4. Special Considerations in the Longterm Management of Individuals with Cerebral Venous Thrombosis

CVT during pregnancy and puerperium is estimated to be 9 per 100,000 deliveries per year, accounting for approximately one-third of pregnancy-related stroke (Swartz et al. 2017). Among women who had sustained a prior CVT, the rate of recurrent CVT is much higher (9 per 1,000 pregnancies), which is approximately 80 times higher than would be expected in the general population (Aguiar de Sousa et al. 2016).

People with lived experienced emphasized the importance of receiving information about CVT and pregnancy that was relevant and tailored to their needs and life goals, as well as delivered at an appropriate time for the individual when they feel ready for such conversations. Information on the possibility of heavy menstrual bleeding on anticoagulation, and referrals to appropriate specialists should this occur, was also highly valued by individuals who menstruate and who were initiating anticoagulation. Individuals with CVT highlighted the importance of receiving information on risk associated with certain medications (e.g., OCP) and education on VTE symptoms for the general population.

1. Systems in place to enable women who become pregnant or are planning pregnancy to access appropriate antenatal care. 
2. Collaborative relationships established between obstetrical/maternal-fetal medicine, thrombosis experts, and stroke specialists to optimize access and management for women who experience CVT before, during or immediately after pregnancy.
3. Protocols to ensure rapid transfer of individuals with CVT who are pregnant to a centre with CVT and obstetrical services available.

System Indicators: 

1. Number of women who experience a CVT during pregnancy or within 6 weeks postpartum. 
2. Proportion of women with a past history of CVT who experience a recurrent stroke (any subtype) during pregnancy or early postpartum. 
   

Process Indicators: 

3. Proportion of women with a history of CVT who are considering becoming pregnant or are pregnant who receive a referral to specialist care.
4. Proportion of women with a history of CVT who are prescribed anticoagulant prophylaxis with LMWH during a subsequent pregnancy.

Patient-oriented outcome and experience indicators: 

5. Pregnancy-related maternal mortality and morbidity (venous thromboembolism, disability, postpartum hypertension) in women with a past history of CVT. 
6. Proportion of women who experience CVT during pregnancy resulting in adverse fetal and neonatal outcomes (congenital anomalies, preterm delivery, perinatal and intrapartum fetal morbidity and mortality).
7. Descriptive statistics of CVT during pregnancy, including proportion of CVT occurring in each trimester, median gestational age at time of stroke, and maternal stroke severity as a result of CVT.

Measurement Notes

None

Resources and tools listed below that are external to Heart & Stroke and the Canadian Stroke Best Practice Recommendations may be useful resources for stroke care. However, their inclusion is not an actual or implied endorsement by the Canadian Stroke Best Practices writing group. The reader is encouraged to review these resources and tools critically and implement them into practice at their discretion.

Healthcare provider information

• Canadian Stroke Best Practices Management of Acute Stroke during Pregnancy Consensus Statement
• CVT Consortium
• Stroke Engine

Information for individuals with lived experience of stroke, including family, friends and caregivers

• Heart & Stroke: Cerebral Venous Thrombosis Infographic
• Heart & Stroke: Signs of stroke
• CVT Consortium
• Heart & Stroke: FAST Signs of Stroke...what are the other signs?
• Heart & Stroke: What is stroke? 
• Heart & Stroke: Your stroke journey
• Heart & Stroke: Post-stroke checklist
• Heart & Stroke: Stroke in young adults: a resource for patients and families
• Heart & Stroke: Online and peer support
• Stroke Engine

Evidence Table and Reference List

Cerebral Venous Thrombosis and Pregnancy

Rates of pregnancy-associated CVT are estimated to be 9/100,000 pregnancies. A meta-analysis of 13 studies found that after a pregnancy-associated CVT, risk of VTE recurrence during a subsequent pregnancy was 9/1,000 (95% CI 3-33) for CVT and 27/1,000 (95% CI 12-61) for peripheral VTE pregnancies. Rate of spontaneous abortion did not differ from that of the general population. The authors concluded that the absolute risk of pregnancy-associated VTE was low, but substantially higher (16-fold risk of CVT and 80-fold risk of VTE) compared to the general population (Aguiar de Sousa et al. 2016). An update to the meta-analysis found a trend towards lower rates of VTE in patients receiving antithrombotic thromboprophylaxis with LMWH in both pregnancy and the puerperium (Aguiar de Sousa et al. 2018a).

Another study assessing recurrent VTE in pregnancy in women with a history of CVT interviewed 119 women who were pre-menopausal at the time of their CVT (10% pregnancy-associated CVT, 24% OCP-associated CVT) at a median of 14 years following their first event. There was 1 recurrent CVT among 82 pregnancies during follow-up (12 per 1000 pregnancies; 95% CI, 2–66) in a woman during her first trimester with protein S deficiency receiving prophylaxis with LWMH. Two other women experienced non-cerebral VTE associated with pregnancy, both in the post-partum period (24 per 1000 pregnancies; 95% CI, 7–85). One woman with recurrence had protein S deficiency and the event occurred on LMWH; the other had an event recovering from Cesarian section and was not on LMWH prophylaxis. 

