Treatment and prognosis of congenital hypothyroidism
- Stephen LaFranchi, MD
Stephen LaFranchi, MD
- Professor of Pediatrics
- Oregon Health & Sciences University
- Section Editors
- Douglas S Ross, MD
Douglas S Ross, MD
- Section Editor — Thyroid Disease
- Professor of Medicine
- Harvard Medical School
- Mitchell E Geffner, MD
Mitchell E Geffner, MD
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Keck School of Medicine, University of Southern California
Congenital hypothyroidism is one of the most common treatable causes of intellectual disability (mental retardation). Screening programs have been established in most developed countries to detect and treat this disorder, which affects approximately 1 in 2000 to 1 in 4000 newborns [1,2]. (See "Clinical features and detection of congenital hypothyroidism".)
Delays in diagnosis and treatment of congenital hypothyroidism will result in impaired neurocognitive outcome (as measured by intelligence quotient [IQ]). Even after diagnosis, IQ and neurologic development may suffer if the infant has hypothyroidism during the first two to three years of life, a time of critical brain dependence on thyroid hormone. Hypothyroidism in such infants may result from inadequate treatment during the first two to three years of life, as might occur with poor adherence to daily administration of medication or lack of appropriate monitoring and thyroid hormone dose adjustments. Thus, appropriate initial therapy and follow-up are essential .
The overall goals of treatment are to assure normal growth and development and psychometric outcome similar to genetic potential, by restoring the serum T4 concentration rapidly to the normal range followed by continued clinical and biochemical euthyroidism.
Oral levothyroxine (L-T4) is the treatment of choice. Although triiodothyronine (T3) is the biologically active hormone, the majority of brain T3 is derived from local deiodination of T4; thus, it is not necessary to use T3. To correct hypothyroxinemia as rapidly as possible, treatment should be initiated in an infant with a clearly positive screening test as soon as confirmatory blood samples have been drawn, pending results. In cases in which screening tests are borderline, a treatment decision can be made after results of the confirmatory tests return . (See "Clinical features and detection of congenital hypothyroidism", section on 'Newborn screening'.)
Dose of L-T4 — Both the timing and dose of thyroid hormone replacement are important [5-7]. The American Academy of Pediatrics (AAP), the European Society for Paediatric Endocrinology (ESPE), and the American Thyroid Association (ATA) recommend a starting L-T4 dose of 10 to 15 mcg/kg/day [4,8,9]. Considering that the lowest dose levothyroxine tablets are 25 or 50 mcg, this usually amounts to 37.5 or 50 mcg/day in full-size term infants . In preterm and other low-birth weight infants, we also recommend using 10 to 15 mcg/kg per day, though in milder cases, often characterized by delayed TSH elevation, a starting dose of 8 to 12 mcg/kg per day is sufficient to normalize thyroid function. (See "Thyroid physiology and screening in preterm infants".)
- Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis 2010; 5:17.
- Grüters A, Krude H. Detection and treatment of congenital hypothyroidism. Nat Rev Endocrinol 2011; 8:104.
- LaFranchi SH. Approach to the diagnosis and treatment of neonatal hypothyroidism. J Clin Endocrinol Metab 2011; 96:2959.
- American Academy of Pediatrics, Rose SR, Section on Endocrinology and Committee on Genetics, American Thyroid Association, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117:2290.
- Selva KA, Harper A, Downs A, et al. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr 2005; 147:775.
- LaFranchi SH, Austin J. How should we be treating children with congenital hypothyroidism? J Pediatr Endocrinol Metab 2007; 20:559.
- Germak JA, Foley TP Jr. Longitudinal assessment of L-thyroxine therapy for congenital hypothyroidism. J Pediatr 1990; 117:211.
- Léger J, Olivieri A, Donaldson M, et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab 2014; 99:363.
- Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid 2014; 24:1670.
- Bongers-Schokking JJ, Koot HM, Wiersma D, et al. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000; 136:292.
