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The Effect of Thyroxine Treatment Started in the Neonatal Period on Development and Growth of Two-Year-Old Down Syndrome Children: A Randomized Clinical Trial

Departments of Paediatric Endocrinology (A.S.P.v.T., T.V., S.L.R.v.R.-M., J.C.D.R., J.J.M.d.V.), Paediatrics (H.S.A.H.), and Cardiology (J.G.P.T.), Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands; and Department of Paediatric Psychology (A.L.v.B.), University of Tilburg, 5000 LE Tilburg, The Netherlands

Address all correspondence and requests for reprints to: Paul van Trotsenburg, Academic Medical Center, University of Amsterdam, Department of Pediatric Endocrinology, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: a.s.vantrotsenburg{at}amc.uva.nl.

	Abstract

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Context: Young Down syndrome children appear to have a mild form of congenital hypothyroidism that is rarely detected by neonatal screening and usually left untreated.

Objective: To investigate the effects of thyroxine treatment on development and growth of young Down syndrome children.

Design, Setting, and Participants: Single-center, randomized, double-blind, 24-month trial (enrollment June 1999 to August 2001) with nationwide recruitment, comparing thyroxine administration with placebo in 196 Down syndrome neonates.

Intervention: Neonates were randomly assigned to treatment for 2 yr with either thyroxine (n = 99; initial dose 8 µg/kg) or placebo (n = 97). Daily thyroxine doses were adjusted at regular intervals to maintain plasma TSH in its normal and free T₄ concentrations in its high-normal range. Placebo dose adjustments mirrored those of thyroxine.

Main Outcome Measures: The primary outcome was mental and motor development at age 24 months, assessed with the Bayley Scales of Infant Development II.

Results: At age 24 months, the developmental testing results of 90 thyroxine-, and 91 placebo-treated children were available for analysis. The thyroxine-treated children had a 0.7-month smaller delay in motor developmental age (95% confidence interval, –1.4 to 0), corresponding to a difference of seven motor developmental index points. The mental developmental age delay was also 0.7 month smaller in the thyroxine group (95% confidence interval, –1.5 to 0.2), but lacked statistical significance. Thyroxine-treated children had greater gains in length (1.1 cm; 95% confidence interval, 0.2 to 2.0) and weight (378 g; 95% confidence interval 55 to 701).

Conclusions: The data of our study provide evidence to support the hypothesis that thyroxine treatment may improve development and growth of young Down syndrome children. Thyroxine treatment should be considered in Down syndrome neonates to maximize their early development and growth.

	Introduction

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THIRTY YEARS AFTER the worldwide introduction of neonatal screening for congenital hypothyroidism, it is beyond doubt that early diagnosis and thyroxine treatment prevent brain damage. Although benefits of early treatment have never been proven in randomized placebo-controlled trials, the changes in the natural course of congenital hypothyroidism are considered sufficient evidence for its efficacy, at least in severe forms (1, 2). A still unsolved question is whether neonates with mild hypothyroidism benefit from treatment, too (3, 4, 5). In the context of neonatal screening the term "mild" is often used for the combination of a normal plasma thyroxine concentration and plasma TSH elevation on recall testing. Nevertheless, the current advice is to treat these children to avoid any risk of brain damage due to hypothyroidism.

In one particular group of children, those with Down syndrome, mild plasma TSH elevation is extremely prevalent: 80–90% in early infancy, and 30–50% thereafter (6, 7, 8, 9, 10). Most of these neonates escape detection by neonatal screening because their thyroxine levels are just above, or their TSH levels are just below the screening cutoffs. In other words, according to the current neonatal screening cutoffs, most Down syndrome neonates are not at risk for brain damage due to hypothyroidism.

