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Emma Children’s Hospital Academic Medical Center, University of Amsterdam, Departments of Pediatric Endocrinology (M.J.E.K., B.M.W., J.J.M.d.V., T.V.) and Pediatric Psychology (L.v.d.S.V., B.F.L., M.A.G.), 1100 DE Amsterdam, The Netherlands; Department of Pediatric Physical Therapy (R.W.G.N.-v.d.S.), Radboud University, Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands; Department of Prevention and Healthcare (C.I.L.), Netherlands Organization of Applied Scientific Research, Quality of Life, 2301 CE Leiden, The Netherlands; and Department of Paediatrics (L.K.), Behavioral Research Unit, Alberta Children’s Hospital, Calgary, Canada T2T 5C7
Address all correspondence and requests for reprints to: Marlies J. E. Kempers, Department of Pediatric Endocrinology, Emma Children’s Hospital Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: m.j.kempers{at}amc.uva.nl.
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Abstract |
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Objective: The present study examined whether advancement of treatment initiation to 20 d had resulted in improved cognitive and motor outcome.
Design/Setting/Patients: In 82 Dutch CH-T patients, born in 1992 to 1993 and treated at a median age of 20 d (mean, 22 d; range, 2–73 d), cognitive and motor outcome was assessed (mean age, 10.5 yr; range, 9.6–11.4 yr). Severity of CH-T was classified according to pretreatment free T4 concentration.
Main Outcome Measure: Cognitive and motor outcome of the 1992–1993 cohort in comparison to the 1981 to 1982 cohort was the main outcome measure.
Results: Patients with severe CH-T had lower full-scale (93.7), verbal (94.9), and performance (93.9) IQ scores than the normative population (P < 0.05), whereas IQ scores of patients with moderate and mild CH-T were comparable to those of the normative population. In all three severity subgroups, significant motor problems were observed, most pronounced in the severe CH-T group. No correlations were found between starting day of treatment and IQ or motor outcome.
Conclusions: Essentially, findings from the 1992–1993 cohort were similar to those of the 1981–1982 cohort. Apparently, advancing initiation of T4 supplementation from 28 to 20 d after birth did not result in improved cognitive or motor outcome in CH-T patients.
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Introduction |
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The Dutch screening procedure has been adapted several times since its introduction in 1981. One of the major changes is the advancement of the heel puncture sampling from 6–14 d initially to 6–8 d in the early 1990s and to d 4 from 1999 onward. This change in timing of the heel puncture sampling enabled us to investigate whether earlier treatment initiation had resulted in improved cognitive and motor outcome. We investigated cognitive and motor outcome at 10.5 yr of age in a nationwide cohort of CH patients born in 1992–1993, in whom treatment was initiated at a median age of 20 d. Outcome was analyzed in relation to etiology and severity of CH and in relation to treatment variables. Furthermore, the results of the present study were compared with those obtained from patients born and screened in 1981–1982, examined at the age of 9.9 yr of age, in whom T4 supplementation was initiated significantly later (1).
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Subjects and Methods |
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The Dutch neonatal CH screening method is primarily based on the measurement of T4 in filter paper blood spots. In 1992–1993, sampling was performed between 6 and 8 d after birth. T4, expressed as SD score, is compared with the day mean. If T4 was –0.8 SD or less, TSH was additionally measured. When T4 was –3.0 SD or less or TSH was 50 µU/ml or more, children were referred immediately. Children with a dubious result [–3.0 < T4 
–2.1 SD, or 28 < TSH <50 µU/ml (in 1992) or 20 < TSH < 50 (in 1993)] underwent a second heel puncture and were referred if the result was again dubious or abnormal. The etiological classification of CH was based on thyroid function determinants and thyroid imaging.
In 1992–1993, Dutch pediatricians were advised to start with 6–8 µg T4/kg·d. In accordance with international guidelines, T4 dose adjustments were based on thyroid function determinants, obtained at regular outpatient follow-up visits.
