Pediatrics 1993 Martinez 470 3

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1993;91;470PediatricsC. Martinez, Jr and M. Jeffrey Maisels

Jorge C. Martinez, Lydia Otheguy, Horacio Garcia, Monica Savorani, Beatriz Mogni, JorgeInterventions

Hyperbilirubinemia in the Breast-Fed Newborn: A Controlled Trial of Four

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H yperb iliru b in em ia in th e B reast-F ed N ew born : A C on tro lled T r ia l o f

470 PED IA TR IC S Vol. 91 N o . 2 F ebruary 19 93

F ou r In terven tion s

Jo rge C . M artin ez , M D *; M . Jeffrey M aise ls , M B , B .C h L yd ia O theguy , M D *; H orac io G arcia , M D *;M onica S avo ran i, M D *; B eatr iz M ogn i, M D *; and Jo rge C . M artinez , Jr*

ABSTRACT . A con tro lled c lin ica l tria l w a s conducted tocom pare th e e ffect o f fou r d ifferen t in terven tion s on hy -p erb ilirub in em ia in 125 fu ll-term brea st-fed in fan ts. O f1685 term in fan ts w ho m et th e in c lu sion cr iter ia , 126(7 .4%) had a serum b ilirub in concen tra tion 291 pm ol!L(17 m gldL ). W hen the bilirub in reached th is leve l, b ab iesw ere assign ed at random to one of fou r in terven tion s: (1 )con tinue brea st-feed ing and ob serv e; (2 ) d iscon tinuebrea st-feed ing , sub stitu te fo rm u la ; (3 ) d iscon tinuebreast-feed in g , subs titu te fo rm ula an d adm in iste r ph o to -th erapy; (4 ) con tinue breast-feed ing , adm in ister photo-th erapy . T he serum b ilirub in concen tration rea ched 342pm ol/L (20 m g /dL ) in 24% of in fan ts in g roup 1 , 19% ingroup 2 , 3% in group 3 , and 14% in group 4 . W hen pho-to th erapy w a s u sed , th e declin e in serum b ilirub in wa ssign if ican tly larger and m ore rap id (com pared w ith nophototh erapy ). In th e m ajo r ity of b reast-fed in fan tsw hose serum b ilirub in leve ls reach 291 pm ol/L (17 m g/dL ) th e b ilirub in w ill d ec lin e spon taneou sly and w ill n otreach 342 m ol/L (20 m g!dL ). If th e in fan t is sign if ican tlyjaund iced and a dec ision is m ade to in tervene , pa ren tscan be g iv en a num ber o f op tion s and can m ake an in -fo rm ed dec is ion rega rd ing w h ich , if any , in terven tionth ey pre fer . Pediatr ics 1993 ;91 :470-473 ; breast- feeding,n ew born , hypenb ilin ub in em ia , p ho to the rapy .

Fu ll-te rm , b reast-fed new bo rns are m uch m orelike ly to deve lop sign if ican t hy pe rb ilin ub in em ia thanth ose fed fo rm ula ,1 2 and the vast m a jo rity o f in fan tsw ho rece ive trea tm en t fo r hyp erb ilirub in em ia areb reast-fed .3 4 W hen ce rta in b ilirub in lev els a rereached , ped ia tric ians recom m end a va rie ty o f in te r-v en tions. T hese m ay in c lude substitu ting fo rm ula -feed ing fo r b reast-feed ing fo r up to 4 8 hours, o r in -stitu ting pho to th erapy , o r a com bina tion of bo thin te rven tion s (e ithe r a t hom e o r in th e ho sp ita l) . W econduc ted a con tro lled clin ica l tria l to com pare thee ffect o f fou r d ifferen t in terven tio ns on hype rb iliru -b inem ia in fu ll- term b reast-fed in fan ts .

