Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment

Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment Sonja Heyerdahl, MD, B e n g t Frode Kase, MD, a n d Sverre O l a f Lie, MD From the Department of Pediatric Research, National Hospital, Rikshospitalet, and Oslo University, Child Psychiatric Clinic, Oslo, Norway

The relationship between the treatment serum thyroxine level and intellectual d e v e l o p m e n t at 2 and 6 years was investigated in 46 Norwegian children with congenital hypothyroidism identified by neonatal screenlng. The level of serum thyroxlne during the first 2 years was positively correlated with the Mental Development Index at 2 years of a g e (Bayley Scales of Infant Development) and the V e r b a l I Q a t 6 years of a g e (Wechsler Preschool and Primary Scale of Intelligence). Children with a mean serum thYroxine level >180 nmol/L (14/~g/dl) during the first year had a significantly higher Mental Development Index at 2 years and Verbal IQ at 6 years than children with serum thyroxine values <129 nmol/L (10/~g/dl). Boys had a l o w e r Mental Development Index at 2 years of a g e than girls (86.9 vs 105.1; p <0.001) and a higher frequency of elevated serum levels of thyroid-stimulating hormone during the first year (p = 0.001). No signs of toxic effects of a high hormone level at the time of IQ assessment were detected. However, high serum levels of thyroxine at ages 2 to 4 years in girls were related to lower Performance IQ at a g e 6 years. The results demonstrate that the serum level of thyroxine is of importance In relation to intellectual development. Thyroxine levels a b o v e the upper reference range durlng the first 2 years were related to best Intellectual d e v e l o p m e n t at 2 and 6 years. (J PEDIArR 1991;118: 850-7) Long-term outcome in congenital hypothyroidism is determined by a variety of prenatal and postnatal factors. Early treatment after diagnosis by neonatal screening programs has improved the prognosis considerably. TM However, follow-up studies of intellectual development in children treated early report diverging results. Some have found that the children's intellectual development is no different from that o f control subjects, 2, 4-_6but slight developmental delay related to signs of prenatal hypothyroidism (retarded skeletal maturation at the time of diagnosis, low initial serum levels of tliyroxine, and athyrosis) has also been reported.4, 6-12

Supported by the Norwegian Research Council for Science and.the Humanities and by a Sommer's grant. Submitted for publication Aug. 1, 1990; accepted Dec. 27, 1990. Reprint requests: Sonja Heyerdahl, MD, Department of Pediatric Research, Rikshospitalet, 0027 Oslo 1, Norway. 9/20/27620 850

The question has been raised whether treatment factors could be the cause of the differing outcomes. 5, 13-15 Inadequate treatment, defined as both serum levels of T4 <103 nmol/L (<8 zg/dl) and serum levels of thyroid-stimulating hormone > 15 m U / L (> 15/~U/ml) more than once during the first year of life, was found to be related to lower IQ at 3 to 5 years of age in the New England Congenital ANCOVA ANOVA CH SES T4 TSH

Analysis of covariance Analysis of variance Congenital hypothyroidism Socioeconomic status Thyroxine Thyroid-stimulating hormone

Hypothyroidism Collaborative Study. 16 The relationship between development and treatment within the recommended range 17, 18 has been less well studied. The aims of this report were to address the following questions:

