Haematological complications continue to represent a major source of morbidity and mortality during pregnancy. 1,2 The challenges which clinicians face in managing these disorders are often compounded by a lack of high-quality evidence to guide decision-making. Pregnant women are frequently excluded from clinical research studies and the lack of high-quality clinical trials in this population has proven to be a major obstacle to the formulation of evidence-based recommendations for the management of specific high-risk clinical scenarios in obstetric haematology. Venous thromboembolism (VTE) remains the leading cause of direct maternal mortality in the developed world.3 The derangements in haemostasis which arise during pregnancy leading to this increased thrombotic risk are well described, but assessment of risk on an individual patient level (in order to inform treatment decisions) remains challenging.1,4-6 Strategies for prevention of VTE in pregnancy are often based on expert consensus or low-quality observational data alone.4-6 This has led to significant variation in practice globally and potentially exposes pregnant women to unnecessary risks. Interestingly, it has been postulated that derangements in coagulation activity may contribute to other forms of pregnancy-related morbidity, including recurrent pregnancy loss, pre-eclampsia and other placental-mediated disorders. This pathological interplay between haemostasis and pregnancy morbidity is perhaps best exemplified by antiphospholipid syndrome, an acquired immune-mediated pro-thrombotic disorder characterised by thrombosis, recurrent pregnancy loss, and other obstetric complications.7 The role of other forms of thrombophilia, particularly inherited thrombophilia (such as Factor V Leiden), in mediating an increased risk of pregnancy loss is less clear and remains a source of much controversy and variation in practice, particularly with regards to the role of anti-thrombotic therapy as a preventative measure.8-11
This lack of high-quality clinical trial data in the setting of obstetric haematology is a source of significant health inequity and unnecessary risk for pregnant women. Fortunately, a number of global leaders in the field of thrombosis, haemostasis and maternal haematology have recently sought to redress this balance by conducting high-quality randomised clinical trials (RCTs), aiming to answer some of these important questions. Despite the major challenges faced by these investigators, 2022 proved to be a landmark year in the completion of RCTs in obstetric haematology with the release of data from both the Highlow and ALIFE2 studies.12,13 These trials aimed to determine the optimal thromboprophylaxis dosing strategy for pregnant women with prior VTE and to determine the effect of low molecular weight heparin (LMWH) in preventing recurrent miscarriage in women with inherited thrombophilia respectively. As we look to 2023 and beyond, these studies will likely have practise-changing implications.
During pregnancy, a hypercoagulable state emerges as a physiological response to the risk of bleeding associated with labour and delivery. This shift in haemostatic balance towards a pro-coagulant state is characterised by an increase in coagulation factor activity (such as fibrinogen, factor VIII and von Willebrand factor), which becomes progressively more marked with advancing gestation. This is accompanied by a reduction in the activity of endogenous anticoagulant and fibrinolytic factor activity.1,2 The hypercoagulability of pregnancy may become further accentuated by anatomical factors, particularly with the compressive effect exerted by the gravid uterus on the venous supply of the lower limbs, leading to venous stasis and increased coagulation activation.14,15
While this physiological response may help to reduce the risk of bleeding, this shift towards a procoagulant phenotype also confers a risk of VTE.3,16 VTE can be rapidly fatal if not adequately treated and among survivors of VTE a substantia burden of chronic morbidity has been reported.17,18 Despite advances in VTE care in recent decades, it remains the leading cause of direct maternal mortality in the UK and Ireland.3 Consequently, the prevention of pregnancy-associated VTE has become a major priority for healthcare providers. VTE can be prevented in many cases through the appropriate use of pharmacological thromboprophylaxis with drugs such as LMWH. However, this treatment strategy is not without risk and is associated with an increased risk of bleeding during pregnancy and peripartum.12 Thromboprophylaxis is also associated with significant healthcare costs as well as significant inconvenience for pregnant women, particularly when prescribed for the entire duration of pregnancy and postpartum. It is therefore recommended that pharmacological thromboprophylaxis is reserved for individuals who are deemed to be at high-risk.6 However, even among such cases, there exists much debate surrounding the optimal dosing strategy. This is particularly the case for women with a prior history of oestrogen-associated or unprovoked VTE. Women in this sub-group are thought to have a risk of VTE recurrence during pregnancy that may be as high as 6 per cent or more in the absence of prophylaxis.19 As a result, some clinical practice guidelines have suggested offering these women an escalated LMWH dose (‘intermediate dose’) for the entire duration of pregnancy, notwithstanding the potential risks and costs associated with this approach. Practice varies considerably between institutions and recommendations in international clinical practice guidelines are somewhat conflicting in this regard.2,6 Consequently, the investigators in the Highlow study aimed to investigate this issue and to determine the safest and most effective thromboprophylaxis regimen for this group of high-risk pregnant women.
