Congenital Hypothyroidism Group Research Articles

Development of Contrast Sensitivity in Infants with Prenatal and Neonatal Thyroid Hormone Insufficiencies

Thyroid hormone is essential for normal brain development including structures critical for visual processing. While chick and rodent models have demonstrated abnormal visual development following prenatal thyroid hormone loss, comparable data do not exist in the human. To determine whether human infants with intrauterine and early postnatal thyroid hormone insufficiencies have compromised visual abilities, we investigated contrast sensitivity and visual acuity development in 13 infant offspring of women with hypothyroidism during pregnancy (HYPO), 16 preterm infants born between 32 and 35 weeks gestation, 12 infants with congenital hypothyroidism (CH), and 20 typically developing infants. All were assessed with the sweep visual evoked potential technique at 3, 4.5, and 6 months (corrected) age. Results showed significantly reduced contrast sensitivity but normal visual acuity in HYPO and CH groups relative to controls (p < 0.003 and p < 0.05 respectively). Stratification of the HYPO group into subgroups based on maternal TSH levels during the first half of pregnancy revealed lower contrast sensitivities for infants whose mothers' TSH values were above than below the median (p < 0.05). In the CH group, those with an absent thyroid gland and/or a newborn TSH value above 200 mIU/L had lower contrast sensitivities than did those with other etiologies or TSH levels below 100 mIU/L (p < 0.05). There were no significant effects involving the preterm group. These results indicate that thyroid hormone is important for human visual development.

Left ventricular function in congenital hypothyroidism neonates before and after thyroxine substitution therapy

To evaluate left the systolic and diastolic functions in neonates with congenital hypothyroidism (CH) as well as the effect of thyroxine substitution therapy on left ventricular function and its correlation with thyroid hormones serum levels. M-mode echocardiography was used to examine the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), pulse wave Doppler was used to examine the peak early diastolic mitral inflow velocity (E(m)) and peak late diastolic mitral inflow velocity (A(m)), quantitative tissue velocity imaging (QTVI) was used to examine the systolic peak mitral annular velocity (s(m)), early diastolic peak mitral annular velocity (E(m)), and the late diastolic peak mitral annular velocity (a(m)), and tissue tracking imaging (TTI) was used to detect the systolic mitral annular displacement (MAD) in 40 neonates with congenital hypothyroidism aged 15-28 days before and after 1-month levothyroxine substitution treatment. Thirty normal neonates were used as controls. Chemiluminescent immunoassay was used to measure the TT(3), TT(4) and TSH levels. Correlation analysis was also made between the ventricular function parameters and the serum TT(3), TT(4), and TSH levels. The left systolic function parameters (LVEF, s(m), MAD, E(m) and e(m)) was 0.61 +/- 0.08, 2.60 cm/s +/- 0.60 cm/s, 0.29 cm +/- 0.06 cm, 0.59 m/s +/- 0.12 m/s and 2.72 cm/s +/- 1.43 cm/s respectively, in CH group, and 0.67 +/- 0.06, 3.25 cm/s +/- 0.51 cm/s, 0.41 cm +/- 0.08 cm, 0.72 m/s +/- 0.11 m/s and 4.51 cm/s +/- 1.23 cm/s in control group (P < 0.01). Left function in CH neonates before treatment were all lower than those of the controls (P < 0.01), which significantly increase after 1-months L-T(4) substitution therapy, 0.69 +/- 0.05, 3.46 cm/s +/- 0.64 cm/s, 0.45 cm +/- 0.08 cm, 0.82 m/s +/- 0.17 m/s and 5.09 cm/s +/- 1.37 cm/s, (P < 0.01). Those parameters were positively correlated with TT(4) serum levels (P < 0.01), and were negatively correlated with TSH (all P < 0.01). In particular, MAD, sm, E(m), and em were highly correlated with serum TT(4) and TSH (r = 0.667, 0.538, 0.478, and 0.599 respectively, all P < 0.001;and r = -0.670, -0.521, -0.490, and -0.583 respectively, all P < 0.001). Neonates with CH have lower left systolic and diastolic functions. Early L-T(4) substitution therapy can reverse these changes.

Congenital hypothyroidism: no adverse effects of high dose thyroxine treatment on adult memory, attention, and behaviour

Background: In congenital hypothyroidism (CH) it has been questioned whether high dose thyroxine replacement therapy has detrimental effects on memory, attention, and behaviour. Aims: To describe memory, attention, and behaviour...

Children With Congenital Hypothyroidism and Their Siblings: Do They Really Differ?

