In search of the optimal therapy for congenital hypothyroidism

Abstract

Neonatal thyroid screening programs were first implemented in the mid- to late 1970s to detect congenital hypothyroidism (CH) as soon after birth as possible and begin therapy before the appearance of clinical symptoms. It was believed that this early diagnosis and treatment would prevent the progressive brain damage typically seen in late-treated cretinism. There is no doubt that newborn CH screening has succeeded. Mental retardation has been eradicated,1.New England Congenital Hypothyroidism CollaborativeEffects of neonatal screening for hypothyroidism: Prevention of mental retardation by treatment before clinical manifestations.Lancet. 1981; 2: 1095-1098PubMed Google Scholar and affected individuals show normal development2.Glorieux J Dussault J.H Letarte J Guyda H Morissette J Preliminary results on the mental development of hypothyroid infants detected by Quebec Screening Program.J Pediatr. 1983; 102: 913-915Abstract Full Text PDF Scopus (74) Google Scholar and achievements into adulthood.3.Oerbeck B Sundet K Kase B.F Heyerdahl S Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults.Pediatrics. 2003; 112: 923-930Crossref PubMed Scopus (136) Google Scholar Nevertheless, a number of prospective cohort studies conducted primarily on first-generation screened CH cases have revealed an average lowering of IQ by ∼6 points4.Derksen-Lubsen G Verkerk P.H Neuropsychologic development in early-treated congenital hypothyroidism: analysis of literature data.Pediatr Res. 1996; 39: 561-566Crossref PubMed Scopus (128) Google Scholar and risk of subtle neuropsychological and motor deficits.5.Rovet J Ehrlich R Sorbara D Neurodevelopment in infants and preschool children with congenital hypothyroidism. Etiological and treatment factors affecting outcome.J Pediatr Psychol. 1992; 17: 187-213Crossref PubMed Scopus (118) Google Scholar, 6.Rovet J Congenital hypothyroidsim. Persisting deficits and associated factors.Child Neuropsychol. 2003; 8: 150-162Crossref Scopus (70) Google Scholar, 7.Song S Daneman D Rovet J The influence of etiology and treatment factors on intellectual outcome in congenital hypothyroidism.J Develop Behav Pediatr. 2001; 22: 376-384Crossref PubMed Scopus (82) Google Scholar, 8.Kooistra L Laane C Vulsma T Schellekens J.M van der Meere J.J Kalverboer A.F Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.J Pediatr. 1994; 124: 903-909Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 9.Fuggle P.W Grant D.B Smith I Murphy G Intelligence, motor skills and behavior at 5 years in early-treated congenital hypothyroidism.Eur J Endocrinol. 1991; 150: 570-574Google Scholar Because these children typically were initiated into treatment with relatively low doses of replacement hormone (eg, 5-10 μg/kg/day L-T4), it was thought that their deficits directly reflected dosage inadequacy because this would prolong the postnatal period of thyroid hormone insufficiency.10.Van Vliet G Neonatal hypothyroidism: treatment and outcome.Thyroid. 1999; 9: 79-84Crossref PubMed Scopus (85) Google Scholar, 11.LaFranchi S Congenital hypothyroidism: etiologies, diagnosis, and management.Thyroid. 1999; 9: 735-740Crossref PubMed Scopus (204) Google ScholarAfter the observation that children with CH who were given higher starting doses of L-thyroxine (L-T4) attained faster normalization times than those given lower doses,12.Fisher D.A Foley T.P Early treatment of congenital hypothyroidism.J Pediatr. 1989; 117: 211-219Google Scholar the American Academy of Pediatrics13.American Academy of Pediatrics Section on Endocrinology and Committee on Genetics American Thyroid Association Committee on Public Health Newborn screening for congenital hypothyroidism: recommended guidelines.Pediatrics. 1993; 91: 1203-1209PubMed Google Scholar and the European Society for Paediatric Endocrinology14.Working group on congenital hypothyroidism of the European Society for Paediatric Endocrinology Guidelines for neonatal screening programmes for congenital hypothyroidism.Eur J Pediatr. 1993; 152: 974-975Crossref PubMed Scopus (51) Google Scholar put forth guidelines recommending that the starting dose of L-T4 be 10 to 15 μg/kg per day. Also recommended were frequent hormonal measurements and dosage adjustments whenever thyroid-stimulating hormone (TSH) deviated outside the normal range. Nevertheless, these recommendations were met with concern by some clinicians who feared the ramifications of iatrogenic hyperthyroidism and the possibility of both craniosynostosis and adverse neurobehavioral effects.15.Gunn A.J Wake M Cutfield W.S High and low dose initial thyroxine therapy for congenital hypothyroidism.J Paediatr Child Health. 1996; 32: 242-245Crossref PubMed Scopus (11) Google Scholar, 16.Hindmarsh P.C Optimisation of thyroxine dose in congenital hypothyroidism.Arch Dis Child. 2002; 86: 73-75Crossref PubMed Scopus (33) Google Scholar For example, several early follow-up studies reported untoward behavioral consequences such as increased temperamental difficulty and attention problems,17.Rovet J Ehrlich R Sorbara D Intellectual outcome in children with fetal hypothyroidism. Implications for neonatal diagnosis.J Pediatr. 