- Email: [email protected]
Low molecular weight heparin for pregnancy complications?
Thrombosis Research (2009) 123 Suppl. 3, S22–S25
intl.elsevierhealth.com/journals/thre
Low molecular weight heparin for pregnancy complications? I.A. Greer* Hull York Medical School, University of York, UK
Introduction Pregnancy complications such as recurrent miscarriage, pre-eclampsia, growth restriction and abruption are commonplace in pregnancy. For example, up to 5% of women will have two or more early pregnancy losses, 1 2% of women will have three or more early pregnancy losses, and pre-eclampsia complicates between 2% and 4% of pregnancies. Increasingly, evidence is accumulating of an association between heritable thrombophilia and adverse pregnancy outcome. Anti-phospholipid syndrome (APS) is associated with an increased risk of these pregnancy complications and evidence of coagulation activation with increased thrombin generation and, pathologically, placental infarction. Further, antithrombotic therapy with low molecular weight heparin (LMWH) and low dose aspirin can substantially improve the likelihood of a favourable pregnancy outcome with APS. These features have resulted in growing pressure to use antithrombotic therapy for other adverse pregnancy complications particularly in the presence of heritable thrombophilia. Such a concept is logical if heritable thrombophilia is associated with prothrombotic changes which in turn lead to an increased risk of adverse pregnancy outcome, as LMWH is the obvious agent to reduce or prevent excessive coagulation activation. However, if LMWH is to be used as an intervention to prevent such pregnancy complications it is important to consider who should be treated and whether or not the intervention is effective. Perhaps the most common strategy under consideration is thrombophilia screening for those women with previous pregnancy complications and LMWH as an intervention in any future * Correspondence: I.A. Greer. E-mail address: Email: [email protected] (I.A. Greer).
pregnancy. For any screening programme to be effective it must be associated with an important health problem where the natural history is understood and where there are identifiable markers before the disease actually occurs. The test to screen for the condition must be simple, safe and acceptable. The treatment must be effective with better outcomes from early treatment than with late treatment. Finally, the screening program must be cost effective. Thus the use of LMWH for pregnancy complications in women with thrombophilia must be considered in the context of these screening criteria. Heritable thrombophilia and adverse pregnancy outcome Many reports have highlighted the association between heritable thrombophilia and adverse pregnancy outcome; however, the extent of association has been variable. This reflects heterogeneity in: study design and methodology; sample size; the inclusion of high risk groups; differing definitions of pregnancy complications such as miscarriage and pre-eclampsia; the number of thrombophilias investigated; and differences in the genetic background of the populations studied. Because of this heterogeneity, several systematic reviews and meta-analyses have been used to assess the level of associated risk. The magnitude of risk in many of these studies is modest [1 3], such as a 1.9-fold (95% confidence interval [CI]: 1.21 2.97) for factor V Leiden heterozygotes and recurrent miscarriage in the study by Robertson et al. (2005) [1](Table 1). A similar modest level of association between other heritable thrombophilias and adverse outcomes such as pre-eclampsia is also reported. For example, Dudding et al. (2008) [4] reported
0049-3848/ $ – see front matter © 2009 Elsevier Ltd. All rights reserved.
Low molecular weight heparin for pregnancy complications? Table 1 Heritable thrombophilia and recurrent miscarriage: risk assessed by meta-analysis a Thrombophilia
Odds ratio
95%CI
homozygous
6.25
1.35 28.87
heterozygous
1.90
1.21 2.97
Prothrombin G20210A
2.49
1.24 5.00
Antithrombin deficiency
0.88
0.17 4.48
Protein C deficiency
2.29
0.20 26.43
Protein S deficiency
3.55
0.35 35.73
Factor V Leiden
a
From Robertson et al. 2006 [1].
