Download Congenital Hypothyroidism: Influence of Disease Severity and L

Congenital Hypothyroidism: Influence of Disease Severity and
L-Thyroxine Treatment on Intellectual, Motor, and School-Associated
Outcomes in Young Adults
Beate Oerbeck, PhD*‡; Kjetil Sundet, PhD§; Bengt F. Kase, MD, PhD储; and Sonja Heyerdahl, MD, PhD*
ABSTRACT. Objective. To describe intellectual, motor, and school-associated outcome in young adults with
early treated congenital hypothyroidism (CH) and to
study the association between long-term outcome and
CH variables acting at different points in time during
early development (CH severity and early L-thyroxine
treatment levels [0 – 6 years]).
Methods. Neuropsychological tests were administered to all 49 subjects with CH identified during the first
3 years of the Norwegian neonatal screening program
(1979 –1981) at a mean age of 20 years and to 41 sibling
control subjects (mean age: 21 years).
Results. The CH group attained significantly lower
scores than control subjects on intellectual, motor, and
school-associated tests (total IQ: 102.4 [standard deviation: 13] vs 111.4 [standard deviation: 13]). Twelve (24%)
of the 49 CH subjects had not completed senior high
school, in contrast to 6% of the control subjects. CH
severity (pretreatment serum thyroxine [T4]) correlated
primarily with motor tests, whereas early L-thyroxine
treatment levels were related to verbal IQ and schoolassociated tests. In multiple regression analysis, initial
L-thyroxine dose (␤ ⴝ 0.32) and mean serum T4 level
during the second year (␤ ⴝ 0.48) predicted Verbal IQ,
whereas mean serum T4 level during the second year
(␤ ⴝ 0.44) predicted Arithmetic.
Conclusions. Long-term outcome revealed enduring
cognitive and motor deficits in young adults with CH
relative to control subjects. Verbal functions and Arithmetic were associated with L-thyroxine treatment variables, suggesting that more optimal treatment might be
possible. Motor outcome was associated with CH severity, indicating a prenatal effect. Pediatrics 2003;112:923–
930; congenital hypothyroidism, thyroid hormone, thyroxine treatment, adult outcome, intelligence, achievement,
motor function.
ABBREVIATIONS: CH, congenital hypothyroidism; T4, thyroxine; SES, socioeconomic status; TSH, thyroid-stimulating hormone; WASI, Wechsler Abbreviated Scale of Intelligence.
From the *Regional Center for Child and Adolescent Psychiatry, Region
East and South, Oslo, Norway; ‡Department of Psychiatry, University of
Oslo, Oslo, Norway; §Department of Psychology, University of Oslo, Oslo,
Norway; and 储Department of Pediatric Research, Rikshospitalet University
Hospital, Oslo, Norway.
Received for publication Dec 20, 2002; accepted Apr 9, 2003.
Reprint requests to (B.O.) Regional Center for Child and Adolescent Psychiatry, Box 23 Taasen, N-0801 Oslo, Norway. E-mail [email protected]
PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Academy of Pediatrics.
T
he prognosis for children with congenital hypothyroidism (CH) is greatly improved with
neonatal screening. Although screening ensures early treatment, developmental problems in
relation to IQ, motor function, and school-associated
outcome are still reported in follow-up studies. Most
studies have shown lower intelligence (IQ) in early
treated children with CH, relative to control subjects,1 although some studies have not found significant group differences.2– 4 Motor deficits are prevalent and most pronounced in fine motor function.1,3,5
Psychoeducational outcome studies show inconsistent results in that some reported normal psychoeducational function,2,6 whereas others found some form
of learning difficulties, including mathematics.7–11
Previous studies have addressed outcome in adolescence,2,6,8,11–13 and adult outcome has not been studied. The understanding of why children with CH
show developmental delay is still a controversial
issue. Derksen-Lubsen and Verkerk1 postulated in a
1996 review article that severity of CH seems to be
the most important independent risk factor for outcome, and the effect of severe CH is assumed to be
attributable to prenatal hypothyroidism. They did
not find that treatment variables have an important
effect on cognitive development. In contrast to this,
some studies advocate that developmental delay
is attributable to nonoptimal treatment.14 –16 Both
American and European treatment recommendations propose higher initial l-thyroxine dose than
previously recommended.17,18 Promising results are
reported in children who are treated early with a
high initial l-thyroxine dose, with which even children with severe hypothyroidism show normal intelligence.14 –16 However, the high-dose treatment
groups were small, and the children studied were 4
years of age or younger. However, others emphasize
that the optimal l-thyroxine dose remains unclear.19,20 Hrytsiuk et al19 summarized findings on
the effect of l-thyroxine starting dose on developmental outcome, concluding that the evidence for
such an effect is weak. Research on the importance of
the l-thyroxine treatment level in relation to developmental outcome thus has yielded inconsistent results. One problem is that most outcome studies do
not report systematic treatment data and often do
not use multivariate statistics to obtain estimates for
the independent effects of different CH variables on
outcome. In a previous study,21 we found treatment
variables during the first 2 years of life to account for
PEDIATRICS Vol. 112 No. 4 October 2003
923
a significant portion of the variance in verbal IQ at
age 6.