METHODSThe study w as approved by the H um an In ves tiga tio n C omm it-

te e o f the H o sp ita l M a tern o- Infan ti l R . Sarda an d in form ed con-sen t w a s ob tain ed from all m oth ers. A ll he alth y term in fan ts in th ish osp ita l a re fu lly b rea st- fed and non e rec eiv e any su pplem ents . Tob e in clu ded in the s tud y , in fan ts h ad to be hea lthy and del ive redb etw een 38 an d 41 w eeks ges ta t ion fo llow in g an uncom p lic ated

From the *Hospita l M ate rno Infan til R . Sarda , B uenos A ires , A rgentina ;and D ep artm ent of Pediatric s, W illiam B eaum ont Ho spi tal, R oya l O ak, M I.R ece ived fo r p ublica tion A ug 14 , 1 99 2; acc ep ted O ct 20 , 19 92 .R ep rin t reque sts to (M .J.M .) D ept of Pediatric s, W illiam B eaum ont Hospita l,3601 W Thirteen M ile Rd , R oya l O ak , M I 48073-6 769 .PED IA TR IC S (ISSN 0031 4005). C opyright 1993 by th e Am erican A cad-em y of Pediat ric s .

p reg nancy . W e exc lud ed infan ts w ith any co ng enita l anom a lies orn eo natal com plicat ion s an d tho se w hose b ir th w e igh ts w e re belowth e 10 th o r abo ve the 90th percen tile fo r th eir ges ta tion .5 W e a lsoexclud ed tho se w ith a v en ous h em ato crit > 65% , any w ho hads ign ific an t bru isin g or la rge cep halhem atom as, or tho se w ithh em oly tic d isea se . W e d iag no sed hem o ly t ic d isea se in th e pre s-ence o f R h or ABO incom patib ili ty an d a po sit ive C oom b s test , o ra serum bil irub in le vel in cre asing by m ore th an 8 .5 pm ol/L (0 .5m g/dL ) p er h ou r in th e f irst 48 h ours.

Tw o experienc ed inv est iga to rs ev alu ated e ach baby da ily forth e pre sen ce of s ign ific an t jaun dice. B a sed o n th eir c lin ical jud g-m ent , a se rum b ili rub in lev el w a s ob tained da ily un til d ischa rge.In fan ts jaun dic ed at d isch arg e w ere fo llow ed d aily as ou tpa tien tsu n ti l the b i liru b in had re ach ed its peak an d s tar ted to d ec line . A tth e Sa rda H osp ita l th e average len g th of s tay for an u ncom plic ate dnew born is 2 day s and for in fan ts de live red by cesare an sect ion 5d ays . If th e serum b ilirub in co ncentrat ion reach ed o r exceed ed 291pm o l/L (1 7 m g/dL )-w h ich occurred af ter d isch arg e in 90% o fth e in fan ts enro lle d in th e ran dom iz ed tria l-co nsen t w a s so ugh tfrom m oth ers to enro ll th eir bab ie s in to the s tud y . D uring th es tud y per iod , 126 (7 .4% ) o f the 16 85 elig ib le bab ies fu lfilled th iscr iter ion for enro llm en t an d al l the m others gave pe rm ission forth eir b ab ies to en ter th e study . A b lo od typ e and C oom bs tes t w aso bta ined fo r all jau ndiced bab ies an d , a t en try in to th e study , a llin fan ts had a com ple te b lo od cel l c ou nt, re ticu locy te cou nt, andu rinaly sis pe rform ed . Se rum bilirub in level w as m easured us ing aB ilit ron E lv i 44 4 b ili rub inom e ter (E lv i E lectron ica , M ila n , I ta ly )s tan dard iz ed ag ain st so lu tions w ith b i liru b in con cen tra tio ns o f32 5 to 34 2 pm ol/L (19 to 20 m g /dL ). T he co eff ic ie n t of v aria tio nwa s 5% .

A fter p erm iss ion w as ob tain ed , w e as sig ned b ab ies a t rand om(u sin g a co mp ute r-g en erate d tab le) to on e of th e fo llow ing in ter-v en tion s: (1 ) co n tin ue b rea st-feed ing and obse rve ; (2 ) d iscon tinu eb rea st- feed ing , sub sti tu te form u la; (3 ) d iscon tinu e b reas t-fe ed ing ,sub stitu te form ula , an d adm in ister pho to therapy ; (4) co n tinueb rea st- feed ing , a dm in is ter ph o to the rap y . In fan ts in group s I and 2w ere fo llow ed da ily as ou tpat ien ts; th ose in gro ups 3 an d 4 w ereho sp ita l ized . G ro up 4 m o the rs w ere re adm itted w ith the ir b ab iesin order to co n tinue nu rsing them .

