SEARCH

SEARCH BY CITATION

Keywords:

  • anticoagulation;
  • low molecular weight heparin;
  • recurrent pregnancy loss

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Summary. Background: The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late non-recurrent pregnancy loss, which has prompted investigators to evaluate the benefit of low molecular weight heparin (LWMH) to achieve live birth. A similar benefit for LMWH has also been proposed independent of thrombophilia status. Objective and methods: We conducted a systematic review of randomized controlled trials to assess the benefit of LMWH in achieving live birth for women with a history of recurrent or late non-recurrent pregnancy loss in the absence of antiphospholipid antibodies. Results: For the five studies that satisfied the eligibility criteria, the risk ratio of live birth for women with a history of pregnancy loss treated with LWMH compared with control ranged from 0.95 to 3.00. There was considerable heterogeneity among studies in terms of treatment effect (Q-value was 41.7, P = 0.000, and I2 = 90.4%) independent of thrombophilia status. There was also a wide variation among all studies in terms of definition of early or late pregnancy loss, thrombophilic risk factors, and number of prior pregnancy losses. Conclusion: There is a trend for increased live births when using LWMH for the prevention of recurrent pregnancy loss. Currently, there is insufficient evidence to support the routine use of LWMH to improve pregnancy outcomes in women with a history of pregnancy loss. Not only are additional studies necessary but standardized criteria for trials evaluating the benefit of an intervention in recurrent pregnancy loss should be established.


Background

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

The incidence of miscarriage is approximately 14% following a single pregnancy loss but increases to over 24% in women with a history of two miscarriages [1]. Commonly identified etiologies for recurrent pregnancy loss include uterine abnormalities, endocrine disturbances including luteal phase defect or diabetes, chromosomal anomalies, and infectious complications. In roughly 60% of cases of recurrent pregnancy loss no abnormalities are identified [2]. The management of women with a history of pregnancy loss without an identified cause is unclear and the role of anticoagulants for women with unexplained pregnancy loss remains uncertain.

The role of anticoagulants in preventing late pregnancy loss is based on the premise that placental circulation can become compromised in women with an underlying prothrombotic tendency. This has classically been described in women with a lupus anticoagulant and/or antiphospholipid antibodies [3]. A link between hereditary thrombophilia and pregnancy loss has been observed in case control studies, particularly for women with unexplained second or third trimester miscarriage [4–6]. In a prospective cohort study of 1524 pregnancies, there was an association between thrombophilia and late but not recurrent early pregnancy loss [7]. Other large cohort studies have failed to demonstrate an association between thrombophilia and recurrent pregnancy loss [8,9]. Based on the potential association between thrombophilia and pregnancy loss, Gris and colleagues [10] conducted a randomized controlled trial in women who previously suffered a single unexplained pregnancy loss after 10 weeks and observed a remarkable benefit from anticoagulation with low molecular weight heparin compared with aspirin alone (OR 15.5 95%CI 7.0–34.0, P < 0.0001). Researchers have proposed that the potential benefit of low molecular weight heparin could extend to women independent of thrombophilia status, especially considering that the association between thrombophilia and miscarriage has not been clearly established [11]. We performed a systematic review in order to determine if the use of low molecular weight heparin achieves more live births when compared to placebo or aspirin in women who have a history of two or more early or one or more late pregnancy losses.

Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Search methods

We performed a literature search using MEDLINE, EMBASE and the Cochrane Collaboration Database. We also performed a hand-search of all references included in a previous meta-analysis. The MEDLINE search strategy employed was ‘(low molecular weight heparin or enoxaparin or tinzaparin or dalteparin or nadroparin) AND pregnancy [MeSH] and random*’. The search was performed on 3 August 2009 and was not restricted to English language publications. Scientific abstracts and meeting proceedings were searched using BIOSIS and Conference Papers Index by searching for ‘(heparin or enoxaparin or tinzaparin or dalteparin or nadroparin) AND (pregnancy or pregnant or miscarriage)’.

