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Neurodevelopmental Outcomes in Congenital Hypothyroidism: Comparison of Initial T4 Dose and Time to Reach Target T4 and TSH
NEURODEVELOPMENTAL OUTCOMES IN CONGENITAL HYPOTHYROIDISM: COMPARISON OF INITIAL T4 DOSE AND TIME TO REACH TARGET T4 AND TSH KARIN A. SELVA, MD, A. HARPER, MD, A. DOWNS, PHD, P. A. BLASCO, MD, AND S. H. LAFRANCHI, MD
Objectives To compare neurodevelopmental outcomes in severe and moderate congenital hypothyroidism (CH) among 3 different initial L-thyroxine doses and to examine the effect of the time to thyroid function normalization on neurodevelopmental outcomes. Study design
Neurodevelopmental assessments of 31 subjects included the Mullen Scales of Early Learning, Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children, Wide-Range Achievement Test, and Child Behavioral Checklist.
Results
Subjects started on higher initial L-thyroxine doses (50 lg) had full-scale IQ scores 11 points higher than those started on lower (37.5 lg) initial doses. However, verbal IQ, performance IQ, and achievement scores did not differ among the 3 treatment cohorts. Subjects with moderate CH had higher full-scale IQ scores than subjects with severe CH, regardless of the initial treatment dose. Subjects who took longer than 2 weeks to normalize thyroid function had significantly lower cognitive, attention, and achievement scores than those who achieved normal thyroid function at 1 or 2 weeks of therapy.
Conclusions Initial L-thyroxine dose and faster time to normalization of thyroid function are important to optimal neurodevelopmental outcome. In severe CH, it is important to choose an initial dose at the higher end of the recommended range to achieve these goals. (J Pediatr 2005;147:775-80) he onset of newborn thyroid screening in the 1970s brought the expectation that early thyroid hormone replacement would prevent mental retardation due to congenital hypothyroidism (CH).1 But recent studies have demonstrated mildly lower IQ scores, subtle neurodevelopmental delays, and motor deficits in children with CH, despite early detection and hormone replacement.2-4 The goal of initial therapy in CH is to minimize neonatal central nervous system exposure to hypothyroidism by normalizing thyroid function, as reflected by thyroxine (T4) and thyroid-stimulating hormone (TSH) levels, as rapidly as possible.5,6 Studies have demonstrated that even a short period (1 to 3 weeks) of neonatal hypothyroidism before initiation of treatment can negatively affect development.4,7-11 In 2002 our group reported results of a treatment study in CH that examined 3 initial treatment doses of L-thyroxine and their patterns of thyroid function normalization over a From the Children’s Diabetes & Endocrine Center, Legacy Emanuel Hospital, 12-week period.12 The 3 treatment doses were 37.5 mg, 50 mg, and a loading dose of 62.5 Portland, Oregon and Department of mg for 3 days, followed by 37.5 mg. We found that T4 and free T4 concentrations were in Pediatrics, Oregon Health Science Unithe target range by 3 days of therapy in the 50- and 62.5/37.5-mg groups and by 1 week versity, Portland, Oregon. Supported in part by U.S. Public of therapy in the 37.5-mg group. A dose of 50 mg/day led to the most rapid normalization Health Service grant 5-M01-RR000334. of TSH, by 2 weeks of therapy. We recommend consideration of a slightly higher increased Submitted for publication Feb 4, 2005; target range of T4 (10 to 18 mg/dL) and free T4 (1.6 to 2.5 ng/dL) during the first month last revision received Jun 28, 2005; accepted Jul 18, 2005. of therapy to quickly normalize T4 and TSH, followed by frequent monitoring and adjustReprint requests: Karin A. Selva, MD, ment of thyroid doses thereafter, to maintain normal thyroid function.
T
CBCL CH ELC FDI FSIQ PIQ SEM T3
Child Behavioral Checklist Congenital hypothyroidism Early Learning Composite Freedom From Distractability Index Full-scale IQ Performance IQ Standard error of the mean Triiodothyronine
T4 TSH VIQ WISC-III WPPSI-R WRAT-III
Thyroxine Thyroid-stimulating hormone Verbal IQ Wechsler Intelligence Scale for Children, Third Edition Wechsler Preschool and Primary Scale of Intelligence-Revised Wide-Range Achievement Test, Revision 3
Children’s Diabetes and Endocrine Center, Legacy Emanuel Hospital, 501 N. Graham Street, Suite 375, Portland, OR 97229. E-mail: kselva@ lhs.org. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.07.024
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The present study was a follow-up study examining neurodevelopmental outcomes in subjects from our original study cohort. Our goal was to compare neurodevelopmental outcomes, particularly cognition, academic achievement, and attention/behavior, among the 3 treatment groups. In addition, we investigated the effect of CH severity, differences (if any) between CH subjects and their unaffected siblings, and the effect of the timing of thyroid function normalization on neurodevelopmental outcomes in all treatment cohorts.
METHODS In our original study, 47 subjects were randomized into 1 of 3 initial L-thyroxine dosage groups: 37.5 mg, 50 mg, and 62.5 mg for 3 days followed by 37.5 mg daily (equivalent to 10.9, 14.5, and 17.7 mg/kg/day for 3 days followed by 10.6 mg/kg/day, respectively). Serum free T4, T4, free triiodothyronine (T3), T3, and TSH levels were measured before treatment and at 3 and 7 days and 2, 4, 8, and 12 weeks after initiation of L-thyroxine therapy. In accordance with the study protocol, no dosage adjustments were made for the first 2 weeks of treatment. After 2 weeks, adjustments were made following the study algorithm.12
Subject Recruitment Power analysis predicted the need for 10 patients from each treatment cohort for statistical significance. We attempted to contact and enroll all 47 original subjects. Thirty-one subjects from the original study cohort (11 from the 37.5mg group, 10 from the 50-mg group, and 10 from the 62.5mg group; age range, 21 months to 8 years, 1 month) agreed to participate in this follow-up study. We asked all consenting parents to involve a sibling as a control, if possible, and 15 unaffected siblings participated in the study as controls, distributed equally among the 3 cohorts. A history for exclusion of confounding preexisting conditions was taken, and the control group did not include any subjects with known medical, neurologic, or psychological conditions. All control subjects underwent TSH and free T4 screening at the time of testing to ensure that they were euthyroid. The study protocol and consent form were approved by the Institutional Review Board at Oregon Health Science University. Those subjects who did not participate were either lost to follow-up or declined to participate based on scheduling conflicts, travel limitations, or disinterest. An outreach testing day was performed to reach subjects in the Idaho area and to test them by the same personnel. Each cohort had similar rates of nonparticipation.
