Analgesic antipyretic use among young children in the TEDDY study: no association with islet autoimmunity

RESEARCH ARTICLE Open Access Analgesic an ipy e ic use among young child en in he TEDDY s udy: no associa ion wi h isle au oimmuni y Ma kus Lundg en 1* , Leigh Johnson S eed 2 , Roy Tamu a 3 , Be glind Jonsdo i 1 , Pa icia Gesualdo 4 , Clai e C ouch 5 , Maija Sjöbe g 6 , Ge ie Hansson 1 , William A. Hagopian 5 , Ane e G. Ziegle 7 , Ma ian J. Rewe s 4 , Åke Le nma k 1 , Jo ma Toppa i 6 , Jin-Xiong She 2 , Beena Akolka 8 , Je ey P. K ische 3 , Michael J. Halle 9 , Helena Elding La sson 1 and o he TEDDY S udy G oup Abs ac Backg ound: The use o analgesic an ipy e ics (ANAP) in child en ha e long been a ma e o con o e sy. Da a on hei p ac ical use on an indi idual le el has, howe e , been sca ce. The e a e indica ions o possible e ec s on glucose homeos asis and immune unc ion ela ed o he use o ANAP. The aim o his s udy was o analyze pa e ns o analgesic an ipy e ic use ac oss he clinical cen e s o The En i onmen al De e minan s o Diabe es in he Young (TEDDY) p ospec i e coho s udy and es i ANAP use was a isk ac o o isle au oimmuni y. Me hods: Da a we e collec ed o 8542 child en in he i s 2.5 yea s o li e. Incidence was analyzed using logis ic eg ession wi h coun y and i s child s a us as independen a iables. Holm’s p ocedu e was used o adjus o mul iplici y o in e coun y compa isons. Time o au oan ibody se ocon e sion was analyzed using a Cox p opo ional haza ds model wi h cumula i e analgesic use as p ima y ime dependen co a ia e o in e es . Fo each ca ego iza ion, a gene alized es ima ing equa ion (GEE) app oach was used. Resul s: Highe p e alence o ANAP use was ound in he U.S. (95.7%) and Sweden (94.8%) compa ed o Finland (78.1%) and Ge many (80.2%). Fi s -bo n child en we e mo e commonly gi en ace aminophen (OR 1.26; 95% CI 1.07, 1.49; p= 0.007) bu less commonly Non-S e oidal An i-in lamma o y D ugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p= 0.002). Ace aminophen and NSAID use in he absence o e e and in ec ion was mo e p e alen in he U.S. (40.4%; 26.3% o doses) compa ed o Sweden, Finland and Ge many (p< 0.001). Ace aminophen o NSAID use be o e age 2.5 yea s did no p edic de elopmen o isle au oimmuni y by age 6 yea s (HR 1.02, 95% CI 0.99-1.09; p= 0.27). In a sub-analysis, ace aminophen use in child en wi h e e weakly p edic ed de elopmen o isle au oimmuni y by age 3 yea s (HR 1.05; 95% CI 1.01-1.09; p= 0.024). Conclusions: ANAP use in young child en is no a isk ac o o se ocon e sion by age 6 yea s. Use o ANAP is widesp ead in young child en, and signi ican ly highe in he U.S. compa ed o o he s udy si es, whe e use iscommonalsoinabsenceo e e andin ec ion. Keywo ds: Type 1 diabe es, Analgesics, Isle au oimmuni y, P ospec i e s udies * Co espondence: [email p o ec ed] 1 Depa men o Clinical Sciences, Diabe es and Celiac disease uni , Lund Uni e si y, Clinical Resea ch Cen e, Jan Waldens öms ga a 35, 205 02 Malmö, Sweden Full lis o au ho in o ma ion is a ailable a he end o he a icle © The Au ho (s). 2017 Open Access This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion 4.0 In e na ional License (h p://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons license, and indica e i changes we e made. The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i ecommons.o g/publicdomain/ze o/1.0/) applies o he da a made a ailable in his a icle, unless o he wise s a ed. Lundg en e al. BMC Pedia ics (2017) 17:127 DOI 10.1186/s12887-017-0884-y Backg ound The adminis a ion o analgesic-an ipy e ic (ANAP) medica ions o child en has been discussed in he li e a- u e o decades. Su eys o Canadian and Ame ican pe- dia icians e lec he ou ine use o ace aminophen and non-s e oidal an i-in lamma o y d ugs (NSAID) o childhood e e and discom o [1, 2]. In he 1980s, he e m “ e e phobia”was used o desc ibe he pa en al p essu e acing pedia ic p ac i ione s o manage e e [3]. Pa en al misconcep ions o en lead pa en s o he in- app op ia e managemen o e e in hei child en [4] and pa en s epo he use o an ipy e ics e en when he e was minimal o no e e [5] as pa en s we e e- quen ly conce ned wi h he need o main ain a “no mal empe a u e”in hei ill child [6]. Ne e heless, add- i ional s udies a e needed o suppo his as e idence- based p ac ice [7, 8]. Ace aminophen and NSAID a e used widely in child en, bu limi ed da a exis ega ding pa e ns o use in coun ies beyond he Uni ed S a es, Uni ed Kingdom, F ance, and Canada [9]. No ably, ace aminophen has been shown o ha e e - ec s on glucose homeos asis. High doses ha e been shown o induce hype glycemia [10], whe eas low and ch onic doses can lowe blood glucose in animal models [11–13]. Possible e ec s on as hma isk ha e also been in es iga ed [14, 15]. NSAIDs ha e also been shown o lowe blood glucose [16, 17], bu ha e addi ional an i- in lamma o y p ope ies ha could ha e an