Anemia dan gangguan psikiatrik pada anak 1

BMC Psychiatry BioMed Central

Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study
Mu-Hong Chen, Tung-Ping Su, [...], and Ya-Mei Bai Additional article infor ation

Abstract
Background
A great deal of e!idence has sho"n that iron is an i #ortant co #onent in cogniti!e, sensori otor, and social-e otional de!elo# ent and functioning, $ecause the de!elo# ent of central ner!ous syste #rocesses is highly de#endent on iron-containing en%y es and #roteins. &eficiency of iron in early life ay increase the ris' of #sychiatric or$idity.

Methods
(tili%ing the )ational Health *nsurance &ata$ase fro +,,- to .//0, children and adolescents "ith a diagnosis of *&A "ere identified and co #ared "ith age and genderatched controls 1+234 in an in!estigation of the increased ris' of #sychiatric disorders.

Results
A total of .,56 #atients "ith *&A, "ith an increased ris' of uni#olar de#ressi!e disorder 178 9 ..:3, ,5; C* 9 +.50 < :.3-4, $i#olar disorder 178 9 5.60, ,5; C* 9 ...: < +5./54, an=iety disorder 178 9 ..+6, ,5; C* 9 +.3, < :.+-4, autis s#ectru disorder 178 9 :./0, ,5; C* 9 +.6, < 5..04, attention deficit hy#eracti!ity disorder 178 9 +.-6, ,5; C* 9 +.., < ..+64, tic disorder 178 9 +.6/, ,5; C* 9 +./: < ..604, de!elo# ental delay 178 9 ..35, ,5; C* 9 ..// < :.//4, and ental retardation 178 9 ..6/, ,5; C* 9 ..// < :.-54, "ere

identified. A gender effect "as noted, in that only fe ale #atients "ith *&A had an increased 78 of $i#olar disorder 178 9 5.5-, ,5; C* 9 +.,0 < +5.6/4 and tic disorder 178 9 ..,5, ,5; C* 9 +..6 < -.0-4.

Conclusion
*ron deficiency increased the ris' of #sychiatric disorders, including ood disorders, autis s#ectru disorder, attention deficit hy#eracti!ity disorder, and de!elo# ental disorders. >urther study is re?uired to clarify the echanis in the association $et"een *&A and #sychiatric disorder. Keywords: *ron deficiency ane ia, Psychiatric disorders, Co or$idity

Background
According to the @orld Health 7rgani%ation, iron deficiency 1*&4 is the ost #re!alent nutritional deficiency. A :/; #re!alence of iron deficiency ane ia 1*&A4, at a ini u , has $een noted a ong children, adolescents, and "o en in non-industriali%ed countries, and *& is also the ost #re!alent nutritional deficiency in industriali%ed countries [+-3]. *&, defined $y t"o or ore a$nor al easure ents 1seru ferritin, transferrin saturation, erythrocyte #roto#or#hyrin4, is insidious and uneasily detected $y #atients the sel!es and ay not de!elo# significant clinical sy #to s [+-3]. *&A is characteri%ed $y a defect in he oglo$in synthesis o"ing to significant *&, resulting in the reduced ca#acity of the red $lood cells to deli!er o=ygen to $ody cells and tissues, and any clinical sy #to s, such as #ale conAuncti!a, shortness of $reath, di%%iness, and lethargy [+-3]. The ain ris' factors for *&A and *& include a lo" inta'e of iron, #oor a$sor#tion of iron fro diets, chronic loss of iron 1i.e., ulcer, etrorrhagia4, and so e s#ecific #eriods of life "hen iron re?uire ents are es#ecially high, such as gro"th and #regnancy [+-3]. *ron is an essential co #onent of he oglo$in, yoglo$in, and any en%y es in cellular eta$olis and &)A re#lication and re#air. *t also #lays a crucial role in the de!elo# ent of the central neurological syste [5-0], autoi une syste [,-++], endocrine syste [+.-+5], and cardio!ascular syste [+-,+6]. *n the de!elo# ent of the $rain, iron accounted for the yelination of "hite atter [+0,+,] and the de!elo# ent and functioning of the different neurotrans itter syste s, including the do#a ine, nore#ine#hrine, and serotonin syste s [./-..]. *n !i!o icrodialysis studies using #ost"eaning iron-deficient rats and ice de onstrated that they e=hi$ited deficits in intracellular do#a ine concentrations and in the density of do#a ine and do#a ine trans#orter rece#tors, "ith !aria$le a ounts of loss $y $rain region [.:-.-]. Anderson et al. sho"ed that decreased iron significantly reduced e=tracellular concentrations of nore#ine#hrine in the caudate #uta en, and altered le!els of nore#ine#hrine due to reduced iron le!els ay $e the result of changes in the e=#ression of nore#ine#hrine trans#ort and nore#ine#hrine rece#tor #roteins in the locus ceruleus and $asal ganglia [.6,.0]. A reduction in serotonin trans#orter $inding "as noted in the nucleus accu $ens

and olfactory tu$ercle in iron-deficient rats [.+], and the serotonin concentration in the $rain "as significantly correlated "ith the non-he e iron le!el [.,]. *n su ary, *&A and *& "ere significantly associated "ith an alteration of onoa ine neurotrans itters and the a$nor al yelination of "hite atter, and is #ro$a$ly related to childhoodBadolescence-onset #sychiatric disorders. There is "ell docu ented e!idence in the literature that *&A has a significant influence on cogniti!e de!elo# ent, intelligence, and de!elo# ental delay [:/,:+]. Ho"e!er, the association $et"een *&A and other childhoodBadolescence-onset #sychiatric disorders is still li ited. So e clinical studies su##osed that $rain *& in!ol!ed in the #atho#hysiology of attention deficit hy#eracti!ity disorder 1A&H&4 [:.] and ferritin le!el "as related to $eha!ioral sy #to s in A&H& #atients [::]. But, Millicha# et al. disclosed no significant difference in se!erity of A&H& sy #to s $et"een children "ith A&H& "ho had the lo"er seru ferritin le!els 1C./ ngB D4 and those "ho had the higher le!els 1E-/ ngB D4 [:3]. And a high #re!alence, u# to :/;, of *&A "as o$ser!ed in children "ith autis s#ectru disorder 1AS&4, "hich "as su##osed to #otentially co #ro ise their co unication and $eha!ior [:5,:-]. As for schi%o#hrenia, $i#olar disorder 1B&4, uni#olar de#ressi!e disorder, and an=iety disorder, the data are ?uite li ited. This study, using a nation"ide #o#ulation-$ased insurance data$ase "ith a caseFcontrol ethod and the largest sa #le si%e, atte #ted to clarify the association $et"een *&A and !arious #sychiatric disorders a ong children and adolescents "ith *&A. @e hy#othesi%ed that children and adolescents "ith A&H& e=hi$ited the higher ris' of ha!ing a #sychiatric disorder.

Methods
Data source
The )ational Health *nsurance 1)H*4 #rogra "as i #le ented in Tai"an in +,,5. Since .//+, Tai"anGs )H* has co!ered ,-.,; of all .:,///,/// residents of Tai"an. The co #leteness and accuracy of the )H* clai s data$ase has $een audited $y the &e#art ent of Health and the Bureau of )H*. The data$ase #ro!ides de ogra#hic and edical infor ation on insured residents, including age, gender, #rescri#tion drugs, #rescri#tion date, and the #rescri#tion and diagnosis using the *nternational Classification of &iseases, ,th 8e!ision, Clinical Modification 1*C&-,-CM4. The )H* 8esearch &ata$ase 1)H*8&4 has $een used e=tensi!ely in any e#ide iologic studies in Tai"an [:6-:,]. 7ur study "as a##ro!ed $y *nstitutional 8e!ie" Board of Tai#ei Heterans Ieneral Hos#ital 1./+.-/3-/+.BC4.

nclusion criteria for DA and psychiatric disorders

*n this study, +,///,/// su$Aects, a##ro=i ately 3.:; of the #o#ulation of Tai"an, "ere rando ly selected fro the )H*8&. The study co #rised all children and adolescents 1aged younger than +04 "ho "ere identified $y the diagnostic code of Jiron deficiency ane iaK 1*C&-,-CM2 .0/4 $et"een Lanuary +, +,,- and &ece $er :+, .//0. &iagnosis "as gi!en $y $oard-certificated #ediatricians and #hysicians. Coe=istent #sychiatric

disorders "ere in!estigated $y s#ecific diagnostic codes, and included schi%o#hrenia 1*C&-,-CM code2 .,54, B& 1*C&-,-CM code2 .,- e=ce#t .,-.. and .,-.:4, uni#olar de#ressi!e disorder 1*C&-,-CM codes2 .,-.., .,-.:, ://.3, and :++ for aAor de#ressi!e disorder, dysthy ic disorder, de#ressi!e disorder, not s#ecified4, o$sessi!e-co #ulsi!e disorder 17C&4 1*C&-,-CM code2 ://.:4, an=iety disorder 1*C&-,-CM code2 :// e=ce#t ://.: and ://.34, AS& 1*C&-,-CM code2 .,,4, A&H& 1*C&-,-CM code2 :+34, tic disorder 1*C&-,-CM2 :/6..4, delayed de!elo# ent 1*C&-,-CM code2 :+54, and ental retardation 1*C&-,-CM code2 :+6 < :+,4. >inally, gastrointestinal ulcer 1*C&-,-CM code2 5:+ < 5:34, etrorrhagia 1*C&-,-CM code2 -.-.. and -.-.-4, and #re eno#ausal enorrhea 1*C&-,-CM code2 -.6./4 "ere used as co!ariates. All #sychiatric diagnoses "ere gi!en $y $oard-certified #sychiatrists. The diagnoses of delayed de!elo# ent and ental retardation "ere gi!en $y $oard-certificated #sychiatrists, reha$ilitation s#ecialists, and #ediatricians.

Control group
The age and gender- atched control grou# 13 for e!ery #atient in the study cohort4 "as rando ly identified fro su$Aects "ho had no aAor #hysical illnesses, including cancer 1*C&-,-CM code2 +3/ < .:,4, he atological disease 1*C&-,-CM code2 .0/ < .0,4, chronic li!er disease 1*C&-,-CM code2 56/ < 56:4, chronic renal disease 1*C&-,-CM code2 505, 50-4, chronic infla atory disease 1*C&-,-CM code2 6+/ for diffuse diseases of connecti!e tissue, 6+3 for rheu atoid arthritis and other infla atory #olyarthro#athies, 6./ for an'ylosing s#ondylitis and other infla atory s#ondylo#athies, 555 for CrohnGs disease, 55- for idio#athic #roctocolitis4, chronic infectious disease 1*C&-,-CM code2 /+/ < /+0 for tu$erculosis, /3. < /33 for hu an i unodeficiency !irus, /6/ for !iral he#atitis, /,/ < /,, for sy#hilis, :,/ < :,. for rheu atic fe!er, 6:/ for osteo yelitis4, endocrine disease 1*C&-,-CM code2 .3/ < .3for thyroid disease, .3, < .5/ for dia$etes ellitus, .5. for #arathyroid disease, .5: for #ituitary disease, .55 for adrenal gland disease4, and nutritional deficiency 1*C&-,-CM code2 .-/ < .-,4.

!tatistical analysis
>or $et"een-grou# co #arisons, the inde#endent t test "as used for continuous !aria$les and PearsonMs X. test or >isherMs e=act test "as a##lied for no inal !aria$les, "here a##ro#riate. Multi#le logistic regressions "ere #erfor ed to calculate the 78 "ith ,5; confidence inter!als 1C*4 after adAusting for ulcer, etrorrhagia, and #re eno#ausal enorrhea 1$ecause ulcer and etrorrhagia "ere t"o i #ortant ris's causing *&A of children and adolescents4. A t"o-tailed P-!alue of less than /./5 "as considered statistically significant. All data #rocessing and statistical analyses "ere #erfor ed "ith Statistical Pac'age for Social Science 1SPSS4 !ersion +6 soft"are 1SPSS *nc4 and Statistical Analysis Soft"are 1SAS4 !ersion ,.+ 1SAS *nstitute, Cary, )C4.

Results

Demographic characteristics of the DA patients and control group

A total of .,56 children and adolescents 1+/-/ ales and +0,6 fe ales4 "ere identified as ha!ing *&A fro the +,///,///-#erson sa #le #o#ulation $et"een Lanuary +, +,,and &ece $er :+, .//0. The ean age "as +/.5, N -./. years and ale #atients "ere significantly younger than the fe ales 16.3- N 5.-0 !s. +..:3 N 5.3-, # C /.//+4. Male *&A #atients e=hi$ited a significantly higher #re!alence of AS& 1+.-; !s. /.3;, # C /.//+4, A&H& 1-./; !s. +.+;, # C /.//+4, tic disorder 1+.:; !s. /.5;, # 9 /./.64, delayed de!elo# ent 10.5; !s. :.3;, # C /.//+4, and ental retardation 13.3; !s. +.5;, # C /.//+4 than the fe ales 1Ta$le +4. *n co #aring the difference $et"een the *&A #atients and the control grou#, the *&A #atients had a significantly increased #re!alence of #sychiatric co or$idities, including uni#olar de#ressi!e disorder 1+.-; !s. /.-;, # C /.//+4, B& 1/.3; !s. /.+;, # C /.//+4, an=iety disorder 1+.5; !s. /.6;, # C /.//+4, AS& 1/.0; !s. /.:;, # C /.//+4, A&H& 1..0; !s. +.0;, # C /.//+4, tic disorder 1/.0; !s. /.5;, # 9 /./334, delayed de!elo# ent 15..; !s. ..3;, # C /.//+4, and ental retardation 1..5; !s. +./;, # C /.//+4 1Ta$le .4.

Ta$le + Characteristics of #atients "ith iron deficiency ane ia 1*&A4

Ta$le . Characteristics of #atients "ith iron deficiency ane ia 1*&A4 and control su$Aects

"dds ratio of psychiatric disorders

*n e=a ining the association $et"een *&A and childhoodBadolescence-onset #sychiatric disorders, ulti#le logistic regression analysis "as used to e!aluate the 78 of #sychiatric co or$idity a ong those "ith *&A, after adAusting for age, gender, ulcer, etrorrhagia, and #re eno#ausal enorrhea. Patients "ith *&A "ere #rone to ha!ing a significantly higher chance of $eing associated "ith uni#olar de#ressi!e disorder 178 9 ..:3, ,5; C* 9 +.5, < :.3-4, B& 178 9 5.0/, ,5; C* 9 ...3 < +5./54, an=iety disorder 178 9 ..+6, ,5; C* 9 +.3, < :.+-4, AS& 178 9 :./0, ,5; C* 9 +.6, < 5..04, A&H& 178 9 +.-6, ,5; C* 9

+.., < ..+64, tic disorder 178 9 +.6/, ,5; C* 9 +./: < ..604, delayed de!elo# ent 178 9 ..35, ,5; C* 9 ..// < :.//4, and ental retardation 178 9 ..6/, ,5; C* 9 ..// < :.-54 1Ta$le :4. @e also in!estigated the gender effect on *&A and associated #sychiatric co or$idities 1Ta$le :4. A significantly increased ris' of uni#olar de#ressi!e disorder 178 9 ..:-, ,5; C* 9 +.+/ < 5.+/4, an=iety disorder 178 9 +.6:, ,5; C* 9 +./. < ..,34, AS& 178 9 ..--, ,5; C* 9 +.3+ < 5.//4, A&H& 178 9 +.5+, ,5; C* 9 +.+. < ../34, delayed de!elo# ent 178 9 +.,5, ,5; C* 9 +.5/ < ..5:4, and ental retardation 178 9 :./,, ,5; C* 9 ../0 < 3.-+4 "ere o$ser!ed in ale *&A #atients in co #arison "ith fe ales, "hile a significantly higher ris' of uni#olar de#ressi!e disorder 178 9 ..:6, ,5; C* 9 +.5+ < :.6:4, B& 178 9 5.5-, ,5; C* 9 +.,0 < +5.6/4, an=iety disorder 178 9 ..-,, ,5; C* 9 +.56 < 3.-.4, AS& 178 9 3./6, ,5; C* 9 +.:, < ++.,/4, A&H& 178 9 ..//, ,5; C* 9 +.+3 < :.3,4, tic disorder 178 9 ..,5, ,5; C* 9 +..6 < -.0-4, delayed de!elo# ent 178 9 :.30, ,5; C* 9 ..30 < 3.004, and ental retardation 178 9 ..+:, ,5; C* 9 +.:3 < :.3/4 "ere noted in fe ale *&A #atients co #ared "ith ales 1Ta$le :4.

Ta$le : Association $et"een iron deficiency ane ia 1*&A4 and #sychiatric disorders

"dds ratio of psychiatric disorder stratified by age

@e #erfor ed adAusted ulti#le logistic regression stratified $y age to elucidate the association $et"een *&A and !arious #sychiatric co or$idities, focusing on children and adolescents "ith *&A, res#ecti!ely 1Ta$le :4. Children "ere defined as those younger than +: and adolescents as those aged +: < +0. Children "ith *&A e=hi$ited a significantly higher ris' of AS& 178 9 :.//, ,5; C* 9 +.6/ < 5..64, A&H& 178 9 +.5/, ,5; C* 9 +.+. < +.,,4, delayed de!elo# ent 178 9 ...:, ,5; C* 9 +.6, < ..604, and ental retardation 178 9 :./+, ,5; C* 9 ../, < 3.:.4 1Ta$le :4. Adolescents "ith *&A "ere significantly associated "ith uni#olar de#ressi!e disorder 178 9 ..0,, ,5; C* 9 +.03 < 3.534, B& 178 9 -./5, ,5; C* 9 +.,6 < +0.504, an=iety disorder 178 9 :.6+, ,5; C* 9 ..+- < -.:64, A&H& 178 9 ..53, ,5; C* 9 +.:+ < 3.,54, tic disorder 178 9 :.6:, ,5; C* 9 +.+. < +..304, delayed de!elo# ent 178 9 :.00, ,5; C* 9 ..+6 < -.,54, and ental retardation 178 9 ../0, ,5; C* 9 +... < :.564 1Ta$le :4.

Discussion
The results of our clinical e#ide iological study su##orted #re!ious findings that *&A is significantly associated "ith increased ris's of uni#olar de#ressi!e disorder, B&, an=iety

disorder, AS&, A&H&, delayed de!elo# ent, and adolescents.

ental retardation a ong children and

Mental retardation and delayed de#elopment

7ur results sho"ed a higher #re!alence of ental retardation and delayed de!elo# ent a ong su$Aects "ith *&A, "hich "as consistent "ith #re!ious findings [:+,3/,3+]. BeltrOn-)a!arro et al. used the Bayley Scales of *nfant &e!elo# ent, #reschool language scales and an en!iron ental sound #erce#tion tas' to assess the effect of *&A on ultifaceted de!elo# ent in infancy 1at - and +3 to +0 onths4 and sho"ed that infants "ith chronic *&A did sho" significantly lo"er scores on language, en!iron ental sound #erce#tion, and otor easures, "hen co #ared "ith infants "ith a nor al iron nutritional status [3.]. Studying the long-ter de!elo# ental outco e of infants "ith *&A, Do%off et al. found lo"er scores on tests of ental 1i.e., intelligence4 and otor functioning at age of 5 and +. a ong those "ith *&A in infancy [:+,3/]. >urther ore, *&A can i #air cogniti!e #erfor ance at all stages of life. Halter an et al. assessed 5:,0 children and adolescents aged - to +- and de onstrated that su$Aects "ith *&A had ore than t"ice the ris' of scoring $elo" a!erage in scholastic achie!e ent than the children "ith a nor al iron status [3:].

Attention deficit hyperacti#ity disorder $AD%D&

Pre!ious studies on iron and the #atho#hysiology of A&H& ha!e had inconsistent results. *n a s all cohort study co #rising 5. A&H& children, 7ner et al. found that lo"er ferritin le!els "ere associated "ith higher hy#eracti!ity scores in A&H& children, $ut did not ha!e a significant influence on cogniti!e easures [::]. (sing agnetic resonance i aging 1M8*4 to in!estigate the association of A&H& and $rain iron le!els in the #uta en, #allidu , caudate, and thala us, Cortese et al. de onstrated children "ith A&H& sho"ed significantly lo"er $rain iron le!els in the right and left thala us co #ared to healthy controls [:.]. 7ther studies, ho"e!er, did not find this association $et"een A&H& and the ferritin le!el [:3,33]. *n our study, an increased ris' of A&H& "as noted a ong those "ith *&A, "hich "as co #ati$le "ith a recent eta-analysis result [35]. @ith regard to the current #atho#hysiology of A&H& as in!ol!ing a dysfunction of the neurotrans itter syste s, *&A significantly distur$ed the de!elo# ent and functioning of nore#ine#hrine and do#a ine neurotrans itter syste s.

Autism spectrum disorder $A!D&

Pre!ious studies ha!e re!ealed that iron "as associated "ith socio-cogniti!e and socioe otional de!elo# ent and functioning [3--30]. A disorder in this area is one of the core sy #to s of AS&. Assessing the #re!alence of *& and *&A a ong ++- children $et"een : and +- years old "ith a diagnosis of AS&, HergPner et al. re!ealed that .3; of #atients "ith AS& had *&, and +5; had *&A [:5]. Datif et al. analy%ed the seru ferritin easure ents of ,- children "ith AS& and suggested there "as a high #re!alence, u# to :/ #ercent, of *& in children "ith AS& [:-]. 7ur result sho"ed an increased ris' of AS& a ong children and adolescents "ith *&A, suggesting a #ossi$le reci#rocal effect

$et"een AS& and *&A. >or e=a #le, ina##ro#riate eating ha$it in those su$Aects ay $e related to *&A and any children "ith AS& are #ic'y eaters, "hich could contri$ute to *&A. >urther ore, diffusion-tensor M8* found i #aired "hite atter integrity and a yelination de!elo# ental a$nor ality in AS& #atients co #ared to nor al su$Aects [3,-5+]. *ron "as regarded as an essential co #onent in yelination and oligodendrogenesis. Myelin synthesis "as li ited and altered $y *&. >urther study "ould $e needed to clarify the co or$idity or causality $et"een AS& and *&A.

'nipolar depressi#e disorder

)u erous studies ha!e re#orted that *&A "as associated "ith uni#olar de#ressi!e disorder, #ossi$ly through an alteration of the onoa ine neurotrans itters $y *& [5.53]. Do"er seru ferritin concentrations "ere significantly correlated "ith de#ressi!e sy #to s [5:,53]. (sing a longitudinal cohort study of +,+ #artici#ants to e!aluate the association $et"een *&A in infancy and affecti!e and de!elo# ental outco es in adolescence, Do%off et al. re!ealed that those "ith *&A in infancy e=hi$ited ore an=iety, de#ression, social #ro$le s, and attentional #ro$le s in later life [3/]. Hahdat Shariat#anaahi et al. studied +,. fe ale edical students and found the ean ferritin le!el of students "ith de#ression "as significantly lo"er than that of healthy students [5:]. Si ilar results "ere o$ser!ed in a La#anese ale #o#ulation. *n a study of :+. en, those "ith lo"er seru ferritin concentration le!els had a higher #re!alence of de#ressi!e sy #to s [53]. 7ur result, sho"ing an increased ris' of uni#olar de#ressi!e disorder a ong those "ith *&A, "as co #ati$le "ith that of #re!ious studies, and reconfir ed the #atho#hysiological association of *&A "ith uni#olar de#ressi!e disorder.

Bipolar disorder $BD&

Q otional dysregulation has $een dee ed as one of the core neuro#sycho#athologies of B& [55-56]. *t has $een "ell docu ented that iron is associated "ith socio-e otional de!elo# ent and that *& ay distur$ the de!elo# ent of e otional regulation [3/,3-,36,50], although clinical studies on the association $et"een *&A and B& are fe". 7ur results sho"ed a higher #re!alence of B& a ong *&A su$Aects. Structural and functional changes related to e otional dysregulation such as in the dorsal and !entral #refrontal cortices and the #refrontal-su$cortical and associated li $ic circuitry ha!e $een considered as a neuro#athology of B& [5-,56]. *& has $een related to #ertur$ations in yelin for ation, alterations of onoa ine neurotrans itter syste s, #articularly in the striatu , and deficits in energy eta$olis , #articularly in the hi##oca #us and #refrontal corte= [5,,-/]. The effect of *&A on B& is still unclear and further study is needed to in!estigate the #ossi$le causality $et"een *&A and B&. >urther ore, a significantly increased 78 of B& "as noted only a ong fe ales "ith *&A after controlling gastrointestinal ulcer, etrorrhagia, and #re eno#ausal enorrhea. Clarifying this gender effect $et"een *&A and B& ay $e needed in future studies.

An(iety disorder

Clinical studies on the association $et"een *&A and an=iety disorder are fe". Do%off et al. found that children "ith se!ere, chronic *& in infancy had a greater #re!alence of an=iety, de#ression, and attention #ro$le s [3/]. So e ani al studies ha!e sho"n an association $et"een *&A and alterations in serotonin, nore#ine#hrine, and ga aa ino$utyric acid 1IABA4 neurotrans ission [.+,-+]. *n assessing "eanling rats "ith either an iron deficient diet or a control diet for - "ee's, Beard et al. found reduced acti!ity and increased an=iety-li'e $eha!iors a ong the iron deficient rats "ith significant decre ents in $rain iron content in the cor#us striatu , #refrontal corte=, and id$rain [-.]. Q otional dysregulation due to *& ay $e a #ossi$le echanis e=#laining the association $et"een an=iety and *&A [-:--5]. *n our study, $oth ales and fe ales "ith *&A had a significantly higher ris' of an=iety disorder. Ho"e!er, esta$lishing causality $et"een *&A and an=iety disorder "ill re?uire further study in the future. 8egarding e otional and cogniti!e #ro$le s, current neuroanato ical i aging studies ha!e #ro!en that $rain de!elo# ent is a continuous #rocess fro infancy to late adolescence or early adulthood [--,-6]. A deficiency of essential co #onents "ill greatly i #air the nor al traAectory of $rain de!elo# ent. *ron is regarded as one of the essential nutritional ele ents related to cogniti!e and socio-e otional de!elo# ent and functioning. A significantly higher ris' of an=iety disorder, AS&, A&H&, delayed de!elo# ent, and ental retardation "as noted a ong children 1$elo" age +:4 "ith *&A. After entering adolescence 1age +: < +04, those "ith *&A had an increased ris' of uni#olar de#ressi!e disorder, B&, an=iety disorder, A&H&, delayed de!elo# ent, and ental retardation. These results ay indicate that *&, "hether in childhood or adolescence, does ha!e a great i #act on #sychiatric co or$idities. Moreo!er, iron deletion in childhood has i ediate and chronic effects on $rain de!elo# ent, in that children "ith *&A e=hi$ited an increased ris' of delayed de!elo# ent and ental retardation "ith #ersistent se?uelae of cogniti!e i #air ent and e otional #ro$le s during adolescence.

)ic disorder
@e found a significantly increased ris' of tic disorder a ong fe ales "ith *&A. The association $et"een *&A and tic disorder is unclear and rarely re#orted in the literature. Cortese et al. entioned a #ossi$le iron hy#othesis in a #ossi$le s#ectru disorder of A&H&, restless leg syndro e, and tic disorder, $ecause these : disorders "ere so eti es co or$id and shared a #athogenesis si ilar to onoa ine neurotrans itter dysfunction [-0]. Q=#loring the associations of ferritin le!els "ith regional $rain !olu es a ong #atients "ith TouretteGs syndro e, Ior an et al. de onstrated ferritin and seru iron le!els "ere significantly lo"er in the TouretteMs syndro e su$Aects and that ferritin correlated #ositi!ely "ith #uta en !olu e [-,]. Co $ining these results "ith ours ay ins#ire further study to clarify the effect of iron on tic disorder or other o!e ent disorders, es#ecially in fe ale #o#ulations. So e li itations in our study should $e entioned here. >irst, the #re!alence of #sychiatric disorders "as dee ed underesti ated $ecause our results "ere deri!ed fro

insurance registry-$ased data. 7nly those indi!iduals "ho used the edical resource to see' #sychiatric hel# "ere identified. Ho"e!er, #atients included in our study "ere gi!en a diagnosis $y $oard-certified #hysicians and the diagnoses "ere ore relia$le than selfre#orted ones. Second, those su$Aects "ho "ere not diagnosed as ha!ing *&A e!er $ut had iron deficiency #ro$le cannot $e detected in our study. The clinical study "ould $e re?uired to elucidate the #ossi$le association $et"een #sychiatric disorders and iron deficiency or su$threshold *&A. Third, *& ay $e due to ina##ro#riate eating ha$its in so e cases $ut the association a ong *&A, eating disorder, and e#isodic ood disorder "ith changed eating #attern is still unclear. *n our study, "e focused on the ris's of #sychiatric co or$idities in #atients "ith *&A and the further study is re?uired to analy%e the effect of ina##ro#riate eating #attern of s#ecific #sychiatric disorder on the ris' of *&A. >ourth, "e had no #ersonal infor ation that could contri$ute to an understanding of the ris' of #sychiatric disorders in #atients, such as en!iron ental factors 1i.e. long-ter life stress, trau atic e=#erience4, and fa ily history of #sychiatric disorder. >orth, the causality $et"een *&A and #sychiatric disorders cannot $e #ro!ed in our study, e!en though our results did indicate a significant association $et"een *&A and #sychiatric disorders.

Conclusions
*n conclusion, #atients "ith *&A did ha!e a higher ris' of #sychiatric disorders, including uni#olar de#ressi!e disorder, B&, an=iety disorder, AS&, A&H&, delayed de!elo# ent, and ental retardation. @hen encountering #atients "ith *&A in clinical #ractice, #ro #t iron su##le entation should $e considered to #re!ent #ossi$le #sychiatric se?uelae, $ecause *& does i #air the de!elo# ent of e otional regulation and cognition. And !ice !ersa, #sychiatrists should chec' the iron le!el in those children and adolescents "ith #sychiatric disorders. >inally, further "ell-designed cohort studies are needed to elucidate the causality or co or$id effect $et"een *&A and #sychiatric disorders.

Competing interests
The authors declare that they ha!e no co #eting interest.

Authors* contributions
MHC and YMB designed the study, "rote the #rotocol and anuscri#ts. YMB, TPS, YSC, L@H, and RDH contri$uted to the #re#aration and #roof-reading of the anuscri#t. YMB, TLC, and @HC #ro!ided the ad!ices on statistical analysis. All authors read and a##ro!ed the final anuscri#t.

+re-publication history
The #re-#u$lication history for this #a#er can $e accessed here2

htt#2BB""".$io edcentral.co B+36+-.33SB+:B+-+B#re#u$

Acknowledgement
The study "as su##orted $y grant fro +4. Tai#ei Heterans Ieneral Hos#ital 1H+/+&-//+-

Article information
BMC Psychiatry. ./+:T +:2 +-+. Pu$lished online ./+: Lune 3. doi2 +/.++0-B+36+-.33S-+:-+-+ PMC*&2 PMC:-0//.. Mu-Hong Chen,+ Tung-Ping Su,+,. Ying-Sheue Chen,+ Lu-@ei Hsu,+ Rai-Din Huang,+ @en-Han Chang,+ T%eng-Li Chen,:,3 and Ya-Mei Bai +,. + &e#art ent of Psychiatry, Tai#ei Heterans Ieneral Hos#ital, Tai#ei, Tai"an . &e#art ent of Psychiatry, College of Medicine, )ational Yang-Ming (ni!ersity, Tai#ei, Tai"an : &e#art ent of >a ily Medicine, Tai#ei Heterans Ieneral Hos#ital, Tai#ei, Tai"an 3 *nstitute of Hos#ital and Health Care Ad inistration, )ational Yang-Ming (ni!ersity, Tai#ei, Tai"an Corres#onding author. Mu-Hong Chen2 're er.chenBatB sa.hinet.netT Tung-Ping Su2 t#suBatB!ght#e.go!.t"T Ying-Sheue Chen2 yschenBatB!ght#e.go!.t"T Lu-@ei Hsu2 A"hsuBatB!ght#e.go!.t"T RaiDin Huang2 'lhuang.BatB!ght#e.go!.t"T @en-Han Chang2 anniecs5+5BatBg ail.co T T%eng-Li Chen2 tAchenBatB!ght#e.go!.t"T Ya-Mei Bai2 y $iBatB ail.///.co .t" 8ecei!ed May ++, ./+.T Acce#ted May .0, ./+:. Co#yright U./+: Chen et al.T licensee BioMed Central Dtd. This is an 7#en Access article distri$uted under the ter s of the Creati!e Co ons Attri$ution Dicense 1htt#2BBcreati!eco ons.orgBlicensesB$yB../4, "hich #er its unrestricted use, distri$ution, and re#roduction in any ediu , #ro!ided the original "or' is #ro#erly cited. Articles fro BMC Psychiatry are #ro!ided here courtesy of BioMed Central

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alternation #erfor ance in rats follo"ing reco!ery fro early iron deficiency. Physiol Beha!. ./+/T+:13425/:F5/0. doi2 +/.+/+-BA.#hys$eh../+/./6./+5. [PMC free article] [Pu$Med] [Cross 8ef] 61. Shu'la A, Agar"al R), Shu'la IS. Datent iron deficiency alters ga aa ino$utyric acid and gluta ate eta$olis in rat $rain. Q=#erientia. +,0,T+:1342:3:F:35. doi2 +/.+//6BB>/+,5636.. [Pu$Med] [Cross 8ef] 62. Beard LD, Qri'son RM, Lones BC. )euro$eha!ioral analysis of de!elo# ental iron deficiency in rats. Beha! Brain 8es. .//.T+:1+F.425+6F5.3. [Pu$Med] 63. Su!eg C, Morelen &, Bre"er IA, Tho assin R. The e otion dysregulation odel of an=iety2 a #reli inary #ath analytic e=a ination. L An=iety &isord. ./+/T+:1042,.3F,:/. doi2 +/.+/+-BA.Aan=dis../+/./-./+0. [Pu$Med] [Cross 8ef] 64. @ee s C>, Sil!er an @R. An integrati!e odel of control2 i #lications for understanding e otion regulation and dysregulation in childhood an=iety. L Affect &isord. .//-T+:1.F:42++:F+.3. [Pu$Med] 65. Mennin &S, Hei $erg 8I, Tur' CD, >resco &M. Preli inary e!idence for an e otion dysregulation odel of generali%ed an=iety disorder. Beha! 8es Ther. .//5T+:1+/42+.0+F+:+/. doi2 +/.+/+-BA.$rat..//3./0.//0. [Pu$Med] [Cross 8ef] 66. Iiedd L), 8a#o#ort LD. Structural M8* of #ediatric $rain de!elo# ent2 "hat ha!e "e learned and "here are "e goingX )euron. ./+/T+:15426.0F6:3. doi2 +/.+/+-BA.neuron../+/./0./3/. [PMC free article] [Pu$Med] [Cross 8ef] 67. Toga A@, Tho #son PM, So"ell Q8. Ma##ing $rain aturation. Trends )eurosci. .//-T+:1:42+30F+5,. doi2 +/.+/+-BA.tins..//-./+.//6. [PMC free article] [Pu$Med] [Cross 8ef] -0. Cortese S, Decendreu= M, Bernardina B&, Mouren MC, S$ar$ati A, Ronofal Q. Attention-deficitBhy#eracti!ity disorder, TouretteMs syndro e, and restless legs syndro e2 the iron hy#othesis. Med Hy#otheses. .//0T+:1-42++.0F++:.. doi2 +/.+/+-BA. ehy..//6.+/./+:. [Pu$Med] [Cross 8ef] 69. Ior an &A, Whu H, Anderson IM, &a!ies M, Peterson BS. >erritin le!els and their association "ith regional $rain !olu es in TouretteMs syndro e. A L Psychiatry. .//-T+:1642+.-3F+.6.. doi2 +/.++6-Ba##i.aA#.+-:.6.+.-3. [PMC free article] [Pu$Med] [Cross 8ef]

2
Tro#ical Medicine Y *nternational Health @iley-Blac'"ell, Lohn @iley Y Sons

Plasmodium falciparum, anaemia and cogniti#e and educational performance

among school children in an area of moderate malaria transmission: baseline results of a cluster randomi-ed trial on the coast of Kenya
Ratherine Q Halliday, Peris RaranAa, [...], and Si on L Broo'er Additional article infor ation

Abstract
"b.ecti#es
Studies ha!e ty#ically in!estigated health and educational conse?uences of alaria a ong school-aged children in areas of high alaria trans ission, $ut fe" ha!e in!estigated these issues in oderate trans ission settings. This study in!estigates the #atterns of and ris's for Plasmodium falciparum and anae ia and their association "ith cogniti!e and education outco es on the Renyan coast, an area of oderate alaria trans ission.

Methods
As #art of a cluster rando ised trial, a $aseline cross-sectional sur!ey assessed the #re!alence of and ris' factors for P. falciparum infection and anae ia and the associations $et"een health status and easures of cognition and educational achie!e ent. 8esults are #resented for .3// rando ly selected children "ho "ere enrolled in the 5+ inter!ention schools.

Results
The o!erall #re!alence of P. falciparum infection and anae ia "as +:./; and 35.5;, res#ecti!ely. There "as ar'ed heterogeneity in the #re!alence of P. falciparum infection $y school. *n ulti!aria$le analysis, $eing ale, younger age, not slee#ing under a os?uito net and household cro"ding "ere adAusted ris' factors for P. falciparum infection, "hilst P. falciparum infection, $eing ale and indicators of #oor nutritional inta'e "ere ris' factors for anae ia. )o association "as o$ser!ed $et"een either P. falciparum or anae ia and #erfor ance on tests of sustained attention, cognition, literacy or nu eracy.

Conclusion

The results indicate that in this oderate alaria trans ission setting, P. falciparum is strongly associated "ith anae ia, $ut there is no clear association $et"een health status and education. *nter!ention studies are under"ay to in!estigate "hether re o!ing the $urden of chronic asy #to atic P. falciparum and related anae ia can i #ro!e education outco es. Keywords: alaria, plasmodium, anae ia, sustained attention, cognition, educational achie!e ent, school children, Renya

ntroduction
The health of school children has recei!ed increasing attention o!er the last t"o decades, and there are increased efforts to i #le ent school health #rogra es, deli!ering anthel intics and icronutrients 1Bundy et al. .//-T Bundy ./++4. Dess e #hasis has $een gi!en to alaria as a health #ro$le facing school children des#ite the e=#eriencing so e of the highest age-s#ecific rates of Plasmodium falciparum infection 1S ith et al. .//6T Hay et al. .//0T Broo'er et al. .//,4, "hich can ha!e a nu $er of direct and indirect conse?uences, including anae ia 1&ra#er +,-/4. The control of alaria is associated "ith significant i #ro!e ents in hae oglo$in le!els a ong $oth young children 1Rorenro # et al. .//34 and children of school age 1&ra#er +,-/T Ieerligs et al. .//:T Clar'e et al. .//0T Barger et al. .//,4. Malaria ay ha!e additional conse?uences for childrenGs cogniti!e #erfor ance and ulti ately educational achie!e ent 1Al Serouri et al. .///T Holding Y Sno" .//+T Rihara et al. .//-T HitorSil!a et al. .//,T >ernando et al. ./+/4. >or instance, alaria has $een related to increased a$senteeis 1Broo'er et al. .///T >ernando et al. .//:aT Ri $i et al. .//54, grade re#etition 1Thuillie% ./+/4 and #oorer educational achie!e ent 1>ernando et al. .//:a, $4. Studies in Ihana, Renya and Sri Dan'a suggest that alaria #re!ention can i #ro!e school attendance, sustained attention and educational achie!e ent 1Col$ourne +,55T >ernando et al. .//-T Lu'es et al. .//-T Clar'e et al. .//04. The conse?uences of alaria for school children and the $enefits of school-$ased alaria control are li'ely to !ary in different settings, #articularly according to intensity of alaria trans ission and the relati!e contri$ution of other causes of anae ia and #oor education outco es. A #re!ious study in an area of #erennial high alaria trans ission in "estern Renya 1Clar'e et al. .//04 in!estigated the i #act of inter ittent #re!enti!e treat ent for alaria in schools and found a large i #act on childrenGs concentration in class and a 30; reduction in the rates of anae ia. Ho"e!er, no effect on educational achie!e ent "as o$ser!ed. To in!estigate this result further and find out "hether the $enefits of alaria control are o$ser!ed in settings "ith different intensities of alaria trans ission and different educational standards, an ongoing cluster rando ised trial is in!estigating the i #act of an alternati!e school-$ased alaria inter!ention, inter ittent screening and treat ent 1*ST4, in an area of oderate alaria trans ission on the coast of Renya 1Broo'er et al. ./+/4. The current #a#er #resents data fro the $aseline crosssectional sur!ey of this trial and in!estigates ris' factors for P. falciparum infection and anae ia as "ell as correlates of cognition, attention and educational achie!e ent.

Methods
The study design and ethods of the inter!ention trial ha!e $een #re!iously detailed 1Broo'er et al. ./+/4 and are $riefly su ari%ed $elo". The *ST inter!ention under in!estigation in the trial co #rises o$ile health tea s consisting of la$oratory technicians and nurses !isiting schools each ter . Children are as'ed to #ro!ide a finger #ric' $lood sa #le to test for the #resence of alaria #arasites using ParaChec'-Pf alaria ra#id diagnostic tests 18&T4 17rchid Bio edical Syste s, Ioa, *ndia4. Children 1"ith or "ithout alaria sy #to s4 found to $e 8&T-#ositi!e are treated "ith arte ether-lu efantrine 1Coarte Z, )o!artis4, an arte isinin-$ased co $ination thera#y. The current in!estigation uses $aseline cross-sectional data collected $et"een >e$ruary and March ./+/ in the 5+ inter!ention schools that "ere allocated to recei!e the inter ittent screening and treat ent for alaria. )o $aseline data "ere collected on P. falciparum infection for the 5/ control schools not recei!ing the alaria inter!ention o"ing to ethical considerations a$out screening for alaria and not #ro!iding treat ent. 8esults re#orted here on P. falciparum infection are $ased on e=#ert icrosco#y. The relia$ility of the 8&Ts e #loyed for the *ST "ill $e e!aluated in future analyses. 8e#orting of the current study has $een !erified in accordance "ith the ST87BQ 1Strengthening the 8e#orting of 7$ser!ational Studies in Q#ide iology4 chec'list.

!tudy setting
The sur!eys "ere conducted in R"ale and Msa $"eni districts on the south Renyan coast, "here alaria trans ission is seasonal follo"ing the t"o rainy seasons 1A#ril-Luly and Se#te $er-)o!e $er4 1Sno" et al. +,,:4. *n econo ic and educational ter s, the districts are ran'ed the se!enth #oorest in Renya and consistently ha!e so e of the "orst-#erfor ing schools in the national school e=a inations 18T* *nternational, .//04. *n .//,, ass al$enda%ole treat ent "as #ro!ided to all schools as #art of the national school de"or ing #rogra e. )o syste atic treat ent for schistoso iasis has $een #ro!ided to date and no s#ecific school-$ased alaria control efforts are ongoing.

Recruitment
A school census of all +/+ schools included in the trial "as conducted $y trained #ersonnel and "as used as a sa #ling fra e fro "hich .5 children fro class + and :/ children fro class 5 "ere rando ly selected using rando nu $er ta$les. >e"er children "ere selected fro class + $ecause of the e=tra educational assess ents underta'en "ith these children and the feasi$ility of conducting the tests in a single day.

%ealth sur#eys
>inger #ric' $lood sa #les "ere o$tained fro all children to assess hae oglo$in concentration 1H$4 using a #orta$le hae oglo$ino eter 1He ocue, [ngelhol , S"eden4. Children "ith se!ere anae ia 1H$ C 0/ gBl4 "ere referred to the nearest health

facility for iron thera#y as #er the national guidelines. Height and "eight "ere easured and a=illary te #erature "as digitally recorded. Thic' and thin $lood s ears, #re#ared for alaria icrosco#y, "ere stained "ith .; Iie sa for :/ inutes Parasite densities "ere deter ined fro thic' $lood s ears $y counting the nu $er of ase=ual #arasites #er .// "hite $lood cells, assu ing a "hite $lood cell count of 0///B\l. A s ear "as considered negati!e after re!ie"ing +// high-#o"ered fields. Thin $lood s ears "ere re!ie"ed for s#ecies identification. T"o inde#endent icrosco#ists read the slides, "ith a third icrosco#ist resol!ing discre#ancies.

