198 Rosta et al., Time-limited phototherapy

J. Perinat. Med.3 (1975) 198

Time-limited phototherapy of term newboms inABO hemolytic disease and hyperbilirubinaemia

J. Rosta, Z. Makoi, D. Bekefi, E. Varady

Ist. Department of Pediatrics, Semmelweis University, Medicäl SchoolBudapest/Hungary (Head: Professor Dr. F. Gerloczy)

Received September 12, 1974. Accepted December 2, 1974.

The National Academy of Sciences, USA [1], haspublished a preliminary report concerning thephototherapy of newborn infants. Despite 16years of favorable experience with this "em-pirical therapeutic procedure" it was suggestedthat this therapy "to be kept to a minimum untilmore is known about its long-term effects".LUCEY [10] called for a more balanced approach.It has to be admitted, that there are no uniformlyaccepted indications for phototherapy atpresent and that its role in the prevention andtreatment of neonatal jaundice is still not clear.Earlier studies have reported on pfophylacticlight tteatment of preterm babies when Irradiationwas started immediately after birth [11,18],Later the 10 mg/100 ml serum indirect bilirubinlevel was proposed äs an indication [5,6].Efficacy was assessed by the change in the meansof daily serum bilirubin levels, compaired tocontrols and the frequency of the necessity inperforming an exchange transfusion despiteIrradiation [7, 21].

l Purpose of the studyAt the Ist Department of Pediatrics, SEMMEL-WEIS University Medicäl School, Budapest, a

"controlled clinical study was set up to findreasonable indications for the phototherapyof term newborns. In view of the controversyon long-term side effects [3, 9], ifradiation waslimited. Though an appropriate°spectroradiometer[12,15] was not available, accurate registration

Curriculum vitaeDr.Budapest (now SEMMELWEIS)University Medicäl School in1950. Since then working tbereat the Ist Department of Pe-diatrics and 2nd Departmentof Obstetrics, in the last 12years äs Head of the NeonatalUnit. Electedin 1964 äs secre-tary, laterfirst secretary of theHungarian Pediatric Associa-tion. Editor of Hungarian andinternational Journals and textbooks on neonatal medicine. Mainresearch int er es t in jaundice of newborns. Thesis9 more t h an 100publications, papers given at international congresses and panelsdeal mostly with perinatal bilirubin metabolism and body com-position.

of methodological details paved the way forfuture rettospective dosimetry.

2 Material and methodsOur material consisted of term babies with abirth weight above 2500g (including 3 casesbetween 2350 and 2500g) and a gestationalage over 37 completed weeks. Under suchcifcumstances phototherapy was indicated onlyat a serum bilirubin value 4—6.0 mg/100 mllower than the critical level calling for ex-change transfusion according to our pre-viously designed diagram for the indicationof exchange transfusion [17]. In both indicationalprograms separate limits were ofFered according

J. Perinat. Med. 3 (1975)

Rosta et al., Time-limited phototherapy 199

to the various types of jaundice, intrauterinedevelopment, postnatal age and neurologicalfindings (Fig. 1).

l

l

20-

18-

g.

4 _

y m

/

Xχ

XχX

Xχχ

***s~

χ̂̂^— -^^^

^^^^*-A N

NG

-B ANG

. r nUfl

^

ABC

o i$o~immunizationormal birth weightesfationo/ age > 38 weBksBO-iso-immunization (?)ormal /Iow- birth - weightestat/ofjo/ age 36-3Θ weeksh-iso-immunizationiw-birth- weightwtattonal oge <36weeks

\2nd 3rd 4th Sth day

Fig. l. Indications for phototherapy in term and near-termjaundiced infants.

The diagram covers the first five days of life slater Irradiation was not initiated.Our guide-lines were based on the hypothesisthat they provide sufficient time for the light toexert its effect by reversing or at least deceleratingbilirubin accumulation and reducing serum levels,whereby exchange transfusions can be avoided.If a bilirubin level surpassed the limit for theindication of an exchange transfusion, photo-therapy was considered inefficient and thuscontraindicated. Light therapy was not used onfebrile newborns, if septicemia or hepatitis wassuspected or when metabolic disease was present.In such cases glucose-albumin infusions werepreferred.For phototherapy a MEDICOR KFL-21 Instrumentequipped with eight 20 W blue TUNGSRAMlamps (450 nm wave-length peak emission) wasused. The lamps were fixed 80 cm from the bedlevel. Ultraviolet waves (below 380 nm) wereshielded by a Plexiglas plate or by the top of theincubator [22]. The eyes of the infants were pro-tected with thick gauze pads or dark glasses.Irradiation was done for 18 hours daily con-sisting of three 6-hour periods with two-hourintervals until a marked drop in the serumindirect bilirubin level was noted. The changeback and fro from prone to supine position,rectal temperature, bowel movements, voiding