Prophylactic anticoagulation during pregnancy and the puerperium is indicated in women who experienced a CVT and are no longer on anticoagulation (Saposnik et al. 2024). The Highlow trial examined dosing regimens for prophylaxis during pregnancy (Bistervels et al. 2022). The trial recruited 1110 women with a history of venous thromboembolism who were currently pregnant and at a gestational age of 14 weeks or less. Participants were randomized 1:1 to weight-adjusted intermediate-dose vs. fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks postpartum. The trial was powered for superiority and the primary efficacy outcome was confirmed VTE recurrence. The primary safety outcome was major bleeding in the antepartum, early post-partum (within 24 h after delivery), and late postpartum (24 h or longer after delivery until 6 weeks postpartum) periods. There were 11 (2%) VTE events (5 antepartum, 6 postpartum) in the intermediate-dose group and in 16 (3%, 5 antepartum, 11 postpartum) in the low-dose group (RR 0.69 (95% CI 0·32–1·47). On-treatment major bleeding (N=1045) occurred in 23 (4%) in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16; 95% CI 0·65–2·09). The authors concluded that fixed low-dose prophylaxis was appropriate given the lack of superiority of a higher-dose strategy. Co-management of pregnant patients with a history of CVT is recommended with thrombosis and maternal-fetal medicine experts.

Anticoagulation and heavy menstrual bleeding

Heavy menstrual bleeding (HMB) or abnormal uterine bleeding (which includes HMB and other differences in frequency, regularity or duration of bleeding) is estimated to occur in 70% of menstruating individuals who are on anticoagulation (De Crem et al. 2015; Micaily and Samuelson Bannow 2021). Underreporting and underascertainment, (Weyand and James 2021) as well as definitions for bleeding events in clinical trials, (Boonyawat et al. 2021) have been barriers in assessing prevalence of this issue with anticoagulation. Multiple definitions, including quantitative measures of blood loss, have been used but may be cumbersome for regular use (Zakherah et al. 2011). A more recent pragmatic definition used by international organizations is “excessive menstrual blood loss which interferes with physical emotional social and material quality of life, and which can occur alone or in combination with other symptoms ”(Fraser et al. 2011).

HMB is associated with reduced quality of life (Lancastle et al. 2023) and can potentially worsen iron deficiency and anemia. One single-centre study identified an increased risk of VTE with HMB, likely due to associated issues with adherence to anticoagulation (Bryk et al. 2016). Importantly, HMB in patients on anticoagulation is treatable (DeLoughery and Bannow 2022). Collaborative management with gynecology and thrombosis medicine is encouraged. Options can include reinitiation or continuation of hormonal therapy while patients are anticoagulated, which is not associated with increased risk of recurrent VTE and reduces risk of bleeding, or procedural management, including endometrial ablation (DeLoughery and Bannow 2022). Evidence to support safety of continued use of oral contraception on anticoagulation after VTE comes from post-hoc analyses of DOAC trials for VTE. Use of oral contraception was not randomized. A sub analysis of 1888 women aged 60 and younger in the EINSTEIN-DVT and PE trials found that hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation (3.7% versus 4.7%, aHR 0.56, 95% CI 0.23 - 1.39) (Martinelli et al. 2016). A similar post-hoc analysis of the RE-COVER trial in 1264 women aged 18-50 found no association between hormonal contraception and VTE recurrence during anticoagulation (OR 0.59, 95% CI 0.20 - 1.72) (Huisman et al. 2018).  However, an international multicentre case-control study of VTE on oral contraceptives identified that the thrombogenic effect of estrogen-containing contraceptives persists within the three months following discontinuation (Venous thromboembolic disease and combined oral contraceptives: Results of international multicentre case-control study. World health organization collaborative study of cardiovascular disease and steroid hormone contraception 1995). Thus, timing of cessation may need to be considered in patients who continue oral contraceptives while on temporary treatment with anticoagulation (Schulman 2016). The safety and efficacy of other strategies used in clinical practice or in individuals with HMB without a history of VTE, including antifibrinolytics, (Hamulyák et al. 2021) and modification of anticoagulation (temporary lower dosing or interruption of therapy), are under investigation (DeLoughery and Bannow 2022). 

Factor Xa inhibitors, but not dabigatran, a direct thrombin inhibitor, have been reported to have higher rates of abnormal uterine bleeding compared to VKA (Brekelmans et al. 2017; Hamulyák et al. 2021; Huisman et al. 2018; Martinelli et al. 2016; Scheres et al. 2018). The ongoing MEDEA trial is randomizing menstruating individuals on Factor Xa inhibitors 1:1:1 to a switch to dabigatran versus current therapy with tranexamic acid 1000 mg tid for four days starting on the first day of the menstrual period, versus current anticoagulant therapy alone. The primary outcome is the difference on the pictorial blood loss assessment chart (PBAC), a validated semi-quantitative score for menstrual product used pre- versus post-intervention.