How Should We Be Treating Children with Congenital Hypothyroidism?

© 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 KEY WORDS Early detection by newborn screening and congenital hypothyroidism, newborn screening, appropriate L-thyroxine treatment leads to thyroid dysgenesis, dyshormonogenesis, L- normal or near-normal neurocognitive outcome thyroxine, neurocognitive outcome, IQ in infants with congenital hypothyroidism. Many newborns with congenital hypothyroidism INTRODUCTION have some residual thyroid hormone production, and even in those with athyreosis, trans- Delay in diagnosis or suboptimal treatment of placental passage of maternal thyroid hormone congenital hypothyroidism results in variable offers some protection for a time. Given the mental retardation, whereas early detection and serum T4 half-life of 6 days, the neonatal T4 appropriate L-thyroxine hormone replacement leads level will fall and disappear over the first 2-3 to normal or near-normal neurocognitive outcome. weeks of life. Thus, there is a crucial ‘window of The developing brain has a critical dependence on opportunity’ to correct the hypothyroidism and thyroid hormone, beginning before birth and minimize the time the brain is exposed to hypo- extending through the first 2-3 years of life. There thyroxinemia. While there are few truly pros- is accumulating evidence that maternal thyroid pective, randomized clinical trials investigating hormone that crosses to the fetus is important for treatment parameters, studies measuring IQ normal brain development, even before onset of outcome support a starting L-thyroxine dose of significant fetal thyroid hormone production1. 10-15 μg/kg/day. Further, studies show that the Thyroid hormone receptor mRNAs (TRα1, TRα2, most severely hypothyroid infants are at risk for and TRβ1) are present from 7-8 weeks gestation in a 5-20 point decrease in IQ. Such infants may the fetal brain2,3. Type 2 or 5´-deiodinase (5´-D2) benefit from a starting dose of 12-17 μg/kg/d, mRNA is measurable from 7-8 weeks gestation3. which has been shown to normalize T4 in 3 days 5´-D2, which converts T4 to the biologically active and TSH in 2 weeks. Target serum T4 or free T4 T3, increases with hypothyroidism. While signifi- levels appear to be higher in the first two weeks cant fetal thyroid hormone production and of treatment. Infants require more frequent secretion does not begin until approximately 20 laboratory monitoring, every 1-2 months in the weeks, T4 can be demonstrated in the coelomic first 6 months and every 3-4 months until age 3 cavity as early as 6 weeks gestation4. The years, as the developing brain has a critical concentration of coelomic fluid T4 correlates dependence on thyroid hormone in the first 2-3 positively with maternal serum T4 levels5. Thus, if years of life. there is a significant role for thyroid hormone in fetal brain development before 20 weeks gestation, Reprint address: it is likely of maternal origin. In addition, it would Stephen H. LaFranchi, M.D. appear that normal maternal thyroid function is Department of Pediatrics [CDRCP] Oregon Health & Science University important for fetal neurodevelopment6. 707 SW Gaines St. Based on cord T4 levels in infants with total Portland, OR 97239, USA organification defects or thyroid agenesis, approxi- e-mail: lafrancs@ohsu.edu VOLUME 20, NO. 5, 2007 559

560 S.H. LaFRANCHI AND J. AUSTIN mately one-third of maternal T4 crosses to the fetus Even if treatment is started before 3 months of age, at birth7. Further, most infants with congenital there appears to be a small decrement in IQ. In the hypothyroidism have some residual thyroid tissue 1960s, most infants were treated with dessicated (the most common etiology of congenital hypothyroid (porcine thyroid, containing both T4 and thyroidism is an ectopic gland), so they are able to T3), with recommended starting doses in the range produce some thyroid hormone. Although the of 15-30 mg daily10. Most experts began combination of the maternal thyroid hormone recommending sodium L-thyroxine in the 1970s; at contribution and fetal thyroid hormone production this time and even in the early 1980s, the is still subnormal, it likely explains why the recommended starting dose was 6-8 μg/kg/day11. majority of newborns with congenital hypothyroidism are normally grown and lack obvious clinical TABLE 1 manifestations of hypothyroidism. Given the serum Inverse relationship between age at clinical diagnosis T4 half-life of approximately 6 days, the maternal of congenital hypothyroidism and IQ outcome9 contribution will fall and disappear over the first 2- 3 weeks of life. Thus, there is a crucial ‘window of Age of treatment IQ opportunity’ to detect this disorder and start treat- (months) mean range ment within this time frame. Further, it is critical to raise the serum T4 into the target range as rapidly 0-3 89 64-107 as possible, to minimize the time the brain is 3-6 71 35-96 exposed to hypothyroidism. Experience has shown that this requires higher starting L-thyroxine doses >6 54 25-80 than were initially recommended by newborn screening programs. In addition, frequent monitor- Congenital hypothyroidism is not usually a ing of thyroid function tests in the first 2-3 years of heritable disorder; the majority of cases are life is also important, to assure that thyroid function sporadic. Thus, it is not possible to identify a remains in the target range during this time of population of pregnant women who are at high-risk continued brain dependence on thyroid hormone. for delivering a newborn with hypothyroidism, and, short of fetal cord blood sampling, no reliable prenatal test has been developed. As described HISTORICAL PERSPECTIVE: CONGENITAL HYPOTHYROIDISM IN THE PRE-SCREENING ERA above, the clinical manifestations are often subtle, non-specific, or even absent at birth, so that most Prior to the onset of screening programs, a cases are not suspected or diagnosed clinically in comprehensive survey in Sweden reported that the the neonatal period. For these reasons, when incidence of congenital hypothyroidism during the technology allowed the measurement of T4 and 1969-1975 period was 1:6,9008. The authors stated TSH in the small volume of blood obtained for that “in spite of an efficient National Health Care newborn screening (eluted from filter paper speci- Program for infants, the diagnosis was delayed mens obtained by heel-prick), testing for congenital until after an age of three months in 52% of the hypothyroidism was added by programs starting in cases”. Klein et al. from Pittsburgh Children’s the mid-1970s12-14. Hospital examined the effect of age at clinical diagnosis and treatment on IQ9. If thyroid hormone TREATMENT OF INFANTS WITH CONGENITAL treatment was started before 3 months of age, the HYPOTHYROIDISM DETECTED BY mean IQ was 89 (see Table 1). If treatment was NEWBORN SCREENING started between 3 and 6 months, mean IQ fell to 71, while if treatment was started after 6 months of Newborn screening programs for the detection age, the mean IQ dropped to 54. Several studies of congenital hypothyroidism have been in place in indicate an inverse relationship between the age of many countries for approximately 30 years (Canada clinical diagnosis and treatment and IQ outcome. and the United States, most countries in Europe, JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TREATING CONGENITAL HYPOTHYROIDISM 561 Israel, Japan, Australia and New Zealand), and they L-THYROXINE TABLETS; T4 VS T4 + T3; have been developed more recently in parts of ADMINISTRATION, AND INHIBITORS Mexico, several countries in South America and L-Thyroxine: tablet vs liquid some in Asia and the Middle East. The incidence of congenital hypothyroidism ranges from 1:3,000 to At present, only L-thyroxine tablets should be 1:4,000 newborns in most reports. In the year 2000 used; there are no U.S. Food and Drug Administ- survey of United States screening programs, 1,635 ration (FDA)-approved liquid preparations. L- cases of permanent primary hypothyroidism were Thyroxine suspensions that may be prepared by detected among 4,125,135 infants, for an incidence individual pharmacists may lead to unreliable of 1:2,52315. The incidence from newborn screen- dosage. There is a report of a liquid T4 preparation ing programs is approximately twice that from the from Europe (manufactured by Henning Berlin; 1 pre-screening era. Most likely, this is the result of drop [50 μl] = 5 μg)18. Using a median starting detection of cases of transient hypothyroidism, dose of 12.3 μg/kg/d, serum TSH normalized milder cases of congenital hypothyroidism, or cases within 2 weeks, while using a slightly higher that would have been diagnosed later in childhood median dose of 12.7 μg/kg/d resulted in TSH and so thought to represent acquired hypothyroid- normalization within 1 week. Infants treated with ism. this liquid L-T4 for up to 2 years appeared to do The advent of newborn screening has resulted well, although follow-up psychometric testing has in dramatic improvement in the neurocognitive yet to be reported. Further studies leading to FDA outcome of infants with congenital hypothyroidism. approval should be carried out before this liquid T4 That said, it is the experience of many programs preparation is used by physicians in the United that undertake follow-up psychometric testing that States. infants tend to have a slight, 5-10 IQ point deficit compared to appropriate control groups16, and that T4 vs T4 + T3 they have an increased likelihood of having subtle learning problems, such as difficulty with voca- L-T4 is the treatment of choice. As T3 is the bulary, reading comprehension, arithmetic, and biologically active thyroid hormone, there has been memory17. It is therefore incumbent to examine recent interest in T4 + T3 combination treatment of ways in which we can improve treatment of infants hypothyroidism. While there is some evidence that detected with congenital hypothyroidism. T4 treatment alone may not normalize intracellular The overall goals of treatment are to assure T3 levels in all tissues19, the majority of brain T3 is normal growth and development, with neuro- derived from local monodeiodination of T420. cognitive outcome similar to the child’s genetic Further, the correct dose of T3 or the exact ratio of potential. Investigators have carried out studies of T4 and T3 in children has yet to be worked out. At the components of treatment to examine which present, the only ‘T4 + T3’ preparations available leads to the best neurocognitive outcome. Such are Armour dessicated thyroid, which may have investigations include examining the effect of variable potency, and thyrolar, a dessicated T4 and different starting L-thyroxine doses on the time- synthetic T3 combination. Given the priority of course of normalization of serum thyroid function protecting the brain from thyroid deficiency and the tests and on psychometric outcome. In addition, years of experience using L-thyroxine with good studies have examined the effects of severity of results, T4 remains the treatment of choice. congenital hypothyroidism and the age of initiation of treatment on psychometric outcome. The Administration following sections address several components of treatment. 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 VOLUME 20, NO. 5, 2007

