AIIMS- NICU protocols 2010

Congenital Hypothyroidism

Vandana Jain1, Ramesh Agarwal2, Ashok Deorari3, Vinod Paul3 1,2 Assistant Professor, 3Professor 1 Division of Pediatric Endocrinology, 2,3Division of Neonatology, Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, Ne Del!i "11##2$

Address for correspondence: Dr Ramesh Agarwal Assistant Professor Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi 110029 mail! aranag"rediffmail#com

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AIIMS- NICU protocols 2010

Abstract
$ongenital %&poth&roidism '$%( is one of the most common pre)enta*le causes of mental retardation with a worldwide incidence of 1! +000,-000 li)e *irths# Ideall& uni)ersal screening at +,- da&s of age should *e done for detecting $%# A*normal )alues on screening should *e confirmed *& a )enous sample 'using age appropriate cut,offs(# .erm as well as preterm infants with low .- and ele)ated .S% should *e started on /,th&ro0ine at a dose of 10, 112g3 4g3 da& as soon as the diagnosis is made# 5egular monitoring should *e done to ensure that .S% is suppressed to within normal range and .- is in the upper half of normal range# .he outcome of $% depends on the time of initiation of therap& and the dose of /,th&ro0ine used with the *est outcome in infants started on treatment *efore 2 wee4s of age with a dose 6 9#12g3 4g3 da&# Keywords: congenital h&poth&roidism, /,th&ro0ine, new*orn

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AIIMS- NICU protocols 2010 $ongenital %&poth&roidism '$%( is one of the most common pre)enta*le causes of mental retardation# .he worldwide incidence is 1!+000,-000 li)e *irths and the estimated incidence in India is 1!2100,2700 li)e *irths# 1 .h&roid d&sgenesis is the commonest cause accounting for 81,709 of all cases of $%# Embryology and physiology of the thyroid in the fetus : .he th&roid gland originates as a proliferation of endodermal epithelial cells at + to wee4s of gestation# S&nthesis and secretion of th&ro0ine '.-( and triiodoth&ronine '.+( starts from 12 wee4s of gestation# %&pothalamic,

pituitar&,th&roid '%P.( a0is *egins to de)elop in the first trimester and th&rotropin,releasing hormone '.5%( and th&roid stimulating hormone '.S%( are also detecta*le *& the end of first trimester# %owe)er, the acti)it& of %P. a0is is low with insufficient production of th&roid hormones *& the fetus until a*out 17,20 wee4s of gestation# In the second half of gestation, the .- and .S% le)els increase progressi)el&# In the first trimester, the fetus is dependent on transplacental passage of th&roid hormones# In the h&poth&roid fetus, this transplacental passage of maternal th&roid hormones is critical for neuroprotection throughout the intra,uterine life# .he cord *lood .- concentration at *irth in infants who are una*le to s&nthesi;e .is 20,+09 of normal# In addition, there is increased con)ersion of .- to .+ in the fetal *rain *& the acti)it& of t&pe 2 deiodinase, resulting in increased local a)aila*ilit& of the ph&siologicall& more important .+# Near normal cogniti)e outcome is possi*le in e)en the most se)erel& affected infants with $% as long as postnatal therap& is initiated earl& in optimum doses and maternal th&roid function is normal# In contrast, when *oth maternal and fetal h&poth&roidism are present as in se)ere iodine deficienc&, there is a significant impairment in neuro,intellectual de)elopment despite ade<uate therap& soon after *irth#2 Similarl&, maternal su*tle or o)ert h&poth&roidism during pregnanc& ha)e also *een seen to ha)e an ad)erse impact on the neuro,intellectual outcome of the offspring#+ Downloaded from www.newbornwhocc.org