impac on he p ocess leading up o T1D [18]. The En i onmen al De e minan s o Diabe es in he Young (TEDDY) S udy is an in e na ional, mul i-cen e s udy designed o iden i y he en i onmen al igge s o T1D in gene ically a - isk child en [19]. The aim o he cu en s udy was o desc ibe he use o ANAP in he TEDDY s udy, as well as di e ences in ela ion o coun- y, bi h o de ( i s child e sus a child wi h olde sib- lings) and e e s a us. Speci ically, we sough o examine i he use o ANAP: (1) is associa ed wi h isk o isle au oimmuni y (IA), (2) di e s be ween coun- ies, (3) is gi en p e e en ially o i s -bo n child en. Me hods The En i onmen al De e minan s o Diabe es in he Young (TEDDY) is a p ospec i e coho s udy unded by he Na ional Ins i u es o Heal h wi h he p ima y goal o iden i y en i onmen al causes o ype 1 diabe es (T1D). I includes six clinical esea ch cen e s - h ee in he US: Colo ado, Geo gia/Flo ida, Washing on and h ee in Eu ope: Finland, Ge many, and Sweden. De- ailed s udy design and me hods ha e been p e iously published [19, 20]. W i en in o med consen s we e ob- ained o all s udy pa icipan s om a pa en o p ima y ca e ake o gene ic sc eening and pa icipa ion in p o- spec i e ollow-up. The s udy was app o ed by local Ins i u ional o E hics Re iew Boa ds (Addi ional ile 1), and is moni o ed by an Ex e nal Ad iso y Boa d o med by he Na ional Ins i u es o Heal h. Da a collec ion The da ase analyzed was he da a ecei ed by he TEDDY Da a Coo dina ing Cen e as o Decembe 31, 2014. The o al numbe o subjec s en olled was 8676. Analysis was es ic ed o con i med HLA eligible sub- jec s and subjec s wi h medica ion in o ma ion in he i s 2 yea s o age. Ou o he en olled subjec s, 134 we e missing medica ion da a and we e excluded om he analysis. In o ma ion ega ding i s child s a us was missing o 919 subjec s who we e also excluded, lea ing a o al o 7623 subjec s (Addi ional ile 2). S udy isi s we e conduc ed e e y 3 mon hs wi h he i s isi occu ing be ween 3 and 4.5 mon hs o age. A each isi , in e iewe s eco ded he name, eason, s a da e and du a ion o epo ed medica ions o he mos ecen isi in e al. Pa en s we e asked o documen e e as ei he “Yes”o “No” o e e y illness en y in a “TEDDY Book.”The “TEDDY Book”p o ided w i en guidance ha “Yes”should only be ma ked o empe a u e equal o o g ea e han 38 °C o 101 °F. App oxima ely 18 mon hs in o he s udy, hese choices we e expanded o “Yes –measu ed,”“Yes –no mea- su ed,”and “No.”The a ionale o his change was o cap u e all uses o ANAP, e en wi h low-g ade e e s. Each use o an ANAP was de ined as an episode. Re- co ded medica ions we e ca ego ized based on ac i e in- g edien . When analyzing speci ic subs ances, all medica ions con aining ha pa icula subs ance we e included. D ugs we e also de ined and g ouped as ei he analgesic o non-s e oidal an i-in lamma o y (NSAID) (Addi ional ile 3). Episodes we e desc ibed as associa ed wi h in ec ion and/o e e . In ec ion was de ined as ei- he an ICD-10 code indica ing In ec ion (Addi ional ile 4) o an acu e illness designa ed as in ec ious wi hin a 15 day ime pe iod o he medica ion da e [21]. Fe e was de ined as ei he an ICD-10 code o e e associa ed wi h he medica ion o an acu e illness associa ed wi h e e wi hin a 15-day ime pe iod o he medica ion da e. Isle au oimmuni y Blood samples we e d awn e e y 3 mon hs be ween 3 and 48 mon hs o age, and e e y 6 mon hs he ea e , excep o au oan ibody posi i e child en, who con inued wi h isi s e e y 3 mon hs. Pe sis en IA was de ined as posi i e an ibodies o insulin (IAA), glu amic acid de- ca boxylase (GAD65), o insulinoma-associa ed an igen 2 (IA-2), each analyzed by adiobinding assay [22, 23], on a leas 2 consecu i e s udy isi s. Two cen al au o- an ibody labo a o ies we e used; one in he U.S. (Ba ba a Lundg en e al. BMC Pedia ics (2017) 17:127 Page 2 o 9 Da is Cen e o Childhood Diabe es a he Uni e si y o Colo ado) and one in Eu ope (Uni e si y o B is ol). All posi i e isle au oan ibodies and 5% o nega i e isle au oan ibodies we e con i med in bo h cen al au oan i- body labo a o ies. Bo h labo a o ies ha e p e iously demons a ed high sensi i i y, speci ici y [24] and con- co dance. Posi i e esul s in he child ha we e deemed o be due o ma e nal IgG ansmission we e excluded om he IA-posi i e g oup. S a is ical me hods A Cox p opo ional haza ds model was used o assess he impac o ANAP use in he i s 90, 180, 365 days o age and 2.5 yea s o age in he isk o posi i e au oan i- bodies h ough 6 yea s o age. The numbe o in ec ions ea ly in li e was included as a ime dependen co a ia e [25]. Coun y was included as a s a i ica ion ac o in he p opo ional haza ds analyses. Addi ional co a ia es included in he model we e i s -deg ee ela i e [26], HLA [27], gende , e e b eas ed [28, 29], p obio ic use p io o 3 mon hs o age [30], and eigh di e en p e i- ously iden i ied single nucleo ide polymo phisms [31]. The