International Journal of

Molecular Sciences

Review
Blue-Green (~480 nm) versus Blue (~460 nm) Light for Newborn
Phototherapy—Safety Considerations
Finn Ebbesen 1,2, * , Hendrik Jan Vreman 3 and Thor Willy Ruud Hansen 4,5

1 Department of Pediatrics, Aalborg University Hospital, 9000 Aalborg, Denmark

2 Department of Clinical Medicine, Aalborg University Hospital, 9000 Aalborg, Denmark
3 Division of Neonatal and Development Medicine, Department of Pediatrics, Stanford University Medical
Center, Stanford, CA 94305-5101, USA
4 Division of Paediatric and Adolescent Medicine, Oslo University Hospital, 0424 Oslo, Norway
5 Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, 0450 Oslo, Norway
* Correspondence: fe@rn.dk; Tel.: +45-97663331; Fax: +95-97663338

Abstract: We have previously shown that the phototherapy of hyperbilirubinemic neonates using
blue-green LED light with a peak wavelength of ~478 nm is 31% more efficient for removing unconju-
gated bilirubin from circulation than blue LED light with a peak wavelength of ~452 nm. Based on
these results, we recommended that the phototherapy of hyperbilirubinemic newborns be practiced
with light of ~480 nm. Aim: Identify and discuss the most prominent potential changes that have been
observed in the health effects of phototherapy using either blue fluorescent- or blue LED light and
speculate on the expected effects of changing to blue-green LED light phototherapy. Search the pho-
totherapy literature using the terms neonate, hyperbilirubinemia, and phototherapy in the PubMed
and Embase databases. Transitioning from blue fluorescent light to blue-green LED light will expose
neonates to less light in the 400–450 nm spectral range, potentially leading to less photo-oxidation
and geno-/cytotoxicity, reduced risk of cancer, and decreased mortality in extremely low-birthweight
neonates. The riboflavin level may decline, and the increased production and retention of bronze
pigments may occur in predisposed neonates due to enhanced lumirubin formation. The production
of pre-inflammatory cytokines may rise. Hemodynamic responses and transepidermal water loss
are less likely to occur. The risk of hyperthermia may decrease with the use of blue-green LED light
and the risk of hypothermia may increase. Parent–neonate attachment and breastfeeding will be
Citation: Ebbesen, F.; Vreman, H.J.;
Hansen, T.W.R. Blue-Green (~480 nm)
positively affected because of the shortened duration of phototherapy. The latter may also lead to a
versus Blue (~460 nm) Light for significant reduction in the cost of phototherapy procedures as well as the hospitalization process.
Newborn Phototherapy—Safety
Considerations. Int. J. Mol. Sci. 2023, Keywords: neonates; hyperbilirubinemia; phototherapy; side effects; safety; fluorescent light; LED
24, 461. https://doi.org/10.3390/ light; blue-green light; blue light
ijms24010461

Academic Editor: Libor Vitek

Received: 2 October 2022 1. Introduction

Revised: 15 November 2022
Currently, in Scandinavia, 2–3% of all late preterm and term (≥35 weeks) neonates
Accepted: 3 December 2022
and 40–80% of preterm neonates with lower gestational ages (<35 weeks) with hyperbiliru-
Published: 27 December 2022
binemia need phototherapy [1,2]. The current standard involves the exposure of neonatal
skin to blue light with a peak wavelength of ~460 nm. This light is absorbed by native
Z,Z-bilirubin molecules which undergo conversion to stereoisomers, the configurational
Copyright: © 2022 by the authors. Z,E- and E,Z-bilirubin, and the structural isomers ZE- and E,E-lumirubin (Scheme 1). These
Licensee MDPI, Basel, Switzerland. more polar isomers can be excreted with the bile and urine. Lumirubin formation is the
This article is an open access article most important process for reducing total serum bilirubin (TSB) because it is produced in
distributed under the terms and large amounts and is excreted rapidly [3,4]. Z,Z-bilirubin also undergoes photo-oxidation
conditions of the Creative Commons with a very small quantum yield, forming, among others, monopyrrolic (BOX A and BOX
Attribution (CC BY) license (https:// B), dipyrrolic, and tripyrrolic oxidation products [5,6].
creativecommons.org/licenses/by/
4.0/).

