ESPE Yearbook of Paediatric Endocrinology

Brief summary: Current guidelines for congenital hypothyroidism recommend a starting dose of 10–15 μg/d of levothyroxine for optimal treatment (1). Over the last years, some studies suggested that overtreatment of patients during infancy by high levothyroxine doses might have negative effects on neurocognitive and behavioral development (2). The presented multicenter prospective randomized trial aimed at comparing the effect of higher (12.5–15.0 μg/d levothyroxine starting dose) versus lower (10.0–12.5 μg/d levothyroxine starting dose) on growth and neurocognitive outcome.

The two treatment groups (higher dose n=24 patients, lower dose n=21 patients) were balanced for sex, gestational age, age at diagnosis and treatment start, biochemical severity of congenital hypothyroidism, and thyroid morphology (dysgenesis versus gland in situ). The main results are the following: First, the authors found no difference concerning growth parameters (weight, height) at 24 and 48 months. Second, they observed Griffiths Mental Development Scales and Subscales at 24 months, and in Wechsler Preschool and Primary scale of Intelligence at 48 months of age for both groups in the normal range without significant differences between the higher versus lower levothyroxine treatment group. Third, despite biochemically optimal treatment over the 48 months of the study 6/45 patients showed IQ below normal range, associated with delayed bone age at diagnosis and lower socioeconomic status.

The so far only randomized trial for different starting doses (37.5 μg/d, 50 μg/d, and 62.5 μg for three days then lowered to 37.5 μg/d) in patients with congenital hypothyroidism was published in 2002 and 2005 by Selva et al. Those authors found differences in TSH and FT4 normalization in the first 4 weeks as well as in full scale IQ at the age of four years (3,4). This randomized clinical trial by Esposito et al. provides for the first-time important prospective data on neurocognitive outcome comparing two starting doses within the recommended starting dose range of 10–15 μg/d. The results show that the higher range of the recommended starting dose (12.5 μg–15.0 μg) did not result in better neurocognitive outcome. If confirmed in a larger cohort, and in the context of potential overtreatment with the higher dose group (12.5 μg–15.0 μg) these results might lead to adaptation of the current dosing recommendations to use rather the 10.0 μg–12.5 μg starting dose than 12.5 μg–15.0 μg starting dose.

References: 1. Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update-An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. van Trotsenburg P, Stoupa A, Léger J, Rohrer T, Peters C, Fugazzola L, Cassio A, Heinrichs C, Beauloye V, Pohlenz J, Rodien P, Coutant R, Szinnai G, Murray P, Bartés B, Luton D, Salerno M, de Sanctis L, Vigone M, Krude H, Persani L, Polak M. Congenital hypothyroidism: A 2020–2021 Consensus Guidelines Update-An ENDO-European Reference Network initiative endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid. 2021 Mar;31(3):387–419. doi: 10.1089/thy.2020.0333. PMID: 33272083. 2. Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment?Bongers-Schokking JJ, Resing WC, de Rijke YB, de Ridder MA, de Muinck Keizer-Schrama SM. Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment? J Clin Endocrinol Metab. 2013 Nov;98(11):4499–4506. doi: 10.1210/jc.2013-2175. Epub 2013 Aug 26. PMID: 23979950. 3. Initial treatment dose of L-thyroxine in congenital hypothyroidism. Selva KA, Mandel SH, Rien L, Sesser D, Miyahira R, Skeels M, Nelson JC, Lafranchi SH. Initial treatment dose of L-thyroxine in congenital hypothyroidism. J Pediatr. 2002 Dec;141(6):786–792. doi: 10.1067/mpd.2002.128887. PMID: 12461494. 4. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. Selva KA, Harper A, Downs A, Blasco PA, Lafranchi SH. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr. 2005 Dec;147(6):775–80. doi: 10.1016/j.jpeds.2005.07.024. PMID: 16356430. 5. Thyroid hormone signaling specifies cone subtypes in human retinal organoids. Eldred KC, Hadyniak SE, Hussey KA, Brenerman B, Zhang PW, Chamling X, Sluch VM, Welsbie DS, Hattar S, Taylor J, Wahlin K, Zack DJ, Johnston RJ Jr. Thyroid hormone signaling specifies cone subtypes in human retinal organoids. Science. 2018 Oct 12;362(6411):eaau6348. doi: 10.1126/science.aau6348. PMID: 30309916.