Even Low Dose of Mycophenolate Mofetil in a Mother Recipient of Heart Transplant Can Seriously Damage the Fetus (2008)

A female patient, 33-years-old came to us in severe congestive heart failure referring an extensive anterior myocardial infarction 3 years before. She had a family history of coronary artery disease and smoked 10 cigarettes a day. She denied any use of forbidden substances and was graduated in Pedagogy. After extensive lipid and vasculitis investigation, including lupus with no conclusive diagnosis, we performed myocardial revascularization and aneurismectomy of the left ventricle, with adequate initial result. After 1 year, she came again with severe congestive heart failure and heart transplantation was indicated. The operation was performed in June 7, 2003, complicated in the early postoperative period by a right ventricle dysfunction that resolved with pulmonary vasodilators. The initial immunosuppressive regimen included cyclosporine, to a target trough level of 400 ng/mL, mycophenolate mofetil (MMF) and prednisone. The MMF dose was 500 mg/TID to this 56 kg recipient. In the second routine heart biopsy, a moderately severe grade 3B rejection was found and resolved with three 500 mg daily bolus of solumedrol. We also decided to convert the cyclosporine to tacrolimus, for higher safety in control of rejection (1–3), and she was again advised not to get pregnant. We also gave her recommendations to attend her gynecologist. After two more negative biopsies, the patient was sent home (2,500 miles away) taking tacrolimus 3 mg/BID, MMF 500 mg/bid which was reduced to keep white blood cells above 4.0×103 cells, prednisone 5 mg/day and pravastatine 40 mg/day. She was also taking diltiazen 60 mg/TID and carbamazepine for an old convulsive disorder with good control. She came to us 1 year after heart transplantation, she was happy with her new marriage, had stopped smoking with normal laboratory and echocardiography data, and with a tacrolimus trough level of 8.5 ng/mL and peak level of 12.5 ng/mL. The patient and her husband were again advised about contraception, until we had more information on the tacrolimus and MMF regimen. After 6 months, however, she came with 5 weeks pregnancy and absolutely normal laboratory and echocardiography data. We decided to keep stable the dose of tacrolimus and to halve the MMF dose as there was more extensive evidence in the literature about the safety of calcineurin inhibitors in pregnancy (4–9), and communications of adverse problems in the fetus with MMF (10). We did not stop this drug completely, because of the severity of the already described rejection, and also because this drug was still considered category C by the FDA, together with calcineurin inhibitors that are, relatively safe drugs for pregnant women. The baby was delivered in September 4, 2005 with extensive craniofacial congenital anomalies: Left eye Microftalmia, complete atresia of the auditory conduit and middle ear bilaterally, palatine gap and bad formation of auricular pavilion. There was also umbilical hernia and a light pulmonary valve stenosis with a gradient of 15 mm Hg. These anomalies were documented by magnetic nuclear resonance examination, and echocardiographic analysis. The probability that MMF played a causative role in the craniofacial malformations in our case is strongly supported by the data recently presented by Sifontids et al. (11). Mycophenolate mofetil should be considered category D or X and not C for pregnant women. In fact, in that article, three of the 4 (75%) of the structural malformations in newborns of mothers taking MMF, included Microtia that could be defined “as an incompletely formed or absent external and middle ear and may be bilateral or unilateral.” Very similar findings were also communicated in the literature by Le Ray et al. (10), concerning a female renal transplant recipient maintained on a MMF low dose regimen, who had a pregnancy terminated at 22 weeks which showed multiple malformations in the fetus that included: Cleft lip and palate, Microtia and external auditorium duct atresia, a similar picture to our present case. The dose used of MMF was 250 mg/BID exactly the same daily dose that we used in our case. Because of the fact that we were unable to carry out monitoring of MMF levels we cannot say for sure that they were low in the mother’s blood, despite the low dose administered. Regardless, this case report adds to and reinforces the existing literature, and should make the medical professional involved in solid organ transplantation, fully aware of the risks of MMF in pregnant woman and to follow strictly, the laboratory recommendations that this drug should definitely not be used in this scenario (12, 13). José Henrique Andrade Vila José Pedro da Silva Claudia Jesus Guilhen José Francisco Baumgratz Luciana da Fonseca Institution Beneficência Portuguesa de São Paulo, Brazil