BackgroundPlacental 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 rationaleThe 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 methodsThe 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).OutcomesFrom 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 implicationsCurrent 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.

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.

Summary Objective Women with pre‐eclampsia have elevated circulating levels of soluble fms‐like tyrosine kinase‐1 (sFlt‐1). Statins can reduce sFlt‐1 from cultured cells and improve pregnancy outcome in animals with a pre‐eclampsia‐like syndrome. We investigated the effect of pravastatin on plasma sFlt‐1 levels during pre‐eclampsia. Design Blinded (clinician and participant), proof of principle, placebo‐controlled trial. Setting Fifteen UK maternity units. Population We used a minimisation algorithm to assign 62 women with early‐onset pre‐eclampsia (24 +0 –31 +6 weeks of gestation) to receive pravastatin 40 mg daily ( n = 30) or matched placebo ( n = 32), from randomisation to childbirth. Primary outcome Difference in mean plasma sFlt‐1 levels over the first 3 days following randomisation. Results The difference in the mean maternal plasma sFlt‐1 levels over the first 3 days after randomisation between the pravastatin ( n = 27) and placebo ( n = 29) groups was 292 pg/ml (95% CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95% CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days (interquartile range [IQR] 5–14 days) for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo‐treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions We found no evidence that pravastatin lowered maternal plasma sFlt‐1 levels once early‐onset pre‐eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract Pravastatin does not improve maternal plasma sFlt‐1 or placental growth factor levels following a diagnosis of early preterm pre‐eclampsia #clinicaltrial finds.

Venous thromboembolism (VTE) is a leading cause of maternal mortality and morbidity. Prophylaxis and management of VTE in pregnancy can impact mortality and morbidity. The overall reported incidence of gestational VTE ranges from 0.5 to 2.2 per 1000 maternities with a relative 5–10-fold increase in risk during pregnancy, increasing to a daily risk of 15–35-fold in the puerperium, compared with non-pregnant women of similar age. Risk factors inform the use of thromboprophylaxis usually with low-molecular-weight heparin, which has a better safety profile than unfractionated heparin. VTE can occur at any time in pregnancy, but over 50% of events occur prior to 20 weeks’ gestation. As clinical diagnosis is unreliable, objective assessment is required when there is clinical suspicion of an event. Less than 10% of clinically suspected cases of VTE are confirmed on objective testing. Compression duplex ultrasonography is the first-line investigation for suspected gestational deep venous thrombosis and thoracic imaging with ventilation–perfusion scanning is required for suspected pulmonary embolism. Low-molecular-weight heparin is usually the first choice treatment for gestational VTE based on safety and efficacy.

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.

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.

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.

Pre-eclampsia, fetal growth restriction, placental abruption, and recurrent miscarriage are common placenta-mediated pregnancy complications. They have overlapping pathological features including deficient placentation, microvascular thrombosis, placental infarction, and an association with thrombophilia, 1 Greer IA Brenner B Gris JC Antithrombotic treatment for pregnancy complications: which path for the journey to precision medicine?. Br J Haematol. 2014; 165: 585-599 Crossref PubMed Scopus (36) Google Scholar , 2 Robertson L Wu O Langhorne P et al. Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006; 132: 171-196 Crossref PubMed Scopus (686) Google Scholar , 3 Rodger MA Betancourt MT Clark P et al. The association of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med. 2010; 7: e1000292 Crossref PubMed Scopus (183) Google Scholar implicating coagulation activation as a disease mechanism. Antithrombotic treatment has been shown to improve the outcome of antiphospholipid syndrome manifested as recurrent pregnancy loss, and low-dose aspirin provides a modest risk reduction in women with previous pre-eclampsia. 1 Greer IA Brenner B Gris JC Antithrombotic treatment for pregnancy complications: which path for the journey to precision medicine?. Br J Haematol. 2014; 165: 585-599 Crossref PubMed Scopus (36) Google Scholar These findings provide a biological plausibility for treating women who have had previous placenta-mediated pregnancy complications with antithrombotic drugs in subsequent pregnancies. Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trialsLow-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. Full-Text PDF