Int. J. Mol. Sci. 2023, 24, 461. https://doi.org/10.3390/ijms24010461 https://www.mdpi.com/journal/ijms

 Light
E,Z-bilirubin ↔ Z,Z-bilirubin ↔ Z,E-bilirubin
↓
E,Z-lumirubin ↔ E,E-lumirubin
Int. J. Mol. Sci. 2023, 24, 461 2 of 13

Scheme 1. Formation of bilirubin isomers during the phototherapy of hyperbilirubinemic neonates.

Scheme 1. Formation of bilirubin isomers during the phototherapy of hyperbilirubinemic
neonates.
From the discovery of phototherapy in the 1950s to the present, broad bandwidth
(~50 nm at 50% peak irradiance) blue fluorescent light with peak emission ~460 nm,
From the
matching the absorption
discovery of phototherapy
spectrum in the 1950s to thecomplex
of the bilirubin–albumin present,inbroad plasma bandwidth
with peak
(~50 nm at 50%
absorption ~460 peak
nm, has irradiance)
been used blue fluorescent
worldwide for light with peakHowever,
phototherapy. emissionfluorescent
~460 nm,
matching
lamps emit thelowabsorption
levels of spectrum
ultravioletoflightthe bilirubin–albumin
A (<400 nm), whichcomplex in plasma
is not always with peak
prevented from
absorption ~460 nm, has been used worldwide for phototherapy.
reaching the treated subjects. In addition, this light source also emits significant levels However, fluorescent
lamps emit low
of infrared levels of
radiation ultraviolet
(heat). In thelight
earlyA2000s,
(<400 nm),
narrowwhich is not always
bandwidth (~20 prevented
nm at 50%from peak
reaching
irradiance)theblue
treatedLED subjects. In addition,
(light emitting diode)thislight
lightwith
source alsoemission
peak emits significant
at ~460 nm levels
beganof
infrared
replacing radiation (heat). In
the fluorescent the early
lamps. During 2000s,thatnarrow
period,bandwidth
using in vivo (~20models
nm at of 50% peak
neonatal
irradiance)
skin, studies blue of LED (light emitting
the action (efficacy)diode)
spectrum lightofwith peak emission
phototherapy at ~460 nmthat
demonstrated beganthe
replacing
optimumthe fluorescentfor
wavelength lamps. During that
phototherapy did period, using
not quite in vivo
occur models
at ~460 nm, of but
neonatal
ratherskin,
at a
studies of thesome
wavelength action 20(efficacy)
nm higher spectrum of phototherapy
[7–10]. Based demonstrated
on these observations, we that the optimum
conducted a series
wavelength for phototherapy
of clinical studies that ultimately diddemonstrated
not quite occur thatatblue-green
~460 nm, but (alsorather at a wavelength
identified as turquoise)
some
LED 20 nmwith
light higher [7–10].bandwidth
a narrow Based on these observations,
of 470–490 nm andwe conducted
a peak at 478 nm a series
was of31% clinical
more
efficientthat
studies than blue LEDdemonstrated
ultimately light with a bandwidth
that blue-green of 450–470
(also nm and a peak
identified at 459 nmLED
as turquoise) [11].
Therefore,
light with abased
narrow on bandwidth
these clinical of data,
470–490we recently
nm and recommended
a peak at 478 nm the use
was of31% thismore
light
source and
efficient than emission
blue LED characteristics
light with a [11,12],
bandwidth as hadof Lamola
450–470[10]nm and and the
a peakAmerican
at 459 Academy
nm [11].
of Pediatrics (AAP) [13].
Therefore, based on these clinical data, we recently recommended the use of this light
sourceThe andgreater efficacy
emission of blue-green [11,12],
characteristics LED light asishad
maybe due to[10]
Lamola severalandfactors: (1) When
the American
the light wavelength
Academy of Pediatricsincreases(AAP) [13]. beyond 459 nm, the quantum yield of lumirubin increases,
while thegreater
The rate of efficacy
the formation of Z,E-bilirubin
of blue-green LED light decreases
is maybe[14,15].
due to Moreover, (2) the(1)competi-
several factors: When
tionlight
the between bilirubin
wavelength and hemoglobin
increases beyond 459 asnm,wellthe
as quantum
melanin for yieldlight absorptionincreases,
of lumirubin decreases
with wavelengths
while the rate of the longer than 459
formation of nm, while back-scattering
Z,E-bilirubin decreases [14,15].is reduced [10]. We
Moreover, (2) have
the
shown clinically that the decline of TSB using blue LED
competition between bilirubin and hemoglobin as well as melanin for light absorption light was negatively related to
the hemoglobin concentration [11,16], while this was not the
decreases with wavelengths longer than 459 nm, while back-scattering is reduced [10]. We case for LED light with peak
emission
have shown,at 478 nm [11].
clinically, that the decline of TSB using blue LED light was negatively related
to theThe most consequential
hemoglobin concentration side [11,16],
effect ofwhile
phototherapy
this wasisnot considered
the case to forbeLED
photodynamic
light with
damage: When the
peak emission at 478 nm [11].bilirubin molecule absorbs a photon to yield isomerization, cyclization,
and The
oxidation products, it can
most consequential sidealso actofasphototherapy
effect a photosensitizer. The absorbed
is considered energy can be
to be photodynamic
damage: When the bilirubin molecule absorbs a photon to yield isomerization,and
transferred to molecular oxygen to form singlet oxygen, superoxide di-anion, its deriva-
cyclization,
tive, the hydroxyl radical. These products can subsequently
and oxidation products, it can also act as a photosensitizer. The absorbed energy can be react with water molecules
to produce to
transferred peroxides,
molecular such as hydrogen
oxygen to form peroxides,
singlet oxygen,and reactive
superoxide oxygen speciesand
di-anion, [17,18].
its
To prevent the formation of oxidants, as well as to repair oxidative damage, cells have
derivative, the hydroxyl radical. These products can subsequently react with water
an armory of enzymatic and non-enzymatic antioxidants, including superoxide dismu-
molecules to produce peroxides, such as hydrogen peroxides, and reactive oxygen species
tase, catalase, glutathione peroxidase, reduced glutathione, vitamins C and E, uric acid,
[17,18]. To prevent the formation of oxidants, as well as to repair oxidative damage, cells
etc. [17,18]. On the other hand, bilirubin has also been shown to act as an antioxidant that
have an armory of enzymatic and non-enzymatic antioxidants, including superoxide
neutralizes tissue oxidants [19]. In fact, it has been suggested that physiologic TSB values
dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamins C and E, uric
are associated with antioxidant effects, while high pathologic values are associated with
prooxidant effects [20].
The evaluation and interpretation of phototherapy studies present unique challenges,
because so many parameters (device used; percent body surface area treated; type of light
source; spectral quality of delivered light; irradiance level delivered; distance of lamp to
skin; use of an appropriate spectrometer; duration of treatment; presence of ultraviolet and
infrared wavelengths, etc.) all contribute to the magnitude of the lowering effect on total
bilirubin in the circulation. However, many reports lack some or most of these essential
parameters, which complicates and limits the interpretation of the reported data and the
comparison of results between studies.
Int. J. Mol. Sci. 2023, 24, 461 3 of 13