Assessments of cognition and educational achie#ement

These ha!e $een detailed else"here 1Broo'er et al. ./+/4. *n $rief, age-a##ro#riate tests of sustained attention "ere conducted in each class2 the #encil-ta# test and the code trans ission test ada#ted fro the Test of e!eryday attention for children 1TQA-Ch4 grou# 1Manly et al. +,,,4 for class + and class 5 children, res#ecti!ely. )on-!er$al reasoning "as assessed in class + $y the 8a!enGs Progressi!e Matrices tas' 18a!en et al. +,,04. A range of class-s#ecific literacy and nu eracy tests "ere conducted in indi!iduali%ed and s all-grou# settings. The tests "ere e=tensi!ely #iloted and ada#ted to the conte=t. TestFretest relia$ilities of /.6 "ere re?uired for inclusion of tests in the $attery.

Risk factors
&uring the infor ed consent #rocess, a ?uestionnaire "as ad inistered to #arentsBguardians to record household infor ation on residence, fa ily si%e, o"nershi# of #ossessions, os?uito net use $y the and their children, recent de"or ing of the child, house construction and education le!el of the #arent. >or children in class +, additional infor ation on household literacy, the language s#o'en in the household and reading #ractices "as recorded. At each school, a ?uestionnaire "as ad inistered to the head teacher to collect infor ation on school de ogra#hy, sanitation facilities, #resence of school feeding and other health #rogra es. School locations "ere a##ed using a Ilo$al Positioning Syste 1IPS4 recei!er 1eTre= Iar in Dtd., 7lathe, RS, (SA4. Qle!ation of schools "as recorded and used as a geogra#hical ar'er of distance fro the coast.

!tatistical analysis
&ata "ere dou$le-entered using custo i%ed data entry screens in Microsoft Access 1Microsoft Cor#oration, Seattle, (SA4. Consistency chec's "ere #erfor ed and all discre#ancies and ?ueries "ere !erified against the original #a#er for s. Health data "ere lin'ed $y school location and a##ed using ArcI*S ,.:.+ 1Qn!iron ental Syste s 8esearch *nstitute *nc., 8edlands, CA, (SA4. Plasmodium falciparum infection "as defined on the $asis of du#licate slide readings. Anae ia "as defined using age- and se=-corrected @H7 thresholds 1Benoist et al. .//04, "ith no correction ade for altitude. The anthro#o etric indices, %-scores of

height-for-age 1HAW4, "eight-for-age 1@AW4 and $ody ass inde=-for-age 1BM*W4, "ere calculated using the AnthroPlus soft"are for children aged 5F+, years 1@H7, .//64, assu ing a id-year age for each child $ecause of dou$ts o!er the correct date of $irth. @eight-for-age %-score "as only calculated for children aged 5F+/ years. Children "ere classified as stunted, under"eight or thin if HAW, @AW and BM*W, res#ecti!ely, "ere less than t"o standard de!iations $elo" the reference edian. Age of the children "as #ro!ided $y the sel!es and $y their #arents. Ages #ro!ided $y the children "ere used to calculate anae ia and anthro#o etric indices as they "ere considered ore relia$le. A sensiti!ity analysis using #arent-re#orted ages for all ulti!aria$le odels indicated ini al sensiti!ity. Age "as odelled as a categorical !aria$le for the P. falciparum and anae ia ris' factor analyses and as a continuous !aria$le for the attention and education analyses o"ing to the s aller age ranges o$ser!ed once stratified $y class. Household asset data "ere used to deri!e an inde= of socio-econo ic status 1SQS4, $ased on the entire trial #o#ulation. The #rinci#al co #onent analysis 1PCA4 a##roach #ro#osed $y >il er and Pritchett 1>il er Y Pritchett .//+4 "as used. Haria$les included into the PCA included o"nershi# of a $icycle, otorcycle, o$ile #hone, radio, tele!ision, as "ell as #resence of electricity, #it latrine, and $ric' and ce ent construction aterials. The first #rinci#al co #onent e=#lained :/.-; of the o!erall !aria$ility and ga!e greatest "eight to the household construction aterials follo"ed $y o"nershi# of a tele!ision. The resultant scores "ere di!ided into ?uintiles so that households could $e classified according to relati!e SQS. )o internal !alidation of the inde= "as underta'en. >inally, ele!ation 1a #ro=y for distance fro the coastline4 "as di!ided into tertiles. Analyses "ere #erfor ed using STATA !ersion ++./ 1STATA Cor#oration, College Station, TS, (SA4. The outco es of interest e=a ined "ere #re!alence of P. falciparum and of anae ia 1$inary outco es4 and scores for s#elling, nu $er identification, nu eracy, co #rehension, code trans ission and #encil-ta##ing tas's 1continuous outco es4. (ni!aria$le associations $et"een the health-related outco es and ris' factors "ere assessed using ultile!el logistic regression, accounting for school-le!el clustering 18a$e-Hes'eth Y S'rondal .//04. Haria$les de onstrating an association at the +/; significance le!el "ere su$se?uently included into a ulti!aria$le, ultile!el logistic regression odel, accounting for school-le!el clustering. Ste#"ise eli ination "as used to create the final odel using a 5; significance le!el for retention in the odel. Age and se= "ere treated as a priori ris' factors and retained in ulti!aria$le odels. A priori interactions $et"een net use "ith age and se= and $et"een school feeding and ele!ation 1distance fro the coast4 "ere in!estigated. Analysis of the cogniti!e and education outco es "as stratified $y class and focused on associations "ith P. falciparum infection and "ith anae ia, additionally accounting for age and se= as a priori ris' factors. >or the #encil-ta# assess ent of sustained attention in class + children, the analysis "as s#lit into t"o $ecause of the significant #ro#ortion of children "ho "ere disengaged and scored %ero. The #ro#ortion of children engaged in the tas' "as e=a ined $y different !aria$les using ultile!el logistic regression accounting for school-le!el clustering. >or each of the s#elling assess ents in classes + 1score /F./4 and 5 1score /F3:4T the nu eracy in classes + 1score /F./4 and 5 1score /F:04T the 8a!ens assess ent in class + 1score /F./4T the sentence co #rehension in class 5 1score

/F3/4T the code trans ission assess ent of sustained attention in class 5 children 1score /F./4T and the analysis of children "ho "ere engaged in the #encil-ta# tas' 1score +F./4, the effect of e=#lanatory !aria$les "as ?uantified $y ean differences in test #erfor ance using linear regression. Bootstra##ing "as used to account for nonnor ality of the scores, "here$y schools "ere resa #led to account for school-le!el clustering 1Qfron Y Ti$shirani +,,34. Bias-corrected confidence inter!als $ased on the $ootstra# resa #les "ere o$tained. Significant 1P C /.+4 !aria$les identified in uni!aria$le analysis "ere considered for the ulti!aria$le odel "hich e #loyed ste#"ise eli ination.

/thical considerations
The study "as a##ro!ed $y the Renya Medical 8esearch *nstitute and )ational Qthics 8e!ie" Co ittee 1SSC )o. +53:4, the Dondon School of Hygiene and Tro#ical Medicine Qthics Co ittee 155/:4, and the Har!ard (ni!ersity Co ittee on the (se of Hu an Su$Aects in 8esearch 1>+6560-+/+4. Meetings "ere held in #artici#ating schools to e=#lain the nature and #ur#ose of the trial to #arents or legal guardians, and "ritten infor ed consent "as o$tained.

Results
7f the :05/ children rando ly selected to #artici#ate in the study, .3// 1++-/ in class + and +.3/ in class 54 "ere included in the analysis 1>igure +4, "ith a ean of 30 children #er school 1range2 .-F-/4. )o syste atic differences in indi!idual and household characteristics "ere o$ser!ed $et"een included children and those children e=cluded $ecause of issing health data 1Ta$le S+, online-only4. The ean age of children in the #resent analysis "as +/.: years 1range2 5F+0 years4 and the aleBfe ale ratio "as /.,5 1Ta$le +4.

>igure + &ata flo" diagra for the education and health sur!eys conducted in school children in 5+ schools on the south coast of Renya, ./+/.

Ta$le + (ni!aria$le analysis for associations $et"een Plasmodium falciparum infection and anae ia and #otential ris' factors for $oth health outco es a ong school children in 5+ schools on the south coast of Renya, ./+/.

Plasmodium falciparum and anaemia

The o!erall #re!alence of P. falciparum "as +:./; 1,5; confidence inter!al [C*]2 0.,F +6./;4T only ++ infected children had docu ented fe!er. *nfection #re!alence !aried ar'edly $y school, ranging fro / to 65./; 1>igure .$4, "ith no infected children found in se!en schools and a #re!alence e=ceeding 3/; in three schools. 7!erall, 35.5; 1,5; C*2 3../F30.,;4 of children "ere anae ic, and +.+; 1,5; C*2 /.6F+.54 "ere se!erely anae ic. The ean hae oglo$in concentration "as ++6.5gBl 1,5; C*2 ++-.3F ++0.-4. Mar'ed heterogeneity "as also o$ser!ed in the school-le!el #re!alence of anae ia 1range2 .-.:F0/./;4 1>igure .c4.

>igure . 1a4 The location of the study site in Renya. 1$4 The geogra#hical distri$ution of Plasmodium falciparum infection in 5+ schools on the south coast of Renya, ./+/. 1c4 The geogra#hical distri$ution of anae ia 1adAusted for age and se=4 in 5+ schools on 000

Risk factors for Plasmodium falciparum infection and anaemia

The relati!e fre?uencies of indi!idual, household and school-le!el ris' factors for P. falciparum infection and anae ia are sho"n in Ta$le +. 7!erall, -..0; 1,5; C*2 50.6F -6./4 of children re#orted slee#ing under a os?uito net, $ut usage !aried ar'edly $y school 1range2 .-.3F,:.:;4. *n uni!aria$le analysis, P. falciparum infection "as significantly associated "ith $eing ale, younger age, stunting, a$sence of de"or ing, education le!el of household head, increased nu $er of #eo#le in the household, fe"er os?uito nets in the household and not slee#ing under a os?uito net. *n the ulti!aria$le odel, higher odds of P. falciparum infection "ere significantly associated "ith $eing ale, younger age grou#s, increasing nu $er of #eo#le li!ing in the childGs household and the child not slee#ing under a net 1Ta$le .4.

Ta$le . Multi!aria$le ris' factor analysis for Plasmodium falciparum infection and anae ia a ong school children in 5+ schools on the south coast of Renya, ./+/ *n uni!aria$le analysis, anae ia "as significantly associated "ith ale se=, younger age, P. falciparum infection, $eing stunted, education le!el of household head, not attending a school "ith an acti!e school feeding #rogra e and attending school at lo"er ele!ation, closer to the coast. *n ulti!aria$le analysis, increased odds of anae ia "ere significantly associated "ith P. falciparum infection, "ith the odds increasing "ith increasing #arasite density 1A78 [adAusted odds ratio], :.-0T ,5; C*2 ..+.F-.:0 P C /.//+4 for children "ith high intensity infection vs. those "ith no infection, and for children "ho "ere stunted. Significantly lo"er odds of anae ia "ere associated "ith children "ho "ere fe ale, and "ith $eing aged +/F+. years old vs. 5F, years old. The effect of a school feeding #rogra e on anae ia "as odified $y ele!ation of school 1distance fro coast4 and thus is #resented $y stratu -s#ecific odds ratios. School feeding "as associated "ith lo"er odds of anae ia in schools closest to the coast 1A78, /.3-T ,5; C*2 /..0F/.6-T P 9 /.//:4, "ith no e!idence of an association for schools #ositioned further fro the coast.

Associations with cognition and educational achie#ement

8esults fro the uni!aria$le analysis of the associations $et"een cognition and educational achie!e ent and health and other factors are #resented in online-only Ta$les S., S: and S3. 8esults fro ulti!aria$le analyses are #resented in Ta$les : 1attention and literacy assess ents4 and and33 1cogniti!e, co #rehension and nu eracy assess ents4, "hich re#ort significant associations $et"een scores and se!eral child-le!el !aria$les. *n all tas's, increasing age "as associated "ith higher scores a ong children in class +, $ut "ith lo"er scores a ong children in class 5. >or se!eral tas's, girls "ere found to ha!e lo"er scores than $oys. )either P. falciparum infection, irres#ecti!e of #arasite density, nor anae ia "as found to $e associated "ith any cogniti!e or educational outco e. *nterestingly, #oor engage ent in the attention tas' for class + "as associated "ith eating $rea'fast and attending a school "ith school feeding, and $etter s#elling #erfor ance in class 5 "as found a ong children "ho "ere classified as thin on the $asis of BM*.

Ta$le : Multi!aria$le ris' factor analysis F associations of Plasmodium falciparum infection and anae ia "ith a test of sustained attention and a test of literacy in children in classes + and 5 on the south coast of Renya, ./+/.

Ta$le 3 Multi!aria$le ris' factor analysis F associations of Plasmodium falciparum infection and anae ia "ith a test of cognition and nu eracy in children in classes + and 5 on the south coast of Renya, ./+/. A nu $er of household factors "ere also associated "ith the scores. Higher household socio-econo ic status "as associated "ith higher scores in the co #rehension tas' in class 5 and the s#elling in $oth classes. Do"er scores "ere associated "ith li!ing in a house "ith a high nu $er of children for the class 5 co #rehension tas'. Higher #arental education le!els "ere associated "ith higher scores in the class 5 co #rehension and class + nu eracy tas's. School en!iron ent and educational ad inistrati!e %ones "ere found to $e associated "ith se!eral of the tas's, "ith lo"er literacy and nu eracy scores associated "ith children learning in classroo s "ithout des's, and significantly higher s#elling and nu eracy scores in class 5 as "ell as attention and cogniti!e scores in class + found in children schooling in coastal &iani %one.

Discussion
The e!idence #resented here sho"s that in this oderate alaria trans ission setting, there is ar'ed !ariation in the #re!alence of P. falciparum, reaching 65; in so e schools. There "as also e!idence that infection is strongly associated "ith anae ia, "ith the odds higher "ith increasing density of infection. The results also sho" #otentially i #ortant !ariation in the alaria $urden $et"een the se=es and age grou#s and $y school. The scale of o$ser!ed health #ro$le s strongly su##orts the need for school health #rogra es ai ed at reducing the health $urden of alaria in school children. &es#ite this health $urden, the analysis of educational data suggested no association

$et"een current health status and achie!e ent.

easure ents of sustained attention and educational

The geogra#hical heterogeneity o$ser!ed in the #re!alence of P. falciparum infection is li'ely to reflect a co #le=ity of factors that influence !ector distri$ution and density as "ell as !ectorFhu an contact and hu an infection 1Ireen"ood +,0,4. The #rinci#al alaria !ectors in the study are Anopheles gambiae s.l. and An. funestus, "hich in our study area ha!e $een sho"n to e=hi$it strong s#atial and te #oral heterogeneity related, in #art, to !ariation in rainfall 1M$ogo et al. .//:4 and, ore recently, !ariation in os?uito net use and ty#e of household construction 1Mutu'u et al. ./++4. Hu anF !ector contact and hu an infection ay also $e influenced $y #ro=i ity to !ector $reeding sites 1Clar'e et al. .//.T Pullan et al. ./+/4 and !ariation in #ersonal #rotection easures 1Sno" et al. +,,04 and net use 1Pullan et al. ./+/4. >uture geostatistical analysis "ill in!estigate the en!iron ental correlates of the o$ser!ed !ariation in infection #atterns. Such geogra#hical heterogeneity in infection ris' has #articular i #lications for the targeting of alaria inter!entions as "ell as for the #ossi$le i #act of inter!ention 1Rleinsch idt et al. .//64. School-le!el !ariation in the #re!alence of anae ia ay reflect the o$ser!ed geogra#hical !ariation in the #re!alence of P. falciparum infection, $ut is also li'ely to $e due to differences in food a!aila$ility and the #re!alence of hel inth infection, i #ortant aetiological factors for anae ia. The #rotecti!e effect of slee#ing under a os?uito net is consistent "ith #re!ious crosssectional findings 1)oor et al. .//0T Pullan et al. ./+/4, "hilst the strong association $et"een P. falciparum infection and anae ia has $een o$ser!ed in other school-aged #o#ulations in Qast Africa 1Stolt%fus et al. +,,6T 7lsen et al. +,,0T Deenstra et al. .//3T Rou'ounari et al. .//04. The i #act of chronic P. falciparum infection on hae oglo$in le!els is attri$uted to increased red $lood cell destruction and decreased red $lood cell #roduction 1A$dalla et al. +,0/T Philli#s Y Pas!ol +,,.T Menende% et al. .///4, "ith high-density infections intensifying these #rocesses. Ho"e!er, anae ia is ultifactorial, and the findings of this study highlight additional contri$utory factors2 stunting, indicati!e of #oor nutritional inta'e for a sustained #eriod during the childhood gro"th #hase, "as associated "ith increased odds of anae ia. This nutritional relationshi# is su##orted $y the finding that at sea le!el, in the schools nearest the coast "here the soil is infertile and the cro#-gro"ing #otential is #oor, the #resence of a school feeding #rogra e at the childGs school a##ears to $e associated "ith a 5/; decrease in odds of anae ia. >e" studies to date ha!e easured the effect of school feeding on anae ia 1Lo aa et al. ./++4, although #ro!ision of iron-fortified #orridge and $iscuits and ca'es as #art of school feeding #rogra es has $een sho"n to $e associated "ith a reduction in anae ia in Renya, South Africa and Peru 1Laco$y et al. +,,0T !an StuiA!en$erg et al. +,,,T AndangGo et al. .//64. Micronutrient deficiency is co only found a ong school-aged children in alaria-ende ic areas 1Best et al. ./+/4, and infection "ith P. falciparum is $ound to further increase the stress on the hae oglo$in status in indi!iduals "ho are already anae ic 1To#ley +,-0T )ussen$latt Y Se $a .//.4. The lac' of o$ser!ed association $et"een health status and sustained attention and education ay not necessarily reflect an a$sence of effect of alaria on education. >irst,

asy #to atic P. falciparum can #ersist for o!er three onths and as children ay $e constantly re-infected, it is #ro$a$le that infection has a cu ulati!e effect on cogniti!e function o!er an e=tended #eriod of ti e. Thus, the single ti e #oint of our crosssectional design ay not sufficiently ca#ture the effects of recurrent, chronic infection o!er an e=tended #eriod 1Lu'es et al. .//.T Thuillie% ./+/4. Second, the cross-sectional design eant that "e "ere una$le to ca#ture infor ation on #ast clinical attac's, "hich ha!e #re!iously $een sho"n to $e related to #oor educational achie!e ent 1>ernando et al. .//:$4. Third, alaria is Aust one of any contri$uting factors to #oorer cogniti!e and educational #erfor ance, "ith socio-econo ic status and the educational en!iron ent of childrenGs ho es #laying an i #ortant role, as highlighted in the #resent study. The association found in $oth classes $et"een higher literacy and attention scores and indicators of SQS is su##orted $y #re!ious findings "here SQS has $een found to $e strongly related to #sycho etric and education test scores in school children 1Lu'es et al. .//.4. *ncreased SQS is li'ely to $e associated "ith increased sti ulation, increased access to reading aterial and o"nershi# of school-related aterials, factors #re!iously sho"n to $e associated "ith increased acade ic achie!e ent 1@al'er et al. +,,04. This is su##orted $y the fact that increased education of household heads and increased literacy "ere associated "ith i #ro!ed #erfor ance in co #rehension in class 5 and nu eracy in class +. As e=#ected, there "as a #ositi!e relationshi# $et"een age and assess ent scores for children in class +. By contrast, increasing age "as associated "ith lo"er scores in assess ents in class 5. This see ingly contradictory o$ser!ation could $e attri$uted to the older children in class 5 ha!ing re#eated earlier years $ecause of #oor educational #erfor ance, as is fre?uently seen in lo"-inco e countries 1Heyne an Y Do=ley +,0:T >ehrler et al. .//,4. Also, #oor children enrol in school later 1>enti an et al. +,,,4. The #oorer scores in attention 1class +4 and literacy 1class 54 assess ents o$ser!ed in fe ales are consistent "ith the recogni%ed dis#arity $et"een se=es in access to education and su##ort in any lo"-inco e settings 1Lu'es et al. .//04. The strong !ariation in educational #erfor ance $y ad inistrati!e di!ision is an indicator that there are as#ects of the school di!isional organi%ation and anage ent, such as the a!aila$ility of $oo's, the teacherFchild contact ti e and the ?uality of teaching, "hich ay influence educational outco es 1Heyne an Y Do=ley +,0:T Boissiere .//3T Bharga!a et al. .//54. The i #ortance of the school en!iron ent is further de onstrated $y the lo"er literacy and nu eracy scores o$ser!ed in class + children "ho learn in classroo s "ith no des's. *n conclusion, "e ha!e found a strong geogra#hical !ariation in the #re!alence of P. falciparum infection, underscoring the need for geogra#hical targeting of alaria inter!entions. The o$ser!ed strong association $et"een infection and anae ia #ro!ides e!idence of the, #resu a$ly cu ulati!e, negati!e effects of asy #to atic P. falciparum infection on the hae oglo$in status of school children. The ongoing trial of *ST "ill #ro!ide an indication of ho" uch of this effect can $e re!ersed and "hether alaria control can also i #ro!e the cogniti!e and educational #erfor ance of children in the current setting. The trial "ill also hel# understand ho" uch of the o$ser!ed #oor #erfor ance is attri$uted to health factors and ho" uch is attri$uted to teaching ?uality and household factors.

Acknowledgments
@e "ould li'e to than' the school children, school teachers, district education officials and the district health anage ent tea for their su##ort, and Tansy Qd"ards for statistical ad!ice. The "or' is funded $y the *nternational *nitiati!e for * #act Q!aluation and the @orld Ban', through the )or"egian Qducation Trust >und, the ulti-donor Qducation Progra e &e!elo# ent >und 1QP&>4 and the S#anish * #act Q!aluation >und. The results re#orted here contri$uted to the @orld Ban' Africa Progra e for Qducation * #act Q!aluation and the Malaria * #act Q!aluation Progra e. Additional funding is #ro!ided $y the @ellco e Trust through a Masters Training >ello"shi# to Ieorge 7'ello 1/,.6-54 and a 8esearch Career &e!elo# ent >ello"shi# to Si on Broo'er 1/0+-6:4.

!upporting nformation
Additional Su##orting *nfor ation ay $e found in the online !ersion of this article2 )able !1 Characteristics of study children "ith health data only or health and education data 1included in analysis4 and study children "ith education data only 1e=cluded fro analysis4. Clic' here to !ie".1+:R, doc=4 )able !2 (ni!aria$le analyses for associations of Plasmodium falciparum infection and anae ia and additional #otential ris' factors "ith a test of cognition 18a!ens test4, nu eracy 1)u $er *dentification test4 and a test of literacy 1S#elling test4 in class + children on the south coast of Renya, ./+/. Clic' here to !ie".1.:R, doc=4 )able !30 (ni!aria$le analyses for associations of Plasmodium falciparum infection and anae ia and additional #otential ris' factors "ith a test of sustained attention 1#encil ta##ing4 in class + children on the south coast of Renya, ./+/. Clic' here to !ie".1./R, doc=4 )able !40 (ni!aria$le analyses for associations of Plasmodium falciparum infection and anae ia and additional #otential ris' factors "ith a test of cognition 1Silly Sentences4, nu eracy 1@ritten )u eracy test4, literacy 1S#elling test4 and sustained attention 1Code Trans ission test4 in class 5 children on the south coast of Renya, ./+/. Clic' here to !ie".1..R, doc=4

Please note2 @iley-Blac'"ell are not res#onsi$le for the content or functionality of any su##orting aterials su##lied $y the authors. Any ?ueries 1other than issing aterial4 should $e directed to the corres#onding author for the article.

Article information
Tro# Med *nt Health. ./+. MayT +61542 5:.F53,. Pu$lished online ./+. A#ril +,. doi2 +/.++++BA.+:-5-:+5-../+../.,6+.= PMC*&2 PMC:5/-6:. Ratherine Q Halliday,+ Peris RaranAa,. Qli%a$eth D Turner,: Ieorge 7'ello,. Ria $o )Aagi,3 Margaret M &u$ec',5 Qli%a$eth Allen,: Matthe" CH Lu'es,- and Si on L Broo'er+,. + >aculty of *nfectious and Tro#ical &iseases, Dondon School of Hygiene and Tro#ical Medicine, (R . Malaria Pu$lic Health and Q#ide iology Irou#, Renya Medical 8esearch *nstitute@ellco e Trust Colla$orati!e Progra e, )airo$i, Renya : >aculty of Q#ide iology and Pu$lic Health, Dondon School of Hygiene and Tro#ical Medicine, (R 3 &i!ision of Malaria Control, Ministry of Pu$lic Health and Sanitation, )airo$i, Renya 5 &e#art ent of Teacher Qducation, College of Charleston, SC, (SA Iraduate School of Qducation, Har!ard (ni!ersity, Ca $ridge, MA, (SA Corresponding Author Katherine /0 %alliday, >aculty of *nfectious and Tro#ical &iseases, Dondon School of Hygiene and Tro#ical Medicine, Re##el Street, Dondon @C+Q 6HT, (R. Tel.2 ]33 1/4 ./6 ,.6 .-+3T >a=2 ]33 1/4 ./6 ,.6 .,+0T Q- ail2 'atherine.hallidayBatBlsht .ac.u' 8e-use of this article is #er itted in accordance "ith the Ter s and Conditions set out at htt#2BB"ileyonlineli$rary.co Bonlineo#en^7nline7#en_Ter s Co#yright U ./+. Blac'"ell Pu$lishing Dtd 8e-use of this article is #er itted in accordance "ith the Creati!e Co ons &eed, Attri$ution ..5, "hich does not #er it co ercial e=#loitation. This article has $een cited $y other articles in PMC. Articles fro @iley-Blac'"ell 7nline 7#en are #ro!ided here courtesy of 5ileyBlackwell, 6ohn 5iley 7 !ons

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Laco$y Q8, Cueto S, Pollitt Q. @hen science and #olitics listen to each other2 good #ros#ects fro a ne" school $rea'fast #rogra in Peru. A erican Lournal of Clinical )utrition. +,,0T-626,5sF6,6s. [Pu$Med] Lo aa DH, Mc&onnell Q, Pro$art C. School feeding #rogra s in de!elo#ing countries2 i #acts on childrenGs health and educational outco es. )utrition 8e!ie". ./++T-,20:F,0. [Pu$Med] Lu'es MCH, )o'es CA, Alcoc' RL, et al. Hea!y schistoso iasis associated "ith #oor short-ter e ory and slo"er reaction ti es in Tan%anian schoolchildren. Tro#ical Medicine Y *nternational Health. .//.T62+/3F++6. [Pu$Med] Lu'es MC, Pinder M, Irigoren'o QD, et al. Dong-ter i #act of alaria che o#ro#hyla=is on cogniti!e a$ilities and educational attain ent2 follo"-u# of a controlled trial. PDoS Clinical Trials. .//-T+2e+,. [PMC free article] [Pu$Med] Lu'es MCH, &ra'e D, Bundy &AP. School Health, )utrition and Qducation for All. @allingford, (R2 CAB* Pu$lishingT .//0. Rihara M, Carter LA, )e"ton C8. The effect of Plasmodium falciparum on cognition2 a syste atic re!ie". Tro#ical Medicine Y *nternational Health. .//-T++2:0-F:,6. [Pu$Med] Ri $i HR, A"ah )@, )da u'ong RL, M$uh LH. Malaria infection and its conse?uences in school children. Qast African Medical Lournal. .//5T0.2,.F,6. [Pu$Med] Rleinsch idt *, Torre% M, Sch"a$e C, et al. >actors influencing the effecti!eness of alaria control in Bio'o *sland, e?uatorial Iuinea. A erican Lournal of Tro#ical Medicine and Hygiene. .//6T6-2+/.6F+/:.. [PMC free article] [Pu$Med] Rorenro # QD, Ar strong-Schellen$erg L8, @illia s BI, )ahlen BD, Sno" 8@. * #act of alaria control on childhood anae ia in Africa F a ?uantitati!e re!ie". Tro#ical Medicine and *nternational Health. .//3T,2+/5/F+/-5. [Pu$Med] Rou'ounari A, Qsta $ale BB, )Aagi LR, et al. 8elationshi#s $et"een anae ia and #arasitic infections in Renyan schoolchildren2 a Bayesian hierarchical odelling a##roach. *nternational Lournal for Parasitology. .//0T:02+--:F+-6+. [PMC free article] [Pu$Med] Deenstra T, Rariu'i SR, Rurtis L&, 7loo AL, Rager PA, ter Ruile >7. Pre!alence and se!erity of ane ia and iron deficiency2 cross-sectional studies in adolescent schoolgirls in "estern Renya. Quro#ean Lournal of Clinical )utrition. .//3T502-0+F-,+. [Pu$Med] Manly T, 8o$ertson *H, Anderson H, )i o-S ith *. Test of Q!eryday Attention for Children2 TQA-Ch. Bury St Qd unds, (R2 Tha es Halley Test Co #anyT +,,,. M$ogo CM, M"angangi LM, )%o!u L, et al. S#atial and te #oral heterogeneity of Ano#heles os?uitoes and Plasmodium falciparum trans ission along the Renyan coast. A erican Lournal of Tro#ical Medicine and Hygiene. .//:T-026:3F63.. [Pu$Med] Menende% C, >le ing A>, Alonso PD. Malaria-related anae ia. Parasitology Today. .///T+-23-,F36-. [Pu$Med]

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!an StuiA!en$erg MQ, R!als!ig L&, >a$er M, Rruger M, Renoyer &I, Benade AL. Qffect of iron-, iodine-, and $eta-carotene-fortified $iscuits on the icronutrient status of #ri ary school children2 a rando i%ed controlled trial. A erican Lournal of Clinical )utrition. +,,,T-,23,6F5/:. [Pu$Med] Hitor-Sil!a S, 8eyes-Decca 8C, Pinheiro T8A, Dacerda MHI. Malaria is associated "ith #oor school #erfor ance in an ende ic area of the Bra%ilian A a%on. Malaria Lournal. .//,T02.:/. [PMC free article] [Pu$Med] @al'er SP, Irantha -McIregor SM, Hi es LH, @illia s S, &uff QM. School #erfor ance in adolescent La aican girls2 associations "ith health, social and $eha!ioural characteristics, and ris' factors for dro#out. Lournal of Adolescence. +,,0T.+2+/,F+... [Pu$Med] @H7. Anthro#lus2 Iro"th 8eference 5F+, years [7nline] Iene!a2 @H7T .//6. htt#2BB"""."ho.intBgro"threfBtoolsBenB

3
The Lournal of urology Author Manuscri#t )*H Pu$lic Access

/nuresis Associated with !leep Disordered Breathing in Children with !ickle Cell Anemia
Iloria C. Deh ann, Teal 8. Bell, [...], and Michael 8. &eBaun Additional article infor ation

Abstract
+urpose
Qnuresis and slee# disordered $reathing are co on a ong children "ith sic'le cell ane ia. @e e!aluated "hether enuresis is associated "ith slee# disordered $reathing in children "ith sic'le cell ane ia.

Materials and Methods

Baseline data "ere used fro a ulticenter #ros#ecti!e cohort study of ..+ unselected children "ith sic'le cell ane ia. A ?uestionnaire "as used to e!aluate, $y #arental re#ort during the #re!ious onth, the #resence of enuresis and its se!erity. 7!ernight

#olyso nogra#hy "as used to deter ine the #resence of slee# disordered $reathing $y the nu $er of o$structi!e a#neas andBor hy#o#neas #er hour of slee#. Dogistic and ordinal regression odels "ere used to e!aluate the association of slee# disordered $reathing and enuresis.

Results
The ean age of #artici#ants "as +/.+ years 1 edian +/./, range 3 to +,4. Qnuresis occurred in :0.,; of #artici#ants and "as significantly associated "ith an o$structi!e a#nea-hy#o#nea inde= of . or ore #er hour after adAusting for age and gender 178 ..+,T ,5; C* +./,, 3.3/T # 9 /./:4. Qnuresis se!erity "as associated "ith o$structi!e a#neas and hy#o#neas "ith :; or ore desaturation . or ore ti es #er hour "ith and "ithout ha$itual snoring 178 :..:T ,5; C* +.5:, -.0+T # 9 /.//+ and 78 ../6T ,5; C* +./,, :.,.T # 9 /./:, res#ecti!ely4.

Conclusions
*n this unselected grou# of children "ith sic'le cell ane ia, slee# disordered $reathing "as associated "ith enuresis. 8esults of this study su##ort that children "ith sic'le cell ane ia "ho #resent "ith enuresis should $e e!aluated $y a #ul onologist for slee# disordered $reathing. Keywords: enuresis, slee#, ane ia, sic'le cell Qnuresis is a co on and #er!asi!e #ro$le in children "ith sic'le cell ane ia, affecting ./; to -,; of children age 5 to +0 years+F5 co #ared to less than +; to +5; of si ilar age children in the general #o#ulation.-,6 >urther ore, enuresis #ersists a ong young adults "ith SCA, affecting a##ro=i ately ,; of indi!iduals older than age +0 years.5 Slee# disordered $reathing, s#ecifically ha$itual snoring and o$structi!e slee# a#neahy#o#nea syndro e, has $een #re!iously in!estigated as a ris' factor for enuresis in nonSCA children.0F+3 Although definitions of ha$itual snoring, o$structi!e slee# a#neahy#o#nea syndro e, enuresis and age ranges ha!e !aried, a study of 5 to +3-year-olds 1after adAusting for age and gender4 de onstrated that enuresis, defined as incontinence "hile aslee# at least + night a "ee', "as :.53 ti es ore #re!alent a ong those "ith ha$itual snoring 1 ore than : nights #er "ee'4 than a ong nonsnorers., Studies e!aluating the association $et"een enuresis and ha$itual snoring, as a #ro=y for S&B, a ong children "ithout SCA ha!e sho"n that enuresis "as ore #re!alent a ong snorers than nonsnorers 1.-.,; !s ++.-;T # C/.////+T 78 ..6,T ,5; C* ..5/, :.+:4.+/ Ho"e!er, the degree of S&B "as not associated "ith the #resence of enuresis. *n select case series of children "ith SCA referred for #olyso nogra#hy due to clinical sy #to s of S&B andBor a$nor al #ulse o=i etry, #re!alence of S&B "as :5; to 6,;.+5,+- To date, these findings ha!e not $een confir ed in an unselected grou# of children "ith SCA. To our 'no"ledge no association $et"een enuresis and S&B in sic'le

cell ane ia, diagnosed using #olyso nogra#hy, has $een analy%ed in detail. Ho"e!er, a recent study using the CSHV 1ChildrenMs Slee# Ha$its Vuestionnaire4 suggests that sy #to atic slee# disordered $reathing is significantly correlated "ith enuresis in children "ith SCA.+6 @e tested the hy#othesis that the #re!alence and se!erity of enuresis are associated "ith S&B in children "ith sic'le cell ane ia "ho are not s#ecifically selected due to sus#icion of S&B.

MA)/R A8! A9D M/)%"D!

!tudy Design
The SAC 1Sic'le Cell Ane ia Slee# and Asth a Cohort4 study 1+8/+HD/6,,:6-/+4, a##ro!ed $y the institutional re!ie" $oard at @ashington (ni!ersity School of Medicine, Case @estern 8eser!e and (nited Ringdo )ational 8esearch Qthics Ser!ice, is a ulticenter cohort study designed to assess asth a and nocturnal o=ygen desaturation e#isodes in children "ith SCA. Baseline infor ation included #hysical e=a ination, CSHV and o!ernight PSI. SAC #artici#ants "ere recruited fro #ediatric he atology clinics in St. Douis, MissouriT Cle!eland, 7hio and Dondon, Qngland fro Lune +, .//- through &ece $er :+, .//,. Qligi$le children "ere $et"een 3 to +0 years old at enroll ent, regularly follo"ed in a he atology clinic, and "ith #arental consent. Children "ere e=cluded fro study if diagnosed "ith H*H infection, chronic lung disease, heart disease or conditions #redis#osing the to S&B. Q=clusion criteria "ere ha!ing recei!ed chronic $lood transfusion thera#yT #artici#ation in clinical trials in!ol!ing $lood transfusions, o=ygen or hydro=yurea inter!entions and those dee ed nonco #liant $y the he atologist or #ediatrician.

+olysomnography
All sites used identical slee# ac?uisition syste s 1Q $la )-3///, Broo field, Colorado4 and sensors. &ata collection #rocedures follo"ed current standards for PSI in children "ith the e=clusion of car$on dio=ide easure ents.+0 Slee# channel easure ents included #ulse o=i etry "ith recordings of nu eric and #lethys ogra#h "a!efor s using a .-second a!eraging ode 1Masi o 8adicalZ4, airflo" $y oronasal ther ocou#le and nasal cannula 1Pro-Tech Ser!ices, Mu'ilteo, @ashington4, heart rate $y electrocardiogra#hy channel "ith a odified :-lead #recordial #lace ent, chest and a$do inal "all acti!ity easured $y inducti!e #lethys ogra#hy "ith noncali$rated su signal, leg o!e ents $y electro yogra#hy, snoring $y icro#hone 1&y edi=4, and $ody #osition using ercury gauge. PSI "as #erfor ed during a single night "ith studies co encing at the childMs usual $edti e and ending at s#ontaneous "a'ing or as late as 62// a .

Definitions

Qnuresis history "as assessed on the night of PSI using a odified CSHV.+, Parents ans"ered JHo" any ti es did the child "et the $ed in the #re!ious onthXK Qnuresis "as defined as at least + $ed"etting e#isode in the last onth. Se!erity "as descri$ed as no enuresis e#isodes, ild 1less than : e#isodes "ee'ly4 or se!ere 1: or ore e#isodes #er "ee'4. @e chose this grou#ing a #riori $ecause it "as $elie!ed that #arents "ould $e a$le to accurately recollect and distinguish a ong no, ild and se!ere enuresis. Ha$itual snoring "as also assessed using the slee# ?uestionnaire $y res#onse to, JHo" any ti es did your child snore in the #re!ious onthXK Ha$itual snoring "as defined dichoto ously as those "ho re#orted snoring : or ore nights #er "ee'. S&B "as defined as the occurrence of . or ore e!ents #er hour of o$structi!e a#neas 1including i=ed a#neas4 or hy#o#neas "ith :; or ore o=ygen desaturation 17AH*: a .4. Central a#neas "ere not included. 8es#iratory e!ent scoring "as $ased on the A erican Acade y of Slee# Medicine Manual for scoring o$structi!e res#iratory e!ents in children "ith inor odifications.+0 Hy#o#neas "ere defined as decreases in nasal #ressure or oronasal flo" of at least 5/; associated "ith a corres#onding decrease in arterial o=ygen saturation of :; or ore fro $aseline. *f a direct airflo" signal "as not a!aila$le, then hy#o#neas "ere defined as a 5/; reduction of the su signal fro the res#iratory inductance #lethys ogra#hy $ands associated "ith a desaturation../ Hy#o#neas associated only "ith arousals "ere not scored. Children "ith 7AH*: a. "ere further characteri%ed in ter s of the #resence or a$sence of ha$itual snoring.

!tatistical Analysis
Means and standard de!iations "ere co #uted for continuous !aria$les. >re?uencies and #ercentages "ere co #uted for categorical !aria$les. 7ne-"ay A)7HA and chi-s?uare tests "ere conducted for continuous and categorical co!ariates, res#ecti!ely. The Rrus'al-@allis test "as used for 7AH*: as this !aria$le "as #ositi!ely s'e"ed. Co!ariates included age, gender, history of adenotonsillecto y, study center and BM* $ased on gender, ethnicity and age #ercentile according to Centers for &isease Control and Pre!ention gro"th charts..+ Dogistic regression analysis, "ith the de#endent !aria$le $eing the #resence or a$sence of enuresis, "as used to e=a ine "hether ha$itual snoring and S&B "ere ris' factors for at least + e#isode of enuresis in the last onth. Assu #tions including a$sence of ulticollinearity "ere et. Bac'"ards eli ination odeling assessed for effect odification and confounding of #otential co!ariates. Potential confounders included age, gender, BM* #ercentile, history of adenoidecto y or tonsillecto y, use of hydro=yurea in the last : years, and history of asth a diagnosis. Potential effect odification due to gender and center "as e!aluated using res#ecti!e interaction ter s in the odel. Potential co!ariates "ere assessed using a @ald chi-s?uare test at a significance le!el of b 9 /.+ and statistically significant co!ariates "ere included in the final odel. Dogistic regression analysis "as re#eated, defining enuresis as se!ere 1: or ore e#isodes #er "ee' in the last onth4.

After the association of enuresis and S&B "as e!aluated, ordinal regression analysis "as used to deter ine if enuresis se!erity 1no enuresis, ild and se!ere4 "as associated "ith ha$itual snoring and S&B. Three ordinal regression odels "ere used to e=a ine "hether +4 ha$itual snoring, .4 S&B "ithout ha$itual snoring and :4 S&B "ith ha$itual snoring "ere significant ris' factors for the fre?uency of enuresis. The #arallel lines assu #tion "as et for all odels, that is ha$itual snoring 1# 9 /.+.4, S&B "ithout ha$itual snoring 1# 9 /.+:4 and S&B "ith ha$itual snoring 1# 9 /./-4. The #ro#ortional odds assu #tion "as et "ith a score test for each odel 1# E/./54. Model fit "as e!aluated using the li'elihood ratio test 1# C/./+4. A $ac'"ards eli ination ethod "ith #redictors entered "ith # C/.+ assessed for effect odification and confounding effects as #re!iously stated. The ordinal regression odels "ere then used to #ro!ide crude and adAusted 78 and corres#onding ,5; C*. &ata "ere analy%ed using PAS@Z Statistics +0./ and SASZ ,...

R/!'8)!
Demographics and +atient Characteristics
A total of 3.3 children "ere a##roached to #artici#ate in this #ros#ecti!e o$ser!ational study, of "ho +3- declined. 7f the .-3 #atients "ho con-sentedBassented to #artici#ate, +0 children had he oglo$in SC and "ere e=cluded fro this analysis. 7f the .3enrolled #artici#ants, .5 "ere e=cluded due to an unacce#ta$le PSI study 1+64 or lac' of res#onse fro caregi!ers regarding $ed"etting or snoring 104. A total of ..+ children had a confir ed diagnosis of he oglo$in SS or $eta thalasse ia 1he oglo$in Sc4, and co #leted the slee# ?uestionnaire and a PSI of acce#ta$le ?uality. Co #ared to children e=cluded fro the analysis 1.54, #artici#ants "ere not significantly different in age, gender, BM* #ercentile, history of adenotonsillecto y, ha$itual snoring and S&B. Mean age of the study cohort "as +/.+ N 3.. years 1 edian +/./, range 3 to +,4 "ith 3,.:; ale 1ta$le +4. A!erage BM* #ercentile "as 5/.+; N .,.,; 1 edian 3,.-, *V8 5+.54. *n the cohort +-.:; had #re!iously undergone adenotonsillecto y due to a #re!ious diagnosis of S&B.

Ta$le + &e ogra#hic and clinical characteristics

+re#alence of /nuresis, %abitual !noring and !DB

Qnuresis "as co on "ith :0.,; of #artici#ants ha!ing at least + $ed"etting e#isode in the onth $efore PSI, occurring in 5-.3; of 3 to --year-olds 1:+ of 554, -:./; of 6 to ,-year-olds 1., of 3-4 and .+.6; of children at least +/ years old 1.- of +./4. A ong the #artici#ants +5.:; 1:34 had ild enuresis and .:.-; 15.4 had se!ere enuresis 1ta$le +4. 7AH*: a. "ith and "ithout ha$itual snoring, and ha$itual snoring alone, "ere also co on, occurring in +5.3;, .:.5; and ::.5; of #artici#ants, res#ecti!ely. A ong ha$itual snorers :3.6; had enuresis "hile ::.6; of children "ithout S&B 1"ith and "ithout ha$itual snoring4 had enuresis. Age and gender "ere significantly different a ong children "ith ild, se!ere, or no enuresis 1# C/.//+4. Co #ared to children "ithout enuresis those "ith se!ere enuresis "ere younger and a greater #ro#ortion "as ale. BM* #ercentile 178 +./T ,5; C* /.,,, +./+T # 9 /.,+4, #re!ious adenoidecto y or tonsillecto y 178 /.55T ,5; C* /..5, +..+T # 9 /.+34, use of hydro=yurea in the last : years 178 /.:-T ,5; C* /./6, +.63T # 9 /../4 and asth a diagnosis 178 +.+.T ,5; C* /.-3, +.,3T # 9 /.6/4 did not differ significantly a ong children "ith se!ere, ild or no enuresis. A##ro=i ately a third of children 1:0.5;, ./ of 5.4 "ith se!ere enuresis had 7AH*: a.. *nterestingly ore than a third 1:3.-;, +0 of 5.4 of children "ith S&B "ere not re#orted as ha$itual snorers.

