Growth of children with biliary atresia living with native livers: impact of corticoid therapy after portoenterostomy

ORIGINAL ARTICLE G ow h o child en wi h bilia y a esia li ing wi h na i e li e s: impac o co icoid he apy a e po oen e os omy Sa u Ma ia Ruuska 1,2 &Mi ja Tapani Lääpe i 3 &Ma ia Hukkinen 2,4 &Hannu Jalanko 5 &Kaija-Leena Kolho 6,7 & Mikko P. Paka inen 2,3,4 Recei ed: 10 Oc obe 2018 /Re ised: 5 No embe 2018 /Accep ed: 27 No embe 2018 /Published online: 5 Decembe 2018 #The Au ho (s) 2019 Abs ac We add essed g ow h o bilia y a esia (BA) pa ien s li ing wi h na i e li e s be ween ages 0–6 and e ec s o pos -su gical co icos e oid ea men on g ow h. G ow h cha s o 28 BA pa ien s bo n in Finland be ween 1987 and 2017 we e e ospec i ely e alua ed. Dosage and leng h o co icos e oid ea men and hyd oco isone subs i u ion we e e iewed. A bi h, BA pa ien s we e sho e (median heigh −0.6 (in e qua ile ange (IQR) −1.3 o −0.1) SDS, n=28,P< 0.001) han gene al popula ion. Heigh emained s able du ing ea ly childhood (median heigh −0.6 (IQR −1.4 o 0.1) SDS o gi ls and −0.4 (IQR −1.6 o 0.2) SDS o boys a 6 yea s o age). Pa ien s we e o no mal heigh adjus ed weigh a 6 yea s wi h a median age and sex-adjus ed body mass index (ISO-BMI) o 20.9 (IQR 19.3 o 25.0) o gi ls and 22.1 (IQR 20.7 o 25.6) o boys. Highe (≥50 mg/kg) cumula i e pos -po oen e os omy p ednisolone dosage esul ed in 0.18 SDS lowe heigh pe ea men week (β−0.18, SE 0.04, P< 0.001) compa ed o lowe dosage (< 50 mg/kg). Conclusion: BA pa ien s g ow no mally du ing ea ly childhood. As high pos ope a i e co icos e oid dosage has a sho - e m nega i e e ec on heigh , e y high dosages should be a oided. Wha Is Known: •G ow h o bilia y a esia pa ien s has mos ly been shown o be wi hin no mal limi s •Co icos e oids may dec ease g ow h a e Wha Is New: •Bilia y a esia pa ien s su i ing wi h hei na i e li e s a e sho e han gene al popula ion and hei mid-pa en al a ge heigh a bi h •A high (> 50 mg/kg) cumula i e p ednisolone dosage has a nega i e ansi o y impac on heigh gain a e po oen e os omy Keywo ds Age and sex-adjus ed body mass index (ISO-BMI) .Bilia y a esia (BA) .Co icos e oids .Po oen e os omy Communica ed by Pe e de Win e *Sa u Ma ia Ruuska sa u. uuska@hus. i Mi ja Tapani Lääpe i mi ja@laape i.com Ma ia Hukkinen ma ia.hukkinen@hus. i Hannu Jalanko hannu.jalanko@hus. i Kaija-Leena Kolho kaija-leena.kolho@helsinki. i Mikko P. Paka inen mikko.paka inen@hus. i 1 Depa men o Gas oen e ology, Child en’s Hospi al, Helsinki Uni e si y Hospi al, PL 347, 00029 HUS Helsinki, Finland 2 Pedia ic Li e and Gu Resea ch G oup, Child en’s Hospi al, Helsinki Uni e si y Hospi al, Helsinki, Finland 3 Pedia ic Resea ch Cen e , Child en’s Hospi al, Helsinki Uni e si y Hospi al, Helsinki, Finland 4 Sec ion o Pedia ic Su ge y, Child en’sHospi al,Helsinki Uni e si y Hospi al, Helsinki, Finland 5 Depa men o Pedia ic Neph ology and T ansplan a ion, Child en’s Hospi al, Helsinki Uni e si y Hospi al, Helsinki, Finland 6 Uni e si y o Tampe e, Tampe e, Finland 7 Tampe e Uni e si y Hospi al, Tampe e, Finland Eu opean Jou nal o Pedia ics (2019) 178:341–349 h ps://doi.o g/10.1007/s00431-018-3302-z Abb e ia ions BA Bilia y a esia BASM Bilia y a esia splenic mal o ma ion COJ Clea ance o jaundice DW% Weigh - o -leng h IQR In e qua ile ange ISO-BMI Age- and sex-adjus ed body mass index LT Li e ansplan a ion MPH Mid-pa en al a ge heigh PE Po oen e os omy SDS S anda d de ia ion sco es