Archives of Sexual Behavior

, Volume 28, Issue 1, pp 31–44 | Cite as

Prenatal Exposure to Anticonvulsants and Psychosexual Development

  • Arianne B. Dessens
  • Peggy T. Cohen-Kettenis
  • Gideon J. Mellenbergh
  • Nanne V.D. Poll
  • Janna G. Koppe
  • Kees Boer

Abstract

Animal studies have shown that prenatal exposureto the anticonvulsant drugs phenobarbital and phenytoinalters steroid hormone levels which consequently leadsto disturbed sexual differentiation. In this study, possible sequelae of prenatal exposureto these anticonvulsants on gender development in humanswere investigated. A follow-up study was carried out inphenobarbital- and phenytoin-exposed subjects and control subjects matched for age, sex, andthe mothers' ages. Subjects were born in the AcademicMedical Center between 1957 and 1972. Out of 243 exposedand 222 control subjects who were asked to volunteer, 147 exposed subjects (72 male, 75 female) andequal numbers of their matched control subjectsparticipated in the follow-up study. They wereinterviewed and were asked to fill out questionnaires ongender role behavior, gender development, and sexualorientation. As a group, exposed and control subjectsdid not differ with respect to gender role behavior,although higher numbers of prenatallyanticonvulsant-exposed subjects reported current or past cross-genderbehavior and/or gender dysphoria. Three prenatallyanticonvulsant-exposed subjects were transsexuals andhad undergone sex reassignment surgery, a remarkably high rate given the rarity of transsexualism.In addition, two exposed males had exclusivelyhomosexual experiences, whereas none of the controlmales reported exclusive homosexual behavior. The groups did not differ in attainment of pubertalpsychosexual milestones.