AIIMS- NICU protocols 2010

Neonatal physiology , After *irth, the term *a*& e0periences a surge of .S% as a ph&siological response to cold en)ironment# .he .S% concentration rises to =0,70 m>3/ within +0 to =0 minutes after deli)er& and falls <uic4l& in the first 2- hours to a*out 20 m>3/, followed *& a slower decrease to *elow 10 m>3/ after the first postnatal wee4# .he rise in .S% initiates increase of .- and free .- to pea4 le)els of 18 2g3d/ and +#1 ng3d/, respecti)el& at 2- to += hours after *irth with a slow decline to adult )alues o)er -,1 wee4s# Preterm infants demonstrate a similar *ut *lunted response due to %P. a0is immaturit&# Etiology of CH $% can *e permanent or transient# %!yroid dysgenesis is the commonest cause of permanent $% affecting 1 in -000 li)e *irths# It is usuall& sporadic with a 2!1 female to male preponderance# Some of the genes proposed as operative in dysgenesis !ave &een recently identified as %I%'1, %I%'2, PA() and %S*+,'.a*le I ( %!yroid !ormone synt!etic defects account for 10,119 of all cases# .hese are inherited as autosomal recessi)e disorders# .he defect can lie in iodide trapping th&roid or organification, iodot&rosine coupling or deiodination and th&roglo*ulin s&nthesis or secretion# .he commonest of these is a defect in the pero0idase '.P?( acti)it& leading to impaired o0idation and organification of iodide to iodine# .hese disorders usuall& result in goitrous h&poth&roidism# Iodine deficiency is responsi*le for endemic cretinism and h&poth&roidism in some regions of India# *ypot!alamic.pituitary !ypot!yroidism has an estimated incidence of 1 in 10,000# It ma& *e isolated or associated with deficienc& of other pituitar& hormones and present with h&pogl&cemia and microphallus# .ransient h&poth&roidism due to transplacental transfer of %S* &inding in!i&itory immunoglo&ulins '%/II0 from mothers with autoimmune th&roid disease is seen Downloaded from www.newbornwhocc.org

AIIMS- NICU protocols 2010 in 1! 10,000 *irths# .heir effect wanes off *& +,= months in the ma@orit& *ut ma& last up to 9 months# E1posure to iodine in sic4 preterm infants 'e#g# application of po)idone iodine for s4in disinfection 'Aolff,$hai4off effect( or inta4e of iodine containing e0pectorants *& pregnant mothers can also induce transient h&poth&roidism# %ransient !ypot!yro1inema of prematurity refers to low serum concentration of th&roid hormones in up to 719 of preterm infants in earl& postnatal life as compared to term infants# .his reflects the underde)elopment of the %P. a0is, which cannot compensate for the loss of maternal th&roid hormone in preterm infants# .he normal le)els of f.- and .S% in preterm infants are presented in .a*le 2#1 .here has *een a concern that transient h&poth&ro0inemia is associated with ad)erse neurode)elopmental outcomes and decreased sur)i)al in affected infants#= Sic2 eut!yroid syndrome reflects suppression of the pituitar&Bs response to .5%, with inappropriatel& low .S% concentrations in the conte0t of low .+ and in the more se)ere cases, low .- concentrations# Diagnosis New*orn screening, Ideall& uni)ersal screening at +,- da&s of age should *e done for detecting $%# Alternati)el& cord *lood can also *e used if screening is *eing done onl& for $% and not other in*orn errors of meta*olism# >ni)ersal new*orn screening is currentl& *eing done in man& parts of the world including Aestern urope, North America, Capan, Australia, and parts of astern urope, Asia, South America, and $entral America# .hree approaches are *eing used for screening! 1# Primar& .S%, *ac4 up.2# Primar& .-, *ac4 up .S% +# $oncomitant .- and .S% In the first approach, .S% is measured first# .- is measured onl& if .S% is 6 20mu3/# .his approach is li4el& to miss central h&poth&roidism, th&roid *inding Downloaded from www.newbornwhocc.org

