Lower Neonatal Screening Thyroxine Concentrations in Down ...

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The Journal of Clinical Endocrinology & Metabolism 88(4):1512–1515 Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2002-021303

Lower Neonatal Screening Thyroxine Concentrations in Down Syndrome Newborns A. S. P.

VAN

TROTSENBURG, T. VULSMA, H. M.

SANTEN, W. CHEUNG,

VAN

AND

J. J. M.

DE

VIJLDER

Department of Pediatric Endocrinology, Emma Children’s Hospital AMC, 1105 AZ Amsterdam, The Netherlands There is an unexplained higher incidence of congenital hypothyroidism (CH) detected by T4-based neonatal screening programs and a very high prevalence of (mild) plasma TSH elevation in young children with Down syndrome (DS). To determine whether newborns with DS have decreased blood T4 concentrations at the time of the neonatal screening, we conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. CH screening results (T4, TSH, and T4-binding globulin concentrations) were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T4 concentration of the studied children with DS

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HILDREN WITH DOWN syndrome (DS) have a very high prevalence of idiopathic mild plasma TSH elevation (4 –10 mIU/liter), up to 100% during their first 6 months of life, that decreases with age (1– 6). Since the 1980s, research on the clinical significance of this mild TSH elevation has focused mainly on effects on childhood growth, with conflicting results (1, 3, 7). However, the most important question is whether the TSH elevation reflects mild hypothyroidism that could harm brain growth and development in the youngest children with DS and contribute to the everpresent mental retardation (8). An often-used argument against this hypothesis is the finding that accompanying plasma thyroid hormone concentrations generally are within the age-specific normal range (3, 9). However, most of these data are derived from studies in older children with DS (1, 3, 9); studies that analyzed plasma thyroid hormone concentrations during the first 2–3 yr of life, the period of life in which the brain is most vulnerable to thyroid hormone deficiency, are not available. In addition, it is unknown whether thyroid hormone concentrations within the low-normal range always guarantee optimal thyroid hormone provision of the developing brain. The only available data on this subject are data on maternal thyroid function during pregnancy that suggest an association between low-normal free T4 (FT4) concentrations and lower infant development test results (10, 11). Based on the very high prevalence of mild plasma TSH elevation in the youngest children with DS (1) and the increased incidence of idiopathic congenital hypothyroidism (CH) in DS in T4-based CH screening programs (12, 13), we hypothesized that essentially all persons with DS have a thyroid (regulation) disorder that may give rise to suboptiAbbreviations: CH, Congenital hypothyroidism; DS, Down syndrome; FT4, free T4; NTI, nonthyroidal illness; TBG, T4-binding globulin.

(n ⴝ 284) was significantly decreased. The individual T4 concentrations were normally (Gaussian) distributed but shifted to lower concentrations. This could not be explained by prematurity, nonthyroidal illness, or iodine exposure. Mean TSH and T4-binding globulin concentrations were significantly increased and normal, respectively. The decreased T4 concentration, left-shifted normal distribution, and mildly elevated TSH concentrations point to a mild hypothyroid state in newborns with DS and support the existence of a DS-specific thyroid (regulation) disorder. The question remains whether this contributes to the brain maldevelopment. (J Clin Endocrinol Metab 88: 1512–1515, 2003)