- Bongers-Schokking JJ, de Muinck Keizer-Schrama SM. Influence of timing and dose of thyroid hormone replacement on mental, psychomotor, and behavioral development in children with congenital hypothyroidism. J Pediatr 2005; 147:768.
- Mathai S, Cutfield WS, Gunn AJ, et al. A novel therapeutic paradigm to treat congenital hypothyroidism. Clin Endocrinol (Oxf) 2008; 69:142.
- Jabbar MA, Larrea J, Shaw RA. Abnormal thyroid function tests in infants with congenital hypothyroidism: the influence of soy-based formula. J Am Coll Nutr 1997; 16:280.
- Balapatabendi M, Harris D, Shenoy SD. Drug interaction of levothyroxine with infant colic drops. Arch Dis Child 2011; 96:888.
- Zeitler P, Solberg P, Pharmacy and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Food and levothyroxine administration in infants and children. J Pediatr 2010; 157:13.
- Chorazy PA, Himelhoch S, Hopwood NJ, et al. Persistent hypothyroidism in an infant receiving a soy formula: case report and review of the literature. Pediatrics 1995; 96:148.
- Conrad SC, Chiu H, Silverman BL. Soy formula complicates management of congenital hypothyroidism. Arch Dis Child 2004; 89:37.
- Characteristics of infantile hypothyroidism discovered on neonatal screening. J Pediatr 1984; 104:539.
- Heyerdahl S, Kase BF, Lie SO. Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment. J Pediatr 1991; 118:850.
- Weichsel ME Jr. Thyroid hormone replacement therapy in the perinatal period: neurologic considerations. J Pediatr 1978; 92:1035.
- Bongers-Schokking JJ, Resing WC, de Rijke YB, et al. Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment? J Clin Endocrinol Metab 2013; 98:4499.
- Rovet JF, Ehrlich RM, Sorbara DL. Effect of thyroid hormone level on temperament in infants with congenital hypothyroidism detected by screening of neonates. J Pediatr 1989; 114:63.
- Rovet J, Alvarez M. Thyroid hormone and attention in congenital hypothyroidism. J Pediatr Endocrinol Metab 1996; 9:63.
- Fisher DA, Foley BL. Early treatment of congenital hypothyroidism. Pediatrics 1989; 83:785.
- Balhara B, Misra M, Levitsky LL. Clinical monitoring guidelines for congenital hypothyroidism: laboratory outcome data in the first year of life. J Pediatr 2011; 158:532.
- Zdraveska N, Anastasovska V, Kocova M. Frequency of thyroid status monitoring in the first year of life and predictors for more frequent monitoring in infants with congenital hypothyroidism. J Pediatr Endocrinol Metab 2016; 29:795.
- Eldar D, Kaiserman I, Sack J. Early identification of congenital hypothyroid infants with abnormalities in pituitary setpoint for T4-induced TSH release. Horm Res 1993; 40:194.
- Kempers MJ, van Trotsenburg AS, van Tijn DA, et al. Disturbance of the fetal thyroid hormone state has long-term consequences for treatment of thyroidal and central congenital hypothyroidism. J Clin Endocrinol Metab 2005; 90:4094.
- Fisher DA, Schoen EJ, La Franchi S, et al. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab 2000; 85:2722.
- Akcay T, Turan S, Guran T, et al. T4 plus T3 treatment in children with hypothyroidism and inappropriately elevated thyroid-stimulating hormone despite euthyroidism on T4 treatment. Horm Res Paediatr 2010; 73:108.
- Paone L, Fleisch AF, Feldman HA, et al. Liothyronine Improves Biochemical Control of Congenital Hypothyroidism in Patients with Central Resistance to Thyroid Hormone. J Pediatr 2016; 175:167.
- Carswell JM, Gordon JH, Popovsky E, et al. Generic and brand-name L-thyroxine are not bioequivalent for children with severe congenital hypothyroidism. J Clin Endocrinol Metab 2013; 98:610.
