Systemic hormonal contraception and risk of venous thromboembolism (May 2022)

The aim of this study was to evaluate the relationships between use of hormonal contraceptives (HC) and the risk of VTE. The cohort consisted of 587,559 fertile women aged 15-49 years and were followed from 2017-2019.

There were 1334 VTE cases observed during the follow-up period, 838 were lower extremity thrombosis, 293 PE, 188 inferior vena cava (caval) thrombosis, eight portal and seven cerebral thrombosis. In the 2017 group there were 782 VTE cases among the HC users compared to 552 in the non-users group. The highest incidence rate was among those aged 40–44 years.

The results also found an increased risk (two-fourfold) of VTE when using combined hormonal contraception containing ethinylestradiol with either third generation progestins or drospirenone. Alternatively, the research found the use of individual estradiol-containing combined preparations or progestin-only contraception was not associated with a modified risk of VTE. Another finding was that none of the individual combined preparations containing natural estradiol or estradiol valerate were linked to an altered risk of VTE (except for cyproterone and estrogen which showed a slightly elevated risk).

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The risk of venous thromboembolism in early pregnancy loss: Review of the literature and current guidelines and the need for guidance (March 2022)

Thromboembolic disease is one of the major causes of mortality and morbidity in pregnancy with VTE risk increasing from conception. With early pregnancy loss common, this review evaluated the uncertainty surrounding the risk of VTE during this event.

The review analysed guidelines from North America, Canada, Australia, Sweden, UK and Ireland. Despite the increased risk of VTE during pregnancy, information relating to the management and evaluation of this risk in early pregnancy loss is lacking. There are studies which suggest this increased risk starts in the first trimester and contributing factors to VTE risk include vascular injury during surgical management of ectopic pregnancy, miscarriage or surgical termination of pregnancy.

It is difficult to conduct large-scale studies among this group, however utilising international registries through ISTH may be a move forward. The development of a pregnancy-specific risk scoring system among women with early pregnancy loss is also recommended.

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Management of venous thromboembolism in pregnancy (March 2022)

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are major factors of maternal mortality; therefore, a detailed assessment of all pregnant women can establish a risk profile that would guide clinical decisions. Timely and accurate diagnosis of VTE is essential for its management 

This review investigated management of VTE in pregnancy and the postpartum period. It is imperative to diagnose DVT early as it has the potential to develop into PE. This is a challenge as some of the symptoms of DVT can mimic pregnancy associated indications such as lower extremity oedema, and pelvic and back pain. Three clinical parameters were proposed: (i) left lower extremity symptoms, (ii) difference in calf circumference of more than 2cm and (iii) presentation in first trimester. For the precise and timely diagnosis of PE patient history and physical examination is important along with laboratory examination and diagnostic imaging.

Anticoagulant therapy is the preferred treatment option for most cases of VTE among pregnant women and is recommended to commence treatment once diagnosed. Therapy should continue for 3-6 months including the puerperium period. Low molecular weight heparin (LMWH) is the optimal choice as it does not cross the placenta and has not been linked with fetal hemorrhage.

Any decisions should be supported by guideline recommendations, with careful consideration of benefits and risks for both the mother and the developing fetus. The risk of systemic anticoagulation needs to be balanced against the risk of VTE-associated morbidity and mortality.

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Management of anticoagulation in pregnant women with venous thromboembolism: An international survey of clinical practice (Feb 2022)

Pregnant women are more at risk of venous thromboembolism (VTE) and VTE is associated with maternal morbidity and mortality. Low-molecular-weight-heparin (LMWH) is the common anticoagulant used to treat VTE during pregnancy. There is a lack of studies assessing the ideal duration and peripartum management of anticoagulant therapy, therefore this electronic survey was created to assess clinical situations for the management of anticoagulation in pregnant women with acute VTE.

The 96 respondents comprised of haematologists, obstetricians, general internists and other specialists. The survey was designed to assess clinician practices, determine variation practice patterns, and assess the perception of bleeding risk associated with the use of anticoagulant therapy for acute VTE throughout pregnancy.

Most respondents prescribe anticoagulation therapy throughout the pregnancy and for 6 weeks postpartum despite which trimester the VTE occurred. If the VTE occurred in the first trimester, 48% of respondents chose to reduce the anticoagulation dose after 3 or 6 months and for the second trimester 37.5% decided to reduce the dose. When treating a VTE in the third trimester, 29.2% of physicians chose bridging with intravenous heparin around delivery time. With regards to bleeding risk, 60.0% of respondents identified an increased risk of antepartum clinically relevant non-major bleeding (CRNMB) and 73.0% perceived an increased risk of CRNMB peripartum and immediately postpartum. However, there is contradictory evidence to support the low risk of bleeding antepartum and postpartum.

This survey emphasises the range of variability in the management of therapeutic anticoagulation during pregnancy. Large scale studies with applicable clinical outcomes involving thrombosis and bleeding risks are warranted.

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Adenovirus-Based Vaccines and Thrombosis in Pregnancy: A Systematic Review and Meta-analysis (Feb 2022)

There have been rare cases of thrombosis and thrombocytopenia (TTS) associated with the AstraZeneca and Johnson & Johnson COVID-19 vaccine. As most cases of TTS occurs in women of childbearing age, pregnancy as an important risk factor was investigated.

