© Freund Publishing House Ltd., London Journal of Pediatric Endocrinology & Metabolism, 20, 559-578 (2007)

How Should We Be Treating Children with Congenital Hypothyroidism?

Stephen H. LaFranchi and Juliana Austin

Department of Pediatrics, Division of Endocrinology, Oregon Health & Science University, Portland, OR, USA

ABSTRACT

Early detection by newborn screening and appropriate L-thyroxine treatment leads to normal or near-normal neurocognitive outcome in infants with congenital hypothyroidism. Many newborns with congenital hypothyroidism have some residual thyroid hormone produc-tion, and even in those with athyreosis, trans-placental passage of maternal thyroid hormone offers some protection for a time. Given the serum T4 half-life of 6 days, the neonatal T4 level will fall and disappear over the first 2-3 weeks of life. Thus, there is a crucial ‘window of opportunity’ to correct the hypothyroidism and minimize the time the brain is exposed to hypo-thyroxinemia. While there are few truly pros-pective, randomized clinical trials investigating treatment parameters, studies measuring IQ outcome support a starting L-thyroxine dose of 10-15 μg/kg/day. Further, studies show that the most severely hypothyroid infants are at risk for a 5-20 point decrease in IQ. Such infants may benefit from a starting dose of 12-17 μg/kg/d, which has been shown to normalize T4 in 3 days and TSH in 2 weeks. Target serum T4 or free T4 levels appear to be higher in the first two weeks of treatment. Infants require more frequent laboratory monitoring, every 1-2 months in the first 6 months and every 3-4 months until age 3 years, as the developing brain has a critical dependence on thyroid hormone in the first 2-3 years of life.

KEY WORDS

congenital hypothyroidism, newborn screening, thyroid dysgenesis, dyshormonogenesis, L-thyroxine, neurocognitive outcome, IQ

INTRODUCTION

Delay in diagnosis or suboptimal treatment of congenital hypothyroidism results in variable mental retardation, whereas early detection and appropriate L-thyroxine hormone replacement leads to normal or near-normal neurocognitive outcome. The developing brain has a critical dependence on thyroid hormone, beginning before birth and extending through the first 2-3 years of life. There is accumulating evidence that maternal thyroid hormone that crosses to the fetus is important for normal brain development, even before onset of significant fetal thyroid hormone production1. Thyroid hormone receptor mRNAs (TRα1, TRα2, and TRβ1) are present from 7-8 weeks gestation in the fetal brain2,3. Type 2 or 5´-deiodinase (5´-D2) mRNA is measurable from 7-8 weeks gestation3. 5´-D2, which converts T4 to the biologically active T3, increases with hypothyroidism. While signifi-cant fetal thyroid hormone production and secretion does not begin until approximately 20 weeks, T4 can be demonstrated in the coelomic cavity as early as 6 weeks gestation4. The concentration of coelomic fluid T4 correlates positively with maternal serum T4 levels5. Thus, if there is a significant role for thyroid hormone in fetal brain development before 20 weeks gestation, it is likely of maternal origin. In addition, it would appear that normal maternal thyroid function is important for fetal neurodevelopment6.

Reprint address: Stephen H. LaFranchi, M.D. Department of Pediatrics [CDRCP] Oregon Health & Science University

Based on cord T4 levels in infants with total organification defects or thyroid agenesis, approxi-

707 SW Gaines St. Portland, OR 97239, USA e-mail: lafrancs@ohsu.edu

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mately one-third of maternal T4 crosses to the fetus at birth7. Further, most infants with congenital hypothyroidism have some residual thyroid tissue (the most common etiology of congenital hypo-thyroidism is an ectopic gland), so they are able to produce some thyroid hormone. Although the combination of the maternal thyroid hormone contribution and fetal thyroid hormone production is still subnormal, it likely explains why the majority of newborns with congenital hypothyroid-ism are normally grown and lack obvious clinical manifestations of hypothyroidism. Given the serum T4 half-life of approximately 6 days, the maternal contribution will fall and disappear over the first 2-3 weeks of life. Thus, there is a crucial ‘window of opportunity’ to detect this disorder and start treat-ment within this time frame. Further, it is critical to raise the serum T4 into the target range as rapidly as possible, to minimize the time the brain is exposed to hypothyroidism. Experience has shown that this requires higher starting L-thyroxine doses than were initially recommended by newborn screening programs. In addition, frequent monitor-ing of thyroid function tests in the first 2-3 years of life is also important, to assure that thyroid function remains in the target range during this time of continued brain dependence on thyroid hormone.

HISTORICAL PERSPECTIVE: CONGENITAL HYPOTHYROIDISM IN THE PRE-SCREENING ERA

Prior to the onset of screening programs, a comprehensive survey in Sweden reported that the incidence of congenital hypothyroidism during the 1969-1975 period was 1:6,9008. The authors stated that “in spite of an efficient National Health Care Program for infants, the diagnosis was delayed until after an age of three months in 52% of the cases”. Klein et al. from Pittsburgh Children’s Hospital examined the effect of age at clinical diagnosis and treatment on IQ9. If thyroid hormone treatment was started before 3 months of age, the mean IQ was 89 (see Table 1). If treatment was started between 3 and 6 months, mean IQ fell to 71, while if treatment was started after 6 months of age, the mean IQ dropped to 54. Several studies indicate an inverse relationship between the age of clinical diagnosis and treatment and IQ outcome.

Even if treatment is started before 3 months of age, there appears to be a small decrement in IQ. In the 1960s, most infants were treated with dessicated thyroid (porcine thyroid, containing both T4 and T3), with recommended starting doses in the range of 15-30 mg daily10. Most experts began recommending sodium L-thyroxine in the 1970s; at this time and even in the early 1980s, the recommended starting dose was 6-8 μg/kg/day11.

TABLE 1

Inverse relationship between age at clinical diagnosis of congenital hypothyroidism and IQ outcome9

IQ Age of treatment (months) mean range

0-3 89 64-107

3-6 71 35-96

>6 54 25-80

Congenital hypothyroidism is not usually a heritable disorder; the majority of cases are sporadic. Thus, it is not possible to identify a population of pregnant women who are at high-risk for delivering a newborn with hypothyroidism, and, short of fetal cord blood sampling, no reliable prenatal test has been developed. As described above, the clinical manifestations are often subtle, non-specific, or even absent at birth, so that most cases are not suspected or diagnosed clinically in the neonatal period. For these reasons, when technology allowed the measurement of T4 and TSH in the small volume of blood obtained for newborn screening (eluted from filter paper speci-mens obtained by heel-prick), testing for congenital hypothyroidism was added by programs starting in the mid-1970s12-14.