- Lomenick JP, Wang L, Ampah SB, et al. Generic levothyroxine compared with synthroid in young children with congenital hypothyroidism. J Clin Endocrinol Metab 2013; 98:653.
- Kemper AR, Ouyang L, Grosse SD. Discontinuation of thyroid hormone treatment among children in the United States with congenital hypothyroidism: findings from health insurance claims data. BMC Pediatr 2010; 10:9.
- Delange F, Dalhem A, Bourdoux P, et al. Increased risk of primary hypothyroidism in preterm infants. J Pediatr 1984; 105:462.
- Pacaud D, Huot C, Gattereau A, et al. Outcome in three siblings with antibody-mediated transient congenital hypothyroidism. J Pediatr 1995; 127:275.
- Eugster EA, LeMay D, Zerin JM, Pescovitz OH. Definitive diagnosis in children with congenital hypothyroidism. J Pediatr 2004; 144:643.
- Messina MF, Aversa T, Salzano G, et al. Early Discrimination between Transient and Permanent Congenital Hypothyroidism in Children with Eutopic Gland. Horm Res Paediatr 2015; 84:159.
- Tiosano D, Even L, Shen Orr Z, Hochberg Z. Recombinant thyrotropin in the diagnosis of congenital hypothyroidism. J Clin Endocrinol Metab 2007; 92:1434.
- Aronson R, Ehrlich RM, Bailey JD, Rovet JF. Growth in children with congenital hypothyroidism detected by neonatal screening. J Pediatr 1990; 116:33.
- Delvecchio M, Salerno M, Acquafredda A, et al. Factors predicting final height in early treated congenital hypothyroid patients. Clin Endocrinol (Oxf) 2006; 65:693.
- Jones JH, Gellén B, Paterson WF, et al. Effect of high versus low initial doses of L-thyroxine for congenital hypothyroidism on thyroid function and somatic growth. Arch Dis Child 2008; 93:940.
- Arenz S, Nennstiel-Ratzel U, Wildner M, et al. Intellectual outcome, motor skills and BMI of children with congenital hypothyroidism: a population-based study. Acta Paediatr 2008; 97:447.
- Salerno M, Oliviero U, Lettiero T, et al. Long-term cardiovascular effects of levothyroxine therapy in young adults with congenital hypothyroidism. J Clin Endocrinol Metab 2008; 93:2486.
- Azar-Kolakez A, Ecosse E, Dos Santos S, Léger J. All-cause and disease-specific mortality and morbidity in patients with congenital hypothyroidism treated since the neonatal period: a national population-based study. J Clin Endocrinol Metab 2013; 98:785.
- Neonatal hypothyroidism screening: status of patients at 6 years of age. New England Congenital Hypothyroidism Collaborative. J Pediatr 1985; 107:915.
- Grant DB, Fuggle P, Tokar S, Smith I. Psychomotor development in infants with congenital hypothyroidism diagnosed by neonatal screening. Acta Med Austriaca 1992; 19 Suppl 1:54.
- Rovet JF. Children with congenital hypothyroidism and their siblings: do they really differ? Pediatrics 2005; 115:e52.
- Derksen-Lubsen G, Verkerk PH. Neuropsychologic development in early treated congenital hypothyroidism: analysis of literature data. Pediatr Res 1996; 39:561.
- Rovet JF, Ehrlich RM, Sorbara DL. Neurodevelopment in infants and preschool children with congenital hypothyroidism: etiological and treatment factors affecting outcome. J Pediatr Psychol 1992; 17:187.
- Oerbeck B, Sundet K, Kase BF, 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.
- Oerbeck B, Sundet K, Kase BF, Heyerdahl S. Congenital hypothyroidism: no adverse effects of high dose thyroxine treatment on adult memory, attention, and behaviour. Arch Dis Child 2005; 90:132.
