Reproductive Toxicology, Vol. 7, pp. 175-177, 1993 0890-6238/93 $6.00 + ,00 Printed in the U.S.A, All fights reserved. Copyright © 1993 Pergamon Press Ltd,

NEUROBEHAVIORAL TERATOLOGY OF ISOTRETINOIN*

JANE ADAMS* AND EDWARD J. LAMMER ? *University of Massachusetts, Boston; *Stanford University, Stanford, California

I. Background Isotretinoin (tradename Accutane, Hoff-

man-LaRoche, Inc.) has been available by prescrip- tion since 1982 in the United States for the treatment of severe recalcitrant cystic acne and other dermato- logic problems.

Isotretinoin was first reported to be a human teratogen in 1985 by Lammer and coworkers based on the outcome of 36 prospectively ascertained preg- nancies (1). An increased incidence of major malfor- mations was reported. The characteristic pattern of malformations involves craniofacial, cardiac, thy- mic, and central nervous system (CNS) structures. The risks for malformation following prenatal expo- sure has been estimated at 25% for fetuses that reach 20 weeks' gestation (2). Isotretinoin is teratogenic in humans at therapeutic doses of 0.5 to 1.5 mg/kg/ day.

Little attention has been focused on the func- tional outcome of animals or humans exposed to retinoic acid in utero, even though the historical foundation for the principles of behavioral teratol- ogy were largely derived from studies of Vitamin A compounds (see review by Vorhees (3,4)). As part of the second phase of the research program directed at describing the outcomes of human pregnancies (1), the children from the prospective cohort are being followed longitudinally. The purpose of this study is to assess physical growth, development, and neuropsychologic functioning in the children, with particular emphasis on the relationship between structural and intellectual outcome (5). II. Phase II or Research on the Outcome of Children

Prenatally Exposed to Isotretinoin A. Selection of subjects

1. Criteria for inclusion of exposed cases a. prospective identification b. exposure must have begun before 60

days after conception c. pregnancy must have been ascertained

*This detai led outl ine was used to supplement an oral presen- tation. Used by ar rangement with Doctor Adams. Parts of this outline were publ ished in Adams and Lammer (5).

175

before prenatal ultrasonography pro- vided information about status

2. Criteria for selection of controls a. majority of cases--random selection

through the primary care physician of the matched exposed child

b. first alternative--"friend" control selected by the mother of the exposed child

c. last resort--selection on the basis of birthdate from patients of the pediatric practice at Massachusetts General Hospital (Boston)

B. Sample characteristics (see Table 1) C. Methods for evaluation of outcome

a. Age at test: 5 years -+ 3 months of age b. Sample size: 31 prospectively ascertained

cases (all exposures during first 60 days of pregnancy), 30 controls

c. Examination by physician (E. J. Lammer) Vineland Scale of Social Maturity Achenback's Child Behavior Checklist Neurologic and dysmorphologic evalua- tions

d. Neuropsychologic testing battery (see Table 2)

D. Results 1. Dysmorphologic characteristics: 12 of

the children in this sample have at least one major malformation.

2. General mental ability. Performance on the Stanford-Binet IV is shown in Figure 1.

3. Neuropsychologic characteristics of non- retarded children exposed to isotretinoin. The areas of greatest difficulty involve attention, visual-motor integration, visual-perceptual, and organizational abilities.

4. Relationship between dysmorphology and intellectual functioning. All of the iso- tretinoin-exposed children who per- formed in the mentally retarded range have major malformations. Of the l0 iso-

76 Reproductive Toxicology Volume 7, Number 2, 1993

Table 1. Sample characteristics

Endpoint Isotretinoin- Controls exposed (31) (24)

Maternal age (years) 25.9 -+ 5.9 28.1 -+ 5.7 Education

<12th grade 13.3% 4.2% High school graduate 23.3% 25.0% Some college 63.3% 70.8%

Maternal ethnicity (% white) 87.0% 96.0% Paternal ethnicity (% white) 83.0% 92.0%

E.

tretinoin-exposed children functioning in the borderline range of intelligence (70 to 85), 4 have major malformations. Two children with major malformations scored in the average to superior range of mental ability. Studies of correlations between minor anomalies and intellectual function- ing are also ongoing, but are now incom- plete.