p ima y a iable o in e es was cumula i e ANAP use h ough 2.5 yea s o li e as a ime dependen co a i- a e. Included co a ia es can be seen in Table 1. The s a is ical analysis o he numbe o episodes pe yea and du a ion pe yea excluded subjec s o which he i s child s a us was missing. Subjec s wi h a missing du a ion o a speci ic analgesic we e excluded om he analysis o ha analgesic. The s a is ical analysis o o al du a ion pe yea was based on log- ans o med da a o be e sa is y he assump ions o he linea models. Subjec incidence was analyzed using logis ic eg ession wi h coun y and i s child s a us as independen a i- ables in he model. In bo h he bina y and con inuous analyses, pai wise compa isons be ween coun ies we e conduc ed using Holm’s p ocedu e o adjus o he mul i- plici y o compa isons. Each speci ic episode o ANAP usage was classi ied by concu en e e (yes/no) o in ec- ion (yes/no). Episodes we e ca ego ized as associa ed wi h Fe e , In ec ion, bo h Fe e and In ec ion, o nei he e e no in ec ion. Fo each ca ego iza ion, a gene alized es i- ma ing equa ion (GEE) was used o analysis wi h coun y and i s child as independen a iables in he model. An igno able wo king ma ix was assumed o he GEE ana- lysis wi h he empi ical sandwich es ima e used o he s anda d e o s. Pai -wise compa isons ac oss coun ies we e conduc ed using Holm’s p ocedu e om he GEE analyses. Analyses on he episode le el excluded subjec s who epo ed no episodes. Table 1 Co a ia es included in he Cox p opo iona e haza ds analysis o ime o pe sis en con i med au oan ibody posi i i y Fixed Co a ia es Haza d Ra io (95% CI) Wald es p- alue a Fi s -Deg ee Rela i e (Re = No) 2.51 (2.06, 3.30) <0.001 HLA (Re = DR3/DR4) DR4/DR4 0.69 (0.54, 0.88) 0.003 DR4/DR8 0.70 (0.54, 0.91) 0.008 DR3/DR3 0.46 (0.35, 0.60) <0.001 All O he s 0.46 (0.29, 0.72) <0.001 Gende (Re = male) 0.77 (0.65, 0.92) 0.003 SNP RS1004446_a 0.84 (0.74, 0.96) 0.010 RS10517086_a 1.14 (1.00, 1.31) 0.050 RS12708716_g 0.87 (0.76, 0.99) 0.034 RS2292239_a 1.24 (1.09, 1.41) <0.001 RS2476601_a 1.55 (1.31, 1.83) <0.001 RS2816316_c 1.07 (0.91, 1.25) 0.429 RS3184504_a 1.33 (1.17, 1.50) <0.001 RS4948088_a 0.74 (0.53, 1.04) 0.086 E e B eas ed (Re = No) 1.96 (1.01, 3.81) 0.042 P obio ics <3 Mo Age (Re = No) 0.72 (0.55, 0.94) 0.015 Time Dependen Co a ia es Cumula i e Numbe o In ec ions 1.02 (0.99, 1.03) 0.407 Cumula i e Weeks Analgesic Use 1.02 (0.99, 1.04) 0.269 Numbe o pe sis en con i med cases = 511 a Ho: Haza d Ra io = 1 Lundg en e al. BMC Pedia ics (2017) 17:127 Page 3 o 9 S a is ical analysis was pe o med using SAS e sion 9.3 (SAS Ins i u e Inc., Ca y, NC, U.S.A). Resul s Use o ANAP below he age o 2.5 yea s The use o bo h ace aminophen and NSAIDs we e e y common in he s udy popula ion. In he o al coho , 87.8% o child en epo ed he use o ace aminophen and 45.4% o NSAIDs be o e he age o 2.5 yea s. The mean numbe o ea men episodes pe yea was 3.6 ± 2.1 and mean du a ion o ea men 8.5 ± 10.8 days pe yea in he o al coho (Fig. 1a–c). Ace aminophen use Swedish pa en s epo ed a signi ican ly highe p e a- lence o ace aminophen use (94.5%), ollowed by U.S. (93.7%), Finnish (73.9%), and Ge man pa en s (70.1%). P e alence di e ed be ween all coun ies (Finland s. Ge many: p= 0.035, all o he p< 0.001). U.S. pa en s e- po ed he highes numbe o ea men episodes pe yea and highes o al du a ion o ea men pe yea (mean 4.0 ± 2.3 episodes; mean 9.8 ± 13.5 days), ollowed by Swedish (mean 3.6 ± 2.1 episodes; mean 8.4 ± 8.6 days), Finnish (mean 2.7 ± 1.9 episodes; mean 6.8 ± 6.4 days), and Ge man pa en s (mean 2.5 ± 1.6 epi- sodes; mean 4.7 ± 3.7 days). All coun y di e ences, ac- co ding o numbe o ea men episodes, we e s a is ically signi ican (Finland s. Ge many: p= 0.014, all o he s p< 0.001) (Fig. 1). Child en bo n as he i s child in he amily had mo e o en been gi en ace - aminophen du ing hei i s 2.5 yea s o li e compa ed o child en wi h olde siblings (OR 1.26; 95% CI 1.07, 1.49; p= 0.007). The numbe o episodes o ea men wi h ace aminophen was also highe (di e ence in leas squa e means 0.15; 95% CI 0.05, 9.24; p= 0.003). No di - e ence could be seen ega ding he numbe o days ea ed (di e ence in leas squa e means 0.11; 95% CI -0.38, 0.60; p= 0.111). NSAID use The highes p e alence o NSAID use was epo ed by U.S. pa en s (58.3%), ollowed by Ge man (44.1%), Finnish (42.3%), and Swedish pa en s (29.0%). All coun y di e ences, excep be ween Finland and Ge many, we e s a is ically signi ican (Finland s. Ge many: p= 0.177, all o he s p< 0.001). U.S. pa - en s epo ed he highes numbe o ea men epi- sodes wi h NSAID pe yea (mean 2.1 ± 1.4 episodes; mean 6.8 ± 11.2 days), ollowed by Swedish, Finnish, and Ge man pa en s (mean 1.6 ± 1.2; mean 1.6 ± 1.2; mean 1.6 ± 1.1) To al du a ion o ea men was highes in he U.S. (mean 6.8 ± 11.2 days), ollowed by Finland (mean 5.3 ± 9.3 days), Ge many (mean 5.2 ± 17.2 days), and Sweden (mean 