The objectives of the present study were to 1)
investigate long-term outcome in young adults with
CH by studying whether all subjects with CH identified during the first 3 years of the national Norwegian screening program differ from sibling control
subjects on intellectual, motor, and school-associated
tests and 2) study how long-term outcome is affected
by severity of hypothyroidism and serum T4 levels
during the first years of life. We also wanted to study
whether prenatal hypothyroidism and thyroxine
treatment in different time periods have effects on
different outcome variables in young adults.
METHODS
Procedure
Informed consent was obtained from the young adults with CH
and their siblings and parents. The Medical Research Ethics Committee approved the study. The first author, without knowledge of
earlier test results and CH characteristics (severity and treatment),
conducted the neuropsychological assessments. However, she
was not blind to whether a CH or a control subject was tested. A
pretrained test assistant participated in test administering, blind to
both CH parameters and subject status, but the first author scored
and interpreted all test results.
Variables
Background Variables
Subjects
The Norwegian national neonatal screening program was
started in 1979 at the Pediatric Research Institute at the National
Hospital in Oslo. Forty-nine children (29 girls) with CH were
identified during the first 3 years of the screening program (November 1978 through 1981). This 3-year cohort was included in the
present follow-up study and has participated in a previous study
at the age of 2 and 6 years.21,22 All subjects agreed to participate in
the present follow-up study at a mean age of 20.2 years (18.3–21.7
years). Forty-one siblings (16 girls) were used as control subjects
(mean age: 21.4 years; 12.3–30.0 years). The sibling closest in age,
preferably of the same sex, was included. One sibling refused.
Exclusion criteria for all subjects were other disorders known to
influence cerebral development or function. None of the CH subjects had central nervous system disorders or a history of head
trauma. One sibling was excluded because of a pervasive developmental disorder. One CH-sibling pair was of foreign origin but
spoke Norwegian well enough to be assessed. Four CH subjects
were not treated early and continuously (3 had delayed start of
treatment because of suspected transitory hypothyroid conditions;
1 was without drug therapy for approximately 1 year). Mean
initial serum T4 level in these subjects was 87.0 nmol/L (⫾26.0
nmol/L), compared with 42.8 nmol/L (⫾ 31.5 nmol/L) in the total
cohort. We present mean neuropsychological test results for the
total CH group (N ⫽ 49) and their sibling control subjects. However, in the CH-sibling comparisons, results were similar even
when these 4 children were excluded (data not shown). In analyses regarding the impact of CH variables on developmental outTABLE 1.
come, only the Norwegian CH subjects with early and continuous
l-thyroxine treatment were included (N ⫽ 44). In analyzing the
group difference in school completion, the siblings who were not
old enough to have finished high school were excluded (N ⫽ 10).
Parental socioeconomic status (SES) was rated blindly on a
5-point scale based on 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.22 Mean SES score was 2.3 (⫾0.9), and there were
no families in the lowest SES level.
CH Variables
Biomedical diagnostic and early treatment data were obtained
previously from the medical records22 and are presented in Table
1. CH severity measures include serum T4 concentration at diagnosis, skeletal maturity at diagnosis (knee epiphyses score [range:
0 – 4; score 0 –1, absent or incipient knee epiphyses, to 4, both
femoral and tibial epiphyseal diameters ⬎3 mm]),23,24 and scintigraphic classification of the type of congenital hypothyroidism. In
the correlations analyses, all CH severity measures were included,
whereas in the regression analyses, we used serum T4 at diagnosis
as measure of CH severity.25 l-Thyroxine treatment measures
include l-thyroxine starting dose, mean serum T4 values calculated for each child from all serum T4 values during defined
periods (first year of life [from after 14 days of treatment], 1.001–2
years, 2.001– 4 years, 4.001– 6 years) and serum hormone measures
at 20 years of age (T4 and thyroid-stimulating hormone [TSH]).