Thromboembolism in pregnancy remains a major cause of direct maternal mortality in the Western world. Thromboembolic events in pregnancy are spread across the three trimesters but the puerperium is the time of greatest risk with a relative risk of around 20-fold compared to the non-pregnant patient. When compared to the non-pregnant population where distal deep vein thrombosis is most common, most events in pregnancy are iliofemoral and left sided. Given the multi-hit nature of the problem, awareness of risk factors is important. The two most significant single risk factors in pregnancy for thromboembolism are history of previous venous thromboembolism and thrombophilia. The identification of risk factors will guide the use of thromboprophylaxis and assist diagnosis; however, objective diagnosis is required. Prophylaxis and treatment focuses on low-molecular-weight heparin, which is considered safe in pregnancy.

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.

Background Placental-mediated pregnancy complications, miscarriage, fetal growth restriction and preeclampsia are a spectrum of disorders sharing overlapping clinical and pathological features. All are associated with thrombotic pathogenic processes, ranging from microvascular fibrin deposition in the glomerular vessels in preeclampsia, to placental infarction in fetal growth restriction. However, a number of disease mechanisms contribute to these outcomes, and it is not clear how critical the thrombotic process is across the various components of the spectrum of disease and between pregnancies. Some predictive and risk factors are known, but the only established preventative measures that exist are antithrombotic agents – low-dose aspirin and low-molecular-weight heparin. However, their efficacy is modest. This approach assumes that antithrombotic processes will impact on the disease outcome, yet the contribution of thrombosis may be highly variable. The benefits of intervention with antithrombotic agents may be best seen in those women where thrombosis is a major factor in the pathophysiology. Identifying those women most likely to benefit from treatment would allow stratification of treatment based on disease process, which in turn may provide more effective use of interventions. Such a stratified or precision medicine approach is already widely used in cancer care, where the direction of oncological research has moved away from analysis of treatment response in cohorts sharing the same diagnosis based on the organ affected and tumor histology, to treatment based on biomarkers specific to the molecular pathology of the tumor. It may now be time for obstetrics to adopt such a personalized medicine approach. However, this requires a biomarker with clinical utility to guide treatment. Recent research suggests that ANXA5 may be such a biomarker.

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.

The authors wish to point out that there is an error in the Abstract (Findings paragraph) of this article, whereby the 47.7% for male ANXA5 M2 only should have been 58.3%, as is in Table 5 and in Results section of the article. The correct Findings paragraph of the Abstract should read as follows: 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 (58.3% vs. 25.0% p = 0.045). 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 OutcomePragmatic 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. Full-Text PDF Open Access

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.

Citing the case of a 38-year-old woman with a BMI of 36 kg/m2 is admitted at 36 weeks of gestation with pre-eclampsia, this chapter discusses the challenges in managing patients at high risk of venous thrombosis (VTE). VTE is associated with substantial morbidity and mortality and varies depending on patient and procedural risk factors. The mechanisms of venous thromboembolism risk in surgical patients are described by Virchow's triad: venous stasis, endothelial injury, and hypercoagulability. These three factors can influence both procedure-related risks and patient-related risks. The chapter also talks about obstetric surgery, management, specific high-risk obstetric situations, specific high-risk gynecologic situations, and case resolution of patients with VTE. The benefits of thromboprophylaxis always have to be balanced against the risks of complications from perioperative bleeding; therefore it is necessary to conduct a careful presurgical risk assessment.

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.

Abstract The management of women with recurrent miscarriage (3 or more consecutive miscarriages) remains challenging, particularly the inability to identify a clear cause in the majority of cases, and lack of proven intervention. All too often, clinicians are tempted to order an indiscriminate battery of tests for these women which guide neither prognosis nor treatment, rather than undertake a thorough clinical assessment and targeted investigation. Moreover, such women are often recommended treatment which lacks clear evidence for benefit. Describing a case of a woman who suffers 5 consecutive miscarriages, this case explores the evidence base behind various laboratory tests, imaging studies, and treatments for recurrent miscarriage, as well as the need for further research in this area.