Herein, we aim to discuss the most likely changes in the side effects of phototherapy
that might be observed if blue-green LED were to substitute blue fluorescent light sources
for the treatment of jaundiced neonates.

2. Results
2.1. Immediate Side Effects
Photodynamic damage (photo-oxidation and geno-/cytotoxicity).

2.1.1. In Vitro Studies

The oxidative effects in cells exposed to fluorescent phototherapy light in the pres-
ence of bilirubin have been studied in cell cultures [6,21–26]. An increased frequency
of chromatid breaks and exchanges was seen only in cells exposed to blue light in the
400–450 nm spectral range [21]. Fewer single DNA strand breaks and longer cell survival
were seen with blue-green fluorescent light in the 490–530 nm spectral range versus shorter
wavelengths [22,23]. Roll et al. [24] found less damage, expressed as the inhibition of cell
growth and necrosis, in cells exposed to blue-green fluorescent light with peak emission at
490 nm than in cells exposed to blue fluorescent light with peak emission at 450 nm. Thus,
these in vitro studies appear to show that the exposure of cells to the higher wavelengths
of blue-green light is associated with less photodynamic damage than blue light, leading
us to speculate that avoiding the use of light in the 400–450 nm spectral range may lead to
safer phototherapy for neonates.
When the bilirubin photoisomers Z,E-bilirubin, E,Z-bilirubin, and lumirubin, as well
as COX A and COX B, were incorporated into growing media, none of these bilirubin
products appeared to exert any toxic effects on cell viability [6,25]. Lumirubin was found
to induce fewer changes in mitochondrial respiration, substrate metabolism, and reactive
oxygen species than bilirubin IXα Z,Z [26].

