Journal of Perinatology (2014), 1–6

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ORIGINAL ARTICLE
Melatonin use for neuroprotection in perinatal asphyxia:
a randomized controlled pilot study
H Aly1, H Elmahdy2, M El-Dib1, M Rowisha2, M Awny2, T El-Gohary3, M Elbatch4, M Hamisa5 and A-R El-Mashad2

OBJECTIVE: Melatonin has been shown to be neuroprotective in animal models. The objective of this study is to examine the effect
of melatonin on clinical, biochemical, neurophysiological and radiological outcomes of neonates with hypoxic–ischemic
encephalopathy (HIE).
STUDY DESIGN: We conducted a prospective trial on 45 newborns, 30 with HIE and 15 healthy controls. HIE infants were randomized
into: hypothermia group (N = 15; received 72-h whole-body cooling) and melatonin/hypothermia group (N = 15; received hypothermia
and five daily enteral doses of melatonin 10 mg kg − 1). Serum melatonin, plasma superoxide dismutase (SOD) and serum nitric oxide
(NO) were measured at enrollment for all infants (N ¼ 45) and at 5 days for the HIE groups (N ¼ 30). In addition to
electroencephalography (EEG) at enrollment, all surviving HIE infants were studied with brain magnetic resonance imaging (MRI) and
repeated EEG at 2 weeks of life. Neurologic evaluations and Denver Developmental Screening Test II were performed at 6 months.
RESULT: Compared with healthy neonates, the two HIE groups had increased melatonin, SOD and NO. At enrollment, the two HIE
groups did not differ in clinical, laboratory or EEG findings. At 5 days, the melatonin/hypothermia group had greater increase in
melatonin (P o 0.001) and decline in NO (P o0.001), but less decline in SOD (P = 0.004). The melatonin/hypothermia group had
fewer seizures on follow-up EEG and less white matter abnormalities on MRI. At 6 months, the melatonin/hypothermia group had
improved survival without neurological or developmental abnormalities (P o0.001).
CONCLUSION: Early administration of melatonin to asphyxiated term neonates is feasible and may ameliorate brain injury.
Journal of Perinatology advance online publication, 13 November 2014; doi:10.1038/jp.2014.186

INTRODUCTION Melatonin has antioxidant, anti-inflammatory and anti-

Hypoxic–ischemic encephalopathy (HIE) affects 1.5 per 1000 live
term births in developed countries.1 Worldwide, asphyxia is the
cause of death in almost one quarter of the 3.6 million neonates
who die each year.2 Following a hypoxic–ischemic insult, two
phases of injury occur; an immediate phase of neuronal cell injury
and exhaustion of energy stores is followed by a secondary phase
largely mediated by oxidative stress, inflammatory cytokines and
apoptosis. Therapeutic hypothermia is neuroprotective through
attenuation of almost all phases of this injury.3 However, even
with therapeutic hypothermia, 40 to 50% of those with moderate
to severe encephalopathy will either die or have severe disability.4
Therefore, it is important to find adjuvant therapies that can be
used in combination with hypothermia. Melatonin (N-acetyl-5-
methoxytryptamine) is an endogenously produced indolamine,
primarily produced by pineal body from serotonin. Melatonin has
important physiological functions including control of circadian
rhythm, sleep, visual, neuroendocrine, cerebrovascular, reproduc-
tive and immunological actions.5 Melatonin increases toward the
end of pregnancy, freely crosses the placenta and crosses the fetal
blood–brain barrier.6 Following birth its production has been
suggested to have a role in brain development and pineal
dysfunction was associated with sudden infant death.7,8
Melatonin supplementation has been studied in adults, children
and neonates. It was studied in neonates with respiratory distress
syndrome,9 sepsis10 and as a preoperative antioxidant.11
apoptotic properties.12 As an antioxidant, it directly neutralizes
reactive oxygen species and reactive nitrogen species including
nitric oxide (NO). It also acts indirectly by stimulating both
antioxidant enzyme activity and their cellular mRNA concen-
trations, including superoxide dismutase (SOD), glutathione
peroxidase and glutathione reductase.13,14 Melatonin has anti-
inflammatory effect itself and via its metabolites.15 It prevents the
translocation of the nuclear factor-kappa B of activated B cells,
thus reducing the production of proinflammatory cytokines;16
reduces the inflammatory-derived activation of phospholipase A2,
lipoxygenase and cyclooxygenases;17 reduces recruitment of poly-
morphonuclear leukocytes to inflammatory sites;18 and reduces
vascular endothelial growth factor concentration.19 Finally, mela-
tonin not only has significant anti-apoptotic activity which mainly
targets the mitochondria, but also enhances several cell rescue
pathways.12
Melatonin is an attractive agent for neuroprotection as it freely
crosses the placenta and the blood–brain barrier. It protects the
brain of asphyxiated animals when used alone20 or in combination
with therapeutic hypothermia.21 In this randomized trial, we
planned to study the feasibility and efficacy of enterally
administered melatonin to neonates with HIE who are receiving
whole-body therapeutic hypothermia. The aim was to examine
biochemical, neurophysiological, radiological and clinical out-
comes associated with this combined treatment in neonates with
moderate to severe HIE.

