Hematologic Agent (Thrombin Inhibitor)
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Animal reproductive studies have not shown developmental toxicity, but the doses used were a small fraction of the human dose. The human pregnancy experience is limited to three case reports where argatroban was used in the 2nd and 3rd trimesters. No drug-induced toxicity, such as hemorrhage, was observed in the three exposed infants. Although there are no reports describing the use of argatroban in the 1st trimester, the lack of teratogenicity in animals and another agent in this subclass (see Lepirudin) is encouraging. Thus, if a pregnant woman requires argatroban therapy the benefits to her appear to outweigh the theoretical risks to the embryo or fetus.
FETAL RISK SUMMARY
Argatroban is a synthetic reversible direct thrombin inhibitor derived from L-arginine. It is in the same anticoagulant subclass as bivalirudin, desirudin, and lepirudin. Argatroban is indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). It is also indicated as an anticoagulant in patients with or at risk for HIT undergoing percutaneous coronary intervention. The drug is administered as a continuous IV infusion and undergoes partial metabolism in the liver. Total serum protein binding is 54%, with 20% bound to albumin and 34% to α1-acid glycoprotein. The terminal elimination half-life is 39–51 minutes (1).
Reproduction studies with IV argatroban have been conducted in pregnant rats and rabbits at doses up to 0.3 and 0.2 times, respectively, the maximum recommended human dose based on BSA. No evidence of impaired fertility or fetal harm was observed in either species (1).
It is not known if argatroban crosses the human placenta. The molecular weight (about 527 for the hydrated form), low metabolism, and moderate serum protein binding suggest that exposure of the embryo–fetus should be expected, especially since the drug is given as a continuous infusion.
The use of argatroban in the 2nd trimester was reported in 2008 (2). A 35-year-old woman with anemia secondary to myelodysplastic syndrome developed a deep vein thrombosis (location and extent not specified) in the 18th week of pregnancy and was treated with unfractionated heparin. Severe thrombocytopenia developed, which was subsequently shown to be caused by bone-marrow dysplasia and not heparin (HIT antibody was negative), and therapy was changed to daily IV doses of danaparoid. In the 22nd week of gestation, pulmonary embolism occurred after a leg massage. An emergency pulmonary embolectomy was performed under cardiopulmonary bypass to remove emboli from the right main pulmonary artery. Anticoagulation during surgery was maintained with argatroban. The woman recovered and eventually delivered a healthy infant by cesarean section at 29 weeks’ gestation. No details on the infant were provided (2).
A second 2008 report described the use of argatroban in the 3rd trimester (3). A 26-year-old woman with a nonocclusive portal vein thrombosis and thrombocytopenia secondary to idiopathic thrombocytopenic purpura was treated with enoxaparin at 31 weeks’ gestation. Two weeks later, because of worsening thrombocytopenia that initially was thought to be HIT but was later found not to be, treatment was changed to a continuous infusion of argatroban. Dexamethasone was given for 4 days before a scheduled cesarean section to increase the platelet count so that epidural anesthesia could be used. Argatroban was discontinued 7 hours before epidural anesthesia was successfully placed. A 3092-g male infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively, was delivered. Examination of the infant revealed a small muscular ventricular septal defect with a patent foramen ovale; neither was due to argatroban. The infant had a normal platelet count at birth. At 6 months of age, the ventricular septal defect had resolved but he still had a patent foramen ovale (3).
Argatroban was used in a 38-year-old woman with an upper extremity deep vein thrombosis who had developed HIT late in the 2nd trimester (4). As the thrombus resolved, her therapy was changed to SC fondaparinux 7.5 mg/day, and this agent was continued until the day before scheduled induction. During labor she was given an IV infusion of argatroban and then discontinued several hours before combined spinal–epidural analgesia. She gave birth to a healthy, 3.8-kg male infant with Apgar scores of 8 and 8 at 1 and 5 minutes, respectively. No bleeding complications were reported in the infant (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 workup, 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 infant details 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 a 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).
BREASTFEEDING SUMMARY
No studies describing the use argatroban during human lactation have been located. The molecular weight (about 527 for the hydrated form), low metabolism, and moderate serum protein binding suggest that the drug will be excreted into breast milk, especially as it is given as a continuous infusion. Both the effect of this exposure on a nursing infant and the potential for oral absorption are unknown. Severe adverse effects have been observed in adults, such as hypotension, fever, nausea/vomiting, and diarrhea (1). Thus, until human data are available, the safest course is to not breastfeed while receiving argatroban.
References
1.Product information. Argatroban. GlaxoSmithKline, 2009.
2.Taniguchi S, Fukuda I, Minakawa M, Watanabe K, Daitoku K, Suzuki Y. Emergency pulmonary embolectomy during the second trimester of pregnancy: report of a case. Surg Today 2008;38:59–61.
3.Young SK, Al-Mondhiry HA, Vaida SJ, Ambrose A, Botti JJ. Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature. Pharmacotherapy 2008;28:1531–6.
4.Ekbatani A, Asaro LR, Malinow AM. Anticoagulation with argatroban in a parturient with heparin-induced thrombocytopenia. Int J Obstet Anesth 2010;19:82–117.
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.