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Fetal Diagn Ther 2006;21:204–209 DOI: 10.1159/000089304

Which Phototherapy System Is Most Effective in Lowering Serum Bilirubin in Very Preterm Infants?

Costantino Romagnoli Enrico Zecca Patrizia Papacci Giovanni Vento Pietro Girlando Caterina Latella

Division of Neonatology, Catholic University of Rome, Rome , Italy

Conclusion: Our data suggest that combined photother-apy should be the method of choice in treating hyper-bilirubinemia in very preterm infants.

Copyright © 2006 S. Karger AG, Basel

Introduction

An increasing number of kernicterus was reported in the 90s among otherwise healthy term and near-term newborn babies [1–7] . In the same period, any case of kernicterus had been reported among preterm infants of-ten affected by neonatal pathologies, which was able to increase the risk of bilirubin neurotoxicity [8] . A more aggressive treatment policy, the presence of diseases con-ditioning brain damage, diffi culties in revealing clinical features of acute and chronic kernicterus among very pre-term infants, and the lack of specifi c follow-up data could be causal factors. On the other hand, many observations point to the possibility that hyperbilirubinemia, even at relatively low serum bilirubin level, may contribute to abnormal neurodevelopmental outcomes [9] . This shows that our incomplete understanding of the basic mecha-nisms of bilirubin neurotoxicity led us to a management

Key Words Neonatal hyperbilirubinemia � Phototherapy � Preterm infants

Abstract Objective: To compare the effectiveness of various pho-totherapy systems in lowering serum bilirubin levels in preterm infants. Methods: This randomized clinical trial enrolled 140 preterm infants with gestational age ̂ 30 weeks and presenting nonhemolytic hyperbilirubine-mia. When total serum bilirubin level reached 6.0 mg/dl (102.6 � mol/l), eligible infants were randomly assigned to four study groups: conventional, fi beroptic Wallaby, fi beroptic Biliblanket, and combined phototherapy. Effi -cacy was assessed by comparing highest serum bilirubin levels, duration of treatment, and number of infants re-quiring exchange transfusion. Results: Our results con-fi rm that fi beroptic phototherapy, both Wallaby and Bili-blanket, had the same effectiveness of conventional phototherapy. The best results have been obtained using combined phototherapy, which allowed to reach lower serum bilirubin levels, a shorter duration of treatment and a signifi cant reduction of exchange transfusions.

Received: July 13, 2004 Accepted after revision: March 3, 2005

Costantino Romagnoli, MDDivision of Neonatology, Policlinico A. GemelliLargo A. Gemelli, 8IT–00168 Rome (Italy)Tel. +39 06 30154357, Fax +39 06 3055301, E-Mail cromagnoli@rm.unicatt.it

© 2006 S. Karger AG, Basel1015–3837/06/0212–0204$23.50/0

Accessible online at:www.karger.com/fdt

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Phototherapy for Very Preterm Infants Fetal Diagn Ther 2006;21:204–209 205

strategy often based on clinical intuition, empirical judg-ment, and weight-related criteria which have never been validated [8, 9] .

Conventional phototherapy and, more recently, fi ber-optic phototherapy have proved their effi cacy in treating neonatal hyperbilirubinemia both in full-term and pre-term infants [1–3, 5–7] ; in very preterm infants data on fi beroptic phototherapy are few and inconclusive [10–17] .

The aim of this study was to compare the effectiveness of various phototherapy systems in lowering serum bilirubin levels in preterm infants with gestational age ̂ 30 weeks. The main study endpoint was the reduc-tion of babies with total serum bilirubin 1 15 mg/dl (256.5 � mol/l).

Materials and Methods

This randomized clinical trial was carried out during a 2-year and a half period, ended on June 2002, in 140 preterm infants with gestational age ̂ 30 weeks admitted to our neonatal intensive care unit. The local ethics committee approved the study, and informed consent was obtained from the parents.

