Acta Clin Croat 2018; 57:458-463 Original Scientific Paper

doi: 10.20471/acc.2018.57.03.08

PRO-OXIDANTS AND ANTIOXIDANTS

IN RETINOPATHY OF PREMATURITY
Lidija Banjac1, Goran Banjac2, Jelena Kotur-Stevuljević3, Vesna Spasojević-Kalimanovska3,
Tamara Gojković3, Nataša Bogavac-Stanojević3, Zorana Jelić-Ivanović3 and Gorica Banjac4

1
Department of Neonatology, Clinical Center of Montenegro, Podgorica, Montenegro;
2
Institute of Children’s Diseases, Clinical Center of Montenegro, Podgorica, Montenegro;
3
Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia;
4
Narodni front Clinic of Gynecology and Obstetrics, Belgrade, Serbia

SUMMARY – Premature infants are susceptible to oxidative stress that causes neonatal disease
such as retinopathy of prematurity (ROP). Oxidative stress is an imbalance between the production
of pro-oxidants and the ability of the body to detoxify their harmful effects by antioxidants. The
proliferative phase 2 ROP occurs at around 33rd postmenstrual week (pmw). The purpose of our study
was to evaluate the pro-oxidant/antioxidant status in preterm infants at 33rd pmw. The study included
59 premature infants. ROP was classified according to the International Classification of Retinopathy
of Prematurity. Total oxidative status (TOS), total antioxidant status (TAS), malondialdehyde (MDA)
and paraoxonase 1 (PON1) activity were determined spectrophotometrically. The values of the pro-
oxidants TOS and MDA were significantly higher in infants with ROP as compared to infants
without ROP (p<0.05 both). There were no significant differences in the values of TAS and PON1
between the infants with and without ROP. According to study results, TOS and MDA are good
markers of oxidative stress, whereas TAS and PON1 activity are unreliable in assessing antioxidant
protection.
Key words: Reactive oxygen species; Antioxidants; Retinopathy of prematurity; Infant, premature;
Oxidative stress

Introduction diseases have also been reported to be oxidative stress-

related neonatal diseases1,2.
Premature infants belong to the category of ‘vul- Retinopathy of prematurity (ROP) is the most im-
nerable newborns’ because of the large proportion of portant disease of prematurity and a major cause of
total perinatal morbidity and mortality. They are espe- blindness in children. ROP continues to be the leading
cially susceptible to oxidative stress, which affects a cause of lifelong visual impairment among children in
variety of organs, often simultaneously, causing neona- developed countries3. ROP occurs in two phases. The
tal diseases such as retinopathy of prematurity (ROP), ischemic phase 1 begins after premature birth with de-
bronchopulmonary dysplasia, necrotizing enterocoli- layed retinal vascular growth. The proliferative phase 2,
tis, intraventricular hemorrhage, periventricular leuko- characterized by pathologic neovascularization, occurs
malacia, respiratory distress syndrome, intrauterine around 33rd postmenstrual week (pmw)4-8.
growth retardation and congenital malformation. These Oxidative stress is imbalance between the produc-
tion of pro-oxidants and the ability of the body to de-
toxify their harmful effects through neutralization by
Correspondence to: Lidija Banjac, PhD, Djoka Miraševića M1
53/7, Podgorica, Montenegro antioxidants. The process of birth itself is an oxidative
E-mail: [email protected] challenge for the newborn. Sharp postnatal transition
Received August 30, 2017, accepted December 27, 2017 from intrauterine environment with a relatively low