2.1.2. Animal Studies

When hyperbilirubinemic homozygous Gunn rats were exposed to 440–520 nm blue-
green LED light [27,28], they excreted considerably less 8-hydroxydesoxyguanosin (8-
OHdG) in the urine than rats exposed to light in the wider spectral range 400 to 520 nm [27].
Furthermore, Gunn rats exposed to 450–520 nm light excreted the same amount of 8-OHdG
as non-exposed animals [28]. 8-OHdG is an oxidation product of guanine, which is the most
light-sensitive base of DNA [29]. This suggests that the exclusion of low wavelength light
in the 400–450 nm range, in favor of that in the 450–500 nm range, reduces photodynamic
DNA damage [27,28]. However, Gunn rats that received intensive phototherapy in the
form of LED light with a peak emission of 467 nm (range 416–544 nm) and irradiance
of 100 µW/cm2 /nm had normal excretion of 8-OHdG and normal content of gamma-
H2AX (a phosphorylated histone protein)-positive cells in the skin, a marker of DNA
repair [28]. Because bilirubin metabolism is somewhat different in humans than in Gunn
rats due to different properties of the albumin molecule [30], the implications of these
results for humans need to be ascertained. Moreover, contrary to humans, the production
and excretion of lumirubin in rats are low compared to ZE- and EZ-bilirubin [31].

2.1.3. Neonatal Studies

Oxidant stress and antioxidant defenses were compared between neonates exposed
to either broad-spectrum blue fluorescent light or narrow-spectrum blue LED light with
peaks of ~460 nm [32–36]. Thus, with LED light, the neonates are exposed to less light in
the 400–450 nm range. Total oxidant substances (TOS) increased, total antioxidant capacity
(TAC) decreased, and the oxidant stress index (OSI = TOS/TAC) increased in all groups,
while the frequency of sister chromatid exchange (SCE) and DNA damage scores increased;
however, the observed changes differed between the light sources [32–36]. In summary, the
described changes in OSI were greatest in neonates exposed to blue fluorescent light [33,35]
or blue LED light [32] or did not differ significantly between light sources [34]. In Mohamed
Int. J. Mol. Sci. 2023, 24, 461 4 of 13

et al.’s study [32] the frequency of SCE and DNA damage score increased most in neonates
receiving LED light, while Karadag et al. [36] failed to find differences in SCE between
groups that received LED phototherapy versus fluorescent phototherapy when compared
to jaundiced controls. SCE frequency and DNA damage correlated positively with TOS [32].
Thus, oxidant stress seems to increase in all groups of jaundiced neonates who receive
fluorescent or LED light, and there seems to be no significant difference between the two
light sources with respect to these parameters. However, because irradiance levels were
different, conclusions must be cautious: thus, the irradiance levels in neonates exposed to
fluorescent light were 10–20 µW/cm2 /nm compared to 30–35 µWatt/cm2 /nm in neonates
exposed to LED light. Blue LED light with peak emission ~460 nm and irradiances up to 35
µW/cm2 /nm did not induce oxidative DNA damage, expressed by the urine excretion of
8-OHdG, in neonates with gestational age ≤ 32 weeks [37].

2.2. Extremely Low Birth Neonates

In particular, during the phototherapy of extremely low-birthweight neonates (ELBW),
potential side effects need to be minimized. In a monumental study [38–40], one group of
ELBW neonates was treated “aggressively”, while another group was treated “conserva-
tively”, i.e., in the aggressively treated group phototherapy was initiated at lower TSB con-
centrations (either >85 µmol/L (5.0 mg/100 mL) or >119 µmol/L (7.0 mg/100 mL) depend-
ing on the body weight range) than in conservatively treated group (either >135 µmol/L
(7.9 mg/100 mL) or >171 µmol/L (10.0 mg/100 mL)). The irradiances were comparable.
As might be expected, the aggressively treated group had significantly lower TSB after
the treatment and, for a given TSB level, a longer duration of treatment than the conserva-
tively treated group. Follow-up at 18 to 22 months of age showed that aggressively treated
neonates with a birth body weight range of 500 to 750 g, who had respiratory failure in need
of mechanical ventilation, had a 5% reduction in the rates of neurodevelopment impairment,
but also a 5% higher mortality. This higher mortality could have been due to photodynamic
damage in these most immature babies with (1) limited photoprotection capacity due
to very thin, translucent skin with significantly reduced stratum corneum, low melanin
content in the immature melanocytes [41], and a low blood hemoglobin concentration,
which might compete with bilirubin for the light [16], and (2) low antioxidant capacity [41].
Another explanation might be a longer period of hemodynamic instability accompanying
phototherapy [42]. The neonates were treated almost equally with either blue fluorescent
light, a halogen spotlight, or blue LED light. The irradiances were maintained between 15
and 40 µW/cm2 /nm [43]. This means that the risk in mortality of future ELBW neonates
might decline by treating all neonates with blue-green LED light due to potentially reduced
photodynamic damage and more hemodynamic stability (see Section 2.6). However, using
longer wavelengths, the formation of lumirubin increases, and in vitro studies have shown
that lumirubin can affect the differentiation of human pluripotent cell-derived stem cells,
i.e., it might affect early neurodevelopment [44].