PRENATAL EXPOSURE-DELAYED EFFECTS PHENOBARBITAL PHENYTOIN GENDER IDENTITYDISORDER PSYCHOSEXUAL DEVELOPMENT 

REFERENCES

  1. Achenbach, T. M., and Edelbrock, C. S. (1981). Behavioral problems and competencies reported by parents of normal and disturbed children aged four through sixteen. Monogr. Soc. Res. Child Dev. 46 (1, Serial No. 188).Google Scholar
  2. Bakker, A., Van Kesteren, P. J. M., Gooren, L. J. G., and Bezemer, P. D. (1993). The prevalence of transsexualism in The Netherlands. Acta Psychiat. Scand. 87: 237-238.Google Scholar
  3. Berenbaum, S. A., and Hines, M. (1992). Early androgens are related to childhood sex-typed toy preferences. Psychol. Sci. 3: 203-206.Google Scholar
  4. Bertollini, R., Källen, B., Mastroiacovo, P., and Robert, E. (1987). Anticonvulsant drugs in monotherapy. Effects on the fetus. Eur. J. Epidemiol. 3: 164-171.Google Scholar
  5. Briggs, G. G., Freeman, R. K., and Yaffe, S. J. (1994). Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk, (4th ed.), Williams and Wilkins, Baltimore, pp. 44a-51a.Google Scholar
  6. Buehler, B. A., Delimont, D., van Waes, M. and Finnell, R. H. (1990). Prenatal pre diction of risk of the fetal hydantoin syndrome. New Engl. J. Med. 322: 1567-1572.Google Scholar
  7. Clemens, L. G., Popham, T. V., and Ruppert, P. H. (1979). Neonatal treatment of hamsters with barbiturate alters adult sexual behavior. Dev. Psychobiol. 12: 49-59.Google Scholar
  8. Collaer, M. L., and Hines, M. (1995). Human behavioral sex differences: a role for gonadal hormones during early developme nt. Psychol. Bull. 118: 55-107.Google Scholar
  9. Cronbach, L. J. (1963). Educational Psychology, 2nd ed., Harcourt Brace Jovanovich, New York.Google Scholar
  10. Delassio D. J. (1985) Seizure disorders and pregnancy. New Engl. J. Med. 312: 559-63.Google Scholar
  11. Dessens, A. B. (1996). Prenatal exposure to phenobarbital and phenytoin, a study on long-lasting consequences. Dissertation, Medical Faculty, Unive rsity of Amsterdam, 40-54.Google Scholar
  12. Dessens, A. B., Boer, K., Koppe, J. G., v.d. Poll, N. E., and Cohen-Kettenis, P. T. (1994). Studies on long-lasting consequences of prenatal exposure to anticonvulsant drugs. Acta Paediat. Scand. 83 (Suppl. 404): 54-64.Google Scholar
  13. Diaz, J., and Schain, R. J. (1978). Phenobarbital: Effects of long term administration on behavior and brian of artificially reared rats. Science 199: 90-91.Google Scholar
  14. Dittmann, R. W., Kappes, M. H., Kappes, M. E., Börger, E., Stegner, H., Willig, H., and Wallis, H. (1990a). Congenital adrenal hyperplasia I: Gender-related behavior and attitudes in female patients and sisters. Psychoneuroendocrinology 15: 401-420.Google Scholar
  15. Dittmann, R. W., Kappes, M. H., Kappes, M. E., Börger, E., Meyer-Bahlburg, H. F. L., Stegner, H., Willig, H., and Wallis, H. (1990b). Congenital adrenal hyperplasia II: Gender-related behavior and attitudes in female salt-wasting and simple-virilizing patients. Psychoneuroend ocrinology 15: 421-434.Google Scholar
  16. Dittmann, R. W., Kappes, M. E., and Kappes, M. H. (1992). Sexual behavior in adolescent and adult females with congenital adrenal hyperplasia. Psychoneuroend ocrinology 17: 153-170.Google Scholar
  17. Ehrhardt, A. A. and Meyer-Bahlburg, H. F. L. (1984). Gender Role Assessment Schedule-Adult (GRAS-A), New York State Psychiatric Institute, Columbia University, New York.Google Scholar
  18. Ehrhardt, A. A., Meyer-Bahlburg, H. F. L., Rosen, L. R., Feldman, J. F., Veridiano, N. P., Zimmerman, I., and McEwen, B. (1985). Sexual orientation after prenatal exposure to exogenous estrogen. Arch. Sex. Behav. 14: 57-77.Google Scholar
  19. Ehrhardt, A. A., Meyer-Bahlburg, H. F. L., and Rosen, L. R. (1989). The deve lopment of gender-related behavior in females following prenatal exposure to diethylstilbestrol (DES). Horm. Behav. 23: 526-541.Google Scholar
  20. Eriksson, M., and Zetterström, R. (1994). Amphetamine addiction during pregnancy: 10 year follow-up. Acta Paediat Scand. 83 (Suppl., 404): 27-31.Google Scholar
  21. Eriksson, M., Larsson, G., Winbladh, B. and Zetterström, R. (1978). The influence of amphetamine addition on pregnancy and the newborn infant. Acta Paediat. Scand. 67: 95-99.Google Scholar
  22. Finnell, R. H. (1981). Phenytoin-induced teratogenesis: A mouse model. Science 211: 483-484.Google Scholar
  23. Fonseca, N. M., Sell, A. B., and Carlini, E. A. (1976). Differential behavioral responses of male and female ratstreated with five psychotropic drugs in the neonatal stage. Psychopharm acologia 46: 263-268.Google Scholar
  24. Golombok, S., and Fivush, R. (1994). Gender Development, Cambridge University Press, CambridgeGoogle Scholar
  25. Gupta, C., and Yaffe, S. J. (1981). Reproductive dysfunction in female offspring after prenatal exposure to phenobarbital: critical period of action. Pediat. Res. 15: 1488-1491.Google Scholar
  26. Gupta, C., Shapiro, B. H., and Yaffe, S. J. (1980a). Reproductive dysfunction in male rats following prenatal exposure to phenobarbital. Pediat. Pharmacol. 1: 55-62.Google Scholar
  27. Gupta, C., Sonawane, B. R., Yaffe, S. J., and Shapiro, B. H. (1980b). Phenobarbital exposure in utero: Alterations in female reproductive function in rats. Science 208: 508-510.Google Scholar
