Fondaparinux as an alternative anticoagulant therapy during pregnancy.

Abstract

Hypersensitivity skin reactions are frequently seen in pregnant patients who use low‐molecular‐weight heparin (LMWH) [1Bank I. Libourel E.J. Middeldorp S. van der Meer J. Buller H.R. High rate of skin complications due to low‐molecular‐weight heparins in pregnant women.J Thromb Haemost. 2003; 1: 859-61Crossref PubMed Scopus (0) Google Scholar]. When this heparin intolerance occurs, alternative choices for anticoagulation are limited. Hypersensitivity skin reactions often recur when another preparation of LMWH is substituted [1Bank I. Libourel E.J. Middeldorp S. van der Meer J. Buller H.R. High rate of skin complications due to low‐molecular‐weight heparins in pregnant women.J Thromb Haemost. 2003; 1: 859-61Crossref PubMed Scopus (0) Google Scholar]. Danaparoid is another preparation of choice which does not pass the placenta [2Greinacher A. Eckhardt T. Mussmann J. Mueller‐Eckhardt C. Pregnancy complicated by heparin associated thrombocytopenia: management by a prospectively in vitro selected heparinoid (Org 10172).Thromb Res. 1993; 71: 123-6Abstract Full Text PDF PubMed Scopus (0) Google Scholar], but is not always available. Most patients strongly wish to avoid vitamin K antagonists, even beyond the 12th week of pregnancy, because of the association with congenital and developmental abnormalities [3Wesseling J. van Driel D. Smrkovsky M. van der Veer E. Geven‐Boere L.M. Sauer P.J. Touwen B.C. Neurological outcome in school‐age children after in utero exposure to coumarins.Early Hum Dev. 2001; 63: 83-95Crossref PubMed Scopus (0) Google Scholar, 4Chan W.S. Anand S. Ginsberg J.S. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature.Arch Intern Med. 2000; 160: 191-6Crossref PubMed Google Scholar]. Fondaparinux, a synthetic selective inhibitor of activated factor X (FXa), is commonly used as an alternative anticoagulant in non‐pregnant patients who develop heparin intolerance. Fondaparinux has been extensively studied for use in surgery prophylaxis and treatment of thromboembolic diseases [5Turpie A.G. Eriksson B.I. Lassen M.R. Bauer K.A. Fondaparinux, the first selective factor Xa inhibitor.Curr Opin Hematol. 2003; 10: 327-32Crossref PubMed Scopus (0) Google Scholar]. However, data on the use of fondaparinux in pregnancy is limited to animal models and a few case reports [6Gerhardt A. Zotz R.B. Stockschlaeder M. Scharf R.E. 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: 496-7Crossref PubMed Scopus (0) Google Scholar, 7Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy.Thromb Res. 2007; 119: 385-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 8Mazzolai L. Hohlfeld P. Spertini F. Hayoz D. Schapira M. Duchosal M.A. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy.Blood. 2006; 108: 1569-70Crossref PubMed Scopus (83) Google Scholar, 9Wijesiriwardana A. Lees D.A. Lush C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy.Blood Coagul Fibrinolysis. 2006; 17: 147-9Crossref PubMed Scopus (0) Google Scholar, 10Schapkaitz E. Jacobson B.F. Delayed hypersensitivity to low‐molecular‐weight heparin (LMWH) in pregnancy.S Afr Med J. 2007; 97: 1255-7PubMed Google Scholar]. Although it has been shown that transplacental passage can occur resulting in low measurable FXa activity in cord blood [11Dempfle C.E. Minor transplacental passage of fondaparinux in vivo.N Engl J Med. 2004; 350: 1914-5Crossref PubMed Scopus (0) Google Scholar], no adverse outcomes in pregnancy have been reported in these four women. The other six separately published cases reported no adverse events to the mother or child [6Gerhardt A. Zotz R.B. Stockschlaeder M. Scharf R.E. 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: 496-7Crossref PubMed Scopus (0) Google Scholar, 7Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy.Thromb Res. 2007; 119: 385-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 8Mazzolai L. Hohlfeld P. Spertini F. Hayoz D. Schapira M. Duchosal M.A. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy.Blood. 2006; 108: 1569-70Crossref PubMed Scopus (83) Google Scholar, 9Wijesiriwardana A. Lees D.A. Lush C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy.Blood Coagul Fibrinolysis. 