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Use of Fondaparinux During Pregnancy

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I felt the comment below from a reader deserved a more thorough response than could be accommodated under the post upon which it was left and also might be of interest to other readers and providers who frequent this site. Anticoagulation during pregnancy has become more widely used to treat, both prophylactically and therapeutically, women who have had problems with thromboembolic complications, unexplained recurrent pregnancy loss, and those who have been identified as being ‘at risk’ because of acquired or genetic thrombophilias (e.g., antiphospholipid antibody syndrome; lupus anticoagulants; Factor V Leiden; MTHFR polymorphisms; prothrombin mutations,; antithrombin III deficiency; protein C and S deficiencies, etc.). The treatment of choice in recent years during pregnancy has been either unfractionated or low-molecular weight heparins. These are used because of their efficacy and relative safety for both mother and baby (they do not cross the placenta to the fetal circulation).

However, their use is not without risks. Prolonged use of heparins can lead to reduction in bone density (osteopenia and osteoporosis), cutaneous and systemic allergic reactions (accompanied in some cases by decreased efficacy), and heparin-induced thrombocytopenias that may place the patient at risk for hemorrhagic complications. When such complications arise, alternative medications such as fondaparinux (Arixtra) have been offered as alternative therapy. Although very few of us have a vast experience with the use of this drug in pregnancy and, currently, I am not aware of recommended regimens for the same, there is a growing need and a growing body of evidence to support that use when in indicated situations. Following our reader’s comment, I provide general information related to fondaparinux and, specifically, to its use during pregnancy….


jen27 has left a new comment on your post "Tales of Two Thrombophilias":

I am so happy to have found your blog! I have another take on thrombophilia and pregnancy. I am 39 years old, first time pregnancy and presented with bilateral PE (pulmonary emboli) at 8 weeks. Was placed on lovenox--allergic! Then placed on Heparin--allergic! I am now on Arixtra and I seem to be tolerating it well. My concern is with the delivery and also with a possible amniocentesis (of course, I am high-risk for Down's). This is a new drug and my OB is has never used it before. How do we plan for delivery? He is talking about inducing me around 37 weeks to have some control over bleeding. My hematologist has not used this drug with a pregnancy before and is not sure how we should proceed. Also, I am scheduled for a possible amniocentesis in two weeks and have started to worry about internal bleeding. Any advice would be most appreciated
!


Fondaparinux is not a heparin substance. It is a synthetic pentasaccharide (5-sugar) compound that has been found to be a selective inhibitor of Factor Xa. In the blood-clotting system, Factor Xa functions at the common point at which both the intrinsic and extrinsic clotting cascades come together and, therefore, it is a highly efficient inhibitor of thrombin formation and, subsequently, fibrin formation (which is the foundation upon which blood clotting occurs). Fondaparinux actually binds, quite specifically, to antithrombin III (ATIII) which then facilitates the binding of ATIII to Factor Xa, inactivating it and interrupting the clotting cascade. Interestingly, once the ATIII-fondaparinux complex binds to Factor Xa, the fondaparinux is actually released intact and can then bind with another ATIII molecule to repeat the process.

Fondaparinux is administered by subcutaneous (not intramuscular) injection. It is rapidly absorbed and reaches peak serum concentrations about 2 hours after dosing. “It has a terminal half-life of 13 to 21 h, permitting once daily dosing” and a “linear pharmacokinetic profile which exhibits minimal intrasubject and intersubject variability, suggesting that individual dose adjustments will not be required for the vast majority of the population and there will be no need for routine hemostatic monitoring.” (Bauer, et al., Cardiovasc Drug Rev 2002;20:37-52). The drug also has minimal binding to plasma proteins usually involved in drug binding, therefore, the risk of complications related to drug interactions associated with displacement of drugs that do bind to these proteins is very low. The drug is cleared intact by the kidneys so dosing regimens in patients with renal compromise must be adjusted accordingly.

In studies performed both in vitro (Lagrange ,et al., Thromb Haemost 2002;87:831-5) and in vivo (Dempfle, N Engl J Med 2004;350:1914-5) there appears to be minimal transplacental passage of fondaparinux, placing the baby at low risk for hemorrhagic complications. Furthermore, studies performed in pregnant rats and rabbits at 32 times and 65 times, respectively, the recommended human dose have not shown impairment of fertility or a teratogenic effect on the fetus, resulting in the drug being classified as "class B." However, it should be recognized that pregnant women were excluded from all controlled clinical trials conducted with fondaparinux so there are to date no controlled trials during the first trimester of pregnancy.

