Journal of Perinatology (2017) 00, 1–5

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved 0743-8346/17
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ORIGINAL ARTICLE
Double versus single intensive phototherapy with LEDs in
treatment of neonatal hyperbilirubinemia
ML Donneborg1,2, PK Vandborg1, BM Hansen3, M Rodrigo-Domingo4 and F Ebbesen1,2

OBJECTIVE: We investigate whether double phototherapy reduces total serum bilirubin concentration faster than single light
during intensive phototherapy with high levels of irradiance using light-emitting diodes.
STUDY DESIGN: Eighty-three infants with gestational age ⩾ 33 weeks and uncomplicated hyperbilirubinemia were randomized to
either double (n = 41) or single phototherapy (n = 42) for 24 h. The mean irradiance was 64.8 μW cm − 2 nm − 1 from above and
39 μW cm − 2 nm − 1 from below.
RESULTS: The percentage decreases of total serum bilirubin after 12 h of double vs single phototherapy were (mean (95%
confidence interval (CI))) 39% (37 to 42) vs 30% (27 to 32), respectively (P o 0.001). After 24 h, the decreases were 58% (56 to 61) vs
47% (44 to 50), respectively (P o 0.001). The results were still significant after adjustment for confounding. The only side effect was
loose stools.
CONCLUSION: Even with intensive phototherapy increasing spectral power by increasing the irradiated body surface area, the
efficacy of phototherapy is improved.
Journal of Perinatology advance online publication, 2 November 2017; doi:10.1038/jp.2017.167

INTRODUCTION
Jaundice is the most common condition requiring medical
attention in newborns. In most infants, the presence of
unconjugated hyperbilirubinemia reflects a normal transitional
phenomenon. However, in some infants plasma levels may rise
excessively that can be of concern because unconjugated bilirubin
is neurotoxic and can cross the blood–brain barrier causing brain
damage.
Phototherapy is the current treatment of choice for neonatal
hyperbilirubinemia and has almost replaced exchange transfu-
sions because of its efficacy and safety. In Scandinavia, ∼ 2 to 3%
of infants born at term or late preterm are treated with
phototherapy that converts bilirubin (Z,Z-bilirubin) in the skin to
other isomers of bilirubin, the configurational isomers Z,E- and E,Z-
bilirubin and the structural photoisomers lumirubins. These
isomers are more water soluble than Z,Z-bilirubin and can be
excreted into bile and urine without conjugation. This causes a
decrease in the bilirubin concentration in the blood. The
photoisomers may not be toxic.1
Three factors have major influence on the efficacy of photo-
therapy: the spectrum of the light, the irradiance of the light and
the body surface area of the infant exposed to light.2 These factors
should always be considered when treating infants with photo-
therapy, especially if the total serum bilirubin concentration (TsB)
is very high, increases rapidly or the infant has symptoms of acute
bilirubin encephalopathy. In these situations, the level of bilirubin
must be lowered as rapidly as possible.
Fluorescent tubes and halogen spots were formerly used as
light sources, but they are now being replaced by light-emitting
diodes (LEDs) because LEDs present several advantages: the
emission spectrum is narrower (they produce less unnecessary
wavelengths), the irradiance decreases more slowly over time and
they generate less heat.
Intensive phototherapy has been defined by the American
Academy of Pediatrics as a spectral irradiance of at least
30 μW cm − 2 nm − 1 in the 430 to 490 nm wavelength band to as
much of the infants’ surface area as possible; the irradiance was
defined by a single measurement at the center of the footprint.3
Maximum irradiance is attained by bringing the light sources as
close to the infant as possible.2 To increase the exposed body
surface area of the infant, the light sources are often placed above
and below the infant, that is, double light.
Thus, previous studies comparing single and double photo-
therapy have found double phototherapy to be more efficient
than single phototherapy in both term and late preterm infants4–7
and in preterm infants.8,9 The levels of irradiance used in these
studies were 7 to 33 μW cm − 2 nm − 1 from above and 8 to
33 μW cm − 2 nm − 1 from below. However, these previous studies
do not show whether the efficacy of intensive phototherapy with
high levels of irradiance can be enhanced by increasing the light-
exposed body surface area (double light), that is, by increasing the
spectral power (irradiance × body surface area). In 2016, Hansen10
called for a study like the present.
The aim of the present study was to investigate whether double
phototherapy reduces TsB faster than single phototherapy during
intensive phototherapy with high levels of irradiance using LEDs.
METHODS
Subjects
A randomized, controlled trial was conducted between 15 June 2014 and 1
February 2015 in the neonatal intensive care unit at Aalborg University
Hospital, Denmark. Inclusion criteria were otherwise healthy newborn

