PEDIATRICS (ISSN 0031 4005). Copyright © 1985 by the American Academy of Pediatrics.
Development,
Design,
and Sample
Composition
Dolores A. Bryla, MPH
From the Biometry Branch, Epidemiology and Biometry Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Following its introduction in 1947 for treatment of erythroblastosis fetalis and in 1949 for hyper-bilirubinemia, exchange transfusion became ac-cepted as the most effective means of preventing increasing serum bilirubin concentrations in the newborn infant from reaching a hazardous level.2 At that time, there was general agreement that the risk of bilirubin encephalopathy increased when serum bilirubin concentrations exceeded 20 mg/dL of serum and that this risk became greater with increasing concentrations. The safety of exchange transfusion was assessed by Boggs and Westphal’4 in 1960 and found acceptable for that time.
In 1958, Cremer et al22 reported a distinct low-ering of serum bilirubin levels in infants exposed to direct sunlight. This observation was followed by development oflight sources for exposure of infants to treat or prevent hyperbilirubinemia (photother-apy).
Although phototherapy had been used and re-ported in Europe and South America, it was not until 1968 that the first study appeared in the pediatric literature of the United States. Other studies36’41’ followed and suggested a potential role for phototherapy in the management of hyperbili-rubinemia of the newborn infant. However, these studies suffered from lack of a sufficient number of patients to accommodate appropriate statistical ad-justment procedures for the many known
confound-ing variables. Also, these studies had inadequate numbers of control infants and phototherapy-treated infants who were followed long enough to perform evaluations of the impact of the mode of therapy on such parameters as hearing, sight, speech, IQ, and behavioral performance.31’74
DEVELOPMENT OF THE STUDY
In May 1972, the National Research Council of the National Academy of Sciences established a Committee on Phototherapy in the Newborn. This Committee focused its attention on the evaluation of phototherapy as a therapeutic modality for hy-perbilirubinemia in newborn infants.9 It was the consensus of the Committee, at that time, that there was insufficient information available to de-termine the efficacy and safety of phototherapy in the treatment of hyperbilirubinemia of the new-born. Therefore, this Committee recommende&#{176} that a collaborative study be undertaken to generate a data set with an appropriate experimental design on which to base definitive conclusions.
In response to the Committee’s recommendation, the Scientific Director of the National Institute of Child Health and Human Development (NICHD) appointed an ad hoc advisory committee on pho-totherapy composed of pediatricians and others engaged in research in the field. This committee was charged to advise the Institute on the need for additional research and to consider experimental protocols designed to meet these needs.
In response to this advisory committee’s recom-mendation, the Scientific Director of NICHD un-dertook the development of a study to address two of the most important questions: (1) Is photother-apy effective in preventing brain injury from hy-perbilirubinemia, when employed to lower serum bilirubin levels?, and (2) Is phototherapy as effec-tive as exchange transfusion at predetermined se-rum bilirubin levels for preventing brain damage from neonatal hyperbilirubinemia? A protocol was designed cooperatively by the advisory committee and NICHD staff.
DESIGN OF THE STUDY
I. Entry to Study
In each hospital, parental consent was obtained for inclusion in the study of newborns eligible for participation (either as phototherapy-treated pa-tients or control patients).
Infants were eligible if: (1) birth weight was less than 2,000 g; or (2) birth weight was between 2,000 to 2,499 g and serum bilirubin levels reached 10 mg/dL within the first 96 hours after birth; or (3) birth weight was 2,500 g or greater and the serum bilirubin levels reached 13 mg/dL in the first 96 hours after birth. (Prior to October 1974, the level of bilirubin for accession in the greater than 2,500 g weight range was 15 mg/dL.)
Infants with the following conditions were ex-cluded from the study: (1) infants with Rh hemo-lytic disease, who had received an intrauterine transfusion or had a capillary hemoglobin less than
12 g/dL in the first 24 hours after birth, or whose serum bilirubin concentration exceeded 10 mg/dL in the first 24 hours of life, and (2) infants with conditions or anomalies (such as severe congenital CNS or heart malformations) whose care, in the opinion of the investigator, would be compromised by strict adherence to the protocol.
II. Methods of Entry of Infants to Treatment or Control Groups
The Biometry Branch, NICHD, fulfilled the role of Data Coordinating Center for the study. Infants were randomly assigned to phototherapy or to con-ventional therapy by the use of a table of random numbers. Sealed manila envelopes with an assign-ment card within were distributed to each partici-pating center. After parental consent was obtained, an envelope was to be opened by the principal investigator for each infant to determine the in-fant’s assignment. Each also contained an assigned individual identification code.
III. Initial Data Required for All Infants
Bilirubin levels (direct and indirect) were ob-tained at 24 ± 12 hours for all infants weighing less than 2,000 g, and at the time of entry into the study for all other infants. Blood type, and Rh, were determined and Coombs test was performed at or before entry to study. Serum albumin levels were determined at time of bilirubin determination. Hematocrit and reticulocyte count were performed at time of bilirubin determination. Bilirubin bind-ing capacity was checked at the same time as bili-rubin determination. Screening for glucose-6-phos-phate dehydrogenase (G-6-PD) was performed at or before entry to study.
