Anticoagulant
PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Although the human pregnancy experience with fondaparinux is limited, no reports of embryo–fetal harm have been located. Several reviews have stated that the agent is safe in pregnancy. Thus, if indicated it should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Fondaparinux is a synthetic selective inhibitor of activated factor X (Xa) that is administered by SC injection. The drug is indicated for the prophylaxis of deep vein thrombosis in patients undergoing hip fracture, hip replacement, or knee replacement surgery. Distribution to extravascular fluid is characterized as minor. The drug is extensively (at least 94%) and specifically bound to antithrombin III but not to other plasma proteins or red blood cells. The binding to antithrombin III significantly potentiates the neutralization of factor Xa by antithrombin III. Fondaparinux has no effect on thrombin or platelet function. The metabolism of fondaparinux has not been investigated, but most of a dose is excreted unchanged in the urine. The drug is contraindicated in patients weighing <50 kg because total clearance in this group is reduced by approximately 30% (1).
Reproduction studies in pregnant rats and rabbits at SC doses up to 32 and 65 times the recommended human dose based on BSA, respectively, revealed no evidence of impaired fertility or fetal harm (1).
Fondaparinux did not cross the placenta in an in vitro human dually perfused, cotyledon model using placentas from six healthy white women approximately 31 years of age (2,3). The dose tested corresponded to the therapeutic plasma concentrations observed with the recommended human dose. The result is consistent with the high molecular weight (about 1728) and minimal extravascular distribution of fondaparinux. However, in a 2004 study of five women treated near delivery, the concentrations of fondaparinux in cord plasma were <5–40 ng/mL (4). The patient with undetectable drug had received only one dose, whereas the other four patients were at steady state with plasma levels of 255–340 ng/mL. The fetal concentrations were about 10% of the maternal levels (4).
A 31-year-old woman in her 12th week of pregnancy completely loss her vision in her right eye for 2 minutes (5). After an extensive work-up, she was diagnosed with hypereosinophilic syndrome and started on heparin and prednisone. HIT developed and her anticoagulant therapy was changed to argatroban (dose not specified). The thrombocytopenia resolved and, after 15 days, she was discharged home on fondaparinux (75 mg/day) and a tapering dose of prednisone. About 6–7 months later, she gave birth to a healthy female infant (no further details on the infant was provided) (5).
In a 2012 case report, a 33-year-old woman, with a history of hereditary antithrombin deficiency, presented at 7 weeks’ gestation with a deep venous thrombosis in her left leg due to the deficiency (6). She was treated with urokinase (24,000 units/day), heparin (20,000 units/day), and antithrombin concentrate (3000 units/day). Ten days later, at 9 weeks, HIT was diagnosed; heparin was discontinued and a continuous infusion of argatroban (2.5 mcg/kg/min) was started. At 21 weeks, argatroban was stopped and fondaparinux (2.5 mg/day) was started at 24 weeks’. Argatroban (2.5–3.5 mcg/kg/min) was restarted during labor induction at 37 weeks. The patient gave birth to 2800-g male infant with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. The newborn had 14% of antithrombin activity. The mother and her newborn were discharged home 15 days later (6).
In addition to the above two reports, four other reports have described the use of fondaparinux during human pregnancy without causing embryo or fetal harm (7–10). In addition, four reviews have stated that the drug can be used safely in pregnancy (11–14).
BREASTFEEDING SUMMARY
No reports describing the use of fondaparinux during human lactation have been located. Despite the high molecular weight (about 1728), the drug may be excreted into milk. The potential effects of this exposure on a nursing infant are unknown but are probably not clinically significant.
References
1.Product information. Arixtra. Sanofi-Synthelabo, 2003.
2.Lagrange F, Brun J-L, Vergnes MC, Paolucci F, Nadal T, Leng J-J, Saux MC, Bannwarth B. Fondaparinux sodium does not cross the placental barrier. Study using the in-vitro human dually perfused cotyledon model. Clin Pharmacokinet 2002;41(Suppl 2):47–9.
3.Lagrange F, Vergnes C, Brun JL, Paolucci F, Nadal T, Leng JJ, Saux MC, Banwarth B. Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra®) in the dually perfused human cotyledon in vitro. Thromb Haemost 2002;87:831–5.
4.Dempfle C-EH. Minor transplacental passage of fondaparinux in vivo. N Engl J Med 2004;350:1914–5.
5.Darki A, Kodali PP, McPheters JP, Virk H, Patel MR, Jacobs W. Hypereosinophilic syndrome with cardiac involvement. Tex Heart Inst J 2011;38:163–5.
6.Tanimura K, Ebina Y, Sonoyama A, Morita H, Miyata S, Yamada H. Argatroban therapy for heparin-induced thrombocytopenia during pregnancy in a woman with hereditary antithrombin deficiency. J Obstet Gynaecol Res 2012;38:749–52.
7.Wijesiriwardana A, Lees DAR, Lush C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy. Blood Coagul Fibrinolysis 2006;17:147–8.
8.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;108:1569–70.
9.Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy. Thromb Res 2007;119:385–8.
10.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;97:496–7.
11.Hawkins D, Evans J. Minimising the risk of heparin-induced osteoporosis during pregnancy. Expert Opin Drug Saf 2005;4:583–90.
12.James AH. Prevention and management of venous thromboembolism in pregnancy. Am J Med 2007;120(10 Suppl 2):S26–34.
13.Deruelle P, Coulon C. The use of low-molecular-weight heparins in pregnancy—how safe are they? Curr Opin Obstet Gynecol 2007;19:573–7.
14.Desai P, Suk M. Orthopedic trauma in pregnancy. Am J Orthop 2007;36:E160–6.