TREATMENT OF INFANTS WITH CONGENITAL HYPOTHYROIDISM DETECTED BY

NEWBORN SCREENING

Newborn screening programs for the detection of congenital hypothyroidism have been in place in many countries for approximately 30 years (Canada and the United States, most countries in Europe,

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Israel, Japan, Australia and New Zealand), and they have been developed more recently in parts of Mexico, several countries in South America and some in Asia and the Middle East. The incidence of congenital hypothyroidism ranges from 1:3,000 to 1:4,000 newborns in most reports. In the year 2000 survey of United States screening programs, 1,635 cases of permanent primary hypothyroidism were detected among 4,125,135 infants, for an incidence of 1:2,52315. The incidence from newborn screen-ing programs is approximately twice that from the pre-screening era. Most likely, this is the result of detection of cases of transient hypothyroidism, milder cases of congenital hypothyroidism, or cases that would have been diagnosed later in childhood and so thought to represent acquired hypothyroid-ism. The advent of newborn screening has resulted in dramatic improvement in the neurocognitive outcome of infants with congenital hypothyroidism. That said, it is the experience of many programs that undertake follow-up psychometric testing that infants tend to have a slight, 5-10 IQ point deficit compared to appropriate control groups16, and that they have an increased likelihood of having subtle learning problems, such as difficulty with voca-bulary, reading comprehension, arithmetic, and memory17. It is therefore incumbent to examine ways in which we can improve treatment of infants detected with congenital hypothyroidism. The overall goals of treatment are to assure normal growth and development, with neuro-cognitive outcome similar to the child’s genetic potential. Investigators have carried out studies of the components of treatment to examine which leads to the best neurocognitive outcome. Such investigations include examining the effect of different starting L-thyroxine doses on the time-course of normalization of serum thyroid function tests and on psychometric outcome. In addition, studies have examined the effects of severity of congenital hypothyroidism and the age of initiation of treatment on psychometric outcome. The following sections address several components of treatment.

L-THYROXINE TABLETS; T4 VS T4 + T3; ADMINISTRATION, AND INHIBITORS

L-Thyroxine: tablet vs liquid

At present, only L-thyroxine tablets should be used; there are no U.S. Food and Drug Administ-ration (FDA)-approved liquid preparations. L-Thyroxine suspensions that may be prepared by individual pharmacists may lead to unreliable dosage. There is a report of a liquid T4 preparation from Europe (manufactured by Henning Berlin; 1 drop [50 μl] = 5 μg)18. Using a median starting dose of 12.3 μg/kg/d, serum TSH normalized within 2 weeks, while using a slightly higher median dose of 12.7 μg/kg/d resulted in TSH normalization within 1 week. Infants treated with this liquid L-T4 for up to 2 years appeared to do well, although follow-up psychometric testing has yet to be reported. Further studies leading to FDA approval should be carried out before this liquid T4 preparation is used by physicians in the United States.

T4 vs T4 + T3

L-T4 is the treatment of choice. As T3 is the biologically active thyroid hormone, there has been recent interest in T4 + T3 combination treatment of hypothyroidism. While there is some evidence that T4 treatment alone may not normalize intracellular T3 levels in all tissues19, the majority of brain T3 is derived from local monodeiodination of T420. Further, the correct dose of T3 or the exact ratio of T4 and T3 in children has yet to be worked out. At present, the only ‘T4 + T3’ preparations available are Armour dessicated thyroid, which may have variable potency, and thyrolar, a dessicated T4 and synthetic T3 combination. Given the priority of protecting the brain from thyroid deficiency and the years of experience using L-thyroxine with good results, T4 remains the treatment of choice.

Administration

The T4 tablet should be crushed (for example, between two spoons, or using a mortar and pestle) and mixed with liquid (e.g., water, expressed breast milk, or formula) to prepare each day’s dose. The daily dose can be drawn up in a plastic syringe and

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squirted into the infant’s cheek pad. Another method is to add the daily suspension to an open bottle nipple and offer it just before a feeding. The crushed T4 tablet should not be added to a full bottle for feeding, as some of the L-T4 may stick to the bottle wall or settle at the bottom and so may not be consumed.

Substances/disorders inhibiting gastrointestinal (G-I) absorption

Approximately 60-80% of ingested L-T4 is absorbed from the G-I tract, primarily from the small intestine21. Several substances are reported to bind thyroxine and interfere with its absorption; these are listed in Table 2. Soy formula has been the best studied in infants with congenital hypo-thyroidism22. In a retrospective analysis, after initiation of T4 treatment, infants fed soy formula took much longer to achieve a serum TSH <10 mU/l than those on non-soy formula (median of 150 vs 40 days)23. In infants in whom soy formula is deemed necessary, L-T4 should be given half way between soy feedings. Thyroid function should be monitored carefully, and the dose of T4 increased as necessary to achieve desired FT4 and TSH levels. In addition, disorders associated with malabsorption, including celiac disease and Helio-bacter pylori infection, are associated with a need for a higher T4 dose. Lastly, prolonged heat exposure of the L-T4 tablets may reduce bioactivity.

TABLE 2

Substances that interfere with L-thyroxine absorption

• Soy protein

• Iron (concentrated)

• Calcium (concentrated)

• Aluminum hydroxide

• Cholestyramine and other resins

• Fiber supplements

• Sucralfate

L-THYROXINE STARTING DOSE; TAILORING TO SEVERITY OF DISEASE; EFFECT OF TIMING, AND

INITIAL TREATMENT GOALS

L-T4 starting dose

The current recommended starting dose is 10-15 μg/kg/day (American Academy of Pediatrics, 2006)24. There is an inverse correlation between the starting L-T4 dose and the time to achieve the desired serum T4 concentration (see Table 3). Guidelines recommend raising the T4 or FT4 level into the upper half of the normal range for age: T4 = 10-16 μg/dl (130-206 nmol/l), FT4 = 1.4-2.3 ng/dl (18-30 pmol/l)24. Studies showed that the historical starting dose of 6 μg/kg/d took 45-90 days to raise the serum T4 to >10 μg/dl25, dropping to an average of 31 days at 10 μg/kg/d28, while using a dose of 10-14 μg/kg/d, the desired T4 was reached in 7 days29. In a study from Oregon of three starting treatment doses, the highest dose (50 μg/ day = 12-17 μg/kg/d) raised the serum T4 to >10 μg/dl by 3 days and normalized the TSH by 2 weeks of treatment31. The intermediate dose (37.5 μg/day = 9.4-12.4 μg/kg/d) or a loading dose followed by the intermediate dose (62.5 μg/d for 3 days followed by 37.5 μg/d), took 1 week to raise the serum T4 to >10 μg/dl, while the serum TSH was normalized at 12 weeks of treatment31. Infants who took longer than 2 weeks to normalize their thyroid function had significantly lower cognitive, attention, and achievement scores than those who achieved normal thyroid function by 1 or 2 weeks after starting therapy32. These studies show that the current recommended starting L-T4 dose of 10-15 μg/kg/d leads to the most rapid normalization of thyroid function. Early reports of psychometric outcome using the recommended starting L-T4 dose of 6-8 μg/kg/d reported that global IQs were similar to control infants. The New England Congenital Hypothyroidism Collaborative reported a verbal IQ score of 109, a performance IQ of 107, and a full scale IQ of 109 at six years of age33. However, other programs have reported that infants started on