AIIMS- NICU protocols 2010 glo*ulin deficienc& and h&poth&ro0inema with dela&ed ele)ation of .S%# In the second approach, .- is chec4ed first and if low .S% is also chec4ed# .his is li4el& to miss milder3 su*clinical cases of $% in which .- is initiall& normal with ele)ated .S%# $oncomitant measurement of .- and .S% is the most sensiti)e approach *ut incurs a higher cost#8 Screening programs use either percentile *ased cut,offs 'e#g, .- *elow 10th centile or .S% a*o)e 90th centile or a*solute cut,offs such as .- D =#1 ug3d/ and .S% 6 20mu3/# Abnormal values on screening should always be confirmed by a venous sam le !using age a ro ria"e cu"#offs given in $able 3 %#1&'( )os" cen"ers ini"ia"e "rea"men" af"er drawing "he infan"s* sam le if $+, - 3& mu./ or $0 is low and "he decision "o con"inue or wi"hhold "rea"men" is "aken af"er ob"aining "he blood re or"( 1or in"ermedia"e screening values of $+,, wi"h normal $0 !if available', "he "rea"men" is ini"ia"ed only af"er confirma"ion of diagnosis based on "he blood re or"( Among infants with pro)en $%, .S% is 6 10 mu3/ in 909 and .- is D =#1 ug3d/ in greater than 819 of cases# In the a*sence of uni)ersal screening, the new*orns with the following indications should *e screened! 1. 2. 3. Eamil& histor& of $% %istor& of th&roid disease or antith&roid medicine inta4e in mother Presence of other conditions li4e DownBs s&ndrome, trisom& 17, neural tu*e defects, congenital heart disease, meta*olic disorders, familial autoimmune disorders and Pierre, 5o*in s&ndrome which are associated with higher pre)alence of $% .h&roid function should *e tested in an& infant with signs3 s&mptoms of h&poth&roidism such as postmaturit&, macrosomia or wide open posterior fontanel at *irth or prolonged @aundice, constipation, poor feeding, h&potonia, hoarse cr&, um*ilical hernia, macroglossia, or dr& edematous s4in in infanc&# .he tests should *e performed e)en in those infants who ha)e a normal Downloaded from www.newbornwhocc.org

AIIMS- NICU protocols 2010 new*orn screening report as it is not entirel& free from pitfalls# .he test results should *e compared to the age related norms as presented in .a*le +# ?nce the diagnosis is esta*lished, further in)estigations to determine the etiolog& should *e done# A nuclear medicine scan using sodium pertechnate '99m.c( is especiall& useful in diagnosing true ath&reosis or ectop& as well as goitrous h&poth&roidism due to d&shormonogenesis# %owe)er, since the scan can *e done onl& *efore initiating treatment, one should not withhold therap& if it is not possi*le to get it performed immediatel&#
11,12

A list of diagnostic

studies useful in infants with congenital h&poth&roidism is presented in .a*le and an algorithmic approach to in)estigation in Eigure 1# ,# 3!en s!ould e as2 for free %- levels4

In most situations, .- 'total( le)els are sufficient for diagnosis of h&poth&roidism and monitoring treatment, *ut free .- can *e o*tained as a more ro*ust mar4er of the *ioa)aila*le .-, when readil& accessi*le# Ahen a)aila*ilit& or cost is a constraint, estimation of free .- should *e definitel& done in the following situations!7, 1+! 1. In premature new*orns, .- 'total( )alues ma& *e low *ecause of a*normal protein *inding or low le)els of th&ro0ine *inding glo*ulin '.FG( due to immaturit& of li)er function, proteinuria or undernutrition# .herefore, free .- )alues pro)ide a *etter estimate of true th&roid function in premature or sic4 new*orns# 2. Eree .- should *e as4ed for in case of finding a low .- with normal .S%# If free .- is normal, it can *e a case of congenital partial 'pre)alence 1!-000,12000 new*orns( or complete 'pre)alence 1!11000 new*orns( .FG deficienc&# .FG le)els should *e e)aluated to confirm this *ut this test is not a)aila*le routinel&# If free .- is also low along with low .with normal .S%, central h&poth&roidism should *e suspected# 3. During monitoring for ade<uac& of treatment, we usuall& monitor with .- 'total( le)el# .his assumes a normal .FG le)el# .his can *e confirmed Downloaded from www.newbornwhocc.org

AIIMS- NICU protocols 2010 *& measuring free .- or .FG le)els once at the time of the first post, treatment .- measurement#