mal plasma thyroid hormone concentrations, at least during infancy. To find out whether newborns with DS indeed have suboptimal plasma T4 concentrations, we compared the neonatal screening results of a large cohort of Dutch children with DS born in 1996 and 1997 with those of the general newborn population. To gain insight into the cause of the presumed suboptimal T4 concentrations and the TSH elevation, we interviewed the parents of children with DS about the presence of some well-known factors that affect thyroid function and regulation during the neonatal period. Patients and Methods The parents of 310 children with DS born in the Netherlands in 1996 and 1997, who had contacted the Dutch DS Foundation, were approached in writing by the foundation and asked to participate in the study. Parents of 294 children gave permission to retrieve the neonatal CH screening results, and 284 of them consented to a structured (telephone) interview to obtain information on the pregnancy (known maternal thyroid disease, gestational age), delivery (birth body mass, Apgar score), child’s condition around the time of the neonatal screening (hospitalization and reason for admission), and medical investigations and procedures performed during that period. Gestational age and birth body mass were cross-checked with the information recorded by the midwife or district nurse on the neonatal screening forms. Eventually, 284 screening results could be retrieved, of which 275 could be coupled to clinical data. The 284 children with DS of whom the screening results were retrieved represent 75.1% of the estimated 378 children with DS that were born in the Netherlands in 1996 and 1997 (14). The interviews were performed before retrieval of the screening results to keep the observers blinded. The CH screening in the Netherlands is primarily T4 based. Between d 4 and 7 after birth (the day of birth is d 0), blood is collected on filter paper and, after elution, the T4 concentration is measured by RIA. The T4 concentration (nanomoles per liter) is compared with the mean concentration of that day and expressed as sd. If the T4 sd is ⫺0.8 or less (the 20% lowest T4 concentrations), the TSH concentration (milliinternational units per liter) is measured in the blood spots. To identify children with T4-binding globulin (TBG) deficiency, the TBG concentration (nanomoles per liter) is measured if the T4 sd is ⫺1.6 or less (the 5% lowest T4 concentrations). T4 con-

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TABLE 1. Patient characteristics as reported by the parents of children with DS born in 1996 and 1997 in The Netherlands

Mean gestational age (wk) Mean birth body mass (kg) Gestational age ⱕ36 wk and birth body mass ⱕ2.5 kg Congenital heart defect Atrioventricular canal Possible NTI Asphyxia Perinatal infection (including 1 case of necrotizing enterocolitis) 10% or more weight loss Congestive heart failure Gastrointestinal surgery (duodenal atresia/stenosis, 10; anal atresia, 2; omphalocele, 1) Probable iodine exposure preceding the neonatal CH screening Maternal thyroid disease Hashimoto’s thyroiditis; T4 therapy Graves’ disease; no medication

DS children (n ⫽ 284)

General population

Reference

38.2 (range, 27.6 – 42.3) 2.985 (range, 0.970 – 4.880) 23 (8.1%) 123 (43.3%) 57/123 (46.3%) 33 (11.6%) 5/33 8/33 3/33 4/33 13/33

39.4 (range, 25– 44) 3.433 (range, 0.780 –5.320) 0.94 –1.72% 0.43– 0.66%

15 15 16, 17 18

Unknown

3 (1.1%) 3 (1.1%) 2/3 (0.7%) 1/3 (0.4%)

Unknown 1% 0.2%

19 20

TABLE 2. Neonatal CH screening results of children with DS born in 1996 and 1997 in The Netherlands

Group I

Number T4 (SD score) [SD] 95% c.i. Number TSH (mIU/liter) [SD] 95% c.i. Number TBG (nmol/liter) [SD] 95% c.i.

a

284 ⫺0.71f [1.11] ⫺0.84 to ⫺0.58 138 9.76h [14.38] 7.34 to 12.18 61 286.6j [88.4] 263.9 to 309.2

General newborn population

b

Control group

Group II

13,740g 3.96 [26.05] 3.52 to 4.39 3580g 274.7 [72.1] 272.3 to 277.0

274 ⫺0.65f [1.06] ⫺0.77 to ⫺0.52 128 7.29i [7.82] 5.92 to 8.65 54 288.7k [83.8] 265.9 to 311.6

383,092e 0

Group III

c

243 ⫺0.58f [1.03] ⫺0.71 to ⫺0.45 108 6.87i [7.83] 5.37 to 8.36 41 272.1k [75.9] 248.1 to 296.0

Group IV

d

217 ⫺0.54f [0.99] ⫺0.68 to ⫺0.41 94 6.18i [6.94] 4.76 to 7.60 33 262.6k [72.9] 236.8 to 288.5

