Pediatrics 2006 Congenital Hypothyroidism Guidelines

DOI: 10.1542/peds.2006-0915 2006;117;2290Pediatrics

Rosalind S. Brown and Lawson Wilkins Pediatric Endocrine SocietyAmerican Academy of Pediatrics, Susan R. Rose, American Thyroid Association,Update of Newborn Screening and Therapy for Congenital Hypothyroidism

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CLINICAL REPORT

Update of Newborn Screening andTherapy for CongenitalHypothyroidismAMERICAN ACADEMY OF PEDIATRICS

Susan R. Rose, MD, and the Section on Endocrinology and Committee on Genetics

AMERICAN THYROID ASSOCIATION

Rosalind S. Brown, MD, and the Public Health Committee

LAWSON WILKINS PEDIATRIC ENDOCRINE SOCIETY

ABSTRACTUnrecognized congenital hypothyroidism leads to mental retardation. Newbornscreening and thyroid therapy started within 2 weeks of age can normalizecognitive development. The primary thyroid-stimulating hormone screening hasbecome standard in many parts of the world. However, newborn thyroid screeningis not yet universal in some countries. Initial dosage of 10 to 15 �g/kg levothy-roxine is recommended. The goals of thyroid hormone therapy should be tomaintain frequent evaluations of total thyroxine or free thyroxine in the upperhalf of the reference range during the first 3 years of life and to normalize theserum thyroid-stimulating hormone concentration to ensure optimal thyroid hor-mone dosage and compliance.

Improvements in screening and therapy have led to improved developmentaloutcomes in adults with congenital hypothyroidism who are now in their 20s and30s. Thyroid hormone regimens used today are more aggressive in targeting earlycorrection of thyroid-stimulating hormone than were those used 20 or even 10years ago. Thus, newborn infants with congenital hypothyroidism today may havean even better intellectual and neurologic prognosis. Efforts are ongoing to estab-lish the optimal therapy that leads to maximum potential for normal developmentfor infants with congenital hypothyroidism.

Remaining controversy centers on infants whose abnormality in neonatal thy-roid function is transient or mild and on optimal care of very low birth weight orpreterm infants. Of note, thyroid-stimulating hormone is not elevated in centralhypothyroidism. An algorithm is proposed for diagnosis and management.

Physicians must not relinquish their clinical judgment and experience in theface of normal newborn thyroid test results. Hypothyroidism can be acquired afterthe newborn screening. When clinical symptoms and signs suggest hypothyroid-ism, regardless of newborn screening results, serum free thyroxine and thyroid-stimulating hormone determinations should be performed.

INTRODUCTIONCongenital hypothyroidism (CH) is one of the most common preventable causes ofmental retardation. In most cases, the disorder is permanent and results from an

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All clinical reports from the AmericanAcademy of Pediatrics automaticallyexpire 5 years after publication unlessreaffirmed, revised, or retired at orbefore that time.

The guidance in this report does notindicate an exclusive course of treatmentor serve as a standard of medical care.Variations, taking into account individualcircumstances, may be appropriate.

KeyWordscongenital hypothyroidism, thyroidhormone, thyroid-stimulating hormone,newborn screening

AbbreviationsCH—congenital hypothyroidismTH—thyroid hormoneT4—thyroxineT3—triiodothyronineTSH-R—thyrotropin receptorTRBAb—thyrotropin receptor-blockingantibodyFT4—free thyroxineTSH—thyroid-stimulating hormoneTBG—thyroid-binding globulinLBW—low birth weightVLBW—very low birth weightL-T4—levothyroxineTRH—thyrotropin-releasing hormone

PEDIATRICS (ISSN Numbers: Print, 0031-4005;Online, 1098-4275). Copyright © 2006 by theAmerican Academy of Pediatrics

2290 AMERICAN ACADEMY OF PEDIATRICS

Guidance for the Clinician in RenderingPediatric Care



abnormality in thyroid gland development (dysgenesisor agenesis) or a defect in thyroid hormonogenesis. Lesscommonly, the altered neonatal thyroid function is tran-sient, attributable to the transplacental passage of ma-ternal medication, maternal blocking antibodies, or io-dine deficiency or excess. In rare cases, CH may resultfrom a pituitary or hypothalamic abnormality (central orsecondary/tertiary hypothyroidism). Recent advances inmolecular and cell biology have led to improved under-standing of normal thyroid physiology and of genes in-volved in thyroid gland development and disease. Inaddition, the mechanism and precise temporal sequenceof thyroid hormone (TH) modulation of target geneexpression are being elucidated.1–8

The initial American Academy of Pediatrics recom-mendation for newborn screening for CH was publishedin 1993.9 Screening for CH is one of dozens of newbornscreening tests conducted. The rapid advances in ourknowledge in the decade since the 1993 publicationhave prompted reevaluation of the problem and theidentification of new questions and concerns.

TH concentrations are low in the fetus during the firsthalf of pregnancy. During this time, the fetus is entirelydependent on maternal TH; its supply to the fetus iscontrolled by the placenta and the thyroid status of themother. The fetal hypothalamic-pituitary-thyroid axisbegins to function by midgestation and is mature in theterm infant at delivery. Despite the critical importance ofTH on multiple organ systems, especially the brain, mostinfants with CH appear normal at birth. The hypothyroidfetus appears to be protected at least in part by placentaltransfer of maternal TH. This was best illustrated by thedemonstration that cord blood thyroxine (T4) concen-tration at birth in infants unable to synthesize T4 wasnonetheless one third to one half that of normal in-fants.10 In addition, there is increased intracerebral con-version of T4 to triiodothyronine (T3), resulting in in-creased local availability of T3 despite the low serumconcentrations.11–13 Indeed, normal or near-normal cog-nitive outcome is possible in even the most severelyaffected infants with CH. This is true as long as postnataltherapy is early and adequate and maternal thyroidfunction is normal. In contrast, when both maternal andfetal hypothyroidism are present, whether attributableto severe iodine deficiency, potent thyrotropin receptor(TSH-R)-blocking antibodies (TRBAbs) (or TSH-blockingimmunoglobulins), or maternal-fetal PIT1 deficiency,there is a significant impairment in neurointellectualdevelopment despite adequate therapy soon afterbirth.6,14,15 Maternal hypothyroidism alone during earlygestation can lead to mild but significant cognitive im-pairment of the offspring.6,15–19 In this report, attention isfocused on the problem of CH alone; identification andtreatment of maternal hypothyroidism has been the sub-ject of several recent reviews.20,21