a genetic association study and meta-analysis showing an odds ratio of 1.49 for a maternal heterozygote for factor V Leiden developing preeclampsia. However, they found no association with intra-uterine growth restriction. Further, within their cohort study the magnitude of risk for pre-eclampsia was higher in association with high body mass index, chronic hypertension and preexisting diabetes than with factor V Leiden. These systematic reviews largely report on case control and cohort studies. A recent large prospective cohort study of almost 4,000 unselected pregnant women found no association between factor V Leiden and adverse pregnancy outcome including fetal growth restriction, or a significant association with pre-eclampsia, although there was a higher point estimate for this with an odds ratio of 1.83 (95% CI: 0.51 6.13) [5] (Table 2). Thus there may be a modest association between certain heritable thrombophilias and Table 2 Results from GOAL: a prospective examination of FVL of pregnancy complications in 4087 women a,b,c Adjusted Odds ratio
95% CI
PIH
1.26
0.64 2.30
PET
1.83
0.54 6.13
IUGR
0.96
0.34 2.74
IUGR + PET
0.91
0.32 2.58
Miscarriage
0.78
0.10 5.77
adverse maternal and fetal outcomes. Screening by way of a thrombophilia screen is simple and acceptable, however, it is restricted to common, currently described thrombophilias and plainly the association between different thrombophilias and adverse pregnancy outcomes is heterogeneous. Therefore, the natural history is not entirely clear for women carrying these thrombophilic traits with regard to pregnancy outcome, particularly if they have had no previous pregnancies. LMWH, thrombophilia and prevention of adverse pregnancy outcome With regard to treatment, low dose aspirin and LMWH or unfractionated heparin can improve the pregnancy outcome in APS associated with recurrent miscarriage [1]. Low molecular weight heparins are safe during pregnancy [6] (Table 3) as is low dose aspirin [1]. Several studies have suggested that LMWH may be beneficial with regard to adverse pregnancy outcome in patients with thrombophilia and a past history of adverse pregnancy outcome [7 9], particularly as compared to previous untreated pregnancies. However, as yet there are no adequately powered, randomised, controlled trials with an untreated or placebo arm in order to confirm the suggestion of benefit. The need for adequately powered and properly controlled trials in this area has been stressed by several commentators [10,11]. Such, much needed, trials are currently underway and their results will be important in informing evidence-based practice in this area. Table 3 LMWH in pregnancy: complication rates on systematic review a Complication Thrombosis
Rate, % (95% CI) 1.37 (0.97 1.87)
VTE
0.86 (0.55 1.28)
Arterial thrombosis
0.50 (0.28 0.84)
Bleeding
1.98 (1.50 2.57)
Antenatal
0.43 (0.22 0.75)
PPH > 500 ml
0.94 (0.61 1.37)
Wound haematoma Allergy
PET: rre-eclampsia; PIH: pregnancy-induced hypertension; IUGR: intrauterine growth restriction. a After Clark et al. 2008 [5]. b Samples suitable for FVL analysis were available in 3944 women; 3.5% had factor V Leiden. c Note: In multivariate regression analysis there was no influence of FVL on a composite outcome of miscarriage, stillbirth, neonatal death, PET, Venous thrombosis or IUGR.
S23
0.61 (0.36 0.98) 1.80 (1.34 2.37)
Thrombocytopenia Platelets
0.11 (0.02 0.32)
HIT
0.00 (0.00 0.11)
Osteoporosis
0.04 (<0.01 0.20)
HIT: heparin-induced thrombocytopenia; PPH: postpartum haemorrhage. a From Greer and Nelson-Piercy 2005 [6].
S24
I.A. Greer Table 4 Cost effectiveness of thrombophilia screening and intervention with LMWH for adverse pregnancy outcome a Complications (n)
UK NHS Cost (£)
No screening
3004
532,446
Universal screening
2889
5,940,763
47,198
Selective screening
2988
1,178,634
42,166
a b
ICER*(£)
After Wu et al. 2006 [13]. ICER: incremental cost effectiveness ratio (ICER) is an estimate of the cost per unit of effectiveness of one strategy in preference to another in a population of 10,000 assuming LMWH 80% effective.
