Mini-ReviewTetrada of the possible mycophenolate mofetil embryopathy: A review☆
Introduction
Mycophenolate mofetil (MFM) is an immunosuppressant agent used in organ transplantation to prevent rejection of allogenic transplants, in rheumatoid arthritis and lupus nephritis. MFM use has become a standard of care after organ transplantation and the number of pregnant women who receive this drug has increased over the last few years. Also, MFM has become a major therapeutic option of induction and maintenance therapy for autoimmune diseases like rheumatoid arthritis and lupus nephritis.
MFM is a prodrug and is converted to biologically active mycophenolic acid after oral administration [1]. Mycophenolic acid is a reversible inhibitor of inosine monophosphate dehydrogenase leading to inhibition of de novo purine synthesis. It has more potent cytostatic effects on lymphocytes than other white blood cells, which can utilize salvage pathways.
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Pharmacokinetics
MFM is well absorbed after oral administration (94%). In the circulation, 97% of this drug is protein-bound. It is completely metabolized in the liver and is rapidly converted to its active form—mycophenolic acid [1]. The drug is excreted essentially in the urine (93%) and a small part in feces (6%). Its molecular weight is relatively small (433) which may explain the possible placental transfer. Plasma concentration of MFM was measured in one newborn and was found to be 3.1 mg/L (therapeutic
Experimental data
Doses roughly equivalent to those used clinically in transplant patients may cause fetal resorption and malformations in pregnant rats and rabbits [3], [4]. A specific pattern of fetal malformations has been attributed to MFM in experimental animals: anophthalmia, agnathia, hydrocephaly, cardiac and renal defects [3], [4].
Human data
Experience in the field of pregnancy after transplantation has been gained through continued case reports, case series and registry data.
Non-teratogenic effects
Data on the adverse effects of MFM are available from large, randomized, multicenter trials [1]. However, data regarding MFM usage during pregnancy and, especially for exposed newborns, are rare.
The rates of abortions, prematurity, intrauterine growth retardation and low-birth weight have been reported in women treated with MFM, but these outcomes may be due to the underlying maternal illness rather than specifically to the medication.
Gastrointestinal effects are typically mild and include
Conclusions
“A reasonable probability is the only certainty”
Combining the data of 9 case reports published until now with the other 3 well-described patients from case series, the most frequent structural anomalies observed in these 12 newborns exposed to MFM were as follows: microtia in 11; auditory canal atresia in 8; cleft lip and palate in 6; micrognathia in 4; hypertelorism in 4; ocular coloboma in 3; short fingers in 2 and hypoplastic nails in 2.
It seems that the potential teratogenicity of MFM
Recommendations
Because of the limited data on MFM treatment during pregnancy and especially during the first trimester, any decision for the mother and physician is a complex one.
Recommendations are as follows:
- 1.
Women of childbearing age taking MFM must receive contraceptive counseling and use effective contraception.
- 2.
The physicians should be aware that MFM reduces blood levels of the hormones of the oral contraceptive pill and could theoretically reduce its effectiveness.
- 3.
Women of childbearing age should have a
Conflicts of interest
There are no conflicting interests. No funding has been provided for any part of this work.
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The important role of RPS14, RPL5 and MDM2 in TP53-associated ribosome stress in mycophenolic acid-induced microtia
2021, International Journal of Pediatric OtorhinolaryngologyCitation Excerpt :Numerous studies in zebrafish [8], rats [9] and mice [19] have led researchers to believe that inhibition of IMPDH, the intrinsic pharmacological effect of MA, interferes with the development, migration, proliferation and differentiation of cranial NCCs and is an important step in auricular developmental disorders [9]. However, there is a lack of empirical evidence that directly links IMPDH and microtia [20–24]. Researchers have used pharmacological induction to construct animal models of microtia to explore its pathogenesis.
Maintenance immunosuppression in myasthenia gravis, an update
2020, Journal of the Neurological SciencesPregnancy After Kidney Transplantation
2017, Kidney Transplantation, Bioengineering, and Regeneration: Kidney Transplantation in the Regenerative Medicine EraMaintenance immunosuppression in myasthenia gravis
2016, Journal of the Neurological SciencesNon-biologic immunosuppressive drugs for inflammatory and autoimmune skin diseases
2024, JDDG - Journal of the German Society of Dermatology
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This review was presented at the 19th Annual Meeting of ENTIS (European Network Teratology Information Services) held in Edinburgh, September 20–22, 2008.