Outcome Variables
IQ, motor function, and school-associated performance are reported. IQ was measured with the Wechsler Abbreviated Scale of
Disease and Treatment Characteristics
CH Variables
N
CH severity
Serum T4 at diagnosis
Skeletal maturity at diagnosis
Type of CH
48
41
42
CH treatment, early years
Age at diagnosis
Age at start of treatment†
T4 starting dose‡
Mean serum T4 ⬍1 y§
Mean serum T4 1–2 y
Mean serum T4 2–4 y
Mean serum T4 4–6 y
CH treatment, at age 20
Serum fT4 at testing㛳
Serum TSH at testing㛳
49
49
49
49
47
47
46
44
44
Mean (SD)
42.8 (31.5 nmol/L)
17.3
24.4
8.4
172.8
151.5
159.1
149.6
Frequencies in Subgroups
Knee epiphyses scores*: 0–1, N ⫽ 17; 2–4, N ⫽ 24
Athyreosis N ⫽ 13/hypoplasia/ectopia N ⫽ 22/
dyshormonogenesis N ⫽ 7
(8.3 d)
(29.2 d)
(3.3 ␮g/kg/24 h)
(38.2 nmol/L)
(39.2 nmol/L)
(24.7 nmol/L)
(21.2 nmol/L)
16.2 (5.2 pmol/L)
12.2 (23.7 mU/L)
SD indicates standard deviation.
* Knee epiphyses scores (0 – 4), score 0 –1: absent or incipient epiphyseal development.
† Treatment was postponed for 3 children because of suspected transitory hypothyroidism, and 1 child had a drug withdrawal period.
Mean age at start of treatment for group with early and continuous treatment (N ⫽ 45): 18.5 ⫾ 9.3 days.
‡ For the group with early and continuous treatment: 8.5 ⫾ 3.3 ␮g/kg/24 h.
§ Mean serum T4 values were computed for each child for defined age periods, for the first year from samples drawn after 14 days of
treatment.
㛳 Drawn at mean of 3.9 ⫾ 7.7 days from day of neuropsychological testing.
924
ADULT OUTCOMES IN CONGENITAL HYPOTHYROIDISM
Intelligence (WASI),26 consisting of 2 subtests (Vocabulary, Similarities) assessing verbal IQ and 2 subtests (Block Design, Matrix
Reasoning) assessing performance IQ. US standards were used. A
study of the psychometric properties of the Norwegian WASI
translation found that mean T scores and IQ results, as well as
intercorrelations of subtests and IQ values, closely resemble published results in the US population.27 Motor speed and coordination were evaluated using the Finger Tapping and the Grooved
Pegboard tests.28 The Grooved Pegboard scores represent seconds
to complete the task; thus, high scores on this test indicate more
problems than low scores. The short form of Bruininks-Oseretsky
Test of Motor Proficiency29 was used as an indication of general
motor proficiency. School-associated performance was assessed in
relation to language and arithmetic and via an interview. The
Norwegian Observational Test of Reading and Writing30 is a
simple test made to screen for dyslexia. It includes an evaluation
of reading speed (words per minute), comprehension, knowledge
of the alphabet, and dictation. The results are used together with
IQ scores to clinically diagnose whether the subject has a generalized learning disorder (reduced IQ in addition to specific language difficulties) or dyslexia (normal IQ and specific language
difficulties). Naming difficulties and verbal fluency were tested
with the Boston Naming Test and the Controlled Oral Word
Association Test.28 The Arithmetic subtest from the Wechsler Intelligence Scales (WAIS-R31; Wechsler Intelligence Scale for Children-Revised32 for the younger siblings) was used as a screening
of arithmetic abilities. Results are expressed as raw scores for all
tests except the WASI and the Arithmetic subtest, for which ageadjusted T scores were adapted from US norms. All subjects
provided information from their school record and filled out the
Botting self-rating scale of school performance33 (1- to 5-point
self-rating of reading, writing, spelling, arithmetic, physical education, and overall cognitive function).
skewed, and Spearman rank correlations were used for these
measures.
