Prior to the newborn screening era, when a diagnosis of congenital hypothyroidism was made after development of clinical manifestations, studies reported an inverse relationship between the age of diagnosis and IQ outcome. A study from Pittsburgh Children's Hospital showed that if thyroid hormone treatment was started between birth and 3 months of age, the mean IQ was 89 (range 64 to 107); if treatment was started between 3 and 6 months of age, the mean IQ was 71 (range 35 to 96), while if treatment did not start until after 6 months of age, the mean IQ dropped to 54 (range 25 to 80) [100
]. A report from Sweden found that "in spite of an efficient National Health Care Program for infants, the diagnosis was delayed until after 3 months in 52 percent of cases"[1
The advent of newborn screening programs in the mid-1970s allowed earlier detection and treatment of infants with congenital hypothyroidism. Such efforts have been successful in achieving a much-improved neurocognitive outcome. Despite this, however, not all studies report a completely normal outcome. In a recent review of 51 published reports of IQ outcome in infants with congenital hypothyroidism as compared to sibling or classmate control subjects, 18 found no significant IQ difference, while 33 found a significant difference, with IQ ranging between 5 and 25 points lower in infants with congenital hypothyroidism [80
]. In evaluating important variables, there is evidence that age of onset of treatment, starting l-thyroxine treatment dose, and severity of hypothyroidism each plays an important role in neurocognitive outcome.
• Age of onset of treatment
- A study from the French National Screening Program reported the effect of age of onset of thyroid hormone treatment, divided into four time periods, and IQ outcome [101
]. In infants started on treatment after 30 days of age, mean global IQ = 109.8; if started between 22 and 30 days of age, mean IQ = 107.7, between 15 and 21 days, mean IQ = 115.3, and before 15 days of age, mean IQ = 119.2 (p=.008). Other programs, however, have not found an effect of age of onset of treatment. In a report from Australia, infants started after 14 days of age had a mean full scale IQ = 98.1, while those started before 14 days of age had a mean IQ = 99.6 (p = NS) [102
]. It should be kept in mind that these were retrospective studies, and that comparisons of age of onset of treatment came about because early in the experience of screening programs infants generally were started on treatment at a later age, and then as screening programs became more experienced, the age of onset of treatment was lowered. A report from Italy compared infants started before and after 21 days of age, subdivided into two treatment groups: those started on 8.1-10 mcg/kg/day had a mean full scale IQ = 91 (> 21 days) vs. 96 (< 21 days). Those started on a higher dose, 10.1-15 mcg/kg/day) had a mean IQ = 98, identical in the group before or after 21 days of age [90
]. Although these results did not reach statistical significance, at the lower starting dose there was a trend toward a better IQ with earlier treatment, whereas with the higher starting dose, the IQ in early vs. later treatment did not affect IQ outcome. Thus, there may have been factors other than age of onset of treatment that influenced IQ outcome, such as initial starting dose. It does appear that it is important to detect most cases and start treatment by 4 weeks of age. In our review of the literature, of 11 studies comparing starting treatment at an earlier age (12-30 days of life) vs. at a later age (> 30 days of life), infants started at the earlier age averaged 15.7 IQ points higher than infants started at a later age [80
• l-thyroxine starting dose
- At the time newborn screening programs were established in the mid-1970s, the recommended starting l-thyroxine dose was approximately 6-8 mcg/kg/day. With experience, it became evident that higher doses were needed to more rapidly correct the hypothyroxinemia and raise the serum T4 into the "target range" and lower serum TSH levels into the normal range (see Table ). Early reports of psychometric outcome using a starting l-thyroxine dose of 6-8 mcg/kg/day showed a good outcome. The New England Congenital Hypothyroidism Collaborative reported a verbal IQ score of 109, performance IQ of 107, and full scale IQ of 109 at six years of age [103
Table 9 Time course of normalization of serum T4 and TSH with initial l-thyroxine treatment dose (modified from: LaFranchi & Austin. J Pediatr Endocrinol Metab 20:559-578, 2007.)
However, as the starting doses were increased, reaching the currently recommended 10-15 mcg/kg/day, programs were able to compare IQ outcomes at various starting l-thryoxine doses. A report from the Toronto screening program compared psychometric outcome in infants started on 6.4 mcg/kg/day vs. 9.0 mcg/kg/day [92
]. Verbal IQ was 98.6 vs. 106.3 (p < .01), performance IQ was 103.8 vs. 108.2 (p = NS), and full scale IQ was 100.0 vs. 107.6 (p < .01) in the low vs. higher dose infants, respectively. A report from Italy compared psychometric outcome in infants started on three different l-thyroxine doses: a "low" dose 6-8 mcg/kg/day, an "intermediate" dose 8.1-10.0 mcg/kg/day, and a "high" dose 10.1-15 mcg/kg/day [90
]. The verbal IQs in the three treatment groups were 92, 94, and 98, respectively (p = NS); performance IQs were 85, 95, and 98, respectively (p < .01), while the full scale IQs were 88, 94, and 98, respectively (p < .01). A report from the U.S. Northwest Regional Screening Program showed that infants started on a higher l-thyroxine dose (50 mcg/day, equivalent to 12-17 mcg/kg/day) had an IQ score 11 points higher than those started on the lower dose (37.5 mcg/day, equivalent to 9.4-12.4 mcg/kg/day) [85
In our review of the literature, of ten studies examining the effect of different starting l-thryoxine doses on psychometric outcome, two reported no effect, six reported a 12.3 higher IQ with higher starting doses, while two actually reported a 8.6 point higher IQ with lower starting doses [80
]. Overall, the preponderance of studies found that children started on the currently recommended l-thyroxine dose of 10-15 mcg/kg/day appear to achieve the best IQ outcome.