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the lower T4 dose did not do as well as control infants. In the Toronto program, a comparison was made of infants started on a dose of 6.4 μg/kg/d vs 9.0 μg/kg/d34. Verbal IQ was 98.6 vs 106.3 (p <0.01),

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performance IQ was 103.8 vs 108.2 (p = NS), and full scale IQ was 100.0 vs 107.6 (p <0.01) in the low vs high dose infants. A report from Italy compared psychometric outcome in infants started on a ‘low’ (6-8 μg/kg/d), ‘intermediate’ (8.1-10 μg/kg/d) or ‘high’ (10.1-15 μg/kg/d) dose of T430. The verbal IQs in the three treatment groups were 92, 94 and 98, respectively (NS), but the perfor-mance IQs were 85, 95, and 98, while the full scale IQs were 88, 94, and 98, respectively (both p <0.01). In another report, the Norwegian neonatal screening program reported psychometric testing in young adults with congenital hypothyroidism detected by newborn screening, also correlating outcome with L-T4 starting dose35. Compared with control subjects, adults with congenital hypo-thyroidism had a lower verbal IQ (102.4 vs 110.2), performance IQ (101.1 vs 110.2), and total IQ (102.4 vs 111.4). A higher initial L-T4 dose cor-related with higher verbal IQ, language tests, and arithmetic screening skills. The starting L-T4 dose in school completers was 9.2 μg/kg/d, higher than in non-completers, 7.1 μg/kg/d. In the study from Oregon quoted above, patients starting on the higher T4 dose (50 μg/d = 12-17 μg/kg/d) had full scale IQ scores 11 points higher than those started on the lower dose (37.5 μg/d = 9.4-12.4 μg/kg/d)32.

In our review of the literature, we found ten studies examining the effect of different starting L-T4 doses on psychometric outcome (see Table 4). Of these, two reported no effect, while six reported that lower starting doses on average correlated with a 12.3 point drop in IQ. Two studies actually reported that a lower T4 starting dose led to a better IQ (average 8.6 points) as compared to the higher dose. On balance, however, most studies found that children started on the currently recommended starting L-T4 dose of 10-15 μg/kg/d have a better neurocognitive outcome than children started on the dose used when newborn screening programs were initiated, 6-8 μg/kg/d.

Tailoring L-thyroxine dose to severity of disease

Several programs have investigated psycho-metric outcome in infants judged to have more severe congenital hypothyroidism. The screening program in England, Wales and Northern Ireland reported that infants with pre-treatment serum T4 <3.3 μg/dl (<42.8 nmol/l) had a global IQ 11.6 points lower than infants with serum T4 >3.3 μg/ dl43. The Quebec Screening Network compared IQ outcome in a cohort of severely affected and moderately affected infants, as judged by a serum

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T4 <2 μg/dl or >2 μg/dl and an epiphyseal surface area <0.05 cm2 or >0.05 cm2, respectively, both treated with a starting L-T4 dose of 6 μg/kg/d44. Serial psychometric testing up to age 12 years showed a global scale IQ 16 points lower in the severely affected cohort. Subsequently, the Quebec group reported that using a starting L-T4 dose of 11.6 μg/kg/d “narrowed the gap”, such that IQs were not statistically different between the mode-rate and severe groups (110 vs 107)45. The Dutch newborn screening program investigated both the effect of initial starting dose (<9.5 or >9.5 μg/kg/d) and age of onset of treatment (<13 or >13 days of age) in infants judged by thyroid scan results to have mild (pre-treatment mean FT4 = 0.67 ng/dl) or severe (pre-treatment FT4 = 0.21 ng/dl) hypothyroidism40. In the infants with more severe hypothyroidism, testing at 10-30 months of age showed IQ 21-27 points lower in the groups treated with the lower dose and/or treated at a later age; the group treated with a high dose and at an early age had the best outcome (IQ = 125). On the other hand, all the infants with mild hypothyroidism did well, except the group treated with a low dose and at a later age, which had an IQ 22-25 points below the other groups. Re-evaluation at 6 years of age showed improvement, with a global IQ score of 104.7 for the entire group, similar to the control group of children, 107.541. The mild group’s IQ was 108.5, while the severe group’s IQ was 99.4, but this difference was not statistically significant. How-ever, the visuomotor scores were higher in the mild vs severe group (96.5 vs 86.3, p = 0.048). In the study from Oregon described above, infants classified as having moderate hypo-thyroidism had an IQ 11 points higher than those with severe hypothyroidism, 100 vs 89 (p = 0.05)32. In our review of the literature, we found 30 studies comparing psychometric outcome in infants with more severe vs moderate or mild congenital hypothyroidism (see Table 5). Of these, nine re-ported no difference in IQ, while 21 reported a 5.5-23 point decrease in IQ in the more severely affected infants. As described above, doses in the upper end of the recommended 10-15 μg/kg/d range lead to more rapid normalization of thyroid

function. Based on the studies comparing outcome with severity of disease, we conclude that it is important to use the higher end of the dosage range, perhaps even extending it to 12-17 μg/kg/d, in those infants judged to have more severe hypo-thyroidism (e.g., serum T4 <5 μg/dl).

Initial biochemical goals

Guidelines recommend raising the serum T4 or free T4 into the upper half of the normal range for age and normalizing the serum TSH level24. As reviewed above, it is important to normalize thyroid function as rapidly as possible to achieve the best neurocognitive outcome. Given the current recommendation to use starting L-T4 doses of 10-15 μg/kg/d, and perhaps even higher doses for the most severely affected infants, 12-17 μg/kg/d, the Oregon program reported that even higher serum T4 or FT4 levels may be seen before TSH normalizes. Using a linear regression analysis of T4 or FT4 vs TSH plot, the intercept at the lower range of normal for TSH (1.7 mU/l) showed T4 = 19.5 μg/dl and FT4 = 5.23 ng/dl31. The Oregon program recommended a higher ‘target range’ for the first 2 weeks of L-T4 treatment: • T4 10-18 μg/dl (130-232 nmol/l) • FT4 2.0-5.0 ng/dl (25.7-64 pmol/l) • TSH 1.7-9.1 mU/l While these levels are high, they are similar to the normal, high ranges seen in the first few weeks after birth64, so that, in a sense, high-dose treatment would be duplicating the ‘hyperthyroxinemia’ seen with the postnatal TSH surge. Also, bear in mind that these ranges are only for the first 2 weeks after starting treatment; after the first 2 weeks, the target ranges drop (see below). Studies examining the age of onset of treatment and psychometric outcome emphasize the impor-tance of starting treatment at as early an age as possible, with frequent monitoring. In our review of the literature, of 11 studies comparing starting treatment at an earlier age (range 12-30 days of life) vs at a later age, infants starting at the earlier age averaged 15.7 IQ points higher than those infants started at a later age (see Table 6).