Discussion Despite the predictive value of knowledge of a child's morphologic features, such knowl- edge alone does not accurately assess risk for abnormal functional outcome in all cases.

The presence of significant functional deficits in individuals without major malformation demonstrates the importance of longitudinal assessment, including evaluations of behav- ioral outcome as additional tools in risk as- sessment. These data suggest the need for the use of multiple sensitive measures of the quality of graded sensory, motor, and cogni- tive functioning since the deficits are ex- pressed along a continuum of dysfunction.

There are three primary conclusions: l) Prenatal exposure to isotretinoin is associ-

ated with very high risk of adverse out-

Table 2. Neuropsychologic testing battery used in longitudinal follow- up of 5-year-old children exposed to isotretinoin in utero

Primary endpoint Assessment tool

General mental ability

Language-based processing

Visual-perceptual processing

Visual-motor integration

Executive control processes

Motor coordination

Articulation Auditory discrimination

Stanford-Binet 1V (SBIV) Vineland Scale (parental report) Vocabulary (SBIV) Sentence Memory (SBIV) Comprehension (SBIV) Picture Vocabulary (TOLD-II) a Logical Memory for Children Alphabet Recitation Creative Story Telling Linguistic Analysis of Speech Bead Memory (SBIV) Pattern Analysis (SBIV) Quantitative (SBIV) Grooved Pegboard Beery's Test of Visual Motor

Integration Draw-A-Person Animal House (WPPSI) b Continuous Performance Task--Auditory Continuous Performance Task--Visual Child Behavior Checklist Grooved Pegboard Finger Localization Neurologic Screen Word Articulation (TOLD-11) Tone Discrimination Word Discrimination (TOLD-II)

aTOLD-II is the Test of Language Development II. bWPPSI is the Wechsler Primary and Preschool Scale of Intelligence.

Neurobehavioral teratology of isotretinoin • J. ADAMS AND E. J. LAMMER 177

80

60

I$OTRI~TINOIN

CONTROl.

40

20

, I I I I

( 70 71-a5 a6-11s n6-1ao )lal

F u l l s c a l e IQ

Figure 1. Distr ibution of fullscale IQ scores in interim sample of isotret inoin-exposed (34) and control children (31).

come, both with respect to structure and, especially, with respect to mental function- ing; 47% of the Isotretinoin-exposed chil- dren in this interim sample are functioning in the subnormal range of intelligence.

2.) Specific types of structural abnormalities are associated with specific functional impairments.

3.) Currently identified structural abnormali- ties do not fully account for the range of functional deficits that are present in 5- year-old children exposed to isotretinoin in utero.

R E F E R E N C E S

1. Lammer E J, Chen DT, Hoar RM, et al. Retinoic acid em- bryopathy. N Engl J Med. 1985;313:837-41.

2. Lammer E J, Hayes EM, Schunior A, et al. Risk for major malformation among human human fetuses exposed to isotreti- noin (13-cis-retinoic acid). Teratology. 1987;35:68A.

3. Vorhees CV, Brunner RL, McDaniel CR, et al. The relation- ship of gestational age to vitamin A induced postnatal dysfunc- tion. Teratology. 1978;17:217-6.

4. Vorhees CV. Principles of behavioral teratology. In: Riley EP, Voorhees CV, eds. Handbook of behavioral teratology. New York: Plenum Press; 1986:23-46.

5. Adams J, Lammer EJ. Relationship between dysmorphology and neuropsychological function in children exposed to iso- tretinoin "in utero." In: Fujii T, Boer GJ, eds. Functional neuroteratology of short term exposure to drugs. Tokyo: Teikyo University Press. 159-170; 1991.