heparin for the prevention of miscar- Group.riage. One treatment could be compared with another or with Trials identified through the searching activities described aboveplacebo. Combinations of therapy could be used. are each assigned to a review topic (or topics). The Trials SearchAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 4Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  7. 7. Co-ordinator searches the register for each review using the topic unaware of the assigned intervention. We assessed other aspects oflist rather than keywords. study quality in the studies which fulfilled the inclusion criteria.In addition, we searched the Cochrane Central Register of Con-trolled Trials (The Cochrane Library 2007, Issue 1), MEDLINE We included all trials in the initial analyses and carried out sen-(January 1966 to March 2007), and EMBASE (1980 to March sitivity analyses to explore the effect of trial quality. We repeated2007) using the search strategy listed in Appendix 1. analyses taking into account factors that could have introduced bias, such as the inclusion of quasi-randomised studies, high levels of exclusions which were unbalanced between the groups, or otherSearching other resources insecure allocation concealment. We interpreted any differences cautiously and only used them to generate hypotheses. DespiteWe scanned bibliographies of all located articles for any unidenti- this quality assessment, we did not exclude any study on the ba-fied articles. sis of quality. We carried out statistical analyses using the ReviewWe did not apply any language restrictions. Manager software (RevMan 2000), with results presented as sum- mary relative risks. We calculated risk ratios using a fixed-effect model (Mantel-Haenszel method).Data collection and analysis In the case of homogenous data, we expressed summary statistics as risk difference (RD) and we used the number needed to treatTwo review authors independently reviewed titles and abstracts (1/RD) to express the final results of the review.from the database searches to determine whether the inclusion We applied tests of heterogeneity between trials to assess the sig-criteria were satisfied. We made decisions regarding inclusion nificance of any differences between trials (I2 method, significantseparately and compared results. We resolved any disagreements if greater than 0.3) and explored possible causes of any hetero-through discussion. Two authors independently reviewed the full geneity. If we detected heterogeneity, we planned to perform sub-text of identified articles, including those where there was disagree- group analyses for the main outcomes by individual quality crite-ment in the initial title or abstract scanning, to ensure that the ria to assess the effect of poorer quality studies on the magnitudeinclusion criteria were met. Where necessary, we contacted trial of the estimate of effect. If data were available, we also plannedauthors for additional information. to perform subgroup analysis to compare outcomes in: (1) dif-Two authors independently extracted the study characteristics us- ferent inherited thrombophilic disorders; (2) preconceptional oring an agreed format and data from included studies, including as- periconceptional anticoagulant use; (3) type of anticoagulant(s)sessments of quality. We resolved any disagreements by consensus used (e.g. single drug, combination of anticoagulant agents); (4)and, if necessary, by involvement of a third author. If we could not dose of anticoagulant(s); (5) duration of anticoagulant use; andreach agreement, we excluded the item until further information (6) women with a history of three or more miscarriages or two orwas available from the trialists. One author scanned conference more miscarriages.proceedings and included them if adequate information could be We assessed publication bias using the funnel plot. Symmetryobtained either from the abstract or from personal communica- would be expected in the absence of any bias, although situationstion. One author identified articles from other sources (experts or other than publication bias may result in asymmetry. We wouldreference lists) as possibly eligible and then two authors indepen- have explored any anomaly, but it was anticipated that the numberdently assessed them for inclusion, as above. Blinding of authors, of eligible studies might be too few to allow adequate assessment.journal of origin, or institutions did not occur. Two authors in-dependently assessed the abstracts of non-English articles, whichhad to be translated, to ascertain if they met the inclusion criteria.We obtained a translation of the full article of those that met thecriteria.We assessed the validity of each included trial according to the RESULTScriteria outlined in the Cochrane Reviewers’ Handbook (Clarke2002). These include generation of randomisation sequence; al-location concealment; blinding of subject, investigator, and out-come assessor; less than 20% loss to follow up; and analysis by Description of studiesintention to treat. Where the method of allocation concealment See: Characteristics of included studies; Characteristics of excludedwas unclear, we attempted to contact authors to provide further studies; Characteristics of ongoing studies.details. Allocation concealment was judged adequate (A), unclear Details for the trials included are in the ’Characteristics of included(B), inadequate (C), or not used (D), depending on the conceal- studies’.ment schemes used. Blinding was considered double or single if We included two studies (189 women) (Dolitzky 2006; Tulppalaboth the physician and the participant or only one of them were 1997) in this review. For the study by Tulppala (Tulppala 1997), weAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 5Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  8. 