1
Department of Newborn Services, George Washington University and Children’s National Medical Center, Washington, DC, USA; 2Department of Neonatology, Tanta University,
Tanta, Egypt; 3Department of Neurology, Tanta University, Tanta, Egypt; 4Department of Biochemistry, Tanta University, Tanta, Egypt and 5Department of Radiology, Tanta
University, Tanta, Egypt. Correspondence: Dr H Aly, Department of Newborn Services, George Washington University and Children’s National Medical Center, 900 23rd Street, NW,
Suite G-2092, Room G-132, Washington 20037, DC, USA.
E-mail: haly@mfa.gwu.edu
Received 13 June 2014; revised 19 August 2014; accepted 26 August 2014
 Melatonin in HIE
H Aly et al
2
METHODS
Patients
We prospectively studied 45 neonates, 30 neonates diagnosed with HIE
and 15 healthy controls. The 30 neonates with HIE were randomly assigned
to one of two groups: hypothermia group (N = 15) and melatonin/
hypothermia group (N = 15). Both HIE groups included newborns who
fulfilled the following inclusion criteria: (1) inborn infants at term gestation
(38 to 42 weeks); (2) Apgar scores ⩽ 3 at 5 min and/or delayed first breath
(45 min after birth); (3) profound metabolic or mixed acidosis with serum
bicarbonate concentrations of o12 mmol l − 1 at initial blood gas analyses;
and (4) evidence of moderate or moderately severe encephalopathy, such
as lethargy, seizures, abnormal reflexes or hypotonia in the immediate
neonatal period. Infants were excluded if they had any of the following:
(1) twin gestation; (2) maternal neuro-endocrinal disturbances including
diabetes mellitus; (3) chorioamnionitis or congenital infections; (4) low
birth weight o2.5 kg; (5) congenital malformations of the central nervous
system or gastrointestinal anomalies; (6) chromosomal abnormalities; or
(7) postnatal age older than 6 h. The study also did not include infants
presenting in extremis such as: (1) severe hypoxemia requiring full-oxygen
supplement (FiO2 = 100%) after delivery room resuscitation; (2) life-
threatening coagulopathy; or (3) deep coma. Patients underwent full
neurologic assessments at enrollment, performed by a single investigator
(HE). The severity of HIE was graded according to a modification of the
system described by Sarnat and Sarnat.22
A group of healthy control (N = 15) neonates were enrolled to compare
different laboratory measurements (Figure 1). The study was conducted at
Tanta University Hospital (Tanta, Egypt) and was approved by the
Pediatrics Ethics Committee at Tanta University. Parental consents were
obtained before enrollment of subjects.
Interventions
Whole-body hypothermia protocol. All HIE infants (N = 30) received whole-
body cooling introduced manually by turning off the heat source of the
radiant warmer or incubator while exposing the infant to ambient
Figure 1. Illustration of the study design.
Journal of Perinatology (2014), 1 – 6
temperature. Ice packs were introduced across the chest and under the
head and shoulders until infant’s temperature decreased below 34 °C.
Temperature was monitored by deep rectal thermometer every 30 min
with goal temperature 33 to 34 °C. The radiant warmer heater output
(or incubator temperature) was manually adjusted every 30 min if the
temperature was below 33 °C. Ice packs were also applied when the
temperature increased 434 °C. Hypothermia was allowed for a total of
72 h; infants were then re-warmed by increasing goal temperature by
0.5 °C every hour until reaching 36.5 °C.
This cooling protocol has been used for several years and therefore the
staff is well experienced with it and the temperature has been reliably
controlled in this population of infants. Similar protocol was previously
reported to be safe and effective in a randomized controlled trial.23 The
use of automated cooling devices is a relatively new technology that was
not available at the time of the study.
Melatonin administration. Melatonin was administered to the melatonin/
hypothermia group (N = 15) in a dose of 10 mg kg − 1 daily for a total of five
doses. This dose was similar to doses used safely in previous neonatal
studies.9,11 Oral route was chosen because oral supplements are readily
available over the counter. Although the half-life of administered mela-
tonin is 45 to 60 min in adults,24 it is up to 15 h in premature infants,25
which justifies single daily dosing in neonates. Melatonin tablets (1 or 3 mg
per tablet; Puritan's Pride, Oakdale, NY, USA) were crushed, then dissolved
in 5 ml of distilled water and administered via an orogastric tube.
Laboratory evaluations
For all infants with HIE (N = 30) and the healthy control (N = 15), blood
samples were obtained for measurement of NO, SOD and melatonin
concentrations immediately at enrollment, before any intervention. This