A previous study showed that more than 25% of infants with gestational age ̂ 30 weeks treated with conventional phototherapy reached a serum bilirubin level 1 15 mg/dl (256.5 � mol/l). Using the sample-size table and the 25% of incidence of serum bilirubin 1 15 mg/dl (256.5 � mol/l) in the conventional phototherapy group and an expected 90% reduction in the double phototherapy group, at least in each group 30 infants were required to detect a differ-ence, allowing a 5% chance of � type I error.

Infants with hemolytic anemia, congenital malformation, con-genital infections, and neonates whose mothers had received phe-nobarbital have been excluded from randomization.

Eligible infants were randomly assigned using sealed envelopes to the following study groups when total serum bilirubin level reached 6.0 mg/dl (102.6 � mol/l):

Group A: Conventional phototherapy. This group included 35 babies treated with standard phototherapy units composed of four fl uorescent lamps (True Light, Duro Test, 20 TH 12 TXC) and four blue lamps (Philips TL 20 W/03T) placed 40 cm above the infant. The total power irradiance reaching the skin of the baby was 22–24 � W/cm 2 /nm. Babies were naked, but diapered with disposable diaper folded to allow maximum skin exposure to phototherapy. Eye protection was used during the treatment, and babies’ position was periodically (every 6 h) turned from prone to supine position and vice versa to produce a uniform exposure to the light.

Group B: Fiberoptic Wallaby phototherapy. In this group there were 35 newborn infants treated with Wallaby II Phototherapy System (Fiberoptic Medical Products, Inc., Allentown, Pa., USA). This system makes use of a fi beroptic cable to deliver light to a 10.1 ! 15.2-cm pad (model EG-2000N) which is placed in contact with the back of the patient or with the thorax and abdomen when the baby is in the prone position. The Wallaby II makes use of a 150-watt quartz halogen lamp (model Vickers FS-110) and a light

fi lter is placed between the lamp and the fi beroptic bundle to allow only the passage of light in the 400–550 nm range. The irradiance level at skin averaged 8–10 � W/cm 2 /nm. Babies’ position was pe-riodically (every 6 h) turned from prone to supine position and vice versa to produce a uniform exposure to the light. Eye pads were not used.

Group C: Fiberoptic Biliblanket phototherapy. In this group we included 35 newborn infants treated with Biliblanket Phototherapy System (Ohmeda Critical Care, Columbia, Md., USA). This system consists of a halogen lamp with an attached cable containing 2,400 optic fi bers spread out in a 11 ! 13-cm illuminated fl at mat which is placed directly on the back of patient or on the thorax and abdo-men when the baby is in the prone position. The Biliblanket incor-porates a 150-watt tungsten halogen lamp and light is fi ltered to cut off all wavelengths falling outside the 400–550 nm spectral inter-vals. We have used the maximum power of the equipment and ir-radiance level at skin averaged 35 � W/cm 2 /nm. Babies’ position was periodically (every 6 h) turned from prone to supine position and vice versa to produce a uniform exposure to the light. Eye pads were not used.

Group D: Combined phototherapy. In this group we enrolled 35 neonates treated with conventional + Wallaby system fi beroptic phototherapy. The irradiance level at skin was the sum of irradi-ance of the other two groups. These babies were nursed as infants of group A.

In all study groups phototherapy was interrupted only for 2 h a day for feeding, nursing care, and blood sampling for bilirubin determinations. To measure the irradiance we used a power meter, modifi ed to read radiant fl ux in the spectral range of 300–700 nm with 4% accuracy and measurements were done for all infants at the beginning and end of treatment. Total serum bilirubin was measured on capillary blood (OHC Photo-Ictometer, model IV, O’Hare & Co. Ltd., Tokyo, Japan) on admission, every 8 h up to the beginning of phototherapy, and then every 12 h until 48 h after the end of phototherapy. Failure of treatment was considered when serum bilirubin level reached 14 mg/dl despite phototherapy. In this case, for infants treated with a single light source a double phototherapy was started adding fi beroptic phototherapy to con-ventional phototherapy and vice versa, while treatment in babies on combined phototherapy remained unchanged. Phototherapy was ended when serum bilirubin values showed decreasing values in two consecutive determinations. Direct-acting bilirubin mea-surements were performed on the 1st, 3rd, and the 7th day of life.