1
Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 3Department of Pediatrics,
Herlev Hospital, Copenhagen, Denmark and 4Department of Research, Education and Innovation, Aalborg University Hospital, Aalborg, Denmark. Correspondence:
Dr ML Donneborg, Department of Pediatrics, Aalborg University Hospital, Reberbansgade 15, 9000 Aalborg, Denmark.
E-mail: mld@rn.dk
Received 8 March 2017; revised 23 August 2017; accepted 5 September 2017
 Double versus single intensive phototherapy
ML Donneborg et al
2
infants with hyperbilirubinemia without signs of hemolytic disease,
gestational age ⩾ 33 weeks, birth weight ⩾ 1800 g, postnatal age 424 h
and ⩽ 14 days and treatable in a crib. The inclusion criterion of birth weight
⩾ 1800 g is incorporated because we have previously seen hypothermia in
infants ⩽ 1800 g. Infants fulfilling the indications for exchange transfusion
or double phototherapy due to a very high initial or rapidly increasing TsB
were excluded. The indications for phototherapy followed existing
guidelines of the North Denmark Region. These guidelines are closely
related to the Norwegian guidelines from 2011.11 For infants ⩾ 37 weeks of
gestation, birth weight 42500 g and postnatal age ⩾ 72 h the limit for
phototherapy was 270 μmol l − 1 during the study period.
The attending physician enrolled the infants consecutively in the study
and randomized them to either double or single phototherapy using
closed opaque envelopes in blocks of 4, 6 or 8 infants.
Ninety-six infants were eligible for the study. The parents of 11 infants
refused to participate. Thus, 85 infants were randomized, 43 infants to
double light and 42 infants to single light. However, two infants were
withdrawn from the study, both in the double phototherapy group, one
because of problems with blood samples and one owing to maternal
noncompliance. Thus, the study groups consisted of 41 infants who
received double lights and 42 infants who received single light. In the
double light group, blue LED light was given from above and light from a
fiber optic, blue LED blanket from below. In the single light group, blue
LED light was only given from above. The distance between the lamp and
the mattress was 30 cm, in practice adjusted with a 30 cm wood template,
that is, the average distance from the light source to the surface of the
infant was 21.5 cm.
All infants received phototherapy for 24 h. They were naked except for
diapers and eye pads. Phototherapy was administered continuously except
during feeding and nursing care (30 min every third hour) and during
blood sampling.12 All infants were weighed before and after phototherapy.
Measurements
The phototherapy device used was neoBLUE LED Phototherapy System
(Natus Medical, San Carlos, CA, USA) emitting blue light in the 420 to
520 nm spectrum, centered at 458 nm and bandwidth of 450 to 470 nm,
the spectral range at half peak irradiance. The fiber optic, blue LED blanket
was Bilisoft Phototherapy System (GE Healthcare, Laurel, MD, USA),
wrapped in a disposable cover, emitting blue light in the 430 to 490 nm
spectrum, centered at 455 nm and bandwidth of 440 to 460 nm. Irradiance
was measured with a neoBLUE Radiometer (Natus Medical, San Carlos, CA,
USA) that measures spectral irradiance from 420 to 500 nm, with maximum
sensitivity in the spectrum of 440 to 480 nm. It was calibrated just before
starting the study.
During phototherapy, irradiance from above was measured three times,
approximately every eighth hour, at the infants’ head, abdomen and
knees, and the mean value was calculated. Because of the height of the
radiometer, these levels of irradiance were measured 3.5 cm above the
infant, giving higher levels of irradiance than at skin level. The ratio
between the irradiance at skin level and the measured irradiance was
calculated to be 0.93. This correction factor was used in the irradiance
calculations.
The irradiance of the biliblanket was measured in a footprint
encompassing the illuminated area of the blanket, measuring 21 × 28 cm,
and was measured in 12 squares of 7 × 7 cm. The mean irradiance of the
footprint was 39.1 μW cm − 2 nm − 1 at the start of the study (Table 1). In the
same way, irradiance of the overhead phototherapy device was measured
at the start of the study. It was measured 8.5 cm above mattress level,
corresponding to the average height over the mattress of the exposed
infants’ skin, using the same measuring points as in the footprint
mentioned above. The mean irradiance of the footprint was
64.8 μW cm − 2 nm − 1. We also measured the irradiance from the overhead
phototherapy device in a larger illuminated area (28 × 49 cm) in 28 squares
of 7 × 7 cm.13 The mean irradiance was 53.1 μW cm − 2 nm − 1. The levels of
irradiance did not change significantly during the study.
TsB was measured in capillary blood drawn by heel sticks at the start
(TsB0), after 12 h (TsB12) and after 24 h (TsB24) of treatment. It was analyzed
with the diazo-method,14 as previously described.13
Relevant infant data were recorded.
Ethics
The study was approved by the Regional Committee on Health Research
Ethics in North Denmark Region (registration number: N-20140010). Verbal
and written informed consent was obtained from the parents of the
infants.
Statistical analyses
Sample size was calculated based on a previous study.15 To be able to
detect a 6% difference in the decrease of TsB between the two groups