of urine, fluid intake (5% glucose water) andany unusual events were recorded every houron a flowsheet. Serum bilirubin levels weredetermined at least twice daily during Irradiationand every 48 hours afterwards, to follow serumbilirubin concentrations.During the first year of "limited" phototherapy(May l, 1973 to May l, 1974) 33 newborns weretreated according to the above criteria. TheirSerologie and hematologic findings proved in17 cases ABO-hemolytic disease, whereas 16cases without any sign of hemolytic diseasewere grouped s "hyperbilirubinemia". Treat-ment of Rh-hemolytic babies is not discussed inthis paper.Selected data of the patients and their treatmentare given in Tab. I.A control group of 44 comparable cases wasgathered from newborns treated before May l,1973, along the same line, who did not receivephototherapy. The control babies were nearlyidentical in weight (± 250 g) and practicallyidentical in serum bilirubin level (±1.0 mgper 100 ml) with the treated ones at the point oftime (± 6 hours) when Irradiation of the latterwas begun.

3 ResultsExchange transfusion, based on identical indica-tions in both periods before and after May, 1973,was necessary in 13 of the 44 babies treatedwithout, and only 3 of the 33 infants treatedwith phototherapy (Tab. II). One of the un-successful cases proved to be a metabolic diseaselater.Means and Standard deviations of serum bilirubinlevels are shown in Fig. 2—3.The bilirubin levels of the treated babieswere lower during the period of Irradiation.This diflerence was significant on the second andthird day of life, in the cases of ABO-hemolyticdisease, and from 4th day of life in cases of hyper-bilirubinemia, respectively. The lower values ofthe Standard deviation in treated babies areparticularly important, s the indication forexchange transfusion is related to this value.Successful Irradiation lasted in the average44 hours (30—72 hours) in cases of ABO-

J. Perinat. Med. 3 (1975) 14*

200 Rosta et al., Time-limited phototherapy

Tab. I. Data of newborns subjected to phototherapy.

PatientNo.

123456789

101112131415161718192021222324252627282930313233

Comments:Result*:

Sex

fmffffmffffffmmmmfmfmmmmfffffmmmm

pos =neg =gern =sfd =

Birthweight[g]

32003100380026DO2350 gern320036002850270035003300290027003100330041003150310031003300280038003800280036502400 sfd265029002350 sfd2450 sfd315035002600

according to [17] noexchange transfusiontwinsmall for dates infant,

Blood-groupmother/child

0 B0 A0 B0 A0 A0 A0 A0 A0 A0 A0 A0 A0 B0 A0 A0 B0 B0 00 0B AA AB 0A AB BAB AA AA ABB BA 0B AA AA 00 0

exchange transfusionwas performed

gestational age over

PhototherapyOnset Duration Indirect serumage [hours] bilirubin level

[hours] [mg/100 ml]initial maximum

2872245096167248968124482824364872

116849686729696867450848496508496

723342304230326042336050304836486034483048363418503030424248664212

16.518.213.617.021.215.220.017.619.821.416.415.814.210.815.518.420.020.820.523.017.816.418.717.026.018.519.023.215.518.516.821.519.5 .

20.5idem18.017.6idem23.520.818.020.022.527.523.414.418.6idem21.420.4idem23.6idem19.818.0idemidemidem20.020.025.020.519.023.0idem24.5

Result*

posposposposposnegposposposposnegposposposposposposposposposposposposposposposposposposposposposneg

was necessary

37 completed weeks

hemolytic disease and 40 hours (18—50 hours)in cases of idiopathic hyperbilirubinemia,respectively.

4 CommentIndication for .phototherapy in term infants is acontroversial issue. The committee report, citedalready in the introduction [1], suggested serumindirect bilirubin values below the 20 mg/100 mllimit to be carefully considered before indicating

Irradiation in term babies. In a diagram plottedby A. BROWN [2] and slightly modified byMAISELS [13] the following dye levels wouldinvocate phototherapy: 5.0—9.0 mg/100 ml onthe first, 10.0—14.0 mg/100 ml on the second,and 10.0—19.0 mg/100 ml on the 3rd and 4thday of life. According to this diagram the sameindications are valid for babies with a birthweight below and above 2500g. Some morerecent papers [4,14] on the other band take

J. Perinat. Med, 3 (1975)

Rosta et al., Timc-limited phototherapy 201

Tab. II. Number of exchange transfusions with and withoutphototherapy.