- Rovet JF, Ehrlich RM. Long-term effects of L-thyroxine therapy for congenital hypothyroidism. J Pediatr 1995; 126:380.
- Dimitropoulos A, Molinari L, Etter K, et al. Children with congenital hypothyroidism: long-term intellectual outcome after early high-dose treatment. Pediatr Res 2009; 65:242.
- Kempers MJ, van der Sluijs Veer L, Nijhuis-van der Sanden MW, et al. Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening. J Clin Endocrinol Metab 2006; 91:418.
- van der Sluijs Veer L, Kempers MJ, Last BF, et al. Quality of life, developmental milestones, and self-esteem of young adults with congenital hypothyroidism diagnosed by neonatal screening. J Clin Endocrinol Metab 2008; 93:2654.
- Léger J, Ecosse E, Roussey M, et al. Subtle health impairment and socioeducational attainment in young adult patients with congenital hypothyroidism diagnosed by neonatal screening: a longitudinal population-based cohort study. J Clin Endocrinol Metab 2011; 96:1771.
- Tillotson SL, Fuggle PW, Smith I, et al. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect. BMJ 1994; 309:440.
- Glorieux J, Dussault J, Van Vliet G. Intellectual development at age 12 years of children with congenital hypothyroidism diagnosed by neonatal screening. J Pediatr 1992; 121:581.
- Correlation of cognitive test scores and adequacy of treatment in adolescents with congenital hypothyroidism. New England Congenital Hypothyroidism Collaborative. J Pediatr 1994; 124:383.
- Dattani M, Brook CG. Outcomes of neonatal screening for congenital hypothyroidism. Curr Opin Pediatr 1996; 8:389.
- Bellman SC, Davies A, Fuggle PW, et al. Mild impairment of neuro-otological function in early treated congenital hypothyroidism. Arch Dis Child 1996; 74:215.
- Lichtenberger-Geslin L, Dos Santos S, Hassani Y, et al. Factors associated with hearing impairment in patients with congenital hypothyroidism treated since the neonatal period: a national population-based study. J Clin Endocrinol Metab 2013; 98:3644.
- Albert BB, Heather N, Derraik JG, et al. Neurodevelopmental and body composition outcomes in children with congenital hypothyroidism treated with high-dose initial replacement and close monitoring. J Clin Endocrinol Metab 2013; 98:3663.
- Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341:549.
- Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999; 50:149.
- Pop VJ, Brouwers EP, Vader HL, et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 2003; 59:282.
- Kooistra L, Crawford S, van Baar AL, et al. Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 2006; 117:161.
- Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 2010; 95:4227.
- Ghassabian A, El Marroun H, Peeters RP, et al. Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children. J Clin Endocrinol Metab 2014; 99:2383.
- Willoughby KA, McAndrews MP, Rovet JF. Effects of maternal hypothyroidism on offspring hippocampus and memory. Thyroid 2014; 24:576.
- Lazarus JH, Bestwick JP, Channon S, et al. Antenatal thyroid screening and childhood cognitive function. N Engl J Med 2012; 366:493.
- American Thyroid Association. Consensus Statement #2: American Thyroid Association statement on early maternal thyroidal insufficiency: recognition, clinical management and research directions. Thyroid 2005; 15:77.
- Sheehan PM, Nankervis A, Araujo Júnior E, Da Silva Costa F. Maternal Thyroid Disease and Preterm Birth: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab 2015; 100:4325.
- Dose of L-T4
- Effect of soy protein
- Treatment goals
- Recommended follow-up
- Assessment of permanent versus transient hypothyroidism
- Long-term management
- Growth and cardiac function
- Psychometric outcome
- - Effect of low versus high starting L-T4 dose
- - Long-term outcomes
- - Severely affected infants
- - Lower serum T4 values during the first years
- - Effect of noncompliance
- Other neurologic sequelae
- Maternal hypothyroidism
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS