cognition and behavior at school entry in children with congenital ...

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levothyroxine were evaluated at 5 years, 9 months, with the McCarthy Scale and ... early with a high dose of levothyroxine have normal global development and.
COGNITION AND BEHAVIOR AT SCHOOL ENTRY IN CHILDREN WITH CONGENITAL HYPOTHYROIDISM TREATED EARLY WITH HIGH-DOSE LEVOTHYROXINE J. SIMONEAU-ROY, MD, FRCPC, S. MARTI, MSC, C. DEAL, PHD, MD, FRCPC, C. HUOT, MD, MSC, FRCPC, P. ROBAEY, MD, PHD, AND GUY VAN VLIET, MD

Objective

To document cognition and behavior at school entry in these patients.

Study design

Eighteen children with congenital hypothyroidism (CH; 9 severe and 9 moderate, based on a surface of the knee epiphyses at diagnosis < or $0.05 cm2) treated from a median of 14 days with a median of 12.0 mg/kg per day of levothyroxine were evaluated at 5 years, 9 months, with the McCarthy Scale and the Questionnaire for Evaluation of Social Behavior, as were 40 control children.

Results The global IQs at 5 years, 9 months, were similar: medians (range) were 102 (87 to 133), 102 (84 to 135), and 115 (88 to 136) (not significant) for severe CH, moderate CH, and control children, respectively. The behavioral scores of CH children were within the normal range. However, the number of times when plasma TSH was >6.0 mIU/L during treatment was correlated positively with anxiety (P = .02) and inattention (P = .05), whereas the number of times TSH was hyperactivity > aggressiveness > prosociality, although all mean scores were within the normal range. This pattern reflects an imbalance in favor of internalizing problems, as previously reported.25 This could be the consequence of a chronic condition that requires regular hospital visits and blood tests and that by generating parental anxiety about their child’s development, may lead to overprotection. Such a pattern has already been shown in other chronic pediatric diseases.26 However, the anxiety and inattention scores were correlated with the undertreatment index, suggesting that this behavioral pattern may also have a biological determinant. The recommendation of a starting dose of levothyroxine of 10 to 15 lg/kg per day has raised concerns about undesirable effects of overtreatment.10,24 However, Selva et al22 have recently demonstrated that these doses are clearly needed to normalize TSH and restore euthyroidism in newborn infants as soon as possible. The persistent elevation of TSH observed in the past with a much lower thyroxine dose was probably misinterpreted as resistance to the normal feedback control mechanisms. It has recently been shown that such resistance occurs in fact in only a minority of newborn infants with CH.27 In our study, the high starting doses of levothyroxine led to a normal mean plasma TSH at 6 weeks in moderate CH, whereas this was only achieved at 3 months in severe CH (Fig 1). The mean plasma levels of free T4 were above the available pediatric reference intervals in both subgroups at 6 weeks.16 However, the target range for the plasma levels of free T4 in infants with CH may be even higher,22 and newborn infants with severe CH may need an even higher initial dose than the one we used. On the other hand, the mean plasma total T3, the biologically active form of thyroid hormone, remained within the normal range throughout the study. No infant had clinical signs or symptoms of hyperthyroidism, and the parents did not report the temperamental difficulties reported by others at younger ages.28 Also consistent with the normal mean plasma total T3 during follow-up, bone maturation was not significantly advanced compared with the standards of Greulich and Pyle.15 The apparent effects of transient periods of undertreatment and overtreatment on behavior and cognition are complex and age-dependent, as illustrated by the apparent paradox that inattention tends to be correlated to a high initial thyroxine dose but is correlated to the undertreatment index after 3 months. On the other hand, the overtreatment index was correlated with lower scores on the verbal subscale of the McCarthy battery. While some of these findings have biological plausibility, our sample size is small, and we did not correct for multiple correlations. Thus, the possible risks of overtreatment have to be confirmed with larger numbers of Cognition and Behavior at School Entry in Children with Congenital Hypothyroidism Treated Early with High-dose Levothyroxine

