Case Report

www. AJOG.org

Sonographic diagnosis of fetal malformations associated
with mycophenolate mofetil exposure in utero
Shang-Yu Huang, MD; Ho-Yen Chueh, MD; Sheng-Wen Shaw, MD; Jin-Chung Shih, MD; Po-Jen Cheng, MD

M

ycophenolate mofetil, a powerful
inhibitor of lymphocyte proliferation, has been used internationally
since the early 1990s as a standard of care
after organ transplantation.1 Recently,
mycophenolate mofetil has gained popularity as induction and maintenance
therapy for systemic lupus erythematosus and a variety of rheumatic illnesses.2
Many patients with lupus are women of
child-bearing age, so the issue of teratogenicity associated with mycophenolate
mofetil is important. When treated
with mycophenolate mofetil, offspring
showed increased frequencies of development abnormalities in animal studies.3,4 There have been reports of
possible teratogenic effects in humans
focusing on facial clefts and ear
abnormalities.
We report a female fetus of 21 gestational weeks with microtia, external auditory duct atresia, and an unreported
nasal bifid anomaly. The patient was
treated with mycophenolate mofetil for

From the Department of Obstetrics and
Gynecology, Chang Gung Memorial
Hospital, Linkou Medical Center, Taoyuan,
Taiwan, and Chang Gung University College
of Medicine, Taoyuan, Taiwan (Drs Huang,
Chueh, Shaw, and Cheng), and the
Department of Obstetrics and Gynecology,
National Taiwan University Hospital and
National Taiwan University College of
Medicine, Taipei, Taiwan (Dr Shih).
Received Feb. 12, 2008; revised March 6,
2008; accepted April 2, 2008.
Reprints: Po-Jen Cheng, MD, Department of
Obstetrics and Gynecology, Chang Gung
Memorial Hospital, 5, Fu-Shin Street, KweiShan, TaoYuan, 333, Taiwan, Republic of
China. pjcheng@cgmh.org.tw.
This work was supported by Research Grant
NSC 96-2314-B-182A-066-MY2 from the
National Science Council, Taiwan, Republic of
China.
0002-9378/free
© 2008 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2008.04.008

e6

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.
Key words: bifid nose, micrognathia, microtia, mycophenolate mofetil, threedimensional ultrasound
systemic lupus erythematosus before
conception and during the first trimester
of pregnancy.

C ASE R EPORT
The patient, a 36-year-old primiparous
Taiwanese woman, was diagnosed 7
years prior to presentation with systemic
lupus erythematosus on the basis of fatigue, arthralgias, arthritis, pleurisy, leucopenia, lymphocytopenia, positive
antibodies to double-stranded deoxyribonucleic acid, and a positive fluorescent
antinuclear antibody test (1:2560).
Paternal age was 39 years. The couple
was not consanguineous, and there was no
history of x-ray exposure or particular
family or personal genetic history. She had
2 flares of class IV lupus nephritis treated in
2004 and 2006 by 6-month courses of intravenous cyclophosphamide. The lupus
had been in remission since the last course
of cyclophosphamide.
She had been on mycophenolate mofetil
maintenance therapy (1000 mg twice
daily) for 8 months until pregnancy was
discovered at 12 weeks of gestation. She
also took prednisolone and hydroxychloroquine during the same period. Initial ultrasonography performed at 13 weeks
showed a live fetus with a crown-rump
length of 78 mm, a nuchal translucency
thickness of 2.7 mm, and no observed
structural anomalies.
After genetic counseling, chorionic
villus sampling was performed uneventfully; testing revealed a normal female
karyotype (46, XX). The patient and
family decided to continue the pregnancy with regular ultrasound examina-