Pilot screening programs for CH were developed in

Quebec, Canada, and Pittsburgh, Pennsylvania, in 1974and have now been established in Western Europe,North America, Japan, Australia, and parts of EasternEurope, Asia, South America, and Central America.22–24

In North America, more than 5 million newborns arescreened and approximately 1400 infants with CH aredetected annually. Certainly the main objective ofscreening, the eradication of mental retardation afterCH, has been achieved. In addition to the profoundclinical benefit, it has been estimated that the cost ofscreening for CH is much lower than the cost of diag-nosing CH at an older age. This estimate does not includethe loss of tax income resulting from impaired intellec-tual capacity in the untreated but noninstitutionalizedperson. Newborn screening also has revealed the prev-alence of the various causes of CH, including a series oftransient disorders found predominantly in preterm in-fants. The incidence of CH has been found to be 4 to 5times more common than phenylketonuria, for whichscreening programs were originally developed. Theoverall incidence of CH ranges from 1 in 3000 to 1 in4000 newborn infants.15,25 The incidence of CH is higherin Hispanic individuals and lower in black individuals.25

There is a 2:1 incidence in females compared with males,and there is an increased risk in infants with Downsyndrome.

Iodine deficiency remains the most common treatablecause of mental retardation worldwide. Associated nu-tritional deficiencies in selenium and iron may have aneffect on neurologic development and on thyroidal re-sponse to iodine therapy.26 Many countries have initi-ated salt iodination.25–28 Although North America is usu-ally considered to be an iodine-sufficient area, recentepidemiologic evidence suggests that a number of preg-nant women may be iodine deficient.29 There is alsosome concern that maternal iodine deficiency may bereappearing in developed countries despite salt iodina-tion because diet-conscious young women may avoidiodine-supplemented salt and breads.30,31 Iodine supple-mentation before or during pregnancy will normalizethyroid function in the mother and the newborn.31,32

The hypothalamic-pituitary-thyroid axis is finelytuned to maintain a fairly stable concentration of freethyroxine (FT4) within any individual.33 Divergencefrom this individual optimal “set point” because of un-derfunction of the thyroid gland results in an increase inthyroid-stimulating hormone/thyrotropin (TSH) con-centration. The exception to this is when the hypothal-amus or pituitary gland is unable to respond (in centralhypothyroidism, rare pituitary resistance to FT4 feed-back, or in an occasional child with Down syndrome).

Thus, TSH is elevated if thyroid gland function isimpaired and FT4 decreases from its individual optimalset point, although TSH concentration is not elevated incentral hypothyroidism.

Although much has been learned, some questions

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remain. These issues include the optimal screening ap-proach and the follow-up of infants with low T4 andnormal TSH concentrations. Finally, continued effortsare ongoing to establish the optimal therapy that leads tomaximum potential for normal development for infantswith CH.

SCREENINGMETHODTwo screening strategies for the detection of CH haveevolved: a primary TSH/backup T4 method and a pri-mary T4/backup TSH method (Fig 1). In addition, anincreasing number of programs use a combined primaryTSH plus T4 approach.

Primary TSHWith Backup T4 MeasurementsMost programs in Europe, Japan, Canada, Mexico, andthe United States screen by using primary TSH measure-ments, supplemented by T4 determinations for infantswith elevated TSH values. With this approach, delayedTSH elevation in infants with thyroid-binding globulin(TBG) deficiency, central hypothyroidism, and hypothy-roxinemia will be missed. Delayed TSH elevation is par-ticularly common in infants with low birth weight (LBW[�2500g]) and very low birth weight (VLBW [�1500g]).In the Quebec study, 2 cases of permanent CH (of 93 000infants screened) would have been missed by the pri-mary TSH approach and detected by the primary T4

approach.34 The recall rate (notification of a physician tocontact the infant’s family to arrange for a blood test)with a primary TSH screening approach is approximately0.05%. At this rate, 2 infants will be recalled for testingfor every case detected.

Current TSH assay techniques (enzyme-linked immu-noassays, chemiluminescent assays, and fluoroimmuno-assays) use nonradioactive labels and have improvedsensitivity with the potential for better separation be-tween normal and abnormal TSH concentrations. Thus,many screening programs are considering switching to aprimary TSH approach. However, the trend toward earlydischarge of mothers and infants (before 48 hours ofage) presents a problem with the switch to a primaryTSH approach because of the normal increase in TSHpostnatally. With early hospital discharge, the firstscreening specimen commonly is obtained before 48hours of age. Recent data using a sensitive and specificimmunofluorometric assay indicate that normal TSHvalues before 24 hours of age are not as high as thoseusing previous assays and usually less than the cutoffvalue of 20 to 25 mU/L.35,36 A 50% reduction in abnor-mal values occurred when age-adjusted TSH cutoffswere used.37 Thus, the current experience using newerassays in a primary TSH screening approach in a popu-lation of infants discharged after 24 hours of age showslower patient recall rates with negligible false-negativetest results.

Primary T4 With Backup TSHMeasurementsAn initial filter-paper blood-spot T4 measurement is fol-lowed by a measurement of TSH for filter-paper speci-mens with low T4 values.9,25 The primary T4 approachwill detect primary hypothyroidism in infants with lowor low-normal T4 with elevated TSH concentrations(prevalence ranging from 1 in 3000 to 1 in 4000 new-born infants). In addition to detecting primary hypothy-roidism, the primary T4/backup TSH approach can alsoidentify infants with TBG deficiency (prevalence rangingfrom 1 in 5000 to 10 000 newborn infants) and centralhypothyroidism (low or low-normal T4 with normal TSHconcentration; prevalence: l in 50 000 newborn infants).Programs that quantify high T4 values also have thepotential to identify infants with hyperthyroxinemia (1in 20 000 to l in 40 000 newborn infants). This ap-proach, however, will miss the condition in an infantwith an initially normal T4 concentration and delayedincrease in TSH. To ensure identification of infants withCH who have low-normal T4 values, most screeningprograms use a T4 concentration cutoff of �10th percen-tile for the days’ assay. Comparison of the primary T4