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AIIMS- NICU protocols 2010 Treatment of CH %erm as ell as preterm infants it! lo %- and elevated %S* should *e started on /,th&ro0ine as soon as the diagnosis is made# .he initial dose of /, th&ro0ine should *e 10,112g3 4g3 da& with the aim to normali;e the .- le)el at the earliest# .hose infants with se)ere h&poth&roidism ')er& low .-, )er& high .S% and a*sence of distal femoral and pro0imal ti*ial epiph&ses on radiograph of 4nee( should *e started with the highest dose of 112g3 4g3 da&#1Monitoring of t!erapy5 .- should *e 4ept in the upper half of normal range '10,1= 2g3d/( or free .- in the 1#- , 2#+ ng3dl range with the .S% suppressed in the normal range# .- and .S% le)els should *e chec4ed according to the following schedule! 0,= months! = months,+ &ears! 6 + &ears! e)er& = wee4s e)er& + months = monthl&

.- and .S% should also *e chec4ed =,7 wee4s after an& dosage change# Growth and de)elopment of the infant should also *e regularl& monitored# It is e<uall& important to a)oid o)er treatment# Ad)erse effects of o)er treatment include premature fusion of cranial sutures, acceleration of s4eletal maturation and pro*lems with temperament and *eha)ior# Asymptomatic !ypert!yrotropinemia! le)ated .S% with normal .- )alues are seen commonl&# .his h&perth&rotropinemia can *e transient or permanent# Perinatal iodine e0posure is the commonest cause of transient ele)ation in .S%# ?ther causes of h&perth&rotropinemia include defects in *iological acti)it& of .S% or .S% receptor, a mild th&roid hormone *ios&nthesis defect, su*tle de)elopmental defects or a distur*ance in the negati)e feed*ac4 control of .S%# %&perth&rotropinemia in new*orns is usuall& treated *ut in the presence of free .- le)els in upper half of normal range, e0pectant management can *e followed# In case of starting treatment, a = wee4 trial of Downloaded from www.newbornwhocc.org

AIIMS- NICU protocols 2010 putting the child off therap& followed *& measuring .S% and .- le)els should *e done at + &ears of age#1Preterm infants it! lo %and normal %S* levels '.ransient

h&poth&ro0inemia of prematurit&(! >se of le)oth&ro0ine in an attempt to Hnormali;eI le)els remains contro)ersial *ecause there is insufficient e)idence that earl& treatment with th&roid hormone leads to impro)ed outcomes# /arger studies, especiall& in the e0tremel& preterm infants are needed to resol)e this issue#11 %ransient *ypot!yroidism! Infants with presumed transient h&poth&roidism due to maternal goitrogenic drugs need not *e treated unless low .- and ele)ated .S% )alues persist *e&ond 2 wee4s# .herap& can *e discontinued after 7,12 wee4s# Inta4e of antith&roid drugs can *e continued *& the h&perth&roid mothers during *reast feeding *ecause concentration of these drugs is )er& low in *reast mil4# If we ha)e *een a*le to document the presence of .FII in an infant and are attri*uting h&poth&roidism to maternal autoimmune th&roiditis, treatment should *e started if .- is low and continued for +,= months 7# %owe)er, when .FII estimation is not a)aila*le it is *est to continue treatment till the age of + &ears and then gi)e a trial off therap& for = wee4s followed *& retesting of .- and .S% to determine the need for continuation of therap&# .he management has *een summari;ed in Panel 1# utcome! .he *est outcome occurs with /,th&ro0ine therap& started *& 2 wee4s of age at 9#1 2g34g or more per da&, compared with lower doses or later start of therap&# 5esidual defects can include impaired )isuospatial processing and selecti)e memor& and sensorimotor defects# More than 709 of infants gi)en replacement therap& *efore three months of age ha)e an IJ greater than 71 *ut ma& show signs of minimal *rain damage, including impairment of arithmetic a*ilit&, speech, or fine motor coordination in later life#8 Ahen Downloaded from www.newbornwhocc.org

AIIMS- NICU protocols 2010 treatment is started *etween +,= months, the mean IJ is 81 and when dela&ed