Tests and Questionnaires All cognitive tests were administered by the same person (A.D.), blinded to study cohort, disease severity, and subject/ control status. The achievement tests were also performed by a single examiner (A.H.). A parent of each subject completed an age-appropriate Child Behavioral Checklist (CBCL) (in English or Spanish). An interpreter was provided for all Spanish-speaking subjects (n = 7; 1 in cohort 1, 2 in cohort 776
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2, and 4 in cohort 3). One month before the study visit, thyroid function tests were done in all subjects with CH, and, if necessary, adjustments in L-thyroxine dosage were made to normalize thyroid hormone levels. Only 1 patient required such an adjustment. All patients and controls were euthyroid at the time of testing. Subjects and controls were given 1 of 3 age-appropriate cognitive tests. Subjects age < 4 years underwent the Mullen Scales of Early Learning, those between 4 and 6 years received the WPPSI-R (Wechsler Preschool and Primary Scale of Intelligence-Revised), and those age > 6 years received the WISC-III (Wechsler Intelligence Scale for Children, Third Edition). The Mullen reports an Early Learning Composite (ELC) score only, whereas the WPPSI-R and WISC-III provide verbal IQ (VIQ), performance IQ (PIQ), and full-scale IQ (FSIQ) scores. The ELC was used as the FSIQ in the younger age group as a measure of general cognition. The ELC and FSIQ scores are comparable measures of intellectual capacity.13 FSIQ scores were compared in all age categories; VIQ and PIQ scores were compared in only the older age groups. Subjects age > 6 years underwent achievement testing in the areas of reading, spelling, and math, using the WRAT-III (Wide-Range Achievement Test Revision 3). Behavior and attention were assessed by parental responses on the CBCL and by Freedom from Distractability Indices (FDIs) obtained for participants completing the WISC-III. The 15 sibling controls ranged in age from 43 months to 14 years. The distribution of tests given in each cohort was as follows: cohort 1: Mullen 1, WPPSI 1, WISC 4; cohort 2: WPPSI 1, WISC 5; cohort 3: WPPSI 1, WISC 2. Subjects were assigned as having either moderate or severe CH in the original study based on confirmatory serum T4 level above (moderate) or below (severe) the median T4 value for the entire group. Imaging studies were not routinely done to determine the underlying etiology of CH. Hollinghead scores were calculated for each subject’s family based on parental educational and occupational levels. The distribution of tests in each study cohort is given in Table I.
Statistical Analysis Results are expressed as mean ± standard error of the mean (SEM). Comparisons between groups were made by 1-way and 2-way analysis of variance tests, where statistical significance was P < .05. One subject in the 37.5-mg cohort was found to be an outlier with an exceptionally low cognitive score that affected the statistical analysis. This subject was excluded from further analysis and was later found to have a conductive hearing deficit that accounted for his poor performance.
RESULTS Comparison of the Original 3 Treatment Cohorts Average FSIQ was 100.6 in the 50-mg loading dose group and 95.3 in the 62.5-mg group. The lower-dose group (37.5 mg) as a whole scored significantly lower than the other The Journal of Pediatrics December 2005
Table I. Distribution of subjects by disease severity and age group by treatment cohort
Study total 37.5 50 67.5/37.5
n
Moderate
Severe
Age < 4 years (Mullen, CBCL)
Age 4 to 6 years (WPPSI, CBCL)
Age > 6 years (WISC, CBCL, WRAT)
31 11* 10 10
18 5 6 7
13 6 4 3
5 5 0 0
7 1 4 7
19 5 6 8
Moderate CH: Confirmatory T4 $ 1.6 mg/dL. Severe CH: Confirmatory T4 < 1.6 mg/dL. *One outlier from this group (in the severe category, age < 4 years) was excluded from the data analysis.
groups, with an average FSIQ of 89.5 (P < .05). In this group, the mean Mullen score of the 4 youngest subjects was 80.75, and the FSIQ scores of the others averaged 95.3; thus the younger subjects scored significantly lower than the older subjects. The 3 treatment cohorts did not differ in terms of VIQ and PIQ scores. There was a trend toward all cohorts scoring higher on PIQ (P = .12) (Figure 1). No significant differences were noted in reading, spelling, or math scores (FDI). Subjects in the 37.5-mg group showed a trend toward lower attention scores (P = .069). There were no significant differences in CBCL total scores between the 3 groups (Table II).
Neurodevelopmental Scores in Moderate and Severe CH In the original study, subjects were grouped by confirmatory pretreatment T4 value into moderate and severe CH groups. The mean FSIQ for the severe CH group was 89, 11 points lower than the mean of 100.3 for the moderate CH group (P = .05). The differences, 4.8 points in VIQ and 9.2 in PIQ, were not statistically significant, however. Again, PIQ trended higher in both groups (Figure 2). In achievement and attention testing, the severe CH group did show a trend toward lower math scores (87 vs 102; P = .061) and toward lower FDI (82 vs 94; P = .085). CBCL total scores were not significantly different in moderate and severe subjects (Table II).
CH Subjects Versus Sibling Controls Overall, CH subjects did not differ significantly from their 15 unaffected siblings. However, a trend toward lower scores in all 3 IQ measures can be seen; FSIQ was 91.6 in the subjects with CH, compared with 100.2 in the controls (P = .15). The smallest difference between the 2 groups was seen in PIQ scores (Figure 3).
Neurodevelopmental Scores and Time to Thyroid Function Normalization To examine the effect of time to normalization of thyroid function, we grouped our subjects into the following categories based on the time to normalization of total T4, free T4, and TSH: # 1 week, 2 weeks, and $ 2 weeks. Normal ranges were defined as follows: T4, 10 to 16 mg/dL; free T4, 1.6 to 2.4 ng/dL; and TSH, < 9.1 mU/L. Each IQ measure was Neurodevelopmental Outcomes In Congenital Hypothyroidism: Comparison Of Initial T4 Dose And Time To Reach Target T4 And TSH
Figure 1. FSIQ, VIQ, and PIQ scores for the original 3 treatment cohorts. Values are mean ± SEM for the original 3 treatment cohorts. The bold line at 100 represents an average IQ score. An * denotes significance compared with the other 2 cohorts. The average score shown for the 37.5-mg group (89.5) includes 4 Mullen scores (mean, 80.75) and 6 WPPSI/WISC FSIQ scores (mean, 95.3). The number of subjects per category is listed at the bottom of each column.