The Highlow study was an open-label RCT in which the investigators sought to determine if a higher, ‘intermediate’ dose of LMWH would be more effective than standard dosing in preventing recurrent VTE during pregnancy in pregnant women with a prior history of VTE.12 In this study, pregnant women with a history of objectively-confirmed VTE, other than that occurring in the context of major provoking factors (such as major surgery), were recruited. This was an international, multi-centre study, recruiting in nine countries worldwide, including at three sites in Ireland and supported by the Irish Network for VTE Research (INViTE). Women eligible for recruitment were randomly assigned to either a weight-adjusted intermediate-dose (approximately 50 per cent of a therapeutic dose) or fixed, standard lowdose LMWH (eg, enoxaparin 40mg OD SC) for the duration of pregnancy and until six weeks post-partum. The primary efficacy outcome was objectively-confirmed VTE and the primary safety outcome was major bleeding. In total, over 1,000 women were recruited.
The findings of the Highlow study were presented at a prestigious late-breaking session at the Annual Congress of the International Society of Thrombosis and Haemostasis (ISTH) in July 2022 and subsequently published in The Lancet in October 2022.12 The INViTE network were also honoured to have the principal investigator of the Highlow trial present this data at the annual international VTE Dublin conference in 2022.
In the final analysis, the investigators reported that VTE occurred in 11 (2 per cent) pregnant women in the intermediate-dose group and in 16 (3 per cent) in the fixed low-dose group (relative risk [RR] 0.69 [95% CI 0.32–1.47]; p=0.33). VTE occurred antenatally in five (1 per cent) women in the intermediate-dose group and also in five (1 per cent) women in the standard-dose group. Postnatally, there were six VTE events (1 per cent) in the intermediate-dose group and in 11 women (2 per cent) in the standard-dose group. On-treatment major bleeding occurred in 23 (4 per cent) of 520 women in the intermediate-dose group and in 20 (4 per cent ) of the women in the low-dose group (RR 1.16 [95% CI 0.65–2.09]).
The Highlow study investigators subsequently concluded that standard prophylactic-dose LMWH is the appropriate dose for the prevention of pregnancy-related recurrent VTE, and have thus provided for the first time an evidence base to support decision-making for clinicians managing these patients. Interestingly, in a post-hoc analysis the investigators also observed that women who were allocated to receive intermediate-dose LMWH had a lower incidence of post-partum pulmonary embolism (one-of-555 women vs seven-of-555 women) and superficial thrombophlebitis (none vs 11) than women allocated to low-dose LMWH. Although the study was not powered to determine efficacy for this particular subgroup analysis, it does suggest that a potential differential effect of the intervention may arise in the postpartum period in contrast to the antepartum period. However, this would, of course, require confirmation in a second randomised trial.12
Up to 5 per cent of women experience recurrent pregnancy loss (defined as two or more successive losses).13 While foetal anatomic or chromosomal defects are frequently implicated, in many cases a cause for the pregnancy loss is not identified. There is some evidence to suggest that derangements in coagulation activity might pre-dispose women to recurrent pregnancy loss, possibly as a result of abnormal activity in the interplay which exists between coagulation, vascular biology, and placental function.