versus primary TSH screening approach was conductedin Quebec (1983).34 One case (of 93 000 infantsscreened) would have been missed by the primary T4

approach and detected by the primary TSH approach.34

Programs using a primary T4 with secondary TSHapproach will follow-up on infants with a low T4 andelevated TSH screening result. The recall rate for primaryhypothyroidism in these screening programs is approx-imately 0.05%, similar to that in primary TSH screeningprograms.38 However, some primary T4 screening pro-grams also report low T4 results below an absolute cutoff(eg, 3.0 �g/dL [39 nmol/L]) in infants even if the TSHwas normal. The recall rate (and therefore the false-positive rate) will be higher (approaching 0.30%) withthis practice. For example, in a 1990 study in California,which did not report low T4 results, the recall rate was0.08%. In contrast, a study performed in Oregon, whichreported infants with 2 low T4 results �3rd percentile,the recall rate was 0.30%.39 This means that up to 12normal infants may be recalled for testing for every 1case of hypothyroidism.

Combined Primary TSH Plus T4 MeasurementsMethods for the simultaneous measurement of T4 andTSH are available (DELFIA data). This represents theideal screening approach, especially once it is possible forFT4 to be measured accurately and cost-effectively in theeluates from filter-paper blood spots. Until T4 and TSHdeterminations can be performed practically for all in-fants, physicians should be aware of the potential limi-tations of each method of screening for CH.

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FIGURE

1New

bornscreeningforCH.aManagem

entofCHissummarized

inTable1.



THE SPECIMENEvery infant should be tested before discharge from thenursery, optimally by 48 hours to 4 days of age. As notedabove, specimens collected in the first 24 to 48 hours oflife may lead to false-positive TSH elevations when usingany screening test approach. However, screening beforehospital discharge or before transfusion is preferable tomissing the diagnosis of hypothyroidism. False-negativeresults may occur by screening a very sick newborn orafter transfusion. Because newborn blood specimens areused for a variety of screening tests and shared amongdifferent laboratories, every effort should be made tocollect adequate and sufficient blood in the recom-mended manner.39

It is highly desirable that the blood be collected whenthe infant is between 2 and 4 days of age, but there aresituations in which this is virtually impossible. In infantsdischarged from the nursery before 48 hours of age,blood should be obtained before discharge. In instancessuch as home births or in the case of a critically ill orpreterm neonate, blood should be obtained by 7 days ofage, recognizing that samples obtained after 4 days ofage are late for screening of congenital adrenal hyper-plasia or metabolic disease. Particular care must be takenwith infants in NICUs. In such cases, more urgent med-ical problems may result in missed newborn screening.When an infant is transferred to another hospital, thefirst hospital must indicate whether the specimen hasbeen collected. The second hospital should obtain a spec-imen if there is no proof that blood was collected beforethe transfer.

Some state screening programs, testing 10% of new-borns in the United States, perform newborn screeningon specimens routinely collected at 2 time periods. Theseprograms report that CH is detected in approximately10% of the affected infants only as a result of collectionof a second specimen. The additional incidence of CHbased on a second screening at 2 weeks of age is approx-imately 1 in 30 000.38,40 Infants with CH detected at thelater screening time tend to be of LBW or VLBW, withmild or delayed TSH elevations.41 Whether these casesrepresent transient or permanent cases is unknown.Some have thyroid dysgenesis (ectopia, aplasia, or hy-poplasia) on thyroid scanning. Others appear to haveincreased uptake and a large thyroid gland, suggestive ofdyshormonogenesis.8 Either these infants have transientdisease or their disease is undiagnosed until a later age,when they appear to have acquired hypothyroidism.

Accurate screening results depend on good-qualityblood spots. The filter paper designed for newbornscreening bears printed circles. Capillary blood samplesare placed in these circular areas to fill and saturatethem. Spotting blood over a previous blood spot, ordouble spotting, causes invalid results, and these bloodspots should not be used. The recall of an infant fortesting because of an unsatisfactory filter-paper speci-

men causes needless delay in diagnosis and treatment ofa newborn with CH. Specimens that are technically un-satisfactory or contain insufficient amounts of bloodshould not be assayed. Blood samples should be col-lected on approved filter-paper forms, dried at roomtemperature, and not subjected to excessive heat. Theblood should completely saturate the filter paper and beapplied to 1 side only. Filter-paper spots should not behandled, placed on wet surfaces, or contaminated bycoffee, milk, or other substances. Any of these have thepotential to invalidate the results regardless of themethod used. Testing of an unsatisfactory specimen (be-cause of insufficient blood) can result in a false-negativeTSH value. False-negative values can also result fromhuman error in the processing of satisfactory specimensor in erroneous reporting of the results.

TEST RESULTS

Transmission of Results and Follow-up TestingNewborn screening test results must be communicatedrapidly back to the physician or hospital identified on thescreening filter-paper card. The responsibility for trans-mission of these results rests with the authority oragency that performed the test. In general, when anabnormal screening result is found, the responsible phy-sician is notified immediately so that he or she canarrange for follow-up testing. Screening test resultsshould be entered into the patient’s record. If the in-formed physician is no longer caring for or cannot locatethe infant, he or she should notify the newborn screen-ing laboratory immediately. In such situations, the localhealth department is often helpful in locating these in-fants to ensure that they are not lost to follow-up.