562 S.H. LaFRANCHI AND J. AUSTIN 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 L-THYROXINE STARTING DOSE; TAILORING TO SEVERITY OF DISEASE; EFFECT OF TIMING, AND the bottle wall or settle at the bottom and so may INITIAL TREATMENT GOALS not be consumed. L-T4 starting dose Substances/disorders inhibiting gastrointestinal (G-I) absorption The current recommended starting dose is 10-15 μg/kg/day (American Academy of Pediatrics, Approximately 60-80% of ingested L-T4 is 2006)24. There is an inverse correlation between the absorbed from the G-I tract, primarily from the starting L-T4 dose and the time to achieve the small intestine21. Several substances are reported to desired serum T4 concentration (see Table 3). bind thyroxine and interfere with its absorption; Guidelines recommend raising the T4 or FT4 level these are listed in Table 2. Soy formula has been into the upper half of the normal range for age: T4 the best studied in infants with congenital hypo- = 10-16 μg/dl (130-206 nmol/l), FT4 = 1.4-2.3 thyroidism22. In a retrospective analysis, after ng/dl (18-30 pmol/l)24. Studies showed that the initiation of T4 treatment, infants fed soy formula historical starting dose of 6 μg/kg/d took 45-90 took much longer to achieve a serum TSH <10 days to raise the serum T4 to >10 μg/dl25, dropping mU/l than those on non-soy formula (median of to an average of 31 days at 10 μg/kg/d28, while 150 vs 40 days)23. In infants in whom soy formula using a dose of 10-14 μg/kg/d, the desired T4 was is deemed necessary, L-T4 should be given half reached in 7 days29. In a study from Oregon of way between soy feedings. Thyroid function should three starting treatment doses, the highest dose (50 be monitored carefully, and the dose of T4 μg/ day = 12-17 μg/kg/d) raised the serum T4 to increased as necessary to achieve desired FT4 and >10 μg/dl by 3 days and normalized the TSH by 2 TSH levels. In addition, disorders associated with weeks of treatment31. The intermediate dose (37.5 malabsorption, including celiac disease and Helio- μg/day = 9.4-12.4 μg/kg/d) or a loading dose bacter pylori infection, are associated with a need followed by the intermediate dose (62.5 μg/d for 3 for a higher T4 dose. Lastly, prolonged heat days followed by 37.5 μg/d), took 1 week to raise exposure of the L-T4 tablets may reduce the serum T4 to >10 μg/dl, while the serum TSH bioactivity. 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 TABLE 2 achieved normal thyroid function by 1 or 2 weeks Substances that interfere with L-thyroxine absorption after starting therapy32. These studies show that the current recommended starting L-T4 dose of 10-15 • Soy protein μg/kg/d leads to the most rapid normalization of • Iron (concentrated) thyroid function. Early reports of psychometric outcome using • Calcium (concentrated) the recommended starting L-T4 dose of 6-8 μg/kg/d • Aluminum hydroxide reported that global IQs were similar to control infants. The New England Congenital • Cholestyramine and other resins Hypothyroidism Collaborative reported a verbal IQ • Fiber supplements score of 109, a performance IQ of 107, and a full scale IQ of 109 at six years of age33. However, • Sucralfate other programs have reported that infants started on JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TREATING CONGENITAL HYPOTHYROIDISM 563 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), VOLUME 20, NO. 5, 2007