2006; 17: 147-9Crossref PubMed Scopus (0) Google Scholar, 10Schapkaitz E. Jacobson B.F. Delayed hypersensitivity to low‐molecular‐weight heparin (LMWH) in pregnancy.S Afr Med J. 2007; 97: 1255-7PubMed Google Scholar]. In our hospital, experience with fondaparinux as an alternative in pregnant women has accumulated. The aim of the present study was to evaluate the use and safety of fondaparinux during pregnancy. From 2003 until the present, we prospectively followed a consecutive cohort of 133 women in our university hospital who used anticoagulant therapy during their pregnancy and puerperium. The indication for anticoagulant therapy was a history of idiopathic, provoked or previous pregnancy‐related venous thrombo‐embolism (VTE) or recurrent fetal loss. Recurrent fetal loss was defined as two or more fetal losses. In all women thrombophilia screening was performed. Applied assays have been described elsewhere [12Folkeringa N. Korteweg F.J. Veeger N.J. Middeldorp S. Hamulyak K. Prins M.H. Erwich J.J. Büller H.R. van der Meer J. Thrombin activatable fibrinolysis inhibitor (TAFI) is not associated with fetal loss, a retrospective study.Thromb Res. 2009; 123: 511-4Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. All women were started on a LMWH (nadroparin or tinzaparin) in early pregnancy with a body weight adjusted therapeutic dosage (175 anti‐Xa IU kg−1 day−1), as soon as a pregnancy test was positive. All women were followed in a combined obstetric/coagulation clinic and seen by a thrombosis specialist every 2 months until 6 weeks post‐partum. Anti‐FXa levels were not routinely monitored in maternal and cord blood and doses of LMWH were not adjusted for increasing bodyweight or increasing renal clearance. If hypersensitivity skin reactions developed, we either switched once to another preparation (tinzaparin or nadroparin), acenocoumarol or started fondaparinux 2.5 mg subcutaneously twice daily. Fondaparinux 7.5 mg once daily (therapeutic dosage) is not available in the Netherlands, and we wished to avoid thrice daily injections. The women had no standard planned induction with withholding of fondaparinux, but anticoagulation was stopped at the start of spontaneous labor and restarted 4–8 h after delivery (when blood loss was normal) and stopped 6 weeks post‐partum. Data were systematically collected by the thrombosis physicians during pregnancy on an indication for anticoagulant therapy; start date of LMWH; trimester of switching to another LMWH, vitamin K antagonist or fondaparinux; bleeding and thrombo‐embolic complications during pregnancy, delivery and post‐partum period; side effects of anticoagulants; gestational age of delivery; blood loss during delivery; birth weight and neonatal bleeding/congenital abnormalities. National legislation and the ethical committee of our institution approve this type of studies without the need for review of the protocol. All women were informed about the risks of the off label use of fondaparinux during pregnancy and agreed with it. In this letter, we report on the 12 out of 190 pregnancies in 133 women in whom fondaparinux was used. We treated 10 patients with fondaparinux during pregnancy and the puerperium in our institution, two of them during two pregnancies. Their median age was 30 years (range 26–34 years). Six of them had a history of VTE during combined oral contraceptive use, three patients had a history of an idiopathic VTE and one patient had a history of recurrent fetal loss. None of the patients had a history of allergy to LMWH. Eight patients were switched to fondaparinux in the 2nd trimester and two patients during the 3rd trimester. All patients were started initially on nadroparin or tinzaparin, two used both preparations and one patient used a vitamin K antagonist during the 2nd trimester before switching to fondaparinux (see Table 1 for detailed information). In all cases, the indication for switching to fondaparinux was hypersensitivity skin reactions to LMWHs, consisting of itching, local redness or subcutaneous infiltrates localized at the injection sites. Two patients were treated during two pregnancies, both started fondaparinux in the first trimester of their second pregnancy. No hypersensitivity