In oduc ion Bilia y a esia (BA) is an idiopa hic ib o-obs uc i e cholangiopa hy mani es ing in in ancy [20].The incidence o BA is a ied be ween 1:8000 and 1:10000 epo ed in Asia o 1:17000–1:20000 in No he n Eu ope [26–28]. Un ea ed, obs uc ion o in a- and ex ahepa ic bilia y acks leads o ib osis, li e ailu e, and dea h in he i s 2 yea s. The cu en i s -line su gical ea men is po oen e os omy (PE). P o ided PE es o es adequa e bile low, be ween 23% and 44% o pa ien s su i e wi h na i e li e s un il he age o 20 [10,29,41]. Li e ansplan a ion (LT) emains a second-line ea men op ion and BA is he mos common indica ion o childhood LTs [20,30]. Following PE, commonly used adjunc pos ope a i e man- agemen includes u sodeoxycholic acid, p ophylac ic an ibi- o ic ea men , and nu i ional managemen [11,47,49]. Co icos e oids may imp o e clea ance o jaundice (COJ) a es bu po en ial side e ec s include an ele a ed isk o in ec ions, gas oin es inal bleeding, os eopo osis, and poo g ow h [5,7,9]. G ow h pa e ns o pa ien s su i ing wi h hei na i eli e sha e a elybeen epo edon,andda aon he e ec pos -PE co icos e oids ha e on g ow h a e e y limi ed [1,5,12,34]. The aim o his s udy was o cha ac e ize g ow h o BA pa ien s su i ing wi h hei na i e li e s be ween he ages 0–6. Fu he mo e, we measu ed he e ec o pos -PE co icos e oids on g ow h. Me hods Pa ien s We included e m BA pa ien s bo n in Finland be ween 1987 and 2017 who had no malized hei bili ubin < 20 μmol/l a e PE, we e a leas 4 mon hs old, and we e li ing wi h hei na i e li e s as o 31s o Decembe 2017. Da a on ges a ional age, bi h heigh , and weigh , associa ed congeni al mal o ma ions, BA- ype [36], age a su ge y, se ial heigh and weigh measu emen s, co icos e oid ea men , and subsequen hyd oco isone subs i u ion we e e ospec i ely collec ed om medical eco ds. Te m in an was de ined as weigh a o abo e 2500 g and ges a ional age be ween 37 and 42 weeks a bi h. Bilia y a esia splenic mal o ma ion (BASM) was de ined as p esence o poly- o asplenia [8]. Clea ance o jaundice was de ined as se um o al bili ubin < 20 μmol/L. G ow h da a Heigh and weigh a bi h as well as a 3, 6, 9, 12, 15, 18, 21, and 24 mon hs and a yea ly in e als be ween 2 and 20 yea s o age we e e ospec i ely collec ed om med- ical eco ds. Heigh and weigh a PE and a 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, and 24 mon hs a e PE we e also e ie ed om medical eco ds. Fo he i s yea , mea- su emen s pe o med wi hin a ± 4-week pe iod o he ex- ac ime poin we e accep ed bu o g ow h da a a e po oen e os omy, o he i s 12 mon hs, he nea es a ailable measu emen was accep ed i i was wi hin a ± 2-week pe iod o he exac ime poin . A e 12 mon hs, measu emen s wi hin a ± 6-week pe iod o he excep ime poin we e accep ed. Heigh was analyzed as s anda dde ia ionsco es (SDS) om he mean o age- and sex-adjus ed na ional alues [39]. No mal heigh was de ined as heigh SDS be ween −2.0 and 2.0. Mid-pa en al a ge heigh SDS we e calcula ed acco ding o he equa ions: 0.791 × mean pa en al heigh SDS −0.147 o gi ls and 0.886 × mean pa en al heigh SDS –0.071 o boys [40]. Be ween bi h and 2 yea s o age, ela i e weigh was analyzed as weigh - o -leng h, i.e., he pe cen age de ia ion o weigh om he median weigh o leng h and sex (DW%) [39, 44]. A e he age o 2, ela i e weigh was analyzed wi h age- and sex-adjus ed body mass index (ISO-BMI) [39]. Du ing he i s 2 yea s, unde weigh was de ined as DW% < −20.0, no mal weigh as