REVIEW

CURRENTOPINION Hypothyroidism in the newborn period

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Ari J. Wassner and Rosalind S. Brown

Purpose of review

This review summarizes significant advances in the epidemiology, pathophysiology and treatment ofcongenital hypothyroidism, with a focus on thyroid dysfunction in preterm infants.

Recent findings

Congenital hypothyroidism appears to be increasing in incidence, primarily due to increased stringency ofscreening strategies, with smaller contributions from changing demographics and improved survival ofincreasingly premature infants. The greatest increase has been in mildly affected infants. Although manysuch cases are transient, some eventually prove to be severe and/or permanent. In preterm infants,transient hypothyroidism is common and may be delayed in onset. The cause is probably multifactorial,and inadequate iodine intake may contribute to some cases. Transient hypothyroxinemia of prematurity,also common in premature infants, is correlated with markers of inflammation. Despite concern about thepotential morbidity of transient hypothyroxinemia of prematurity, the benefits and safety of treatment havenot been established. Novel genetic causes of congenital hypothyroidism continue to be identified, andaccumulating data support the sensitivity of infants with severe congenital hypothyroidism to small changesin levothyroxine formulation.

Summary

Changes in newborn screening strategies have increasingly identified thyroid function abnormalities ofunclear clinical significance. Novel causes of congenital hypothyroidism continue to be identified, and newdata continue to emerge regarding optimal therapy.

Keywords

congenital hypothyroidism, low birth weight, prematurity, preterm, thyroid

INTRODUCTION

Thyroid hormone is critical for normal growth andbrain development, and hypothyroidism in infancyis the leading cause of intellectual impairmentworldwide. This update will discuss significantnew contributions to this field since the subjectwas last reviewed in February 2010 [1]. Particularattention will be given to the emerging understand-ing of thyroid dysfunction in preterm infants.

Division of Endocrinology, Boston Children’s Hospital, Harvard MedicalSchool, Boston, Massachusetts, USA

Correspondence to Rosalind S. Brown, Division of Endocrinology,Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA02115, USA. Tel: +1 617 355 7476; e-mail: rosalind.brown@childrens.harvard.edu

Curr Opin Endocrinol Diabetes Obes 2013, 20:449–454

DOI:10.1097/01.med.0000433063.78799.c2

INCIDENCE OF CONGENITALHYPOTHYROIDISM

Beginning in the 1980s, newborn screening pro-grammes have reported a rise in the incidence ofcongenital hypothyroidism to 1 : 1400–1 : 2800infants from the rate of 1 : 3000–1 : 4000 whenscreening was first introduced [2–5]. This increasehas been attributed to the widespread shiftfrom primary T4 to primary thyroid stimulatinghormone (TSH) screening strategies and to thediagnosis of milder cases of congenital hypo-thyroidism [6]. Deladoey et al. [4] retrospectively

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analysed 1.6 million infants screened in Quebecover 20 years and found that the increase in overallincidence of congenital hypothyroidism (from1 : 2898 to 1 : 2450) was entirely attributable to adecrease in the screening TSH threshold. Theadditional cases identified were milder, with a lowermedian TSH concentration (18 vs. 106.5 mIU/l)and a higher median T4 concentration (15.0 vs.5.9 mg/dl). Because 90% of patients with congenitalhypothyroidism in Quebec undergo thyroid scinti-graphy, the investigators were further able to assesschanges in congenital hypothyroidism incidenceby cause. They observed a stable incidence ofthyroid dysgenesis and dyshormonogenetic goiter

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KEY POINTS

� The incidence of congenital hypothyroidism has risenover the last several decades, primarily due to changesin newborn screening strategies.

� Preterm newborns are at a high risk for thyroiddysfunction, including THOP and congenitalhypothyroidism with delayed TSH rise, but the clinicalsignificance of these conditions remains uncertain.

� Patients with severe congenital hypothyroidism remainat risk for subtle neurocognitive deficits and may besensitive to small variations in L-thyroxine dose.

Thyroid

(generally more severe forms of congenital hypo-thyroidism); a rise was seen only in cases with anormal thyroid gland in situ, consistent with theirmilder phenotype [4].