examined separately. The results for FSIQ, VIQ, and PIQ are shown in Figure 4. The numbers for VIQ and PIQ total 26; the 4 subjects tested on the Mullen did not receive such scores. The differences were examined regardless of the initial treatment cohort. Most of the subjects had normal total and free T4 by 1 week of therapy. As expected, it took longer for the TSH to fall. Although most subjects normalized TSH at 2 weeks, a significant proportion took longer than 2 weeks. Subjects who achieved normal thyroid function by 1 week of therapy had FSIQ scores close to the test mean (total T4, 98.4; free T4, 99.2; TSH, 99.2) (Figure 4). Those subjects how achieved total T4 normalization at 2 weeks (4 patients) had a significantly lower average FSIQ (79.75) than those who achieved normalization before 1 week (P < .05). This difference was not seen in those subjects who achieved normalization of free T4 and TSH at 2 weeks. When the T4, free T4, and TSH were not normalized until after 2 weeks, FSIQ scores were significantly lower for all 3 measures of thyroid function: total T4, 64; free T4, 80.7; and TSH, 85.3 (P < .05 for all) (Figure 4). A similar pattern can be seen when examining VIQ scores (Figure 4). Those subjects who achieved normal thyroid function by 1 week had scores at the test mean (total T4, 99; free T4, 98; TSH, 99). VIQ scores were 777
Table II. Average Behavior and Achievement Scores with Comparisons WRAT
Cohort
Severity T4 Normalization
FreeT4 Normalization
TSH Normalization
1 2 3 Moderate Severe ,/=1 week 2 weeks . 2 weeks* ,/=1 week 2 weeks . 2 weeks ,/=1 week 2 weeks . 2 weeks
FDI
p
CBCL
p
Reading
p
Spelling
p
Math
p
83.40 91.33 90.00 94.18 82.00 91.65 69.00 58.00 94.00 84.00 73.75 104.00 93.91 78.29
0.64
54.20 47.50 50.60 47.56 53.69 52.16 42.00 51.00 49.48 50.00 54.88 45.25 54.67 47.45
0.45
99.80 106.67 94.88 102.55 95.43 102.71 102.00 50.00 105.31 104.50 80.00 100.00 106.00 90.00
0.54
93.40 105.17 92.75 100.00 91.43 99.18 100.00 54.00 101.54 98.50 80.75 106.00 102.90 87.29
0.39
90.00 99.83 97.00 102.00 87.00 98.59 85.00 64.00 100.54 95.50 82.25 107.00 101.45 86.00
0.62
0.07 0.01
0.03
0.03
0.16 0.28
0.12
0.18
0.50 0.03
0.09
0.28
0.34 0.03
0.11
0.19
0.06 0.09
0.14
0.11
FDI: Freedom from Distractibility Index; CBCL: Child Behaviour Checklist, WRAT: Wide Range Achievement Test. Scores for FDI and WRAT based on mean of 100. Normal score for CBCL is <60; where as >64 is likely to have a behavioural or attention problem. Comparisons between groups made by two way ANOVA where p < 0.05 is significant (indicated in bold). *n = 1 for this category.
Figure 2. IQ scores: Moderate versus severe CH. Mean FSIQ, VIQ, and PIQ scores ± SEM for moderate versus severe CH are shown. The bold line at 100 represents an average IQ score. An * denotes significance in moderate compared to severe. The number of subjects per category is listed at the bottom of each column.
significantly lower in those with total T4 normalized at 2 weeks (76) and > 2 weeks (54) and those with free T4 and TSH after 2 weeks (77.4 and 87.8, respectively) (P < .05). A similar pattern can be seen for PIQ (Figure 4), with earlier normalization trending higher; however, comparing the different times to thyroid function normalization reveals no statistically significant differences. Taken as a whole, the PIQ scores were higher than the other IQ scores, as was seen in previous analyses. It should be pointed out that the number of subjects is small in some groups. Other neurodevelopmental differences in the timing of thyroid function normalization were noted. Subjects who achieved total T4 normalization after 2 weeks had significantly lower scores in reading (50, compared with 102 in those who 778
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Figure 3. IQ scores: Subjects versus sibling controls. Mean FSIQ, VIQ, and PIQ scores ± SEM for subjects and controls are shown. The number of subjects per category is listed at the bottom of each column.
achieved normalization at 2 weeks and 102.7 in those who did so at < 1 week; P < .05). This same trend also occurred in spelling (P < .05) and math scores (P = .085). Reading scores trended lower in those in whom free T4 normalization occurred after 2 weeks than in those in the other 2 categories (P = 0.085). In addition, FDI scores were significantly lower in subjects with total T4, free T4, and TSH normalization after 2 weeks (P < .05 for all) (Table II). No significant differences were found in CBCL total scores in relation to normalization time (Table II). Spanish-speaking subjects scored significantly lower than English-speaking subjects in FSIQ (84.3 vs 98.7) and VIQ (80.7 vs 99.9) (P < .05). However, this difference was not seen in PIQ, where the average scores were 98 for Spanish-speaking subjects and 100.9 for English-speaking subjects. The Journal of Pediatrics December 2005
Socioeconomic status, ascertained by Hollingshead score, did not differ between the 37.5-mg and 50-mg loading dose cohorts (45.3 ± 12 vs 43.4 ± 17, respectively). The 62.6-mg loading dose group had a significantly lower SES score than the other 2 cohorts (29.5 ± 16; P = .03). This group contained 5 Spanish-speaking subject families who, when evaluated alone, had lower SES scores (16.2 ± 9) than the English-speaking families in that cohort (42.8 ± 8). The SES scores trended lower in the moderate subgroup (35.5) than in the severe subgroup (43.1) (P = .07).