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MONITORING L-THYROXINE TREATMENT: THYROID FUNCTION TESTS; FREQUENCY;

BIOCHEMICAL AND CLINICAL OBJECTIVES; AVOIDING PROLONGED OVER-TREATMENT

Thyroid function tests

• T4 or FT4 • TSH Measurement of serum TSH is the single most sensitive test to monitor L-T4 treatment. However, a TSH test alone is not adequate to monitor treatment of congenital hypothyroidism. After initiation of L-T4, serum TSH may take several weeks or longer to fall into the normal range. Some infants may manifest a persistently elevated TSH level, despite other evidence, both clinical and biochemical, that the T4 dose is correct (see below, ‘patients with altered hypothalamic-pituitary-thyroid axis feedback’). Thus, in general it is safest to measure both T4 or FT4 and TSH levels to make correct decisions about dose adjustments. It is important to compare the result to the normal range for age. Measurement of serum T3 or free T3 (FT3) is not useful in monitoring treatment, as these tests may be normal, despite a low T4 or FT4 and elevated TSH level.

Frequency of monitoring thyroid function tests

When treating infants with congenital hypo-thyroidism, it is important to carry out thyroid function tests more frequently than in, for example, older children with acquired hypothyroidism. Infants undergo rapid growth and development in the first 2-3 years of life, and more frequent dose changes may be necessary. Further, during this time of

critical brain dependence on normal thyroid levels, it is important to try to prevent prolonged periods of either under- or over-treatment. Whereas the effects of under- or over-treatment are reversible in adolescents, they may have permanent effects in infancy. The current guidelines for frequency of monitoring thyroid tests are presented in Table 7. Testing may need to be carried out at more frequent intervals when compliance is questioned, abnormal values are obtained, or the source of thyroid hormone is changed, e.g., from one brand to another brand, to a generic, or from one generic to another generic L-thyroxine.

Biochemical and clinical objectives of treatment

As before, the biochemical goals are to keep the serum T4 or FT4 in the upper half of the normal range for age, with the TSH now suppressed to the lower half of the normal range. After the first two weeks of treatment, serum thyroid test target range guidelines are24: • T4 10-16 μg/dl (130-206 nmol/l) • FT4 1.4-2.3 ng/dl (18-30 pmol/l) • TSH 0.5-2.0 mU/l As stated previously, the overall goal of treat-ment is to assure normal growth and development. The treatment dose does not appear to be as critical for growth, as essentially all studies show normal growth of infants with congenital hypothyroidism detected by newborn screening programs. Salerno et al. from Italy reported that, while onset and progression of puberty were normal in girls and boys, girls started on an initial L-T4 dose >8 μg/kg/d entered puberty a year earlier, with

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menarche also a year earlier, as compared to girls started on a lower dose65. However, all the children in the study (boys and girls) reached a similar adult height (0.1 ± 1.1 SDS), which was actually greater than mid-parental target height (-0.9 ± 0.9 SDS). No significant correlation was found between adult height and specific etiology or severity of con-genital hypothyroidism or initial starting T4 dose.

Avoiding prolonged over-treatment

Prolonged over-treatment, typically presenting as a serum T4 or FT4 above the normal range accompanied by a suppressed TSH level, may lead to adverse effects. Animal studies report that prolonged over-treatment accelerates the tempo of brain development, resulting in premature comple-tion of brain development with fewer neurons and disordered myelination66. In infancy, over-treatment has been associated with premature fusion of the skull bones and craniosynostosis. Behavior issues, including problems with temperament67 and short attention span68, have been reported. With appropriate monitoring and T4 dose adjustments, these adverse effects are generally avoided or reversible.

PATIENTS WITH ALTERED HYPOTHALAMIC-PITUITARY-THYROID AXIS FEEDBACK (‘THYROID HORMONE RESISTANCE’)

VS COMPLIANCE ISSUES

Under normal conditions, there is a log-linear relationship between serum FT4 and TSH69. Some treated children with congenital hypothyroidism, however, manifest a persistently elevated serum TSH level, typically in the 10-20 mU/l range, despite FT4 or T4 in the upper half of the normal range. If the T4 dose is raised to normalize the TSH level, the serum FT4 or T4 is elevated above the normal range and some patients will manifest hyperthyroid symptoms. This mild pituitary-thyroid resistance is speculated to be a result of a resetting of the hypothalamic-pituitary-thyroid feedback axis70. This abnormal feedback threshold was seen in 43% of infants <1 year of age, decreasing to 10% of children by age 10 years70. It appears to be a characteristic of congenital hypothyroidism, as it was not found in children with acquired hypo-

thyroidism71. If there is evidence for an abnormal feedback threshold, we recommend using primarily the serum FT4 or T4 and clinical assessment to adjust the L-T4 dose, allowing the serum TSH to remain slightly elevated. Most cases resolve with time. Some treated children with congenital hypo-thyroidism will manifest an elevated serum TSH with FT4 or T4 in the upper half of the normal range as a result of irregular compliance. Such children will typically have had normalization of the serum TSH and FT4 in the past, evidence that they do not have a feedback axis abnormality. The explanation for these findings appears to be irregular administration of T4 until just before an appointment and blood testing, when missed doses are quickly made up. Under these circumstances, serum FT4 or T4 will increase quickly, over 24 h, while serum TSH may take several weeks to fall into the normal range69.

PERMANENT VS TRANSIENT CONGENITAL HYPOTHYROIDISM

Some patients detected by newborn screening will have a transient form of hypothyroidism. In North America, it is estimated that 10-20% of cases are transient15, while in Europe the frequency appears to be higher, primarily a result of transient cases in infants born in areas of iodine deficiency72. Some clinicians elect to carry out thyroid scinti-graphy or ultrasonography at the time of detection by newborn screening. If such imaging studies show an ectopic gland, or absent thyroid uptake, confirmed by ultrasonography, a permanent form of hypothyroidism is present. If an inborn error of thyroid hormone biosynthesis is suspected, for example, with a goiter and elevated radioiodine uptake, this is evidence for a permanent defect. Permanent hypothyroidism can also be assumed if the serum TSH concentration rises to >10 mU/l after 6 months of life, as the infant outgrows the T4 replacement dose or there are issues with compli-ance. If permanent hypothyroidism has not been established, guidelines recommend stopping T4 treatment sometime after 3 years of age, waiting 4 weeks, and then checking serum FT4 or T4 and

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TSH24. If the TSH is elevated and FT4 or T4 is low, permanent hypothyroidism is confirmed. On the other hand, if thyroid function tests are normal, transient hypothyroidism is presumed. If results are inconclusive (e.g., normal FT4 or T4 and slightly elevated TSH), careful follow-up and retesting are indicated. In cases of transient congenital hypothyroidism, one may sometimes not be sure whether there truly was transient hypothyroidism, or whether the infant had false positive thyroid screening tests. Fortu-nately, studies of infants with transient congenital hypothyroidism, treated for anywhere from 6 weeks to 2 years, showed normal growth and development out to 6-14 years of age73.