2.3. Riboflavin Level

Riboflavin is highly sensitive to light. The absorption maximum of the riboflavin
molecule in vitro is at 447 nm, close to the absorption maximum of the bilirubin–albumin
complex [45] and close to the peak emission wavelengths of blue fluorescent and LED
light at ~460 nm. However, the peak of the action spectrum of riboflavin in neonates
may be altered due to the back-scattering of light and competing photon absorption by
oxyhemoglobin, desoxyhemoglobin, and melanin, as has been determined for bilirubin [10].
By the absorption of a photon, riboflavin in the skin can act as a photosensitizer and
transfer energy to molecular oxygen, yielding hydrogen peroxide and oxidative products
of riboflavin itself [46], thereby reducing the riboflavin level [45,47,48]. Using blue-green
LED light instead of blue light, we hypothesize that the decomposition rate of riboflavin
will most likely be increased.
Int. J. Mol. Sci. 2023, 24, 461 5 of 13

Studies in vitro as well as in Gunn rats showed that riboflavin also enhances the photo-
dynamic destruction of bilirubin, resulting in decreased TSB [49–51]. Presumably, this
will also occur in neonates [49,52]. Thus, a change in phototherapy light quality to longer
wavelengths may also cause a change in the rate of bilirubin alteration via this mechanism.

2.4. Bronze Baby Syndrome

The bronze baby syndrome is a rare, visible side effect of phototherapy strongly
associated with liver diseases. The atresia of extra- or intrahepatic bile ducts, severe
hemolysis especially due to Rhesus and AB0 blood types isohemolytic diseases and severe
bacterial sepsis are predisposing factors [53–56]. The syndrome was thought to be caused
by the retention of copper–porphyrin complexes changed to bronze pigments by the
photosensitization of bilirubin [54]. However, this hypothesis has been shown to be
unlikely [57]. Ito et al. [42] suggest that the syndrome is caused by the accumulation
of polymerized products of bilirubin photoisomers, predominantly lumirubin. If this
hypothesis is correct, the use of LED light with longer wavelengths than 460 nm could,
by increasing the production of lumirubin, presumably also increase the production and
retention of bronze pigments in neonates with predisposing factors, if this compound is
not excreted rapidly. Although it is generally believed that the syndrome is harmless, there
are some suggestions that it may constitute an additional risk of KSD [55,56].

2.5. Immune System

Phototherapy can affect the immature immune system via the alteration of cytokine
production (Table 1) [25,58–60]. The exposure of hyperbilirubinemic neonates to a mixture
of blue and white fluorescent light was found to increase the plasma concentrations of the
pro-inflammatory cytokines TNF-α, IL-1ß, and IL-8, and reduce the lymphocyte subset
CD3+, while the concentration of IL-6 remained unchanged [58]. Using the same types of
light the phototherapy resulted in a significant decrease in IL-6, but without significant
changes in TNF-α, IL-1ß, IL-8, and IL-10 [59]. An increase in irradiance was associated with
a greater decline in IL-6 [59]. Furthermore, during phototherapy, the production of IL-1ß by
peripheral blood monocytes decreased, and IL-2 and the anti-inflammatory cytokine IL-10
increased [60]. Jasprova et al. [6] showed that lumirubin upregulated the gene expression
of TNF-α, IL-1ß, and IL-6 in rat hippocampal slices. However, immunologic studies com-
paring different light qualities have not been performed, and it will be apparent from the
results cited above that the reported impact of phototherapy on immunological processes
varies considerably, presumably due to methodological differences, including wavelength
determinations and irradiance measurements. Thus, further studies are needed to eluci-
date these phenomena. As an example, blue-green LED light increases the production of
lumirubin [3,4], which, according to the findings of Jasprova et al. [6], may perhaps induce
a greater immune response.

Table 1. Immunological effects.

