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The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

A Randomized Trial of Phototherapy


with Filtered Sunlight in African Neonates
TinaM. Slusher, M.D., BolajokoO. Olusanya, F.R.C.P.C.H., Ph.D.,
HendrikJ. Vreman, Ph.D., AnnM. Brearley, Ph.D.,
YvonneE. Vaucher, M.D., M.P.H., TroyC. Lund, M.D., Ph.D.,
RonaldJ. Wong, B.A., AbieyuwaA. Emokpae, M.B., B.S., F.M.C.Paed.,
and DavidK. Stevenson, M.D.

A BS T R AC T

BACKGROUND
Sequelae of severe neonatal hyperbilirubinemia constitute a substantial disease From the Department of Pediatrics
burden in areas where effective conventional phototherapy is unavailable. We pre- (T.M.S., T.C.L.) and the Biostatistical De-
sign and Analysis Center, Clinical and
viously found that the use of filtered sunlight for the purpose of phototherapy is Translational Science Institute (A.M.B.),
a safe and efficacious method for reducing total bilirubin. However, its relative University of Minnesota, and Hennepin
safety and efficacy as compared with conventional phototherapy are unknown. County Medical Center (T.M.S.) both
in Minneapolis; Center for Healthy Start
Initiative (B.O.O.) and Massey Street Chil-
METHODS drens Hospital (A.A.E.), Lagos, Nigeria;
We conducted a randomized, controlled noninferiority trial in which filtered sun- and Department of Pediatrics, Stanford
University, Stanford (H.J.V., R.J.W., D.K.S.),
light was compared with conventional phototherapy for the treatment of hyper- and the University of California, San Diego,
bilirubinemia in term and late-preterm neonates in a large, urban Nigerian mater- San Diego (Y.E.V.) both in California.
nity hospital. The primary end point was efficacy, which was defined as a rate of Address reprint requests to Dr. Slusher at
the Center for Global Pediatrics, Depart-
increase in total serum bilirubin of less than 0.2 mg per deciliter per hour for ment of Pediatrics, University of Minne-
infants up to 72 hours of age or a decrease in total serum bilirubin for infants sota, 717 Delaware St. SE, 3rd Fl., Minneap-
older than 72 hours of age who received at least 5 hours of phototherapy; we pre- olis, MN 55414, or at tslusher@umn.edu.
specified a noninferiority margin of 10% for the difference in efficacy rates be- N Engl J Med 2015;373:1115-24.
tween groups. The need for an exchange transfusion was a secondary end point. DOI: 10.1056/NEJMoa1501074
Copyright 2015 Massachusetts Medical Society.
We also assessed safety, which was defined as the absence of the need to withdraw
therapy because of hyperthermia, hypothermia, dehydration, or sunburn.

RESULTS
We enrolled 447 infants and randomly assigned 224 to filtered sunlight and 223 to
conventional phototherapy. Filtered sunlight was efficacious on 93% of treatment
days that could be evaluated, as compared with 90% for conventional phototherapy,
and had a higher mean level of irradiance (40 vs. 17 W per square centimeter per
nanometer, P<0.001). Temperatures higher than 38.0C occurred in 5% of the in-
fants receiving filtered sunlight and in 1% of those receiving conventional photo-
therapy (P<0.001), but no infant met the criteria for withdrawal from the study for
reasons of safety or required an exchange transfusion.

CONCLUSIONS
Filtered sunlight was noninferior to conventional phototherapy for the treatment
of neonatal hyperbilirubinemia and did not result in any study withdrawals for
reasons of safety. (Funded by the Thrasher Research Fund, Salt Lake City, and the
National Center for Advancing Translational Sciences of the National Institutes of
Health; Clinical Trials.gov number, NCT01434810.)