/nuresis Associated with !DB

After adAusting for age and gender, the #resence of enuresis "as associated "ith 7AH*: a. 178 ..+,T ,5; C* +./,, 3.3/T # 9 /./:, ta$le .4. A si ilar association "ith 7AH*: a. "as noted in crude and adAusted odels a ong those "ith se!ere enuresis, defined as : or ore e#isodes "ee'ly in the last onth 1adAusted 78 ...-T ,5; C* +./,, 3.6/T # 9 /./:4.

Ta$le . Multi!aria$le logistic regression descri$ing association of S&B and enuresis *n : se#arate ordinal regression odels enuresis se!erity 1no enuresis, ild and se!ere4 "as significantly associated "ith +4 ha$itual snoring, .4 7AH*: a. "ithout ha$itual snoring and :4 7AH*: a. "ith ha$itual snoring 1ta$le :4. The association of ha$itual snoring alone and se!ere enuresis a ong children "ith SCA "as statistically significant after adAusting for age and gender 178 +.0:T ,5; C* +./., :..,T # 9 /./3:4. Si ilarly for children "ith 7AH*: a. "ith and "ithout ha$itual snoring, the adAusted 78s of se!ere enuresis "ere significant 178 :..:T ,5; C* +.5:, -.0+T # 9 /.//. and 78 ../6T ,5; C* +./,, :.,.T # 9 /./.5, res#ecti!ely4.

Ta$le : Q!aluation of ha$itual snoring, and S&B "ith and "ithout ha$itual snoring as ris' factors for se!ere enuresis

D !C'!! "9
A ong children "ith SCA, enuresis is co on, and a cause for significant #sychosocial 3,.. #ro$le s and decreased ?uality of life. *n SCA #olyuria due to renal concentrating defects li'ely contri$utes to the high rate of enuresis, $ut other factors ay also $e i #ortant. 7ur data #ro!ide su##ort for the hy#otheses that the #re!alence as "ell as the se!erity of enuresis are associated "ith slee# disordered $reathing in children "ith SCA. This study de onstrates that ha$itual snoring and S&B "ith and "ithout ha$itual snoring are associated "ith enuresis in children "ith SCA, consistent "ith the findings of studies conducted in the general #ediatric #o#ulation.+/,++,+3 *n this study the #re!alence of enuresis in children "ith SCA "ithout slee# disordered $reathing "as higher than that in the general #ediatric #o#ulation. >uture studies can $e done to e!aluate "hether children "ith SCA "ithout slee# disordered $reathing are at increased ris' for enuresis co #ared to historical controls. To our 'no"ledge this is the first cross-sectional study of an unselected cohort of children "ith SCA "ho "ere e!aluated for snoring, S&B "ith and "ithout snoring, and enuresis. Although a history of ha$itual snoring ay alert to the #ossi$ility that a child "ith SCA and enuresis ay ha!e S&B as a #otentially odifia$le cause, a su$stantial #ro#ortion of children "ith SCA and enuresis in this cohort had S&B "ithout ha$itual snoring. Thus, an i #ortant research #riority is to deter ine "hether S&B "ithout ha$itual snoring is a odifia$le cause of enuresis in those "ith and "ithout SCA. >or children "ith SCA and enuresis the results of this study should #ro #t clinicians to increase sur!eillance for S&B. *n a school-age child "ith SCA, enuresis and a history of snoring, one ust strongly consider a ore for al assess ent $y a slee# s#ecialist or #ul onologist. *f S&B is found and the child has significant adenotonsillar hy#ertro#hy, then adenotonsillecto y "ould $e the ne=t line of thera#y. .: Pre!ious studies in the general #ediatric #o#ulation ha!e sho"n reduction of enuresis after adenotonsillecto y..3,.5 Although history of adenotonsillecto y did not a##ear to significantly reduce enuresis in this cohort, the sa #le si%e "as s all and #oint esti ates had "ide confidence inter!als. There is contro!ersy regarding "hether this surgery is an efficacious treat ent for enuresis as a recent #ros#ecti!e controlled study found no association $et"een tonsillar hy#ertro#hy and urinary incontinence $efore or any change in enuresis after tonsil-lecto y..- >urther studies e!aluating the effect of edical and

surgical anage ent strategies for S&B on enuresis, in #arallel "ith the effect on PSI, are "arranted..6 This study had li itations. @e did not #erfor a for al analysis differentiating #atients "ith #ri ary and secondary enuresis 1#re!iously dry #eriod of at least - onths4, although a aAority of children "ith SCA are e=#ected to ha!e secondary enuresis. This study also did not differentiate $et"een onosy #to atic and non onosy #to atic enuresis 1enuresis "ith lo"er urinary tract dysfunction4. &es#ite $eing the largest study of an unselected cohort of children "ith sic'le cell ane ia "ho under"ent PSI, our sa #le si%e #recluded a eaningful su$-grou# analysis 1ie children older than 5 years4 as it "as not #lanned a #riori and the #ri ary hy#othesis of this study "as to e!aluate "hether enuresis "as associated "ith S&B. >urther e=#loration is "arranted to deter ine "hether high ris' grou#s can $e identified "ith a stronger association $et"een enuresis and S&B, "hich "ould facilitate the identification of those re?uiring PSI. Another li itation in this study "as the use of cross-sectional analyses of the SAC study cohort rather than longitudinal analysis, li iting strong inferences a$out causality. &es#ite these li itations, the #atterns of association $et"een enuresis and ha$itual snoring as "ell as S&B "ith and "ithout ha$itual snoring "ere consistent.

C"9C8'! "9!
*n su ary, "e ha!e #ro!ided e!idence that a child "ith SCA "ho anifests "ith enuresis should $e considered at significant ris' for S&B e!en in the a$sence of ha$itual snoring. >urther research is needed to confir this association and to e=#lore targeted treat ent o#tions s#ecific to slee# disordered $reathing to decrease enuresis in children "ith SCA.

ACK9"58/D:M/9)!
*rene 8o$erts, Anne Yardu ian, Marilyn 8o$erts-Hare"ood, Sin%iana Seicean and (rsula Lohnson enrolled #atients in this study. Du'e Iood#aster also #ro!ided assistance. Study recei!ed institutional re!ie" $oard a##ro!al. Su##orted $y the )ational Heart, Dung, and Blood *nstitute 8/+ HD/6,,:6 1M8&, >LR, CD8, 8CS4, Irant (D+ 88/.3,0, fro the )ational Center for 8esearch 8esources 1CD84 and the Burroughs @ellco e >oundation 1M8&4. The contents are solely the res#onsi$ility of the authors and do not necessarily re#resent the official !ie" of the )ational Center for 8esearch 8esources or the )ational *nstitutes of Health.

Abbre#iations and Acronyms

BM*

$ody 7AH*:

ass inde=

o$structi!e a#nea-hy#o#nea inde= at :; desaturation 7AH*: a. o$structi!e a#neas and hy#o#neas "ith :; or ore desaturation . or #er hour PSI #olyso nogra#hy SCA sic'le cell ane ia S&B slee# disordered $reathing

ore ti es

Article information
L (rol. Author anuscri#tT a!aila$le in PMC ./+: Luly .5. Pu$lished in final edited for as2 L (rol. ./+. 7cto$erT +0013 /42 +56.F+56-. Pu$lished online ./+. August +,. doi2 +/.+/+-BA.Auro../+../../.+ PMC*&2 PMC:6..0,)*HMS*&2 )*HMS3,.-,6 Iloria C. Deh ann, Teal 8. Bell, >enella L. Rir'ha , Lohanna C. Ia!la', Te'eda >. >erguson, 8o$ert C. Strun', Paul Austin,d Carol D. 8osen, Melanie L. Marshall, 7lu @il'ey, Mar' L. 8odeghier, Lohn 7. @arner, and Michael 8. &eBaune &e#art ents of Pediatrics 1ICD, 8CS4 and Surgery, &i!ision of (rology 1PA4, @ashington (ni!ersity School of Medicine, and &e#art ent of Q#ide iology, Saint Douis (ni!ersity School of Pu$lic Health 1T8B, T>>4, St. Douis, MissouriT (ni!ersity College Dondon *nstitute of Child Health 1>LR, LCI, MLM4, )orth Middlese= (ni!ersity Hos#ital 17@4, and Bio edical Centre, * #erial College and * #erial College Healthcare )HS Trust 1L7@4, Dondon, (nited Ringdo T &e#art ent of Pediatrics, &i!ision of Pediatric Pul onology, Case @estern 8eser!e (ni!ersity, Cle!eland, 7hio 1CD84T Chicago, *llinois 1ML84T and &e#art ent of Pediatrics, Hander$ilt (ni!ersity School of Medicine and Monroe Carell Lr. ChildrenMs Hos#ital at Hander$ilt, )ash!ille, Tennessee 1M8&4 d >inancial interest andBor other relationshi# "ith Allergan, >erring and @arner-Chilcott. e Corres#ondence2 &e#art ent of Pediatrics, Hander$ilt (ni!ersity School of Medicine and Monroe Carell Lr. ChildrenMs Hos#ital at Hander$ilt, )ash!ille, Tennessee :6.:. 1tele#hone2 -+5-:..-036+T >AS2 -+5-,:---05.T Q ail2 .de$aunBatB!ander$ilt.edu4. Co#yright notice and &isclai er The #u$lisherMs final edited !ersion of this article is a!aila$le at L (rol

R/;/R/9C/!
+. Suster I, 7s'i >A. Qnuresis in sic'le cell ane ia. A [Pu$Med] L &is Child. +,-6T++:2:++.

.. R"a' RL, Scott 8B, >erguson A&. Studies in sic'le-cell ane ia. SSS*H. 7$ser!ations on enuresis in childhood and nocturia in adults. Clin Pediatr 1Phila4 +,-,T02:33. [Pu$Med] :. )oll LB, )e" an AL, Iross S. Qnuresis and nocturia in sic'le cell disease. L Pediatr. +,-6T6/2,-5. [Pu$Med] 3. Bara'at DP, S ith-@hitley R, Schul an S, et al. )octurnal enuresis in #ediatric sic'le cell disease. L &e! Beha! Pediatr. .//+T..2://. [Pu$Med] 5. >ield LL, Austin P>, An P, et al. Qnuresis is a co on and #ersistent #ro$le a ong children and young adults "ith sic'le cell ane ia. (rology. .//0T6.20+. [PMC free article] [Pu$Med] -. Hellstrf AD, Hanson Q, Hansson S, et al. Micturition ha$its and incontinence in 6year-old S"edish school entrants. Qur L Pediatr. +,,/T+3,23:3. [Pu$Med] 6. >orsythe @*, 8ed ond A. Qnuresis and s#ontaneous cure rate. Study of ++., enuretics. Arch &is Child. +,63T3,2.5,. [PMC free article] [Pu$Med] 0. Broo's DL, To#ol H*. Qnuresis in children "ith slee# a#nea. L Pediatr. .//:T+3.25+5. [Pu$Med] ,. Ale=o#oulos Q*, Rostadi a Q, Pagonari *, et al. Association $et"een #ri ary nocturnal enuresis and ha$itual snoring in children. (rology. .//-T-023/-. [Pu$Med] +/. Sans Ca#de!ila 7, Cra$tree HM, Rheirandish-Io%al D, et al. *ncreased orning $rain natriuretic #e#tide le!els in children "ith nocturnal enuresis and slee#-disordered $reathing2 a co unity-$ased study. Pediatrics. .//0T+.+2e+./0. [Pu$Med] ++. Stone L, Malone PS, At"ill &, et al. Sy #to s of slee#-disordered $reathing in children "ith nocturnal enuresis. L Pediatr (rol. .//0T32+,6. [Pu$Med] +.. Su W, Cheu' &R, Dee SD. Clinical e!aluation in #redicting childhood o$structi!e slee# a#nea. Chest. .//-T+:/2+6-5. [Pu$Med] +:. Aydil (, *seri Q, Ri%il Y, et al. 7$structi!e u##er air"ay #ro$le s and #ri ary enuresis nocturnal relationshi# in #ediatric #atients2 reci#rocal study. L 7tolaryngol Head )ec' Surg. .//0T:62.:5. [Pu$Med] +3. Barone LI, Hanson C, &aLusta &I, et al. )octurnal enuresis and o!er"eight are associated "ith o$structi!e slee# a#nea. Pediatrics. .//,T+.32e5:. [Pu$Med] +5. Raleyias L, Mostofi ), Irant M, et al. Se!erity of o$structi!e slee# a#nea in children "ith sic'le cell disease. L Pediatr He atol 7ncol. .//0T:/2-5,. [Pu$Med] +-. S#i!ey L>, (ong QC, Strun' 8, et al. Do" dayti e #ulse o=i etry reading is associated "ith nocturnal desaturation and o$structi!e slee# a#nea in children "ith sic'le cell ane ia. Pediatr Blood Cancer. .//0T5/2:5,. [PMC free article] [Pu$Med] +6. &aniel DC, Irant M, Rothare SH, et al. Slee# #atterns in #ediatric sic'le cell disease. Pediatr Blood Cancer. ./+/T5525/+. [Pu$Med] +0. *$er C, Ancoli-*srael S, Chesson A, et al. Ter inology and Technical S#ecifications. A erican Acade y of Slee# MedicineT @estchester, *llinois2 .//6. The AASM Manual for the Scoring of Slee# and Associated Q!ents2 8ules. +,. 7"ens LA, S#irito A, McIuinn M. The ChildrenMs Slee# Ha$its Vuestionnaire 1CSHV42 #sycho etric #ro#erties of a sur!ey instru ent for school-aged children. Slee#. .///T.:2+/3:. [Pu$Med] ./. Tang 8B, Chen SL, Soong @L, et al. Circulating adhesion olecules in sera of asth atic children. Pediatr Pul onol. .//.T::2.3,. [Pu$Med]

.+. &i!ision of )utrition, Physical Acti!ity, and 7$esity. Centers for &isease Control and Pre!ention [Accessed Lune ./, ./+/]TChildrenMs BM* Tool for Schools. ./+/ Se# +:T A!aila$le at """.cdc.go!Bhealthy"eightBassessingB$ iBchildrens_$ iBtool_for_schools.ht l. ... Lordan SS, Hil'er RA, Sto##el$ein D, et al. )octurnal enuresis and #sychosocial #ro$le s in #ediatric sic'le cell disease and si$ling controls. L &e! Beha! Pediatr. .//5T.-23/3. [Pu$Med] .:. Section on Pediatric Pul onology. Su$co ittee on 7$structi!e Slee# A#nea Syndro e. A erican Acade y of Pediatrics Clinical #ractice guideline2 diagnosis and anage ent of childhood o$structi!e slee# a#nea syndro e. Pediatrics. .//.T+/,26/3. [Pu$Med] .3. Basha S, Bialo"as C, Qnde R, et al. Qffecti!eness of adenotonsillecto y in the resolution of nocturnal enuresis secondary to o$structi!e slee# a#nea. Daryngosco#e. .//5T++52++/+. [Pu$Med] .5. >iroo%i >, BatniAi 8, Aslan A8, et al. 8esolution of diurnal incontinence and nocturnal enuresis after adenotonsillecto y in children. L (rol. .//-T+652+005. [Pu$Med] .-. Ralorin CM, Mou%a'es L, Ia!in LP, et al. Tonsil-lecto y does not i #ro!e $ed"etting2 results of a #ros#ecti!e controlled trial. L (rol. ./+/T+032.5.6. [Pu$Med] .6. Marshall ML, Buc's 8S, Hogan AM, et al. Auto-adAusting #ositi!e air"ay #ressure in children "ith sic'le cell ane ia2 results of a #hase * rando i%ed controlled trial. Hae atologica. .//,T,32+//-. [PMC free article] [Pu$Med]

4
)e#hrology &ialysis Trans#lantation 7=ford (ni!ersity Press

)he conse<uences of chronic kidney disease on bone metabolism and growth in children
Lustine Bacchetta, Lgrh e Hara $at, [...], and Ratherine @esseling-Perry Additional article infor ation

Abstract
Iro"th retardation, decreased final height and renal osteodystro#hy 187&4 are co on co #lications of childhood chronic 'idney disease 1CR&4, resulting fro a co $ination of a$nor alities in the gro"th hor one 1IH4 a=is, !ita in & deficiency, hy#er#arathyroidis , hy#ogonadis , inade?uate nutrition, cache=ia and drug to=icity. The i #act of CR&-associated $one and ineral disorders 1CR&FMB&4 ay $e

i ediate 1seru #hos#hateBcalciu dise?uili$riu 4 or delayed 1#oor gro"th, 87&, fractures, !ascular calcifications, increased or$idity and ortality4. *n ./+., the clinical anage ent of CR&FMB& in children needs to focus on three ain o$Aecti!es2 1i4 to #ro!ide an o#ti al gro"th in order to a=i i%e the final height "ith an early anage ent "ith reco $inant IH thera#y "hen re?uired, 1ii4 to e?uili$rate calciu B#hos#hate eta$olis so as to o$tain acce#ta$le $one ?uality and cardio!ascular status and 1iii4 to correct all eta$olic and clinical a$nor alities that can "orsen $one disease, gro"th and cardio!ascular disease, i.e. eta$olic acidosis, anae ia, alnutrition and .517H4!ita in & deficiency. The ai of this re!ie" is to #ro!ide an o!er!ie" of the ineral, $one and !ascular a$nor alities associated "ith CR& in children in ter s of #atho#hysiology, diagnosis and clinical anage ent. Keywords: $one, chronic 'idney disease, gro"th, #aediatrics, !ascular calcifications

ntroduction
Iro"th retardation, decreased final adult height and renal osteodystro#hy 187&4 are co on co #lications of childhood chronic 'idney disease 1CR&4, resulting fro a co $ination of factors, such as resistance to gro"th hor one 1IH4, odifications of the IH-insulin-li'e gro"th factor ty#e + 1*I>+4 a=is, !ita in & deficiency, hy#er#arathyroidis , hy#ogonadis , alnutrition and drug to=icity 1corticosteroids, calcineurin inhi$itors4 [+, .]. )ot only do these co #lications i #act o!erall ?uality of life through their effects on $oth #hysical and ental "ell-$eing in children "ith CR&, $ut also alterations in ineral eta$olis and $one disease are lin'ed to cardio!ascular disease, contri$uting to a significant decrease in life e=#ectancy. 8eflecting the co #le= inter#lay $et"een $one disease, ineral eta$olis and cardio!ascular disease in #atients "ith renal dysfunction, the CR& ineral and $one disorder 1CR&FMB&4 is a ter used to descri$e one or a co $ination of the follo"ing2 1i4 a$nor alities of calciu , #hos#horus, #arathyroid hor one 1PTH4 or !ita in & eta$olis , 1ii4 a$nor alities in $one histology, linear gro"th or strength and 1iii4 !ascular or other soft tissue calcification [:]. The i #act of CR&FMB& in children ay $e i ediate 1$iological dise?uili$riu of calciu B#hos#hateB!ita in & eta$olis deter inants4 or delayed 1gro"th retardation, CR&FMB&, fractures, !ascular calcifications, increased or$idity and ortality4 [3]. *n contrast, the ter 87& currently refers s#ecifically to the different $one lesions as defined $y $one histo or#ho etry. The $one and gro"th conse?uences of CR& ha!e $een highlighted in a cohort of .3, young &utch adults "ith onset of end-stage renal failure $efore the age of +3 years2 in this cohort, -+; of #atients had se!ere gro"th retardation, :6; se!ere $one disease 1as defined $y at least one of the follo"ing conditions2 defor ing $one a$nor alities, chronic #ain related to the s'eletal syste , disa$ling $one a$nor alities, ase#tic $one necrosis and lo"-trau atic fractures4 and +0; disa$ilities resulting fro $one i #air ent [5]. *n addition, e!idence of !ascular calcifications has $een de onstrated in young adult dialysis #atients "ith QS8& thera#y initiated in childhood [-, 6].

The ai of this re!ie" is therefore to #ro!ide an o!er!ie" of the ineral, $one and !ascular a$nor alities associated "ith CR& in children in ter s of #atho#hysiology, diagnosis and clinical anage ent.

+hysiology of normal growth and bone formation

Dinear gro"th is a uni?ue feature of childhood, occurring through the odelling of ne" $one $y s'eletal accretion and longitudinal gro"th in the gro"th #late. *n this #rocess, chondrocytes #lay a 'ey role, as "ell as IH [0, ,]. 7ne-third of the total gro"th occurs during the first . years of life, on a #ri arily nutrition-de#endent $asis [0]. Dater childhood is ar'ed $y a lesser, although constant, gro"th !elocity 15F6 c Byear4, dri!en #ri arily $y the actions of IH and thyroid hor one. At the onset of #u$erty, oestrogen and testosterone induce a second increase of gro"th !elocity. &uring gro"th, the e#i#hyseal cartilage goes through a #rocess of #rogressi!e aturation, and "hen no additional e#i#hyseal cartilage re ains to #ro!ide further long $one gro"th, $one fusion occurs $et"een the shaft and the e#i#hysis, ending the linear gro"th #rocess [+/]. IH, also ter ed `so atotro#inG, is a +,+-a ino acid hor one "ith ana$olic effects on ulti#le tissues including sti ulation of $ody gro"th and #rotein synthesis and odulation of the car$ohydrate, li#id and #rotein eta$olis [+/]. IH is the 'ey endocrine factor regulating #ost-natal gro"th2 the #ulsatile release of IH $y the so atotro#e cells of the anterior #ituitary gland is sti ulated $y the hy#othala ic IHreleasing hor one and regulated $y se!eral other factors [+/]. IH has a short half-ti e in $lood 1C./ in4T therefore, the effects of IH on al ost all tissues of the $ody, are ediated #ri arily through he#atic inter ediate su$stances 1so ato edins4 including so ato edin C 1or *I>+4, although, in ouse odels, IH itself has $een sho"n to ha!e so e direct actions on #u$ertal s'eletal de!elo# ent, as "ell [++]. *I>+ is also an ana$olic hor oneT it is trans#orted in #las a $ound to si= different *I>-$inding #roteins 1*I>BP4 to increase its half-life and e=erts its $iological effect "hen $inding to its s#ecific tyrosine 'inase rece#tor 1*I>+-84 [0]. *n healthy children, the ost #re!alent *I>BP is *I>BP:, accounting for 65; of the circulating *I>s [0]. Bone for ation in children occurs $y t"o distinct echanis s2 the first one is si ilar to that o$ser!ed in adults 1i.e. s'eletal re odelling of e=isting inerali%ed tissue that is controlled $y osteoclasts and osteo$lasts4, "hereas the second one is s#ecific to the #aediatric #o#ulation 1i.e. odelling of ne" $one $y s'eletal accretion and longitudinal gro"th fro the gro"th #late, through the action of chondrocytes4 [,]. The gro"th #late is an a!ascular tissue $et"een the e#i#hyses and eta#hyses of long $onesT endochondral $one for ation corres#onds to its #rogressi!e re#lace ent $y $one. The regulation of this #rocess is co #le=, "ith a 'ey role for IH and the PTHBPTH-related #roteinrece#tor 1PTHrP4 a=is [+.]. IH e=erts at least four ain actions on the gro"th #late2 1i4 an increased local #roduction of *I>+ that "ill later acts in a #aracrine anner to sti ulate the clonal e=#ansion of #roliferating chondrocytes, 1ii4 a #ositi!e effect on cellular differentiation, con!erting chondrocytes into osteogenic cells, 1iii4 an increased rate of cellular #roliferation and 1i!4 an increased de#osition of #roteins $y the chondrocytic and osteogenic cells, leading to further $one gro"th [+/, +.].

Changes in mineral metabolism with progressi#e CKD

Since $one consists #ri arily of calciu and #hos#horus, in the for of hydro=ya#atite, it is not sur#rising that alterations in ineral eta$olis , as occur "ith #rogressi!e CR&, lead to $one disease. The earliest $ioche ical a$nor ality in CR& is an increase in circulating fi$ro$last gro"th factor .: 1>I>.:4 le!els [+:]. >I>.:, in conAunction "ith its co-rece#tor, Rlotho, acti!ates >I> rece#tor + 1>I>8+4 and acts on the 'idney to induce renal #hos#hate "asting and to su##ress renal +b-hydro=ylase acti!ity. >I>.: also acts on the #arathyroid gland and ay #lay a role in su##ressing PTH le!els [+3]. >I>.: is sti ulated $y #hos#hate and +,.517H4.!ita in & and, in $oth adults and children, and >I>.: increases as glo erular filtration rate 1I>84 decreases, "ith ele!ations in circulating concentrations occurring in !ery early stages of CR&, #rior to any a##arent alterations in circulating ineral content [+5, +-]. This increase could $e e=#lained $y different factors, including a decreased renal clearance of >I>.:, a co #ensatory echanis to e=crete an increased #hos#hate load, a res#onse to treat ent "ith acti!e !ita in & analogues, andBor a co #ensatory echanis to the loss of the 'idney-secreted Rlotho #rotein. Although these increased circulating le!els of >I>.: in #atients "ith CR& consist al ost e=clusi!ely of the intact, acti!e for of the olecule [+6], it is not clear "hether the $iological effects of >I>.: are increased or decreased in the conte=t of decreased 'idney function [+0, +,]. *ndeed, decreased e=#ression of >I>8+ and Rlotho in #arathyroid cells fro dialysis #atients and a resistance to the su##ressi!e effects of >I>.: on PTH in urae ic rats suggest that #arathyroid gland >I>.: signalling #ath"ay is do"n-regulated in $oth ani als and hu ans "ith CR& o$ser!ations "hich ay e=#lain, at least in #art, the refractory secondary hy#er#arathyroidis o$ser!ed in CR& #atients [./F..]. 7n the other hand, as >I>.: le!els increase, tu$ular #hos#hate rea$sor#tion increases and +,.517H4.!ita in & synthesis decreases, suggesting that >I>.: signalling re ains intact in the 'idney. Su$se?uently, a$nor alities in other #ara eters of ineral eta$olis #rogressi!ely a##ear. &uring ild CR& 1stages . and :4, calcitriol le!els decline in res#onse to increased >I>.: concentrations. Since calcitriol su##resses PTH secretion, declining +,.517H4.!ita in & le!els are follo"ed, in oderate 1stages : and 34 CR&, $y increasing PTH concentrations and $y loss of #ulsatility in PTH secretion [.:]. (lti ately, in late stage 3 CR&, hy#ocalcae ia and hy#er#hos#hatae ia de!elo# in res#onse to decreased intestinal calciu a$sor#tion 1fro critically lo" calcitriol concentrations4 and decreased #hos#hate e=cretion 1fro critically lo" renal ass4, res#ecti!ely [+:]. >inally, .517H4!ita in & deficiency, "hich is #re!alent "orld"ide, li'ely also contri$utes to the de!elo# ent of secondary hy#er#arathyroidis . Patients "ith CR& are #articularly #rone to .517H4!ita in & deficiency 1currently defined $y !alues $elo" :/ ngB D or 65 n olBD4, due to se!eral co $ined factors including decreased sunlight e=#osure, relati!e scarcity of !ita in & in occidental diets, lac' of su##le entation in !ita in & due to the current underesti ation for reco ended daily inta'e and increased $ody fat ass in #o#ulations [.3]. 8ecent data fro four studies in children ha!e docu ented a 3/F66; #re!alence of .517H4!ita in & deficiencyBinsufficiency in children "ith CR& [.5]. *n addition to #ro!iding a su$strate for the for ation of calcitriol, thus indirectly su##ressing PTH le!els, 8itter et al. [.-]

recently identified that .517H4!ita in & continues to directly su##ress PTH synthesis e!en "hen #arathyroid gland +al#ha hydro=ylase is inhi$ited, thus de onstrating a direct effect of .517H4!ita in & on PTH synthesis, inde#endent of +,.517H4.!ita in &. Moreo!er, a recent #lace$o-controlled rando i%ed trial de onstrated that ergocalciferol "as a$le to delay the onset of secondary hy#er#arathyroidis in #aediatric #atients "ith #re-dialysis CR& [.6]. .517H4!ita in & li'ely also has a direct effect on $one $iology, inde#endent of its effects on ineral eta$olis T indeed, Prie el et al. [.5] de onstrated in a cohort of -65 deceased adults that #athological inerali%ation defects could occur "hen the seru .517H4 !ita in & le!el "as $elo" :/ ngB D. )e" roles of !ita in & in glo$al health ha!e also recently $een highlighted2 !ita in & ay re#resent a #rotecti!e factor against infections, autoi une diseases, cardio!ascular diseases and cancer [.0].

)he impact of altered bone metabolism on growth in children with CKD

:rowth retardation in CKD
*n #aediatric #atients "ith CR&, gro"th failure de!elo#s early in the course of CR& and affects u# to :5; of this #o#ulationT $y the ti e of renal trans#lantation, a significant #ro#ortion of children #resent "ith se!ere short stature [.,F:.]. The aetiology of this #oor gro"th is ultifactorial and includes $oth #otentially odifia$le factors 1e.g. #rotein and calorie alnutrition, anae ia, eta$olic acidosis, hy#othyroidis and salt "asting4 and less odifia$le factors such as a$nor alities in the IHF*I>+ a=is, resistance to IH, 87& and thera#ies [:+, ::, :3]. Ho"e!er, des#ite the correction of these factors, any children "ith CR& continue to gro" #oorly [::]. Altered IH eta$olis and organ resistance to IH ha!e $een i #licated as aAor contri$utors to gro"th retardation in CR&, as su ari%ed in Ta$le + [0, :5F:0]. *n teenagers "ith CR&, the loss of the #ulsatile release of the gonadotro#in-releasing hor one also e=#lains the delay and the shortening of the #u$ertal gro"th s#urt, in association "ith a reduced gro"th !elocity [0].

Ta$le +. The i #air ent of the IHB*I>+ a=is in CR& children

)he contribution of R"D to growth failure

Bone e!aluation in CR& children re ains challenging [+] since 1i4 the eta$olis of $one $io ar'ers is not "ell 'no"n during CR&, "ith an accu ulation of ost of $one $io ar'ers as I>8 decreases [:,, 3/]T 1ii4 $one $io ar'ers !ary according to age and gender in a #aediatric #o#ulation [3+]T and 1iii4 the only $one i aging techni?ue that is "idely a!aila$le 1i.e. dual S-ray a$sor#tio etry or &SA4 is a #oor etric for assessing $one status in CR&, as recently discussed in international #aediatric guidelines [3., 3:]. Ho"e!er, childhood and adolescence are critical #eriods for $one ass gain since a$out ,/; of #ea' $one ass is ac?uired $efore the age of +0 years and a decreased #ea' $one ass ay induce an increased ris' of fractures and osteo#orosis during adulthood [33]. Bone $io#sy fro the anterior iliac crest after dou$le-tetracycline la$elling 1+/F+5 gB'g #er day, ta'en orally three ti es a day during t"o .-day #eriods se#arated $y a +.-day free inter!al4 re ains the reference standard to e!aluate $one status in CR& #atients [35]. Q!en though it is rarely #erfor ed in clinical #ractice, it is the only a!aila$le techni?ue leading to an accurate e!aluation of 87& [3-]. Histo or#ho etry allo"s the diagnosis of the different s'eletal lesions of 87& [36]T so e reference !alues esta$lished in children "ith nor al renal function ha!e $een descri$ed [30, 3,]. *n all cases, histo or#ho etric results should $e re#orted using the ter inology esta$lished $y the )o enclature Co ittee of the A erican Society for Bone and Mineral 8esearch [5/], and $y the TMH classification syste esta$lished $y the R&*I7 "or'ing grou# to s#ecifically define 87& [5+], as su ari%ed in Ta$le . [5.].

Ta$le .. The s#ectru

of 87& according to the TMH classification [5+]

87& is characteri%ed $y alterations in $one turno!er, inerali%ation and !olu eT these three co #onents should $e e!aluated inde#endently to characteri%e the different su$ty#es of 87&, as defined $y the R-&*I7 in .//- and su ari%ed in Ta$le . [5+]. High $one turno!er 1secondary hy#er#arathyroidis , osteitis fibrosa cystica4 is the #ri ary s'eletal lesion of #aediatric 87&, and is #resent in !irtually all untreated incident #aediatric dialysis #atients. This lesion is caused $y a long-ter e=#osure to high seru PTH le!els and +,.517H4.!ita in & deficiency. *n contrast, lo"-turno!er lesions 1i.e. adyna ic $one disease4 ay occur as a result of e=cess treat ent "ith !ita in & analogues and calciu salts and are characteri%ed $y lo" PTH and al'aline #hos#hatase le!els as "ell as high seru calciu le!els. Do" $one turno!er has $een associated "ith an increased ris' of !ascular calcifications, fractures and ore se!ere gro"th retardation [:, 5:]. &efects in s'eletal inerali%ation are also #re!alent in #aediatric #atients "ith CR&i occurring in :/; in stage . CR& and increasing in #re!alence as CR& #rogresses, e!en though $one turno!er re ains nor al in the earliest CR& stages and $eco es a##arent "hile I>8 decreases [+:]. )early 0/; of dialysis #atients dis#lay so e defect in s'eletal

inerali%ation, a #ro$le that is not corrected $y traditional thera#y "ith !ita in & sterols and #hos#hate $inders [53]. Although alterations in s'eletal inerali%ation 1i.e. ric'ets4 contri$ute to increased fracture rates, $one defor ities and gro"th retardation in children "ith nor al renal function, their e=act role in these clinical sy #to s in children "ith CR&, re ains to $e elucidated [:]. *n contrast to $one turno!er and inerali%ation, assess ent of $one a ount and structure are $est assessed !ia i aging techni?ues [55]. Although "idely used in #aediatric #o#ulations, the areal easure ent of $one ineral density 1BM&4 $y &SA has three aAor li itations in #aediatric CR& #o#ulations2 1i4 its reliance on areal density rather than !olu etric density that can $e odified only $y gro"thT 1ii4 its ina$ility to distinguish $et"een tra$ecular and cortical $one that can $e inde#endently da aged in CR&T and 1iii4 its ina$ility to e!aluate tra$ecular icroarchitecture "hereas it is a strong deter inant of $one ?uality [:,, 3:]. *n contrast, ne" i aging techni?ues, including $one agnetic resonance i aging or high-resolution #eri#heral ?uantitati!e co #uted to ogra#hy ha!e led to an i #ro!e ent in $one e!aluation "ith an assess ent of $oth co #art ental !olu etric densities and tra$ecular icroarchitecture [5-F50]. These $one i aging de!ices are #articularly challenging in children, "hose $ones continually gro" in si%e, sha#e and ass [5,]T ho"e!er, they #resent se!eral ad!antages, na ely, safety and lo" radiation e=#osure. At this ti e, these techni?ues are not "idely a!aila$le and their e=act role in #aediatric CR& #atients re ains to $e defined [-/F-3].

Clinical management of growth retardation in children with CKD

Control of R"D
*n clinical #ractice, the recent guidelines on a$nor alities of $one and ineral eta$olis in CR& ha!e esta$lished that a regular onitoring of calciu , #hos#horus, PTH and al'aline #hos#hatase should $e #erfor ed at regular inter!als [-5]. Since $oth adyna ic $one and se!ere hy#er#arathyroidis increase the se!erity of gro"th retardation [:], current guidelines suggest that seru PTH and $one-s#ecific al'aline #hos#hatase !alues $e used for the e!aluation of $one disease 1R&*I7 guidelines, e!idence +C in adults and .& in children4, "ith seru PTH !alues 'e#t "ithin a range a##ro#riate to the stage of CR& [--]. (nfortunately, PTH !alues are #oor #redictors of 87&, li'ely due to a co $ination of factors including the de!elo# ent of end-organ resistance to the hor one as CR& #rogresses and an accu ulation of PTH frag ents as renal function declines [-6]. Thus, a $one $io#sy should $e #erfor ed for the follo"ing indications2 une=#lained fractures, #ersistent $one #ain, une=#lained hy#ercalcae ia, #ossi$le alu iniu to=icity and $efore $is#hos#honates thera#y [-5]. Ta$le : su ari%es the targets of PTH seru le!els according to the different stages of CR&, according to the .//, R&*I7 international guidelines [-5]T ho"e!er, o#ti al targets de#end on the geogra#hy [-0] and are nota$ly different $et"een Quro#e and A erica [:3]. *ndeed, Quro#ean #aediatric ne#hrologists are #rone to acce#t lo"er le!els of PTH 1i.e. not a$o!e t"o ti es the u##er nor al li it4, [-,] noting that PTH is an inde#endent ris' factor for yocardial fi$rosis, arteriolar thic'ening and hy#ertension $oth in adults

[6/] and in children treated "ith aintenance dialysis [6+]T they ha!e re#orted no negati!e i #act on gro"th "ith these !alues [6.]. A consensus on the o#ti al target for PTH le!els de#ending on the different CR& stages is therefore i #ossi$le to deter ine at the current ti eT ho"e!er, o#ti al gro"th and nor al #hos#horusBcalciu B.517H4!ita in & le!els should $e the #ri ary targets of daily anage ent of CR&FMB& in children.

Ta$le :. PTH seru le!els according to the stage of CR&iada#ted fro R&*I7 guidelinesa [+/.]

the .//, international

Current guidelines for anaging CR&FMB& in adults consist in decreasing high circulating #hos#horus le!els aintaining calciu le!els, and controlling secondary hy#er#arathyroidis [-5]. &ecreased #hos#hate inta'e and #hos#hate $inders are used to control seru #hos#hate and calciu concentrations. Currently, calciu -containing salts are the ost "idely a!aila$le and used #hos#hate $inder in children, although calciu free, #re#arations ha!e recently $een introduced. )ota$ly, se!ela er hydrochloride has $een sho"n to $e a safe and effecti!e #hos#hate $inder, controlling $oth the s'eletal lesions associated "ith hy#er#arathyroidis and !ascular calcifications. *ndeed, fe"er e#isodes of hy#ercalcae ia ha!e $een de onstrated in #atients recei!ing se!ela er [6:], thus i #ro!ing the argin of safety for acti!e !ita in & sterol use in a rando i%ed trial in children undergoing #eritoneal dialysis [63]. Ho"e!er, se!ela er hydrochloride has also $een associated "ith a "orsening of eta$olic acidosis in a dose-de#endent anner in a i=ed cohort of 33 Ier an children "ith different stages of CR& and a #ro#ortion of the treated "ith dialysis [65]. More recently, a #ros#ecti!e study has sho"n that se!ela er car$onate ay $e a safe and effecti!e #hos#hate $inder and results in less eta$olic acidosis in #aediatric dialysis #atients [6-]. .517H4!ita in & su##le entation and acti!e !ita in & analogues are used to decrease PTH circulating le!els [-5]. Current guidelines suggest that increased PTH le!els, in the face of .517H4!ita in & insufficiencyBdeficiency 1defined as a !alue C:/ ngB D4 $e first treated "ith .517H4!ita in & su##le entation. A recent rando i%ed, controlled trial has !alidated this reco endation, de onstrating a delayed onset of secondary hy#er#arathyroidis in children "ith CR& recei!ing thera#y for .517H4 !ita in & deficiency [.6]. >ollo"ing .517H4 !ita in & re#letion, acti!e !ita in & sterols should $e initiated to control seru PTH !alues. A recent 1./+/4 Cochrane eta-analysis e #hasi%ed the #aucity of long-ter data on the relati!e safety and efficacy of different acti!e !ita in & sterols for the treat ent of secondary hy#er#arathyroidis in childrenT ho"e!er, PTH le!els ha!e $een sho"n to decrease si ilarly "ith all #re#arations [6:].

Moreo!er, one rando i%ed, controlled trial de onstrated e?ui!alent su##ression of PTH le!els and $one turno!er "ith $oth calcitriol and do=ercalciferol, suggesting that $oth for ulations are e?ui!alent for the control of secondary hy#er#arathyroidis [53]. Although !ita in & sterols are currently the ainstay of thera#y for ele!ated PTH le!els, o!er-su##ression of PTH le!els in dialysed children ay lead to adyna ic $one disease "hich is associated "ith gro"th failure and cardio!ascular calcifications [66]. Moreo!er, acti!e !ita in & sterols, #articularly calcitriol, ay also inhi$it the gro"th #late [60]. Ta'en together, these data illustrate that acti!e !ita in & sterols e=ert a #ositi!e role in controlling PTH le!els and osteitis fibrosa $ut, "ith e=cessi!e use, ay result in e=cessi!e PTH su##ression, adyna ic $one disease, gro"th failure and #rogressi!e cardio!ascular calcifications. >urther ore, since acti!e !ita in & analogues are #otent sti ulators of s'eletal >I>.: secretion [53, 6,], current data i #licating >I>.: in the #athogenesis of secondary hy#er#arathyroidis call into ?uestion the "isdo of early acti!e !ita in & sterol thera#y. Since there are currently no data de onstrating any differences on the control of secondary hy#er#arathyroidis or 87& $et"een the !arious acti!e !ita in & sterols [53] the choice ay de#end on the geogra#hical locali%ationT for e=a #le, >rench #aediatric ne#hrologists tend to use alfacalcidol "hile A ericans #rescri$e calcitriol. Currently, calci i etics and $one-targeted thera#ies 1i.e. $is#hos#honates, teri#aratide and ralo=ifene4 are not a##ro!ed for use in #aediatric #atients "ith CR& and long-ter data on their effects on $one, gro"th and $ioche ical #ara eters in children are lac'ing. Thus, further studies are "arranted to deter ine the o#ti al strategy for controlling secondary hy#er#arathyroidis in the #aediatric CR& #o#ulation. The ne" drug, cinacalcet, is highly #ro ising, since it has intriguing $enefits "hen co #ared "ith acti!e !ita in & $y inducing daily PTH fluctuations [0/, 0+]T ho"e!er, #aediatric e=#erience is li ited to o$ser!ational data [0.]. 7f note, the use of this drug in addition to lanthanu car$onate thera#y in one child "as associated "ith #recocious #u$erty, calling into ?uestion its safety for the #aediatric #o#ulation [0:]. Paediatric rando i%ed controlled trials are ongoing and should yield additional #aediatric #har aco'inetic, #har acodyna ic and safety data.

rh:% therapy
After correcting all eta$olic a$nor alities that can "orsen gro"th status such as eta$olic acidosis, anae ia, CR&FMB& and alnutrition in #aediatric #atients "ith ild-to- oderate renal insufficiency 1CR& stages .F34, the use of su#ra#hysiological doses of reco $inant hu an IH 1rhIH4 has $een #ro!ed to $e safe and effecti!e in increasing gro"th and final adult height [:/, 03F0-], $y #artly correcting the altered IHF *I>+ a=is, $y increasing IH and *I>+ seru le!els, and $y decreasing *I>BP+ and *I>BP5 seru le!els si ultaneously [0]. The .//5 A erican R-&7V* guidelines concerning the use of rhIH in CR& children are su ari%ed in Ta$le 3 [06]. 7f note, such a thera#y is contra-indicated in the case of se!ere secondary hy#er#arathyroidis , history of alignancy, hy#erglycae ia, hy#erinsulinae ia or significant scoliosis [00]. The #ri ary actions of rhIH are on the cartilaginous gro"th #late and ani al odels 1rats4 ha!e de onstrated that secondary hy#er#arathyroidis influences $oth the

e#i#hyseal gro"th #late or#hology and the e=#ression of different $io ar'ers of #roliferation and differentiation in this tissue [+.]. Although there is little data in hu ans on the i #act of CR& on gro"th #late, ar'ed chondroclastic erosions and a$nor al !asculari%ation "ere found in the gro"th #lates of auto#sy aterial fro children "ith osteitis fibrosa "ho "ere treated "ith aintenance hae odialysis [0,]. Se!eral studies ha!e de onstrated a #ositi!e effect of rhIH on linear gro"th $ut "ith !aria$le results according to CR& stage2 in the )AP8TCS data$ase, catch-u# "as o$ser!ed in .6; of children "ith chronic renal insufficiency and in .5; of trans#lanted children, $ut only in ++; of children undergoing renal re#lace ent thera#y treated "ith rhIH thera#y [,/]. Moreo!er, the a=i al effect of rhIH thera#y occurs during the first year of thera#y. The "aning efficacy of rhIH "ith a longer thera#y duration, ay #artly $e e=#lained $y the difficulty of adhering to a daily su$cutaneous inAection regi en andBor an increasing resistance to the actions rhIH at the le!el of the gro"th #late [,+].