564 S.H. LaFRANCHI AND J. AUSTIN performance IQ was 103.8 vs 108.2 (p = NS), and In our review of the literature, we found ten full scale IQ was 100.0 vs 107.6 (p <0.01) in the studies examining the effect of different starting L- low vs high dose infants. A report from Italy T4 doses on psychometric outcome (see Table 4). compared psychometric outcome in infants started Of these, two reported no effect, while six reported on a ‘low’ (6-8 μg/kg/d), ‘intermediate’ (8.1-10 that lower starting doses on average correlated with μg/kg/d) or ‘high’ (10.1-15 μg/kg/d) dose of T430. a 12.3 point drop in IQ. Two studies actually The verbal IQs in the three treatment groups were reported that a lower T4 starting dose led to a better 92, 94 and 98, respectively (NS), but the perfor- IQ (average 8.6 points) as compared to the higher mance IQs were 85, 95, and 98, while the full scale dose. On balance, however, most studies found that IQs were 88, 94, and 98, respectively (both p children started on the currently recommended <0.01). In another report, the Norwegian neonatal starting L-T4 dose of 10-15 μg/kg/d have a better screening program reported psychometric testing neurocognitive outcome than children started on in young adults with congenital hypothyroidism the dose used when newborn screening programs detected by newborn screening, also correlating were initiated, 6-8 μg/kg/d. outcome with L-T4 starting dose35. Compared with control subjects, adults with congenital hypo- Tailoring L-thyroxine dose to severity of disease thyroidism had a lower verbal IQ (102.4 vs 110.2), performance IQ (101.1 vs 110.2), and total IQ Several programs have investigated psycho- (102.4 vs 111.4). A higher initial L-T4 dose cor- metric outcome in infants judged to have more related with higher verbal IQ, language tests, and severe congenital hypothyroidism. The screening arithmetic screening skills. The starting L-T4 dose program in England, Wales and Northern Ireland in school completers was 9.2 μg/kg/d, higher than reported that infants with pre-treatment serum T4 in non-completers, 7.1 μg/kg/d. In the study from <3.3 μg/dl (<42.8 nmol/l) had a global IQ 11.6 Oregon quoted above, patients starting on the points lower than infants with serum T4 >3.3 μg/ higher T4 dose (50 μg/d = 12-17 μg/kg/d) had full dl43. The Quebec Screening Network compared IQ scale IQ scores 11 points higher than those started outcome in a cohort of severely affected and on the lower dose (37.5 μg/d = 9.4-12.4 μg/kg/d)32. moderately affected infants, as judged by a serum JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TREATING CONGENITAL HYPOTHYROIDISM 565 T4 <2 μg/dl or >2 μg/dl and an epiphyseal surface function. Based on the studies comparing outcome area <0.05 cm2 or >0.05 cm2, respectively, both with severity of disease, we conclude that it is treated with a starting L-T4 dose of 6 μg/kg/d44. important to use the higher end of the dosage Serial psychometric testing up to age 12 years range, perhaps even extending it to 12-17 μg/kg/d, showed a global scale IQ 16 points lower in the in those infants judged to have more severe hypo- severely affected cohort. Subsequently, the Quebec thyroidism (e.g., serum T4 <5 μg/dl). group reported that using a starting L-T4 dose of 11.6 μg/kg/d “narrowed the gap”, such that IQs Initial biochemical goals were not statistically different between the moderate and severe groups (110 vs 107)45. Guidelines recommend raising the serum T4 or The Dutch newborn screening program free T4 into the upper half of the normal range for investigated both the effect of initial starting dose age and normalizing the serum TSH level24. (<9.5 or >9.5 μg/kg/d) and age of onset of As reviewed above, it is important to normalize treatment (<13 or >13 days of age) in infants thyroid function as rapidly as possible to achieve judged by thyroid scan results to have mild (pre- the best neurocognitive outcome. Given the current treatment mean FT4 = 0.67 ng/dl) or severe (pre- recommendation to use starting L-T4 doses of 10- treatment FT4 = 0.21 ng/dl) hypothyroidism40. In 15 μg/kg/d, and perhaps even higher doses for the the infants with more severe hypothyroidism, most severely affected infants, 12-17 μg/kg/d, the testing at 10-30 months of age showed IQ 21-27 Oregon program reported that even higher serum points lower in the groups treated with the lower T4 or FT4 levels may be seen before TSH dose and/or treated at a later age; the group treated normalizes. Using a linear regression analysis of with a high dose and at an early age had the best T4 or FT4 vs TSH plot, the intercept at the lower outcome (IQ = 125). On the other hand, all the range of normal for TSH (1.7 mU/l) showed T4 = infants with mild hypothyroidism did well, except 19.5 μg/dl and FT4 = 5.23 ng/dl31. The Oregon the group treated with a low dose and at a later age, program recommended a higher ‘target range’ for which had an IQ 22-25 points below the other the first groups. Re-evaluation at 6 years of age showed 2 weeks of L-T4 treatment: improvement, with a global IQ score of 104.7 for • T4 10-18 μg/dl (130-232 nmol/l) the entire group, similar to the control group of • FT4 2.0-5.0 ng/dl (25.7-64 pmol/l) children, 107.541. The mild group’s IQ was 108.5, while the severe group’s IQ was 99.4, but this • TSH 1.7-9.1 mU/l difference was not statistically significant. How- While these levels are high, they are similar to ever, the visuomotor scores were higher in the mild the normal, high ranges seen in the first few weeks vs severe group (96.5 vs 86.3, p = 0.048). after birth64, so that, in a sense, high-dose treatment In the study from Oregon described above, would be duplicating the ‘hyperthyroxinemia’ seen infants classified as having moderate hypo- with the postnatal TSH surge. Also, bear in mind thyroidism had an IQ 11 points higher than those that these ranges are only for the first 2 weeks after with severe hypothyroidism, 100 vs 89 (p = 0.05)32. starting treatment; after the first 2 weeks, the target In our review of the literature, we found 30 ranges drop (see below). studies comparing psychometric outcome in infants Studies examining the age of onset of treatment with more severe vs moderate or mild congenital and psychometric outcome emphasize the impor- hypothyroidism (see Table 5). Of these, nine re- tance of starting treatment at as early an age as ported no difference in IQ, while 21 reported a 5.5- possible, with frequent monitoring. In our review 23 point decrease in IQ in the more severely of the literature, of 11 studies comparing starting affected infants. As described above, doses in the treatment at an earlier age (range 12-30 days of upper end of the recommended 10-15 μg/kg/d life) vs at a later age, infants starting at the earlier range lead to more rapid normalization of thyroid age averaged 15.7 IQ points higher than those infants started at a later age (see Table 6). VOLUME 20, NO. 5, 2007

566 S.H. LaFRANCHI AND J. AUSTIN JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TREATING CONGENITAL HYPOTHYROIDISM 567 MONITORING L-THYROXINE TREATMENT: critical brain dependence on normal thyroid levels, THYROID FUNCTION TESTS; FREQUENCY; it is important to try to prevent prolonged periods BIOCHEMICAL AND CLINICAL OBJECTIVES; of either under- or over-treatment. Whereas the AVOIDING PROLONGED OVER-TREATMENT effects of under- or over-treatment are reversible in Thyroid function tests adolescents, they may have permanent effects in infancy. The current guidelines for frequency of • T4 or FT4 monitoring thyroid tests are presented in Table 7. • TSH Testing may need to be carried out at more frequent intervals when compliance is questioned, abnormal Measurement of serum TSH is the single most values are obtained, or the source of thyroid sensitive test to monitor L-T4 treatment. However, hormone is changed, e.g., from one brand to a TSH test alone is not adequate to monitor another brand, to a generic, or from one generic to treatment of congenital hypothyroidism. After another generic L-thyroxine. initiation of L-T4, serum TSH may take several weeks or longer to fall into the normal range. Some Biochemical and clinical objectives of treatment infants may manifest a persistently elevated TSH level, despite other evidence, both clinical and As before, the biochemical goals are to keep the biochemical, that the T4 dose is correct (see below, serum T4 or FT4 in the upper half of the normal ‘patients with altered hypothalamic-pituitary- range for age, with the TSH now suppressed to the thyroid axis feedback’). Thus, in general it is safest lower half of the normal range. After the first two to measure both T4 or FT4 and TSH levels to make weeks of treatment, serum thyroid test target range correct decisions about dose adjustments. It is guidelines are24: important to compare the result to the normal range for age. Measurement of serum T3 or free T3 (FT3) • T4 10-16 μg/dl (130-206 nmol/l) is not useful in monitoring treatment, as these tests • FT4 1.4-2.3 ng/dl (18-30 pmol/l) may be normal, despite a low T4 or FT4 and • TSH 0.5-2.0 mU/l elevated TSH level. As stated previously, the overall goal of treat- Frequency of monitoring thyroid function tests ment is to assure normal growth and development. The treatment dose does not appear to be as critical When treating infants with congenital hypo- for growth, as essentially all studies show normal thyroidism, it is important to carry out thyroid growth of infants with congenital hypothyroidism function tests more frequently than in, for example, detected by newborn screening programs. Salerno older children with acquired hypothyroidism. Infants et al. from Italy reported that, while onset and undergo rapid growth and development in the first progression of puberty were normal in girls and 2-3 years of life, and more frequent dose changes boys, girls started on an initial L-T4 dose >8 may be necessary. Further, during this time of μg/kg/d entered puberty a year earlier, with VOLUME 20, NO. 5, 2007