Although favorable outcome is typically described in follow-up studies of children with congenital hypothyroidism (CH) identified by newborn screening, IQ reductions and persistent cognitive deficits are still reported. These findings are accounted for by disease and treatment variables as well as methodologic factors including choice of comparison group. Although siblings are ideal because they control for genetic and environmental influences, by definition they have different ages when tested, which can also introduce bias. Because we followed children with CH and their siblings over an extended period of time, there were a number of occasions when both groups were tested at the same age. The purpose of this study was to compare the results of children with CH and their unaffected siblings at the same age and with the same test. The sample consisted of 42 children with CH detected between 1975 and 1985 and their 42 siblings, all of whom were tested with the McCarthy or Wechsler Intelligence Scale for Children-Revised (WISC-R) intelligence tests. Nineteen pairs of children were evaluated at 6 years with the McCarthy, and 30 pairs of children were evaluated at 7 or 9 years with the WISC-R. Recorded for children with CH were disease etiology, bone age and thyroxine levels at diagnosis, age at onset of treatment, and starting dosage of levothyroxine. Paired t tests revealed that the CH group scored lower than siblings by 8.1 IQ points on the McCarthy and 6.2 points on the WISC-R. Factors contributing to the size of the CH-sibling IQ difference were (1) the etiology of hypothyroidism, reflecting the larger differences by those with athyreosis or an ectopic gland than dyshormonogenesis, and (2) the starting dosage of levothyroxine, with those initially treated with >or=8.2 microg/kg per day having smaller CH-sibling differences than those given lower starting doses. There were no effects of bone age, thyroxine levels at diagnosis, or age at treatment onset. Children with CH treated early in life due to newborn screening may have reduced IQ relative to siblings.

Dopamine infusion and hypothyroxinaemia in very low birth weight preterm infants.

The purpose of this study was to assess the relationship between transient hypothyroxinaemia of prematurity (THOP) in very low birth weight newborns and dopamine administration. A total of 172 newborns was enrolled in a prospective observational study and divided into three groups: group A included newborns who were never treated with dopamine; group B were infants in whom dopamine treatment was discontinued for at least 6 h before the congenital hypothyroidism screening and group C included infants who were given dopamine during the screening. Among those newborns given dopamine, the THOP incidence was higher (11.6% in group A; 53.8% in group B; 89.3% in group C), and the vales of TSH (1.67+/-2.32 microU/ml in group A; 1.29+/-1.74 microU/ml in group B; 0.89+/-1.34 microU/ml in group C) and thyroxine (6.1+/-2.2 microg/dl in group A; 3.9+/-1.9 microg/dl in group B; 2.4+/-1.4 microg/dl in group C) were significantly lower. These differences were further confirmed even after gestational age stratification and mathematical correction for differences in clinical conditions. The effects of dopamine appear to be dose-dependent. Even if it cannot be excluded that reduced thyroid stimulating hormone and thyroxine concentrations are caused by non-thyroidal illness, the results suggest that the infusion of dopamine reduces the thyroid stimulating hormone and thyroxine levels in very low birth weight newborns.

Dissociating attention deficits in children with ADHD and congenital hypothyroidism using multiple CPTs.

Recent studies suggest that children with different etiologies of attention disorder also differ as to the types of errors they make on attention tasks. Because these errors are reflective of the core deficits underlying their attention problems, we sought to compare error patterns in children with different attention disorders. Studied were 144 children aged 7-12 years, 43 with attention deficit hyperactivity disorder (ADHD), 35 with congenital hypothyroidism (CH), and 68 controls. Two variations of the continuous performance task (CPT) that differed in demands on inhibitory control and memory were used. One variation, the CPT:A-not-X task, required subjects to observe a continuous stream of letters shown at different rates on the computer screen and respond to all stimuli except "X". The other variation, the CPT:AX task, required them to respond whenever a specified combination of letter such as "A" followed by "X" appeared on the screen. On the CPT:A-not-X task, children with ADHD differed from controls in commission errors, signifying difficulty with inhibitory control, whereas children with CH differed in perceptual sensitivity or signal detection. Although the CH and ADHD groups both performed more poorly than controls on the CPT:AX task, children with CH made more errors to the first stimulus item, suggesting a problem holding information in memory, whereas children with ADHD made more errors to the second item, suggesting impulsivity. These results therefore signify the utility of these tasks in identifying the different mechanisms underlying the specific attention deficits of different groups of children.

The importance of early management in optimizing IQ in infants with congenital hypothyroidism

The importance of early management in optimizing IQ in infants with congenital hypothyroidism

Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism

Objectives: To test whether early treatment with a high initial dose of levothyroxine can prevent suboptimal mental development in all neonates with congenital hypothyroidism (CH). Study design: Sixty-one patients, 27 with severe CH and 34 with mild CH, were treated either early (<13 days) or late (≥13 days) with either a high initial dose of levothyroxine (≥9.5 μg/kg/d) or a low initial dose (<9.5 μg/kg/d). With these criteria, 4 treatment groups were formed. The results of the Bayley test, performed at the age of 10 to 30 months and expressed as mental developmental index (MDI) and psychomotor developmental index (PDI), were related to socioeconomic status, treatment group, initial free thyroxine (FT4) concentration, and mean FT4 concentration during the first 3 months of treatment (FT4-A) and the ensuing 9 months (FT4-B). Results: Mean (± SD) MDI was 113 ± 14, and mean PDI was 114 ± 12. In the severe CH group, only the patients treated early with a high initial dose had normal MDI scores (124 ± 16), whereas the scores of the other groups ranged from 97 to 103. In contrast, all patients in the mild CH group had normal scores (range, 122-125), except those in the group treated late with a low initial dose, whose score was 110 ± 10. Forty-three percent of the variance in MDI and PDI scores was explained by treatment factors, such as the treatment group, initial FT4 concentration, FT4-A, and FT4-B. Conclusions: Our data suggest that optimal treatment includes achievement of euthyroidism before the third week of life by initiation of therapy before 13 days with a levothyroxine dose above 9.5 μg/kg/d and maintenance of FT4 concentrations in the upper normal range during the first year. Thus treated, patients with CH can achieve normal psychomotor development at 10 to 30 months, irrespective of the severity of the disease. (J Pediatr 2000;136:292-7)

Cytotoxic antibodies in congenital hypothyroidism.