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The n e w e ng l a n d j o u r na l of m e dic i n e

W
orldwide, severe neonatal hy- State Government. The light-filtering films used
perbilirubinemia affects at least 481,000 in the study were approved by the National Agency
term or near-term newborn infants for Food and Drug Administration and Control
annually, of whom 114,000 die and more than of Nigeria and were donated by CPFilms, which
63,000 survive with moderate or severe disabili- had no other role in the study. The study proto-
ties.1-3 The majority of affected infants (>75%) col is available with the full text of this article at
reside in low-to-middle-income countries, partic- NEJM.org. The first and second authors take
ularly in sub-Saharan Africa.1-5 Severe neonatal responsibility for the accuracy and completeness
hyperbilirubinemia that progresses to acute bili- of reporting and the fidelity of the report to the
rubin encephalopathy or kernicterus is devastat- protocol.
A Quick Take is
available at ing for infants, children, and their families,
NEJM.org since surviving children may have severe long- Study Procedures
term impairments, including choreoathetoid All infants who were up to 14 days of age and
cerebral palsy, deafness, language-processing had a gestational age of least 35 weeks (or
disorders, and general developmental delays.6-10 weighed >2.2 kg, if the gestational age was un-
These outcomes are rare in high-income coun- known) were eligible for participation. Although
tries, where there is timely recognition of clini- skin color varies widely, especially at birth, all
cally significant hyperbilirubinemia and access infants in this study were black Africans. Infants
to effective treatment with phototherapy.11-13 Lev- in hospital were screened daily in accordance
els of bilirubin have long been known to be with routine hospital protocol, and infants who
altered by light.14 Building on this knowledge, returned for evaluation of jaundice were also
investigators developed modern phototherapy as screened, with the use of the JM-103 transcuta-
the primary treatment for neonatal hyperbiliru- neous bilirubinometer (Draeger Medical).22 If the
binemia.15 However, in areas with limited re- transcutaneous bilirubin level was elevated, then
sources, conventional phototherapy, defined as total serum bilirubin was measured with the use
irradiance of at least 8 to 10 W per square of the Advanced BR2 Bilirubin Stat-Analyzer (Ad-
centimeter per nanometer,16 is often unavailable vanced Instruments). If the total serum bilirubin
because of its cost or ineffective because of the was elevated (as defined in our protocol), the
inconsistent supply of electrical power or the low infant was eligible for enrollment and treatment,
levels of irradiance emitted by the phototherapy and written informed consent was obtained from
bulbs available, which may be inferior in quality the parent or guardian. The screening and treat-
or limited in quantity or may have deteriorated.17-20 ment thresholds for bilirubin levels (Table S1 in the
We previously reported the results of the ini- Supplementary Appendix, available at NEJM.org)
tial phase of this study, in which phototherapy were 3 mg per deciliter lower than the guideline
with filtered sunlight was found to be safe and recommended by the American Academy of Pedi-
efficacious when used to reduce excessive total atrics16 as a safety precaution, since filtered sun-
serum bilirubin.21-23 We now report the results of light had not been used for this purpose previ-
the second phase of the study, a randomized ously and hemolysis resulting from a deficiency
trial in which filtered sunlight is directly com- of glucose-6-phosphate dehydrogenase or from
pared with conventional phototherapy. blood-group incompatibilities is common in
Nigeria.24
The exclusion criteria included the need for
Me thods
medical treatment elsewhere, a life expectancy
Study Design of less than 24 hours, the need for oxygen
This randomized, controlled, nonblinded, non- therapy, clinical dehydration or sunburn, a tem-
inferiority trial was conducted at Island Mater- perature lower than 35.5C or higher than 38.0C,
nity Hospital, a large inner-city hospital in Lagos, a diagnosis of acute bilirubin encephalopathy, or
Nigeria, in accordance with our previously pub- the need for exchange transfusion. Enrolled in-
lished protocol.22 We obtained approval from the fants were randomly assigned to receive filtered
institutional review boards and ethics commit- sunlight or conventional phototherapy with the
tees of the University of Minnesota, the Minne- use of a block randomization procedure, with
sota Medical Research Foundation, and the Lagos block sizes of 2, 4, 6, 8, and 10. Treatment as-

