Use of anticoagulants to improve pregnancy outcomes in couples positive for M2 haplotype: A systematic review.

BACKGROUND: Placental mediated pregnancy complications (PMPC) are common, often recurring, and pose a significant health risk to mother and fetus. Evidence suggests that the hypercoagulable state associated with many PMPC, could reflect reduced expression of Annexin 5 (ANXA5), a naturally occurring anticoagulant protein in placental tissue. The ANXA5 M2 haplotype is a genetic variant, which results in reduced expression of ANXA5 protein. M2 haplotype carrier couples may therefore be at increased risk of PMPC. Evidence regarding the effectiveness of anticoagulation to prevent PMPC is inconsistent. Furthermore, studies have not selected or stratified for M2 haplotype carriers, in whom there is a predisposition to hypercoagulability, to assess the effectiveness of anticoagulation, which may vary from those without the M2 haplotype. OBJECTIVES AND RATIONALE: The aim of this study was to systematically review the current evidence to assess whether anticoagulant treatment improves pregnancy outcomes in couples positive for M2 haplotype. SEARCH METHODS: The review was registered on PROSPERO (CRD42022343943). A comprehensive literature search was performed using MEDLINE, Embase and Cochrane collaboration databases from inception to January 2023. Two reviewers assessed the articles for eligibility and extracted the data simultaneously. Primary outcome was successful pregnancy and live birth. Secondary outcomes included PMPC (implantation failure, miscarriage, pre-eclampsia, preterm birth and fetal growth restriction). OUTCOMES: From a pool of 410 references, 10 were selected for full text review, of which three studies (a post hoc analysis of a randomised controlled trial, cohort study and a case report) were included in this review. Included studies comprised of 223 individuals, 129 of whom who received anticoagulation treatment after testing positive for M2 haplotype. The studies collectively showed an improvement in pregnancy outcomes in M2 haplotype positive individuals however, given the heterogeneity of studies, it was not possible to conduct a meta-analysis and draw firm conclusions. WIDER IMPLICATIONS: Current evidence is limited, such that the value of screening couples for the M2 haplotype to select or stratify for treatment with prophylactic anticoagulation remains unknown. Thus, further studies including well designed, large, multi-centre randomised controlled trials are required to assess whether anticoagulation treatment will be effective in improving pregnancy outcomes in M2 haplotype couples.

Assessment-based management of placenta-mediated pregnancy complications: Pragmatism until a precision medicine approach evolves.

The management of pregnant women with thrombophilia and a history of gestational vascular complications remains debatable. Treatment of the latter is often based on clinical outcome rather than disease mechanism. While the use of venous thromboembolism prophylaxis in pregnancy is recommended for those at increased risk, the ability of anticoagulant and/or antiplatelet agents to lower the risk of placenta-mediated complications in this clinical setting remains controversial. The available guidelines are inconsistent in some situations, which reflects the limited evidence base. This review critically discusses risk assessment models (RAMs) and management strategies of women with thrombophilia and pregnancy complications, using clinical vignettes. RAMs, taking into account obstetric and thrombotic history as well as thrombophilia status, could drive a precision medicine approach, based on disease mechanism, and guide individual therapeutic interventions in high-risk clinical settings.

Welfare, Work and the Conditions of Social Solidarity: British Campaigns to Defend Healthcare and Social Security.

When the welfare state is under attack from neoliberal reformers, how can trade unionists and other campaigners build solidarity to defend it? Based on 45 qualitative interviews, this article compares campaigns to defend British health services and social security benefits between 2007 and 2016. Building on the macro-insights of comparative welfare-state literature and the more micro-level insights of studies on mobilisation, community unionism and union strategy, it examines the factors that help or hinder the construction of solidarity. This research finds that building solidarity is more difficult when defending targeted benefits than universal ones, not only because of differences in public opinion and political support for services, but also because the labour process associated with targeting benefits, namely the assessing and sanctioning of clients, can generate conflicts among campaigners.

United Kingdom recommendations for obstetric venous thromboembolism prophylaxis: Evidence and rationale.

Venous thromboembolism (VTE) is a leading cause of maternal death in the United Kingdom. To address this problem guidance from the Royal College of Obstetricians and Gynaecologists (RCOG) has been developed that recommends the assessment of a woman's risk of thrombosis at specific time-points during pregnancy and postnatally at the time of delivery. The RCOG guidelines provide clinicians with a framework to inform decision-making on the use of thromboprophylaxis and are based on the premise that the higher risk a woman has for VTE, the more likely she is to benefit from prophylaxis - determining her level of risk is based on the number and characteristics of the risk factors that she has. This article will address the pathophysiology of VTE in pregnancy, evidence behind the risk factors for VTE and the use of thromboprophylactic agents. Further, it will reflect on the rationale behind the RCOG guidance.