DISCUSSION Overall, IQ scores were similar in the original 3 treatment cohorts. The 37.5-mg group did score lower in FSIQ, possibly reflecting the larger proportion of younger subjects in this group who took the Mullen test (because cognitive scores tend to be less reliable in very young children). The Mullen test emphasizes speech and language development, whereas Wechsler tests measure verbal abilities, so this pattern may reflect the delayed language acquisition with later catchup in the younger subjects with CH. The trend toward lower VIQ scores may be explained by the fact that 6 subjects were primarily Spanish-speaking or bilingual. Although the tests were administered to these subjects in Spanish with an interpreter, these subjects’ lower VIQ scores may be due to language differences. This trend can be seen in the different analyses in this report. Our group as a whole achieved an average FSIQ of 95.1, which is not significantly lower than the test mean or the performance of their siblings. However, IQ differences within our treatment cohort surfaced when looking at different aspects of CH, including severity and time to normalization of thyroid function. In our original study, differences in T4 level between moderate CH and severe CH groups were not evident by 3 days of therapy in the 50-mg group and by 1 week in the other 2 dosage groups.12 But the outcomes show differences in IQ scores between the moderate and severe CH groups, with the severe group demonstrating lower FSIQ in all treatment cohorts. This finding suggests that severe CH, with presumably severe late in utero or early neonatal hypothyroidism, has a lasting impact on cognitive development. Several other investigators have reported similar results, which may be exacerbated by late initiation and low-dose L-thyroxine replacement.7,14 Rovet suggested that the time when thyroid hormone is needed varies in different areas of the developing brain, and thus hypothyroidism in early neonatal life may affect specific parts of the brain, resulting in various deficits in visual-spatial, memory, attention, and language abilities.3 Although in our study CIQ and PIQ scores were not statistically different between the moderate and severe CH groups, the trend toward lower scores is a matter of concern. These findings further illustrate the clinical importance of higher initial L-thyroxine dosages in severe CH patients, to produce normalized thyroid function as rapidly as possible. The fact that our CH subjects’ scores did not differ from those of their unaffected siblings suggests that the impact of Neurodevelopmental Outcomes In Congenital Hypothyroidism: Comparison Of Initial T4 Dose And Time To Reach Target T4 And TSH
Figure 4. Cognitive scores and thyroid function normalization. Mean FSIQ, VIQ, and PIQ scores ± SEM for CH subjects based on time to thyroid function normalization ( 2 weeks) are shown. The bold line at 100 represents an average IQ score. An * denotes significance compared with the other 2 time categories. The number of subjects per category is listed at the bottom of each column.
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social factors, such as socioeconomic status, genetic factors, and family situations, were similar in subjects and siblings. The small number of controls may have prevented a difference from reaching statistical significance. Other studies have reported statistically significant differences between CH subjects and siblings (siblings, 111.4; CH, 102.4),15 with such differences persisting into late childhood, adolescence, and even adulthood.2 The SES scores demonstrated no difference between the 37.5-mg and 50-mg groups, but the 62.5-mg group had significantly lower scores, presumably due to the higher percentage of Hispanic families in this group. The parents in these families had lower Hollinghead scores, reflecting their educational level and occupational background. Spanish-speaking subjects also scored lower in FSIQ and VIQ, but not in PIQ. Even though the 62.5-mg group had lower SES scores, this did not negatively impact their cognitive scores as a whole compared with the other 2 groups (Figure 1). Our results demonstrate that the time to achieve normal thyroid function plays a critical role in neurodevelopmental outcome. Subjects who had achieved total T4 normalization at 2 weeks and beyond had significantly lower FSIQ and VIQ scores than those who achieved normalization by 1 week. Those subjects whose free T4 and TSH levels did not normalize until > 2 weeks after treatment had significantly lower FSIQ and VIQ scores. Academic achievement (reading, spelling, math) and behavior (FDI) all reflected similar deficiencies in the late normalization groups. It must be noted, however, that our sample size is small, especially in the late normalizing category. Interestingly, no statistically significant differences in PIQ scores were found. The fact that our subjects consistently had higher PIQ scores suggests that neurologic facets involved in perceptual-motor processing are not as affected by perinatal hypothyroidism as those involved in language-related functions, particularly when treatment is initiated early. This finding also supports Rovet’s hypothesis that neonatal hypothyroidism affects differing areas of the brain at different times.16 Another possibility, as mentioned earlier, is that verbal scores were lower overall because of language issues. The premise behind newborn screening for CH is to allow early initiation of treatment to prevent neurodevelopmental sequelae. In concert with early detection, rapid normalization of thyroid function to minimize exposure of the neonatal brain to the hypothyroid state is a prime goal of treatment. In our original report we suggested using an initial dose of 50 mg (12 to 17 mg/kg/dose) to rapidly raise thyroid function to normal (3 days for free T4 and total T4 and 2 weeks for TSH). We also suggested considering higher target ranges for T4 and free T4 during the first 2 weeks of therapy, to optimize these goals.12 Our current results confirm the importance of these recomendations, as reflected in the significantly lower IO scores in those subjects who normalized thyroid function at 2 weeks for total T4 and at > 2 weeks for free T4 and TSH. Our findings support those of Bongers-Schokking et al,7 who reported that as little as a 1-week delay in normalization
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of serum T4 resulted in lower IQ scores (by as much as 20 points) in children with severe CH. Certain aspects of CH, such as the severity of the disease based on etiology, cannot be changed. But treatment variables can be improved on, however. The findings of the present follow-up study illustrate the need for early initiation with optimal-dose L-thyroxine replacement to achieve rapid normalization of thyroid function, especially in subjects with severe forms of CH. Our original dosing study investigated 3 different starting treatment doses for CH and found that 50 mg/day achieved these goals. This is especially important in neonates with severe CH (pretreatment serum T4 < 3 ug/ dL), in whom doses of 12 to 17 mg/kg/day raised serum T4 levels into the target range by 3 days, the time frame associated with the best cognitive outcome.
REFERENCES 1. 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. 2. Oerbeck B, Sundet K, Kase BF, Heyerdahl S. Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults. Pediatrics 2003; 112:923-30. 3. Rovet JF. Long-term neuropsychological sequelae of early-treated congenital hypothyroidism: effects in adolescence. Acta Paediatr Suppl 1999;8: 888-95. 4. Rovet JF. In search of the optimal therapy for congenital hypothyroidism. J Pediatr 2004;144:698-700. 5. Fisher DA. The importance of early management in optimizing IQ in infants with congenital hypothyroidism. J Pediatr 2000;136:273-4. 6. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid 1999;9:735-40. 7. 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. 8. Tsiao PH, Chiu YN, Tsai WY, Su SC, Lee JS, Soong WT. Intellectual outcome of patients with congenital hypothyroidism detected by neonatal screening. J Formos Med Assoc 2001;100:40-4. 9. Mirabella GF, Astzalos E, Perlman K, Rovet J. The effect of abnormal intrauterine thyroid hormone economies on infant cognitive abilities. J Pediatr Endocrinol Metab 2000;13:191-4. 10. 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. 11. Law WY, Bradley DM, Lazarus JH, John R, Gregory JW. Congenital hypothyroidism in Wales (1982–1993): demographic features, clinical presentation and effects on early neurodevelopment. Clin Endocrinol (Oxf) 1998;48: 201-7. 12. 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. 13. Mullen EM. Mullen scales of early learning. Circle Pines, MN: American Guidance Services; 1995. p. 58-64. 14. Bongers-Schokking JJ. Pre- and postnatal brain development in neonates with congenital hypothyroidism. J Pediatr Endocrinol Metab 2001; 14(suppl 6):1463-8. 15. Rovet JF, Ehrlich R. Psychoeducational outcome in children with earlytreated congenital hypothyroidism. Pediatrics 2000;105:515-22. 16. Rovet J, Daneman D. Congenital hypothyroidism: a review of current diagnostic and treatment practices in relation to neuropsychologic outcome. Paediatr Drugs 2003;5:141-9.