During the study period, patient care practices have been uni-form among the neonatologists, according to the standard protocols of the unit who were not changed. Gestational age of studied infants was determined according to the maternal history and Ballard scor-ing system [18] . All the newborn infants were placed in incubators (Drager 8000 SC) with the same environmental conditions of neu-tral temperature and humidity (50–60%). All babies underwent parenteral nutrition and fl uid intake was planned according to the following protocol: 60 ml/kg on the 1st day of life, 70 ml/kg on the 2nd day, 80 ml/kg on the 3rd day, 100 ml/kg on the 4th day, 120 ml/kg on the 5th day, and up to 150 ml/kg at the 1st week of life. Daily adjustments were made individually on the basis of body weight, urine output, and serum electrolytes. At the beginning of treatment a 15% fl uid intake increase was provided. Enteral feed-ing using preterm-formula was started, as vital signs were stable, usually by 2nd to 3rd days of life.

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In our unit infants with gestational age ̂ 30 weeks with serum bilirubin 1 15 mg/dl (256.5 � mol/l) were considered for exchange transfusion, considering clinical conditions, birth weight (BW) and day of life as well.

Student’s t test was used for comparison of means of continuous variables; � 2 was used for comparison of categorical variables. A p value ! 0.05 was considered statistically signifi cant.

Results

There were no signifi cant differences in body weight changes among the study groups during and after treat-ment.

In particular, percentage of weight loss (mean 8 SD) was 10.2 8 4.6, 11.0 8 5.2, 10.1 8 5.5, and 10.9 8 5.3 for groups A, B, C, and D, respectively, while day of life (mean 8 SD) of BW regain was 12.2 8 5, 12.8 8 4, 13 8 4, and 13.1 8 5 for groups A, B, C, and D, respec-tively.

All neonates were fed with formula milk during pho-totherapy at the rate of 15–25% of total daily fl uid intake without any difference among study groups.

We observed a transient erythema in 10 infants during conventional phototherapy, in 9 and 8 during fi beroptic phototherapy with Wallaby and Biliblanket, respectively, and in 12 infants treated with combined phototherapy. Two babies of either group A and D failed to have com-plete serum bilirubin data and were excluded from the fi nal evaluation. Direct acting bilirubin levels have been

always in the normal range without differences among study groups.

Sex ratio, gestational age, BW, appropriate-for-gesta-tional-age/small-for-gestational-age ratio, antenatal ste-roids, and operative delivery were similar in all study groups as well as the incidence of respiratory distress syn-drome, patent ductus arteriosus, renal acute failure (se-rum creatinine 1 1.6 mg/dl), intracranial hemorrhage [19] , and sepsis during the 1st week of life ( table 1 ).

Table 2 shows laboratory data and the response to pho-totherapy of the study groups. We have not found sig-nifi cant differences among groups in chronological age, total serum bilirubin level, and hematocrit at the begin-ning of phototherapy. Mean serum bilirubin level in-creased in all study groups during the fi rst 24 h of treat-ment, but the increase observed in groups A, B, and C was signifi cantly higher than that observed in the group D. After 48 h of treatment the babies of group D showed a signifi cantly lower increase of serum bilirubin level. Be-tween 48 and 72 h of phototherapy the mean serum bili-rubin concentration decreased in all groups, but this de-crease was again signifi cantly more evident in babies of group D. Furthermore the mean of highest serum biliru-bin level of group D was signifi cantly lower than that ob-served in the other three groups. Only 2 babies in group D reached 10 mg/dl (171.0 � mol/l) of serum bilirubin compared with 7 in group A, and 11 in groups B and C. Serum bilirubin exceeded 15 mg/dl (256.5 � mol/l) in 2 infants of groups A and B, and in 1 infant of group C re-