Antiphospholipid syndrome is an acquired immune-mediated thrombophilia characterised by recurrent thrombosis and specific obstetric morbidity, including recurrent miscarriage. In women with obstetric antiphospholipid syndrome, treatment with aspirin and LMWH has been shown to reduce the risk of miscarriage.7 The use of LMWH and/or aspirin has not been shown to prevent miscarriage in unselected women with recurrent pregnancy losses in the absence of antiphospholipid syndrome.10
However, the effect of inherited thrombophilia on miscarriage risk (and the potential for antithrombotic therapy to prevent miscarriage in this setting) has represented a major source of clinical debate in recent years. While some observational studies have suggested a potential association between inherited thrombophilia (such as Factor V Leiden) and recurrent miscarriage, a benefit with anti-thrombotic therapy in preventing miscarriage in this setting has never been proven.9,11,20 Notwithstanding the lack of evidence for the safety or efficacy of these agents in the setting of inherited thrombophilia, LMWH and anti-platelet agents have been widely used to prevent pregnancy loss in women with inherited thrombophilia. The ALIFE2 trial, the final results of which were presented for the first time at the annual meeting and exposition of the American Society of Hematology (ASH) in December 2022, aimed to determine if any benefit existed with the use of LMWH for prevention of recurrent miscarriage in this setting.
The ALIFE2 trial was another international open-label RCT, with recruitment across 41 sites in the UK and Europe between August 2012 and January 2021 (EudraCT reference, UK: 2015-002357-35). Women who had two or more pregnancy losses and a confirmed inherited thrombophilia who were trying to conceive or who were less than seven weeks pregnant were eligible for inclusion.13 Once pregnancy was confirmed, eligible women were randomly assigned to either prophylactic-dose LMWH or standard pregnancy surveillance only. The primary outcome was the rate of live births. Over 10,000 women with recurrent miscarriage were screened for eligibility, with 428 women meeting criteria for inclusion, of whom 326 eventually conceived. Of these, 164 were randomised to LMWH and 162 to the control arm. The mean age of participants was 33 years.
Strikingly, there was no significant difference in the observed live birth rate between groups. In total, there were 116 live births from 162 pregnancies (71.6 per cent) in the LMWH group and 112/158 (70.9 per cent) in the standard surveillance group [adjusted OR 1.08 (95% CI 0.65-1.78)]. Based on these data, the ALIFE2 investigators have concluded that the use of prophylactic LMWH cannot be justified for the purposes of preventing miscarriage in women with inherited thrombophilia and recurrent miscarriage. Moreover, these data also suggest that routine screening for inherited thrombophilia is not indicated in women with history of recurrent miscarriage as the outcome of testing would not be expected to have any treatment implications.
The Highlow and ALIFE2 studies have succeeded in answering two important clinical questions which arise frequently for clinicians involved in the care of pregnant women. The Highlow study confirmed that a standard fixed-dose LMWH is the appropriate regimen for preventing recurrent VTE in pregnancy, although the role of escalated dosing in the postpartum period remains to be clarified. The ALIFE2 study has confirmed that women with inherited thrombophilia and recurrent pregnancy loss do not benefit from LMWH for prevention of further miscarriage and that, consequently, screening for inherited thrombophilia is of no clear benefit in this population.
