how-should-we-be-treating-children-with-congenital-hypothyroidism1421.pdf

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© 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 andappropriate L -thyroxine treatment leads tonormal or near-normal neurocognitive outcomein infants with congenital hypothyroidism.Many newborns with congenital hypothyroidismhave some residual thyroid hormone produc-tion, and even in those with athyreosis, trans-placental passage of maternal thyroid hormoneoffers some protection for a time. Given theserum T4 half-life of 6 days, the neonatal T4level will fall and disappear over the first 2-3weeks of life. Thus, there is a crucial ‘window ofopportunity’ to correct the hypothyroidism andminimize the time the brain is exposed to hypo-thyroxinemia. While there are few truly pros-pective, randomized clinical trials investigatingtreatment parameters, studies measuring IQoutcome support a starting L -thyroxine dose of10-15 g/kg/day. Further, studies show that themost severely hypothyroid infants are at risk fora 5-20 point decrease in IQ. Such infants maybenefit from a starting dose of 12-17 g/kg/d,

which has been shown to normalize T4 in 3 daysand TSH in 2 weeks. Target serum T4 or free T4levels appear to be higher in the first two weeksof treatment. Infants require more frequentlaboratory monitoring, every 1-2 months in thefirst 6 months and every 3-4 months until age 3

KEY WORDS

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

INTRODUCTION

Delay in diagnosis or suboptimal treatment ofcongenital hypothyroidism results in variablemental retardation, whereas early detection andappropriate L-thyroxine hormone replacement leadsto normal or near-normal neurocognitive outcome.The developing brain has a critical dependence onthyroid hormone, beginning before birth andextending through the first 2-3 years of life. There

is accumulating evidence that maternal thyroidhormone that crosses to the fetus is important fornormal brain development, even before onset ofsignificant fetal thyroid hormone production 1.Thyroid hormone receptor mRNAs (TR α1, TR α2,and TR β1) are present from 7-8 weeks gestation inthe fetal brain 2,3 . Type 2 or 5´-deiodinase (5´-D2)mRNA is measurable from 7-8 weeks gestation 3.5´-D2, which converts T4 to the biologically activeT3, increases with hypothyroidism. While signifi-cant fetal thyroid hormone production andsecretion does not begin until approximately 20weeks, T4 can be demonstrated in the coelomiccavity as early as 6 weeks gestation 4 The


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560 S.H. LaFRANCHI AND J. AUSTIN

mately one-third of maternal T4 crosses to the fetusat birth 7. 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 thecombination of the maternal thyroid hormonecontribution and fetal thyroid hormone productionis still subnormal, it likely explains why themajority of newborns with congenital hypothyroid-ism are normally grown and lack obvious clinicalmanifestations of hypothyroidism. Given the serumT4 half-life of approximately 6 days, the maternalcontribution will fall and disappear over the first 2-3 weeks of life. Thus, there is a crucial ‘window ofopportunity’ 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 rapidlyas possible, to minimize the time the brain isexposed to hypothyroidism. Experience has shownthat this requires higher starting L-thyroxine dosesthan were initially recommended by newbornscreening programs. In addition, frequent monitor-ing of thyroid function tests in the first 2-3 years oflife is also important, to assure that thyroid function

remains in the target range during this time ofcontinued brain dependence on thyroid hormone.

HISTORICAL PERSPECTIVE: CONGENITALHYPOTHYROIDISM IN THE PRE-SCREENING ERA

Prior to the onset of screening programs, acomprehensive survey in Sweden reported that theincidence of congenital hypothyroidism during the1969-1975 period was 1:6,900 8. The authors statedthat “in spite of an efficient National Health CareProgram for infants, the diagnosis was delayeduntil after an age of three months in 52% of the

” Kl i l f Pi b h Child ’

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 dessicatedthyroid (porcine thyroid, containing both T4 andT3), with recommended starting doses in the rangeof 15-30 mg daily 10. Most experts beganrecommending sodium L-thyroxine in the 1970s; atthis time and even in the early 1980s, therecommended starting dose was 6-8 μ g/kg/day 11 .