ABO hemolytic diseasewith phototherapywithout phototherapy

(controls)Hyperbilirubinemiawith phototherapywithout phototherapy

(controls)

Number ofpatients

1728

1616

Number ofexchange

transfusions

29

14

25-

20-

15-*$

ABO /ncompat/Wfuo phototheropy• confrol

1 2 3 4 5 doy

Fig. 2. Serum indirect bilirubin levels — means and± l SD — in ABO hemolytic disease with and withoutphototherapy.

Huperbilirubmemfao phofotherapy• confrol

·\

20-i15-

3 4 5 day

Fig. 3. Serum indirect bilirubin levels — means and± l SD — in cases of hyperbilirubinemia with and with-out phototherapy.

phototherapy into consideration if serum bilirubinvalues fall into the intermediate zone on Po-LACEK'S diagram for indicating an exchangetransfusion [16].Our phototherapy diagram is similar to thatof POLACEK and differs from BROWN'S by givingcontinuously rising limit-curves and notstepwise changing ones. The sudden rise of5.0 mg/100 ml at the end of each 24 hours ofpostnatal life makes BROWN'S diagram difficultto adapt to these special periods.Another advantage of our diagram is the possi-bility of using separate guide-lines accordingto the etiology of jaundice and the gestationalage (maturity) of the newborn infant. It hasto be stressed, however, that babies not reachingtheir completed 35 weeks of gestation or weighingless than 2000g have to be judged for photo-therapy or exchange transfusion individually andaccording to another diagram.In cases where the risk of kernicterus is high(if hypoxia, acidosis, hypothermia is present, ordrugs competing for albumin binding sites wereused), phototherapy should be begun at lowerindicative values.There are few papers dealing with phototherapyin ABO-hemolytic disease. SISSON et al. [19]and KAPLAN and coworkers [7] reported favor-able results. Our experience confirms theirobservations.TABB et al. were the first to suggest a time-limited phototherapy of 12—48 hours toprevent hyperbilirubinemia in preterm in-fants [20], We have attained a good effect withtherapeutic Irradiation of ABO-isoimmunizedand hyperbilirubinemic term infants, whentherapy was begun only at relatively high serumbilirubin levels. The originally proposed irradia-tion, lasting 144 hours seems excessive in terminfants [8].Short term phototherapy has two corner-stones:reserved indications and the lifting of Irradiationäs soon äs an evident fall or harmless Stagnationof bilirubin level is observed. We were neverforced to resume phototherapy on account ofa re-elevation of the bilirubin level, when theIrradiation was once finished.

J. Perinat. Med. 3 (1975)

202 Rosta et al, Time-limited phototherapy

Summary"Limited" phototherapy was used to treat füll term babieswith and without ABO-isoimmunization. Serum indirectbilirubin levels calling for Irradiation during the firstfive days of life are summarized in a diagram (Fig. 1).Separate indications were given for babies with difFerentetiologies of jaundice, maturity (gestational age and birth-weight) and indicational levels were correlated with thepostnatal age (days and hours) of the infant.

After a fall or harmless Stagnation of bilirubin levels irradia-tion was stopped.

Clinical assessment of the treatment of 17 babies withABO-isoimmunization, and 16 newborns without itand with hyperbilirubinemia is given in detail (Tab.II and Figs. 2 and 3).

Results were compaired with the outcome of treatmentof 44 newborns who received the same care in every

respect, but phototherapy. Tfhese control cases, selectedby pairs, were similar.Exchange transfusion, based on identical indications,was necessary in 13 of the 44 babies treated without,and only 3 of the 33 infants treated with phototherapy.The bilirubin levels of the treated babies were lower duringthe whole course of the Irradiation. The difference in favorof the treated babies was significant on the second andthird days of life in cases of ABO-hemolytic disease, andfrom the 4th day of life in cases of hyperbilirubinemia.The values of Standard deviätions, important in view ofthe indication for exchange transfusion were also lower inthe light treated babies.Successful Irradiation required on average of 44 hours(30—72 hours) in cases of ABO-isoimmunization and40 hours (18—50 hours) in cases of hyperbilirubinemia,respectively. Re^elevation of the bilirubin level after finish-ing phototherapy was not observed.