Volume 118 Number 6

1. Is variation within the recommended range of treatment related to variation in intellectual development? 2. Is a relationship between serum T4 levels and intellectua ! development linear, or is there a threshold effect for low or high serum T4 levels in relation to development? 3. Do children with very high levels of thyroid hormones have any signs of toxic effects? METHODS This longitudinal cohort study assessed intellectual development at 2 and 6 years of age in 46 children with CH identified in Norway during the first 3 years of a national neonatal screening program. Subjects. Forty-nine children (29 girls) with CH were identified from November 1978 through 1981. This report is based on 46 children; three children were lost to the register, and their developmental assessments were not performed until age 9 or 10 years. These three children were not representative of the population of CH children; a transitory hypothyroid condition was initially suspected in two of them. The mean initial serum T4 level in these three children was 83 nmol/L (6.5 /~g/dl) compared with 40.1 nmol/L (3.1/~g/dl) for the other 46 children; their mean IQ was 113 ~7, compared with a mean IQ of 90.0 for the 46. For 42 children the diagnosis was made in the TSH screening program; the diagnosis was made by clinical criteria in three children at ages 1, 9, and 23 days, respectively, before the screening result was known, and one was identified at age 45 days after a false-negative screening result. In one child with an elevated TSH concentration but a high initial serum T4 concentration, transitory hypothyroidism was suspected, and treatment was not started until age 200 days: data from this period are excluded from the analyses. One family refused participation in the 6-year assessments, and one Pakistani child with poor skills in the Norwegian language was not tested for verbal IQ. None of the children had defects or diseases, other than CH, known to influence development. When the child with CH had a sibling of appropriate age, the sibling closest in age, preferably of the same gender, was tested for IQ at the time of the 6-year assessments of the patient (sibling n -- 27). Seven siblings were younger than the child with CH (mean [ _ SD] age: 4.4 _+ 0.4 years); 20 were older (10.8 ___2.3 years of age). Procedure. The screening program is national, but the children were treated in regional pediatric departments. The follow-up study with developmental assessments were performed at one center, at age 2 years (mean [ ___SD] age: 2.05 _+ 0.25 years) and at age 6 years (6.2 _+ 0.18 years). The children with CH were tested in hospitals by one psychologist or the first author at 2 years of age, and 89% were tested by another psychologist at 6 years of age. Siblings

1Q and treatment of hypothyroidism

8 51

were tested at home. Testers were unaware of somatic and previous developmental data, and information about treatment, growth, and intercurrent diseases was obtained from medical records after the 6-year developmental assessments. Parents received oral and written information about the study, which was approved by the Norwegian Research Council for Science and the Humanities Ethical Committee and permitted by the Norwegian Data Inspectorate. Variables. Variables were grouped as follows: 1. Severity of CH: initial serum T4 level (n -- 45), skeletal maturation at time of diagnosis (n -- 39), and type of CH (n -- 42) 2. Treatment variables: serum T4 levels (first year In = 45], 1 to 2 years [n -- 45], 2 to 4 years [n -- 45], 4 to 6 years In = 42]), serum TSH level and dose of levothyroxine 3. Background variables: socioeconomic status and gender 4. Outcome developmental variables: Mental Development Index and IQ Missing data for CH variables were not systematically distributed: no child had missing data for more than two variables. Severity of CH. The mean ( __+_SD) initial serum T4 concentration was 40 _+ 29 nmol/L (3.1 _+ 2.3/~g/dl). Skeletal maturation at the time of diagnosis was assessed by one radiologist, using epiphyseal development of the knee (score 0 to 4). 19,20 Sixteen children had absent or incipient epiphyseal development of the knee (score 0 or 1); 23 children had higher scores. Type of CH was determined in 42 children by thyroid gland scintigraphy, performed either at the time of diagnosis or after brief withdrawal of therapy, at a mean age of 1.7 ___0.5 years. Thirteen children were classified as having athyrosis, 22 had hypoplastic (usually ectopic) glands, and seven had enlarged glands probably caused by dyshormonogenesis. Treatment. The medication used was Thyroxine-Natrium (Nycomed Pharma, OSlo). The mean ( + SD) age at diagnosis was 16.9 ___7.1 days, and the mean age at the start of treatment was 18.9 ___8.6 days. The mean starting dose of levothyroxine was 8.4 ___3.4 #g/kg. Serum levels of T4 and TSH were measured at 24 regional and county hospitals with various commercially available kits, those from the United States being predominant. All the laboratories took part in a regional quality control program, ensuring stable and uniform quality of the results. Some also took part in international quality control programs, and the laboratory data obtained should therefore be comparable to those obtained elsewhere. Serum T4 levels were measured by radioimmunoassay. The mean serum T4 concentration was computed for each child for specific age periods: first year, 1 to 2 years of age (from 1 year 1 day), 2 to 4 years of age (from 2 years 1 day), and 4 to 6 years

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The Journal of Pediatrics June 1991

Table I. Serum T4 level and dose of 1-thyroxine at different ages (N = 46) Serum 1'4 level nmol/L