8. extracted data on the subgroup of women fulfilling the inclusion Given the paucity of data, we were unable to carry out the sensi-criteria of the review. tivity and subgroup analysis as planned. In the study by DolitzkyDolitzky 2006 evaluated the effect of aspirin or low-molecular- et al (Dolitzky 2006), 54 patients were randomized to enoxaparinweight heparin in women with unexplained RM. RM was defined and 50 patients to aspirin. The mean age did not differ betweenas three or more consecutive first trimester miscarriages or at least the enoxaparin and aspirin groups, respectively 31.73 +/- 5.3 andtwo consecutive second trimester miscarriages. The objective was 30.65 +/- 6.18. Also the number of previous miscarriages did notto compare the effect of aspirin and enoxaparin on live-birth rate. differ between the enoxaparin and aspirin groups, respectively 3.8Women were only included if there was no apparent cause for the +/- 1.4 and 3.9 +/- 1.4. The number lost to follow up was threemiscarriages including absence of hereditary thrombophilia (fac- (2.8%). Both groups had similar live birth rates, 82% in the enoxa-tor V Leiden, prothrombin mutation (G20210A), homozygous parin group and 84% in the aspirin group. The RR for enoxa-MTHFR mutation, deficiency of protein C,S or antithrombin). parin versus aspirin was 0.97 (95% CI 0.81 to 1.16). In a post-hocThe treatment with enoxaparin (40 mg/day) or aspirin (100 mg/ analysis of women who had no live children (primary aborters),day) was started from the time of detection of a fetal heart beat women allocated to enoxaparin had a non-significantly increasedat 6 to 12 weeks gestation. Of the 107 included women, 54 re- live birth, 94% as compared to 81% in those who had been al-ceived enoxaparin, 50 aspirin and 3 were lost to follow up. Besides located to aspirin. The number of preterm deliveries and casesthe primary outcome measure of live-birth rate secondary out- of intrauterine growth restriction did not differ between the twocomes like preterm delivery, intrauterine growth restriction, and groups. Pre-eclampsia was found in three women in the aspirinpre-eclampsia were reported. group and in none in the enoxaparin group. Placental doppler blood flow studies were similar in both groups. No maternal sideTulppala 1997 evaluated the effect of low-dose aspirin (50 mg/ effects were seen. In the aspirin group, one infant was born with aday) on live-birth rate in pregnant women with preceding RM necrotic testis and one had a convulsion caused by hypoglycaemia.with or without detectable anticardiolipin antibodies and no other In each group, one baby with a congenital anomaly was found.apparent cause for their previous miscarriages. RM was defined as One fetus was detected with tricuspid insufficiency (the pregnancythree or more consecutive miscarriages (occurring before 22 weeks was terminated) in the aspirin group and one infant had an im-of gestational age). Aspirin was compared to placebo, with med- perforate hymen in the enoxaparin group.ication started as soon as a home urinary pregnancy test became For the study by Tulppala et al (Tulppala 1997), we extracted datapositive. From this trial, we extracted data for the 54 women neg- for the subgroup of women fulfilling the inclusion criteria of theative for anticardiolipin antibodies. Of these, 27 were assigned to review. We could not extract data on mean age or mean numberaspirin and 27 to placebo. Secondary outcomes, such as preterm of miscarriages in the obstetric history in both groups. Fifty-fourdelivery, obstetric complications, and bleeding rate could not be pregnant women with recurrent miscarriage without detectableextracted separately for the group of women with negative anti- anticardiolipin antibodies were randomised to low-dose aspirincardiolipin antibodies. or placebo. In both groups, 81% of the pregnancies resulted in aOverall, we excluded 18 studies from the review. We have provided live birth (RR 1.00, 95% CI 0.78 to 1.29). We could not extractthe reasons for exclusion in the ’Characteristics of excluded studies’ data on secondary outcomes, such as preterm delivery, obstetrictable. complications, or bleeding rate.Risk of bias in included studiesDetails for the two included studies are in the ’Characteristics DISCUSSIONof included studies’ table. The study by Dolitzky 2006 was not The results of this systematic review show a paucity of publishedblinded and not placebo controlled. The randomisation method intervention trials with anticoagulants in women with unexplainedwas clearly described with adequate concealment of allocation. recurrent miscarriage without antiphospholipid antibodies. We in-The study by Tulppala 1997 was a double-blind, placebo-con- cluded only two randomised controlled trials in this review; in onetrolled trial. The method of randomisation was not stated and of them we could include data of only a small subgroup of womenconcealment of allocation was not clear. fulfilling the inclusion criteria of the review (Tulppala 1997). Nei- ther study, one using low-dose aspirin and placebo (Tulppala 1997) and one comparing enoxaparin with aspirin (Dolitzky 2006), showed improvement of gestational outcome. Therefore, the useEffects of interventions of either aspirin or low-molecular-weight heparin to prevent mis-We have included two trials, involving 189 participants, in this carriage in women with two or more miscarriages without appar-review. ent causes other than inherited thrombophilia, is not based on evi-Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 6Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  9. 9. dence and should be discouraged. Currently, properly randomised Implications for researchcontrolled trials using placebo or no treatment arms are ongoing. From a public health perspective, even a moderate benefit from aspirin or anticoagulants in this high-risk group of women might be worthwhile, and large studies of strong methodological qualityAUTHORS’ CONCLUSIONS are awaited to clarify the real risk-benefit of such an approach. Moreover, the inclusion of a placebo or no-treatment arm in theseImplications for practice studies is necessary since it would provide an adequate control toThere is a paucity in evidence on the efficacy and safety of aspirin the active treatment and allows assessing a risk-benefit ratio.and heparin in women with a history of at least two miscarriageswithout apparent causes other than inherited thrombophilia. Thetwo reviewed trials studied different treatments and only one studywas placebo-controlled. None of the studies