An important clinical question is whether thesemilder cases of congenital hypothyroidism aretransient or require permanent treatment. Tworecent retrospective studies from Italy directlyaddress this question. Of note, both studies used astandardized assessment of the need for ongoingtreatment after age 2–3 years, overcoming a limita-tion of many prior studies. Olivieri et al. [7

&

]reviewed 1676 cases of congenital hypothyroidismand found that 21.6% of patients with permanentcongenital hypothyroidism had only mild TSHelevation (<15 mIU/l) on screening. Surprisingly,19.6% of these patients had thyroid dysgenesis.Similar results were obtained by Rabbiosi et al. [8

&

]who found that 34% of 84 babies with a normal-appearing, eutopic thyroid gland had permanenthypothyroidism irrespective of whether the initialTSH elevation was mild (<20 mIU/l) or severe(�20 mIU/l). Furthermore, in 20% of initially mildcases, the serum TSH concentration eventually roseabove 100 mIU/l. These data support the conclusionthat newborns with mild abnormalities on neonatalscreening nonetheless have a significant risk ofpermanent congenital hypothyroidism that maybecome more severe in the future.

Another factor in the increasing incidence ofcongenital hypothyroidism is changing demo-graphy, as initially suggested by data from theUSA [9]. Albert et al. [5] reviewed all cases of con-genital hypothyroidism diagnosed in New Zealandover 17 years and documented a rising incidence(1 : 3846 to 1 : 2778) due entirely to an increased rateof dyshormonogenesis, with no change in the rate ofthyroid dysgenesis. On the basis of national demo-graphic data and the increased risk of dyshor-monogenesis in Asians and Pacific Islanders, theinvestigators concluded that the rise in incidence

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of congenital hypothyroidism was due solely toincreased birth rates in these ethnic populations.

In recent years, survival has improved dramatic-ally for low birth weight (LBW, 1500–2500 g) andvery low birth weight (VLBW, <1500 g) infants.Although these infants are at a high risk of thyroiddysfunction, they are probably not the major reasonfor the overall increase in congenital hypothyroid-ism incidence. Mitchell et al. reviewed 304 cases ofcongenital hypothyroidism diagnosed by the NewEngland regional screening programme over arecent decade (Fig. 1) [3]. The proportion of patientswith congenital hypothyroidism with LBW rose(from 5 to 17%), but the proportion with VLBWactually fell slightly (from 23 to 19%); overall, theincrease in LBW and VLBW infants accounted foronly a small fraction of the near-doubling in overallcongenital hypothyroidism incidence (1 : 3010 to1 : 1660). Notably, a similar conclusion was reachedby the group from Quebec [4].

THYROID FUNCTION IN PRETERMINFANTS

Although advances in neonatal care have dramatic-ally improved the survival of extremely pretermnewborns, many such infants suffer from compli-cations that include cerebral palsy, developmentaldelay and blindness. In addition to their medicalmorbidity, caring for these lifelong complicationsimposes significant costs on the medical system(estimated at $1 million per patient with cerebralpalsy) [10]. Thyroid hormone is essential for normalneurodevelopment, and hypothyroxinemia is cor-related with poor outcomes in preterm infants [11].It remains unclear whether thyroid dysfunctionactually contributes to neurodevelopmental deficitsin these patients, but if so, treatment might bothimprove outcomes and reduce healthcare costs.

Several patterns of thyroid dysfunction are seenin preterm infants. The most common pattern istransient hypothyroxinemia of prematurity (THOP;low T4 with normal TSH), which is observed in up to50% of infants born before 28 weeks [10]. The onlyinterventional trial to assess the effect of L-thyro-xine treatment of THOP on developmental outcomeshowed an initial benefit at 2 years of age in infantsborn at less than 27 weeks gestation, but a lowerintelligence quotient (IQ) in more mature infants,with no significant difference in either group by theage of 10 years [12,13]. A recent study [14] fromJapan also suggests that treatment of THOP may notbe benign. In a nationwide case–control study, therisk of circulatory collapse was higher in VLBWinfants treated with L-thyroxine than in untreatedcontrols (4.2 vs. 1.8%). This finding, along with

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FIGURE 1. The increasing incidence of congenital hypothyroidism in New England is due to a rise in mild cases, with nochange in the rate of severe congenital hypothyroidism [3]. Reproduced with permission of John Wiley & Sons, Inc.

Table 1. Clinical characteristics of infants withdelayed TSH rise detected on newborn screening

VLBW andELBW �1500 g

Number of cases 19 3

Gestational age, mean (weeks) 25.9 –

Birth weight, mean (g) 790 –

Age at initial TSH elevation,mean (days)

22 25

Initial T4, mean (mg/dl) 4.7 8.1

Initial T4 <5 mg/dl, n (%) 10 (52.6) 1 (33.3)

Peak TSH, mean (mIU/l) 62.28 26.05

Peak TSH >40 mIU/l, n (%) 4 (21.1) 0 (0)

Peak TSH >100 mIU/l, n (%) 3 (15.8) 0 (0)

Age at resolution, mean (days) 51.1 –

Dash (—) indicate data not reported. ELBW, extremely low birth weight; TSH,thyroid stimulating hormone; VLBW, very low birth weight. Modified withpermission from [18].