American Journal of Obstetrics & Gynecology AUGUST 2008

tions. Irbesartan (150 mg/day) was given
in place of mycophenolate mofetil along
with felodipine (5 mg/day), hydroxychloroquine (200 mg/day), and prednisolone (30 mg/day).
At 21 weeks, routine fetal ultrasound
revealed an abnormal fetal facial profile.
Consequently, we performed a detailed
fetal sonographic examination; 3-dimensional sonography (Voluson 730
PRO; General Electric Medical Systems,
Waukesha, WI) of the face of the fetus
showed downward slanting palpebral
fissures, micrognathia, bilateral low-set
microtia (Figure 1) and bifid nasal tip
(Figure 2).
Fetal growth was appropriate for gestational age, but the amniotic fluid index
was 36.2 cm, indicating polyhydramnios. Treacher-Collin syndrome, first
pharyngeal arch syndrome, or mycophenolate mofetil-associated embryopathy
were suspected. Treacher CollinsFranceschetti syndrome 1 (Tcof1) gene
analysis was negative after follow-up amniocentesis. Both parents were negative
for the carrier test for the Tcof1 gene.
Mycophenolate mofetil embryopathy
was the most likely diagnosis.
The parents were made aware of the
implications of the diagnosis and made a
fully informed choice to terminate the
pregnancy at 22 weeks. Fetopathologic
examination noted micrognathia, ocular
hypertelorism, bilateral microtia and external auditory duct atresia, and a nasal
bifid anomaly (Figure 1). The limbs, thorax, abdomen, kidneys, and genital organs appeared to be normal. Results of

microtia with cleft lip and palate (1). Mycophenolate signs. and neonatal death with microtia. arrows indicate microtia (MT) and micrognathia (MG). Mycophenolic acid reversibly inhibits inosine monophosphate dehydrogenase and inhibits de novo synthesis of purine nucle- otides.4 In these reproductive toxicology studies. Structural malformations were reported in 4 of the 18 live births (22. Three-dimensional surface-rendered image of the left lateral facial profile of the fetus demonstrating low-set microtia (MT) and severe micrognathia (MG). pathologic examination of the placenta were normal. There were 15 spontaneous abortions (45. and congenital heart defects (1). leading to decreased B. Mycophenolate signs. Two-dimensional ultrasound image of the fetal nose demonstrating nasal duplication (arrow). Confirmation of the diagnosis at necropsy. indicating that studies in pregnant women (controlled and observational) have demonstrated a risk to the fetus. microtia alone (1). Three-dimensional surface-rendered image of the fetal facial profile demonstrating a typical nasal bifid anomaly (arrow). and hydrocephaly in rats.AJOG. This first case involved a female kidney transplant recipient who became pregnant and used mycophenolate mofetil during the first trimester. Am J Obstet Gynecol 2008. ocular hypertelorism.7 After birth.Case Report www. The second case involved a woman with a renal transplant who became pregnant receiving immunosuppression with mycophenolate mofetil. B. umbilical hernia. microtia. left pelvic ectopic kidney. ectopic kidney. Teratogenic effects of mycophenolate mofetil have been shown in animal models: ectopia cordis.and T-cell proliferation and decreased antibody production. and complete agenesis of the corpus callosum.3 Fetal development abnormalities were observed in animal studies when mycophenolate mofetil was administered during the period of organogenesis. teratogenic effects appeared at doses below those causing maternal toxicity and at dosages yielding plasma concentrations half the therapeutic levels found in humans. B. the female baby presented with a pattern of malformations comprising cleft lip and palate. cleft lip and palate. Am J Obstet Gynecol 2008. Huang. 2 cases of major fetal malformations after maternal organ transplantation were reported. congenital diaphragmatic hernia. with subsequent fetopathology examination revealing a large cleft lip and palate. Recently. AUGUST 2008 American Journal of Obstetrics & Gynecology e7 . C OMMENT Mycophenolate mofetil is rapidly absorbed and hydrolyzed to mycophenolic acid after oral administration. agnathia. El Sebaaly et al8 reported the first case of nontransplant mycophenolate mofetil-exposed fetal malformation. and diaphragmatic hernia in rabbits and anophthalmia. microtia and external auditory conduct atresia.3. US Food and Drug Administration.4 Currently. C. external auditory duct atresia. Sifontis et al5 reviewed a total of 33 pregnancies in 24 women who had received solid organ transplants and were exposed to mycophenolate mofetil during pregnancy. micrognathia and hypertelorism.2%). arrow indicates the bifid nose.org FIGURE 1 Fetal ear anomaly A. micrognathia. mycophenolate mofetil and mycophenolic acid are classified as pregnancy category D according to the FIGURE 2 Fetal nose anomaly A. Additionally. including hypoplastic nails and shortened fifth fingers (1). Huang. Confirmation of the diagnosis at necropsy.5%).6 The pregnancy was terminated at 22 weeks of gestation.