Cost effectiveness of thrombophilia screening Thus there is a modest level of association between inherited thrombophilia and adverse maternal and fetal outcome in pregnancy, but this is not consistent across all thrombophilias and all pregnancy complications. Screening for common thrombophilias is straightforward, but as yet we have no clear evidence from adequately powered and adequately controlled trials to confirm the benefit of such an intervention. If such a screening and intervention programme were to be introduced, it is also important to assess whether it would be cost effective. Two studies have assessed this, one screening for Factor V Leiden alone and the other for the common heritable thrombophilias. Neither study which modelled the outcomes and cost benefits and assumed substantial efficacy from intervention with LMWH found universal unselected screening for heritable thrombophilia to be cost effective in pregnancy (Table 4) [12 14]. Is thrombophilia screening required to guide intervention with LMWH? It may be that we have been too specific in our consideration of the mechanisms underlying adverse pregnancy outcome and thrombophilia. There is an association between both heritable and acquired thrombophilia, which suggests that “excessive coagulation” in general, rather than acquired or heritable thrombophilias in particular, may be implicated with regard to causation. This raises the possibility of intervening using LMWH for patients with previous adverse pregnancy outcomes, based not on thrombophilia screening but on the previous pregnancy outcome itself. Such a pragmatic approach assumes that the maternal phenotype, manifest through adverse pregnancy outcome, reflects an underlying prothrombotic tendency in pregnancy leading to placental damage and that such damage can be prevented or ameliorated by LMWH. It also
avoids the need for costly thrombophilia screening, which will not identify all prothrombotic tendencies. The patient will be treated on the basis of clinical features rather than genotype or an identified thrombophilia. Such studies are under way and may have more utility than those involving laboratory-based screening and incorporating previous adverse events. Conclusion There is a clear association between heritable thrombophilia and adverse maternal and fetal outcome largely based on systematic reviews of case control and cohort studies and metaanalyses. There are few prospective data to inform the natural history of thrombophilia in pregnancy in unselected populations. Thrombophilia screening is straightforward and can identify the common heritable forms of thrombophilia. However, although there is a suggestion of benefit from intervention with LMWH in women with problems such as recurrent miscarriage and heritable thrombophilia there remains an urgent need for randomised trials of intervention which are adequately powered and adequately controlled to reach a firm conclusion as to whether such intervention would be effective. Thus, despite the proven safety of LMWH in pregnancy and the exciting possibility of an effective intervention in an area where there are limited or even no treatment options at present, we cannot yet unequivocally advocate LMWH for pregnancy complications other than in APS. Although low molecular weight heparin is safe in pregnancy it is not completely without risk, and until clear benefits from such intervention are available such treatment must be considered experimental while we await the results of randomised controlled trials. Meantime clinicians and their patient must consider this treatment option on the basis of the available evidence, recognising both that we often have little else to offer these women and that they are at
Low molecular weight heparin for pregnancy complications? risk of devastating pregnancy complications. This emphasises the urgency for the results of current trials in this area.
[8]
Conflicts of interest: The author has no conflicts of interest to declare. [9]
References [1] Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, et al. Thrombophilia and pregnancy a systematic review procedure. Br J Haematol 2006;132:171 96. [2] Lin J, August P. Genetic thrombophilias and preeclampsia: a meta analysis. Obstet Gynecol 2005;105: 182 92. [3] Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta analysis. Thromb Haemost 2004;91: 700 11. [4] Dudding T, Heron J, Thakkinstian A, Nurk E, Golding J, Pembrey N, et al. Factor V Leiden is associated with preeclampsia but not with fetal growth restriction: a genetic association study and meta analysis. J Thromb Haemost 2008;6(11):1869 75. [5] Clark P, Walker ID, Govan L, Wu O, Greer IA. The GOAL study: a prospective examination of the impact of factor V Leiden and ABO (H) blood groups on haemorrhagic and thrombotic pregnancy complications. Br J Haematol 2008; 140:236 40. [6] Greer IA, Nelson-Piercy C. Low molecular weight heparins for thrombophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401 7. [7] Dolitzky M, Inbal A, Segel Y, Weiss A, Brenner B, Carp H. A randomized study of thrombophylaxis in women with
[10]
[11]
[12]
[13]
[14]
S25
unexplained consecutive recurrent miscarriages. Fertil Steril 2006;86:362 6. Brenner B, Bar J, Ellis M, Yarom I, Yohai D. Samueloff A. Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study. Fertil Steril 2005;84:770 3. 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;3:227 9. Roger MA, Paidas N, Claire M, Middeldorp S, Kahn S, Martinelli I, et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol 2008;112: 320 4. Middeldorp S. Thrombophilia and pregnancy complications: cause or association? J Thromb Haemost 2007; 5(Suppl 1):276 82. Clark P, Twaddle S, Walker ID, Scott L, Greer IA. Cost effectiveness of screening for the factor V Leiden mutation in pregnant women. Lancet 2002;359: 1919 20. Wu O, Robertson L, Twaddle S, Lowe GD, Clark P, Greaves M, et al. Screening for thrombophilia in highrisk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess 2006;10(11):1 110. Wu O, Robertson L, Twaddle S, Lowe G, Clark P, Walker I, et al. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis. Br J Haematol 2005;131: 80 90.