Table 1. Clinical data and major morbidity of the study groups

Group A Group B Group C Group D

n (M/F) 33 (19/14) 35 (18/17) 35 (17/18) 33 (18/15)Gestational age, weeks 27.981.3 (25–30) 27.981.4 (25–30) 27.981.5 (25–30) 28.081.4 (25–30)Birth weight, g 1,0008294 (610–1,660) 1,0508309 (550–1,685) 1,0148283 (550–1,610) 1,0108251 (560–1,530)SGA infants 12 (36.4) 8 (22.9) 6 (17.1) 7 (21.2)Antenatal steroids 22 (66.6) 25 (71.4) 26 (74.3) 23 (69.7)Cesarean section 29 (87.9) 31 (88.6) 32 (91.4) 30 (90.9)Respiratory distress syndrome 23 (69.7) 24 (68.6) 21 (60) 22 (66.7)Mechanical ventilation 28 (84.8) 28 (80) 29 (82.9) 28 (87.9)Patent ductus arteriosus 12 (36.4) 11 (31.4) 9 (25.7) 11 (33.3)Renal acute failure 6 (18.2) 5 (14.3) 3 (8.6) 4 (12.1)Intracranial hemorrhage

>2nd degree 4 (12.1) 2 (5.7) 2 (5.7) 4 (12.1)Sepsis 6 (18.2) 7 (20) 7 (20) 6 (18.2)

Values expressed as mean 8 SD (range) or number (%).SGA = Small for gestational age.

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Phototherapy for Very Preterm Infants Fetal Diagn Ther 2006;21:204–209 207

spectively, while any infant in group D reached this value. There were 7 failure of treatment: 2 in group A, 4 in group B, and 1 in group C. Five infants required exchange trans-fusion: 2 in group A, 2 in group B, and 1 in group C. Pho-totherapy exposure was signifi cantly shorter in group D.

Table 3 shows the number of babies who had an in-creasing, unchanged, or decreasing serum bilirubin, mea-

sured every 24 h during the fi rst 72 h of therapy. A sig-nifi cantly lower number of group D infants showed an increasing bilirubin during the fi rst 24 h of treatment compared to fi beroptic phototherapy groups and in the following 24 h the number of infants with decreasing se-rum bilirubin was signifi cantly higher in group D com-pared to the other three groups. In the last 24 h almost all babies showed a decrease of serum bilirubin, statistically signifi cant in group D compared to group B and C.

Discussion

Our study focused on the best treatment modality for phototherapy in preterm infants with gestational age ̂ 30 weeks, the main aim being to minimize the risk of high serum bilirubin levels exposure.

The strength of our study is the choice of a very se-lected study population of preterm infants, and the ab-sence of confounding factors and crossed treatments; this allowed us to accurately evaluate the effectiveness of light treatments on serum bilirubin levels. The major limita-tions of the study could be the small sample size, the use of suboptimal conventional phototherapy and the lack of follow-up data on neurodevelopmental outcomes.

In the past years, autopsy fi ndings of kernicterus in deceased premature infants with low plasma bilirubin

Table 2. Laboratory data and response to phototherapy of the study groups

Group A Group B Group C Group D

Hours of age at start of phototherapy 38.187.2 (24–48) 37.887.4 (24–48) 39.086.9 (24–48) 38.587.2 (24–48)Hematocrit at start of phototherapy (%) 5287 (42–61) 5486 (43–60) 5587 (41–61) 5385 (45–59)Serum bilirubin at start of phototherapy

mg/dl 6.480.3 (6–7) 6.480.3(6–6.9) 6.580.3 (6–7) 6.380.2 (6–6.8)�mol/l 109.485.1 (102.6–119.7) 109.485.1 (102.6–118.0) 112.285.1 (102.6–119.7) 107.783.4 (102.6–116.3)

Change in serum bilirubin concentration from baseline (%)0–24 h 26.8817.5 29.2820.1 27.4817.6 16.0812.8a