showed an effect ofone treatment over the other. Therefore, the use of anticoagulants ACKNOWLEDGEMENTSin this setting is not recommended. However, large, randomised,placebo-controlled trials are urgently needed. Louisette Peters was an author on the first version of this review. REFERENCESReferences to studies included in this review Bick 2000 {published data only} Bick RL. Recurrent miscarriage syndrome due to bloodDolitzky 2006 {published data only} coagulation protein/platelet defects: prevalence, treatment Dolitzky M, Inbal A, Segal Y, Weiss A, Brenner B, Carp H. and outcome results. DRW Metroplex Recurrent A randomized study of thromboprophylaxis in women with Miscarriage Syndrome Cooperative Group. Clinical and unexplained consecutive recurrent miscarriages. Fertility Applied Thrombosis/Hemostasis 2000;6(3):115–25. and Sterility 2006;86(2):362–6. Brenner 2000 {published data only} Brenner B, Hoffman, Blumenfeld Z, Weiner Z, YounisTulppala 1997 {published data only} JS. Gestational outcome in thrombophilic women with Tulppala M, Marttunen M, Soderstrom-Anttila V, Ailus K, recurrent pregnancy loss treated by enoxaparin. Thrombosis Palosuo T, Ylikorkala O. Low dose aspirin in the prevention and Haemostasis 2000;83:693–7. of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and Brenner 2005 {published and unpublished data} thromboxane A2 production. Human Reproduction 1997; Brenner B, Bar J, Ellis M, Yarom I, Yohai D, Samueloff 12(1):191. A. Effects of enoxaparin on late pregnancy complications Tulppala M, Marttunen M, Soderstrom-Anttila V, Foudila and neonatal outcome in women with recurrent pregnancy T, Ailus K, Palosuo T, et al.Low-dose aspirin in the loss and thrombophilia: results from the Live-Enox study. prevention of miscarriage in women with unexplained Fertility and Sterility 2005;84(3):770–3. or autoimmune related recurrent miscarriage: effect on Brenner B, for the LIVE-ENOX Investigators. Efficacy and prostacyclin and thromboxane A2 production. Human safety of two doses of enoxaparin in pregnant women with Reproduction 1997;12(7):1567–72. thrombophilia and recurrent pregnancy loss. The LIVE- ENOX study. Blood 2002;100(11 Pt 1):702a.References to studies excluded from this review Brenner B, Hoffman R, Carp H, Dulitsky M, Samueloff A, Yohal D, et al.Efficacy and safety of two doses of enoxaparin in pregnant women with thrombophilia andBar 2000 {published data only} recurrent pregnancy loss: the LIVE-ENOX study. Journal Bar J, Cohen-Sacher B, Hod M, Blickstein D, Lahav J, of Thrombosis and Haemostasis 2003;1 Suppl 1:Abstract Merlob P. Low-molecular-weight heparin for thrombophilia number: OC084. in pregnant women. International Journal of Gynecology & Brenner B, Hoffman R, Carp H, Dulitsky M, Younis J. Obstetrics 2000;69:209–13. Efficacy and safety of two doses of enoxaparin in womenBar 2001 {published data only} with thrombophilia and recurrent pregnancy loss: the Bar J, Mashiah R, Cohen-Sacher B, Hod M, Orvieto R, LIVE-ENOX study. Journal of Thrombosis and Haemostasis Ben-Rafael Z, et al.Effect of thromboprophylaxis on uterine 2005;3(2):227–9. and fetal circulation in pregnant women with a history of Thaler I, Brenner B. Efficacy of enoxaparin for improving pregnancy complications. Thrombosis Research 2001;101: pregnancy outcomes and uteroplacental blood flow in 235–41. women with thrombophilia and recurrent pregnancy loss.Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 7Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  10. 10. American Journal of Obstetrics and Gynecology 2004;191(6 Sorensen 2000 {published data only} Suppl 1):S7. Sorensen HT, Johnsen SP, Larsen H, Pedersen L, NielsenCarp 2003 {published data only} GL, Moller M. Birth outcomes in pregnant women treated Carp H, Dolitzky M, Inbal A. Thromboprophylaxis with low-molecular-weight heparin. Acta Obstetricia et improves the live birth rate in women with consecutive Gynecologica Scandinavica 2000;79:655–9. recurrent miscarriages and hereditary thrombophilia. Tzafettas 2002 {published data only} Journal of Thrombosis and Haemostasis 2003;1:433–8. Tzafettas J, Mamopoulos A, Anapliotis A, Loufopoulos A, Psarra A, Klearchou N, et al.ThromboprophylaxisGrandone 2002 {published data only} throughout pregnancy in women with previous history of Grandone E, Brancaccio V, Colaizzo D, Sciannamé N, recurrent miscarriage of unknown etiology. Clinical and Pavone G, Di Minno G, et al.Preventing adverse obstetric Experimental Obstetrics and Gynecology 2002;29(4):267–70. outcomes in women with genetic thrombophilia. Fertility and Sterility 2002;78(2):371–5. Younis 2000 {published data only} Younis JS, Ohel G, Brenner B, Haddad S, Lanir N, Ben-Gris 1995 {published data only} Ami M. The effect of thromboprophylaxis on pregnancy Gris JC, Neveu S, Tailland ML, Courtieu C, Mares P, Schved outcome in patients with recurrent pregnancy loss associated JF. Use of a low-molecular-weight heparin (enoxaparin) with factor V mutation. BJOG: an international journal of or of a phenformin-like substance (moroxydine chloride) obstetrics and gynaecology 2000;107:415–9. in primary early recurrent aborters with an impaired fibrinolytic capacity. Thrombosis and Haemostasis 1995;73 References to ongoing studies (3):362–7.Gris 2004 {published data only} ALIFE study {published data only} Gris JC, Mercier E, Quéré I, Lavigne-Lissalde G, Cochery- Middeldorp S. Aspirin and/or low molecular weight heparin Nouvellon E, Hoffet M, et al.Low-molecular-weight for women with unexplained recurrent miscarriage and/or heparin versus low-dose aspirin in women with one fetal loss intra-uterine fetal death. Netherlands Trial Register (http:// and a constitutional thrombophilic disorder. Blood 2004; www.trialregister.nl) (accessed 1 November 2005). 