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40. Bongers-Schokking JJ, Koot HM, Wiersma D, Verkerk PH, de Muinck Keizer-Schrama SM. Influence of timing and dose of thyroid hormone replacement on develop-ment in infants with congenital hypothyroidism. J Pediatr 2000; 136: 292-297.

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48. Rovet J, Ehrlich R, Sorbara D. Intellectual outcome in children with fetal hypothyroidism. J Pediatr 1987; 110: 700-704.

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53. Chiovato L, Giusti L, Tonacchera M, Ciampi M, Mammoli C, Lippi F, Lapi P, Bargagna S, Dini P, Ferretti G, et al. Evaluation of L-thyroxine replacement therapy in children with congenital hypothyroidism. J Endocrinol Invest 1991; 14: 957-964.

54. Bargagna S, Canepa G, Costagli C, Dinetti D, Marcheschi M, Millepiedi S, Montanelli L, Pinchera A, Chiovato L. Neuropsychological follow-up in early-treated congenital hypothyroidism: a problem-oriented approach. Thyroid 2000; 10: 243-249.

55. Kooistra L, Laane C, Vulsma T, Schellekens JMH, van der Meere JJ, Kalverboer AF. Motor and cognitive development in children with congenital hypothyroid-ism: a long-term evaluation of the effects of neonatal treatment. J Pediatr 1994; 124: 903-909.

56. Kempers MJE, van der Sluijs Veer L, Nijhuis-van der Sanden MW, Kooistra L, Wiedijk BM, Faber I, Last BF, de Vijlder JJ, Grootenhuis MA, Vulsma T. Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening. J Clin Endocrinol Metab 2006; 91: 418-424.

57. Illig R, Largo RH, Weber M, Augsburger T, Lipp A, Wissler D, Perrenoud AE, Torresani T. Sixty children with congenital hypothyroidism detected by neonatal thyroid: mental developmental at 1, 4, and 7 years: a longitudinal study. Acta Endocrinol 1986; Suppl 279: 346-353.

58. Hsiao PH, Chiu YN, Tsai WY, Su SC, Lee JS, Soong WT. Intellectual outcome of patients with congenital hypo-thyroidism detected by neonatal screening. J Formosan Med Assoc 2001; 100: 40-44.

59. Murphy G, Hulse JA, Jackson D, Tyrer P, Glossop J, Smith I, Grant D. Early treated hypothyroidism: development at 3 years. Arch Dis Child 1986; 61: 761-765.

60. Murphy GH, Hulse JA, Smith I, Grant DB. Congenital hypothyroidism: physiological and psychological factors in early development. J Child Psych Psychiat 1990; 31: 711-725.

61. Fuggle PW, Grant DB, Smith I, Murphy G. Intelligence, motor skills and behavior at 5 years in early-treated

congenital hypothyroidism. Eur J Pediatr 1991; 150: 570-574.

62. Simons WF, Fuggle PW, Grant DB, Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism. Arch Dis Child 1994; 71: 232-234.

63. Campos SP, Sandberg DE, Barrick C, Voorhess ML, MacGillivray MH. Outcome of lower l-thyroxine dose for treatment of congenital hypothyroidism. Clin Pediatr 1995; 34: 514-520.

64. Nelson JC, Clark SJ, Borut DL, Tomei RT, Carlton EI. Age-related changes in serum free thyroxine during child-hood and adolescence. J Pediatr 1993; 123: 889-905.

65. Salerno M, Micillo M, Di Maio S, Capalbo D, Ferri P, Lettiero T, Tenore A. Longitudinal growth, sexual maturation and final height in patients with congenital hypothyroidism detected by neonatal screening. Eur J Endocrinol 2001; 145: 377-383.

66. Weichsel ME Jr. Thyroid hormone replacement therapy in the perinatal period: neurologic considerations. J Pediatr 1978; 92: 1035-1038.

67. Rovet J, Ehrlich RM, Sorbara DL. Effect of thyroid hormone levels on temperament in infants with con-genital hypothyroidism detected by screening of neonates. J Pediatr 1989; 114: 63-68.

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69. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruf J, Smyth PP, Spencer CA, Stockigt JR; Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid diseases. Thyroid 2003; 13: 3-126.

70. Fisher DA, Schoen EJ, LaFranchi S, Mandel SH, Nelson JC, Carlton EI, Goshi JH. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab 2000; 85: 2722-2727.

71. Kempers MJ, van Trotsenburg AS, van Tijn DA, Bakker E, Wiedijk BM, Endert E, de Vijlder JJ, Vulsma T. 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: 4094-5000.

72. Delange F, Heidemann P, Bourdoux P, Larsson A, Vigneri R, Klett M, Beckers C, Stubbe P. Regional variations of iodine nutrition and thyroid function during the neonatal period in Europe. Biol Neonate 1986; 49: 322-330.

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572 S.H. LaFRANCHI AND J. AUSTIN

TABLE 3

Time course of thyroid function with initial L-T4 treatment dose

Screening program T4 dose (μg/kg/d)

Time to serum T4 >10 μg/dl

(days)

Time to serum TSH <9.1 mU/l

(days)

Quebec25 6 45-90

Toronto26 7-9 74

France27 8 15 60

New England28 10 31

US (Pennsylvania)29 10-14 7 150

Italy30 10-15 30 30

US (Oregon)31 12-17 3 14

TABLE 7

Frequency of monitoring serum T4 or FT4 and TSH24

• 2 and 4 weeks after initiation of L-T4 treatment

• Every 1 to 2 months in the first 6 months of life

• Every 3 to 4 months between 6 months and 3 years

• Every 6 to 12 months until growth is completed

• 4 weeks after any change in L-T4 dose

JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TABLE 4

Studies comparing different starting L-thyroxine doses and effect on IQ

Study by location

No. of patients

L-T4 dose Age of psycho-metric test

Type of test Results

FSIQ 101.9 vs 98.1 (NS) VIQ 103.3 vs 98.9 (NS) <8 μ g/kg/d vs >8 μ g/kg/d PIQ 99.5 vs 98.4 (NS)

FSIQ 101.8 vs 95.9 (p=0.05) VIQ 103.2 vs 96.4 (p=0.04)

Australia Connelly et al.36 2001

95

<10 μ g/kg/d vs >10 μ g/kg/d

8 yr WISC-R

PIQ 99.9 vs 97.0 (NS)

FSIQ 100 vs 107.6 (p=0.01) VIQ 98.6 vs 106.3 (p=0.01) 91 7 yr WISC-R PIQ 103.8 vs 108.2 (NS)

McCarthy Memory 46.6 vs 53.8 (p=0.01)

Toronto, Canada Rovet & Ehrlich34

1995 88

≤7.7 μg/kg/d vs ≥7.8 μg/kg/d

8 yr Woodcock Reading Mastery-Revised 50.1 vs 59.3 (P=0.05)

<6.0 μg/kg/d vs 6.2-7.8 μg/kg/d vs 8.2-12.3 μg/kg/d 95.9 vs 102.5 vs 109.3 (NS) Toronto, Canada