intl.elsevierhealth.com/journals/thre
Low molecular weight heparin for pregnancy complications? I.A. Greer* Hull York Medical School, University of York, UK
Introduction Pregnancy complications such as recurrent miscarriage, pre-eclampsia, growth restriction and abruption are commonplace in pregnancy. For example, up to 5% of women will have two or more early pregnancy losses, 1 2% of women will have three or more early pregnancy losses, and pre-eclampsia complicates between 2% and 4% of pregnancies. Increasingly, evidence is accumulating of an association between heritable thrombophilia and adverse pregnancy outcome. Anti-phospholipid syndrome (APS) is associated with an increased risk of these pregnancy complications and evidence of coagulation activation with increased thrombin generation and, pathologically, placental infarction. Further, antithrombotic therapy with low molecular weight heparin (LMWH) and low dose aspirin can substantially improve the likelihood of a favourable pregnancy outcome with APS. These features have resulted in growing pressure to use antithrombotic therapy for other adverse pregnancy complications particularly in the presence of heritable thrombophilia. Such a concept is logical if heritable thrombophilia is associated with prothrombotic changes which in turn lead to an increased risk of adverse pregnancy outcome, as LMWH is the obvious agent to reduce or prevent excessive coagulation activation. However, if LMWH is to be used as an intervention to prevent such pregnancy complications it is important to consider who should be treated and whether or not the intervention is effective. Perhaps the most common strategy under consideration is thrombophilia screening for those women with previous pregnancy complications and LMWH as an intervention in any future * Correspondence: I.A. Greer. E-mail address: Email: [email protected] (I.A. Greer).
pregnancy. For any screening programme to be effective it must be associated with an important health problem where the natural history is understood and where there are identifiable markers before the disease actually occurs. The test to screen for the condition must be simple, safe and acceptable. The treatment must be effective with better outcomes from early treatment than with late treatment. Finally, the screening program must be cost effective. Thus the use of LMWH for pregnancy complications in women with thrombophilia must be considered in the context of these screening criteria. Heritable thrombophilia and adverse pregnancy outcome Many reports have highlighted the association between heritable thrombophilia and adverse pregnancy outcome; however, the extent of association has been variable. This reflects heterogeneity in: study design and methodology; sample size; the inclusion of high risk groups; differing definitions of pregnancy complications such as miscarriage and pre-eclampsia; the number of thrombophilias investigated; and differences in the genetic background of the populations studied. Because of this heterogeneity, several systematic reviews and meta-analyses have been used to assess the level of associated risk. The magnitude of risk in many of these studies is modest [1 3], such as a 1.9-fold (95% confidence interval [CI]: 1.21 2.97) for factor V Leiden heterozygotes and recurrent miscarriage in the study by Robertson et al. (2005) [1](Table 1). A similar modest level of association between other heritable thrombophilias and adverse outcomes such as pre-eclampsia is also reported. For example, Dudding et al. (2008) [4] reported
0049-3848/ $ – see front matter © 2009 Elsevier Ltd. All rights reserved.
Low molecular weight heparin for pregnancy complications? Table 1 Heritable thrombophilia and recurrent miscarriage: risk assessed by meta-analysis a Thrombophilia
Odds ratio
95%CI
homozygous
6.25
1.35 28.87
heterozygous
1.90
1.21 2.97
Prothrombin G20210A
2.49
1.24 5.00
Antithrombin deficiency
0.88
0.17 4.48
Protein C deficiency
2.29
0.20 26.43
Protein S deficiency
3.55
0.35 35.73
Factor V Leiden
a
From Robertson et al. 2006 [1].
