Clinical Endocrinology (2008) 69, 142–147 doi: 10.1111/j.1365-2265.2008.03172.x © 2008 The Authors 142 Journal compilation © 2008 Blackwell Publishing Ltd ORIGINAL ARTICLE Blackwell Publishing Ltd A novel therapeutic paradigm to treat congenital hypothyroidism Sarah Mathai*, Wayne S. Cutfield*, Alistair J. Gunn†, Dianne Webster‡, Craig Jefferies*, Elizabeth Robinson§ and Paul Hofman* *Paediatric Endocrinology, Liggins Institute, University of Auckland and Starship Children’s Health, Auckland, New Zealand, †Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand, ‡National Testing Centre, Auckland, New Zealand and §Department of Epidemiology and Biostatistics, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand Summary Objective To determine the effectiveness of a novel therapeutic paradigm to treat congenital hypothyroidism (CH) incorporating variable initial doses of L-T4 based on the underlying aetiology and frequent monitoring, up to 2 years of age. Design Retrospective cohort study. Patients Infants with primary CH diagnosed by newborn screening. Measurements Treatment with L-T4 suspension initiated at 10, 12 and 15 μg/kg/day for dyshormonogenesis, ectopia and athyreosis, respectively. Serum TSH and free T4 (FT4) levels monitored weekly during the first 4 weeks, at 6 weeks, thereafter monthly during the first 2 years. Dose changes were made to keep FT4 level in upper half of the normal range. Results Sixty-nine infants; 17 had dyshormonogenesis, 35 ectopia and 17 athyreosis. Seventy-eight percent of subjects normalized FT4 levels within 7 days of treatment and 100% within 14 days. TSH levels normalized in 26% of infants within 7 days and in 92% by 21 days. Supraphysiological levels of FT4 were noted in 28% of infants, for a maximum of 2 weeks. 48% infants needed one dose adjustment and 30% needed at least two in the first month. In 52 infants over the first 2 years, mean FT4 levels were consistently in the upper half of the normal range. Two or more dose adjustments every 3 months were made 57 times in the first year as compared to 19 times in the second year. Conclusions A variable initial dose paradigm based on aetiology with frequent testing and using T4 suspension rapidly normalizes FT4 levels without producing persistent hyperthyroxinaemia. (Received 9 September 2007; returned for revision 18 September 2007; finally revised 24 October 2007; accepted 18 December 2007) Introduction The introduction of newborn thyroid screening and early L-T4 therapy for children with congenital hypothyroidism (CH) has dramatically improved neurocognitive outcomes. Despite this improvement there is concern that mild but persistent reductions in motor, verbal and cognitive performance may still occur in some children. 1,2 Although such mild neurocognitive impairment is associated with aetiology and initial T4 level, it is also affected by the initial dose and age at initiation of L-T4 and time to normalize thyroid hormone function. 3–7 These latter associations suggest that the prenatal effects of hypothyroidism may be at least partially overcome by optimizing early therapy. 8 Consistent with this, initial doses of L-T4 in the range of 10 – 15 μg/kg/day can rapidly normalize thyroid function and improve long-term developmental outcome compared to lower dose strategies. 7,9 This approach is now endorsed by the European Society for Pediatric Endocrinology and the American Academy of Pediatrics. 8,10–12 The major potential limitation of this approach is that there is an increased risk of supraphysiological free T4 (FT4) levels. 6 Given that neurodevelopmental and behavioural problems can occur with early hyperthyroidism 13 frequent thyroid function tests are needed to maintain euthyroidism. The optimal testing frequency is unclear. 14–21 The American Academy of Pediatrics recommends that thyroid function is assessed 2 and 4 weeks after starting the therapy, then 1–2 monthly till 6 months of age, 3–4 monthly from 6 months to 3 years and then every 6–12 months till the end of growth. 11 However, there are indications that even more frequent testing may be needed to limit the duration of iatrogenic hyperthyroidism. 15 Most studies of CH have not modified the initial L-T4 dose based on severity, 5–7,9 and at present a single initial dose paradigm is recommended for all patients. 11 However, there is considerable variability in the severity of CH at presentation, typically most severe with athyreosis and milder with ectopia and dyshormonogenesis 14,20 raising the possibility that varying initial dosing based on severity may be more appropriate. 22 Since 1993 our institution has used a variable initial dose strategy based on aetiology and incorporating frequent thyroid function testing during the neonatal period and over the first 2 years of treatment. This algorithm was developed based on the best Correspondence: Paul Hofman, Department of Paediatric Endocrinology, Liggins Institute, 2–6 Park Ave, Grafton, Private Bag 92019, Auckland, New Zealand. Tel.: +64 9 3737599 ext 86453; Fax: +64 9 3738763; E-mail: p.hofman@auckland.ac.nz