process was repeated on the fifth day of life only for the two HIE groups
(N = 30).
Serum melatonin analysis. Melatonin was measured at enrollment as a
baseline measurement of endogenous melanin production in study groups
with and without HIE. It was repeated in both the HIE groups at day 5 to
examine if melatonin was absorbed when administered enterally. Samples
were analyzed for melatonin concentration using an enzyme immunoassay
method (Melatonin ELISA, IBL International, Germany).
Superoxide dismutase activity. SOD activity was measured at enrollment in
all study groups to detect baseline oxidative stress with and without HIE.
It was repeated at day 5 in both HIE groups to examine the effect of
melatonin on oxidative stress. SOD activity was determined in plasma
supernatants after centrifugation of the chloroform–ethanol-treated
plasma samples. Plasma was assayed by a well-defined spectrophoto-
metric method26 using Bioxytech SOD-525 commercial research kit (Oxis
International, Portland, USA).
Serum nitric oxide concentration. NO concentration was measured at
enrollment in all study groups to detect free radical production with and
without HIE. It was repeated at day 5 in both HIE groups to examine the
effect of melatonin on free radicals. NO concentration in serum was
determined using the nitric oxide assay kit (Thermo Fisher scientific Inc.,
Rockford, USA).
Electroencephalography
Electroencephalography (EEG) was performed at enrollment and was
repeated after 2 weeks of age with a digital computerized apparatus
(Neurofax EEG-9000, Nihon Kohden, Tokyo, Japan). Recording was
performed with a 16-channel, EEG polygraph system; bipolar montage
was used, with electrodes placed on the basis of the 10 to 20 system, as
modified for newborns. The single neurologist (TE-G) who interpreted all
EEG tracings was not aware of the treatment group. Constantly
discontinuous tracings was defined when there was constant alternation
between relatively high amplitude bursts and low-voltage intervals that
were further classified as exhibiting extreme discontinuity (maximal
interval duration of 440 s), severe discontinuity (maximal interval duration
of 20 to 40 s) or moderate discontinuity (maximal interval duration of
o20 s).27 Moreover, the incidences of paroxysmal abnormalities (abnormal
EEG transients) and ictal EEG discharges were evaluated.
© 2014 Nature America, Inc.
 Melatonin in HIE
H Aly et al
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Brain magnetic resonance imaging
Table 1. Demographic data and clinical characteristics for infants with
Infants with HIE who survived in both groups were transported to the
HIE
magnetic resonance imaging (MRI) unit after 2 weeks and when they were
clinically stable. Imaging of the brain was performed using the Siemens Hypothermia Melatonin/ P
Magnetom Symphony 1.5-T system (Siemens, Munich, Germany). Images group hypothermia
were obtained in the transverse plane, with T1-weighted spin echo, T2- (N = 15) group (N = 15)
weighted spin echo and age-related inversion recovery sequences. The
posterior limb of the internal capsule was assessed as normal, equivocal or Birth weight (kg)a 3.6 ± 0.4 3.56 ± 0.37 0.74
abnormal. The basal ganglia and thalami are assessed as normal or with Gestational age (weeks)a 38.9 ± 0.8 38.7 ± 0.9 0.67
minimal, moderate or severe abnormalities.28 Abnormalities were classified Sex (% male) 12 (80) 11 (73) 0.99
as: (1) minimal, if focal lesions were seen but the posterior limb of the Apgar score at 1 minb 2 (1–2) 2 (1–2) 0.2
internal capsule was normal; (2) moderate, if focal abnormalities involving Apgar score at 5 minb 3 (2–3) 3 (2–3) 0.3
the posterior lentiform nuclei and ventrolateral nuclei of the thalami were
seen, with equivocal or abnormal signal intensity within the posterior limb Delivery mode
of the internal capsule; and (3) severe, if widespread abnormalities were Cesarean section 5 (33) 4 (27) 0.91
seen in all regions of the basal ganglia and thalami and abnormal signal Spontaneous vaginal 6 (40) 7 (47)
intensity within the posterior limb of the internal capsule. White matter Instrumental 4 (27) 4 (27)
abnormalities were documented according to which lobes of the brain
were involved, whether there was a hemorrhagic element to the lesions Meconium in amniotic fluid 10 (67) 6 (40) 0.27
and whether they were subcortical, periventicular or widespread. White Fetal bradycardia 9 (60) 7 (47) 0.71
matter abnormalities were graded as moderate or severe: (1) moderate,
indicated small focal lesions with short T1 and short T2, consistent with Resuscitation at delivery room
hemorrhage and/or areas of exaggerated long T1 and long T2 but no loss Positive pressure 10 (67) 9 (60) 0.99