Rovet37 2005

? <6.0 μg/kg/day vs 8.2-12.3 μg/kg/d

6, 7, or 9 yr McCarthy, WISC-R 95.9 vs 109.3 (p<0.05)

GIQ 112.1 vs 117.3 (p<0.03) VIQ 109.1 vs 112.8 (NS) <6 μg/kg/d vs ≥6 μg/kg/d PIQ 112.8 vs 117.3 (p<0.02)

GIQ 110.2 vs 114.2 vs 116.9 (NS) VIQ 107.3 vs 111.0 vs 112.7 (NS)

131

<5 μg/kg/d vs 5-7 μg/kg/d vs ≥7 μg/kg/d

PIQ 110.9 vs 115.0 vs 117.6 (NS)

76 < 21 days: GIQ 116.4 vs 118.4 (NS)

France Boileau et al.38 2004

55 <6 μg/kg/d vs ≥6 μg/kg/d

7 yr WISC-R and WISC-III

> 21 days: GIQ 108.0 vs 113.0 (NS)

Italy Salerno et al.39 1995

47 <7 μg/kg/d vs ≥7 μg/kg/d 7 yr Stanford-Binet test 96 vs 94 (NS)

Study by location

No. of patients

L-T4 dose Age of psycho-metric test

Type of test Results

FSIQ 88 vs 94 vs 98 (p=0.009)

VIQ 92 vs 94 vs 98 (NS) 83 6-8 μg/kg/d vs 8.1-10 μg/kg/d vs 10.1-15 μg/kg/d

PIQ 85 vs 95 vs 98 (p<0.0001)

FSIQ 84 vs 97 (p<0.05) VIQ 89 vs 98 (NS)

Italy Salerno et al.30 2002

32 6-8 μg/kg/d vs 10.1-15 μg/kg/d

4 yr WPPSI-R

PIQ 80 vs 96 (p<0.05)

Mild: MDI 124 vs 110 vs 125 vs 122 (p=0.016) 34 Early/Low vs Late/Low vs

Early/High vs Late/High PDI 123 vs 111 vs 120 vs 117 (NS)

Severe: MDI 103 vs 97 vs 124 vs 99 (p=0.035)

The Netherlands Bongers-Schokking et al.40

2000 27 Early/Low vs Late/Low vs Early/High vs Late/High

21.7 mo

Bayley Test: Mental Development Index

(MDI) and Psychomotor

Development Index (PDI) PDI 109 vs 113 vs 123 vs 101 (p=0.001)

Early (<13 days): Rakit 106.5 vs 104.6 (NS)

VMI 89.0 vs 96.3 (NS) 19

Verbal Score 92.7 vs 91.0 (NS)

Late (>13 days): Rakit 100.1 vs 108.2 (NS)

VMI 90.9 vs 93.3 (NS)

The Netherlands Bongers-Schokking & de Muinck Keizer-Schrama41

2005 26

Low (<9.5 μg/kg/d) vs

High (>9.5 μg/kg/day)

72.5 mo

Rakit; Beery-Buktenica Developmental Test for

Visual-Motor Integration; Language

Test for Children

Verbal Score 64.3 vs 99.4 (p=0.001)

FSIQ 109 vs 98 (NS) Language 105.6 vs 96.2 (NS) Visuomotor 108.9 vs 95.2 (p=0.035)

Kansas City, MO Schwartz et al.42 1994

14 <7.5 μg/kg/d vs >7.5 μg/kg/d (1 to 3 mo) 9.6 yr WISC-R; Beery VMI;

WRAT-R

Perceptual/Numerical 103.3 vs 98.1 (NS)

37.5 μg/day (10.9 μg/kg/d) vs Mullen Scales of Early Learning (<4 yr)

FSIQ 89.5 vs 95.3 vs 100.6 (p<0.05, low vs high dose)

62.5 μg/day x 3 days, then 37.5 μg/day WPPSI-R (4-6 yr) VIQ NS

Portland, OR Selva et al.32 2005

31

50 μg/day (14.5 μg/kg/d)

WISC-III and WRAT-III (>6 yr) PIQ NS

2

TABLE 5

Studies comparing severity of congenital hypothyroidism and effect on IQ

Study by Location

No. of patients

Criterion Age of psycho-metric Test

Type of test Results

FSIQ 96.1 vs 101.1 vs 101.5 (NS)

VIQ 95.8 vs 99.4 vs 102.8 (NS) 119 athyreosis vs dyshormonogenesis vs ectopia

PIQ 97.7 vs 101.2 vs 100.0 (NS)

FSIQ 96.7 vs 103.0 (p=0.03)

VIQ 96.9 vs 103.7 (p=0.03) 106 TT4 <3.1 vs >3.1 μg/dl

PIQ 97.4 vs 101.6 (NS)

FSIQ 97.5 vs 101.8 (NS) VIQ 98.2 vs 101.8 (NS)

Victoria, Australia Connelly et al.36

2001

88 BA ≤36 wk vs >36 wk

8 yr WISC-R

PIQ 97.9 vs 101.2 (NS)

FSIQ 91.4 vs 102.73 (NS) VIQ 91.75 vs 104.55 vs (p=0.030)

Brazil Kreisner et al.46

2004 31 T4 ≤2.5 μg/dl vs >2.5 μg/dl >4 yr WPPSI (4-6 yr),

WISC (6 yr-15 yr 11 mo) PIQ 92.70 vs 99.64 (NS)

GIQ 86 vs 102 (p<0.001) VIQ 83 vs 99 (p<0.001)

Quebec, Canada Glorieux et al.25

1988 19

T4 <2 μg/dl and bone surface <0.05 cm2 vs T4 >2 μg/dl and/or

bone surface ≥0.05 cm29 yr WISC-R

NVIQ 92 vs 107 (p<0.001)

GIQ 89 vs 104 (p<0.007) VIQ 84 vs 99 (p<0.009)

Quebec, Canada Glorieux et al.44

1992 27

T4 <2 μg/dl and bone surface <0.05 cm2 vs T4 >2 μg/dl and/or

bone surface ≥0.05 cm212 yr WISC-R

NVIQ 96 vs 109 (p<0.02)

Quebec, Canada Dubuis et al.45

1996 45 Area of the knee epiphyses

<0.05 cm2 vs ≥0.05 cm2 18 mo Griffiths’ Scales 107 vs 110 (NS)

Quebec, Canada Simoneau-Roy et al.47 2004

18 Area of the knee epiphyses <0.05 cm2 vs ≥0.05 cm2 5 yr 9 mo McCarthy Scale General Cognitive Index 102 vs 102 (NS)

3

Study by Location

No. of patients

Criterion Age of psycho-metric Test

Type of test Results

FSIQ 97.8 vs 109.2 (p=0.02) PIQ 96.8 vs 109.1 (p=0.01) WPPSI VIQ 9.9 vs 11.9 (p=0.04)

Beery-Buktenica Developmental Test of

Visual Motor Integration 42.3 vs 72.4 (p=0.02)