Each laboratory used the Jendrassik and Grof
method44 for bilirubin determination. The agree-ment between laboratories was checked monthly by use of Versatol Bilirubin (General Diagnostics, Morris Plains, NJ) standards (5 and 20 mg/dL) and an unknown standard supplied by NICHD.
IV. Subsequent Laboratory Data Required
Direct and total bilirubin determinations were performed every 24 hours for the six days following entry, or more often if indicated. Serum albumin and hematocrit levels and serum for bilirubin bind-ing studies were obtained daily at 24-hour intervals. Reticulocyte count was obtained at 48 ± 12 hours after entry into the study.
V. Procedure for Phototherapy-Treated Infants
Phototherapy was administered continuously. The lights were not off more than 30 minutes per four-hour period for feeding, bathing, phelebotomy, or parent visiting. Time of initiation of photother-apy was as follows: For infants weighing less than 2,000 g (group A), therapy began at 24 ± 12 hours after birth. For treated infants with birth weight between 2,000 and 2,499 g (group B) phototherapy began as soon as possible after the bilirubin level reached 10 mg/dL in the first 96 hours of life. For infants weighing more than 2,500 g (group C), pho-totherapy began at the time the bilirubin level reached 13 mg/dL in the first 96 hours.
Duration of phototherapy was 96 hours for all infants except those in groups B and C in which phototherapy could be discontinued earlier if the morning bilirubin level reached 5 mg/dL (group B) and 8 mg/dL (group C).
Laboratory tests continued for 48 hours after termination of phototherapy. Phototherapy units (Air Shields, Hatboro, PA) were used with West-inghouse daylight fluorescent bulbs. Distance from the top of the light unit to the pad of the bassinet or incubator was maintained at a distance between 35 and 55 cm (14 and 22 in). The bulbs were changed after 2,000 hours of use. A Beckman light monitoring badge was attached to the infant’s thorax so as to remain between the infant and the phototherapy unit, and it was thus exposed to the light source at all times. The badge was checked with a Beckman Photodosimeter initially and at 24-hour intervals during phototherapy, and optical density was recorded. Further discussion of the badges is presented by Scheidt et a! (p 437).
VI. Procedure for Control Infants
The infants who did not receive treatment were kept at sufficient distance from treated infants so that they received minima! additional light expo-sure from the phototherapy units. These infants were monitored for light exposure using the Beck-man badge system in the same way as the photo-therapy-treated infants were monitored. The badge was placed on the rim of the incubator or on the mattress. Other measures to lower bi!irubin levels, such as administering ph#{233}nobarbital or agar, were not used.
VII. Other Infant Care
All infants received standard care practices in the nursery. The infants who received phototherapy were scheduled to receive 25 mL/kg of body weight more of fluid intake than control infants. Daily weight, axi!!ary temperature, and fluid and calorie intake were recorded, as well as volume of blood withdrawn. Blood transfusions were given if clini-cally indicated; for any blood products given, the type and volume transfused were recorded.
VIII. Criteria for Exchange Transfusion
Exchange transfusion was used in both the con-trol and phototherapy groups when the serum bi!i-rubin level exceeded the values shown in Table 1. The standard-risk group is represented by those infants who had an uncomplicated course other than hyperbilirubinemia. An infant was considered in the high-risk group when one or more of the following findings was present: (1) perinatal as-phyxia (Apgar score less than 3 at five minutes); (2) respiratory distress (Pa02 less than 40 mm Hg for more than two hours); (3) acidosis (pH 7.15 or below for more than one hour); (4) persistent hy-pothermia (recta! temperature at 4 cm <35#{176}Cfor more than four hours); (5) !ow serum protein (<4 g/dL) or albumin (<2.5 g/100 mL) measured at least two times; (6) hemolysis; (7) signs of clinical or CNS deterioration, including sepsis; and (8) birth weight !ess than 1,000 g.
Any infant in either group could have an ex-change transfusion at any time if in the judgment of the physician, it was indicated, without regard to the above criteria. (Note: In the final analysis, infants who received an exchange transfusion met either standard or high-risk criteria.)
IX. Examination of Infants
Each infant in the study received a physical examination within the first 24 hours of life, with relevant prenatal, delivery, and postnatal informa-tion collected. Physical examination was repeated
TABLE 1. Serum Bilirubin Level (Milligrams per Dec-iliter) as Criterion for Exchange Transfusion
Birth Weight (g)
<1,250 1,250- 1,500- 2,000- 2,500 1,499 1,999 2,499
Standard risk 13 15 17 18 20
High risk 10 13 15 17 18
at 144 hours from entry to the study. The latter examination also reported data on the infant’s course in the hospital, including feeding behavior, stooling, vomiting, crying, activity, and alertness. Autopsy information on infants who died was ob-tained whenever possible. Follow-up examinations were performed on survivors at 1 and 6 years of age.