Table 1. Baseline demographic, clinical and irradiance data of the infants

Single phototherapy Double phototherapy P-value

Infants (n) 42 41
Gender female/male (n) 20/22 13/28 0.14
Non-Caucasian ethnicity (n) 4 3
Maternal diabetes mellitus/gestational diabetes (n) 5 3
Cephalhematoma (n) 1 0

Age
Gestational age (days)a 266 (242 to 292) 261 (239 to 293) 0.73
Postnatal age (h)a 76 (47 to 265) 96 (44 to 207) 0.04

Weight
Birth weight (g)a 3250 (1835 to 5090) 2990 (1840 to 4465) 0.32
Weight change, birth to phototherapy (%)a − 4.5 (−10.2 to 1.6) − 4.6 (−8.3 to 6.2) 0.74
Weight change during phototherapy (%)a 0.4 (−2.5 to 7.6) 0.7 (−2.3 to 3.7) 0.15

Feeding during phototherapyb (n)

Breast milk exclusively 16 23
Formula exclusively 4 1 0.10
Mixed 22 17

Light irradiance (μW cm − 2 nm − 1)

From above, unadjusteda,c 71.5 (57.3 to 84.0) 70.1 (50.1 to 88.3) 0.27
From above, adjusteda,d 66.5 (53.3 to 78.1) 65.2 (46.6 to 82.1)
From belowe (mean) 39.1
a
Median (range). bThe P-value focuses on exclusively breastfeeding vs exclusively formula plus mixed feeding. cLight irradiance: mean of all three
measurements for each single infant. dThe irradiance was measured 3.5 cm above the infant, and therefore the value given for the measurement was too high.
The correction factor was 0.93. eMeasured under standardized conditions.