4.9 ± 4.8 days). Bo h he mean numbe o ea men episodes and mean o al du a ion o ea men we e signi ican ly highe in he U.S. compa ed o he o he coun ies (p< 0.001). No o he signi ican coun y di e ences could be seen (Fig. 1). The p e alence o NSAID use du ing he i s 2.5 yea s o li e we e lowe in i s - bo n child en (OR 0.86; 95% CI 0.78, 0.95; p=0.002) and hey we e also ea ed ewe imes (di e ence in leas squa e means −0.14; 95% CI -0.22, −0.05; p= 0.001). No di e ences could be seen ega ding he numbe o days ea ed (di e ence in leas squa e means −0.22; 95% CI -0.92, 0.48; p= 0.143). A B C Fig. 1 Use o ANAP below 2,5 yea s o age. *:p< 0.05, n.s.: non signi ican . All signi icances co ec ed o mul iple compa isons using Holm p ocedu e. aP e alence o analgesic/an ipy e ic use. b T ea men episodes pe yea . cDu a ion o medica ion use pe yea Lundg en e al. BMC Pedia ics (2017) 17:127 Page 4 o 9 Di e ences in use o eb ile/in ec ious episodes and nonin ec ious use In he o al coho , 74.1% o ace aminophen use and 82.0% o NSAID use was gi en in conjunc ion wi h ei- he e e , in ec ion o bo h, wi h 43.8% ace aminophen use and 51.0% NSAID episodes being combined e e and in ec ion. U.S. pa en s epo ed a signi ican ly highe p opo ion o doses gi en wi hou e e o in ec ion o bo h ace aminophen (40.4%) and NSAID (26.3%) com- pa ed o he o he h ee coun ies (p< 0.001). Ace - aminophen use in e e ish in ec ious episodes had he highes p opo ion among Ge man and Swedish child en (68.5% and 63.2%;), ollowed by Finland wi h 57.9% and he U.S. wi h 23.5% (all p- alues o di e ences be ween coun ies we e p< 0.001, excep be ween Ge many and Swedenwas p= 0.003). Fo NSAID use wi hou e e o in ec ion, he U.S. pa en s epo ed he highes p opo ion (26.3%), ollowed by Finland (7.7%), Ge many (5.9%), and Sweden (3.7%) (di e ence be ween Finland and Sweden p= 0.006; be ween Ge many and Sweden p= 0.01; all o he s p< 0.001) (Fig. 2, Table 2). Isle au oimmuni y Haza d a ios o isle au oimmuni y we e es ima ed o cumula i e use o ace aminophen and NSAID wi h o wi hou concomi an e e and o a join a iable o cu- mula i e o al ANAP use wi h o wi hou e e . A sig- ni ican haza d was only ound o use o ace aminophen in he p esence o e e o isle au oimmuni y a age 3 yea s (HR 1.05; 95% CI 1.01-1.09; p= 0.024). The haza d was no signi ican o isle au oimmuni y a 6 yea s o age (p= 0.193). Sepa a e analysis o exposu e be o e 90, 180 and 365 days o li e ound a signi ican haza d o se ocon- e sion a age 3 yea s (HR 1.06; 95% CI 1.00-1.12; p= 0.011) o use o ace aminophen wi h concu en e e be o e 1 yea o age, bu no be o e 90 o 180 days o li e (p= 0.91 and p= 0.54, espec i ely). No o he sig- ni ican haza ds could be seen o ea men wi h ace - aminophen o NSAID in he p esence o absence o e e (Table 3). Discussion In his s udy, we in es iga ed he use o ANAP in chil- d en below he age o 2.5 yea s, and he impac o such use on he de elopmen o isle au oimmuni y be o e 6 yea s o age in he la ge, longi udinal, in e na ional TEDDY coho . The widesp ead use o ace aminophen among young child en has been o in e es due no only o possible side e ec s, bu also possible immunological e ec s. Se e al pape s ha e in es iga ed he impac on im- mune esponse and he de elopmen o au oimmuni y [11, 12, 32, 33]. The da a on childhood as hma is con lic ing, wi h some s udies showing an inc eased isk and o he s showing none [14, 15, 34]. The use o p ophylac ic ace aminophen in conjunc ion wi h childhood accina ions has also shown possible e ec s on an ibody esponses [1, 7, 35]. In his s udy, we ound a signi ican bu weak inc eased haza d a io associa ed wi h he use o ace aminophen and con- comi an e e be o e he age o 2.5 yea s and pe sis - en con i med isle au oimmuni y a age 3 yea s. Howe e , his e ec was no seen wi h isle au o- immuni y a age 6 yea s o i ace aminophen was used o o he easons. I is he e o e unlikely, al- hough possible, ha his is a ue e ec . The ype o in ec ion causing he e e may be a con ounding ac- o . No such e ec was seen wi h he use o NSAIDs o he combina ion o ace aminophen and NSAIDs, ei he when gi en wi h o wi hou e e . The use o ace aminophen and NSAIDs o he ea - men o child en has been p e iously desc ibed om a medical s andpoin [36, 37]. On he o he hand, e y li - le has been desc ibed ega ding p ac ical use in he pedia ic popula ion. This analysis wi hin a la ge in e - na ional coho p o ides some o he i s da a ega ding pedia ic use o ANAP. As expec ed, he majo i y o ea men episodes o his young coho we e in con- junc ion wi h e e and/o in ec ion. I is wo h men- ioning ha he e a e signi ican di e ences be ween he TEDDY coun ies ega ding he use o bo h ace amino- phen and NSAIDs. The U.S. s ands ou o bo h g ea e p e alence o use and g ea e numbe o episodes o ea men pe yea , ollowed closely by Sweden in ega ds o ace aminophen use. U.S. pa en s we e also jus as likely o epo using hese