568 S.H. LaFRANCHI AND J. AUSTIN menarche also a year earlier, as compared to girls thyroidism71. If there is evidence for an abnormal started on a lower dose65. However, all the children feedback threshold, we recommend using primarily in the study (boys and girls) reached a similar adult the serum FT4 or T4 and clinical assessment to height (0.1 ± 1.1 SDS), which was actually greater adjust the L-T4 dose, allowing the serum TSH to than mid-parental target height (-0.9 ± 0.9 SDS). remain slightly elevated. Most cases resolve with No significant correlation was found between adult time. height and specific etiology or severity of con- Some treated children with congenital hypo- genital hypothyroidism or initial starting T4 dose. thyroidism will manifest an elevated serum TSH with FT4 or T4 in the upper half of the normal Avoiding prolonged over-treatment range as a result of irregular compliance. Such children will typically have had normalization of Prolonged over-treatment, typically presenting the serum TSH and FT4 in the past, evidence that as a serum T4 or FT4 above the normal range they do not have a feedback axis abnormality. The accompanied by a suppressed TSH level, may lead explanation for these findings appears to be to adverse effects. Animal studies report that irregular administration of T4 until just before an prolonged over-treatment accelerates the tempo of appointment and blood testing, when missed doses brain development, resulting in premature comple- are quickly made up. Under these circumstances, tion of brain development with fewer neurons and serum FT4 or T4 will increase quickly, over 24 h, disordered myelination66. In infancy, over- while serum TSH may take several weeks to fall treatment has been associated with premature into the normal range69. fusion of the skull bones and craniosynostosis. Behavior issues, including problems with temperament67 and short attention span68, have PERMANENT VS TRANSIENT been reported. With appropriate monitoring and T4 CONGENITAL HYPOTHYROIDISM dose adjustments, these adverse effects are generally avoided or reversible. Some patients detected by newborn screening will have a transient form of hypothyroidism. In North America, it is estimated that 10-20% of cases PATIENTS WITH ALTERED HYPOTHALAMIC- are transient15, while in Europe the frequency PITUITARY-THYROID AXIS FEEDBACK appears to be higher, primarily a result of transient (‘THYROID HORMONE RESISTANCE’) VS COMPLIANCE ISSUES cases in infants born in areas of iodine deficiency72. Some clinicians elect to carry out thyroid scinti- Under normal conditions, there is a log-linear graphy or ultrasonography at the time of detection relationship between serum FT4 and TSH69. Some by newborn screening. If such imaging studies treated children with congenital hypothyroidism, show an ectopic gland, or absent thyroid uptake, however, manifest a persistently elevated serum confirmed by ultrasonography, a permanent form TSH level, typically in the 10-20 mU/l range, of hypothyroidism is present. If an inborn error of despite FT4 or T4 in the upper half of the normal thyroid hormone biosynthesis is suspected, for range. If the T4 dose is raised to normalize the TSH example, with a goiter and elevated radioiodine level, the serum FT4 or T4 is elevated above the uptake, this is evidence for a permanent defect. normal range and some patients will manifest Permanent hypothyroidism can also be assumed if hyperthyroid symptoms. This mild pituitary-thyroid the serum TSH concentration rises to >10 mU/l resistance is speculated to be a result of a resetting after 6 months of life, as the infant outgrows the T4 of the hypothalamic-pituitary-thyroid feedback replacement dose or there are issues with compli- axis70. This abnormal feedback threshold was seen ance. in 43% of infants <1 year of age, decreasing to If permanent hypothyroidism has not been 10% of children by age 10 years70. It appears to be established, guidelines recommend stopping T4 a characteristic of congenital hypothyroidism, as it treatment sometime after 3 years of age, waiting was not found in children with acquired hypo- 4 weeks, and then checking serum FT4 or T4 and JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TREATING CONGENITAL HYPOTHYROIDISM 569 TSH24. If the TSH is elevated and FT4 or T4 is 8. Alm J Larsson A, Zetterstrom R. Congenital hypo- low, permanent hypothyroidism is confirmed. On thyroidism in Sweden. Incidence and age at diagnosis. Acta Paediatr Scand 1978; 67: 1-3. the other hand, if thyroid function tests are normal, 9. Klein AH, Meltzer S, Kenny FM. Improved prognosis transient hypothyroidism is presumed. If results are in congenital hypothyroidism treated before age three inconclusive (e.g., normal FT4 or T4 and slightly months. J Pediatr 1972; 81: 912-915. elevated TSH), careful follow-up and retesting are 10. DiGeorge A. Disorders of the thyroid gland. In: Nelson indicated. WD. Textbook of Pediatrics. Philadelphia, PA: W.B. In cases of transient congenital hypothyroidism, Saunders Co., 1964; 1268-1282. 11. DiGeorge A. Disorders of the thyroid gland. In: one may sometimes not be sure whether there truly Behrman RE, Vaughan VC III, eds. Nelson Textbook of was transient hypothyroidism, or whether the infant Pediatrics. Philadelphia, PA: W.B. Saunders Co., 1987; had false positive thyroid screening tests. Fortu- 1193-1207. nately, studies of infants with transient congenital 12. Dussault JH, Coulombe P, Laberge, Letarte J, Guyda H, hypothyroidism, treated for anywhere from 6 Khoury K. Preliminary report on a mass screening weeks to 2 years, showed normal growth and program for neonatal hypothyroidism. J Pediatr 1975; 86: 670-674. development out to 6-14 years of age73. 13. Larsen PR, Merker A, Parlow AF. Immunoassay of human TSH using dried blood samples. J Clin Endo- crinol Metab 1976; 42: 987-990. REFERENCES 14. LaFranchi SH, Murphey WH, Foley TP Jr, Larsen PR, Buist NR. Neonatal hypothyroidism detected by the 1. Morreale de Escobar G, Obregon MJ, Escobar del Rey. Northwest Regional Screening Program. Pediatrics Is neuropsychological development related to maternal 1979; 63: 180-191. hypothyroidism or maternal hypothyroxinemia? J Clin 15. National Newborn Screening and Genetics Resource Endocrinol Metab 2000; 85: 3975-3987. Center. National Newborn Screening Report - 2000. 2. Iskaros J, Pickard M, Evans I, Sinha A, Hardiman P, Austin, TX: NNSGRC, February 2003. Ekins R. Thyroid hormone receptor gene expression in 16. Grant DB, Fuggle P, Tokar S, Smith I. Psychomotor the first trimester human fetal brain. Endocrinology development in infants with congenital hypothyroidism 2000; 85: 2620-2623. diagnaosed by newborn screening. Acta Med Aust 1992; 3. Chan S, Kachilele S, McCabe CJ, Tannahill LA, 19 (Suppl 1): 54-56. Boelaert K, Gittoes NJ, Vissr TJ, Franklyn JA, Kilby 17. Rovet JF, Ehrlich R. Psychoeducational outcome in MD. Early expression of thyroid hormone deiodinases children with early-treated congenital hypothyroidism. and receptors in human fetal cerebral cortex. Dev Brain Pediatrics 2000; 105: 515-522. Res 2002; 138: 109-116. 18. von Heppe JH, Krude H, l’Allemand D, Schnabel D, 4. Contempre B, Jauniaux E. Calvo R, Jurkovic D, Gruters A. The use of L-T4 as liquid solution improves Campbell S, de Escobar GM. Detection of thyroid the practicability and individualized dosage in newborns hormones in human embryonic cavities during the first and infants with congenital hypothyroidism. J Pediatr trimester of pregnancy. J Clin Endocrinol Metab 1993; Endocrinol Metab 2004; 17: 967-974. 77: 1719-1722. 19. Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, 5. Calvo R, Jauniaux E, Gulbis B, Asuncion M, Gervy C, Morreale de Escobar G. Replacement therapy for Contempre B, Morreale de Escobar G. Fetal tissues are hypothyroidism with thyroxine alone does not ensure exposed to biologically relevant free thyroxine con- euthyroidism in all tissues, as studied in centrations during early phases of development. J Clin thyroidectomized rats. J Clin Invest 1995; 96: 2828- Endocrinol Metab 2002; 87: 1768-1777. 2838. 6. Haddow JE, Palomaki FE, Allan WC, Williams JR, 20. Obregón MJ, Ruiz de Oña C, Calvo R, Escobar del Rey Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos F, Morreale de Escobar G. Outer ring iodothyronine RJ, Waisbren SE, Faix JD, Klein RZ. Maternal thyroid deiodinases and thyroid hormone economy: responses to deficiency during pregnancy and subsequent neuro- iodine deficiency in the rat fetus and neonate. Endo- psychological development of the child. N Engl J Med crinology 1991; 129: 2663-2673. 1999; 341: 549-555. 21. Hays MT. Thyroid hormone and the gut. Endocr Res 7. Vulsma T, Gons MH, deVijlder JJM. Maternal-fetal 1988; 14: 203-224. transfer of thyroxine in congenital hypothyroidism due 22. Jabbar MA, Larrea J, Shaw RA. Abnormal thyroid to a total organification defect or thyroid agenesis. N function tests in infants with congenital hypothyroidism: Engl J Med 1989; 321: 13-16. the influence of soy-based formula. J Am Coll Nutr 1997; 16: 280-282. VOLUME 20, NO. 5, 2007