The Journal of Pediatrics December 2005
Objectives To compare neurodevelopmental outcomes in severe and moderate congenital hypothyroidism (CH) among 3 different initial L-thyroxine doses and to examine the effect of the time to thyroid function normalization on neurodevelopmental outcomes. Study design
Neurodevelopmental assessments of 31 subjects included the Mullen Scales of Early Learning, Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children, Wide-Range Achievement Test, and Child Behavioral Checklist.
Results
Subjects started on higher initial L-thyroxine doses (50 lg) had full-scale IQ scores 11 points higher than those started on lower (37.5 lg) initial doses. However, verbal IQ, performance IQ, and achievement scores did not differ among the 3 treatment cohorts. Subjects with moderate CH had higher full-scale IQ scores than subjects with severe CH, regardless of the initial treatment dose. Subjects who took longer than 2 weeks to normalize thyroid function had significantly lower cognitive, attention, and achievement scores than those who achieved normal thyroid function at 1 or 2 weeks of therapy.
Conclusions Initial L-thyroxine dose and faster time to normalization of thyroid function are important to optimal neurodevelopmental outcome. In severe CH, it is important to choose an initial dose at the higher end of the recommended range to achieve these goals. (J Pediatr 2005;147:775-80) he onset of newborn thyroid screening in the 1970s brought the expectation that early thyroid hormone replacement would prevent mental retardation due to congenital hypothyroidism (CH).1 But recent studies have demonstrated mildly lower IQ scores, subtle neurodevelopmental delays, and motor deficits in children with CH, despite early detection and hormone replacement.2-4 The goal of initial therapy in CH is to minimize neonatal central nervous system exposure to hypothyroidism by normalizing thyroid function, as reflected by thyroxine (T4) and thyroid-stimulating hormone (TSH) levels, as rapidly as possible.5,6 Studies have demonstrated that even a short period (1 to 3 weeks) of neonatal hypothyroidism before initiation of treatment can negatively affect development.4,7-11 In 2002 our group reported results of a treatment study in CH that examined 3 initial treatment doses of L-thyroxine and their patterns of thyroid function normalization over a From the Children’s Diabetes & Endocrine Center, Legacy Emanuel Hospital, 12-week period.12 The 3 treatment doses were 37.5 mg, 50 mg, and a loading dose of 62.5 Portland, Oregon and Department of mg for 3 days, followed by 37.5 mg. We found that T4 and free T4 concentrations were in Pediatrics, Oregon Health Science Unithe target range by 3 days of therapy in the 50- and 62.5/37.5-mg groups and by 1 week versity, Portland, Oregon. Supported in part by U.S. Public of therapy in the 37.5-mg group. A dose of 50 mg/day led to the most rapid normalization Health Service grant 5-M01-RR000334. of TSH, by 2 weeks of therapy. We recommend consideration of a slightly higher increased Submitted for publication Feb 4, 2005; target range of T4 (10 to 18 mg/dL) and free T4 (1.6 to 2.5 ng/dL) during the first month last revision received Jun 28, 2005; accepted Jul 18, 2005. of therapy to quickly normalize T4 and TSH, followed by frequent monitoring and adjustReprint requests: Karin A. Selva, MD, ment of thyroid doses thereafter, to maintain normal thyroid function.
T
CBCL CH ELC FDI FSIQ PIQ SEM T3
Child Behavioral Checklist Congenital hypothyroidism Early Learning Composite Freedom From Distractability Index Full-scale IQ Performance IQ Standard error of the mean Triiodothyronine
T4 TSH VIQ WISC-III WPPSI-R WRAT-III
Thyroxine Thyroid-stimulating hormone Verbal IQ Wechsler Intelligence Scale for Children, Third Edition Wechsler Preschool and Primary Scale of Intelligence-Revised Wide-Range Achievement Test, Revision 3
Children’s Diabetes and Endocrine Center, Legacy Emanuel Hospital, 501 N. Graham Street, Suite 375, Portland, OR 97229. E-mail: kselva@ lhs.org. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.07.024
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The present study was a follow-up study examining neurodevelopmental outcomes in subjects from our original study cohort. Our goal was to compare neurodevelopmental outcomes, particularly cognition, academic achievement, and attention/behavior, among the 3 treatment groups. In addition, we investigated the effect of CH severity, differences (if any) between CH subjects and their unaffected siblings, and the effect of the timing of thyroid function normalization on neurodevelopmental outcomes in all treatment cohorts.
METHODS In our original study, 47 subjects were randomized into 1 of 3 initial L-thyroxine dosage groups: 37.5 mg, 50 mg, and 62.5 mg for 3 days followed by 37.5 mg daily (equivalent to 10.9, 14.5, and 17.7 mg/kg/day for 3 days followed by 10.6 mg/kg/day, respectively). Serum free T4, T4, free triiodothyronine (T3), T3, and TSH levels were measured before treatment and at 3 and 7 days and 2, 4, 8, and 12 weeks after initiation of L-thyroxine therapy. In accordance with the study protocol, no dosage adjustments were made for the first 2 weeks of treatment. After 2 weeks, adjustments were made following the study algorithm.12
Subject Recruitment Power analysis predicted the need for 10 patients from each treatment cohort for statistical significance. We attempted to contact and enroll all 47 original subjects. Thirty-one subjects from the original study cohort (11 from the 37.5mg group, 10 from the 50-mg group, and 10 from the 62.5mg group; age range, 21 months to 8 years, 1 month) agreed to participate in this follow-up study. We asked all consenting parents to involve a sibling as a control, if possible, and 15 unaffected siblings participated in the study as controls, distributed equally among the 3 cohorts. A history for exclusion of confounding preexisting conditions was taken, and the control group did not include any subjects with known medical, neurologic, or psychological conditions. All control subjects underwent TSH and free T4 screening at the time of testing to ensure that they were euthyroid. The study protocol and consent form were approved by the Institutional Review Board at Oregon Health Science University. Those subjects who did not participate were either lost to follow-up or declined to participate based on scheduling conflicts, travel limitations, or disinterest. An outreach testing day was performed to reach subjects in the Idaho area and to test them by the same personnel. Each cohort had similar rates of nonparticipation.