medica ions du ing episodes associa ed wi h in ec ion han non-in ec ious episodes. Addi ionally, hey we e mo e likely o use ANAP when he e was no associa ed e e . I may be a common p ac ice o Ame ican physicians o p esc ibe a Fig. 2 F ac ion o ea men wi hou e e and in ec ion. *:p< 0.05, n.s.: non-signi ican . All signi icances co ec ed o mul iple compa isons using Holm p ocedu e Lundg en e al. BMC Pedia ics (2017) 17:127 Page 5 o 9 combina ion he apy app oach o he use o analgesics and an ipy e ics o he sus ained managemen o e e . Howe e , pa en s may hen assume ha e en p ophylac- ic use should be a combina ion he apy. We also ound ha i s -bo n child en we e p e e en- ially gi en ace aminophen, bo h in p e alence o use and in he highe numbe o ea men episodes han o hei younge siblings. The in e se ela ionship was ob- se ed o NSAID use, in which bo h he p e alence and numbe o ea men episodes we e lowe o i s -bo n child en. We can only specula e on he possible a ionale behind his inding since, o ou knowledge, no ea lie s udy has p esen ed simila da a. I is possible ha ace aminophen is pe cei ed by i s - ime pa en s as a be e ole a ed ea men han NSAIDS, a pe cep ion ha ades by he ime younge siblings equi e ea men . Coun y-speci ic di e ences in he use o analge- sics may be cul u ally in luenced. The lowe inci- dence o use o all s anda d analgesics in Ge many could e lec he p e alence o Complimen a y Al e - na i e Medicine (CAM) in his coun y. Acco ding Table 2 Summa y o ea men episodes associa ed wi h e e and/o in ec ion US Finland Ge many Sweden To al Coho Coun y di e ences U-F U-G U-S F-G F-S G-S To al episodes n 25,340 7427 2091 17,285 52,643 Ace aminophen Fe e and in ec ion n 4272 2907 983 9224 17,386 <0.001 <0.001 <0.001 <0.001 <0.001 0.003 Fe e o in ec ion 6557 1277 311 3421 12,066 No e e and no in ec ion n 7348 841 141 1953 10,283 <0.001 <0.001 <0.001 <0.001 0.006 0.01 NSAID Fe e and in ec ion n 2680 1273 477 1572 6002 <0.001 <0.001 <0.001 <0.001 <0.001 0.024 Fe e o in ec ion n 2472 717 125 330 3644 No e e and no in ec ion n 1841 167 38 74 2120 <0.001 <0.001 <0.001 0.174 <0.001 0.041 Coun y di e ences: U = US, G = Ge many, F = Finland, S = Sweden, Coun y di e ences desc ibed as p- alue o di e ence be ween he espec i e coun ies Table 3 Haza d a ios o se ocon e sion o pe sis en isle au oimmuni y a 3 and 6 yea s o age o analgesic a iables o in e es Analgesic Va iable Exposed subjec s n (%) 3 Yea Analysis 6 Yea Analysis 398 an ibody + subjec s 511 an ibody + subjec s HR (95% CI) p- alue HR (95% CI) p- alue Ace aminophen, any exposu e 7496 (87.8%) 1.01 (0.97, 1.05) 0.603 1.01 (0.98, 1.05) 0.576 Ace aminophen wi h e e + in ec ion 5179 (60.6%) 1.05 (1.01, 1.09) 0.022 1.03 (0.99, 1.08) 0.189 Exposed <90 days o li e 220 (2.6%) 0.97 (0.59, 1.61) 0.914 1.00 (0.68, 1.46) 0.986 Exposed <180 days o li e 1519 (17.8%) 1.07 (0.87, 1.32) 0.542 1.06 (0.88, 1.27) 0.527 Exposed <365 days o li e 3795 (44.4%) 1.06 (1.00, 1.12) 0.011 1.05 (0.99, 1.11) 0.101 Ace aminophen wi hou e e o in ec ion 5941 (69.6%) 1.02 (0.98, 1.06) 0.346 1.01 (0.96, 1.05) 0.769 Exposed <90 days o li e 4016 (47.0%) 1.00 (0.90, 1.11) 0.994 0.99 (0.85, 1.14) 0.837 Exposed <180 days o li e 4597 (53.8%) 0.98 (0.84, 1.14) 0.814 0.97 (0.84, 1.13) 0.729 Exposed <365 days o li e 5310 (62.2%) 1.03 (0.99, 1.06) 0.114 1.02 (0.99, 1.06) 0.228 NSAID, any exposu e 3874 (45.4%) 1.01 (0.97, 1.05) 0.753 1.01 (0.97, 1.04) 0.763 NSAID wi h e e + in ec ion 2652 (31.0%) 1.01 (0.97, 1.05) 0.673 1.01 (0.98, 1.05) 0.459 Exposed <90 days o li e 22 (0.3%) 1.01 (0.92, 1.10) 0.897 1.00 (0.92, 1.09) 0.960 Exposed <180 days o li e 223 (2.6%) 0.99 (0.88, 1.11) 0.822 1.00 (0.94, 1.07) 0.927 Exposed <365 days o li e 1318 (15.4%) 1.01 (0.97, 1.06) 0.530 1.02 (0.98, 1.05) 0.378 NSAID wi hou e e o in ec ion 1955 (22.9%) 1.00 (0.96, 1.05) 0.856 1.01 (0.97, 1.05) 0.623 Exposed <90 days o li e 222 (2.6%) 1.00 (0.88, 1.12) 0.943 0.99 (0.88, 1.12) 0.874 Exposed <180 days o li e 458 (5.4%) 0.99 (0.88, 1.11) 0.815 1.00 (0.94, 1.07) 0.956 Exposed <365 days o li e 1120 (13.1%) 1.01 (0.96, 1.06) 0.824 1.01 (0.97, 1.05) 0.638 Any analgesic, any exposu e 7744 (91%) 1.02 (0.99, 1.05) 0.130 1.02 (0.99, 1.04) 0.267 Any analgesic wi h e e + in ec ion 5699 (67%) 1.06 (0.97, 1.15) 0.219 1.02 (0.94, 1.10) 0.667 Each haza d a io is calcula ed om a Cox p opo ional haza ds model wi h he analgesic a iable and co a ia es indica ed in ex Lundg en e al. BMC Pedia ics (2017) 17:127 Page 6 o 9 o a c oss-sec ional su ey o Ge man physicians in 2007, mo e han wo- hi ds o pa ien s in Ge many use CAM p o ided ei he by physicians o non-medical p ac i- ione s (“Heilp ak ike ”) [38]. In 2007, only 40% o adul s in he U.S. had used CAM he apy in he pas 12 mon hs. Child en in he U.S. whose pa en s used CAM we e almos i e imes as likely (23.9%) o use CAM han child en whosepa en didno useCAM(5.1%)[39].The easons unde