Mycophenolate Mofetil During Pregnancy: Some Words of Caution

I TRANSPLANT REGISTRIES have accounted for more than 14 000 deliveries in solid organ transplant recipient women up to 2002; thus, the possibility of becoming pregnant has been considered an additional benefit of organ transplantation.1 Improvement in organ transplantation outcome has been linked with the development of more effective immunosuppressive drugs. Hence, in recent years new pharmacologic agents have been incorporated into the armamentarium for organ transplant recipients and patients with autoimmune diseases. Among the new drugs, mycophenolate mofetil (MMF) has acquired special relevance.1 In addition, MMF has also been added to the treatment of autoimmune diseases such as lupus, because its use has been found to be more effective than cyclophosphamide, the standard treatment modality, in inducing remission of lupus nephritis and has a more favorable safety profile.2 MMF is a newly available ester derived from mycophenolic acid. After oral ingestion, MMF is hydrolyzed rapidly to mycophenolic acid, the active compound (a potent noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase), which leads to depletion of intracellular guanosine triphosphate and 2 -deoxyguanosine 5 -triphosphate pools. This, in turn, blocks the de novo guanosine synthesis of precursors for RNA/DNA synthesis.3 Regarding the use of MMF in pregnancy, a specific pattern of fetal malformation has been attributed to MMF in experimental animals.4 Rat offspring whose mothers had been exposed to MMF exhibited anophthalmia, agnathia, hydrocephaly, and fetal resorptions. In rabbits exposed in utero, malformations included cardiovascular and renal abnormalities.5 Therefore, the information provided by MMF manufacturers underscores the relative risk of teratogenicity in animal models and includes a warning indicating that MMF has been upgraded in its classification as a pregnancy category D medication.6 It is important to note that in the last decade malformations described in human fetuses exposed to MMF were found to be similar to those documented in the experimental setting. However, it has not been until recently that a characteristic pattern has been identified and associated with the intake of MMF during pregnancy5 (Table 1). In an extensive review of the literature including Medline (PubMed), Embase, and the journal Reactions (ISNN 0114–9954), which specifically addresses information about adverse drug effects, we detected 10 cases of newborn infants with malformations associated with the intake of MMF during early stages of gestation (for references, see Table 1). Treatment with MMF was initiated in 7 cases after renal transplantation and in 3 cases for treatment of corticoid-resistant lupus glomerulonephritis. However, medication was immediately interrupted as soon as pregnancy was diagnosed between 8 and 10 weeks’ gestation. In 2 cases (3 and 10), the gestations were voluntarily interrupted in the 22nd and 17th weeks, respectively, but in most cases preterm infants were delivered; only 2 case pregnancies reached term. Fetal malformations were detected by routine prenatal sonogram and were not specifically sought by the obstetrician. Considering the different malformations described in the various clinical reports, a specific and consistent pattern of malformation was present in all of them. Hence, this phenotype includes craniofacial malformations affecting the oral cavity (thick everted lower lip, cleft lip and cleft palate) and ears (microtia and aural atresia) and ocular anomalies (hypertelorism, arching eyebrows). In addition, less-consistent findings have been limb abnormalities (hypoplastic finger and toe nails, bilateral shortened fifth finger, polydactyly) and congenital cardiovascular, renal, or central nervous system malformations. Developmental delay, however, has been an inconsistent finding that has not been specifically studied in most of the cases described in the literature. Thus, Perez-Aytes et al5 described their patient at 9 months of age as having had a normal structured neurologic evaluation and Bayley Developmental Index scores. In addition, Pérgola et al7 and Sifontis et al8 described both of theirs patients as having normal psychomotor development. However, the patient reported by Velinov and Zellers9 exhibited at 20 months of age an overall motor development delay and had a significant expressive speech delay. The above-described pattern establishes a link between exposure to MMF and development of the structures derived from the frontonasal prominence and first pharyngeal arch.5 The pattern is distinctive and unique