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?