American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.

BACKGROUND: Venous thromboembolism (VTE) complicates ∼1.2 of every 1000 deliveries. Despite these low absolute risks, pregnancy-associated VTE is a leading cause of maternal morbidity and mortality. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and others in decisions about the prevention and management of pregnancy-associated VTE. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations. RESULTS: The panel agreed on 31 recommendations related to the treatment of VTE and superficial vein thrombosis, diagnosis of VTE, and thrombosis prophylaxis. CONCLUSIONS: There was a strong recommendation for low-molecular-weight heparin (LWMH) over unfractionated heparin for acute VTE. Most recommendations were conditional, including those for either twice-per-day or once-per-day LMWH dosing for the treatment of acute VTE and initial outpatient therapy over hospital admission with low-risk acute VTE, as well as against routine anti-factor Xa (FXa) monitoring to guide dosing with LMWH for VTE treatment. There was a strong recommendation (low certainty in evidence) for antepartum anticoagulant prophylaxis with a history of unprovoked or hormonally associated VTE and a conditional recommendation against antepartum anticoagulant prophylaxis with prior VTE associated with a resolved nonhormonal provoking risk factor.

'To test or not to test', the arguments for and against thrombophilia testing in obstetrics.

Clinicians increasingly investigate women for thrombophilias due to their associations with venous thromboembolism and placenta-mediated pregnancy complication. These associations, however, are modest and based largely on retrospective data from studies with heterogeneous classifications and populations, leading to discordance between evidence and guidelines. Current evidence suggests a contributory rather than causative role for thrombophilia in placenta-mediated pregnancy complication and venous thromboembolism. With little evidence of benefit from antithrombotic therapy in placenta-mediated pregnancy complication, thrombophilia screening remains controversial. Given the low absolute risk of placenta-mediated pregnancy complication and gestational venous thromboembolism with heritable thrombophilia, universal screening is inappropriate. Selective screening for antiphospholipid syndrome is supported by robust evidence of benefit. Conversely, selective screening for heritable thrombophilia has not been shown to effectively manage placenta-mediated pregnancy complication. Therefore, at present heritable thrombophilia screening is not warranted for placenta-mediated pregnancy complication. Until we have better evidence from better stratified patient groups, caution should remain if we wish to practice evidence-based medicine.

LMWH in IVF - Biomarkers and benefits.

There is biological plausibility that coagulation activation underlies a proportion of in vitro fertilisation IVF failures and recurrent early clinical pregnancy loss (RPL). However, low-molecular-weight heparin (LMWH) use, based upon previous clinical outcome alone, is not effective in preventing RPL. RPL is heterogeneous in mechanism. Identifying those with an underlying thrombotic mechanism would allow stratification for LMWH treatment. Annexin A5 is an anticoagulant protein expressed on the trophoblast surface. The annexin A5 M2 haplotype (ANXA5 M2) is associated with several placenta mediated pregnancy complications (PMPC) and poor IVF outcome. It is transmitted equally by males and females. A pragmatic observational study of IVF couples screened for M2 carriage and treated with LMWH achieved a 37.9% live birth rate, similar to an unscreened and untreated group with fewer adverse risk factors for conception and a better prognosis from assisted conception. This suggests that LMWH may counteract the adverse effects of M2 carriage. Using this biomarker to stratify IVF and PMPC patients for LMWH treatment merits further evaluation.

Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium.

