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Absence of teratogenicity of sirolimus used during early pregnancy in a liver transplant recipient
Absence of Teratogenicity of Sirolimus Used During Early Pregnancy in a Liver Transplant Recipient I. Jankowska, U. Oldakowska-Jedynak, Z. Jabiry-Zieniewicz, A. Cyganek, J. Pawlowska, M. Teisseyre, P. Kalicinski, M. Markiewicz, L. Paczek, and J. Socha ABSTRACT We describe the case of successful delivery in a 21-year-old woman who became pregnant 3 years after liver transplantation and who received sirolimus during the first 6 weeks of gestation. Sirolimus was discontinued when ultrasonography revealed a pregnancy, she was switched to tacrolimus and prednisone was continued. The course of pregnancy was uneventful; there were no signs or symptoms of graft rejection. Due to fetal intrauterine threatening asphyxia the pregnancy was concluded by cesearean section in the 39th gestational week, delivering a healthy, 2950 g, Apgar 10, female infant.
S
IROLIMUS WAS INTRODUCED for renal transplantation in 1999. It has recently been used by an increasing number of liver transplant centers. The drug acts through inhibition of signal transduction pathways, producing many biological effects: inhibition of lymphocyte proliferation, of fibrosis and fibroblast proliferation, and of neoplastic progression.1 The clinical side effects of the drug include hyperlipidemia and hepatic artery thrombosis. However, there is little information on the possible effects of sirolimus on the human fetus. In this article we present a case of a successful delivery in an orthotopic liver transplant patient treated with sirolimus during early pregnancy. CASE REPORT A 21-year-old woman had undergone liver transplantation (LTx) for cirrhosis due to biliary atresia, portal hypertension, and esophageal varices at the age of 16 years. Initial immunosuppressive therapy included cyclosporine and prednisone. Six days after LTx she developed an acute rejection episode confirmed by liver biopsy. Treatment with steroid pulses yielded a good result. Cyclosporine was maintained, prednisone doses were modified, and additionally, azathioprine was administered. After a second episode of acute rejection (2 months later), cyclosporine was replaced with tacrolimus, and steroid therapy continued. One year after liver transplantation, sirolimus was introduced due to renal dysfunction (GFR/1.75 m2 46 ml/min; hippuran clearance 167 mL/min; urea 52 mg/dL; creatinine 1.3 mg/dL). The tacrolimus dose was reduced by half to maintain a level of 4 to 8 ng/mL. The regimen of sirolimus, steroids, and tacrolimus was well tolerated by the patient. The liver function was good and renal function improved significantly (5 months later GFR/1.75 m2 75 mL/min, hippuran clearance 511 mL/min; urea 27 mg/dL; creatinine 0.8 mg/dL). Three years after liver transplantation the patient developed amenorrhea; ultrasonography revealed a 6-week gestation. Sirolimus was immediately discontinued, but prednisone and
tacrolimus were maintained throughout the full course of her pregnancy, delivery, and postpartum period. Liver function tests and serum creatinine remained normal. FK levels were maintained within the range of 6 to 8 ng/mL. In the 34th geststional week an ultrasound showed normal fetal anatomy with breech presentation, normal fetal growth, and normal amniotic fluid. The placenta was anterior and grade II/III. KTG showed a normal heart rate about 140 to 150 per minute with acceleration. In the 39th gestation week the patient was admitted without contractions of the uterus. The biophysical profile scoring was 8 points. Observation confirmed by KTG showed short periodic decreases in term variability. Umbilical artery flow was S/D 4.04, PJ 1.05, RJ 0.66. Due to fetal intrauterine threatening asphyxia with a breech presentation, she underwent cesearean section yielding a healthy, Apgar 10, female infant whose weight was 2950 g. The postoperative course was ancomplicated. There were no congenital malformations or unusual infections. Postnatal follow-up showed normal physical development.
DISCUSSION
The number of pregnancies following liver transplantation has been increasing due to improved patient and graft From the Department of Gastroenterology, Hepatology and Immunology (I.J., J.P., M.T., J.S.), The Children’s Memorial Health Institute, Warsaw, Poland; Department of Immunology, Transplantology and Internal Diseases (U.O.-J., L.P.), University Medical School, Warsaw, Poland; Department of Obstetrics and Gynecology (Z.J.-Z., A.C.), University Medical School, Warsaw, Poland; and Department of Pediatric Surgery and Organ Transplantation (P.K., M.M.), The Children’s Memorial Health Institute, Warsaw, Poland. Address reprint requests to Dr Irena Jankowska, Children’s Memorial Health Institute, Department of Gastroenterology, Hepatology and Immunology, Warsaw, Poland.