X. Data Analysis
The Biometry Branch, in conjunction with the Computer Science Section, NICHD, coordinated the editing and coding of the data collected at each center. Analysis of the data was performed in co-operation with the principal investigators.
XI. Supplementary Studies
gener-ally, but not always used. However, eye shields were always used. (6) Most hospitals reported no short-term adverse effects. If adverse effects were re-ported, then rash and bronze baby syndrome were the most frequent.
It was in this practice context that this trial of phototherapy was initiated.
STUDY IMPLEMENTATION
The National Institute of Child Health and Hu-man Development Randomized, Controlled Trial of Phototherapy for Neonatal Hyperbilirubinemia was initiated in April 1974. The six centers awarded contracts to conduct the study were: Albert Em-stein College of Medicine, University of Cincinnati, Schneider Childrens Hospital, Long Island Jewish-Hillside Medical Center, Medical College of Vir-ginia, Los Angeles County/University of Southern California Medical Center, and State University of New York/Downstate Medical Center. The study was funded through individual competitive awards. Patient intake was completed in 1976.
Prior to the awarding of contracts, staff of the Biometry Branch, NICHD, determined the desired sample size based on the prevalence of certain abnormalities in the nonexposed group at 1 year of age. For conditions evaluated at the 1-year exami-nation that could be measured as “normal” or normal,” the power of the study to detect increases in the percent abnormal with different sample sizes was assessed.
A sample size of 900 in each group was deter-mined to be large enough so that a relative risk of 2.2 for hearing defects between the exposed and nonexposed group could be detected 80% of the time (f3 < 0.2) while incorrectly concluding a
differ-ence between the two groups no more than 5% of the time by a two-tailed test (a = 0.05). In actuality,
the sample size obtained was smaller than originally projected, 672 infants in the phototherapy group and 667 infants in the control group. Based on this sample size, a relative risk of 2.5 can be detected
for hearing defects with the same significance at 0.05 and power of 0.8. The relative risks for a number of defects is shown in Table 2.
Basic descriptive epidemiologic data of the study are presented in Tables 3 to 7. The distribution of infants by birth weight, treatment, and institution is presented in Table 3. Within each institution, the distribution of phototherapy-treated infants and control infants is evenly distributed by birth weight category as expected based on the random-ization procedure. The varying proportions of study infants by birth weight in the six different institu-tions are also shown in Table 3. Overall, 69% of study infants had birth weight less than 2,000 g. However, in one institution (Medical College of Virginia) 93% of the study infants had birth weight less than 2,000 g, and in another institution (Uni-versity of Southern California) only 49% of the study infants had birth weight less than 2,000 g. These varying proportions reflect the different birth populations at the six institutions according to varying racial, ethnic, demographic, and other factors that predispose for low-birth-weight deliv-eries.
Characteristics of the entire sample including race, sex, gestational age based on the last men-strual period, and age at entry are presented in
TABLE 2. Relative Risks Detectable with Tests of Sig-nificance at 0.05 and Power of 0.8 with Total Sample Sizes (Treatment Plus Control Groups) of 1,200 or 1,800 Patients
Defect Prevalence of Relative Risk
Abnormality Detectable in Control
Patients
-1,200 1,800 Patients Patients
Hearing loss 0.01
0.02
3.4 2.8
2.5 2.2
Dyskinesia
Suspect 0.01 3.4 2.8
Definite <0.001 15.7 11.0
Mental retardation 0.03 0.10
2.1 1.9
1.5 1.4
TABLE 3. Distribution of Study Inf (P) and Control (C) Groups
ants by Instit ution, Birth Weight, and Phototherapy
Birth Weight (g)
<2,000 2,000-2,499 2,500 Total
P C P C P C P C
University of Southern California University of Cincinnati
Einstein (NY)
Long Island Jewish Hospital SUNY, Downstate
Medical College of Virginia
78 77
89 93
53 51
41 42
52 50
149 147
20 20 64 60
29 23 28 36
5 6 20 16
4 7 7 6
9 10 13 13
3 5 8 5
162 157
146 152
78 73
52 55
74 73
160 157
TABLE 7. Distribution of Study Infants by Age at En-try (Hours), Birth Weight, and Phototherapy (P) and Control (C) Groups
Black
Mexican-American
Nonblack
Total
Tables 4 to 7. The race of the infant was taken to be that of the mother. In Table 4, a breakdown of study infants by race and ethnicity is shown for the three birth weight categories. Approximately 50% ofthe very low-birth-weight infants (<2,000 g) were black. There were relatively more Mexican-Amen-cans (38%) among infants who did not have low-birth-weight (2,500 g), although in the entire study, Mexican-American births represented only 19% of the infants. Randomization was not per-formed within different racial and ethnic groups. However, as shown in Table 4, a balanced assign-ment was achieved.