TABLE 1

Inverse relationship between age at clinical diagnosisof congenital hypothyroidism and IQ outcome 9

IQAge of treatment(months)

mean range

0-3 89 64-107

3-6 71 35-96

>6 54 25-80

Congenital hypothyroidism is not usually aheritable disorder; the majority of cases aresporadic. Thus, it is not possible to identify a

population of pregnant women who are at high-riskfor delivering a newborn with hypothyroidism, and,short of fetal cord blood sampling, no reliable

prenatal test has been developed. As describedabove, the clinical manifestations are often subtle,non-specific, or even absent at birth, so that mostcases are not suspected or diagnosed clinically inthe neonatal period. For these reasons, whentechnology allowed the measurement of T4 andTSH in the small volume of blood obtained fornewborn screening (eluted from filter paper speci-mens obtained by heel-prick), testing for congenitalhypothyroidism was added by programs starting inth id 1970 12-14


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TREATING CONGENITAL HYPOTHYROIDISM 561

Israel, Japan, Australia and New Zealand), and theyhave been developed more recently in parts of

Mexico, several countries in South America andsome in Asia and the Middle East. The incidence ofcongenital hypothyroidism ranges from 1:3,000 to1:4,000 newborns in most reports. In the year 2000survey of United States screening programs, 1,635cases of permanent primary hypothyroidism weredetected among 4,125,135 infants, for an incidenceof 1:2,523 15. The incidence from newborn screen-ing programs is approximately twice that from the

pre-screening era. Most likely, this is the result ofdetection of cases of transient hypothyroidism,milder cases of congenital hypothyroidism, or casesthat would have been diagnosed later in childhoodand so thought to represent acquired hypothyroid-ism.

The advent of newborn screening has resultedin dramatic improvement in the neurocognitiveoutcome of infants with congenital hypothyroidism.That said, it is the experience of many programsthat undertake follow-up psychometric testing thatinfants tend to have a slight, 5-10 IQ point deficitcompared to appropriate control groups 16, and thatthey have an increased likelihood of having subtle

learning problems, such as difficulty with voca- bulary, reading comprehension, arithmetic, andmemory 17. It is therefore incumbent to examineways in which we can improve treatment of infantsdetected with congenital hypothyroidism.

The overall goals of treatment are to assurenormal growth and development, with neuro-cognitive outcome similar to the child’s genetic

potential. Investigators have carried out studies ofthe components of treatment to examine whichleads to the best neurocognitive outcome. Suchinvestigations include examining the effect ofdifferent starting L-thyroxine doses on the time-course of normalization of serum thyroid function

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

L -Thyroxine: tablet vs liquid

At present, only L-thyroxine tablets should beused; there are no U.S. Food and Drug Administ-ration (FDA)-approved liquid preparations. L-Thyroxine suspensions that may be prepared byindividual pharmacists may lead to unreliable

dosage. There is a report of a liquid T4 preparationfrom Europe (manufactured by Henning Berlin; 1drop [50 μ l] = 5 μ g)18. Using a median startingdose of 12.3 μ g/kg/d, serum TSH normalizedwithin 2 weeks, while using a slightly highermedian dose of 12.7 μ g/kg/d resulted in TSHnormalization within 1 week. Infants treated withthis liquid L-T4 for up to 2 years appeared to do

well, although follow-up psychometric testing hasyet to be reported. Further studies leading to FDAapproval should be carried out before this liquid T4

preparation is used by physicians in the UnitedStates.

T4 vs T4 + T3

L-T4 is the treatment of choice. As T3 is the biologically active thyroid hormone, there has beenrecent interest in T4 + T3 combination treatment ofhypothyroidism. While there is some evidence thatT4 treatment alone may not normalize intracellularT3 levels in all tissues 19, the majority of brain T3 isderived from local monodeiodination of T4 20.Further, the correct dose of T3 or the exact ratio ofT4 and T3 in children has yet to be worked out. At

present, the only ‘T4 + T3’ preparations availableare Armour dessicated thyroid, which may havevariable potency, and thyrolar, a dessicated T4 andsynthetic T3 combination. Given the priority ofprotecting the brain from thyroid deficiency and the


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squirted into the infant’s cheek pad. Anothermethod is to add the daily suspension to an open

bottle nipple and offer it just before a feeding. Thecrushed T4 tablet should not be added to a full

bottle for feeding, as some of the L-T4 may stick tothe bottle wall or settle at the bottom and so maynot be consumed.