lying g ea e use o ace aminophen among Swedish pa en s is mo e unclea bu may be he esul o ace - aminophen being widely a ailable and pe cei ed as sa e and e ec i e. TheTEDDYs udyisoneo hela ges longi udinal pedia ic coho s s udied. The da a analyzed he ein has been collec ed om pa en epo s gi en in w i - ing and a e discussion wi h a TEDDY nu se. Fo pa icipa ing child en, missing da a is uncommon. Follow-up is con inuous om age 3 mon hs which minimizes ecall bias. The possibili y o adjus o con ounding ac o s in he s a is ical analysis is g ea due o he a ailabili y o comp ehensi e da a on he child’s li ing condi ions. All p e iously desc ibed isk ac o s o T1D and isle au oimmuni y a e also en- e ed in o he s a is ical analysis o he e ec o anal- gesics on isle au oimmuni y. The limi a ions o his s udy include ou eliance on pa en - epo ed symp oms and dosages o ANAP. The size o he coho also makes i challenging o con i m diagnoses and ea men plans ia pa ien e- co ds. No ably, mos o he epo ed in ec ions we e p esumed o be i al in ec ions o which no medical ad ice had been sough . In addi ion, he widesp ead use o ANAP in his age g oup poses a signi ican s a is ical p oblem since he exposed g oup widely su passes he non-exposed g oup. E en wi h he la ge sample size, he esul ing co ela ion be ween IA and ace aminophen in combina ion wi h e e mus he e- o e be in e p e ed wi h cau ion. Conclusions In conclusion, he use o ANAP o ea e e and in ec ion is widesp ead in he TEDDY coho bu shows signi ican di e ences depending on s udy si e. The p e alence o use o bo h ace aminophen and NSAIDs a e highes in he U.S. and lowes in Finland and Ge many. Use o bo h NSAIDs and ace aminophen o non-in ec ious pu poses a e sig- ni ican ly mo e common among child en in he U.S. compa ed o hose in Eu ope. No con incing e ec on isk o au oimmuni y can be seen in he analysis excep o a small e ec by ace aminophen in com- bina ion wi h e e , and hen only o au oimmuni y a 3 yea s o age. Addi ional iles Addi ional ile 1: E hical e iew boa ds and Commi ees g an ing e hical app o al o he TEDDY s udy. Lis ing o all e hical e iew boa ds and commi es ha has g an ed app o al o he TEDDY s udy o he espec i e si es. (DOCX 59 kb) Addi ional ile 2: Cha ac e is ics o he subjec s used in analysis o analgesic use and isle cell au oimmuni y. A able he p e alence o co a ia es in he p esen analysis including HLA-DQ geno ype, Gende , i s deg ee ela i e, b eas eeding, p obio ic use and p esence o included single nucleo ide polymo phisms. (DOCX 106 kb) Addi ional ile 3: Lis o D ugs de ined as analgesics used in i s 2.5 yea s in he TEDDY s udy. Lis o all included d ugs, eco ded o ha ing been gi en o TEDDY child en be o e age 2.5 yea s and classi ied as analgesics. D ugs classi ied as NSAID’s a e ma ked wi h a s a (*). (DOCX 30 kb) Addi ional ile 4: Lis o all ICD-10 codes, eco ded among TEDDY child en be o e age 2.5 yea s, and classi ied as an in ec ion. (DOCX 72 kb) Abb e ia ions ANAP: Analgesic-An ipy e ic; CAM: Complimen a y al e na i e medicine; GEE: Gene alized es ima ing eq.; IA: Isle Au oimmuni y; NSAID: Non-s e oidal an i-in lamma o y d ugs; T1D: Type 1 Diabe es; TEDDY: The en i onmen al de e minan s o diabe es in he young s udy Acknowledgemen s The Teddy s udy g oup. Funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, and Con ac No. HHSN267200700014C om he Na ional Ins i u e o Diabe es and Diges i e and Kidney Diseases (NIDDK), Na ional Ins i u e o Alle gy and In ec ious Diseases (NIAID), Na ional Ins i u e o Child Heal h and Human De elopmen (NICHD), Na ional Ins i u e o En i onmen al Heal h Sciences (NIEHS), Ju enile Diabe es Resea ch Founda ion (JDRF), and Cen e s o Disease Con ol and P e en ion (CDC). This wo k suppo ed in pa by he NIH/NCATS Clinical and T ansla ional Science Awa ds o he Uni e si y o Flo ida (UL1 TR000064) and he Uni e si y o Colo ado (UL1 TR001082). Colo ado Clinical Cen e : Ma ian Rewe s, M.D., Ph.D., PI 1, 4–6, 10, 11 , Kimbe ly Bau is a 12 , Judi h Bax e 9, 10, 12, 15 , Ru h Bedoy 2 , Daniel Felipe-Mo ales, Kimbe ly D iscoll, Ph.D. 9 , B igi e I. F ohne , M.D. 2, 14 , Pa icia Gesualdo 2, 6, 12, 14, 15 , Michelle Ho man 12–14 , Rachel Ka ban 12 , Edwin Liu, M.D. 13 , Jill No is, Ph.D. 2, 3, 12 , Adela Sampe -Imaz, And ea S eck, M.D. 3, 14 , Ka hleen Waugh 6, 7, 12, 15 , Hali W igh 12 . Uni e si y o Colo ado, Anschu z Medical Campus, Ba ba a Da is Cen e o Childhood Diabe es. Finland Clinical Cen e : Jo ma Toppa i, M.D., Ph.D., PI ¥^1,4,11,14 , Olli G. Simell, M.D., Ph.D. ¥^1,4,11,13 , Annika Adamsson, Ph.D. ^12 , Su i Ahonen* ±§ , Heikki Hyö y, M.D., Ph.D.* ±6 , Jo ma Ilonen, M.D., Ph.D. ¥¶3 , Sanna Jokipuu ^ , Tiina Kallio ^ , Leena Ka lsson ^ , Miia Kähönen μ¤ , Mikael Knip, M.D., Ph.D.* ±5 , Lea Ko anen* ±§ , Mi a Ko easalo* ±§2 , Kalle Ku ppa, M.D., Ph.D.* ±13 , Tiina La a- aho μ¤ , Ma ia Lönn o , M.D., Ph.D.