Immunologic Agent (Immunosuppressant)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY 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 (1,2), 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. When used as an immunosuppressant, the disease process itself makes these pregnancies high risk and subject to numerous potential problems, of which the most common is growth restriction. 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. If cyclosporine is used in pregnancy for the treatment of rheumatoid arthritis or psoriasis, healthcare professionals are encouraged to call the toll-free number (877-311-8972) for information about patient enrollment in the OTIS Rheumatoid Arthritis study.
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. Other indications for the drug are the treatment of severe, active rheumatoid arthritis and severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis (1).
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 BSA) and in rabbits (5.4 times the human dose). Toxic effects included increased pre- and postnatal mortality, and reduced fetal weight and related skeletal restriction. No teratogenic effects were observed (1).
Cyclosporine readily crosses the placenta to the fetus (3–7). In a 1983 study, the cord blood:maternal plasma ratio at delivery was 0.63 (3). 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 (4). 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 (5). A similar ratio of 0.40 was reported in a case delivered at 31 weeks’ gestation (6).
Several case reports describing the use of cyclosporine throughout gestation have been published (3–14). Maternal doses ranged between 260 and 550 mg/day (3–5,8,10,11,14). Cases usually involved maternal renal transplantation (3–5,7–13), but one report described a successful pregnancy in a woman after heart transplantation (6), one involved a combined transplant of a kidney and paratropic segmental pancreas in a diabetic woman (11), and one involved a patient with a liver transplant (14). In addition, a report has described a successful pregnancy in a woman with aplastic anemia who was treated with bone marrow transplantation (15). 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 (16).
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) (16). 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.
A 1989 case report described an infant with hypoplasia of the right leg and foot after in utero exposure to cyclosporine (12). 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 (12).
Many of the liveborn infants were growth restricted (4,8,10–14). Birth weights of full-term newborns ranged from 2160 to 3200 g (13,14) (A. Poploski and D.A. Colasante, personal communication, 1987). A 1985 review article observed that growth restriction was common in the offspring of renal transplant patients, occurring in 8%–45% of reported pregnancies (17). 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 (17).
Follow-up of children exposed in utero to cyclosporine has been conducted in a few cases (5,11) (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 restriction. Postnatal development of 10 children followed from 1 to 13 months revealed normal physical and mental development. No abnormal renal or liver function has been reported in the exposed newborns (5,11) (A. Poploski and D.A. Colasante, personal communication, 1987).
A 2006 report described 71 pregnancies among 45 women after liver transplantation (2). Tacrolimus and cyclosporine were used in 42 and 29 of the pregnancies, respectively. The outcomes of the pregnancies were live births (29 vs. 21), spontaneous abortions (7 vs. 6), elective abortions (5 vs. 1), molar pregnancy (1 vs. 0), and intrauterine death (0 vs. 1) (all ns). The median gestation and birth weight were 37.5 vs. 37 weeks, and 2660 vs. 2951 g, respectively (all ns). Pregnancies occurring within 1 year of transplantation had the highest incidence of prematurity and lowest birth weight. There were no congenital anomalies observed (2).
Two reviews discussing the treatment of psoriasis, one in 2002 (18) and the other in 2005 (19), considered the use of cyclosporine to be appropriate for the management of severe psoriasis.
BREASTFEEDING SUMMARY
Cyclosporine is excreted into breast milk. 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 (3). 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, whereas maternal blood levels were 52 ng/mL, a milk:plasma ratio of 0.31 (4). A milk:plasma ratio of 0.40 was reported in one study (6) and a ratio of approximately 0.17 was measured in another (7). Breastfeeding 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 (13,14,16).
A 2001 study reported the use of cyclosporin in a woman who was breastfeeding (20). 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 75–173 ng/mL (therapeutic range 100–125 ng/mL in whole blood) but were not determined at birth. The cord blood cyclosporine concentration was 67 ng/mL. Breastfeeding 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 breastfed (20).