Start of treatment* At 6 wk At 6 mo At 1 Yr At 2 yr At 6 yr

40 193 166 156 160 149

+ 29 +_ 57 _+ 52 _+ 52 --- 35 _+ 25

T4 dose (~g/kg)

~g/dl

3.1 15.0 12.9 12.1 12.5 11,6

_+ 2.3 +__4.4 _+ 4.0 _+ 4.0 _+ 2.7 + 1.9

(n (n (n (n (n (n

= = = = = =

45) 43) 45) 46) 45) 40)

8.5 8.6 5.0 4.8 4.4 3.6

_+ 3.3 _+ 3.5 _+ 2.4 _+ 2.2 _+ 1.7 + 1.0

(n (n (n (n (n (n

= 45) = 44) = 45) = 46) -- 46) = 45)

Values are expressed as mean + SD. "18.9 + 8.6 days.

Table II. t Q in children with C H and siblings

1Q Verbal IQ Performance IQ

CH children at 6 years (n = 46)

CH children with siblings (n - 27)

Siblings (n = 27)

p"

90.0 z 13.1 87.1 z 14.34 94.4 ___ 13.5

87.6 +__ 11.9 84.6 ___ 13.1 93.0 _+ 13.6

99.4 _+ 15.0 93.9 _+ 12.6 105.5 + 16.4

0.001 0.003 0.002

Values are expressed as mean ~_SD. *Based on paired t test comparing the 27 CH children with their siblings. § = 45 for Verbal IQ.

of age (from 4 years 1 day). Hormone levels for the first year were computed from serum samples drawn after 14 days of treatment; 93% of the children had serum Ta levels > 129 n m o l / L (10 #g/dl) in their first sample after 14 days of treatment. If only the mean serum T4 concentration for a period were used for each child, extreme values that might be of clinical importance would be leveled out. Frequency (percentage) of extreme results for serum T4 concentrations (<103 n m o l / L [8 txg/dt] and >180 n m o l / L [14 ~zg/dl]) were therefore also computed. These cutoff values were chosen because a serum T4 concentration <103 n m o l / L (8 /~g/dl) has been considered inadequate. 16, 17 It has been recommended that the serum T4 concentration should be in the upper half of the reference range for age 17, 18 ( 129 to 180 n m o l / L [10 to 14 #g/dl])16 and these limits were used for grouping of mean serum T4 levels. Serum hormone levels at specified ages were also recorded; serum samples were drawn at a mean (_+ SD) of 57.4 + 51.8 days from the exact time of IQ testing. Background. Socioeconomic status was rated blindly on a 5-point scale, according to the profession and education of head of household; SES-1 corresponded to university degree or head of own business; SES-5 indicated unemployed or receiving medical or social security. The mean ( + SD) S E S score for the families was 2.3 ___ 0.9. Developmental assessments. The Mental Development Index, obtained from the Bayley Scales of Infant Development, 21 was assessed at age 2 years. The Bayley Scales are

not standardized in Scandinavia, and American norms with expected means (_+ SD) of 1 0 0 _+ 16 were used. Full Sca!e IQ, Verbal IQ, and Performance I Q were assessed by the Wechsler Preschool and Primary Scale of Intelligence 22 at age 6 years. Depending on age, Siblings were assessed with the same methods or with the Wechsle r Intelligence Scale for C h i l d r e n - - R e v i s e d Y which is a comParable method for children older than 6 years of age. Both Wechsler Scales have been recently standardized in Norway. 22, 23 Statistical analyses. Developmental variables were reasonably normally distributed; some C H variables, especially serum T S H values, were skewed. Nonparametric statistics were used for data that were not normally distributed. Means + S D are reported, except when explicitly stated as means _+ S E M . Pearson correlation coefficients for simple product moment correlations were computed on ranked C H data. Two-tailed tests of probability are reported. The independent t test was used for comparing two independent samples, and a matched-pair t test for paired data. Analysis of variance, with correction for multiple comparisons (Scheff6), and analysis of covariance, with control for covariates, were used for comparison of groups. Assumptions of normality and equal variance were checked, and found unequal for initial serum T4 and mean serum T4 levels at 6 to 12 months of age. For these variables the Kruskal-Wallis test was also used. In using the A N C O V A to analyze the relationship between hormone level and intellectual development, we wanted to ensure control for the