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.11.102
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3232
Transplantation Proceedings, 36, 3232–3233 (2004)
SIROLIMUS IN EARLY PREGNANCY
survival and a better quality of life.2 There are no current data on the use of sirolimus during early pregnancy, or on its effect on the human fetus. Albengres et al evaluated possible toxic effects of immunosuppressive drugs in human subjects.3 Experimental and clinical data demonstrated that the use of immunosuppressants was not a contraindication for pregnancy. Animal studies showed that immunosuppressants are not carcinogenic for the fetus; however, some of them may be teratogenic, although the risk, seems to be very low. The course of pregnancy in our patient was uneventful; there were no signs or symptoms of graft rejection. Also, there was no evidence of teratogenicity in the infant. Since there have been no reports regarding pregnancies on
3233
sirolimus therapy we decided to discontinue the therapy. Our data seem to confirm that successful pregnancies after liver transplantation, under careful management by transplant specialists, obstetrician, and perinatalogists, may have a good outcome. REFERENCES 1. Trotter JF: Sirolimus in liver transplantation. Transplant Proc 35(Suppl):193S, 2003 2. Armenti VT, Radomski JS, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 123, 2000 3. Albengres E, Le Louet H, Tillement JP: Immunosuppressive drugs and pregnancy: experimental and clinical data. Transplant Proc 29:2461, 1997
S
IROLIMUS WAS INTRODUCED for renal transplantation in 1999. It has recently been used by an increasing number of liver transplant centers. The drug acts through inhibition of signal transduction pathways, producing many biological effects: inhibition of lymphocyte proliferation, of fibrosis and fibroblast proliferation, and of neoplastic progression.1 The clinical side effects of the drug include hyperlipidemia and hepatic artery thrombosis. However, there is little information on the possible effects of sirolimus on the human fetus. In this article we present a case of a successful delivery in an orthotopic liver transplant patient treated with sirolimus during early pregnancy. CASE REPORT A 21-year-old woman had undergone liver transplantation (LTx) for cirrhosis due to biliary atresia, portal hypertension, and esophageal varices at the age of 16 years. Initial immunosuppressive therapy included cyclosporine and prednisone. Six days after LTx she developed an acute rejection episode confirmed by liver biopsy. Treatment with steroid pulses yielded a good result. Cyclosporine was maintained, prednisone doses were modified, and additionally, azathioprine was administered. After a second episode of acute rejection (2 months later), cyclosporine was replaced with tacrolimus, and steroid therapy continued. One year after liver transplantation, sirolimus was introduced due to renal dysfunction (GFR/1.75 m2 46 ml/min; hippuran clearance 167 mL/min; urea 52 mg/dL; creatinine 1.3 mg/dL). The tacrolimus dose was reduced by half to maintain a level of 4 to 8 ng/mL. The regimen of sirolimus, steroids, and tacrolimus was well tolerated by the patient. The liver function was good and renal function improved significantly (5 months later GFR/1.75 m2 75 mL/min, hippuran clearance 511 mL/min; urea 27 mg/dL; creatinine 0.8 mg/dL). Three years after liver transplantation the patient developed amenorrhea; ultrasonography revealed a 6-week gestation. Sirolimus was immediately discontinued, but prednisone and
tacrolimus were maintained throughout the full course of her pregnancy, delivery, and postpartum period. Liver function tests and serum creatinine remained normal. FK levels were maintained within the range of 6 to 8 ng/mL. In the 34th geststional week an ultrasound showed normal fetal anatomy with breech presentation, normal fetal growth, and normal amniotic fluid. The placenta was anterior and grade II/III. KTG showed a normal heart rate about 140 to 150 per minute with acceleration. In the 39th gestation week the patient was admitted without contractions of the uterus. The biophysical profile scoring was 8 points. Observation confirmed by KTG showed short periodic decreases in term variability. Umbilical artery flow was S/D 4.04, PJ 1.05, RJ 0.66. Due to fetal intrauterine threatening asphyxia with a breech presentation, she underwent cesearean section yielding a healthy, Apgar 10, female infant whose weight was 2950 g. The postoperative course was ancomplicated. There were no congenital malformations or unusual infections. Postnatal follow-up showed normal physical development.
DISCUSSION
The number of pregnancies following liver transplantation has been increasing due to improved patient and graft From the Department of Gastroenterology, Hepatology and Immunology (I.J., J.P., M.T., J.S.), The Children’s Memorial Health Institute, Warsaw, Poland; Department of Immunology, Transplantology and Internal Diseases (U.O.-J., L.P.), University Medical School, Warsaw, Poland; Department of Obstetrics and Gynecology (Z.J.-Z., A.C.), University Medical School, Warsaw, Poland; and Department of Pediatric Surgery and Organ Transplantation (P.K., M.M.), The Children’s Memorial Health Institute, Warsaw, Poland. Address reprint requests to Dr Irena Jankowska, Children’s Memorial Health Institute, Department of Gastroenterology, Hepatology and Immunology, Warsaw, Poland.
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.11.102
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3232
Transplantation Proceedings, 36, 3232–3233 (2004)
SIROLIMUS IN EARLY PREGNANCY
survival and a better quality of life.2 There are no current data on the use of sirolimus during early pregnancy, or on its effect on the human fetus. Albengres et al evaluated possible toxic effects of immunosuppressive drugs in human subjects.3 Experimental and clinical data demonstrated that the use of immunosuppressants was not a contraindication for pregnancy. Animal studies showed that immunosuppressants are not carcinogenic for the fetus; however, some of them may be teratogenic, although the risk, seems to be very low. The course of pregnancy in our patient was uneventful; there were no signs or symptoms of graft rejection. Also, there was no evidence of teratogenicity in the infant. Since there have been no reports regarding pregnancies on
3233
sirolimus therapy we decided to discontinue the therapy. Our data seem to confirm that successful pregnancies after liver transplantation, under careful management by transplant specialists, obstetrician, and perinatalogists, may have a good outcome. REFERENCES 1. Trotter JF: Sirolimus in liver transplantation. Transplant Proc 35(Suppl):193S, 2003 2. Armenti VT, Radomski JS, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 123, 2000 3. Albengres E, Le Louet H, Tillement JP: Immunosuppressive drugs and pregnancy: experimental and clinical data. Transplant Proc 29:2461, 1997