Journal of Perinatology (2017), 1 – 5 © 2017 Nature America, Inc., part of Springer Nature.

after 24 h of phototherapy at a significance level of 5% and a power of
80%, the required sample size should be at least 36 infants in each group.
A difference of 6% was chosen as it was considered clinically relevant.
Differences between demographic and clinical variables between the
two groups were investigated. For categorical variables, χ2 tests for
association were used; for continuous variables, median tests were used.
TsB0, TsB12, TsB24 and changes in TsB (in percent) were described by
their mean and 95% confidence intervals (CIs). The differences between
the two treatment groups were investigated by means of t-tests.
Simple linear regressions were performed with the percentage change
in TsB after 12 (ΔTsB0–12) or 24 h (ΔTsB0–24) of treatment as response
variables, and phototherapy group, TsB0, gestational age, birth weight,
postnatal age or infants receiving formula (exclusively or as supplementa-
tion) as explanatory variables. For each response variable, the significant
explanatory variables from the simple linear regressions were included in
an initial multiple linear regression model. Because of the strong
associations between some of the explanatory variables, some were not
significantly associated with the response variable in this initial multiple
regression. Therefore, a final multiple linear regression was fitted that
included only explanatory variables with a statistically significant associa-
tion with the response variable. Statistical analyses were performed in
Stata 13 (StataCorp, College Station, TX, USA). Results with P-values of
o0.05 were considered statistically significant.
RESULTS
Baseline demographic and clinical data of the 83 infants are
shown in Table 1. The two groups were comparable, but a
significant difference was found between the infants’
postnatal age.
As shown in Table 2, there were no significant differences in
TsB0 between the two groups. Regarding TsB12, TsB24, ΔTsB0–12
and ΔTsB0–24, infants treated with double phototherapy decreased
significantly more than infants treated with single phototherapy.
The boxplots show the percentage change in TsB for each group
after 12 and 24 h of therapy (Figure 1).
Regression analyses were performed to adjust for confounding
variables (Table 3). The simple linear regression analyses showed
that the following variables had a significant effect on both
ΔTsB0–12 (%) and ΔTsB0–24 (%): phototherapy group, TsB0,
gestational age, birth weight and postnatal age. The final model
included phototherapy group, birth weight and postnatal age. The
estimated coefficients did not change substantially between the
two multiple linear regressions.
In the final model, we demonstrated a highly significant
difference between double and single light, in favor of double
light, both after 12 and 24 h of treatment. After adjusting for birth
weight and postnatal age, the differences in the decrease of TsB
between double and single phototherapy were 7.7 percentage
points after 12 h of therapy and 9.0 percentage points after 24 h of
therapy. Birth weight had a significant negative effect on the
decrease in TsB, whereas postnatal age had a significant positive
effect on the decrease in TsB, both after 12 and after 24 h of
therapy.
Double versus single intensive phototherapy
ML Donneborg et al
3
The median of the levels of irradiance from above measured for
each single infant was 70.1 μW cm − 2 nm − 1 for the double light
group and 71.5 μW cm − 2 nm − 1 for the single light group.
Adjusted to skin level, the levels of irradiance in the single and
double light groups were 66.5 and 65.2 μW cm − 2 nm − 1, respec-
tively (Table 1), corresponding to the irradiance of the most
centered footprint, 64.8 μW cm − 2 nm − 1.
Despite using high levels of irradiance, no side effects of
phototherapy other than loose stools were observed. No infants
had hypo- or hyperthermia and no rashes were seen.
DISCUSSION
This is an important addition to former findings regarding double
phototherapy with lower levels of irradiance. Even when single
phototherapy was intensive, then the overall results showed that
double phototherapy reduced TsB significantly faster. After 12 h of
phototherapy, TsB decreased 30% with single phototherapy vs
39% with double phototherapy. After 24 h of phototherapy, the
decrease in TsB was 47% with single phototherapy vs 58% with
double phototherapy. Adjusted for confounders, double photo-
therapy reduced TsB with 7.7 and 9.0 percentage points more
than single phototherapy after 12 and 24 h of therapy, respec-
tively. Thus our study validates the use of double phototherapy
even when the light irradiance is 430 μW cm − 2 nm − 1.
It has been discussed whether there is a ‘saturation point’
(upper limit) for the efficacy of phototherapy. In 1982, Tan16 found
a ‘saturation point’ for the efficacy of phototherapy at an
irradiance of ∼ 30 μW cm − 2 nm − 1 using multidirectional photo-
therapy. Contributing factors might be the level of irradiance, a
limited excretion capacity of photobilirubins or other factors. On
the basis of the study of Tan,16 it was not clear whether the
efficacy of phototherapy could be improved by increasing the
Figure 1. The boxplots show the percentage decrease in total serum
bilirubin after 12 and 24 h of single and double phototherapy.