* ±6 , Elina Män ymäki ^ , Ka ja Mul asuo μ¤ , Juha Mykkänen, Ph.D. ¥3 , Tiina Niininen ± * 12 , Sa i Niinis ö ±§ , Mia Nyblom* ± , Pe a Rajala ^ , Jenna Rau anen ±§ , Anne Riikonen* ±§ ,MikaRiikonen ^ , Jenni Rouhiainen ^ , Minna Romo ^ , Tuula Simell, Ph.D., Ville Simell ^¥13 , Maija Sjöbe g ¥^12,14 ,AinoS enius μ¤12 , Ma ia Leppänen ^ , Sini Vainionpää ^ ,Ee a Va jonen ¥^12 , Rii a Veijola, M.D., Ph.D. μ¤14 ,Su iM.Vi anen,M.D., Ph.D.* ±§2 , Ma i Vähä-Mäkilä ^ , Ma i Åke lund* ±§ , Ka i Lind o s, Ph.D.* 13 ¥ Uni e si y o Tu ku, *Uni e si y o Tampe e, μ Uni e si y o Oulu, ^ Tu ku Uni e si y Hospi al, Hospi al Dis ic o Sou hwes Finland, ± Tampe e Uni e si y Hospi al, ¤ Oulu Uni e si y Hospi al, §Na ional Ins i u e o Heal h and Wel a e, Finland, ¶ Uni e si y o Kuopio. Geo gia/Flo ida Clinical Cen e : Jin-Xiong She, Ph.D., PI 1, 3, 4, 11 , Desmond Scha z, M.D.* 4, 5, 7, 8 , Diane Hopkins 12 , Leigh S eed 12–15 , Jamie Thomas* 6, 12 , Janey Adams* 12 , Ka he ine Sil is 2 , Michael Halle , M.D.* 14 , Melissa Ga dine , Richa d McIndoe, Ph.D., Ashok Sha ma, Joshua Williams, Gab iela Young, S ephen W. Ande son, M.D. ^ , Lau a Jacobsen, M.D. *14 Cen e o Bio echnology and Genomic Medicine, Augus a Uni e si y. *Uni e si y o Flo ida, ^ Pedia ic Endoc ine Associa es, A lan a. Lundg en e al. BMC Pedia ics (2017) 17:127 Page 7 o 9 Ge many Clinical Cen e : Ane e G. Ziegle , M.D., PI 1, 3, 4, 11 , And eas Beye lein, Ph.D. 2 , Ezio Boni acio Ph.D.* 5 , Michael Hummel, M.D. 13 , Sand a Hummel, Ph.D. 2 , K is ina Fo e ek ¥2 , Nicole Janz, Ma hilde Ke s ing, Ph.D. ¥2 , Anne e Knop 7 , Sibylle Kole zko, M.D. ¶13 , Claudia Peplow 12 , Roswi h Ro h, Ph.D. 9 , Ma lon Scholz, Joanna S ock 9, 12, 14 , Ka ha ina Wa ncke, M.D. 14 , Lo ena Wendel, Ch is iane Winkle , Ph.D. 2, 12, 15 . Fo sche g uppe Diabe es e.V. and Ins i u e o Diabe es Resea ch, Helmhol z Zen um München, and Klinikum ech s de Isa , Technische Uni e si ä München. *Cen e o Regene a i e The apies, TU D esden, ¶ D . on Haune Child en’s Hospi al, Depa men o Gas oen e ology, Ludwig Maximillians Uni e si y Munich, ¥ Resea ch Ins i u e o Child Nu i ion, Do mund. Sweden Clinical Cen e : Åke Le nma k, Ph.D., PI 1, 3–6, 8, 10, 11, 15 , Daniel Aga dh, M.D., Ph.D. 13 , Ca in And én A onsson 2,12,13 , Ma ia Ask, Jenny B eme , Ulla-Ma ie Ca lsson, Co ado Cilio, Ph.D., M.D. 5 , Emelie E icson-Halls öm, Lina F ansson, Thomas Ga d, Joanna Ge a dsson, Rasmus Benne , Monica Hansen, Ge ie Hansson, Susanne Hybe g, F ed ik Johansen, Be glind Jonsdo i , M.D., Helena Elding La sson, M.D., Ph.D. 6,14 , Ma ielle Linds öm, Ma kus Lundg en, M.D. 14 , Ma ia Månsson-Ma inez, Ma ia Ma kan, Jessica Melin 12 , Zeliha Mes an, Ka in O osson, Kob a Rahma i, Ani a Ramelius, Falas in Salami, Sa a Sib ho pe, Bi gi a Sjöbe g, Ul ica Swa ling, Ph.D. 9,12 , E elyn Tekum Amboh, Ca ina Tö n, Ph.D. 3,15 , Anne Wallin, Åsa Wima 12,14 , So ie Åbe g. Lund Uni e si y. Washing on Clinical Cen e : William A. Hagopian, M.D., Ph.D., PI 1,3,4, 5, 6,7,11,13, 14 , Michael Killian 6,7,12,13 , Clai e Cowen C ouch 12,14,15 , Jenni e Skidmo e 2 , Josephine Ca son, Ma ia Dalzell, Kayleen Dunson, Rachel He ey, Co bin Johnson, Rachel Lyons, A lene Meye , Denise Mulenga, Alexande Ta , Mo gan Uland, John Willis. Paci ic No hwes Diabe es Resea ch Ins i u e. Pennsyl ania Sa elli e Cen e : Do o hy Becke , M.D., Ma ga e F anciscus, Ma yEllen Dalmag o-Elias Smi h 2 , Ashi Da a y, M.D., Ma y Be h Klein, Ch ys al Ya es. Child en’s Hospi al o Pi sbu gh o UPMC. Da a Coo dina ing Cen e : Je ey P. K ische , Ph.D.,PI 1,4,5,10,11 , Michael Abbondondolo, Sa ah Aus in-Gonzalez, Ma you i A endano, Sand a Bae hke, Rasheedah B own 12,15 , B an Bu kha d , Ph.D. 5,6 , Ma ha Bu e wo h 2 , Joanna Clasen, Da id Cu hbe son, Ch is ophe Ebe ha d, S e en Fiske 9 , Dena Ga cia, Jenni e Ga meson, Veena Gowda, Ka hleen Heyman, F ancisco Pe ez La as, Hye-Seung Lee, Ph.D. 1,2,13,15 , Shu Liu, Xiang Liu, Ph.D. 2,3,9,14 , K is ian Lynch, Ph.D. 5,6,9,15 , Jamie Malloy, C is ina McCa hy 12,15 , S e en Meulemans, Hemang Pa ikh, Ph.D. 3 , Ch is Sha e , Lau a Smi h, Ph.D. 9,12 , Susan Smi h 12,15 , Noah Sulman, Ph.D., Roy Tamu a, Ph.D. 1,2,13 , Ulla Uusi alo, Ph.D. 2,15 , Kend a Vehik, Ph.D. 4,5,6,14,15 , Ponni Vijayakandipan, Kei h Wood, Jimin Yang, Ph.D., R.D. 2,15 . Pas s a : Lo i Balla d, Da id Hadley, Ph.D., Wendy McLeod. Uni e si y o Sou h Flo ida. P ojec scien is : Beena Akolka , Ph.D. 1,3,4,5,6,7,10,11 . Na ional Ins i u es o Diabe es and Diges i e and Kidney Diseases. Au oan ibody Re e ence Labo a o ies: Liping Yu, M.D. ^5 , Dongmei Miao, M.D. ^ , Polly Bingley, M.D., FRCP* 5 , Alis ai Williams*, Kyla Chandle *, Saba Rokni*, Clai e Williams*, Rebecca Wya *, Gi y Geo ge*, Sian G ace*. ^ Ba ba a Da is Cen e o Childhood Diabe es, Uni e si y o Colo ado Den e , *School o Clinical Sciences, Uni e si y o B is ol UK. HLA Re e ence Labo a o y: Hen y E lich, Ph.D. 3 , S e