Substances/disorders inhibiting gastrointestinal(G-I) absorption

Approximately 60-80% of ingested L-T4 isabsorbed from the G-I tract, primarily from thesmall intestine 21. Several substances are reported to

bind thyroxine and interfere with its absorption;these are listed in Table 2. Soy formula has beenthe best studied in infants with congenital hypo-thyroidism 22. In a retrospective analysis, afterinitiation of T4 treatment, infants fed soy formulatook much longer to achieve a serum TSH 10 μ g/dl 25, droppingto an average of 31 days at 10 μ g/kg/d 28, whileusing a dose of 10-14 μ g/kg/d, the desired T4 wasreached in 7 days 29. In a study from Oregon ofthree starting treatment doses, the highest dose (50μ g/ day = 12-17 μ g/kg/d) raised the serum T4 to

>10 μ g/dl by 3 days and normalized the TSH by 2weeks of treatment 31. The intermediate dose (37.5μ g/day = 9.4-12.4 μ g/kg/d) or a loading dosefollowed by the intermediate dose (62.5 μ g/d for 3days followed by 37.5 μ g/d), took 1 week to raisethe serum T4 to >10 μ g/dl, while the serum TSHwas normalized at 12 weeks of treatment 31. Infantswho took longer than 2 weeks to normalize theirthyroid function had significantly lower cognitive,attention, and achievement scores than those whoachieved normal thyroid function by 1 or 2 weeksafter starting therapy 32. These studies show that thecurrent recommended starting L-T4 dose of 10-15

g/kg/d leads to the most rapid normalization of


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the lower T4 dose did not do as well as controlinfants. In the Toronto program, a comparison was

made of infants started on a dose of 6.4 μ g/kg/d vs9.0 μ g/kg/d 34. Verbal IQ was 98.6 vs 106.3 (p


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performance IQ was 103.8 vs 108.2 (p = NS), andfull scale IQ was 100.0 vs 107.6 (p


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T4 2 μ g/dl and an epiphyseal surfacearea 0.05 cm 2, respectively, both

treated with a starting L-T4 dose of 6 μ g/kg/d44

.Serial psychometric testing up to age 12 yearsshowed a global scale IQ 16 points lower in theseverely affected cohort. Subsequently, the Quebecgroup reported that using a starting L-T4 dose of11.6 μ g/kg/d “narrowed the gap”, such that IQswere not statistically different between the mode-rate and severe groups (110 vs 107) 45.

The Dutch newborn screening programinvestigated both the effect of initial starting dose(9.5 μ g/kg/d) and age of onset oftreatment (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) hypothyroidism 40. Inthe infants with more severe hypothyroidism,testing at 10-30 months of age showed IQ 21-27

points lower in the groups treated with the lowerdose and/or treated at a later age; the group treatedwith a high dose and at an early age had the bestoutcome (IQ = 125). On the other hand, all theinfants with mild hypothyroidism did well, exceptthe group treated with a low dose and at a later age,

which had an IQ 22-25 points below the othergroups. Re-evaluation at 6 years of age showedimprovement, with a global IQ score of 104.7 forthe entire group, similar to the control group ofchildren, 107.5 41. The mild group’s IQ was 108.5,while the severe group’s IQ was 99.4, but thisdifference was not statistically significant. How-ever, the visuomotor scores were higher in the mildvs 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 thosewith severe hypothyroidism, 100 vs 89 (p = 0.05) 32.

In our review of the literature we found 30

function. Based on the studies comparing outcomewith severity of disease, we conclude that it is

important to use the higher end of the dosagerange, perhaps even extending it to 12-17 μ g/kg/d,in those infants judged to have more severe hypo-thyroidism (e.g., serum T4


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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 monitortreatment of congenital hypothyroidism. Afterinitiation of L-T4, serum TSH may take severalweeks or longer to fall into the normal range. Someinfants may manifest a persistently elevated TSHlevel, 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 safestto measure both T4 or FT4 and TSH levels to makecorrect decisions about dose adjustments. It isimportant to compare the result to the normal rangefor age. Measurement of serum T3 or free T3 (FT3)is not useful in monitoring treatment, as these testsmay be normal, despite a low T4 or FT4 andelevated TSH level.