Table 2. Total serum bilirubin concentrations and the percentage decreases during the treatment

Single phototherapy (n = 42) Double phototherapy (n = 41) P-values

TsB0, μmol l − 1,a 260 (248 to 272) 258 (246 to 270) 0.83
TsB12, μmol l − 1,a 183 (172 to 195) 157 (145 to 170) 0.002
TsB24, μmol l − 1,a 139 (128 to 150) 109 (99 to 119) o0.001
ΔTsB0–12, %a 30 (27 to 32) 39 (37 to 42) o0.001
ΔTsB0–24, %a 47 (44 to 50) 58 (56 to 61) o0.001
Abbreviations: TsB0, total serum bilirubin concentration at start of phototherapy; TsB12, total serum bilirubin concentration after 12 h of phototherapy; TsB24,
total serum bilirubin concentration after 24 h of phototherapy; ΔTsB0-–12, difference between TsB0 and TsB12; ΔTsB0-–24, difference between TsB0 and TsB24.
a
Mean, (95% confidence interval).

© 2017 Nature America, Inc., part of Springer Nature. Journal of Perinatology (2017), 1 – 5
 Double versus single intensive phototherapy
ML Donneborg et al
4
Table 3. Regression analysis: simple linear regression, initial multiple linear regression and the final model

Response variable Explanatory variables Simple linear regressions Initial multiple linear Final model
regression

Coefficient P-value Coefficient P-value Coefficient (95% CI) P-value

ΔTsB0–12 (%) Double light 9.72 o0.001 7.72 o0.001 7.73 (4.42 to 11.04) o0.001
TSB0, μmol l − 1 − 0.08 0.009 − 0.004 0.91
Gestational age, days − 0.21 0.004 − 0.04 0.60
Birth weight, kg − 6.81 o0.001 − 5.06 0.008 − 5.78 (−8.14 to − 3.41) o0.001
Postnatal age, h 0.09 0.002 0.07 0.003 0.06 (0.02 to 0.11) 0.003
Formulaa − 0.38 0.86
ΔTsB0–24 (%) Double light 11.43 o0.001 9.02 o0.001 9.02 (5.72 to 12.31) o0.001
TSB0, μmol l − 1 − 0.09 0.005 − 0.006 0.87
Gestational age, days − 0.25 0.002 − 0.06 0.42
Birth weight, kg − 8.00 o0.001 − 5.60 0.003 − 6.71 (−9.10 to − 4.33) o0.001
Postnatal age, h 0.11 o0.001 0.09 o0.001 0.09 (0.05 to 0.13) o0.001
Formulaa − 1.08 0.66
Abbreviations: TsB0, total serum bilirubin concentration at start of phototherapy; TsB12, total serum bilirubin concentration after 12 h of phototherapy; TsB24,
total serum bilirubin concentration after 24 h of phototherapy; ΔTsB0-12, difference between TsB0 and TsB12; ΔTsB0–24; Difference between TsB0 and TsB24.
a
Infants receiving formula.

