Assessing the Gravidy of Direct Oral Anticoagulants in Pregnancy

The safety and efficacy of direct oral anticoagulants (DOACs) is not well characterized in pregnancy, as published randomized controlled trials have excluded pregnant women. Apixaban, dabigatran, edoxaban, and rivaroxaban are all considered to have unknown or unproven safety during human pregnancies and are known to cross the placenta.^1-4  Apixaban is considered “Pregnancy Class B” by the U.S. Food and Drug Administration, whereas the others are considered “Pregnancy Class C” based on animal studies. Current recommendations for patients on a DOAC who are planning pregnancy are to transition to low-molecular-weight heparin (LMWH). For patients with unplanned pregnancy on a DOAC, the recommendation is to transition to LMWH when discovered but not to terminate the pregnancy based on concern for fetal malformations.¹ 

In this study, Dr. Jan Beyer-Westendorf and colleagues expand on previous work⁵  and add significantly to our knowledge of pregnancy risk with DOAC exposure. They performed a retrospective cohort study obtaining data from multiple sources including case reports from specialists using standardized questionnaires, pharmacovigilance databases from pharmaceutical drug manufacturers, and multinational regulatory agencies. Data collected included mother’s age, indication for DOAC treatment, date of confirmed pregnancy, details of pregnancy outcome (miscarriage, termination, or delivery), and details on health and status of the child (height and weight, anatomical abnormalities, and organ dysfunction). Data were reviewed by two independent physicians, and all confirmed or possibly duplicated reports were excluded. Any fetal or neonatal abnormalities were reviewed by two independent teratology experts with classification into four categories based on relation to DOAC exposure (likely, possible, unlikely, or unrelated).

A total of 1,193 pregnancies were evaluated, and after exclusion of duplicates, 614 unique pregnancies were examined (apixaban [n=50], dabigatran [n=36], edoxaban [n=23], rivaroxaban [n=505]) with exposures between February 1, 2007, and July 9, 2020. Outcomes were known in only 336 of these pregnancies, with 188 resulting in live births, 74 in miscarriages, and 74 in elective pregnancy terminations. Most women were on DOACs for treatment or prevention of venous thromboembolism (VTE; 94%) and the median exposure during the pregnancy was 5.3 weeks (interquartile range, 4.0-7.0). A congenital or acquired thrombophilia was present in 42 women, and 39 had experienced a prior miscarriage. Fetal abnormalities occurred in 21 (6%) of these pregnancies, of which 15 were classified as major birth defects. Adjudication of these events determined that 12 (4%) were possibly related to DOAC exposure. The authors conclude that major birth defects seem to be lower with DOACs than what has been previously reported for warfarin (7.4%-10.8%), with no specific birth defect pattern observed, and overall miscarriage rates similar to the general population.⁶