Tests and Questionnaires All cognitive tests were administered by the same person (A.D.), blinded to study cohort, disease severity, and subject/ control status. The achievement tests were also performed by a single examiner (A.H.). A parent of each subject completed an age-appropriate Child Behavioral Checklist (CBCL) (in English or Spanish). An interpreter was provided for all Spanish-speaking subjects (n = 7; 1 in cohort 1, 2 in cohort 776
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2, and 4 in cohort 3). One month before the study visit, thyroid function tests were done in all subjects with CH, and, if necessary, adjustments in L-thyroxine dosage were made to normalize thyroid hormone levels. Only 1 patient required such an adjustment. All patients and controls were euthyroid at the time of testing. Subjects and controls were given 1 of 3 age-appropriate cognitive tests. Subjects age < 4 years underwent the Mullen Scales of Early Learning, those between 4 and 6 years received the WPPSI-R (Wechsler Preschool and Primary Scale of Intelligence-Revised), and those age > 6 years received the WISC-III (Wechsler Intelligence Scale for Children, Third Edition). The Mullen reports an Early Learning Composite (ELC) score only, whereas the WPPSI-R and WISC-III provide verbal IQ (VIQ), performance IQ (PIQ), and full-scale IQ (FSIQ) scores. The ELC was used as the FSIQ in the younger age group as a measure of general cognition. The ELC and FSIQ scores are comparable measures of intellectual capacity.13 FSIQ scores were compared in all age categories; VIQ and PIQ scores were compared in only the older age groups. Subjects age > 6 years underwent achievement testing in the areas of reading, spelling, and math, using the WRAT-III (Wide-Range Achievement Test Revision 3). Behavior and attention were assessed by parental responses on the CBCL and by Freedom from Distractability Indices (FDIs) obtained for participants completing the WISC-III. The 15 sibling controls ranged in age from 43 months to 14 years. The distribution of tests given in each cohort was as follows: cohort 1: Mullen 1, WPPSI 1, WISC 4; cohort 2: WPPSI 1, WISC 5; cohort 3: WPPSI 1, WISC 2. Subjects were assigned as having either moderate or severe CH in the original study based on confirmatory serum T4 level above (moderate) or below (severe) the median T4 value for the entire group. Imaging studies were not routinely done to determine the underlying etiology of CH. Hollinghead scores were calculated for each subject’s family based on parental educational and occupational levels. The distribution of tests in each study cohort is given in Table I.
Statistical Analysis Results are expressed as mean ± standard error of the mean (SEM). Comparisons between groups were made by 1-way and 2-way analysis of variance tests, where statistical significance was P < .05. One subject in the 37.5-mg cohort was found to be an outlier with an exceptionally low cognitive score that affected the statistical analysis. This subject was excluded from further analysis and was later found to have a conductive hearing deficit that accounted for his poor performance.
RESULTS Comparison of the Original 3 Treatment Cohorts Average FSIQ was 100.6 in the 50-mg loading dose group and 95.3 in the 62.5-mg group. The lower-dose group (37.5 mg) as a whole scored significantly lower than the other The Journal of Pediatrics December 2005
Table I. Distribution of subjects by disease severity and age group by treatment cohort
Study total 37.5 50 67.5/37.5
n
Moderate
Severe
Age < 4 years (Mullen, CBCL)
Age 4 to 6 years (WPPSI, CBCL)
Age > 6 years (WISC, CBCL, WRAT)
31 11* 10 10
18 5 6 7
13 6 4 3
5 5 0 0
7 1 4 7
19 5 6 8
Moderate CH: Confirmatory T4 $ 1.6 mg/dL. Severe CH: Confirmatory T4 < 1.6 mg/dL. *One outlier from this group (in the severe category, age < 4 years) was excluded from the data analysis.
groups, with an average FSIQ of 89.5 (P < .05). In this group, the mean Mullen score of the 4 youngest subjects was 80.75, and the FSIQ scores of the others averaged 95.3; thus the younger subjects scored significantly lower than the older subjects. The 3 treatment cohorts did not differ in terms of VIQ and PIQ scores. There was a trend toward all cohorts scoring higher on PIQ (P = .12) (Figure 1). No significant differences were noted in reading, spelling, or math scores (FDI). Subjects in the 37.5-mg group showed a trend toward lower attention scores (P = .069). There were no significant differences in CBCL total scores between the 3 groups (Table II).
Neurodevelopmental Scores in Moderate and Severe CH In the original study, subjects were grouped by confirmatory pretreatment T4 value into moderate and severe CH groups. The mean FSIQ for the severe CH group was 89, 11 points lower than the mean of 100.3 for the moderate CH group (P = .05). The differences, 4.8 points in VIQ and 9.2 in PIQ, were not statistically significant, however. Again, PIQ trended higher in both groups (Figure 2). In achievement and attention testing, the severe CH group did show a trend toward lower math scores (87 vs 102; P = .061) and toward lower FDI (82 vs 94; P = .085). CBCL total scores were not significantly different in moderate and severe subjects (Table II).
CH Subjects Versus Sibling Controls Overall, CH subjects did not differ significantly from their 15 unaffected siblings. However, a trend toward lower scores in all 3 IQ measures can be seen; FSIQ was 91.6 in the subjects with CH, compared with 100.2 in the controls (P = .15). The smallest difference between the 2 groups was seen in PIQ scores (Figure 3).
Neurodevelopmental Scores and Time to Thyroid Function Normalization To examine the effect of time to normalization of thyroid function, we grouped our subjects into the following categories based on the time to normalization of total T4, free T4, and TSH: # 1 week, 2 weeks, and $ 2 weeks. Normal ranges were defined as follows: T4, 10 to 16 mg/dL; free T4, 1.6 to 2.4 ng/dL; and TSH, < 9.1 mU/L. Each IQ measure was Neurodevelopmental Outcomes In Congenital Hypothyroidism: Comparison Of Initial T4 Dose And Time To Reach Target T4 And TSH
Figure 1. FSIQ, VIQ, and PIQ scores for the original 3 treatment cohorts. Values are mean ± SEM for the original 3 treatment cohorts. The bold line at 100 represents an average IQ score. An * denotes significance compared with the other 2 cohorts. The average score shown for the 37.5-mg group (89.5) includes 4 Mullen scores (mean, 80.75) and 6 WPPSI/WISC FSIQ scores (mean, 95.3). The number of subjects per category is listed at the bottom of each column.
