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Role of the Astute
Clinician and Epidemiologist in
Recognizing Teratogens
John C. Carey, MD, MPH
UUniversity
of Utah
Role of the Astute Clinician and Epidemiologist in
Recognizing Teratogens
Purpose of this presentation:
• Discuss clinical evidence as a
method in the determination of
human teratogenicity
• Review the evidence that MMF is a
human teratogen as an
illustration of method
Astute Clinician Methodology
In the Determination of
Teratogenicity
Role of the Astute Clinician and
Epidemiologist in
Recognizing Teratogens:
Classical Teratogens
• Thalidomide
• Aminopterin/
Methotrexate
• Warfarin
• Alcohol
• Trimethadione
• Hydantoin
• Valproic acid
• Isotretinoin
• ACE inhibitors
• Penicillamine
• Fluconazole
• Misoprostol
Jorde et al., Medical Genetics
4th edition, 2010
Proof of Causation in Teratology
• Epidemiological studies
• Clinical Evidence
• Biologic Plausibility - supportive
Animal Models
Pharmacology
Clinical Evidence
The Astute Clinician Model:
Rare Exposure, Distinctive Outcome
Carey, AJMG 111:54, 2002
Carey et al., BDR 85:63, 2009
Example of Human TeratogensBased on Clinical Evidence
• Aminopterin/methotrexate
• D-Penicillamine
• Fluconazole
• MMF
Carey et al., 2009
Jones & Carey, 2011
Examples of Established Human TeratogensRecognized by Astute Observer and Confirmed
by Epidemiological Methods/Animal Models
• Alcohol
• Valproic acid
• Isotretinoin
• Warfarin
Jones & Carey, 2011
Astute Clinician Method
• “Rare malformation/rare exposure method”
“Alert clinician”
• Criteria:
Critical time
Rare exposure/rare outcome
3 or more cases
• Biologic plausibility - supportive
Shepard, 1994
Carey et al., 2009
• Rare exposure – prevalence < 1 in 1000
• Rare outcome – prevalence < 1 in 10,000
* Multiple defects and
distinctive outcome
increase likelihood of causal inference
Astute Clinician Method
Carey et al., 2009
AJMG 72:253, 1997
4th case of fluconazole embryopathy
MMF As a Potential Teratogen
The Clinical Evidence
• Background MMF therapeutics
• MMF as a Potential Teratogen: The Evidence
• Summary and Future Directions
Update on Teratogens:Mycophenolate Mofetil (MMF)
as a Potential Teratogen
MMF As a Potential Teratogen
Background: MMF Therapeutics
• Immunosuppressant used in organ transplantation and in lupus/RA
• Reversible inhibitor of inosinemonophosphate dehydrogenase
→ inhibition of purine synthesis in T/B lymphocytes
• Fetal malformations in rats: anophthalmia, agnathia, CDH
Perez Aytes et al., AJMG, 2008
Submitted 2007
Schoner et al., Ob Gyn, 2008
Carey, Ob Gyn, 2008
Velinov & Zellers, 2008
LeRay et al., 2004
Tjeertes et al., 2007
Carey et al., 2009
Ten Cases As of 2008
Ang et al., 2008
Parisi et al., 2009
Jackson et al., 2009
Anderka et al., 2009
Case # Reference Indication
For MMF
Time of
Exposure
(weeks)
Other
Related Exposures
Key Defects
1 Le Ray et al. Kidney
transplant
0 – 13 Tacrolimus, prednisone,
azathioprine
CL/P, microtia
2 Sifontis et al Kidney
transplant
0 – 24 Prednisone, tacrolimus CL/P,
microtia
3 Sifontis et al.
(Parisi et al.)
Kidney
transplant
0 – 35 Prednisone, tacrolimus CL/P, microtia, CDH,
CHD
4 Sifontis et al. Kidney
transplant
0 – 15 Prednisone, tacrolimus Microtia
5 Tjeertes et al. Kidney
transplant
0 – 12 Tacrolimus Microtia, hydrops
6 Perez-Aytes et al. Kidney
transplant
0 – 10 Tacrolimus Microtia, CL/P,
coloboma
7 Schoner et al. Lupus 0 – 8 Cyclophosphamide,
azathioprine
CL/P, microtia,
coloboma, CHD, TEF
Summary of Clinical Data on the Reported Cases of the
Mycophenolate Mofetil Embryopathy
CL/P- cleft lip or palate CHD- congenital heart defect CDH- congenital diaphragmatic hernia TEF-tracheo-esophageal fistula
Case # Reference Indication
For MMF
Time of
Exposure
(weeks)
Other
Related Exposures
Key Defects
8 El Sebally et al. Lupus 0 – 25 Prednisone,
hydroxychloroquine
Anotia, polydactyly,
CHD
9 Velino and
Zellers
Lupus 0 – 8 Adalimumab Microtia, cleft palate
10 Jackson et al. Liver
transplant
0 – 40 Prednisone, tacrolimus CL/P, microtia, CHD,
microphthalmia
11 Ang et al. EM 7th week None Microtia, coloboma
12 Anderka et al. Lupus 0 – 12 Lisonopril, HCQ Microtia
13 Andrade Vila
et al.
Heart
transplant
0 – 40 Tacrolimus, prednisone,
pravastatine, diltiazen,
CBZ
CP, CHD, PS, microtia
14 Huang et al. Lupus 0 – 12 Prednisone, HCQ Microtia, bifidnose
Summary of Clinical Data on the Reported Cases of the
Mycophenolate Mofetil Embryopathy
CL/P- cleft lip or palate CHD- congenital heart defect CDH- congenital diaphragmatic hernia TEF-tracheo-esophageal fistula
MMF As A Potential Teratogen
Four other cases (2009 – 2011)
• 2 Unpublished
• 1 Retinal coloboma only
• 1 Microtia/bifid uvula
MMF As A Potential Teratogen Summary
• Microtia 1 – 3 , Aural Atresia 15/15
Bilateral 11/11
• Orofacial Clefts 8/15
• CHD 5/15
• CDH 1/15
• Microphthalmia/Coloboma 4/15
• Prevalence of OFCs – 1/500
• Prevalence of microtia – 1/5000
Combined occurrence = 1 in 2.5 million
• Usage of MMF in pregnancy < < 1/1000
MMF As A Potential Teratogen
~
Astute Clinician Method
• “Rare malformation/rare exposure method”
“Alert clinician”
• Criteria:
Critical time
Rare exposure/rare outcome
3 or more cases
• Biologic plausibility - supportive
Shepard, 1994
Carey et al., 2009
Conclusions: MMF
• Multiple defects / Rare patterns,
rare exposure
• Various indications
• Critical time
• 15 cases – 6 U.S.
• Biological plausibility
[ No animal model ]
Future Directions
• What is the risk if exposed in 1st
trimester?
• What is the developmental outcome of
surviving infants?
• What is the pathogenic mechanism?