Inclusion criteria

The following criteria were predefined for inclusion of a study: (i) randomized controlled, clinical trial; (ii) randomization must include a low molecular weight heparin compared with a control arm, which could be a placebo or an alternative medication (e.g. aspirin) but not another anticoagulant; (iii) viable pregnancy at time of drug initiation; (iv) history of ≥ 2 early miscarriages or ≥ 1 late fetal loss (definition of early or late as specified in the studies); (v) exclusion of women with evidence of antiphospholipid antibodies; (vi) a thorough evaluation for underlying cause of recurrent miscarriage performed, including parental karyotype, uterine abnormalities (hysterography or similar), endocrine disorder and infection; (vii) no indication for therapeutic anticoagulation; and (viii) live birth as an endpoint.

Data collection

Two reviewers (J.Z. and S.M.) independently reviewed all the titles and abstracts from the database searches. Both reviewers evaluated the full text of studies that potentially met the inclusion criteria. Both reviewers independently compiled a list of eligible studies and discordant determinations, prompting a discussion; a mutual consensus was required for study inclusion. An additional reviewer (K.B.) verified the inclusion and exclusion of randomized studies. The titles and abstracts of non-English papers were reviewed, with a plan for translation of the full text if inclusion criteria were satisfied. The quality of the trials was evaluated using the Jadad scale based on the description of randomization, blinding, and drop-outs (0–5 point scale) [12].

Data analysis

The data analysis plan was established prior to a database search. Risk ratio of live birth was the metamer selected. We planned a random-effects analysis as the primary summary model due to the anticipated variations in enrollment criteria and interventions between the studies. Heterogeneity was evaluated by Cochran’s chi-squared test and I2 test for heterogeneity. Heterogeneity was defined as chi-square < 0.10 and I2 > 50%. Sensitivity analysis was planned for two subgroups: women with vs. women without hereditary thrombophilia, and women with a history of recurrent early pregnancy loss vs. women with late pregnancy loss. Statistical analysis was performed using the Comprehensive Meta-Analysis Version 2.0 software package (Biostat, Englewood, NJ, USA). Data were collected, analyzed and reported according to QUORUM guidelines for meta-analysis [13].

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

A total of 329 studies were identified by database search and no additional references were identified by hand review of a prior meta-analysis [14]. Database review of scientific conference proceedings did not yield additional unpublished studies. Reasons for first-pass exclusions included: duplicate records, summary data such as reviews or editorials, animal studies, or topics not relevant to the systematic review (Fig. 1). A total of 24 trials were evaluated in more detail; additional studies were excluded due to lack of randomization, inability to extract data for women without antiphospholipid antibodies [15], absence of non-anticoagulant controls [16], administration of the study drug before established pregnancy [17,18], and inclusion of women with a diagnosis other than non-recurrent pregnancy loss (e.g. pre-eclampsia) [19]. A total of five studies were identified as meeting all criteria for inclusion in the systematic review.

image

Figure 1.  Flow diagram of search strategy.

Download figure to PowerPoint

Study characteristics

The study populations of the included studies are shown in Table 1. The birth rates for a total of 757 women in the five studies were analyzed. All studies provided a detailed description of the evaluation for cause of prior pregnancy loss, including hysteroscopy, karyotype of both partners, and endocrine studies. Gris et al. [10] was the only study that included women with a history of non-recurrent pregnancy loss. The other four studies included women with at least two prior pregnancy losses occurring in the first trimester [20], before the third trimester [21,22], or up to 32 weeks [23].