Low T4 and Elevated TSH ValuesAny infant with a low T4 concentration and TSH con-centration greater than 40 mU/L* is considered to haveprimary hypothyroidism. Such infants should be exam-ined immediately and have confirmatory serum testingperformed to verify the diagnosis. Treatment with re-placement levothyroxine (L-T4) should be initiated assoon as confirmatory tests have been drawn and beforethe results of the confirmatory tests are available. (Clin-ical management of infants with hypothyroidism is de-scribed in the following section.) For cases in which thescreening TSH concentration is only slightly elevated butless than 40 mU/L, another filter-paper specimen shouldbe obtained for a second newborn screening. Ten per-cent of infants with confirmed CH have TSH valuesbetween 20 and 40 mU/L. It is important that age-appropriate normative values be used. The reference

* All filter-paper TSH [and T4] levels here are reported as serum equivalents. Some laboratoriesreport screening results per unit of blood, a value that is approximately half the concentrationin serum.We recommend that all laboratories report results per unit of serum, because TSH andT4 are preferentially distributed into the serum.



range for TSH for the most common time of TSH reeval-uation (between 2 and 6 weeks of age) is 1.7 to 9.1mU/L.42

Normal T4 and Elevated TSH ValuesHyperthyrotropinemia is characterized by elevated se-rum TSH concentrations during the neonatal period de-spite normal T4 and FT4 concentrations. The etiology isprobably heterogeneous and can be either a transient orpermanent thyroid abnormality43–46 or delayed matura-tion of the hypothalamic-pituitary axis. Inactivation mu-tations in the TSH-R cause compensated, mild (subclin-ical) primary hypothyroidism in the neonatal period.The incidence of both transient and persistent hyperthy-rotropinemia and CH appears to be higher in infantswith Down syndrome. In some cases, transient neonatalhyperthyrotropinemia persists until 10 years of age orlater.

There is controversy regarding the need for TH ther-apy in this setting. There have been no long-term studiesto evaluate cognitive development in this group of pa-tients. TSH concentration is the most sensitive indicatorthat the hypothalamic-pituitary axis is sensing less T4

than the body “perceives” as optimal. Most physicianswould consider a persistent basal TSH concentrationhigher than 10 mU/L (after the first 2 weeks of age) to beabnormal.42 Therefore, if the TSH elevation persists, theinfant should be treated. If such infants are not treated,measurement of FT4 and TSH should be repeated in 2and 4 weeks, and treatment should be initiated promptlyif the FT4 and TSH concentrations have not normalized.

The management of infants with TSH elevations be-tween 6 and 10 mU/L that persist after the first month oflife is even more controversial. TSH concentrations areslightly higher in the first few months of life. A TSHrange of 1.7 to 9.1 mU/L has been reported for children2 to 20 weeks of age (Quest Diagnostics reference values,Lyndhurst, NJ). Thus, using the adult reference range forTSH will result in treatment of many euthyroid children.Consequently, if a decision is made to treat such chil-dren, a trial off therapy at 3 years of age should beperformed.

Low T4 and Normal TSH ValuesInfants with normal TSH but low T4 values (defined as 2SDs below the mean for the reference range for age,usually below 10 �g/dL in the newborn infant) mayhave thyroid insufficiency. The low T4 with normal TSHprofile is seen in 3% to 5% of neonates. This patternmay result from hypothalamic immaturity (particularlyin preterm infants, 12% of all newborn infants). Low T4

but normal TSH results are also observed during illness,with protein-binding disturbances such as TBG defi-ciency (1 in 5000), in central hypothyroidism (l in25 000 to l in 50 000 newborn infants; see next 3 para-graphs),47 or with primary hypothyroidism and delayed

TSH elevation (l in 100 000 newborn infants). Newborninfants who are preterm or ill are found with dispropor-tionate frequency among those with this set of labora-tory values.48 In neonates/infants, inhibition of TSH(causing low T4 concentrations) can result from constantinfusions of dopamine or high-dose glucocorticoids.

Transient hypothyroxinemia is seen to some extent inmany preterm infants.36,48 Immaturity of the hypotha-lamic-pituitary axis may be physiologically normal forthe infant’s gestational age. Preterm serum T4 and FT4

concentrations are lower than those of term infants, butthe TSH concentrations are comparable to term in-fants.49,50 Serum TBG concentrations are only slightlylow in preterm infants and do not account for the degreeof hypothyroxinemia. Consequently, the FT4 is rarely aslow as the total T4. Serum inhibitors of T4 binding,present in many patients with nonthyroidal illness, maybe an additional contributor to the decreased T4 values.

In contrast to transient hypothyroxinemia, the pres-ence of midline facial abnormalities, hypoglycemia, mi-crophallus, or visual abnormalities should suggest thepossibility of a hypothalamic-pituitary abnormality.Septo-optic dysplasia, often associated with pituitaryhormone deficiencies, can manifest as central hypothy-roidism.51,52 Genetic mutation in HESX-1 has been de-scribed in septo-optic dysplasia. Clinical symptoms ofhypopituitarism, such as neonatal hypoglycemia (fromgrowth hormone and adrenocorticotropic hormone de-ficiencies), polyuria (from antidiuretic hormone defi-ciency), or small phallus in boys (from gonadotropindeficiencies), along with the presence of blindness, con-genital nystagmus, or midline defects of the brain,should alert the physician to suspect the diagnosis ofsepto-optic dysplasia. Alternatively, multiple pituitaryhormone deficiencies suggest a genetic defect in thecascade leading to fetal pituitary formation, such asPROP1, LHX3, and POU1F1.4,53 DNA screening for thesemolecular abnormalities could be beneficial in the futurefor the rapid and accurate detection of these affectedinfants during the first weeks of life, but is not yetavailable clinically.

Isolated TSH-releasing hormone (TRH) deficiencymay cause low-normal T4 and low or normal TSH con-centrations. Secondary (or central) hypothyroidism maybe suspected in infants with low T4 and FT4 and low TSHconcentrations.32,43 Mutations have been identified inthe � subunit of TSH, TRH gene, and TRH receptorgene.54,55 Finally, congenital TSH and growth hormonedeficiencies may occur as a result of a difficult birth oranoxia.56

In programs that report low T4 with normal TSHresults, there is no clear consensus regarding optimalfollow-up. Such programs have elected to take no fur-ther action, to follow-up with serial filter-paper screen-ing tests until the T4 value becomes normal, or to requesta second blood sample for measurement of FT4 and TSH



concentrations. Most infants with low T4 and normalTSH have normal FT4 values, and subsequent thyroidfunction test results are normal. Programs that choose topursue further laboratory testing must weigh the benefitof detecting TBG deficiency or the rare case of hypopi-tuitary-hypothyroidism or delayed TSH increase againstthe cost and the psychological effect on the family. Theresponsibility of deciding which course of action to fol-low rests with the physician providing the care of theinfant. Treatment of these infants (with the exception ofthose with central hypothyroidism or delayed TSH in-crease) with L-T4 has not yet been shown to be benefi-cial.48,57–59