570 S.H. LaFRANCHI AND J. AUSTIN 23. Conrad SC, Chiu H, Silverman BL. Soy formula com- 36. Connelly JF, Rickards AL, Coakley JC, Price GJ, plicates management of congenital hypothyroidism. Francis I, Mathur KS, Wolfe R. Newborn screening for Arch Dis Child 2004; 89: 37. congenital hypothyroidism, Victoria, Australia, 1977- 24. American Academy of Pediatrics; Rose SR; Section on 1997. Part 2: Treatment, progress and outcome. J Pediatr Endocrinology and Committee on Genetics, American Endocrinol Metab 2001; 14: 1611-1634. Thyroid Association; Brown RS; Public Health Com- 37. Rovet JF. Children with congenital hypothyroidism and mittee, Lawson Wilkins Pediatric Endocrine Society; their siblings: do they really differ? Pediatrics 2005; Foley T, Kaplowitz PB, Kaye CI, Sundararajan S, 115: 52-57. Varma SK. Update of newborn screening and therapy 38. Boileau P, Bain P, Rives S, Toublan JE. Earlier onset of for congenital hypothyroidism. Pediatrics 2006; 117: treatment or increment in l-T4 dose in screened con- 2290-2303. genital hypothyroidism: which was the more important 25. Glorieux J, Desjardins M, Letarte J, Morissette J, factor for IQ at 7 years? Horm Res 2004; 61: 228-233. Dussault JH. Useful parameters to predict the eventual 39. Salerno M, Di Maio S, Militerni R, Argenziano A, mental outcome of hypothyroid children. Pediatr Res Valerio G, Tenore A. Prognostic factors in the intellec- 1988; 24: 6-8. tual development at 7 years of age in children with 26. Rovet JF, Ehrlich RM. Long-term effects of l-thyroxine congenital hypothyroidism. J Endocrinol Invest 1995; therapy for congenital hypothyroidism. J Pediatr 1995; 18: 774-779. 126: 380-386. 40. Bongers-Schokking JJ, Koot HM, Wiersma D, Verkerk 27. Touati G, Leger J, Toublanc JE, Farriaux JP, Stuckens PH, de Muinck Keizer-Schrama SM. Influence of timing C, Ponte C, David M, Rochiccioli P, Porquet D, and dose of thyroid hormone replacement on develop- Czernichow P. A thyroxine dosage of 8 µg/kg per day is ment in infants with congenital hypothyroidism. J appropriate for the initial treatment of the majority of Pediatr 2000; 136: 292-297. infants with congenital hypothyroidism. Eur J Pediatr 41. Bongers-Schokking JJ, de Muinck Keizer-Schrama SM. 1997; 156: 94-98. Influence of timing and dose of thyroid hormone 28. New England Congenital Hypothyroidism replacement on mental, psychomotor, and behavioral Collaborative. Screening for congenital hypothyroidism development in children with congenital [Letter]. Lancet 1986; ii: 403. hypothyroidism. J Pediatr 2005; 147: 768-774. 29. Germak JA, Foley TP Jr. Longitudinal assessment of 42. Schwartz IR, Turner K, Kruger T, Bennett D, Howard l-thyroxine therapy for congenital hypothyroidism. CP, Grunt JA. Neuropsychological outcome in children J Pediatr 1990; 117: 211. with congenital hypothyroidism treated with varying 30. Salerno M, Militerni R, Bravaccio C, Micillo M, amounts of levothyroxine during the first 2 years of life. Capalbo D, Di Maio S, Tenore A. Effect of different Int Pediatr 1994; 9: 254-259. starting doses of levothyroxine on growth and intel- 43. Tillotson SL, Fuggle PW Smith I, Ades AE, Grant DB. lectual outcome at four years of age in congenital Relation between biochemical severity and intelligence hypothyroidism. Thyroid 2002; 12: 45-52. in early treated congenital hypothyroidism: a threshold 31. Selva K, Mandel SH, Rein L, Miyahira R, Skeels M, effect. Br Med J 1994; 309: 440-445. LaFranchi S. Initial treatment dose of l-thyroxine in 44. Glorieux J, Dussualt J, Van Vliet G. Intellectual deve- congenital hypothyroidism. J Pediatr 2002; 141: 786- lopment at age 12 years of children with congenital 792. hypothyroidism diagnosed by newborn screening. 32. Selva KA, Harper A, Downs A, Blasco PA, LaFranchi J Pediatr 1992; 121: 581-584. SH. Neurodevelopmental outcomes in congenital hypo- 45. Dubuis JM, Glorieux J, Richer F, Deal CL, Dussault JH, thyroidism: comparison of initial T4 dose and time to Van Vliet G. Outcome of severe congenital hypo- reach target T4 and TSH. J Pediatrics 2005; 147: 775- thyroidism: closing the developmental gap with early 780. high dose levothyroxine treatment. J Clin Endocrinol 33. New England Congenital Hypothyroidism Metab 1996; 81: 222-227. Collaborative. Neonatal hypothyroidism screening: 46. Kreisner E, Schermann L, Camargo-Neto E, Gross JL. status of patients at 6 years of age. J Pediatr 1985; 107: Predictors of intellectual outcome in a cohort of 915-919. Brazilian children with congenital hypothyroidism. Clin 34. Rovet JF, Ehrlich RM. Long-term effects of L-thyroxine Endocrinol 2004; 60: 250-255. therapy for congenital hypothyroidism. J Pediatr 1995; 47. Simoneau-Roy J, Marti S, Deal C, Huot C, Robaey P, 126: 380-386. Van Vliet G. Cognition and behavior at school entry in 35. Oerbeck B, Sundet K, Kase BF, Heyerdahl S. children with congenital hypothyroidism treated early Congenital hypothyroidism: influence of disease with high-dose levothyroxine. J Pediatr 2004; 144: 747- severity and L-thyroxine treatment on intellectual, 752. motor, and school-associated outcomes in young adults. 48. Rovet J, Ehrlich R, Sorbara D. Intellectual outcome in Pediatrics 2003; 112: 923-930. children with fetal hypothyroidism. J Pediatr 1987; 110: 700-704. JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TREATING CONGENITAL HYPOTHYROIDISM 571 49. Rovet JF, Ehrlich RM, Sorbara DL. Neurodevelopment congenital hypothyroidism. Eur J Pediatr 1991; 150: in infants and preschool children with congenital hypo- 570-574. thyroidism: etiological and treatment factors affecting 62. Simons WF, Fuggle PW, Grant DB, Smith I. Intellectual outcome. J Pediatr Psychol 1992; 17: 187-213. development at 10 years in early treated congenital 50. Rovet JF. Congenital hypothyroidism: long-term out- hypothyroidism. Arch Dis Child 1994; 71: 232-234. come. Thyroid 1999; 9: 741-748. 63. Campos SP, Sandberg DE, Barrick C, Voorhess ML, 51. Song SI, Daneman D, Rovet J. The influence of etiology MacGillivray MH. Outcome of lower l-thyroxine dose and treatment factors on intellectual outcome in con- for treatment of congenital hypothyroidism. Clin Pediatr genital hypothyroidism. J Dev Behav Pediatr 2001; 22: 1995; 34: 514-520. 376-383. 64. Nelson JC, Clark SJ, Borut DL, Tomei RT, Carlton EI. 52. Salerno M, Militerni R, Di Maio S, Bravaccio C, Age-related changes in serum free thyroxine during child- Gasparini N, Tenore A. Intellectual outcome at 12 years hood and adolescence. J Pediatr 1993; 123: 889-905. of age in congenital hypothyroidism. Eur J Endocrinol 65. Salerno M, Micillo M, Di Maio S, Capalbo D, Ferri P, 1999; 141: 105-110. Lettiero T, Tenore A. Longitudinal growth, sexual 53. Chiovato L, Giusti L, Tonacchera M, Ciampi M, maturation and final height in patients with congenital Mammoli C, Lippi F, Lapi P, Bargagna S, Dini P, hypothyroidism detected by neonatal screening. Eur J Ferretti G, et al. Evaluation of L-thyroxine replacement Endocrinol 2001; 145: 377-383. therapy in children with congenital hypothyroidism. 66. Weichsel ME Jr. Thyroid hormone replacement therapy J Endocrinol Invest 1991; 14: 957-964. in the perinatal period: neurologic considerations. 54. Bargagna S, Canepa G, Costagli C, Dinetti D, J Pediatr 1978; 92: 1035-1038. Marcheschi M, Millepiedi S, Montanelli L, Pinchera A, 67. Rovet J, Ehrlich RM, Sorbara DL. Effect of thyroid Chiovato L. Neuropsychological follow-up in early- hormone levels on temperament in infants with con- treated congenital hypothyroidism: a problem-oriented genital hypothyroidism detected by screening of approach. Thyroid 2000; 10: 243-249. neonates. J Pediatr 1989; 114: 63-68. 55. Kooistra L, Laane C, Vulsma T, Schellekens JMH, van 68. Rovet, J, Alvarez, M. Thyroid hormone and attention in der Meere JJ, Kalverboer AF. Motor and cognitive congenital hypothyroidism. J Pediatr Endocrinol Metab development in children with congenital hypothyroid- 1996; 9: 63-66. ism: a long-term evaluation of the effects of neonatal 69. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, treatment. J Pediatr 1994; 124: 903-909. Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire 56. Kempers MJE, van der Sluijs Veer L, Nijhuis-van der P, John R, Ruf J, Smyth PP, Spencer CA, Stockigt JR; Sanden MW, Kooistra L, Wiedijk BM, Faber I, Last BF, Guidelines Committee, National Academy of Clinical de Vijlder JJ, Grootenhuis MA, Vulsma T. Intellectual Biochemistry. Laboratory medicine practice guidelines. and motor development of young adults with congenital Laboratory support for the diagnosis and monitoring of hypothyroidism diagnosed by neonatal screening. J Clin thyroid diseases. Thyroid 2003; 13: 3-126. Endocrinol Metab 2006; 91: 418-424. 70. Fisher DA, Schoen EJ, LaFranchi S, Mandel SH, Nelson 57. Illig R, Largo RH, Weber M, Augsburger T, Lipp A, JC, Carlton EI, Goshi JH. The hypothalamic-pituitary- Wissler D, Perrenoud AE, Torresani T. Sixty children thyroid negative feedback control axis in children with with congenital hypothyroidism detected by neonatal treated congenital hypothyroidism. J Clin Endocrinol thyroid: mental developmental at 1, 4, and 7 years: a Metab 2000; 85: 2722-2727. longitudinal study. Acta Endocrinol 1986; Suppl 279: 71. Kempers MJ, van Trotsenburg AS, van Tijn DA, Bakker 346-353. E, Wiedijk BM, Endert E, de Vijlder JJ, Vulsma T. 58. Hsiao PH, Chiu YN, Tsai WY, Su SC, Lee JS, Soong Disturbance of the fetal thyroid hormone state has long- WT. Intellectual outcome of patients with congenital hypo- term consequences for treatment of thyroidal and central thyroidism detected by neonatal screening. J Formosan congenital hypothyroidism. J Clin Endocrinol Metab Med Assoc 2001; 100: 40-44. 2005; 90: 4094-5000. 59. Murphy G, Hulse JA, Jackson D, Tyrer P, Glossop J, 72. Delange F, Heidemann P, Bourdoux P, Larsson A, Smith I, Grant D. Early treated hypothyroidism: Vigneri R, Klett M, Beckers C, Stubbe P. Regional development at 3 years. Arch Dis Child 1986; 61: 761- variations of iodine nutrition and thyroid function 765. during the neonatal period in Europe. Biol Neonate 60. Murphy GH, Hulse JA, Smith I, Grant DB. Congenital 1986; 49: 322-330. hypothyroidism: physiological and psychological factors 73. Kohler B Schnabel D, Biebermann H, Gruters A. Tran- in early development. J Child Psych Psychiat 1990; 31: sient congenital hypothyroidism and hyperthyrotropin- 711-725. emia: normal thyroid function and physical development 61. Fuggle PW, Grant DB, Smith I, Murphy G. Intelligence, at ages of 6-14 years. J Clin Endocrinol Metab 1996; 81: motor skills and behavior at 5 years in early-treated 1563-1567. VOLUME 20, NO. 5, 2007