Table 1.   Study characteristics and quality assessment of included randomized clinical trials
StudyThrombophilia evaluationThrombophilia status (excluded or required)Number of women randomizedNumber of women excluded from analysis Arm A: LMWH Arm B: ControlEarly pregnancy lossLate pregnancy lossJadad quality assessment scale
  1. FVL, factor V leiden; C, protein C deficiency; S, protein S deficiency; PT, prothrombin G20210A mutation; MTHFR, methylenetetrahydrofolate reductase mutation; HC, hyperhomocysteinemia; AT, antithrombin deficiency; APL, antiphospholipid antibodies; LMWH, low molecular weight heparin. *Excluded third arm that treated women with prednisone/progesterone/aspirin.

Gris, 2004 [10]FVL,PT,SRequired17412 with early pregnancy loss prior to beginning therapy at 8 weeks 1 after 10 weeks2
Dolitzky, 2006 [21]C,S, AT, FVL, PT, MTHFRExcluded1073 patients lost to follow-up3+ 1st trimester or 2+ 2nd trimester3
Badawy, 2008 [20]FVL, C, S, ATExcluded350Arm A: 4 lost to follow-up Arm B: 6 lost to follow-up3 +  prior 12 weeks3
Fawzy, 2008 [22]C,S,AT, FVL,PT, HCExcluded109*Arm A: 2 lost to follow-up Arm B: None3 +  prior 24 weeks3
Laskin, 2009 [23]C,S,FVL, PT, MTHFR, ANARequired88 (includes APL)None2+ prior 32 weeks3

There was some variation in the thrombophilia evaluation between studies. All studies screened for the factor V Leiden mutation, prothrombin G20210A gene mutation, and protein S deficiency. The methylenetetrahydrofolate reductase variant (MTHFR C677T) was included in the thrombophilia evaluation in two of the studies [21,23]. Partial trial data were extracted from two of the studies for inclusion in the summary effect analysis. Laskin et al. [23] included 88 women randomized to aspirin with or without enoxaparin, but only the 46 women without evidence of antiphospholipid antibodies were utilized in our analysis. The study by Fawzy et al. [22] randomized women with ≥ 3 pregnancy losses prior to 24 weeks of gestation to enoxaparin, a hormone-combination arm, or placebo. The combination arm consisted of oral prednisone (20 mg day−1) and progesterone (75 mg day−1) for 12 weeks as well as aspirin for 32 weeks. The prednisone-progesterone-aspirin arm was not included in the summary analysis as it was considered a unique control regimen that would be problematic to group together with the other control arms that used either aspirin alone or no medication.

Quality assessment

The overall quality of the trials is considered ‘high’ by the Jadad Quality Assessment Scale based on randomization and description of dropouts [12]. The number of women lost to follow-up was small across all studies as shown in Table 1. In the study by Gris et al. [10], randomization to treatment allocation was performed prior to pregnancy and a total of 12 women suffered early miscarriage prior to the 8th week and prior to initiation of therapy. These 12 women were not included in an intention-to-treat analysis by the authors. However, the treatment randomization was performed earlier than the other trials, which only included women who were already eligible for drug therapy at time of enrollment. There were also two additional women that were unaccounted for in the analysis without additional details given. None of the studies were blinded nor was there inclusion of a placebo equivalent for low molecular weight heparin injection (Table 2).

Table 2.   Treatment regimens and rate of live births for randomized clinical trials included in the systematic review
StudyTime of treatment initiationLMWH groupLive birth LMWH group (%)Control groupLive birth control (%)
Gris, 20048th weekEnoxaparin 40 mg day−169/80 (86)ASA 100 mg day−123/80 (29)
Dolitzky, 20066–12 weeksEnoxaparin 40 mg day−144/54 (81)ASA 100 mg day−142/50 (84)
Badawy, 2008Ultrasound viabilityEnoxaparin 20 mg day−1161/170 (95)No anticoagulant151/170 (88)
Fawzy, 2008Not listedEnoxaparin 20 mg day−146/57 (81)Placebo24/50 (48)
Laskin, 2009Not listedDalteparin 5000 IU + ASA 81 mg day−119/23 (83)ASA 81 mg day−120/23 (87)