a genetic association study and meta-analysis showing an odds ratio of 1.49 for a maternal heterozygote for factor V Leiden developing preeclampsia. However, they found no association with intra-uterine growth restriction. Further, within their cohort study the magnitude of risk for pre-eclampsia was higher in association with high body mass index, chronic hypertension and preexisting diabetes than with factor V Leiden. These systematic reviews largely report on case control and cohort studies. A recent large prospective cohort study of almost 4,000 unselected pregnant women found no association between factor V Leiden and adverse pregnancy outcome including fetal growth restriction, or a significant association with pre-eclampsia, although there was a higher point estimate for this with an odds ratio of 1.83 (95% CI: 0.51 6.13) [5] (Table 2). Thus there may be a modest association between certain heritable thrombophilias and Table 2 Results from GOAL: a prospective examination of FVL of pregnancy complications in 4087 women a,b,c Adjusted Odds ratio
95% CI
PIH
1.26
0.64 2.30
PET
1.83
0.54 6.13
IUGR
0.96
0.34 2.74
IUGR + PET
0.91
0.32 2.58
Miscarriage
0.78
0.10 5.77
adverse maternal and fetal outcomes. Screening by way of a thrombophilia screen is simple and acceptable, however, it is restricted to common, currently described thrombophilias and plainly the association between different thrombophilias and adverse pregnancy outcomes is heterogeneous. Therefore, the natural history is not entirely clear for women carrying these thrombophilic traits with regard to pregnancy outcome, particularly if they have had no previous pregnancies. LMWH, thrombophilia and prevention of adverse pregnancy outcome With regard to treatment, low dose aspirin and LMWH or unfractionated heparin can improve the pregnancy outcome in APS associated with recurrent miscarriage [1]. Low molecular weight heparins are safe during pregnancy [6] (Table 3) as is low dose aspirin [1]. Several studies have suggested that LMWH may be beneficial with regard to adverse pregnancy outcome in patients with thrombophilia and a past history of adverse pregnancy outcome [7 9], particularly as compared to previous untreated pregnancies. However, as yet there are no adequately powered, randomised, controlled trials with an untreated or placebo arm in order to confirm the suggestion of benefit. The need for adequately powered and properly controlled trials in this area has been stressed by several commentators [10,11]. Such, much needed, trials are currently underway and their results will be important in informing evidence-based practice in this area. Table 3 LMWH in pregnancy: complication rates on systematic review a Complication Thrombosis
Rate, % (95% CI) 1.37 (0.97 1.87)
VTE
0.86 (0.55 1.28)
Arterial thrombosis
0.50 (0.28 0.84)
Bleeding
1.98 (1.50 2.57)
Antenatal
0.43 (0.22 0.75)
PPH > 500 ml
0.94 (0.61 1.37)
Wound haematoma Allergy
PET: rre-eclampsia; PIH: pregnancy-induced hypertension; IUGR: intrauterine growth restriction. a After Clark et al. 2008 [5]. b Samples suitable for FVL analysis were available in 3944 women; 3.5% had factor V Leiden. c Note: In multivariate regression analysis there was no influence of FVL on a composite outcome of miscarriage, stillbirth, neonatal death, PET, Venous thrombosis or IUGR.
S23
0.61 (0.36 0.98) 1.80 (1.34 2.37)
Thrombocytopenia Platelets
0.11 (0.02 0.32)
HIT
0.00 (0.00 0.11)
Osteoporosis
0.04 (<0.01 0.20)
HIT: heparin-induced thrombocytopenia; PPH: postpartum haemorrhage. a From Greer and Nelson-Piercy 2005 [6].
S24
I.A. Greer Table 4 Cost effectiveness of thrombophilia screening and intervention with LMWH for adverse pregnancy outcome a Complications (n)
UK NHS Cost (£)
No screening
3004
532,446
Universal screening
2889
5,940,763
47,198
Selective screening
2988
1,178,634
42,166
a b
ICER*(£)
After Wu et al. 2006 [13]. ICER: incremental cost effectiveness ratio (ICER) is an estimate of the cost per unit of effectiveness of one strategy in preference to another in a population of 10,000 assuming LMWH 80% effective.