Hypothyroidism in the newborn period Wassner and Brown

previous concerns for an increased risk of necrotiz-ing enterocolitis [15], warrants close attention infuture interventional trials of therapy for THOP.

In addition to THOP, VLBW infants have a riskof primary hypothyroidism (low T4 with elevatedTSH) about 14 times higher than that of normalbirth weight babies (1 : 250) [16]. Of VLBW infantswith congenital hypothyroidism detected on new-born screening, nearly two-thirds exhibit a patternof ‘delayed TSH rise’, in which the TSH is initiallynormal but later becomes elevated [16,17]. Wooet al. retrospectively studied 22 patients withcongenital hypothyroidism and delayed TSH riseidentified by screening 92 800 infants over 7 yearsin Rhode Island, USA. The incidence of congenitalhypothyroidism with delayed TSH rise increasedstrikingly with lower birth weight: 1 : 58 inextremely low birth weight (ELBW, <1000 g)infants, 1 : 95 in VLBW infants and 1 : 30 329 ininfants with birth weight at least 1500 g [18]. In19 ELBW/VLBW infants, a delayed rise in TSH wasdetected at a mean age of 22 days, the mean initialT4 concentration was low (4.7 mg/dl) and the meanpeak TSH concentration was 62.3 mIU/l (Table 1).Three of 19 infants (15.8%) had a peak TSH con-centration of more than 100 mIU/l and weretreated with L-thyroxine, whereas the remainingpatients were untreated. All cases of congenitalhypothyroidism with delayed TSH rise were transi-ent and resolved at an average age of 51 days, incontrast to another series in which 30% of caseswere permanent [3]. Follow-up data, includingdevelopmental assessments, were obtained at

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18 months of age in nine of 16 surviving patients(55%). Compared with matched controls, patientswith delayed TSH rise showed no difference inneurological examination or mental or psycho-motor development but had an increased incidenceof small head circumference less than the 10thpercentile (33 vs. 0%), a finding of unclear clinicalsignificance [18].

The high incidence of thyroid dysfunction inpreterm infants has multiple causes. These infantsare often critically ill and therefore may have low

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serum T4 and T3 concentrations due to nonthyroi-dal illness (NTI). Because inflammatory cytokineshave been implicated in the pathophysiology ofNTI, Dilli and Dilmen [19] investigated the relation-ship of markers of systemic inflammation withthyroid function in 148 infants born at less than33 weeks gestational age. The authors confirmed anegative correlation between serum T3 concen-tration and levels of inflammatory markers [inter-leukin (IL)-6 and C-reactive protein (CRP)], as well asa significantly higher rate of sepsis in patients with alow T3 concentration (<65 ng/dl).

Because the ability to escape from the Wolff–Chaikoff effect does not mature until 36 weeks,preterm infants are at a risk of hypothyroidism fromexcess iodine exposure. Recognition of this risk hasled to the removal of iodine-containing antisepticsfrom most intensive care nurseries and has greatlyreduced this cause of hypothyroidism. However,because preterm infants have lower iodine storesand greater iodine requirements than term infants,they are also at a risk for hypothyroxinemia due toiodine deficiency. The potential importance of thisrisk is highlighted by a study of iodine content in thenutrition provided to hospitalized preterm infants[20

&

]. Belfort et al. [20&

] demonstrated that ahypothetical 1 kg preterm infant would receive lessthan the recommended 30 mg/kg/day of iodine withnearly any standard nutritional regimen. The com-mercial preterm formulas tested contained only16–26 mg/kg/day of iodine, even when concentratedto maximum caloric density. Samples of pooleddonor breast milk contained surprisingly little iodine(median 9.0 mg/kg/day, range 5.0–17.6 mg/kg/day),and even fortification with human mild fortifier(HMF) failed to raise their iodine content to recom-mended levels. Notably, the parenteral nutritionsolutions tested contained virtually no iodine(0.2–0.3 mg/kg/day) [20

&

].