Low T4 and Delayed TSH IncreaseMany infants with low T4 concentrations and normalTSH values on initial screening (l in 100 000 newborninfants) who are subsequently found to have an elevatedTSH concentration are LBW, VLBW, or critically ill pre-term and term neonates. Serum TSH values in theseinfants increase during the first few weeks of life toconcentrations characteristic of primary hypothyroid-ism. It is unclear whether infants with this delayed TSHelevation have an abnormality of pituitary-thyroid feed-back regulation, transient hypothyroidism (eg, iodineinduced), or a mild form of permanent CH. Long-termfollow-up of these infants has not been reported. It isimportant, therefore, that serum FT4 and TSH be testedin infants with overtly low T4 concentrations or in anyinfant with suggestive signs of hypothyroidism. Infantswith low T4 and a delay in elevation of TSH values andthose with normal T4 concentrations and elevated TSHvalues might be missed on initial screening. Neither aprimary T4/backup TSH nor a primary TSH/backup T4

screening strategy will detect the rare infant with a nor-mal T4 at birth but delayed TSH increase. Even in theabsence of technical and human errors, 5% to 10% ofLBW and VLBW newborn infants with CH may havenormal screening hormone concentrations regardless ofthe approach used.

Some screening programs routinely obtain a secondspecimen at 2 to 6 weeks of age and/or obtain a serumsample from any infant with 2 successive T4 values be-low an absolute cutoff (�3rd percentile). Whateverstrategy is used, subsequent testing should be performedon serum during infancy whenever there is a perceivedrisk of hypothyroidism, as in familial dyshormonogen-esis or in infants with clinical suspicion of hypothyroid-ism. In addition, a second specimen should be drawn at2 weeks of age in monozygotic twins, because fetal bloodmixing may mask the screening test results.60

However, a second screen has not become routinebecause of (1) increased cost, (2) relatively low yield ofcases, (3) diversion and dilution of key personnel, (4)inability to implement new programs, and (5) absence ofsuch cases missed in primary TSH screening programs.

Finally, the cognitive and developmental prognosis ofthis cohort is uncertain because the etiology in mostcases is unknown and there are no definitive follow-updata.

As an alternative strategy, other programs have at-tempted to identify high-risk patient groups so that rou-tine rescreening can be targeted to these infants. There isa disproportionate incidence of delayed TSH increase inVLBW infants (incidence of CH: 1 in 250), LBW infants(incidence of CH: 1 in 1589), and neonates in intensivecare settings or with cardiovascular abnormalities.61

Therefore, some screening programs routinely screenagain at 2 weeks and 6 weeks of age all VLBW and allLBW infants in the NICU, especially in newborns knownto have cardiac disease. It is likely that most of theseinfants do not have permanent CH. If hyperthyro-tropinemia persists at 6 weeks of age, TH replacementshould be started, consistent with therapy of other formsof transient CH, and the infant should be retested after 3years of age (after stopping therapy for 4–6 weeks) (see“Assessment of Permanence of Hypothyroidism”).

Transient TSH ElevationA small number of infants with abnormal screeningvalues will have transient hypothyroidism as demon-strated by normal serum T4 and TSH concentrations onthe confirmatory (follow-up to screening) laboratorytests. Transient hypothyroidism is relatively rare inNorth America (estimated at 1 in 50 000) in contrast toiodine-deficient areas of the world; it is much morecommon in preterm infants but may occur in apparentlyhealthy term infants. Transient hypothyroidism may re-sult from intrauterine exposure to maternal antithyroiddrugs, maternal TRBAbs, heterozygous thyroid oxidase 2deficiency, germ-line mutations in the TSH-R, endemiciodine deficiency, or prenatal or postnatal exposure toexcess iodides (povidone iodine, iodinated contrast ma-terials).31,32,43,62,63 Transient iodine-induced CH is notusually evident at birth and, therefore, may not be de-tected if newborn screening is performed in the first fewdays postnatally.

Transplacental passage of potent maternal TRBAbs(incidence: 1 in 180 000) is a much less common causeof transient CH but should be suspected if there is amaternal history of autoimmune thyroid disease or ifthere is a history of previous affected offspring. In thissetting, cord serum can be collected and rapidly testedfor thyroid abnormalities. The half-life of immunoglob-ulin G in the neonate is approximately 3 to 4 weeks,64

and TRBAbs usually disappear from serum of affectedinfants by 3 to 6 months of age, depending on theantibody potency.

Because the transient nature of the hypothyroidismwill not be recognized clinically or through laboratorytests in some infants, initial treatment will be similar tothat in any infant with permanent CH. In these cases, it



is important to determine at some later time whether thehypothyroidism is permanent and whether the infant infact requires lifelong treatment (see “Assessment of Per-manence of Hypothyroidism”). However, in the new-born infant with transient hypothyroidism whosemother is receiving an antithyroid drug, the T4 and TSHvalues tend to return to normal within 1 to 3 weeks afterbirth without treatment.

CLINICALMANAGEMENT OF NEWBORN INFANTSWITH LOWT4 AND ELEVATED TSH VALUESInfants with low T4 and elevated TSH concentrationshave CH until proven otherwise. Management shouldinclude the following (Table 1):

1. The infant should be seen by his or her physicianwithout delay. Consultation with a pediatric endocri-nologist is recommended to facilitate diagnostic eval-uation and optimal management.

2. A complete history, including prenatal thyroid status(maternal drugs and medications) and family historyshould be obtained, and physical examination shouldbe performed.

3. Serum should be obtained for confirmatory measure-ments of TSH and FT4. An elevated thyroglobulinconcentration may suggest dyshormonogenesis. Caremust be taken to compare the serum results to nor-mal TH concentration for age. When there is historyof a maternal autoimmune thyroid disorder or a pre-viously affected infant, measurement of TRBAbs inthe infant and/or mother may identify a transientform of neonatal hypothyroidism.

4. Education of parents by trained personnel usingbooklets or visual aids is highly desirable. Educationshould focus on (a) the etiology of CH, (b) the lack of

correlation of parental lifestyle during pregnancywith causes of the disease, (c) the benefit of earlydiagnosis in preventing mental retardation, (d) theappropriate manner in which TH is administered andthe substances (eg, soy, iron, calcium, and fiber) thatcan interfere with TH absorption, (e) the importanceof adherence to the treatment plan, and (f) the im-portance of periodic follow-up care.