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Photother apy with Filtered Sunlight in African Neonates

signments recorded on sequentially numbered tested film canopies (donated by CPFilms) de-
sheets of paper, enclosed in opaque, sealed, pending on whether the sky was overcast, in which
matching, numbered envelopes, were shipped to case the Air Blue 80 film was used, or sunny, in
Lagos and opened sequentially for each enrolled which case Gila Titanium film was used. Infants
infant. were rotated between canopies as needed.21-23
Laboratory tests included total serum biliru- Both films filter out most ultraviolet A light
bin, hematocrit, maternal and infant blood group- (>99%), virtually all ultraviolet B and C light,
ing, and screening for glucose-6-phosphate de- and some infrared (heat) radiation while allow-
hydrogenase.25 Irradiance was measured hourly ing passage of 84% (Air Blue 80) and 39% (Tita-
outdoors and under a canopy that filtered sun- nium) of therapeutic blue light (400 to 520 nm).
light and once daily under conventional photo- Detailed characteristics of these films have been
therapy units with the use of the BiliBlanket described.21-23 Infants assigned to receive conven-
Meter II (GE Healthcare), which has a wavelength tional phototherapy were placed under photo-
sensitivity of 400 to 520 nm, with a peak sensi- therapy constructed according to published
tivity of 450 nm. specifications with the use of locally available
Total serum bilirubin was measured at the materials,26 with maintenance of irradiances of
start and end of each treatment day, which was at least 8 to 10 W per square centimeter per
defined as at least 5 hours of phototherapy, gen- nanometer27,28 (Fig. S1 in the Supplementary Ap-
erally from 10 a.m. to 4 p.m. Measurement of pendix). The indication for the use of conven-
axillary body temperatures and a clinical evalu- tional nighttime phototherapy in both groups
ation for dehydration and sunburn were obtained was an afternoon total serum bilirubin that was
hourly. at least the treatment level for age-in-hours recom-
On the basis of data from our previous mended by the American Academy of Pediatrics.
study,23 hyperthermia was managed prophylacti-
cally with wet white towels placed under and, if Study End Points
needed, around the infant with temperatures The primary end point was efficacy, with a non-
higher than 37.5C and up to 38.0C and thera- inferiority margin of 10%. The criteria for effi-
peutically with temperatures higher than 38.0C cacy were unchanged from our previous study23
with brief removal from phototherapy to a shaded and included a rate of increase in total serum
area. Hypothermia (temperature <35.5C) was bilirubin of less than 0.2 mg per deciliter per
managed by swaddling the infant in cloth briefly, hour for infants up to 72 hours of age or a de-
by providing skin-to-skin care with the mother crease in total serum bilirubin for infants older
(also called kangaroo care), or both. Infants with than 72 hours of age who were receiving at least
temperatures higher than 38.0C or lower than 5 hours of phototherapy. These levels were cho-
35.5C for more than 1 hour or higher than sen on the basis of expert consultation, the guide-
39.0C or lower than 35.0C on two or more oc- line from the American Academy of Pediatrics,16
casions, or who received treatment for sunburn and data from Johnson et al.29 The secondary
or dehydration (excluding breast-feeding) met the end point was the proportion of infants requir-
criteria for study withdrawal. Additional criteria ing exchange transfusion, with a noninferiority
for withdrawal included the need for an ex- margin of 5%.
change transfusion, the presence of an intercur- We followed the previously published safety
rent illness incompatible with phototherapy, protocol from the first phase of the study.23 Photo
parental request, death, or hospital transfer. The therapy was deemed safe if an infant was able to
protocol was completed when the infants total receive phototherapy without meeting the study
serum bilirubin no longer met the criteria for criteria for withdrawal for hyperthermia, hypo-
study entry. Safety data were reviewed by the thermia, dehydration, or sunburn.
data and safety monitoring board at the mid-
point of the study (June 2013). Sample Size
A total of 560 treatment days that could be
Interventions evaluated was required to have 80% power for a
Infants assigned to the group receiving filtered test of noninferiority with a margin of 10%, as-
sunlight were placed under one of two previously suming at least 5 hours of exposure to photo-