patients and on other cohorts and to be weighed against the well-documented harmful effects of thyroxine deficiency in the auditory/verbal domain such as mild hearing loss (mainly sensorineural loss in high frequencies), early speech delay, and deficits in later receptive language and auditory discrimination skills.29 The very narrow range of age at treatment initiation (Table I) probably explains why we did not find an effect of this variable on outcome. However, it is possible that treating at an even earlier age may improve some abilities. Likewise, it is possible that closer biochemical monitoring and more frequent or precise dose adjustments would abolish all cognitive and behavioral differences between children with CH and control children. Some authors draw blood every 4 to 5 days during the first few weeks of treatment,30 whereas others sample much less frequently.31 The schedule recommended by the American Academy of Pediatrics has been evaluated in one study of children treated with 6.6 to 10 lg/kg per day, which did not include IQ as the outcome.32 We follow the recommendation of Fisher and Foley9 and wait until at least 4 half-lives of thyroxine have elapsed before taking the first sample on treatment, and then follow the schedule outlined above. In the absence of questionable compliance, we think that much more frequent sampling and dose adjustments may unduly increase parental anxiety. Our results also confirm that developmental evaluations in the first 2 years of life are predictive of the intelligence quotient later in childhood.8,33 Thus, the disappearance of the previously described developmental gap between severe and moderate CH, which we had shown with early treatment and a high initial dose at 18 months, is now confirmed at school entry. Further longitudinal study of the present cohort of children with CH will focus on school progress. Indeed, delayed school progression during elementary school has been shown to be correlated with a low initial dose and with the number of episodes of undertreatment.34

REFERENCES 1. Klein R. History of congenital hypothyroidism. In: Burrow GN, Dussault JH, editors. Neonatal thyroid screening. New York: Raven Press; 1980. p. 51-9. 2. Tillotson SL, Fuggle PW, Smith I, Ades AE, Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect. BMJ 1994;309:440-5. 3. Dattani M, Brook CG. Outcomes of neonatal screening for congenital hypothyroidism. Curr Opin Pediatr 1996;8:389-95. 4. Wolter R, Noel P, De Cock P, Craen M, Ernould C, Malvaux P, et al. Neuropsychological study in treated thyroid dysgenesis. Acta Paediatr Scand Suppl 1979;277:41-6. 5. Dussault JH, Laberge C. [Thyroxine (T4) determination by radioimmunological method in dried blood eluate: new diagnostic method of neonatal hypothyroidism?]. Union Med Can 1973;102:2062-4. 6. New England Congenital Hypothyroidism Collaborative. Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations. Lancet 1981;2:1095-8. 7. Oerbeck B, Sundet K, Kase BF, Heyerdahl S. Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual,

751

motor, and school-associated outcomes in young adults. Pediatrics 2003;112:923-30. 8. Glorieux J, Dussault J, Van Vliet G. Intellectual development at age 12 years of children with congenital hypothyroidism diagnosed by neonatal screening. J Pediatr 1992;121:581-4. 9. Fisher DA, Foley BL. Early treatment of congenital hypothyroidism. Pediatrics 1989;83:785-9. 10. Campos SP, Sandberg DE, Barrick C, Voorhess ML, MacGillivray MH. Outcome of lower L-thyroxine dose for treatment of congenital hypothyroidism. Clin Pediatr (Phila) 1995;34:514-20. 11. Dubuis JM, Glorieux J, Richer F, Deal CL, Dussault JH, Van Vliet G. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment. J Clin Endocrinol Metab 1996; 81:222-7. 12. Bongers-Schokking JJ, Koot HM, Wiersma D, Verkerk PH, de Muinck Keizer-Schrama SM. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000;136:292-7. 13. Perry R, Heinrichs C, Bourdoux P, Khoury K, Szots F, Dussault JH, et al. Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology. J Clin Endocrinol Metab 2002;87:4072-7. 14. Vitaro F, Tremblay RE, Gagnon C. Adversite´ familiale et troubles du comportement au de´but de la pe´riode de fre´quentation scolaire. Revue canadienne de sante´ mentale communautaire 1992;11:45-61. 15. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. Stanford, Calif: Stanford University Press; 1959. 16. Zurakowski D, Di Canzio J, Majzoub JA. Pediatric reference intervals for serum thyroxine, triiodothyronine, thyrotropin, and free thyroxine. Clin Chem 1999;45:1087-91. 17. McCarthy D. The McCarthy scales of children’s abilities. San Antonio (TX): Psychological Corp; 1972. 18. Kaufman AS, Kaufman NL. Clinical evaluation of young children with the McCarthy. New York: Grune and Stratton; 1977. 19. Rutter M. A children’s behaviour questionnaire for completion by teachers: preliminary findings. J Child Psychol Psychiatry 1967;8:1-11. 20. Behar L, Stringfield S. A behaviour rating scale for the preschoool child. Dev Psychol 1974;10:601-10. 21. Tremblay RE, Zhou RM. Le de´pistage des difficulte´s d’adaptation sociale chez les garcxons de milieux socio-e´conomiques faibles: de la maternelle a` la fin de l’e´cole primaire. Rapport de recherche au CQRS et au FCAR. 1991.