Cost effectiveness of thrombophilia screening Thus there is a modest level of association between inherited thrombophilia and adverse maternal and fetal outcome in pregnancy, but this is not consistent across all thrombophilias and all pregnancy complications. Screening for common thrombophilias is straightforward, but as yet we have no clear evidence from adequately powered and adequately controlled trials to confirm the benefit of such an intervention. If such a screening and intervention programme were to be introduced, it is also important to assess whether it would be cost effective. Two studies have assessed this, one screening for Factor V Leiden alone and the other for the common heritable thrombophilias. Neither study which modelled the outcomes and cost benefits and assumed substantial efficacy from intervention with LMWH found universal unselected screening for heritable thrombophilia to be cost effective in pregnancy (Table 4) [12 14]. Is thrombophilia screening required to guide intervention with LMWH? It may be that we have been too specific in our consideration of the mechanisms underlying adverse pregnancy outcome and thrombophilia. There is an association between both heritable and acquired thrombophilia, which suggests that “excessive coagulation” in general, rather than acquired or heritable thrombophilias in particular, may be implicated with regard to causation. This raises the possibility of intervening using LMWH for patients with previous adverse pregnancy outcomes, based not on thrombophilia screening but on the previous pregnancy outcome itself. Such a pragmatic approach assumes that the maternal phenotype, manifest through adverse pregnancy outcome, reflects an underlying prothrombotic tendency in pregnancy leading to placental damage and that such damage can be prevented or ameliorated by LMWH. It also
avoids the need for costly thrombophilia screening, which will not identify all prothrombotic tendencies. The patient will be treated on the basis of clinical features rather than genotype or an identified thrombophilia. Such studies are under way and may have more utility than those involving laboratory-based screening and incorporating previous adverse events. Conclusion There is a clear association between heritable thrombophilia and adverse maternal and fetal outcome largely based on systematic reviews of case control and cohort studies and metaanalyses. There are few prospective data to inform the natural history of thrombophilia in pregnancy in unselected populations. Thrombophilia screening is straightforward and can identify the common heritable forms of thrombophilia. However, although there is a suggestion of benefit from intervention with LMWH in women with problems such as recurrent miscarriage and heritable thrombophilia there remains an urgent need for randomised trials of intervention which are adequately powered and adequately controlled to reach a firm conclusion as to whether such intervention would be effective. Thus, despite the proven safety of LMWH in pregnancy and the exciting possibility of an effective intervention in an area where there are limited or even no treatment options at present, we cannot yet unequivocally advocate LMWH for pregnancy complications other than in APS. Although low molecular weight heparin is safe in pregnancy it is not completely without risk, and until clear benefits from such intervention are available such treatment must be considered experimental while we await the results of randomised controlled trials. Meantime clinicians and their patient must consider this treatment option on the basis of the available evidence, recognising both that we often have little else to offer these women and that they are at
Low molecular weight heparin for pregnancy complications? risk of devastating pregnancy complications. This emphasises the urgency for the results of current trials in this area.
[8]
Conflicts of interest: The author has no conflicts of interest to declare. [9]
References [1] Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, et al. Thrombophilia and pregnancy a systematic review procedure. Br J Haematol 2006;132:171 96. [2] Lin J, August P. Genetic thrombophilias and preeclampsia: a meta analysis. Obstet Gynecol 2005;105: 182 92. [3] Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta analysis. Thromb Haemost 2004;91: 700 11. [4] Dudding T, Heron J, Thakkinstian A, Nurk E, Golding J, Pembrey N, et al. Factor V Leiden is associated with preeclampsia but not with fetal growth restriction: a genetic association study and meta analysis. J Thromb Haemost 2008;6(11):1869 75. [5] Clark P, Walker ID, Govan L, Wu O, Greer IA. The GOAL study: a prospective examination of the impact of factor V Leiden and ABO (H) blood groups on haemorrhagic and thrombotic pregnancy complications. Br J Haematol 2008; 140:236 40. [6] Greer IA, Nelson-Piercy C. Low molecular weight heparins for thrombophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401 7. [7] Dolitzky M, Inbal A, Segel Y, Weiss A, Brenner B, Carp H. A randomized study of thrombophylaxis in women with
[10]
[11]
[12]
[13]
[14]
S25
unexplained consecutive recurrent miscarriages. Fertil Steril 2006;86:362 6. Brenner B, Bar J, Ellis M, Yarom I, Yohai D. Samueloff A. Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study. Fertil Steril 2005;84:770 3. 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;3:227 9. Roger MA, Paidas N, Claire M, Middeldorp S, Kahn S, Martinelli I, et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol 2008;112: 320 4. Middeldorp S. Thrombophilia and pregnancy complications: cause or association? J Thromb Haemost 2007; 5(Suppl 1):276 82. Clark P, Twaddle S, Walker ID, Scott L, Greer IA. Cost effectiveness of screening for the factor V Leiden mutation in pregnant women. Lancet 2002;359: 1919 20. Wu O, Robertson L, Twaddle S, Lowe GD, Clark P, Greaves M, et al. Screening for thrombophilia in highrisk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess 2006;10(11):1 110. Wu O, Robertson L, Twaddle S, Lowe G, Clark P, Walker I, et al. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis. Br J Haematol 2005;131: 80 90.