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effect of background factors and C H severity. Gender, SES, and initial serum T4 concentration were therefore used as covariates even if not significant on partial F tests. The initial serum T4 concentration was used as a measure of severity of C H in A N C O V A , because this is a continuous measure with few missing values, correlated with type of hypothyroidism and skeletal maturation at time of diagnosis. The software for the analyses was S P S S PC Version 3.0 (Statistical Package for the Social Sciences, SPSS Inc., Chicago, Ill.). RESULTS Treatment variables. Treatment variables are presented in Table I. None of the children was inadequately treated during the first year of life, as adequate treatment was defined by Klein, 16 but 20% of the children had at least one low serum W4 concentration (<103 n m o l / L [8 #g/dl]) during the first year, and 20% the second year; 78% had at least one high serum T4 result (>180 n m o l / L [14 izg/dl]) during the first year, and 38% the second year. After 2 months of treatment, 92% of the children (35/38) had T S H values <20 m U / L (20 # U / m l ) , with all values <40 m U / L (40 tzU/ml). However, despite a mean serum level of Ta in the recommended range, elevated T S H values were frequent. The incidence of children with at least one T S H result per year >10 m U / L ( 1 0 / z U / d l ) was 60% in the first year (after 14 days of treatment), 43% at 1 to 2 years, 49% at 2 to 4 years, and 38% at 4 to 6 years. Problems of compliance were not reported by physicians or parents, or suspected because of miskept appointments. The mean ( + SD) number of laboratory tests after diagnostic tests during the first year was 6.5 + 2.7, and from 1 to 6 years it was 11.5 _ 3.5. During the first year, five children had only three sets of laboratory values, and four children had four; the mean serum concentration of T4 during the first year for these children did not differ from that in the others (p = 0.57). Development. The Mental Development Index at 2 years of age w a s 97.6 ___ 15.4. Verbal, Performance, and Full Scale IQ scores at 6 years of age were lower in the children with C H than in siblings (Table II). Background variables and the variables that reflect severity of C H might influence the treatment-development relationship; correlations between these groups of variables and development are presented in Table III. Both the serum levels of T4 during the first and second years of life and the severity of C H were related to 2- and 6-year development; C H severity and SES showed no significant correlations with any measures of serum concentrations of T4 (p >0.20). The serum level of T4 during the first 2 years was generally more strongly correlated with the 6-year Verbal IQ than with the Performance IQ; correlations for C H severity were more pronounced with Performance IQ. Specifically, the 13 children with

1Q and treatment o f hypothyroidism

110-

*

853

Mean T4

(<10 pg/dl)

o~, o~ ~

90 O 129-180 nmol/I (10-14 pg/dl)

80

9 >180 nmol/I (>14 gg/dl)

70 first yr 1-2 yrs Mean T4

Fig. I. Mental Development Index at 2 years of age by mean serum T4 level at age periods. Bars represent mean + SEM of the Mental Development Index at 2 years of age for children with different mean serum levels of T 4 in the specified age period. Number of children in serum T4 groups varies with age periods: first year, n = 45 (hatched bar, n = 4; clear bar, n = 27; dark bar, n = 14); 1 to 2 years of age, n = 45 (hatched bar, n = 11; clear bar, n = 23; dark bar, n = 11). Asterisk indicates p <0.01 by ANCOVA, with gender, SES, and initial serum T4 level as covariates. Serum T4 first year/Mental Development Index at 2 years of age: F = 5.64; df = 2,42; p = 0.007.