Ta$le 3. Su ary of the .//5 R-&7V* guidelines for using rhIH in CR& children [06] *nde#endent of its action on the gro"th #late, the effects of IH on $one ?uality and $one re odelling are not "ell 'no"n [,.]. )e!ertheless, rhIH ay sti ulate osteo$lastic #roliferation and ne" $one for ation, illustrated in clinical #ractice $y higher osteo$lastic acti!ity, $one for ation rate and $one ass in #atients "ith acro egaly on the one hand, and $y decreased $one ass and oseto$lastic acti!ity in #atients "ith IH deficiency on the other. Moreo!er, IH can #ro ote the #roliferation of osteo$lasts and increase ne" $one for ation, through the *I>+ #ath"ay [,]. *n children recei!ing longter corticosteroids, rhIH thera#y increases osteo$lastic acti!ity, $one for ation and #ro$a$ly also $one turno!er [,:]. 7ther data also suggest a #ositi!e effect of rhIH thera#y on BM& [,., ,3F,6]. Moreo!er, rhIH thera#y ay also counteract the negati!e effect of high-dose calcitriol thera#y on $one turno!er during childhood CR& [,0]. Although se!eral side effects of rhIH thera#y ha!e $een discussed in the #ast 1e.g. #otential increased ris' of acute reAection and ad!erse effect on the #reser!ation of renal function in trans#lanted children, increased ris' of sli##ed ca#ital fe oral e#i#hysis and $enign intracranial hy#ertension, increased ris' of hy#er#arathyroidis 4, a Cochrane syste atic re!ie" #erfor ed in .//- to e!aluate the $enefits and har s of rhIH thera#y in CR& children 1+5 trials, -., children4 failed to de onstrate a #ositi!e effect of rhIH thera#y on final adult height since ost of the #u$lished trials "ere too short to dra" such conclusions. Ho"e!er, a dosage of .0 *(B . #er "ee' 1or +/ gB . #er "ee'4 for + year of rhIH resulted in a :.0 c Byear increase in height !elocity in CR& children recei!ing rhIH thera#y in co #arison to untreated #atients [:/].

After initiating rhIH thera#y, the #hysician ay o$ser!e !ery different clinical res#onses that are #artly e=#lained $y confounding factors such as indi!idual #ri ary renal disease, CR& stage, degree of alnutrition, eta$olic distur$ances, genetic $ac'ground, concurrent diseases and thera#ies and thera#eutic co #liance [:+, 00]. Since there "as an in!erse relationshi# $et"een age and rhIH res#onse in a cohort of .6/ CR& #re#u$ertal naj!e-to-treat ent children issued fro the )CIS registry, rhIH thera#y should $e $egun early in the course of CR& [:+]. *t is also i #ortant to note that a recent study e #hasi%ed the under-#rescri#tion of rhIH thera#y in #aediatric CR& #atients since ore than half of short CR& children 1as defined $y a height $elo" the fifth #ercentile4 did not recei!e rhIH in a retros#ecti!e ulticentre A erican study "hose ain o$Aecti!e "as to identify the #otential o$stacles #re!enting CR& children to recei!e rhIH thera#y. The ost co on reasons to e=#lain the a$sence of rhIH "ere fa ily refusal, se!ere secondary hy#er#arathyroidis and non-co #lianceT ho"e!er, in u# to .5; of cases, no e!ident rationale "as found. 7f note, the need for "aiting on insurance co #any a##ro!al induced a significant delay in the initiation of rhIH thera#y in +0; of #atients [,,]. Ta'en together, these o$ser!ations confir that further easures are still needed to o#ti i%e gro"th in children "ith CR&. *n conclusion, since children "ith early stages of CR& ha!e a $etter res#onse to rhIH thera#y than dialysis #atients on the one hand, and since a young age at the onset of CR& is associated "ith a greater agnitude of gro"th retardation on the other hand, rhIH thera#y should $e introduced as soon as #ossi$le in children "ith CR& 1i.e. "ith a I>8 $elo" 65 DB in #er +.6: .4 "hen their S&S for height is ore negati!e than k. 1and k+.00 according so e authors4 [00]. *n the future, ne"er treat ent odalities, targeting #referentially IH resistance 1such as reco $inant *I>+, reco $inant *I>BP: or *I>BP dis#lacers4, are under in!estigation for the treat ent of gro"th retardation in #aediatric #atients "ith CR& [0]. *n children $elo" . years of age, since gro"th ainly de#ends on nutritional #ara eters, the o#ti i%ation of nutritional status is a cornerstone in the anage ent of such #atients, usually through an enteral nutritional su##ort [+//].

Conclusion and perspecti#es

Since gro"th failure during CR& has $een "ell de onstrated to $e associated "ith increased hos#itali%ation rates and increased or$idityB ortality [+/+], and since $one status #ro$a$ly re#resents only the ti# of the ice$erg of cardio!ascular health and !ascular calcifications, large #ros#ecti!e ulticentre trials are urgently re?uired in this s#ecific #aediatric #o#ulation to e!aluate the i #act of rhIH thera#y, !ita in & analogues, #hos#hate-$inders and calci i etics not only on final adult height $ut also on $one status, fracture ris' and glo$al cardio!ascular status. *n this setting, $one histo or#ho etry re ains an i #ortant co #onent of "ell-designed clinical studies $ut the role of ne" non-in!asi!e i aging techni?ues should also $e e!aluated. The e!aluation of gro"th and $one status re ains challenging in CR& children e!en though the recent descri#tion of the >I>.: $oneB'idneyB#arathyroid a=is highlights ne" #ro ising and e=citing hy#otheses to i #ro!e diagnosis and clinical anage ent of CR&FMB&. Therefore, at the current ti e, the daily clinical anage ent of CR&FMB&

in children should still focus on three ain o$Aecti!es2 1i4 to #ro!ide an o#ti al nutritional su##ort to a=i i%e the final height and a!oid $one defor ations, 1ii4 to e?uili$rate calciu B#hos#hate eta$olis so as to #ro!ide acce#ta$le $one ?uality and cardio!ascular status and 1iii4 to correct all eta$olic and clinical a$nor alities that can "orsen $oth $one and gro"th 1 ainly eta$olic acidosis, anae ia, alnutrition and .517H4!ita in & deficiency4.

;unding
This "or' "as also su##orted in #art $y (SPHS grants &R--65-:, &R-:53.:, &R5+/0+, &R-/6:/:, and (D+88-/::+6-, and funds fro the Casey Dee Ball >oundation.

Conflict of interest statement

)one declared.

Acknowledgements
Lustine Bacchetta recei!ed educational grants fro l'Acadmie Franaise 1Lean @alter WellidAa4, la Runion Pdiatri ue de la Rgion Rh!ne Alpes 18P88A4, la "ocit Franaise de Pdiatrie 1Q!ian4, la Fondation pour la Recherche #dicale and the Phili##e >oundation for her "or' on the inter#lay $et"een !ita in & and >I>.: during #aediatric CR&FMB&.

Article information
)e#hrol &ial Trans#lant. ./+. AugustT .61042 :/-:F:/6+. doi2 +/.+/,:BndtBgfs.,, PMC*&2 PMC:36+55. Lustine Bacchetta,+,.,: Lgrh e Hara $at,3 Pierre Cochat,+,. *sidro B. Salus'y,5 and Ratherine @esseling-Perry5 + Centre de 8gfgrence des Maladies 8gnales 8ares, Ser!ice de )g#hrologie et 8hu atologie Pgdiatri?ues, Hh#ital >e e Mlre Qnfant, Bron, >rance . (ni!ersitg de Dyon, Dyon, >rance : *nstitut de Igno i?ue >onctionnelle de Dyon 1*I>D4, Qcole )or ale Su#grieure, Dyon, >rance 3 (nitg de )g#hrologie Pgdiatri?ue, Hh#ital Pellegrin et (ni!ersitg de Bordeau=, Bordeau=, >rance 5 &e#art ent of Pediatrics, &a!id Ieffen School of Medicine at (ni!ersity of California Dos Angeles, Dos Angeles, CA, (SA $orrespondence and offprint re uests to% Lustine BacchettaT Q- ail2 Austine.$acchettaBatBchu-lyon.fr 8ecei!ed A#ril 6, ./+.T Acce#ted A#ril .,, ./+..

Co#yright U The Author ./+.. Pu$lished $y 7=ford (ni!ersity Press on $ehalf of Q8AQ&TA. All rights reser!ed. >or Per issions, #lease e- ail2 Aournals.#er issionsmou#.co Articles fro )e#hrology &ialysis Trans#lantation are #ro!ided here courtesy of "(ford 'ni#ersity +ress

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-3. Bacchetta L, Boutroy S, Hilay#hiou ), et al. Bone assess ent in children "ith chronic 'idney disease2 data fro t"o ne" $one i aging techni?ues in a single-center #ilot study. Pediatr )e#hrol. ./++T.-2506F5,5. [8esearch Su##ort, )on-(.S. Io!Mt]. [Pu$Med] -5. R&*I7 clinical #ractice guideline for the diagnosis, e!aluation, #re!ention, and treat ent of Chronic Ridney &isease-Mineral and Bone &isorder 1CR&FMB&4 Ridney *nt Su##l. .//,T++:2S+FS+:/. [Pu$Med] --. @aller SC, 8idout &, Cantor T, et al. Parathyroid hor one and gro"th in children "ith chronic renal failure. Ridney *nt. .//5T-62.::0F.:35. [Pu$Med] -6. Dondon IM, Marchais SL, Iuerin AP, et al. Association of $one acti!ity, calciu load, aortic stiffness, and calcifications in QS8&. L A Soc )e#hrol. .//0T+,2+0.6F +0:5. [8esearch Su##ort, )on-(.S. Io!Mt] [PMC free article] [Pu$Med] -0. Sch itt CP, Mehls 7. Mineral and $one disorders in children "ith chronic 'idney disease. )at 8e! )e#hrol. ./++T62-.3F-:3. [Pu$Med] -,. 8ees D. @hat #arathyroid hor one le!els should "e ai for in children "ith stage 5 chronic 'idney diseaseT "hat is the e!idenceX Pediatr )e#hrol. .//0T.:2+6,F+03. [PMC free article] [Pu$Med] 6/. 8ostand SI, &rue'e TB. Parathyroid hor one, !ita in &, and cardio!ascular disease in chronic renal failure. Ridney *nt. +,,,T5-2:0:F:,.. [8esearch Su##ort, (.S. Io!Mt, P.H.S. 8e!ie"] [Pu$Med] 6+. Shroff 8C, &onald AQ, Hiorns MP, et al. Mineral eta$olis and !ascular da age in children on dialysis. L A Soc )e#hrol. .//6T+02.,,-F://:. [8esearch Su##ort, )on(.S. Io!Mt] [Pu$Med] 6.. Cansic' L, @aller S, 8idout &, et al. Iro"th and PTH in #re#u$ertal children on long-ter dialysis. Pediatr )e#hrol. .//6T..2+:3,F+:53. [Pu$Med] 6:. Ieary &>, Hodson QM, Craig LC. *nter!entions for $one disease in children "ith chronic 'idney disease. Cochrane &ata$ase Syst 8e!. ./+/2C&//0:.6. [Pu$Med] 63. Salus'y *B, Iood an @I, Sahney S, et al. Se!ela er controls #arathyroid hor oneinduced $one disease as efficiently as calciu car$onate "ithout increasing seru calciu le!els during thera#y "ith acti!e !ita in & sterols. L A Soc )e#hrol. .//5T+-2.5/+F.5/0. [Pu$Med] 65. Pie#er AR, Haffner &, Ho##e B, et al. A rando i%ed crosso!er trial co #aring se!ela er "ith calciu acetate in children "ith CR&. A L Ridney &is. .//-T362-.5F -:5. [Pu$Med] 6-. Ion%ale% Q, Scho $erg L, A in ), et al. Se!ela er car$onate increases seru $icar$onate in #ediatric dialysis #atients. Pediatr )e#hrol. ./+/T.52:6:F:65. [Pu$Med] 66. Salus'y *B, Iood an @I. Iro"th hor one and calcitriol as odifiers of $one for ation in renal osteodystro#hy. Ridney *nt. +,,5T302-56F--5. [8esearch Su##ort, )on-(.S. Io!Mt 8esearch Su##ort, (.S. Io!Mt, P.H.S. 8e!ie"]. [Pu$Med] 60. Sanche% CP, Salus'y *B, Rui%on B&, et al. Iro"th of long $ones in renal failure2 roles of hy#er#arathyroidis , gro"th hor one and calcitriol. Ridney *nt. +,,0T532+06,F +006. [8esearch Su##ort, )on-(.S. Io!Mt 8esearch Su##ort, (.S. Io!Mt, P.H.S.] [Pu$Med] 6,. * el QA, &iMeglio DA, Hui SD, et al. Treat ent of S-lin'ed hy#o#hos#hate ia "ith calcitriol and #hos#hate increases circulating fi$ro$last gro"th factor .: concentrations. L

Clin Qndocrinol Meta$. ./+/T,52+03-F+05/. [Clinical Trial 8esearch Su##ort, ).*.H., Q=tra ural] [PMC free article] [Pu$Med] 0/. Serra AD, Braun SC, Star'e A, et al. Phar aco'inetics and #har acodyna ics of cinacalcet in #atients "ith hy#er#arathyroidis after renal trans#lantation. A L Trans#lant. .//0T020/:F0+/. [8esearch Su##ort, )on-(.S. Io!Mt] [Pu$Med] 0+. >inch LD, To'u oto M, )a'a ura H, et al. Qffect of #aricalcitol and cinacalcet on seru #hos#hate, >I>-.:, and $one in rats "ith chronic 'idney disease. A L Physiol 8enal Physiol. ./+/T.,02>+:+5F>+:... [Co #arati!e Study 8esearch Su##ort, ).*.H., Q=tra ural 8esearch Su##ort, )on-(.S. Io!Mt] [PMC free article] [Pu$Med] 0.. Muscheites L, @igger M, &ruec'ler Q, et al. Cinacalcet for secondary hy#er#arathyroidis in children "ith end-stage renal disease. Pediatr )e#hrol. .//0T.:2+0.:F+0.,. [Pu$Med] 0:. Bacchetta L, Plotton *, 8anchin B, et al. Precocious #u$erty and unlicensed #aediatric drugs for se!ere hy#er#arathyroidis . )e#hrol &ialysis, Trans#lant. .//,T.32.5,5F.5,0. [Pu$Med] 03. >ine 8), Rohaut QC, Bro"n &, et al. Iro"th after reco $inant hu an gro"th hor one treat ent in children "ith chronic renal failure2 re#ort of a ulticenter rando i%ed dou$le-$lind #lace$o-controlled study. Ienentech Coo#erati!e Study Irou#. L Pediatr. +,,3T+.32:63F:0.. [Pu$Med] 05. Ho''en-Roelega AC, StiAnen T, de Muinc' Rei%er-Schra a SM, et al. Place$ocontrolled, dou$le-$lind, cross-o!er trial of gro"th hor one treat ent in #re#u$ertal children "ith chronic renal failure. Dancet. +,,+T::02505F5,/. [Pu$Med] 0-. Haffner &, Schaefer >, )issel 8, et al. Qffect of gro"th hor one treat ent on the adult height of children "ith chronic renal failure. Ier an study grou# for gro"th hor one treat ent in chronic renal failure. ) Qngl L Med. .///T:3:2,.:F,:/. [Pu$Med] 06. RB&7V* Clinical #ractice guidelines for $one eta$olis and disease in children "ith chronic 'idney disease. A L Ridney &is. .//5T3-1Su##l +42+F+... 00. >ine 8). Qtiology and treat ent of gro"th retardation in children "ith chronic 'idney disease and end-stage renal disease2 a historical #ers#ecti!e. Pediatr )e#hrol. ./+/T.526.5F6:.. [Pu$Med] 0,. Rre #ien B, Mehls 7, 8it% Q. Mor#hological studies on #athogenesis of e#i#hyseal sli##ing in ure ic children. Hircho"s Arch A Pathol Anat Histol. +,63T:-.2+.,F+3:. [Pu$Med] ,/. Sei'aly MI, Salha$ ), @arady BA, et al. (se of rhIH in children "ith chronic 'idney disease2 lessons fro )AP8TCS. Pediatr )e#hrol. .//6T..2++,5F+./3. [Pu$Med] ,+. Berard Q, Andre LD, Iuest I, et al. Dong-ter results of rhIH treat ent in children "ith renal failure2 e=#erience of the >rench Society of Pediatric )e#hrology. Pediatr )e#hrol. .//0T.:2./:+F./:0. [Pu$Med] ,.. Tritos )A, Biller BM. Iro"th hor one and $one. Curr 7#in Qndocrinol &ia$etes 7$es. .//,T+-23+5F3... [Pu$Med] ,:. Sanche% CP, Iood an @I, Brandli &, et al. S'eletal res#onse to reco $inant hu an gro"th hor one 1rhIH4 in children treated "ith long-ter corticosteroids. L Bone Miner 8es. +,,5T+/2.F-. [Pu$Med]

,3. Baroncelli I*, Bertelloni S, Sodini >, et al. Ac?uisition of $one ass in nor al indi!iduals and in #atients "ith gro"th hor one deficiency. L Pediatr Qndocrinol Meta$. .//:T+-1Su##l .42:.6F::5. [Pu$Med] ,5. Murray 8&, Ada s LQ, Shalet SM. Adults "ith #artial gro"th hor one deficiency ha!e an ad!erse $ody co #osition. L Clin Qndocrinol Meta$. .//3T0,2+50-F+5,+. [Pu$Med] ,-. Colao A, &i So a C, Pi!onello 8, et al. Bone loss is correlated to the se!erity of gro"th hor one deficiency in adult #atients "ith hy#o#ituitaris . L Clin Qndocrinol Meta$. +,,,T032+,+,F+,.3. [Pu$Med] ,6. Bau HB, Biller BM, >in'elstein LS, et al. Qffects of #hysiologic gro"th hor one thera#y on $one density and $ody co #osition in #atients "ith adult-onset gro"th hor one deficiency. A rando i%ed, #lace$o-controlled trial. Ann *ntern Med. +,,-T+.5200:F0,/. [Pu$Med] ,0. Bacchetta L, @esseling-Perry R, Rui%on B, et al. The s'eletal conse?uences of gro"th hor one thera#y in children undergoing #eritoneal dialysis. ./++ 1su$ itted4 ,,. Ireen$au DA, Hidalgo I, Chand &, et al. 7$stacles to the #rescri$ing of gro"th hor one in children "ith chronic 'idney disease. Pediatr )e#hrol. .//0T.:2+5:+F+5:5. [Pu$Med] +//. R&7V* Clinical Practice Iuideline for )utrition in Children "ith CR&2 .//0 u#date. Q=ecuti!e su ary. A L Ridney &is. .//,T5:1: Su##l .42S++FS+/3. [Practice Iuideline] [Pu$Med] +/+. >urth SD, Sta$lein &, >ine 8), et al. Ad!erse clinical outco es associated "ith short stature at dialysis initiation2 a re#ort of the )orth A erican Pediatric 8enal Trans#lant Coo#erati!e Study. Pediatrics. .//.T+/,2,/,F,+:. [Pu$Med] +/.. *$rahi S, 8ashed D. Seru fi$ro$last gro"th factor-.: le!els in chronic hae odialysis #atients. *nt (rol )e#hrol. .//,T3+2+-:F+-,. [Pu$Med]

5
Lournal of trace ele ents in Trace Qle ents 1IMS4 Author Manuscri#t )*H Pu$lic Access edicine and $iology 2 organ of the Society for Minerals and

9)/:RA)/D !)RA)/: /! 9//D/D )" +R/=/9) R"9 D/; C /9C> A9D )" +R"M")/ /AR8> C% 8D D/=/8"+M/9)
Maureen M. Blac' Additional article infor ation

Abstract
*ron deficiency 1*&4 and iron deficiency ane ia 1*&A4 are glo$al #u$lic health #ro$le s that differentially i #act #regnant "o en and infants in lo" and iddle inco e countries. *&A during the first +/// days of life 1#renatally through .3 onths4 has $een associated "ith long ter deficits in childrenGs socio-e otional, otor, cogniti!e, and #hysiological functioning. Mechanis s lin'ing iron deficiency to childrenGs de!elo# ent ay include alterations to do#a ine eta$olis , yelination, and hi##oca #al structure and functionT as "ell as aternal de#ression and unres#onsi!e caregi!ing, #otentially associated "ith aternal *&. *ron su##le entation trials ha!e had i=ed success in #ro oting childrenGs de!elo# ent. Q!idence suggests that the ost effecti!e inter!entions to #re!ent iron deficiency and to #ro ote early child de!elo# ent $egin early in life and integrate strategies to ensure ade?uate iron and nutritional status, along "ith strategies to #ro ote res#onsi!e other-child interactions and early learning o##ortunities. Keywords: aternal iron deficiency, infant iron deficiency, aternal de#ression, caregi!ing other-child interaction,

ntroduction
*ron deficiency 1*&4 and iron deficiency ane ia 1*&A4 are aAor #u$lic health #ro$le s during #regnancy and infancy in ost lo" and iddle inco e countries [+,.]. Although rates of *&A ha!e declined in high inco e countries, iron deficiency re ains a concern in the (SA during #regnancy and infancy [:,3]. )ational esti ates of *& during #regnancy $ased on the )ational Health and )utrition Q=a ination Sur!ey 1)HA)QS4 are +0;, "ith ane ia at 5.3; [:]. *n contrast, in *ndia, the national rate of ane ia 1#ri arily *&A4 a ong #regnant "o en is -5F65; [5]. Causes of *&B*&A are thought to $e inade?uate inta'e of dietary iron, #oor $ioa!aila$ility of dietary iron fro fi$er and #hytate-rich diets, and increased iron re?uire ents during #regnancy. )ational data fro *ndia indicate that a ong young children, rates of *& are increasing, "ith the ost recent rates a ong +.F.: onth old children at 0/; [-].

nfant ron Re<uirements

*nfants $orn to others "ith *&A are at ris' for *& [6] and #otentially at ris' for lo" $rain aturation, es#ecially "hen cou#led "ith #re aturity [0]. The effects of lo" #renatal iron a##ear to contri$ute to #oor #erfor ance on tests of language co #rehension and the ina$ility to follo" directions o!er at least the first fi!e years of life, as sho"n in a follo"-u# of children "ith u $ilical cord seru ferritin concentrations C6- gBD [,]. The first +/// days of life 1#renatal and through .3 onths4 include high nutritional de ands to su##ort the ra#id gro"th and de!elo# ent that occur during this #eriod 1see >igure +4 [+/]. The *nstitute of Medicine esti ates that full-ter infants ha!e ade?uate iron stores for the first 3F- onths, "ith a dietary iron re?uire ent of /..6 gBday, "ell "ithin the a!erage iron content of $reast il' [6]. &uring the second -

onths of life, the de#letion of #renatally ac?uired iron stores, together "ith ra#id de!elo# ent and high nutritional de ands, increase the iron re?uire ent to ++ gBday [6]. )ot only is this le!el $eyond "hat is a!aila$le fro $reast il', $ut co #le entary foods are often lo" in iron, a'ing -F+. onth-old infants !ulnera$le to *&. After +. onths, the iron re?uire ent dro#s to 6 gBday through age : years [6]. Young children "ho consu e an iron-rich diet can eet this re?uire ent.

>igure + Qarly $rain de!elo# ent, the first +/// days, and iron re?uire ents, ada#ted fro Tho #son and )elson, .//+ [+/].

ron Deficiency and Child De#elopment

*& has $een lin'ed to delays in socio-e otional, cogniti!e, otor, and neuro#hysiological functioning [++,+.]. *& often occurs in the conte=t of other nutritional deficiencies as "ell as social and en!iron ental challenges, such as #o!erty and fa ily stress, a'ing it difficult to isolate the effects of *&. Chronic iron deficiency ay alter do#a ine eta$olis , yelination, and hi##oca #al structure and function, including long-ter geno ic changes [+:]. Both ani al studies [+:] and longitudinal follo"-u# studies of children "ho e=#erienced *& early in life [+3] ha!e suggested that the irre!ersi$ility of chronic *& #rior to .3 onths is #lausi$le, $ut not confir ed.

Mechanisms 8inking ron Deficiency and Child De#elopment

Although there is not conclusi!e e!idence regarding the direct effects of iron on childrenGs de!elo# ent, one #ossi$ility is through the neurotrans itter syste , #articularly do#a ine eta$olis [+5]. &o#a ine clearance has strong effects on attention, #erce#tion, e ory, oti!ation, and otor controlT lo" iron ay affect these functions $y interfering "ith yelination and do#a inergic function [+5]. Another #ossi$ility is that there ay also $e indirect effects of iron deficiency on childrenGs de!elo# ent. The hesitation and "ariness associated "ith *& ay a'e children less a$le to e!o'e and $enefit fro the social and en!iron ental o##ortunities necessary to facilitate early de!elo# ent. Alternati!ely, others of children "ith *& ay also $e *&, $ecause they often share the sa e diet [+-,+6]. Mothers "ith *& are less res#onsi!e than iron-sufficient others [+-] and #otentially less a$le to #ro!ide sti ulating caregi!ing $eha!ior.

Maternal ron Deficiency

A recent re!ie" re#orted e!idence lin'ing *& "ith aternal de#ressi!e disorders [+0]. Q!idence for a #ath"ay lin'ing *& "ith aternal de#ressi!e disorders co es t"o studies. 7ne sho"ed an association $et"een lo" aternal he oglo$in status and #ost#artu de#ression a ong (SA others 1n9:64 [+,] and the other "as a rando i%ed controlled trial a ong -3 others "ith *&A in South AfricaT others "ho recei!ed iron su##le ents sho"ed i #ro!e ent in de#ression, stress, and #arent res#onsi!ity [./F..]. Although these studies suggest an association $et"een *& and de#ression, they "ere conducted in settings "here rates of *&A a ong #regnant "o en are relati!ely lo" 1South Africa ,F+.; and (SA 5.3;4 [.:,.3], raising concerns that "o en "ith *&A ay $e uni?ue in other "ays that relate to their childrenGs de!elo# ent, such as #o!erty. Additional research is needed to understand ho" aternal iron deficiency is associated "ith care gi!ing $eha!ior. *& has $een lin'ed to de#ression through neurotrans itter #ath"ays, #articularly do#a ine [.5], raising the #ossi$ility that high rates of aternal de#ression in lo" and iddle inco e countries ay $e #artially attri$uta$le to the high rates of *&B*&A. Beha!ioral interaction #atterns, such as aternal sensiti!ity and res#onsi!ity also o#erate through do#a inergic #ath"ays [.-], raising the #ossi$ility that the association $et"een aternal de#ression and #oor caregi!ing $eha!ior ay $e #artially attri$uted to aternal *&B*&A.

Maternal Depressi#e Disorders

&e#ressi!e disorders are co on causes of or$idity throughout the "orld [.6]. The @orld Health 7rgani%ation esti ates that $y ././, de#ression "ill $e the second largest cause of disa$ility adAusted life years across all ages and $oth genders [.0]. 8ates of #erinatal de#ressi!e disorders are #articularly high in lo" and iddle inco e countries, "here they are often associated "ith #o!erty and gender dis#arities [.,]. The sy #to s associated "ith #erinatal ood disorders, including lethargy, difficulty "ith concentration, and lac' of attention to daily tas's can co #ro ise "o enGs caregi!ing $eha!ior [.,,:/]. &e#ressi!e disorders during #regnancy and throughout the first year of #arenting are relati!ely co on a ong "o en in lo" and iddle inco e countries, affecting +5F56; of others and co #rising a##ro=i ately +3; of the glo$al $urden of disease [.6]. )ot only do de#ressi!e disorders interfere "ith aternal functioning and caregi!ing $eha!ior, they often e=tend to the ne=t generation, co #ro ising infantsG gro"th and de!elo# ent [.,]. @ith e=tre ely li ited o#tions for treat ent [.,, :+], illions of "o en $egin #arenting "ith de#ressi!e disorders [:., ::]. *n a recent eta-analysis of aternal de#ressi!e disorders and early childhood gro"th, aternal de#ressi!e disorders had negati!e effects on childrenGs early gro"th, #articularly stunting, an indicator of chronic nutritional deficiencies [:3] that is often associated "ith unres#onsi!e care gi!ing #ractices. Maternal de#ressi!e ood has also $een associated "ith delays in childrenGs cogniti!e de!elo# ent a ong Bangladeshi children, ediated through unres#onsi!e care gi!ing #ractices [:5]. >indings lin'ing $oth nutrition and care gi!ing to childrenGs early gro"th de!elo# ent argue for the integration

of nutritional su##le ental #rogra s "ith early ho e !isiting and sti ulation #rogra s to ensure that children ha!e $oth the nutrients they need early in life and the care gi!ing o##ortunities to #ractice the s'ills they are ac?uiring.

ron !upplementation?;ortification
The @orld Health 7rgani%ation reco ends that in countries "here rates of *& are high and young children do not ha!e access to iron-rich food 1either through lac' of a!aila$ility, se!ere #o!erty, or religious or cultural tradition4, direct ethods, including su##le entation andBor fortification $e i #le ented to #re!ent *& [:-]. Although in o$ser!ational studies, iron deficiency has $een associated "ith ental and otor deficiencies [++,+.,:6], findings fro su##le entation trials ha!e not $een consistent. T"o re!ie"s on iron su##le entation a ong children under :- onths found no effects on early ental #erfor anceT a recent eta-analysis of fi!e iron su##le entation trials [:0] and a Cochrane re!ie" of short-ter iron su##le entation [:,] . T"o follo"-u# studies of school-age children 1age 6F, years4 "ho recei!ed iron ] %inc su##le entation during infancy sho"ed no long ter effects on cognition [3/,3+]. *n one study fro Thailand, iron ] %inc su##le entation "as gi!en for - onths $eginning at 3F - onths of age and cogniti!e functioning "as easured "ith glo$al easures and school #erfor ance [3/]. *n the other study fro )e#al, iron-folic acid or %inc "as gi!en to +.F:- onth old children "ho had #artici#ated in an antenatal su##le entation trial of iron or %inc, se#arately, and in co $ination [3+]. The iddle-childhood e!aluation included general easures of cognition, along "ith s#ecific easures of e=ecuti!e functioning and otor de!elo# ent, "ith no effects of the antenatal su##le entation. *n contrast, three follo"-u# studies of children "ho recei!ed iron su##le entation #renatally andBor during infancy ha!e sho"n long ter effects on cognition. *n a 6F, year follo"-u# of children "hose others recei!ed icronutrients during and shortly after #regnancy, there "ere $eneficial effects of iron-folic acid su##le entation on childrenGs "or'ing e ory, inhi$itory control, and fine otor functioning [3.]. *n a second e=a #le, a study fro China #ro!ided iron su##le ents "ith the goal of correcting the iron status of infants "ith iron deficiency ane ia 1*&A4. Children "hose iron deficiency "as corrected #rior to .3 onths did not differ in socio-e otional s'ills at age 3 years fro children "ho had ne!er e=#erienced iron deficiency [3:]. >inally, a rando i%ed trial of early ho e inter!ention in Chile recruited children "ith and "ithout *&A at - or +. onths of age and follo"ed the until age +/ years [33]. Qarly iron su##le entation and ho e inter!ention had $eneficial effects on childrenGs cogniti!e #erfor ance. These findings suggest that there ay $e long ter $eneficial effects of early iron su##le entation, #articularly "hen childrenGs iron deficiency is corrected and "hen they are in a sti ulating en!iron ent. At least t"o inter!ention trials highlight the i #ortance of considering the caregi!ing en!iron ent and the household conte=t "hen e!aluating the effects of icronutrient su##le entation on childrenGs de!elo# ent. *n La aica, the $eneficial effects of a %inc su##le entation trial on otor de!elo# ent "ere a##arent only in the conte=t of an early

sti ulation inter!ention [35], #resu a$ly $ecause the children had o##ortunities to #ractice the s'ills they "ere ac?uiring. Si ilarly, the trial conducted in Chile [33] included $oth iron su##le entation and a ho e inter!ention.

Conclusions
*& and *&A are aAor #u$lic health #ro$le s that can ha!e life-long negati!e conse?uences on childrenGs de!elo# ent. Q!idence suggests that the se?uelae of *& ay $e co #ro ised $y aternal de#ressi!e sy #to s and unres#onsi!e care gi!ing $eha!ior, "hich ay $e secondary to aternal *&. *nter!entions that integrate iron su##le entation and early caregi!ing o##ortunities ha!e $een reco ended as ideal strategies to #ro ote early child de!elo# entT ho"e!er e!idence on the efficacy of integrated inter!entions is li ited. >uture integrated trials are needed to e!aluate "hether inter!ention strategies that ensure $oth ade?uate iron status for young children and o##ortunities for early learning and res#onsi!e care gi!ing are successful in #ro oting early child de!elo# ent.

;ootnotes
+ublisher@s Disclaimer: This is a P&> file of an unedited anuscri#t that has $een acce#ted for #u$lication. As a ser!ice to our custo ers "e are #ro!iding this early !ersion of the anuscri#t. The anuscri#t "ill undergo co#yediting, ty#esetting, and re!ie" of the resulting #roof $efore it is #u$lished in its final cita$le for . Please note that during the #roduction #rocess errors ay $e disco!ered "hich could affect the content, and all legal disclai ers that a##ly to the Aournal #ertain.

Article information
L Trace Qle Med Biol. Author anuscri#tT a!aila$le in PMC ./+: Luly :/. Pu$lished in final edited for as2 L Trace Qle Med Biol. ./+. LuneT .-1/42 +./F+.:. Pu$lished online ./+. Lune .. doi2 +/.+/+-BA.Ate $../+../3././ PMC*&2 PMC:6.-,3/ )*HMS*&2 )*HMS:6.03+ Maureen M. Blac'a,d a &i!ision of Iro"th and )utrition, &e#art ent of Pediatrics, (ni!ersity of Maryland School of Medicine, Balti ore, Maryland. (SA d Corres#onding author2 Maureen M. Blac'T &e#art ent of Pediatrics, (ni!ersity of Maryland School of Medicine, 6:6 @. Do $ard Street, 8oo +-+, Balti ore, Maryland, .+./+, (SA2 Q ail2 $lac'BatB#eds.u aryland.edu Co#yright notice and &isclai er Pu$lisherMs &isclai er The #u$lisherMs final edited !ersion of this article is a!aila$le at L Trace Qle Med Biol

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Ad!ertising &isclai er

State-of-the-Art 8e!ie" Article

)he Diet ;actor in AttentionDeficit?%yperacti#ity Disorder

+. L. Iordon Millicha#, M& and .. Michelle M. Yee, CP)P ] Author Affiliations &. 'ivision of (eurology, $hildren)s #emorial *ospital, and 'epartment of Pediatrics, (orth+estern ,niversity #edical "chool, $hicago, -llinois )e=t Section

Abstract
This article is intended to #ro!ide a co #rehensi!e o!er!ie" of the role of dietary ethods for treat ent of children "ith attention-deficitBhy#eracti!ity disorder 1A&H&4 "hen #har acothera#y has #ro!en unsatisfactory or unacce#ta$le. 8esults of recent research and controlled studies, $ased on a Pu$Med search, are e #hasi%ed and co #ared "ith earlier re#orts. The recent increase of interest in this for of thera#y for A&H&, and es#ecially in the use of o ega su##le ents, significance of iron deficiency, and the a!oidance of the J@estern #atternK diet, a'e the discussion ti ely. &iets to reduce sy #to s associated "ith A&H& include sugar-restricted, additi!eB#reser!ati!e-free, oligoantigenicBeli ination, and fatty acid su##le ents. 7 egak: su##le ent is the latest dietary treat ent "ith #ositi!e re#orts of efficacy, and interest in the additi!e-free diet of the +,6/s is occasionally re!i!ed. A #ro!ocati!e re#ort dra"s attention to the A&H&-associated J@estern-styleK diet, high in fat and refined sugars, and the A&H&-free JhealthyK diet, containing fi$er, folate, and o ega-: fatty acids.

The literature on diets and A&H&, listed $y Pu$Med, is re!ie"ed "ith e #hasis on recent controlled studies. 8eco endations for the use of diets are $ased on current o#inion of #u$lished re#orts and our #ractice e=#erience. *ndications for dietary thera#y include edication failure, #arental or #atient #reference, iron deficiency, and, "hen a##ro#riate, change fro an A&H&-lin'ed @estern diet to an A&H&-free healthy diet. >oods associated "ith A&H& to $e a!oided and those not lin'ed "ith A&H& and #referred are listed. *n #ractice, additi!e-free and oligoantigenicBeli ination diets are ti e-consu ing and disru#ti!e to the householdT they are indicated only in selected #atients. *ron and %inc are su##le ented in #atients "ith 'no"n deficienciesT they ay also enhance the effecti!eness of sti ulant thera#y. *n #atients failing to res#ond or "ith #arents o##osed to edication, o ega-: su##le ents ay "arrant a trial. A greater attention to the education of #arents and children in a healthy dietary #attern, o itting ite s sho"n to #redis#ose to A&H&, is #erha#s the ost #ro ising and #ractical co #le entary or alternati!e treat ent of A&H&. RQY @78&S additi!e-free attention $eha!ior diet eli ination hy#eracti!ity iron 'etogenic oligoantigenic o ega-: #ediatrics sucrose %inc n A$$re!iations2 A&H& i attention-deficitBhy#eracti!ity disorder Q>A i essential fatty acids QP& i en%y e-#otentiated desensiti%ation *Ig i i unoglo$ulin I DC i long chain P(>A i #olyunsaturated fatty acids

The role of diet and dietary su##le ents in the cause and treat ent of attentiondeficitBhy#eracti!ity disorder 1A&H&4 in children is contro!ersial, $ut the to#ic continues to interest #arents and #hysicians "ho #refer an alternati!e to sti ulant edication or see' a co #le entary thera#y. Although #rescri#tion of edications for A&H& has sho"n a steady increase since their introduction in the +,-/s, the #o#ularity of !arious diets has risen andBor fallen in the sa e ti e #eriod, so eti es sho"ing a Phoenician re!i!al. *n the selection of a thera#y for A&H&, #hysicians generally #refer a edication of !alue #ro!en $y controlled trial. &iets are ore difficult to e!aluate, and trials re?uiring eli ination of certain foods and dyes ay need the su#er!ision of #hysician and dietician. The list of #ro#osed dietary treat ents includes sugar-restricted, additi!e- and salicylatefree 1>eingold diet4, oligoantigenic 1eli ination4, 'etogenic, ega!ita in, and #olyunsaturated fatty acid su##le ents 1P(>A4 diets. The P(>A or o ega-: su##le ent is the latest dietary A&H& treat ent to recei!e #ositi!e re#orts, "hereas the additi!e-free >eingold diet that enAoyed its initial #o#ularity in the +,0/s sho"s an occasional, s oldering re!i!al, es#ecially in the (nited Ringdo , Quro#e, and Australia. A recent #ro!ocati!e #u$lication fro Australia, the 8aine study, lin's A&H& in adolescents "ith a J@estern-styleK dietary #attern, high in fat, refined sugars, and sodiu and lo" in fi$er, folate, and o ega-: fatty acids.+ This re!ie" focuses on the literature concerning diets and A&H& selected fro a Pu$Med search. 8esults of recent research and controlled studies are e #hasi%ed. &iet reco endations in #ractice are $ased on the data #resented and on our e=#erience in a neurology clinic for children and adolescents "ith A&H&. *n addition to #har acothera#y, alternati!e andBor co #le entary ethods ay "arrant trial, including a JhealthyK diet #attern,+ eli ination of dyes or food antigens, or o ega-: P(>A su##le entation. Pre!ious Section)e=t Section

"mega-3 and -A ;atty Acid !upplements

Do" le!els of long-chain 1DC4 P(>A are re#orted in the #las a and red cells of children "ith A&H& co #ared "ith controls..,: The #otential echanis s leading to a$nor al essential fatty acid 1Q>A4 le!els in A&H& #atients ay include reduced Q>A inta'e, reduced con!ersion of Q>A to DC-P(>As and increased eta$olis of DC-P(>As.3 These and other si ilar re#orts #ro #ted trials of P(>A su##le ents in treat ent of children "ith A&H& and learning #ro$le s. A fre?uently cited trial, the 7=ford-&urha study,5 co #ared the effects of dietary su##le entation "ith o ega-: and o ega-- 1in a ratio of 0/; to ./;4 to #lace$o in ++6 children "ith de!elo# ental coordination disorder, one-third ha!ing sy #to s of A&H&. Co #aring the ConnersG Teacher 8ating Scale-DBA&H& scores, a reduction and i #ro!e ent of E/.5 S& occurred during the :- onth treat ent #hase, "hereas no change "as seen in the #lace$o grou# 1P C .///+4. &uring a :- to -- onth follo"-u#

#hase, a gain in reading "as : ti es that e=#ected, and s#elling ad!anced t"ice that e=#ected. *ncoordination, a co on A&H& co or$idity, "as not $enefited. )o ad!erse effects "ere re#orted.5 Although the #ri ary ai of this study directed to"ard alle!iation of incoordination "as not et, the results de onstrate a reduction of sy #to s of A&H&, an effect du#licated in other P(>A su##le ent trials.-,6 Ho"e!er, so e studies fail to sho" a $eneficial P(>A res#onse,0,, leading to the hy#othesis of a genetically i #aired fatty acid eta$olis in so e A&H& #atients.+/,++ 8e!ie" of +- studies of P(>A $lood le!els and P(>A dietary su##le entation in children "ith A&H& found only isolated re#orts fro +,,5 to .//- and a flurry of interest fro .//6 through ./++. Heterogeneity of design and other factors ay ha!e influenced res#onses and results2 the ty#e and dose of fatty acid e #loyed 1o ega-: or o ega-- or co $ination4, ethod of ad inistration, duration of treat ent, and easure ent of res#onse. 7n the $asis of re#orts of efficacy and safety, "e use doses of :// to -// gBday of o ega-: and :/ to -/ gBday of o ega-- >AS, continued for . or : onths, or longer if indicated. Ta$le + lists a sa #le of fatty acid su##le ents a!aila$le and the ?uantities of o ega-:, --, and -, in each. The "ide !ariation in o ega-: content is note"orthy. As initial or add-on thera#y, "e ha!e occasional re#orts of i #ro!ed school grades and lessening of sy #to s of A&H&, "ithout occurrence of ad!erse effects. Hie" this ta$le2 *n this "indo" *n a ne" "indo" TABDQ + 7 ega >atty Acid Su##le ents for Treat ent of Children "ith A&H& Most #arents are enthusiastic a$out trying the diet su##le ents, des#ite our e=#lanation of only #ossi$le $enefit and lac' of #roof of efficacy. *n al ost all cases, for treat ent to $e anaged effecti!ely, edication is also re?uired. Additional controlled studies of P(>A are "arranted, including larger nu $ers of #atients "ith different age ranges 1young and older children4, as "ell as !arious doses of o ega-: and o ega-- fatty acid, onitored "ith $lood le!els. Su$Aects "ith and "ithout Q>A deficiency should $e distinguished. @e agree "ith other in!estigators+. that although a lin' e=ists $et"een lo" DC-P(>A and A&H&, the $eneficial effects of o ega-: and o ega-- su##le ents are not clearly de onstrated. Pre!ious Section)e=t Section