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therapy on 90% of treatment days, with an aver- R e sult s


age efficacy of 80%. Given a conservative estimate
of the need for 1 day of phototherapy per infant, Enrollment and Follow-up
and with an estimated 40% of enrolled infants Between November 2012 and September 2013, a
expected to go without treatment because their total of 1468 term and late-preterm infants were
total serum bilirubin made them ineligible or screened for jaundice with the use of transcuta-
because of rain or withdrawal of consent, we neous bilirubinometry, in accordance with the
planned to enroll 924 infants. protocol. Because of lower-than-anticipated rates
of nontreatment and a higher-than-anticipated
Statistical Analysis number of days required for phototherapy, we
Study data were recorded on paper forms and reached the required number of treatment days
then transferred to a secure, Web-based REDCap that could be evaluated (560 days) in 10 months
database.30 Data cleaning and statistical analyses with 447 eligible infants who were enrolled and
were carried out with the use of statistical soft- randomly assigned to receive either filtered sun-
ware package R, version 3.1.1. light (224) or conventional phototherapy (223).
The following data were summarized: demo- Fourteen randomized infants (3%) did not re-
graphics, blood groups for motherinfant pairs, ceive phototherapy (Fig.1). Of 433 treated infants,
irradiance levels inside and outside filtered sun- 384 (89%) completed treatment and 49 withdrew
light canopies and inside conventional photo- early. (Reasons for withdrawal are shown in
therapy cots, and days of phototherapy received. Fig.1.)
Differences according to assigned treatment A total of 213 infants received 268 days of
were tested with the use of Wilcoxon rank-sum filtered-sunlight phototherapy, and 220 infants
tests for continuous variables and Pearson chi- received 325 days of conventional phototherapy
square tests or exact binomial 95% confidence (Table S2 in the Supplementary Appendix). Only
intervals for categorical variables. The safety and 5 infants required more than 4 days of photo-
efficacy of filtered-sunlight and conventional therapy; all were in the conventional phototherapy
phototherapy were compared on an intention-to- group. Two mothers of infants receiving conven-
treat basis. Additional comparisons were planned tional phototherapy requested transfer to photo-
on an as-treated basis for treatment actually re- therapy with filtered sunlight on the last treat-
ceived and on a per-protocol basis for infants ment day (day 6). Nighttime phototherapy for
receiving the assigned treatment on all treatment one night or more was indicated for 28 infants
days. All treatment days were analyzed, includ- (13%) in the filtered-sunlight group and 35 infants
ing those days on which treatment was received (16%) in the conventional phototherapy group.
by infants who were later withdrawn from the Safety was assessed for all 593 treatment days,
study. Safety was compared with the use of and efficacy was assessed for the 561 days that
Fishers exact test. Efficacy was compared with could be evaluated (95%). Efficacy could not be
the use of one-sided chi-square tests of noninfe- evaluated for 32 treatment days because the pho-
riority with a prespecified margin of 10%. totherapy time was less than 5 hours (17 days),
Post hoc exploratory analyses of the effects of afternoon measurements of bilirubin were miss-
initial bilirubin level, average irradiance level, ing (5 days), or the data for phototherapy time
and treatment (filtered sunlight vs. conventional were missing (10 days).
phototherapy) on bilirubin kinetics were con-
ducted with the use of Wilcoxon rank-sum tests Participant Characteristics
and general linear mixed models. The rate of The demographic and baseline characteristics of
change in total serum bilirubin was modeled as enrolled infants, including the results of labora-
a linear function of initial bilirubin level, aver- tory analyses, are shown in Table1. There were
age irradiance level, and treatment group, with a no significant differences between the filtered-
random effect of the individual infant to account sunlight and conventional phototherapy groups
for potential correlation. Models were compared at baseline. Overall, 83 infants had glucose-
with the use of Akaikes information criterion 6-phosphate deficiency, 76 were at risk for ABO
without attempting to correct for multiple com- incompatibility, and 13 were at risk for Rh in-
parisons. compatibility (Table1).