1987; 110: 700-704Abstract Full Text PDF PubMed Scopus (152) Google Scholar, 18.Rovet J.F Neurobehavioral consequences of congenital hypothyroidism identified by newborn screening.in: Stabler B Bercu B.B Therapeutic outcome of endocrine disorders. Efficacy, innovation, and quality of life. Springer-Verlag, New York (NY)2000: 235-254Crossref Google Scholar even though the IQs were consistently higher and school performance better in the children receiving the larger starting dosages of L-T4.19.Rovet J.F Ehrlich R.M Long-term effects of L-thyroxine therapy for congenital hypothyroidism.J Pediatr. 1995; 126: 380-386Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 20.Connelly J.F Rickards A.L Coakley J.C Price G.J Francis I Mathur K.S et al.Newborn screening for congenital hypothyroidism, Victoria, Australia, 1977-1997. Part 2: treatment, progress, and outcome.J Pediatr Endocrinol Metab. 2001; 14: 1611-1634PubMed Google Scholar, 21.Salerno M Militerni R Bravaccio C Micillo M Capalbo D Di Maio S et al.Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism.Thyroid. 2002; 12: 45-52Crossref PubMed Scopus (93) Google Scholar, 22.Heyerdahl S Kase F.B Lie S.O Intellectual development in children with congenital hypothyroidism is relation to recommended thyroxine treatment.J Pediatr. 1991; 118: 850-857Abstract Full Text PDF PubMed Scopus (104) Google Scholar, 23.Hrytsiuk K Gilbert R Logan S Pindoria S Brook C.G Starting dose of levothyroxine for the treatment of congenital hypothyroidism: a systematic review.Arch Pediatr Adolesc Med. 2002; 156: 485-491Crossref PubMed Scopus (44) Google Scholar, 24.Léger J Larroque B Norton J Association Francaise pour le Depistage et al Prevention des Handicaps de l'Enfant Influence of severity of congenital hypothyroidism and adequacy of treatment on school achievement in young adolescents: a population-based cohort study.Acta Paediatr. 2001; 90: 1249-1256Crossref PubMed Scopus (73) Google ScholarMore recently, a number of studies have attempted to examine outcomes in children with CH stratified according to variables such as timing of treatment onset, etiology, and disease severity, as well as L-T4 dosage.25.Bongers-Schokking J.J Koot H.M Wiersma D Verkerk P.H de Muinck Keizer-Schrama S.M 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 (168) Google Scholar, 26.Dubuis J.M Gloriueux J Richer F Deal C.L Dussault J.H Van Vliet G Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose of levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (170) Google Scholar The findings typically indicate that a higher dose is beneficial in closing the IQ gap between moderate and more severe forms of the disease.26.Dubuis J.M Gloriueux J Richer F Deal C.L Dussault J.H Van Vliet G Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose of levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (170) Google Scholar The one randomized treatment study to date reported higher IQ levels in children assigned to the higher starting dose condition,21.Salerno M Militerni R Bravaccio C Micillo M Capalbo D Di Maio S et al.Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism.Thyroid. 2002; 12: 45-52Crossref PubMed Scopus (93) Google Scholar with the greatest benefit for those who were more severely affected initially. However, the safety of a higher starting dose level for children with mild forms of CH remains an issue, particularly in light of an increased incidence of hyperthyroxinemia in these patients15.Gunn A.J Wake M Cutfield W.S High and low dose initial thyroxine therapy for congenital hypothyroidism.J Paediatr Child Health. 1996; 32: 242-245Crossref PubMed Scopus (11) Google Scholar and the association in rodents between hyperthyroxinemia and adverse neurodevelopmental effects.27.Davenport J.W Gonzalez L.M Neonatal thyroxine stimulation in rats: accelerated behavioral maturation and subsequent learning deficit.J Comp Physiol. 1973; 54: 397-408Google Scholar, 28.Stone J.M Greenough W.T Excess neonatal thyroxine effects on learning in infant adolescent rats.Dev Psychobiol. 1975; 8: 469-488Crossref Scopus (24) Google ScholarThe paper by Simoneau-Roy et al29.Simoneau-Roy J Marti S Deal C Huot C Robaey P Van Vliet G Cognition and behavior at school entry in children with congenital hypothyroidism treated early with high-dose levothyroxine.J Pediatr. 2004; 144: 748-753Abstract Full Text Full Text PDF Scopus (77) Google Scholar in this issue of The Journal attempts to address these concerns by examining outcome in five-year-old children with severe and moderate CH who received a high starting dose of L-T4. In this study, 18 children with CH (9 severe, 9 moderate) were compared with 40 nonhypothyroid age-matched controls on two instruments: the McCarthy Scales of Children's Abilities,30.McCarthy D The McCarthy Scales of Children's Abilities. Psychological Corp, New York1972Google Scholar an appropriate and sensitive instrument of cognitive and motor development for this age range; and the Questionnaire for the Evaluation of Social Behavior by Rutter31.Rutter M.A A children's behaviour questionnaire for completion by teachers: preliminary findings.J Child Psychol Psychiatry. 1967; 8: 1-11Crossref PubMed Scopus (1034) Google Scholar and adapted for North American use by Behar and Stringfield.32.Behar L Stringfield S A behavior rating scale for the preschool child.Dev Psychol. 