exposed body surface area at the high spectral power used in the
present study. Thus, the average spectral power during single
phototherapy presumably was nearly the same as the correspond-
ing spectral power at the ‘saturation point’ in the study of Tan,16
and the efficacy of the treatments was equal. However, we
observed a significantly faster reduction in TsB with considerably
higher spectral power during double phototherapy. We used LED
light centered at 455 and 458 nm, respectively, whereas Tan16
used blue fluorescent light, with peak irradiance at 452 nm, that is,
the two light sources were comparable. It should be pointed out
that measurement of a certain irradiance by different types of
radiometers might show variable readings.17 From a biochemical
point of view, it is doubtful whether a ‘saturation point’ for the
efficacy of phototherapy exists. The formation of lumirubins is
essentially irreversible, the accumulation in plasma is very limited,
the plasma half-life is short and they are the major excretion
product in both bile and urine.18,19 The result of the present study
is in agreement with the hypothesis that no upper limit exists for
the efficacy of phototherapy.
TsB was determined by the diazo-method. Therefore, it includes
both the native Z,Z-bilirubin and the configurational isomers Z,E-
and E,Z-bilirubin.20 The latter account for only a very small
fraction.21 After a few hours of phototherapy, an equilibrium
between Z,Z- and Z,E-bilirubin is obtained, and the photoisomers
make up 26% of TsB when infants are exposed to LED light.21 At
photo-equilibrium, the percentage of configurational isomers is
independent of the irradiance,22 that is, it is the same for single
and double phototherapy.
Phototherapy has been used and studied for decades, and there
is still room to increase theoretical knowledge and improve clinical
practice. The present study optimized the infant’s light-exposed
surface area, and used high levels of irradiance. The use of
intensive phototherapy seems successful in reducing TsB rapidly.
According to Hansen et al.,23 a strong argument for this aggressive
approach is that the intermediate to advanced stages of acute
bilirubin encephalopathy may occasionally be reversible, and the
present study demonstrates the benefits of intensive photother-
apy as double phototherapy when an aggressive approach is
required for late preterm and term infants.
Another clinical aspect of our study is that the duration of
phototherapy could be reduced to 12 h for many of the infants
using the double phototherapy described in this study. Use of this
12 h strategy minimizes the separation between mother and
infant, and reduces the hospital stay and costs without causing
the infants further discomfort. Although the only side effect
observed in our study was loose stools, other side effects
associated with phototherapy for late preterm and term infants
have to be considered if intensive phototherapy with high levels
of irradiance is also applied to infants without clear symptoms of
bilirubin encephalopathy.
Aydemir et al.24 found that phototherapy with LEDs with
irradiance levels of 60 to 120 μW cm − 2 nm − 1 significantly
increased body temperature. However, we did not see any infants
in our study with hyper- or hypothermia.
In preterm infants Bertini et al.25 found that phototherapy with
LED light, in contrast to fluorescent light, did not induce
significant changes in transepidermal water loss because LED
light emits minimal infrared light. Correspondingly, we observed
the same changes in body weight during phototherapy for infants
treated with single and double phototherapy.
Other, more subtle side effects associated with phototherapy
have been considered. Phototherapy may cause oxidative stress,
because the total oxidative status in plasma is increased during
the treatment.26,27 Phototherapy may also cause changes in
specific areas of the erythrocyte membrane without affecting the
membranes mechanical properties.28 Phototherapy caused DNA
damage in peripheral lymphocytes,29,30 though the changes were
temporary.29 It has also been debated whether phototherapy
affects the infants’ immune system.31,32
Although the mentioned side effects suggests a cautious use of
phototherapy, their clinical relevance has not been documented;
for example, Brewster et al.33 found that there is no evidence of
skin cancer following neonatal phototherapy.
The strengths of the study were: (1) use of LEDs (the
phototherapy light sources of the future) (2) that neoBLUE
radiometer with maximum sensitivity 440 to 480 nm matches
well both the neoBLUE Phototherapy System centered at 458 nm
and the Bilisoft Phototherapy System centered at 455 nm; and (3)
that the patient population was homogenous.
A limitation of the study was that infants with very high TsB
were not included, but it would have been unethical to randomize
this group, because rapid reduction of TsB is mandatory to avoid
brain damage.
CONCLUSION
Even with intensive phototherapy increasing spectral power by
increasing the irradiated body surface area, the efficacy of

Journal of Perinatology (2017), 1 – 5 © 2017 Nature America, Inc., part of Springer Nature.

phototherapy is improved. Our findings support the fairly
common use of intensive double phototherapy. We suggest the
continued use of double phototherapy with high levels of
irradiance in the treatment of severe hyperbilirubinemia for late
preterm and term infants.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
We thank the nurses, doctors in charge and the laboratory technicians for their
excellent assistance.
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