Summary analysis of low molecular weight heparin

The forest plot for the five studies that fulfilled eligibility is shown in Fig. 2. There was significant statistical heterogeneity observed between studies. The Q-value was 41.7, P = 0.000, and I2 = 90.4%. A priori, we identified the presence or absence of a hereditary thrombophilia as a potential source of heterogeneity. However, subgroup analysis of the studies according to the inclusion or exclusion of women with hereditary thrombophilia did not resolve the observed heterogeneity among studies (Q-Value 36.3, P = 0.00 within groups). We also planned heterogeneity analysis for women enrolled with a history of recurrent early vs. late pregnancy losses. However, the entry criteria for timing of prior pregnancy losses varied across all studies, which precluded such analysis. Eligibility for the Gris et al. [10] study required women to have experienced only a single, non-recurrent pregnancy loss, which differed from the other studies that required a minimum of two or more pregnancy losses prior to enrollment. The inclusion of the study of Gris et al. [10] contributed, in large part, to the observed heterogeneity, whereby exclusion of this study lowered the Q value to 9.9, P = 0.02, and I2 = 69%. Considering the observed heterogeneity across studies both from a statistical and clinical perspective, the determination was made that a pooled risk ratio across studies would not be appropriate.

image

Figure 2.  Forest plot of risk ratio of live birth for pregnant women treated with or without low molecular weight heparin. Risk ratio represents the ratio of live birth rates for low molecular weight heparin over controls. Significance testing (z and P values) performed on a log scale relative to a risk ratio of 1.0.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

The administration of low molecular weight heparin to women with a history of unexplained late or recurrent early pregnancy loss is controversial. The publication of the study by Gris et al. [10], which demonstrated a marked improvement in live birth rates as compared to aspirin following a single late pregnancy loss in women with thrombophilic disorders, has contributed to the discord in the field. Some researchers contend that anticoagulants should be prescribed routinely based on the strength of the observed treatment effect in this and other studies [24]. However, other groups feel that additional randomized studies are required as the existing data are not definitive [11,25,26]. In this context, we performed a systematic review of the published trials using low molecular weight heparin to prevent miscarriage or fetal loss in women with a history of unexplained pregnancy loss. Because of the significant heterogeneity observed between studies, a pooled risk ratio analysis for the effect of low molecular heparin in achieving live birth was not performed.

In order to evaluate the published literature we opted for broad inclusion criteria, including trials that enrolled women with either ≥ 2 early miscarriages or ≥ 1 late miscarriage. This inclusive approach contrasts with that of a recently published Cochrane Review for women with a history of recurrent miscarriage in the absence of antiphospholipid antibody syndrome [14]. The inclusion criteria for this review required women to have experienced at least two miscarriages prior to 20 weeks of gestation. Based on this definition, only the trial by Dolitzky et al. [21] was included in the Cochrane Review. Considering that the study by Dolitzky et al. [21] included women with second trimester losses that were not specifically restricted to 20 weeks, arguably this paper should have been excluded as well.

We explored the basis for heterogeneity in the meta-analysis by evaluating differences between studies based on the presence or absence of hereditary thrombophilia. Thrombophilia status did not appear to drive the observed heterogeneity, whereas there was a strong contribution from inclusion of the study by Gris et al. [10]. This trial was the only study to offer anticoagulation to women who experienced only a single late pregnancy loss. The birth rates were significantly lower than the other two trials included in this meta-analysis with aspirin-only arms (29% vs. 84% or 87%, chi-square < 0.001) [10,21,23]. Women with a prior history of late (e.g. second trimester) loss are at an increased risk for a recurrent late pregnancy loss, which may explain some of the observed differences between the studies [27]. However, the other four studies also included women with a history of later pregnancy losses (roughly 20% of women in the studies that provided such information [20,23]). Given that the likelihood of a live birth following a single pregnancy loss is greater than that for women who experience recurrent pregnancy loss [1,28], it is even more striking that the live birth rate for the aspirin-treated women in the Gris et al. [10] study was even lower than for women with antiphospholipid antibodies and recurrent pregnancy loss treated with aspirin alone [29,30]. Based on the poor outcomes of the aspirin-only arm there is the potential that aspirin has a deleterious effect on pregnancy. However, in a randomized trial by Tulppala and colleagues, the rate of live birth in women with a history of recurrent spontaneous abortion treated with aspirin was similar to that of placebo [31] and aspirin alone has been used successfully in pregnant women with antiphospholipid antibody syndrome [32]. We conclude that confirmatory studies are required before applying the results of Gris et al. [10] to clinical practise.