Keywords: ABO-hemolytic disease, hyperbilirubinemia, neonatal jaundice, phototherapy.

ZusammenfassungZeitlich begrenzte Phototherapie bei reifen Neuge-borenen (hämolytische Erkrankung im ABO-Systemund Hyperbilirubinämie)Die zeitlich begrenzte Phototherapie wurde eingesetzt umam Termin geborene Kinder mit und ohne ABO-Isoim-munisierung zu behandeln. Die indirekten Serum-Bili-rubinspiegel, welche für die Bestrahlung während derersten 5 Lebenstage maßgeblich waren, sind in einemDiagramm zusammengefaßt (Fig. 1). Neugeborene mitGelbsucht verschiedener Ätiologien wurden in getrenntenIndikationsgruppen zusammengefaßt, desgleichen jene mitunterschiedlicher Reife, unterschiedlichem Gestationsalterund differentem Geburtsgewicht. Die Indikationsgruppenwurden zum postnatalen Alter des Neugeborenen (in Tagenund Stunden) korreliert.Nach einem definitiven Abfall oder bei gefahrloser Konstanzder Bilirubinspiegel, wurde die Bestrahlung gestoppt.Die klinischen Behandlungsresultate von 17 Neugebore-nen mit ABO-Isoimmunisation und von 16 Neuge-borenen ohne dieselbe jedoch mit Hyperbilirubinämiewerden in Tab. II und Fig. 2 und 3 im Detail angegeben.Die Resultate wurden mit dem Behandlungsergebnis von

44 Neugeborenen verglichen, die in jeder Hinsicht dieselbeBehandlung erfahren haben mit Ausnahme der Photöthera-pie. Diese Kontrollfälle, welche paarweise ausgelesen wur^den, waren ähnlich.Eine Austauschtransfusion wurde bei ein und derselbenIndikationsstellung in 13 Fällen der 44 Neugeborenen ohneund nur in 3 von 33 Kindern mit erfolgter Phototherapienotwendig. Die Bilirubinspiegel der bestrahlten Neu-geborenen waren während der gesamten Bestrahlungs-periode niedriger. Die Differenz zugunsten der behan-delten Neugeborenen war signifikant beim Vergleich des2. und 3. Lebenstages bei den ABO-Inkompatibilitäten unddes 4. Lebenstages bei den Fällen mit Hyperbilirubinämie.Die numerischen Werte der Standarddeviationen, die hin-sichtlich der Indikationsstellung für die Austauschtrans-fusion wichtig sind, waren ebenfalls niedriger bei den mitLicht behandelten Neonaten.Die erfolgreiche Bestrahlung belief sich im Mittel auf44 Stunden (minimal 30, maximal 72 Stunden) bei denFällen mit ABO-Isoimmunisation, auf 40 Stunden(18 bis 50 Stunden) bei Fällen mit Hyperbilirubinämie.Ein Wiederansteigen des Bilirubinspiegels nach Abschlußder Phototherapie wurde nicht beobachtet.

Schlüsselwörter: ABO-Inkompatibilität, Gelbsucht des Neonaten, Hyperbilirubinämie, Phototherapie.

ResumePhototherapie ä temps limit£ des b6bes n£s a terme(maladie hemolytique ABO et hyperbilirubinemie)La photothorapie «limitee» a ete utilisee pour traiter lesbebes nes . terme avec et sans isoimmunisation ABO. Lestaux de bilirubine indirecte du serum indiquant lan£cessite d'irradiation durant les cinq premiers jours

apres la naissance ont £t£ class6es dans im diagramme(Fig. 1). Des indications separees ont 6te donn6es pourles nouveaux-nes ayant des 6tiologies d'ictere differentes;maturite (age de gestation et poids la naissance) et lestaux indicationnels ont ete corrolationnes avec l'äge post-natal (jours et heures) de l'enfant.