DW% be ween −20.0 and + 20.0 and o e weigh as DW% > 20.0 [39,44]. Fo ela i e weigh be ween ages 2–6, he ollowing ISO-BMI ca ego ies we e used: unde weigh (< 17 kg/m 2 ), no mal weigh (17–25 kg/m 2 ), o e weigh (> 25 kg/ m 2 ), and obesi y (> 30 kg/m 2 )[39]. While calcula ing changes in ela i e weigh a e po oen e os omy, ela i e weigh was analyzed as weigh - o -leng h o consis ency. The mos ecen ly published na ional e e ence da a was used o calcula ion o SDS o weigh and leng h [39]. Co icos e oid ea men Cumula i e dosage o glucoco icoid ea men a e PE, he leng h and dosage o subsequen hyd oco isone sub- s i u ion egimen, and measu ed se um co isol alues 342 Eu J Pedia (2019) 178:341–349 a e co icos e oid ea men we e e iewed om pa ien eco ds. Co icos e oid dosage was con e ed o equi alen s o p ednisolone, and o al cumula i e dosage o p ednisolone (mg) pe weigh (kg) was calcula ed. In con e ing, 5 mg o p ednisolone was conside ed o be equi alen o 5 mg o p ed- nisone, 20 mg o hyd oco isone, 670 μg o dexame hasone, and 4 mg o me hylp ednisolone [31]. A high o al p edniso- lone dosage was conside ed o be ≥50 mg/kg [9]. All possible glucoco icoid usages ela ed o un ela ed o BA a e he ini- ial ea men pe iod we e eco ded. The ela ionship o cumu- la i e glucoco icoid dosage o changes in ela i e heigh and weigh 2 yea s a e PE we e analyzed. While analyzing he impac co icos e oids had on g ow h, possible impac was hypo hesized o s a a he beginning o medica ion and con- inue un il 24 mon hs. P io o na ional cen aliza ion o BA ea men in 2005 [26], a ied pos ope a i e managemen p o- ocols we e used wi h a median cumula i e pos su gical co - icos e oid dosage co esponding o 50 mg/kg (IQR 26 o 62) o p ednisolone. A e cen aliza ion, adju an co icos e oid he apy a e PE has been used [22]. Be ween 2005 and 2014, co icos e oid he apy wi h o al dexame hasone co esponded o cumula i e dosage o 45 mg/kg o p ednisolone; since 2015, he dosage has co esponded o 75 mg/kg o p ednisolone. S a is ical me hods Values a e exp essed as medians wi h in e qua ile ange (IQR) unless o he wise s a ed. Wilcoxon signed- ank es was used o compa e ma ched g oups. G ow h o pa ien s was modeled using linea mixed models [4]. Models in- cluded andom e ec o pa icipan s on all ime e ms. Analyses we e ca ied ou in R e sion 3.4.1 using pack- ages lme4 and lme Tes [25,38]. Deg ees o eedom we e es ima ed using Sa e hwai e app oxima ions. The s a is ically signi ican le el was se o P<0.05. Resul s Pa ien cha ac e is ics Du ing he s udy pe iod, 96 pa ien s we e diagnosed wi h BA in Finland. O hese, 30 pa ien s had died, 28 we e ali e wi h a li e ansplan (median age a ansplan a ion 1.45 (0.84 o 2.51) yea s), 3 we e bo n p e e m and 1 had a bi hweigh < 2500 g. Thus, 34 pa ien s ul illed he ini ial inclusion c i e ia. Six pa ien s we e excluded as ollows: wo because o missing heigh measu emen s a bi h and ou because bo h pa en s we e non-Eu opean. AsshowninTable1, median ges a ional age was 39 weeks. Mos pa ien s we e diagnosed wi h BA ype 3 and PE was pe o med a median age 63 days. Median ollow-up age was 8.1 yea s and pa ien s had well- p ese ed li e unc ion. Heigh gain be ween 0 and 6 yea s A bi h, BA pa ien s we e sho e (median heigh −0.6 (−1.3 o −0.1) SDS o all pa ien s, n=28,P< 0.001) han he gen- e al popula ion. Median heigh SDS o pa ien s wi h mid- pa en al a ge heigh (MPH) da a (n= 20) was −0.2 (−1.2 o 0.2), which was 0.1 SDS below hei median