Published online July 1, 2008
PEDIATRICS Vol. 122 No. 1 July 2008, pp. 184-185 (doi:10.1542/peds.2008-0348)

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COMMENTARY

Mycophenolate Mofetil During Pregnancy: Some Words of Caution

Maximo Vento, PhD, MD^a, Antonio Perez Aytes, MD^a, Ana Ledo, MD^a, Virginia Boso, PhD^b and John C. Carey, MD, MPH^c

^a Servicio de Neonatología, Hospital Universitario Materno Infantil La Fe, Valencia, Spain
^b Servicio de Farmacología, Hospital Universitario La Fe, Valencia, Spain
^c Division of Medical Genetics, Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah

Abbreviations: MMF, mycophenolate mofetil

INTERNATIONAL TRANSPLANT REGISTRIES have accounted for more than 14000 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.

View this table: [in this window] [in a new window]   TABLE 1 Summary of Clinical Reports of Fetal/Newborn Malformations Associated With Maternal Exposure to MMF During Pregnancy (Updated January 2008)

 
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 enough that, given the rarity of exposure to MMF in pregnancy and biological plausibility, causation can likely be inferred.

We would like to draw attention to this new fetal embryofetopathy based on clinical evidence and supported by biological plausibility. Moreover, all women treated with MMF after organ transplantation or for autoimmune disease should be counseled to stop the medication at least 6 weeks before getting pregnant,¹⁰ thus avoiding the possibility of having an offspring affected with the MMF embryofetopathy.

	FOOTNOTES

 
Accepted Mar 10, 2008.

Address correspondence to Maximo Vento, PhD, MD, Neonatal Research Unit, Servicio de Neonatología, Hospital Universitario Materno Infantil La Fe, Avenida de Campanar, 21, E46009 Valencia, Spain. E-mail: maximo.vento{at}uv.es or maximovento{at}telefonica.net

The authors have indicated they have no financial relationships relevant to this article to disclose.

Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.

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This Article Extract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Vento, M. Articles by Carey, J. C. Search for Related Content PubMed PubMed Citation Articles by Vento, M. Articles by Carey, J. C. Related Collections Office Practice Social Bookmarking                         What's this?