Correspondence
Minor Transplacental Passage of Fondaparinux in Vivo
N Engl J Med 2004; 350:1914-1915April 29, 2004
- Article
To the Editor:
Low-molecular-weight heparin remains the anticoagulant of choice for pregnant women with previous thromboembolic events. Fondaparinux (Arixtra, Sanofi-Synthelabo) is a chemically synthesized derivative of the natural pentasaccharide sequence that mediates the interaction of heparin with antithrombin.1 It has been recommended for prophylaxis against thromboembolism after hip or knee surgery.2,3
My colleagues and I have treated five pregnant patients in whom anticoagulant therapy was indicated and who had severe cutaneous allergic reactions to low-molecular-weight heparin with fondaparinux at a dose of 2.5 mg per day. No allergic reactions at injection sites, thromboembolic events, or abnormal bleeding was observed. No adverse effects were noted in the newborns.
In four of the patients, anti–factor Xa activity in umbilical-cord blood was elevated (Table 1Table 1
Results of Coagulation and Anti–Factor Xa Assays in Umbilical-Cord Blood from Five Patients and in Plasma from Normal Adults.). Fondaparinux concentrations were between 11 and 40 ng per milliliter of plasma (Biophen heparin assay, Hyphen BioMed). Anti–factor Xa clotting times in these four patients were between 37.5 and 50.9 seconds (Heptest, Haemachem). The patient who did not have elevated anti–factor Xa activity had received only a single injection of fondaparinux, 22 hours before delivery.Subcutaneous injection of fondaparinux results in mean peak plasma levels of 300 ng per milliliter.4 Steady-state conditions are reached after three or four daily injections.4 The mean values for anti–factor Xa activity in plasma from our patients during fondaparinux treatment were 310, 340, 255, and 293 ng per milliliter. The concentration of fondaparinux detected in umbilical-cord plasma by the chromogenic assay was approximately 1/10 the concentration in maternal plasma. The ratio of the anti–factor Xa clotting time (in seconds) to the activated partial-thromboplastin time (in seconds) correlates with the anti–factor Xa activity measured by the chromogenic method. Since fondaparinux does not influence the activated partial-thromboplastin time, this ratio may serve as an indicator of measurable anti–factor Xa activity in umbilical-cord blood and support the results of the chromogenic assay.
Lagrange et al. did not observe placental transfer of fondaparinux in an ex vivo model with the use of dually perfused human cotyledon.5 However, the current results indicate that fondaparinux may pass the placental barrier in vivo, resulting in measurable anti–factor Xa activity in umbilical-cord blood. The concentration of fondaparinux in umbilical-cord blood is well below the concentration required for effective anticoagulation, but a potentially hazardous effect cannot be ruled out. Therefore, the use of fondaparinux in pregnant women might best be limited to those for whom there are no obvious therapeutic alternatives, such as patients with heparin-induced thrombocytopenia type 2 or severe allergic reactions to heparin.
5 ReferencesCarl-Erik H. Dempfle, M.D.
University Hospital of Mannheim, D-68167 Mannheim, Germany1
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