of gray/white matter differentiation; and (2) severe, indicated more marked ventilation
areas of abnormality, with larger areas of hemorrhage or exaggerated long Chest compression 11 (73) 9 (60) 0.69
T1 and T2 with loss of gray/white matter differentiation, consistent with Tracheal intubation 10 (67) 9 (60) 0.99
infarction.29 All images were assessed by an experienced radiologist (MH),
who was masked to EEG readings and treatment groups. Initial blood gas a
pH 7.06 ± 0.13 7.08 ± 0.12 0.601
Base deficit (mEq l − 1) 16.01 ± 1.64 17.04 ± 1.19 0.059
Neurologic and developmental outcomes
Detailed neurologic examinations at the age of 6 months were performed HIE grading
by a single pediatric neurologist, not aware of treatment group allocation. Moderate 11 (73) 13 (87) 0.65
The patients were further evaluated with the Denver Developmental Severe 4 (27) 2 (13)
Screening Test II (DDST-II).30 The test includes multiple items to examine
four major categories (gross motor, language, fine motor-adaptive and Ventilator support 8 (53) 5 (53) 0.27
personal-social). Infants were scored for each test item as advanced, Inotropic support 4 (27) 1 (7) 0.13
normal, caution or delayed. The overall developmental assessment of an
infant was considered failed if there were ⩾ 2 delays, questionable if there Abbreviation: HIE, hypoxic–ischemic encephalopathy. Data are presented
were one delay and/or ⩾ 2 cautions and normal if there were no delays as number (%) except. aPresented as mean ± s.d. bPresented as median
and a maximum of one caution. DDST-II is a simple, easily administered (interquartile range).
screening test that was shown to accurately predict severe adverse
outcomes.31
At day of life 5, melatonin in the hypothermia group increased
Statistical analyses from 20.6 ± 2.5 to 32.1 ± 3.5 pg ml − 1 (Po 0.001) while in the
Data were analyzed using SPSS (Statistical Package for the Social Science, melatonin/hypothermia group it increased from 21 ± 2.4 to
Chicago, IL, USA) version 18. Data were summarized using mean, s.d. for 42.7 ± 5.1 pg ml − 1 (P o 0.001). The difference between baseline
continuous variables and percentage for categorical variables. Compar- and follow-up melatonin was significantly more in the melatonin/
isons between groups were done using t-test for continuous variables and hypothermia group (P o 0.001; Figure 3).
chi square/Fisher’s exact test for categorical variables. Repeated contin- SOD in the hypothermia group decreased from 308.2 ± 58.7 to
uous measures were compared using paired t-test. Correlation was 235.3 ± 36.7 U ml − 1 (P o 0.001), while in the melatonin/hypother-
measured using Spearman's rank correlation coefficient. Differences were mia group it decreased from 312.9 ± 51.6 to 278.7 ± 41.5 U ml − 1
considered significant when P values were o0.05. A convenient sample of
(P o 0.001). The difference between baseline and follow-up SOD
45 patients was chosen; because of the pilot nature of the study, power
analysis was not feasible. was significantly less in the melatonin/hypothermia group
(P = 0.004; Figure 3).
NO in the hypothermia group decreased from 169.5 ± 35.9
RESULTS to146.2 ± 35.7 μmol l − 1 (P o0.001), while in the melatonin/
Thirty newborns with HIE were enrolled and randomized to the hypothermia group it decreased from 170.5 ± 18.5 to 112.2 ± 19
hypothermia group (N = 15) and the melatonin/hypothermia μmol l − 1 (P o0.001). The difference between baseline and follow-
group (N = 15). The two HIE groups were similar in demographic up NO was significantly more in the melatonin/hypothermia
and clinical characteristics (Table 1). Baseline metabolic panel, group (P o 0.001; Figure 3).
complete blood count and coagulation profile did not differ Of the hypothermia group, four died while only one patient
between groups. At day 5, follow-up labs were all similar except died in the melatonin/hypothermia group (P = 0.33). MRI in
that the melatonin/hypothermia group had greater hemoglobin survivors (N = 25) did not differ in the incidence of basal ganglia
concentration and less ionized calcium when compared to and thalamus abnormalities between groups. However, white
hypothermia group (Table 2). matter abnormalities were noted in four in the hypothermia group
Baseline SOD, NO and melatonin concentrations were signifi- and none in the melatonin/hypothermia group (P = 0.014; Table 3).
cantly higher in both HIE groups when compared to the healthy Baseline EEG did not differ between the two HIE groups
control group (P o 0.001). The hypothermia and the melatonin/ (Table 3). On follow-up EEG, background abnormalities did not
hypothermia groups did not differ in their baseline concentrations differ between groups; however, the melatonin/hypothermia
(Figure 2). group had less seizure activity (P = 0.032; Table 3). Normal

