Hematologic Agent (Thrombin Inhibitor)
PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The animal data suggest low risk, but the near absence of human pregnancy experience prevents a more complete assessment of embryo/fetal risk. The passage of lepirudin across the rat placenta suggests that the agent might also cross the human placenta. The effects of this potential exposure on a human embryo or fetus, including hemorrhage, are unknown. However, if a pregnant woman requires lepirudin therapy for heparin-induced thrombocytopenia (HIT), the benefits to her appear to outweigh the theoretical risks to her embryo–fetus.
FETAL RISK SUMMARY
The polypeptide lepirudin (rDNA) is a recombinant hirudin derived from yeast cells that is indicated for anticoagulation in patients with HIT and associated thromboembolic disease. It is composed of 65 amino acids and is administered as a continuous IV infusion. Lepirudin binds to thrombin to directly block the thrombogenic activity of thrombin (1).
Reproduction studies with lepirudin have been conducted in rats and rabbits. In pregnant rats, IV doses up to 1.2 times the maximum recommended daily human dose based on BSA (MRHD) during organogenesis and the perinatal–postnatal period revealed no evidence of fetal harm. However, increased rat maternal mortality from undetermined causes was noted. Studies with pregnant rabbits at IV doses up to 2.4 times the MRHD also found no evidence of embryo or fetal harm (1).
Despite the high molecular weight of lepirudin (about 6970), the drug crosses the placenta of pregnant rats (1). Because of the similarities between rat and human placentas, exposure of the human embryo–fetus might occur.
Several case reports (2–6) and a review (7) have described the successful use of lepirudin for the treatment of HIT in pregnancy. In another case report, lepirudin was used in the 3rd trimester when heparin-induced thrombosis occurred (8). Developmental toxicity was not observed in any of these cases.
BREASTFEEDING SUMMARY
One report has described the use of lepirudin (recombinant hirudin) during lactation. A 34-year-old woman, breastfeeding a 7-week-old infant, developed a deep vein thrombosis in her calf and was treated with low-molecular-weight heparin (9). She developed HIT on day 20 of treatment. Therapy was changed to lepirudin 50 mg twice daily. Although therapeutic levels of hirudin were measured in her plasma (0.5–1.0 mg/L), it was not detected in her milk (detection level 0.1 mg/L). The woman continued breastfeeding for the next 6 months while being treated with lepirudin. No adverse effects were observed in the mother or infant (9).
The above report is consistent with the high molecular weight (about 6970) of lepirudin that suggests excretion into milk does not occur. Even if small amounts are excreted, the polypeptide probably would be digested in the stomach of the infant.
References
1.Product information. Refludan. Aventis Pharmaceuticals, 2002.
2.Huhle G, Geberth M, Hoffmann U, Heene DL, Harenberg J. Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin. Gynecol Obstet Invest 2000;49:67–9.
3.Mehta R, Golichowski A. Treatment of heparin-induced thrombocytopenia and thrombosis during the first trimester of pregnancy. J Thromb Haemost 2004;2:1665–6.
4.Harenberg J, Jorg I, Bayer C, Fiehn C. Treatment of a woman with lupus pernio, thrombosis and cutaneous intolerance to heparins using lepirudin during pregnancy. Lupus 2005;14:411–2.
5.Furlan A, Vianello F, Clementi M, Prandoni P. Heparin-induced thrombocytopenia occurring in the first trimester of pregnancy: successful treatment with lepirudin. A case report. Haematologica 2006;91(8 Suppl):ECR40.
6.Plesinac S, Babovic I, Plesinac Karapandzic V. Successful pregnancy after pulmonary embolism and heparin-induced thrombocytopenia—case report. Clin Exp Obstet Gynecol 2013;40:307–8.
7.Lindhoff-Last E, Bauersachs R. Heparin-induced thrombocytopenia—alternative anticoagulation in pregnancy and lactation. Semin Thromb Hemost 2002;28:439–46.
8.Chapman ML, Martinez-Borges AR, Mertz HL. Lepirudin for treatment of acute thrombosis during pregnancy. Obstet Gynecol 2008;112:432–3.
9.Lindhoff-Last E, Willeke A, Thalhammer C, Nowak G, Bauersachs R. Hirudin treatment in a breastfeeding woman. Lancet 2000;355:467–8.