skin reactions to fondaparinux were seen and patients reported no other side effects. No early or late fetal losses occurred. The median gestational age at delivery was 39 weeks (range 33 5/7–42 0/7 weeks). One patient delivered preterm twins as a result of preterm prelabor rupture of the membranes. The median blood loss during delivery was 450 mL (range 200–2000 mL); three patients had a greater than 1000‐mL blood loss. The patient with 2000 mL blood loss had an atony of the uterus; she received her last injection of fondaparinux more than 12 h before delivery. One patient had 1200 mL blood loss during a secondary caesarean section; she received her last injection 48 h before delivery. The third patient had 1000 mL blood loss because of atony of the uterus and a preterm delivery of a twin; she received her last injection 7 h before delivery. None of these women with a greater than 1000‐mL blood loss needed a blood transfusion. Postpartum, 4–8 h after cessation of the bleeding, these patients restarted on fondaparinux 2.5 mg twice daily. No bleeding recurred after restarting the drug. None of the 13 infants had congenital abnormalities or neonatal bleeding. Their median birth weight was 3685 g (range 1795–4330 g). No minor or major bleedings or thromboembolic events were reported during the pregnancy or post‐partum period.Table 1Detailed patient characteristicsCase no.AgeIndication for anticoagulationThrombophiliaAnticoagulation before fondaparinuxTrimester start fondaparinuxGestational age at deliveryBirth weight (gram)Blood loss during delivery (mL)Last injection before delivery (hrs)132PE during COCPS def type I/hetzg FV leidennadroparin3rd40 4/7367020025134PE during COCPS def. type I/hetzg FV leiden–1st40 4/7433030020230Idiopathic DVTHetzg FV leidentinzaparin2nd38 6/73450700> 12330Recurrent fetal lossNonadroparin2nd38 2/735701200*48332Recurrent fetal lossNo–1st39 0/7397550017430CVT during COCNonadroparin/VKA2nd42 0/739292000†> 12530DVT during COCNonadroparin/tinzaparin2nd37 0/7307040022632Idiopathic DVTNonadroparin2nd40 3/737003007726Idiopathic PENonadroparin2nd33 5/71990/17951000†7828DVT during COCPS def.type III/hetzg FV leidennadroparin2nd37 6/731102009933PE during COCPS def type Inadroparin3rd41 1/73795300311029DVT during COCNonadroparin/tinzaparin2nd42 0/7379570030CVT, cerebral venous thrombosis; DVT, deep venous thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; COC, combined oral contraceptive use; PS, protein S; def, deficiency; FV, factor V; hetzg, heterozygous. *Atony of uterus †Secondary caesarean section. Open table in a new tab CVT, cerebral venous thrombosis; DVT, deep venous thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; COC, combined oral contraceptive use; PS, protein S; def, deficiency; FV, factor V; hetzg, heterozygous. *Atony of uterus †Secondary caesarean section. We report on all 12 pregnancies in our centre in which fondaparinux was used during the past 6 years. These data are derived from a prospective cohort study. We show that fondaparinux was not associated with increased bleeding, thromboembolic complications or fetal abnormalities. To our knowledge, this is the largest prospective study that reports on the use of fondaparinux during pregnancy. In concurrence with others [6Gerhardt A. Zotz R.B. Stockschlaeder M. Scharf R.E. 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: 496-7Crossref PubMed Scopus (0) Google Scholar, 7Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy.Thromb Res. 2007; 119: 385-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 8Mazzolai L. Hohlfeld P. Spertini F. Hayoz D. Schapira M. Duchosal M.A. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy.Blood. 2006; 108: 1569-70Crossref PubMed Scopus (83) Google Scholar, 9Wijesiriwardana A. Lees D.A. Lush C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy.Blood Coagul Fibrinolysis. 