athyrosis had lower mean Performance IQ scores at 6 years of age than the 22 children with ectopic glands (87.7 _+ 11.2 vs 99.8 ___ 12.6; p = 0.03). Seven children with defects of synthesis had a mean Performance IQ of 90.3 + 16.1. The relationship between dose of T4 and development was generally weak and inconsistent but was statistically significant for dose of T4 at 1 year and Verbal IQ at 6 years of age (r = 0.40; p = 0.006). Intellectual development at ages 2 and 6 years in children with different serum levels of T4 is shown in Figs. 1 and 2. Because the serum level of T4 was not consistently stable in each child, the number of children in the groups varied with time. Group differences were also analyzed by controlling for covariates (gender, SES, initial serum T4 value) to obtain the main effect of treatment at the specified age. Children with a mean serum T4 concentration < 129 n m o l / L ( 10 # g / d l ) during the first and second years had significantly lower Verbal IQ at 6 years than children with a mean serum T4 concentration >180 n m o l / L (14 #g/dl). When the effect of serum T4 level during the second year was analyzed, with control also for first-year serum T4 levels, the serum T4 level during the second year was no longer significantly related to Verbal IQ. The children were also grouped by their Verbal IQ at 6 years, so that their pattern of treatment could be followed (Fig. 3). Children with a Verbal IQ <80 had lower mean serum T4 levels from 6 months to 2 years than the group with Verbal IQ >95; however, the mean serum T4 level for the low-scoring IQ group was > 129

854

Heyerdahl, Kase, and Lie

110

*

The Journal o f Pediatrics June 1991

*

]110

Mean T4 <129 nmol/I (<10 IJg/dl)

g

90

90

8o

8o

70

70 first yr 1-2 yrs 2-4 yrs 4-6 yrs

first yr 1-2 yrs 2-4 yrs 4-6 yrs

Mean T4

Mean T4

o~

I"1 129-180 nmol/I (10-14 pg/dl) 9 >180 nmol/I (>14 IJg/dl)

Fig. 2. IQ by mean serum T4 level at age periods. Bars represent mean _+ SEM IQ at 6 years of age for children with different mean serum levels of T4 in the specified age period. Number of children in serum T4 groups varies with age periods. First year, n = 44 (hatched bar, n = 4; clear bar, n = 27; dark bar, n = 13); 1 to 2 years of age, n = 45 (11/23/11); 2 to 4 years of age, n = 44 (hatched bar, n -- 0; clear bar, n = 36; dark bar, n = 8); 4 to 6 years of age, n = 42 (hatched bar, n -- 5; clear bar, n = 34; dark bar, n = 3). Asterisks indicate p <0.05 by ANCOVA, with gender, SES, and initial serum "I"4level as covariates. Serum "I"4level, first year/Verbal IQ, 6 years of age: F = 3.62; d f = 2,41; p = 0.04. Serum T4 level, 1 to 2 years of age/Verbal IQ, 6 years of age: F = 3.48; d f = 2,42; p = 0.04 (also serum T4 in first year as covariate: F = 0.89; d f = 2,42; p = 0.43). n m o l / L (>10 #g/dl). After 2 years, differences in serum T4 levels between and within IQ groups were small. Treatment versus development in relation to gender. The Mental Development Index at 2 years of age was higher for girls than for boys (105,1 _+ 11.1 vs 86.9 _+ 11.5; p <0.001), but hormone levels also differed: the T S H level was more frequently elevated in boys during the first year (p = 0.001) although the mean serum T4 level was not significantly different (p = 0. i0). This gender difference in serum hormone Ievels did not, however, explain the gender difference in 2-year mental development; the difference was still highly significant when the serum T4 values during treatment, the initial T4 values, and S E S were controlled for in A N C O V A (F = 18.9; d f = 1,42;p = 0.001). At 6 years of age there was no difference in mean Verbal or Performance IQ by gender. A puzzling result was found in relation to Performance IQ. Correlation coefficients between the mean serum T4 value and Performance IQ were positive but not significant for boys; for girls, however, a high serum T4 level was associated with lower performance IQ between 2 and 4 years of age (r = -0.53; p = 0.006). Hyperthyroid effects at the time of IQ assessment. At the time of the 6-year assessment, no clinical signs of hyperthyroidism were found, and no significant differences in IQ or in IQ subtest results were detected between children with serum T4 concentrations above (n = 20) and those with concentrations below (n = 25) the upper reference range. DISCUSSION W e found that the serum T4 concentration during the first and second years of life was related to mental develop-