The distribution of study infants by sex and birth weight category is provided in Table 5. The percent of male births increases with increasing birth weight (ie, 49%, 53%, and 57%). This trend does not reflect any substantially increased risk for the male sex in requiring treatment for hyperbilirubi-nemia. The randomization procedure did not take into account the infant’s sex, and there was some imbalance in the assignment to phototherapy or control groups among the very low-birth-weight infants (<2,000 g).
A detailed breakdown of study infants by gesta-tional age in weeks and birth weight categories is shown in Table 6. Overall, 15% of study infants were of 30 or fewer weeks of gestation, and all these infants had birth weight less than 2,000 g. Of the term infants (37 weeks or more of gestation) in the study, 63% had birth weight greater than 2,500 g, 13% had birth weight between 2,000 and 2,499 g, and 24% had birth weight less than 2,000 g. This latter figure (24%) indicates that a considerable number of the study infants were small for gesta-tional age. This will be the subject of further anal-yses by Hodgman et a! (p 413).
The distribution of study infants by age at entry in hours after birth and by birth weight category is shown in Table 7 for both phototherapy-treated
infants and control infants. The median age at entry was slightly less than 24 hours for infants weighing less than 2,000 g. For infants weighing between 2,000 and 2,499 g, the median age at entry
TABLE 4. Distribution of Study Infants by Race, Birth Weight, and Phototherapy (P) and Control (C) Groups
Birth Weight (g)
<2,000 2,000- 2,500 Total 2,499
P C PC P C P C
232 224 23 18 35 36 290 278
54 58 15 17 57 49 126 124
176 178 32 36 48 51 256 265
462 460 70 71 140 136 672 667
TABLE 5. Weight, and
Distribution of Study Infants by Sex, Birth Phototherapy (P) and Control (C) Groups
Birth Weight (g)
<2,000 2,000- 2,500 Total
2,499
P C P C P C P C
Male Female
217 236 37 38 81 76 335 350
245 224 33 33 59 60 337 317
Total 462 460 70 71 140 136 672 667
TABLE 6. Distribution of Study Infants by Gestational Age (Weeks), Birth Weight, and Phototherapy (P) and Control (C) Groups
Birth Weight (g)
2,500 Total
<2, 000
C
2,000-2,499
P C P C P C
27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 11 15 21 45 44 66 59 60 53 41 15 14 3 10 4 1 10 9 39 49 45 61 58 43 54 38 22 23 4 5 1 2 3 1 5 11 9 13 22 21 11 3 12 14 6 4 1 1 1 1 2 6 10 25 22 46 23 5 1 1 5 11 18 28 45 18 9 11 15 21 45 44 67 62 66 64 69 36 51 31 57 27 6 10 9 39 49 45 63 59 55 69 64 36 55 36 51 19 9
Total 462 460 70 71 140 136 672 667
Birth W eight (g)
<2,000 2,000-2,499
>2,500 Total
P C P C P C P C
1-12 13-24 25-36 37-48 49-60 61-72 73-84 85-96 18 223 216 5 . . . . . . 24 243 186 5 1 1
. .. 2
2 9 8 10 13 18 24 15 16 12 7 5
1 . . .
2 .. .
14 9 17 14 25 21 33 33 28 36 20 23 19 225 232 30 38 57 44 27 24 245 204 29 40 48 48 28
Total 462 460 70 71 140 136 672 667
median age at entry overall was only slightly greater than 24 hours, or 1.2 days of age.
The results of bilirubin binding studies; the effect of hemolytic diseases, exchange transfusions, and metabolism; the results in the babies who were small for gestational age; and the efficacy of pho-totherapy are provided in detail in the articles that follow. Results obtained from the initial intake information and evaluation are summarized in this supplement (the immediate postnatal period).
The study was designed to obtain extensive fol-low-up data through the first 6 years of life. The evaluation at age 1 year included an eye examina-tion, hearing test, testing with Bayley Infant De-velopment Scales, a physical examination assessing growth and development, and a neurologic exami-nation. In addition, annual physical examinations including assessment of growth and development were performed. At 6 years of age, the infants
received thorough physical and neurologic exami-nations. Hearing, intelligence, and speech were also tested. Analysis of data from these follow-up ex-aminations will be reported in subsequent publica-tions.
ACKNOWLEDGMENT
The NICHD scientific staff who participated in the initiation and design of this study included: Drs Charles U. Lowe (former Scientific Director, NICHD), Duane F. Alexander, Samuel W. Greenhouse, and Daniel G. Seigel. Drs Joseph D. Schulman and James B. Sidbury served as project officers, and Drs Emanuel Landau and Frank E. Lundin, Jr, of the Center for Devices and Radiological Health, Food and Drug Administration, provided scien-tific support as well as financial support from that agency.
used in the clinical trial of phototherapy demon- considered reliable. Problems such as these must strated potential for efficiently obtaining light ex- be resolved before the photodosimeter system could posure data integrated over time for a large number reach widespread clinical usefulness.
