Fondaparinux in pregnancy: Could it be a safe option? A review of the literature.

During pregnancy thrombo-prophylaxis could be required in high risk women. If a severe allergic reaction to low-molecular-weight-heparin (LMWH) or a heparin-induced-thrombocytopenia (HIT) occurs, it's mandatory to stop the drug. Fondaparinux could be an effective option. In the present review, the maternal and pregnancy outcomes of 65 pregnancies in women using Fondaparinux were reported. It was well-tolerated and rate of pregnancy complications was similar to that observed in general population. Regarding congenital malformations, further studies are necessary to investigate the safety of the drug. Over the past few years, low-molecular-weight heparin (LMWH) has replaced unfractionated heparin as the agent of choice for the treatment and prevention of venous thromboembolism (VTE) during pregnancy because it has a better safety profile with respect to heparin-associated osteoporosis and heparin-induced thrombocytopenia (HIT), as well as reduced monitoring requirements [1]. However, adverse reactions to LMWH can occur via a type I hypersensitivity reaction (urticarial rash), skin necrosis due to vasculitis (type III reaction) or a heparin-induced-thrombocytopenia (HIT). Fondaparinux sodium is a synthetic pentasaccharide that strongly binds to antithrombin and enhances the inactivation of factor Xa without interaction with factor II or platelets. Several studies showed that fondaparinux has an efficacy comparable to LMWH or UFH in the prevention of VTE in major orthopedic surgery, in the treatment of deep vein thrombosis (DVT) as well as pulmonary embolism (PE) without any increase of major bleeding [2]. Fondaparinux sodium has a very low cross-reactivity with both LMWH and UFH and few case reports describe reactions at the injection site of a single dose [3]. Rarely, anti PF4/heparin antibodies are generated during fondaparinux treatment, but they are not able to cause thrombocytopenia, because they do not bind PF4/fondaparinux complexes [4]. When heparin intolerance or HIT occurs in pregnant women who need thromboprophylaxis, there are limited alternative anticoagulant choices, fondaparinux could been suggested as an option. Warfarin and hirudin cross the placenta and are associated with embryo and fetal toxicities. Lagrange et al. [5] did not observe placental transfer of fondaparinux in an in vitro model with the use of dually perfused human cotyledon. On the other hand, fondaparinux has been reported to pass in vivo the placental barrier, resulting in low but measurable anti–factor Xa activity in umbilical-cord blood, so that a potential hazard cannot be ruled out [6] and [7]. However, the use of fondaparinux in pregnant women is suggested by a level 2C recommendation from the American College of Chest Physicians for the treatment of those cases with severe allergic reactions to heparin (e.g. HIT) that cannot receive danaparoid [8]. Out of 68 pregnancies so far reported [6], [7], [9], [10], [11], [12], [13], [14], [15] and [16] (Table 1), three were considered not evaluable, because in two cases fondaparinux had been administered one and nine days before delivery [6], and in one case the pregnancy outcome had not been described [11]. Of the remaining 65 cases, none was associated with major bleeding. Pregnancy was complicated by recurrent VTE in one case (1,5%). In this woman, who weighed 99 kg and suffered from three previous VTE events, the initial dose of fondaparinux was 7,5 mg daily. Considering that the recommended dose is 10 mg for weight 100 kg, it could be considered that the recurrent DVT was due to inadequate anticoagulation, rather than treatment failure [15]. As the number of women receiving fondaparinux because of a history of previous DVT was 27, the failure rate for this indication was 3.7% (95% CI; 0.6%-18.3%).