mycophenolic-acid and Abnormalities--Multiple

Mycophenolate mofetil (MMF) (CellCept) is an immunosuppressant drug that is teratogenic in rats and rabbits. Reports of malformations in 13 offspring of women exposed to MMF in pregnancy raise concern that MMF is also a human teratogen. We report an additional child with malformations following prenatal exposure to MMF and review the other 13 reports. We identified a Cambodian male born at 31 weeks' gestation to a mother who had been treated for lupus nephritis with MMF from before conception to 12 weeks' gestational age. He had bilateral moderate-to-severe microtia, external auditory canal atresia, bilateral conductive hearing loss, mild microcephaly, and apparently normal development. Among the 14 MMF-exposed offspring now reported, the underlying maternal conditions were kidney transplantation (7), lupus nephritis (4), liver transplantation (1), heart transplantation (1), and recurrent erythema multiforme (1). All were exposed in early pregnancy. The most distinctive malformation was moderate-to-severe microtia or anotia (12), with external auditory canal atresia in 9. Other common craniofacial malformations and minor anomalies included orofacial clefts (7), hypertelorism (3), coloboma (3), and micrognathia (3). Six had cardiovascular malformations, of which three were either conotruncal or aortic arch defects. MMF dose, reported in 12 patients, was <1 g/day in 4 and 1 g or more/day in 8; no correlation between dose and phenotype severity was apparent. While case reports have limited value in identifying human teratogens, the unusual distribution of malformations among the 14 reported exposed offspring identifies a phenotype suggesting that MMF is likely a human teratogen.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Maternal-Fetal Exchange; Mycophenolic Acid; Pregnancy; Teratogens; Young Adult

Mycophenolate mofetil (MFM) is an immunosuppressant agent used in organ transplantation, rheumatoid arthritis and lupus nephritis. Experimental data show that doses roughly equivalent to those used clinically in transplant patients may cause fetal resorption and malformations in pregnant rats and rabbits. There are limited data regarding the use of MFM in pregnant women. The human experience is based on 9 case reports, 1 case series, and 2 registry data. The most frequent structural anomalies described in 12 newborns exposed to MFM were as follows: microtia (11); auditory canal atresia (8); cleft lip and palate (6); micrognathia (4); hypertelorism (4); ocular coloboma (3); short fingers (2) and hypoplasic nails (2). The distinctive and unique phenotype associated with MFM exposure during pregnancy (EMFO tetrada: Ear, Mouth, Fingers, Ocular/Organ malformation) raised the hypothesis that MFM may be a real teratogenic drug. Appropriate recommendations to prevent this possible new embryopathy are given.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adult; Animals; Consumer Product Safety; Embryo, Mammalian; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Mycophenolic Acid; Practice Guidelines as Topic; Pregnancy; Rabbits; Rats; Registries; Risk Assessment; Teratogens

Mycophenolate mofetil (MMF) is probably the most common employed immunosuppressant drug in recipients of solid organ transplant and in many autoimmune diseases. In vitro studies, a significant number of single clinical observations and a recent study from a group of different European teratogen information services, have provided very consistent data supporting the existence of a specific MMF embryopathy. The typical malformative pattern of MMF embryopathy includes external ear anomalies ranging from hypoplastic pinna (microtia) to complete absence of pinna (anotia); cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia. Other less frequent features are congenital heart defects, distal limbs anomalies, esophageal atresia, vertebral malformations, diaphragmatic hernia, and kidney and central nervous system anomalies. Neurodevelopmental outcome seems favorable in the small number of patients where information about this issue is available, but neurological deficits have been documented. Physicians in charge of women under MMF therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least six weeks before becoming pregnant.

Topics: Abnormalities, Multiple; Ear, External; Esophageal Atresia; Female; Fetal Diseases; Hernias, Diaphragmatic, Congenital; Humans; Infant, Newborn; Maternal Exposure; Mycophenolic Acid; Pregnancy; Teratogenesis; Teratogens

We report on a case of a multiple congenital anomalies in a newborn infant whose mother was on allopurinol treatment through the pregnancy. The pattern of congenital anomalies that was noted in our patient was similar to the pattern described in a number of published reports following mycophenolate mofetil [CellCept®] treatment during pregnancy. The anomalies present in our patient include: diaphragmatic hernia, unilateral microtia and absence of external auditory canal, micrognathia, microphthalmia, optic nerve hypoplasia, hypoplasia of the corpus callosum, unilateral renal agenesis, pulmonary agenesis, and cleft lip and palate. Since both allopurinol and mycophenolate mofetil act by disrupting purine biosynthesis and given the similarities in anomalies seen after prenatal exposure, we suggest that allopurinol should also be considered a teratogen.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Allopurinol; Antimetabolites; Female; Humans; Infant, Newborn; Kidney Calculi; Male; Mycophenolic Acid; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Purines; Teratogens

