Case Report: Successful use of fondaparinux in a case of heparin intolerance during pregnancy [version 1; peer review: 2 not approved]

Heparin is the anticoagulant of choice during pregnancy. However, in cases of intolerance or adverse effects, another anti-coagulant agent should be administered. Here, we describe a case of hypersensitivity skin reaction seen in a 37-year-old pregnant patient at 11 weeks of gestation who used low-molecular-weight heparin (LMWH). Fondaparinux was used as an alternative during her pregnancy with a successful outcome.


Introduction
Low-molecular-weight heparin (LMWH), such as enoxaparin, is the preferred anticoagulant for pregnant women due to its effectiveness, safety, and availability.However, if the pregnant patient experiences an allergy, side effect or intolerance, she should be switched to alternative anticoagulation medication.Unfortunately, in such circumstances, the other anti-coagulation options are limited due to teratogenicity, lack of literature support, or cross-reactivity with LMWH.
Fondaparinux, which is a synthetic polysaccharide inhibitor of activated factor X (FXa), has been reported to be a successful alternative anticoagulant in pregnant patients who develop heparin intolerance, such as hypersensitivity skin reaction, which is frequently seen in pregnant patients 1 .Although it crosses the placental barrier and results in low measurable anti-factor Xa activity in umbilical-cord blood 2 , it is considered relatively safe since there are no significant reported unfavorable side effects for the mother or child during pregnancy or the postpartum period.

Case report
A 37-year-old Saudi female homemaker (G6P4+1) with a history of hypothyroidism on thyroxin and a history of miscarriage and intrauterine fetal death (IUFD) presented to our thrombosis clinic.She explained to us that this is an important pregnancy for her and that she wished to deliver a healthy baby.Her gynecological history comprised of: preeclampsia during her first pregnancy, resulting in premature labor; fetal distress during her second pregnancy; a third pregnancy resulting in premature labor at 30 weeks; a fourth pregnancy resulting in IUFD at 25 weeks; fetal distress in the 31 st week of her fifth pregnancy in 2012; and a sixth pregnancy resulting in IUFD in 2015.Therefore, she was referred to our tertiary care hospital and to our clinic to prevent morbidity and mortality in the current pregnancy.She presented to our clinic in 2016, 11 weeks pregnant, and on physical examination, cardiac and respiratory exams were normal.Abdominal examination showed a gravid uterus.Thrombophilia work up including protein C, protein S, antithrombin III, factor V Leiden mutation, prothrombin gene mutation G20210A, and antiphospholipid antibodies were within normal limits (Table 1).
The patient was started on aspirin 81 mg once daily, and low-molecular-weight-heparin (LMWH) 4000 units via subcutaneous injection once daily.We explained to the patient the rationale for using heparin was to prevent placental microvascular thrombosis and therefore, prevent placental mediated complications such as preeclampsia and IUFD.This is an internationally recommended evidence-based practice.
Five days later, she developed a severe rash, as depicted in Figures 1A-1D.Hence, LMWH was discontinued, and she was asked to resume taking aspirin 81 mg once daily.She was found to be allergic to LMWH (such as enoxaparin and tinzaparin), resulting in symptoms such as swelling, itching, and erythema, which slowly resolved one week after discontinuation of heparin.One month later, on her scheduled follow-up appointment with us, she no longer had any skin rash or any other hypersensitivity reaction symptoms.We suggested fondaparinux 2.5 mg delivered subcutaneously once daily.We explained to the patient that fondaparinux was an alternative anticoagulant for patients intolerant to heparin, with no reported hypersensitivity reactions or adverse effects on the fetus.She agreed, and hence we discontinued aspirin and started her on fondaparinux.We monitored her health through monthly follow-up clinic visits with regular laboratory tests and ultrasounds in the maternal fetal medicine and thrombosis clinics (Table 1).The ultrasounds had no significant findings, with a single viable fetus and normal growth.She was well with no allergic symptoms or discomfort, and kept taking fondaparinux for five months until her planned induction of labor at 38 weeks gestation with cessation of fondaparinux for 24 hours.She delivered a normal healthy baby and we followed up regularly with the patient for six weeks postpartum (Table 1).

Discussion
Heparin has always been the anticoagulant of choice to prevent and treat a thrombotic event during pregnancy 1 .However, its use is limited when adverse reactions such as skin rash (type I hypersensitivity reaction) or heparin-induced thrombocytopenia occurs.Hence, in the setting of heparin intolerance with a high risk of thrombosis, alternative choices for anticoagulation becomes limited.
Current evidence shows that fondaparinux is a safe and effective alternative option in the circumstances, such as seen in our case [2][3][4] .For instance, a retrospective study comparing the efficacy of fondaparinux to enoxaparin in terms of pregnancy success rate, gestational age, birth weight, and major bleeding complications concluded that both anticoagulants have comparable results 5 .In addition, a prospective study evaluating the effect of a prophylactic dose of fondaparinux in pregnant women with a history of venous thromboembolism reported 100% uneventful pregnancies without thromboembolic complications 6 .However, there is limited experience in the use of fondaparinux in pregnancy, but it has been used in patients with heparin intolerance with no reported adverse effects to the fetus or the mother 7 .
In concordance with the literature, our patient had an uneventful pregnancy without developing an adverse reaction to fondaparinux.With regards to the long-term safety of fondaparinux, several studies in the literature reported no significant difference in safety profile compared to enoxaparin over a period of therapy ranging between a few weeks to eight months.
On the other hand, umbilical blood sampling showed a detectable level of anti-factor Xa, indicating the passage of fondaparinux to fetal circulation.However, the accumulative level is measured and found to be subtherapeutic, and no study reported any complications during pregnancy or post-partum 8 .

Conclusion
In conclusion, our case demonstrates that fondaparinux is a safe and effective anticoagulant option in the presence of heparin intolerance.

Figure 1 .
Figure 1.A-D) The composite figure illustrates clinical findings, showing the patient's rash, when she was administered low-molecular weight heparin.