Notably, all the randomized trials evaluated in this systematic review differed in terms of timing of recurrent pregnancy loss. In order to accurately compare the results of future trials, standardization of terms and criteria will be necessary. The evaluation of thrombophilic disorders relative to pregnancy loss is also an area of uncertainty. In a couple of studies, homozygosity for the MTHFR C677T mutation was considered as a criteria for inclusion [23] or exclusion [21] but its association with deep vein thrombosis is doubtful [33,34] and its influence on fetal loss has not been established [4,35]. The absence of equipoise relative to the significance of thrombophilia and pregnancy loss was evident by the specific exclusion of thrombophilic patients in three of the five randomized studies. One of these studies [22] demonstrated a significant benefit for low molecular weight heparin treated women, second only to that observed by Gris et al. [10].

What guidance can be offered, based on this analysis, to the treating physician faced with the all-to-common dilemma of how to appropriately manage a woman with a history of unexplained pregnancy loss? Until additional studies are published, the benefit of low molecular weight heparin cannot be conclusively stated. There is a suggestion from this analysis that low molecular weight heparin may offer a benefit, but the markedly favorable effect observed in Gris et al. [10] has not been replicated. The only study other than Gris et al. [10] to include women with thrombophilia failed to demonstrate any improvement in outcomes in the low molecular weight heparin treated arm [23]. The largest of the individual studies included in our systematic review (Badawy et al. [20]) demonstrated a modest improvement in outcomes for women with recurrent pregnancy loss without thrombophilia treated with low molecular weight heparin over no treatment (live birth risk ratio 1.07, 95% CI 1.00–1.14). We conclude that there is currently insufficient evidence at this time to routinely recommend low molecular weight heparin to women with a history of unexplained non-recurrent late or recurrent pregnancy loss independent of a woman’s thrombophilia status.