There is very little data linking the use of immunomodulating agents following solid organ transplantation in pregnant women with specific congenital anomalies in the offspring. Here we report on a late preterm infant with multiple, nonsyndromic, congenital anomalies including microtia/anotia, cleft lip and palate, micrognathia, ocular hypertelorism, microphthalmia and cataracts, complex congenital heart disease, rib anomalies, and intestinal malrotation. The similarity of the complex anomalies in our case to other reported cases suggests that the abnormalities are likely due to mycophenolate mofetil alone or in combination with other immunosuppressive medications taken by the mother during pregnancy.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Maternal Exposure; Maternal-Fetal Exchange; Mycophenolic Acid; Pregnancy; Prenatal Exposure Delayed Effects

A newborn female infant born to a woman on immunosuppressive medications including mycophenolate mofetil (MMF) for a renal graft secondary to lupus nephritis presented with congenital diaphragmatic hernia (CDH) and additional findings of microtia, esophageal atresia with tracheoesophageal fistula, cleft palate, congenital heart defect, digital anomalies, and dysmorphic facial features. Pulmonary hypoplasia resulted in death at day 2 of life. She was presumed to have Fryns syndrome based on diagnostic criteria established for this recessive disorder with prominent features including CDH, facial anomalies, and nail hypoplasia. In retrospect, this infant's findings are more likely the result of teratogenic exposure to MMF, as more recent data have emerged linking aural atresia, digital anomalies, and dysmorphic features to this drug. To date, this is the only human report of CDH in an infant with prenatal exposure to MMF, although the manufacturer's package insert alludes to animal studies with a broad spectrum of malformations, including CDH. Thus, a teratogenic exposure can mimic a known Mendelian genetic syndrome, and caution is urged in presuming a genetic etiology for infants with potential teratogenic exposure to relatively new drugs with limited published animal data.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Autopsy; Ear; Fatal Outcome; Female; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Immunosuppressive Agents; Infant, Newborn; Mycophenolic Acid; Pregnancy; Radiography; Syndrome; Teratogens

Mycophenolate mofetil (MMF) is an immunosuppressive agent that has now been recognized as teratogenic in humans. A pattern of malformations from in utero exposure to MMF has recently been described, and includes cleft lip and palate, microtia and atresia of the external auditory canal. We present a nulliparous mother who had taken MMF for recurrent erythema multiforme for the first 5 weeks of her pregnancy, and developed a spontaneous miscarriage during the seventh week of pregnancy. For her second pregnancy, she took MMF on her own accord for four days in the seventh week after her last menstrual period. The newborn had bilateral microtia, absence of the external auditory canals, and right iris and chorioretinal coloboma, consistent with the pattern recognized as part of the MMF embryopathy phenotype. As the newborn was not exposed to other immunosuppressive agents in utero, we believe that the phenotype described to be the result of the teratogenic effect of MMF. The spontaneous miscarriage in the first pregnancy may be due to the higher dose and longer duration of MMF exposure. The second pregnancy, with MMF exposure of 4 days, proceeded to term with the resultant phenotype. We conclude that the effect and severity of the embryopathy may be dependent on the dose, timing, and duration of MMF exposure. The manufacturer and the United States Food and Drug Administration have now disseminated information regarding the teratogenic risk of MMF. Women should be fully counseled and advised about contraception during the course of treatment with MMF.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adult; Child, Preschool; Coloboma; Dose-Response Relationship, Drug; Ear Canal; Ear, External; Erythema Multiforme; Female; Humans; Immunosuppressive Agents; Iris; Maternal Exposure; Mycophenolic Acid; Pregnancy; Time Factors

Topics: Abnormalities, Multiple; Female; Humans; Infant, Newborn; Mycophenolic Acid; Syndrome

Mycophenolate mofetil has been shown to have teratogenic properties in animal studies and clinical reports. We report a case of major fetal malformation likely caused by mycophenolate mofetil exposure in utero in a 36 year old patient with systemic lupus erythematosus. The diagnosis was made by ultrasonography at 22 weeks of gestation.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adult; Ear, External; Facies; Female; Fetus; Humans; Imaging, Three-Dimensional; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mycophenolic Acid; Nose; Pregnancy; Pregnancy Complications; Ultrasonography, Prenatal