Hierarchical linear multiple regression analyses were used to
analyze the effect of the l-thyroxine treatment variables on outcome measures, controlling for background (sex and SES) and CH
severity (serum T4 at diagnosis). Forced entry of background and
CH severity and stepwise introduction of T4 variables were performed. Missing mean substitution was used. R2 adjusted was
used as an expression of explained variance, and in evaluating the
significance of explained variances, we used Cohen’s criteria: 2%
to 13% is small, 13% to 26% is medium, and ⬎26% is large.35
RESULTS
Long-term Outcome in CH Versus Sibling Control
Subjects
Neuropsychological test results are presented in
Table 2.
IQ
The CH group performed two thirds of a standard
deviation below sibling control subjects. The differences are statistically significant.
Motor Function
The groups did not differ in simple motor speed
(Finger Tapping), but the CH group was significantly
impaired in motor coordination (Grooved Pegboard)
and global motor proficiency (Bruininks-Oseretsky)
compared with control subjects.
Statistical Analyses
Developmental variables were reasonably normally distributed. Means (⫾standard deviation) are reported. A linear mixed
model34 was used to analyze group differences controlling for age
and sex. For adjusting for dependence between siblings, variation
between sibling pairs was introduced as a random effect in the
mixed model. Significance level was set to .05. Bonferroni correction was applied to adjust for multiple comparisons within each
neuropsychological domain, thus setting the critical values to P ⫽
.02 for the IQ measures and P ⫽ .01 for the motor measures and
the 4 school-associated measures. The ␹2 test was used to assess
whether the groups differed in the presence of dyslexia. Within
the CH group, independent t tests were used to evaluate outcome
differences between the school completers (N ⫽ 37) and noncompleters (N ⫽ 12). Bivariate correlation analysis (Pearson) was used
between CH variables (severity and treatment), background variables, and outcome at age 20. Serum hormone levels at age 20 were
TABLE 2.
School-Associated Performance
On the basis of the performance on the administered reading and writing tests, along with IQ, 4 CH
subjects were classified as having either a generalized learning disorder (2) or dyslexia (2), compared
with 5 subjects showing signs of dyslexia in the
sibling control group. The difference is nonsignificant (␹2 ⫽ 2.05, P ⫽ .15). The CH group showed no
impairment in verbal fluency (Controlled Oral Word
Association Test) compared with sibling control subjects, but significant differences were found in naming ability (Boston Naming Test) and on the arithmetic screening (Wechsler Arithmetic subtest).
Neuropsychological Outcome in Young Adults With CH and Their Sibling Control Group*
Outcome
IQ
Motor tests
School-associated
Language
Arithmetic
Tests
CH (N ⫽ 49;
Mean [SD])
Siblings (N ⫽ 41;
Mean [SD])
Estimated Group
Differences (95% CI)
Total IQ (WASI)
Verbal IQ (WASI)
Performance IQ (WASI)
Finger Tapping
Dominant hand
Nondominant hand
Grooved Pegboard
Dominant hand‡
Nondominant hand‡
Bruininks/Oseretsky Test, short form
102.4 (13)
102.4 (13)
101.2 (10)
111.4 (13)
110.2 (16)
110.2 (11)
7.96 (3.1–12.8)
7.05 (1.3–12.8)
7.51 (3.3–11.7)
.002B
.017B
.001B
47.1 (7)
44.6 (7)
51.8 (7)
47.7 (6)
3.02 (0.4–5.7)
3.87 (⫺0.6–⫺8.4)
.028
.24
70.8 (10)
79.7 (13)
66.6 (10)
61.1 (7)
71.2 (11)
80.3 (7)
⫺11.06 (⫺14.6–⫺8.5)
⫺8.70 (⫺13.7–⫺3.7)
12.10 (9.3–15.0)
Boston Naming Test
Verbal fluency (COWAT)
Speed of reading (words per minute)
Arithmetic (Wechsler subtest)
47.7 (5)
32.4 (10)
136.8 (40)
9.1 (2.4)
50.7 (7)
34.7 (10)
129.2 (32)
10.9 (3)
2.63 (0.6–4.6)
1.28 (⫺2.2–4.7)
⫺1.70 (⫺12.1–8.7)
1.76 (0.7–2.8)
P†
⬍.001B
.001B
⬍.001B
.011B
.28
.74
.001B
CI indicates confidence interval; COWAT, Controlled Oral Word Association Test.
* Group differences were analyzed with a linear mixed model adjusted for age and sex.
† P values are the original ones from the mixed model analysis. The B’s mark the ones that are significant after Bonferroni corrections.
‡ The Grooved Pegboard scores represent seconds to complete the task; thus, high scores on this test indicate more problems than low
scores.