TNF-α IL-1ß IL-2 IL-3 IL-6 IL-8 IL-10 CD3+

No
Kurt, A. et al. [58] ↑ ↑ ↑ ↓
change
No No No
Sirota, L. et al. [60] ↓ ↑ ↑
difference change change
No No No
Procianoy, R. S. et al. [59] No change ↓*
change change change
Jasprova, J. et al. [6] ** ↑ ↑ ↑
* Decline in IL-6 significantly correlated with irradiance; ** refers to gene expression in hippocampal slices exposed
to lumirubin. ↑ increased concentration; ↓ decreased concentration.
Int. J. Mol. Sci. 2023, 24, 461 6 of 13

2.6. Hemodynamic Changes

The exposure of preterm neonates to blue fluorescent light has been shown to change
the hemodynamics in various organs. Peripheral blood flow increased due to the relaxation
of the blood vessels in the skin [61,62], presumably caused by visual light with wavelengths
above 530 nm and/or infrared light (heat) [63]. This was followed by the redistribution
of the blood flow: cerebral blood flow increased, while renal, as well as postprandial
mesenteric blood flow and cardiac output, decreased [64–66]. A small but significant drop in
blood pressure and an increase in heart rate occurred in low-birthweight neonates [66]. The
incidence of open ductus arteriosus was increased in ELBW neonates, thus a reopening of
the duct may occur [66]. The dilatation of the skin blood vessels may result from a changed
dynamic balance between the vasodilator nitric oxide and the constrictor endothelin, in the
form of an increased ratio of nitric oxide to endothelin, the plasma concentrations of which
both rise during phototherapy with fluorescent light [67]. However, cerebral blood flow
did not increase in thermally stable preterm neonates exposed to blue fluorescent light (care
was taken to avoid heat stress caused by irradiation from the phototherapy equipment) [68].
In neonates exposed to blue LED light, changes in cerebral and mesenteric blood flows
were not seen, most likely because this light source emits very little light with wavelengths
> 530 nm, including infrared light [63]. Most likely, similar results will be seen in response
to treatment with blue-green LED light.

2.7. Transepidermal Water Loss

In neonates treated with daylight or blue fluorescent light, a rise in transepidermal wa-
ter loss (TEWL) was seen [63,69,70], presumably caused by light with wavelengths > 530 nm,
including infrared light [63], while in thermally stable term neonates, TELW did not change,
as expected [69]. In preterm neonates receiving blue LED phototherapy of standard irradi-
ance, TELW did not change, most likely because this light source emits very little heat in
the above-mentioned spectral range [63]. Therefore, such neonates do not need extra fluid
during phototherapy. It is very likely that similar results will be obtained using blue-green
LED light.

2.8. Hyper- and Hypothermia

Blue fluorescent phototherapy increased the body temperature in both preterm and
term neonates, while blue LED phototherapy with an irradiance < 60 µW/cm2 /nm did not
cause a change in body temperature. However, at irradiances > 60 µW/cm2 /nm, a risk of
hyperthermia was observed, even with the use of LED light [71]. Blue LED phototherapy
involved a low risk of hyperthermia because LEDs emit little heat [72]. However, depending
on the distance of the body to the light source, neonates, especially premature ones, may
be at risk for hypothermia. Thus, it is recommended that the body temperature also be
monitored during LED phototherapy, especially when the neonate is treated in a bassinet.
It is most likely that body temperature will behave similarly with the use of blue-green
LED phototherapy.

2.9. Vision
It is deemed unlikely that a switch in use from short wavelength blue to longer
wavelength blue-green light will cause eye damage, as there are no clinical reports that
the shorter blue wavelength causes any measurable eye damage. However, the eyes of
hospitalized neonates are routinely protected by eye patches when under phototherapy.
The evidence for this practice has been derived from a limited number of controversial rat
studies [73,74]. When Crigler-Najjar patients, who typically receive high irradiance levels of
phototherapy (up to 100 µW/cm2 /nm) over large proportions (>30%) of their body surfaces
for 8–10 h/day for many years, were tested for visual acuity and color discrimination score,
no significant difference in these qualities were found when compared to age-matched
non-Crigler-Najjar sibling controls. The Crigler-Najjar subjects typically do not wear eye
protection while receiving phototherapy [75,76].
Int. J. Mol. Sci. 2023, 24, 461 7 of 13

2.10. Hypocalcemia
During phototherapy with blue or white fluorescent light, a usually asymptomatic
hypocalcemia was found [77–80]. Plasma levels usually returned to normal by 24 h post-
phototherapy [77]. It was hypothesized that the hypocalcemia was due to a decrease
in pineal melatonin secretion, induced by transcranial penetration of the light [81]. By
Covering the head, the decline of serum calcium was reduced, but it was still significant [80].
As neonates wear eye pads during phototherapy, the hypocalcemic effect may involve
extra-ocular pathways. It was suggested that melatonin may block the absorbing effect of
cortisol on bone calcium [81]. Finally, the decline in serum calcium during phototherapy
was neither correlated to TSB [78] nor plasma melatonin concentrations [79]. More studies
are needed to show whether the risk of hypocalcemia will change with the use of blue-green
LED phototherapy.