MPH o − 0.1 (−0.4 o0.4)SDS(mediandi e ence0.3,n= 20, P<0.05). G ow h a e appea ed o slow down du ing he i s 3 mon hs, as median heigh o all pa ien s a 3 mon hs was −1.70 (−2.3 o −1.1) SDS. Change in g ow h a e was mo e d as ic o boys (n= 13); hei median SDS changed om − 0.6 (−1.5 o −0.1) a bi h o −1.8 (−2.5 o −0.8) a 3 mon hs while gi ls’(n= 15) median SDS changed om −0.7 (−0.7 o 0.4) SDS o −1.4 (−1.8 o −1.1) SDS (Fig. 1). A 6 mon hs, boys’g ow h a e accele a ed as median heigh o all pa ien s was −1.2 (−2.2 o −0.7) SDS, −1.2 (−2.1 o −0.5) SDS o boys and −1.3 (−2.3 o −0.7) SDS o gi ls. Be ween 6 and 24 mon hs, g ow h a e was s able (Fig. 1). A 2 yea s, pa ien s emained sho e (median heigh o all pa ien s −0.8 (−1.2 o −0.1) SDS) han he gene al popula ion. A 2 yea s, 11/13 (85%) o he pa ien s had heigh SDS below MPH (median di e ence = 0.8, n=13,P<0.05). Heigh gain was s able be ween ages 2–6. Gi ls’heigh was unal e ed wi h median heigh a −0.6 (−1.2 o −0.1 and −1.4 o 0.1 a 2 and 6 yea s, espec i ely) SDS while boys’median heigh changed om −0.9 (−1.3 o 0.0) SDS o −0.4 (−1.6 o 0.2) SDS. Weigh gain be ween 0 and 6 yea s A bi h, pa ien s we e o no mal weigh wi h median 0.0 (− 5.0 o 5.5) DW% o all, 2.0 (−5.0 o 6.0) DW% o gi ls and 0.0 (−6.0 o 4.5) DW% o boys. Du ing he i s 2 yea s, bo h gende s emained o no mal weigh wi h median o 2.5 (−1.0 o 10.5) DW% o all, −1.0 (−3.5 o 4.0) DW% o gi ls and 8.0 (2.5 o 17.5) DW% o boys a 2 yea s o age (Fig. 1). When analyzing wi h ISO-BMI, a 2 yea s, o e all me- dian ISO-BMI was 24.1 (20.5 o 28.8), i.e., on he uppe ma gin o no mal ange. The e was a dis inc di e ence be ween gende s; gi ls we e o no mal weigh wi h medi- an o 21.1 (19.7 o 23.3) ISO-BMI while boys we e o e - weigh wi h a median o 25.9 (24.1 o 32.3) ISO-BMI (Fig. 2).Gi ls’weigh emained cons an be ween ages 2–6 yea s wi h a median o 20.9 (19.3 o 25.0) ISO- BMI a 6 yea s. Boys’weigh dec eased sligh ly wi h − 1.06 (β−1.06, SE 0.33, P< 0.05) ISO-BMI yea ly wi h median ISO-BMI a 22.1 (20.7 o 25.6) a 6 yea s (Fig. 2). Eu J Pedia (2019) 178:341–349 343 Pos ope a i e co icos e oid ea men and g ow h Comple e da a o pos su gical co icos e oid ea men was a ailable o 24 ou o 28 pa ien s, including 3 pa ien s no ea ed wi h co icos e oids. Co icos e oid ea men s a ed a median 5 ( ange 4–17) days a e PE a median age o 70 ( ange 18–167) days. The median leng h o co icos e oid- ea men was 18.5 ( ange 0–49) days. Six een pa ien s e- cei ed hyd oco isone subs i u ion. To al median cumula i e co icos e oid dosage was 277.6 (186.6 o 374.2) mg and 63.6 (47.7 o 74.6) mg/kg o p ednisolone excluding hyd oco i- sone subs i u ion. Median hyd oco isone dosage du ing he i s 30 days o subs i u ion was 8.2 ( ange 5.0–21.2) mg/m 2 / day and median ea men leng h was 37 ( ange 12–133) days. Se um co isol alues we e supp essed a e glucoco icoid ea men in 12 ou o 19 pa ien s (63%) wi h measu ed alues. A PE (median age 65 (IQR 26 o 90) days), pa ien s we e 1.51 (β−1.51, SE 0.19, P< 0.001) SDS sho e han he gene al popula ion. A g ow h model o cumula i e p ednis- olone dosage showed 0.16 (β−0.16, SE 0.04, P<0.001)SDS dec ease in heigh o each 100 mg o p ednisolone. In a mixed model, he e was 0.18 (β−0.18, SE 0.04, P<0.001) SDS dec ease in heigh o each 100 mg o p ednisolone while hyd oco isone subs i u ion caused ain 0.07 (β0.07, SE 0.02, P< 0.05) SDS inc ease in heigh pe ea men week. A weigh -adjus ed dosage model showed nega i e e ec on heigh wi