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June Machover Reinisch, PhD; Stephanie A. Sanders, PhD; Erik Lykke Mortensen; Donald B. Rubin, PhD

JAMA. 1995;274(19):1518-1525.

Abstract
Objective.
—To test whether exposure to phenobarbital in utero is associated with deficits in intelligence scores in adult men and whether the magnitude of the postnatal effect is mediated by exposure parameters and/or postnatal environmental factors.

Design.
—Two double-blind studies were conducted on independent samples of adult men prenatally exposed to phenobarbital and matched control samples using different measures of general intelligence. Based on data from control subjects, regression models were built relating intelligence scores to relevant pre-exposure matching variables and age at testing. Models generated predicted scores for each exposed subject. Group mean differences between the individually predicted and observed scores estimated exposure effects.

Setting.
—Copenhagen, Denmark.

Participants.
—Exposed subjects were adult men born at the largest hospital in Copenhagen between 1959 and 1961 who were exposed to phenobarbital during gestation via maternal medical treatment and whose mothers had no history of a central nervous system disorder and no treatment during pregnancy with any other psychopharmacological drug. Study 1 included 33 men and study 2,81 men. Controls were unexposed members of the same birth cohort matched on a wide spectrum of maternal variables recorded prenatally and perinatally. Controls for studies 1 and 2 included 52 and 101 men, respectively.

Main Outcome Measures.
—In study 1: Wechsler Adult Intelligence Scale (Danish version); in study 2: Danish Military Draft Board Intelligence Test (Børge Priens Prove).

Result.
—Men exposed prenatally to phenobarbital had significantly lower verbal intelligence scores (approximately 0.5 SD) than predicted. Lower socioeconomic status and being the offspring of an "unwanted" pregnancy increased the magnitude of the negative effects. Exposure that included the last trimester was the most detrimental.

Conclusion.
—Phenobarbital exposure during early development can have long-term deleterious effects on cognitive performance. Detrimental environmental conditions can interact with prenatal biological insult to magnify negative outcomes. Physicians are urged to use increased caution in prescribing such medications during pregnancy.

(JAMA. 1995;274:1518-1525)

Author Affiliations
From The Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington (Drs Reinisch and Sanders); Institute of Preventive Medicine, Copenhagen (Denmark) Hospital Corporation (Drs Mortensen and Reinisch); and the Department of Statistics, Harvard University, Cambridge, Mass (Dr Rubin). Dr Reinisch is now Director Emerita of The Kinsey Institute and president of R2 Science Communications, Inc, Bloomington, Ind, and Brooklyn, NY.

Footnotes
Reprint requests to The Kinsey Institute for Research in Sex, Gender, and Reproduction, Morrison Hall— Third Floor, Indiana University, Bloomington, IN 47405 (Dr Reinisch).

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