The importance of early management in optimizing IQ in infants with congenital hypothyroidism
2000; Elsevier BV; Volume: 136; Issue: 3 Linguagem: Inglês
10.1067/mpd.2000.104286
ISSN1097-6833
Autores Tópico(s)Metabolism and Genetic Disorders
ResumoSee related article, p. 292. The essential role of thyroid hormones in central nervous system maturation has been clearly demonstrated, and the critical period for this CNS dependency is known to extend from fetal life to 24 to 36 months of age.1Morreale de Escobar G Obregon MJ Calvo R Escobar del Rey F. Effects of iodine deficiency on thyroid hormone metabolism and the brain in fetal rats: the role of the maternal transfer of thyroxine.Am J Clin Nutr Suppl. 1993; 57: 2805-2855Google Scholar, 2Xue-Yi C Xin-Min J Zhi Hong D Rakeman A Ming-Li Z O’Donnell K et al.Timing of vulnerability of the brain to iodine deficiency in endemic cretinism.N Engl J Med. 1994; 331: 1739-1744Crossref PubMed Scopus (351) Google Scholar The benefit of early postnatal treatment of congenital hypothyroidism was demonstrated by a number of clinical investigators, but early treatment was not usually possible because of the delayed appearance of classical signs and symptoms.3Raiti S Newns GA Cretinism: early diagnosis and its relation to mental prognosis.Arch Dis Child. 1971; 46: 692-694Crossref PubMed Scopus (108) Google Scholar, 4Klein AH Meltzer S Kenney FH Improved prognosis in congenital hypothyroidism treated before 3 months.J Pediatr. 1972; 89: 912-915Abstract Full Text PDF Scopus (240) Google Scholar The management of CH was dramatically improved with introduction of newborn CH screening in 1975.5Dussault JH Coulombe P Laberge C Letarte J Guyda H Khoury J. Preliminary report on a mass screening program for neonatal hypothyroidism.J Pediatr. 1975; 86: 670-674Abstract Full Text PDF PubMed Scopus (252) Google Scholar This advance was made possible by the availability of highly sensitive immunoassay methods for direct measurement of serum thyroxine and thyroid-stimulating hormone and adaptation of these methods to the filter paper blood spots used for phenylketonuria screening. With screening and neonatal diagnosis, levothyroxine therapy of CH by 4 to 6 weeks of life became the standard of care, and the majority of children who were treated early experienced normal growth and neurologic development and normal-range IQ values.6Fisher DA Dussault JH Foley Jr, TP Klein AH LaFranchi S Larsen PR et al.Screening for congenital hypothyroidism: results of screening 1 million North American infants.J Pediatr. 1979; 94: 700-705Abstract Full Text PDF PubMed Scopus (296) Google Scholar, 7Derksen-Lubsen G Verkerk PH Neuropsychologic development in early treated congenital hypothyroidism: analysis of literature data.Pediatr Res. 1996; 39: 561-566Crossref PubMed Scopus (130) Google Scholar It was interesting that the majority of infants with CH diagnosed by screening had few if any signs of their hypothyroid state.6Fisher DA Dussault JH Foley Jr, TP Klein AH LaFranchi S Larsen PR et al.Screening for congenital hypothyroidism: results of screening 1 million North American infants.J Pediatr. 1979; 94: 700-705Abstract Full Text PDF PubMed Scopus (296) Google Scholar Research in animals and humans has suggested that this is due to the protective effect of the limited placental transfer of maternal thyroid hormone, residual thyroid hormone secretion from any remnant dysgenetic thyroid gland, and increased conversion of thyroxine to active triiodothyronine in CH brain tissues.1Morreale de Escobar G Obregon MJ Calvo R Escobar del Rey F. Effects of iodine deficiency on thyroid hormone metabolism and the brain in fetal rats: the role of the maternal transfer of thyroxine.Am J Clin Nutr Suppl. 1993; 57: 2805-2855Google Scholar, 6Fisher DA Dussault JH Foley Jr, TP Klein AH LaFranchi S Larsen PR et al.Screening for congenital hypothyroidism: results of screening 1 million North American infants.J Pediatr. 1979; 94: 700-705Abstract Full Text PDF PubMed Scopus (296) Google Scholar, 8Vulsma T Gons MH de Viljder J. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid dysgenesis.N Engl J Med. 1989; 321: 13-16Crossref PubMed Scopus (619) Google Scholar Subsequent clinical studies have demonstrated that a number of variables influence eventual IQ in children with CH. These include severity of CH (low initial serum thyroxine concentration, delayed skeletal maturation at birth), dose of levothyroxine, timing of treatment onset, and serum free thyroxine concentrations during the first year.7Derksen-Lubsen G Verkerk PH Neuropsychologic development in early treated congenital hypothyroidism: analysis of literature data.Pediatr Res. 1996; 39: 561-566Crossref PubMed Scopus (130) Google Scholar, 9Dubuis JM Glorieux J Richer F Deal CL Dussault JH Van Vliet G. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (172) Google Scholar, 10Heyerdahl S Kase BF Lie SO Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment.J Pediatr. 1991; 118: 850-857Abstract Full Text PDF PubMed Scopus (106) Google Scholar Bongers-Schokking et al,11Bongers-Schokking JJ Koot HM Wiersma D Verkerk PH de Muinck Keizer-Shrama SMPF Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism.J Pediatr. 2000; 136: 292-297Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar in this issue of The Journal, have focused further on the early treatment variables in a retrospective assessment of treatment outcome for a group of children with severe (agenesis or total dyshormonogenesis, n = 27) and mild (dysgenesis or partial dyshormonogenesis, n = 34) CH treated in the Netherlands between 1986 and 1996.11Bongers-Schokking JJ Koot HM Wiersma D Verkerk PH de Muinck Keizer-Shrama SMPF Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism.J Pediatr. 2000; 136: 292-297Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar Initial dosage of levothyroxine was 6 to 8 μg/kg/d from 1986 to 1993 and 10 μg/kg/d from 1993 to 1996. Outcome was measured by blinded Bayley assessment (mental development index and psychomotor development index) at 10 to 30 months of age (mean age, 22 months) relative to a group of 207 healthy infants 7 to 18 months of age. Variables assessed included socioeconomic status, initial FT4 concentration, initial dose of levothyroxine, time of treatment onset (mean, 10-11 days vs 14-19 days of age), and FT4 concentration during the first 3 months (FT4-A) and 3 to 12 months (FT4-B). There were significant positive correlations of initial FT4, FT4-A, and dose/age (initial dose levothyroxine/age at onset) with MDI and of initial FT4, FT4-B, and dose/age with psychomotor development index. As in earlier studies, the mean MDI values in the mild and severe CH groups did not differ significantly from the control mean (118 and 106 vs 113).11Bongers-Schokking JJ Koot HM Wiersma D Verkerk PH de Muinck Keizer-Shrama SMPF Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism.J Pediatr. 2000; 136: 292-297Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar The mean MDI varied from 97 in the late treatment–low-dose–severe CH group to 125 in the early treatment–high-dose–mild CH group. The late treatment–low-dose regimen had lesser impact in the children with mild CH (mean MDI, 110). These results are in agreement with most earlier studies but emphasize more clearly the importance of a few days’ delay in treatment in infants with severe CH. An average 6-day delay in the high-dose group was associated with a lower mean MDI (99 vs 124). The timing of treatment was not significant in the high-dose, mild CH group, but a few days’ delay with low-dose treatment in these infants was associated with a mean reduction in MDI from 124 to 110. Before the introduction of newborn CH screening, Klein et al4Klein AH Meltzer S Kenney FH Improved prognosis in congenital hypothyroidism treated before 3 months.J Pediatr. 1972; 89: 912-915Abstract Full Text PDF Scopus (240) Google Scholar assessed the effect of several months’ treatment delay on eventual IQ; a 5- to 6-month delay in treatment was associated with an average IQ approximating 70. This amounts to a loss of 5 to 6 IQ points per month, assuming a linear effect. The study by Bongers-Schokking et al11Bongers-Schokking JJ Koot HM Wiersma D Verkerk PH de Muinck Keizer-Shrama SMPF Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism.J Pediatr. 