of infants. However, because of variation in per-formance of the badge and probable deterioration
in some badges over time, the system cannot yet be REFERENCES (see page 439)
References
1. Albrecht RM, Roney PL: Phototherapy for neonatal hy-perbilirubinemia: A survey of US hospitals in 1974, in
Symposium on Biological Effects and Measurement of Light
Sources. DHHS publication No. (FDA) 81-8156, 1981, pp
55-68
2. Allen FH Jr, Diamond LK: Erythroblo.stosis Fetalis. Boston, Little, Brown and Co, 1957
3. Arkans HD, Cassady G: Estimation of unbound serum bilirubin by peroxidase assay method: Effect of exchange transfusion on unbound bilirubin and serum bindings. J Pediatr 1978;92:1001-1005
4. Bakken AF: Temporary intestinal lactase deficiency in light-treated jaundiced infants. Acta Paediatr Scand
1977;66:91-96
5. Bakken AF, Thaler MM, Schmid R: Metabolic regulation of heme catabolism and bilirubin production: I. Hormonal control of hepatic heme oxygenase activity. J Clin Invest 1972;51:530-536
6. Barrett PVD: Effects of caloric and noncaloric materials in fasting hyperbilirubinemia. Gastroenterology 1975;68:
361-369
7. Barrett PVD: Hyperbilirubinemia of fasting. JAMA 1971;217:1349-1353
8. Battaglia FC, Lubchenco LO: A practical classification of newborn infants by weight and gestational age. J Pediatr
1967;71:159
9. Behrman RE, Brown AK, Currie MR, et al: Preliminary report of the committee on phototherapy in the newborn infant. J Pediatr 1974;84:135-143
10. Behrman RE (chairman): Final Report of the Committee
on Phototherapy in the Newborn. National Academy of
Sciences, Washington, DC, 1974
11. Bevan BR, Holton JB: Inhibition of bilirubin conjugation in rat liver slices by free fatty acids, with relevance to the problem of breast milk jaundice. Clin Chim Acta 1972;41:101-107
12. Bloomer JR, Barrett PV, Rodkey FL, et al: Studies on the mechanism of fasting hyperbilirubinemia. Goat roenterology
1971;61:479-487
13. Bloomer JR, Berk PD, Vergalla J, et al: Influence of albumin on the hepatic uptake of unconjugated bilirubin.
Clin Sci 1973;45:505-516
14. Boggs TR, Westphal MC: Mortality of exchange transfu-sion. Pediatrics 1960;26:745-755
15. Bratlid D: Reserve albumin binding capacity, salicylate saturation index, and red cell binding of bilirubin in neo-natal jaundice. Arch Dis Child 1973;48:393-397
16. Brown AK, Kim MH, Wu PYK, et al: Efficacy of photo-therapy in prevention and management of neonatal hyper-bilirubinemia. Pediatrics 1985;75(suppl):393-400
17. Brown AK, McDonagh AF: Phototherapy for neonatal hyperbilirubinemia: Efficacy, mechanism and toxicity. Adv Pediatr 1980;27:341-389
18. Bryla DA: Development, design, and sample composition.
Pediatrics 1985;75(suppl):387-392
19. Cashore WJ, Gartner LM, Oh W, et al: Clinical application
of neonatal bilirubin-binding determinations: Current sta-tus. J Pediatr 1978;93:827-.832
20. Cashore WJ, Karotkin EH, Stern L, et al: The lack of effect of phototherapy on serum bilirubin-binding capacity in newborn infants. J Pediatr 1975;87:977-980
21. Chan G, Schiff D, Stern L: Competitive binding of free fatty acids and bilirubin to albumin: Differences in HBABA dye versus Sephadex G-25 interpretation of results. Clin
Biochem 1971;4:208-214
22. Cremer RJ, Parryman PW, Richards DH: Influence of light on the hyperbilirubinemia of infants. Lancet 1958;1:1094-1097
23. Dalton J, Milgrom LR, Bonnett R: Luminescence of bili-rubin. Chem Phys Lett 1979;61:242-244
24. Doumas BT, Biggs HG: Determination of serum albumin, in Cooper GR (ed): Standard Methods of Clinical Chemis-try. New York, Academic Press, 1972, pp 175-188 25. Dubowitz LMS, Dubowitz V, Goldberg C: Clinical
assess-ment of gestational age in the newborn infant. J Pediatr 1970;77:1-10
26. Edgren B, Wester P0: Effect of starvation on renal func-tion. Lancet 1970;1:613-614
27. Feisher BF, Carpio NM: Caloric intake and unconjugated hyperbilirubinemia. Gostroenterology 1975;69:42-47
28. Felsher BF, Rickard D, Redeker AG: The reciprocal rela-tion between caloric intake and the degree of hyperbili-rubinemia in Gilbert’s syndrome. N EngI J Med 1970; 283:170-172
29. Foliot A, Housset E, Ploussard JP, et al: Study of Y and Z, two cytoplasmic bilirubin binding proteins: Their devel-opment in the liver of fetal and newborn Wistar and Gunn rats. Biomedicine 1973;19:488-491
30. Friedman L, Lewis PJ, Clifton P, et al: Factors influencing the incidence of neonatal jaundice. Br Med J 1978;1:1235-1237
31. Friederiszich FK: “Co-twin control” study of the long-term effects of phototherapy, in Brown AK, Showacre J (eds):
Phototherapy for Neonatal Hyperbilirubinemia. Long-Term
Implications. DHEW publication No. (NIH) 76-1075, 1976,
pp 111-122
32. Gartner LM, Lee KS: Effect of starvation and milk feed-ing on intestinal bilirubin absorption. Gastroenterology 1979;77:A13
33. Gartner LM, Lee K, Keenan WJ, et al: Effect of photo-therapy on albumin binding of bilirubin. Pediatrics
1985;75(suppl):401-406
34. Gartner LM, Zarafu I, Kwang SL, et al: Prophylactic use of phototherapy in low-birth-weight infants: Experience with a controlled clinical trial pilot study, in Brown AK, Showacre J (eds): Phototherapy for Neonatal
Hyperbiliru-binemia: Long-Term Implications. DHEW publication No.