ment at 2 years of age and to Verbal IQ at 6 years. This seems to be a real effect of treatment, because the effect persisted when possibly confounding factors were controlled. Severity of C H was also related to intellectual development, but the serum level of T4 was not related to C H severity factors, which were also controlled in the analyses. The fact that siblings were tested at home and the C H children in the hospital could account for some difference in test results but could not explain the difference found. The absolute tQ values reported cannot be compared with the results of studies from other countries, because different standardizations of tests have been used, and tests and test conditions also have differed. The Norwegian standardization is recent, 22 so the mean normal value in a random sample would be expected to be 100, whereas in many other countries with older standardizations the mean would be expected to be higher because of the secular increase in IQ. 24 We chose standardized testing conditions (unfamiliar tester in a hospital setting) in contrast to eliciting optimal performance. Both very low and very high serum levels of T4 could be hypothesized, on the basis of studies in a n i m a l s Y to have harmful effects. Low serum levels of T 4 during the first 2 years were negatively related to development at 2 and 6 years of age, and a serum T4 level >180 n m o l / L (>14 ~ g / dl) was positively correlated with later development. The only indication of negative effects of high serum T4 values was that a high value tended to be associated with lower Performance IQ in girls. The significance of this finding remains unclear; it is difficult to interpret because the period from 2 to 4 years of age is not expected to be an especially

Volume ! 18 ?Cumber 6

IQ and treatment o f hypothyroidism

nmol/I

ug/dl

280 -

-22

o 9

!

O

9

230 -

9

:8."

0

9

-18

to

0

oo

"0

z~

:%0

o

"~

8S5

e~

180

9

9

9z o Qp e9

t~

\

:

..............

" ~9 1 I

.....

:

o8 t

't1' . . . . . . . . . . .

~o

-14

" 00

.......

z~;-"~'~-

~L

~

5'

- - ~--:-:z" "-"-'~-_".-.-.- .- -.-. . . . . . . e-l"

O~

._~

131]

-10

p-

" o11'

.

,r-

oo e

t

,,

I

o.

8| ClL

:~

80

Verbal IO < 8 0 N = 1 3 Verbal IQ 8 0 - 9 4 N = 17

30

Verbal IQ > 9 4 N = 1 4 ~"'

- 0.5

i

!

!

0.5-1

i

!

!

!

1-2 Age

2-4 in

i

;

4-6

years

Fig. 3. Mean serum T4 level in age periods plotted by level of Verbal [Q at 6 years of age. Each child's mean serum T4 level in the specified age period is plotted with symbolsshowing level of IQ at 6 years, Lines are drawn through the means for IQ groups. Asterisks indicate p <0.05 by one-wayANOVA. Serum T4 level, 0.5 to 1 year of age/Verbal IQ, 6 years of age: F = 3.42; df= 2, 42; p = 0.04 (by Kruskal-Wallis test, p = 0.08); serum T4 level, t to 2 years of age/Verbal IQ 6 years of age: F = 3.44; dr= 2, 41;p = 0.04.

vulnerable period in brain development. Early hyperthyroidism in rats leads to accelerated early development but retarded adult development, very much the same final result as in experimental hypothyroidism but through different mechanisms.25 Hyperthyroidism in human neonates has also been found to result in an increased frequency of cognitive problems26; some but not all studies of adults treated for hyperthyroidism have reported similar results. 27,28 Negative tissue effects after overtreatment of hypothyroidism in adults are also increasingly being reported. 29 Our finding that severity of CH was correlated with Performance IQ, whereas the serum T4 level during treatment was more strongly related to Verbal IQ, could be an effect of different thyroid influences at different stages of cerebral development.3o, 31 The gender difference in mental development at 2 years of age could be interpreted in the same context. Rutter et al. 32 suggested that biologic immaturity of the male leads to greater susceptibility to stresses of all kinds. Normal development at age 9 or 10 years has been reported in 72 children with CH by the New England Congenital Hypothyroidism Collaborative Study, 5 and in 60 children at age 7 years by Ilicki and Larsson 2 in Sweden,