Patients of the 1992–1993 cohort
The institutional review board of the Emma Children’s Hospital Academic Medical Center (AMC) and the privacy committee of the CH Screening Board approved the study protocol. The Netherlands Organization of Applied Scientific Research (TNO) documents the screening results and diagnostic findings of all children screened for CH in The Netherlands.
For the majority of children referred because of an abnormal CH screening result, blood and/or urine samples are sent to the AMC; for each patient, a record is made. Combination of the records (TNO and AMC) revealed that the complete cohort of CH patients born in The Netherlands in 1992–1993 consisted of 141 patients (Table 1
). Of them, three had died, four had moved abroad, and four had transient CH. The parents of the remaining 130 patients were approached by their pediatricians, whose responses led to the exclusion of patients with a known or suspected syndrome (n = 12), exceptionally late start of treatment (n = 3, initiation of treatment > 300 d after birth), (treatment for) brain tumor (n = 1), blindness (n = 1), encephalopathy after hypoxia (n = 2), or hypoglycemia (n = 1); and patients of whom the mother was treated with T4 during pregnancy (n = 2) (Table 1, "not suitable"). The parents of 18 patients refused participation (Table 1, "not willing").
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, "not suitable").
Of the 87 participating patients (62% of the original cohort), 82 had CH-T, and five had central CH (CH-C). The test results of patients with CH-C are presented separately, because of difference in etiology and treatment; all of them received besides T4 supplementation, cortisol, and GH. Patients with CH-T were classified to subgroups based on their pretreatment free T4 (FT4) concentration: severe CH, initial FT4 0.3 ng/dl (4 pmol/liter); moderate CH, 0.3 < initial FT4 0.6 ng/dl (4.0 < initial FT4 8.0 pmol/liter); or mild CH, initial FT4 > 0.6 ng/dl (>8.0 pmol/liter). FT4 reference range for children aged 2–6 wk was 0.9–2.2 ng/dl (12–28 pmol/liter) (8).
Assessments
Cognitive and motor assessments were performed in the AMC (except for seven patients who were tested in their local hospitals) by the same psychologist, who was blinded for the patient’s medical details. Patients were tested at a mean age of 10.5 yr (range, 9.6–11.4 yr).
Cognitive assessments
Intelligence was assessed with the Dutch version of the Wechsler Intelligence Scale for Children, third edition (WISC-III) (9), except for the first 10 patients who were tested with the WISC-R (10) because the WISC-III was not yet available. With the subjects’ performance on 10 subtests, three IQ scores were derived: full-scale IQ (FSIQ); verbal IQ (VIQ); and performance IQ (PIQ). In the normative population, each IQ score has a mean of 100 (SD 15). The scores of the WISC-R were recalculated into WISC-III scores in accordance with the guidelines provided in the WISC-III manual (9, 11).
Motor assessments
Motor skills were assessed with the Movement Assessment Battery for Children (MABC) (12, 13), designed for identification of impairments of motor function in children aged 4–12 yr. The test results are expressed in terms of a total motor impairment score (range, 0 to 40; mean, 5.0 in the normative population; in the text referred to as total MABC score), a manual dexterity score (0–15), a ball skills score (0–10), and a balance score (0–15); higher scores indicate more motor problems. In the normative population, 85% have no motor problems (total MABC score 9.5), 10% have borderline motor problems (9.5 < total MABC score < 13.5), and 5% have definite motor problems (total MABC score 
13.5).
Patients of the 1981–1982 cohort
Data of 58 patients with CH-T born in 1981–1982 (43% of a total cohort of 136 CH patients) who were studied at a mean age of 9.9 yr (range, 9.0–10.9 yr) (1) were available for retrospective analysis. IQ was measured with the WISC-R (10). Motor skills were tested with the Test of Motor Impairment (TOMI) (14). The TOMI later evolved into the MABC, and both contain comparable items. The total motor impairment score (referred to in the text as total TOMI score) ranges from 0 to 20; higher scores indicate more motor problems. In the normative population, 85% have no motor problems (total TOMI score < 4), 10% have borderline motor problems (4 total TOMI score < 6), and 5% have definite motor problems (total TOMI score 6).
