The Transfer Of Dabigatran and Rivaroxaban Across a Dually Perfused Isolated Human Placental Cotyledon – Implications For Therapy In Pregnancy

Abstract

BackgroundAnticoagulant therapy is often required in cases of high-risk pregnancy for the prophylaxis of venous thromboembolism following surgery, atrial fibrillation, and congestive heart failure, and for the prevention of pregnancy loss in thrombophilic women. During pregnancy, the concentrations of many blood-clotting factors rise, thereby increasing the need for anticoagulants that are safe to use throughout gestation. Dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) are newer generation oral anticoagulants that are increasingly being prescribed to women of reproductive age for the treatment of thromboembolic disorders. Dabigatran acts by directly inhibiting thrombin, and rivaroxaban acts as a direct factor Xa inhibitor. However, the information regarding fetal safety and placental transfer of these drugs is currently lacking. If there is limited transfer of either drug across the placenta, then it may not increase the risk of bleeding in the fetus. The objective of this study was to determine the transplacental kinetics of dabigatran and rivaroxaban. MethodsPlacentae were obtained with informed consent after elective caesarean section of healthy term pregnancies in Toronto, Ontario. The transplacental transfer of dabigatran and rivaroxaban were separately assessed using ex vivo dual perfusion of an isolated human placental cotyledon. Dabigatran, at a concentration of 35 ng/ml, was added to the maternal circulation at the start of the experimental phase. Maternal and fetal samples were taken throughout the pre-experimental (1 h) and experimental (3 h) phases for measurement of dabigatran and markers of placental viability. Separate placenta perfusions with rivaroxaban were conducted at an initial maternal concentration of 250 ng/ml. The perfused drug was measured in maternal and fetal samples using liquid chromatography-mass spectrometry (LC/MS). ResultsThere was slow transfer of dabigatran from the maternal to fetal circulation. The fetal-to-maternal (F:M) concentration ratio was 0.33 ± 0.13 after 3 hours (n=3). In contrast, the transfer of rivaroxaban from maternal to fetal circulation was much more rapid, as characterized by a F:M ratio of 0.72 ± 0.12 at 3 hour (n=4), suggesting rapid equilibrium between maternal and fetal circulations. Placental viability markers for all perfusions were within normal ranges. ConclusionsThis is the first direct evidence of the transfer of dabigatran and rivaroxaban across the human placenta from the mother to fetus. It suggests less fetal exposure to dabigatran. Disclosures:No relevant conflicts of interest to declare.