Addendum

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

S. Mantha performed the literature search, systematic review and manuscript preparation. K. A. Bauer reviewed the eligible studies and co-authored the manuscript. J. I. Zwicker performed the literature search and systematic review, and co-authored the manuscript.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Funding supported, in part by K23 HL084052 (J.I. Zwicker). J.I. Zwicker also reports research funding from Sanofi-Aventis for anticoagualant trials in cancer patients. The other authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  • 1
    Stirrat GM. Recurrent miscarriage. Lancet 1990; 336: 6735.
  • 2
    Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril 2009; doi:10.1016/j.fertnstert.2009.01.166.
  • 3
    Salafia CM, Cowchock FS. Placental pathology and antiphospholipid antibodies: a descriptive study. Am J Perinatol 1997; 14: 43541.
  • 4
    Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, Bozzo M, Mannucci PM. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343: 10158.
  • 5
    Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, Hill JA. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998; 128: 10003.
  • 6
    Sarig G, Younis JS, Hoffman R, Lanir N, Blumenfeld Z, Brenner B. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002; 77: 3427.
  • 7
    Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, Van Der Meer FJ. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 9136.
  • 8
    Lindqvist PG, Svensson PJ, Marsaal K, Grennert L, Luterkort M, Dahlback B. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost 1999; 81: 5327.
  • 9
    Rai R, Shlebak A, Cohen H, Backos M, Holmes Z, Marriott K, Regan L. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 2001; 16: 9615.
  • 10
    Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, Mares P. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103: 36959.
  • 11
    Walker ID, Kujovich JL, Greer IA, Rey E, David M, Salmon JE, Hunt BJ, Zotz RB, Gerhardt A, Scharf RE, Middeldorf S, Martinelli I, Cetin I, Grandone E. The use of LMWH in pregnancies at risk: new evidence or perception? J Thromb Haemost 2005; 3: 77893.
  • 12
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 112.
  • 13
    Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. quality of reporting of meta-analyses. Lancet 1999; 354: 1896900.
  • 14
    Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev 2009: CD004734.
  • 15
    Dendrinos S, Kalogirou I, Makrakis E, Theodoridis T, Mahmound EA, Christopoulou-Cokkinou V, Creatsas G. Safety and effectiveness of tinzaparin sodium in the management of recurrent pregnancy loss. Clin Exp Obstet Gynecol 2007; 34: 1435.
  • 16
    Brenner B, Hoffman R, Carp H, Dulitsky M, Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study. J Thromb Haemost 2005; 3: 2279.
  • 17
    Qublan H, Amarin Z, Dabbas M, Farraj AE, Beni-Merei Z, Al-Akash H, Bdoor AN, Nawasreh M, Malkawi S, Diab F, Al-Ahmad N, Balawneh M, Abu-Salim A. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil (Camb) 2008; 11: 24653.
  • 18
    Gris JC, Neveu S, Tailland ML, Courtieu C, Mares P, Schved JF. Use of a low-molecular weight heparin (enoxaparin) or of a phenformin-like substance (moroxydine chloride) in primary early recurrent aborters with an impaired fibrinolytic capacity. Thromb Haemost 1995; 73: 3627.
  • 19
    Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, Morin F, Demers C, Kahn SR, Magee LA, Rodger M. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost 2009; 7: 5864.
  • 20
    Badawy AM, Khiary M, Sherif LS, Hassan M, Ragab A, Abdelall I. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008; 28: 2804.
  • 21
    Dolitzky M, Inbal A, Segal Y, Weiss A, Brenner B, Carp H. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 2006; 86: 3626.
  • 22
    Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey AA, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet 2008; 278: 338.
  • 23
    Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, Kingdom JC, Barrett J, Gent M. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol 2009; 36: 27987.
  • 24
    Brenner B. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications – yes. J Thromb Haemost 2003; 1: 20702.
  • 25
    Lindqvist PG, Merlo J. Low molecular weight heparin for repeated pregnancy loss: is it based on solid evidence? J Thromb Haemost 2005; 3: 2213.
  • 26
    Dao V, Rodger M. Anticoagulants to prevent placenta-mediated pregnancy complications: a review of current evidence. Curr Opin Hematol 2009; 16: 38690.
  • 27
    Edlow AG, Srinivas SK, Elovitz MA. Second-trimester loss and subsequent pregnancy outcomes: what is the real risk? Am J Obstet Gynecol 2007; 197: 581 e581–586.
  • 28
    Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 60111.
  • 29
    Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174: 15849.
  • 30
    Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 2537.
  • 31
    Tulppala M, Marttunen M, Soderstrom-Anttila V, Foudila T, Ailus K, Palosuo T, Ylikorkala O. Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production. Hum Reprod 1997; 12: 156772.
  • 32
    Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002; 100: 40813.
  • 33
    Bezemer ID, Doggen CJ, Vos HL, Rosendaal FR. No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med 2007; 167: 497501.
  • 34
    Naess IA, Christiansen SC, Romundstad PR, Cannegieter SC, Blom HJ, Rosendaal FR, Hammerstrom J. Prospective study of homocysteine and MTHFR 677TT genotype and risk for venous thrombosis in a general population – results from the HUNT 2 study. Br J Haematol 2008; 141: 52935.
  • 35
    Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril 2006; 86: 171622.