Immunologic Agent (Immunosuppressant)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Only a few reports of exposure to sirolimus in human pregnancy have been located. The animal reproduction data suggest a potential for toxicity, but not for teratogenicity. The in vitro study described suggests that sirolimus could affect growth of the fetal and neonatal heart. Although the clinical significance of the concentrations used in that study is unknown, there was no attempt to determine the no-effect concentration. The very limited human pregnancy experience prevents a full assessment of the risk. Reviews discussing transplantation in pregnancy are ambivalent regarding the use of sirolimus; with some not recommending its use (1) and others implying that it may be continued in pregnancy (2). Until human data are available, however, the safest course is to avoid the drug in pregnancy. If sirolimus is used in pregnancy, or in the event of inadvertent exposure, close monitoring of the embryo–fetus for developmental toxicity is warranted. The manufacturer recommends that women of childbearing potential use effective contraception before and during therapy, and for 12 weeks after therapy is stopped (3).
FETAL RISK SUMMARY
Sirolimus (rapamycin) is a distinct, oral immunosuppressant that is indicated for the prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that it initially be used in combination with cyclosporine and corticosteroids. Chemically, the drug is a macrocyclic lactone produced by Streptomyces hygroscopicus. Sirolimus inhibits T-lymphocyte activation and proliferation induced by antigenic and cytokine (interleukin-2 [IL-2], IL-4, and IL-15) stimulation. Sirolimus is classified as a small-molecule immunosuppressant agent (4). It is highly protein bound to plasma albumin and other proteins (about 92%) and has a mean terminal half-life in renal transplant patients of about 62 hours (3).
Reproduction studies have been conducted in rats and rabbits. In rats, doses about 0.2–0.5 times the human clinical dose based on BSA (HCD) were embryo–fetal toxic (death; reduced fetal weights with associated delays in skeletal ossification). However, structural defects were not observed. No effect on female rat fertility was observed at doses about 1–3 times the HCD. When combined with cyclosporine, increased embryo–fetal death compared with sirolimus alone was observed in rats. In pregnant rabbits, there were no effects on development at a maternal toxic dose about 0.3–0.8 times the HCD (3).
In carcinogenesis studies in mice and rats, there was a significant increase in malignant lymphoma at all doses tested (about 16–135 times the HCD). In mice, a lower dose (about 3–16 times the HCD) was associated with hepatocellular adenoma and carcinoma (males). In rats, a dose approximately equivalent to the HCD significantly increased the incidence of testicular adenoma. Sirolimus was not genotoxic in a variety of assays (3).
A 1998 in vitro study examined the effect of sirolimus on heart cell growth (5). Cardiac myocytes were isolated from 15-day-old fetal rats and exposed for 5 days in culture medium to various concentrations of sirolimus. (Note: The lowest concentration tested [0.5 ng/mL] was about 1.3% of the adult mean maximum concentration [37.4 ng/mL] obtained with a 5 mg/day dose). The exposed cells were then washed and grown in culture medium without sirolimus for an additional 5 days. Sirolimus inhibited both short-term and subsequent proliferation of cardiac myocytes. The investigators noted that fetal and neonatal heart growth occurs predominantly through myocyte proliferation (5).
It is not known if sirolimus crosses the human placenta. The molecular weight (about 914) is within the range for passive diffusion, and the elimination half-life will allow the drug to be present at the maternal:fetal interface for a long interval. However, the high protein binding should limit the amount of drug available to cross the placenta.
A 2003 report from the National Transplantation Pregnancy Registry briefly described four female kidney recipients who were treated during pregnancy with sirolimus and other immunosuppressants (6). The outcomes of the pregnancies were three live births (at 31, 36, and 38 weeks’ gestation) and one spontaneous abortion (at 8 weeks’ gestation). The only structural defect observed in the four cases was a cleft lip/palate and an ear deformity in a 1531-g infant delivered at 31 weeks’ gestation. Immunosuppression during the first 24 weeks consisted of mycophenolate mofetil, tacrolimus, and prednisone (6). Sirolimus, added at 24 weeks’ gestation for biopsy-proven acute rejection, was not related to the anomalies.
A 2004 case report described the use of sirolimus in a 21-year-old woman who became pregnant 3 years after liver transplantation (7). At the time of conception, immunosuppression was maintained with sirolimus, tacrolimus, and corticosteroids (doses not specified). Pregnancy was diagnosed at 6 weeks’ gestation and sirolimus was discontinued, but corticosteroids and tacrolimus were continued throughout pregnancy. At 39 weeks’ gestation, a healthy, 2950-g female infant was delivered by cesarean section. The infant’s physical development has been normal, and no unusual infections have been observed (7).
BREASTFEEDING SUMMARY
No reports describing the use of sirolimus during human lactation have been located. The molecular weight (about 914) and the prolonged half-life (about 62 hours) suggest that the drug will be excreted into breast milk. The effect of this potential exposure on a nursing infant is unknown, but consideration should be given to the carcinogenic properties of sirolimus, especially with long-term exposures. A 2002 review concluded that because of possible drug transfer into milk, women taking sirolimus should not breastfeed (1).
References
1.EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients. Nephrol Dial Transplant 2002;17 (Suppl 4):50–5.
2.Danesi R, Del Tacca M. Teratogenesis and immunosuppressive treatment. Transplant Proc 2004;36:705–7
3.Product information. Rapamune. Wyeth Pharmaceuticals, 2005.
4.Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715–29.
5.Burton PBJ, Yacoub MH, Barton PJR. Rapamycin (sirolimus) inhibits heart cell growth in vitro. Pediatr Cardiol 1998;19:468–70.
6.Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 2003;131–41.
7.Jankowska I, Oldakowska-Jedynak U, Jabiry-Zieniewicz Z, Cyganek A, Pawlowska J, Teisseyre M, Kalicinski P, Markiewicz M, Paczek L, Socha J. Absence of teratogenicity of sirolimus used during early pregnancy in a liver transplant recipient. Transplant Proc 2004;36:3232–3.