572 S.H. LaFRANCHI AND J. AUSTIN TABLE 3 Time course of thyroid function with initial L-T4 treatment dose Screening program T4 dose Time to serum Time to serum (μg/kg/d) T4 >10 μg/dl TSH <9.1 mU/l (days) (days) Quebec25 6 45-90 26 Toronto 7-9 74 27 France 8 15 60 28 New England 10 31 29 US (Pennsylvania) 10-14 7 150 30 Italy 10-15 30 30 31 US (Oregon) 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 No. of L-T4 dose Age of psycho- Type of test Results location patients metric test FSIQ 101.9 vs 98.1 (NS) <8 μ g/kg/d vs >8 μ g/kg/d VIQ 103.3 vs 98.9 (NS) Australia PIQ 99.5 vs 98.4 (NS) Connelly et al.36 95 8 yr WISC-R FSIQ 101.8 vs 95.9 (p=0.05) 2001 <10 μ g/kg/d vs >10 μ g/kg/d VIQ 103.2 vs 96.4 (p=0.04) PIQ 99.9 vs 97.0 (NS) FSIQ 100 vs 107.6 (p=0.01) 91 7 yr WISC-R VIQ 98.6 vs 106.3 (p=0.01) Toronto, Canada PIQ 103.8 vs 108.2 (NS) Rovet & Ehrlich34 ≤7.7 μg/kg/d vs ≥7.8 μg/kg/d 1995 McCarthy Memory 46.6 vs 53.8 (p=0.01) 88 8 yr Woodcock Reading 50.1 vs 59.3 (P=0.05) Mastery-Revised <6.0 μg/kg/d vs 6.2-7.8 μg/kg/d Toronto, Canada 95.9 vs 102.5 vs 109.3 (NS) vs 8.2-12.3 μg/kg/d Rovet37 ? 6, 7, or 9 yr McCarthy, WISC-R 2005 <6.0 μg/kg/day vs 95.9 vs 109.3 (p<0.05) 8.2-12.3 μg/kg/d GIQ 112.1 vs 117.3 (p<0.03) <6 μg/kg/d vs ≥6 μg/kg/d VIQ 109.1 vs 112.8 (NS) PIQ 112.8 vs 117.3 (p<0.02) France 131 GIQ 110.2 vs 114.2 vs 116.9 (NS) Boileau et al.38 <5 μg/kg/d vs 5-7 μg/kg/d vs 7 yr WISC-R and WISC-III VIQ 107.3 vs 111.0 vs 112.7 (NS) 2004 ≥7 μg/kg/d PIQ 110.9 vs 115.0 vs 117.6 (NS) 76 < 21 days: GIQ 116.4 vs 118.4 (NS) <6 μg/kg/d vs ≥6 μg/kg/d 55 > 21 days: GIQ 108.0 vs 113.0 (NS) Italy Salerno et al.39 47 <7 μg/kg/d vs ≥7 μg/kg/d 7 yr Stanford-Binet test 96 vs 94 (NS) 1995

Study by No. of L-T4 dose Age of psycho- Type of test Results location patients metric test FSIQ 88 vs 94 vs 98 (p=0.009) 6-8 μg/kg/d vs 8.1-10 μg/kg/d 83 VIQ 92 vs 94 vs 98 (NS) Italy vs 10.1-15 μg/kg/d PIQ 85 vs 95 vs 98 (p<0.0001) Salerno et al.30 4 yr WPPSI-R FSIQ 84 vs 97 (p<0.05) 2002 32 6-8 μg/kg/d vs 10.1-15 μg/kg/d VIQ 89 vs 98 (NS) PIQ 80 vs 96 (p<0.05) Early/Low vs Late/Low vs Bayley Test: Mental Mild: MDI 124 vs 110 vs 125 vs 122 (p=0.016) The Netherlands 34 Development Index Early/High vs Late/High PDI 123 vs 111 vs 120 vs 117 (NS) Bongers- (MDI) and 21.7 mo Severe: MDI 103 vs 97 vs 124 vs 99 (p=0.035) Schokking et al.40 Early/Low vs Late/Low vs Psychomotor 2000 27 Development Index Early/High vs Late/High PDI 109 vs 113 vs 123 vs 101 (p=0.001) (PDI) Early (<13 days): Rakit 106.5 vs 104.6 (NS) The Netherlands 19 Low (<9.5 μg/kg/d) vs Rakit; Beery-Buktenica VMI 89.0 vs 96.3 (NS) Bongers- Developmental Test for Verbal Score 92.7 vs 91.0 (NS) Schokking & 72.5 mo Visual-Motor de Muinck Keizer- Late (>13 days): Rakit 100.1 vs 108.2 (NS) Integration; Language Schrama41 26 High (>9.5 μg/kg/day) Test for Children VMI 90.9 vs 93.3 (NS) 2005 Verbal Score 64.3 vs 99.4 (p=0.001) FSIQ 109 vs 98 (NS) Kansas City, MO <7.5 μg/kg/d vs >7.5 μg/kg/d WISC-R; Beery VMI; Language 105.6 vs 96.2 (NS) Schwartz et al.42 14 9.6 yr (1 to 3 mo) WRAT-R Visuomotor 108.9 vs 95.2 (p=0.035) 1994 Perceptual/Numerical 103.3 vs 98.1 (NS) Mullen Scales of Early FSIQ 89.5 vs 95.3 vs 100.6 (p<0.05, low vs 37.5 μg/day (10.9 μg/kg/d) vs Learning (<4 yr) high dose) Portland, OR 62.5 μg/day x 3 days, Selva et al.32 31 WPPSI-R (4-6 yr) VIQ NS then 37.5 μg/day 2005 WISC-III and WRAT- 50 μg/day (14.5 μg/kg/d) PIQ NS III (>6 yr) 2