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Photother apy with Filtered Sunlight in African Neonates

1468 Infants were screened

1021 Did not have high level of TcB, had


high level of TB but did not meet inclusion
criteria or met exclusion criteria, or did not
provide consent

447 Were enrolled and underwent


randomization

224 Were assigned to filtered-sunlight 223 Were assigned to conventional


phototherapy phototherapy

11 Were not treated


4 Were not treated
owing to heavy rainfall 3 Were not treated
4 Were too ill 2 Were febrile
1 Needed EBT 1 Was preterm
2 Had consent
withdrawn

213 (in 268 days) Were treated with 220 (in 325 days) were treated with
filtered-sunlight phototherapy conventional phototherapy

18 (in 18 days) Could 13 (in 14 days) Could


not be evaluated not be evaluated
6 Had missing time 4 Had missing time
in phototherapy in phototherapy
11 Received <5 hr 6 Received <5 hr
of phototherapy of phototherapy
1 Had missing 4 Had missing
afternoon TB afternoon TB

201 (in 250 days) Could 231 (in 311 days) Could
be evaluated for efficacy be evaluated for efficacy

Figure 1. Enrollment, Randomization, Treatment, and Evaluation.


Among the 433 treated infants, 384 (89%) completed treatment and 49 (11%) withdrew after 1 or more days of
treatment owing to the need for nighttime conventional phototherapy (30) or to parental request (10), heavy rainfall
(5) or infant illness (4). EBT denotes exchange blood transfusion, TB total serum bilirubin, and TcB transcutaneous
bilirubin.

Irradiance Measurements wider for filtered sunlight than it was for con-
The irradiance from filtered sunlight was mea- ventional phototherapy (Fig.2A), with highest
sured 2959 times (with 88% of the measurements irradiances occurring between noon and 2 p.m.
performed under the Air Blue 80 canopy and 12% (Fig.2B).
under the Gila Titanium canopy), and the irradi-
ance from conventional phototherapy was mea- Efficacy
sured 293 times. Mean irradiance levels were Filtered-sunlight phototherapy was efficacious
significantly higher with filtered sunlight than on 93% of days that could be evaluated as com-
with conventional phototherapy (40 vs. 17 W per pared with 90% for conventional phototherapy ac-
square centimeter per nanometer, P<0.001). As cording to an intention-to-treat analysis (Table2).
expected, the spread of irradiances was much As-treated and per-protocol analyses yielded sim-

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Table 1. Baseline Characteristics of the Study Population.*


