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Published on: November 20, 2015
Birth defects in juvenile Wistar rats after exposure to immunosuppressive drugs during pregnancy
Joanna Kabat-Koperska1, Agnieszka Kolasa-Wołosiuk2, Anna Pilutin2
1Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Szczecin, Poland. askodom@poczta.onet.pl.
Insights
Certain immunosuppressive drugs like mycophenolate mofetil can cause birth defects in rats. Combination therapy with calcineurin inhibitors and prednisone further reduced live births, highlighting risks during pregnancy.
Area of Science:
- Pharmacology
- Toxicology
- Reproductive Biology
Background:
- Immunosuppressive drugs and their metabolites can cross the placental barrier, potentially harming the fetus.
- Adverse fetal effects include chromosomal aberrations, malformations, organ toxicity, and growth retardation.
Purpose of the Study:
- To investigate the impact of "safe" and "contraindicated" immunosuppressive drugs on birth defects in juvenile Wistar rats.
- To assess the effects of drug exposure on pregnant female rats and their offspring.
Main Methods:
- 32 female Wistar rats were used, receiving immunosuppressive regimens common in human kidney transplant therapy.
- Drugs were administered via oral gavage two weeks before pregnancy and throughout the first three weeks of gestation.
Main Results:
- Mycophenolate mofetil and everolimus treatments were toxic, significantly reducing live births when combined with calcineurin inhibitors and prednisone.
- Malformations and histological fetal organ changes were confirmed following mycophenolate mofetil exposure during pregnancy.
Conclusions:
- Mycophenolate mofetil demonstrated higher toxicity with tacrolimus compared to cyclosporin.
- Everolimus combined with cyclosporin suppressed fetal maturation but did not induce malformations.
Introduction:
Immunosuppressive drugs and their active metabolites can cross the placental barrier and enter fetal circulation. The adverse effects on the fetus include chromosomal aberrations, structural malformations, organ-specific toxicity and intrauterine growth retardation. The aim of our study was to investigate the impact of "safe" and "contraindicated" immunosuppressive drugs on birth defects in juvenile Wistar rats after exposure of pregnant female rats to these drugs.
Material And Methods:
The study was conducted on 32 female Wistar rats, subjected to immunosuppressive regimens most commonly used in therapy of human kidney transplant recipients. The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy.
Results:
Treatment with mycophenolate mofetil and everolimus turned out to be toxic. We have noticed a significantly reduced number of live births in all pregnant rats exposed to these drugs in combination with calcineurin inhibitors and prednisone. Malformations and histological changes of fetal organs were confirmed after mycophenolate mofetil exposure during pregnancy.
Conclusions:
Mycophenolate mofetil turned out to be more toxic when used with tacrolimus than with cyclosporin (delivery of live offspring was possible only in the latter group). Everolimus in combination with cyclosporin effectively suppressed the fetal maturation in utero, but did not contribute to the development of malformations.