(NIH) 76-1075, 1976, pp 71-93
35. Gilbert A, Herscher M: Surles variations de la cholemie physiologique. Presse Med 1906;14:209-21 1
Pediat-rics1969;44:162-167
37. Glass L: Thermal effects of the bilirubin reduction lamp,
in Proceedings of the American Pediatric Society Meeting,
Atlantic City, NJ, 1969, p 51
38. Gruenwald P: Infants of low birth weight among 5,000 deliveries. Pediatrics 1964;34:157-162
39. Hegyi T, Hiatt IM, Vogl TP, et al: Use of the Beckman film badge for monitoring during phototherapy. J Pediatr 1976;89:473-474
40. Heirwegh KPM, Van Hess GP, Blanckaert N, et al: Com-parative studies on the structure of conjugated bilirubin IX- and changes in cholestasis, in Taylor W (ed): The
Hepatobiliary System. New York, Plenum Press, 1976, pp
339-354
41. Hodgman JE, Schwartz A: Phototherapy and hyperbiliru-binemia of the premature. Am J Di.s Child 1970;119:473-477
42. Hubbell JP, Drorbaugh JE, Rudolph AJ, et al: “Early” versus “late” feeding of infants of diabetic mothers. N EngI J Med 1961;265:835-837
43. Humbert JR, Abelson H, Hathaway WE, et al: Polycythe-mia in small for gest.ational age infants. J Pediatr 1969;75:812-819
44. Jendrassik K, Grof P: Vereinfachte photometrische meth-oden zur Bestimmung des Blut-Bilirubins. Biochem Z
1939;297:81
45. Johnson L, Boggs TR: Bilirubin-dependent brain damage: Incidence and indications for treatment, in Odell GB, Schaffer R, Simopoulous AP (eds): Phototherapy in the
Newborn: An Overview. Washington, DC, National
Acad-emy of Sciences, 1974, pp 122-149
46. Kapitulnik J, Kaufmann NA, Alayoff A, et al: Character-istics of a photo-product of bilirubin found in vitro and in vivo, and its effect on bilirubin binding affinity of serum, in Bergsma DL, Blondheim SH (eds): Bilirubin Metabolism
in the Newborn. New York, American Elsevier, 1976, vol
2, pp 53-60
47. Kapitulnik J, Kaufmann NA, Blondheim SH, et al: Effect of light on bilirubin binding by serum, in Brown AK, Showacre J (eds): Phototherapy for Neonatal
Hyperbiliru-binemiw Long-Term Implications. DHEW publication No.
(NIH) 76-1075, 1976, pp 191-197
48. Kapitulnik J, Valaes T, Kaufmann NA, et al: Clinical evaluation of sephadex gel filtration in the estimation of bilirubin binding in serum in neonatal jaundice. Arch Dis Child 1974;49:886
49. Kaplan E, Herz F, Scheye E, et al: Phototherapy in ABO hemolytic disease of the newborn infant. J Pediatr 1971;79:91 1
50. Karabus CD: Phototherapy of neonatal jaundice at a gen-eral children’s hospital, in Brown AK, Showacre J (eds):
Phototherapy for Neonatal Hyperbilirubinemia: Long-Term
Implications. DHEW publication No. (NIH) 76-1075, 1976,
pp 95-110
51. Keenan WJ, Novak KK, Sutherland JM, et al: Morbidity and mortality associated with exchange transfusion. Pedi-atrics 1985;75(suppl):417-421
52. Kitchen WH: Neonatal mortality in infants receiving an exchange transfusion. Aust Paediatr J 1970;6:30-40
53. Landry BA, Anderson FA: Optical radiation measurements: Instrumentation and source of error. J NatI Cancer Inst 1982;69:155-161
54. Landry R4J, Scheidt PC, Hammond RW: Ambient light and phototherapy conditions of eight neonatal care units: A summary report. Pediatrics 1985;75(suppl):434-436
55. Lee KS, Gartner LM: Bilirubin binding by plasma proteins: A critical evaluation of methods and clinical implications, in Scarpelli EM, Cosmi EV (eds): Reviews in Perinatal
Medicine. New York, Raven Press, 1978, pp 319-343
56. Lee KS, Gartner LM, Vaisman SL: Measurement of bili-rubin-albumin binding: I. Comparative analysis of four methods and four human serum albumin preparations.
