Hematologic Agent (Thrombin Inhibitor)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Antithrombin III (human) has been used in the 2nd and 3rd trimesters for the treatment of preeclampsia. Preliminary evidence suggests that this treatment may be beneficial, but further studies are needed to confirm these outcomes. Although the limited animal data are reassuring, there is no human 1st trimester experience with this agent.
FETAL RISK SUMMARY
This product is prepared from pooled units of human plasma from screened normal plasma donors. Although the risk of transmitting infectious agents, such as viruses, has been reduced by measures taken during production, there is still a potential for transmitting disease (1). Antithrombin III is an α2-glycoprotein that normally is present in human plasma at a concentration of approximately 12.5 mg/dL (1). It is the major plasma inhibitor of thrombin.
Reproduction studies have been conducted with antithrombin III in pregnant rats and rabbits. No evidence of impaired fertility or fetal harm was observed with doses up to four times the human dose (1).
It is not known whether there are physiologic processes that can carry maternal antithrombin to the embryo or fetus. The molecular weight of the protein, about 58,000, should prevent passive diffusion.
Two reports have described the use of antithrombin III in the treatment of preeclampsia (2,3). In both cases, the beneficial effects of antithrombin III were theorized to be related to the inhibition of thrombin, resulting in a reduction in maternal hypertension and an increase in placental circulation (2,3). In a nonrandomized study, women with severe early-onset preeclampsia (mean gestational age at onset 28–29 weeks) with intrauterine growth restriction were treated for 7 days with antithrombin III 1500 IU/day and heparin 5000 U/day (N = 14) or heparin 5000 U/day alone (N = 15) (2). None of the women received antihypertensive agents. The mean gestational age at the beginning of treatment was 30–31 weeks with delivery in both groups occurring at about 32 weeks’ gestation. There was no difference in the mean birth weights (1280 vs. 1135 g), but the estimated fetal weight gain (g/day) was higher in the antithrombin group (29.5 vs. 15.3 g, p < 0.05). No information was provided on the status of the newborns, but there were no differences between the groups in the fetal biochemical profile score (2).
A total of 133 women with severe preeclampsia (24–35 weeks’ gestation) were enrolled in a randomized, double-blind, placebo-controlled trial (3). The patients received either antithrombin III 3000 units once daily for 7 days (N = 66) or albumin once daily for 7 days (N = 67). The mean gestational age at the start of treatment was about 32 weeks in both groups. Treatment was interrupted in 23 and 29 patients in the antithrombin III and placebo groups, respectively, because of worsening of maternal and fetal findings. Patients in each group received antihypertensive agents and/or magnesium sulfate when indicated. There were no significant differences between the groups in the fetal biochemical profile score, but the antithrombin III group had a greater estimated fetal gain (p = 0.029). Pregnancy outcomes all favored the treatment group: gestational age at delivery (34.1 vs. 33.0 weeks, p = 0.007), birth weight (1749 vs. 1409 g, p = 0.004), and number of small-for-gestational-age newborns (65.6% vs. 83.3%, p = 0.020). No adverse effects in the newborns were observed (3).
BREASTFEEDING SUMMARY
No reports describing the use of antithrombin III during lactation have been located. The high molecular weight of the protein (about 58,000) suggests that it will not be excreted into breast milk. However, even if small amounts did enter the milk they likely would be digested in the infant’s stomach. Therefore, the risk to a nursing infant from this agent appears to be nil.
References
1.Product information. Thrombate III. Bayer Corporation, Pharmaceutical Division, Biological Products, 2003.
2.Nakabayashi M, Asami M, Nakatani A. Efficacy of antithrombin replacement therapy in severe early-onset preeclampsia. Semin Thromb Hemost 1999;25:463–6.
3.Maki M, Kobayashi T, Terao T, Ikenoue T, Satoh K, Nakabayashi M, Sagara Y, Kajiwara Y, Urata M. Antithrombin therapy for severe preeclampsia. Results of a double-blind, randomized, placebo-controlled trial. Thromb Haemost 2000;84:583–90.