Hematologic Agent (Thrombolytic)
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The lack of animal reproductive studies and the near absence of human pregnancy experience prevent an assessment of the embryo–fetal risk. The drug does not appear to cross the placenta so that a direct risk to the embryo or fetus seems unlikely. However, drotrecogin alfa (activated) has been associated with a nonsignificant trend to more maternal hemorrhage and this would be a major risk to both the mother and fetus (1). Nevertheless, as demonstrated by the two case reports below, if the drug is indicated, it should not be withheld because of pregnancy (2,3).
FETAL RISK SUMMARY
Drotrecogin alfa (activated), a serine protease, is a recombinant (from a human cell line) form of human activated protein C. This glycoprotein is indicated for the reduction of mortality in adult patients with severe sepsis who have a high risk of death. It is administered as a continuous IV infusion because of its very short elimination half-life. The antithrombotic action of drotrecogin alfa (activated) is a result of inhibition of Factors Va and VIIIa. The agent is inactivated by endogenous plasma protease inhibitors. Animal reproduction studies have not been conducted with drotrecogin alfa (activated) (4).
It is not known if drotrecogin alfa (activated) crosses the human placenta to the embryo or fetus, but the molecular weight (about 55,000) of this glycoprotein should inhibit transfer. In addition, because the fetus can synthesize coagulation factors from early in gestation, there are no known physiologic processes in which endogenous maternal activated protein C would be actively transported across the placenta (1). Further, in vitro studies have found no evidence that endogenous protein C crosses the placenta or that it is metabolized by the placenta (1). However, the effect on these processes from high maternal plasma concentrations of activated protein C resulting from infusion of the drug has not been studied.
Drotrecogin alfa (activated) has been recommended for the treatment of preeclampsia because this disease is similar in some ways to severe sepsis: diffuse effects on the maternal vascular endothelium resulting in multiple organ dysfunctions (1,5). A 2002 publication reviewed previous reports on the pathogenesis of preeclampsia to determine whether administration of drotrecogin alfa (activated) could be beneficial in the treatment of this disease (1). The authors of this in-depth assessment concluded that, although the data were limited, there was adequate evidence to support phase II clinical studies in women with early-onset preeclampsia (before 33 weeks’ gestation) or severe or worsening postpartum disease (1).
A preliminary report of a phase II study describing the use of human activated protein C for the treatment of disseminated intravascular coagulation (DIC) was published in 1999. A total of 16 women with moderate-to-severe placental abruption were treated over a 2-day period (4). The activated protein C was prepared by extracting protein C from human plasma and activating it with human thrombin. Clinical signs were markedly improved and all coagulation/fibrinolysis parameters, except for the number of platelets, demonstrated significant changes toward normal values. No adverse effects attributable to the treatment were observed (6).
Two case reports described the successful use of drotrecogin alfa (activated) in the 2nd and 3rd trimesters of two women with severe sepsis (2,3). Use of the drug in these cases was indicated because severe sepsis is characterized, among other problems, by dysregulation of coagulation. The women received a continuous infusion of drotrecogin alfa (activated) for 96 hours and their conditions significantly improved. Both eventually gave birth to normal infants (2,3).
BREASTFEEDING SUMMARY
No reports describing the use of drotrecogin alfa (activated) during human lactation have been located. It is doubtful if a nursing infant would have access to the breast milk of a woman treated with this drug because of its indication for severe, life-threatening disease. The very high molecular weight of this glycoprotein (about 55,000) should inhibit excretion into milk, but even if such excretion occurred, the drug would most likely be digested in the infant’s gut.
References
1.von Dadelszen P, Magee LA, Lee SK, Stewart SD, Simone C, Koren G, Walley KR, Russell JA. Activated protein C in normal human pregnancy and pregnancies complicated by severe preeclampsia: a therapeutic opportunity? Crit Care Med 2002;30:1883–92.
2.Gupta R, Strickland KM, Mertz HL. Successful treatment of severe sepsis with recombinant activated protein C during the third trimester of pregnancy. Obstet Gynecol 2011;118:492–4.
3.Eppert HD, Goddard KB, King CL. Successful treatment with drotrecogin alfa (activated) in a pregnant women with severe sepsis. Pharmacotherapy 2011;31:333. doi:10.1592/phco.31.3.333.
4.Product information. Xigris. Eli Lilly and Company, 2003.
5.Lapinsky SE, Mehta S. Activated protein C for preeclampsia: tailoring the disease to the therapy. Crit Care Med 2002;30:1929–30.
6.Kobayashi T, Terao T, Maki M, Ikenoue T. Activated protein C is effective for disseminated intravascular coagulation associated with placental abruption. Throm Haemost 1999;82:1363.