1974; 10: 601-610Crossref Scopus (463) Google Scholar As expected, children with severe hypothyroidism showed substantial benefits from a high starting dose of L-T4 and did not differ in global intelligence from controls or the moderate severity group. However, controls did score higher than CH on indices of verbal IQ and memory. The median global IQs were reported as 102 for severe CH, 102 for moderate CH, and 115 for control and their mean IQs were 109, 103, and 115 respectively. A nonparametric test revealed that these scores were not significantly different. Furthermore, children with moderate CH severity did not show any adverse effects on the behavioral scales. However, correlations were observed between indices of overtreatment, but not undertreatment, and degree of anxiety and inattention.At first glance, this study is reassuring in showing that a high starting dose is both efficacious and safe. Nevertheless, close scrutiny reveals several limitations. The study is underpowered with only 9 children in each CH group. Indeed, a power analysis based on the mean scores listed previously indicates that by increasing the sample sizes to 100 and 26 for the severe and moderate groups, a significant difference from controls could be achieved. Moreover, the two CH severity groups would also differ significantly from each other, with the severe group doing better, if there were 100 children in each group. With regard to the behavioral data, the severe CH group would be significantly more anxious and inattentive than controls and the moderate CH group would have more social problems, with 26 and 12 subjects respectively.In this study, severity was evaluated by one variable—the size of the distal femoral epiphysis. Etiology or initial hormone levels were not used, as is common in the research literature.33.Tillotson S.L Fuggle P.W Smith I Ades A.E Grant D.B Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.BMJ. 1994; 309: 440-445Crossref PubMed Scopus (165) Google Scholar, 34.Hanukoglu A Perlman K Shamis I Brnjac L Rovet J Daneman D Relationship of etiology to treatment in congenital hypothyroidism.J Clin Endocrinol Metab. 2001; 86: 186-191Crossref PubMed Scopus (76) Google Scholar It should be noted that considerable overlap was observed between the two CH severity groups in terms of etiology and thyroxine and TSH levels at diagnosis. In addition, there was only one child with athyrosis (5.5% of the sample), which is generally considered as the most severe category of CH and has been reported in 25% to 33% of cases in other samples. Thus, the current sample may not be appropriately representative of children with CH.The authors are aware of the limitations of their study and suggest the need for a larger controlled study. Current findings are in line with the extant literature, which supports treating children with severe CH (diagnosed on the basis of etiology or initial thyroid levels) with a dose of 10 to 15 μg/kg per day of L-T4 and shows that a higher dose level does yield IQ levels and growth parameters at par with controls without any apparent harm. However, the evidence is less clear for the moderate severity group, whose behavior and intelligence should be studied via a randomized controlled trial. Given current findings of reduced IQ, weak memory, and social problems in the moderate severity group treated with a high starting dose, the challenge will be to identify a dose that provides the best outcome with no adverse effects on behavior. As such, it may be necessary to tailor treatment approaches to specific etiologies or severity of hypothyroidism with children with only the more severe forms receiving the higher dosage.It should be recognized that despite optimized treatment regimens, some children with CH will still have subtle, persisting cognitive deficits. These deficits most likely reflect their thyroid hormone insufficiency in utero as well as in the first month or so of life until treatment takes effect.35.Rovet J Daneman D Congenital hypothyroidism. A review of current diagnostic and treatment practices in relation to neuropsychologic outcome.Pediatr Drugs. 2003; 5: 141-149Crossref PubMed Scopus (91) Google Scholar Although the mother provides a supplemental source of thyroid hormone during pregnancy, this does not appear to fulfill all fetal needs in the latter part of gestation.36.Vulsma T Gons M.H de Vijlder J.J Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis.N Engl J Med. 1989; 321: 13-16Crossref PubMed Scopus (599) Google Scholar Particularly vulnerable to prenatal thyroid hormone insufficiency will be those abilities supported by brain regions that need thyroid hormone at this time.37.Morreale de Escobar G Obregon M.J Escobar del Rey F Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia?.J Clin Endocrinol Metab. 