• Severity of hypothyroidism
- Infants with congenital hypothyroidism have varying degrees of thyroid hormone deficiency; the severity of hypothyroidism likely is related to the underlying etiology (e.g, agenesis vs. hypoplasia/ectopia vs. dyshormonogenesis). It is important to bear in mind, however, that the degree of hypothyroidism is not simply related to the size of the residual thyroid gland. Some cases of dyshormonogenesis, with an enlarged gland, have severe hypothyroidism. Several screening programs have investigated psychometric outcome in relationship to severity of hypothyroidism, addressing the question of whether the most severely affected infants may have suffered prenatal damage that is not reversible even with early detection and treatment. The screening program in England, Wales, and Northern Ireland reported that infants with pre-treatment serum T4 < 3.3 ug/dL had a global IQ 11.6 points lower than infants with a serum T4 > 3.3 ug/dL [104
]. The Quebec Screening Network compared IQ outcome in a cohort of infants with severe hypothyroidism, as assessed by a pre-treatment T4 < 2 ug/dL and an epiphyseal surface area < .05 cm2 vs. infants with more moderate hypothyroidism, with a pre-treatment T4 > 2 ud/dL and an epiphyseal surface area > .05 cm2 [105
]. These infants were studied relatively early in the experience of their screening program, and so were started on a dose of 6 mcg/kg/day. The infants underwent serial psychometric testing; at age 12 years, the cohort with severe hypothyroidism had an IQ 16 points lower than the moderate group (p < .007). A report from the Northwest U.S. Regional Screening Program reported that infants with severe hypothyroidism (pre-treatment serum T4 < 2.2 ug/dL) had an IQ 11 points lower than a group with more moderate hypothyroidism (p < .05) [85
Part of the explanation for a worse psychometric outcome in the most severely affected infants may be the lower starting l-thyroxine doses used in the early history of newborn screening. The Dutch newborn screening program investigated the effect of initial starting dose (< 9.5 or > 9.5 mcg/kg/day) and age of onset of treatment (< 13 days or > 13 days of age) in infants judged to have severe vs. milder hypothyroidism (pre-treatment serum free T4 0.21 ng/dL vs. 0.67 ng/dL, respectively) [106
]. In the infants with severe hypothyroidism, psychometric testing at 10 to 30 months of age showed IQ 21 to 27 points lower in the groups treated with the lower starting dose and/or later age of onset; the group started on the higher dose and at the earlier age had the best IQ outcome (IQ = 125). On the other hand, all of the infants with milder hypothyroidism did well except the group treated with the lower dose and later age of onset, which had an IQ 22-25 points lower than the other groups [106
]. These results support the concept of tailoring the initial starting l-thyroxine dose to the severity of hypothyroidism [107
]. When the Quebec Screening Network used a higher starting dose, averaging 11.6 mcg/kg/day, they reported that psychometric testing did not show a difference in IQ in infants judged to have severe vs. more moderate hypothyroidism (107 vs. 110, respectively) [108
• Effect of lower serumT4 levels in the first two years of life and non-compliance
- Normal brain development depends on delivery of adequate thyroid hormone for the first two to three years of life. Low thyroid levels during this time may result in irreversible damage, whereas the effects of hypothyroidism after age 3 years generally are reversible when corrected. The New England Congenital Hypothyroidism Collaborative reported that a subgroup of 18 infants who had low serum T4 levels (average T4 8.6 ug/dL) and low l-thyroxine dosing (< 5 mcg/kg/day) with a history of poor compliance in the first three years of life, had a mean IQ of 87 [109
]. The larger, adequately treated group, with a serum T4 in the target range (average T4 11.2 ug/dL), had an IQ score of 105. This study underscored the importance of frequent monitoring with dose adjustments to keep serum free T4 or T4 in the target range in the first two-three years of life.
The New England Congenital Hypothyroidism Collaborative also found that noncompliance beyond the first three years of life can affect cognitive performance. In a study of 14 year old adolescents with congenital hypothyroidism, the investigators made home visits without forewarning. Testing showed that 44% were inadequately treated, as judged by serum TSH > 15 mU/L, with serum T4 < 6.6 ug/dL (< 85 nmol/L) in the majority [110
]. Psychometric testing showed a mean IQ of 106. Compliance with thyroid hormone treatment was stressed (the dose was not changed), and one to two years later, when thyroid testing was now improved, repeat psychometric testing showed a mean IQ of 112 (p < .002). This study showed that noncompliance in adolescents is common, and that improvement in compliance and thyroid levels was associated with improved cognitive function.