103:3695–9. ETHIGII {published data only}Li 2003 {published data only} Schleussner E. Effectiveness of dalteparin therapy as Li DK, Liu L, Odouli R. Exposure to non-steroidal intervention in recurrent pregnancy loss. http://controlled- anti-inflammatory drugs during pregnancy and risk of trials.com (accessed 15.02.2007). miscarriage: population based cohort study. BMJ 2003; SPIN study {published data only} 327:368–72. Clark P. The Scottish pregnancy intervention study: theOgasawara 2001 {published data only} effect of low molecular weight heparin and aspirin therapy Ogasawara MS, Iinuma Y, Aoki K, Katano K, Ozaki Y, on recurrent pregnancy loss. National Research Register Suzumori K. Low-dose aspirin is effective for treatment of (www.nrr.nhs.uk) (accessed 6 July 2006). recurrent miscarriage in patients with decreased coagulation TIPPS study {published data only} factor XII. Fertility and Sterility 2001;76(1):203–4. Rodgers M. Thrombophilia in pregnancy prophylaxisRai 2000 {published data only} study (TIPPS). Ottawa Health Research Institute - http:// Rai R, Backos M, Baxter N, Chilcott I, Regan L. Recurrent www.ohri.ca (accessed 2002). miscarriage-an aspirin a day?. Human Reproduction 2000; 15(10):2220–3. Additional referencesReznikoff-Etievant 1999 {published data only} ACOG 2001 Reznikoff-Etievant MF, Cayol V, Zou GM, Abuaf N, American College of Obstetricians and Gynaecologists. Robert A, Johanet C, et al.Habitual abortions in 678 ACOG practice bulletin: management of recurrent early healthy patients: investigation and prevention. Human pregnancy loss. International Journal of Gynecology & Reproduction 1999;14(8):2106–9. Obstetrics 2002;78:179–90.Sarig 2003 {published data only} Braekeleer 1990 Sarig G, Aharon A, Lanir N, Goshen H, Drugan A, Braekeleer M, Dao TN. Cytogenetic studies in couples Blumenfeld Z, et al.Modulation of systemic and placental experiencing repeated pregnancy losses. Human hemostatic mechanisms by enoxaparin in women with Reproduction 1990;5:519–28. gestational vascular complications. Journal of Thrombosis Brigham 1999 and Haemostasis 2003;1 Suppl 1:Abstract number: OC083. Brigham SA, Conlon C, Farquharson RG. A longitudinalSarto 2001 {published data only} study of pregnancy outcome following idiopathic recurrent Sarto A, Rocha M, Geller M, Capmany C, Martinez M, miscarriage. Human Reproduction 1999;14:2868–71. Quintans C, et al.Treatment with enoxaparin adapted to the Christiansen 2005 fertility programs in women with recurrent abortion and Christiansen OB, Nybo Andersen A, Bosch E, Salim Daya thrombophilia. Medicina 2001;61(4):406–12. S, Delves P, Hviid T, et al.Evidence-based investigations andAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 8Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  11. 11. treatments of recurrent pregnancy loss. Fertility and Sterility Haas 2008 2005;83:821–39. Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2008,Christiansen 2006 Issue 2. [DOI: 10.1002/14651858.CD003511.pub2] Christiansen OB. Evidence-based investigations and treatments of recurrent pregnancy loss. Current Opinion in Huisjes 1984 Obstetrics and Gynecology 2006;18:304–12. Huisjes HJ. Spontaneous abortion. London: Churchill Livingstone, 1984:6.Clarke 2002 Infante-Reviard 1991 Clarke M, Oxman AD. Cochrane Reviewers’ Handbook Infante-Reviard C, David M, Gauthier R, Rivard GE. 4.1.5 [updated April 2002]. In: The Cochrane Library. Lupus anticoagulants, anticardiolipin antibodies, and fetal Issue 2, 2002. Oxford: Updated Software. updated loss. A case-control study. New England Journal of Medicine quarterly. 1991;325:1063–6.Clifford 1994 Jauniaux 2006 Clifford K, Rai R, Watson H, Regan L. An informative Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. protocol for the investigation of recurrent miscarriage: Evidence-based guidelines for the investigation and medical preliminary experience of 500 consecutive cases. Human treatment of recurrent miscarriage. Human Reproduction Reproduction 1994;9:1328–32. 2006;21:2216–22.Cook 1995 Kupferminc 1999 Cook CL, Pridman DD. Recurrent pregnancy loss. Current Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Opinion in Obstetrics and Gynecology 1995;7:357–66. Jaffa A, et al.Increased frequency of genetic thrombophilia in women with complications of pregnancy. New EnglandDizon 1997 Journal of Medicine 1999;340:9–13. Dizon TD, Meline L, Nelson LM, Varner M, Ward K. Kutteh 1996 Fetal carriers of the factor V Leiden mutation are prone to Kutteh WH. Antiphospholipid antibody-associated miscarriage and placental infarction. American Journal of recurrent pregnancy loss: treatment with heparin and low- Obstetrics and Gynecology 1997;177:402–5. dose aspirin is superior to low-dose aspirin alone. AmericanEmpson 2005 Journal of Obstetrics and Gynecology 1996;174:1584–9. Empson M, Lassere M, Craig J, Scott J. Prevention of Lee 1996 recurrent miscarriage for women with antiphospholipid Lee C, Slade P. Miscarriage as a traumatic event: a review of antibody or lupus anticoagulant. Cochrane Database of the literature and new implications for intervention. Journal Systematic Reviews 2005, Issue 2. [Art. No.: CD002859. of Psychosomatic Research 1996;40(3):235–44. DOI: 10.1002/14651858.CD002859.pub2] Levine 2002Everett 1997 Levine JS, Branch W, Rauch J. The antiphospholipid Everett C. Incidence and outcome of bleeding before the syndrome. New England Journal of Medicine 2002;346: 20th week of pregnancy: prospective study from general 752–63. practice. BMJ 1997;315:32–4. Lindqvist 2006Farquharson 2002 Lindqvist PG, Merlo J. The natural course of women with Farquharson RG, Quenby S, Greaves M. Antiphospholipid recurrent fetal loss. Journal of Thrombosis and Haemostasis syndrome in pregnancy: a randomized, controlled trial of 2006;4:896–7. treatment. Obstetrics & Gynecology 2002;100:408–13. Lockshin 1999 Lockshin MD. Pregnancy loss in the antiphospholipidFranssen 2005 syndrome. Thrombosis and Haemostasis 1999;82:641–8. Franssen MT, Korevaar JC, Leschot NJ, Bossuyt PM, Knegt AC, Gerssen-Schoorl KB, et al.Selective chromosome Meinardi 1999 analysis in couples with two or more miscarriages: case- Meinardi JR, Middeldorp S, de Kam PJ, Koopman MMW, control study. BMJ 2005;331:137–41. van Pampus ECM, Hamulyak K, et al.Increased risk for fetal loss in carriers of the factor V Leiden. Annals of InternalGinsberg 2001 Medicine 1999;130:736–9. Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents Middeldorp 2007 during pregnancy. Chest 2001;119(Suppl):122–31. Middeldorp S. Thrombophilia and pregnancyGoyaux 2001 complications: cause or association?. Journal of Thrombosis Goyaux N, Alihonou E, Diadhiou F, Leke R, Thonneau and Haemostasis 2007;5 Suppl 1:276–82. PF. Complications of induced abortion and miscarriage Mousa 2000 in three African Countries: a hospital-based study among Mousa HA, Alfirevic Z. Do placental lesions reflect WHO collaborating centres. Acta Obstetricia et Gynecologica thrombophilia state in women with adverse pregnancy Scandinavica 2001;80:568–73. outcome?. Human Reproduction 2000;15:1830–3.Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 9Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  12. 12. NHMRC 2001 Rey 2003 National Health and Medical Research Council. Report on Rey E, Kahn SR, David M, Shrier I. Thrombophilic Maternal Deaths in Australia 1994-96. Canberra. Australian disorders and fetal loss: a meta-analysis. Lancet 2003;361: Institute of Health and Welfare National Perinatal Statistics 901–8. Unit, 2001. Rushton 1988NVOG 2007 Rushton DI. Placental pathology in spontaneous Ankum WM, Erwich JJHM, Geraedts JPM, Goddijn M, miscarriage. In: Beard RW, Sharp F editor(s). Early Land JA, Macklon NS, et al.Recurrent miscarriage (dutch: pregnancy loss: mechanisms and treatment. London: RCOG, herhaalde miskraam). www.nvog.nl (Dutch obstetrics & 1988:149–58. gynaecology guidelines) 08–06–2007. Sanson 1996Porter 2006 Sanson BJ, Friederich PW, Simioni P, Zanardi S, Huisman Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for MV, Girolami A, et al.The risk of abortion and stillbirth in recurrent miscarriage. Cochrane Database of Systematic antithrombin-, protein C-, and protein S-deficient women. Reviews 2006, Issue 2. [Art. No.: CD000112. DOI: Thrombosis and Haemostasis 1996;75(3):387–8. 10.1002/14651858.CD000112.pub2]Preston 1996 Sanson 1999 Preston F, Rosendaal FR, Walker ID, Briet E, Berntorp E, Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan Conard J, et al.Increased fetal loss in women with heritable ZS, Lavenne-Pardonge E. Safety of low-molecular-weight thrombophilia. Lancet 1996;348:913–6. heparin in pregnancy. A systematic review. Thrombosis and Haemostasis 1999;81:668–72.Rai 1995 Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie Stirrat 1990 I, et al.Antiphospholipid antibodies and beta2-glycoprotein- Stirrat GM. Recurrent miscarriage: definition and I in 500 women with recurrent miscarriage: results of a epidemiology. Lancet 1990;336:673–5. comprehensive approach. Human Reproduction 1995;10: 2001–5. Walker 2003 Walker MC, Ferguson SE, Allen VM. Heparin for pregnantRai 1996 women with acquired or inherited thrombophilias. Rai RS, Regan L, Chitolie A, Donald JG, Cohen H. Cochrane Database of Systematic Reviews 2003, Issue 2. [Art. Placental thrombosis and second trimester miscarriage in No.: CD003580. DOI: 10.1002/14651858.CD003580] association with activated protein C resistance. British Journal of Obstetrics and Gynaecology 1996;103:842–4. WHO 1977Rai 1997 World Health Organization. Recommended definitions; Rai R, Cohen H, Dave M, Regan L. Randomised controlled terminology and format for statistical tables related to trial of aspirin and aspirin plus heparin in pregnant women the perinatal period. Acta Obstetricia et Gynecologica with recurrent miscarriage associated with phospholipid Scandinavica 1977;56:246–53. antibodies (or antiphospholipid antibodies). BMJ 1997; 314:253–7. References to other published versions of this reviewRegan 1988 Regan L. A prospective study of spontaneous abortion. CDSR 2005 Early pregnancy loss: mechanisms and treatment. RCOG, Di Nisio M, Peters LW, Middeldorp S. Aspirin or 1988. anticoagulants for the treatment of recurrent miscarriageRevMan 2000 in women without antiphospholipid syndrome. Cochrane The Cochrane Collaboration. Review Manager (RevMan). Database of Systematic Reviews 2005, Issue 2. [DOI: 4.1 for Windows. Oxford, England: The Cochrane 10.1002/14651858.CD004734.pub2] Collaboration, 2000. ∗ Indicates the major publication for the studyAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 10Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  13. 13. CHARACTERISTICS OF STUDIESCharacteristics of included studies [ordered by study ID]Dolitzky 2006Methods Open label, random allocation with adequate concealment.Participants Women (n = 107) with a history of three or more consecutive fetal losses in the first trimester or at least two second trimester fetal losses in whom no cause for their previous pregnancy losses was foundInterventions Subcutaneous enoxaparin (40 mg/daily) versus aspirin (100 mg/daily) from the time of detection of a fetal heart beatOutcomes Primary: live birth rates. Secondary: intrauterine growth restriction, birth weight, uterine and umbilical blood flow, pre-eclampsia, haemorrhage, thrombocytopenia, allergic reactions and congenital malforma- tionsNotesRisk of biasItem Authors’ judgement DescriptionAllocation concealment? Yes A - AdequateTulppala 1997Methods Double-blind, placebo-controlled.Participants Women (n = 82) with a history of at least 3 consecutive miscarriages in whom no obvious cause for their previous pregnancy losses was foundInterventions Aspirin (50 mg/daily) versus placebo, started as soon as a urinary pregnancy test became positiveOutcomes To assess the effect of low-dose aspirin on PGI2 and TXA2 production and on the rate of abortion in pregnant women with recurrent spontaneous abortion with or without detectable anticardiolipin anti- bodiesNotes Participants included in the present review: subcategory of 54 women negative for anticardiolipin anti- bodiesRisk of biasItem Authors’ judgement DescriptionAllocation concealment? Unclear B - UnclearPGI2: prostacyclin 2Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 11Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  14. 