Frequency of monitoring thyroid function tests

When treating infants with congenital hypo-thyroidism, it is important to carry out thyroidfunction tests more frequently than in, for example,older children with acquired hypothyroidism. Infantsundergo rapid growth and development in the first2-3 years of life, and more frequent dose changesmay 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 theeffects of under- or over-treatment are reversible inadolescents, they may have permanent effects ininfancy. The current guidelines for frequency ofmonitoring thyroid tests are presented in Table 7.Testing may need to be carried out at more frequentintervals when compliance is questioned, abnormalvalues are obtained, or the source of thyroidhormone is changed, e.g., from one brand toanother brand, to a generic, or from one generic toanother generic L-thyroxine.

Biochemical and clinical objectives of treatment

As before, the biochemical goals are to keep theserum T4 or FT4 in the upper half of the normalrange for age, with the TSH now suppressed to thelower half of the normal range. After the first twoweeks of treatment, serum thyroid test target rangeguidelines are 24:

• T4 10-16 μ g/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 criticalfor growth, as essentially all studies show normalgrowth of infants with congenital hypothyroidismdetected by newborn screening programs. Salernoet 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 >8μ g/kg/d entered puberty a year earlier, with


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menarche also a year earlier, as compared to girlsstarted on a lower dose 65. However, all the children

in the study (boys and girls) reached a similar adultheight (0.1 ± 1.1 SDS), which was actually greaterthan mid-parental target height (-0.9 ± 0.9 SDS).

No significant correlation was found between adultheight and specific etiology or severity of con-genital hypothyroidism or initial starting T4 dose.

Avoiding prolonged over-treatment

Prolonged over-treatment, typically presentingas a serum T4 or FT4 above the normal rangeaccompanied by a suppressed TSH level, may leadto 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 anddisordered myelination 66. In infancy, over-treatment has been associated with prematurefusion of the skull bones and craniosynostosis.Behavior issues, including problems withtemperament 67 and short attention span 68, have

been reported. With appropriate monitoring and T4dose adjustments, these adverse effects aregenerally 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

. Sometreated children with congenital hypothyroidism,however, manifest a persistently elevated serumTSH level, typically in the 10-20 mU/l range,despite FT4 or T4 in the upper half of the normalrange. If the T4 dose is raised to normalize the TSH

thyroidism 71. If there is evidence for an abnormalfeedback threshold, we recommend using primarily

the serum FT4 or T4 and clinical assessment toadjust the L-T4 dose, allowing the serum TSH toremain slightly elevated. Most cases resolve withtime.

Some treated children with congenital hypo-thyroidism will manifest an elevated serum TSHwith FT4 or T4 in the upper half of the normalrange as a result of irregular compliance. Suchchildren will typically have had normalization ofthe serum TSH and FT4 in the past, evidence thatthey do not have a feedback axis abnormality. Theexplanation for these findings appears to beirregular administration of T4 until just before anappointment and blood testing, when missed dosesare quickly made up. Under these circumstances,serum FT4 or T4 will increase quickly, over 24 h,while serum TSH may take several weeks to fallinto the normal range 69.

PERMANENT VS TRANSIENTCONGENITAL HYPOTHYROIDISM

Some patients detected by newborn screeningwill have a transient form of hypothyroidism. In

North America, it is estimated that 10-20% of casesare transient 15, while in Europe the frequencyappears to be higher, primarily a result of transientcases in infants born in areas of iodine deficiency 72.Some clinicians elect to carry out thyroid scinti-graphy or ultrasonography at the time of detection

by newborn screening. If such imaging studiesshow an ectopic gland, or absent thyroid uptake,confirmed by ultrasonography, a permanent formof hypothyroidism is present. If an inborn error ofthyroid hormone biosynthesis is suspected, forexample, with a goiter and elevated radioiodine


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TSH 24. If the TSH is elevated and FT4 or T4 islow, permanent hypothyroidism is confirmed. On

the other hand, if thyroid function tests are normal,transient hypothyroidism is presumed. If results areinconclusive (e.g., normal FT4 or T4 and slightlyelevated TSH), careful follow-up and retesting areindicated.