ARTICLES
925
On the Botting self-rating of school performance,
the CH group rated themselves lower in arithmetic
(P ⫽ .04) and in overall cognitive functioning at
school (P ⫽ .02), whereas there were no differences
in their self-rating of other school performances, such
as reading, writing and physical education (data not
shown). All subjects completed 9 years of compulsory education. Twelve (24%) of the 49 CH subjects
started but did not graduate from senior high school,
in contrast to only 2 of the 41 sibling control subjects
(6% of the 31 of the siblings who were old enough to
have completed senior high school). Some CH subjects failed final math examinations; some just left for
no obvious reason, whereas some explicitly stated
that they found school too demanding. SES did not
influence school dropout: 10 of the 12 dropouts come
from the highest (N ⫽ 2) and the next highest (N ⫽ 8)
SES level. Verbal IQ was 94.7 (⫾12) in the 12 CH
subjects who did not complete senior high school, in
contrast to 105 (⫾12) in the completers, a significant
difference (t ⫽ 2.53, P ⫽ .015). Analyses across other
motor or school-associated tests did not reveal significant group differences.
Long-Term Outcome Related to CH Variables
Neuropsychological Test Results
The bivariate correlations in Table 3 show that the
CH severity factors primarily correlated with motor
outcome. The l-thyroxine treatment during the first 6
years correlated primarily with verbal IQ, other language tests, and the arithmetic screening. Regression
analyses generally confirmed the results from bivariate correlations (Tables 4 and 5). Early treatment
variables were significant predictors of verbal IQ,
language, and the arithmetic screening. The starting
dose of l-thyroxine and mean serum T4 during the
second year of life explained 21% of the variance (R2
adjusted) in verbal IQ at age 20. Treatment variables
did not significantly predict performance IQ. In general, severity of CH (serum T4 at diagnosis) predicted motor performance. An inverse relationship
was found on 1 motor test (Bruininks-Oseretsky), in
that high mean serum T4 level during 4 to 6 years
was negatively related to performance. SES was not
significantly related to outcome at age 20. At 20 years
of age, 44.9% of the CH subjects (N ⫽ 22) had serum
TSH values above upper reference range. However,
neither serum fT4 nor serum TSH at 20 years of age
correlated significantly with outcome measures.
School-Associated Outcome
The starting dose of l-thyroxine was significantly
higher in the school completers (N ⫽ 37) compared
with the school noncompleters (N ⫽ 12; 9.2 [⫾3.5]
␮g/kg vs 7.1 [⫾2.1] ␮g/kg; t ⫽ 1.99, P ⫽ .018).
DISCUSSION
Long-Term Outcome in CH Versus Sibling Control
Subjects
The CH group showed a mean IQ deficit compared with sibling control subjects at 20 years of age,
which was similar to the difference found at age 6.22
This indicates an enduring but not increasing IQ
926
deficit in these CH subjects. Consistent with the literature,1,3,5 the CH group experienced motor deficits
compared with control subjects, and group differences increased with the complexity of the motor
task performed. There were no significant group differences in verbal fluency or in the prevalence of
dyslexia. We propose that the reading difficulties
reported in the CH literature11 is related more to a
general verbal deficit rather than to a specific language disorder. The deficit found on the arithmetic
screening is consistent with that of other studies,8,11
possibly caused by impaired concentration as well as
difficulties with handling numbers in the CH group.
Consistent with their test results, the CH group rated
themselves lower than did sibling control subjects on
the Botting scales of arithmetic and of overall cognitive functioning at school. Despite their weaker motor test results, the CH group did not rate themselves
different from sibling control subjects in physical
education, and this finding could suggest a successful integration of students with different degrees of
motor fitness in this subject. The relatively greater
percentage of CH subjects who did not complete
senior high school is a matter of concern. SES did not
account for significant variation in outcome at age 20.
This might be because the study does not comprise
subjects from the lowest SES level and that Norway
is a relatively homogeneous society compared with
most European and American countries. In this article we have focused on selected outcome measures
(IQ, motor function, and school-associated outcome)
and cannot conclude on other functions possibly affected in adult CH subjects.