Statistical analysis
Comparisons of IQ and motor scores were made between the following subgroups: severe vs. moderate vs. mild CH-T and early-treated vs. late-treated patients with severe, moderate, or mild CH-T (i.e. before or after the mean starting day of treatment). FSIQ scores and the percentage of patients with motor problems of the 1992–1993 and 1981–1982 cohorts were compared.
One-sample t tests were used to determine whether the IQ scores in the total CH-T group and the severity subgroups differed from the norm of 100. Binomial tests were conducted to test whether the percentage of CH-T patients in the severity subgroups that had a motor score more than 9.5 differed from the percentage in the normative population.
ANOVA was used for group comparisons on continuous variables; post hoc group comparisons were performed with Bonferroni post hoc analysis. 
2 tests were used for categorical variables. For variables in which the distributions of scores differed significantly from the normal distribution, nonparametric tests such as the Mann-Whitney U tests were used. Linear regression models were fitted for IQ and motor scores with severity (initial T4 concentration) and starting day of treatment as independent variables. In addition, bivariate correlation analyses between severity of CH-T, starting day of treatment, or initial T4 dose, and IQ or motor scores were performed and between FSIQ and total MABC score. It was not necessary to correct for parental educational level, a potential confounder, because this appeared to be distributed equally over the subgroups: parental educational level by severity (2 = 1.260; P = 0.868) and parental educational level by early or late treatment (2 = 2.435; P = 0.296).
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Results |
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Characteristics of the participants are given in Table 2. Of the 82 patients with CH-T (53 girls, 65%), 50% had severe CH-T, of whom the majority had thyroid agenesis (39%) or dysgenesis (39%), and 50% had moderate or mild CH-T, of whom the majority had thyroid dysgenesis (78%). In patients with severe and moderate CH-T, the mean age at initiation of T4 supplementation was younger than in patients with mild CH-T. The median age at initiation of T4 supplementation for the total CH-T group was 20 d (mean, 22 d).
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Mean FSIQ, VIQ, and PIQ scores of the total CH-T group were not significantly different from the population means (Table 3). The mean total MABC score was subnormal for the total CH-T group and significantly different from the mean of the normative population (P < 0.001; Table 4).
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), whereas in the moderate and mild CH-T group mean IQ scores were not significantly different from the population means. In the severe CH-T group, FSIQ and PIQ scores were significantly lower than in the mild CH-T group (P = 0.007, P = 0.005, respectively; Table 3).
The mean total MABC scores in the severe, moderate, and mild CH-T subgroups were significantly different from the mean of the normative population (P < 0.001, P = 0.003, P = 0.001, respectively; Table 4). Patients with severe CH-T had significantly worse scores on total MABC and manual dexterity than patients with moderate CH-T (P = 0.023, P = 0.004, respectively; Table 4). The percentages of patients in the severe, moderate, and mild CH-T subgroups, with a subnormal total MABC score (70, 37, and 59%, respectively) were significantly higher than in the normative population (P < 0.001, P = 0.016, P < 0.001, respectively). The difference between severe and moderate CH-T in percentages of patients with a subnormal total MABC score was significant (P = 0.023).
In the severe CH-T group, IQ and motor scores did not differ in patients treated less than 19 d after birth vs. patients treated 19 d or more after birth. IQ and motor scores were not different in the moderate and mild CH-T group when treatment was initiated before or after 19 and 31 d, respectively.
In a multiple regression analysis with severity of CH-T (expressed as the initial plasma FT4 concentration) and starting day of treatment as independent variables, only the severity of CH-T appeared to be a significant predictor of FSIQ (Table 5).
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FSIQ and total MABC score were not significantly correlated (r = –0.204; P = 0.073).
