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
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The Journal of Pediatrics June 2004