As we look to 2023 and beyond, we can expect this data to shape clinical practice guidelines in this field. Moreover, we also anticipate that the success of these studies, despite the inherent challenges in conducting academic clinical trials in pregnancy, will drive further work in this area. Future RCTs on the horizon, which may further impact on the care of pregnant women at risk of haematological morbidity include the Partum trial (ClinicalTrials.gov identifier NCT04153760), an RCT investigating the role of aspirin in VTE prevention in other, less high-risk women. Supporting these and other studies will continue to be a priority for clinicians in this country, as we aim to address these major knowledge gaps and ultimately improve the standard of care offered to pregnant women at risk of these complications. molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): An openlabel, multicentre, randomised, controlled trial. Lancet, 2022. 400(10365): p. 1777-1787 13. de Jong PG, et al. ALIFE2 study: Low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia – study protocol for a randomised controlled trial. Trials, 2015. 16: p. 208 14. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: Diagnosis, management and prevention. Thromb Haemost, 2009. 101(3): p. 428-38 15. James AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol, 2009. 29(3): p. 326-31 16. Shennan AH, Green M, Chappell LC. Maternal deaths in the UK: Pre-eclampsia deaths are avoidable. Lancet, 2017. 389(10069): p. 582-584 17. Kahn SR, et al. Quality-of-life, dyspnoea, and functional exercise capacity following a first episode of pulmonary embolism: Results of the ELOPE Cohort Study. Am J Med, 2017. 130(8): p. 990 e9-990 e21 18. Kahn SR. The post-thrombotic syndrome. Hematology Am Soc Hematol Educ Programme, 2016. 2016(1): p. 413-418 19. Pabinger I, et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost, 2005. 3(5): p. 949-54 20. Skeith L, Rodger M. Anticoagulants to prevent recurrent placentamediated pregnancy complications: Is it time to put the needles away? Thromb Res, 2017. 151 Suppl 1: p. S38-S42
1. Kevane B, et al. Risk factors for pregnancy-associated venous thromboembolism: A review. J Perinat Med, 2014. 42(4): p. 417-25
2. Bates SM, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141(2 Suppl): p. e691S-736S
3. Knight M, Tuffnell D. A view from the UK: The UK and Ireland confidential enquiry into maternal deaths and morbidity. Clin Obstet Gynecol, 2018. 61(2): p. 347-358
4. O’Shaughnessy F, et al. Prevalence of postpartum venous thromboembolism risk factors in an Irish urban obstetric population. J Thromb Haemost, 2019. 17(11): p. 1875-1885
5. O’Shaughnessy F, et al. Thrombocalc: Implementation and uptake of personalised postpartum venous thromboembolism risk assessment in a high-throughput obstetric environment. Acta Obstet Gynecol Scand, 2017. 96(11): p. 1382-1390
6. RCOG. Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Royal College of Obstetricians and Gynaecologists; Green-top Guideline No.37a, 2015
7. Keeling D, et al. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol, 2012. 157(1): p. 47-58
8. Shehata H, et al. Thrombophilia screening in women with recurrent first trimester miscarriage: Is it time to stop testing? – A cohort study and systematic review of the literature. BMJ Open, 2022. 12(7): p. e059519
9. Liu X, et al. Hereditary thrombophilia and recurrent pregnancy loss: A systematic review and meta-analysis. Hum Reprod, 2021. 36(5): p. 1213-1229
10. Clark P, et al. SPIN (Scottish Pregnancy Intervention) study: A multicenter, randomised controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood, 2010. 115(21): p. 4162-7
11. Kaandorp S, et al. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev, 2009(1): p. CD004734
12. Bistervels IM, et molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): An openlabel, multicentre, randomised, controlled trial. Lancet, 2022. 400(10365): p. 1777-1787
13. de Jong PG, et al. ALIFE2 study: Low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia – study protocol for a randomised controlled trial. Trials, 2015. 16: p. 208
14. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: Diagnosis, management and prevention. Thromb Haemost, 2009. 101(3): p. 428-38
15. James AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol, 2009. 29(3): p. 326-31
16. Shennan AH, Green M, Chappell LC. Maternal deaths in the UK: Pre-eclampsia deaths are avoidable. Lancet, 2017. 389(10069): p. 582-584
17. Kahn SR, et al. Quality-of-life, dyspnoea, and functional exercise capacity following a first episode of pulmonary embolism: Results of the ELOPE Cohort Study. Am J Med, 2017. 130(8): p. 990 e9-990 e21
18. Kahn SR. The post-thrombotic syndrome. Hematology Am Soc Hematol Educ Programme, 2016. 2016(1): p. 413-418
19. Pabinger I, et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost, 2005. 3(5): p. 949-54
20. Skeith L, Rodger M. Anticoagulants to prevent recurrent placentamediated pregnancy complications: Is it time to put the needles away? Thromb Res, 2017. 151 Suppl 1: p. S38-S42
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