J. Perinat. Med. 3 (1975)

Rosta et al., Time-limited photothcrapy 203

L'irradiation a dto stoppoe apres une baisse ou unc Stagna-tion non mauvaise des taux de bilirubine.L'ovaluation cliniquc du traitemcnt de 17 b£b£s avcc iso-immunisation ABO et de 16 nouveaux-n£s sans iso-immunisation ABO/hyperbilirubinlmie est donnoe defagon dotailloe (Tab. II et Fig. 2 et 3).Les re*sultats ont e*t£ compards avcc l'issue du traitemcntde 44 nouveaux-nos ayant re$u les marnes soins moins laphotothorapie. Ces cas de contröle, solectionnös parpaires, otaient similaircs.La transfusion d'achange, basoe sur des indications iden-tiques, a nocessaire chez 13 des 44 nouveaux-ne*sayant £t£ trait£s sans photothorapie et seulement chez3 des 33 b6b£s traitos avec photothorapie.

Les taux de bilirubine des b6bos trait6s ont eto moins£levos durant tout le temps de Pirradiation. La difforenceen faveur des bobos traitos s'cst rovdlde significative lesdcuxicme et troisicme jours apres la naissance dans les casde maladic homolytiquc ABO et a partir du quatrieme jourdans les cas d'hyperbilirubinomie. Les valeurs des devia-tions Standard, importantes pour Pindication d'une trans-fusion d'öchange, ont donc 6t6 moins olevoes chez lesnouveaux-nos traites par photothorapie.Une Irradiation re"ussie fut dur£e rcspectivement a uncmoyenne de 44 heures (30—72 heures) dans les cas d'iso-immunisation ABO et de 40 heures (18—50 heures)dans les cas d'hyperbilirubinomie. Aucune remontoe dutaux de bilirubine apres phototherapie n'a 6te observoe.

Mots-clos: Hyperbilirubinomie, ictere naonatal, maladic homolytique ABO, photothorapie.

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[2] BROWN, A. K.: Neonatal jaundice. In: BEHRMAN, R.E.: The diagnosis and treatment of diseases of theneonatal infant. Mosby, St. Louis 1973

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[7] KAPLAN, E., F. HERZ, E. SCHEYE, L. D. ROBINSONJr.: Phototherapy in ABO hemolytic disease of thenewborn infant. J. Pediat. 79 (1971) 911

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[9] LUCEY, J. F.: The effect of light on the newly borninfant. J. Perinat. Med. l (1973) 147

[10] LUCEY, J. F.: Another view of phototherapy. Com-ment. J. Pediat. 84 (1974) 14

[11] LUCEY, J. F., M. FERREIO, J. HEWITT: Prevention ofhyperbilirubinemia of prematurity by phototherapy.Pediatrics 41 (1968) 1047

[12] LUND, T. H., J. GUDUM, W. KOP: The "blue" meter,a photometer designed to measure light emissionduring phototherapy of hyperbilirubinaemia. Actapaediat. scand. 63 (1974) 89

[13] MAISELS, M.: Bilirubin. Pediat. Clin. N. Amer. 19(1972) 447

[14] MENSEL, K., K. SCHAMBACH: Fototherapie bei ikte-rischen Neu- und Frühgeboernen. Dtsch. Gesundh.Wes. 29 (1974) 408

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[16] POLACEK, K.: Unser Verfahren bei der Indikations-stellung zur Austausch transfusion. Pädiat. Pädol. l(1965) 313

[17] ROSTA, J., D. BEKEFI: A new chart for indicating ex-change transfusion in neonatal hyperbilirubinaemia.Acta paediat. Acad. Sei. hung. 12 (1971) 311

[18] SCHWARZ, A., J. E. HODGMAN: Phototherapy andhyperbiiirubinemia of the premature. Amer. J. Dis.Child. 119 (1970) 473

[19] SISSON, T. R. C., N. KENDALL, S. C. GLAUSER, S.KNUTSON, E. BUNYAROVICH: Phototherapy of jaundicein newborn infants. I. ABO blood group incompati-bility. J. Pediat. 79 (1971) 904

[20] TABB, P. A., D. C. L. SA VAGE, J. INGLIS, C. H. M.WALKER: Controlled trial of phototherapy of limitedduration in the treatment of physiological hyperbili-rubinaemia in low-birth-weight infants. Lancet II(1972) 1211

[21] WONG, Y. K., B. S. B. WOOD: Relative roles of photo-therapy and phenobarbitone in treatment of nonhae-molytic neonatal jaundice. Arch. Dis. Childh. 48 (1973)704

[22] YASUNAGA, S., E. H. KEAN: The effect of plexiglas in-cubators on phototherapy. J. Pediatr. 81 (1972) 89

Dr. J. RostaÜllöi-ut 78/a1083-Budapcst/Hungary

J. Perinat. Med. 3 (1975)