Clinical Research StudyFirst Trimester Anticoagulant Exposure and Adverse Pregnancy Outcomes in Women with Preconception Venous Thromboembolism: A Nationwide Cohort Study
Introduction
Venous thromboembolism, which refers to deep venous thrombosis plus pulmonary embolism, is a concern in women of childbearing age. Pregnancy is associated with a hypercoagulable state, such that pregnant women carry a four- to fivefold higher risk of venous thromboembolism compared with the general female population of reproductive age.1 Venous thromboembolism incidence during pregnancy ranges from 0.6-2.0 events per 1000 deliveries,1,2 with higher incidence in patients at high baseline risk such as thrombophilia or previous venous thromboembolism. In fact, the venous thromboembolism risk is nearly 25-fold higher in women with a history of venous thromboembolism;2, 3, 4 therefore, anticoagulant prophylaxis is generally recommended for pregnant women with prior venous thromboembolism,5, 6, 7 and is absolutely indicated for women with venous thromboembolism within 3 months prior to conception. However, it remains challenging to find a balance between maternal risk of recurrent venous thromboembolism and bleeding and ensuring fetal safety.
Low-molecular-weight heparin (LMWH) is recommended for venous thromboembolism prevention and treatment during pregnancy5,6 because it does not cross the placenta and appears safe for the fetus.8,9 However, although the literature about LMWH in pregnancy is generally reassuring, this recommendation is largely based on case reports, case series of few pregnant women, or findings extrapolated from studies of non-pregnant women. Moreover, maternal anticoagulation may be suboptimal, and the adequate monitoring methods and intervals remain controversial.10, 11, 12, 13, 14 Vitamin K antagonists (VKAs) cross the placenta and are associated with teratogenicity, pregnancy loss, and fetal bleeding,8,15 and thus are not recommended for venous thromboembolism in pregnancy.5 Non-VKA oral anticoagulants (NOACs) also cross the placenta,16,17 and may carry a risk of fetal hemorrhage or embryopathy, although data on this topic are scarce.18, 19, 20 Current guidelines recommend against NOACs during pregnancy. However, with increasing use of NOACs for venous thromboembolism treatment—including in women of childbearing age—there is a growing risk of inadvertent NOAC exposure during early pregnancy.21 Thus, there is a clear need for up-to-date data on the safety of anticoagulant exposure during early pregnancy.
Here we performed a nationwide cohort study of pregnant women with preconception venous thromboembolism. We described exposure to anticoagulation therapy during pregnancy, and investigated whether first trimester anticoagulant exposure was associated with adverse pregnancy outcomes.
Section snippets
Methods
We conducted a cohort study of all pregnant women in Denmark who had preconception venous thromboembolism from 2000-2017. From linked nationwide health registries, we collected individual-level information about the pregnant women and their fetuses.
Results
After exclusions, this study included 5041 pregnancies among 3251 women with preconception venous thromboembolism at the time of the first antenatal GP consultation, resulting in 4418 births (Figure 1).
Principal Findings
This nationwide cohort study included over 5000 pregnancies among about 3200 women with preconception venous thromboembolism over an 18-year period. Our analysis revealed increasing use over time of anticoagulants during pregnancy in women with preconception venous thromboembolism. LMWH was the predominantly prescribed agent. Among initially untreated women, 30%-34% started treatment with LMWH, and among patients initially treated with VKA or NOAC, 40%-50% were switched to LMWH after the first
Conclusions
Understanding the balance of benefits and risks to the mother and fetus is imperative for providing adequate pre-conceptive counseling. However, for clinicians caring for women who require anticoagulation during pregnancy, the competing potential harm and benefits, and the limitations of the currently available evidence create a challenging dilemma. It is unclear how best to provide adequate anticoagulation of the mother while ensuring fetal safety. In the present study, fetal risk was lowest
Acknowledgment
The analyzed data were provided by the Danish Health Data Authority.
References (36)
- et al.
Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): A multinational open-label randomised trial
Lancet
(2014) - et al.
Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality
Am J Obstet Gynecol
(2006) - et al.
Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism
Blood
(2002) - et al.
American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy
Blood Adv
(2018) - et al.
Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy
Blood
(2005) - et al.
Anticoagulant therapy forvenous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature
J Thromb Haemost
(2013) - et al.
Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective?
J Thromb Haemost
(2011) - et al.
The incidence and risk factors of recurrent venous thromboembolism during pregnancy
Thromb Res
(2014) - et al.
Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy
Blood
(2005) - et al.
Effectiveness and safety of thromboprophylaxis with enoxaparin for prevention of pregnancy-associated venous thromboembolism
J Thromb Haemost
(2019)
VTE, thrombophilia, antithrombotic therapy, and pregnancy
Chest
Examining the transplacental passage of apixaban using the dually perfused human placenta
J Thromb Haemost
Rivaroxaban transfer across the dually perfused isolated human placental cotyledon
Am J Obstet Gynecol
Efficacy and safety of direct oral anticoagulants during pregnancy; a systematic literature review
Thromb Res
Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case-control study
J Thromb Haemost
Risk of recurrent venous thromboembolism: a Danish nationwide cohort study
Am J Med
Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH
J Thromb Haemost
Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study
Ann Intern Med
Cited by (4)
Novel Antithrombotic Agents in Pregnancy Anticoagulants and Antiplatelet Agents
2023, Clinical Obstetrics and GynecologyAnticoagulant Therapy in Patients with Antiphospholipid Syndrome
2022, Journal of Clinical MedicineLong-Term Management of Pulmonary Embolism: A Review of Consequences, Treatment, and Rehabilitation
2022, Journal of Clinical Medicine
Funding: This research was partly funded by an unrestricted grant from the Obel Family Foundation. The sponsor had no role in the study design and conduct; the data collection, management, analysis, and interpretation; the writing of the report; or the decision to submit the paper for publication.
Conflicts of Interest: MS and FS have received consulting fees from Bayer. PBN has received speaking fees from Boehringer Ingelheim, consulting fees from Bayer and Daiichi-Sankyo, and grant support from Bristol-Myers Squibb/Pfizer and Daiichi-Sankyo. JB-W has received research grants and honoraria for lectures and consultancy from Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Doasense, Pfizer, and Portola. TBL has served as an investigator for Janssen Scientific Affairs, LLC and Boehringer Ingelheim, and has received speaking fees from Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, MSD, and AstraZeneca.
Authorship: MS and FS are the guarantors; they had full access to all data in this study, and take responsibility for the data integrity and the accuracy of the data analysis. All authors contributed to the study design, analyzed and interpreted the data, drafted the article or critically revised it for important intellectual content, and approved the final version. MS: Data curation, formal analysis, funding acquisition, methodology, writing – original draft, review, and editing; FS: Data curation, formal analysis, funding acquisition, methodology, writing – original draft, review, and editing; PBN: Formal analysis, funding acquisition, methodology, writing – original draft, review, and editing; JB-W: Formal analysis, funding acquisition, methodology, writing – original draft, review, and editing; TBL: Formal analysis, funding acquisition, methodology, writing – original draft, review, and editing.
Paper presentation: An abstract based on parts of these data was presented at the European Society of Cardiology Congress 2019, Paris.