TABLE 5 Studies comparing severity of congenital hypothyroidism and effect on IQ Study by No. of Criterion Age of psycho- Type of test Results Location patients metric Test FSIQ 96.1 vs 101.1 vs 101.5 (NS) athyreosis vs 119 VIQ 95.8 vs 99.4 vs 102.8 (NS) dyshormonogenesis vs ectopia PIQ 97.7 vs 101.2 vs 100.0 (NS) Victoria, Australia FSIQ 96.7 vs 103.0 (p=0.03) Connelly et al.36 106 TT4 <3.1 vs >3.1 μg/dl 8 yr WISC-R VIQ 96.9 vs 103.7 (p=0.03) 2001 PIQ 97.4 vs 101.6 (NS) FSIQ 97.5 vs 101.8 (NS) 88 BA ≤36 wk vs >36 wk VIQ 98.2 vs 101.8 (NS) PIQ 97.9 vs 101.2 (NS) Brazil FSIQ 91.4 vs 102.73 (NS) WPPSI (4-6 yr), Kreisner et al.46 31 T4 ≤2.5 μg/dl vs >2.5 μg/dl >4 yr VIQ 91.75 vs 104.55 vs (p=0.030) WISC (6 yr-15 yr 11 mo) 2004 PIQ 92.70 vs 99.64 (NS) Quebec, Canada T4 <2 μg/dl and bone surface GIQ 86 vs 102 (p<0.001) Glorieux et al.25 19 <0.05 cm2 vs T4 >2 μg/dl and/or 9 yr WISC-R VIQ 83 vs 99 (p<0.001) 1988 bone surface ≥0.05 cm2 NVIQ 92 vs 107 (p<0.001) Quebec, Canada T4 <2 μg/dl and bone surface GIQ 89 vs 104 (p<0.007) Glorieux et al.44 27 <0.05 cm2 vs T4 >2 μg/dl and/or 12 yr WISC-R VIQ 84 vs 99 (p<0.009) 1992 bone surface ≥0.05 cm2 NVIQ 96 vs 109 (p<0.02) Quebec, Canada Area of the knee epiphyses Dubuis et al.45 45 18 mo Griffiths’ Scales 107 vs 110 (NS) <0.05 cm2 vs ≥0.05 cm2 1996 Quebec, Canada Area of the knee epiphyses Simoneau-Roy et 18 5 yr 9 mo McCarthy Scale General Cognitive Index 102 vs 102 (NS) <0.05 cm2 vs ≥0.05 cm2 al.47 2004 3

Study by No. of Criterion Age of psycho- Type of test Results Location patients metric Test FSIQ 97.8 vs 109.2 (p=0.02) WPPSI PIQ 96.8 vs 109.1 (p=0.01) VIQ 9.9 vs 11.9 (p=0.04) Toronto, Canada Beery-Buktenica Rovet et al.48 34 BA ≤36 wk vs >36 wk 5 yr Developmental Test of 42.3 vs 72.4 (p=0.02) 1987 Visual Motor Integration McCarthy Scale 45.5 vs 53.9(p=0.02) Reynell Developmental -0.233 vs 0.692 (p=0.02) Language Scales (Revised) FSIQ 103.4 vs 106.7 vs 107.1 (NS) athyreosis vs Toronto, Canada 95 VIQ 102.9 vs 110 vs 105.1 (NS) dyshormonogenesis vs ectopia Rovet et al.49 5 yr WPPSI PIQ 10.2 vs 10.7 vs 11.3 vs 12.1 (NS) 1992 BA ≤36 wk vs >36 wk FSIQ 104 vs 109.8 (p=0.045) 108 T4 <4.0 μg/dl vs >4.0 μg/dl NS Toronto, Canada athyreosis vs dyshomonogenesis Rovet50 48 >13 yr WISC-III 97.1 vs 106.3 vs 102.1 (NS) vs ectopia 1999 Toronto, Canada FSIQ 91.6 vs 98.1 vs 102.9 (p=0.05) athyreosis vs Song et al.51 62 8.8 yr WISC-III VIQ 94.9 vs 96.4 vs 101.6 (NS) dyshormonogenesis vs ectopia 2001 PIQ 89.3 vs 97.8 vs 106.2 (p=0.01) Toronto, Canada 33 BA ≤36 wk vs >36 wk 97.5 vs 105.9 (NS) Rovet37 6, 7, or 9 yr McCarthy, WISC-R ? T4 <3.5 μg/dl vs >3.5 μg/dl 102.2 vs 103.1 (NS) 2005 France GIQ 111.5 vs 118.4 vs 113.1 (NS) athyreosis vs Boileau et al.38 131 7 yr WISC-R and WISC-III VIQ 108.0 vs 116.8 vs 109.3 (NS) dyshormonogenesis vs ectopia 2004 PIQ 113.0 vs 117.0 vs 114.1 (NS) 4

Study by No. of Criterion Age of psycho- Type of test Results Location patients metric Test T4 1.1 μg/dl and BA 31.5 wk vs 27 93 vs 99 (p<0.05) Italy T4 6.3 μg/dl and BA 40.1 wk Salerno et al.39 T4 <2 μg/dl vs >2 μg/dl; 7 yr Stanford-Binet test 1995 47 BA 33.1 wk 92 vs 98 (p<0.02) vs 36.8 wk (p<0.01) Italy FSIQ 78.5 vs 90.8 (p=0.02) Salerno et al.52 40 athyreosis vs other 12.25 yr WISC-R VIQ 83.6 vs 95.6 (p=0.04) 1999 PIQ 76.4 vs 87.0 (p<0.04) 6-8 mg/kg/day: FSIQ 84 vs 92 (p<0.05) 42 VIQ 89 vs 95 (NS) PIQ 80 vs 87 (p<0.05) Italy 8.1-10 mg/kg/day: FSIQ 93 vs 95 (NS) Salerno et al.30 21 T4 <3.1 μg/dl vs ≥3.1 μg/dl 4 yr WPPSI-R VIQ 94 vs 94 (NS) 2002 PIQ 92 vs 98 (NS) 10.1-15 mg/kg/day: FSIQ 97 vs 99 (NS) 20 VIQ 98 vs 98 (NS) PIQ 96 vs 100 (NS) Italy Chiovato et al.53 19 hypoplasia/aplasia vs ectopia 3 yr Stanford Binet Scales 97 vs 105 (NS) 1991 Pisa, Italy Bargagna et al.54 24 T4 <2 μg/dl vs >2 μg/dl 7 yr WISC-R 101.7 vs 107.7 (NS) 2000 GIQ 91.8 vs 99.1 (NS) 46 athyreosis vs other VIQ 93.1 vs 96.8 (NS) The Netherlands PIQ 92.1 vs 101.8 (NS) Kooistra et al.55 9½ yr WISC-R GIQ 94.8 vs 101.4 (p<0.01) 1994 61 T4 <3.9 μg/dl vs ≥3.9 μg/dl VIQ 93.9 vs 98.6 (p<0.01) PIQ 97.0 vs 104.5 (NS) 5

