Routine newborn screening
Newborn screening is recommended on all neonates at approximately 2–5 days after birth.[1, 2, 7] In Australasia, the primary screening test for congenital hypothyroidism is a TSH assay. This detects newborns with primary hypothyroidism, but not those with central congenital hypothyroidism who have a normal or low TSH. Conventional newborn screening capillary TSH cut offs (10 to 15 mU/L) fail to detect all infants with congenital hypothyroidism, particularly in sick and very low birthweight or premature infants.[8-10] TSH screening should be repeated in very low birth weight or premature infants a few weeks after the initial specimen to detect those babies where immaturity of the hypothalamic-pituitary- thyroid axis may initially mask primary congenital hypothyroidism. It is recommended that the test be repeated two weeks after birth in babies 1000–1500 g and at four weeks in those <1000 g.[1]
Capillary TSH and free T4 correlation
A newborn screening capillary TSH threshold >40 mU/L has 90.3% sensitivity and 65.9% specificity for predicting a venous fT4 of <10 pmol/L (moderate hypothyroidism), whereas a TSH >20 mU/L has 96% sensitivity and 36% specificity.[11] If the capillary TSH concentration from newborn screening is >40 mU/L whole blood, The European Society for Paediatric Endocrinology recommends starting treatment as soon as a good venous sample can be obtained without waiting for the venous blood test result, unless venous thyroid function test (TFT) results are available on the same day. If capillary TSH concentration is <40 mU/l of whole blood, the clinician may wait for the results of venous TFT, provided that these results are available on the following day.[2]
There is also insufficient evidence to determine the accuracy of a heel prick (capillary) TSH and fT4 for diagnosis of congenital hypothyroidism (ie predicting a simultaneously taken venous TSH and free T4). Limited data in school-age Down Syndrome children suggests a capillary sample may underestimate the venous TSH, although only a single child had a fT4 <10 pmol/L.[12] Conclusion: A venous TSH and fT4 sample is preferred for diagnosis of congenital hypothyroidism.
Replacement therapy for hypothyroidism
The European Society for Paediatric Endocrinology consensus group on congenital hypothyroidism defined the severity of hypothyroidism in terms of fT4 ranges, with <5 pmol/L as severe, 5–10 pmol/L as moderate and 10–15 pmol/L as mild hypothyroidism. The goal of newborn screening for congenital hypothyroidism is to ensure that affected infants start treatment as soon as possible, so that neurological impairment is either prevented or minimised. The European Society for Paediatric Endocrinology (ESPE) consensus states that thyroxine treatment should be started as soon as possible and not later than within the first 2 weeks of life. [2]
The criteria for recall and arrangements for evaluation vary according to country and newborn screening program.[1, 7, 13-16] For TSH levels triggering immediate recall for diagnostic testing, there should be immediate notification by phone to the responsible health team, followed by electronic and printed notification giving details of the mother and baby and screening results.[1, 14] For TSH levels triggering recall for repeat capillary screening, there should be electronic and printed notification giving details of the mother and baby and screening results to enable retesting within 7–10 days.[1, 14] The UK National Screening Committee recommend standards for initiation of treatment for congenital hypothyroidism suspected on initial screening sample by 17 days of age and, for infants suspected on a repeat blood spot sample that follows a borderline TSH, treatment is initiated by 24 days of age.[17]
Higher versus lower dose of thyroxine replacement therapy for hypothyroidism
The Australian Paediatric Endocrine Group guidelines recommend levothyroxine treatment is started as soon as the diagnosis has been confirmed by thyroid function tests (preferably the same day as the evaluation). A recommended starting dose is 10 microgram/kg/day. Dosage needs to be adjusted at follow-up visits with the aim of increasing the free T4 concentration to the upper end of the normal range within 2 weeks of starting therapy and decreasing the TSH to <20 mU/L within the first month.[1]
A systematic review of high versus low dose of initial thyroid hormone replacement for congenital hypothyroidism identified only one RCT evaluating the effects of high (10 to 15 microgram/kg/day) versus low dose (5 to 9.9 microgram/kg/day) of initial thyroid hormone replacement for CHT. [18] The single RCT [19, 20] reported initial dosing of 50 microgram/day (12–17 microgram/kg per day) raised serum T4 and free T4 concentrations to target range by 3 days and normalised TSH by 2 weeks of therapy. Infants commenced on higher initial levothyroxine doses (50 microgram) had full-scale IQ scores 11 points higher than those started on lower (37.5 microgram g) initial doses. However, verbal IQ, performance IQ, and achievement scores did not differ. (LOE II)
A systematic review of controlled studies that reported an association between cognitive outcome, severity of CHT and dosage at start of treatment found 11 studies that reported outcomes on 438 patients with CH: 156 with severe CHT (initial serum T4 ≤2 mg/dL or fT4 ≤3 pmol/L) and 282 with moderate or mild CHT (initial serum T4 >2 mg/dL or fT4 >3 pmol/L) [23–32]. The initial levothyroxine dose was classified as high (>10 microgram /kg), median (8 to 10 microgram /kg) or low (<8 microgram /kg). Patients with severe CH treated with a low initial levothyroxine dose had significantly lower IQ scores than patients with moderate/mild CH (pooled mean difference, 26.0; 95% CI: 29.1, 23.0) as well as patients with severe CH treated with a median levothyroxine dose (pooled mean difference, 29.2; 95% CI: 215.1, 23.3). Only in the subgroup treated with a high initial levothyroxine dose >10 microgram /kg per day was there no significant IQ difference between patients affected by severe CH vs mild/moderate CH. (LOE III – 2) A second systematic review of controlled studies found 17 studies that assessed the starting treatment dose in children with CHT.[21] Although most studies favoured a high initial treatment dose, some studies reported an increased incidence of overtreatment with high-dose thyroxine. In addition, one study reported that although infants initiated on higher dose levothyroxine had better performances and indexes of intelligence, verbal ability, and memory, they also had more behavioural problems, including increased anxiety, poorer concentration and social withdrawal.[22]
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