Additi#e and !alicylate-free $;eingold& Diet

The history of the >eingold diet is "ell 'no"n to #hysicians "ho #racticed in the +,6/s.+: A elioration of sy #to s "as clai ed in E5/; of hy#eracti!e children treated. The

enthusias generated $y the edia led to #arental ad!ocacy grou#s, necessitating federally su##orted scientific trials. Controlled studies failed to confir the effecti!eness of the diet to the e=tent clai ed.+3,+5 )e!ertheless, a s all su$grou# of #reschool children res#onded ad!ersely to additi!es and #reser!ati!es ad inistered as a challenge.+- An occasional child ight react ad!ersely to dyes and #reser!ati!es in foods and ight $enefit fro their eli ination. *nterest in additi!es in relation to A&H& has "aned in the (nited States. *n the decade +,6,F+,00, a Pu$Med search lists ./ #ertinent articlesT in the . decades fro +,,/ through ./+/, only . are recorded. Articles a##earing in ./+/F./++ #oint to a rene"ed interest in food additi!es and A&H&.+6F+, *n the latest article,+, referring to :5 years of research on dietary sensiti!ities and A&H& sy #to s, a literature re!ie" sho"s that of children "ith sus#ected sensiti!ities, -5; to 0,; react "hen challenged "ith +// g of artificial food colors. *n addition to $eing sensiti!e to these additi!es, so e children are sensiti!e to co on nonsalicylic foods, and cosensiti!ity is ore the rule than the e=ce#tion. A trial co $ination antigen- and additi!e-free diet ay $e a##ro#riate thera#y for children "ith sensiti!ities to food antigens or allergens and to dyes../,.+ Ato#ic children "ith A&H& ha!e a significantly higher res#onse rate to a ulti#le-ite eli ination 1foods, artificial colorings, and #reser!ati!es4 diet than does a nonato#ic grou#... According to the >eingold diet,+: foods to $e a!oided include a##les, gra#es, luncheon eats, sausage, hot dogs, and cold drin's containing artificial fla!ors and coloring agents. 8ed and orange synthetic dyes are es#ecially sus#ect, as "ell as #reser!ati!es, $utylated hydro=ytoluene and $utylated hydro=yanisole. >oods #er itted include gra#efruit, #ears, #inea##le, and $ananas, $eef and la $, #lain $read, selected cereals, il', eggs, and !ita ins free of coloring. A #arent "ishing to follo" this diet needs #atience, #erse!erance, and fre?uent e!aluation $y an understanding #hysician and dietician. The sa e degree of #atience and follo"-u# is re?uired "ith the oligoantigenic 1eli ination4 diet for A&H&. Pre!ious Section)e=t Section

"ligoantigenic $%ypoallergenic?/limination& Diet

An oligoantigenic diet eli inates ost 'no"n sensiti%ing food antigens or allergens. >oods often found to $e allergenic include co"Gs il', cheese, "heat cereals, egg, chocolate, nuts, and citrus fruits. Q=a #les of hy#oallergenic foods include la $, #otato, ta#ioca, carrots, #eas, and #ears. S'in tests for allergic reacti!ity to foods are unrelia$le, and eli ination diets are re?uired to test for s#ecific food intolerances. An early controlled trial of an oligoantigenic diet in 6- hy#er'inetic children found that sy #to s i #ro!ed in -. 10.;4, and nor al $eha!ior "as achie!ed in .. 1.,;4..: The diet consisted of . eats 1la $ and chic'en4, . car$ohydrates 1rice and #otatoes4, . fruits 1$anana and a##le4, !egeta$les and calciu and !ita ins for 3 "ee's. A su$se?uent dou$le-$lind study, using a Jfe" foodsK eli ination diet, re#orted i #ro!e ent in 6-;

#atients and "orsening of $eha!ior ratings and cogniti!e tests after #ro!o'ing food challenge..3 The ter Jeli ination dietK is no" ore #o#ular than Joligoantigenic,K "ith Pu$Med listing +3 articles under the for er and 3 using the latter title, the aAority fro the (nited Ringdo and Quro#e. *nterest in the oligoantigenicBeli ination diet has increased, $ut studies ha!e #ro!ided i=ed o#inions of efficacy. A #artial $enefit of the diet "as de onstrated in a s all cohort of .+ children tested "ith $oth su$Aecti!e and o$Aecti!e easures..5 The effect "as significant for su$Aecti!e, $ut not o$Aecti!e, easures. The oligoantigenic diet ay influence only certain di ensions of the A&H& syndro e. A ore fa!ora$le effect follo"ed a fe" foods eli ination diet 1containing rice, tur'ey, #ear, and lettuce4 in 3/ children, :- $oys and 3 girls, aged : to 6 years, diagnosed "ith A&H&..- T"enty-fi!e #atients 1-.;4 sho"ed an i #ro!e ent in $eha!ior of a5/;, , 1.:;4 "ithdre" fro the study, and +/ 1.5;4 had i #ro!ed #arent and teacher ratings. *n this controlled study, the eli ination diet resulted in a statistically significant decrease in sy #to s of A&H&. The effecti!eness of the diet is de onstrated $y a larger rando i%ed controlled trial in an unselected grou# of +// children.6 in the * #act of )utrition on Children "ith A&H& study in the )etherlands. This study consisted of an o#en-la$el #hase 1#hase +T 5 "ee's of a restricted eli ination diet or healthy control diet4 follo"ed $y a dou$le-$lind crosso!er, challenge #hase 1#hase .4. 8es#onders to challenge "ith high- or lo" i unoglo$ulin 1*g4 I foods sho"ed an increase of ./.0 #oints on the A&H& rating scale 1P C .///+4 and an ++.- increase of a ConnersG Score 1P C .///+4. After the challenge, rela#se of A&H& sy #to s occurred in +, of :/ 1-:;4 children, inde#endent of the *gI $lood le!els. The utility of *gI $lood tests is unsu##orted, $ut the effecti!eness of a su#er!ised, restricted eli ination diet is an indication of the influence of food on A&H&. >or so e in!estigators, ho"e!er, the role of the eli ination diet in the treat ent of A&H& re ains uncertain..0,., The re#ort generated criticis that the study did not #er it the un?ualified reco endation of dietary treat ent in all children "ith A&H&,:/ and a #lace$o effect could not $e e=cluded.:+ The diagnosis of food sensiti!ity is co #le=, ti e-consu ing, and so eti es too $urdenso e for #atient, fa ily, and #hysician. *n selected #atients "ith diligent #arents, a short .- to :-"ee' #eriod of restricted eli ination diet is Austified. *n #atients $enefited $y the diet, restricted foods are introduced each "ee', + at a ti e, until the offending ite or ite s are identified. * #ro!e ents in $eha!ior ay $e delayed for +/ days to . "ee's, and food #referred and consu ed ost is often the offending ite . Pre!ious Section)e=t Section

;ood Antigen Desensiti-ation

Ter s used for food intolerance include Jfood sensiti!ity,K Jfood allergy,K or Jfood hy#ersensiti!ity,K and J#sychologically deter ined food a!ersions.K:. >ood allergy "as in!estigated $y a trial of en%y e-#otentiated desensiti%ation 1QP&4 in 3/ children "ith food-induced hy#er'inetic $eha!ior disorder.:: 7f ./ "ho recei!ed acti!e QP& treat ent, +- $eca e tolerant of #ro!o'ing foods co #ared "ith 3 of ./ ta'ing #lace$o 1P C .//+4. QP& #er itted children to eat foods #re!iously 'no"n to #ro!o'e sy #to s. >ood allergy is a #ossi$le echanis of the hy#er'inetic syndro e, and research in!ol!ing the influence of food triggers could infor clinicians on !ia$le alternati!e andBor su##orti!e i unothera#y.:3 Pre!ious Section)e=t Section

!ugar, Aspartame, and AD%D

Parents of children "ith A&H& fre?uently re#ort a "orsening of hy#eracti!ity after an e=cessi!e ingestion of candy or diet soda. *solated re#orts su##ort the #arentsG o$ser!ations, $ut the aAority of controlled studies fail to de onstrate a significant ad!erse effect of sucrose or as#arta e. A Pu$Med search for Jsugar, as#arta e, and A&H&K listed 0 articles, dated +,03 through +,,5. *n a controlled trial in!ol!ing #reschool and school-age children descri$ed $y #arents as sensiti!e to sugar, diets high in sucrose or containing as#arta e and free of additi!e had no effect on childrenGs $eha!ior or cogniti!e function.:5 This article #ro!o'ed uch corres#ondence, ainly critical of the negati!e conclusion. The authorsG su$se?uent eta-analysis of +- re#orted studies, identified through Medline and Psych*)>7 data$ases, concluded that sugar does not usually affect the $eha!ior or cogniti!e #erfor ance of children, $ut a s all effect on su$sets of children cannot $e ruled out.:- *n #reschool $oys aged . to - years rated $y #arents as Jsugar res#ondersK and Jnonres#onders,K neither acute sugar loading nor as#arta e increased acti!ity le!el or aggression, $ut the daily sucrose inta'e and total sugar consu #tion correlated "ith duration of aggression.:6 *nattention "as increased after sugar inta'e, $ut not as#arta e or saccharine. The sugar and #lace$o challenges "ere gi!en "ith a $rea'fast high in car$ohydrate, a #ossi$le reason for the ad!erse effect of the sucrose challenge.:0 The hy#eracti!e res#onse is $loc'ed if a #rotein eal is ingested $efore or "ith the sugar.:,

Reacti#e %ypoglycemic Response to !ugar 8oad

An alternati!e e=#lanation for sugar-induced cogniti!e i #air ent and inattention ay $e a reacti!e hy#oglyce ia. Co #ared "ith adults, children are ore !ulnera$le to the effects of hy#oglyce ia on cogniti!e function. A easure of cogniti!e function using auditory e!o'ed #otentials "as significantly reduced "hen $lood glucose "as lo"ered C65 gBdD in children $ut "as #reser!ed in adults until the le!el fell to 53 gBdD.3/ As#arta e used as a control had no ad!erse effects on $eha!ior or cognition in children "ith attention-deficit disorder.3+ The a!oidance of ra#idly a$sor$ed sucrose-containing foods in young children ay #re!ent diet-related e=acer$ations of A&H&.

*n a study of adolescents "ith insulin-de#endent dia$etes ellitus, ild hy#oglyce ia 1-/ gBdD4 caused a significant transient decline in #erfor ance of a $attery of cogniti!e tests, "hereas hy#erglyce ia had no effect.3. The frontal corte=, 'no"n to $e in!ol!ed in the control of attention, "as ore highly acti!ated than other $rain regions during acute hy#oglyce ia.3: Children "ith food-induced A&H& sho" an increase in c acti!ity in frontote #oral areas during QQI to#ogra#hic a##ing of $rain electrical acti!ity after ingestion of #ro!ocati!e foods.33

!ugar and the //:

The effects of sugar and es#ecially hy#oglyce ia on the QQI ha!e $een studied since the late +,:/s.35,3- Do" $lood sugar le!els are associated "ith an i #air ent of the nor al electrical acti!ity of the cere$ral corte=. A deficiency of glucose to the $rain causes the a##earance of slo" rhyth s in the QQI, "ith fall in the do inant b fre?uency and a##earance of o and finally p fre?uency. *t is not sur#rising that a sugar load "ould cause an increase in faster c rhyth s in the QQI.33 An electro#hysiologic a##roach, using QQI $iofeed$ac' 1neurofeed$ac'4, in su##ort of a #ossi$le relation $et"een sugar and sy #to s of A&H& re?uires additional study. Ho"e!er, studies of QQI $iofeed$ac' in the treat ent of A&H& #ro!ide i=ed results and #ossi$le $enefit, "ith i #ro!e ent in only selected attentional $rain functions.36 *n #ractice, the lin' $et"een sugar and hy#eracti!e $eha!ior is so uni!ersal in the o#inion of #arents of children "ith A&H& that no controlled study or #hysician counsel is li'ely to change this #erce#tion. Parents "ill continue to restrict the allo"ance of candy for their hy#eracti!e child at Hallo"een in the $elief that this "ill cur$ the le!el of e=u$erant acti!ity, an e=a #le of the Ha"thorne effect. The s#ecific ty#e of thera#y or disci#line ay $e less i #ortant than the attention #ro!ided $y the treat ent..+

)he Ketogenic Diet and AD%D

The 'etogenic diet, a diet high in fat content and lo" in car$ohydrate, "as introduced for the treat ent of e#ile#sy in +,.+.30 The echanis is still unclear, $ut eta$olic $alance studies in children "ith a$sence sei%ures sho" that the antie#ile#tic effect of the diet is correlated closely "ith a negati!e $alance of sodiu and #otassiu .3, The reintroduction of car$ohydrate to the diet is associated "ith recurrence of s#i'e-and-"a!e e#ile#tifor discharges in the QQI. *n -5 children "ith intracta$le sei%ures, treat ent "ith the 'etogenic diet "as effecti!e in control of sei%ures at +-year follo"-u#, and de!elo# ental ?uotients, $eha!ior, attention, and social functioning "ere significantly i #ro!ed.5/ Children "ith e#ile#sy fre?uently e=hi$it sy #to s of A&H&, and children "ith A&H& ha!e a high fre?uency of e#ile#tifor discharges in the QQI.5+ Ani als recei!ing a 'etogenic diet sho" a re!ersi$le decrease in acti!ity le!el.5. The QQI, of !alue in #rediction of a sustained anticon!ulsant effect,5: ay also #ro!e indicati!e of a $eha!ioral res#onse to the 'etogenic diet. Pre!ious Section)e=t Section

ron Deficiency and AD%D

*ron deficiency is associated "ith a nu $er of neurologic disorders, including $reathholding, restless leg syndro e, and fe$rile sei%ures. A re#ort of lo" seru ferritin in children "ith cogniti!e and learning disorders53 #ro #ted the inclusion of a seru ferritin le!el in the $attery of la$oratory tests o$tained on #atients attending our neurology clinic for A&H&. *n our hos#ital la$oratory, the range of control seru ferritin le!els is :// ngB D "ith a lo" of .. ngB D in ales and +/ ngB D in fe ales. *n -0 consecuti!e #atients 1aged 5F+- yearsT 53 ale, +3 fe ale4, the ean seru ferritin le!el in #atients "ith A&H& "as :,., ngB D and "as not different fro control su$Aects. T"el!e 1+0;4 #atients had !alues C./ ngB D that "ere considered a$nor al and suggesti!e of iron deficiency "ithout ane ia, and a si ilar nu $er had le!els E-/ ngB D and "ere not iron deficient. A co #arison of clinical characteristics of the lo"-ferritin and high-ferritin grou#s disclosed no significant difference in se!erity or fre?uency of A&H& and co or$id sy #to s or res#onse to drug thera#y. *n this #atient cohort, a causati!e role for lo" seru ferritin and iron deficiency in A&H& "as not confir ed.55 *n an earlier study of the effects of iron su##le ents in A&H& children in *srael, a significant increase in seru ferritin le!els 1.5.,F33.- ngB D4 "as associated "ith a significant decrease in the ConnersG Parent 8ating Scale $ut not in the TeachersG 8ating Scales.5- *n later studies of children "ith A&H& in >rance, the #ro#ortion "ith lo" 1C:/ ngB D4 and !ery lo" 1C+5 ngB D4 seru ferritin le!els "as greater than that of our #atients in the (nited States2 03; !ersus :.;.56 Do" seru ferritin le!els "ere correlated "ith ore se!ere A&H& sy #to s easured "ith ConnersG Parent 8ating Scale and greater cogniti!e deficits. A trial of iron su##le entation found i #ro!e ents in $eha!ior rating scales, $ut this finding did not reach significance.50 A threshold effect ay $e i #ortant in the e!aluation of a #ro#osed causati!e role of iron deficiency in A&H&, and additional controlled studies are #ro$a$ly "arranted. The unusually lo" ferritin le!els 1 ean2 +0.3 ngB DT .:; #artici#ants C6 ngB D4 encountered in a recent study of A&H& children in *o"a City ay e=#lain the o$ser!ed correlation "ith A&H& sy #to scores.5, Do" seru ferritin "as correlated "ith $aseline inattention, hy#eracti!ity, and i #ulsi!ity and also "ith the dose of a #heta ine re?uired to o#ti i%e a clinical res#onse. Seru ferritin and iron su##le entation as #otential #redictor or inter!ention to o#ti i%e sti ulant thera#y is a no!el indication for additional study of iron deficiency and A&H&. Pre!ious Section)e=t Section

Binc Deficiency and AD%D

Pu$lished re#orts of the role of %inc in A&H& sho" lo" %inc le!els in seru , red cells, hair, urine, and nails of affected children.-/ Most re#orts are fro the Middle Qastern countries, Tur'ey and *ran, areas "ith sus#ected ende ic %inc deficiency. T"o #lace$ocontrolled trials, one of %inc onothera#y and the other of %inc su##le entation of

ethyl#henidate, re#ort significant $enefit.-+,-. *n one study in!ol!ing children in the (nited States, lo" seru %inc le!els correlated "ith #arentBteacher-rated inattention $ut not "ith hy#eracti!ityBi #ulsi!ity. -: Winc su##le ents enhanced the $enefit fro da #heta ineT the o#ti al dose of sti ulant "as :6; lo"er "ith %inc than "ith #lace$o.-3 Winc is a cofactor for eta$olis of neurotrans itters and fatty acids and also regulates do#a ine eta$olis in!ol!ed in A&H&. The relationshi# of %inc to Q>A su##le ents and sti ulants e!aluated in treat ent of A&H& found that the d-a #heta ine res#onse "as linear "ith %inc nutrition. >atty acids ay $enefit A&H& $y i #ro!ing or co #ensating for $orderline %inc nutrition.-5 Although %inc su##le ents are of !alue in treat ent of Middle Qastern children "ith A&H& associated "ith ende ic %inc deficiency, the incor#oration of %inc in the thera#y of A&H& in the (nited States is less "ell defined. Pre!ious Section)e=t Section

"ther Alternati#e Dietary )herapies for AD%D

The conce#t of ortho olecular 1Jright oleculeK4 edicine and ega!ita in thera#y refers to the use of a co $ination of nutrients and inerals alleged to #ro!ide the o#ti u olecular en!iron ent for the ind. The treat ent, su$se?uently ad!ocated for children "ith hy#eracti!ity, as "ell as for ental retardation and &o"nGs syndro e, -- is of un#ro!en !alue. *n a dou$le-$lind crosso!er study of ega!ita in thera#y in 3+ children "ith A&H&, no significant i #ro!e ent "as de onstrated in $eha!ior scores, and .5; "ere ore disru#ti!e 1P C ./+4.-6 Seru transa inase le!els e=ceeded the u##er li its of nor al in 3.; children "hile recei!ing !ita ins. Megadoses of so e !ita ins are not "ithout danger of he#atoto=icity, and their efficacy is unconfir ed. Mineral analyses, es#ecially iron and %inc, ay $e "arranted in children "ith A&H& and learning disorders, $ut the need for ade?uate controls and $lood le!els is e #hasi%ed. Treat ent $ased on inaccurate easure ent techni?ues ay lead to ad!erse reactions..+ Pre!ious Section)e=t Section

C%ealthyD Diet +attern in +re#ention and )reatment of AD%D

*n the Australian 8aine study, the relationshi# $et"een dietary #atterns and A&H& "as e=a ined in a #o#ulation-$ased cohort of li!e $irths follo"ed to age +3.+ T"o aAor dietary #atterns "ere identified as JHealthyK and J@estern,K according to foods considered the ain contri$utors. 1Ta$le .4 The @estern dietary #attern associated "ith an A&H& diagnosis contains higher inta'es of total fat, saturated fat, refined sugars, and sodiu and is deficient in o ega-: fatty acids, fi$er, and folate. The Healthy diet #attern,

not associated "ith A&H& diagnosis, is rich in fish, !egeta$les, fruit, legu es, and "hole-grain foods. A higher ris' of ha!ing an A&H& diagnosis, inattenti!e or co $ined ty#es, is o$ser!ed for $oys co #ared "ith girls. The aAor s#ecific foods in a @estern diet are also contri$utory to an increased tendency to o$esity a ong non edicated A&H& children and adolescents.-0 Hie" this ta$le2 *n this "indo" *n a ne" "indo" TABDQ . >oods to A!oid and >oods Preferred in Children "ith A&H& The relationshi# $et"een a @estern dietary #attern and A&H& ay $e ediated $y other factors, such as #oor fa ily functioning and e otional distress, leading to a cra!ing for fat-rich snac' foods. @hate!er the s#ecific cause, a odification of the childGs dietary #attern ay offer an alternati!e ethod of treat ent of A&H& and less reliance on edications. Pre!ious Section)e=t Section

!ummary and Conclusions

Harious alternati!e thera#ies for A&H& are offered as su$stitutes or su##le ents to edication and $eha!ioral treat ents. The e!aluation of clai s for thera#ies in a disorder such as A&H&, "ithout a single, "ell-defined cause, is a scientific challenge re?uiring controls and a##ro#riate neuro#sychological testing. The indications for diet thera#y include the follo"ing2 1+4 edication failure or ad!erse reaction, 1.4 #arent or #atient #reference, 1:4 sy #to s or signs of ineral deficiency, and 134 the need to su$stitute an A&H&-free healthy diet for an A&H&-lin'ed diet.+ &iet is one en!iron ental etiology of A&H& that is a ena$le to odification.-, 7ligoantigenic, eli ination, and additi!e-free diets are co #licated, disru#ti!e to the household, and often i #ractical, e=ce#t for selected #atients. Su##le ental diet thera#y is si #le, relati!ely ine=#ensi!e, and ore acce#ta$le to #atient and #arent. Pu$lic education regarding a healthy diet #attern and lifestyle to #re!ent or control A&H& ay ha!e greater long-ter success. Pre!ious Section)e=t Section

;ootnotes
o

Acce#ted 7cto$er 5, ./++.

Address corres#ondence to L. Iordon Millicha#, M&, &i!ision of )eurology, ChildrenGs Me orial Hos#ital, .:// ChildrenGs Pla%a, Bo= 5+, Chicago, *D -/-+3. Q- ail2 g illicha#mchildrens e orial.org &r Millicha# re!ie"ed the literatureT researched and selected a##ro#riate articlesT and organi%ed, drafted, and re!ised the anuscri#t in its final !ersion. )urse Practitioner Yee is clinical associate to the neurology clinic for attentiondeficitBhy#eracti!ity disorder. Yee assisted in the selection of articles and references, collected the data for the ta$le of q su##le ents, read the anuscri#t, and ade suggestions for re!ision in its final for . ; 9A9C A8 D !C8"!'R/: The authors ha!e indicated they ha!e no financial relationshi#s rele!ant to this article to disclose.

Pre!ious Section

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7
Journal of the International Neuropsychological ociety ! JIN "uthor #anuscript NI$ %u&lic "ccess

9octurnal "(ygen Desaturation and Disordered !leep as a +otential ;actor in /(ecuti#e Dysfunction in !ickle Cell Anemia
Matthe" L. Holloc's, Tessa B. Ro', [...], and Michelle de Haan Additional article infor ation

Abstract
Pre!ious research has identified cogniti!e i #air ent in children "ith sic'le cell ane ia 1SCA, He oglo$in SS4 co #ared "ith controls, #artly accounted for $y o!ert neuro#athology after clinical stro'e, Jco!ertK 1JsilentK4 infarction, and se!erity of ane ia. Ho"e!er, cogniti!e deficits ha!e also $een identified in children "ith SCA "ith no history of stro'e and a nor al T.-"eighted agnetic resonance i aging 1M8*4 scan. 7ur ai "as to in!estigate "hether nocturnal he oglo$in o=ygen desaturation and slee#

frag entation could $e associated "ith cogniti!e i #air ent in children "ith SCA. @e assessed +/ children "ith SCA 1, "ith nor al M8*4 using neuro#sychological easures of e=ecuti!e function. Cogniti!e assess ent "as i ediately follo"ed $y o!ernight #olyso nogra#hy to record nocturnal he oglo$in o=ygen saturation and slee# arousals. &ecreases in he oglo$in o=ygen saturation andBor increased slee# arousals "ere associated "ith reduced #erfor ance on cogniti!e assess ent. )octurnal he oglo$in o=ygen desaturation and slee# frag entation ay $e a contri$uting factor to e=ecuti!e dysfunction in SCA.
Keywords: "ne'ia( ic)le cell( Intelligence( Neuropsychology( *+i'etry( leep arousal ,isor,ers( %olyso'nography

9)R"D'C) "9
Ho o%ygous sic'le cell ane ia 1SCAT H$SS4 is a disorder in "hich a gene utation leads to the for ation of a sic'le he oglo$in olecule containing an a$nor al glo$in #rotein. Although retaining the a$ility to carry o=ygen, the a$nor ality causes the cell to #oly eri%e after deo=ygenating, for ing the rigid sic'le sha#e "hich has #athological conse?uences 1Schat% Y McClellan, .//-4. The incidence of stro'e is high and the #athology ty#ically in!ol!es the large arteries su##lying anteriorF iddle cere$ral $oundary %ones 18oth an, >ulling, Y )elson, +,0-4.

Mechanisms of 9europsychological mpairment in !CA

So e children "ith SCA and neuro#sychological deficit ha!e Jco!ertK or JsilentK infarction, "hich refers to infarctions detecta$le on T.-"eighted M8* at +.5 Tesla 1T4 $ut "ithout a focal neurological deficit lasting E.3 hr and ty#ically s aller than those associated "ith o!ert stro'e. Q!en in the a$sence of o!ert infarction, *V is significantly lo"er in children "ith SCA than age atched controls 105.- vs. ,+..T Schat%, Bro"n, Pascual, Hsu, Y &eBaun, .//+T Schat%, >in'e, Rellett Y Rra er, .//.4. The cause of cogniti!e i #air ent in the a$sence of o$!ious infarction on T.-"eighted M8* is unclear, $ut in #art ay $e related to hy#o=ia related to ane ia, a hall ar' of the disease 1Iold, Lohnson, Tread"ell, Hans, Y Hichins'y, .//0T Steen et al., .//54.

!CA and /(ecuti#e ;unctions

*n addition to a significant reduction in intellectual functioning children "ith SCA are at ris' for deficits in any s#ecific cogniti!e do ains, including e=ecuti!e functioning. 7ne study re#orted that 5:; of H$SS children "ith silent infarction had deficits in e=ecuti!e function, co #ared to +:; of H$SS children "ith no infarctions and /; of control si$lings "ithout SCA 1Schat% et al., .//+4.

/ffects of 9octurnal hemoglobin desaturation and disrupted sleep

7ne echanis "hich ay account for the #resence of e=ecuti!e dysfunction in the a$sence of o$!ious neuro#athology is lo" he oglo$in o=ygen saturation associated "ith

slee#-disordered $reathing 1S&B4 and the resulting slee# frag entation caused $y increased slee# arousals. S&B is relati!ely co on in children "ith SCA, "ith one grou# re#orting 3/; affected 1)eedle an et al., +,,,4. Slee# disru#tion has $een sho"n to ha!e a negati!e i #act on attention and e=ecuti!e function in adults 1@aters Y Buc's, ./++4. Children "ith S&B e=hi$it disru#ted slee# and o=ygen desaturation lin'ed to a degree of e=ecuti!e dysfunction not accounted for $y dayti e slee#iness 1Bee$e and Io%al, .//.T Bour'e et al., ./++4. The ai of this study "as to in!estigate any association of nocturnal o=ygen saturation and slee# ?uality "ith neuro#sychological easures of e=ecuti!e functioning. There "as a #articular focus on neurologically nor al children "ith SCA "ho had a nor al T."eighted M8* to #ro!ide insight into #otential echanis s related to cogniti!e #ro$le s in the a$sence of infarction.

M/)%"D!
+articipants
This study "as re!ie"ed and a##ro!ed $y the Brent )ational Health Ser!ice research ethics co ittee. Partici#ants "ith ho o%ygous SCA "ere recruited in Dondon during A#ril to Se#te $er .//, fro a sa #le enrolled "ith the Slee# Asth a Cohort study, a three-site 5-year 1.//5F./+/4 o$ser!ational study 1Lohnson et al., ./+/4, "hich included .:- children. 7n arri!al, consentBassent fro the #arentBguardian and child "ere confir ed and the neuro#sychological assess ent "as ad inistered, ta'ing a##ro=i ately 5/ in. >ollo"ing a short $rea', the child "as #re#ared for and under"ent o!ernight #olyso nogra#hy 1Lohnson et al., ./+/4. The follo"ing orning, #artici#ants under"ent a transcranial &o##ler 1TC&4.

Materials

)ests of e(ecuti#e function

Delis-Kaplan Executive Function Systems (D-KEFS)
Q=ecuti!e functioning "as assessed using t"o su$tests fro the &-RQ>S assess ent $attery 1&elis, Ra#lan, Y Rra er, .//+4. The &-RQ>S To"er test easures s#atial #lanning, rule learning, and inhi$ition of i #ulsi!e res#onding. The o!erall achie!e ent score is $ased u#on the nu $er of correct to"ers and ho" any o!es ta'en to co #lete the to"er. The &-RQ>S Sorting test easures #ro$le sol!ing, conce#t for ation and conce#tual reasoning. Scores for the &-RQ>S sorting test are gi!en for the accuracy of sorts and descri#tion of sorts.

Behaviour Rating Inventory of Executive Functions (BRIEF) Form

!arent

The B8*Q> #arent for is a #arental rating ?uestionnaire containing 0- ?uestions relating to eight clinical scales $elonging to one of t"o do ains, $eha!ioral regulation inde= 1B8*4 and the eta-cognition inde= 1MC*4, "hich are co $ined to gi!e the general e=ecuti!e co #osite 1IQC4 score. The scale #ro!ides age and gender $ased t scores "ith a higher score indicating #oorer e=ecuti!e functions 1Mean 9 5/T "' 9 +/4 1Iioia, *s?uith, Iuy, Y Ren"orthy, .///4.

)ests of intelligence
"echsler #$$reviate% Scale of Intelligence ("#SI)
The @AS* "as selected as a relia$le $ut $rief easure of intelligenceT due to ti e constraints, only the t"o ite !ersion "as ad inistered in +5 in. This for contains only the !oca$ulary and atri= reasoning ite s $ut #ro!ides an esti ate for full-scale *V 1>S*VT @echsler, +,,,4.

+olysomnography
Standard slee# ac?uisition syste s 1Q $la )-3///, Broo field, C74, sensors, and data collection #rocedures "ere used and follo"ed current #rofessional society standards for o!ernight collection of slee# and $reathing data in children e=ce#t that car$on dio=ide "as not easured 1Lohnson et al., ./+/4. Cardiores#iratory sensors in the SAC #rotocol included2 chest and a$do inal "all otion $y inducti!e #lethys ogra#hy 1Q $la SactTracer $ands, Broo field, C74, airflo" $y $oth nasal #ressure cannula and $y oronasal $y ther ocou#le 1Pro-Tech Ser!ices, @oodin!ille, @A4, and he oglo$in o=ygen saturation $y #ulse o=i etry 1S#7.4 1Masi or 8ad-0 o=i eter, *r!ine, CA4. >ull-channel o!ernight #olyso nogra#hy started at the childGs usual $edti e and ended at the childGs s#ontaneous "a'ing or as late as 62// a. . Studies "ere centrally scored $y research assistants at the Case Slee# 8eading Center 1Cle!eland, 7H4 "ho "ere $linded to clinical correlates 1Lohnson et al., ./+/4. Arousals and res#iratory e!ents "ere scored using reco ended #ediatric criteria, e=ce#t that arousals alone "ere not used to define hy#o#neas. 8es#iratory !aria$les included the o$structi!e a#nea hy#o#nea inde= [hy#o#nea corro$orated $y at least a :; desaturation 17AH*4, ean and ini u S#7., and #ercent of total slee# ti e "ith saturation !alues $elo" ,5;].

Data Analysis
Rey !aria$les "ere not nor ally distri$uted so non-#ara etric statistics "ere used. &ata analysis, first, consisted of an e=#loratory analysis of the #artici#antsG #erfor ance on neuro#sychological easures of e=ecuti!e and intellectual functioning co #ared to nor ati!e scaled scores using one-sa #le @ilco=on Signed 8an' Tests. The second analysis consisted of correlations, using S#ear anGs ran' 1S#ear anGs rho4 correlation

coefficients ai ing to identify any associations $et"een nocturnal S#7., slee# frag entation, and neuro#sychological easures.

R/!'8)!
This analysis included +/ #artici#ants 13 ale and - fe ale4, ean age +. years 1range, 0F+- years4. >or three #artici#ants, the head of the household had a MasterGs degree, for fi!e, he or she had so e college education $ut no degree, "hile one #arent had co #leted high school only and one refused to ans"er. Three fa ilies "ere single #arent. There "ere ., :, and 3 children in the household aged C+- years for -, ., and . #artici#ants, res#ecti!ely. )ine #artici#ants had #re!iously undergone a screening M8* as #art of the Silent *nfarct Transfusion trial 1Casella et al., ./+/4 and the other had an M8* after a transient e#isode of !isual loss. 7n T.-"eighted M8*, the sy #to atic #artici#ant had a s all lesion in the left te #oral lo$eT the re aining M8*s "ere nor al. Cere$ral $lood flo" !elocity on TC& "as in the nor al range in all #artici#ants. There "ere no differences in fre?uency of snoring 15B+/ recruited sa #le4 or any of the slee# !aria$les or in de ogra#hics 1 arital status, education of head of household4 $et"een these #atients and the total of ..- or the su$grou# of +5. #atients aged a0 years not recruited. A!erage nocturnal S#7. 1 ean 9 ,-.-;T edian 9 ,0.3;T range, 0,.:F,,.-4 fell "ithin the nor al range ty#ically o$ser!ed in a #ediatric #o#ulation although the ini u S#7. 1 ean 9 00.,;T edian 9 ,/;T range, 6-.,F,-;4 "as considera$ly lo"er than the ini u S#7. !alue of ,3.-; re#orted in the nor al #o#ulation 1(liel, Tau an, Ireenfeld, Y Si!an, .//34. Mean Arousal *nde= 1A*T ean 9 ,.0T edian 9 +/..T range, 5.,F+..54 "as arginally higher than the #re!iously #u$lished ean arousals fro the nor al #o#ulation 1 ean 9 0.0T "' 9 :.0T Traeger et al., .//54. The ean 7AH* !alue "as .,0 1 edian 9 .+,T range, /.//F5./04. Three of our #artici#ants had an 7AH* of +./ or a$o!e "hich could $e considered outside the nor al range 1Traeger et al., .//54. Mean scores on the neuro#sychological tests are #resented in Ta$le +.

-a&le 1 #ean scale scores fro' the neuropsychological assess'ent

/(ecuti#e ;unction and E

A one sa #le @ilco=on Signed 8an' Test "as carried out to co #are the &-RQ>S su$test scores "ith the nor ati!e ean of +/. Both the Sorting accuracy score 1N 9 k..0T

p C./+4 and the Sorting descri#tion score 1N 9 k..0T p C./+4 "ere significantly $elo" the nor ati!e ean $ut the To"er total achie!e ent score "as not 1N 9 k+.3T p 9 .+64. *V "as also significantly lo"er than the #o#ulation ean of +// 1N 9 k..5T p 9 ./+:4. Q=ecuti!e function scores "ere not correlated "ith *V scores and sorting scores did not correlate "ith To"er scores. The t"o Sorting scores "ere highly correlated 1rho 9 .,0T p C.//+4 so only the correct sorts score "ere used for analysis. The B8*Q> IQC t score 1 ean 9 -/.:T edian 9 -+./T range, :,F004 indicated ildly ele!ated #ro$le s in e=ecuti!e functioning $ut "ithin the nor al range.

Relation of /(ecuti#e ;unction and E to !leep =ariables

A su ary of the associations is sho"n in Ta$le . and >igure +. The To"er tas' total achie!e ent score de onstrated significant correlations "ith $oth ean 1rho 9 .6+T p 9 . /.+4 and ini u S#7. 1rho 9 .-0T p 9 ./:+4. Si ilarly an in!erse correlation "as identified $et"een #ercentage of the study "ith S#7. C,5; and To"er #erfor ance 1rho 9 k.-:T p 9 ./54. The arousal inde= "as also in!ersely correlated "ith the To"er achie!e ent score 1rho 9 k.60T p 9 .//04 $ut 7AH* "as not 1Ta$le .4.

.ig. 1 catterplots sho/ing the relationship &et/een the 0elis12aplan -o/er achie3e'ent scale, score an, 4a5 "rousal In,e+( 4&5 "3erage o3ernight he'oglo&in o+ygen saturation 4 p*25 an, 4c5 #ini'u' o3ernight he'oglo&in o+ygen saturation. %atients /ith nor'al ...

-a&le 2 pear'an6s rho correlations &et/een "rousal In,e+( Nocturnal $e'oglo&in *+ygen saturation 4 p*25( *&structi3e "pnea7$ypopnea In,e+( an, neuropsychological 'easure'ents

Correlations $et"een the Card Sort tas' and slee# !aria$les re!ealed a single trend for association $et"een the nu $er of correct sorts and ean S#7. 1rho 9 .5-T p 9 ./,.4. *V "as significantly correlated "ith #ercentage of the study "ith S#7. C,5; 1rho 9 k.66T p 9 ./+4 and "as additionally associated "ith ini u S#7. 1rho 9 .50T p 9 ./04 and A* 1rho 9 .55T p 9 ./,04. @hen the data "ere re-analy%ed e=cluding the #artici#ant "ith the M8* lesion, si ilar associations "ere identified, although "ith a reduced effect si%e 1see Ta$le .4. A!erage dayti e saturation "as not significantly related to neuro#sychological easures.

D !C'!! "9
9europsychological ;unctioning
The #re!ious literature suggests that children "ith sic'le cell disease are at ris' of general and s#ecific cogniti!e #ro$le s, including e=ecuti!e functioning. *n our sa #le the ean *V "as al ost +5 #oints $elo" the #o#ulation a!erage 1+ "'4, that is, in the lo" a!erage range. This le!el of i #air ent is si ilar to that re#orted in #re!ious studies of those "ithout cere$ral infarction 1Schat% et al., .//.4. Ho"e!er the scores on the B8*Q> "ere "orse than #re!iously re#orted in a grou# "ith none of the standard #redictors of #athology such as an a$nor al TC& 1Rral et al., .//:4 or e!idence of infarction on a standard T.-"eighted M8*, "hich ust $e considered "hen inter#reting our results. Although in ter s of #hysiological #ara eters and de ogra#hics, our sa #le is co #ara$le to the re ainder of our SCA cohort, their neuro#sychological #rofile ay $e ore se!ere, #erha#s $ecause fa ilies "ere self-selecting in that fa ilies "ith children e=#eriencing #ro$le s at school "ere ore li'ely to #artici#ate. *n line "ith the #re!ious literature, "e found e!idence of i #air ent in e=ecuti!e functioning. *n our sa #le, #erfor ance on the Sorting test "as i #aired to a greater degree than To"er tas' #erfor ance. Irou# ean scores on the To"er test "ere "ithin + "', and did not significantly differ fro the nor ati!e ean. Ho"e!er, the eans for $oth Sorting tas' easures in these +/ children "ere ore than one standard de!iation $elo" the nor ati!e ean, and 3B+/ #erfor ed $elo" t"o standard de!iations. This, along "ith the high B8*Q> scores, su##orts #re!ious suggestions that children "ith SCA sho" so e i #air ent in e=ecuti!e functioning.

mpact of "(ygen Desaturation and !leep fragmentation on /(ecuti#e ;unctions

Ii!en the high #re!alence of nocturnal o=ygen desaturation in children "ith SCA 1)eedle an et al., +,,,4, "e hy#othesi%ed that this ay $e one #otential echanis leading to deficits in e=ecuti!e functioning. 7ur results suggested an association $et"een easures of nocturnal o=ygen saturation and the To"er tas'. Mean and ini u o!ernight S#7. "ere significantly correlated "ith #erfor ance on the To"er tas' and there "as a trend for an association "ith slee#-ti e s#ent "ith S#7. C,5; saturation, #ro!iding e!idence that desaturation is lin'ed to #oorer e=ecuti!e function. *n contrast,

the Sorting tas' de onstrated no association "ith o=ygen saturation !aria$les. *t is #ossi$le that our study lac'ed the re?uired #o"er to detect such differences, a #ro$le e=acer$ated $ecause the aAority of our sa #le #erfor ed #oorly on this tas'. @e hy#othesi%ed that increased slee# arousals "ould ha!e an i #act on e=ecuti!e functioning. The results indicate that there "as a significant association $et"een the A* and the To"er tas', su##orting #re!ious literature suggesting that slee# frag entation ay i #act on e=ecuti!e functioning 1@aters Y Buc's, ./++4. Prefrontal cortical areas !ital for e=ecuti!e functioning ay $e #articularly !ulnera$le to disru#tions in slee# as 8QM-slee# #eriods a##ear !ital for recu#eration of these areas o!ernight 1Mu%ur, PaceSchott, Y Ho$son, .//.4.

ntellectual ;unctioning
7ur analyses also re!ealed associations $et"een slee# !aria$les and general intellectual functioning. *n #articular, greater slee#-ti e s#ent "ith S#7. C,5; "as associated "ith lo"er *V. This suggests a #ossi$le role for disordered slee# in $oth general functioning and s#ecific e=ecuti!e do ains. Although scores on tests of *V and e=ecuti!e functioning did not correlate, a larger sa #le si%e "ould ha!e allo"ed us to in!estigate the inter#lay of these t"o constructs. This should $e an i #ortant consideration in future research.

Association Between Reduced 9octurnal "(ygen !aturation and !leep Arousals

7ur results re!ealed that slee# easure ents of o=ygen saturation and arousal inde= score are highly correlated "ith each other. S#ecifically, decreases in o=ygen saturation o!er the slee# #eriod "ere highly correlated to arousals. This is not sur#rising as it is "ell 'no"n that arousal fro slee# is an i #ortant echanis of defense against night ti e hy#o=ic e!ents. Significant di#s in o=ygen saturation ay result in slee# frag entation, #otentially related to neuro#sychological #ro$le s 1Lohnston, Irant, @il'inson, Y @al'er, +,,04. 7f interest, dayti e saturation did not sho" the sa e association "ith neuro#sychological scores, although #re!ious research has sho"n that dayti e saturation is highly correlated "ith o!ernight saturation 1Lohnson et al., ./+/4.

8imitations
This study "as carried out as a no!el #reli inary in!estigation into associations $et"een nocturnal !aria$les and te #orally related neuro#sychological assess ents. &ue to its e=#loratory nature this research suffers fro se!eral li itations. The #ri ary li itation is the s all sa #le si%e "hich has li ited the #o"er of our analyses and also li ited us to use of non-#ara etric statistics. *n addition our grou# a##ears to contain those "ith ore se!ere e=ecuti!e #ro$le s than "ould $e #redicted $y the #re!ious literature. >uture re#lication of these results "ill re?uire a larger and ore re#resentati!e sa #le. &es#ite identifying #otentially i #ortant associations $et"een #hysiological !aria$les and cogniti!e #erfor ance "e are, at this stage, una$le to tease a#art the relati!e i #ortance

of each. >urther studies "ill $e needed to e=a ine the relati!e i #ortance of nocturnal di#s in saturation and lo" $aseline saturation. *n su ary, data has $een #resented su##orting #re!ious literature "hich suggests deficits in *V and e=ecuti!e functions in SCA and #resents an initial argu ent for the i #ortance of nocturnal syste ic o=ygen saturation and slee# frag entation as echanis s for such deficits in the a$sence of clear neuro#athology. The identification of such echanis s for neuro#sychological #ro$le s in SCA ay $e #articularly i #ortant gi!en that treat ent for ane ia and nocturnal desaturation are o#tions in the SCA #o#ulation.

Acknowledgments
@e than' the children and their fa ilies "ho too' #art in the study and &r. Carol 8osen for ad!ice a$out the inter#retation of the #olyso nogra#hy. The study "as su##orted $y the )ational Heart, Dung, and Blood *nstitute 15-87+-HD/6,,:64.

;ootnotes
To the $est of our 'no"ledge no conflicts of interest e=ist.

Article information
J Int Neuropsychol oc. "uthor 'anuscript8 a3aila&le in %#9 2013 July 31. %u&lishe, in final e,ite, for' as! J Int Neuropsychol oc. 2012 January8 18415! 168:173. %u&lishe, online 2011 No3e'&er 24. ,oi! 10.10177 1355617711001469 %#9I0! %#93729265 NI$# I0! NI$# 492720 #atthe/ J. $olloc)s(1 -essa ;. 2o)(1 .enella J. 2ir)ha'(1 Johanna <a3la)(2 ;a&a %. Inusa(3 #ichael =. 0e;aun(4 an, #ichelle ,e $aan1 1 Neurosciences > #ental $ealth( Institute of 9hil, $ealth( ?ni3ersity 9ollege @on,on( @on,on( ?nite, 2ing,o' 2 %orte+ ?nit( Institute of 9hil, $ealth( ?ni3ersity 9ollege @on,on( @on,on( ?nite, 2ing,o' 3 A3elina 9hil,ren6s $ospital( <uy6s an, t -ho'as $ospital( @on,on( ?nite, 2ing,o' 4 0epart'ent of %e,iatrics( Ban,er&ilt ?ni3ersity( Nash3ille( -ennessee 9orrespon,ence an, reprint reCuests to! #atthe/ J. $olloc)s( 0epart'ent of 9hil, > ",olescent %sychiatry %*85( Institute of %sychiatry( 0e9respigny %ar)( 0en'ar) $ill( @on,on( ?nite, 2ing,o' A5 8".. A'ail! 'atthe/.holloc)s7at7)cl.ac.u) 9opyright notice an, 0isclai'er -he pu&lisherDs final e,ite, 3ersion of this article is a3aila&le at J Int Neuropsychol oc

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17. -raeger N( chultF ;( %olloc) "N( #ason -( #arcus 9@( "rens =. %olyso'nographic 3alues in chil,ren 2:9 years ol,! ",,itional ,ata an, re3ie/ of the literature. %e,iatric %ul'onology. 2005840!22:30. G%u&#e,H 18. ?liel ( -au'an =( <reenfel, #( i3an I. Nor'al polyso'nographic respiratory 3alues in chil,ren an, a,olescents. 9hest. 20048125!872:878. G%u&#e,H 19. Eaters .( ;uc)s = . Neuropsychological effects of sleep loss! I'plication for neuropsychologists. Journal of the International Neuropsychological ociety. 2011817!571:586. G%u&#e,H 20. Eechsler 0. Eechsler scale of intelligence 'anual 4trans5 an "ntonio( -J! $arcourt ;race > 9o'pany8 1999.

)his article has been corrected0 See Slee#. ./+. Lune +T :51-42 6.5.

+eriodic 8imb Mo#ements and Disrupted !leep in Children with !ickle Cell Disease
Halerie Q. 8ogers, Ph&, Carole D. Marcus, MBBCh, [...], and Thornton B. A. Mason, M&, Ph&, MSCQ Additional article infor ation

Abstract
!tudy "b.ecti#es:
To descri$e the rate, distri$ution and correlates of #eriodic li $ 1PDMS4 in children "ith sic'le cell disease 1SC&4. o!e ents in slee#

Design:
Pros#ecti!e, cross-sectional.

!etting:

Hos#ital-$ased slee# la$oratory.

+articipants:
Si=ty-four children aged .F+0 years "ith SC&, he oglo$in SS-ty#e "ho had an o!ernight #olyso nogra and a #arent-co #leted Pediatric Slee# Vuestionnaire. Mean age "as 0.3 years 1S& 3.04T 5/; "ere ale.

nter#entions:
)BA

Measurements and Results:

The ean PDMS inde= "as :.6 1-.-4 and ranged fro / to :+.0, "ith .:.3; of the sa #le ha!ing PDMS a 5Bh. Slee# efficiency "as decreased 1P 9 /./:4, and the total arousal inde= 1P 9 /.//:4 and PDMS arousal inde= 1P C /.//+4 "ere increased in children "ith PDMS a 5Bh co #ared to those "ith PDMS C 5Bh. PDMS "ere ost fre?uent in )8QM stage . slee# and during the fourth hour of slee#. *nter- o!e ent inter!al duration #ea'ed at .5F:/ s. JIro"ing #ains "orst in $edK or Jrestlessness of the legsK, suggesting restless legs syndro e 18DS4, "ere re#orted in +..5; of the total sa #le and "ere ore co on in children "ith ele!ated PDMS. A PDMS score for identifying ele!ated PDMS in children, $ased on ite s fro the Pediatric Slee# Vuestionnaire, did not significantly #redict PDMS a 5Bh.

Conclusions:
Qle!ated PDMS are co on in children "ith SC& and are associated "ith slee# disru#tion and sy #to s of 8DS. >uture research into the ti e structure of PDMS, their causes and conse?uences, and de!elo# ent of a disease-s#ecific slee# disorders screening ?uestionnaire, is needed in children "ith SC&.

Citation:
8ogers HQT Marcus CDT La"ad A>T S ith-@hitley RT 7hene->re #ong RT Bo"dre CT Allen LT Arens 8T Mason TBA. Periodic li $ o!e ents and disru#ted slee# in children "ith sic'le cell disease. "@EEP ./++T:316420,,-,/0.
Keywords: %erio,ic li'& 'o3e'ents in sleep( ane'ia( sic)le cell( chil,( a,olescent( sleep ,isor,ers( inter1'o3e'ent inter3al( sleep stages

9)R"D'C) "9
Sic'le cell disease 1SC&4 is a grou# of inherited, chronic he olytic ane ias in "hich a #oint utation on the he oglo$in olecule causes #oly eri%ation under certain

conditions including hy#o=e ia. As a result of disease-related #athology, children "ith SC& e=#erience neurocogniti!e deficits,+,. fre?uent hos#itali%ation and e=cessi!e health care costs,:,3 and an ele!ated death rate in nearly e!ery age grou# co #ared to healthy African A ericans.5 Slee#-related disorders are e erging as a #otential contri$utor to SC& se!erity. )early half of children "ith SC& e=#erience nocturnal o=yhe oglo$in desaturation,-,6 and lo" o=ygen saturation has $een i #licated in the de!elo# ent of !aso-occlusi!e #ain crises0 and #ul onary hy#ertension., 7$structi!e slee# a#nea 17SA4 is ore #re!alent and ore se!ere in children "ith SC& than unaffected children.+/F+. Dittle is 'no"n, ho"e!er, a$out other slee# disorders in children "ith SC&, including the occurrence of #eriodic li $ o!e ents in slee# 1PDMS4. Periodic li $ o!e ents in slee# are re#etiti!e, highly stereoty#ed o!e ents of the ar s or legs occurring during slee#. Q!idence increasingly suggests that dysfunction of the do#a inergic neurotrans itter syste #lays a #art in the #athogenesis of PDMS.+: A PDMS inde= e=ceeding 5Bh in children indicates #eriodic li $ o!e ent disorder, #ro!ided additional diagnostic criteria are et including clinical slee# distur$ance and a$sence of another #ri ary disorder that "ould e=#lain the PDMS.+3 Periodic li $ o!e ents are relati!ely unusual in healthy children,+5 $ut ha!e $een associated "ith se!eral co or$id conditions including 7SA,+- attention deficit hy#eracti!ity disorder 1A&H&4,+6,+0 restless legs syndro e 18DS4,+, and iron deficiency../ >e" studies ha!e e=#lored the occurrence of PDMS in children "ith SC&. This study "as #art of a #ros#ecti!e, longitudinal in!estigation of the #re!alence, contri$utory echanis s, and #ul onary and !ascular conse?uences of o=yhe oglo$in desaturation in children and adolescents "ith SC&, ho o%ygous he oglo$in SS-ty#e 1SC&-SS4. The ai s of this study "ere to descri$e o$Aecti!e easures of PDMS including their rate, slee# stage and ti e-of-night distri$ution, and ti e structureT the relationshi# of PDMS to su$Aecti!ely re#orted sy #to sT and the utility of a PDMS score, $ased on ite s fro the Pediatric Slee# Vuestionnaire 1PSV4,.+ for identifying ele!ated PDMS in a #ros#ecti!e, unreferred, ho ogenous sa #le of children "ith SC&SS.

M/)%"D!
+articipants
This "as a #ros#ecti!e, cross-sectional study. Children "ere recruited if they recei!ed care at the Sic'le Cell Center of The ChildrenMs Hos#ital of Philadel#hia. *nclusion criteria at the #oint of study entry "ere age . to +0 years "ith docu ented SC&-SS and not currently recei!ing chronic transfusion or hydro=yurea thera#ies, or ha!ing recei!ed either during the #re!ious : onths. Su$Aects "ere e=cluded if they "ere currently #regnant or had congenital heart disease or a chronic lung condition unrelated to SC&, "ith the e=ce#tion of asth a. Studies "ere #erfor ed if su$Aects "ere at their $aseline state of health "ithout ha!ing e=#erienced acute chest syndro e or other e=acer$ations

"ithin the last . onths. *n addition, for these analyses su$Aects re?uired a co #leted #olyso nogra and PSV..+ The study "as a##ro!ed $y the *nstitutional 8e!ie" Board at The ChildrenMs Hos#ital of Philadel#hia. All #arentsBguardians signed infor ed consent, and children 6 years of age or older signed their assent #rior to #artici#ation.

+rocedure

+olysomnogram
Partici#ants under"ent o!ernight #olyso nogra#hy at $aseline, and so e #artici#ants co #leted a #olyso nogra at one-year follo"-u# or #ost-adenotonsillecto y. The first #olyso nogra "as included in this study. >our #artici#ants did not co #lete a PSV at the ti e of their $aseline slee# study, and in these cases, the second #olyso nogra "as included. &uring the study, a 8e $randt #olyso nogra#hy syste 1Q $la, Broo field, C74 recorded the follo"ing #ara eters2 electroence#halogra 1C:BA., C3BA+, 7+BA., and 7.BA+, "ith later studies also including frontal electroence#halogra#hy leads4, left and right electroculogra s, su$ ental and ti$ial electro yogra , electrocardiogra , oronasal airflo" "ith a :-#ronged ther istor 1Pro-Tech Ser!ices, *nc., Mu'ilteo, @A4, nasal #ressure "ith a #ressure transducer 1Pro-Tech Ser!ices, *nc.4, ri$ cage and a$do inal "all otion using res#iratory inductance #lethys ogra#hy 1Hiasys Healthcare, Yor$a Dinda, CA4, end-tidal car$on dio=ide le!el 1)o!a etri= Medical Syste s, *nc., @allingford, CT4, and arterial o=ygen saturation 1S#7.4 "ith #ulse "a!efor 1Masi o, *r!ine, CA4. Su$Aects "ere also recorded using infrared !ideogra#hy. Slee# architecture, arousals and res#iratory e!ents "ere scored according to A erican Acade y of Slee# Medicine criteria, using #ediatric res#iratory scoring rules for all su$Aects... The o$structi!e a#nea-hy#o#nea inde= 17AH*4 "as the nu $er of o$structi!e a#neas, o$structi!e hy#o#neas, and i=ed a#neas #er hour of slee#. Su$Aects had 7SA if their 7AH* "as a +.5..:F.5 Periodic li $ o!e ents "ere easured using . surface electro yogra#hy electrodes #laced o!er the anterior ti$ialis uscle, using se#arate channels for each leg. They "ere defined as a series of a 3 consecuti!e leg o!e ents, each lasting $et"een /.5 and +/ sec, ha!ing an a #litude increase in electro yogra#hy !oltage a 0 \H a$o!e resting $aseline and a #eriod length $et"een leg o!e ents of 5 to ,/ sec. Di $ o!e ents "ere not scored if they occurred "ithin /.5 sec #receding or follo"ing an a#nea or hy#o#nea... A PDMS inde= a 5Bh of slee# "as considered a$nor al.+3 Polyso nogra s "ere inter#reted $y #hysicians "ho "ere $oard certified in slee# edicine 1CM, TM4. >or analysis of PDMS distri$ution, hour of slee# "as defined as the hour #ost slee# onset regardless of inter!ening "a'e ti e. 7nly #eriodic li $ o!e ents occurring during slee# "ere analy%ed. >ourteen children did not slee# through the entire eighth hour 1 ean slee# for short slee#ers 6.5 h, S& /.3 h4, and no correction factor "as a##lied to account for inco #lete data collection during that hour. *nter- o!e ent inter!al 1*M*4 "as defined as the ti e $et"een the onset of . su$se?uent PDMS in a single PDMS se?uence.

All *M* "ere $inned into ti e inter!al classes accounting for 5-sec s#ans of ti e, co!ering the range fro 5 to ,/ sec 1e.g., 5s s inter!al C +/s, +/s s inter!al C +5s, +5s s inter!al C ./s,t05s s inter!al s ,/s4.

+ediatric !leep Euestionnaire

The PSV.+ is a "idely used #arent-re#ort ?uestionnaire "ith esta$lished relia$ility and !alidity de!elo#ed to identify children aged . to +0 years "ith slee# disorders. *te s fro the PSV ha!e $een used in the de!elo# ent of a PDMS score,.- a "eighted co #osite score of - PSV ite s associated "ith PDMS in children. The PDMS score "as de!elo#ed to assist in clinical discri ination of PDMS a 5Bh of slee#. *te s in the PDMS score include 1A+:4 J&oes your child descri$e restlessness of the legs "hen in $edXKT 1A+:$4 J&oes your child ha!e `gro"ing #ainsG that are "orst in $edXKT 1A+-4 JAt night does your child usually get out of $ed 1for any reason4XKT 1A334 J&oes your child "a'e ore than t"ice a night, on a!erageXKT 1B+4 J&oes your child "a'e u# feeling unrefreshed in the orningXKT and 1B64 J&oes your child "a'e u# "ith headaches in the orningKX *te res#onses include no 9 /, yes 9 +, and donMt 'no" 9 issing. These scores are su ed, "ith ite s A+: and A+:$ dou$le-scored to i #ro!e s#ecificity of the score for PDMS, and the su is di!ided $y the nu $er of ite s, yielding a score ranging fro / to +. (sing a recei!er o#erator characteristic 187C4 cur!e, authors identified a PDMS score E /.:: as suggesti!e of PDMS a 5Bh in a !alidation sa #le of ++: children aged . to +0 years of age referred for #olyso nogra#hy. .- The PDMS score had a #ositi!e #redicti!e !alue of /.:0, negati!e #redicti!e !alue of /.0,, sensiti!ity of /.6,, and s#ecificity of /.5- to detect PDMS a 5Bh. The PDMS score de onstrated reasona$le initial !alidity, internal consistency and test-retest relia$ility, although #redicti!e !alues, sensiti!ity, and s#ecificity de onstrated li ited effecti!eness in screening children for PDMS a 5Bh in the clinical setting..The PSV "as co #leted on the day of the #olyso nogra . Because of the nu $er of tests in!ol!ed in the #arent study, ho"e!er, so e su$Aects "ere una$le to co #lete the PSV at the ti e of the slee# study, and co #leted it at the ne=t clinical or study contact. Se!enty-si= #ercent 13,B-34 of su$Aects co #leted the PSV "ithin a day of the slee# study 1i ediate co #leters4. Co #letion of the PSV for the re aining su$Aects ranged fro +. to :/+ days after the slee# study 1delayed co #leters4. * ediate co #leters "ere co #ared to delayed co #leters on the dichoto i%ed PDMS inde=, age, gender, and 7AH*, and no significant differences "ere found. Conse?uently, all data "ere analy%ed together.

!tatistical Analysis
&escri#ti!e statistics, including ean 1standard de!iation [S&]4, range and #ercent "ere used to descri$e the data. S#ear an correlation 1u4 "as e #loyed to esti ate the association of de ogra#hic and clinical !aria$les "ith the PDMS inde=. The PDMS inde= "as dichoto i%ed into C 5Bh 1nor al4 and a 5Bh 1ele!ated4. The inde#endent t-test or Mann-@hitney test "as used to test differences $et"een grou#s on !aria$les easured on

a continuous scale. >isher e=act tests or v. tests "ere used for co #aring fre?uencies and #ro#ortions. Age "as ar$itrarily dichoto i%ed into C +/ years and a +/ years of age for co #arison of fre?uency distri$utions of PDMS $y slee# stages, hour of slee#, and duration of *M*. >or these analyses, indi!idual PDMS "ere $inned for each #olyso nogra , across categories 1slee# stage, hour of slee#4 and inter!al classes 1*M* duration4. A ean and standard error of the ean "as calculated across all #olyso nogra s, and for children C +/ and a +/ years of age, for each category and inter!al class. Prediction of the dichoto i%ed PDMS inde= fro indi!idual PSV ite s and the PDMS score "as acco #lished using logistic regression ethods. *te s on the PSV ha!ing E . res#onse categories "ere dichoto i%ed 1/ 9 Jdoes not a##lyK or Ja##lies Aust a littleK !ersus + 9 Ja##lies ?uite a $itK or Jdefinitely a##lies ost of the ti eK4. An 87C cur!e odeled the a$ility of the PDMS score to discri inate a PDMS inde= C 5 !ersus a 5Bh. Post hoc e=#loration "as #erfor ed using uni!ariate logistic regression, "ith b set at P C /../. Analysis of PDMS distri$utions "as #erfor ed using Q=cel .//6 1Microsoft Cor#., 8ed ond, @A4. All other analyses "ere #erfor ed using the Statistical Pac'age for the Social Sciences, !ersion +6./ 1SPSS, *nc., Chicago, *D4. Al#ha "as set at /./5. )o correction "as ade for ulti#le co #arisons as this "as an e=#loratory, o$ser!ational study, and clinically eaningful directions for future research ight other"ise $e issed..6

R/!'8)!
Si=ty-four su$Aects co #leted $oth a #olyso nogra and a PSV. All su$Aects "ere African A erican. Characteristics of the sa #le are sho"n in Ta$le +. Medications ta'en on a daily or as needed $asis a ong su$Aects during the study included #enicillin 1n 9 564, folic acid 1n 9 -+4, al$uterol 1n 9 04, inhaled corticosteroid 1n 9 +/4, antihista ine 1n 9 34, hydro=yurea 1n 9 +4, deferasiro= 1n 9 +4, ethyl#henidate 1n 9 +4, lanso#ra%ole 1n 9 +4, le!etiraceta 1n 9 +4, i$u#rofen 1n 9 54, and aceta ino#hen "ith codeine 1n 9 :4. )o #arent re#orted the use of selecti!e serotonin reu#ta'e inhi$itors or any antide#ressant edications $y their child.

-a&le 1 9haracteristics of chil,ren /ith sic)le cell ,isease for all su&Kects an, &y perio,ic li'& 'o3e'ents in sleep in,e+ L 5 an, M 5

+olysomnography ;indings
The ean PDMS inde= "as :.6 1S& -.-4, and ranged fro / to :+.0. >ifteen 1.:.3;4 su$Aects had a PDMS inde= a 5. Co #arison of #olyso nogra#hic #ara eters $et"een su$Aects ha!ing a PDMS inde= C 5 !ersus a 5 is sho"n in Ta$le .. As e=#ected, the PDMS inde= 1P C /.//+4 and PDMS arousal inde= 1P C /.//+4 "ere significantly higher in su$Aects "ith ele!ated PDMS. The total arousal inde= "as also significantly increased in su$Aects "ith ele!ated PDMS 1P 9 /.//34. Slee# efficiency "as decreased in su$Aects "ith ele!ated PDMS co #ared to those "ith PDMS C 5Bh 1P 9 /./:4. There "as a trend to"ard longer slee# onset latency in su$Aects "ith ele!ated PDMS 1P 9 /./04. )either total slee# ti e nor slee# stages differed in children "ith nor al !ersus ele!ated PDMS. 7$structi!e slee# a#nea "as identified in .-.-; 1+6B-34 of the sa #le. 7f the children "ith 7SA, +6.-; 1:B+64 had a PDMS inde= a 5, "hile .5.5; 1+.B364 of children had an ele!ated PDMS inde= $ut did not ha!e 7SA, differences that "ere not significant.

-a&le 2 %olyso'nography fin,ings in chil,ren /ith sic)le cell ,isease for all su&Kects an, &y perio,ic li'& 'o3e'ents in sleep in,e+ L 5 an, M 5

T"el!e children had a second #olyso nogra during the course of this study. Ti e $et"een slee# studies a!eraged +/.- onths 13.. onths4 and ranged fro +./ to +5./ onths. The change in PDMS inde= fro the first to the second slee# study a!eraged /.3 1:.04, ranging fro :., to ++.,, "ith no child changing diagnostic classification 1PDMS inde= a$o!e or $elo" 5Bh4 fro the first to the second study. There "as no correlation of the PDMS inde= "ith age. >orty-four #olyso nogra s containing +-.- indi!idual PDMS "ere a!aila$le for analysis of the fre?uency distri$ution of PDMS across slee# stages, ti e of night, and duration of *M*. Considering all PDMS across the sa #le #rior to $inning $y indi!idual su$Aect, the aAority 1-0.,;4 of PDMS occurred during )8QM slee# stage 1)4 ., "ith +3.6; occurring during )+, +:.+; during ): or slo" "a!e slee#, and :.:; during 8QM slee#. Binned PDMS across slee# stages de onstrated a si ilar distri$ution 1>igure +, Ta$le :4, "ith the greatest ean nu $er of PDMS for the total sa #le and in children C +/ years of age occurring during )., "hile PDMS in children a +/ years "ere a##ro=i ately e?ually distri$uted $et"een ). and ):. The ean nu $er of $inned PDMS across hours of slee# 1>igure .4 for the total sa #le #ea'ed during hour 3. Ho"e!er, "hen e=a ined $et"een younger !ersus older children, the #ea' "as ainly seen in children C +/ years of age. *n the older children, PDMS "ere ore fre?uent during the first hour of slee# than in the younger children, di##ed during hours . and :,

then #ea'ed again during hours 3 and 5. Both age grou#s de onstrated a di# in PDMS fre?uency during hour -, "ith a s all #ea' again during the 6th hour of slee#. The ean nu $er of $inned PDMS across *M* 5-sec ti e inter!al classes 1>igure :4 for the total sa #le #ea'ed at .5- C :/ s, "ith the #ea' e=tending fro +5- C ./ s through 55- C -/ s. *n children C +/ years of age, *M*s "ere of slightly shorter duration than in the older children, $ut follo"ed the sa e course of decreasing fre?uency as *M* duration lengthened.

.igure 1 0istri&ution of the 'ean of &inne, perio,ic li'& 'o3e'ents in sleep 4%@# 5 occurring in N=A# 4N5 an, =A# sleep stages ,uring polyso'nography (A) across all chil,ren /ith sic)le cell ,isease an, %@# ( an, ( ) co'paring chil,ren L 10 3ersus M ...

.igure 2 0istri&ution of the 'ean nu'&er of &inne, perio,ic li'& 'o3e'ents in sleep 4%@# 5 occurring in each hour of sleep ,uring polyso'nography (A) across all chil,ren /ith sic)le cell ,isease an, %@# ( an, ( ) co'paring chil,ren L 10 3ersus M ...

.igure 3 0istri&ution of the 'ean nu'&er of &inne, perio,ic li'& 'o3e'ents in sleep 4%@# 5 inter1'o3e'ent inter3als 4I#I5 in each 51sec inter3al class (A) across all chil,ren /ith sic)le cell ,isease an, %@# ( an, ( ) co'paring chil,ren L 10 3ersus M ...

-a&le 3 0istri&ution of 'ean perio,ic li'& 'o3e'ents in sleep 4%@# 5 across hour of sleep an, sleep stages in chil,ren /ith sic)le cell ,isease an, %@#

!ub.ecti#e !ymptoms and +8M! !core

7nly 3 su$Aects et A erican Acade y of Slee# Medicine criteria for #eriodic li $ o!e ent disorder.+3 Con!ersely, -/; 1,B+54 of children "ith a PDMS inde= a 5

re#orted no clinical sy #to s, and any children "ho did not ha!e ele!ated PDMS re#orted one or ore sy #to s, including -5.-; 1.+B:.4 of children "ith a PDMS inde= C + and 5..,; 1,B+64 of children "ith a PDMS inde= $et"een + and C 5. Select res#onses to the PSV for the full sa #le and $y PDMS C 5Bh !ersus a 5Bh are sho"n in Ta$le 3. Qither gro"ing #ains "orst in $ed or restlessness of the legs "as re#orted $y +..5; of the sa #le, including -.+; 1:B3,4 of children "ith PDMS C 5Bh and ::.:; 15B+54 of children "ith PDMS a 5Bh 1P 9 /./+34. *te s fro the PSV "ere used to calculate a Slee#-8elated Breathing &isorder score, an *nattentionBHy#eracti!ity score and a &ayti e Slee#iness score.+ 1Ta$le 34. 7!erall, there "as no correlation $et"een the PDMS inde= and any of the scores. Ho"e!er, "hen only children "ith PDMS a 5Bh "ere included in the analysis, the correlation $et"een the PDMS inde= and the *nattentionBHy#eracti!ity score 1$ut not the Slee#-8elated Breathing &isorder or the &ayti e Slee#iness scores4 $eca e significant 1u 9 /.5,., P 9 /./.4. Children "ith clinical sy #to s of slee# distur$ance and ele!ated PDMS had a higher *nattentionBHy#eracti!ity score than did children "ith ele!ated PDMS "ithout clinical sy #to s 1 ean /.:, [/.:,] !s. /.+6 [/..0], res#ecti!ely4, $ut this difference "as not significant.

-a&le 4 %ositi3e responses to select %e,iatric leep Nuestionnaire ite's for all chil,ren /ith sic)le cell ,isease an, &y perio,ic li'& 'o3e'ents in sleep in,e+ L 5 3ersus M 5

The ean PDMS score "as /../ 1/.+34, and ranged fro / to /.-:. The dichoto i%ed PDMS inde= "as regressed on the PDMS score in an unadAusted logistic regression odel 1Ta$le 54. The PDMS score "as not a significant #redictor of PDMS a 5Bh. The odds ratio "as su$stantial 178 +..+4, yet the ,5; confidence inter!al "as e=cessi!ely large and classification of PDMS a 5Bh, the #rediction of interest, "as #oor at -.6;. The area under the 87C cur!e 1/.-/04 "as not significantly $etter than that #redicted $y chance. The odel "as then adAusted for age, se=, nightly snoring, 7AH*, and nadir S#7...- *n the adAusted odel, #rediction of PDMS a 5Bh "as +:.:;, an i #ro!e ent o!er the unadAusted odelT ho"e!er, this odel "as li'e"ise not significant.

-a&le 5 ?na,Kuste, an, a,Kuste, logistic regression 'o,els of perio,ic li'& 'o3e'ents in sleep 4%@# 5 M 57h pre,icte, &y the %@# score in chil,ren /ith sic)le cell ,isease( n O 57

To e=#lore reasons for the lac' of #redicti!e !alue of the PDMS score in children "ith SC&, "e #erfor ed post hoc testing of !aria$les included in the PDMS score, and additionally tested other PSV ite s that ight $e associated "ith PDMS in children "ith SC&. Additional ite s included those related to restless slee#, leg 'ic's during slee#, slee# disru#tion, dayti e slee#iness, slee# disordered $reathing sy #to s, and inattenti!eBhy#eracti!e $eha!iors. *te s achie!ing P C /../ in uni!ariate logistic regression odels of the dichoto i%ed PDMS inde= are sho"n in Ta$le -. 7nly one ite in the PDMS score, 1A+:4 restless legs, et this criterion in the e=#ected direction 1e.g., #ro$le atic slee# $eha!ior re#orted ore often in children "ith ele!ated PDMS4. Additional significant ite s in the e=#ected direction included 1A+34 J@hile your child slee#s, ha!e you seen re#eated 'ic's or Aer's of the legs at regular inter!alsXKT 1B54 J&oes your child usually ta'e a na# during the dayXKT and 1C+/4 JThis child often fidgets "ith hands or feet or s?uir s in seat.K (ne=#ectedly, children "ith PDMS a 5Bh had fe"er re#orted #ro$le atic slee# $eha!iors than children "ith nor al PDMS for the ite s 1A+-4 JAt night, does your child usually get out of $ed 1for any reason4KXT 1A+64 JAt night, does your child usually get out of $ed to urinateXKT 1B34 JHas a teacher or other su#er!isor co ented that your child a##ears slee#y during the dayXKT and 1B+-4 JHas your child felt an irresisti$le urge to ta'e a na# at ti es, forcing hi or her to sto# "hat he or she is doing in order to slee#XK

-a&le 6 ?ni3ariate logistic regression of perio,ic li'& 'o3e'ents in sleep 4L 57h 3ersus M 57h5 on %e,iatric leep Nuestionnaire ite's achie3ing % L 0.20 in chil,ren /ith sic)le cell ,isease

D !C'!! "9

This study descri$ed PDMS in a sa #le of children "ith SC&-SS, including their rate, slee# stage and ti e-of-night distri$ution, ti e structure, and association "ith clinical characteristics and su$Aecti!e sy #to s. *t further e=#lored the usefulness of a screening algorith for identifying ele!ated PDMS in clinical #ractice, de!elo#ed fro a #arentre#ort ?uestionnaire of slee# related sy #to s. *n children, PDMS ha!e $een associated "ith 8DS,+, A&H&,+6,+0 lo" iron stores,./ and the use of antide#ressant edications..0 >actors associated "ith PDMS in children "ith SC& are un'no"n. This study de onstrated a high rate of PDMS in these children, "hich "as associated "ith slee# frag entation and an ele!ated sy #to score for 8DS.

+olysomnography ;indings
This "as the first identified study to re#ort ele!ated PDMS in a #ros#ecti!e, unreferred sa #le of children "ith SC&. )early one-?uarter of our sa #le had a PDMS inde= a 5. This is a re ar'a$le finding, considering that PDMS are unusual in children. *n co #arison to our findings, #re!alence esti ates for PDMS a 5Bh in other"ise healthy children range fro +..; to 0;.+5,.: *n the one recently #u$lished study re#orting PDMS in children "ith SC&, a rate of PDMS E 5Bh of .-; "as found in a retros#ecti!e sa #le of children "ith SC& referred to a slee# center for e!aluation of slee# disordered $reathing,+. si ilar to the findings of our study. Measures of slee# disru#tion "ere e!ident on #olyso nogra#hy in children "ith ele!ated PDMS. Slee# efficiency "as decreased and arousals "ere increased in children "ith PDMS a 5Bh o!er those "ith nor al PDMS. There is no" e=tensi!e research sho"ing that icroarousals, in the a$sence of fran' a"a'enings, cause significant or$idity, including ad!erse neurocogniti!e outco es and cardio!ascular disease..,,:/ PDMS ha!e also $een associated "ith transient $ut #ronounced cardiac acceleration, changes in cardio!ascular !aria$ility,:+ and nocturnal hy#ertension in children,:. and fluctuations in cere$ral he odyna ics in adults.:: These findings, considered together "ith e!idence fro one study de onstrating that 8DS 1and associated PDMS4 in the #resence of stro'e ris' factors #osed an increased ris' of silent stro'e,:3 and another de onstrating an increase in the relati!e odds of ische ic stro'e in iddle-aged en re#orting 8DS sy #to s on ?uestionnaire,:5 are #articularly concerning in children "ith SC&. Sic'le cell disease is the ost co on cause of childhood stro'e, "ith a stro'e ris' ::: ti es that of a healthy child "ithout SC& or heart disease.:- Additionally, their cardio!ascular syste is already stressed due to the increased cardiac "or'load caused $y se!ere ane ia. Thus, the #ossi$ility e=ists that PDMS ay contri$ute to ad!erse cardio!ascular and cere$ro!ascular outco es including stro'e in children "ith SC&. Ho"e!er, these theoretical connections are far fro su##orted, and further in!estigation is needed $efore a causal connection can $e esta$lished. )either su$Aecti!ely re#orted fre?uent night a"a'enings nor a"a'enings on #olyso nogra#hy differed $et"een children "ith nor al !ersus ele!ated PDMS, suggesting that so e co #onents of slee# disru#tion ay $e influenced $y SC&-related #athology, such as #ain or 'idney dysfunction, rather than slee# disorders.

7$structi!e slee# a#nea "as co on and "as diagnosed $y #olyso nogra#hy in o!er one-?uarter of our sa #le. Periodic li $ o!e ents are often associated "ith 7SA, and o$structi!e res#iratory e!ents can confound the scoring of PDMS.+-,:6 )e!ertheless, in our sa #le the PDMS inde= "as not significantly associated "ith the 7AH*, and 7SA "as ore co on in children "ith nor al PDMS than in those "ith a PDMS inde= a 5Bh, suggesting that the #resence of 7SA did not influence the occurrence of PDMS in these children. Periodic li $ o!e ents sho" a high degree of !aria$ility fro night to night,:0 and in adults they increase in fre?uency "ith age.:, @hile no consecuti!e night #olyso nogra s "ere #erfor ed in our study, re#eat #olyso nogra#hy de onstrated sur#rising sta$ility o!er ti e, "ith no child crossing the diagnostic threshold for #eriodic li $ o!e ent disorder of 5Bh fro the first to the second #olyso nogra , des#ite the la#se of one year $et"een ost studies. Moreo!er, PDMS "ere not associated "ith age. (nfortunately, only one child undergoing re#eat #olyso nogra#hy had a PDMS inde= E 5. These findings suggest that children "ith fe" PDMS are unli'ely to de!elo# ele!ated PDMS o!er ti e. >urther, the lac' of correlation $et"een PDMS and age #reli inarily suggests that change o!er ti e in children "ith ele!ated PDMS ay also $e unli'ely, although further in!estigation is re?uired to $etter esta$lish !aria$ility o!er ti e in children "ith ele!ated PDMS. 7ur finding of a #redo inance of PDMS during ). and slo" "a!e slee# 1):4 differ so e"hat fro other studies in "hich the highest fre?uency of PDMS occurred in )+ slee# and sho"ed a decrease across ). and slo" "a!e slee#, "ith the lo"est occurrence in 8QM slee#.+-,3/ *n our sa #le, PDMS occurred "ith lo" $ut a##ro=i ately e?ual fre?uency in )+ and ): slee#. Ho"e!er, si ilar to other studies, fe" occurred during 8QM slee#. *n the younger children, the fre?uency of PDMS #ea'ed during ). follo"ed $y a decrease to less than half that ean !alue in ):, "hile in the older children, PDMS occurred "ith a$out e?ual fre?uency during ). and ): slee#. The distri$ution of PDMS across hours of slee# in our sa #le #ea'ed a$out half"ay through the night, during hour 3, "ith a s aller #ea' during hour 6. This is in contrast to studies in adults "ith 8DS sho"ing a decline in the nu $er of PDMS fro the $eginning to the end of the slee# #eriod, $ut in agree ent "ith the findings of >erri et al.,3+ in "hich this circadian !ariation "as not a##arent in children "ith 8DS under the age of +5 years. The findings of our study could relate to the young age of our su$Aects, or it could $e that the occurrence of PDMS in children "ith SC& is ore closely related to their disease #rocesses than to circadian influences or 8DS. *nter- o!e ent inter!als of PDMS in our sa #le s#anned the range of ti e inter!al classes fro 5- C +/ s through 05-,/ s, "ith a #ea' in the fre?uency distri$ution in the .5- C :/ s inter!al class. Co #ared to older children, the #ea' *M* in the younger children "as of slightly shorter duration $ut follo"ed essentially the sa e distri$ution. @hile this #ea' in the distri$ution of *M* duration "as s all, it is still unusual in that the fe" other #u$lished studies of #ediatric data found no #ea' in the *M* either in children "ith 8DS3+ or in healthy children,:, "ith the e=ce#tion of a nu $er of short *M* 1e.g., C +/ s4, "hich it has $een suggested ay re#resent ore fre?uent o!e ent in children

during slee# rather than PDMS.:, Preli inary "or' in #ediatric A&H& also re#ortedly de onstrated a PDMS #ea' at less than +/ seconds,:0 si ilar to other #ediatric studies. Much ore "or' needs to $e done to further elucidate ti e-of-night, slee# stage #attern, and ti e structure of PDMS in healthy children and in children "ith disorders that ay disru#t slee# or ay $e affected $y slee# disorders, such as SC&. The significance of our findings is un'no"n, yet the fre?uency distri$ution of PDMS during slee# and across slee# stages, and their ti e structure, ay $e ar'ers of SC& #henoty#es or ay suggest differences in the #atho#hysiological echanis s of PDMS3. in children "ith SC& that differ fro other children.

!ub.ecti#e !ymptoms and +8M! !core

)early all indi!iduals "ith 8DS ha!e ele!ated PDMS, and there is e!idence that the t"o disorders ay $e associated through co on do#a inergic #ath"ays.3:,33 7ccurrence of 8DS sy #to s in children "ith SC& has not $een #re!iously e=a ined. *n our sa #le, o!er +.; of children had co #laints of restlessness of the legs or gro"ing #ains "orst in $ed, and these sy #to s "ere ore co on in children "ith PDMS a 5Bh. *n co #arison, a large #o#ulation-$ased study found a #re!alence of 8DS of a$out .; in children 0 to +6 years of age,35 "hile a rate of 5.,; "as found in a sa #le of children referred to a #ediatric slee# disorders clinic.3- These findings suggest that 8DS ay $e ore co on in children "ith SC& than in the general #o#ulation of children. >urther in!estigation of the #re!alence of 8DS in children "ith SC& is needed, using 8DS diagnostic criteria,36 to further elucidate a #ossi$le lin' $et"een 8DS sy #to s and PDMS in this #o#ulation and to identify children "ho ight $enefit fro treat ent. Children "ith A&H& also fre?uently ha!e ele!ated PDMS.+-,+0 @e did not ha!e an A&H& diagnosis for children in our sa #le, and did not easure inattentionBhy#eracti!ity using an instru ent !alidated to screen for A&H&. @e did, ho"e!er, screen for inattenti!eBhy#eracti!e $eha!iors using the su$scale score re#orted $y Cher!in, et al..+ @e found that a ong children "ith PDMS a 5Bh, there "as a significant association $et"een the PDMS inde= and the *nattentionBHy#eracti!ity score. 7ur sa #le "as too s all to test for differences in inattentionBhy#eracti!ity in children eeting the A erican Acade y of Slee# Medicine *nternational Classification of Slee# &isorders-. criteria+3 for #eriodic li $ o!e ent disorder. )e!ertheless, an association of slee# distur$ance and short slee# "ith $eha!ior dysregulation is "ell esta$lished.30,3, *n a larger sa #le, this relationshi# ay ha!e held true for children "ith SC& as "ell. The PDMS Score, as designed $y Cher!in and Hedger,.- did not #erfor "ell in our sa #le. 8esults of $oth logistic regression and 87C analysis of the PDMS score "ere nonsignificant. At least #art of the lac' of fit in our sa #le can $e attri$uted to our finding that ite s on the PSV are not necessarily a##ro#riate for children "ith chronic illnesses such as SC&. >or e=a #le, o$esity is relati!ely unusual in children "ith SC& due to their high eta$olic de ands. Di'e"ise, the #hysical de ands of chronic illness, including #ain and fatigue, ay contri$ute to differences in res#onses to other ite s including ore restlessness, increased nightti e arousals, slee# initiation and aintenance difficulties, unrefreshing slee#, and dayti e slee#iness o!er those of healthy

children. *ndeed, the finding that certain ite s nor ally inter#reted as #ro$le atic slee# $eha!iors "ere ore co on a ong children "ith nor al le!els of PDMS in our sa #le de onstrated so e of the shortco ings of using the PSV in children "ith SC&. These findings #oint out the need to de!elo# disease-s#ecific easures of slee# disorders for children "ith SC& that $etter account for their uni?ue slee#- and disease-related sy #to s. Moreo!er, ta'en together "ith our finding that PDMS occurred "ith e?ual fre?uency in children "ith and "ithout 7SA, they further suggest that distinctions $et"een PDMS a 5Bhour and #eriodic li $ o!e ent disorder $ased on additional clinical criteria and a$sence of a co or$id slee# disorder ay $e less eaningful in children "ith SC& than in other #ediatric #o#ulations.

+ossible Mechanisms of +8M! in !ickle Cell Disease

@e can only s#eculate as to the #ossi$le #atho#hysiology of PDMS in children "ith SC&, gi!en the lac' of research in this area. *ron dysregulation is i #licated in the #athogenesis of PDMS. Yet, deficient iron storage as a cause of PDMS in SC& #resents a #arado=. >erritin le!els are often ele!ated, rather than decreased, in SC& due to #rior $lood transfusions and recurrent acute #hase res#onse to ongoing !aso-occlusi!e tissue da age.5/ Ho"e!er, there is e!idence in indi!iduals "ith 8DS, a disorder that is genetically lin'ed to PDMS,5+,5. that des#ite nor al seru le!els, iron stores in the central ner!ous syste ay $e deficient.5:,53 *n a study of t"o adult #atients "ith he ochro atosis and se!ere 8DS, these #atients "ere found to ha!e decreased $rain iron le!els $y agnetic resonance i aging, des#ite syste ic iron o!erload, co #ared to healthy controls,55 underscoring the #ossi$ility that 8DS sy #to s are lin'ed to lo" regional $rain iron rather than #eri#heral iron a!aila$ility. Brain iron stores ha!e not $een studied in children "ith SC&, $ut this #resents a #ossi$le echanis for ele!ated PDMS. An alternati!e echanis is suggested $y recent e!idence de onstrating differences in the control of iron eta$olis in SC& co #ared to unaffected indi!iduals. S#ecifically, infla ation in SC& ay #re!ent the release of iron fro storage sites, #articularly acro#hages, there$y decreasing iron trans#ort to tissues "ith high iron re?uire ents.5This finding is suggesti!e in light of e!idence of iron eta$olis a$nor alities in #eri#heral ly #hocytes in "o en "ith early-onset 8DS !ersus control su$Aects, des#ite co #ara$le ferritin su$ty#es and transferrin le!els.56 *ron regulation in SC& as a cause of PDMS re ain une=#lored $ut #resents intriguing direction for future research. @e cannot reconcile the difference in reticulocyte count $et"een children "ith nor al !ersus ele!ated PDMS $ased on "hat is 'no"n or hy#othesi%ed a$out their se?uelae. @e antici#ated that children "ith ore se!ere SC& "ould $e the ones "ith higher PDMS indices and "ould, as a result of increased he olysis, ha!e greater reticulocytosis. @hat "e found instead "as the re!erse, that the children "ith nor al PDMS had higher reticulocyte counts. As he oglo$in le!els "ere co #ara$le $et"een grou#s, and the difference in reticulocytes "as s all 1:;4, "e sus#ect that this finding is erely of statistical rather than of clinical significance. )e!ertheless, the #ossi$ility that PDMS ight $e associated "ith he atological changes "arrants further study.

8imitations

This study had so e i #ortant li itations. The PSV for a s all nu $er of children "as co #leted su$stantially later than their slee# study, and changes in childrenMs slee# and slee#-related sy #to s ight ha!e occurred during the ti e la#se $et"een the t"o easures. Certain easures, including seru iron and ferritin le!els "ere not collected during this research, so that associations of PDMS "ith correlates #re!iously identified in children "ith other disorders, such as lo" $ody iron stores, could not $e tested in our sa #le. )ight-to-night !aria$ility of PDMS could not $e e!aluated due to the lac' of consecuti!e #olyso nogra s, thus "e "ere una$le to account for children in our study "ith nor al PDMS "ho ay ha!e e=hi$ited ele!ated PDMS on re#eat #olyso nogra and "hose change in diagnostic classification ay ha!e significantly altered our results. >inally, there is a difference $et"een ha!ing ele!ated PDMS and ha!ing #eriodic li $ o!e ent disorder, a diagnosis "hich re?uires, in addition to a PDMS inde= a 5Bh on #olyso nogra#hy, e!idence of clinical slee# distur$ance and lac' of confounding slee# disorders. @e had only 3 su$Aects "ho et these criteria, a sa #le si%e too s all to carry out eaningful co #arisons. A larger sa #le is re?uired to ore fully e=#lore the i #act of PDMS a 5Bh !ersus #eriodic li $ o!e ent disorder on dayti e functioning and health outco es in children "ith SC&.

C"9C8'! "9
@e identified a high rate of a$nor ally ele!ated PDMS in a #ros#ecti!e, unreferred sa #le of children "ith SC&. >urther ore, PDMS "ere associated "ith slee# distur$ances and 8DS sy #to s. @hile the clinical significance of our findings are un'no"n, deficient slee# in children has $een associated "ith $eha!ioral and acade ic deficits,50 and children "ith SC& are already at ris' for neurocogniti!e deficits.5, Moreo!er, PDMS are associated "ith sy #athetic $ursts:+ and changes in cere$ral he odyna ics:: "hich ay, theoretically, increase the ris' of stro'e in an at-ris' #o#ulation. Therefore, gi!en the #ossi$le i #act on the health of children "ith SC& and PDMS o!er a lifeti e, there is a need for e=#anded research in this area, in order to $etter identify the causes and long-ter outco es of PDMS in children "ith SC&.

