Can fondaparinux be used during pregnancy?/nThe question concerns a woman treated with fondaparinux

Fråga: Can fondaparinux be used during pregnancy?

The question concerns a woman treated with fondaparinux (Arixtra) due to dalteparin hypersensitivity. She is now planning a pregnancy.

Sammanfattning: There is very limited information concerning the use of fondaparinux during pregnancy. It has been shown that the transfer of fondaparinux over the placenta is minor and no abnormalities have been reported in the few cases published. Until more information is available, fondaparinux use during pregnancy should med limited to patients with a clear indication and a known hypersensitivity to heparins.

Svar: Fondaparinux is an anticoagulant approved in Sweden in 2002. It is a selective factor Xa inhibitor that binds with high affinity to antithrombin causing an irreversible conformational change in antithrombin resulting in a potent inhibition of factor Xa without any effect on factor IIa or on the thrombocytes (1,2).

Heparins, which do not cross the placenta, are the anticoagulants recommended during pregnancy. A low-molecular-weight heparin (LMWH) is often preferred over unfractionated heparin because LMWH has a longer half-life and is presumed to have fewer side effects (3). In heparin induced immunomodulated thrombocytopenia, the antibodies cross-react with LMWHs in 80 percent of the cases. It cannot be excluded that there is similar cross-reactivity concerning allergic reactions such as urticaria and angioneurotic edema (4). Therefore, heparin or LMWHs are contraindicated in patients with a known hypersensitivity to dalteparin (5). Fondaparinux has in several cases been shown to be an alternative for patients (non-pregnant) with hypersensitivity to heparins and heparinoids (4,6,7).

The knowledge of fondaparinux during pregnancy is very limited. In an in-vitro study, no apparent placental transfer of fondapariux was found (2). However, in vivo data show that it may pass the placenta to a limited extent. In a small study, five pregnant women who had severe cutaneous allergic reactions to LMWH had been treated with 2.5 mg fondaparinux per day for 1 to 101 days at delivery. Umbilical-cord plasma was measured and the concentration of fondaparinux detected there was approximately one tenth of the concentration in maternal plasma. No adverse effects in the newborns were noted (8).

Only one report of treatment with fondaparinux during the first trimester of pregnancy has been located. The woman was heparin intolerant and was treated with 2.5 mg fondaparinux daily during the whole pregnancy (fondaparinux was omitted at the day of delivery). During pregnancy, the anticoagulant effect of fondaparinux was determined by factor Xa inhibition assays. The treatment was safe and effective, and it was calculated that only a minimal amount of fondaparinux would be found in foetal and neonatal plasma (9). Four reports of successful treatment with fondaparinux (2.5 mg daily) during the last two trimesters in heparin intolerant women have also been located. No adverse effects were noted in the newborns (10,11,12).

In the Swedish Medical Birth Register there are no reports of fondaparinux use during pregnancy (13). Arixtra (fondaparinux). Summary of Product Characteristics (SPC). Available via: www.fass.se (updated 2008-03-13) Lagrange F, Vergnes C, Brun JL, Paolucci F, Nadal T, Leng JJ et al. Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro. Thromb Haemost 2002;87(5):831-835

James AH. Prevention and management of venous thromboembolism in pregnancy. Am J Med 2007;120(10 Suppl 2):S26-S34
Drugline no 23153 (year 2006)
Fragmin (dalteparin). Summary of product characteristics (SPC). Avaliable via: www.fass.se (updated 2007-08-16)

Jappe U, Juschka U, Kuner N, Hausen BM, Krohn K. Fondaparinux: a suitable alternative in cases of delayed-type allergy to heparins and semisynthetic heparinoids? A study of 7 cases. Contact Dermatitis 2004;51(2):67-72 Harenberg J, Jorg I, Fenyvesi T. Treatment of heparin-induced thrombocytopenia with fondaparinux. Haematologica 2004;89(8):1017-1018 Dempfle CE. Minor transplacental passage of fondaparinux in vivo. N Engl J Med 2004;350(18):1914-1915 Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy. Thromb Res 2007;119(3):385-388 Mazzolai L, Hohlfeld P, Spertini F, Hayoz D, Schapira M, Duchosal MA. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 2006;108(5):1569-1570 Wijesiriwardana A, Lees DA, Lush C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy. Blood Coagul Fibrinolysis 2006;17(2):147-149 Gerhardt A, Zotz RB, Stockschlaeder M, Scharf RE. Fondaparinux is an effective alternative anticoagulant in pregnant women with high risk of venous thromboembolism and intolerance to low-molecular-weight heparins and heparinoids. Thromb Haemost 2007;97(3):496-497 Läkemedel och fosterskada. Uppdated 2007-09-01. Available from: http://www.janusinfo.se