examined separately. The results for FSIQ, VIQ, and PIQ are shown in Figure 4. The numbers for VIQ and PIQ total 26; the 4 subjects tested on the Mullen did not receive such scores. The differences were examined regardless of the initial treatment cohort. Most of the subjects had normal total and free T4 by 1 week of therapy. As expected, it took longer for the TSH to fall. Although most subjects normalized TSH at 2 weeks, a significant proportion took longer than 2 weeks. Subjects who achieved normal thyroid function by 1 week of therapy had FSIQ scores close to the test mean (total T4, 98.4; free T4, 99.2; TSH, 99.2) (Figure 4). Those subjects how achieved total T4 normalization at 2 weeks (4 patients) had a significantly lower average FSIQ (79.75) than those who achieved normalization before 1 week (P < .05). This difference was not seen in those subjects who achieved normalization of free T4 and TSH at 2 weeks. When the T4, free T4, and TSH were not normalized until after 2 weeks, FSIQ scores were significantly lower for all 3 measures of thyroid function: total T4, 64; free T4, 80.7; and TSH, 85.3 (P < .05 for all) (Figure 4). A similar pattern can be seen when examining VIQ scores (Figure 4). Those subjects who achieved normal thyroid function by 1 week had scores at the test mean (total T4, 99; free T4, 98; TSH, 99). VIQ scores were 777
Table II. Average Behavior and Achievement Scores with Comparisons WRAT
Cohort
Severity T4 Normalization
FreeT4 Normalization
TSH Normalization
1 2 3 Moderate Severe ,/=1 week 2 weeks . 2 weeks* ,/=1 week 2 weeks . 2 weeks ,/=1 week 2 weeks . 2 weeks
FDI
p
CBCL
p
Reading
p
Spelling
p
Math
p
83.40 91.33 90.00 94.18 82.00 91.65 69.00 58.00 94.00 84.00 73.75 104.00 93.91 78.29
0.64
54.20 47.50 50.60 47.56 53.69 52.16 42.00 51.00 49.48 50.00 54.88 45.25 54.67 47.45
0.45
99.80 106.67 94.88 102.55 95.43 102.71 102.00 50.00 105.31 104.50 80.00 100.00 106.00 90.00
0.54
93.40 105.17 92.75 100.00 91.43 99.18 100.00 54.00 101.54 98.50 80.75 106.00 102.90 87.29
0.39
90.00 99.83 97.00 102.00 87.00 98.59 85.00 64.00 100.54 95.50 82.25 107.00 101.45 86.00
0.62
0.07 0.01
0.03
0.03
0.16 0.28
0.12
0.18
0.50 0.03
0.09
0.28
0.34 0.03
0.11
0.19
0.06 0.09
0.14
0.11
FDI: Freedom from Distractibility Index; CBCL: Child Behaviour Checklist, WRAT: Wide Range Achievement Test. Scores for FDI and WRAT based on mean of 100. Normal score for CBCL is <60; where as >64 is likely to have a behavioural or attention problem. Comparisons between groups made by two way ANOVA where p < 0.05 is significant (indicated in bold). *n = 1 for this category.
Figure 2. IQ scores: Moderate versus severe CH. Mean FSIQ, VIQ, and PIQ scores ± SEM for moderate versus severe CH are shown. The bold line at 100 represents an average IQ score. An * denotes significance in moderate compared to severe. The number of subjects per category is listed at the bottom of each column.
significantly lower in those with total T4 normalized at 2 weeks (76) and > 2 weeks (54) and those with free T4 and TSH after 2 weeks (77.4 and 87.8, respectively) (P < .05). A similar pattern can be seen for PIQ (Figure 4), with earlier normalization trending higher; however, comparing the different times to thyroid function normalization reveals no statistically significant differences. Taken as a whole, the PIQ scores were higher than the other IQ scores, as was seen in previous analyses. It should be pointed out that the number of subjects is small in some groups. Other neurodevelopmental differences in the timing of thyroid function normalization were noted. Subjects who achieved total T4 normalization after 2 weeks had significantly lower scores in reading (50, compared with 102 in those who 778
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Figure 3. IQ scores: Subjects versus sibling controls. Mean FSIQ, VIQ, and PIQ scores ± SEM for subjects and controls are shown. The number of subjects per category is listed at the bottom of each column.
achieved normalization at 2 weeks and 102.7 in those who did so at < 1 week; P < .05). This same trend also occurred in spelling (P < .05) and math scores (P = .085). Reading scores trended lower in those in whom free T4 normalization occurred after 2 weeks than in those in the other 2 categories (P = 0.085). In addition, FDI scores were significantly lower in subjects with total T4, free T4, and TSH normalization after 2 weeks (P < .05 for all) (Table II). No significant differences were found in CBCL total scores in relation to normalization time (Table II). Spanish-speaking subjects scored significantly lower than English-speaking subjects in FSIQ (84.3 vs 98.7) and VIQ (80.7 vs 99.9) (P < .05). However, this difference was not seen in PIQ, where the average scores were 98 for Spanish-speaking subjects and 100.9 for English-speaking subjects. The Journal of Pediatrics December 2005
Socioeconomic status, ascertained by Hollingshead score, did not differ between the 37.5-mg and 50-mg loading dose cohorts (45.3 ± 12 vs 43.4 ± 17, respectively). The 62.6-mg loading dose group had a significantly lower SES score than the other 2 cohorts (29.5 ± 16; P = .03). This group contained 5 Spanish-speaking subject families who, when evaluated alone, had lower SES scores (16.2 ± 9) than the English-speaking families in that cohort (42.8 ± 8). The SES scores trended lower in the moderate subgroup (35.5) than in the severe subgroup (43.1) (P = .07).
DISCUSSION Overall, IQ scores were similar in the original 3 treatment cohorts. The 37.5-mg group did score lower in FSIQ, possibly reflecting the larger proportion of younger subjects in this group who took the Mullen test (because cognitive scores tend to be less reliable in very young children). The Mullen test emphasizes speech and language development, whereas Wechsler tests measure verbal abilities, so this pattern may reflect the delayed language acquisition with later catchup in the younger subjects with CH. The trend toward lower VIQ scores may be explained by the fact that 6 subjects were primarily Spanish-speaking or bilingual. Although the tests were administered to these subjects in Spanish with an interpreter, these subjects’ lower VIQ scores may be due to language differences. This trend can be seen in the different analyses in this report. Our group as a whole achieved an average FSIQ of 95.1, which is not significantly lower than the test mean or the performance of their siblings. However, IQ differences within our treatment cohort surfaced when looking at different aspects of CH, including severity and time to normalization of thyroid function. In our original study, differences in T4 level between moderate CH and severe CH groups were not evident by 3 days of therapy in the 50-mg group and by 1 week in the other 2 dosage groups.12 But the outcomes show differences in IQ scores between the moderate and severe CH groups, with the severe group demonstrating lower FSIQ in all treatment cohorts. This finding suggests that severe CH, with presumably severe late in utero or early neonatal hypothyroidism, has a lasting impact on cognitive development. Several other investigators have reported similar results, which may be exacerbated by late initiation and low-dose L-thyroxine replacement.7,14 Rovet suggested that the time when thyroid hormone is needed varies in different areas of the developing brain, and thus hypothyroidism in early neonatal life may affect specific parts of the brain, resulting in various deficits in visual-spatial, memory, attention, and language abilities.3 Although in our study CIQ and PIQ scores were not statistically different between the moderate and severe CH groups, the trend toward lower scores is a matter of concern. These findings further illustrate the clinical importance of higher initial L-thyroxine dosages in severe CH patients, to produce normalized thyroid function as rapidly as possible. The fact that our CH subjects’ scores did not differ from those of their unaffected siblings suggests that the impact of Neurodevelopmental Outcomes In Congenital Hypothyroidism: Comparison Of Initial T4 Dose And Time To Reach Target T4 And TSH
Figure 4. Cognitive scores and thyroid function normalization. Mean FSIQ, VIQ, and PIQ scores ± SEM for CH subjects based on time to thyroid function normalization ( 2 weeks) are shown. The bold line at 100 represents an average IQ score. An * denotes significance compared with the other 2 time categories. The number of subjects per category is listed at the bottom of each column.