2000; 85: 3975-3987Crossref PubMed Scopus (555) Google Scholar To assess for these effects, one may need to examine basic or core cognitive processes, which are not strictly measured by intelligence tests. It should also be noted that while some critical abilities (such as attention) are assessed by intelligence tests, these are not a standard component of the global intelligence quotient or IQ score.In addition, although the index used currently of initial disease severity, namely femoral epiphysis size, represents a sensitive measure,38.Glorieux J Desjardins M Letarte J Morissette J Dussault J.H Useful parameters to predict the eventual mental outcome of hypothyroid children.Pediatr Res. 1988; 24: 6-8Crossref PubMed Scopus (80) Google Scholar consensus is needed as to what best determines severe disease at diagnosis. Etiology and hormonal thresholds, which are used by most other groups, are not without problems because some children can be misdiagnosed using technetium scans and there is variable severity in the dyshormonogenesis group, depending on whether there is a total organification defect or not. Although the ectopic condition is generally considered the least severe, children in this group vary in how well their thyroid remnants function at birth. Furthermore, while the maternal thyroid hormone contribution through the placenta is thought to be protective, the benefits may be decreasing given declining iodine levels in the US population.39.Hollowell J.G Staeling N.W Hannon W.H Flanders D.W Gunter E.W Maberly G.F et al.Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994).J Clin Endocrinol Metab. 1998; 83: 3398-3400PubMed Google Scholar Other factors also need to be considered such as (1) when a particular IQ test was standardized in relation to when a study is conducted given secular rises in population IQ, (2) the actual age at which the child is tested and the types of skills measured by different tests at different ages, and (3) socioeconomic, family background, and cultural status of the sample.40.Flynn J.R Massive IQ gains in 14 nations: what IQ tests really measure.Psychol Bull. 1987; 101: 171-191Crossref Scopus (1268) Google Scholar For example, Dubuis et al26.Dubuis J.M Gloriueux J Richer F Deal C.L Dussault J.H Van Vliet G Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose of levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (170) Google Scholar provide the results of the current sample at 18 months of age and report IQ levels of 106 and 110 in severe and moderate groups on the Griffiths test, which was developed in the 1950s. Assuming a 0.3-point rise in IQ yearly from time of test standardization, a phenomenon, known as the Flynn effect,41.Chiovato L Bargagna S Invited commentary: congenital hypothyroidism: treat children but don't forget their parents.Eur J Endocrinol. 1999; 14: 101-104Crossref Scopus (9) Google Scholar the results of a high starting dose might actually be less favorable than originally thought.A further concern involves subsequent therapy beyond initial treatment and its role in later outcome.42.Heyerdahl S Long-term outcome in children with congenital hypothyroidism.Acta Paediatr. 2001; 90: 1220-1222Crossref PubMed Google Scholar For example, Hanokoglu et al34.Hanukoglu A Perlman K Shamis I Brnjac L Rovet J Daneman D Relationship of etiology to treatment in congenital hypothyroidism.J Clin Endocrinol Metab. 2001; 86: 186-191Crossref PubMed Scopus (76) Google Scholar reported that while children with athyrosis needed more frequent monitoring and more frequent dose adjustments initially, there were specific time points later in infancy or early childhood when children with the other etiologies also needed special attention. In our experience, some children with CH who are not followed in a specialty setting may have inadequate treatment, with some being overtreated and others never receiving a dose change throughout childhood.35.Rovet J Daneman D Congenital hypothyroidism. A review of current diagnostic and treatment practices in relation to neuropsychologic outcome.Pediatr Drugs. 2003; 5: 141-149Crossref PubMed Scopus (91) Google Scholar This, therefore, speaks to the need for continued follow-up of children with CH by pediatric endocrinologists. In the event that this is not possible, better education of primary care pediatricians and family physicians of these issues is needed. Certainly papers such as the one by Simoneau-Roy et al29.Simoneau-Roy J Marti S Deal C Huot C Robaey P Van Vliet G Cognition and behavior at school entry in children with congenital hypothyroidism treated early with high-dose levothyroxine.J Pediatr. 2004; 144: 748-753Abstract Full Text Full Text PDF Scopus (77) Google Scholar will help bring these concerns to the fore.In conclusion, the jury is still out on what constitutes the optimal therapy for all children with CH. Certainly, a higher dose is efficacious for children with more severe hypothyroidism at diagnosis but it is not clear yet whether this is totally safe and effective for those with more moderate forms of the disease. The study by Simoneau-Roy et al29.Simoneau-Roy J Marti S Deal C Huot C Robaey P Van Vliet G Cognition and behavior at school entry in children with congenital hypothyroidism treated early with high-dose levothyroxine.J Pediatr. 2004; 144: 748-753Abstract Full Text Full Text PDF Scopus (77) Google Scholar adds to our knowledge on optimizing that starting dose and attests to the need for further research, particularly a large-scale multicenter trial that controls for and measures all the factors discussed above. Future studies also need to evaluate a broad array of cognitive and behavioral indices including those that are directly relevant for school performance. New approaches such as neuroimaging techniques might also be considered. Until such time, however, a differential treatment approach that individualizes therapies by severity of hypothyroidism at diagnosis might be considered.I thank Denis Daneman for his helpful comments on an early draft of this editorial. Neonatal thyroid screening programs were first implemented in the mid- to late 1970s to detect congenital hypothyroidism (CH) as soon after birth as possible and begin therapy before the appearance of clinical symptoms. It was believed that this early diagnosis and treatment would prevent the progressive brain damage typically seen in late-treated cretinism. There is no doubt that newborn CH screening has succeeded. Mental retardation has been eradicated,1.New England Congenital Hypothyroidism CollaborativeEffects of neonatal screening for hypothyroidism: Prevention of mental retardation by treatment before clinical manifestations.Lancet. 