In utero exposure to phenobarbital and intelligence deficits in adult men.

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 Prøve). 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.

[1]  Great Britain. Foreign Office.,et al.  Classification of occupations, 1950 , 1951 .

[2]  S. G. Armitage.  The effects of barbiturates on the behavior of rat offspring as measured in learning and reasoning situations. , 1952, Journal of comparative and physiological psychology.

[3]  D. Wechsler.  Manual for the Wechsler Adult Intelligence Scale. , 1955 .

[4]  F. Klipstein.  SUBNORMAL SERUM FOLATE AND MACROCYTOSIS ASSOCIATED WITH ANTICONVULSANT DRUG THERAPY. , 1964, Blood.

[5]  R. Gorski,et al.  Critical exposure time for androgenization of the developing hypothalamus in the female rat. , 1968, Endocrinology.

[6]  R. Gorski,et al.  Protection against the neural organizing effect of exogenous androgen in the neonatal female rat. , 1968, Endocrinology.

[7]  A. Villumsen.  Environmental factors in congenital malformations : a prospective study of 9,006 human pregnancies , 1970 .

[8]  John T. Wilson.  Caution with Phenobarbital , 1971, Clinical pediatrics.

[9]  W. G. Cochran,et al.  Controlling Bias in Observational Studies: A Review. , 1974 .

[10]  E. Ross,et al.  Babies: Human development during the first year. , 1975 .

[11]  Some effects of prenatal exposure to d-amphetamine sulfate and phenobarbital on developmental neurochemistry and on behavior. , 1975 .

[12]  D B Rubin,et al.  Criminality in XYY and XXY men. , 1976, Science.

[13]  David E. Smith,et al.  Barbiturates: Their Use, Misuse and Abuse , 1977 .

[14]  [Study of children of mothers treated with anticonvulsants during pregnancy]. , 1977, Neurologia i neurochirurgia polska.

[15]  B. Friis,et al.  Neonatal hypocalcaemia after intrauterine exposure to anticonvulsant drugs. , 1977, Archives of disease in childhood.

[16]  T. Helenius,et al.  THYROID FUNCTION TESTS IN PATIENTS ON LONG‐TERM TREATMENT WITH VARIOUS ANTICONVULSANT DRUGS , 1978, Clinical endocrinology.

[17]  B. Rodgers.  Feeding in Infancy and Later Ability and Attainment: a Longitudinal Study , 1978, Developmental medicine and child neurology.

[18]  B. Mackler,et al.  Effects of maternal absorption of phenobarbital upon rat offspring development and function. , 1979, Neurobehavioral toxicology.

[19]  C. Camfield,et al.  Side effects of phenobarbital in toddlers; behavioral and cognitive aspects. , 1979, The Journal of pediatrics.

[20]  T. Valaes,et al.  Effectiveness and Safety of Prenatal Phenobarbital for the Prevention of Neonatal Jaundice , 1980, Pediatric Research.

[21]  Drug and chemical risks to the fetus and newborn. Summary: pediatrician's view. , 1980 .

[22]  J. Yanai,et al.  Neuronal deficits after neonatal exposure to phenobarbital , 1981, Experimental Neurology.

[23]  S. Scarr.  Race, social class, and individual differences in I.Q , 1982 .

[24]  Donald B. Rubin,et al.  Further meta-analytic procedures for assessing cognitive gender differences. , 1982 .

[25]  Donald B. Rubin,et al.  A Simple, General Purpose Display of Magnitude of Experimental Effect , 1982 .

[26]  J. Reinisch,et al.  Early barbiturate exposure: The brain, sexually dimorphic behavior and learning , 1982, Neuroscience & Biobehavioral Reviews.

[27]  J. Yanai,et al.  Long-lasting effects of early barbiturates on central nervous system and behavior , 1983, Neuroscience & Biobehavioral Reviews.

[28]  C. Hertzog,et al.  Fourteen-year cohort-sequential analyses of adult intellectual development. , 1983 .

[29]  L. Boréus,et al.  Phenobarbital Prophylaxis for Hyperbilirubinemia in Preterm Infants , 1984, Acta paediatrica Scandinavica.

[30]  D. Rubin,et al.  The Bias Due to Incomplete Matching , 1985 .

[31]  D. Rubin,et al.  Constructing a Control Group Using Multivariate Matched Sampling Methods That Incorporate the Propensity Score , 1985 .