Comparison of the 1992–1993 and 1981–1982 cohorts
Mean FSIQ and the percentage of patients with motor problems of patients born in 1992–1993 and in 1981–1982 with severe, moderate, and mild CH-T are presented in Table 6. In patients with severe and mild CH-T, the age at start of T4 supplementation was significantly different between the 1981–1982 cohort and the 1992–1993 cohort (P < 0.001, P = 0.003, respectively), but not in patients with moderate CH-T (P = 0.087). The initial T4 dose of patients in the severity subgroups was not significantly different between the 1981–1982 and the 1992–1993 cohort (P = 0.086, P = 0.938, P = 0.248 for severe, moderate, and mild CH-T, respectively). FSIQ scores of the severity subgroups were not significantly different between the two cohorts. In patients with mild CH-T, the percentage of patients with a subnormal total motor impairment score was higher in the 1992–1993 cohort than in the 1981–1982 cohort (P = 0.013); for severe and moderate CH-T, differences were not significant.
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The five patients with CH-C (four boys) had a mean initial FT4 concentration between that of patients with moderate and mild CH-T (Table 2); none of the CH-C patients had an initial FT4 concentration less than 0.3 ng/dl (<4 pmol/liter). T4 supplementation was initiated at a mean age of 34 d after birth. Patients with CH-C had a mean FSIQ of 99.0 (range, 92.5–105.5); mean VIQ was 96.6 and mean PIQ was 102.2. The mean manual dexterity score was 8.4, ball skills 1.2, and balance 4.9. The mean total MABC score (14.5) was substantially higher than the mean of the normative population (5.0), four of the five patients had a subnormal score (i.e. >9.5).
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Discussion |
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The current findings are in line with our recent observations of persistent cognitive and motor deficits in adult Dutch CH-T patients, born in 1981–1982, in whom treatment was initiated at a median age of 28 d (range, 4–293 d). Also in the 1981–1982 cohort, severity of CH-T was an important predictor of long-term outcome, but not timing of treatment initiation (2). Over the course of the first decade after introduction of the nationwide CH screening, treatment initiation for CH patients was substantially advanced; patients with severe CH-T born in 1981–1982 were treated from a mean age of 29 d (median, 29 d), whereas those born in 1992–1993 were treated from a mean age of 19 d (median, 17 d). Apparently, this advancement did not result in an improvement in intellectual development. It is conceivable that also in the 1992–1993 cohort the time frame for a preventive effect of early treatment initiation had elapsed, as was previously supposed for the 1981–1982 cohort (2). Alternatively, (irreversible) brain damage in severe CH might have accrued in the prenatal period. The importance of the in utero thyroid hormone state has been illustrated by the fact that maternal hypothyroidism during pregnancy is known to result in cognitive and motor deficits in the offspring (15). One has to keep in mind that CH is already expressed in fetal life and that maternal T4, transferred via the placenta, is not sufficient to fill the gap in fetal T4 production.
The conviction prevailing in the prescreening era that early treatment would prevent mental retardation has led to the introduction of neonatal screening once the appropriate techniques (Guthrie card and radioimmunoassays) became available. However, a series of follow-up studies on the cohorts who were originally screened showed that children still had persistent subtle deficits, despite early treatment (1, 2). Several studies have investigated the possible benefits of advancing the initiation of T4 supplementation on outcome in CH patients detected by neonatal screening. As in our study, Boileau et al. (16) investigated the impact of changes in the screening procedure over a 15-yr period: IQ scores of CH patients in whom T4 supplementation was initiated before 21 d after birth were similar to controls, whereas IQ scores of patients treated after this age were significantly lower. This study, however, did not investigate outcome of patients with severe CH as a subgroup. Dubuis et al. and Simoneau-Roy et al. have shown that intellectual outcome in patients with severe CH, in whom treatment was initiated at a median age of 14 d with a mean initial T4 dose of 12.1 µg/kg·d, was normal both at 18 months (3) and 5 yr of age (17). Their patient groups, however, were rather small (n = 8 and 9, respectively). In a sample of Dutch CH patients born between 1993 and 1996, Bongers-Schokking et al. (4) have shown that in severe CH, a treatment delay of 6 d, in patients receiving an initial T4 dose of 10.8 µg/kg·d, led to a loss of 25 points on the Mental Developmental Index of the Dutch version of the Bayley Scales of Infant Development, when measured between 11 and 30 months of age. Remarkably, retesting at 5.5–7 yr of age gave contrasting results: a treatment delay of 7 d resulted in a small increase of 3.6 IQ points (5). No distinction was made according to severity of CH because of small group size.