© 2014 Nature America, Inc. Journal of Perinatology (2014), 1 – 6

 Melatonin in HIE
H Aly et al
4
Table 2. General laboratory investigations in study groups

Hypothermia Melatonin/hypothermia P
group group

Hemoglobin (g dl − 1)
Pre-treatment 14.5 ± 1.7 14.3 ± 1.7 0.75
Post-treatment 11.4 ± 0.9 12.1 ± 0.8 0.03

Platelet count (103 ml − 1)

Pre-treatment 205 ± 63 238 ± 58 0.16
Post-treatment 112 ± 41 176 ± 20 0.25

White blood cell count (103 ml − 1)

Pre-treatment 7.2 ± 1.8 7.1 ± 2.1 0.84
Post-treatment 10.7 ± 2.4 9 ± 2.9 0.08

Blood urea nitrogen (mg dl − 1)

Pre-treatment 42.4 ± 15.3 40.6 ± 11.7 0.72
Post-treatment 35.6 ± 22.4 25.3 ± 15.6 0.16

Creatinine (mg dl − 1)
Pre-treatment 1.1 ± 0.3 1 ± 0.2 0.28
Post-treatment 0.8 ± 0.7 0.6 ± 0.4 0.18

Alanine transaminase (IU l − 1)

Pre-treatment 49.3 ± 11.7 45.1 ± 8.5 0.24
Post-treatment 44.4 ± 20.2 37.3 ± 13.6 0.27

Prothrombin time (s)

Pre-treatment 15.6 ± 3 14.4 ± 1.7 0.17
Post-treatment 26.3 ± 7.1 22.4 ± 6.5 0.12

Partial thromboplastin time (s) Figure 2. Baseline serum melatonin, plasma superoxide dismutase
Pre-treatment 33 ± 3.1 31 ± 3.8 0.15 (SOD) and serum nitric oxide (NO) concentrations in the three study
Post-treatment 52.2 ± 14.5 46.3 ± 21.9 0.39 groups: healthy control (white), hypothermia group (gray) and
melatonin/hypothermia group (black).
Ionized calcium (mmol l − 1)
Pre-treatment 0.89 ± 0.25 0.72 ± 0.33 0.12
Post-treatment 1.47 ± 0.31 1.21 ± 0.32 0.04
Abbreviations: HIE, hypoxic–ischemic encephalopathy; NO, nitric oxide;
SOD, superoxide dismutase. Data presented as mean ± s.d.