14. TXA2: thromboxane A2Characteristics of excluded studies [ordered by study ID]Study Reason for exclusionBar 2000 Data for women without apparent causes of recurrent pregnancy loss other than inherited thrombophilia cannot be extracted to be analysed separatelyBar 2001 Data for women without apparent causes of recurrent pregnancy loss other than inherited thrombophilia cannot be extracted to be analysed separately. Uncontrolled trialBick 2000 Non-randomised, uncontrolled trial.Brenner 2000 Non-randomised trial, historical controls.Brenner 2005 Data for women without apparent causes of recurrent pregnancy loss other than inherited thrombophilia cannot be extracted to be analysed separatelyCarp 2003 Non-randomised trial, historical controls.Grandone 2002 Non-randomised trial. Data for women without apparent causes of recurrent pregnancy loss other than inherited thrombophilia cannot be extracted to be analysed separatelyGris 1995 Moroxydine chloride is not an intervention of interest in this reviewGris 2004 Not all included women had recurrent miscarriage; also women with one miscarriage with a gestational age of 10 or more weeks were includedLi 2003 Non-randomised trial.Ogasawara 2001 Non-randomised trial. Data for women without apparent causes of recurrent pregnancy loss other than inherited thrombophilia cannot be extracted to be analysed separatelyRai 2000 Non-randomised trial.Reznikoff-Etievant 1999 Non-randomised trial.Sarig 2003 Data for women without apparent causes of recurrent pregnancy loss other than inherited thrombophilia cannot be extracted to be analysed separatelySarto 2001 Non-randomised trial, historical controls.Sorensen 2000 Non-randomised, uncontrolled trial. Data from women without apparent causes of recurrent pregnancy loss other than inherited thrombophilia cannot be extracted to be analysed separatelyTzafettas 2002 Non-randomised, uncontrolled trial.Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 12Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  15. 15. (Continued)Younis 2000 Non-randomised, uncontrolled trial.Characteristics of ongoing studies [ordered by study ID]ALIFE studyTrial name or title Anticoagulants for living fetuses studyMethodsParticipants Women with at least two or more pregnancy losses without apparent causes other than inherited throm- bophiliasInterventions Aspirin (100 mg/day) + nadroparine 2850 IE/day versus aspirin (100 mg/day) versus placebo. Medication is started preconceptional or with a gestation less than 6 weeks. Nadroparine is started when there is a fetal hart beat (+/- 6 weeks)Outcomes Primary outcome is live birth rate, secondary outcomes are prevalence of adverse pregnancy outcomes: preeclampsia, HELLP, intrauterine growth restriction, premature delivery, congenital malformations, throm- boembolic and hemorrhagic complications, thrombocytopenia, allergic reactionsStarting date 2004Contact information Dr. S.Middeldorp, Leiden University Medical Center, departments of Clinical Epidemiology and General Internal Medicine C9-P, PO Box 9600, 3500 RC Leiden, The Netherlands. e-mail: alife@amc.uva.nlNotes Trial register number: ISRCTN 58496168ETHIGIITrial name or title Effectiveness of dalteparin therapy as intervention in recurrent pregnancy lossMethodsParticipants Women with a history with at least two early pregnancy losses (< 12 wks) or one late pregnancy loss (> 12 wks) without apparent causes other than inherited thrombophiliasInterventions Dalteparin (5000 IE/day) + two tablets multivitamin/day versus only two tablets multivitamin/day. Inclusion between 5 and 8 weeks’ gestation and foetal heart activityOutcomes Primary outcome is an ongoing pregnancy at 24 weeks of gestation. Secondary outcomes: preterm delivery, placental insufficiency, intrauterine growth restriction, preeclampsia, abruptio placentae, structural anomalies, thromboembolic events, side effects of dalteparinStarting date 13-11-2006Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 13Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  16. 16. ETHIGII (Continued)Contact information Prof E.Schleussner, department of Obstetrics, Friedrich Schiller University, Bachstr. 18 Jena, GermanyNotes Trial register number: ISRCTN 53717039SPIN studyTrial name or title The Scottish Pregnancy Intervention studyMethodsParticipants Women with at least two or more consecutive early pregnancy losses without apparent causesInterventions Low molecular weight heparin versus aspirin + intense surveillance versus intense surveillance only. Inclusion until 7 weeks of gestationOutcomes Primary outcome is live birth rate; secondary outcomes are: preeclampsia, intrauterine growth retardation, premature delivery, congenital malformations, admission to special care, side effects of the drug, thromboem- bolic complicationsStarting date 01-06-2004Contact information Dr. P. Clark, Scottish National Blood Transfusion Service, East of Scotland Blood Transfusion Centre, Ninewells Hospital, Dundee, DD1 9SY, United KingdomNotes Trial register number: ISRCTN 06774126TIPPS studyTrial name or title Thrombophilia in Pregnancy Prophylaxis StudyMethodsParticipants Pregnant women with confirmed thrombophilia.Interventions Dalteparin versus no medication. Inclusion until 17 weeks of gestationOutcomes Primary objective is to identify if low-molecular-weight heparin prophylaxis in thrombophilic women reduces the relative risk in venous thromboembolism, pre-eclampsia, intrauterine growth restriction, and foetal lossStarting date 01-07-2000Contact information Dr Marc Rodger, The Ottawa hospital, 1053 Carling Ave, CEP F650, CanadaAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 14Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  17. 17. TIPPS study (Continued)Notes Trial register number: ISRCTN 87441504Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 15Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  18. 18. DATA AND ANALYSESComparison 1. Aspirin versus placebo No. of No. ofOutcome or subgroup title studies participants Statistical method Effect size1 Live-birth rate 1 54 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.78, 1.29]Comparison 2. Enoxaparin versus aspirin No. of No. ofOutcome or subgroup title studies participants Statistical method Effect size1 Live-birth rate 1 104 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.81, 1.16]2 Preterm delivery 1 104 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.28, 3.01]3 Obstetric complications; 1 104 Risk Ratio (M-H, Fixed, 95% CI) 0.13 [0.01, 2.50] pre-eclampsia4 Obstetric complications; 1 104 Risk Ratio (M-H, Fixed, 95% CI) 2.78 [0.12, 66.75] intrauterine growth restriction Analysis 1.1. Comparison 1 Aspirin versus placebo, Outcome 1 Live-birth rate. Review: Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome Comparison: 1 Aspirin versus placebo Outcome: 1 Live-birth rate Study or subgroup Aspirin Placebo Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Tulppala 1997 22/27 22/27 100.0 % 1.00 [ 0.78, 1.29 ] Total (95% CI) 27 27 100.0 % 1.00 [ 0.78, 1.29 ] Total events: 22 (Aspirin), 22 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) 0.1 0.2 0.5 1 2 5 10 Favours placebo Favours aspirinAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 16Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  19. 