h 0.25 (β−0.25, SE 0.05, P< 0.001) SDS dec ease o each 100 mg o p ednisolone pe ea men week. In a mixed model, weigh -adjus ed dosage o p ednisolone dem- ons a ed 0.27 (β−0.27, SE 0.05, P< 0.001) SDS dec ease o each 100 mg o p ednisolone pe ea men week while hyd oco isone subs i u ion caused 0.07 (β0.07, SE 0.02, P< 0.01) SDS inc ease in heigh pe week. A highe o al co icos e oid dosage (> 50 mg/kg) esul ed in 0.18 (β− 0.18, SE 0.04, P< 0.001) SDS lowe heigh pe ea men week compa ed o lowe dosage. The e ec emained in a Table 1 Pa ien cha ac e is ics All pa ien s Pa ien s wi h glucoco icoid da a Numbe o pa ien s 28 24 Ges a ional age, wk, median (IQR) 39 (38–40) 39 (38–40) Females, n(%) 15(54) 12(50) Bi h weigh , median (IQR) kg 3.340 (3.081–3.669) 3.363 (3.081–3.669) %0.0(−5.0–5.5) 0.0 (−6.5–5.5) Bi h heigh , median (IQR) cm 50.0 (48.6–51.0) 50.0 (49.0–51.0) SD −0.6 (−2.2–(−0.1)) −0.6 (−1.0–0.3) Bilia y a esia ype n(%) 1 0 (0.0) 0 (0.0) 2 2 (7.1) 0 (0.0) 3 26 (92.9) 24 (100) Bilia y a esia splenic mal o ma ion, n(%) 3 (11) 3 (13) Any o he anomaly, n(%) 10 (36) 8 (33) Age a po oen e os omy (PE), days, median (IQR) 63 (24–83) 65 (26–90) Time o clea ance o jaundice, mon hs, median (IQR) 2 (1–3) 2.5 (1–3.8) Diagnosed wi h po al hype ension, n(%) 12 (43) 12 (50) Age a las ollow-up, yea s, median ( ange) 8.1 (0.3–19.7) 7.8 (0.3–19.7) Biochemical ma ke s a las ollow-up: Bili ubin, μmol/L, median (IQR) 8.5 (7–14) 8.5 (5.5–14.8) Conjuga ed bili ubin, μmol/L, median (IQR) 4 (3–7) 4.0 (3–7.8) Alanine amino ans e ase, U/L, median (IQR) 40 (19–76) 55 (27–77) Aspa a e amino ans e ase, U/L, median (IQR) 54 (34–90) 57 (42–100) Glu amyl ans e ase, U/L, median (IQR) 48 (21–100) 65 (27–105) Albumin, g/L, median (IQR) 38 (32–40) 37 (32–40) Th omboplas in ime %, median (IQR) 87 (73–100) 87 (73–105) Th ombocy es, × 10 9 /L, median (IQR) 174 (79–268) 155 (71–268) IQR in e qua ile ange, PE = po oen e os omy. Bilia y a esia ypes as de ined by Ohi e al. [18], po al hype ension as de ined by Shneide e al. [42] 344 Eu J Pedia (2019) 178:341–349 a. b. c. d. e. . Fig. 1 G ow h o BA pa ien s du ing i s 2 yea s, pos na al age, 3-mon h in e als. aHeigh SDS o all pa ien s. bHeigh SDS o gi ls. cHeigh SDS o boys. dWeigh - o -leng h (DW%) o all pa ien s. eWeigh - o - leng h (DW%) o gi ls. Weigh - o -leng h o boys (DW%). G ay a ea be ween dashed lines: no mal weigh wi h DW%. Da a a e p esen ed wi h median and in e qua ile ange (pe cen ile 25–75). SDS, s anda d de ia- ion sco es om he mean o age- and sex-adjus ed alue; DW%, pe - cen age de ia ion o weigh om median weigh o leng h and sex; MPH, mid-pa en al a ge heigh Fig. 2 G ow h o BA pa ien s be ween 2 o 6 yea s wi h yea ly in e als. aHeigh SDS o all pa ien s. bHeigh SDS o gi ls. cHeigh SDS o boys. dWeigh ISO-BMI o all pa ien s. eWeigh ISO-BMI o gi ls. . Weigh ISO-BMI o boys. G ay a ea be ween dashed lines: no mal weigh wi h ISO-BMI. Da a a e p esen ed wi h median and in e qua ile ange (pe cen ile 25–75). SDS, s anda d de ia ion sco es om he mean o age- and sex-adjus ed alue; ISO-BMI, age- and sex-adjus ed body mass index Eu J Pedia (2019) 178:341–349 345 model including highe co icos e oid dosage (β−0.21, SE 0.04, P< 0.001) and hyd oco isone subs i u ion (β−0.05, SE 0.02, P< 0.01). Supp ession o co isol p oduc ion caused 1.37 (β−1.37, SE 0.55, P< 0.05) SDS dec ease pe week in heigh compa ed o unsupp essed pa ien s (Table 2). Pa ien s we e o no mal weigh wi h −0.44 (β−0.44, SE 