1981; 2: 1095-1098PubMed Google Scholar and affected individuals show normal development2.Glorieux J Dussault J.H Letarte J Guyda H Morissette J Preliminary results on the mental development of hypothyroid infants detected by Quebec Screening Program.J Pediatr. 1983; 102: 913-915Abstract Full Text PDF Scopus (74) Google Scholar and achievements into adulthood.3.Oerbeck B Sundet K Kase B.F Heyerdahl S Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults.Pediatrics. 2003; 112: 923-930Crossref PubMed Scopus (136) Google Scholar Nevertheless, a number of prospective cohort studies conducted primarily on first-generation screened CH cases have revealed an average lowering of IQ by ∼6 points4.Derksen-Lubsen G Verkerk P.H Neuropsychologic development in early-treated congenital hypothyroidism: analysis of literature data.Pediatr Res. 1996; 39: 561-566Crossref PubMed Scopus (128) Google Scholar and risk of subtle neuropsychological and motor deficits.5.Rovet J Ehrlich R Sorbara D Neurodevelopment in infants and preschool children with congenital hypothyroidism. Etiological and treatment factors affecting outcome.J Pediatr Psychol. 1992; 17: 187-213Crossref PubMed Scopus (118) Google Scholar, 6.Rovet J Congenital hypothyroidsim. Persisting deficits and associated factors.Child Neuropsychol. 2003; 8: 150-162Crossref Scopus (70) Google Scholar, 7.Song S Daneman D Rovet J The influence of etiology and treatment factors on intellectual outcome in congenital hypothyroidism.J Develop Behav Pediatr. 2001; 22: 376-384Crossref PubMed Scopus (82) Google Scholar, 8.Kooistra L Laane C Vulsma T Schellekens J.M van der Meere J.J Kalverboer A.F Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.J Pediatr. 1994; 124: 903-909Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 9.Fuggle P.W Grant D.B Smith I Murphy G Intelligence, motor skills and behavior at 5 years in early-treated congenital hypothyroidism.Eur J Endocrinol. 1991; 150: 570-574Google Scholar Because these children typically were initiated into treatment with relatively low doses of replacement hormone (eg, 5-10 μg/kg/day L-T4), it was thought that their deficits directly reflected dosage inadequacy because this would prolong the postnatal period of thyroid hormone insufficiency.10.Van Vliet G Neonatal hypothyroidism: treatment and outcome.Thyroid. 1999; 9: 79-84Crossref PubMed Scopus (85) Google Scholar, 11.LaFranchi S Congenital hypothyroidism: etiologies, diagnosis, and management.Thyroid. 1999; 9: 735-740Crossref PubMed Scopus (204) Google Scholar After the observation that children with CH who were given higher starting doses of L-thyroxine (L-T4) attained faster normalization times than those given lower doses,12.Fisher D.A Foley T.P Early treatment of congenital hypothyroidism.J Pediatr. 1989; 117: 211-219Google Scholar the American Academy of Pediatrics13.American Academy of Pediatrics Section on Endocrinology and Committee on Genetics American Thyroid Association Committee on Public Health Newborn screening for congenital hypothyroidism: recommended guidelines.Pediatrics. 1993; 91: 1203-1209PubMed Google Scholar and the European Society for Paediatric Endocrinology14.Working group on congenital hypothyroidism of the European Society for Paediatric Endocrinology Guidelines for neonatal screening programmes for congenital hypothyroidism.Eur J Pediatr. 1993; 152: 974-975Crossref PubMed Scopus (51) Google Scholar put forth guidelines recommending that the starting dose of L-T4 be 10 to 15 μg/kg per day. Also recommended were frequent hormonal measurements and dosage adjustments whenever thyroid-stimulating hormone (TSH) deviated outside the normal range. Nevertheless, these recommendations were met with concern by some clinicians who feared the ramifications of iatrogenic hyperthyroidism and the possibility of both craniosynostosis and adverse neurobehavioral effects.15.Gunn A.J Wake M Cutfield W.S High and low dose initial thyroxine therapy for congenital hypothyroidism.J Paediatr Child Health. 1996; 32: 242-245Crossref PubMed Scopus (11) Google Scholar, 16.Hindmarsh P.C Optimisation of thyroxine dose in congenital hypothyroidism.Arch Dis Child. 2002; 86: 73-75Crossref PubMed Scopus (33) Google Scholar For example, several early follow-up studies reported untoward behavioral consequences such as increased temperamental difficulty and attention problems,17.Rovet J Ehrlich R Sorbara D Intellectual outcome in children with fetal hypothyroidism. Implications for neonatal diagnosis.J Pediatr. 