en J. Mack, Ph.D., Anna Lisa Fea . Cen e o Gene ics, Child en’s Hospi al Oakland Resea ch Ins i u e. Reposi o y: Sand a Ke, Ni een Mulholland, Ph.D. NIDDK Biosample Reposi o y a Fishe BioSe ices. SNP Labo a o y: S ephen S. Rich, Ph.D. 3 , Wei-Min Chen, Ph.D. 3 , Suna Onengu -Gumuscu, Ph.D. 3 , Emily Fa be , Rebecca Roche Pickin, Ph.D., Jo dan Da is, Dan Gallo, Jessica Bonnie, Paul Campolie o. Cen e o Public Heal h Genomics, Uni e si y o Vi ginia. O he con ibu o s: Kasia Bou cie , Ph.D. 5 , Na ional Ins i u es o Alle gy and In ec ious Diseases. Thomas B iese, Ph.D. 6,15 , Columbia Uni e si y. Suzanne Benne Johnson, Ph.D. 9,12 , Flo ida S a e Uni e si y. E ic T iple , Ph.D. 6 , Uni e si y o Flo ida. Commi ees: 1 Ancilla y S udies, 2 Die , 3 Gene ics, 4 Human Subjec s/Publici y/Publica ions, 5 Immune Ma ke s, 6 In ec ious Agen s, 7 Labo a o y Implemen a ion, 8 Ma e nal S udies, 9 Psychosocial, 10 Quali y Assu ance, 11 S ee ing, 12 S udy Coo dina o s, 13 Celiac Disease, 14 Clinical Implemen a ion, 15 Quali y Assu ance Subcommi ee on Da a Quali y. Funding Funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, and Con ac No. HHSN267200700014C om he Na ional Ins i u e o Diabe es and Diges i e and Kidney Diseases (NIDDK), Na ional Ins i u e o Alle gy and In ec ious Diseases (NIAID), Na ional Ins i u e o Child Heal h and Human De elopmen (NICHD), Na ional Ins i u e o En i onmen al Heal h Sciences (NIEHS), Ju enile Diabe es Resea ch Founda ion (JDRF), and Cen e s o Disease Con ol and P e en ion (CDC). This wo k suppo ed in pa by he NIH/NCATS Clinical and T ansla ional Science Awa ds o he Uni e si y o Flo ida (UL1 TR000064) and he Uni e si y o Colo ado (UL1 TR001082). A ailabili y o da a and ma e ials The da a ha suppo he indings o his s udy a e a ailable om he NIDDK eposi o y (h p://niddk eposi o y.o g) app oxima ely 6 mon hs a e he manusc ip has appea ed in p in . Access o he da a submi ed o he NIDDK Da a Reposi o y will be de e mined by he NIDDK. All in es iga o s who ecei e TEDDY esou ces mus ag ee o acknowledge he TEDDY S udy and he NIDDK cen al eposi o y. This app oach is ully complian wi h he NIH public da a sha ing policy (h p://g an s.nih.go /g an s/policy/da a_sha ing). Au ho s’con ibu ions ML esea ched he da a and w o e he manusc ip . LJS was in ol ed in he d a ing o he manusc ip and e iewed/edi ed he manusc ip . RT made he s a is ical analyses, esea ched da a and e iewed/edi ed he manusc ip . MH, HEL, BJ, PG, CC, MS, GH esea ched da a and e iewed/edi ed he manusc ip . WH, AGZ, MR, ÅL, JT, JS, BA and JK designed he s udy, esea ched da a, and e iewed/edi ed he manusc ip . All au ho s app o ed he inal manusc ip as submi ed and ag ee o be accoun able o all aspec s o he wo k. Compe ing in e es s The au ho s ha e no con lic s o in e es ele an o his a icle o disclose. The unding agencies did no include any inpu in o he design and conduc o he s udy; collec ion, managemen , analysis, o in e p e a ion o da a; o p epa a ion, e iew, o app o al o manusc ip . Consen o publica ion No applicable. E hics app o al and consen o pa icipa e The s udy was app o ed by he local Ins i u ional o E hics Re iew Boa ds and is moni o ed by an Ex e nal Ad iso y Boa d o med by he Na ional Ins i u es o Heal h. Publishe ’sNo e Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in published maps and ins i u ional a ilia ions. Au ho de ails 1 Depa men o Clinical Sciences, Diabe es and Celiac disease uni , Lund Uni e si y, Clinical Resea ch Cen e, Jan Waldens öms ga a 35, 205 02 Malmö, Sweden. 2 Cen e o Bio echnology and Genomic Medicine, Medical College o Geo gia, Augus a Uni e si y, Augus a, GA, USA. 3 Heal h In o ma ics Ins i u e, Mo sani College o Medicine, Uni e si y o Sou h Flo ida, Tampa, FL, USA. 4 Ba ba a Da is Cen e o Childhood Diabe es, Uni e si y o Colo ado, Au o a, CO, USA. 5 Paci ic No hwes Diabe es Resea ch Ins i u e, Sea le, WA, USA. 6 Depa men o Physiology, Ins i u e o Biomedicine, Uni e si y o Tu ku, and Depa men o Pedia ics, Tu ku Uni e si y Hospi al, Tu ku, Finland. 7 Ins i u e o Diabe es Resea ch, Helmhol z Zen um München, and Klinikum ech s de Isa , Technische Uni e si ä München, and Fo sche g uppe Diabe es e.V, Neuhe be g, Ge many. 8 Na ional Ins i u e o Diabe es & Diges i e & Kidney Diseases, Be hesda, MD, USA. 9 Depa men o Pedia ics, Uni e si y o Flo ida, Gaines ille, FL, USA. 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Na l Heal h S a Repo . 2008;10(12):1–23. • We accep p e-submission inqui ies • Ou selec o ool helps you o ind he mos ele an jou nal • We p o ide ound he clock cus ome suppo • Con enien online submission • Tho ough pee e iew • Inclusion in PubMed and all majo indexing se ices • Maximum isibili y o you esea ch Submi you manusc ip a www.biomedcen al.com/submi Submi you nex manusc ip o BioMed Cen al and we will help you a e e y s ep: Lundg en e al. BMC Pedia ics (2017) 17:127 Page 9 o 9