Long-Term Outcome Related to CH Variables
In this study, neuropsychological outcome at 20
years of age was associated with both CH severity
and early treatment factors. In multiple regression
analysis, several motor tests were consistently associated with serum T4 at diagnosis, a measure of CH
severity, whereas verbal functions and the arithmetic
screening were associated with l-thyroxine starting
dose and mean serum T4 level during the first 6
years. Treatment factors explained 4% to 29% of the
variance in different IQ and school-associated measures (R2 adjusted). Specifically, l-thyroxine starting
dose and mean T4 during the second year explained
21% of the variance in verbal IQ at 20 years, and this
is considered a medium effect size.35
As already mentioned, a greater percentage of the
CH subjects did not finish high school. Additional
weight to this finding is added by the fact that the
noncompleters were given a lower starting dose of
l-thyroxine than the completers. This result is in line
with a large population-based cohort study of young
CH adolescents in France,6 where early l-thyroxine
treatment level was important in relation to school
delay.
That long-term outcome was associated with lthyroxine treatment levels during childhood is consistent with some other studies,6,11,14 –16,36 and supports the view that treatment might be improved by
higher treatment levels.14 –17 However, the importance of l-thyroxine treatment levels after infancy
ADULT OUTCOMES IN CONGENITAL HYPOTHYROIDISM
ARTICLES
927
0.09
⫺0.12
⫺0.18
0.05
0.22
0.25
0.44*
0.30*
0.02
0.16
⫺0.13
0.09
⫺0.04
⫺0.09
0.07
0.22
0.23
0.25
0.17
⫺0.09
0.12
⫺0.14
0.27
0.11
0.00
0.19
⫺0.15
⫺0.15
0.15
⫺0.05
⫺0.07
⫺0.12
0.32*
0.03
0.23
0.01
⫺0.36*
FT-d
0.09
0.17
0.14
0.03
0.02
⫺0.17
0.07
0.10
0.07
⫺0.29
⫺0.08
P-IQ
0.11
⫺0.04
0.23
0.04
0.09
0.12
⫺0.18
⫺0.17
0.29*
0.00
0.14
⫺0.03
⫺0.41*
FT-nd
0.04
0.15
0.04
0.05
0.26
⫺0.08
0.09
0.00
0.19
0.29
⫺0.37*
0.00
⫺0.27
⫺0.35*
⫺0.21
⫺0.25
0.10
⫺0.18
⫺0.26
⫺0.10
⫺0.05
0.24
0.14
⫺0.01
GP-nd¶
0.24
⫺0.38*
GP-d¶
Motor Tests (FT; GP, dominant and
nondominant hand; B/O)
0.14
⫺0.17
0.04
⫺0.20
0.19
0.33*
0.29
0.35*
⫺0.03
⫺0.02
⫺0.25
0.01
⫺0.24
⫺0.18
⫺0.03
0.15
0.00
⫺0.23
⫺0.19
0.01
0.03
BNT
⫺0.02
⫺0.14
0.03
⫺0.05
0.03
0.36*
0.05
0.06
0.05
⫺0.17
⫺0.29
⫺0.17
0.25
Cowat
⫺0.07
⫺0.02
⫺0.07
0.20
0.40†
0.31*
0.37*
0.27
⫺0.06
⫺0.21
⫺0.09
⫺0.07
0.35*
Speed
⫺0.24
0.27
⫺0.04
0.13
0.07
0.46†
0.16
⫺0.02
0.12
⫺0.16
⫺0.13
⫺0.12
⫺0.08
Arithmetic
School-Associated (Language [BNT],
verbal fluency [COWAT], speed of
reading, Arithmetic)
0.40†
⫺0.05
0.36*
⫺0.13
⫺0.52†
B/O
FT indicates Finger tap; GP, Grooved Pegboard; ⫺d, dominant; ⫺nd, nondominant; B/O, Bruininks-Oseretsky, short form; BNT, Boston Naming Test.
* P ⬍ .05.
† P ⬍ .01.
‡ Pearson product-moment correlation.
§ Spearman rank correlation.
㛳 Dyshormonogenetic glands are not included.
¶ High scores on this test indicate more problems than low scores.
⫺0.06
0.06
V-IQ
⫺0.19
0.00
IQ
IQ (Total IQ, Verbal IQ,
Performance IQ)
Neuropsychological Outcome
Correlations Between Background Variables, CH Severity, CH Treatment, and Neuropsychological Outcome at Age 20
Background
SES (N ⫽ 14)‡
Sex (M ⫽ 1/F ⫽ 2; N ⫽ 44)‡
CH severity
Serum T4 at diagnosis (N ⫽ 43)‡
Skeletal maturity at diagnosis (N ⫽ 37)‡
Athyreotic vs ectopic gland (N ⫽ 33)‡㛳
CH treatment, early years
Age at start of treatment (N ⫽ 44)‡
Levothyroxine starting dose (N ⫽ 44)‡
Mean serum T4 ⬍ 1 y (N ⫽ 44)‡
Mean serum T4 1–2 y (N ⫽ 43)‡
Mean serum T4 2–4 y (N ⫽ 43)‡
Mean serum T4 4–6 y (N ⫽ 41)‡
CH treatment, at age 20
Serum T4 at testing (N ⫽ 44)§
Serum TSH at testing (N ⫽ 44)§
TABLE 3.