ilar results (efficacy, 93% vs. 90% in both cases).
No infant in either group required an exchange
Filtered-Sunlight Conventional transfusion.
Phototherapy Phototherapy
Characteristic (N=224) (N=223)
Safety
Male sex no. (%) 122 (54) 120 (54)
No infant in either group met the criteria for with-
Estimated gestational age wk
drawal related to safety. Axillary temperature
Median 38 38
exceeded 39.0C once, for 1 infant, but returned
Interquartile range 3839 3839
to the normal range within 25 minutes after the
Birth weight kg
infant was moved to the shade and treated with
Median 3.2 3.2
wet towels. Axillary temperature exceeded 38.0C
Interquartile range 2.93.5 2.93.6
in 5% of temperature checks in the filtered-
Hematocrit %
sunlight group versus 1% in the conventional
Median 53 55
phototherapy group (P<0.001) (Table2, and Fig. S2
Interquartile range 4758 4760
in the Supplementary Appendix). Axillary temper
Initial total serum bilirubin on day 1 mg/dl
ature exceeded 38.0C in one or more measure-
Median 5.9 6.2
ments in 61 of the infants receiving filtered
Interquartile range 4.97.7 5.08.0
Infants blood type no./total no. (%)
sunlight (29%) and 13 of those receiving conven-
A 45/221 (20) 47/222 (21)
tional phototherapy (6%), and the temperature
B 45/221 (20) 42/222 (19)
exceeded 38.0C more than twice in 16 of the in-
AB 6/221 (3) 6/222 (3)
fants exposed to filtered sunlight (8%) and none
O 103/221 (47) 110/222 (50)
of those exposed to conventional phototherapy.
Unknown 22/221 (10) 17/222 (8)
Wet white towels were used prophylactically or
Mothers blood type no./total no. (%) therapeutically for 68% of infants receiving fil-
A 39/223 (17) 43/222 (19) tered sunlight in 34% of the periodic checks ver-
B 35/223 (16) 26/222 (12) sus 24% for those receiving conventional photo-
AB 4/223 (2) 3/222 (1) therapy in 7% of periodic checks. Hypothermia
O 110/223 (49) 110/222 (50) (axillary temperature, <35.5C) occurred infre-
Unknown 35/223 (16) 40/222 (18) quently (8 of 1863 checks in the filtered-sunlight
ABO incompatibility no./total no. (%) group vs. 2 of 2160 checks in the conventional
No 135/221 (61) 123/221 (56) phototherapy group [P=0.03]) and was treated
Yes 34/221 (15) 42/221 (19) in accordance with the protocol, as noted earlier.
Unknown 52/221 (24) 56/221 (25)
Infants Rh status no./total no. (%) Post Hoc Exploratory Analyses
Positive 186/222 (84) 191/222 (86) Total serum bilirubin fell more rapidly on treat-
Negative 13/222 (6) 14/222 (6) ment with filtered sunlight than with conven-
Unknown 23/222 (10) 17/222 (8) tional phototherapy (Table2). With filtered sun-
Mothers Rh status no./total no. (%) light, the median rate of change in bilirubin was
Positive 175/224 (78) 173/222 (78) 0.07 mg per deciliter per hour, and with con-
Negative 12/224 (5) 9/222 (4) ventional phototherapy, the median rate of change
Unknown 37/224 (17) 40/222 (18) was 0.00 mg per deciliter per hour (P<0.001).
Rh incompatibility no./total no. (%) Bilirubin levels fell significantly more rapidly
No 160/222 (72) 160/221 (72) when the initial (morning) bilirubin level was at
Yes 8/222 (4) 5/221 (2) least 12 mg per deciliter (Table S3 in the Supple-
Unknown 54/222 (24) 56/221 (25) mentary Appendix) and on days when the aver-
Glucose-6-phosphate dehydrogenase age irradiance was at least 30 W per square
status no./total no. (%) centimeter per nanometer (Table S3 in the Sup-
Present 184/224 (82) 169/221 (76) plementary Appendix). Higher initial bilirubin
Deficient 35/224 (16) 48/221 (22) levels, higher average irradiance, and filtered
Unknown 5/224 (2) 4/221 (2) sunlight were all associated with a more rapid
* None of the between-group differences were significant at P<0.05.
decline in bilirubin level (Table S4 in the Supple-
mentary Appendix).

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Photother apy with Filtered Sunlight in African Neonates

Discussion A Spread of Irradiances

This randomized trial involving African neonates Filtered-Sunlight Phototherapy


300
showed that phototherapy with filtered sunlight

No. of Measurements
was safe and noninferior in efficacy as compared
200
with conventional phototherapy, the standard
treatment for neonatal hyperbilirubinemia. Both
types of phototherapy were highly and similarly 100

efficacious (93% of treatment days for filtered


sunlight and 90% for conventional phototherapy). 0
0 20 40 60 80 100
Our original study showed that average irra-
diance levels delivered by filtered sunlight were 120
Conventional Phototherapy
above the threshold for intensive phototherapy

No. of Measurements
(at least 30 W per square centimeter per nano- 80
meter).16,28 A previous in vitro study conducted
in the Middle East showed that sunlight was
6.5 times as effective as conventional photo- 40

therapy in isomerizing aqueous bilirubin solu-


tions.31 Given the higher irradiance derived from 0
sunlight than is used in conventional photo- 0 20 40 60 80 100
therapy, we hypothesized that filtered-sunlight Irradiance (W/cm2/nm)
phototherapy should be superior to conventional
B Time of Highest Irradiance
phototherapy in reducing bilirubin levels over
time. The present trial was not designed as a 50
superiority trial and did not include infants with
Average Irradiance Inside Canopy

bilirubin levels greater than 15 mg per deciliter.