Recently, we found that Down syndrome neonates as a group have a lower thyroxine concentration than non-Down syndrome neonates, caused by a shift to lower values of their individual thyroxine concentrations (11). We hypothesized that this might point to a Down syndrome-specific thyroid (regulation) disorder affecting all children and that the lower thyroxine tissue availability might be disadvantageous for these children’s already severely compromised brain development and somatic growth (12). We suggested that Down syndrome infants might benefit from thyroxine treatment. To test our hypothesis, we carried out a randomized clinical trial in which either thyroxine or placebo was administered to Down syndrome children during their first 2 yr of life, with mental and motor development as primary outcome measures.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

All Dutch Down syndrome neonates born between June 1999 and August 2001 were potential candidates for the study. Exclusion criteria were: abnormal congenital hypothyroidism screening, postnatal age more than 28 d, gestational age less than 252 d, 5-min Apgar score less than 7, or insufficient parental command of the Dutch language. Neonates were referred by pediatricians and the Down Syndrome Foundation. The study was conducted in the Academic Medical Center, University of Amsterdam, after approval by its ethics committee. Written informed consent was obtained from all parents.

Study design

Down syndrome neonates were randomized to receive either thyroxine (8 µg/kg per day) or placebo, started within 24 h after randomization and continued until age 24 months. Thyroxine tablets contained 25 µg L-thyroxine, and were divisible in quarters. Placebo tablets were identical in appearance. Starting doses were rounded off to the nearest 6.25 µg. Thyroxine doses were adjusted to reach and maintain normal plasma TSH (0.4–4.0 mIU/liter) and high-normal plasma free T₄ (FT₄) concentrations [1.40–1.86 ng/dl (18–24 pmol/liter)]. Dose adjustments were made by a pediatric endocrinologist who did not have any contact with participants during the study. To ensure blinding, 1) only this endocrinologist had access to laboratory data; 2) placebo dose adjustments were matched to the thyroxine dose adjustments of the preceding week; 3) all dosing communication with principal investigators (pediatric endocrinologist, research nurse, and developmental psychologist) went through standard forms; and 4) parents were informed about new doses only by principal investigators. The principal investigators and the participants were blinded to treatment assignment throughout the study. Besides the nonblinded endocrinologist and a hospital pharmacist, only members of the data monitoring committee were privy to data by treatment, but none had contact with participants.

The probability of assignment to the thyroxine or placebo group was equal for all children. Balance of maternal educational levels (high, medium, low) and numbers of children in both groups was ensured by using a computer-generated randomization list with three strata (maternal educational levels high, medium, and low) and block size 10.

Assessments

Study visits were at randomization and at ages 2, 3, 6, 9, 12, 15, 18, 21, and 24 months. Data collected at randomization included parental information on the perinatal period and their socioeconomic condition. Measurements to guide dose adjustments (weight, plasma TSH, FT₄, T₄, T₃, and thyroxine-binding globulin) were carried out at all study visits. TSH and FT₄ were measured by time-resolved fluoroimmunoassay (Delfia hTSH and FT₄ Ultra; PerkinElmer, Wallac Oy, Turku, Finland). T₄ and T₃ were measured by in-house RIA methods. Thyroxine-binding globulin was determined by RIA (Eiken Chemical Co., Tokyo, Japan). If parents were unable to visit the Academic Medical Center, the weight measurement and blood collection were performed by the child’s local pediatrician.

At randomization and at ages 2, 6, 12, 18, and 24 months, length, head circumference, anterior fontanel size, and heart rate were measured. In addition, parents were interviewed about their child’s condition, hospital admissions, and medical checks, diagnoses, and procedures in the preceding period. The means of three consecutive length and head circumference measurements were used. Length, weight, and head circumference SD scores were calculated using current Dutch standards (13).

At ages 6, 12, and 24 months, development was assessed with the Bayley Scales of Infant Development II (BSID-II), and the Dutch version of the Kent Infant Development Scale (KID) (14, 15). All children were tested at age 24 months, irrespective of premature discontinuation of study medication. The BSID-II was adjusted by starting with items younger than the actual age at testing (2, 5, and 9 months instead of 6, 12, and 24 months). All developmental tests were carried out by one developmental psychologist. Parents completed the KID questionnaire in the week before these study visits. Adherence to study medication was assessed by counting tablets at all study visits. The effectiveness of the blinding was assessed by telephone interview 3–6 months after the last study visit, in which parents were asked whether during the study they had had knowledge of the kind of study medication their child received.