1987; 110: 700-704Abstract Full Text PDF PubMed Scopus (152) Google Scholar, 18.Rovet J.F Neurobehavioral consequences of congenital hypothyroidism identified by newborn screening.in: Stabler B Bercu B.B Therapeutic outcome of endocrine disorders. Efficacy, innovation, and quality of life. Springer-Verlag, New York (NY)2000: 235-254Crossref Google Scholar even though the IQs were consistently higher and school performance better in the children receiving the larger starting dosages of L-T4.19.Rovet J.F Ehrlich R.M Long-term effects of L-thyroxine therapy for congenital hypothyroidism.J Pediatr. 1995; 126: 380-386Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 20.Connelly J.F Rickards A.L Coakley J.C Price G.J Francis I Mathur K.S et al.Newborn screening for congenital hypothyroidism, Victoria, Australia, 1977-1997. Part 2: treatment, progress, and outcome.J Pediatr Endocrinol Metab. 2001; 14: 1611-1634PubMed Google Scholar, 21.Salerno M Militerni R Bravaccio C Micillo M Capalbo D Di Maio S et al.Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism.Thyroid. 2002; 12: 45-52Crossref PubMed Scopus (93) Google Scholar, 22.Heyerdahl S Kase F.B Lie S.O Intellectual development in children with congenital hypothyroidism is relation to recommended thyroxine treatment.J Pediatr. 1991; 118: 850-857Abstract Full Text PDF PubMed Scopus (104) Google Scholar, 23.Hrytsiuk K Gilbert R Logan S Pindoria S Brook C.G Starting dose of levothyroxine for the treatment of congenital hypothyroidism: a systematic review.Arch Pediatr Adolesc Med. 2002; 156: 485-491Crossref PubMed Scopus (44) Google Scholar, 24.Léger J Larroque B Norton J Association Francaise pour le Depistage et al Prevention des Handicaps de l'Enfant Influence of severity of congenital hypothyroidism and adequacy of treatment on school achievement in young adolescents: a population-based cohort study.Acta Paediatr. 2001; 90: 1249-1256Crossref PubMed Scopus (73) Google Scholar More recently, a number of studies have attempted to examine outcomes in children with CH stratified according to variables such as timing of treatment onset, etiology, and disease severity, as well as L-T4 dosage.25.Bongers-Schokking J.J Koot H.M Wiersma D Verkerk P.H de Muinck Keizer-Schrama S.M 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 (168) Google Scholar, 26.Dubuis J.M Gloriueux J Richer F Deal C.L Dussault J.H Van Vliet G Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose of levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (170) Google Scholar The findings typically indicate that a higher dose is beneficial in closing the IQ gap between moderate and more severe forms of the disease.26.Dubuis J.M Gloriueux J Richer F Deal C.L Dussault J.H Van Vliet G Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose of levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (170) Google Scholar The one randomized treatment study to date reported higher IQ levels in children assigned to the higher starting dose condition,21.Salerno M Militerni R Bravaccio C Micillo M Capalbo D Di Maio S et al.Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism.Thyroid. 2002; 12: 45-52Crossref PubMed Scopus (93) Google Scholar with the greatest benefit for those who were more severely affected initially. However, the safety of a higher starting dose level for children with mild forms of CH remains an issue, particularly in light of an increased incidence of hyperthyroxinemia in these patients15.Gunn A.J Wake M Cutfield W.S High and low dose initial thyroxine therapy for congenital hypothyroidism.J Paediatr Child Health. 1996; 32: 242-245Crossref PubMed Scopus (11) Google Scholar and the association in rodents between hyperthyroxinemia and adverse neurodevelopmental effects.27.Davenport J.W Gonzalez L.M Neonatal thyroxine stimulation in rats: accelerated behavioral maturation and subsequent learning deficit.J Comp Physiol. 1973; 54: 397-408Google Scholar, 28.Stone J.M Greenough W.T Excess neonatal thyroxine effects on learning in infant adolescent rats.Dev Psychobiol. 1975; 8: 469-488Crossref Scopus (24) Google Scholar The paper by Simoneau-Roy et al29.Simoneau-Roy J Marti S Deal C Huot C Robaey P Van Vliet G Cognition and behavior at school entry in children with congenital hypothyroidism treated early with high-dose levothyroxine.J Pediatr. 2004; 144: 748-753Abstract Full Text Full Text PDF Scopus (77) Google Scholar in this issue of The Journal attempts to address these concerns by examining outcome in five-year-old children with severe and moderate CH who received a high starting dose of L-T4. In this study, 18 children with CH (9 severe, 9 moderate) were compared with 40 nonhypothyroid age-matched controls on two instruments: the McCarthy Scales of Children's Abilities,30.McCarthy D The McCarthy Scales of Children's Abilities. Psychological Corp, New York1972Google Scholar an appropriate and sensitive instrument of cognitive and motor development for this age range; and the Questionnaire for the Evaluation of Social Behavior by Rutter31.Rutter M.A A children's behaviour questionnaire for completion by teachers: preliminary findings.J Child Psychol Psychiatry. 1967; 8: 1-11Crossref PubMed Scopus (1034) Google Scholar and adapted for North American use by Behar and Stringfield.32.Behar L Stringfield S A behavior rating scale for the preschool child.Dev Psychol. 