5. Optional diagnostic studies include thyroid ultra-sonography or iodine 123 (123I) or sodium techne-tium 99m pertechnetate (99mTc) thyroid uptakeand/or scan to identify functional thyroid tissue. Al-though 123I tends to give a more accurate uptake andscan picture, it may not be readily available in allhospitals. 99mTc is generally more readily availableand a much less expensive radioisotope. The half-lifeof 123I is 13.3 hours, compared with 8 days for iodine131 (131I). 123I exposes the infant to much lowerdoses of ionizing radiation compared with 131I (prob-ably one 100th of the 131I dose [H.-M. Park, MD,Professor Emeritus, Radiology, Indiana University,personal communication, September 16, 2004]).

There remains some controversy regarding the risk-benefit ratio of early thyroid scanning of infants withsuspected hypothyroidism. For physicians who opt forimaging, the benefits can be summarized as follows:

1. If an ectopic gland is demonstrated, a permanentform of thyroid disease and CH has been established.

2. The absence of thyroid gland uptake is most oftenassociated with thyroid aplasia or hypoplasia. Whenradioiodine uptake is absent but ultrasonographic ex-amination reveals a normal gland, a TSH-R defect,iodine-transport defect, or maternal transfer of TRB-Abs may be present.

3. Normal scan findings (or a goiter) indicate a function-ing thyroid gland with regard to iodine uptake andalert the physician to a probable hereditary defect inT4 synthesis. Measurement of serum thyroglobulinwill help to separate thyroglobulin synthetic defectsfrom other causes of hypothyroidism.65 Exposure toan exogenous goitrogen other than iodine, such asantithyroid drugs, will produce a similar picture. Fi-nally, some infants exposed to maternal TRBAbs mayhave a normal scan if their hypothyroidism is par-tially compensated. The identification of a geneticallymediated thyroid synthetic enzyme defect is espe-cially important for families planning on having ad-ditional children. In such cases, the scan enables thephysician to arrange for genetic counseling.

4. Some infants with normal scan findings at birth whodo not fall into one of the above categories may havea transient form of hypothyroidism. These infantsshould undergo a careful follow-up evaluation after 3

TABLE 1 Management of CH

Initial workupDetailed history and physical examinationReferral to pediatric endocrinologistRecheck serum TSH and FT4Thyroid ultrasonography and/or thyroid scan (see text for recommendations)

MedicationsL-T4: 10–15 �g/kg by mouth once daily

MonitoringRecheck T4, TSH2–4 wk after initial treatment is begunEvery 1–2 mo in the first 6 moEvery 3–4 mo between 6 mo and 3 y of ageEvery 6–12 mo from 3 y of age to end of growth

Goal of therapyNormalize TSH and maintain T4 and FT4 in upper half of reference range

Assess permanence of CHIf initial thyroid scan shows ectopic/absent gland, CH is permanentIf initial TSH is �50 mU/L and there is no increase in TSH after newborn period,

then trial off therapy at 3 y of ageIf TSH increases off therapy, consider permanent CH



years of age, when it is safe to discontinue treatmenttemporarily under the conditions described in “As-sessment of Permanence of Hypothyroidism.”

Treatment need not be delayed to perform the scan. Athyroid scan can be performed within the first few daysof treatment, because the elevated TSH found in patientswith permanent CH rarely normalizes within this timeperiod. A serum TSH measurement should be obtainedat the time of the scan. If L-T4 therapy has caused theTSH concentration to be �30 mU/L, ultrasonographycan still be performed. A scan can be performed after thechild is 3 years of age, when TH treatment can be inter-rupted without danger to the developing central nervoussystem.

The usual dose of 123I, the preferred isotope, is 0.925MBq (25 �Ci). This represents a small amount of radia-tion exposure, equivalent to the amount of exposurewith 2 to 3 chest radiographs. However, the radiationexposure is potentially 100 times greater if 131I or largedoses of isotope are administered. For this reason, theprocedure should be performed by experienced person-nel with optimal equipment, using the minimally rec-ommended tracer dose.

To avoid unnecessary radiation, some investigatorsprefer ultrasonography as the initial imaging procedureto identify the presence and location of thyroid tis-sue.66–68 However, gray-scale ultrasonography is muchless sensitive than scintigraphy in detecting the presenceof ectopic thyroid tissue, the most common cause of CH.Recent studies have indicated markedly improved sen-sitivity of color Doppler ultrasonography in diagnosingectopic thyroid tissue.69 If these studies are confirmed,color Doppler ultrasonography may become the optimalimaging procedure for the initial investigation of sus-pected CH.

TREATMENTAll infants with hypothyroidism, with or without goiter,should be rendered euthyroid as promptly as possible byreplacement therapy with TH.21,70–72 An optimal cogni-tive outcome depends on both the adequacy and timingof postnatal therapy, particularly in severe cases of CH(T4 � 5 �g/dL). However, what constitutes optimal THtherapy is not yet certain. The goal of therapy is tonormalize T4 within 2 weeks and TSH within 1 month.An initial dosage of 10 to 15 �g/kg of L-T4 (depending onthe severity of the initial hypothyroidism) has been rec-ommended. When a higher initial dose of L-T4 (50 �g[ie, 12–17 �g/kg]) is used, the serum T4 normalizes in 3days and the TSH returns to the target range by 2 weeksof therapy.72 In the long run, evaluation of cognitiveoutcome is important after use of this increased dose.Currently the evidence base does not indicate cognitivebenefit from thyroid therapy of hypothyroxinemia ofprematurity in the absence of TSH elevation.48–50,57–59