2000; 136: 292-297Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar suggests that the effect is nonlinear, with the most impact during the early weeks of life. Quantitatively, these new data suggest that delayed treatment might lower IQ several points per week during the early weeks of extrauterine life. More definitive quantitation could be obtained by retesting the children with standard IQ tests at 6 to 8 years of age. The data from the study by Bongers-Schokking et al11Bongers-Schokking JJ Koot HM Wiersma D Verkerk PH de Muinck Keizer-Shrama SMPF Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism.J Pediatr. 2000; 136: 292-297Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar also support the recent findings of Dubuis et al,9Dubuis JM Glorieux J Richer F Deal CL Dussault JH Van Vliet G. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (172) Google Scholar indicating that early high-dose levothyroxine treatment eliminates the negative impact of severe versus mild CH on IQ. This implies that early high-dose therapy corrects the delay in CNS maturation associated with the intrauterine hypothyroidism manifest by delayed bone maturation in infants with severe CH and suggests a therapeutic effect more than a replacement therapy. The beneficial effect of the higher levothyroxine dose on MDI of infants with severe CH also suggests that maternal to fetal transfer of thyroxine is inadequate to protect the CNS of most infants with thyroid agenesis or a complete organification defect. Thus although newborn screening and early treatment have dramatically improved the prognosis of infants with CH, there has been a continuing effort to optimize outcome. Accumulated experience has indicated that the most important treatment variables are the dose and timing of thyroxine therapy, and there is a growing consensus that an initial thyroxine dose of 10 to 15 μg/kg/d should be provided as early as possible. Such therapy raises average peak serum FT4 concentrations to the 30 to 45 pmol/L (2.3-3.5 ng/dL) range, determined by immunoassay, with levels ranging to 80 pmol/L (6.2 ng/dL).9Dubuis JM Glorieux J Richer F Deal CL Dussault JH Van Vliet G. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (172) Google Scholar, 11Bongers-Schokking JJ Koot HM Wiersma D Verkerk PH de Muinck Keizer-Shrama SMPF Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism.J Pediatr. 2000; 136: 292-297Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar The mean value remains supraphysiologic for the first months of life, falling to the upper limit of the normal range thereafter.9Dubuis JM Glorieux J Richer F Deal CL Dussault JH Van Vliet G. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (172) Google Scholar Therapy is monitored by regular measurements of serum FT4 and thyroid-stimulating hormone concentrations. Careful follow-up and dosage adjustment will prevent untoward hyperthyroxinemia. As Bongers-Schokking et al11Bongers-Schokking JJ Koot HM Wiersma D Verkerk PH de Muinck Keizer-Shrama SMPF Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism.J Pediatr. 2000; 136: 292-297Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar point out, fear of untoward CNS effects of overtreatment are unwarranted; healthy term infants experience a transient hyperthyroxinemic state during the neonatal period with FT4 values in the 50 to 75 pmol/L (3.9-5.8 ng/dL) range as determined by direct dialysis, and 28 to 68 pmol/L (2.2-5.3 ng/dL) as determined by immunoassay.12Adams L Emery JR Clack SJ Carlton EI Nelson JC Reference ranges for newer thyroid function tests in premature infants.J Pediatr. 1995; 126: 122-127Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 13Bongers-Schokking JJ De Muinck Keizer-Schrama SMPF Docter R. Pitfalls in serum free thyroxine measurements in infants with and without congenital hypothyroidism [abstract].Horm Res. 1999; 51: 17Google Scholar Available FT4 immunoassay methods provide varying results and considerably lower values (55%-67%) than the direct dialysis method.13Bongers-Schokking JJ De Muinck Keizer-Schrama SMPF Docter R. Pitfalls in serum free thyroxine measurements in infants with and without congenital hypothyroidism [abstract].Horm Res. 1999; 51: 17Google Scholar Results should be interpreted relative to the range in healthy infants for the method used. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidismThe Journal of PediatricsVol. 136Issue 3PreviewObjectives: 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). Full-Text PDF
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