24–48 h 9.4811.8 12.4813.8 11.1812.4 1.189.2b

48–72 h –5.185.4 –2.889.4 –5.688.3 –13.588.3c

Highest bilirubin levelmg/dl 9.282.5 (6.8–16.8) 9.983.3 (6.3–17) 9.482.6 (6.3–16.9) 7.681.3 (6.2–11.3)c

�mol/l 157.3842.8 (116.3–287.3) 169.3856.4 (107.7–290.7) 160.7844.5 (107.7–289.0) 130.0822.2 (106.0–193.2)Number of babies exceeding specifi ed serum bilirubin levels

>10 mg/dl (171.0 �mol/l) 7 (21.2) 11 (31.4) 11 (31.4) 2 (6.5)d

>12 mg/dl (205.2 �mol/l) 2 (6.1) 6 (17.1) 5 (14.3) 0e

>15 mg/dl (256.5 �mol/l) 2 (6.1) 4 (11.4) 1 (2.9) 0e

Number of babies requiring EXT, n (%) 2 (6.1) 2 (5.7) 1 (2.9) 0Duration of phototherapy, h 90.2824.3 (43–144) 92.1843.3 (24–207) 94.5843.3 (48–172) 75.1823.6e, f (36–120)

Values presented as mean 8 SD (range) or number (%). EXT = Exchange transfusion.a p < 0.01 group D vs. A, B, and C; b p < 0.0001 group D vs. A, B, and C; c p < 0.001 group D vs. A, B, and C; d p < 0.02 group D vs. B and C; e p < 0.05

group D vs. B and C; f p < 0.01 group D vs. A.

Table 3. Response to light treatment of study groups reported as increase, no change, or decrease of serum bilirubin in epochs of24 h during the fi rst 72 h of treatment

Group A Group B Group C Group D

From 0 to 24 hIncrease 32 35 35 28a

No change/decrease 1 0 0 5From 24 to 48 h

Increase 31 27 29 14Decrease 2 8 6 19b, c

From 48 to 72 hIncrease 6 10 9 2Decrease 27 25 26 31a

a p < 0.05 group D vs. B and C.b p < 0.0001 group D vs. A.c p < 0.01 group D vs. B and C.

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levels [20–22] , lower plasma albumin concentration in preterm babies [23] and the hypothesis that moderate hyperbilirubinemia was associated with central nervous system dysfunction [24] led to recommend a preventive phototherapy approach in low-BW infants. In the last de-cade, low bilirubin kernicterus virtually disappeared from autopsy of low-BW infants but it cannot be ascribed to any specifi c treatment, and in particular to the early institution of phototherapy. In many intensive care units, prophylactic phototherapy has been therefore changed to therapeutic phototherapy based on weight-related criteria not yet validated. At the same time, serum bilirubin lev-el at which exchange transfusion has to be performed re-mained undefi ned and varied among intensive care units. Moreover, follow-up data are not still available because outcome studies on the bilirubin neurotoxicity in low-BW infants to validate single therapeutic approaches have been impossible to design [8] .

We started phototherapy when serum bilirubin ex-ceeded 6 mg/dl (102.6 � mol/l) with the aim to reduce the number of preterm infants reaching potentially danger-ous serum bilirubin levels [25] . This approach cannot be defi ned as prophylactic use of phototherapy. It is well known that the bilirubin increase of the fi rst days of life is gestational-age-dependent [26] : starting phototherapy between 24 and 48 h of life will not be able to prevent such an increase, leaving bilirubin to have its antioxidant physiological functions [8, 27] .

Fiberoptic phototherapy is a new method of photo-therapy, which is reported to lower serum bilirubin while minimizing disruption of normal infant care and for these reasons it has a place in the management of neonatal hy-perbilirubinemia [11, 14, 17] . A recent Cochrane review [16] reports that in full-term infants fi beroptic photother-apy is less effective in lowering serum bilirubin than con-ventional phototherapy except when two Biliblanket are used simultaneously, in which case fi beroptic is equally effective. While data that suggest the superiority of one fi beroptic device over another do not exist, the addiction of a fi beroptic device to conventional phototherapy is more effective than conventional alone [11, 14, 16] .