In our trial, no infant required exchange trans- 40

fusion or was withdrawn from treatment for


(W/cm2/nm)

reasons of safety. Little is known about the


30
longer-term toxicity associated with brief expo-
sures to high-intensity, broad-spectrum visible
light, but some U.S. studies of phototherapy units 20
have reported irradiance levels of up to 76 W per
square centimeter per nanometer.28 A follow-up
study of patients with the CriglerNajjar syn- 10
drome who received lifelong treatment with 0
nightly (810 hours), high-intensity (up to 100 W 0 8 10 12 14 16
per square centimeter per nanometer) photo- Time of Day (24-hr clock)
therapy (>75,000 lifetime hours of high-intensity
blue light) did not show any serious health con- Figure 2. Spread of Irradiances and Time of Highest Irradiance for Filtered-
sequences associated with this exposure.32 In Sunlight Phototherapy versus Conventional Phototherapy.
our trial, phototherapy was of short duration Panel A shows the measured canopy irradiances for infants assigned to
5 to 6 hours per day for 1 to 2 days for most f iltered-sunlight phototherapy (upper graph) and conventional phototherapy
infants. The risk of skin cancer was also low, (lower graph). Panel B shows the average canopy irradiance as a function
of time of day for all treatment days for filtered-sunlight phototherapy (cir-
since our films filtered out more than 99% of cles) and conventional phototherapy (triangles).
ultraviolet radiation. The development of films
whose filtering characteristics automatically ad-
just in response to the intensity of sunlight (simi-
lar to light-sensitive lenses in eyeglasses) could or unknown risks of brief exposures to high-
provide more consistent levels of irradiance. intensity light must be weighed against the risk
From a practical perspective, especially in a de- of death or severe disability associated with
veloping country such as Nigeria, the theoretical acute bilirubin encephalopathy and kernicterus.

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Table 2. Efficacy and Safety.*