D !C8"!'R/ !)A)/M/9)
This "as not an industry su##orted study. &r. Marcus has recei!ed research su##ort and e?ui# ent fro Philli#s 8es#ironics unrelated to this study. The other authors ha!e indicated no financial conflicts of interest.

ACK9"58/D:M/9)!
The authors than' Loel Traylor, BS, 8PsgT, for his assistance in the collection of data fro the 8e $randt #olyso nogra#hy syste #ertaining to the distri$ution and ti e structure of #eriodic li $ o!e ents, and La es 8. 8ogers, Ph& for his assistance in the analysis of #eriodic li $ o!e ent distri$ution and inter- o!e ent inter!al data.

This study "as #erfor ed at The ChildrenMs Hos#ital of Philadel#hia, PA. 8esearch "as s#onsored $y )ational *nstitutes of HealthB)HDB* grant ^587+HD/6,,++-/3.

ABBR/= A) "9!
"0$0 "ttention ,eficit hyperacti3ity ,isor,er "?9 "rea un,er the recei3er operator characteristic cur3e I#I Inter1'o3e'ent inter3al N N=A# sleep stage *"$I *&structi3e apnea1hypopnea in,e+ * " *&structi3e sleep apnea %@# %erio,ic li'& 'o3e'ents in sleep % N %e,iatric leep Nuestionnaire 49her3in( et al.( 20005 =@ =estless legs syn,ro'e =*9 =ecei3er operator characteristic 4cur3e5 90 ic)le cell ,isease 901 ic)le cell ,isease( ho'oFygous he'oglo&in 0 tan,ar, ,e3iation p*2 "rterial o+ygen saturation genotype

Article information
leep. 2011 July 18 34475! 899:908. ,oi! 10.56657 @AA%.1124 %#9I0! %#93119832 Balerie A. =ogers( %h0(1 9arole @. #arcus( #;;9h(1(2 "&&as .. Ja/a,( %h0(1(2 2i' 'ith1Ehitley( #0(2 2/a)u *hene1.re'pong( #0(1(2 9heryl ;o/,re( %h0(2 Julian "llen( #0(2 =aanan "rens( #0(3 an, -hornton ;. ". #ason( #0( %h0( # 9A1(2 1 ?ni3ersity of %ennsyl3ania( %hila,elphia( %" 2 -he 9hil,renDs $ospital of %hila,elphia( %hila,elphia( %" 3 -he 9hil,renDs $ospital at #ontefiore( ;ron+( NI ",,ress correspon,ence to! -hornton ;. ". #ason( #0( 0i3ision of Neurology( -he 9hil,renDs $ospital of %hila,elphia( 3350 9i3ic 9enter ;l3,.( %hila,elphia( %" 19104%hone! 42155 59011719.a+! 42155 59011771( 8 A'ail! 'asont7at7e'ail.chop.e,u =ecei3e, No3e'&er 20108 =e3ise, .e&ruary 20118 "ccepte, .e&ruary 2011.

9opyright P 2011 "ssociate, %rofessional leep ocieties( @@9. !"is arti#$e "as %een #orre#ted. ee leep. 2012 June 18 35465! 725. "rticles fro' leep are pro3i,e, here courtesy of Asso#iated &ro'essiona$ ($eep (o#ieties) **+

R/;/R/9C/!
1. $ogan "#( %it1ten 9ate I#( Bargha12ha,e' .( %rengler #( 2ir)ha' .J. %hysiological correlates of intellectual function in chil,ren /ith sic)le cell ,isease! hypo+ae'ia( hyperae'ia( an, &rain infarction. 0e3el ci. 200689!379:87. G%u&#e,H 2. teen =<( Jiong J( #ulhern =2( @angston JE( Eang E9. u&tle &rain a&nor'alities in chil,ren /ith sic)le cell ,isease! relationship to &loo, he'atocrit. "nn Neurol. 1999845!279:86. G%u&#e,H 3. @anF)ron ( $ay/oo, 9( Jr( egal J;( 0o3er <J. $ospitaliFation rates an, costs of care of patients /ith sic)le1cell ane'ia in the state of #arylan, in the era of hy,ro+yurea. "' J $e'atol. 2006881!927:32. G%u&#e,H 4. ;allas 2. -he cost of health care for patients /ith sic)le cell ,isease. "' J $e'atol. 2009884!320:2. G%u&#e,H 5. han)ar #( "r&ogast %0( #itchel A( 9ooper E*( Eang E9( <riffin #=. #e,ical care utiliFation an, 'ortality in sic)le cell ,isease! a population1&ase, stu,y. "' J $e'atol. 2005880!262:70. G%u&#e,H 6. Nee,le'an J%( .ranco #A( Barlotta @( et al. #echanis's of nocturnal o+yhe'oglo&in ,esaturation in chil,ren an, a,olescents /ith sic)le cell ,isease. %e,iatr %ul'onol. 1999828!418:22. G%u&#e,H 7. Nuinn 9-( "h'a, N. 9linical correlates of stea,y1state o+yhae'oglo&in ,esaturation in chil,ren /ho ha3e sic)le cell ,isease. ;r J $ae'atol. 20058131!129:34. G%#9 free articleH G%u&#e,H 8. $argra3e 0=( Ea,e "( A3ans J%( $e/es 02( 2ir)ha' .J. Nocturnal o+ygen saturation an, painful sic)le cell crises in chil,ren. ;loo,. 20038101!846:8. G%u&#e,H 9. %ashan)ar .0( 9ar&onella J( ;aFFy1"saa, "( .rie,'an ". @ongitu,inal follo/ up of ele3ate, pul'onary artery pressures in chil,ren /ith sic)le cell ,isease. ;r J $ae'atol. 20098144!736:41. G%u&#e,H 10. 2aleyias J( #ostofi N( <rant #( et al. e3erity of o&structi3e sleep apnea in chil,ren /ith sic)le cell ,isease. J %e,iatr $e'atol *ncol. 2008830!659:65. G%u&#e,H 11. pi3ey J.( ?ong A9( trun) =( ;oslaugh A( 0e;aun #=. @o/ ,ayti'e pulse o+i'etry rea,ing is associate, /ith nocturnal ,esaturation an, o&structi3e sleep apnea in chil,ren /ith sic)le cell ane'ia. %e,iatr ;loo, 9ancer. 2008850!359:62. G%#9 free articleH G%u&#e,H 12. =ogers BA( @e/in 0 ( Einnie <;( <eiger1;ro/n J. %olyso'nographic characteristics of a referre, sa'ple of chil,ren /ith sic)le cell ,isease. J 9lin leep #e,. 201086!374:81. G%#9 free articleH G%u&#e,H 13. Betrugno =( %ro3ini .( #ontagna %. =estless legs syn,ro'e an, perio,ic li'& 'o3e'ents. =e3 Neurol 0is. 200683!61:70. G%u&#e,H 14. "'erican "ca,e'y of leep #e,icine. International classification of sleep ,isor,ers! ,iagnostic an, co,ing 'anual. 2n, e,. Eestchester( I@! "'erican "ca,e'y of leep #e,icine8 2005. 15. 2ir) B<( ;ohn . %erio,ic li'& 'o3e'ents in chil,ren! pre3alence in a referre, population. leep. 2004827!313:5. G%u&#e,H 16. ;o))ala ( Napalinga 2( %inninti N( et al. 9orrelates of perio,ic li'& 'o3e'ents of sleep in the pe,iatric population. %e,iatr Neurol. 2008839!33:9. G%u&#e,H

17. %icchietti 0@( Anglan, J( Ealters " ( Eillis 2( Berrico -. %erio,ic li'& 'o3e'ent ,isor,er an, restless legs syn,ro'e in chil,ren /ith attention1,eficit hyperacti3ity ,isor,er. J 9hil, Neurol. 1998813!588:94. G%u&#e,H 18. 9ra&tree B#( I3anen)o "( <oFal 0. 9linical an, parental assess'ent of sleep in chil,ren /ith attention1,eficit7hyperacti3ity ,isor,er referre, to a pe,iatric sleep 'e,icine center. 9lin %e,iatr. 2003842!807:13. G%u&#e,H 19. %icchietti 0@( te3ens $A. Aarly 'anifestations of restless legs syn,ro'e in chil,hoo, an, a,olescence. leep #e,. 200889!770:81. G%u&#e,H 20. i'a)aKorn&oon N( <oFal 0( Blasic B( #ac) 9( haron 0( #c<inley ;#. %erio,ic li'& 'o3e'ents in sleep an, iron status in chil,ren. leep. 2003826!735:8. G%u&#e,H 21. 9her3in =0( $e,ger 2( 0illon JA( %ituch 2J. %e,iatric leep Nuestionnaire 4% N5! 3ali,ity an, relia&ility of scales for sleep1,isor,ere, &reathing( snoring( sleepiness( an, &eha3ioral pro&le's. leep #e,. 200081!21:32. G%u&#e,H 22. I&er 9( "ncoli1Israel ( 9hesson "( Nuan .. "'erican "ca,e'y of leep #e,icine. Eestchester( I@! "'erican "ca,e'y of leep #e,icine8 2007. -he "" # 'anual for the scoring of sleep an, associate, e3ent! rules( ter'inology an, technical specifications. 23. -raeger N( chultF ;( %olloc) "N( #ason -( #arcus 9@( "rens =. %olyso'nographic 3alues in chil,ren 2:9 years ol,! a,,itional ,ata an, re3ie/ of the literature. %e,iatr %ul'onol. 2005840!22:30. G%u&#e,H 24. Eit'ans #;( 2eens -<( 0a3i,son Ear, @( #arcus 9@. *&structi3e hypopneas in chil,ren an, a,olescents! nor'al 3alues. "' J =espir 9rit 9are #e,. 20038168!1540. G%u&#e,H 25. ?liel ( -au'an =( <reenfel, #( i3an I. Nor'al polyso'nographic respiratory 3alues in chil,ren an, a,olescents. 9hest. 20048125!872:8. G%u&#e,H 26. 9her3in =0( $e,ger 2#. 9linical pre,iction of perio,ic leg 'o3e'ents ,uring sleep in chil,ren. leep #e,. 200182!501:10. G%u&#e,H 27. =oth'an 2J. No a,Kust'ents are nee,e, for 'ultiple co'parisons. Api,e'iology. 199081!43:6. G%u&#e,H 28. $oCue =( 9hesson "@.( Jr %har'acologically in,uce,7e+acer&ate, restless legs syn,ro'e( perio,ic li'& 'o3e'ents of sleep( an, =A# &eha3ior ,isor,er7=A# sleep /ithout atonia! literature re3ie/( Cualitati3e scoring( an, co'parati3e analysis. J 9lin leep #e,. 201086!79:83. G%#9 free articleH G%u&#e,H 29. *D;rien @#( I3anen)o "( 9ra&tree B#( et al. leep ,istur&ances in chil,ren /ith attention ,eficit hyperacti3ity ,isor,er. %e,iatr =es. 2003854!237:43. G%u&#e,H 30. Ja3aheri . leep an, car,io3ascular ,isease! present an, future. In! 2ryger #$( =oth -( 0e'ent E9( e,itors. %rinciples an, practice of sleep 'e,icine. 4th e,. %hila,elphia( %"! Alse3ier aun,ers8 2005. pp. 1157:60. 31. Ealter @#( .oster "#( %atterson ==( et al. 9ar,io3ascular 3aria&ility ,uring perio,ic leg 'o3e'ents in sleep in chil,ren. leep. 2009832!1093:9. G%#9 free articleH G%u&#e,H 32. Eing I2( Qhang J( $o 92( "u 9-( @i "#. %erio,ic li'& 'o3e'ent ,uring sleep is associate, /ith nocturnal hypertension in chil,ren. leep. 2010833!759:65. G%#9 free articleH G%u&#e,H 33. %iFFa .( ;iallas #( Eolf #( Bal)o %*( ;assetti 9@. %erio,ic leg 'o3e'ents ,uring sleep an, cere&ral he'o,yna'ic changes ,etecte, &y NI= . 9lin Neurophysiol. 20098120!1329:34. G%u&#e,H 34. Ealters " ( =ye 0;. =e3ie/ of the relationship of restless legs syn,ro'e an, perio,ic li'& 'o3e'ents in sleep to hypertension( heart ,isease( an, stro)e. leep. 2009832!589:97. G%#9 free articleH G%u&#e,H 35. Al/oo, %( $ac) #( %ic)ering J( $ughs J( <allacher J. leep ,istur&ance( stro)e( an, heart ,isease e3ents! e3i,ence fro' the 9aerphilly cohort. J Api,e'iol 9o''unity $ealth. 2006860!69:73. G%#9 free articleH G%u&#e,H

36. Ber,uFco @"( Nathan 0<. ic)le cell ,isease an, stro)e. ;loo,. 20098114!5117:25. G%u&#e,H 37. A+ar AN( 9ollop N". -he association of upper air/ay resistance /ith perio,ic li'& 'o3e'ents. leep. 2001824!188:92. G%u&#e,H 38. %icchietti #"( %icchietti 0@( Anglan, J( et al. 9hil,ren sho/ in,i3i,ual night1to1night 3aria&ility of perio,ic li'& 'o3e'ents in sleep. leep. 2009832!530:5. G%#9 free articleH G%u&#e,H 39. %ennestri #$( Ehitto' ( ",a' ;( %etit 0( 9arrier J( #ontplaisir J. %@# an, %@#E in healthy su&Kects as a function of age! pre3alence an, inter3al ,istri&ution. leep. 2006829!1183:7. G%u&#e,H 40. %oll'acher -( chulF $. %erio,ic leg 'o3e'ents 4%@#5! their relationship to sleep stages. leep. 1993816!572:7. G%u&#e,H 41. .erri =( #anconi #( @anuFFa ;( et al. "ge1relate, changes in perio,ic leg 'o3e'ents ,uring sleep in patients /ith restless legs syn,ro'e. leep #e,. 200889!790:8. G%u&#e,H 42. .erri =( Qucconi #( #anconi #( %laFFi <( ;runi *( .erini1 tra'&i @. Ne/ approaches to the stu,y of perio,ic leg 'o3e'ents ,uring sleep in restless legs syn,ro'e. leep. 2006829!759:69. G%u&#e,H 43. -ren)/al,er 9( $ening E"( Ealters " ( 9a'p&ell ( =ah'an 2( 9ho)ro3erty . 9irca,ian rhyth' of perio,ic li'& 'o3e'ents an, sensory sy'pto's of restless legs syn,ro'e. #o3 0isor,. 1999814!102:10. G%u&#e,H 44. %ar)er 2%( =ye 0;. =estless legs syn,ro'e an, perio,ic li'& 'o3e'ent ,isor,er. Nurs 9lin North "'. 2002837!655:73. G%u&#e,H 45. %icchietti 0( "llen =%( Ealters " ( 0a3i,son JA( #yers "( .erini1 tra'&i @. =estless legs syn,ro'e! pre3alence an, i'pact in chil,ren an, a,olescents11-he %e,s =A tu,y. %e,iatrics. 20078120!253:66. G%u&#e,H 46. 2otagal ( il&er #$. 9hil,hoo,1onset restless legs syn,ro'e. "nn Neurol. 2004856!803:7. G%u&#e,H 47. "llen =%( %icchietti 0( $ening E"( -ren)/al,er 9( Ealters " ( #ontplaisir J. =estless legs syn,ro'e! ,iagnostic criteria( special consi,erations( an, epi,e'iology. " report fro' the restless legs syn,ro'e ,iagnosis an, epi,e'iology /or)shop at the National Institutes of $ealth. leep #e,. 200384!101:19. G%u&#e,H 48. Eiater "$( #itsch)e "=( 3on Ei,,ern ( .ric)e @( ;reuer ?( @eh')uhl <. leep ,isor,ers an, &eha3ioural pro&le's a'ong 81 to 111year1ol, chil,ren. o'nologie. 200589!210:4. 49. 'e,Ke $( ;ro'an JA( $etta J. "ssociations &et/een ,istur&e, sleep an, &eha3ioural ,ifficulties in 635 chil,ren age, si+ to eight years! a stu,y &ase, on parentsD perceptions. Aur 9hil, ",olesc %sychiatry. 2001810!1:9. G%u&#e,H 50. $e,o 99( ")enDo3a "I( *)pala IA( 0uroKaiye "*( ali'onu @ . "cute phase reactants an, the se3erity of ho'oFygous sic)le cell ,isease. J Intern #e,. 19938233!467:70. G%u&#e,H 51. tefansson $( =ye 0;( $ic)s "( et al. " genetic ris) factor for perio,ic li'& 'o3e'ents in sleep. N Angl J #e,. 20078357!639:47. G%u&#e,H 52. Ein)el'ann J( chor'air ;( @ichtner %( et al. <eno'e1/i,e association stu,y of restless legs syn,ro'e i,entifies co''on 3ariants in three geno'ic regions. Nat <enet. 2007839!1000:6. G%u&#e,H 53. #iFuno ( #ihara -( #iyao)a -( Inaga)i -( $origuchi J. 9 . iron( ferritin an, transferrin le3els in restless legs syn,ro'e. J leep =es. 2005814!43:7. G%u&#e,H 54. Aarley 9J( ;ar)er %;( $ors)a "( "llen =%. #=I1,eter'ine, regional &rain iron concentrations in early1 an, late1onset restless legs syn,ro'e. leep #e,. 200687!458: 61. G%u&#e,H

55. $a&a1=u&io J( taner @( %etiau 9( chunc) -( #acher J%. =estless legs syn,ro'e an, lo/ &rain iron le3els in patients /ith hae'ochro'atosis. J Neurol Neurosurg %sychiatry. 2005876!1009:10. G%#9 free articleH G%u&#e,H 56. Ealter %;( $ar'atF %( Bichins)y A. Iron 'eta&olis' an, iron chelation in sic)le cell ,isease. "cta $ae'atol. 20098122!174:83. G%u&#e,H 57. Aarley 9J( %onnuru %( Eang J( et al. "ltere, iron 'eta&olis' in ly'phocytes fro' su&Kects /ith restless legs syn,ro'e. leep. 2008831!847:52. G%#9 free articleH G%u&#e,H 58. a,eh "( <ru&er =( =a3i3 ". leep( neuro&eha3ioral functioning( an, &eha3ior pro&le's in school1age chil,ren. 9hil, 0e3. 2002873!405:17. G%u&#e,H 59. chatF J( .in)e =@( 2ellett J#( 2ra'er J$. 9ogniti3e functioning in chil,ren /ith sic)le cell ,isease! a 'eta1analysis. J %e,iatr %sychol. 2002827!739:48. G%u&#e,H

"rticle

ron-Deficiency Anemia in nfancy and !ocial /motional De#elopment in +reschool-Aged Chinese Children
1. 2. 3. 4. 5. 6. 7. uying 9hang( # a(&( @i Eang( %h0c( Iuying Eang( %h0a( Inge 0. ;rou/er( %h0&( .rans J. 2o)( %h0&( ;etsy @oFoff( #0,( 9hun'ing 9hen( # a

] Author Affiliations &. 2. $hinese $enter for 'isease $ontrol and Prevention, FeiPing, $hina4 'ivision of *uman (utrition, /ageningen ,niversity, /ageningen, (etherlands4 9. cPsychology 'epartment, PeIing ,niversity, FeiPing, $hina4 and 8. d$enter for *uman Kro+th and 'evelopment, ,niversity of #ichigan, Ann Arbor, #ichigan
b a

Ne+t ection

Abstract
"B6/C) =/: @e ai ed to co #are affect and $eha!ior of : grou#s of nonane ic 3year-old children2 children "ith iron-deficiency ane ia 1*&A4 in infancy "hose ane ia

"as not corrected $efore .3 onths 1chronic *&A4 1n 9 .64T children "ith *&A in infancy "hose ane ia "as corrected $efore .3 onths 1corrected *&A4 1n 9 6/4T and children "ho "ere nonane ic in infancy and at .3 onths 1n 9 -34. M/)%"D: Mother and child dyads "ere in!ited to a local clinic roo . ChildrenMs social referencing, "ariness, frustration-tolerance $eha!ior, and affect "ere o$ser!ed during a set of situations encountered in the la$oratory, including free #lay, stranger a##roach, no!el toy, and delay of gratification. The "hole #rocedure "as !ideota#ed. The childrenMs affecti!e and $eha!ioral dis#lays "ere coded $y using a ti e-sa #ling 15-second seg ents4 code sche e. *ron status of children "as deter ined on the $asis of he oglo$in concentration easured "ith the cyano ethe oglo$in ethod in $lood sa #les o$tained $y fingerstic' in infancy and at the ages of .3 onths and 3 years. R/!'8)!: Children "ho had chronic *&A in infancy dis#layed less #ositi!e affect, less frustration tolerance, ore #assi!e $eha!ior, and ore #hysical self-soothing in the stranger a##roach and delay of gratification. *n contrast, the $eha!ior and affect of children "hose ane ia "as corrected $efore the age of .3 onths "ere co #ara$le to those of children "ho "ere nonane ic throughout infancy. C"9C8'! "9: The results #oint to the #otential $enefits of #re!enting iron deficiency in infancy and treating it $efore it $eco es chronic or se!ere.
2ey Eor,s! iron1,eficiency ane'ia infants social1e'otional ,e3elop'ental preschool1age, chil,ren

5%A)@! K9"59 "9 )% ! !'B6/C):

Preschool follo"-u# studies of children "ho had chronic, se!ere iron deficiency in infancy ha!e re!ealed that these children ha!e #oorer cogniti!e and otor de!elo# ent and lo"er le!els of alertness, #hysical acti!ity, #ositi!e affect, and !er$ali%ation than children "ith good iron status in infancy.

5%A) )% ! !)'D> ADD!:

This study "as an in!estigation of "hether nonane ic #reschool-aged children "ho had chronic iron-deficiency ane ia in infancy "ould sho" altered affect and $eha!ior co #ared to children "ho "ere nonane ic throughout infancy. *ron deficiency 1*&4 is considered to $e the ost co on nutritional disorder in the "orld, and infants are #articularly at ris'.+ A sur!ey of Chinese children #erfor ed in .//+ sho"ed the #re!alence of *& and iron-deficiency ane ia 1*&A4 to $e -5.5; and ./.0;, res#ecti!ely, a ong infants younger than +. onths and 3:.6; and 6.0;, res#ecti!ely, a ong children aged +. to :- onths..

8esults of nu erous studies ha!e de onstrated that infants "ith *&A ha!e lo"er cogniti!e and otor test scores than infants "ith good iron status.:,F,0 >ollo"-u# studies ha!e re!ealed #ersistent lo"er scores a ong children "ho had *&A in infancy e!en though they recei!ed iron treat ent as young children.,,F,++ Although ental and otor findings ha!e generally recei!ed the ost attention, alterations in the socialBe otional do ain also ha!e $een consistently o$ser!ed in infants "ith *&A. Co #ared "ith nonane ic infants, infants "ith *&A !ocali%e less and are ore li'ely to $e fearful, hesitantB"ary, unha##y, inacti!e, easily fatigued, ha!e less endurance, and $e in close contact "ith others.:,, Such $eha!ioral and affecti!e alterations ha!e $een inter#reted as e!idence of Jfunctional isolation.K+. According to the functional-isolation hy#othesis, nutritional deficiencies contri$ute to changes in infantsM affect, acti!ity, and attention that lead the to see' less sti ulation fro their #hysical and social en!iron ents. +: *n res#onse to infantsM $eha!ior, caregi!ers ay offer less sti ulation. 7!er ti e the alterations in child and caregi!er $eha!ior interfere "ith the childMs nor al ac?uisition of en!iron ental infor ation and ad!ersely affect the childMs de!elo# ent.+3 Preschool follo"-u# studies re!ealed that children "ith chronic, se!ere *& in infancy had #oorer cogniti!e and otor de!elo# ent,+5,F,+0 as "ell as lo"er le!els of alertness, #hysical acti!ity, #ositi!e affect, and !er$ali%ation than children "ith good iron status in infancy.+,,./ *n this study children "ere e=#osed to ore stressful la$oratory conte=ts to elicit $eha!iors that "ould reflect the long-ter social and e otional i #acts of *&A in infancy. 7n the $asis of the functional-isolation hy#othesis and #ast research, "e hy#othesi%ed that affecti!e and $eha!ior differences associated "ith *&A during infancy "ould $e long lasting. S#ecifically, "e #redicted that nonane ic #reschool-aged children "ho had chronic *&A in infancy "ould sho" altered affect and $eha!ior co #ared "ith children "ho "ere nonane ic throughout infancy.
%re3ious ectionNe+t ection

!'B6/C)! A9D M/)%"D!

This study focused on affect and $eha!ior at the follo"-u# assess ent #erfor ed at the age of 3 years in children "ho "ere #artici#ating in a longitudinal co #le entary foodsu##le ent #roAect. The ai of the original #roAect "as to e!aluate the effects of a co #le entary food su##le ent a ong infants and young children in 5 #oor counties of Iansu #ro!ince in the north"estern #art of China during .//+F.//:. *n each county, : !illages "ere rando ly chosen. @ith the hel# of !illage doctors, "e enrolled all children aged 3 to +. onths in the !illages until the nu $er of study #artici#ants reached .// #er county. These children "ere recruited as the e=#eri ental grou#. (sing the sa e sa #ling ethods, "e selected another +// children #er county in the near$y !illages as the control grou#. 7ne thousand children in the e=#eri ental grou# recei!ed a sachet containing +/ g of nutrient-dense co #le entary food su##le ent to $e added to their nor al diet. The co #osition of the su##le ent "as as follo"s2 - g of iron, 3.+ g of %inc, :05 g calciu , /.. g of !ita in B., 6./ \g of !ita in &, and :.0 g of #rotein.

The total energy of a sachet "as +-6 'L. >i!e hundred children in the control grou# recei!ed a sachet of rice flour "ith added !egeta$le oil to atch the total energy of the e=#eri ental su##le ent. All children "ere gi!en su##le ents u# to the age of .3 onths, and all "ere gi!en !ita in A ca#sules e!ery - onths..+ @eight and height easure ents "ere ta'en e!ery : onths, and he oglo$in concentration "as tested e!ery - onths. The nu $er of children "ho attended the .3- onth-old assess ent in the e=#eri ental and control grou#s "as -3. and :5., res#ecti!ely. *n .//3, children recruited in the original study "ere e!aluated at 3 years of age. @eight, height, and he oglo$in concentration "ere easured, and $eha!ior and de!elo# ent "ere assessed. A total of 3/3 children attended the 3-year follo"-u# assess ent. All ethods "ere re!ie"ed and a##ro!ed $y the ethics re!ie" co ittee of the China Center for &isease Control, and infor ed !er$al consent "as o$tained fro all #arents. &etails of the original sur!ey and follo"-u# study ha!e $een #u$lished else"here..+ The #resent study focused on children "ho attended the $aseline sur!ey, .3- onth assess ent, and 3-year follo"-u#2 .:. children et this inclusion criterion. @e e=cluded 6+ children "ho "ere ane ic at the 3-year follo"-u# assess ent, $ecause #reschool-aged children "ith *&A ay sho" altered affect and $eha!ior... &ata for +-+ children are re#orted here. They did not differ in $ac'ground characteristics fro children "ith inco #lete data. )one of children in!ol!ed attended #reschool or day care and E,6; of the others "ere far ers. The children "ere categori%ed into grou#s as follo"s2 .6 children "ho "ere ane ic $efore +. onths, still ane ic at the .3- onth assess ent, and nonane ic at the 3-year follo"-u# "ere in the chronic-*&A grou#. Se!enty children "ho "ere ane ic $efore +. onths and nonane ic at the .3- onth and 3-year follo"-u# assess ents "ere in the corrected-*&A grou#. Si=ty-four children "ho "ere nonane ic at all ti e #oints "ere in the nonane ic grou#.

Data Collection
7n the $asis of cross-cultural research $y Chen and colleagues.: and the assess ent $attery of Iolds ith et al 1H. H. Iolds ith, Ph&, L. 8eilly, Ph&, R. S. De ery, Ph&, S. Dongley, Ph&, and A. Prescott, Ahe @aboratory Aemperament Assessment Fattery% Preschool Rersion, un#u$lished anuscri#t, +,,,4, "e designed a set of la$oratory conte=ts in "hich to easure childrenMs social referencing, "arinessBinhi$ition, frustration tolerance, and affect. Mother and child "ere in!ited to a clinic roo and s#ent +/ inutes in free #lay. &uring this #eriod, "e #ro!ided so e toys and #u%%le tas's. After free #lay, a ale stranger ca e in, sat in front of the child, and engaged the child in a scri#ted con!ersation for 5 inutes 1stranger a##roach4. The stranger then left after telling the child that he "ould sho" so ething s#ecial to hi or her. The stranger ca e $ac' "ith a $o=, #ut the $o= on the ta$le "here the child "as seated, and then re o!ed the co!er of the $o=. A s#ecial toy #o##ed out, and the stranger sho"ed an e=#ression of astonish ent 1no!el toy4. *n the last e#isode, the e=#eri enter ca e in and ga!e the child a snac', as'ing the child not to touch or eat it until the e=#eri enter ca e $ac' again

1delay of gratification4. The e=#eri enter returned in + inute. The "hole #rocedure "as !ideota#ed. The other "as #resent throughout the #rocess and "as infor ed that she should not gi!e any instructions to the child.

Beha#ior Coding
@e coded child affecti!e dis#lay using a ti e-sa #ling 15-second inter!al4 coding sche e. Positi!e affect "as coded for clear !er$al and non!er$al e=#ressions of Aoy and #leasure in other-child interactions, such as laughing, s iling, singing ha##ily, Au #ing "ith Aoy, or saying J* a so ha##ywK )egati!e affect "as coded for the #resence of anger, sadness, or crying. (nengaged affect "as coded for ?uiet and unin!ol!ed $eha!ior. Social referencing "as coded as loo'ing to"ard the other or tal'ing to the other during the con!ersation "ith the stranger or $efore touching the no!el toy or the snac' during the frustration situation. Datency to touch the no!el toy, "hether $eing in #ro=i ity 1"ithin ar Ms length4 to the other during the stranger a##roach, "hether res#onse to the stranger, and the ti e s#ent "ith #assi!e $eha!iors in the delay of gratification "ere coded to inde= "ariness or inhi$ition $eha!ior. Passi!e $eha!ior "as defined as doing nothing, only loo'ing at the snac'. Datency to touch the snac' and #hysical self-soothing in the snac'-delay situation "ere also coded. Physical selfsoothing included thu $ suc'ing, cloth or hair t"isting, and using soft or fa iliar o$Aects, #resu a$ly for co fort or security. The !ideota#es "ere coded $y 3 Chinese graduate students in #sychology "ho "ere trained $y the second author. *nterrater agree ent a!eraged 05; for childMs affect, social referencing, and inhi$ited $eha!ior on the $asis of ./; of the sa #le. )either the e=#eri enters nor the coders "ere a"are of the childrenMs iron status.

ron !tatus
*ron status "as deter ined on the $asis of the concentration of he oglo$in in a fingerstic' $lood sa #le o$tained at age 3 to +. onths, .3 onths, and 3 years. He oglo$in concentration "as deter ined $y the cyano ethe oglo$in ethod. The cutoff for ane ia "as a he oglo$in concentration of C++/ gBD at sea le!el. Because the study areas "ere +:// to :/// a$o!e sea le!el, the he oglo$in cutoff "as corrected according to the altitude of each county..3

!tatistical Analysis
*nde#endent sa #le t tests and v. tests "ere used to assess differences in $ac'ground characteristics $et"een the grou#s. Affecti!e and $eha!ioral outco es "ere co #ared $et"een the chronic-*&A-grou# and the nonane ic-grou# and the corrected-*&A-grou# and the nonane ic-grou#. >or affecti!e and $eha!ioral outco es that "ere coded as continuous !aria$les 1such as latency to touch the no!el toy4, a general linear odel "as used "ith control for confounding !aria$les. >or the outco es treated as categorical data 1such as #ercentage of children "ho ate the snac'4, "e #erfor ed logistic regressions to assess the effect of the grou# status of iron on affecti!e and $eha!ioral outco es. Child

gender "as included as a co!ariate in all analyses, gi!en that a greater #ro#ortion of the children in the corrected-*&A grou# "ere ale. The childMs age and otherMs education "ere also considered as #otential confounding !aria$les. @eight-for-age D scores 1@AW4 "ere calculated $y using Q#i *nfo 1(S Centers for &isease Control4 to deter ine the childrenMs nutritional status. @AW did not correlate "ith the outco e !aria$les and therefore "as not included as a co!ariate in the analysis. Statistical significance "as set at P C ./5. All data "ere analy%ed "ith SAS ,.+ 1SAS *nstitute, Cary, )C4.
%re3ious ectionNe+t ection

R/!'8)!
&escri#ti!e characteristics for the children and their others are #resented according to iron status grou# 1Ta$le +4. The #ro#ortion of ale children in the corrected-*&A grou# "as higher than that in the nonane ic grou#. The #ercentage of @AWs less than k. in the corrected-*&A grou# "as lo"er than that in the nonane ic grou# at $aseline sur!ey and .3- onth assess ent. There "ere no other statistically significant differences $et"een the chronic-*&A grou# and the nonane ic grou# or $et"een the corrected-*&A grou# and the nonane ic grou# "ith regard to $ac'ground characteristics, such as childMs age and gro"th and othersM age and education at the 3-year follo"-u# assess ent.
Bie/ this ta&le! In this /in,o/ In a ne/ /in,o/ -";@A 1

Child and >a ily Characteristics According to *ron Irou#s

5ariness and nhibited Beha#ior

Children in the chronic-*&A grou# s#ent ore ti e in #assi!e $eha!iors 1P C ./54 than those in the nonane ic grou#. There "ere no statistically significant grou# differences in the latency to touch the no!el toy $efore or after co!ariate control. The #ro#ortion of children in #ro=i ity to their others during the stranger a##roach and the #ro#ortion of children "ho res#onded to the strangerMs ?uestions did not differ $et"een the . grou#s. @ith regard to social referencing, a greater #ro#ortion of children in the chronic-*&A grou# sho"ed social referencing to their other $efore tal'ing to the stranger and $efore and after #ic'ing u# the no!el toy, $ut the differences "ere not significant 1P E ./54 1Ta$le .4.
Bie/ this ta&le! In this /in,o/ In a ne/ /in,o/ -";@A 2

Child Affect and Beha!ior According to *ron-Status Irou# @e did not find significant differences in "arinessBinhi$ited $eha!iors $et"een the children in the corrected-*&A grou# and nonane ic grou#.

;rustration )olerance
Co #ared "ith children in the nonane ic grou#, chronic-*&A grou# childrenMs latency to touchB#ic' u# a snac' "as significantly less 1P C ./54, and they s#ent a longer ti e #hysically self-soothing 1P C ./+4. There "ere no statistically significant differences $et"een children in the corrected-*&A grou# and nonane ic grou# in the a$o!eentioned $eha!iors. *n $oth the corrected-*&A grou# and chronic-*&A grou# a higher #ro#ortion of children ate the snac' during the o$ser!ation #eriod co #ared "ith the nonane ic grou# 1odds ratios [78s] for children in the chronic-*&A grou#2 5.5/ [P C . /5]T 78 for children in the corrected-*&A grou#2 ..:- [P C ./5]4.

Affect
@e found significant differences in #ositi!e affect $et"een the chronic-*&A grou# and the nonane ic grou# during the delay-of-gratification tas'T children in the chronic-*&A grou# s#ent less ti e s iling 1P C ./54. &uring stranger a##roach, logistic analysis results indicated that the odds of ha!ing a ore #ositi!e affect "ere 6-..; lo"er for children in the chronic-*&A grou# co #ared "ith children in the nonane ic grou# 1P C . /54, and the #ro#ortion of children "ho sho"ed unengaged affect "as significantly higher in the chronic-*&A grou# 1P C ./54. *n the o$ser!ation of free #lay and no!el toy sessions, children in the chronic-*&A grou# a!eraged less ti e s iling than those in the nonane ic grou#, $ut the difference did not reach statistical significance. The affecti!e $eha!iors of children in the corrected-*&A grou# "ere co #ara$le to those of children in nonane ic grou#. )egati!e affect "as not analy%ed $ecause C.; of children cried or fussed during the o$ser!ation #eriod.
%re3ious ectionNe+t ection

D !C'!! "9
7ur findings su##ort the #rediction of long-ter social-e otional effects of chronic *&A during infancy. @e found that des#ite correction of *&A $y 3 years of age, children "ho had chronic *&A in infancy sho"ed less #ositi!e affect and frustration tolerance and ore #assi!e $eha!ior, unengaged affect, and #hysical self-soothing than children "ho "ere nonane ic throughout infancy. >urther ore, "e found that children "hose ane ia "as corrected $efore .3 onths "ere co #ara$le in $eha!ior to children "ho "ere nonane ic throughout infancy.

The #resent study used ore e=tensi!e o$ser!ations than #re!ious studies to e=a ine the affect and $eha!ior of for er *&A, nonane ic #reschool-aged children. @e #erfor ed a delay-of-gratification tas' to assess the effects of *&A on #reschoolersM ca#acity for selfcontrol in the face of te #tation..5 &elay-of-gratification tas's ha!e not #re!iously $een used in *& studies. 8esults of research in other areas ha!e sho"n that "hen 3-year-old children "ho are ore successful at "aiting in delay of gratification situations reach adolescence, they are ore attenti!e and $etter a$le to concentrate, and e=hi$it greater self-control and frustration tolerance than their #eers..5 @e included no!el toy and stranger a##roach situations s#ecifically to #ursue earlier o$ser!ations of "ary, hesitant $eha!ior in infants "ith *&A. )o!el toy and stranger a##roach #aradig s ha!e $een used to e=a ine indi!idual differences in #reschoolersM $eha!ior in reaction to no!el situations..- @ary or $eha!iorally inhi$ited children ty#ically dis#lay lo" a##roach $eha!ior and stay in close #ro=i ity to their others "hen confronted "ith a range of no!el sti uli, including #eo#le, o$Aects, and situations... There is increasing e!idence that this "aryBinhi$ited $eha!ioral #attern is a ris' factor for future #ro$le s, such as an=iety, de#ression, and negati!e self-#erce#tions of co #etence...,.6 *n our study, affect and $eha!ioral alterations see ed es#ecially a##arent "ith increased no!elty, unfa iliarity, or stress..0,., @e found little difference in affect and $eha!ior during free #lay or ne" toy #resentation, $ut affect and $eha!ioral differences $eca e a##arent in the stranger-a##roach session and delay-of-gratification tas'. @e found that children in the chronic-*&A grou# "ere less successful at "aiting, and sho"ed ore #hysical self-soothing and #assi!e $eha!iors, and less #ositi!e affect. Do%off et al found that #reschoolers "ith *&A sho"ed less social loo'ing "ith their others during a #lay o$ser!ation that in!ol!ed fa iliar and unfa iliar toys... 7ur finding on increased social loo'ing in the chronic-*&A grou# is not directly co #ara$le to the results of Do%off et al $ecause all of the children in our study "ere nonane ic. 7ur results re?uire re#lication in other sa #les and settings, es#ecially $ecause of our s all sa #le si%e. )onetheless, our o$ser!ations of $eha!ioral alterations in #reschool children "ith chronic *&A in infancy su##ort the findings of other research. A study in >rance follo"ed childrenMs iron status and de!elo# ent ?uotient, including #ostural, coordination, language, and socia$ility ?uotients. The study results indicated that *&A at +/ onths did not correlate "ith de!elo# ent ?uotient, "hereas he oglo$in concentration at . years didT it "as #ositi!ely associated "ith o!erall de!elo# ental, #ostural, coordination, and social ?uotients in children aged . years.+- A longitudinal study in Costa 8ica included a structured other-child interaction tas' for children aged 5 years. Children "ith chronic *& in infancy dis#layed lo"er le!els of #hysical acti!ity, #ositi!e affect, !er$ali%ation, and reci#rocal interaction co #ared "ith children "ith good iron status, des#ite the correction of their *&A in infancy../ *n early adolescence, others and teachers rated the children "ho had chronic *& in infancy as ha!ing ore internali%ing $eha!ior #ro$le s 1such as an=ietyBde#ression and social #ro$le s4.+/ These findings #oint to the #otential Jfunctional isolationK significance of early $eha!ior alterations in children "ith chronic *&A in infancy. Social-e otional alterations in children "ith *& ha!e $een inter#reted in light of the role of iron in the function of the

do#a ine syste .:/,:+ 8ats "ith *& ha!e alterations in do#a ine eta$olis and e=hi$ited $eha!iorsT they sho" ore an=ious-li'e $eha!iors, ha!e reduced e=#loration in ne" en!iron ents, and de onstrate a slo"er rate of ha$ituation.:.,:: 8esults of studies of the affecti!e changes in infants "ith *&A 1"ariness, hesitance, a$sence of #ositi!e affect4 see to a'e sense in this conte=t., )eonatal do#a ine ter inal da age leads to a lifelong hy#erreacti!ity to no!el o$Aects and e=#eriences in an unfa iliar en!iron ent:+ and see s to ha!e long-ter effects on conte=t-de#endent attention and affecti!e res#onses., These findings #artially account for the altered affect and $eha!ior of the chronic-*&A grou# in the stranger-a##roach session and delay-of-gratification tas'. @e cannot eli inate the #ossi$ility that the altered $eha!ior of the chronic-*&A grou# in this study "as caused $y so e rele!ant $ut un easured factor1s4, although the grou#s "ere generally co #ara$le in $ac'ground characteristics, such as aternal de#ression and other en!iron ental disad!antages, "hich could account for $oth #oor infant-feeding #ractices 1leading to *&A4 and lac' of sti ulation 1leading to altered $eha!ior and de!elo# ent4. The study "as li ited "ith res#ect to easure ent of iron status. *&A "as esti ated according to he oglo$in concentration. He oglo$in concentration generally o!eresti ates the #re!alence of *&A, $ecause it does not account for ane ia attri$uta$le to other nutritional deficiencies 1eg, !ita in A deficiency4, infections, he oglo$ino#athies, or ethnic differences in nor al he oglo$in distri$ution.:3 Ho"e!er, it see s that *& "as a aAor cause of ane ia in this #o#ulationT he oglo$in concentrations sho"ed an o!erall increase of +/.5 gBD after the su##le entation inter!ention in infancy.:5,:- 7f the .6 children in the chronic-*&A grou# in the follo"-u# sa #le "hose ane ia "as not corrected $y the ti e of the .3- onth assess ent, +- did not recei!e su##le entation 1control grou#4 and ++ recei!ed su##le entation. 8egarding #ossi$le reasons for #ersistent ane ia in these ++ children, it should $e noted that the food su##le ent #ro!ided a lo" dose of iron 1- g #er day4. This a ount of iron "as uch lo"er than the @orld Health 7rgani%ation reco ended dose for *&A treat ent 1. .3 gB'g #er day4. *t is #ossi$le that a higher a ount of iron "ould ha!e corrected *&A in the study children $y the age of .3 onths.
%re3ious ectionNe+t ection

C"9C8'! "9! A9D M+8 CA) "9!

The results of this study sho"ed that #reschool-aged children "ho had chronic *&A in infancy sho"ed less #ositi!e affect, less frustration tolerance, ore #assi!e $eha!ior, and ore #hysical self-soothing during a delay-of-gratification situation. Children "hose ane ia "as corrected $efore age .3 onths "ere co #ara$le in social-e otional $eha!ior to children "ho "ere nonane ic throughout infancy and early childhood. These results #oint to the #otential $enefits of #re!enting *& in infancy and treating it $efore it $eco es chronic or se!ere.
%re3ious ectionNe+t ection

ACK9"58/D:M/9)!
The 3-year follo"-u# sur!ey and this "or' "ere su##orted $y *nternational Dife Sciences *nstitute and Qllison Medical >oundation-*nternational )utrition >oundation. @e are grateful to the fa ilies for their co it ent and their continued #artici#ation. @e es#ecially a##reciate the efforts of students in BeiAing (ni!ersity in coding the childrenMs $eha!ior.
%re3ious ectionNe+t ection

;ootnotes

"ccepte, January 5( 2011. ",,ress correspon,ence to 9hun'ing 9hen( # ( 9hinese 9enters for 0isease 9ontrol an, %re3ention( 27 Nan Eei =,( ;eiKing 100050( 9hina8 e1'ail! chenc'Rilsichina.org. uying 9hang( # ( ?NI9A. *ffice for 9hina( 12 anlitun =oa,( ;eiKing 100600( 9hina8 e1'ail! schangR?NI9A..org or changsuyingRhot'ail.co'
o

; 9A9C A8 D !C8"!'R/: The authors ha!e indicated they ha!e no financial relationshi#s rele!ant to this article to disclose.

