Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting

Summary

Today, direct oral anticoagulants (DOAC) are widely used alternatives to Vitamin-K antagonists (VKA). Women of reproductive age may become pregnant during anticoagulation and, while VKA carry an embryotoxic potential, the risk of DOAC embryopathy is unknown. As a result, some patients elect to terminate pregnancy for fear of DOAC embryotoxicity. To assess the risk of DOAC embryopathy, we reviewed cases of DOAC exposure in pregnancy collected from physicians, literature and pharmacovigilance systems of drug authorities and manufacturers. A total of 357 reports including duplicates were available from which 233 unique cases could be identified. Information on pregnancy outcome was available in only 137/233 cases (58.8 %): 67 live births (48.9 %); 31 miscarriages (22.6 %); 39 elective pregnancy terminations (28.5 %). In 93 cases (39.9 %) no outcome data were available (including 3 cases of ongoing pregnancy). Of the 137 pregnancies with reported outcomes, seven showed abnormalities (5.1 %) of which three (2.2 %) could potentially be interpreted as embryopathy: live birth with facial dysmorphism; miscarriage in week 10 with limb abnormality; elective pregnancy termination due to a foetal cardiac defect in a woman who had to terminate a previous pregnancy due to Fallot tetralogy. Within its limitations (small numbers, incomplete outcome data) our results do not indicate that DOAC exposure in pregnancy carries a high risk of embryopathy or that DOAC exposure per se should be used to direct patient counselling towards pregnancy termination. Pregnancy outcome data are inconsistently captured in pharmacovigilance databases indicating the strong need for a more robust system of reporting.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Pregnancy - direct oral anticoagulants - outcome