Pho to therapy w as de liv ered by a qua rtz h alid e (sp o t) un i t p o-s itio ned to d eliv er an irra d ia nce of ap prox im ately 10 pW /cm 2 /nm(in the 4 00 to 48 0 nm ran ge ) to th e in fan t. In fan ts rece iv in g pho-to the rap y w ere p lac ed n ak ed in a bas sine tte and the ir ey es w erep atched . In grou ps I an d 2 , if th e serum biliru b in lev el rea ched 342pm o l/L (20 m g /dL ), p ho to therapy w as starte d and b rea st-feed ingin te rru p ted in group 1 . E nro llm ent com m enced on A pri l 1 , 19 91 ,and en ded on A ugust 30 , 199 1 .

Sam p le S ize and O u tcom e V ar iab lesW e used tre atm en t failu re as the m ajor ou tcom e var iab le . T rea t-

m en t w a s co ns ide red a fa ilu re if th e se rum b ilirub in lev el reached342 pm ol/L (2 0 m g /dL ). W e estim a ted that th is m igh t o ccu r inabo ut 5 0% of infan ts in group I (no in terven tio n) and 5% of in fan tsin g rou p 3 . B ased on th ose assum ptio ns, w e requ ired 2 3 p atien ts ine ach gro up to h ave a 9 0% ch ance o f sh ow ing a sig n if ican t d if fer -e nce be tw een gro up s I and 3 (P < .05 ). O th er o utcom e variab le ssele cte d w ere the p ro por tion of b ab ie s w ho se serum b ili rub inleve ls fell to below 231 pm ol/L (13 .5 m g/dL ) by 48 hou rs a fter thein te rven tio n an d th e ch ang e in serum b ili rub in con cen tra tio n 48hou rs af ter the in terv en tion . Th e pra ctic e in the S ard a un it is tod iscon tinu e photo the rap y when the b iliru b in leve l fa l ls b elow 231pm o l/L (1 3 .5 m g /dL ).

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ARTICLES 47 1

S t a tis t ic a l M et h od sWe compared the continuous background variables across the

four interventio ns us ing one -w ay analy sis o f variance proceduresin BMD P for binary backg round variables , S tatX act7 w as used toobtain ex act P values for the Pearson i statis tic . For the outcomevariable chang e in bil irubin leve l, w e first used the W elch F te stsfor one-w ay analys is of v ariance ; since this result w as sig nif icant(P < .00 01) , and the v ariances o f the change s do not appear equal ,t tests for unequal variances w ere then used to compare pairs ofthe rapies. For binary outcomes, S tatX ac t w as used to obtain anov erall ex ac t P value for all fo ur therapies ; tw o -tailed Fisher exac ttests fo r pairs of treatments w ere used as a fo llow -up analys is forthe se outcome variables. To correct for multiple comparisons , re -suits for fo l low -up analy se s w ere compared w ith a more stringentcutoff po int us ing the B onferroni co rrec tio n.9 For six comparisons,a P value 0 08 3 is required to reach sig nif icance at the .0 5 level(.05 /6) and a P value < .01 34 is required to reach sig nificance at the.1 0 leve l. Confidence inte rvals fo r relativ e risk w ere obtained bymaking appropriate chang es (g iven in Fle iss#{ 17 6} ) to the exac t conf i-dence interval fo r the odds ratio pro vided by S tatX ac t.

R E S U L T SOf 2897 liv ebirths , 1 685 term infants met the crite -

na for inc lusion. Of these , 12 6 (7 .4%) had a serumbilirubin concentration 29 1 pmol/L (1 7 mg /dL).This represented 4 .3% of all liv ebirths during thestudy period. One o f these infants did no t re turn fo rfo llow -up, leav ing 125 infants available for s tudy .(Eleven o ther infants w ere jaundiced at discharge[serum bilirubin 34pmol/L (2 mg/dL).