Statistical analysis

The primary outcome was development at age 24 months, assessed with the BSID-II. All other results were secondary outcomes. The primary outcome analyses were based on all available data, including measurements after premature discontinuation of the intervention. Secondary outcome analyses were based on the data of children who did not discontinue their treatment.

In general, the BSID-II test result is expressed as mental and motor developmental indexes, with a mean of 100 and a SD of 15. However, because of severe developmental delay, in the majority of Down syndrome children developmental indexes cannot be determined. Therefore, developmental outcome was expressed as mental and motor developmental age delay (which corrects for differences in age at testing). Mental and motor developmental index differences were deduced from the differences in mental and motor raw score between the thyroxine and placebo group (14). To detect a clinically relevant difference in mental and motor developmental index of 7.5 points (or 0.5 SD) at chronological age 24 months, with a power of 90% and a two-tailed P value of 0.05, it was calculated that 84 Down syndrome children were required on each treatment (16). To compensate for anticipated loss to follow-up, 100 children were planned on each treatment.

A preplanned interim analysis was carried out after 100 children had undergone BSID-II testing at age 12 months. At this time, several children were diagnosed with central nervous system disease, among which children with infantile spasms. Thyroxine treatment could neither statistically nor causally be connected with the occurrence of infantile spasms or other central nervous disease (17). Therefore, the data and safety monitoring committee recommended that the study be continued as planned. Because central nervous system disease was considered a major negative influence on the primary outcome, the committee advised additional analyses of the primary outcome, excluding affected children.

Primary and secondary outcomes were compared using the independent samples t test. Plasma TSH, thyroid hormone, thyroxine-binding globulin concentrations, and study medication doses were compared using general linear model repeated measures analysis. All reported P values are two-sided. Comorbidity and cointerventions were compared using the independent samples t test (numerical data), and Pearson ² test or Fisher exact test (categorical data). All statistical analyses were done with SPSS for Windows, Release 11.0.1 (15 Nov 2001).

	Results

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Characteristics of the patients

During the recruitment period, 335 Down syndrome neonates were assessed for eligibility, of whom 196 underwent randomization (Fig. 1). Fifteen children discontinued the intervention: 10 were lost to follow-up, five returned for primary outcome measurement. Treatment was never discontinued because of adverse events. In five of the children who continued the intervention, the primary outcome was not available; in four, the primary outcome could not be measured for technical reasons (hyperactive behavior obstructing developmental assessment, two children in both treatment groups), and one test report got lost (thyroxine group). Thus, 90 patients in the thyroxine group and 91 patients in the placebo group were included in the primary outcome analyses. Clinical and laboratory data were similar in the two treatment groups at baseline (Table 1 and Fig. 2). In both groups one child had suffered from neonatal convulsions.

View larger version (40K): [in this window] [in a new window]   FIG. 1. Trial profile. CNS, Central nervous system. *, Death, one child; trial too demanding, three children; without reason, two children. , Death, one child; thyroxine prescription and use outside the study, two children; trial too demanding, one child. , Trial too demanding.

View larger version (28K): [in this window] [in a new window]   FIG. 2. Thyroid function parameters and study medication doses at baseline and during the study. TSH is expressed as median and interquartile range. FT4, T4, T3, thyroxine-binding globulin, and study medication doses are means ± SD. At all ages, calculations were based on 84–90 measurements in the thyroxine group and 84–91 measurements in the placebo group. P values refer to the comparison of measurements in the thyroxine and the placebo group from age 2–24 months by general linear model repeated measures analysis. SI conversion factors: to convert FT4 to picomoles per liter and T4 to nanomoles per liter, multiply values by 12.87; T3 to nanomoles per liter, multiply by 0.0154; thyroxine-binding globulin to nanomoles per liter, multiply by 185.19.