• References

• 1 Astedt B.. Thrombotic and hemostatic problems in pregnancy and labor and their significance for the fetus and newborn infant. Padiatr Padol 1990; 25: 43-53.
• 2 Bates SM, Ginsberg JS.. Anticoagulants in pregnancy: fetal effects. Baillieres Clin Obstet Gynaecol 1997; 11: 479-488.
• 3 Walfisch A, Koren G.. The „warfarin window” in pregnancy: the importance of half-life. J Obstet Gynaecol Can 2010; 32: 988-989.
• 4 Pauli RM, Hall JG.. Warfarin embryopathy. Lancet 1979; 02: 144.
• 5 Sathienkijkanchai A, Wasant P.. Fetal warfarin syndrome. J Med Assoc Thai 2005; 88 (08) S246-250.
• 6 Kumar M, Bhasker SK, Singh R. et al. Di Sala syndrome. Br Med J Case Rep. 2012 2012
• 7 Mehndiratta S, Suneja A, Gupta B. et al. Fetotoxicity of warfarin anticoagulation. Arch Gynecol Obstet 2010; 282: 335-357.
• 8 Hetzel PG, Glanzmann R, Hasler PW. et al. Coumarin embryopathy in an extremely low birth weight infant associated with neonatal hepatitis and ocular malformations. Eur J Pediatr 2006; 165: 358-360.
• 9 van Driel D, Wesseling J, Sauer PJ. et al Teratogen update: fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology 2002; 66: 127-140.
• 10 Iturbe-Alessio I, Fonseca MC, Mutchinik O. et al Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315: 1390-1393.
• 11 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.
• 12 Baglin T, Bauer K, Douketis J. et al. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2012; 10: 698-702.
• 13 van Es N, Coppens M, Schulman S. et al Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124: 1968-1975.
• 14 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-962.
• 15 Bapat P, Kedar R, Lubetsky A. et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol 2014; 123: 1256-1261.
• 16 Bapat P, Pinto LS, Lubetsky A. et al. Rivaroxaban transfer across the dually perfused isolated human placental cotyledon. Am J Obstet Gynecol 2015; 213: 710 e1-6.
• 17 SmPC rivaroxaban, July. Available at: http://www.medicines.org.uk/emc/medicine/25586/SPC Accessed January 6, 2016
• 18 SmPC apixaban, October. Available at: http://www.medicines.org.uk/emc/medicine/24988 Accessed January 6, 2016
• 19 SmPC dabigatran, September. Available at: http://www.medicines.org.uk/EMC/medicine/24839/SPC/Pradaxa+150 Accessed January 6, 2016
• 20 SmPC edoxaban, July. Available at: http://www.medicines.org.uk/emc/medicine/30512 Accessed January 6, 2016
• 21 Konigsbrugge O, Langer M, Hayde M. et al. Oral anticoagulation with riva-roxaban during pregnancy: a case report. Thromb Haemost 2014; 112: 1323-1324.
• 22 Hoeltzenbein M, Beck E, Meixner K. et al. 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. 2015 Epub ahead of print.
• 23 US Food and Drug Administration, Center for Drug Evaluation and Research, 202155Orig1s000, Apixaban Clinical Review Addendum. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155orig1s000medr.pdf Accessed January 6, 2016
• 24 ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006; 107: 1453-1472.
• 25 Culwell KR, Curtis KM.. Use of contraceptive methods by women with current venous thrombosis on anticoagulant therapy: a systematic review. Contraception 2009; 80: 337-345.
• 26 Vaillant-Roussel H, Ouchchane L, Dauphin C. et al Risk factors for recurrence of venous thromboembolism associated with the use of oral contraceptives. Contraception 2011; 84: e23-30.
• 27 WHO. Medical Eligibility Criteria for Contraceptive Use, World Health Organization. 2010
• 28 Martinelli I, Lensing AW, Middeldorp S. et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood. 2015 Epub ahead of print.
• 29 Cohen H, Arachchillage D, Middeldorp S. et al. Management of Direct Oral Anticoagulants in Women of Childbearing Potential: Guidance from the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2016 Epub ahead of print.
• 30 Duhl AJ, Paidas MJ, Ural SH. et al. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol 2007; 197: 457.e1-21.
• 31 Bates SM, Greer IA, Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141. (02) e691S-736S.
• 32 Savitz DA, Hertz-Picciotto I, Poole C. et al. Epidemiologic measures of the course and outcome of pregnancy. Epidemiol Rev 2002; 24: 91-101.
• 33 Garcia-Enguidanos A, Calle ME, Valero J. et al Risk factors in miscarriage: a review. Eur J Obstet Gynecol Reprod Biol 2002; 102: 111-119.
• 34 Buss L, Tolstrup J, Munk C. et al. Spontaneous abortion: a prospective cohort study of younger women from the general population in Denmark. Validation, occurrence and risk determinants. Acta Obstet Gynecol Scand 2006; 85: 467-475.
• 35 Hothi DK, Wade AS, Gilbert R. et al. Mild fetal renal pelvis dilatation: much ado about nothing?. Clin J Am Soc Nephrol 2009; 04: 168-177.
• 36 Sewell MD, Rosendahl K, Eastwood DM.. Developmental dysplasia of the hip. Br Med J 2009; 339: b4454.
• 37 Irvine B, Luo W, Leon JA.. Congenital anomalies in Canada 2013: a perinatal health surveillance report by the Public Health Agency of Canada's Canadian Perinatal Surveillance System. Health Promot Chronic Dis Prev Can 2015; 35: 21-22.
• 38 SSC: Women's Health Issues in T&H. Available at: http://www.isth.org/members/group.aspx?id=100375 Accessed February 9, 2016
• 39 Wang L, He K, Maxwell B. et al. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos 2011; 39: 256-264.
• 40 Boehringer Ingelheim. Advisory committee briefing document on dabigatran etexilate. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisory-Committee/UCM226009.pdf Accessed May 24, 2016
• 41 Lock, IBD, Bayer HealthCare. INVESTIGATOR'S BROCHURE.. Available at: http://quovadis-ass.it/resources/Altre/Rivaroxaban_Investigator-Brochure_BAY-59–7939_V2L0.pdf Accessed May 24, 2016.