Clinical Research Study
First Trimester Anticoagulant Exposure and Adverse Pregnancy Outcomes in Women with Preconception Venous Thromboembolism: A Nationwide Cohort Study

https://doi.org/10.1016/j.amjmed.2021.10.023Get rights and content

Abstract

Objective

The purpose of this study was to investigate first trimester anticoagulant exposure and risks of adverse pregnancy-related and fetal outcomes.

Methods

Using Danish nationwide registries, we identified all pregnant women with preconception venous thromboembolism, 2000-2017, and linked data on exposure to low-molecular-weight heparin (LMWH), vitamin K antagonist (VKA), or non-VKA oral anticoagulant (NOAC) during pregnancy. We assessed pregnancy-related and fetal outcomes associated with first trimester anticoagulant exposure.

Results

Among 4490 pregnancies in women with preconception venous thromboembolism (mean age 31 years, 40% nulliparous) during the first trimester, 63.1% were unexposed, 25.9% were exposed to LMWH, 10.4% VKA, and 0.6% NOAC. Adverse outcomes were lowest in unexposed and LMWH exposed. Compared with unexposed, VKA was associated with higher risks of preterm (adjusted odds ratio [OR] 2.26; 95% confidence interval [CI], 1.70-2.99) and very preterm birth (adjusted OR 3.78; 95% CI, 1.91-7.49), shorter mean gestational age was associated with VKA (−7.5 days; 95% CI, −9.1 to −5.9 days) or NOAC (−2.3 days; 95% CI, −8.4-3.8), and lower mean birthweight with VKA (−55 g; 95% CI, −103.1 to −8.5) or NOAC (−190 g; 95% CI, −364.1 to −16.4). Adjusted ORs for small-for-gestational-age infants were 1.07 (95% CI, 0.77-1.50) with VKA, and 3.29 (95% CI, 1.26-7.95) with NOAC. Mean 5-minute Apgar score (9.8) and congenital defect prevalence (8.4%-10%) varied little across exposure groups.

Conclusions

Fetal risk was lowest in unexposed and LMWH-exposed pregnancies, supporting the recommendation of LMWH during pregnancy. NOAC safety during pregnancy is unclear due to the rarity of NOAC exposure.

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)

Cited by (4)

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.

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