Table I lists the clinical charac teristic s o f the studypopulatio ns. There w ere no significant differencesbetw een the groups w ith respec t to birth w e ight,g estation, sex ratio s, method of deliv ery , parity , pre -sentation (vertex or breech), history of sibling w ithjaundice, or serum bilirubin lev el at entry into thestudy . Table 2 show s the e ffec t o f the different inter-ventio ns and Table 3 the be tw een-group statisticalcomparisons. The ov erall P values comparing all fourtherapie s for the three outcom e variables w ere .06 85fo r serum bilirubin leve l 3 42 pmo l/L, .0 003 for se-

rum bilirubin lev el < 231 pmol/L by 48 hours, and< .000 1 fo r the chang e in serum bilirubin concentra-tion.

W hen pho to therapy w as used (in groups 3 and 4),the dec line in serum bilirubin lev el w as sig nificantlylarg er and a signif icantly greater propo rtion had bi-lirubin leve ls o f


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TABLE 2 . E ffect o f In te rven tio ns*

472 HYPERB IL IRUB IN EM IA IN THE BREAST -FED NEW BORN

Group t1 2 3 4

No . 2 5 26 38 36Se rum bili rub in 342 pm o l/L 6 (24 ) 5 (19 .2 ) 1 (3) 5 (1 3.9 )Se rum bili rub in < 231 pm ol/L by 48 h4 0 5 (19 .2 ) 17 (44 .7) 15 (4 1 .6 )zB i l i r ub in at 48 h , pm ol/L -17 (32 ) -34 (51) -77 (41) -6 5 (3 4)* D ata are shown a s N o . (% ) or m ean (SD ). I m g/dL = 1 7.1 pm ol/L .t G ro ups : (1 ) con tinu e b rea st- feed ing ; (2 ) d is con tin ue bre ast- feed in g , sub sti tu te form u la; (3 ) d iscon -tin ue bre ast-fe ed in g , sub sti tu te form ula , adm in is ter pho to therapy ; (4) co n tinue b rea st-feed ing , adm in-i st er p ho to th er ap y.1: F orty -e igh t ho urs after in it ia tion of in terven tio n .

TABLE 3. S ta t istical C om parison o f G rou ps b y O utcom e V a riab les*Gr o up t

P

B iliru b in 34 2 pm ol/L

RR : 9 5% CL

Bil i rub in < 231 pm ol/Lby48h

Bil i rub inat48h

RR 95% CL I v s 2 .743 0 .80 0 .22 , 2 .75 .0 51 J .145I vs 3 .013 0 .11 0 .002 5 , 0 .83 .0001 J


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A s pediatric ians, w e should do ev erything in ourp ow er t o en co u r a ge b r ea s t -feed in g . On e w ay of do -ing this is to encourag e mo thers o f jaundiced infantsto continue nursing . If , neverthe less , intervention isdeem ed necessary , these data can be used to counse lparents about the options for treatment.

A C K N OW L E D G M E N T SW e t h a n k M ar y C offey , P h D , fo r h er st a t is t ic a l a ssis t a n ce, D r s

Maria del Rosario Castifle iras and B lanca Ruiz for he lp w ith lab-o ratory measurements, and Medix ICSA for prov iding the photo-therapy e quipm ent.

R E F E R E N C E S1 . Schne ide r A P. B reast m ilk jaundice in the newborn: a real entity . J AMA .

1986;255:3270-32742 . Maise ls M J, G ifford K , A ntle CE, at al. N ormal serum bilirubin levels in

the new bo rn and the e ffe ct of breas t fe eding . Pedia tr ic s . 1986;78:837-8433 . Eggert LD , Pollary RA , Folland DS ,Jung A L Home pho totherapy treat-

ment o f neonatal jaundic e. Ped ia trics. 1985;76:579-5844 . Maise ls M J, Kring E. Risk o f sepsis in new borns w ith seve re hyperbi-

lirubinemia. Pedia tr ic s . 1992;90:741-7435. Le jarrag a H, D iaz B alve C. Grow th chart o f 14 01 healthy newborns in a

maternity ho spital of B ueno s A ire s. C hild H osp J. 1976;15:19-21

6 . D ix on W J. BMDP Sta tis tic a l So f twa re . B erkeley , CA : Unive rsity o f Cali-fo rnia Pre ss; 1990