The daily thyroxine dose decreased from 8 µg/kg at randomization to a little more than 4 µg/kg at age 9 months and after (Fig. 2). Placebo doses and the total number of dose adjustments during the study (thyroxine group, 318; placebo group, 322) were similar.

From age 2 months onward, median plasma TSH concentrations were always normal in the thyroxine group and elevated in the placebo group. Under thyroxine treatment, mean FT₄ and T₄ concentrations were always higher [differences, 0.51–0.67 ng/dl (6.6–8.6 pmol/liter) and 2.41–3.50 µg/dl (31–45 nmol/liter), respectively], whereas mean T₃ concentrations were always lower [difference, 13.0–39.0 ng/dl (0.2–0.6 nmol/liter)]. Mean thyroxine-binding globulin concentrations were about similar. During the study, none of the children developed overt hypothyroidism or hyperthyroidism.

In both treatment groups, parents reported similar numbers of missed study medication administrations [thyroxine group, 2.2 (3.6); placebo group, 3.3 (4.7)]. After completion of the study, parents of two children (one in the thyroxine group and one in the placebo group) indicated that they knew about the kind of study medication their child received through self-organized laboratory testing.

Primary outcome

The thyroxine-treated children had a smaller mental developmental age delay than the placebo-treated children (9.5 ± 2.6 vs. 10.2 ± 3.0; difference, 0.7 months) (Table 2). The thyroxine-treated children also had a smaller motor developmental age delay (12.3 ± 2.1 vs. 13.0 ± 2.4; difference, 0.7 months). These differences correspond to approximately six mental and seven motor developmental index points. Only the difference in motor developmental age delay was statistically significant. Similar results were obtained when the analyses were repeated in the subset of 176 children who did not discontinue their treatment (data not shown).

Thyroxine-treated children had a greater length and weight than placebo-treated children at all three measurements, with differences increasing over time (Table 3). These differences reached statistical significance at age 24 months when corrected for age at measurement [length difference, 0.3 SD (= 0.9 cm), P = 0.046; weight difference, 0.3 SD (= 364 g), P = 0.022]. Gains in length and weight between randomization and age 24 months were also greater and statistically significant in the thyroxine group [31.3 (3.0) vs. 30.2 (3.1) cm, difference, 1.1; P = 0.016; and 7550 (1101) vs. 7172 (1102) g, difference, 378; P = 0.022]. Throughout the study, there were no significant differences in head circumference.

Comorbidity, cointerventions, and adverse events

Comorbidity and cointerventions did not significantly differ between the two treatment groups, except that in the thyroxine group five children were diagnosed with "other central nervous system disease" (Table 4). In both groups, three children were diagnosed with infantile spasms.

Additional analyses

After exclusion of the 13 children with central nervous system disease (at baseline and comorbidity during the study), the differences in mental and motor developmental age delay between the thyroxine and placebo-treated children were 0.8 months (Table 2, additional analysis). These differences correspond to approximately six mental and eight motor developmental index points. Both developmental age delay differences were statistically significant.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In this randomized trial, we found that thyroxine treatment of a representative sample of Down syndrome children during their first 2 yr of life resulted in modest improvements in motor development and growth. This supports our hypothesis that the mild plasma TSH elevation encountered in almost all young Down syndrome children and the lowered thyroxine concentrations in Down syndrome neonates at the end of their first week of life indicate genuine hypothyroidism that is disadvantageous to their early development and growth (11). Although the clinical significance of the improvement in growth may be disputed, the improvement in motor development seems more relevant. The magnitude of the improvement (0.7 months, corresponding to approximately seven motor developmental index points) compares to the small developmental delays of four to 10 intelligence quotient points found in (non-Down syndrome) children of mothers who were hypothyroid or hypothyroxinemic at the end of the first trimester of their pregnancy, and for which (mass) screening and thyroxine treatment during pregnancy has been proposed (18, 19, 20). Because the earlier attainment of (just) a few developmental milestones may be even more important for a child with a substantial developmental delay (like in Down syndrome) than for a normally developing child, thyroxine treatment of young Down syndrome children may be beneficial to maximize their early development and growth.