The review included studies from 1966 to 2021 and from 28 studies containing 1731 women. Analysis comprised of adenovirus-based vector vaccines to document cases of thrombocytopenia and coagulopathy. Over this period of time, no coagulopathy events were reported.

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Systematic review and meta-analysis of the effectiveness and perinatal outcomes of COVID-19 vaccination in pregnancy (Jan 2022)

This review included 54 relevant studies reporting on 117,552 vaccinated pregnant women and found the mRNA vaccines appear highly effective against SARS-CoV-2 in pregnancy. The incidence of adverse pregnancy outcomes was not increased among vaccinated compared with unvaccinated pregnancies. There was no increased risk of miscarriage following COVID-19 vaccination and the incidence of stillbirths was also significantly lower.

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D-dimer level significance for deep vein thrombosis screening in the third trimester: a retrospective study (Jan 2022)

VTE is a common occurrence after surgery and childbirth, and although early detection of DVT has shown to predict pulmonary embolism, there is a lack of screening methods available to identify DVT among pregnant women. This study examined D-dimer levels among 497 pregnant women from mid-pregnancy to postpartum examination from 2013 to 2019. The researchers utilised serum D-dimer levels as a screening tool and lower-limb compression ultrasonography to determine frequency of asymptomatic DVT.

D-dimer levels increase during pregnancy, and researchers cannot agree on what the correct cut-off value should be to understand what increases the risk of thromboembolism among this group. This study used D-dimer levels ≥ 3 μg/ml and found that no DVT was evident among participants. Also, none of the patients presented with VTE within 4 postoperative weeks. Therefore, it was concluded there may be low effectiveness or practicality in using D-dimer levels as a prescreening tool for VTE risk.

As none of the participants presented with high-risk factors which cause raised D-dimer levels, a multivariant analysis was carried out on low-risk factors for VTE which had a high frequency (age ≥35 years; BMI ≥25 kg/m2; history of hospitalisation during pregnancy; multiple pregnancies; and hypersensitive disorder of pregnancy (HDP). HDP was identified to be a high risk for DVT.

The study did find that postoperative anticoagulation may be useful for women after having a cesarean section. The risk of VTE after a cesarean section (CS) increases 3.7-fold compared to vaginal delivery. D-dimer levels of ≥10μg/ml the day after CS is considered high risk of DVT; however, administration of enoxaparin at the time could prevent DVT. The research team administered enoxaparin in 36.2% of patients after CS, with none showing VTE.

[A systematic review and meta-analysis also found investigating D-dimer levels could potentially be a useful and safe method to rule out VTE in non-high-risk pregnant women, without the need for imaging. Physiologically, D-dimer levels increase during pregnancy, therefore it is essential that a determined cut-off value be established. Bellessini, M. et al., October 2021. D-dimer to rule out venous thromboembolism during pregnancy. J. Thromb Haemost. DOI:10.1111/jth.15432]

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Bleeding issues in women prescribed anticoagulation (Dec 2021)

Women taking anticoagulants or their physician is considering prescribing them to treat or reduce the risk of thrombosis should be aware of the associated implications of abnormal uterine bleeding (AUB). Up to a third of women of childbearing age will experience AUB or excessive bleeding in their lifetime. Women that experience AUB may consider discontinuing anticoagulation therapy which could then increase the risk of VTE recurrence.

This paper investigated views on best practice and ideal management of VTE risk, oral contraception and AUB from expert opinion and clinical practitioners and found differing opinions and directives. More than 70% of thrombosis experts agree with continuing oral contraception while on anticoagulation therapy. However, those in clinical practice would discontinue contraceptives upon a VTE event. The articles suggests that the option to withhold anticoagulants should be determined by an individual’s risk of thrombosis and the severity of their bleeding.

Ongoing research is also looking to identify the best types of anticoagulation with studies comparing Rivaroxaban and Apixaban; and Factor Xa inhibitor treatment. The PERIOD study will look to develop optimal administration and advice for women affected by abnormal or excessive bleeding after the commencement of anticoagulation treatment for VTE.

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VTE and anticoagulation in menstruating women (Dec 2021)

Women of childbearing age have a high prevalence of venous thromboembolism (VTE), due to high oestrogen levels associated with pregnancy and oestrogen-containing contraceptives. Post-menopausal women using hormone replacement therapy are also at an increased risk of VTE.

Oral anticoagulants (OAC) are often the treatment option to reduce the risk of VTE among this group. OACs reduce the risk of thrombotic events, however they can also increase bleeding. Finding a balance between potentially escalating menstrual bleeding and that of thrombosis risk can be difficult. AUB affects one-third of menstruating women and this increases to approximately 70% for those on OACs.

Rivaroxaban and apixaban are the most prescribed OACs. Research has shown that Rivaroxaban has a higher incidence of excess bleeding or AUB and adjustments to dose may be warranted.

Women who are on OACs and are planning to become pregnant, the type of OAC is important. Generally, unfractionated heparin or low molecular weight heparin (LMWH) is the preferred OAC as they cannot cross the placental barrier. Warfarin, dabigatran, apixaban, rivaroxaban and edoxaban should be avoided, and if a woman is on one of these and becomes pregnant, it is recommended to switch to LMWH.