7. Mehta CR, Patel N R. S ta tX ac t M an ual. Cambridge, MA : CYTEL Soft-w are C orp ora ti on ; 1991

8. Miller RG. B eyond ANOVA : B as ics o f A pp lie d S ta tistic s. N ew Y ork, NY :John W iley & Sons; 1986:57

9 . Snedecor GW , Cochran WG. S ta tis tic al M eth od s. 7th ed. Ames, IA : Iow aState U nive rsity Press ; 198 0:1 66

10 . Fleis s JL. S ta tistica l M e thod s for R a te s a nd P rop ort ions . 2nd ed. N ew Y ork,NY : John W iley & Sons; 1 981 :75

11 . N ewman TB , M aisels M J. Evaluatio n o f jaundic e in the term newborn:a kinder, g entler approach. Pedia tr ic s . 1992;89:809-818

12 . D e Carvalho M , Klaus MH, Merkatz RB . Frequency of breas tfe edingand se rum bilirubin co nce ntratio n. A JDC . 1982;136:737-73813 . Y amauchi Y , Y amanouchi I. B reast-fe eding frequency during the first 24

hours afte r birth in full-term neonates . Pedia tr ic s . 1990;86:171-17514 . V ain N , A cquav ita AM , Maise ls M J, de B lanco NV Cohen A , D iGreg re-

gorio J. The e ffe ct of breast feeding frequency on serum bilirubin levels.P edia tr R e s. 1990;27:259A

15 . Amato M , How ald H , von Muralt G. Interruption o f breast feedingversus photo therapy as treatment of hyperbilirubinem ia in full terminfants. H elv P aed ia tr A c ta . 1985;40:127-131

16 . Osborn LM , B olus R . B reast fe eding and jaundic e in the firs t w eek o f life .J Fam P ra ct. 1985;20:475-480

17 . Ho ltrop PC, Ruedisuel i K , Maisels M J. D ouble v ersus sing le pho tother-apy in low birth w eight infants. Pedia tr ic s . 199290:674-677

TH E D ISR U P T IV E BE H AV IO R AL D ISO R D E R IN C H IL DR E N ANDADO L E SC E NT S : C O M O R B ID IT Y AND C L IN I C A L C O UR SE

Martin B . Ke ller, M D , P h ilip W . L a vor i, P hD , W illia m R . B ea r d slee, M D ,J o a n n e W u n d er , BA , C a r l E . S ch w a r t z , M D , J oa n R ot h , B S ,

a n d J osep h B ied e r m a n , M D

Abstrac t. Comorbidity , tim e to recovery , rate o f chronic ity , and probability o frecurrence fo llow ing recovery w ere studied in 51 children diagnosed w ith attentiond e ficit d iso r d er , co n d u ct d iso r d e r , a n d o p p osit ion a l d efia n t d iso r d e r . T h ir t y - t h r eep e r cen t o f t h e ch ild r en had tw o o f the abov e diagnoses, and one child had all threediagno ses . The mean duration of attention de fic it disorder w as 8 years up to thet im e of t h e in t er v iew ; t h e m ea n d u r a t io n of o p p osit ion a l d e fia n t d iso r d e r w a s 4 .5y ears, and the mean duration o f conduct disorder w as 3 y ears. Life-table e stimatesshow ed that 14% of the children w ould not have recov ered 15 years after the onseto f the ir diso rder. Rates o f recurrence w ere high fo llow ing recov ery from each oft h ese d iso r de r s. J . Am . Acad . C h ild A do lesc. P sych ia tr y. 1992; 3 1(2 );2 04-20 9 . Key -W or d s: d is r u p t ive b eh a v io r a l d iso r d e r , ch ild r en , a d o le scen t s .

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1993;91;470Pediatrics

C. Martinez, Jr and M. Jeffrey MaiselsJorge C. Martinez, Lydia Otheguy, Horacio Garcia, Monica Savorani, Beatriz Mogni, Jorge

InterventionsHyperbilirubinemia in the Breast-Fed Newborn: A Controlled Trial of Four

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