Antibody-dependent cell-mediated cytotoxicity was determined in serum samples from 61 patients with congenital hypothyroidism (CH) and 46 of their mothers, using a 51chromium release assay with human thyroid cells. Such cytotoxic antibodies were found in 31% of the children and 24% of their mothers. In the 12 (of 37) newborn infants with hypothyroidism (group 1) who had positive tests, the median cell lysis was 20.1% compared to 4% in healthy newborns. In the 7 (of 29) mothers who had positive tests, the median lysis was 21.3%. In 24 older children with CH (group 2), cytotoxic activity was found in 6, and in them the median lysis was 19.7%; 4 of their mothers had increased lytic activity (median, 20.6%). In 96% of the mother-infant pairs concordance existed between the cytotoxic activity in mothers and their children. Increased thyroid cell lysis was found in 6 of 20 children with athyrosis (30%) and in 6 of 23 children with an ectopic gland (50%), but in only 1 of 14 children with a normal gland. Thyroglobulin antibodies were detected in 2 and antithyroid microsomal antibodies in 3 children-mother pairs. TSH receptor antibodies were present in 5 children and 3 of their mothers. The results indicate that intrauterine autoimmune thyroiditis could be involved in the pathogenesis of CH in some patients.

25 METABOLISM OF a FETOPROTEIN IN CONGENITAL HYPOTHYROIDISM

a-Fetoprotein (a-FP) levels are increased in congenital hypothyroidism (CH) for unknown reasons. To explore this, we studied the half-life of a-FP during the first month of life in neonates with CH and neonates with transient hyperthyrotropinaemia (TH), which we considered as the control group. Between the 3rd and 7th day of life a-FP was measured in 60 cases with CH with a mean gestational age of 39.9±1.5 weeks and in 184 cases with TH with a mean gestational age of 39.3±1.9 weeks. The mean log a-FP levels in the two groups were 4.35±0.39ng/ml and 3.97±0.36ng/ml respectively (p<0,01). Levels of a-FP were also measured in 61 cases with CH at a mean age of 29.8±12.9 days and in 37 cases with TH at a mean age of 36.5±13.1 days. The respective mean values of log a-FP were 3.84±0.46ng/ml and 2.71±0.55ng/ml, after adjustment for conceptional age differences (p < 0,001). The half-life of a-FP was 15.7 days for the CH group and 7.7 days for the TH group. The half-life of a-FP was also calculated in each of 39 cases with CH and 8 cases with TH for which there were serial measurements of a-FP. The half-life of a-FP in the two groups was 12 days and 4.9 days, respectively. We conclude that catabolism of a-FP is delayed in CH group, resulting in inceased serum levels of a-FP. The lack of thyroid hormones, and especially of T3, is probably responsible for that.

ALPHA-FETOPROTEIN (α-FP) MEASUREMENT IN DRIED BLOOD SPOTS: A DISCRIMINATING FACTOR BETWEEN TRANSIENT HYPERTHYROTROPINAEMIA AND CONGENITAL HYPOTHYROIDISM

α-FP was measured in dried blood spots obtained between the 3rd and 7th day of life by heel-prick from newborns within the operation of the Greek screening programme for congenital hypothyroidism (CH) in newborns, in order to check, if this analyte could serve as a second biochemical index in addition to thyrotropin (TSH) measurement for discriminating newborns with CH from those with transient hyperthyrotropinaemia (TH). α-FP was measured by a RIA method. We studied 60 newborns with CH and 184 newborns with TH. The mean gestational age (GA) of CH group was 39,9±1,5 weeks (mean±SD) and of TH group 39,2±1,9 weeks. Discriminant analysis was used after logarithmic transformation of α-FP values, in order to find the linear combination of α-FPand GA, which best discriminates between CH and TH cases. The mean±SD of α-FP in CH group was 32,6±31,1μg/ml, whereas the corresponding figure for TH group was 13,8±16,0μg/ml, difference statistically significant (p<0,001). The discriminant function of log α-FP and GA was 35,57(log α-FP)+4,89(GA)-341,91. This equation classifies a case to the CH group if it has a positive value and to the TH group otherwise. The misclassification rate is about 26%. In conclusion α-FP values in dried blood spots are significantly higher in CH newborns than in TH ones and the measurement of α-FP in CH screening programmes could offer a diagnostic aid in differentiating CH from TH newborns, especially those with border line TSH values.