Lavelanet AF. Figiel J. was reported. 7. 11. Steinhard J.9 In addition. Fetal malformations associated with mycophenolate mofetil for lupus nephritis. Ledo A. during therapy. The pregnancy was terminated because fetal ultrasonography showed multiple malformations. Coscia LA. 8. Armenti VT. anterior positioning of the aorta.17:121-30. Aranow C.18:357-61. should also be aware of the need to undergo a pregnant test and to evaluate the contraceptive status for their patients within 1 week of beginning mycophenolate mofetil therapy. 2. Coulomb A. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Nephrol Dial Transplant 2007. Boso V. EBPG Expert Group on Renal Transplantation. Schoner K. a female child presenting at birth with mycophenolate mofetil syndrome. European best practice guidelines for renal transplantation. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. 2008. Sollinger HW. 7(Suppl): 50-5. decision making. Pregnancy in renal transplant recipients. microtia. rheumatologists. 6. and for at least 6 weeks after therapy has stopped. Frydman R. Section IV: Long-term management of the transplant recipient. The mother had been treated with high doses of the immunosuppressant mycophenolate mofetil in early pregnancy for systemic lupus erythematosus. The fetopathology examination showed bilateral anotia. and management.103:1091-4. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. Zellers N. genetic counseling should be provided regarding the possibility of fetal malformation. El Sebaaly Z. cleft palate.82:1698-702. a typical nasal bifid anomaly was first detected in our case during prenatal 3-dimensional ultrasound scanning. Transplantation 2006. Ther Drug Monit 1996. Attempts at prenatal diagnosis of mycophenolate mofetil embryopathy by repeat fetal sonography may be advisable. hypertelorism. The fetal mycophenolate mofetil syndrome. and external auditory duct atresia. and asymmetric kidneys. Because the patient had no contact with other known teratogenic agents and we ex- e8 www.11 It is important that health care providers. Schoner et al10 reported a female fetus with acrofacial dysostosis and facial clefts of hitherto unreported extension. we reported the case of a woman who was treated with mycophenolate mofetil for systemic lupus erythematosus before conception and during the first trimester of pregnancy. Decramer S. 10. its long elimination half-life. Velinov M. In cases of women who conceive while receiving mycophenolate mofetil therapy. Elefant E. and recent reports with human data. Ginzler EM. Her mother had been taking mycophenolate mofetil and adalimumab during the first 8 weeks of the pregnancy for lupus nephritis. nail hypoplasia. Gouyon JB. and epicanthic folds. Le Ray C. Mycophenolate mofetil in pregnancy after renal transplantation: a case of major fetal malformations.353:2219-28.10. In utero exposure to mycophenolate mofetil: a characteristic phenotype? Am J Med Genet A 2008. In utero exposure to immunosuppressive drugs: experimental and clinical studies.146:1-7. Clin Dysmorphol 2008. Perez-Aytes A. In this case. and obstetricians. . polydactylia. Rehder H. our experience shows that 3-dimensional ultrasound has the advantage of providing a realistic image and offering the patient an improved visual perspective of the condition of the fetus. Obstet Gynecol 2004. Sollinger HW. Nephrol Dial Transplant 2002. US Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995. including micrognathia.111: 483-6. The current recommendation is that effective contraception must be used before beginning mycophenolate mofetil therapy. Sifontis NM. It is important to realize that mycophenolate mofetil should not be used in pregnancy and that it should be stopped immediately upon detection of pregnancy because of its proven teratogenic potential in animals. enabling her to prepare psychologically for diagnosis. Specifically.17:77-8.60:225-32. including physicians involved in organ transplant. IV. 3. Snanoudj R. et al. Pediatr Nephrol 2002. N Engl J Med 2005. Constantinescu S. Moritz MJ. 5. More recently. Tendron A. it seems reasonable to assume a causal relationship between the anomalies present in this fetus and mycophenolate mofetil exposure during early pregnancy.org cluded any chromosomal aberration or gene mutation. 9. The fetus exhibited malformations similar to those seen in animal models and reported human cases. f American Journal of Obstetrics & Gynecology AUGUST 2008 REFERENCES 1. Dooley MA. Mycophenolate mofetil— clinical and experimental experience. The obstetrician is therefore better equipped to counsel the patient about the finding. including micrognathia. external auditory duct atresia.AJOG. In this article. coinciding with the time of conception and the entire period of active organogenesis. et al. Audibert F.Case Report The woman had been on mycophenolate mofetil maintenance therapy for lupus nephritis when pregnancy was discovered at 25 weeks of gestation. Charpentier B. Pirsch JD. 4.22:2722. Severe facial clefts in acrofacial dysostosis: A consequence of prenatal exposure to mycophenolate mofetil? Obstet Gynecol. bilateral microtia with aural atresia.