TABLE 4.
Multiple Regression Analyses: Effects of Background Variables, CH Severity, and CH Treatment Variables on Intellectual
and School-Associated Outcome*
Verbal IQ
␤
Performance
IQ
BNT
Verbal
Fluency:
COWAT
Speed of
Reading
Arithmetic
␤
P
␤
P
␤
P
␤
P
␤
P
␤
P
⫺0.28
⫺0.08
0.02
.07
.60
.88
⫺0.27
⫺0.04
0.08
0.32
.10
.77
.60
.050
⫺0.01
0.05
0.05
.94
.73
.73
⫺0.21
0.31
⫺0.04
.24
.03
.76
⫺0.17
0.34
⫺0.03
0.32
.22
.01
.81
.031
⫺0.13
⫺0.03
⫺0.08
.37
.85
.59
0.46
.002
P
SES
⫺0.18
.24
Sex
0.07
.59
Serum T4 at diagnosis
0.07
.64
l-thyroxine starting
0.32
.035
dose
Mean serum T4 ⬍ 1 y
Mean serum T4 1–2 y
0.48
.001
Mean serum T4 2–4 y
Mean serum T4 4–6 y
0.21
R2 adjusted
Significance of model F (5,38) ⫽ 3.24
P ⫽ .016
Total IQ
0.44
0.42
0.02
F(3,43) ⫽ 1.31
P ⫽ .29
0.04
F(4,39) ⫽ 1.45
P ⫽ .24
0.37 .023
0.04
F(4,39) ⫽ 1.41
P ⫽ .25
.004
0.20
F(4,39) ⫽ 3.67
P ⫽ .012
0.29
F(5,38) ⫽ 4.45
P ⫽ .003
.004
0.14
F(4,39) ⫽ 2.80
P ⫽ .039
* Background (SES, sex) and CH severity (serum T4 at diagnosis) included by forced entry in the regression analyses and CH treatment
variables (starting dose, mean serum T4 levels) included by stepwise entry in the regression analyses.
TABLE 5.
Outcome*
Multiple Regression Analyses: Effects of Background Variables, CH Severity, and CH Treatment Variables on Motor
FT-d
SES
Sex
Serum T4 at diagnosis
l-thyroxine starting dose
Mean serum T4 ⬍1 y
Mean serum T4 1–2 y
Mean serum T4 2–4 y
Mean serum T4 4–6 y
R2 adjusted
Significance of model
FT-nd
GP-d
GP-nd
B/O
␤
P
␤
P
␤
P
␤
P
␤
P
0.07
⫺0.38
0.36
.61
.008
.014
0.03
⫺0.43
0.32
.82
.003
.024
0.19
⫺0.36
⫺0.29
.17
.011
.038
0.09
⫺0.01
⫺0.36
.57
.93
.020
⫺0.05
⫺0.60
0.39
.69
.000
.002
⫺0.25
0.20
F (3, 40) ⫽ 4.47
P ⫽ .008
0.22
F(3,40) ⫽ 4.93
P ⫽ .005
0.23
F (3,40) ⫽ 5.22
P ⫽ .004
0.08
F (3,40) ⫽ 2.27
P ⫽ .095
.038
0.46
F(4,39) ⫽ 10.06
P ⬍ .001
* Background (SES, sex) and CH severity (serum T4 at diagnosis) included by forced entry in the regression analyses and CH treatment
variables (starting dose, mean serum T4 levels) included by stepwise entry in the regression analyses.
has not been systematically examined in most earlier
studies. The CH subjects who were included in this
study were born 20 years ago and were not treated
according to present recommendations in infancy.
Still, the children did not receive inadequate treatment, as defined by the New England Congenital
Hypothyroidism Collaborative (TSH ⬎15 mU/L after 2 weeks of treatment and T4 concentration ⬍103
nmol/L on ⬎1 occasion during the first year of
life),37 but the initial dose was lower than recent
recommendations.17,18 Several of the early treatment
variables correlated with verbal IQ and school-associated abilities. We studied effects of the initial lthyroxine starting dose and serum T4 levels from
start of treatment until age 6 years and found significant correlations between mean serum T4 levels
throughout these age periods and verbal outcome.