Pediatr Res 1978;12:301-307
57. Lester R, Schmid R: Intestinal absorption of bile pigments: I. The enterohepatic circulation of bilirubin in the rat. J
Clin Invest 1963;42:736-746
58. Lester R, Schmid R: Intestinal absorption ofbile pigments: II. Bilirubin absorption in man. N EngI J Med
1963;269:178-182
59. Levi AJ, Gatmaitan Z, Arias IM: Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein and other anions. J Clin Invest 1969;48:2156-2167
60. Lightner DA, Wooldridge TA, McDonagh AF: Photobili-rubin: An early bilirubin photoproduct detected by absorb-ance difference spectroscopy. Proc NatI Acad Sci USA 1979;76:29-32
61. Lightner DA, Wooldridge TA, McDonagh AF: Configura-tional isomerization of bilirubin and the mechanism of jaundice phototherapy. Biochem Biophys Res Commun
1979;86:235-243
62. Lubchenco LO: Assessment of gestational age and devel-opment at birth. Pediatr Clin North Am 1970;17:125-145 63. Lubchenco LO, Searls DT, Brazie JV: Neonatal mortality
rate: Relationship to birth weight and gestational age. J
Pediatr 1972;81:814-822
64. Lucey JF, Ferreiro M, Hewitt J: Prevention of hyperbili-rubinemia of prematurity by phototherapy. Pediatrics
1968;41:1047-1054
65. Lundh B, Johansson B, Mercke C: Enhancement of heme catabolism by caloric restriction in man. Scand J Clin Lab Invest 1963;42:1300-1312
66. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem-other Rep 1966;50:163-170
67. Maurer HM, Kirkpatrick BV, McWilliams NB, et al: Pho-totherapy for hyperbilirubinemia of hemolytic disease of the newborn. Pediatrics 1985;75(suppl):407-412
68. McDonagh AF, Lightner DA, Wooldridge TA: Geometric isomerization of bilirubin IXa and its diethyl ester. JCS Chem Comm 1979;110-112
69. McDonagh AF, Palma LA, Lightner DA: Blue light and bilirubin excretion. Science 1980;208:145-151
70. McDonagh AF, Ramonas LM: Jaundice phototherapy: Mi-cro flowcell photometry reveals rapid biliary response of Gunn rats to light. Science 1978;201:829-831
71. Ockner RK, Manning JA, Poppenhausen RB, et al: A binding protein for fatty acids in cytosol of intestinal mucosa, liver, myocardium and other tissues. Science 1972;177:56-58
72. Odell GB, Brown RS, Holtzman NA: Dye-sensitized pho-tooxidation of albumin associated with a decreased capacity for protein-binding of bilirubin. Birth Defects 1970;6:31-35 73. Odell GB, Storey GNB, Rosenberg LA: Studies in
kernic-tents: III. The saturation of serum proteins with bilirubin during neonatal life and its relationship to brain damage at five years. J Pediatr 1971;76:12-21
74. Ogawa J, Ogawa Y, Onishi 5, et al: Five years’ experience in phototherapy, in Brown AK, Showacre J (eds):
Photo-therapy for Neonatal Hyperbilirubinemia: Long-Term
Im-plications. DHEW publication No. (NIH) 76-1075, 1976,
pp 49-66
75. Oh W, Karecki H: Phototherapy and insensible water loss in newborn infant. Am J Dis Child 1972;124:230-232
76. Oh W, Yao AC, Hanson JS, et al: Peripheral circulatory response to phototherapy in newborn infants. Acta Poe-diatr Scand 1973;62:49-54
77. Owens D, Sherlock 5: Diagnosis of Gilbert’s syndrome: role of reduced caloric intake tests. Br Med J 1973;3:559-563 78. Panagopoulos G, Valaes T, Doxiadis SA: Morbidity and
mortality related to exchange transfusions. J Pediatr
1969;74:247-254
79. Patel DA, Pildes RS, Behrman RE: Failure of phototherapy to reduce serum bilirubin in newborn infants. J Pediatr
1970;77:1048-1051
80. Peevy K, Wiseman HJ: ABO hemolytic disease of the newborn: Evaluation of management and identification of racial and antigenic factors. Pediatrics 1978;61:475-478 81. Perl H, Nijjar A, Ebara H, et al: Bilirubin toxicity without
82. Porter EG, Waters WJ: A rapid micromethod for measur-ing the reserve albumin binding capacity in serum from newborn infants with hyperbilirubinemia. J Lab Clin Med
1966;67:660-668
83. Porto S, Hsia DY: Mechanism of blue light on neonatal jaundice. J Pediatr 1969;74:812-813
