Birth defects in juvenile Wistar rats after exposure to immunosuppressive drugs during pregnancy

Joanna Kabat-Koperska¹, Agnieszka Kolasa-Wołosiuk², Anna Pilutin², Krzysztof Safranow³, Danuta Kosik-Bogacka⁴, Irena Baranowska-Bosiacka³, Edyta Gołembiewska¹, Karolina Kędzierska¹, Leszek Domański¹ and Kazimierz Ciechanowski<sup>1

1</sup>Department of Nephrology, Transplantology and Internal Medicine, ²Department of Histology and Embryology, Pomeranian Medical University, ³Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstancow Wielkopolskich and ⁴Department of Biology and Medical Parasitology, Pomeranian Medical University, Szczecin, Poland

Offprint requests to: Joanna Kabat-Koperska, Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland. e-mail: askodom@poczta.onet.pl

Summary. 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. Histol Histopathol 32, 43-55 (2017)

Key words: Congenital malformation, Rats, Pregnancy, Immunosuppressive Drugs, Transplantation

DOI: 10.14670/HH-11-769