Differences in serum T4 level do not explain why our results differ from those in the New England Congenital Hypothyroidism Collaborative Study. 5, 33 In the Swedish study, 2 serum T4 concentrations were higher than in our study at both 6 weeks and 1 year of age (at 6 weeks, 223 _+ 62 nmol/L [17.3 _+ 4.8 gm/dl]; at age 1 year, 179 _+ 38 nmol/L [13.9 +_ 3.0/~g/dl] [personal communication]). Children with inadequate treatment during the first year have been found to have delayed development.6, ~6 Rover et al. 34 reported both negative and positive associations with high early serum T4 values; high serum T 4 values from 1 to 3 months of age were associated with a difficult temperament but were also positively correlated with locomotor skills and eye-hand coordination at 3 years. Optimal treatment of children with CH should promote normal cerebral development. In spite of maintaining serum T 4 levels within the recommended range, treatment has probably not been oPtimal in this study. We cannot, however, draw conclusions about what treatment is preferable, because the effect of systematic treatment to sustain higher serum T4 levels has not been studied. Our results indicate that relatively high early serum T4 levels may be beneficial. The optimal dose of thyroxine has recently been dis-

856

Heyerdahl, Kase, and Lie

The Journal of Pediatrics June 1991

T a b l e III. Correlations between C H variables, background variables, and development Development At 6 yr MDI at 2 yr

CH treatment Mean serum T4 level <1 yr (n = 45) 1-2 yr (n = 45) 2-4 yr (n = 45) 4-6 yr (n = 43) Laboratory results %T4 <103 nmol/L (<8 #g/dl) <1 yr 1-2 yr %']'4 >180 nmol/L (>14 #g/dt) <1 yr 1-2 yr Age at start of treatment CH severity Initial T4 level (n = 45) Skeletal maturation at diagnosis (n = 39) Athyrotic/ectopic gland (n = 35) Background Socioeconomic status Gender (M/F)

VIQ

PIQ

IQ

0.38"~ 0.01

0.25 0.40t 0.01 -0.05

0.12 0.00 -0.20 -0.17

0.23 0.23 -0.11 -0.13

-0.44t -0.37*

-0.35* -0.25

-0.23 -0.22

-0.35 -0.28

0.41~ -0.04 0.06

0.19 0.40"~ 0.17

0.08 -0.03 0,25

0.16 0.21 0.21

0.37* 0.17 0.14

0.19 0.10 -0.06

0.26 0.27 0.44t

0.26 0.20 0.22

-0.19 0.59~

-0.20 0.03

-0.33* 0.18

-0.26 0.14

Pearson product moment correlations were based on ranked CH data. MDL Mental DevelopmentIndex; VIQ, Verbal IQ; PIQ, Performance IQ. *p <0.05. ?p
1. Aim J, Larsson A, Zetterstr6m R. Congenital hypothyroidism in Sweden. Acta Paediatr Scand 1981;70:907-12.

2. llicki A, Larsson AI Psychological development at 7 years of age in children with congenital hypothyroidism: timing and dosage of initial treatment. Acta Paediatr Scand 1991 ;80:199204. 3. Hulse JA. Outcome for congenital hypothyroidism. Arch Dis Child 1984;59:23-30. 4. Murphy G, Hulse JA, Jackson D, et al. Early treated hypothyroidism: development at 3 years. Arch Dis Child 1986;61: 761-5. 5. New England Congenital Hypothyroidism Collaborative. Elementary school performance of children with congenital hypothyroidism. J PEDIATR 1990;116:27-32. 6. Toublanc JE, Rives S, Acosta A, Chicaud J. Le d6velopement psychomoteur et intellectuel chez 52 enfants atteints d'hypothyroi'die eong6nitale d6pist6e a la naissance. Arch Fr Pediatr 1990;47:191-5. 7. Glorieux J, Desjardins M, Letarte J, Morisette J, Dussault JH. Useful parameters to predict the eventual mental outcome of hypothyroid children. Pediatr Res 1988;24:6-8. 8. Rovet J, Ehrlieh R, Sorbara D. Intellectual outcome in children with fetal hypothyroidism. J PEDIATR 1987;110: 700-4. 9. Rickards A, Coakley J, Francis I, Armstrong S, Medson H, Connelly J. Results of follow-up at 5 years in a group of hypothyroid Australian children detected by newborn screening. In: Delange F, ed. Research in congenital hypothyroidism. New York: Plenum Press, 1989:341. 10. Virtanen M, Santavuori P, Hirvonen E, Perheentupa J. Mul-

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11.

12.

13. 14. 15. 16.

17.

18.

19.

20.

21. 22.

23.

IQ and treatment o f hypothyroidism

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