84. Porto SO, Pildes RS, Goodman H: Studies on the effect of phototherapy on neonatal hyperbilirubinemia among low birth weight infants: II. Protein binding capacity. J Pediatr
1969;75:1048
85. Rubaltelli FF, Largajolli G: Effect of light exposure on gut transit time in jaundiced newborns. Acta Paediatr Scand
1973;62:146-148
86. Scheidt PC, Mellits ED, Hardy JB, et al: Toxicity to bilirubin in neonates: Infant development during first year in relation to maximum neonatal serum bilirubin concen-tration. J Pediatr 1977;91:292-297
87. Schiff D, Aranda J, Chan G, et al: Metabolic effects of exchange transfusion: I. Effect of citrated and of heparin-ized blood on glucose, nonesterified fatty acids, 2-(4 hy-droxybenzeneazo) benzoic acid bindings, and insulin. J Pediatr 1971;78:603-609
88. Seem E, Wille L: Salicylate saturation index in neonatal jaundice. Biol Neonate 1975;26:67-75
89. Sisson TR: Advantages of a lactose-free formula for jaun-diced infants undergoing phototherapy. In Bachhuber WL, Benson JD, Dame MC, et al (eds): Proceedings of Ross Clinical Research Conference: Low-Birth- Weight Infants Fed Isomil. Columbus, OH, Ross Laboratories, 1979, pp 101-107
90. Sisson T: Discussion, in Bilirubin metabolism in the new-born. Birth Defects 1970;6:36
91. Sisson TRC, Kendall N, Glauser SC, et al: Phototherapy ofjaundice in newborn infants: I. ABO blood group incom-patability. J Pediatr 1971;79:904-910
92. Sliney DH, Wolbarsht ML: Safety with Lasers and Other Optical Sources: A Comprehensive Handbook. New York, Plenum Press, 1980
93. Smallpiece V, Davies PA: Immediate feeding of premature infants with undiluted breast-milk. Lancet
1964;2:1349-1352
94. Stevenson DK, Bartoletti AL, Ostrander CR, et al: Effect of fasting on bilirubin production in the first postnatal week. Clin Res 1980;1:126A
95. Stoll MA, Zenone EA, Ostrow JD, et al: Preparation and properties of bilirubin photoisomers. Biochem J 1979; 183:139-146
96. Svenningsen NW, Lindquist A: HBABA index in neonatal jaundice, in: Proceedings of the XIIIth International Con-gress of Pediatrics, Vienna, Austria, 1971, vol 1, p 305 97. Tan KL: Phototherapy for neonatal hyperbilirubinemia in
“healthy” and “ill” infants. Pediatrics 1976;57:836-838 98. Tan KL: The influence of gestational age and birth weight
on the infant response to phototherapy for neonatal hy-perbilirubinaemia. Aust Paediat J 1977;13:22-24
99. Teberg A, Hodgman JE, Wu PYK, et al: Recent improve-ment in outcome for the small premature infant. Clin Pediatr 1977;16:307-313
100. Ulstrom RA, Eisenklam E: The enterohepatic shunting of bilirubin in newborn infant. J Pediatr 1974;65:27-37 101. Warkany J, Monroe BB, Sutherland BS: Intrauterine
growth retardation. Am J Dis Child 1961;102:249-279 102. Weldon VV, Odell GB: Mortality risk of exchange
trans-fusion. Pediatrics 1968;41:797-801
103. Wennberg RP, Schwartz R, Sweet AY: Early versus delayed feeding of low birth weight infants: Effects of physiologic jaundice. J Pediatr 1966;68:860-866
104. Wong YK, Wood BSB: Relative roles of phototherapy and phenobarbitone in treatment of nonhaemolytic neonatal jaundice. Arch Dis Child 1973;48:704-708
105. Wu PYK, Hodgman JE: Insensible water loss in preterm infants: Changes with postnatal development and non-ionizing radiant energy. Pediatrics 1974;54:704-712
106. Wu PYK, Moosa AS: Effect of phototherapy on nitrogen and electrolyte levels and water balance in jaundiced pre-term infants. Pediatrics 1978;61:193-198
107. Wu PYK, Teilman P, Gabler M, et al: “Early” versus “late” feeding of low birth weight neonates: Effect on serum bilirubin, blood sugar, and responses to glucagon and epi-nephrine tolerance tests. Pediatrics 1967;39:733-739
108. Wu PYK, Wong WH, Hodgman JE, et al: Changes in blood flow in the skin and muscle with phototherapy. Pediatr Res 1974;8:257-262
109. Wu PYK, Hodgman JE, Kirkpatrick BV, et al: Metabolic aspects ofphototherapy. Pediatrics 1985;75(suppl):427-433 110. Yerushalmy J: The classification of newborn infants by
birth weight and gestational age. J Pediatr