follow-up EEG was reported in 10 of the 14 survivors of the

melatonin/hypothermia group; all of whom had normal MRI
except one who showed mild abnormalities. In the hypothermia
group, 4 out of 11 had normal EEGs, all of whom had normal MRI.
EEG abnormalities correlated significantly with MRI abnormalities
(r = 0.92, P o 0.001).
At 6 months of age, all surviving infants (n = 25) presented for
follow-up neurological examination and developmental screening
(11 in the hypothermia group and 14 in the melatonin/
hypothermia group). Only 3 infants in the hypothermia group
had normal neurological evaluation and normal DDST-II, while 10
infants in the melatonin/hypothermia group had normal examina-
tion and DDST-II. Survival without abnormalities at 6 months was
significantly increased in the melatonin/hypothermia groups Figure 3. Changes in superoxide dismutase (SOD), nitric oxide (NO)
(P o 0.001). and melatonin concentration in the hypothermia group (white) and
melatonin/hypothermia group (black).

DISCUSSION
This is the first clinical trial to demonstrate the feasibility and
potential efficacy of melatonin when administered in combination
with hypothermia to infants with HIE. Melatonin was associated
with favorable biochemical and clinical outcomes without notice-
able side effects.
Melatonin concentration in the serum was greater in infants
with HIE at baseline than healthy control. This can be attributed
to endogenous production of melatonin in response to an
HIE-related oxidative stress. Following melatonin administration,
the melatonin/hypothermia group had a greater increase in serum
melatonin concentration, which confirms the adequate absorption
of the enterally administered melatonin in HIE neonates.
Plasma SOD was increased in both HIE groups when compared
to the healthy controls. Previous studies correlated the greater

Journal of Perinatology (2014), 1 – 6 © 2014 Nature America, Inc.

 Melatonin in HIE
H Aly et al
5
This is the first study to use melatonin as an adjuvant therapy in
Table 3. EEG and MRI findings in the study groups
neonates receiving therapeutic hypothermia for the management
Hypothermia Melatonin/ P-value of HIE. This combination was reported only in a piglet model of
group hypothermia perinatal asphyxia, where melatonin augmented neuroprotective
group role of hypothermia with improved cerebral energy metabolism
and reduced brain damage.21 The improved outcomes observed
Initial EEG (n = 30)
with melatonin treatment could not be related to other biases.
Background
Normal 4 (26.7) 5 (33.3) 0.431 Investigators performing laboratory evaluations, EEG and MRI
Moderate 6 (40) 8 (53.3) interpretations and developmental screening were all masked to
abnormalities group assignments. The study was randomized to eliminate the
Severe abnormalities 5 (33.3) 2 (13.3) chance of any selection bias. We could not find a specific
difference in management between groups to which we could
Follow-up EEG (n = 25) attribute the improvement in the melatonin group.
Background
Normal 6 (54.5) 10 (71.4) 0.383
A limitation of this study is the small number of patients. Four
Moderate 5 (45.5) 4 (28.6) patients had severe encephalopathy in the hypothermia group
abnormalities whereas only two in the melatonin/hypothermia group were
Seizure activity 7 (63.6) 3 (21.4) 0.032 diagnosed with severe encephalopathy. Although that was not
statistically significant, it can be a source of bias in the presence of
MRI (n = 25) a small sample size. We should also be cautious with the
Basal ganglia and thalamus interpretation of the neurodevelopmental follow-up data since it
Normal 7 (63.6) 9 (64.3) 0.893
Mild abnormalities 3 (27.3) 3 (21.4) was limited to only 6 months of age. Larger studies with extended
Moderate 1 (9.1) 2 (14.3) follow-up are needed to examine long-term protective effects. In
abnormalities addition, studies utilizing different dosing regimen would be
helpful to establish the most efficacious dose of this simple, yet
White matter powerful supplement.
Normal 7 (63.6) 14 (100) 0.014
Moderate 4 (36.4) 0
abnormalities CONCLUSION
Abbreviation: EEG, electroencephalography; MRI, magnetic resonance Combination of melatonin to therapeutic hypothermia in infants
imaging. Data presented as number (%). with moderate to severe HIE was efficacious in reducing oxidative
stress and improving survival with favorable neurodevelopmental
outcomes at 6 months of age.
SOD activities with the more severe cases of HIE.32 Following both
hypothermia and melatonin/hypothermia, there was a significant
decline in SOD concentrations denoting an amelioration of the CONFLICT OF INTEREST
HIE-related oxidative stress. Unexpectedly, the decline in SOD was The authors declare no conflict of interest.
less significant in the melatonin/hypothermia group as compared
to the hypothermia group, which could be explained by the
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