LONG-TERM FOLLOW-UP OF PRENATALLY DEXAMETHASONE-TREATED CHILDREN AT RISK FOR CONGENITAL ADRENAL HYPERPLASIA

Congenital adrenal hyperplasia (CAH) is a disorder of steroid genesis affecting approximately 1:10 000 children and leading to increased levels of androgens during foetal life and subsequent virilization of external genitalia in affected girls. However, prenatal virilization can be eliminated by antenatal dexamethasone (DEX) treatment. To be fully effective, DEX treatment has to be started in the 6–7th postmenstrual week and continued until the results of the prenatal diagnosis are available at gestational week 11– 12. This means that 7 out of 8 foetuses (boys and unaffected girls) are treated unnecessarily during early gestation. CAH-affected girls are treated to term. We performed a long-term follow-up of children treated in Sweden during the years 1985–1995, and 26 of the 40 treated individuals participated in the study. The control group consisted of 35 sexand age-matched healthy children. In general, the DEX-treated children were as well adjusted as the controls (Studies I and II). There were no between-group differences in major cognitive measures such as IQ, learning and memory. Parents reported that the DEX-treated children performed just as well at school as the controls. However, in a test of verbal working memory (WM), significantly lower results were observed in CAH-unaffected short-term treated children. The CAH-affected children did not differ from the control group, probably owing to small sample size and, consequently, low power. The verbal WM was correlated with the children‟s self-perception of difficulties in scholastic ability, another measure in which CAH-unaffected children differed from the controls. In measures of temperament, psychopathology and well-being, parents reported generally as good health in the DEXexposed group as in the control group. The only difference was an observed increase in sociability in DEX-exposed children. In the children‟s self-ratings, however, increased social anxiety was observed. This difference was significant in CAH-unaffected shortterm-treated children. In order to study gender role behaviour (Studies III and IV), we developed a new instrument, the Karolinska Inventory of Gender Role Behaviour (KI-GRB), which was evaluated in an additional group of 180 school-age children. The underlying dimensions of the inventory were described by the factor structure and the KI-GRB subscales were also associated with sex-specific cognition. In prenatally DEX-exposed, CAH-unaffected boys, more neutral behaviours were observed, while in girls no group differences emerged after controlling for site of residence. A similar pattern was found when CAH-affected children were included in the analyses In summary, these studies indicate that prenatal DEX treatment of CAH may have negative effects on certain aspects of cognitive and affective development, as well as affect gender role behaviour. LIST OF PUBLICATIONS IN THIS THESIS I. Hirvikoski, T. , Nordenstrom, A. , Lindholm, T. , Lindblad, F. , Ritzen, E. M. , Wedell, A. , Lajic S. (2007). Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. Journal of Clinical Endocrinology and Metabolism, 92(2), 542-548. II. Hirvikoski, T. , Nordenstrom, A. , Lindholm, T. , Lindblad, F. , Ritzen, E. M. , Lajic, S. (2008). Long-term follow-up of prenatally treated children at risk for congenital adrenal hyperplasia: does dexamethasone cause behavioural problems? European Journal of Endocrinology, 159(3), 309-316. III. Hirvikoski, T. , Lindholm, T. , Lajic, S. , & Nordenström, A. Gender role behavior in prenatally dexamethasone treated children at risk for congenital adrenal hyperplasia – a pilot study. Acta Paediarica, 2011 Mar 9. doi: 10.1111/j.1651-2227.2011. 02260.x. [Epub ahead of print]. IV. Hirvikoski, T. , Lindholm, T. , Nordenström, A. , & Lajic, S. Sex-specific cognition, gender role behavior and sex role identification in 8–15 year-old children (submitted to Archives of Sexual Behaviour, article in review). PUBLICATIONS NOT INCLUDED IN THIS THESIS I. Lajic S, Nordenström A, Hirvikoski T. (2011). Long-term outcome of prenatal dexamethasone treatment of 21-hydroxylase deficiency. Endocr Dev, 20:96-105. II. Lajic, S. , Nordenström, A. , & Hirvikoski, T. (2008). Long-term outcome of prenatal treatment of CAH,. In Flück CE, Miller WL (eds): Disorders of the Human Adrenal Cortex. Endocr Dev. Basel, Karger, vol 13, s. 82-98. III. Hirvikoski, T. , Waaler, E. , Alfredsson, J., Pihlgren, C. , Holmström, A. , Johnson, A, Rück, J, Wiwe, C, Bothén, P, Nordström, A-L. (2011). Reduced ADHD symptoms in adults with ADHD after Skills Training group – results from a randomized controlled trial. Behaviour Research and Therapy, 14;49:175-85. IV. Hirvikoski, T. , Olsson, E. , Nordenström, A. , Lindholm, T. , Nordström, AL., & Lajic, S. (2011). Deficient cardiovascular stress reactivity is associated with poorer cognitive performance in adults with ADHD (attention deficit hyperactivity disorder). J Clin Exp Neuropsychol, 33 (1), 63–73. V. Hirvikoski, T. , Lindholm, T. , Nordenström, A. , Nordström, A-L. , & Lajic, S. (2009). High self-perceived stress and many stressors, but normal diurnal cortisol rhythm in adults with ADHD (attention deficit hyperactivity disorder). Hormones and Behaviour, 55(3):418-24. VI. Ginsberg, Y. , Hirvikoski, T. Lindefors, N. (2010). Attention Deficit Hyperactivity Disorder (AD/HD) in male prison inmates is a prevalent, persistent and disabling disorder. BMC Psychiatry, 10: 112. VII. Westerberg, H. , Hirvikoski, T. , Forssberg, H. & Klingberg, T. (2004). Visuo-spatial working memory span: a sensitive measure of cognitive deficits in children with ADHD. Child Neuropsychology, 10; 155 – 161. VIII. Westerberg, H. , Jacobaeus, H. , Hirvikoski, T. , Clevberger, P., Östensson, M-L, Bartfai, A. , Forssberg, H. , & Klingberg, T. (2007). Computerized working memory training after stroke – A pilot study, Brain Injury; 21(1): 21–29. IX. Sinai, C. , Hirvikoski, T. , Dencker Vansvik, E. , Nordström, A-L. , Linder, J., Nordström, P., & Jokinen, J. (2009). Thyroid hormones and personality traits in attempted suicide. Psychoneuroendocrinology, 34(10):1526-32. X. Hirvikoski, T. , & Jokinen, J. Personality traits in attempted and completed suicide. European Journal of Psychiatry, in press, doi: 10.1016/j.eurpsy. 2011.04. 004).