Cellcept immunosuppressant further linked to birth defects

Feb 7 2008

A new study documents malformations seen in an infant born to a kidney transplant recipient who had taken mycophenolate mofetil (MMF), a widely used immunosuppressant available commercially as Cellcept.

The findings suggest a specific birth defect pattern particular to this drug, reinforcing its potential to harm to the fetus. The study was published in the January 2008 issue of the American Journal of Medical Genetics, available online via Wiley InterScience at http://www3.interscience.wiley.com/journal/117869018/issue.

Approximately 14,000 births to organ transplant recipients, primarily kidney transplant patients, have been reported worldwide. Although pregnancy was initially ill-advised for these women, the American Society of Transplantation concluded in 2003 that pregnancy is usually safe following the first year of a transplant, provided that organ rejection or other complications have not occurred. The fetal side-effects of several immunosuppressant drugs have been studied, though not for widely used newer medications, such as (MMF).

The use of immunosuppressant drugs is a required, life-long treatment for solid organ transplant recipients. They are used to prevent, inhibit or reduce the natural reaction of the immune system against foreign tissues. However, these drugs have important side effects that sometimes preclude their use. The FDA divides immunosuppressants into four categories (A, B, C and D) regarding toxicity to the fetus. MMF has recently been upgraded to class D during pregnancy, meaning that its use is precluded for the high risk of fetal malformations. Immunosupressants are also given to women with severe autoimmune diseases, such as generalized lupus. In fact, 3 out of 10 babies described in the literature regarding these defects had mothers on MMF because of lupus nephritis.

Led by Dr. Antonio Perez-Aytes and Dr. Maximo Vento of the Newborn Research Unit at the Hospital Universitario Materno-Infantil La Fe, in Valencia, Spain, the study describes a 25-year-old Spanish woman who had undergone two kidney transplants. Following the second transplant she took the immunosuppressant drugs tacrolimus and MMF. Two years later she became pregnant and MMF was discontinued at 10 weeks gestation, while tacrolimus, one of the drugs that has been studied in pregnant women, was maintained. She delivered a female infant who had cleft lip and palate, as well as defects of the jaw, eyes and ears, including no external ear canals. At nine months her child was developing normally, although she needed hearing aids.

The pattern of defects seen in this infant is very similar to previous reports of birth defects in infants who were exposed to MMF in utero. The study describes these infants, noting that the pattern of cleft lip/palate and ear malformations was seen in every case but one. Although defects of the eye had not been seen in humans before, studies in rats and rabbits have shown ocular malformations following exposure to MMF. The authors suggest that the pattern of defects seen with MMF establishes a possible link between use of this drug during pregnancy and a specific malformation pattern in structures derived from the frontal-nasal prominence (which develops into the forehead, nose, upper lip and palate) and the first pharyngeal arch (which develops into the jaw and ear).

It should be noted, however, that if a transplant recipient is of fertile age, she can give birth to a healthy baby. “The patient needs to be adequately counseled, and withdraw from immunosuppressants that may be deleterious to the baby within sufficient of becoming pregnant to avoid any interference during the first 12 weeks of gestation,” says Dr. Maximo Vento, co-author of the study.