I0 O iron ,eficiency S I0" O iron1,eficiency ane'ia S E"Q O /eight1for1age z score S *= O o,,s ratio %re3ious ection

R/;/R/9C/!
1. 1. 1. @eung "2( 2. 9han 2E . Iron deficiency anemia. Adv Pediatr. 2001;48:385408 #e,line 2. 2. 1. Qhu I( 2. @iao N

. Prevalence of iron deficiency in children a ed ! month" to ! year" in #hina. $hon h%a &r 'e $a $hi. 2004;42(12):88*8+1 #e,line 3. 3. 1. @oFoff ; . Iron deficiency and child develo,ment. -ood .%tr /%ll. 200!;28(4 "%,,l):05*0 05!1 #e,lineEe& of cience 4. 4. 1. 2. 3. 4. @oFoff ;( ;rittenha' <#( Eolf "E( et al

. Iron deficiency anemia and iron thera,y effect" on infant develo,mental te"t ,erformance. Pediatric". 1+8!;!+(*):+81++5 "&stract7.=AA .ull -e+t 5. 5. 1. @oFoff ;( 2. Eolf "E( 3. Ji'eneF A . Iron1deficiency anemia and infant develo,ment: effect" of e2tended oral iron thera,y. 3 Pediatr. 1++*;12+(3):38238+ 9ross=ef#e,lineEe& of cience 6. 6. 1. $o)a'a -( 2. <ushi 2en #( 3. Noso)o N . Iron deficiency anaemia and child develo,ment. A"ia Pac 3 P%4lic 5ealth. 2005;1!(1):1+21 "&stract7.=AA .ull -e+t 7. 7. 1. Ealter -( 2. 2o3als)ys J( 3. te)el "

. &ffect of mild iron deficiency on infant mental develo,ment "core". 3 Pediatr. 1+83;102(4):51+522 9ross=ef#e,lineEe& of cience 8. 8. 1. 2. 3. 4. 5. @oFoff ;( ;rittenha' <#( Biteri .A( Eolf "E( ?rrutia JJ

. 6he effect" of "hort1term oral iron thera,y on develo,mental deficit" in iron1 deficient anemic infant". 3 Pediatr. 1+82;100(3):35135! 9ross=ef#e,lineEe& of cience 9. 9. 1. 2. 3. 4. 5. 6. @oFoff ;( ;ear, J( 9onnor J( ;ar&ara .( <eorgieff #( challert -

. 7on 1la"tin ne%ral and 4ehavioral effect" of iron deficiency in infancy. .%tr 8ev. 200*;*4(5 ,t 2):034043; di"c%""ion 0!20+1 9ross=ef#e,lineEe& of cience 10. 10. 1. 2. 3. 4. 5. @oFoff ;( Ji'eneF A( $agen J( #ollen A( Eolf "E

. Poorer 4ehavioral and develo,mental o%tcome more than 10 year" after treatment for iron deficiency in infancy. Pediatric". 2000;105(4). Availa4le at: 999.,ediatric".or :c i:content:f%ll:105:4:e51 11. 11. 1. toltFfus =J( 2. #ullany @( 3. ;lac) =A . Iron deficiency anemia. In: &zzati ;< 7o,ez A=< 8od er" A< ;%rray # ed". #om,arative >%antification of 5ealth 8i"'": ?lo4al and 8e ional /%rden of =i"ea"e Attri4%ta4le to 0elected ;a@or 8i"' -actor". ?eneva< 09itzerland: Aorld 5ealth Br anization; 2004

earch <oogle cholar 12. 12. 1. @e3its)y 0" . ;aln%trition and h%n er to learn. In: 7evit"'y =A ed". ;aln%trition< &nvironment< and /ehavior. Ithaca< .C: #ornell Dniver"ity; 1+!+:1*11!+ earch <oogle cholar 13. 13. 1. ;ro/n J@( 2. %ollitt A . ;aln%trition< ,overty and intellect%al develo,ment. 0ci Am. 1++*;2!4(2):3843 #e,lineEe& of cience 14. 14. 1. <rantha'1#c<regor ( 2. "ni 9 . A revie9 of "t%die" on the effect of iron deficiency on co nitive develo,ment in children. 3 .%tr. 2001;131(2012):*4+**8 earch <oogle cholar 15. 15. 1. 0e "n,raca I( 2. Ealter -( 3. 9astillo # . Iron deficiency anemia and it" effect" %,on ,"ycholo ical develo,ment at ,re"chool a e: a lon it%dinal "t%dy. In: .e"tle -o%ndation .%trition Ann%al 8e,ort (1++0). Eevey< 09itzerland: .e"tec 7td; 1++1:53*2 earch <oogle cholar 16. 16. 1. 2. 3. 4. 0o''ergues J%( "rcha'&eau, #%( 0ucot ;( et al

. Iron deficiency and ,"ychomotor develo,ment te"t": lon it%dinal "t%dy 4et9een 10 month" and 4 year" of a e Fin -renchG. Arch -r Pediatr. 1+8+;4*(!):48!4+0 #e,lineEe& of cience

17. 17. 1. %alti $( 2. %e3sner ;( 3. ",ler ; . =oe" anemia in infancy affect achievement on develo,mental and intelli ence te"t"H 5%m /iol. 1+83;55(1):1831+4 #e,lineEe& of cience 18. 18. 1. @oFoff ;( 2. Ji'eneF A( 3. Eolf "E . 7on 1term develo,mental o%tcome of infant" 9ith iron deficiency. . &n l 3 ;ed. 1++1;325(10):*8!*+4 #e,lineEe& of cience 19. 19. 1. 2. 3. 4. -a'ura -( <ol,en&erg =@( $ou J( et al

. #ord "er%m ferritin concentration" and mental and ,"ychomotor develo,ment of children at five year" of a e. 3 Pediatr. 2002;140(2):1*51!0 9ross=ef#e,lineEe& of cience 20. 20. 1. 9orapci .( 2. =a,an "A( 3. @oFoff ; . Iron deficiency in infancy and mother1child interaction at 5 year". 3 =ev /ehav Pediatr. 200*;2!(5):3!13!8 9ross=ef#e,lineEe& of cience 21. 21. 1. 9hen 9( 2. Eang I( 3. 9hang . &ffect of in1home fortification of com,lementary feedin on intellect%al develo,ment of #hine"e children. /iomed &nviron 0ci. 2010;23(2):83+1

9ross=ef#e,lineEe& of cience 22. 22. 1. 2. 3. 4. @oFoff ;( 9orapci .( ;ur,en #J( et al

. Pre"chool1a ed children 9ith iron deficiency anemia "ho9 altered affect and 4ehavior. 3 .%tr. 200!;13!(3):*83*8+ "&stract7.=AA .ull -e+t 23. 23. 1. 2. 3. 4. 5. 6. 9hen J( $astings %0( =u&&in 2$( 9hen $( 9en <( te/art @

. #hild1rearin attit%de" and 4ehavioral inhi4ition in #hine"e and #anadian toddler": a cro""1c%lt%ral "t%dy. =ev P"ychol. 1++8;34(4):*!!*8* 9ross=ef#e,lineEe& of cience 24. 24. Aorld 5ealth Br anization. Iron =eficiency Anemia: A""e""ment< Prevention< and #ontrol. A ?%ide for Pro ramme ;ana er". ?eneva< 09itzerland: Aorld 5ealth Br anization; 2001.Availa4le at: 999.9ho.int:n%trition:,%4lication":micron%trient":anaemiaIironIdeficiency:A5B I.5=I01.3:en:inde2.html. Acce""ed -e4r%ary 2< 2011 25. 25. 1. #ischel E( 2. ho,a I( 3. =o,rigueF #@ . =elay of ratification in children. 0cience. 1+8+;244(4+0!):+33+38 "&stract7.=AA .ull -e+t 26. 26. 1. 2. 3. 4. 5. =u&in 2$( $astings %0( te/art @( $en,erson $"( 9hen JI

. 6he con"i"tency and concomitant" of inhi4ition: 0ome of the children< all of the time. #hild =ev. 1++!;*8(3):4*!483 9ross=ef#e,lineEe& of cience 27. 27. 1. 2. 3. 4. 5. 9aspi "( $enry ;( #c<ee =*( #offitt -A( il3a %"

. 6em,eramental ori in" of child and adole"cent 4ehavior ,ro4lem": from a e 3 to a e 15. #hild =ev. 1++5;**(1):55*8 9ross=ef#e,lineEe& of cience 28. 28. 1. 2. 3. 4. 5. 6. @oFoff ;( 2lein N2( Nelson A9( #c9lish 02( #anuel #( 9hacon #A

. /ehavior of infant" 9ith iron1deficiency anemia. #hild =ev. 1++8;*+(1):243* 9ross=ef#e,lineEe& of cience 29. 29. 1. 2. 3. 4. 5. 6. "ngulo12inFler =#( %eirano %( @in A( "lgarin 9( <arri,o #( @oFoff ;

. 69enty1fo%r1ho%r motor activity in h%man infant" 9ith and 9itho%t iron deficiency anemia. &arly 5%m =ev. 2002;!0(12):85101 9ross=ef#e,lineEe& of cience 30. 30. 1. 2. 3. 4. 5. 6. @oFoff ;( 9lar) 2#( Jing I( "r'ony1 i3an =( "ngelilli #=( Jaco&son E

. =o"e1re",on"e relation"hi," 4et9een iron deficiency 9ith or 9itho%t anemia and infant "ocial1emotional 4ehavior. 3 Pediatr. 2008;152(5):*+*!02 9ross=ef#e,lineEe& of cience 31. 31. 1. 2. 3. 4. 5. 6. ;ear, J( .elt ;( challert -( ;urhans #( 9onnor J( <eorgieff #

. ;oderate iron deficiency in infancy: 4iolo y and 4ehavior in yo%n rat". /ehav /rain 8e". 200*;1!0(2):224232 9ross=ef#e,lineEe& of cience 32. 32. 1. 2. 3. 4. ;ear, J( 9hen N( 9onnor J( Jones ;

. Altered monoamine meta4oli"m in ca%date1,%tamen of iron1deficient rat. Pharmacol /iochem /ehav. 1++4;3(48):*21*24 earch <oogle cholar 33. 33. 1. ;ear, J@( 2. 9onnor J= . Iron "tat%" and ne%ral f%nctionin . Ann% 8ev .%tr. 2003(23):4158 earch <oogle cholar 34. 34. 1. Qi''er'ann #;( 2. $urrell =. . .%tritional iron deficiency. 7ancet. 200!;3!0(+58*):511520 9ross=ef#e,lineEe& of cience 35. 35. 1. Eang I( 2. 9hen 9( 3. Jia #(

4. .ang J . &ffect of com,lementary food "%,,lement" on anemia in infant and yo%n children. Aei 0hen Can 3i%. 2004;33(3):33433* #e,line 36. 36. 1. 2. 3. 4. 0all'an %=( =ee3es J0( 0riggers 0"( @o AI

. =ia no"i" of iron deficiency: the limitation" of la4oratory te"t" in ,redictin re",on"e to iron treatment in 11year1old infant". 3 Pediatr. 1+81;++(3):3!*381 9ross=ef#e,lineEe& of cience

9opyright P 2011 &y the "'erican "

1Lournal of attention disorders Author Manuscri#t )*H Pu$lic Access

ron !tatus in )oddlerhood +redicts !ensiti#ity to +sychostimulants in Children

Catharyn Turner, M.Qd., &i?iong Sie, M.S., and Bridget Wi Additional article infor ation er an, Ph.&.

Abstract
ntroduction
*ron deficiency is associated "ith i #aired do#a inergic signaling and e=ternali%ing $eha!ior. Ho"e!er, "hether iron stores in toddlerhood influence later res#onse to #sychosti ulants is un'no"n.

Methods

Youths #artici#ating in a study onitoring the long-ter safety of ris#eridone "ere included in this analysis if they had recei!ed #sychosti ulant onothera#y for at least : "ee's and had a co #lete $lood count o$tained #rior to #sychosti ulant treat ent. Sensiti!ity to #sychosti ulants "as defined $ased on the "eight-adAusted dose during the first year of treat ent. 8egression analysis e=a ined "hether the he atological tests $ased on the characteristics of red $lood cells "ere associated "ith sensiti!ity to #sychosti ulants.

Results
T"enty nine #artici#ants 1,:; ales, 6-; Caucasians4, #ri arily "ith A&H& 1,:;4, co #rised the current sa #le. The he atological tests "ere o$tained, on a!erage, : years $efore the initiation of #sychosti ulants onothera#y "hich occurred at 5.0 years of age and continued for a edian of /.05 years, at an a!erage daily dose of /.,0 gB'g 1S&9/.:04 in ethyl#henidate-e?ui!alent. Co #ared to those that "ere #oorly sensiti!e to #sychosti ulants, after adAusting for age, ean cor#uscular !olu e "as significantly higher in the highly and oderately sensiti!e grou#s.

Conclusions
*f re#licated, our findings suggest that iron in early childhood. ore attention should $e #aid to o#ti i%ing $ody

ntroduction
Attention deficit hy#eracti!ity disorder 1A&H&4 is one of the ost co on neuro#sychiatric disorders in children 1APA, .///4. Psychosocial inter!entions effecti!ely reduce sy #to se!erity and i #air ent though #sychotro#ics are often #rescri$ed, es#ecially in se!ere cases 1Plis%'a, .//64. Most of the #ro!en #har acological agents alter the do#a inergic syste , consistent "ith research i #licating do#a ine in the !arious neuro#sychological #rocesses i #aired in A&H& 1Plis%'a, .//64. *n #articular, #sychosti ulants, "hich re#resent the first-line treat ent for A&H& 1Plis%'a, .//64, $loc' the do#a ine trans#orter and release catechola ines fro storage granules in the #resyna#tic neurons 1>ord et al., .//:4. Ho"e!er, "hile any studies ha!e esta$lished the efficacy of #sychosti ulants for A&H&, #redictors of res#onse re ain so e"hat elusi!e 1Plis%'a, .//64. A ong the ost consistent findings, $rain a$nor alities ha!e $een associated "ith decreased clinical efficacy. *ron is a critical nutrient in!ol!ed in $rain de!elo# ent in general and that of the do#a inergic syste in #articular. *n fact, it is a cofactor for tyrosine hydro=ylase, the rate-li iting en%y e for catechola ine synthesis 1Sachde!, +,,:4. *n addition, iron deficiency 1*&4 in rats results in reduced density of the do#a ine trans#orter as "ell as the &+ and &. do#a ine rece#tors in the $asal ganglia 1Beard et al., +,,3T Burhans et al., .//5T Qri'son et al., .///T Qri'son et al., .//+T )elson et al., +,,64. This effect a##ears ore #ronounced in ales 1Burhans et al., .//5T Qri'son et al., .//+4. Moreo!er, the res#onse to cocaine, a #otent inhi$itor of the do#a ine trans#orter, is attenuated in *&

rats 1Qri'son et al., .///T )elson et al., +,,64. Additional su##ort co es fro studies in children "ith *& sho"ing reduced #rolactin res#onse to a clonidine challenge, again reflecting dysfunctional do#a inergic signaling 1>elt et al., .//-a4. @ith iron #laying a 'ey role in neurotrans ission, dendritogenesis, syna#togenesis, and yelination, concerns ha!e $een raised a$out the i #act *& ight ha!e on cogniti!e, $eha!ioral, and e otional de!elo# ent 1Do%off et al., .//-4. This is #articularly true since u# to 6; of young children and +-; of adolescent fe ales in the (nited States are affected $y *& 1C&C, .//.4. This is an age "hen the $rain is undergoing su$stantial gro"th and aturation. *n fact, *& ane ia has $een lin'ed to socio-e otional and acade ic i #air ent 1>elt et al., .//-$T Do%off et al., .//-T Do%off et al., .///T @achs et al., .//54. *n addition, studies in #atients "ith A&H& ha!e re#orted an in!erse association $et"een seru ferritin, a easure of $ody iron, and the se!erity of inattention, hy#eracti!ity and i #ulsi!ity, or slee# distur$ances 1Cortese et al., .//,T Ronofal et al., .//3T 7ner et al., .//04. Moreo!er, it is #articularly distur$ing that #ros#ecti!e studies ha!e found #ersistent cogniti!e and neuroche ical a$nor alities, long after the resolution of *& identified #ostnatally 1Burhans et al., .//5T >elt et al., .//-$T Do%off et al., .///4. >or e=a #le, ore than ten years after their iron stores had $een re#lenished, children "ith a history of *& "ere ore li'ely to ha!e re#eated a grade andBor recei!ed educational ser!ices, co #ared to children "ith a nor al iron status 1Do%off et al., .///4. They also e=hi$ited increased $eha!ior #ro$le s, including inattention 1Do%off et al., .///4. >urther ore, these children had altered #rolactin res#onse to a clonidine challenge 1>elt et al., .//-$4. These findings suggest that, at least to so e e=tent, *& in infancy ight ha!e a longlasting effect on $rain de!elo# ent in general and on the do#a inergic syste in #articular. This "ould also $e consistent "ith so e studies in *& rats sho"ing only #artial reco!ery of neurotrans ission follo"ing iron su##le entation 1Burhans et al., .//54. *n fact, the se!erity of *& and the ti ing of iron re#letion a##ear crucial in deter ining the e=tent to "hich reco!ery "ill $e co #lete 1Do%off et al., .//-4. *n su , #reclinical and hu an research suggests that *&, inattention or A&H&, and i #aired do#a inergic signaling ay $e interrelated, $oth acutely, during iron deficiency, and chronically, after it has $een corrected. Ho"e!er, to our 'no"ledge, only one #u$lished study has in!estigated the association $et"een seru ferritin and res#onse to treat ent in A&H& 1Millicha# et al., .//-4. *n that study, there "as no difference in clinical res#onse to #sychosti ulants $et"een children "ith lo" 1C./ ngB l4 !ersus high 1E-/ ngB l4 seru ferritin concentration. This ?uestion is #articularly #ertinent in light of ani al studies sho"ing that *& da #ens the inhi$itory effect of cocaine on the do#a ine trans#orter 1Qri'son et al., .///T )elson et al., +,,64. Such e!idence raises the #ossi$ility of a odulatory effect of iron status on the efficacy of #sychosti ulant treat ent in #atients "ith A&H& since, as noted earlier, they act $y $loc'ing the do#a ine trans#orter 1>ord et al., .//:4. Therefore, "e here e=a ine "hether iron status in infancy and toddlerhood #redicts res#onse to #sychosti ulant treat ent. @e used he atological tests $ased on

characteristics of red $lood cells [i.e., he oglo$in concentration 1H$4, he atocrit 1Htc4, ean cell !olu e 1MCH4, and red $lood cell distri$ution "idth 18&@4] as #ro=ies for iron status and tested the hy#othesis that these #ara eters are associated "ith the dose of #sychosti ulants used to successfully treat A&H& sy #to s. The dose of #sychosti ulants, "e #resu ed, reflects the integrity of the central do#a inergic syste .

Methods
+articipants
This analysis uses data collected in an ongoing study e!aluating the safety of ris#eridone during long-ter treat ent. The study ai s, rationale, and initial findings ha!e $een descri$ed else"here 1Calarge et al., .//,aT Calarge et al., .//,$4. Briefly, 6 to +6 yearold ales and fe ales "ere enrolled if they had $een ta'ing ris#eridone, irres#ecti!e of indication, for a ini u of si= onths. Conco itant #sychotro#ic treat ent "as allo"ed, e=ce#t for other anti#sychotic edications. Patients "ith intellectual disa$ility, trau atic $rain inAury, other neurological disorders, or significant edical conditions "ere e=cluded as "ere #regnant fe ales and those recei!ing hor onal contrace#tion.

+rocedures
The study "as a##ro!ed $y the local *nstitutional 8e!ie" Board. @ritten assent "as o$tained fro children ++ years old or younger and "ritten consent fro adolescents and #arentsBguardians. All edical and #sychiatric records "ere o$tained. *n the aAority of the cases, records "ere a!aila$le since $irth. @e e=tracted all rele!ant clinical infor ation including the #sychiatric diagnoses and the edication history. @e recorded the start and sto# dates of each edication as "ell as changes in the dosage and for ulation 1Calarge et al., .//,a4. This docu entation, confir ed $y a #hysician, also reflected any #otential de!iation fro the #rescri$ed treat ents. All dosages of #sychosti ulants "ere e=#ressed in ethyl#henidate 1MPH4 e?ui!alents for a #heta ines 1= .4 1Calarge et al., .//,aT S"anson et al., .//64. &uring the chart re!ie", "e also e=tracted all the results of he atological tests $ased on characteristics of red $lood cells as "ell as the "eight of the #artici#ants at each ti e #oint. The latter allo"ed us to adAust the dose of MPH for "eight 1i.e., co #uting a gB'gBday dose4. A ti e #oint for data entry "as created in the data set e!ery ti e a "eight easure ent "as a!aila$le in the edical record or a edication change too' #lace. (#on enroll ent, the #arent "as as'ed to co #lete a ?uestionnaire a$out the #regnancy, including the age of the #arent at the ti e of the #regnancy as "ell as the gestational age u#on $irth, fro the last enstrual #eriod. @e defined #re aturity as $irth $efore :6 "ee's. These !aria$les are rele!ant to ruling out the #ossi$ility of ane ia resulting fro gestational factors, including #re aturity 1Mar's et al., +,,04.

The #sychiatric diagnoses "ere also o$tained fro the edical record. Ho"e!er, in order to e!aluate the !alidity of these clinical diagnoses, a $est-esti ate diagnosis "as generated in ,- su$Aects $ased on a re!ie" of all a!aila$le clinical data, including a standardi%ed inter!ie" of the #arent and the youth 1if ++ years old or older4 using the )*MH &iagnostic *nter!ie" Schedule for Children 1&*SC-*H4 1Shaffer et al., .///4. Agree ent $et"een the clinical diagnosis and the research-generated $est-esti ate diagnosis "as co #ared, using S statistic 1Cohen, +,-/4, for fi!e diagnostic categories2 A&H&, disru#ti!e $eha!ior disorders, #er!asi!e de!elo# ental disorders, tic disorders, and ood disorders. The S !alues "ere /.6+ 1,5; confidence inter!al 1C*42 /.5/F/.,:4, /.:- 1,5; C*2 /.+6F/.5-4, /.60 1,5; C*2 /.-/F/.,64, /.03 1,5; C*2 /.6.F/.,-4, and /.:, 1,5; C*2 /.+6F/.-+4, res#ecti!ely, reflecting fair to su$stantial agree ent. The lo"er agree ent for ood disorders li'ely reflects the rela#singBre itting nature of this disorder, a'ing it less li'ely that the sy #to s "ould re ain unaltered $y the ti e su$Aects under"ent the standardi%ed assess ent u#on study enroll ent.

!tatistical Analysis
7ur o!erall hy#othesis "as that iron status, as reflected $y the he atological indices, "ill $e associated "ith Jsensiti!ity to MPHK treat ent. &ue to the e=#loratory nature of this analysis, the a$sence of standardi%ed easures for clinical res#onse in this retros#ecti!e study, and the antici#ated !aria$ility in the dose and duration of #sychosti ulant treat ent in a clinical setting, "e defined Jsensiti!ity to MPHK as follo"s2 >irst, "e co #uted the a!erage daily dose of MPH and adAusted it for "eight 1i.e., gB'gBd4. @e then deter ined, during the first year of treat ent, the #ercentage of ti e s#ent ta'ing a lo" 1i.e., s /.- gB'gBd4, a high 1i.e., E +.. gB'gBd4, or a ediu daily dose of MPH 1)igg et al., +,,-4. This !aria$le ca#tures the dose and duration co #onents of res#onse to #sychosti ulants, "hich are $oth i #ortant to consider "hen assessing res#onsi!eness to treat ent. Their distri$utions, ho"e!er, "ere se!erely s'e"ed, "hich #re!ented us fro using these #ercentages as de#endent !aria$les 1the regression diagnostics re!ealed se!ere !iolations of odel assu #tions4. Therefore, "e defined three grou#s reflecting declining sensiti!ity to MPH2 The first grou#, referred to as Jhighly sensiti!eK, included those #artici#ants "ho too' a lo" dose of MPH for at least 5/; of the ti e $ut too' a high dose for less than ./; of the ti e. The Jlo" sensiti!eK grou# included those "ho too' a high MPH dose for a5/; of the ti e $ut a lo" dose for C ./; of the ti e. The J oderately sensiti!eK grou# included the rest of the #artici#ants. @e ha!e assu ed that the treating clinicians odified the dose of #sychosti ulants $ased on clinical res#onse and that aintenance treat ent reflected #atient and #arental satisfaction. @e restricted the analysis to those #artici#ants "hose he atological tests "ere o$tained $efore a #sychosti ulant "as initiated and "ho had recei!ed the edication for at least three "ee's $efore it "as sto##ed or another #sychotro#ic "as added 1>igure +4. @hen ulti#le easure ents for the sa e he atological #ara eter "ere #resent, "e selected the one that "as o$tained closest to +.5 years of age. This is $ecause children are at the highest ris' for *& $et"een the ages of , and +0 onths, coinciding "ith their ra#id rate of gro"th 1Mar's et al., +,,04. @e also e=cluded easure ents that "ere o$tained

$efore three onths of age since these usually reflect iron stores accrued in utero 1Mar's et al., +,,04.

>igure + Ti e Course for a Prototy#ical Patient As noted earlier, "e used the #artici#antsG "eight at each ti e #oint to co #ute a daily, "eight-adAusted dose of MPH. Ho"e!er, since clinicians do not easure or record "eight at e!ery clinic !isit, "eight infor ation "as issing in .6.5; of all the ti e #oints in the entire data set 1n90,::4. *n those instances, "e used the last "eight a!aila$le #rior to the issing one and the first one a!aila$le after"ards to esti ate the issing "eight. To confir the accuracy of this linear inter#olation ethod, "e conducted a si ulation analysis "here$y "e rando ly e=cluded :/; of the non- issing "eight !alues o$tained after age 3 and inter#olated the using the sa e linear ethod. The #ercentage difference $et"een the inter#olated and o$ser!ed !alues "as then co #uted 1i.e., [o$ser!ed "eight k inter#olated "eight] x +//;Bo$ser!ed "eight4 1Bland et al., +,,,4. The ean 1S&4 of this #ercentage "as k/./. 1:.5-4. The ,5; confidence inter!al for the #ercent $ias "as [k-.,-, -.,-] 1>igure .4 1Bland et al., +,,,4. *n other "ords, ,5; of the inter#olated "eight !alues fell "ithin N 6; of the actual !alues. This suggests that our linear inter#olation ethod is a##ro#riate to esti ate issing "eight !alues in the dataset.

>igure . Percent difference $et"een o$ser!ed and inter#olated "eight easure ents #lotted against o$ser!ed "eight. The ean #ercent difference is / 1full line4 "ith a ,5; confidence inter!al of N -.,- 1dash-dotted lines4. &e ogra#hic and clinical !aria$les across the three MPH Jsensiti!ityK grou#s "ere co #ared using analysis of !ariance for continuous !aria$les and the >isherGs e=act test for categorical !aria$les. *n order to test our #ri ary hy#otheses, "e used analysis of co!ariance 1A)C7HA4 "ith each he atological inde= odeled as the de#endent !aria$le and the JMPH sensiti!ityK grou#ing ser!ing as the #redictor !aria$les. Since the age at "hich the $lood test "as o$tained and the age at "hich #sychosti ulants "ere initiated !aried across the #artici#ants, though not across the JMPH sensiti!ityK grou#s, "e controlled for these t"o !aria$les in the analyses. All the statistical tests #erfor ed "ere t"o-tailed. Ii!en the e=#loratory nature of this analysis, "e did not adAust statistical significance for the nu $er of co #arisons "e conducted. @e #erfor ed all the analyses using SAS !ersion ,.. for @indo"s 1SAS *nstitute *nc., Cary, )C4.

Results
7f +33 #artici#ants "ith co #lete data recruited into the original study, ., had at least one he atological test o$tained $efore #sychosti ulants "ere started and recei!ed #sychosti ulants for at least three "ee's during their first year of treat ent. @e found no differences $et"een the ., #artici#ants included in this analysis and those not 1n9++54 in se= 1,:; ales !s. 0,;, #E/.64, racialBethnic co #osition 16-; Caucasians !s. 03;, #E/..4, age 1++.. years N ..0 !s. +../ N ..0, #E/.+4, or age "hen #sychosti ulants "ere started 15.0 years N +.6 !s. -.. N :.., #E/.34. There "ere also no differences in the clinical diagnoses or in the indication for ris#eridone treat ent across the t"o grou#s 1all #E/..4. Ta$le + sho"s the de ogra#hic and clinical characteristics of the ., #artici#ants included in this analysis di!ided in three grou#s $ased on the #ercentage of ti e, during the first year of #sychosti ulant treat ent, they recei!ed a lo", ediu , or high "eight-adAusted MPH dose. By study design, all #artici#ants "ere ta'ing ris#eridone, u#on recruit ent, to target aggression and irrita$ility in ,:; 1n9.64 of the cases, i #ulsi!ity in one case 1:;4, and tics in another 1:;4. The ost co on clinical diagnosis, u#on enroll ent, "as attention deficit hy#eracti!ity disorder #resent in .6 1,:;4 of the children. Ho"e!er, co or$idity "as the rule "ith .. 16-;4 children ha!ing a disru#ti!e $eha!ior disorder, +: 135;4 an an=iety disorder, 3 1+3;4 a de#ressi!e disorder, 5 1+6;4 a tic disorder, and t"o children 16;4 carrying a diagnosis of #er!asi!e de!elo# ental disorder.

Ta$le * &ifferences in &e ogra#hic, Treat ent Characteristics, and Iestational &ata Across the Three JMPH Sensiti!ityK Irou#s. Since the ai of the current in!estigation is to e=#lore the association $et"een iron status in toddlerhood and sensiti!ity to #sychosti ulants, "e restricted the analysis to the initial #sychiatric treat ent #eriod "hen the #artici#ants recei!ed only #sychosti ulants 1>igure +4. 7n a!erage, the #artici#ants "ere 5.0 years old 1S&9+.64 "hen they started ta'ing #sychosti ulants. Their a!erage daily dose "as /.,0 gB'g 1S&9/.:04 and the edian duration of treat ent "as /.05 years 1*V89/.6.4. As noted earlier, the sa #le "as di!ided in three grou#s $ased on the #ercentage of ti e each #artici#ant too' MPH at a lo", ediu , and high dose. (sing this definition, eight #artici#ants "ere considered to ha!e high sensiti!ity to MPH, nine ha!ing ediu sensiti!ity, and +. ha!ing lo" sensiti!ity. )o de ogra#hic or clinical differences "ere significant across the three grou#s, e=ce#t those related to MPH dosage 1Ta$le *4.

The he atological tests "ere o$tained at a ean age of ..0 years 1S&9+.04, on a!erage, :./ years 1S&9+.54 $efore the onset of #sychosti ulant treat ent. The ean H$ concentration "as ++., gBdl 1S&9+.+, range2 +/F+3.:4, Htc :3.3; 1S&9..6, range2 .-.5F :0.34, MCH 6-.: fe toliters 1S&95.0, range2 -:.3F03.34, and 8&@ +:., 1S&9+.,, range2 +/.0F+6.:4. (sing the cutoffs for the different he atological tests, as defined $y Mar's et al. $ased on age and se= 1Mar's et al., +,,04, lo" H$ "as #resent in +0; 1n954 of the sa #le, lo" Htc in ..; 1n954, icrocytosis in 30; 1n9+/4, and large 8&@ in 3.; 1n954. The indication to o$tain the tests included a "or' u# for a edical illness 1n9+-, 55;4, screening during yearly #hysicals 1n90, .0;4, a "or' u# for ane ia 1n9:, +/;4, and screening during a #sychiatric e!aluation 1n9., 6;4. There "ere no significant differences across the three JMPH sensiti!ityK grou#s in the indications for the test 1#E.64. Ta$le ** #resents the results of the he atological tests across the three JMPH sensiti!ityK grou#s. MCH "as significantly different across the grou#s "ith the Jhigh sensiti!ityK grou# ha!ing the largest !alue, follo"ed $y the J ediu sensiti!ityK grou#. The Jlo" sensiti!ityK grou# had the s allest MCH as "ould $e e=#ected if iron deficiency did, as hy#othesi%ed, reduce the susce#ti$ility of the do#a inergic syste to #sychosti ulants. Though none of the other he atological #ara eters "as significantly different across the three grou#s, all the o$ser!ed differences "ere in the e=#ected directions. The rates of icrocytocis and large 8&@ "ere nu erically different across the three grou#s 1Ta$le **4. Ho"e!er, these differences did not reach statistical significance, li'ely due to the s all sa #le si%e.

Ta$le ** &ifferences in He atological Tests Across the Three JMPH Sensiti!ityK Irou#s. A)C7HA "as then used to #redict the four he atological #ara eters, after adAusting for the age "hen a #sychosti ulant "as started as "ell as the age "hen the he atological test "as o$tained. Ta$le *** lists the $eta esti ates of the odels #redicting the four he atological #ara eters along "ith their standard errors. Co #ared to those that "ere #oorly sensiti!e to #sychosti ulants, after adAusting for age, ean MCH "as higher $y 0.- fD 1#C.//.4 in the highly sensiti!e grou# and $y 6.+ fD 1#C.//-4 in the oderately sensiti!e one. An alternati!e analysis, "ith the three JMPH sensiti!ityK grou#s, ran' ordered 1lo", oderate, high4, also sho"ed a significant association of MCH "ith MPH sensiti!ity 1#artial S#ear anGs r9/.5-, #C/./+4.

Ta$le *** Multi#le Dinear 8egression Models Predicting *ndi!idual He atological Tests as a >unction of JMPH Sensiti!ityK, AdAusting for the Age "hen Psychosti ulants 1MPH4 "ere Started and "hen the He atological Test "as 7$tained.

Discussion
*& has $een associated "ith altered do#a inergic signaling, cogniti!e i #air ent, inattention, and e=ternali%ing sy #to s, including A&H&. *n this analysis, "e e=#lored "hether tests $ased on characteristics of red $lood cells o$tained, on a!erage, : years #rior to the onset of treat ent "ith #sychosti ulants "as correlated "ith res#onse to sti ulant treat ent. MCH "as significantly associated "ith sensiti!ity to #sychosti ulants as inde=ed $y recei!ing a lo"er dose of #sychosti ulants during the first year of treat ent. Prior research has lin'ed reduced seru ferritin "ith the se!erity of inattention, hy#eracti!ity, and i #ulsi!ity 1Ronofal et al., .//3T 7ner et al., .//04. Ho"e!er, seru ferritin "as easured around the sa e ti e the clinical ratings "ere o$tained. @hile such findings contri$ute to esta$lishing an association $et"een iron stores and A&H&, they fail to address the essential #oint raised $y #reclinical and hu an studies that *&, early during de!elo# ent, ay lead to #ersistent changes in do#a inergic signaling and $eha!ioralBcogniti!e se?uelae 1Burhans et al., .//5T >elt et al., .//-$T Do%off et al., .///4. The alteration in do#a inergic neurotrans ission affects !arious $rain regions including the $asal ganglia, a structure consistently i #licated in A&H& 1&ic'stein et al., .//-4. &ue to the nature of our data$ase, "e "ere a$le to s#ecifically test "hether iron stores in the toddler years "ere associated "ith a differential sensiti!ity to #sychosti ulants in grade school. @hile MCH "as strongly associated "ith JMPH sensiti!ityK, no other inde= reached significance, li'ely due to the s all sa #le si%e. )e!ertheless, the trends "ere in the e=#ected duration "ith H$ and Hct $eing #ositi!ely associated "ith JMPH sensiti!ityK and 8&@ negati!ely so. *n the one other #u$lished study, "e are a"are of, that in!estigated the association $et"een seru ferritin and res#onse to #sychosti ulant treat ent, Millicha# et al. found no difference in the res#onse rate to #sychosti ulants $ased on ferritin concentration 1Millicha# et al., .//-4. *t "as not clear, ho"e!er, ho" res#onse to treat ent "as defined. Moreo!er, #atients "ith lo" seru ferritin "ere gi!en iron su##le ents $efore treat ent "ith #sychosti ulants "as initiated 1Millicha# et al., .//-4. Therefore, it is #ossi$le that iron re#letion as'ed the #otential lin' $et"een seru ferritin and

sensiti!ity to #sychosti ulants $y attenuating A&H& sy #to s as has $een sho"n in a recent dou$le-$lind #lace$o-controlled trial 1Ronofal et al., .//04. By contrast, using a different sa #le in a ulti#hase clinical trial, our grou# has recently found that $aseline ferritin concentration "as negati!ely correlated "ith the "eight-adAusted dose of a #heta ine necessary to o#ti i%e clinical res#onse in youths "ith A&H& 1Calarge et al., (nder 8e!ie"4. This $eing a retros#ecti!e study, "e could not e!aluate ho" any of the #artici#ants had fran' ane ia u#on the initiation of #sychosti ulants. These data "ere not a!aila$le. Ho"e!er, a nu $er of the #artici#ants did ha!e a$nor alities in their he atological #ara eters #rior to treat ent onset, as descri$ed in ta$le **. Still, only one child "ith *& ane ia a##eared to ha!e recei!ed iron su##le entation. *t is #ossi$le that the clinicians did not dee the a$nor alities se!ere enough to treat, es#ecially that the $lood tests "ere o$tained in order to s#ecifically e!aluate for ane ia in only : of the children. )e!ertheless, the a$sence of infor ation regarding ane ia at the start of #sychosti ulants should not detract fro the significance of our findings since *& has $een sho"n to affect cogniti!e and $eha!ioral functioning e!en in the a$sence of fran' ane ia 1Irantha -McIregor et al., .//+T Halter an et al., .//+T Do%off et al., .///4. This is li'ely $ecause, "hen inta'e is li ited, iron is di!erted to"ards he oglo$in synthesis, resulting in a reduction in $rain iron concentration $efore ane ia $eco es anifested 1Do%off et al., .//-4. Though our findings contri$ute to the gro"ing literature lin'ing *&, A&H&, and do#a inergic signaling, a nu $er of li itations are "orth noting. >irst, the retros#ecti!e design of the study could ha!e $iased the results in one of se!eral "ays. *t is #ossi$le that the indication for la$oratory testing "as itself the #ri ary cause underlying the differences in JMPH sensiti!ity.K @hile "e cannot rule out this #ossi$ility due to the s all sa #le si%e, "e $elie!e it is unli'ely since the indication for the $lood test did not differ across the grou#s. Moreo!er, in se!eral #artici#ants, the test "as o$tained as #art of a general edical screen, in the a$sence of any #articular edical condition. *n addition, our findings "ould ha!e $een stronger had "e had sy #to ratings at the initiation of #sychosti ulants and later on during the course of the treat ent. >urther ore, our sa #le is not re#resentati!e of children "ith A&H& since co or$idity "as #re!alent and since, $y study design, all the #artici#ants e!entually recei!ed an anti#sychotic edication. Therefore, it is necessary to re#licate our findings in a larger sa #le of children "hose A&H& "as "ell-controlled "ith #sychosti ulants alone and "here $oth ales and fe ales are e?ually re#resented. This "ould also ini i%e the ris' for ty#e + errors. )e!ertheless, it is of interest that in the !ast aAority of our #artici#ants, ris#eridone "as #rescri$ed to treat irrita$ility and aggression. *n-utero iron de#ri!ation in on'eys leads to i #ulsi!ity "hile, #ostnatally, it results in increased e otionality. Si ilarly, #erinatal iron stores in hu ans are correlated "ith negati!e e otionality 1@achs et al., .//54. This te #era ental trait is often o$ser!ed in aggressi!e children "ith disru#ti!e $eha!ior 1Briggs-Io"an et al., .//-4. >inally, this $eing a con!enience sa #le, "e used he atological tests $ased on the characteristics of red $lood cells as ar'ers of iron stores. @hile the co $ination of lo" MCH and high 8&@ is an acce#ted

inde= of *&, additional #ara eters could ha!e included seru $inding ca#acity, transferrin, and ferritin.

iron concentration, iron

*n su , "ith food enrich ent, *& has significantly declined in the de!elo#ed countries, including the (S. Ho"e!er, in at-ris' #o#ulations, such as inorities and indi!iduals fro disad!antaged $ac'grounds, *& in infancy and the toddler years re ains co on 1C&C, .//.T Mar's et al., +,,04. These grou#s are also at an ele!ated ris' for e=ternali%ing disorders. This co $ination of ris's not only a'es the !ulnera$le to de!elo#ing A&H& $ut, $ased on our findings re#orted here and else"here 1Calarge et al., (nder 8e!ie"4, it ight attenuate their res#onse to the gold standard treat ent. Therefore, it is essential to o#ti i%e efforts to #re!ent *& early on in de!elo# ent "hile a!oiding the ad!erse e!ents associated "ith e=cessi!e iron su##le entation 1*annotti et al., .//-4.

Acknowledgments
;unding !upport: This study "as funded $y a .//5 Young *n!estigator A"ard, $y the )ational *nstitute of Health 188/.3,6,, 8.+MH/0/,-0, and R.:MH/05//54, and through a Medical Student Su er 8esearch >ello"shi# fro A erican Acade y of Child and Adolescent Psychiatry s#onsored $y the Ca #aign for A ericaGs Rids. &r. Bridget Wi er an su#er!ised the statistical analysis. @e "ould li'e to than' the #atients and their fa ilies for their co it ent to this research, the staff of the (ni!ersity of *o"a child #sychiatry di!ision, the research coordinators, and the Clinical 8esearch (nit Staff.

Biographies
y Catharyn A0 )urner, recei!ed her A.B at Bryn Ma"r College in +,,+ and an M.Qd. fro To"son (ni!ersity in .//:. She "or'ed as a classroo teacher in Maryland Pu$lic Schools, $efore enrolling at The (ni!ersity of *o"a Car!er College of Medicine "here she is e=#ected to graduate in May of ./+/. Her research interests include general adolescent edicine and #sychiatric health of adolescents. y Di<uiong Fie, M0!0

;ootnotes
Conflict of nterest The authors re#ort no co #eting interests.

+re#ious presentation As#ects of this "or' ha!e $een #resented at the annual eeting of the A erican Acade y of Child and Adolescent Psychiatry, 7cto$er, .//,, Honolulu, H*.

Contributor nformation
Catharyn Turner, Medical Student, The (ni!ersity of *o"a Car!er College of Medicine. &i?iong Sie, Iraduate Student, The (ni!ersity of *o"a College of Pu$lic Health. Bridget Wi er an, The (ni!ersity of *o"a College of Pu$lic Health, &irector, Biostatistics Consultation Center.

Article information
L Atten &isord. Author anuscri#tT a!aila$le in PMC ./+: May +. Pu$lished in final edited for as2 L Atten &isord. ./+. MayT +-1342 .,5F:/:. Pu$lished online ./+/ 7cto$er .-. doi2 +/.++66B+/06/536+/:05/-6 PMC*&2 PMC:55-5+. )*HMS*&2 )*HMS3::6+Catharyn Turner, M.Qd., &i?iong Sie, M.S., and Bridget Wi er an, Ph.&. Catharyn Turner, Medical Student, The (ni!ersity of *o"a Car!er College of MedicineT Contri$utor *nfor ation. Chadi Calarge, M.&. 1corres#onding author and to "ho re#rint re?uests should $e sent42 Assistant Professor, &e#art ent of Psychiatry, The (ni!ersity of *o"a Car!er College of Medicine, Psychiatry 8esearch, .-./, MQB, 5// )e"ton 8oad, *o"a City, *A 5..3., Tel2 :+,-::5-066+, >a=2 :+,-:5:-://:, Q ail2 chadi-calargeBatBuio"a.edu Co#yright notice and &isclai er The #u$lisherMs final edited !ersion of this article is a!aila$le at L Atten &isord

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