1974; 10: 601-610Crossref Scopus (463) Google Scholar As expected, children with severe hypothyroidism showed substantial benefits from a high starting dose of L-T4 and did not differ in global intelligence from controls or the moderate severity group. However, controls did score higher than CH on indices of verbal IQ and memory. The median global IQs were reported as 102 for severe CH, 102 for moderate CH, and 115 for control and their mean IQs were 109, 103, and 115 respectively. A nonparametric test revealed that these scores were not significantly different. Furthermore, children with moderate CH severity did not show any adverse effects on the behavioral scales. However, correlations were observed between indices of overtreatment, but not undertreatment, and degree of anxiety and inattention. At first glance, this study is reassuring in showing that a high starting dose is both efficacious and safe. Nevertheless, close scrutiny reveals several limitations. The study is underpowered with only 9 children in each CH group. Indeed, a power analysis based on the mean scores listed previously indicates that by increasing the sample sizes to 100 and 26 for the severe and moderate groups, a significant difference from controls could be achieved. Moreover, the two CH severity groups would also differ significantly from each other, with the severe group doing better, if there were 100 children in each group. With regard to the behavioral data, the severe CH group would be significantly more anxious and inattentive than controls and the moderate CH group would have more social problems, with 26 and 12 subjects respectively. In this study, severity was evaluated by one variable—the size of the distal femoral epiphysis. Etiology or initial hormone levels were not used, as is common in the research literature.33.Tillotson S.L Fuggle P.W Smith I Ades A.E Grant D.B Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.BMJ. 1994; 309: 440-445Crossref PubMed Scopus (165) Google Scholar, 34.Hanukoglu A Perlman K Shamis I Brnjac L Rovet J Daneman D Relationship of etiology to treatment in congenital hypothyroidism.J Clin Endocrinol Metab. 2001; 86: 186-191Crossref PubMed Scopus (76) Google Scholar It should be noted that considerable overlap was observed between the two CH severity groups in terms of etiology and thyroxine and TSH levels at diagnosis. In addition, there was only one child with athyrosis (5.5% of the sample), which is generally considered as the most severe category of CH and has been reported in 25% to 33% of cases in other samples. Thus, the current sample may not be appropriately representative of children with CH. The authors are aware of the limitations of their study and suggest the need for a larger controlled study. Current findings are in line with the extant literature, which supports treating children with severe CH (diagnosed on the basis of etiology or initial thyroid levels) with a dose of 10 to 15 μg/kg per day of L-T4 and shows that a higher dose level does yield IQ levels and growth parameters at par with controls without any apparent harm. However, the evidence is less clear for the moderate severity group, whose behavior and intelligence should be studied via a randomized controlled trial. Given current findings of reduced IQ, weak memory, and social problems in the moderate severity group treated with a high starting dose, the challenge will be to identify a dose that provides the best outcome with no adverse effects on behavior. As such, it may be necessary to tailor treatment approaches to specific etiologies or severity of hypothyroidism with children with only the more severe forms receiving the higher dosage. It should be recognized that despite optimized treatment regimens, some children with CH will still have subtle, persisting cognitive deficits. These deficits most likely reflect their thyroid hormone insufficiency in utero as well as in the first month or so of life until treatment takes effect.35.Rovet J Daneman D Congenital hypothyroidism. A review of current diagnostic and treatment practices in relation to neuropsychologic outcome.Pediatr Drugs. 2003; 5: 141-149Crossref PubMed Scopus (91) Google Scholar Although the mother provides a supplemental source of thyroid hormone during pregnancy, this does not appear to fulfill all fetal needs in the latter part of gestation.36.Vulsma T Gons M.H de Vijlder J.J Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis.N Engl J Med. 1989; 321: 13-16Crossref PubMed Scopus (599) Google Scholar Particularly vulnerable to prenatal thyroid hormone insufficiency will be those abilities supported by brain regions that need thyroid hormone at this time.37.Morreale de Escobar G Obregon M.J Escobar del Rey F Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia?.J Clin Endocrinol Metab. 