Administration of L-T4 is the treatment of choice.Although T3 is the more biologically active TH, mostbrain T3 is derived from local monodeiodination of T4, soT3 should not be used. The pill should be crushed andsuspended in a few milliliters of formula, breast milk, orwater. Care should be taken to avoid concomitant ad-ministration of soy, fiber, or iron. Breastfeeding cancontinue. Only T4 tablets should be used; currently thereare no liquid formulations licensed by the US Food andDrug Administration. T4 suspensions that may be pre-pared by individual pharmacists may lead to unreliabledosage. T4 is expected to increase to more than 10 �g/dL,FT4 is expected to increase to more than 2 ng/dL by 2weeks after initiating therapy, and TSH should normal-ize by 1 month.73 FT4 measurement at 1 week of therapycan confirm whether the serum concentration is increas-ing appropriately. The L-T4 dose should be adjusted ac-cording to the infant’s clinical response and serum FT4

and TSH concentrations.During therapy, the serum total T4 or FT4 should and

might be in the upper half of the reference range (targetvalues depend on the assay method used [T4: 10–16�g/dL (130–206 nmol/L); FT4: 1.4–2.3 ng/dL (18–30pmol/L)]) during the first 3 years of life with a low-normal serum TSH. The latter may sometimes be de-layed because of relative pituitary resistance. In suchcases, characterized by a normal or increased serum T4

and an inappropriately high TSH concentration, the T4

value is used to titrate the dose. Nonadherence to thetreatment is the most common cause of persistent TSHelevation and should be excluded. Those infants withlow serum T4 concentrations (below 10 �g/dL [129nmol/L]) and a TSH concentration greater than 15 mU/Lduring the first year of life have lower IQ values thanpatients whose T4 concentrations were held constant athigher concentrations.35 Thereafter, thyroid function testvalues should be kept at age-appropriate concentrations,which in children differ from those for adults.74 On TH-replacement therapy, TSH levels should be maintainedbetween 0.5 and 2.0 mU/L during the first 3 years oflife.75 Clinical evaluation of the infant by the practitionershould be conducted at frequent intervals during thefirst 3 years of age (see “Follow-up”). Because poorcompliance and noncompliance have major sequelae,initial and ongoing counseling of parents is of greatimportance.

Current international organizations such as theAmerican Clinical Laboratory Association recommendthat the FT4, rather than the total T4, be measured toassess the concentration of the biologically relevant, un-bound or free form of circulating T4.75 The cost of total T4

plus TBG or T3 resin uptake, versus the FT4 by mostmethods (excluding the more costly direct dialyzable orultrafiltration methods), should be comparable. How-ever, although the total T4 is a robust measure, it shouldbe recognized that most direct FT4 assays are influenced,



to some extent, by protein binding. Consequently, theFT4 values obtained vary between assays.

During TH therapy, 4 or more episodes of insuffi-ciently suppressed TSH (�5 mU/L) after the age of 6months were the most important variables associatedwith school delay.75 Usually, these episodes are causedby poor parental compliance or impaired T4 bioavailabil-ity. The latter may be caused by inhibition of T4 intesti-nal uptake by specific foods (soy, fiber) and medications(iron, calcium), malabsorption, or increased degradation(anticonvulsants; large hemangiomas with high deiodi-nase activity). The Food and Drug Administration hasdeemed several generic L-T4 products to be equivalent tosome currently branded preparations. Any change insource of the L-T4, especially if not a standard brand,requires retitration of the dose.

FOLLOW-UPClinical examination, including assessment of growthand development, should be performed every fewmonths during the first 3 years of life. Infants with CHappear to be at increased risk of other congenital anom-alies (approximately 10% of infants with CH, comparedwith 3% in the general population). Cardiovascularanomalies, including pulmonary stenosis, atrial septaldefect, and ventricular septal defect, are the most com-mon.

Infants need to undergo frequent laboratory and clin-ical evaluations of thyroid function, growth, and devel-opment to ensure optimal T4 dosage and adherence totheir therapy regimen. Serum T4 and TSH measurementsshould be performed:

1. at 2 and 4 weeks after the initiation of L-T4 treatment;

2. every 1 to 2 months during the first 6 months of life;

3. every 3 to 4 months between 6 months and 3 years;

4. every 6 to 12 months until growth is completed; and

5. at more frequent intervals when compliance is ques-tioned, abnormal values are obtained, or dose orsource of medication has been changed; FT4 and TSHmeasurements should be repeated 4 weeks after anychange in L-T4 dosage.

The aim of therapy is to ensure normal growth anddevelopment by maintaining the serum total T4 or FT4

concentration in the upper half of the reference range inthe first year of life, with a serum TSH in the referencerange (optimally 0.5–2.0 mU/L).

Some infants will have serum TSH concentrations inthe range of 10 to 20 mU/L despite T4 concentrations inthe upper half of the reference range. Rarely, the ele-vated TSH relative to the FT4 value is hypothesized toresult from in utero hypothyroidism, producing a reset-ting of the pituitary-thyroid feedback threshold. A fail-ure of the serum FT4 concentration to increase into the

upper half of the reference range by 2 weeks and/orfailure of the TSH concentration to decrease to less than20 mU/L within 4 weeks after initiation of L-T4 admin-istration should alert the physician that the child maynot be receiving adequate L-T4 regularly. At this point,careful inquiry should be made regarding compliance,dose of medication, and method of administration.When attempting to achieve the optimal concentrationof circulating FT4, physicians should always bear in mindthe adverse effects of excessive medication and thus beprepared to monitor blood concentrations of FT4 at closeintervals. Prolonged hyperthyroidism has been associ-ated with premature craniosynostosis.

DEVELOPMENTAL OUTCOMEGrowth rate and adult height are normal in childrenwith CH in whom TH therapy is consistently main-tained.68,76,77 The best outcome occurred with TH therapystarted by 2 weeks of age at 9.5 �g/kg or more per day,compared with lower doses or later start of therapy.71

There are only minor differences in intelligence, schoolachievement, and neuropsychological tests in adultswith CH that was treated early with TH compared withcontrol groups of classmates and siblings.78–82 Residualdefects can include impaired visuospatial processing andselective memory and sensorimotor defects. Whetherthese minor differences are preventable by further opti-mizing postnatal therapy remains controversial.

In contrast to the excellent outcome in infants withCH that is treated early, the prognosis for normal mentaland neurologic performance is less certain for infantswith CH that is not detected early by newborn screening.Although physical recovery is good and stature is nor-mal,77 when replacement therapy is begun later butwithin the first 2 months of life, infants with severehypothyroidism at birth and intrauterine hypothyroid-ism (retarded skeletal maturation at birth) may still havea low-to-normal IQ.18 Similarly, although more than80% of infants given replacement therapy before 3months of age have an IQ greater than 85, 77% of theseinfants show some signs of minimal brain damage, in-cluding impairment of arithmetic ability, speech, or finemotor coordination in later life. Even in early-treatedpatients with CH, auditory brainstem evoked potentialswere abnormal in 25% of 27 children studied. The rea-son for this is not known but might suggest that prenatalmaternal T4 production does not provide complete pro-tection for the developing central nervous system.84 Inanother study, processing of visuospatial relationshipsremained affected in adolescents with CH.85 The effect ofunderlying severity of CH combines with the effects ofTH dose and of age at onset of TH therapy.35 Otherwise,neurologic and intellectual outcome do not correlatewell with the degree of T4 deficiency found in neonatalscreening.