McCarthy Scale 45.5 vs 53.9(p=0.02)

Toronto, Canada Rovet et al.48

1987 34 BA ≤36 wk vs >36 wk 5 yr

Reynell Developmental Language Scales (Revised) -0.233 vs 0.692 (p=0.02)

FSIQ 103.4 vs 106.7 vs 107.1 (NS) VIQ 102.9 vs 110 vs 105.1 (NS) 95 athyreosis vs

dyshormonogenesis vs ectopia PIQ 10.2 vs 10.7 vs 11.3 vs 12.1 (NS)

BA ≤36 wk vs >36 wk FSIQ 104 vs 109.8 (p=0.045)

Toronto, Canada Rovet et al.49

1992 108

T4 <4.0 μg/dl vs >4.0 μg/dl

5 yr WPPSI

NS

Toronto, Canada Rovet50

1999 48 athyreosis vs dyshomonogenesis

vs ectopia >13 yr WISC-III 97.1 vs 106.3 vs 102.1 (NS)

FSIQ 91.6 vs 98.1 vs 102.9 (p=0.05) VIQ 94.9 vs 96.4 vs 101.6 (NS)

Toronto, Canada Song et al.51

2001 62 athyreosis vs

dyshormonogenesis vs ectopia 8.8 yr WISC-III PIQ 89.3 vs 97.8 vs 106.2 (p=0.01)

33 BA ≤36 wk vs >36 wk 97.5 vs 105.9 (NS) Toronto, Canada Rovet37

2005 ? T4 <3.5 μg/dl vs >3.5 μg/dl 6, 7, or 9 yr McCarthy, WISC-R

102.2 vs 103.1 (NS)

GIQ 111.5 vs 118.4 vs 113.1 (NS) VIQ 108.0 vs 116.8 vs 109.3 (NS)

France Boileau et al.38

2004 131 athyreosis vs

dyshormonogenesis vs ectopia 7 yr WISC-R and WISC-III PIQ 113.0 vs 117.0 vs 114.1 (NS)

4

Study by Location

No. of patients

Criterion Age of psycho-metric Test

Type of test Results

T4 1.1 μg/dl and BA 31.5 wk vs 27

T4 6.3 μg/dl and BA 40.1 wk 93 vs 99 (p<0.05) Italy

Salerno et al.39

1995 47 T4 <2 μg/dl vs >2 μg/dl;

BA 33.1 wk vs 36.8 wk (p<0.01)

7 yr Stanford-Binet test 92 vs 98 (p<0.02)

FSIQ 78.5 vs 90.8 (p=0.02) VIQ 83.6 vs 95.6 (p=0.04)

Italy Salerno et al.52

1999 40 athyreosis vs other 12.25 yr WISC-R

PIQ 76.4 vs 87.0 (p<0.04)

6-8 mg/kg/day: FSIQ 84 vs 92 (p<0.05) VIQ 89 vs 95 (NS) 42 PIQ 80 vs 87 (p<0.05)

8.1-10 mg/kg/day: FSIQ 93 vs 95 (NS) VIQ 94 vs 94 (NS) 21 PIQ 92 vs 98 (NS)

10.1-15 mg/kg/day: FSIQ 97 vs 99 (NS) VIQ 98 vs 98 (NS)

Italy Salerno et al.30

2002

20

T4 <3.1 μg/dl vs ≥3.1 μg/dl 4 yr WPPSI-R

PIQ 96 vs 100 (NS)

Italy Chiovato et al.53

1991 19 hypoplasia/aplasia vs ectopia 3 yr Stanford Binet Scales 97 vs 105 (NS)

Pisa, Italy Bargagna et al.54

2000 24 T4 <2 μg/dl vs >2 μg/dl 7 yr WISC-R 101.7 vs 107.7 (NS)

GIQ 91.8 vs 99.1 (NS) VIQ 93.1 vs 96.8 (NS) 46 athyreosis vs other PIQ 92.1 vs 101.8 (NS)

GIQ 94.8 vs 101.4 (p<0.01) VIQ 93.9 vs 98.6 (p<0.01)

The Netherlands Kooistra et al.55

1994 61 T4 <3.9 μg/dl vs ≥3.9 μg/dl

9½ yr WISC-R

PIQ 97.0 vs 104.5 (NS)

5

Study by Location

No. of patients

Criterion Age of psycho-metric Test

Type of test Results

MDI 106 vs 118 (p=0.002) 61

PDI 111 vs 117 (NS)

Low/Late: MDI 97 vs 110 (NS) 16

PDI 113 vs 111(NS)

Low/Early: MDI 103 vs 124 (p<0.005) 16

PDI 109 vs 123 (p<0.005)

High/Late: MDI 99 vs 122 (p<0.005) 12

PDI 101 vs 117 (p<0.005)

High/Early: MDI 124 vs 125 (NS)

The Netherlands Bongers-Schokking et al.40

2000

17

severe (athyreosis/total dyshomonogenesis) vs mild

(dystopic gland/partial dyshormonogenesis)

21.7 mo

Bayley Test: Mental Development Index (MDI)

and Psychomotor Development Index (PDI)

PDI 123 vs 120 (NS)

Rakit 99.4 vs 108.5 (NS)

Beery-Buktenica Developmental Test for

Visual-Motor Integration 86.3 vs 96.5 (p=0.048)

The Netherlands Bongers-Schokking & de Muinck Keizer-Schrama41 2005

45 severe vs mild (see above) 72.5 mo

Language Test for Children 82.8 vs 88.4 (NS)

FSIQ 91.3 vs 99.1 vs 101.3 (severe vs mild p=0.043) VIQ 92.9 vs 97.8 vs 101.8 (NS) PIQ 90.4 vs101.3 vs 100.4

The Netherlands Kempers et al.56

2006 70 T4 <2.3 μg/dl vs 2.3 μg/dl –

4.7 μg/dl vs ≥4.7 μg/dl 21.5 yr WISC-III

(severe vs moderate p=0.031, severe vs mild p=0.037)

athyreosis vs ectopia NS Zurich, Switzerland Illig et al.57

1986

13 prenatal BA vs normal skeletal maturation

7 yr The German version of WPPSI (HAWIVA) NS

62 T4 <2 μg/dl vs ≥2 μg/dl 95 vs106 (p<0.05)

48 <3 vs ≥3 ossification centers 91 vs 104 (p<0.05)

36 femoral epiphysis area <0.1 cm2 vs ≥0.1 cm2 92 vs 106 (p<0.05)

Taipei, Taiwan Hsiao et al.58

2001

62 athyreosis vs dyshormonogenesis vs ectopia

3.8 yr Chinese Fourth Revision of Binet-Simon Scales

95 vs 97 vs 103 (NS)

6

Study by Location

No. of patients

Criterion Age of psycho-metric Test

Type of test Results

36 T4 <1.6 μg/dl vs >4.7 μg/dl 94 vs 106 (p=0.013) UK Murphy et al.59

1986 35 T3 ≤130 ng/dl vs >130 ng/dl 3 yr McCarthy Scale

93 vs 105 (p<0.01)