Infant cyclosporine exposure was quantified in five mother–infant pairs in a 2003 report (21). The five mothers had taken cyclosporine throughout pregnancy and continued the drug while nursing their infants. In two cases, the milk:maternal blood ratios were 0.45 and 1.4 (not specified in the other three cases). In the latter case, the infant’s dose from milk was about 1% of the therapeutic dose (weight basis). The infant’s blood levels were as high as 78% of the corresponding maternal trough concentrations that were in the therapeutic range. Cyclosporine was not detected in the blood of three other infants (not tested in one infant). In the five cases, the estimated infant dose from milk, based on a milk consumption of 150 mL/kg/day, ranged from 0.2% to 2.1% of the mother’s weight-adjusted dose. No adverse effects in the infants were observed, but specific immunologic effects were not investigated (21).
The American Academy of Pediatrics classifies cyclosporine as a drug that may interfere with cellular metabolism in the nursing infant (22).
References
1.Product information. Neoral, Sandimmune. Novartis Pharmaceuticals, 2005.
2.Christopher V, Al-Chalabi T, Richardson PD, Muiesan P, Rela M, Heaton ND, O’Grady JG, Heneghan MA. Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipients. Liver Transpl 2006;12:1138–43.
3.Lewis GJ, Lamont CAR, Lee HA, Slapak M. Successful pregnancy in a renal transplant recipient taking cyclosporin A. Br Med J 1983;286:603.
4.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;5:60–3.
5.Burrows DA, O’Neil TJ, Sorrells TL. Successful twin pregnancy after renal transplant maintained on cyclosporine A immunosuppression. Obstet Gynecol 1988;72:459–61.
6.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;158:589–90.
7.Ziegenhagen DJ, Grombach G, Dieckmann M, Zehnter E, Wienand P, Baldamus CA. Pregnancy under cyclosporine administration after renal transplantation. Dtsch Med Wochenschr 1988;113:260–3.
8.Klintmalm G, Althoff P, Appleby G, Segerbrandt E. Renal function in a newborn baby delivered of a renal transplant patient taking cyclosporine. Transplantation 1984;38:198–9.
9.Grischke E, Kaufmann M, Dreikorn K, Linderkamp O, Kubli F. Successful pregnancy after kidney transplantation and cyclosporin A. Geburtshilfe Frauenheilkd 1986;46:176–9.
10.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.
11.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.
12.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.
13.Al-Khader AA, Absy M, Al-Hasani MK, Joyce B, Sabbagh T. Successful pregnancy in renal transplant recipients treated with cyclosporine. Transplantation 1988;45:987–8.
14.Sims CJ, Porter KB, Knuppel RA. Successful pregnancy after a liver transplant. Am J Obstet Gynecol 1989;161:532–3.
15.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.
16.Kossoy LR, Herbert CM III, Wentz AC. Management of heart transplant recipients: guidelines for the obstetrician—gynecologist. Am J Obstet Gynecol 1988;159:490–9.
17.Lau RJ, Scott JR. Pregnancy following renal transplantation. Clin Obstet Gynecol 1985;28:339–50.
18.Tauscher AE, Fleischer AB Jr, Phelps KC, Feldman SR. Psoriasis and pregnancy. J Cutan Med Surg 2002;6:561–70.
19.Lebwohl M. A clinician’s paradigm in the treatment of psoriasis. J Am Acad Dermatol 2005;53:S59–69.
20.Thiagarajan (Munoz-Flores) KD, Easterling T, Davis C, Bond EF. Breast-feeding by a cyclosporin-treated mother. Obstet Gynecol 2001;97:816–8.
21.Moretti ME, Sgro M, Johnson DW, Sauve RS, Woolgar MJ, Taddio A, Verjee Z, Giesbrecht E, Koren G, Ito S. Cyclosporin excretion into breast milk. Transplantation 2003;75:2144–6.
22.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.