In cases of transient congenital hypothyroidism,one may sometimes not be sure whether there trulywas transient hypothyroidism, or whether the infanthad false positive thyroid screening tests. Fortu-nately, studies of infants with transient congenitalhypothyroidism, treated for anywhere from 6weeks to 2 years, showed normal growth anddevelopment out to 6-14 years of age 73.

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TABLE 4

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

Study bylocation

No. ofpatients

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

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)

AustraliaConnelly et al. 36 2001

95

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, CanadaRovet & Ehrlich 34

199588

≤7.7 μ g/kg/d vs ≥7.8 μ g/kg/d

8 yr Woodcock ReadingMastery-Revised

50.1 vs 59.3 (P=0.05)


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Study bylocation

No. ofpatients

L -T4 dose Age of psycho-metric test


FSIQ 88 vs 94 vs 98 (p=0.009)

VIQ 92 vs 94 vs 98 (NS)836-8 μ g/kg/d vs 8.1-10 μ g/kg/d

vs 10.1-15 μ g/kg/dPIQ 85 vs 95 vs 98 (p


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TABLE 5

Studies comparing severity of congenital hypothyroidism and effect on IQ

Study byLocation

No. ofpatients

Criterion Age of psycho-metric Test


FSIQ 96.1 vs 101.1 vs 101.5 (NS)VIQ 95.8 vs 99.4 vs 102.8 (NS)119

athyreosis vsdyshormonogenesis 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 μ g/dl

PIQ 97.4 vs 101.6 (NS)

FSIQ 97.5 vs 101.8 (NS)

VIQ 98.2 vs 101.8 (NS)

Victoria, AustraliaConnelly 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)BrazilKreisner et al. 46

200431 T4 ≤2.5 μ g/dl vs >2.5 μ g/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


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Study byLocation

No. ofpatients



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-BuktenicaDevelopmental Test of

Visual Motor Integration42.3 vs 72.4 (p=0.02)

McCarthy Scale 45.5 vs 53.9(p=0.02)

Toronto, CanadaRovet et al. 48

198734 BA ≤36 wk vs >36 wk 5 yr

Reynell DevelopmentalLanguage 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 vsdyshormonogenesis vs ectopiaPIQ 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, CanadaRovet et al. 49

1992108

T4 4.0 μ g/dl

5 yr WPPSI

NS

Toronto, CanadaRovet 50

1999

48athyreosis 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, CanadaSong et al. 51

200162


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, CanadaRovet 37

2005 ? T4 3.5 μ g/dl6, 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)FranceBoileau et al. 38

2004131


7 yr WISC-R and WISC-III

PIQ 113.0 vs 117.0 vs 114.1 (NS)

4


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Study byLocation

No. ofpatients



T4 1.1 μ g/dl and BA 31.5 wk vs27

T4 6.3 μ g/dl and BA 40.1 wk93 vs 99 (p


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Study byLocation

No. ofpatients



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


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Study byLocation

No. ofpatients



36 T4 4.7 μ g/dl 94 vs 106 (p=0.013)UKMurphy et al. 59

1986 35 T3 ≤130 ng/dl vs >130 ng/dl3 yr McCarthy Scale

93 vs 105 (p500 mU/l vs 250-500mU/l vs


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TABLE 6

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

Study by location No. ofpatients

Age of onset oftreatment

Age of psycho-metric test


FSIQ 98.1 vs 99.6 (NS)VIQ 98.2 vs 100.4 (NS)

Victoria, AustraliaConnelly 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 yrWPPSI (4-6 yrs),

WISC (6 yrs-15 yrs 11 mos)PIQ 91.43 vs 103.00 (p=0.036)

Toronto, Canada

Rovet 37

2005? >12 days vs


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Study by location No. ofpatients

Age of onset oftreatment

Age of psycho-metric test


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

late/low vs late/high vsearly/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 etal. 40

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

21.7 moBayley Test: Mental Development

Index (MDI) and PsychomotorDevelopment Index (PDI)

PDI 111 vs 117 vs 123 vs 120 (NS)

Low (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-Schrama 41

2005 24

late ( ≥13 days) vsearly (

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