Indeed, there are only a few case reports published in the scientific literature (Dempfle, N Engl J Med 2004;350:1914-5; Wijesiriwardana, et al., Blood Coagul Fibrinolysis 2006;17:147-9; Mazzolai, et al., Blood 2006;108:1569-70; Harenberg, Thromb Res 2007;119:385-8; Gerhardt, et al., Thromb Haemost 2007;97:496-7). Although the drug appeared safe and was well-tolerated with no untoward maternal or fetal effects in any of these reports, and none of the few patients described developed recurrent episodes of thromboembolic disease or allergic reaction, it is hard to generalize the safety and efficacy of the drug during pregnancy based on only a handful of patients. Safety of the drug in nursing women has also not been studied to date although, again, in lactating rats, only a small amount were found in breast milk.

With all that said and done, how should fondaparinux be used during pregnancy? None of the case reports agreed on a common regimen. In most of the clinical trials leading to its approval, fondaparinux has been employed only as a prophylactic agent in the perioperative period in ‘at risk’ patients or in the acute management of a thromboembolic condition while the patient was being transferred to warfarin over the course of 5 to 9 days. For both of these indications, fondaparinux has been found to be more efficacious than either heparin or low-molecular-weight heparin and to have comparable safety profiles. It has been found that fondaparinux is associated with hemorrhagic complications if given less than 6 hours after an operative procedure.

In the case reports, various approaches to therapy during pregnancy were described. As examples, Wijesiriwardana and colleagues (referenced above) described the case of a woman who had had deep venous thrombosis in a previous pregnancy who then developed an allergic reaction to low molecular weight heparin after three weeks of therapy during a subsequent pregnancy. She was placed on warfarin until 36 weeks’ gestation and then switched to fondaparinux 2.5 mg SQ daily. The latter was discontinued the day she began induction of labor and then restarted 6 hours after her uncomplicated vaginal delivery while she was transitioned back to a therapeutic level of warfarin. Neither she nor the baby had hemorrhagic complications related to this approach, nor did she develop recurrent thrombosis during the treatment period. In the report by Mazzolai and colleagues (also referenced above), a woman with protein S deficiency, who also had a history of deep venous thrombosis and developed allergies to both heparin and low-molecular weight heparin, was treated successfully, and without complications, for 150 days during pregnancy. Either approach seems very reasonable in the patient at high risk for thromboembolic complications and hypersensitivity to heparin compounds. Indeed, judging from the safety profile of fondaparinux to date, some thought may have to be given to its use as a first-line agent under these circumstances at some point in the future.

I realize that I have been long-winded, so in fairness to our reader, I should try to answer her questions! It would be helpful, however, if I had some more information, specifically, related to her medical history and identified risk factors for her bilateral pulmonary emboli in early pregnancy. Regardless, I would offer the following suggestions: 1) Consider maternal serum screening and a ‘targeted ultrasound’ to reevaluate your risk for Down syndrome and trisomy 18 before proceeding with an amniocentesis based on your ‘age alone’ risk; 2) If you do decide to proceed with the amniocentesis, stop the fondaparinux take your last dose 24 hours before the procedure and then resume dosing 6-8 hours afterwards; 3) Unless you have or develop other risk factors, elective delivery before 39 weeks is probably not indicated (unless you have another amniocentesis to document fetal lung maturity first); 4) Since anticoagulation therapy places you at increased risk for complications related to spinal and epidural anesthesia, and the effects of fondaparinux cannot be readily ‘reversed’ in a short period of time, consider third trimester consultation with an anesthesiologist who can suggest a plan of management in the peripartum period; 5) If an induction is planned, discontinue the drug the day before and resume 6-8 hours following delivery; 6) Consider leg compression boots throughout the time you are not taking fondaparinux before, during, and after delivery to minimize your risks for deep venous thrombosis; 7) Convert to warfarin after delivery while being covered with fondaparinux until a therapeutic INR level is reached.

Thanks for a great comment Jen and best wishes for the rest of the pregnancy! Please let us know how things turn out.
Dr T
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