Cyclosporine

Risk Factor: CM
Class: Immunologic agents / Immunosuppressants

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Fetal Risk Summary

Cyclosporine (cyclosporin A), an antibiotic produced by certain fungi, is used as an immunosuppressive agent to prevent rejection of kidney, liver, or heart allografts.

In reproduction studies, cyclosporine produced embryo and fetal toxicity only at maternally toxic dose levels in rats (0.8 times the human transplant dose of 6 mg/kg corrected for body surface area) and in rabbits (5.4 times the human dose) (1). Toxic effects included increased pre- and postnatal mortality, and reduced fetal weight and related skeletal retardation. No teratogenic effects were observed.

Cyclosporine readily crosses the placenta to the fetus (2,3,4,5 and 6). In a 1983 study, the cord blood:maternal plasma ratio at delivery was 0.63 (2). In a second study, cord blood and amniotic fluid levels 8 hours after a dose of 325 mg were 57 and 234 ng/mL, respectively (3). Concentrations in the newborn fell to 14 ng/mL at 14 hours and were undetectable (<4 ng/mL) at 7 days. Cord blood:maternal plasma ratios in twins delivered at 35 weeks' gestation were 0.35 and 0.57, respectively (4). A similar ratio of 0.40 was reported in a case delivered at 31 weeks' gestation (5).

Several case reports describing the use of cyclosporine throughout gestation have been published (2,3,4,5,6,7,8,9,10,11,12 and 13). Maternal doses ranged between 260 and 550 mg/day (2,3 and 4,7,9,10,13). Cases usually involved maternal renal transplantation (2,3 and 4,6,7,8,9,10,11 and 12), but one report described a successful pregnancy in a woman after heart transplantation (5), one involved a combined transplant of a kidney and paratropic segmental pancreas in a diabetic woman (10), and one involved a patient with a liver transplant (13). In addition, a report has described a successful pregnancy in a woman with aplastic anemia who was treated with bone marrow transplantation (14). In this case, however, cyclosporine therapy had been stopped prior to conception. Guidelines for counseling heart transplant patients who wish to become pregnant have been published (15).

As of October, 1987, the manufacturer had knowledge of 34 pregnancies involving cyclosporine (A. Poploski and D.A. Colasante, personal communication, Sandoz Pharmaceuticals Corporation, 1987) (15). Some of these cases are described above. These pregnancies resulted in six abortions (one after early detection of anencephaly, three elective, and two spontaneous abortions, one at 20 weeks' gestation), one pregnancy still ongoing, and 27 live births. One of the newborns died at age 3 days. Autopsy revealed a complete absence of the corpus callosum. Other problems observed in individual newborns exposed in utero to cyclosporine were: thrombocytopenia (thought to be due to hydralazine taken by the mother for hypertension) (7), a hydrocele that resolved spontaneously (9), asphyxia and intracerebral bleeding in an extremely premature infant (A. Poploski and D.A. Colasante, personal communication, 1987), physiologic jaundice (A. Poploski and D.A. Colasante, personal communication), leukopenia (4) (A. Poploski and D.A. Colasante, personal communication, 1987), hypoglycemia and mild disseminated intravascular coagulation that resolved spontaneously (A. Poploski and D.A. Colasante, personal communication, 1987), and bilateral cataracts (A. Poploski and D.A. Colasante, personal communication, 1987). A 1989 case report described an infant with hypoplasia of the right leg and foot after in utero exposure to cyclosporine (11). The right leg was 2 cm shorter than the left. Hypoplasia of the muscles and subcutaneous tissue of the right leg was also present. The authors proposed a possible mechanism for the defect, which involved cyclosporine inhibition of lymphocytic interleukin-2 release and subsequent interference with the differentiation of osteoclasts (11).

Many of the liveborn infants were growth retarded (3,7,9,10,11,12 and 13). Birth weights of fullterm newborns ranged from 21603200 g (12,13) (A. Poploski and D.A. Colasante, personal communication, 1987). A 1985 review article observed that growth retardation was common in the offspring of renal transplant patients, occurring in 8%45% of reported pregnancies (16). Although the specific cause of the diminished growth could not be determined, the most likely processes involved were considered to be maternal hypertension, renal function, and immunosuppressive drugs (16).

Followup of children exposed in utero to cyclosporine has been conducted in a few cases (4,10) (A. Poploski and D.A. Colasante, personal communication, 1987). In 15 of 27 surviving neonates, early postnatal development was normal except for one infant with slight growth retardation (4,10) (A. Poploski and D.A. Colasante, personal communication, 1987). Postnatal development of 10 children followed from 113 months revealed normal physical and mental development (4,10) (A. Poploski and D.A. Colasante, personal communication, 1987). No abnormal renal or liver function has been reported in the exposed newborns.

In summary, based on relatively small numbers, the use of cyclosporine during pregnancy apparently does not pose a major risk to the fetus. Cyclosporine is not an animal teratogen (1,17), and the limited experience in women indicates that it is unlikely to be a human teratogen. No pattern of defects has emerged in the few newborns with anomalies. Skeletal defects, other than the single case of osseous malformation, have not been observed. The disease process itself, for which cyclosporine is indicated, makes these pregnancies high risk and subject to numerous potential problems, of which the most common is growth retardation. This latter problem is probably related to the mother's disease rather than to her drug therapy, but a contribution from cyclosporine and corticosteroids cannot be excluded. Long-term follow-up studies are warranted, however, to detect latent effects including those in subsequent generations.