Venous thromboembolism (VTE) is a leading cause of maternal mortality. Few studies have evaluated the individual risk of gestational VTE associated with heritable thrombophilia, and current recommendations for antenatal thromboprophylaxis in women with severe thrombophilia such as homozygous factor V Leiden mutation (FVL) depend on a positive family history of VTE. To better stratify thromboprophylaxis in pregnancy, we aimed to estimate the individual probability (absolute risk) of gestational VTE associated with thrombophilia and to see whether these risk factors are independent of a family history of VTE in first-degree relatives. We studied 243 women with the first VTE during pregnancy and the puerperium and 243 age-matched normal women. Baseline incidence of VTE of 1:483 pregnancies in women ≥35 years and 1:741 deliveries in women <35 years was assumed, according to a recent population-based study. In women ≥35 years (<35 years), the individual probability of gestational VTE was as follows: 0.7% (0.5%) for heterozygous FVL; 3.4% (2.2%) for homozygous FVL; 0.6% (0.4%) for heterozygous prothrombin G20210A; 8.2% (5.5%) for compound heterozygotes for FVL and prothrombin G20210A; 9.0% (6.1%) for antithrombin deficiency; 1.1% (0.7%) for protein C deficiency; and 1.0% (0.7%) for protein S deficiency. These results were independent of a positive family history of VTE. We provide evidence that unselected women with these thrombophilias have an increased risk of gestational VTE independent of a positive family history of VTE. In contrast to current guidelines, these data suggest that women with high-risk thrombophilia should be considered for antenatal thromboprophylaxis regardless of family history of VTE.

Management of inherited thrombophilia in pregnancy.

Adverse pregnancy outcomes, such as pregnancy loss and pre-eclampsia, are associated with thrombotic mechanisms and thrombophilia. Antithrombotic interventions, particularly low-molecular-weight heparin, have been investigated in women identified by previous pregnancy outcome; however, the results have been inconsistent. This may reflect heterogeneity of both the study groups and the disease processes resulting in inadequate stratification to guide antithrombotic interventions. Furthermore, the variation in gestation at initiation of low-molecular-weight heparin treatment might be important. Despite limited evidence of efficacy, low-molecular-weight heparin is often used in an attempt to prevent these complications, owing to the lack of other effective treatments and its perceived safety in pregnancy. Research is required to better understand the disease processes, identify possible biomarkers and thereby more homogeneous groups for targeted treatment.

Precision Medicine in Assisted Conception: A Multicenter Observational Treatment Cohort Study of the Annexin A5 M2 Haplotype as a Biomarker for Antithrombotic Treatment to Improve Pregnancy Outcome.

BACKGROUND: Pregnancy failure and placenta mediated pregnancy complications affect >25% of pregnancies. Although there is biological plausibility for a procoagulant mechanism underlying some of these events, antithrombotic intervention trials demonstrate limited benefit, possibly through lack of stratification in heterogeneous patient groups. The ANXA5 M2 haplotype is a possible procoagulant biomarker and was tested pragmatically to determine whether this screening and LMWH treatment normalized the outcome for ANXA5 M2 positive couples. This was a pragmatic study that aimed to measure the effectiveness of a testing (for the M2 haplotype) and treatment (LMWH) pathway in routine clinical practice where there is variation between patients. Such a study in couples with fertility problems can inform choices between treatments; it is then the management protocol which is the subject of the investigation, not the individual treatments. METHODS: Couples (N=77) with one or both partners ANXA5 M2 positive demonstrated association of this haplotype with adverse IVF outcome. A pragmatic, multicenter, prospective cohort study of ANXA5 M2 haplotype screening, and LWMH treatment following embryo transfer (ET) in 103 IVF couples positive for ANXA5 M2 was performed. They were compared with a group of 1000 contemporaneous randomly selected unscreened and untreated couples undergoing assisted conception, from which 103 matched control couples were derived. The primary outcome measure was live birth incidence. Secondary outcomes were results following embryo transfer (ET) and live birth outcome by gender and M2 carriage, and allelic dose influence. FINDINGS: The tested and treated cohort of ANXA5 M2 carriers achieved a similar live birth rate (37.9%) per ET cycle compared to both the more fertile comparison group (38.5%), and to the 103 matched controls (33.0%). Significantly more treated male carrier only couples had a live birth versus female M2 only (47.7% vs. 25.0% p=0.045). INTERPRETATION: Pragmatic ANXA5 M5 screening and treatment with LMWH in couples undergoing IVF is associated with similar outcome to couples with more favorable prognostic factors. The difference in live birth outcome for treated male only carrier couples may be consistent with an additional maternal thrombophilic factor that may adversely affect pregnancy, although other mechanisms are possible. This study suggests that LMWH treatment should be started prior to clinical pregnancy.

Guidance for the treatment and prevention of obstetric-associated venous thromboembolism.

Venous thromboembolism (VTE), which may manifest as pulmonary embolism (PE) or deep vein thrombosis (DVT), is a serious and potentially fatal condition. Treatment and prevention of obstetric-related VTE is complicated by the need to consider fetal, as well as maternal, wellbeing when making management decisions. Although absolute VTE rates in this population are low, obstetric-associated VTE is an important cause of maternal morbidity and mortality. This manuscript, initiated by the Anticoagulation Forum, provides practical clinical guidance on the prevention and treatment of obstetric-associated VTE based on existing guidelines and consensus expert opinion based on available literature where guidelines are lacking.