[32]  D. Jackson,et al.  The factor structure of the Wechsler scales: A brief review , 1985 .

[33]  Middaugh Ld.  Phenobarbital during pregnancy in mouse and man. , 1986 .

[34]  L. Finnegan,et al.  Neonatal abstinence syndrome, pharmacotherapy and developmental outcome. , 1986, Neurobehavioral toxicology and teratology.

[35]  D. Hirtz,et al.  Survey on the management of febrile seizures. , 1986, American journal of diseases of children.

[36]  M. Jc.  Irreversible changes in mature and aging animals following intrauterine drug exposure. , 1986 .

[37]  J. Koerten,et al.  Prevention of Intraventricular Hemorrhage in Very Low Birth Weight Infants by Maternally Administered Phenobarbital , 1986, Obstetrics and gynecology.

[38]  B. Schraeder.  Developmental Progress in Very Low Birth Weight Infants During the First Year of Life , 1986, Nursing research.

[39]  E. Vining,et al.  Psychologic and behavioral effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid. , 1987, Pediatrics.

[40]  D. R. Owen,et al.  National secular trends in intelligence and education: a twenty-year cross-sectional study , 1987, Nature.

[41]  D. Rubin,et al.  Statistical Analysis with Missing Data. , 1989 .

[42]  W. Rayburn,et al.  Antenatal phenobarbital and bilirubin metabolism in the very low birth weight infant. , 1988, American journal of obstetrics and gynecology.

[43]  D. R. Owen,et al.  REGIONAL DIFFERENCES IN INTELLIGENCE AND EDUCATIONAL LEVEL IN DENMARK , 1988 .

[44]  W. Dodson.  Deleterious effects of drugs on the developing nervous system. , 1989, Clinics in perinatology.

[45]  T. Teasdale,et al.  Intelligence as measured by the WAIS and a military draft board group test , 1989 .

[46]  Abraham Weizman,et al.  Neural and behavioral alterations after early exposure to phenobarbital. , 1989, Neurotoxicology.

[47]  W. Rayburn,et al.  Oral phenobarbital given antenatally to reduce neonatal intraventricular hemorrhage. A comparison between maternal and umbilical cord serum levels at delivery. , 1989, Journal of perinatology : official journal of the California Perinatal Association.

[48]  Donald C. Martin,et al.  IQ at Age 4 in Relation to Maternal Alcohol Use and Smoking During Pregnancy , 1989 .

[49]  D. Hirtz,et al.  Phenobarbital for febrile seizures--effects on intelligence and on seizure recurrence. , 1990, The New England journal of medicine.

[50]  A. Nehlig,et al.  Influence of early neonatal phenobarbital exposure on cerebral energy metabolism and behavior , 1990, Experimental Neurology.

[51]  P. Crumrine,et al.  Phenobarbital treatment and major depressive disorder in children with epilepsy: a naturalistic follow-up. , 1990, Pediatrics.

[52]  Effects of prenatal treatment with phenobarbital. , 1990, Developmental pharmacology and therapeutics.

[53]  S. Pfeiffer,et al.  Outcome for Preschoolers of Very Low Birthweight: Sociocultural and Environmental Influences , 1990, Perceptual and motor skills.

[54]  E. Gaily,et al.  SPECIFIC COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPTIC MOTHERS , 1990, Developmental medicine and child neurology.

[55]  M. Hadders‐Algra,et al.  Antiepileptic medication in pregnancy: Late effects on the children's central nervous system development , 1991, American journal of obstetrics and gynecology.

[56]  D. R. Owen,et al.  Intelligence and educational level in adult males at the extremes of stature. , 1991, Human biology.

[57]  A. Ades,et al.  Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. , 1991, Archives of disease in childhood.

[58]  M. Russell,et al.  Measures of maternal alcohol use as predictors of development in early childhood. , 1991, Alcoholism, clinical and experimental research.

[59]  T. Cole,et al.  Breast milk and subsequent intelligence quotient in children born preterm , 1992, The Lancet.

[60]  J. Reinisch,et al.  The Prenatal Development Project , 1993, Acta psychiatrica Scandinavica. Supplementum.

[61]  C. Feingold.  Correlates of cognitive development in low-birth-weight infants from low-income families. , 1994, Journal of pediatric nursing.