Until now, it was actually unknown whether the mild hypothyroidism that young Down syndrome children experience affects their thyroid hormone-dependent brain development. Several observational studies and (thyroid hormone vs. placebo) trials in Down syndrome lacked a proper design to answer this question (no information on the thyroid hormone state during the first months of life, triiodothyronine instead of thyroxine, study participants too old, and no developmental assessment) (21, 22, 23, 24, 25). Well-designed randomized trials or observational studies in young non-Down syndrome children with mild sporadic congenital hypothyroidism have not been conducted. So, the results of our trial not only provide the first proof of harm done by untreated mild congenital hypothyroidism in young Down syndrome children, but they may also be a clue to the possible negative effects of mild congenital hypothyroidism not detected by neonatal screening in young children without Down syndrome.

Our study had some limitations. Although our thyroxine-dosing strategy resulted in plasma thyroid hormone and TSH concentrations comparable to those of thyroxine-treated children with thyroidal (primary) congenital hypothyroidism (26), treatment could not be started until the mean age of 24 d. If treatment could have been initiated directly after the clinical diagnosis of Down syndrome, it is possible that a greater effect could have been achieved (27). Furthermore, the thyroid hormone (steady) state of the thyroxine-treated children differed substantially from the placebo-treated children at the moment of developmental testing, raising the question whether this also might have influenced test performances. However, to our best knowledge, abnormally high as well as abnormally low thyroid hormone concentrations only have a negative influence on performance on tests of attention (28). Therefore, we feel that the differences in development, like the differences in somatic growth, must be ascribed to the long-term, central nervous system development and maturation promoting effects of thyroxine rather than to its direct metabolic effects. Finally, an important issue to address is the duration of the developmental follow-up. A criticism could be that 2 yr is too short to draw any conclusions on the possible long-term benefits of our intervention. However, several long-term follow-up studies in early-treated children with moderate to severe congenital hypothyroidism have shown that developmental outcome later in life is strongly correlated to early developmental assessments (29, 30, 31, 32). We could not think of any argument that this is different in Down syndrome children with mild congenital hypothyroidism. Yet, only thorough developmental follow-up of this cohort of children will reveal the actual long-term benefits of early childhood thyroxine treatment. In this follow-up, the use of neuropsychological tests that are more sensitive than the BSID-II in detecting specific hypothyroidism-related defects in early brain development may show which neuropsychological domains benefit most from early thyroxine treatment (28).

In summary, the data of our study are consistent with the presumption that the mild hypothyroidism of young Down syndrome children is not a harmless phenomenon and provide evidence to support the hypothesis that thyroxine treatment may improve development and growth of young Down syndrome children. Given the observed benefits, the absence of adverse events, and the low treatment costs, we feel that thyroxine treatment should be considered in Down syndrome neonates to maximize their early development and growth.

	Acknowledgments

 
We are indebted to all Down syndrome children and their parents for their participation in the study; to Organon Inc. for providing the study medication; to Erik A. B. de Graaf and the Dutch Down Syndrome Foundation, and the Dutch pediatricians for providing and caring for the participating children; to Marjo J. Geerlings, Marijke Dekker-van der Sloot, Marlies J. E. Kempers, Hanneke M. van Santen, Kamil Wojciechowicz, and Richard Schol for collecting data; and to Raoul C. Hennekam for critically reviewing the study proposal.

	Footnotes

 
This work was supported by The Netherlands Organization for Health Research and Development Grant 2100.0025.

First Published Online March 8, 2005

Abbreviations: BSID-II, Bayley Scales of Infant Development II; FT₄, free T₄; KID, Kent Infant Development Scale.

Received January 20, 2005.

Accepted March 1, 2005.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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