Thrombophilia and Pregnancy Complications.

There is a paucity of strong evidence associated with adverse pregnancy outcomes and thrombophilia in pregnancy. These problems include both early (recurrent miscarriage) and late placental vascular-mediated problems (fetal loss, pre-eclampsia, placental abruption and intra-uterine growth restriction). Due to poor quality case-control and cohort study designs, there is often an increase in the relative risk of these complications associated with thrombophilia, particularly recurrent early pregnancy loss, late fetal loss and pre-eclampsia, but the absolute risk remains very small. It appears that low-molecular weight heparin has other benefits on the placental vascular system besides its anticoagulant properties. Its use is in the context of antiphospholipid syndrome and recurrent pregnancy loss and also in women with implantation failure to improve live birth rates. There is currently no role for low-molecular weight heparin to prevent late placental-mediated complications in patients with inherited thrombophilia and this may be due to small patient numbers in the studies involved in summarising the evidence. There is potential for low-molecular weight heparin to improve pregnancy outcomes in women with prior severe vascular complications of pregnancy such as early-onset intra-uterine growth restriction and pre-eclampsia but further high quality randomised controlled trials are required to answer this question.

When does marketisation lead to privatisation? Profit-making in English health services after the 2012 Health and Social Care Act.

Governments world-wide have attempted to use market mechanisms and privatisation to increase the quality and/or reduce the cost of healthcare. England's Health and Social Care Act 2012 is an attempt to promote privatisation through marketisation in the National Health Service (NHS). While the health policy literature tends to assume that privatisation follows from private-sector entry points, we argue that this is more likely if firms expect to make a profit. This paper examines the link between privatisation and marketisation in England drawing on 32 semi-structured interviews with private-sector and public-sector respondents, campaigners, and other experts conducted 6-10 months after the implementation of the 2012 Act. By generating a theoretical framework on the conditions of profitability we seek a better understanding of the conditions under which marketisation leads to privatisation. We find that significant barriers to profit-making remain after the reforms, including a top-down squeeze on prices, uncertainty in market rules, state dominance of funding and provision, and failures to depoliticise the market. These factors restrict private-sector involvement by frustrating profit-making. Where profits are made they are through reduced unit costs and high volumes by a longstanding incumbent in a particular market segment. This, however, restricts marketisation by reinforcing entry barriers.

Pulmonary thrombo-embolism in pregnancy: diagnosis and management.

KEY POINTS: Venous thromboembolism (VTE) in pregnancy remains a leading cause of direct maternal mortality in the developed world and identifiable risk factors are increasing in incidence.VTE is approximately 10-times more common in the pregnant population (compared with non-pregnant women) with an incidence of 1 in 1000 and the highest risk in the postnatal period.If pulmonary imaging is required, ventilation perfusion scanning is usually the preferred initial test to detect pulmonary embolism within pregnancy. Treatment should be commenced on clinical suspicion and not be withheld until an objective diagnosis is obtained.The mainstay of treatment for pulmonary thromboembolism in pregnancy is anticoagulation with low molecular weight heparin for a minimum of 3 months in total duration and until at least 6 weeks postnatal. Low molecular weight heparin is safe, effective and has a low associated bleeding risk. EDUCATIONAL AIMS: To inform readers about the current guidance for diagnosis and management of pulmonary thromboembolism in pregnancy.To highlight the risks of venous thromboembolism during pregnancy.To introduce the issues surrounding management of pulmonary thromboembolism around labour and delivery.

Coagulation and placenta-mediated complications.

Pregnancy is a physiological hypercoagulable state, preparing the mother for the hemostatic challenge of delivery. However, this is associated with an increased risk of venous thrombosis and placenta-mediated complications, which present major challenges for mother and fetus. Although these conditions are heterogeneous in their pathophysiology, hereditary and acquired thrombophilia has been associated with recurrent pregnancy loss and gestational vascular complications, such as early-onset pre-eclampsia and placental abruption. Prevention of such placenta-mediated complications, which collectively complicate up to 15% of pregnancies, is a major issue for women's health. Prospective interventional studies stratified by current knowledge of pathophysiological mechanisms related to placental and systemic hemostatic alterations will impact on the management of pregnancies at risk of these complications.