Correlations were most pronounced and consistent
for treatment variables during the first 2 years. However, as the treatment variables during different time
periods were correlated and to control for confounding variables (in particular, severity of hypothyroidism), multiple regression analyses were conducted.
The effects of treatment variables persisted in these
analyses, and l-thyroxine starting dose and mean
serum T4 level during the second year of life were
928
the strongest predictors. The exact effect of each
treatment variable on outcome is difficult to determine in our study. The effect of each single factor
was weakened by a relatively low N and by the fact
that several of the early treatment variables, which
were entered into the regression analyses, correlated
with each other and with outcome measures. On 1 of
the motor tests (Bruininks-Oseretsky), mean serum
T4 level at age 4 to 6 was inversely related to outcome in the regression analysis. The significance of
this finding remains unclear: whether it is a coincidence or a negative effect of a higher l-thyroxine
treatment level on some functions in CH children.
There were no significant relations between serum
hormone levels at age 20 and outcome, in line with
our previous study at age 6 years.22 This is in contrast to some studies on children with CH, in which
negative associations were reported between T4 levels at time of testing and attention measures38 and
positive associations between thyroid hormone levels at time of testing and several outcome measures
(memory, speed of processing, fine motor function,
and language).36 Many of the CH subjects had serum
TSH above upper reference range at age 20, which
could suggest nonoptimal follow-up or poor compliance by the young adults.
ADULT OUTCOMES IN CONGENITAL HYPOTHYROIDISM
Severity of CH correlated with motor outcome,
whereas early l-thyroxine treatment levels were related to verbal and mathematical abilities. We hypothesize that these contrasting findings result from
different thyroid effects at different stages of development. Severe hypothyroidism, as found in children with low serum T4 at diagnosis, is assumed to
be associated with prenatal hypothyroidism. Motor
outcome at age 20 correlated with initial serum T4 at
diagnosis, also in multivariate analyses controlling
for treatment variables, indicating an irreversible effect of prenatal hypothyroidism on motor functions.
This is consistent with animal studies showing that
hypothyroidism leads to dendritic spread reduction
in the Purkinje cells of the rat cerebellum. To prevent
this reduction, l-thyroxine supplementation had to
be given before postnatal week 2, which is equivalent
to the prenatal period in humans. Later l-thyroxine
supply had no effect.39
Strengths and Limitations
The strength of this study is the inclusion of a total
3-year cohort of CH subjects who were followed
from infancy to young adulthood and a sibling control group. We had systematic data on the l-thyroxine treatment until 6 years of age. The relatively low
N imposed limitations to the analyses that could be
performed. That these children started their treatment 20 years ago may limit the representativeness
of the study for present cohorts.
Implications
Our study highlights the importance of the l-thyroxine treatment level during both infancy and early
childhood years for the adult outcome in CH subjects.
CONCLUSIONS
The present study, focusing on IQ, motor function,
and school-associated outcome, found significant
differences between young adults with CH and sibling control subjects. Although the children were
treated adequately according to recommendations at
that time, we found that early l-thyroxine treatment
level was associated with outcome. Different thyroid
variables acting at different points in early development had effects on different outcome variables. Motor outcome was not associated with treatment variables but with the severity of CH, indicating an
irreversible prenatal effect on motor functions. Verbal IQ and school-associated outcome was associated
with l-thyroxine treatment variables, suggesting that
more optimal treatment might be possible.
ACKNOWLEDGMENTS
This study was supported by grants from the Norwegian Research Council and The Norwegian Research Fund For Mental
Deficiency.
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PROFITEERING ON PATIENTS’ MISERIES
“The crazy-quilt pattern of medical financing in this country often makes it
impossible to tell what a patient is really paying for and whether the price is fair.
That is especially true in the case of cancer doctors who provide chemotherapy
treatments in offices and clinics outside of the hospital setting.
As the New York Times reported recently, cancer doctors buy these drugs at
discount prices, but bill the patients and their insurers at much higher rates,
making a substantial profit on the differential.”
Abelson R. Overpriced cancer drugs [editorial]. New York Times. February 6, 2003
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ADULT OUTCOMES IN CONGENITAL HYPOTHYROIDISM