GENETICS OF CONGENITALHYPOTHYROIDISM

Congenital hypothyroidism may be caused bymutations in a variety of genes involved in thyroiddevelopment or thyroid hormone biosynthesis. Thedual oxidase (DUOX) enzymes expressed in thyroidfollicular cells generate the hydrogen peroxidenecessary for the organification of iodide. Defectsin DUOX2 cause a broad spectrum of thyroiddysfunction ranging from permanent or transientcongenital hypothyroidism to euthyroid goitre inadults. A suggested explanation for this phenotypicvariability is partial compensation of deficientDUOX2 function by the closely related DUOX1.In a mouse model, Grasberger et al. [21] showed

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that although DUOX2 deficiency causes mild hypo-thyroidism, animals lacking both DUOX2 andDUOX1 function are severely hypothyroid. As iso-lated DUOX1 deficiency has never been found tocause thyroid dysfunction, this report representsthe first in-vivo evidence of a physiologic role forDUOX1 in the thyroid.

Although most congenital hypothyroidism isdue to defects of the thyroid gland, a small pro-portion of congenital hypothyroidism is central inorigin. Sun et al. [22] recently described a novelgenetic cause of central hypothyroidism due tomutations in IGSF1. Deficiency of IGSF1 results inX-linked central congenital hypothyroidism, eitherin isolation or in combination with prolactin orgrowth hormone deficiency. Patients with IGSF1deficiency also develop macroorchidism andmay have pubertal delay, although gonadotropindeficiency has not been described.

TREATMENT OF CONGENITALHYPOTHYROIDISM

Since the introduction of newborn screening40 years ago, early detection and treatment hasessentially eradicated severe intellectual impair-ment due to congenital hypothyroidism in thedeveloped world. However, individuals with con-genital hypothyroidism may still have subtle neuro-developmental problems, including motor delays,behavioural difficulties, attention deficit and alter-ations in memory [11]. Whether these deficits aresimply due to inadequate postnatal treatment wasaddressed by a recent Dutch study. van der SluijsVeer et al. [23

&

] studied 95 toddlers with congenitalhypothyroidism in whom L-thyroxine treatmenthad been started at a median age of 9 days, withnormalization of the serum free T4 concentrationwithin 2.1 days and of the serum TSH level within18.6 days. Nevertheless, at age 2 years, patients withsevere congenital hypothyroidism had delays inmental development relative to the general popu-lation (mental development index 88 vs. 100,P<0.001), and similar delays in psychomotor devel-opment were evident regardless of the severity ofcongenital hypothyroidism (psychomotor develop-ment index 89 vs. 100, P<0.001). Deficits weremore pronounced in patients with lower initialfree T4 levels, but were unrelated to the initialL-thyroxine dose or to the timing of treatment.The authors argue that prenatal hypothyroxinemiamay be important in the long-term sequelae ofcongenital hypothyroidism, but further studiesare needed to determine whether these deficitsare sustained at an older age, when cognitive testingis more reliable.

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Hypothyroidism in the newborn period Wassner and Brown

A longstanding question in the treatment ofhypothyroidism is the bioequivalence of variousformulations of L-thyroxine. This issue is especiallyrelevant to young children with congenital hypo-thyroidism in whom maintaining consistenteuthyroidism is critical to normal brain develop-ment. A study directly assessing this question inchildren with severe congenital hypothyroidismwas recently performed by Carswell et al. [24

&

]. Theseinvestigators conducted a randomized, controlledcrossover trial to assess control of hypothyroidismin individual patients when using a brand nameL-thyroxine formulation vs. a single generic for-mulation that is deemed ‘bioequivalent’ by regu-latory standards. They demonstrated that TSHvalues were significantly lower (by 1.4 mIU/l) onbrand name than on generic L-thyroxine, with nodifference in the serum free T4 or total T3 concen-tration (Fig. 2).

Apparently contradictory findings were reportedby Lomenick et al. [25

&

], who retrospectively studied62 patients with congenital hypothyroidism underage 3 years taking a generic L-thyroxine product or aspecific brand name formulation. They found nodifference in the number of TSH checks or L-thyro-xine dose adjustments but noted a possible decreasein variance of the serum TSH concentration in thegeneric group. The authors concluded that genericand brand name L-thyroxine are equally effective inyoung children with congenital hypothyroidism.A limitation of this study was that only 19%of individuals changed from one formulationto another; therefore, the interchangeability of

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L-thyroxine formulations in a given patient wasnot assessed. It is also notable that the majority ofpatients studied by Carswell et al. [24

&

] had thyroiddysgenesis, resulting in more severe congenital hypo-thyroidism (median serum TSH concentration>200mIU/l) than those studied by Lomenick et al.[25

&

] (median TSH 58 and 81 mIU/l in the genericand brand name groups, respectively). In patientswith severe acquired hypothyroidism, Carswellet al. [24

&

] found no significant difference betweentreatment groups (Fig. 2), similar to the result ofLomenick et al. [25

&

]. Taken together, both studiessupport the conclusion that brand name and genericL-thyroxine formulations may not be interchange-able in patients with little or no thyroid reserve, butthat the small difference between preparations is lessimportant in patients with milder functional impair-ment.