752

Simoneau-Roy et al

22. Selva KA, Mandel SH, Rien L, Sesser D, Miyahira R, Skeels M, et al. Initial treatment dose of L-thyroxine in congenital hypothyroidism. J Pediatr 2002;141:786-92. 23. Hrytsiuk I, Gilbert R, Logan S, Pindoria S, Brook CG. Starting dose of levothyroxine for the treatment of congenital hypothyroidism: a systematic review. Arch Pediatr Adolesc Med 2002;156:485-91. 24. Song SI, Daneman D, Rovet J. The influence of etiology and treatment factors on intellectual outcome in congenital hypothyroidism. J Dev Behav Pediatr 2001;22:376-84. 25. Rovet JF, Ehrlich RM. Long-term effects of L-thyroxine therapy for congenital hypothyroidism. J Pediatr 1995;126:380-6. 26. Hauser ST. The study of families with chronic illnesses: ways of coping and interacting. In: Brody GH, Siegel IE, editors. Methods of family research: biographies of research projects. Hillsdale, NJ: Lawrence Eribaum Associates; 1990. p. 59-86. 27. Fisher DA, Schoen EJ, La Franchi S, Mandel SH, Nelson JC, Carlton EI, et al. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab 2000;85:2722-7. 28. Rovet JF, Ehrlich RM, Sorbara DL. Effect of thyroid hormone level on temperament in infants with congenital hypothyroidism detected by screening of neonates. J Pediatr 1989;114:63-8. 29. Rovet J, Walker W, Bliss B, Buchanan L, Ehrlich R. Long-term sequelae of hearing impairment in congenital hypothyroidism. J Pediatr 1996;128:776-83. 30. Bakker B, Kempers MJ, de Vijlder JJ, Van Tijn DA, Wiedijk BM, Van Bruggen M, et al. Dynamics of the plasma concentrations of TSH, FT4 and T3 following thyroxine supplementation in congenital hypothyroidism. Clin Endocrinol (Oxf) 2002;57:529-37. 31. Brown JJ, Datta V, Sutton AJ, Swift PG. Suppression of TSH in congenital hypothyroidism is significantly related to serum levels and dosage of thyroxine. Horm Res 2003;59:85-90. 32. Vogiatzi MG, Kirkland JL. Frequency and necessity of thyroid function tests in neonates and infants with congenital hypothyroidism. Pediatrics 1997;100:E6. 33. Salerno M, Militerni R, Di Maio S, Bravaccio C, Gasparini N, Tenore A. Intellectual outcome at 12 years of age in congenital hypothyroidism. Eur J Endocrinol 1999;141:105-10. 34. Leger J, Larroque B, Norton J. Influence of severity of congenital hypothyroidism and adequacy of treatment on school achievement in young adolescents: a population-based cohort study. Acta Paediatr 2001;90:1249-56.

The Journal of Pediatrics  June 2004