To what extent the initial T4 dose is a key factor in preserving optimal brain development in CH patients is unclear (18); even recent reports about this issue gave contradictory results. Selva et al. (6), considering a mean initial T4 dose of 10.9 µg/kg·d as relatively low, found that patients with CH, receiving this dose at a mean postnatal age of 10.9 d, had lower FSIQ scores than controls (89.7 vs. 100.2). However, Bongers-Schokking and de Muinck Keizer-Schrama (5), considering a similar dose of 10.6 µg/kg·d, as relatively high, found that patients with CH, receiving this dose at a mean postnatal age of 10.8 d, scored equal to controls (104.6 vs. 105.0 Rakit IQ score). Any effect of both initial and long-term T4 supplementation on cerebral development is ultimately mediated by the intracellular thyroid hormone receptor occupation, established via the plasma FT4 concentration. Consequently, establishing adequate plasma FT4 concentrations as soon as possible after initiation of T4 supplementation and the maintenance of adequate FT4 concentrations thereafter are considered important factors determining outcome of CH patients. However, in a previous study we could not demonstrate a solid correlation between the height of the initial T4 dose and the time needed to reach a plasma FT4 concentration within the reference range (19). This probably explains why we could not find a correlation between the height of the initial T4 dose and outcome.
A limitation of the current study is that motor performance in both CH cohorts had to be assessed with slightly different test methods, as they evolved over time. The MABC, used in the 1992–1993 cohort, contains test items comparable to the TOMI, used in the 1981–1982 cohort, but is considered more sensitive because items are scored on a six-point instead of a three-point scale and because a larger reference group is used (12, 14). Therefore, although it may seem that motor outcome in the 1992–1993 cohort is worse in comparison to the 1981–1982 cohort, this effect may be the consequence of the higher sensitivity of the MABC.
An advantage of the current study is that the design provided the opportunity to study the influence of substantially advanced treatment initiation by comparing data of two large nationwide recruited cohorts of CH patients. In fact, age at treatment initiation was the only variable that essentially distinguished the two cohorts.
Finally, this is the first report on developmental outcome of patients with central CH detected by neonatal screening. The challenge in this group is timely and adequate multiple hormonal supplementations to establish normal growth and brain development, and, especially, to prevent hypoglycemia. The percentage of CH-C patients considered not suitable to participate was relatively high, inherent to their (syndromal) condition of multiple pituitary hormone deficiencies. However, the results of the participating patients are encouraging in that timely and adequate hormonal supplementation established IQ and motor scores not different from patients with moderate CH-T.
In conclusion, this study has shown substantial cognitive and motor deficits in patients with severe CH-T, whose treatment with T4 was initiated at a mean age of 19 d after birth. Mildly and moderately affected CH-T patients had a fair prognosis for IQ, but they too experienced motor problems. Despite a substantially advanced treatment initiation, as spinoff of a decade of experience with neonatal screening, improvement of cognitive or motor outcome failed to occur. Although it is possible that with further advancement of treatment initiation or adaptations in T4 dose intellectual and motor deficits will disappear, the observed deficits might also be the consequence of the prenatal hypothyroid state.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: The authors have nothing to declare.
First Published Online December 12. 2006
Abbreviations: CH, Congenital hypothyroidism; CH-C, central CH; CH-T, thyroidal CH; FSIQ, full-scale intelligence quotient; FT4, free T4; MABC, Movement Assessment Battery for Children; PIQ, performance IQ; TOMI, Test of Motor Impairment; VIQ, verbal IQ; WISC, Wechsler Intelligence Scale for Children.
Received July 14, 2006.
Accepted December 4, 2006.
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