A*normal )alues on screening should alwa&s *e confirmed *& a )enous sample using age appropriate cut,offs# In)estigations to determine the etiolog& such as scintigraph& should *e done as soon as the diagnosis is made# If it is not possi*le, the therap& should *e started without dela&#

.he initial dose of /,th&ro0ine should *e 10,112g3 4g3 da& with the aim to normali;e the .- le)el at the earliest# .- should *e 4ept in the upper half of normal range '10,1= 2g3d/( with .S% le)el suppressed in the normal range#

As&mptomatic h&perth&rotropinemia should *e treated unless the free .- le)els are in upper half of normal range# Ahen treatment has *een started in an infant with suspected transient h&poth&roidism or isolated increase in .S% or *orderline )alues of .and .S%, a = wee4 trial of putting the child off therap& followed *&

measuring .S% and .- le)els should *e done at + &ears of age# to *e&ond = months, the mean IJ drops to 1-#1=

Panel 1

MANAG M N. ?E $?NG NI.A/ %KP?.%K5?IDISM

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AIIMS- NICU protocols 2010 References 1. Desai MP, >padh&e P, $olaco MP, Mehre M, Nai4 SP, La;

E , Nair N, .homas M# Neonatal screening for congenital h&poth&roidism using the filter paper th&ro0ine techni<ue# Indian C Med 5es 199-M 100! +=,-2# 2. +# Eisher DA, Nlein A%# .h&roid de)elopment and disorders of %addow C , Paloma4i G5, Allan A$ et al# Maternal th&roid th&roid function in the new*orn# N ngl C Med# 1971M +0-!802:812# deficienc& during pregnanc& and su*se<uent neuro,ps&chological de)elopment of the child# 4. Macchia P# 5ecent ad)ances in understanding the molecular *asis of primar& congenital h&poth&roidism# Mol Med .oda& 2000M=!+=:-2 5. Adams /M, mer& C5, $lar4 SC, $arlton I, Nelson C$# 5eference ranges for newer th&roid function tests in premature infants# C Pediatr 1991M12=!122:8# =# 8# Ni4ta Eorghani, .and& A&e# %&poth&ro0inemia and prematurit&# Neore)iews 2007M 9! e==,81# American Academ& of Pediatrics, 5ose S5M Section on and $ommittee Societ&, on Genetics, ., American PF, .h&roid Na&e $I, ndocrinolog& Pediatric

Association, Frown 5SM Pu*lic %ealth $ommittee, /awson Ail4ins ndocrine Eole& Naplowit; Sundarara@an S, Larma SN# >pdate of new*orn screening and therap& for congenital h&poth&roidism# Pediatrics 200=M 118!2290,+0+# 8. Eisher DA# Disorders of the th&roid in new*orns and infants# ndocrinolog&, 2nd edition# Philadelphia! In Sperling MA, ed# Pediatric Saunders, 2002M 1=1,7=# 9. =99,802# Downloaded from www.newbornwhocc.org Soldin ?P, Cang M, Guo ., Soldin SC# Pedistric reference inter)als for free th&ro0ine and free triiodoth&ronine# .h&roid 2009M 19!

AIIMS- NICU protocols 2010 10. Eisher DA# Disorders of the th&roid in childhood and ndocrinolog&, 2 nd edition# etiologies,

adolescence# In Sperling MA, ed# Pediatric Philadelphia! Saunders, 2002M 178,210# 11# 12. 13. /aEranchi S# $ongenital

h&poth&roidism!