Control group minus the abnormal screening results

13,361 3.05 [3.50] 2.99 to 3.11 3211 278.8 [68.7] 276.4 to 281.2

a

All children with DS. All children with DS, but minus those with an abnormal neonatal screening result. c The children with DS from group II, but minus those without interview or gestational age ⱕ36 wk and birth body mass ⱕ2.5 kg (mean gestational age, 38.5 wk; birth body mass, 3.082 kg; see Table 1). d The children with DS from group III, but minus those with NTI or iodine exposure preceding the neonatal screening. e Number of children born in The Netherlands in 1996 and 1997 who underwent neonatal screening. f The mean T4 concentration of the four groups of children with DS compared with the mean T4 concentration of the general newborn population (177 nmol/liter; SD ⫽ 38 nmol/liter; conversion to ␮g/dl: multiply by 0.0777); significant (P ⬍ 0.05). g All children born in 1996 and 1997 with a T4 concentration ⫺0.8 SD or less from one of the five Dutch screening laboratories in whom TSH and TBG was measured. h The mean TSH concentration of the children with DS in whom TSH was measured, compared with the mean TSH concentration of the control group; significant (P ⬍ 0.05). i The mean TSH concentrations of the children with DS from groups II to IV in whom TSH was measured, compared with the mean TSH concentration of the control group from which the abnormal screening results were excluded; significant (P ⬍ 0.05). j The mean TBG concentration of the children with DS in whom TBG was measured, compared with the mean TBG concentration of the control group (conversion to mg/dl: multiply by 0.0054); not significant. k The mean TBG concentrations of the children with DS from groups II to IV in whom TBG was measured, compared with the mean TBG concentration of the control group from which the abnormal screening results were excluded; not significant. b

centrations ⫺3.0 sd or less and/or TSH concentrations of 50 mIU/liter or more are considered abnormal and reason for immediate referral, diagnostic work-up, and, if indicated, T4 treatment. Children born at a gestational age of 36 weeks or less and with a birth body mass of 2.5 kg or less are judged on their TSH concentration only (ⱖ50 mIU/liter is abnormal; 20 – 49 mIU/liter is dubious). The mean T4 concentration of the children with DS was compared with the mean T4 concentration of the general newborn population (number of children born in the Netherlands in 1996 and 1997 who underwent neonatal screening: 383,092) which, by definition, is 0 sd. To compare the mean TSH and TBG concentrations with those of children without DS, we used a large control group, consisting of all children born in 1996 and 1997 with a T4 concentration of ⫺0.8 sd or less from one of the five Dutch screening laboratories (13,740 of 70,513 newborns screened in the Amsterdam screen-

ing laboratory). All screening laboratories use the same T4, TSH, and TBG assays. Quarterly nationwide quality controls guarantee high reproducibility and comparability. Children with DS were classified as having “possible nonthyroidal illness” (NTI) when the interview revealed asphyxia (5-min Apgar score ⬍7), perinatal infection (necessitating iv administration of antibiotics), 10% or more weight loss (often resulting from feeding problems and leading to hospital admission), congestive heart failure (necessitating treatment with oxygen, diuretics, or digoxin), or gastrointestinal surgery (before the time of the screening). Written informed consent was obtained from all parents, and the institutional Medical Ethics Committee and the National CH Screening Guidance Committee approved the study.

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Statistical analysis Means, sd, and 95% confidence intervals were calculated with SPSS, Inc. for Windows (release 10.0.7; SPSS, Inc., Chicago, IL). The one-sided t test was used to compare means.

Results

Table 1 shows the characteristics of the 284 children with DS for whom clinical data were available, compared with values in the general population (15–20). The mean gestational age and birth body mass are slightly lower than normal. A considerable number of the children had a gestational age of 36 weeks or less and a birth body mass of 2.5 kg or less and/or were classified as having possible NTI. The prevalence of congenital heart defects fully corresponds with previously reported prevalence figures (21). Perinatal iodine exposure and overt maternal thyroid disease both occurred in 1.1%. Table 2 shows the mean blood T4 concentration of the children with DS, compared with the mean of the general newborn population, and the mean TSH and TBG concentrations, compared with the means of the control group. TSH and TBG were determined in 138 (48.6%) and 61 (21.5%) of the 284 children with DS, respectively. In the total group of children with DS, the mean T4 concentration is significantly lower and the mean TSH concentration is significantly higher, but mean TBG concentrations are similar. Figure 1 shows the frequency distribution of the T4 concentrations to be left-shifted. The left side of this distribution shows a separate small “peak” as well as a “shoulder.” Ten (3.5%) of the 284 retrieved screening results of the