2.11. Loose Stools

During phototherapy with blue fluorescent light, loose green stool is frequently seen,
and the gut transit time is decreased in a dose-dependent manner [82]. The increased
intestinal secretion of water and electrolytes during phototherapy may be induced by the
increased production of vasoactive intestinal peptides, possibly caused by bilirubin isomers
or bilirubin degradation products [83]. Future investigations may show whether a change
to blue-green LED light will change the gut transit time.

2.12. Parent–Neonate Attachment and Breastfeeding

Parent–neonate separation during phototherapy from above and/or below has been
reported to have a negative influence on the establishment of parent–neonate social in-
teraction and breastfeeding, as well as making nursing access and observations more
cumbersome. In addition, a number of families and caregivers have reported issues when
exposed to blue and blue-green fluorescent light (14). It is likely that these consequences
will be reduced by a switch from blue- to blue-green LED phototherapy due to the shorter
duration of phototherapy. However, the caregivers’ tolerance of blue and blue-green
fluorescent light was equal (14).

3. Long-Term Side Effects (Epidemiologic Studies)

3.1. Cancer
Among the long-term side effects of phototherapy, the risk of cancer is potentially the
most serious and often-discussed topic. As mentioned above, the phototherapy of neonates
may damage DNA, increase oxidant stress, and produce cytokines, factors that have all
been implicated in the pathogenesis of cancer [84]. Thus, phototherapy has carcinogenic
potential [85].
Newman et al. [84] found a slightly positive association between phototherapy and any
leukemia, non-lymphocytic cancer, and liver cancer, but after adjustment for confounders,
including TSB, these associations were eliminated or diminished and were no longer signif-
icant. Both for neonates who either received or did not receive phototherapy, in adjusted
analyses significant positive associations were found between hyperbilirubinemia and
infantile myeloid leukemia and kidney cancer [86], any childhood leukemia [84], childhood
myeloid leukemia [87], and solid tumors, especially CNS and nervous system tumors [85].
TSB below the phototherapy limit was also associated with cancer development [84,86],
but the associations were stronger for TSB values above the phototherapy limit in neonates
in need of phototherapy [85–88]. These associations may either simply reflect groups of
infants exposed to more severe hyperbilirubinemia or may reflect added cancer risk due to
phototherapy. In other studies, no association was found between neonatal hyperbilirubine-
mia and leukemia in neonates, who either received or did not receive phototherapy [89,90].
To our knowledge, no cases of cancer have been reported in patients suffering from Crigler-
Najjar syndrome. In summary, based on the current state of knowledge, we cannot rule
out a possible association between phototherapy and the risk of tumor development, but
Int. J. Mol. Sci. 2023, 24, 461 8 of 13

the evidence for such a side effect is very weak, especially as the vast majority of these
neonates have, in all probability, been exposed to blue fluorescent light. We speculate that,
if neonates are treated with blue-green LED light, both DNA damage and oxidative stress
will decrease, and possibly also the cancer risk.

3.2. Allergic Diseases

An association between the incidence of allergic diseases (asthma, allergic conjunc-
tivitis and rhinitis, atopic dermatitis, and urticaria) and neonatal hyperbilirubinemia has
been observed in several studies, both in children who either received or did not receive
phototherapy [91–93]. These associations may be enhanced by phototherapy, as it increases
the production of Th-2 pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-8 [58],
and also decreases IL-6 [59], which promotes a Th-2 shift in a pro-allergic direction [93,94].
Because the changes in interleukin concentrations may be induced by lumirubin [23], the
association may become stronger using blue-green LED light than blue LED light due to
the increased lumirubin production [14,15].
Eosinophils have a role in the pathogenesis of childhood asthma. After the phototherapy
of jaundiced neonates using blue LED light, the blood levels of eosinophils and eosinophilic
cationic protein increased as an expression of the activation of eosinophils [95–97].

3.3. Diabetes Type 1

A small but significant association between diabetes mellitus type 1 and neonatal
hyperbilirubinemia, with or without the need for phototherapy, has been described [98,99].
However, Newman et al. [100] could not confirm this association.