1.53, P0.776) DW% a ime o po oen e os omy. A g ow h model o o al cumula i e p ednisolone showed no e ec on weigh , no did a g ow h model combining cumula i e p ednis- olone and hyd oco isone subs i u ion (Table 2). A g ow h model wi h weigh -adjus ed co icos e oid dosage showed no e ec o p ednisolone on weigh no did a model combining weigh -adjus ed dosage and hyd oco isone subs i u ion (Table 2).A highe o al co icos e oid dosage caused 1.12 (β 1.12, SE 0.36, P< 0.01) DW% inc ease in weigh pe ea men week compa ed o lowe dosage, he e ec emained (β0.87, SE 0.38, P< 0.05) in a mixed model including hyd oco isone subs i u ion (β0.32, SE 0.15, P< 0.05). Supp ession o co isol p oduc ion had no e ec (Table 2). Discussion We desc ibe g ow h pa e ns o e m BA pa ien s li ing wi h na i e li e s om bi h un il ea ly childhood. We ound ha hey a e sho e han gene al popula ion and hei mid-pa en al a ge heigh a bi h. Thei heigh gain emains cons an du - ing in ancy and ea ly childhood. BA pa ien s we e bo n o no mal weigh and emained o no mal weigh du ing i s 2 yea s. Gi ls emained o no mal weigh be ween 2 and 6 yea s whe eas boys’weigh , while analyzed wi h ISO- BMI, slimmed down om o e weigh o no mal weigh . A high cumula i e co icos e oid ea men dosage had a ma ked empo a y nega i e impac on heigh gain. Table 2 Linea mixed models’ esul s o heigh and weigh o di e en pa ame e s. The es ima es a e o ei he changes in s anda dized heigh (SD) o ISO-BMI. Models o (1.) ime only, (2.) ime and cumula i e p ednisolone, (3a.) ime and weigh -adjus ed p ednisolone, (4a.) ime and high p ednisolone dosage, and (5.) ime and co isol supp ession. The (b) models ex ended he (a) models wi h hyd oco isone subs i u ion Models o heigh a : Pa ame e Es ima e, βS anda d e o , SE P 1. In e cep −1.51 0.19 <0.001 Time, 1 mon h 0.05 0.01 <0.001 2 a. Cumula i e p ednisolone pe 100 mg −0.16 0.04 <0.001 b. Cumula i e p ednisolone pe 100 mg −0.18 0.04 <0.001 Hyd oco isone subs i u ion pe week 0.07 0.02 0.007 3 a. Weigh -adjus ed p ednisolone pe 100 mg pe week −0.25 0.05 <0.001 b. Weigh -adjus ed p ednisolone pe 100 mg pe week −0.27 0.05 <0.001 Hyd oco isone subs i u ion pe week 0.07 0.02 0.004 4a. Highdosagepe week −0.18 0.04 <0.001 b. High dosage pe week −0.21 0.04 <0.001 Hyd oco isone subs i u ion pe week −0.05 0.02 0.006 5. Co isol supp ession pe week −1.37 0.55 0.014 Models o weigh a : 1. In e cep −0.44 1.53 0.776 Time, 1 mon h 0.31 0.11 0.011 2 a. Cumula i e p ednisolone pe 100 mg 0.58 0.40 0.144 b. Cumula i e p ednisolone pe 100 mg 0.47 0.42 0.263 Hyd oco isone subs i u ion pe week 0.15 0.17 0.384 3 a. Weigh -adjus ed p ednisolone pe 100 mg pe week 0.32 0.47 0.496 b. Weigh -adjus ed p ednisolone pe 100 mg pe week 0.16 0.49 0.751 Hyd oco isone subs i u ion pe week 0.19 0.17 0.259 4 a. High dosage pe week 1.12 0.36 0.002 b. High dosage pe week 0.87 0.38 0.024 Hyd oco isone subs i u ion pe week 0.32 0.15 0.033 5. Co isol supp ession pe weeks 2.43 5.15 0.638 a All models adjus ed o ollow-up ime, excep o he i s (1.) ime only uni a ia e model 346 Eu J Pedia (2019) 178:341–349 Resul s on weigh a ied a 2 yea s o age depending whe he ela i e weigh was analyzed wi h DW% o ISO- BMI; when analyzed wi h DW%, bo h gi ls and boys we e o no mal weigh whe eas boys we e o e weigh when ana- lyzed wi h ISO-BMI. This disc epancy likely s ems om he ac ha he e is no known co ela ion o DW% and ISO-BMI be ween ages 0 o 2. Single USA-based s udy comp ising 4348 child en