burn.36 However, many clinicians, even those in
high-income countries, recommend the exposure
Filtered-Sunlight Conventional of jaundiced babies to direct sunlight.37 Some
Variable Phototherapy Phototherapy
mothers, without the endorsement of health care
Efficacy workers, also continue to expose babies with
Days treatment received no. 268 325 jaundice to direct sunlight.36,38 In this trial, we
Days that could be evaluated no. 250 311 used films that excluded virtually all ultraviolet
Rate of change in total bilirubin
light and some infrared light, maintained close
mg/dl/hr surveillance, and used wet towels to avoid or treat
Median 0.07 0.00 hyperthermia.21,23 Our earlier survey of mothers
showed that 98% would use filtered-sunlight
Interquartile range 0.20 to 0.02 0.14 to 0.09
phototherapy again and would recommend it to
Efficacy % (95% CI) 93 (89 to 96) 90 (86 to 93)
others.39 Caregivers should therefore be educated
Safety on the essential differences between filtered sun-
Temperature checks no. 1863 2160 light and direct exposure to sunlight.
Axillary temperature C The current advantages of filtered sunlight
Median 37.1 36.9 include its availability in remote locations, the
Interquartile range 36.7 to 37.5 36.6 to 37.2
provision of treatment at the safest and most
efficacious wavelength, and, when a large canopy
Abnormal axillary temperature no. (%)
is used, the increased opportunity for maternal
>39.0C 1 (<1) 0
infant bonding, for the provision of skin-to-skin
>38.0C 85 (5) 15 (1) care, and for the feeding of infants when they
<35.5C 8 (<1) 2 (<1) are hungry. The energy source is free, and the
<35.0C 0 0 cost of the film is low ($0.55 and $1.50 per
Signs of dehydration no. (%) 0 0 square foot and $44 and $120 for a canopy for
six to eight motherinfant pairs with Titanium
Signs of sunburn no. (%) 0 0
and Air Blue 80 films, respectively, as compared
Doctor called for any reason 1 (<1) 0
no. (%) with commercial phototherapy devices that cost
between $2,000 and $3,500 per unit).21,40 How-
* Efficacy is calculated as a percentage of treatment days that could be evaluated. ever, open-air canopies require warm, sunny
Safety measures are expressed as a percentage of periodic temperature checks climates, which may not be available year-round
in infants. CI denotes confidence interval.
Days that could be evaluated are defined as days on which the infant was able in some low-to-middleincome countries,23 and
to tolerate at least 5 hours of phototherapy without meeting safety withdrawal protection from storms and heavy rains. The
criteria and on which both morning and afternoon bilirubin levels were measured. provision of sunlight-based phototherapy in more
P<0.05.
The doctor was called by the study nurse for one infant who had peripheral durable, climate-controlled rooms rather than
cyanosis, which is normal in newborns. canopies would reduce the risks of hyperthermia
and hypothermia but would also probably in-
crease costs. Some infants treated with sunlight-
In our post hoc exploratory analyses, higher based phototherapy (13% in our trial) also re-
levels of both bilirubin and of irradiance were quired nighttime phototherapy. Combining
associated with an increased rate of decline in filtered sunlight with solar-powered phototherapy
bilirubin levels. These findings are consistent is one potential solution.
with those of previous studies of conventional A limitation of the present trial is that we did
phototherapy.33,34 not have infants with severe hyperbilirubinemia
Existing guidelines for managing neonatal (bilirubin levels >15 mg per deciliter), who are at
hyperbilirubinemia do not recommend and greater risk of acute bilirubin encephalopathy
some explicitly discourage the use of sunlight and are most likely to be admitted for treat-
for the treatment of neonatal hyperbilirubine- ment.10,24 Further studies are warranted to estab-
mia.16,35 Reservations about the use of photo- lish the efficacy of filtered-sunlight phototherapy
therapy with sunlight have reflected safety among infants with severe hyperbilirubinemia
concerns regarding exposure to infrared and who are not brought for treatment early in the
ultraviolet radiation, hyperthermia, and sun- course of disease.

1122 n engl j med 373;12nejm.org September 17, 2015

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Photother apy with Filtered Sunlight in African Neonates

In conclusion, among infants with mild-to- The JM-103 transcutaneous bilirubinometer was loaned to the
study by Draeger Medical; CPFilms, a subsidiary of Eastman
moderate hyperbilirubinemia in tropical regions, Chemical Company, donated the films; Advanced Instruments
the use of filtered-sunlight phototherapy result- donated the Advanced BR2 Bilirubin Stat-Analyzer and provided
ed in manageable aberrations in temperature the BR2 kits at a reduced cost; Dr. Lund donated the glucose-
6-phosphate testing supplies; and Dr. Vreman donated most of
without serious adverse events. The treatment the supplies for the canopy frames.
was no less efficacious than conventional photo- Disclosure forms provided by the authors are available with
therapy. the full text of this article at NEJM.org.
We thank Dr. Vinod K. Bhutani, Stanford University School of
The preliminary findings of this study were presented at the Medicine, for his expert consultation regarding the efficacy cri-
Annual Pediatric Academic Societies Meeting, Vancouver, BC, teria; our dedicated study staff and all the physicians, nurses,
Canada, May 36, 2014 (Late Breaker Session: Abstract No. other health care providers and support staff at Island Maternity
2823.7). Hospital in Lagos, Nigeria, without whom this study would not
Supported by the Thrasher Research Fund, Salt Lake City, and have been possible; and the research team at the Center for
by the National Center for Advancing Translational Sciences of Health Start Initiative, Ikoyi, Lagos, for administrative support
the National Institutes of Health (award number UL1TR000114). and assistance with data management.

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