37 BA <30 wk vs >30 wk 93 vs 103 (p=0.03) UK Murphy et al.60

1990 51 athyreosis vs other 3 yr McCarthy Scale

89.5 vs 103.2 (NS)

T4 <1.6 μg/dl vs 1.6-4.7 μg/dl vs >4.7 μg/dl FSIQ 100.4 vs 109.3 vs 115.4 UK

Fuggle et al.61

1991 57

TSH >500 mU/l vs 250-500 mU/l vs <250 mU/l

5 yr WPPSI FSIQ 108.1 vs 107.4 vs 110.9 (NS)

FSIQ 104.7 vs 114.6 (p<0.05) VIQ 105.4 vs 114.2 (p<0.05)

UK Simons et al.62

1994 59 T4 ≤3.1 μg/dl vs >3.1 μg/dl 10 yr WISC-R

PIQ 103.1 vs 112.0 (p<0.05)

325 T4 0.1-0.9 μg/dl vs 1.0-1.6 vs 1.6-2.3 vs 2.4-3.1 vs 3.2-4.7 vs

4.7-6.2 vs 6.3-18.5 μg/dl

101.5 vs 100.6 vs 103.3 vs 103.1 vs 112 vs 110.3 vs 111.5 (linear trend p=0.003, analysis of variance p<0.0001)

186 T4 <3.3 μg/dl vs ≥3.3 μg/dl (manual and unemployed) 97.5 vs 109.1

UK Tillotson et al.43

1994

159 T4 <3.3 μg/dl vs ≥3.3 μg/dl (non-manual)

5 yr WPPSI

107.6 vs 115.5

FSIQ 95.9 vs 106.8 (NS) PIQ 95.9 vs 105.8 (NS) 15 BA ≤32 wk vs >32 wk VIQ 96.7 vs 106.1 (p=0.05)

FSIQ 95.5 vs 105.0 (NS) PIQ 96.5 vs 103.5 (NS)

Buffalo, NY Campos et al.63

1995 16 T4 <2 μg/dl vs >2 μg/dl

5 yr WPPSI-R

VIQ 95.5 vs 105.2 (p=0.04)

FSIQ 89 vs 100.3 (p=0.05) VIQ 4.8 difference (NS) PIQ 9.2 difference (NS)

Portland, OR Selva et al.32

2005 30 T4 <1.6 μg/dl vs ≥1.6 μg/dl

Mullen Scales of Early Learning (< 4 yr), WPPSI-R

(4-6 yr), WISC-III and Wide-Range achievement

Test Revision 3 (WRAT-III) (> 6 yr)

7

TABLE 6

Studies comparing timing of onset of L-thyroxine therapy and effect on IQ

Study by location No. of patients

Age of onset of treatment

Age of psycho-metric test

Type of test Results

FSIQ 98.1 vs 99.6 (NS)

VIQ 98.2 vs 100.4 (NS) Victoria, Australia Connelly et al.36

2001 109 >14 days vs ≤14 days 8 yr WISC-R

PIQ 98.3 vs 99.3 (NS)

FSIQ 91.67 vs 103.30 (NS)

VIQ 93.48 vs 102.20 (NS) Brazil Kreisner et al.46

2004 31 >30 days vs ≤30 days >4 yr

WPPSI (4-6 yrs), WISC (6 yrs-15 yrs 11 mos)

PIQ 91.43 vs 103.00 (p=0.036)

Toronto, Canada Rovet37

2005 ? >12 days vs <12 days 6, 7, or 9 yr McCarthy, WISC-R 105.1 vs 100.5 (NS)

GIQ 108.6 vs 117.1 (p<0.01)

VIQ 105.4 vs 113.5 (p<0.017) >21 days vs ≤21 days

PIQ 109.7 vs 117.6 (p<0.008)

GIQ 109.8 vs 107.7 vs 115.3 vs 119.2 (p=0.0008)

VIQ 106.3 vs 104.7 vs 111.6 vs 115.8 (p=0.007)

131 >30 days vs 22-30 days

vs 15-21 days vs <15 days PIQ 110.4 vs 109.1 vs 116.5 vs 118.8 (p=0.0009)

95 <6 mg/kg/day: GIQ 108.0 vs 116.4 (p=0.0009)

France Boileau et al.38

2004

36 >21 days vs ≤21 days

7 yr WISC-R and WISC-III

>6 mg/kg/day: GIQ 113.0 vs 118.4 (NS)

Italy Salerno et al.39

1995 24 42.4 vs 18.3 days 7 yr Stanford-Binet test 98 vs 95 (NS)

8.1-10 mg/kg/day: FSIQ 91 vs 96 (NS)

VIQ 93 vs 98 (NS) 21

PIQ 90 vs 95 (NS)

10.1-15 mg/kg/day: FSIQ 98 vs 98 (NS)

VIQ 98 vs 98 (NS)

Italy Salerno et al.30

2002 20

>21 days vs <21 days 4 yr WPPSI-R

PIQ 98 vs 99 (NS)

8

Study by location No. of patients

Age of onset of treatment

Age of psycho-metric test

Type of test Results

Severe: MDI 97 vs 99 vs 103 vs 124 (p=0.035) 34

late/low vs late/high vs early/low vs early/high PDI 113 vs 101 vs 109 v. 123 (p=0.001)

Mild: MDI 110 vs 122 vs 124 vs 125 (p=0.016)

The Netherlands Bongers-Schokking et al.40

2000 27 late/low vs late/high vs early/low vs early/high

21.7 mo Bayley Test: Mental Development

Index (MDI) and Psychomotor Development Index (PDI)

PDI 111 vs 117 vs 123 vs 120 (NS)

Low (<9.5 mg/kg/day): Rakit 100.1 vs 106.5 (NS)

VMI 90.9 vs 89.0 (NS) 21

Verbal Score 64.3 vs 92.7 (p=0.001)

High (>9.5 mg/kg/day): Rakit 108.2 vs 104.6 (NS)

VMI 93.3 vs 96.3 (NS)

The Netherlands Bongers-Schokking & de Muinck Keizer-Schrama41

2005 24

late (≥13 days) vs early (<13 days)

72.5 mo

Rakit; Beery-Buktenica Developmental Test for Visual-

Motor Integration; Language Test for Children

Verbal Score 99.4 vs 91.0 (NS)

Taipei, Taiwan Hsiao et al.58

2001 62 ≥30 days vs <30 days 3.8 yr

Chinese Fourth Revision of Binet-Simon Scales

102 vs 101 (NS)

UK Fuggle et al.61

1991 57

>30 days vs 22-30 days vs 0-21 days

5 yr WPPSI FSIQ 104.5 vs 109.6 vs 111.7

UK Tillotson et al.43

1994 361

26-173 vs 21-25 vs 16-20 vs 11-15 vs 1-10

5 yr WPPSI 106.3 vs 110.7 vs 105.9 vs 104.5 vs 104.2 (NS)

9