Transplacental transfer of maternal T4 in the first



trimester may protect the brain during early develop-ment.15 For the same reason, maternal hypothyroidismduring fetal development can have persistent neurode-velopmental effects on the child.15,16,19 Serum T4 concen-trations at term in athyreotic infants are 25% to 50% ofthose in normal neonates. These concentrations, al-though low, may contribute to fetal brain development.It is thought that the low-to-normal intelligence of pa-tients with CH treated early in life results most com-monly from inadequate treatment or poor compliance.

It must be noted that TH treatment regimens usedtoday are more aggressive in targeting early correction ofTSH than were the regimens used 20 or even 10 yearsago. Thus, newborn infants with CH today may have aneven better intellectual and neurologic prognosis thanadults with CH who were evaluated in the reports dis-cussed above.

ASSESSMENT OF PERMANENCE OF HYPOTHYROIDISMCH is permanent if the thyroid scan reveals an ectopicgland or absent thyroid tissue (confirmed by ultrasono-graphic examination) or if the serum TSH is seen toincrease above 10 mU/L after the first year of life, pre-sumably because of insufficient T4 replacement.

If no permanent cause of CH was found by scan orthere was no TSH increase after the newborn period,then L-T4 administration should be discontinued for 30days at some point after the child is 3 years of age.86 After30 days, serum should be obtained for measurement ofFT4 and TSH values. It is critical that this follow-uplaboratory assessment be obtained in a timely mannerand that there be no loss of follow-up. If the FT4 is lowand the TSH value is elevated, permanent hypothyroid-ism is confirmed and TH therapy should be reinstituted.If the FT4 and TSH concentrations remain in the refer-ence range, euthyroidism is assumed and a diagnosis oftransient hypothyroidism recorded. It is important thatthe child not be lost to follow-up. The physician shouldmonitor the child carefully and repeat the thyroid func-tion tests at the slightest suspicion of recurrence of hypo-thyroid symptoms. If the results are inconclusive, carefulfollow-up and subsequent testing will be necessary.

More severely affected children may become clini-cally hypothyroid when treatment is discontinued for 30days. An alternative option is to reduce the TH-replace-ment dosage by half. If after 30 days the TSH is elevatedabove 20 mU/L, the permanence of hypothyroidism isconfirmed and full replacement therapy should be re-sumed. If the serum TSH value has not increased, thenTH treatment should be discontinued for another 30days with repeated serum FT4 and TSH determination asdescribed above.

ADMONITIONFinally, physicians cannot and must not relinquish theirclinical judgment and experience in the face of normal

newborn thyroid test results. Failure of normal develop-ment can result from hypothyroidism in infants who hadnormal T4 and TSH newborn screening results. Hypothy-roidism can manifest or be acquired after the newbornscreening. Rarely, the newborn screening test results canbe in error, or human error can result in failure to notifythe infant’s physician of abnormal test results.87 Whenclinical symptoms and signs suggest hypothyroidism, re-gardless of newborn screening results, serum FT4 andTSH determinations should be performed.

WRITING PANEL

Susan R. Rose, MD, ChairpersonRosalind S. Brown, MDThomas Foley, MDPaul B. Kaplowitz, MDCelia I. Kaye, MD, PhDSumana Sundararajan, MDSurendra K. Varma, MD

AAP SECTION ON ENDOCRINOLOGY, 2005–2006

Surendra K. Varma, MD, ChairpersonStuart J. Brink, MDWilliam L. Clarke, MDPaul B. Kaplowitz, MDSusan R. Rose, MDJanet Silverstein, MD

LIAISON

Rosemary Scales, MS, RNPediatric Endocrinology Nursing Society

STAFF

Laura Laskosz, MPH

AAP COMMITTEE ON GENETICS, 2005–2006

G. Bradley Schaefer, MD, ChairpersonMarilyn J. Bull, MDGregory M. Enns, MDJeffrey R. Gruen, MDJoseph H. Hersh, MDNancy J. Mendelsohn, MDHoward M. Saal, MD

LIAISONS

James D. Goldberg, MDAmerican College of Obstetricians and Gynecologists

James W. Hanson, MDAmerican College of Medical Genetics

Michele A. Lloyd-Puryear, MD, PhDHealth Resources and Services Administration

Sonja A. Rasmussen, MD, MSCenters for Disease Control and Prevention



STAFF

Paul Spire

AMERICAN THYROID ASSOCIATION, PUBLIC HEALTH COMMITTEE, 2006

Joseph G. Hollowell, Jr, MD, MPH, ChairVictor J. Bernet, LTC, MC, MDRuth M. Belin, MDRosalind S. Brown, MD, CMKenneth D. Burman, MDHenry G. Fein, MDJames V. Hennessey, MDSteven H. Lamm, MDMarvin L. Mitchell, MDHee-Myung Park, MDRichard J. Robbins, MDRebecca S. Bahn, MD, Council LiaisonDavid V. Becker, MD, AdvisorJayne A. Franklyn, Corresponding Member AdvisorJacob Robbins, MD, AdvisorLester Van Middlesworth, MD, PhD, Advisor

LAWSONWILKINS PEDIATRIC ENDOCRINE SOCIETY

Lynne L. Levitsky, MD, PresidentAlan D. Rogol, MD, SecretarySally Radovich, MD, Chair, Drug and Therapeutics

Committee

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DOI: 10.1542/peds.2006-0915 2006;117;2290Pediatrics

Rosalind S. Brown and Lawson Wilkins Pediatric Endocrine SocietyAmerican Academy of Pediatrics, Susan R. Rose, American Thyroid Association,Update of Newborn Screening and Therapy for Congenital Hypothyroidism

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Pediatrics 2006 Congenital Hypothyroidism Guidelines