The use of fi beroptic phototherapy in preterm infants has been less widespread. Tan [11] while studying infants less preterm than ours, reported that effi cacy of the fi ber-optic mat (Biliblanket) was almost as good as that of day-light lamps. Donzelli et al. [13] found that special blue conventional phototherapy was more effi cacious than daylight and fi beroptic phototherapy (Biliblanket) whose effectiveness was quite similar. Van Kaam et al. [15] , comparing early treatment with fi beroptic and conven-

tional phototherapy in preterm infants according to BW, concluded that the median duration of each treatment was similar and without signifi cant differences within separate weight groups.

Our results confi rm that fi beroptic phototherapy, both Wallaby and Biliblanket, had the same clinical effective-ness as conventional phototherapy. We have not found signifi cant differences in serum bilirubin variations be-tween groups A, B, and C in the fi rst 72 h of treatment and the highest serum bilirubin levels and the duration of light exposure were similar too. The best results were obtained with combined phototherapy. Indeed, the group D showed a signifi cant lower highest serum bilirubin lev-el and a shorter duration of treatment than any other study groups. Moreover, any infant of this group reached 12 mg/dl (205.2 � mol/l) of serum bilirubin and the ma-jority of babies had their serum bilirubin reduced into the fi rst 48 h of light exposure. These results, according to those reported by Tan [11] , are not surprising because light dosage was signifi cantly increased in this setting of phototherapy, being equal to the sum of the two forms of phototherapy.

Our study is to be considered the fi rst one that compar-ing different phototherapy patterns in four groups of pre-term infants with gestational age ̂ 30 weeks had similar clinical variables, eventually infl uencing the serum bili-rubin level, mainly the age and the serum bilirubin level at the beginning of phototherapy. Indeed, Tan [11] stud-ied more mature preterm infants than ours starting pho-totherapy at 72–96 h of life with serum bilirubin levels of 250.2 8 34 to 266.3 8 30 � mol/l (14.6 8 2 to 15.6 8 1.8 mg/dl), and without data about the highest serum bil-irubin level. Donzelli et al. [13] included preterm infants with a wide range of gestational age and BW, treated at different postnatal age (30–130 h) and with different pre-treatment serum bilirubin (169.3–348.8 � mol/l; 9.9–20.4 mg/dl) and they have not reported data about the highest serum bilirubin reached in each group. The study of van Kaam et al. [15] had a signifi cant bias because an additional conventional lamp was initiated in the 52% of patients on fi beroptic phototherapy and in the 40% of patients on conventional phototherapy. About half of the infants received thereafter a combined phototherapy and data were not shown separately. In this study, data about exchange transfusion (4 in fi beroptic and 3 in conven-tional phototherapy) confi rmed that in very premature infants single phototherapy is not able to avoid the use of this potentially dangerous procedure. Therefore it is very diffi cult to obtain useful information about effectiveness of treatments on preterm infants from these studies.

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Phototherapy for Very Preterm Infants Fetal Diagn Ther 2006;21:204–209 209

Conventional phototherapy or fi beroptic photother-apy with actual devices failed to prevent very preterm infants from reaching potentially dangerous serum bili-rubin levels. The size of fi beroptic luminous pad to be used on a relatively small skin area and the spectral emis-sion in less effective region are actually important limi-tations of available devices. On the other hand, it is not conceivable to start phototherapy earlier before jaun-dice appears and light can work, and increasing the spec-tral radiance of lamps is useless given the pattern of re-

sponse of hyperbilirubinemia to increasing irradiance [28, 29] .

In conclusion, our experience suggests that combined phototherapy is the best way to lower serum bilirubin levels in preterm infants with gestational age ̂ 30 weeks, since combination of conventional with fi beroptic photo-therapy is easier to use than double conventional photo-therapy. A follow-up is still in progress to verify possible positive effects of this approach on neurodevelopmental outcomes.

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