Liquid formulations of L-thyroxine have tradi-tionally been avoided for treating congenital hypo-thyroidism in the USA due to concerns aboutvariable bioavailability. Cassio et al. [26

&

] investi-gated a new liquid formulation of L-thyroxine byrandomizing infants with congenital hypothyroid-ism to receive a standard dose of L-thyroxine ineither liquid or tablet form. The two preparationsresulted in equally effective treatment of hypothyr-oidism in patients with mild or moderate congenitalhypothyroidism, but the liquid formulation causedsignificantly more TSH suppression. These datasuggest that liquid and tablet formulations ofL-thyroxine are not equally bioavailable. In addi-tion, the liquid formulation contains ethanol as an

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excipient, and the effect on neonates of prolongedexposure to this dose of ethanol is unknown.

CONCLUSION

Recent data continue to illuminate the incidence,cause, optimal treatment and outcome of congen-ital hypothyroidism, including the disorders ofthyroid function seen predominantly in infantsborn preterm. However, new data have raised newquestions. Increased understanding of the basicpathophysiology of thyroid dysfunction and of vari-ables underlying developmental complications incongenital hypothyroidism will hopefully lead tofurther optimization of treatment and improvementin outcomes in the future.

Acknowledgements

This work was supported by National Institutes of HealthGrant K12 HD052896-06 (to A.J.W.).

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDEDREADINGPapers of particular interest, published within the annual period of review, havebeen highlighted as:

& of special interest&& of outstanding interest Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (pp. 498–499).

1. Raymond J, LaFranchi SH. Fetal and neonatal thyroid function: review andsummary of significant new findings. Curr Opin Endocrinol Diabetes Obesity2010; 17:1–7.

2. Fisher DA, Dussault JH, Foley TP Jr, et al. Screening for congenital hypo-thyroidism: results of screening one million North American infants. J Pediatr1979; 94:700–705.

3. Mitchell ML, Hsu HW, Sahai I. The increased incidence of congenitalhypothyroidism: fact or fancy? Clin Endocrinol (Oxf) 2011; 75:806–810.

4. Deladoey J, Ruel J, Giguere Y, Van Vliet G. Is the incidence of congenitalhypothyroidism really increasing? A 20-year retrospective population-basedstudy in Quebec. J Clin Endocrinol Metab 2011; 96:2422–2429.

5. Albert BB, Cutfield WS, Webster D, et al. Etiology of increasing incidence ofcongenital hypothyroidism in New Zealand from 1993-2010. J Clin EndocrinolMetab 2012; 97:3155–3160.

6. Corbetta C, Weber G, Cortinovis F, et al. A 7-year experience with low bloodTSH cutoff levels for neonatal screening reveals an unsuspected frequencyof congenital hypothyroidism (CH). Clin Endocrinol (Oxf) 2009; 71:739–745.

7.&

Olivieri A, Corbetta C, Weber G, et al. Congenital hypothyroidism due todefects of thyroid development and mild increase of TSH at Screening: datafrom the Italian National Registry of Infants with congenital hypothyroidism.J Clin Endocrinol Metab 2013; 98:1403–1408.

A substantial proportion of neonates with mild hypothyroidism at screening mayrequire permanent therapy.

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Rabbiosi S, Vigone MC, Cortinovis F, et al. Congenital hypothyroidism witheutopic thyroid gland: analysis of clinical and biochemical features at diag-nosis and after re-evaluation. J Clin Endocrinol Metab 2013; 98:1395–1402.

Congenital hypothyroidism in infants with a normal-appearing thyroid gland in situmay later prove to be permanent and/or severe even if initial TSH elevation is mild.9. Hinton CF, Harris KB, Borgfeld L, et al. Trends in incidence rates of congenital

hypothyroidism related to select demographic factors: data from the UnitedStates, California, Massachusetts, New York, and Texas. Pediatrics 2010;125 (Suppl 2):S37–S47.