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social factors, such as socioeconomic status, genetic factors, and family situations, were similar in subjects and siblings. The small number of controls may have prevented a difference from reaching statistical significance. Other studies have reported statistically significant differences between CH subjects and siblings (siblings, 111.4; CH, 102.4),15 with such differences persisting into late childhood, adolescence, and even adulthood.2 The SES scores demonstrated no difference between the 37.5-mg and 50-mg groups, but the 62.5-mg group had significantly lower scores, presumably due to the higher percentage of Hispanic families in this group. The parents in these families had lower Hollinghead scores, reflecting their educational level and occupational background. Spanish-speaking subjects also scored lower in FSIQ and VIQ, but not in PIQ. Even though the 62.5-mg group had lower SES scores, this did not negatively impact their cognitive scores as a whole compared with the other 2 groups (Figure 1). Our results demonstrate that the time to achieve normal thyroid function plays a critical role in neurodevelopmental outcome. Subjects who had achieved total T4 normalization at 2 weeks and beyond had significantly lower FSIQ and VIQ scores than those who achieved normalization by 1 week. Those subjects whose free T4 and TSH levels did not normalize until > 2 weeks after treatment had significantly lower FSIQ and VIQ scores. Academic achievement (reading, spelling, math) and behavior (FDI) all reflected similar deficiencies in the late normalization groups. It must be noted, however, that our sample size is small, especially in the late normalizing category. Interestingly, no statistically significant differences in PIQ scores were found. The fact that our subjects consistently had higher PIQ scores suggests that neurologic facets involved in perceptual-motor processing are not as affected by perinatal hypothyroidism as those involved in language-related functions, particularly when treatment is initiated early. This finding also supports Rovet’s hypothesis that neonatal hypothyroidism affects differing areas of the brain at different times.16 Another possibility, as mentioned earlier, is that verbal scores were lower overall because of language issues. The premise behind newborn screening for CH is to allow early initiation of treatment to prevent neurodevelopmental sequelae. In concert with early detection, rapid normalization of thyroid function to minimize exposure of the neonatal brain to the hypothyroid state is a prime goal of treatment. In our original report we suggested using an initial dose of 50 mg (12 to 17 mg/kg/dose) to rapidly raise thyroid function to normal (3 days for free T4 and total T4 and 2 weeks for TSH). We also suggested considering higher target ranges for T4 and free T4 during the first 2 weeks of therapy, to optimize these goals.12 Our current results confirm the importance of these recomendations, as reflected in the significantly lower IO scores in those subjects who normalized thyroid function at 2 weeks for total T4 and at > 2 weeks for free T4 and TSH. Our findings support those of Bongers-Schokking et al,7 who reported that as little as a 1-week delay in normalization
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of serum T4 resulted in lower IQ scores (by as much as 20 points) in children with severe CH. Certain aspects of CH, such as the severity of the disease based on etiology, cannot be changed. But treatment variables can be improved on, however. The findings of the present follow-up study illustrate the need for early initiation with optimal-dose L-thyroxine replacement to achieve rapid normalization of thyroid function, especially in subjects with severe forms of CH. Our original dosing study investigated 3 different starting treatment doses for CH and found that 50 mg/day achieved these goals. This is especially important in neonates with severe CH (pretreatment serum T4 < 3 ug/ dL), in whom doses of 12 to 17 mg/kg/day raised serum T4 levels into the target range by 3 days, the time frame associated with the best cognitive outcome.
REFERENCES 1. 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. 2. Oerbeck B, Sundet K, Kase BF, Heyerdahl S. Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults. Pediatrics 2003; 112:923-30. 3. Rovet JF. Long-term neuropsychological sequelae of early-treated congenital hypothyroidism: effects in adolescence. Acta Paediatr Suppl 1999;8: 888-95. 4. Rovet JF. In search of the optimal therapy for congenital hypothyroidism. J Pediatr 2004;144:698-700. 5. Fisher DA. The importance of early management in optimizing IQ in infants with congenital hypothyroidism. J Pediatr 2000;136:273-4. 6. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid 1999;9:735-40. 7. 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. 8. Tsiao PH, Chiu YN, Tsai WY, Su SC, Lee JS, Soong WT. Intellectual outcome of patients with congenital hypothyroidism detected by neonatal screening. J Formos Med Assoc 2001;100:40-4. 9. Mirabella GF, Astzalos E, Perlman K, Rovet J. The effect of abnormal intrauterine thyroid hormone economies on infant cognitive abilities. J Pediatr Endocrinol Metab 2000;13:191-4. 10. 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. 11. Law WY, Bradley DM, Lazarus JH, John R, Gregory JW. Congenital hypothyroidism in Wales (1982–1993): demographic features, clinical presentation and effects on early neurodevelopment. Clin Endocrinol (Oxf) 1998;48: 201-7. 12. 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. 13. Mullen EM. Mullen scales of early learning. Circle Pines, MN: American Guidance Services; 1995. p. 58-64. 14. Bongers-Schokking JJ. Pre- and postnatal brain development in neonates with congenital hypothyroidism. J Pediatr Endocrinol Metab 2001; 14(suppl 6):1463-8. 15. Rovet JF, Ehrlich R. Psychoeducational outcome in children with earlytreated congenital hypothyroidism. Pediatrics 2000;105:515-22. 16. Rovet J, Daneman D. Congenital hypothyroidism: a review of current diagnostic and treatment practices in relation to neuropsychologic outcome. Paediatr Drugs 2003;5:141-9.
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