Breast Feeding Summary

Cyclosporine is excreted into human breast milk (2,3,5,6,18). In a patient taking 450 mg of cyclosporine/day, milk levels on postpartum days 2, 3, and 4 were 101, 109, and 263 ng/mL, respectively (2). No details were given about the relationship of maternal doses with these levels. In another patient, milk concentrations 22 hours after a dose of 325 mg were 16 ng/mL while maternal blood levels were 52 ng/mL, a milk:plasma ratio of 0.31 (3). A milk:plasma ratio of 0.40 was reported in one study (5) and a ratio of approximately 0.17 was measured in another (6). Breast feeding was not allowed in any of these studies and has been actively discouraged by most sources because of concerns for potential toxicity in the nursing infant (12,13,15,17) (A. Poploski and D.A. Colasante, personal communication, 1987).

A 2001 study reported the use of cyclosporin in a woman who was breast-feeding (18). The woman had a simultaneous kidney-pancreas transplant 13 months before conception. She was treated before, during, and after pregnancy with cyclosporine (300 mg twice daily), azathioprine (100 mg/day), and prednisone (10 mg/day). At 34 weeks' gestation, she delivered an 1800-g male infant with Apgar scores of 5 and 8 at 1 and 5 minutes, respectively. Mild hyperbilirubinemia, treated with phototherapy, was the infant's only complication. The mother's cyclosporine levels during pregnancy were 75173 ng/mL (therapeutic range 100125 ng/mL in whole blood) but were not determined at birth. The cord blood cyclosporine concentration was 67 ng/mL. Breast feeding was initiated 2 hours after birth and continued exclusively for the first 10.5 months of life. Random cyclosporine levels in the infant's serum were<25 ng/mL at approximately 1, 1.5, 2.5, 4, and 10.5 months of age. Maternal serum cyclosporine levels at approximately 1, 1.5, and 2.5 months were 193, 273, and 123 ng/mL, respectively, and breast milk levels were 160, 286, and 79 ng/mL, respectively. No adverse effects from exposure to cyclosporine were observed in the infant. At 12 months of age, his weight and height were at the 46th and 55th percentile, respectively. The mother has subsequently delivered a second child that was also breast-fed (18).

The American Academy of Pediatrics considers cyclosporine to be contraindicated during breast feeding due to the potential for immune suppression and neutropenia, an unknown effect on growth, and a possible association with carcinogenesis (19).

References

  1. Product information. Neoral. Novartis Pharmaceuticals, 2000.
  2. Lewis GJ, Lamont CAR, Lee HA, Slapak M. Successful pregnancy in a renal transplant recipient taking cyclosporin A. Br Med J 1983;286:603.
  3. Flechner SM, Katz AR, Rogers AJ, Van Buren C, Kahan BD. The presence of cyclosporine in body tissues and fluids during pregnancy. Am J Kidney Dis 1985;5:603.
  4. Burrows DA, O'Neil TJ, Sorrells TL. Successful twin pregnancy after renal transplant maintained on cyclosporine A immunosuppression. Obstet Gynecol 1988;72:45961.
  5. Lowenstein BR, Vain NW, Perrone SV, Wright DR, Boullon FJ, Favaloro RG. Successful pregnancy and vaginal delivery after heart transplantation. Am J Obstet Gynecol 1988;158:58990.
  6. Ziegenhagen DJ, Grombach G, Dieckmann M, Zehnter E, Wienand P, Baldamus CA. Pregnancy under cyclosporine administration after renal transplantation. Dtsch Med Wochenschr 1988;113:2603.
  7. Klintmalm G, Althoff P, Appleby G, Segerbrandt E. Renal function in a newborn baby delivered of a renal transplant patient taking cyclosporine. Transplantation 1984;38:1989.
  8. Grischke E, Kaufmann M, Dreikorn K, Linderkamp O, Kubli F. Successful pregnancy after kidney transplantation and cyclosporin A. Geburtshilfe Frauenheilkd 1986;46:1769.
  9. Pikrell MD, Sawers R, Michael J. Pregnancy after renal transplantation: severe intrauterine growth retardation during treatment with cyclosporin A. Br Med J 1988;296:825.
  10. Calne RY, Brons IGM, Williams PF, Evans DB, Robinson RE, Dossa M. Successful pregnancy after paratopic segmental pancreas and kidney transplantation. Br Med J 1988;296:1709.
  11. Pujals JM, Figueras G, Puig JM, Lloveras J, Aubia J, Masramon J. Osseous malformation in baby born to woman on cyclosporin. Lancet 1989;1:667.
  12. AlKhader AA, Absy M, AlHasani MK, Joyce B, Sabbagh T. Successful pregnancy in renal transplant recipients treated with cyclosporine. Transplantation 1988;45:9878.
  13. Sims CJ, Porter KB, Knuppel RA. Successful pregnancy after a liver transplant. Am J Obstet Gynecol 1989;161:5323.
  14. Deeg HJ, Kennedy MS, Sanders JE, Thomas ED, Storb R. Successful pregnancy after marrow transplantation for severe aplastic anemia and immunosuppression with cyclosporine. JAMA 1983;250:647.
  15. Kossoy LR, Herbert CM III, Wentz AC. Management of heart transplant recipients: guidelines for the obstetrician gynecologist. Am J Obstet Gynecol 1988;159:4909.
  16. Lau RJ, Scott JR. Pregnancy following renal transplantation. Clin Obstet Gynecol 1985;28:33950.
  17. Product information. Sandimmune. Sandoz Pharmaceutical Corporation, 1986.
  18. Thiagarajan (Munoz-Flores) KD, Easterling T, Davis C, Bond EF. Breast-feeding by a cyclosporin-treated mother. Obstet Gynecol 2001;97:8168.
  19. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.

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