  28. Gupta, C., Yaffe, S. J., and Shapiro, B. H. (1982). Prenatal exposure to phenobarbital permane ntly decreases testosterone and causes reproductive dysfunction. Science 216: 640-641.Google Scholar
  29. ITS-Classifications of Professions (ITS-Beroepenklapper). (1992). Institute for Applied Social Research ( Instituut voor Toegepaste Sociale Wetenschappen), Nijmegen, The Netherlands.Google Scholar
  30. Kalter, H., and Warkany, J. (1983). Congenital malformations (second of two parts). New Engl. J. Med. 308: 491-497.Google Scholar
  31. Kester, P., Green, R., Finch, S. J., and Williams, K. (1980). Prenatal "female hormone " administration and psychosexual development in human males. Psychoneuroen docrinology 5: 269-285.Google Scholar
  32. Kinsey, A. C., Pomeroy, W. B., and Martin, C. E. (1948). Sexual Behavior in the Human Male, W. B. Saunders, Philadelphia.Google Scholar
  33. Klein, F., Sepekoff, B., and Wolf, T. J. (1985). Sexual orientation: a multi-variable dynamic process. J. Homosex. 11(1-2): 35-49.Google Scholar
  34. Loftus, E. F., and Marburger, W. (1983). Since the eruption of Mt. St. Helens, has anyone beaten you up? Improving the accuracy of retrospective reports with landmark event. Memory Cognit. 11: 114-120.Google Scholar
  35. Meyer-Bahlburg, H. F. L., Ehrhardt, A. A., Feldman, J. F., Rosen, L. R., Veridiano, N. P., and Zimmerman, I. (1985). Sexual activity and sexual functioning in women prenatally exposed to diethylstilbestrol. Psychosom. Med. 47: 497-511.Google Scholar
  36. Meyer-Bahlburg, H. F. L., Ehrhardt, A. A., Rosen, L. R., Gruen, R. S., Veridiano, N. P., Vann, F. H., and Neuwalder, H. F. (1995). Prenatal estrogens and the development of homosexual orientation. Dev. Psychol. 31: 12-21.Google Scholar
  37. Middaugh, L. D., Santos, C. A., III, and Zemp, J. W. (1975a). Effects of phenobarbital given to pregnant mice on behavior of mature offspring. Dev. Psychobiol. 8: 305-313.Google Scholar
  38. Middaugh, L. D., Santos, C. A., III, and Zemp, J. W. (1975b). Phenobarbital during pregnancy alters operant behavior of offspring in C57BL 6J mice. Pharmacol. Biochem. Behav. 3: 1137-1139.Google Scholar
  39. Mullenix, P., Tassinari, M. S., and Keith, D. A. (1983). Behavioral outcome after prenatal exposure to phenytoin in rats. Teratology 27: 149-157.Google Scholar
  40. Pinto, W., Gardner, L. I., and Rosenbaum, P. (1977). Abnormal genitalia as a presenting sign in two male infants with hydantoin embryopathy syndrome. Am. J. Dis. Child. 131: 452-455.Google Scholar
  41. Reinisch, J. M. (1981). Prenatal exposure to synthetic progestins increases potential for aggression in humans. Science 211: 1171-1173.Google Scholar
  42. Reinisch, J. M., and Sanders, S. A. (1982). Early barbiturate exposure: The brain, sexually dimorphic behavior and learning. Neurosci. Biobehav. Rev. 6: 311-319.Google Scholar
  43. Rubin, R. T., Reinisch, J. M., and Haskett, R. F. (1981). Postnatal gonadal steroid e ffects on human behavior. Science 211: 1318-1324.Google Scholar
  44. Sandberg, D. E., Meyer-Bahlburg, H. F. L., Rosen, T. S., and Johnson, H. L. (1990). Effects of prenatal methadone exposure on sex-dimorphic behavior in early school-age children. Psychoneuroend ocrinology 15: 77-82.Google Scholar
  45. Slijper, F. M. E. (1984). Androgens and gender role behavior in girls with congenital adrenal hyperplasia (CAH). Prog. Brain Res. 61: 417-422.Google Scholar
  46. Sonawane, B. R., and Yaffe, S. J. (1982). Delayed effects of drug exposure during pregnancy: reproductive function. Biol. Res. Pregnancy 3: 14-22.Google Scholar
  47. Verhulst, F. C., Akkerhuis G. W., and Althaus M. (1985) Mental health in Dutch children (I) A cross-cultural comparison. Acta Psychiat. Scand. Suppl. 323: 1-108.Google Scholar
  48. Vogels, R., and van der Vliet, R. W. F. (1990). Adolescents and Sex (Jeugd en sex), Dutch Institute for Social Sexological Research (Nederlands Instituut voor Sociaal Seksuologisch Onderzoek—NISSO), Utrecht, The Netherlands.Google Scholar
  49. Vorhees, C. V. (1986). Behavioral teratology of anticonvulsant and antianxiety medication. In Riley, E. P., and Vorhees, C. V., (eds.), Handbook of Behavioral Teratology, Plenum Press, New York, pp. 211-241.Google Scholar
  50. Wani, J. H., Agrawal, A. K., and Shapiro, B. H. (1996). Neonatal phenobarbital-induced persistent alterations in plasma testosterone profiles and testicular function. Toxicol. Appl. Pharmacol. 137: 295-300.Google Scholar
  51. Yaffe, S. J., and Dorn, L. D. (1990). Effects of prenatal treatment with phenobarbital. Dev. Pharmacol. Ther. 15: 215-225.Google Scholar
  52. Zemp, J. W., and Middaugh, L. D. ( 1975). Some effects of prenatal exposure to D-amphetamine sulphate and phenobarbital on developmental neurochemistry and on behavior. Addict. Dis. 2: 307-331.Google Scholar

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Arianne B. Dessens
  • Peggy T. Cohen-Kettenis
  • Gideon J. Mellenbergh
  • Nanne V.D. Poll
  • Janna G. Koppe
  • Kees Boer

There are no affiliations available

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