ound poo co ela ion be ween weigh - o - heigh and BMI- o -age be ween ages 2–5. In line wi h ou indings, high pe cen age (63.4%) o child en had lowe weigh - o -heigh pe cen ile han BMI- o -age pe cen ile a he same age [16]. Pa ien s in ou s udy a e sho e han gene al popula ion and hei mid-pa en al a ge heigh a bi h. BA associa ed wi h cy omegalo i us in ec ion has been desc ibed o ha e wo se clinical ou come wi h inc eased mo ali y [50], al- hough a p e ious s udy om Sweden yielded equal clinical esul s independen o cy omegalo i us s a us [15]. Symp oma ic congeni al cy omegalo i us in ec ion may man- i es as s un ed g ow h especially a ec ing bi h weigh , how- e e , he as majo i y o child en wi h congeni al cy omega- lo i us in ec ion a e asymp oma ic [6,13,33]. As none o he pa ien s in ou s udy we e diagnosed wi h cy omegalo i us in ec ion, i is unlikely ha his i us caused he diminished bi h heigh . Published da a assessing g ow h o nonjaundiced child en wi h BA li ing wi h na i e li e s in ea ly childhood a e spa se. Sokol e al. [43] ound dep essed heigh and weigh z-sco es bu no mal weigh - o -heigh z-sco es o 32 BA pa ien s in ea ly childhood. Howe e , as 21 ou o 32 pa ien s in hei coho had signs o ci hosis al hough pa ien s we e clinically s able, i is likely ha ou s udy g oup consis s o heal hie pa ien s. Ka e e al. [23] epo ed no mal heigh sco es o he majo i y o 30 pa ien s su i ing a leas 10 yea s a e po oen e os omy bu hei esul s also included ansplan ed pa ien s. Thi y- i e ou o 38 nonjaundiced BA pa ien s su - i ing wi h na i e li e s a leas 10 yea s we e epo ed o ha e no mal g ow h by Valaye [46]. Hadziće al. [19] ound no mal heigh and weigh z-sco es a ollow-up in 28 BA pa ien s li ing wi h na i e li e s, hese pa ien s we e also con- side able olde adolescen s compa ed o ou coho (median age 13.4 ( ange 10.2–22.2) yea s s 8.1 ( ange 0.3–19.7) yea s in ou coho ). Ng e al. [34] epo ed no mal median heigh and weigh z-sco es o 219 BA pa ien s (median age 9.7 ( ange 5.1–17.9)) li ing wi h na i e li e s a leas 5 yea s a e po oen e os omy. Simila ly o ou indings, A ay e al. [2] desc ibed dec eased heigh - o -age and no mal weigh - o -age in a g oup o 10 BA pa ien s li ing wi h na i e li e s be ween ages 1 o 12. In e es ingly, hey ound BMI and weigh - o -age z-sco es in e sely co ela ed wi h age [2]. In ou s udy, boys weigh dec eased be ween ages 2 o 6. While i is possible o a gue ha lowe ela i e weigh migh e lec poo e nu i ion- al s a us, pa ien s in ou s udy demons a ed unal e ed heigh gain and we e o no mal weigh a he end o ollow-up sugges ing adequa e ene gy and p o ein in ake o sus ain g ow h. Pos na al co icos e oids ha e been used o p e en ion and ea men o ch onic lung disease in p e e m in an s since 1980s [3]. In p e e m in an s, sys emic co icos e- oidsha ebeenshown osupp essg ow h[ 45,48]. To ou bes knowledge, he e is only one p io s udy on he e ec o pos ope a i e co icos e oid ea men on g ow h o BA pa ien s [1]. The ole o pos su gical co icos e oids emains polemic as p e ious s udies om Asia [24,32], Eu ope [9], and he USA [14] ha e shown highe clea - ance o jaundice a es o pa ien s ea ed wi h co icos e- oids, bu his bene icial inding was no ecip oca ed in a la ge No h-Ame ican placebo-con olled ial [5]. The START ial [1,5] ecen ly epo ed lowe han no ms z- sco es o leng h om po oen e os omy (69 pa ien s) un- il 24 mon hs o age (35 pa ien s) and o weigh om po oen e os omy (70 pa