19. Analysis 2.1. Comparison 2 Enoxaparin versus aspirin, Outcome 1 Live-birth rate. Review: Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome Comparison: 2 Enoxaparin versus aspirin Outcome: 1 Live-birth rate Study or subgroup enoxaparin aspirin Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dolitzky 2006 44/54 42/50 100.0 % 0.97 [ 0.81, 1.16 ] Total (95% CI) 54 50 100.0 % 0.97 [ 0.81, 1.16 ] Total events: 44 (enoxaparin), 42 (aspirin) Heterogeneity: not applicable Test for overall effect: Z = 0.34 (P = 0.73) 0.01 0.1 1 10 100 Favours aspirin Favours enoxaparin Analysis 2.2. Comparison 2 Enoxaparin versus aspirin, Outcome 2 Preterm delivery. Review: Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome Comparison: 2 Enoxaparin versus aspirin Outcome: 2 Preterm delivery Study or subgroup Enoxaparin aspirin Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dolitzky 2006 5/54 5/50 100.0 % 0.93 [ 0.28, 3.01 ] Total (95% CI) 54 50 100.0 % 0.93 [ 0.28, 3.01 ] Total events: 5 (Enoxaparin), 5 (aspirin) Heterogeneity: not applicable Test for overall effect: Z = 0.13 (P = 0.90) 0.01 0.1 1 10 100 Favours enoxaparin Favours aspirinAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 17Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  20. 20. Analysis 2.3. Comparison 2 Enoxaparin versus aspirin, Outcome 3 Obstetric complications; pre-eclampsia. Review: Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome Comparison: 2 Enoxaparin versus aspirin Outcome: 3 Obstetric complications; pre-eclampsia Study or subgroup enoxaparin aspirin Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dolitzky 2006 0/54 3/50 100.0 % 0.13 [ 0.01, 2.50 ] Total (95% CI) 54 50 100.0 % 0.13 [ 0.01, 2.50 ] Total events: 0 (enoxaparin), 3 (aspirin) Heterogeneity: not applicable Test for overall effect: Z = 1.35 (P = 0.18) 0.01 0.1 1 10 100 Favours enoxaparin Favours aspirin Analysis 2.4. Comparison 2 Enoxaparin versus aspirin, Outcome 4 Obstetric complications; intrauterine growth restriction. Review: Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome Comparison: 2 Enoxaparin versus aspirin Outcome: 4 Obstetric complications; intrauterine growth restriction Study or subgroup enoxaparin aspirin Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dolitzky 2006 1/54 0/50 100.0 % 2.78 [ 0.12, 66.75 ] Total (95% CI) 54 50 100.0 % 2.78 [ 0.12, 66.75 ] Total events: 1 (enoxaparin), 0 (aspirin) Heterogeneity: not applicable Test for overall effect: Z = 0.63 (P = 0.53) 0.1 0.2 0.5 1 2 5 10 Favours treatment Favours controlAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 18Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  21. 21. APPENDICESAppendix 1. Search StrategyCochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 1), MEDLINE (January 1966 to April 2008), andEMBASE (1980 to March 2007), adapted for each database.1 randomized controlled trial.pt.2 randomized controlled trials/3 controlled clinical trial.pt.4 random allocation/5 comparative study/6 1 or 2 or 3 or 4 or 57 clinical trial.pt.8 clinical trials/9 (clin$ adj trial$).tw10 random$.tw11 7 or 8 or 9 or 1012 6 or 1113 miscarriage$.tw14 recurrent miscarriage$.tw15 abortion spontaneous/16 recurrent abortion$.tw17 abortion habitual/18 spontaneous pregnancy loss$.tw19 recurrent pregnancy loss$.tw20 early pregnancy loss$.tw21 early pregnancy bleeding$.tw22 habitual fetal loss$.tw23 fetal death/24 fetal resorption/25 stillbirth.tw26 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 2527 aspirin/28 heparin/29 low-molecular-weight heparin/30 anticoagulants/31 anticoagulant agent/32 antithrombotic$.tw33 27 or 28 or 29 or 30 or 31 or 3234 12 and 2635 33 and 34Lines 1, 3 and 7 were omitted in the search of EMBASE as it does not have a .pt. field.Lines 1-12 were not used for the search of CENTRALThe “/” refers to MeSH, medical subject headings, and (tw) to text word in the title or abstract.The $ is a truncation character which allows all possible suffix variations of the root word.Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 19Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  22. 22. FEEDBACKCundiff, September 2007SummarySince aspirin was ineffective compared with placebo in increasing live births, it should not be used as the control treatment in randomisedtrials for this indication.The trial of low molecular weight heparin (enoxaparin) versus low dose aspirin (n = 20) is much too small to assess the risk of potentialadverse effects, such as heparin induced thrombocytopenia with thrombosis and bleeding. Observational or population based studiesshould be used to help assess these hazards. Major, fatal, and intracranial bleeding should be included in the primary or secondaryendpoints.Rebound hypercoagulability after heparin withdrawal [1, 2] should also be assessed by follow up for at least two months after delivery.Due to potential risks to the mother and baby, heparin or low molecular weight heparin should not be used for this indication outsiderandomised trials.The background section cites the prognosis in subsequent pregnancies of women without antiphospholipid antibody syndrome whohave recurrent pregnancy loss ranges from 50% to 80%. Consequently, in this patient population, the chances for a healthy live babywithin three pregnancies would range from 87.5% to 99.2% (i.e. 1 - [0.50 x 0.50 x 0.50] = .875 and [1 - 0.20 x 0.20 x0.20] = .992).Given the risks of heparin and the potential for harm if tens of thousands of women have heparin treatment during pregnancy, themain endpoint in the recommended randomised trial, of anticoagulant versus placebo, should be a live healthy baby in up to threepregnancies rather than in a single pregnancy.There is an undisclosed financial conflict of interest in this review, as one of the review authors, Dr. Middledorp, was also one ofthe Matisse investigators, who investigated fondaparinux supported by a grant from NV Organon (The Netherlands) and Sanofi-Synthelabo (France) [3].References1. Granger CB, Miller JM, Bovill EG, et al. Rebound increase in thrombin generation and activity after cessation of intravenous heparinin patients with acute coronary syndromes. Circulation 1995; 91(7):1929-1935.2. Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease(FRISC) study group. Lancet 1996; 347(9001):561-568.3. The Matisse Investigators. Subcutaneous Fondaparinux versus Intravenous Unfractionated Heparin in the Initial Treatment ofPulmonary Embolism. N Engl J Med 2003; 349(18):1695-1702.(Summary of comment from David K Cundiff, September 2007)ReplyWe agree aspirin was ineffective compared with placebo in increasing live births, and so should not be used as the control treatmentin randomised trials assessing anticoagulants for women with recurrent miscarriage. As we describe in ’Implications for research’, theinclusion of a placebo or no treatment arm in these studies is necessary to provide an adequate control for active treatment.We also agree that trials in this field are generally too small to assess the risk of rare but potentially serious adverse effects. Observationaland population-based studies are useful to assess these hazards; however this review is limited to randomised trials.Following recurrent miscarriage, the calculation that the chance of having a healthy live baby within three pregnancies ranges from87.5% to 99.2% is probably slightly optimistic. It does not take account of the fact that the chance of a successful pregnancy declinesafter each miscarriage, thus the chance of live birth will also decline.The proposal that a live healthy baby in up to three pregnancies, rather than in one, would be a better endpoint is interesting. However,the primary outcome of a live birth in a single pregnancy in a well-designed randomised placebo controlled trial will allow betterassessment of possible hazards of the intervention. Also, we doubt whether couples with recurrent miscarriage would regard a healthybaby after three pregnancies as the ideal outcome.Finally, although Dr. Middeldorp has been involved in trials of anticoagulants for venous thrombosis that were sponsored by pharma-ceutical companies, this does not necessarily lead to a conflict of interest. She has published papers in which she has opposed the use ofanticoagulants for the prevention of pregnancy loss or pregnancy complications. She is also principle investigator of the ALIFE studythat is assessing the efficacy and safety of aspirin, and aspirin combined with low-molecular-weight heparin, compared with placebo(International Standard Randomised Controlled Trial Number Register: 58496168).Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 20Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  23. 23. (Reply from Stef Kaandorp, November 2007)ContributorsFeedback: David K CundiffWHAT’S NEWLast assessed as up-to-date: 29 April 2008.Date Event Description30 April 2008 New search has been performed Search updated. Scope of review changed, resulting in a previously included study being excluded (Gris 2004). Please see ’Differences between protocol and review’ for further details Authors replied to feedback.30 April 2008 New citation required but conclusions have not changed Changes to scope of review and team of authors.11 January 2008 Amended Converted to new review format.HISTORYProtocol first published: Issue 2, 2004Review first published: Issue 2, 2005Date Event Description13 November 2008 Feedback has been incorporated Feedback from David K Cundiff added.CONTRIBUTIONS OF AUTHORSStef Kaandorp updated the search and wrote the revised review. Mariette Goddijn commented on the revision.Marcello Di Nisio wrote the first and the revised drafts of the protocol and review, and commented on the draft of the updated review.Saskia Middeldorp supervised the development of the review in all of its phases.Louisette Peters commented on the drafts of the first version of this review.Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 21Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  24. 24. DECLARATIONS OF INTERESTDrs Kaandorp, Goddijn, and Middeldorp are involved in the running randomised controlled trial ÄLIFE study. This trial is assessingthe efficacy and safety of aspirin, and aspirin combined with low-molecular-weight heparin, compared with placebo for the preventionof pregnancy loss in women with recurrent miscarriage (International Standard Randomised Controlled Trial Number Register:58496168). Besides being the principal investigator of the ALIFE study, Dr. Middeldorp has also been and is involved in phase 2and phase 3 trials that assessing the efficacy and safety of anticoagulant drugs for the indication of venous thrombosis or superficialthrombophlebitis. These trials were or are being sponsored by various pharmaceutical companies.DIFFERENCES BETWEEN PROTOCOL AND REVIEWFor this update, we decided to limit our systematic review to women with recurrent miscarriage only. In the first version of the reviewalso women with one later intrauterine fetal death were included. However, given the presumed differences in etiology and differentprognosis, we judged it not appropriate to pool results of interventions in these different patient populations. This decision has resultedin the exclusion of a trial (Gris 2004) in which a subgroup had been included in the former version of the review.INDEX TERMSMedical Subject Headings (MeSH)Abortion, Habitual [∗ drug therapy; etiology]; Anticoagulants [∗ therapeutic use]; Antiphospholipid Syndrome [complications]; Aspirin[therapeutic use]; Heparin, Low-Molecular-Weight [therapeutic use]; Pregnancy Complications, Hematologic [∗ drug therapy; etiology];Randomized Controlled Trials as Topic; Thrombophilia [complications; ∗ drug therapy]MeSH check wordsFemale; Humans; PregnancyAspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome (Review) 22Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

×