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

Published:November 16, 2021DOI:



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


      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.


      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.


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Heit JA
        • Kobbervig CE
        • James AH
        • Petterson TM
        • Bailey KR
        • Melton LJ
        Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study.
        Ann Intern Med. 2005; 143: 697-706
        • Rodger MA
        • Hague WM
        • Kingdom J
        • 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; 384: 1673-1683
        • James AH
        • Jamison MG
        • Brancazio LR
        • Myers ER
        Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality.
        Am J Obstet Gynecol. 2006; 194: 1311-1315
        • Pabinger I
        • Grafenhofer H
        • Kyrle PA
        • et al.
        Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism.
        Blood. 2002; 100: 1060-1062
      1. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. 2018;39(34):3165-3241.

        • Bates SM
        • Middeldorp S
        • Rodger M
        • James AH
        • Greer I
        Guidance for the treatment and prevention of obstetric-associated venous thromboembolism.
        J Thromb Thrombolysis. 2016; 41: 92-128
        • Bates SM
        • Rajasekhar A
        • Middeldorp S
        • et al.
        American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
        Blood Adv. 2018; 2: 3317-3359
        • Yarrington CD
        • Valente AM
        • Economy KE
        Cardiovascular management in pregnancy.
        Circulation. 2015; 132: 1354-1364
        • Greer IA
        • Nelson-Piercy C
        Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy.
        Blood. 2005; 106: 401-407
        • Romualdi E
        • Dentali F
        • Rancan E
        • et al.
        Anticoagulant therapy forvenous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature.
        J Thromb Haemost. 2013; 11: 270-281
        • Roeters Van Lennep JE
        • Meijer E
        • Klumper FJCM
        • Middeldorp JM
        • Bloemenkamp KWM
        • Middeldorp S
        Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective?.
        J Thromb Haemost. 2011; 9: 473-480
        • Galambosi PJ
        • Ulander V-M
        • Kaaja RJ
        The incidence and risk factors of recurrent venous thromboembolism during pregnancy.
        Thromb Res. 2014; 134: 240-245
        • Greer IA
        • Nelson-Piercy C
        Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy.
        Blood. 2005; 106: 401-407
        • Cox S
        • Eslick R
        • McLintock C
        Effectiveness and safety of thromboprophylaxis with enoxaparin for prevention of pregnancy-associated venous thromboembolism.
        J Thromb Haemost. 2019; 17: 1160-1170
        • Bates SM
        • Greer IA
        • Middeldorp S
        • Veenstra DL
        • Prabulos A-M
        • Vandvik PO
        VTE, thrombophilia, antithrombotic therapy, and pregnancy.
        Chest. 2012; 141: e691S-e736S
        • Bapat P
        • Pinto LSR
        • Lubetsky A
        • et al.
        Examining the transplacental passage of apixaban using the dually perfused human placenta.
        J Thromb Haemost. 2016; 14: 1436-1441
        • Bapat P
        • Pinto LSR
        • Lubetsky A
        • Berger H
        • Koren G
        Rivaroxaban transfer across the dually perfused isolated human placental cotyledon.
        Am J Obstet Gynecol. 2015; 213: 710.e1-710.e6
        • Beyer-Westendorf J
        • Michalski F
        • Tittl L
        • et al.
        Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting.
        Thromb Haemost. 2016; 116: 651-658
        • Hoeltzenbein M
        • Beck E
        • Meixner K
        • Schaefer C
        • Kreutz R
        Pregnancy outcome after exposure to the novel oral anticoagulant rivaroxaban in women at suspected risk for thromboembolic events: a case series from the German Embryotox Pharmacovigilance Centre.
        Clin Res Cardiol. 2016; 105: 117-126
        • Lameijer H
        • Aalberts JJJ
        • van Veldhuisen DJ
        • Meijer K
        • Pieper PG
        Efficacy and safety of direct oral anticoagulants during pregnancy; a systematic literature review.
        Thromb Res. 2018; 169: 123-127
        • Beyer-Westendorf J
        • Naue C
        • Tittl L
        • Marten S
        Outcome of DOAC exposure during pregnancy (…and the problem of event reporting…).
        Res Pract Thromb Haemost. 2020; 4: 32
        • Andersen JS
        • Olivarius NDF
        • Krasnik A
        The Danish National Health Service Register.
        Scand J Public Health. 2011; 39: 34-37
        • Schmidt M
        • Schmidt SAJ
        • Sandegaard JL
        • Ehrenstein V
        • Pedersen L
        • Sørensen HT
        The Danish National Patient Registry: a review of content, data quality, and research potential.
        Clin Epidemiol. 2015; 7: 449-490
        • Pottegård A
        • Schmidt SAJ
        • Wallach-Kildemoes H
        • Sørensen HT
        • Hallas J
        • Schmidt M
        Data resource profile: the Danish National Prescription Registry.
        Int J Epidemiol. 2017; 46 (798-798f)
        • Schmidt M
        • Pedersen L
        • Sørensen HT
        The Danish Civil Registration System as a tool in epidemiology.
        Eur J Epidemiol. 2014; 29: 541-549
        • Bliddal M
        • Broe A
        • Pottegård A
        • Olsen J
        • Langhoff-Roos J
        The Danish Medical Birth Register.
        Eur J Epidemiol. 2018; 33: 27-36
        • Sundbøll J
        • Adelborg K
        • Munch T
        • et al.
        Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study.
        BMJ Open. 2016; 6e012832
        • Schmidt M
        • Cannegieter SC
        • Johannesdottir SA
        • Dekkers OM
        • Horváth-Puhó E
        • Sørensen HT
        Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case-control study.
        J Thromb Haemost. 2014; 12: 1207-1215
        • Bird ST
        • Toh S
        • Sahin L
        • et al.
        Misclassification in assessment of first trimester in-utero exposure to drugs used proximally to conception: the example of letrozole utilization for infertility treatment.
        Am J Epidemiol. 2019; 188: 418-425
        • Albertsen IE
        • Nielsen PB
        • Søgaard M
        • et al.
        Risk of recurrent venous thromboembolism: a Danish nationwide cohort study.
        Am J Med. 2018; 131: 1067-1074.e4
        • van Driel D
        • Wesseling J
        • Sauer PJJ
        • Touwen BCL
        • van der Veer E
        • Heymans HSA
        Teratogen update: fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis.
        Teratology. 2002; 66: 127-140
        • Schaefer C
        • Hannemann D
        • Meister R
        • et al.
        Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study.
        Thromb Haemost. 2006; 95: 949-957
        • Pedersen LH
        • Petersen OB
        • Nørgaard M
        • et al.
        Linkage between the Danish National Health Service Prescription Database, the Danish Fetal Medicine Database, and other Danish registries as a tool for the study of drug safety in pregnancy.
        Clin Epidemiol. 2016; 8: 91-95
        • Larsen H
        • Nielsen GL
        • Bendsen J
        • Flint C
        • Olsen J
        • Sørensen HT
        Predictive value and completeness of the registration of congenital abnormalities in three Danish population-based registries.
        Scand J Public Health. 2003; 31: 12-16
        • Bain E
        • Wilson A
        • Tooher R
        • Gates S
        • Davis L-J
        • Middleton P
        Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period.
        Cochrane Database Syst Rev. 2014; CD001689
        • Cohen H
        • Arachchillage DR
        • Middeldorp S
        • Beyer-Westendorf J
        • Abdul-Kadir R
        Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH.
        J Thromb Haemost. 2016; 14: 1673-1676