diagnosis and management# .h&roid 1999M9!8+1,-0# Eisher DA# Management of congenital h&poth&roidism# C Frown 5S# .he th&roid gland# In Froo4 $GD, %indmarsh P$ ndocrinolog&, -th edition# /ondon! Flac4well $lin ndocrinol Meta* 1991M82!121,7# eds# $linical Pediatric Science, 2001M 277,+20# 14. 20!119,87# 11# $D0019-1# 1=# Nlien A%, Melt;er S, Nenn& EM# Impro)ed prognosis in congenital h&poth&roidism treated *efore age three months# C Pediatr 1982M71!912,1# Table ! tiolog& of $% 1# Permanent h&poth&roidism# *# c# d# e# 2# a# *# c# .h&roid d&sgenesis 'aplasia, h&poplasia or ectopia( .h&roid hormone *ios&nthetic defects Iodine deficienc& 'endemic cretinism( %&pothalamic,pituitar& h&poth&roidism .S% *inding inhi*itor& immunoglo*ulins 0posure to goitrogens 'iodides or antith&roid drugs( .ransient h&poth&ro0inemia of prematurit& Downloaded from www.newbornwhocc.org Postnatal th&roid hormones for preterm infants with transient h&poth&ro0inaemia# $ochrane Data*ase S&st 5e)# 2008! /aEranchi S%, Austin C# %ow should we *e treating children ndocrinol Meta* 2008M with congenital h&poth&roidismO C Pediatr

.ransient h&poth&roidism#

AIIMS- NICU protocols 2010 d# Sic4 euth&roid s&ndrome

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AIIMS- NICU protocols 2010 Table " 5eference ranges for serum free .- 'f.-( and .S% in preterm infants Age in wee4s 21,28 27,+0 +1,++ +-,+= Eree .- 'ng3dl( 0=,2#2 0#=,+#1#0,+#7 1#2,-#.S% 'mu3l( 0#2,+0#+ 0#2,20#= 0#8,20#9 1#2,21#=

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AIIMS- NICU protocols 2010 Table # Reference ranges for T$% fT$ and T&H in term infants according to age7, 9, 10 Age T$ 'Pg3dl( mean 'range( $ord *lood 1,+ da&s -,8 da&s 1,2 wee4s 2,= wee4s = wee4s to 10#7 '=#=,11( Q 12#8 18#2( =#1,1=#+QQ 12 11#1 '1#9,1#+( fT$ 'pg3ml( mean range 1+#7 '+#1( 22#+ '+#9( '7#2, Q 9#0,22#0QQ 1+#0,2-#0QQ T&H 'P>3ml( 'SD(3 mean 'range( 10#0 '1,20( 1#= '1,10( Q 2#+ '0#1,=#1( 1#8,9#1QQ 2#+'0#1,=#1(

1=#1 '11,21#1( Q

months QNo data a)aila*le QQ data for median3mean not a)aila*le

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AIIMS- NICU protocols 2010 Table $ Diagnostic studies for e)aluation of $% 1# Imaging Studies! will determine location and si;e a# Scintigraph& '99m.c or 12+ I( *# Sonograph& 'less sensiti)e than scintigraph&( 2# Eunction Studies a# 12+ I upta4e *# Serum th&roglo*ulin +# Suspected in*orn error of .- s&nthesis a# 12+ I upta4e and perchlorate discharge -# Suspected autoimmune th&roid disease a# Maternal and neonatal serum .FII measurement 'not routinel& a)aila*le( 1# Suspected iodine e0posure or deficienc& a# >rinar& iodine measurement =# Ancillar& test to determine se)erit& of fetal h&poth&roidism a# 5adiograph of 4nee for s4eletal maturation #

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AIIMS- NICU protocols 2010 (igure ! Approach to a new*orn infant with positi)e screening test for $% Positi)e screening test on filter paper sample Serum .-3 Eree .-, .S%

Normal A*normal .h&roid scan

Normal ctopic .g Measurement

A*sent upta4e

>ltrasound

Normal or tissue %/II measurementQ

A*sent

Normal gland

No th&roid

%/II measurementQ

Positi)e

Negati)e

Negati)e

Positi)e

.ransient .% s&nthetic .g .S% receptor .ransient .h&roid ctopic $% defect or s&nthetic or agenesis th&roid drug effect defect .% *ios&nthetic gland defect or iodine *loc4ade

$%

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AIIMS- NICU protocols 2010 .FIIR .S% *inding inhi*itor& immunoglo*ulin 'Qnot routinel& a)aila*le( .gR th&roglo*ulin, .%R th&roid hormone Adapted from Eisher DA# Management of congenital h&poth&roidism# C $lin ndocrinol Meta* 1991M82!121,7#1+

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