ien s) un il 18 mon hs o age (42 pa ien s) o BA pa ien s ea ed wi h pos -su gical co icos e oids (cumula i e p ednisolone dosage 116 mg/kg). They also ound signi ican di e ence be ween leng h z-sco es a 1, 2, and 3 mon hs a e po oen e os omy be ween pa ien g oups ea ed wi h co icos e oids o placebo (70 pa ien s in each g oup) [1]. In line wi h hese indings, in ou s udy, a highe cumula i e co icos e oid dosage (> 50 mg/kg) nega- i ely associa ed wi h g ow h by empo a ily signi ican ly slowing heigh gain. In con as o START ial, we did no obse e a long- e m nega i e impac o co icos e oids on weigh o heigh ; his is mos likely due o he lowe dosage o co icos e oids used in ou coho . In ou coho , g ow h accele a ed be ween 3 and 6 mon hs o age (median age a po oen e os omy o all pa ien s was 63 days) and heigh gain was s able a e ha . Al hough in choles a ic li e disease in ea ly childhood he e a e mul iple ac o s, such as changes in g ow h ho mone unc ion [17,21], inadequa e eso p ion o nu i ion [35], and ele a ed ene gy consump ion [18,37]pos- sibly a ec ing g ow h; he impac o co icos e oids was clea - ly obse able in ou coho o child en wi h well-p ese ed li e unc ion. Ou s udy has some limi a ions. Because da a we e collec - ed e ospec i ely, we we e unable o cap u e comple e g ow h da a o all pa ien s a all ime poin s. Secondly, pa ien s’nu- i ional s a us be o e PE and ene gy and p o ein in ake du ing ollow-up could no be assessed eliably. In conclusion, we ound ha BA pa ien s su i ing wi h hei na i e li e s a e sho e han hei backg ound popula ion a bi h. Thei heigh gain s ays s able du ing ea ly childhood. High pos -PE co icos e oid ea men dosage has a nega i e impac on heigh gain and an obse able posi i e impac on weigh gain compa ed o lowe dosage, bu hese e ec s a e o sho du a ion. Howe e , as he e a e con lic ing esul s ega d- ing he bene icial e ec s o pos su gical co icos e oid Eu J Pedia (2019) 178:341–349 347 ea men o BA pa ien s, i is wise o minimize he possible isks o ea men and o a oid e y high co icos e oid dosages. Au ho s’con ibu ions Sa u Ruuska: acqui ed and analyzed he da a, d a ed his manusc ip , and ag eed on he inal e sion o his manusc ip . Mi ja Lääpe i: un s a is ical analysis o he s udy da a oge he wi h Sa u Ruuska and ag eed on he inal e sion o his manusc ip . Ma ia Hukkinen: e ised he manusc ip c i ically and ag eed on he inal e sion o his manusc ip . Hannu Jalanko: pa icipa ed on he design o his s udy, e ised he manusc ip c i ically, and ag eed on he inal e sion o his manusc ip . Kaija-Leena Kolho: designed he s udy, c i ically e ised his manu- sc ip , and ag eed on he inal e sion o his manusc ip . Mikko P Paka inen: designed he s udy, p o ided unding o he s udy, c i ically e ised his manusc ip , and ag eed on he inal e sion o his manusc ip . Funding Open access unding p o ided by Uni e si y o Helsinki includ- ing Helsinki Uni e si y Cen al Hospi al. This s udy was suppo ed wi h esea ch g an s by he Sig id Jusélius Founda ion, he Finnish Pedia ic Resea ch Founda ion, and he Helsinki Uni e si y Cen al Hospi al G an . Compliance wi h e hical s anda ds Con lic o in e es The au ho s decla e ha hey ha e no con lic o in e es . E hical app o al This s udy was app o ed by he E hical Commi ee o Helsinki Uni e si y Hospi al and in acco dance wi h he 1964 Helsinki decla a ion and i s la e amendmen s o compa able e hical s anda ds. 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