3.4. Childhood Epilepsy

Hyperbilirubinemia was associated with an increased risk for childhood epilepsy,
primarily in boys, both in children who had received versus had not received photother-
apy [101,102]. These investigations confirmed earlier studies showing a positive association
between neonatal hyperbilirubinemia and childhood epilepsy [103,104].

3.5. Autism Spectrum Disorders

Studies on the association between autism spectrum disorders, hyperbilirubinemia,
and phototherapy have shown divergent results: both a positive relationship [105,106] or a
lack of a relationship have been demonstrated [107–109]. These inconsistent results may be
due to methodological differences.

4. Summary
An overview of the potential immediate and long-term side effects resulting from a
switch from blue fluorescent light to blue-green LED light is shown in Table 2.
In the epidemiological studies of diabetes type 1, childhood epilepsy, and autism
spectrum disorders, the types of light sources were not reported, but the vast majority of
children have, in all probability, been exposed to blue fluorescent light. Whether these
potentially weak side effects will be confirmed or even more diminished with the use of
blue-green LED light needs to be determined with future investigations.
Int. J. Mol. Sci. 2023, 24, 461 9 of 13

Table 2. Changes in potential side effects affected by a transition of blue fluorescent light to blue-green
LED light phototherapy of hyperbilirubinemic neonates.

Parameters Effect Reason References

Photo-dynamic damage Decrease Reduced photo-oxidation and geno-cytotoxicity [21–24,27,28]
Reduced photo-dynamic damage and hemodynamic
Mortality of ELBW neonates Decrease [21–24,27,28,42]
responses
Riboflavin deficiency Decrease Photo-oxidation of riboflavin [45–48]
Bronze Baby Syndrome Increase Increased production and retention of bronze pigments [42]
Immune response Increase Increased production of pre-inflammatory cytokines [6]
Decreased exposure to visible light with wavelength
Hemodynamic responses Decrease [63]
>530 nm and infrared light (heat)
Transepidermal water loss Decrease As under hemodynamic responses [63]
Hypo-/hyperthermia Increase/Decrease As under hemodynamic responses [71,72]
Parent–neonate attachment
Increase Shorter duration of phototherapy [11]
and breast feeding
Cancer frequency Decrease Decreased photo-dynamic damage [84,85]
Allergic diseases Increase Increased immune response [6]

5. Material and Methods

A search of the literature with the terms neonate, hyperbilirubinemia, and photother-
apy in PubMed and Embase.

6. Conclusions
Transitioning from the traditional blue fluorescent light to blue-green LED photother-
apy will expose neonates to less light in the 400–450 nm spectral range, hypothetically
leading to less photodynamic damage, reduced risk of cancer, and decreased mortality
in ELBW neonates. The degree of riboflavin deficiency may be greater, and the increased
production and retention of bronze pigments may possibly occur in predisposed neonates
due to the enhanced formation of lumirubin. The production of pre-inflammatory cytokines
may increase. Changes in hemodynamic responses and TEWL may not occur. The risk of
hypothermia is expected to increase during blue-green phototherapy, while the risk of hy-
perthermia is expected to decrease. The negative influence on parent–neonate attachment
and breastfeeding may be reduced due to the shorter duration of the phototherapy. The
risk of allergic diseases may increase due to a greater immune response.
Currently, we cannot predict with reasonable certainty whether the possible risks of
immediate side effects such as hypocalcemia and loose stool, as well as long-term side
effects such as diabetes type 1, epilepsy, and autism spectrum disorders, will change upon
transitioning from blue to blue-green LED light. This will need to be explored in future
investigations. However, we wish to emphasize that the major benefit of shifting from blue
to blue-green phototherapy is the very significant increase in efficacy (30%) leading to a: a
reduction in time under phototherapy; b: a shorter exposure of the body to phototherapy
light and its consequences; c: a shorter exposure to elevated, unconjugated bilirubin
concentrations; d: reductions in the costs of phototherapy; and finally e: a reduction in the
cost of phototherapy involving hospitalizations.
Finally, although some associations were shown in the epidemiologic studies, this does
not constitute proof of a cause–effect relationship. Indeed, they may be epiphenomena.

Author Contributions: F.E. conceptualized and designed the study, drafted the initial manuscript,
and is responsible for the final manuscript. H.J.V. and T.W.R.H. reviewed and made recommendations
towards the improvement of the manuscript. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: None of the authors have any conflict of interest to disclose. None of the
authors have any financial support to disclose.
Int. J. Mol. Sci. 2023, 24, 461 10 of 13

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