Study by No. of Criterion Age of psycho- Type of test Results Location patients metric Test MDI 106 vs 118 (p=0.002) 61 PDI 111 vs 117 (NS) Low/Late: MDI 97 vs 110 (NS) 16 The Netherlands PDI 113 vs 111(NS) severe (athyreosis/total Bayley Test: Mental Bongers- dyshomonogenesis) vs mild Development Index (MDI) Low/Early: MDI 103 vs 124 (p<0.005) 16 21.7 mo Schokking et al.40 (dystopic gland/partial and Psychomotor PDI 109 vs 123 (p<0.005) 2000 dyshormonogenesis) Development Index (PDI) High/Late: MDI 99 vs 122 (p<0.005) 12 PDI 101 vs 117 (p<0.005) High/Early: MDI 124 vs 125 (NS) 17 PDI 123 vs 120 (NS) The Netherlands Rakit 99.4 vs 108.5 (NS) Bongers- Beery-Buktenica Schokking & de 45 severe vs mild (see above) 72.5 mo Developmental Test for 86.3 vs 96.5 (p=0.048) Muinck Keizer- Visual-Motor Integration Schrama41 2005 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) The Netherlands T4 <2.3 μg/dl vs 2.3 μg/dl – VIQ 92.9 vs 97.8 vs 101.8 (NS) Kempers et al.56 70 21.5 yr WISC-III 4.7 μg/dl vs ≥4.7 μg/dl PIQ 90.4 vs101.3 vs 100.4 2006 (severe vs moderate p=0.031, severe vs mild p=0.037) Zurich, athyreosis vs ectopia NS Switzerland The German version of 13 prenatal BA vs normal 7 yr Illig et al.57 WPPSI (HAWIVA) NS skeletal maturation 1986 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) Taipei, Taiwan femoral epiphysis area Chinese Fourth Revision of Hsiao et al.58 36 3.8 yr 92 vs 106 (p<0.05) <0.1 cm2 vs ≥0.1 cm2 Binet-Simon Scales 2001 athyreosis vs 62 95 vs 97 vs 103 (NS) dyshormonogenesis vs ectopia 6

Study by No. of Criterion Age of psycho- Type of test Results Location patients metric Test UK 36 T4 <1.6 μg/dl vs >4.7 μg/dl 94 vs 106 (p=0.013) Murphy et al.59 3 yr McCarthy Scale 35 T3 ≤130 ng/dl vs >130 ng/dl 93 vs 105 (p<0.01) 1986 UK 37 BA <30 wk vs >30 wk 93 vs 103 (p=0.03) Murphy et al.60 3 yr McCarthy Scale 51 athyreosis vs other 89.5 vs 103.2 (NS) 1990 T4 <1.6 μg/dl vs 1.6-4.7 μg/dl UK FSIQ 100.4 vs 109.3 vs 115.4 vs >4.7 μg/dl Fuggle et al.61 57 5 yr WPPSI 1991 TSH >500 mU/l vs 250-500 FSIQ 108.1 vs 107.4 vs 110.9 (NS) mU/l vs <250 mU/l UK FSIQ 104.7 vs 114.6 (p<0.05) Simons et al.62 59 T4 ≤3.1 μg/dl vs >3.1 μg/dl 10 yr WISC-R VIQ 105.4 vs 114.2 (p<0.05) 1994 PIQ 103.1 vs 112.0 (p<0.05) T4 0.1-0.9 μg/dl vs 1.0-1.6 vs 101.5 vs 100.6 vs 103.3 vs 103.1 vs 112 vs 325 1.6-2.3 vs 2.4-3.1 vs 3.2-4.7 vs 110.3 vs 111.5 (linear trend p=0.003, analysis 4.7-6.2 vs 6.3-18.5 μg/dl of variance p<0.0001) UK Tillotson et al.43 T4 <3.3 μg/dl vs ≥3.3 μg/dl 5 yr WPPSI 186 97.5 vs 109.1 1994 (manual and unemployed) T4 <3.3 μg/dl vs ≥3.3 μg/dl 159 107.6 vs 115.5 (non-manual) FSIQ 95.9 vs 106.8 (NS) 15 BA ≤32 wk vs >32 wk PIQ 95.9 vs 105.8 (NS) Buffalo, NY VIQ 96.7 vs 106.1 (p=0.05) Campos et al.63 5 yr WPPSI-R FSIQ 95.5 vs 105.0 (NS) 1995 16 T4 <2 μg/dl vs >2 μg/dl PIQ 96.5 vs 103.5 (NS) VIQ 95.5 vs 105.2 (p=0.04) Mullen Scales of Early FSIQ 89 vs 100.3 (p=0.05) Portland, OR Learning (< 4 yr), WPPSI-R VIQ 4.8 difference (NS) (4-6 yr), WISC-III and Selva et al.32 30 T4 <1.6 μg/dl vs ≥1.6 μg/dl PIQ 9.2 difference (NS) Wide-Range achievement 2005 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 Age of onset of Age of psycho- Type of test Results patients treatment metric test Victoria, Australia FSIQ 98.1 vs 99.6 (NS) Connelly et al.36 109 >14 days vs ≤14 days 8 yr WISC-R VIQ 98.2 vs 100.4 (NS) 2001 PIQ 98.3 vs 99.3 (NS) Brazil FSIQ 91.67 vs 103.30 (NS) WPPSI (4-6 yrs), Kreisner et al.46 31 >30 days vs ≤30 days >4 yr VIQ 93.48 vs 102.20 (NS) WISC (6 yrs-15 yrs 11 mos) 2004 PIQ 91.43 vs 103.00 (p=0.036) Toronto, Canada Rovet37 ? >12 days vs <12 days 6, 7, or 9 yr McCarthy, WISC-R 105.1 vs 100.5 (NS) 2005 GIQ 108.6 vs 117.1 (p<0.01) >21 days vs ≤21 days VIQ 105.4 vs 113.5 (p<0.017) PIQ 109.7 vs 117.6 (p<0.008) France 131 >30 days vs 22-30 days GIQ 109.8 vs 107.7 vs 115.3 vs 119.2 (p=0.0008) Boileau et al.38 7 yr WISC-R and WISC-III vs 15-21 days VIQ 106.3 vs 104.7 vs 111.6 vs 115.8 (p=0.007) 2004 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) >21 days vs ≤21 days 36 >6 mg/kg/day: GIQ 113.0 vs 118.4 (NS) Italy Salerno et al.39 24 42.4 vs 18.3 days 7 yr Stanford-Binet test 98 vs 95 (NS) 1995 8.1-10 mg/kg/day: FSIQ 91 vs 96 (NS) 21 VIQ 93 vs 98 (NS) Italy PIQ 90 vs 95 (NS) Salerno et al.30 >21 days vs <21 days 4 yr WPPSI-R 10.1-15 mg/kg/day: FSIQ 98 vs 98 (NS) 2002 20 VIQ 98 vs 98 (NS) PIQ 98 vs 99 (NS) 8

Study by location No. of Age of onset of Age of psycho- Type of test Results patients treatment metric test The Netherlands late/low vs late/high vs Severe: MDI 97 vs 99 vs 103 vs 124 (p=0.035) 34 Bayley Test: Mental Development Bongers-Schokking et early/low vs early/high PDI 113 vs 101 vs 109 v. 123 (p=0.001) 21.7 mo Index (MDI) and Psychomotor al.40 late/low vs late/high vs Mild: MDI 110 vs 122 vs 124 vs 125 (p=0.016) 27 Development Index (PDI) 2000 early/low vs early/high PDI 111 vs 117 vs 123 vs 120 (NS) Low (<9.5 mg/kg/day): Rakit 100.1 vs 106.5 (NS) The Netherlands 21 VMI 90.9 vs 89.0 (NS) Rakit; Beery-Buktenica Bongers-Schokking & late (≥13 days) vs Developmental Test for Visual- Verbal Score 64.3 vs 92.7 (p=0.001) de Muinck Keizer- 72.5 mo early (<13 days) Motor Integration; Language Test High (>9.5 mg/kg/day): Rakit 108.2 vs 104.6 (NS) Schrama41 for Children 2005 24 VMI 93.3 vs 96.3 (NS) Verbal Score 99.4 vs 91.0 (NS) Taipei, Taiwan Chinese Fourth Revision of Binet- Hsiao et al.58 62 ≥30 days vs <30 days 3.8 yr 102 vs 101 (NS) Simon Scales 2001 UK >30 days vs 22-30 days Fuggle et al.61 57 5 yr WPPSI FSIQ 104.5 vs 109.6 vs 111.7 vs 0-21 days 1991 UK 26-173 vs 21-25 vs 16-20 Tillotson et al.43 361 5 yr WPPSI 106.3 vs 110.7 vs 105.9 vs 104.5 vs 104.2 (NS) vs 11-15 vs 1-10 1994 9

How Should We Be Treating Children with Congenital Hypothyroidism?

by roger961 on Oct 21, 2010

Accessibility

Upload Details

Usage Rights

Statistics

How Should We Be Treating Children with Congenital Hypothyroidism? Document Transcript