FIG. 1. The blood T4 concentration distribution curves of the children with DS vs. the general newborn population. Group I, All children with DS (n ⫽ 284); group II, all children with DS but minus those with an abnormal neonatal screening result (n ⫽ 274); group III, the children with DS from group II but minus those without interview or gestational age 36 weeks or less and birth body mass 2.5 kg or less (n ⫽ 243); group IV, the children with DS from group III but minus those with NTI or iodine exposure preceding the neonatal screening (n ⫽ 217).


children with DS were abnormal. Four children had a T4 sd of ⫺3.0 or less, and six others had a TSH concentration of 50 mIU/liter or more. Two of the 10 children were diagnosed with thyroidal CH (based on plasma TSH and FT4 determination only) and subsequently treated with T4. In both children T4 treatment was discontinued at the age of 3 yr. Afterward one child had normal thyroid function and the other had mild TSH elevation. In the control group, 379 (0.5%) children had an abnormal screening result. Exclusion of the children with DS with an abnormal neonatal screening result, gestational age of 36 weeks or less and birth body mass of 2.5 kg or less, and possible NTI or probable iodine exposure preceding the neonatal screening resulted in disappearance of the small peak and shoulder in the T4 concentration frequency distribution (Fig. 1). Nevertheless, the differences in mean T4 and TSH concentrations remained, and the shape of the frequency distribution approached a normal (Gaussian) distribution (Table 2 and Fig. 1). Discussion

The present study demonstrates substantially decreased blood T4 concentrations in a large and representative cohort of newborns with DS, compared with the general newborn population. Because mean TBG concentrations do not differ, FT4 concentrations must also be lowered. In combination with a significantly increased mean blood TSH concentration, this strongly suggests that children with DS are mildly hypothyroid, at least during their first weeks of life. This mild hypothyroid state seems not to be caused by pre-


maturity, low birth body mass, NTI, iodine exposure preceding the neonatal screening, or overt maternal thyroid disease. Because these conditions are known causes of transient disturbance of the newborn thyroid hormone state (8, 22, 23), it is likely that the observed abnormalities represent an inborn error in thyroid hormone metabolism or its regulatory system. The disappearance of the TSH elevation months to years after birth might reflect the gradually decreasing need for thyroid hormone in relation to body mass. On the basis of the response of TSH to TRH administration, some authors have ascribed the TSH elevation in children with DS to immaturity of the hypothalamic pituitary axis (3, 24). However, the recently observed normal TSH bioactivity in children with DS does not support a hypothalamic cause (25). Obviously more functional and molecular studies are needed to clarify the etiology. Also, the exact clinical consequences of the mild hypothyroid state remain unclear. The fact that newborns with DS have 21–27 nmol/liter lower blood T4 concentration implicates a lower T4 tissue availability, which may be unfavorable for brain growth and development, especially if such a deficit persists for a longer period. This, however, is unproven. Probably the only way to find out whether the decreased T4 concentrations represent a clinically significant problem is to conduct a randomized controlled trial in which either T4 or placebo is administered to children with DS during their first years of life, with cognitive and motor development as main clinical outcomes. The only two clinical trials in which persons with DS were treated with thyroid hormone or placebo did not clarify this issue (26, 27). In the first trial, T3 was used to influence cognitive and motor development, and in the second trial, only two young children with DS (2 and 2.5 yr old) were treated. In conclusion, the present study demonstrates that newborns with DS generally are mildly hypothyroid. This implies that the highly prevalent TSH elevation in young children with DS may not be as harmless as is assumed until now. Acknowledgments We thank Erik A. B. de Graaf, director of the Dutch Down Syndrome Foundation, for approaching the parents of children with DS and Erik Endert for providing the neonatal screening results of the control group. Received August 30, 2002. Accepted December 27, 2002. Address all correspondence and requests for reprints to: A. S. Paul van Trotsenburg, M.D., Department of Pediatric Endocrinology, Emma Children’s Hospital AMC, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: [email protected]. This work was partly supported by a grant from the Stichting tot Steun Emma Kinderziekenhuis AMC.

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