10. La Gamma EF, Paneth N. Clinical importance of hypothyroxinemia in thepreterm infant and a discussion of treatment concerns. Curr Opin Pediatr2012; 24:172–180.

11. Delahunty C, Falconer S, Hume R, et al. Levels of neonatal thyroid hormone inpreterm infants and neurodevelopmental outcome at 5 1/2 years: millenniumcohort study. J Clin Endocrinol Metab 2010; 95:4898–4908.

12. van Wassenaer AG, Kok JH, de Vijlder JJ, et al. Effects of thyroxine supple-mentation on neurologic development in infants born at less than 30 weeks’gestation. N Engl J Med 1997; 336:21–26.

13. van Wassenaer AG, Westera J, Houtzager BA, Kok JH. Ten-year follow-up ofchildren born at <30 weeks’ gestational age supplemented with thyroxine inthe neonatal period in a randomized, controlled trial. Pediatrics 2005;116:e613–e618.

14. Kawai M, Kusuda S, Cho K, et al. Nationwide surveillance of circulatorycollapse associated with levothyroxine administration in very-low-birthweightinfants in Japan. Pediatr Int 2012; 54:177–181.

15. La Gamma EF, van Wassenaer AG, Ares S, et al. Phase 1 trial of 4 thyroidhormone regimens for transient hypothyroxinemia in neonates of <28 weeks’gestation. Pediatrics 2009; 124:e258–e268.

16. Larson C, Hermos R, Delaney A, et al. Risk factors associated with delayedthyrotropin elevations in congenital hypothyroidism. J Pediatr 2003; 143:587–591.

17. Mitchell ML, Walraven C, Rojas DA, et al. Screening very-low-birthweightinfants for congenital hypothyroidism. Lancet 1994; 343:60–61.

18. Woo HC, Lizarda A, Tucker R, et al. Congenital hypothyroidism with a delayedthyroid-stimulating hormone elevation in very premature infants: incidence andgrowth and developmental outcomes. J Pediatr 2011; 158:538–542.

19. Dilli D, Dilmen U. The role of interleukin-6 and C-reactive protein in nonthyr-oidal illness in premature infants followed in neonatal intensive care unit. J ClinRes Pediatr Endocrinol 2012; 4:66–71.

20.&

Belfort MB, Pearce EN, Braverman LE, et al. Low iodine content in the diets ofhospitalized preterm infants. J Clin Endocrinol Metab 2012; 97:E632–636.

Nutritional regimens for hospitalized preterm infants may provide less than therecommended dietary intake of iodine, which may contribute to their high rate ofthyroid dysfunction.21. Grasberger H, De Deken X, Mayo OB, et al. Mice deficient in dual oxidase

maturation factors are severely hypothyroid. Mol Endocrinol 2012; 26:481–492.

22. Sun Y, Bak B, Schoenmakers N, et al. Loss-of-function mutations in IGSF1cause an X-linked syndrome of central hypothyroidism and testicular enlarge-ment. Nat Genet 2012; 44:1375–1381.

23.&

van der Sluijs Veer L, Kempers MJ, Wiedijk BM, et al. Evaluation of cognitiveand motor development in toddlers with congenital hypothyroidism diagnosedby neonatal screening. J Dev Behav Pediatr 2012; 33:633–640.

Patients with severe congenital hypothyroidism may have mild cognitive andpsychomotor delays despite early and apparently adequate treatment.24.&

Carswell JM, Gordon JH, Popovsky E, et al. Generic and brand-nameL-thyroxine are not bioequivalent for children with severe congenital hypo-thyroidism. J Clin Endocrinol Metab 2013; 98:610–617.

This randomized crossover study demonstrated that generic and brand nameL-thyroxine are not bioequivalent in children with severe congenital hypothyroidismbut are equally effective in children with acquired hypothyroidism.25.&

Lomenick JP, Wang L, Ampah SB, et al. Generic levothyroxine compared withsynthroid in young children with congenital hypothyroidism. J Clin EndocrinolMetab 2013; 98:653–658.

This retrospective study found no difference between generic and brand nameL-thyroxine in the treatment of children with less severe congenital hypothyroidism.26.&

Cassio A, Monti S, Rizzello A, et al. Comparison between liquid and tabletformulations of levothyroxine in the initial treatment of congenital hypothyroid-ism. J Pediatr 2013; 162:1264–1269.

This randomized, controlled trial showed that liquid and tablet formulations ofL-thyroxine are not completely bioequivalent in infants with congenital hypo-thyroidism.

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