2000; 85: 3975-3987Crossref PubMed Scopus (555) Google Scholar To assess for these effects, one may need to examine basic or core cognitive processes, which are not strictly measured by intelligence tests. It should also be noted that while some critical abilities (such as attention) are assessed by intelligence tests, these are not a standard component of the global intelligence quotient or IQ score. In addition, although the index used currently of initial disease severity, namely femoral epiphysis size, represents a sensitive measure,38.Glorieux J Desjardins M Letarte J Morissette J Dussault J.H Useful parameters to predict the eventual mental outcome of hypothyroid children.Pediatr Res. 1988; 24: 6-8Crossref PubMed Scopus (80) Google Scholar consensus is needed as to what best determines severe disease at diagnosis. Etiology and hormonal thresholds, which are used by most other groups, are not without problems because some children can be misdiagnosed using technetium scans and there is variable severity in the dyshormonogenesis group, depending on whether there is a total organification defect or not. Although the ectopic condition is generally considered the least severe, children in this group vary in how well their thyroid remnants function at birth. Furthermore, while the maternal thyroid hormone contribution through the placenta is thought to be protective, the benefits may be decreasing given declining iodine levels in the US population.39.Hollowell J.G Staeling N.W Hannon W.H Flanders D.W Gunter E.W Maberly G.F et al.Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994).J Clin Endocrinol Metab. 1998; 83: 3398-3400PubMed Google Scholar Other factors also need to be considered such as (1) when a particular IQ test was standardized in relation to when a study is conducted given secular rises in population IQ, (2) the actual age at which the child is tested and the types of skills measured by different tests at different ages, and (3) socioeconomic, family background, and cultural status of the sample.40.Flynn J.R Massive IQ gains in 14 nations: what IQ tests really measure.Psychol Bull. 1987; 101: 171-191Crossref Scopus (1268) Google Scholar For example, Dubuis et al26.Dubuis J.M Gloriueux J Richer F Deal C.L Dussault J.H Van Vliet G Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose of levothyroxine treatment.J Clin Endocrinol Metab. 1996; 81: 222-227Crossref PubMed Scopus (170) Google Scholar provide the results of the current sample at 18 months of age and report IQ levels of 106 and 110 in severe and moderate groups on the Griffiths test, which was developed in the 1950s. Assuming a 0.3-point rise in IQ yearly from time of test standardization, a phenomenon, known as the Flynn effect,41.Chiovato L Bargagna S Invited commentary: congenital hypothyroidism: treat children but don't forget their parents.Eur J Endocrinol. 1999; 14: 101-104Crossref Scopus (9) Google Scholar the results of a high starting dose might actually be less favorable than originally thought. A further concern involves subsequent therapy beyond initial treatment and its role in later outcome.42.Heyerdahl S Long-term outcome in children with congenital hypothyroidism.Acta Paediatr. 2001; 90: 1220-1222Crossref PubMed Google Scholar For example, Hanokoglu et al34.Hanukoglu A Perlman K Shamis I Brnjac L Rovet J Daneman D Relationship of etiology to treatment in congenital hypothyroidism.J Clin Endocrinol Metab. 2001; 86: 186-191Crossref PubMed Scopus (76) Google Scholar reported that while children with athyrosis needed more frequent monitoring and more frequent dose adjustments initially, there were specific time points later in infancy or early childhood when children with the other etiologies also needed special attention. In our experience, some children with CH who are not followed in a specialty setting may have inadequate treatment, with some being overtreated and others never receiving a dose change throughout childhood.35.Rovet J Daneman D Congenital hypothyroidism. A review of current diagnostic and treatment practices in relation to neuropsychologic outcome.Pediatr Drugs. 2003; 5: 141-149Crossref PubMed Scopus (91) Google Scholar This, therefore, speaks to the need for continued follow-up of children with CH by pediatric endocrinologists. In the event that this is not possible, better education of primary care pediatricians and family physicians of these issues is needed. Certainly papers such as the one by Simoneau-Roy et al29.Simoneau-Roy J Marti S Deal C Huot C Robaey P Van Vliet G Cognition and behavior at school entry in children with congenital hypothyroidism treated early with high-dose levothyroxine.J Pediatr. 2004; 144: 748-753Abstract Full Text Full Text PDF Scopus (77) Google Scholar will help bring these concerns to the fore. In conclusion, the jury is still out on what constitutes the optimal therapy for all children with CH. Certainly, a higher dose is efficacious for children with more severe hypothyroidism at diagnosis but it is not clear yet whether this is totally safe and effective for those with more moderate forms of the disease. The study by Simoneau-Roy et al29.Simoneau-Roy J Marti S Deal C Huot C Robaey P Van Vliet G Cognition and behavior at school entry in children with congenital hypothyroidism treated early with high-dose levothyroxine.J Pediatr. 2004; 144: 748-753Abstract Full Text Full Text PDF Scopus (77) Google Scholar adds to our knowledge on optimizing that starting dose and attests to the need for further research, particularly a large-scale multicenter trial that controls for and measures all the factors discussed above. Future studies also need to evaluate a broad array of cognitive and behavioral indices including those that are directly relevant for school performance. New approaches such as neuroimaging techniques might also be considered. Until such time, however, a differential treatment approach that individualizes therapies by severity of hypothyroidism at diagnosis might be considered. I thank Denis Daneman for his helpful comments on an early draft of this editorial.