2006; 17: 147-9Crossref PubMed Scopus (0) Google Scholar, 10Schapkaitz E. Jacobson B.F. Delayed hypersensitivity to low‐molecular‐weight heparin (LMWH) in pregnancy.S Afr Med J. 2007; 97: 1255-7PubMed Google Scholar, 11Dempfle C.E. Minor transplacental passage of fondaparinux in vivo.N Engl J Med. 2004; 350: 1914-5Crossref PubMed Scopus (0) Google Scholar], we did not observe hypersensitivity skin reactions using fondaparinux, although all women had had hypersensitivity skin reactions to LMWHs. Recurrence of hypersensitivity skin reactions when switching to another preparation of LMWH in pregnant women is a known phenomenon [1Bank I. Libourel E.J. Middeldorp S. van der Meer J. Buller H.R. High rate of skin complications due to low‐molecular‐weight heparins in pregnant women.J Thromb Haemost. 2003; 1: 859-61Crossref PubMed Scopus (0) Google Scholar]. Fetal safety is an important issue when considering a new anticoagulant therapy in pregnancy. LMWHs do not cross the placenta, so can not cause teratogenicity or neonatal bleeding [13Deruelle P. Coulon C. The use of low‐molecular‐weight heparins in pregnancy‐‐how safe are they?.Curr Opin Obstet Gynecol. 2007; 19: 573-7Crossref PubMed Scopus (0) Google Scholar, 14Lepercq J. Conard J. Borel‐Derlon A. Darmon J.Y. Boudignat O. Francoual C. Priollet P. Cohen C. Yvelin N. Schved J.F. Tournaire M. Borg J.Y. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies.BJOG. 2001; 108: 1134-40Crossref PubMed Google Scholar, 15Sanson B.J. Lensing A.W. Prins M.H. Ginsberg J.S. Barkagan Z.S. Lavenne‐Pardonge E. Brenner B. Dulitzky M. Nielsen J.D. Boda Z. Turi S. Mac Gillavry M.R. Hamulyák K. Theunissen I.M. Hunt B.J. Büller H.R. Safety of low‐molecular‐weight heparin in pregnancy: a systematic review.Thromb Haemost. 1999; 81: 668-72Crossref PubMed Google Scholar]. A study by Dempfle et al. [11Dempfle C.E. Minor transplacental passage of fondaparinux in vivo.N Engl J Med. 2004; 350: 1914-5Crossref PubMed Scopus (0) Google Scholar] demonstrated that fondaparinux passes the placental barrier in vivo, resulting in low measurable anti‐FXa levels in umbilical cord blood. That study described five pregnant women, in four of whom low anti‐FXa levels were measured. These levels were approximately 1/10 the concentration in maternal plasma, which is well below the concentration required for effective anticoagulation [16Forestier F. Daffos F. Rainaut M. Toulemonde F. Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy.Thromb Haemost. 1987; 57: 234Crossref PubMed Scopus (0) Google Scholar]. Neonatal bleeding did not occur in the infants of these women. In the fifth woman, no elevated anti‐FXa level was measured, probably because she received her last injection of fondaparinux 22 h before delivery. Based on these data, fondaparinux has the potential to affect the fetus. In a recently published retrospective study by Winger et al. [17Winger E.E. Reed J.L. A retrospective analysis of fondaparinux versus enoxaparin treatment in women with infertility or pregnancy loss.Am J Reprod Immunol. 2009; 62: 253-60Crossref PubMed Scopus (0) Google Scholar], 29 women with a history of unexplained recurrent fetal loss and infertility using fondaparinux 2.5 mg once daily during the 1st trimester of pregnancy were described. They reported no adverse events, in particular no fetal abnormalities. In the 13 infants in our study, no congenital abnormalities or bleeding occurred. Our data are obviously limited by the size of our study, although it is the largest prospective series reported. Of note, only two infants were exposed during the first trimester. A limitation of our study is the missing anti‐FXa levels in maternal and cord blood during labor because of the possibility of passage through the placenta and the potential side effects for mother and child. Nevertheless, none of the children had neonatal bleeding or fetal abnormalities. In conclusion, we report here an alternative treatment with fondaparinux in 12 pregnancies in 10 women who had hypersensitivity skin reactions to LMWH. Fondaparinux did not cause hypersensitivity skin reactions and was not associated with bleeding or other complications in the mother and child. However, given the limited data, the use of fondaparinux during the first trimester should still be avoided. H.M. Knol and K. Meijer conceived the study idea and all authors contributed to the study design, data abstraction and interpretation. H.M. Knol wrote the manuscript and all authors took part in its revision and approved the final version. The authors declare that there are no conflict of interest.