458 Acta Clin Croat, Vol. 57, No. 3, 2018

Lidija Banjac et al. Pro-oxidants and antioxidants in retinopathy of prematurity

oxygen content into an environment with significantly The purpose of our study was to evaluate and com-
higher oxygen content exposes the infant to oxidative pare the pro-oxidant/antioxidant status in preterm in-
stress, which is emphasized in premature infants due fants (with and without ROP) at 33rd pmw (the begin-
to low efficiency of antioxidant protection9. In prema- ning of phase 2 ROP) by measuring the TOS, MDA,
ture infants, autoregulation of the blood network of TAS and PON1 activity.
retina is adequate in a narrow range of perfusion pres-
sure. The absence of autoregulation leads to hyperoxia
of retina10. Disturbance in the equilibrium of pro-oxi- Materials and Methods
dants and antioxidants initiates an inflammatory
Study design and patients
process in retinal tissue leading to development of
ROP11,12. The study (cohort, prospective) was conducted in
Free radicals are reactive and short-lived species so the Department of Neonatology, Clinical Centre of
that direct measurement is usually not possible. How- Montenegro, Podgorica, with parental informed writ-
ever, hundreds of reactive oxygen species are known to ten consent and after institutional ethical clearance.
be derived from the interaction of free radicals with The study included 59 premature infants, gestational
biomolecules1. age (GA) of 33 weeks or less. Venous blood sample
Alternatively to measurements of oxidation prod- was obtained from every infant included in the study
ucts, a test measuring total oxidative status (TOS) was in the 33rd pmw. All parameters were determined at
recently developed13. Malondialdehyde (MDA) is the 33rd pmw. Preterm neonates with gross congenital ab-
end product of lipid peroxidation and a good marker normalities were excluded from the study.
of oxidative stress. This aldehyde is a highly toxic mol- Screening for ROP was done by indirect ophthal-
ecule. Its interaction with DNA and proteins has often moscopy. ROP was classified according to the Interna-
been referred to as potentially mutagenic and athero- tional Classification (ICROP) and subdivided into 5
genic12,14,15. stages. Proliferative ROP (ROP+) was defined as stage
Total antioxidant status (TAS) is not just a simple 3, stage 4 or stage 5. These infants required treatment
sum of the individual activities of antioxidant sub- for ROP (laser therapy or anti-VEGF treatment). In-
stances. It is actually a dynamic system of interdepen- fants with correct ophthalmologic findings and mod-
dent individual serum antioxidant parameters. TAS erate ROP (stage 1 and stage 2) were defined as in-
assay has been designed to determine the overall anti- fants without ROP (ROP-).
oxidant power of samples contributed by antioxidants Ethics Committee of the Clinical Centre of Mon-
and their interactions. Evaluation of TAS in body fluid tenegro in Podgorica approved the study protocol
has been used as one of the biological markers for
(consent number 03/01-3813/4), in accordance with
monitoring oxidative stress in humans16.
standard procedures of the Ethics Committee of the
Paraoxonase (PON) is a Ca2+-dependent enzyme
Clinical Center of Montenegro and international
that is synthesized in the liver and is found in various
guidelines for the performance of biomedical research
tissues and plasma. The enzyme takes place in the
on humans.
structure of high-density lipoprotein (HDL) in plas-
ma17. PON1 has antioxidant property because it pre-
Measurement of pro-oxidant markers
vents the increase of reactive oxygen species quantity
by hydrolyzing lipid peroxidation products. It also pro- Since the measurement of different oxidant mole-
tects cell from damage caused by oxidative stress18. cules separately is not practical, TOS of a sample was
PON family members were upregulated in late-gesta- measured. We used Erel’s colorimetric method for
tion human fetuses and are a candidate therapeutic in measuring TOS. The assay is based on the oxidation of
premature human infants19. ferrous ion to ferric ion. Color intensity, which can be
Studies have confirmed that oxidative stress leads measured spectrophotometrically, is related to the total
to tissue damage during pregnancy, and clinical prac- amount of oxidant molecules present in the sample.
tice has confirmed that the application of antioxidants The assay is calibrated with hydrogen peroxide (H2O2)
can prevent and reduce the diseases caused by oxida- and the results were expressed in terms of micromolar
tive stress20-22. hydrogen peroxide equivalent per liter (μmol H2O2

Acta Clin Croat, Vol. 57, No. 3, 2018 459

Lidija Banjac et al. Pro-oxidants and antioxidants in retinopathy of prematurity

Eq/L)13. MDA was determined as a thiobarbituric Table 1. Mean gestational age and birth weight
acid-reacting substance (TBARS) spectrophotometri- of premature infants with and without retinopathy
cally. Thiobarbituric acid (TBA) is widely used to mea- of prematurity (ROP)
sure TBARS of lipid oxidation. TBA reacts with
ROP+ ROP-
MDA, a product of lipid oxidation, to give a red, fluo- Parameter p
(n=18) (n=41)
rescent MDA/TBA adducts with maximum absor-
Gestational age
bance at 532 nm. The results are expressed in μmol/L15. 30.6±2.1 31.8±1.4 p<0.01*
(weeks)
Birth weight (g) 1587±418 1822±370 p<0.05*
Measurement of antioxidant markers
Data are expressed as mean ± standard deviation; continuous vari-
Total antioxidant status assays have been designed ables were compared using Student’s t-test; *statistically significant
to determine overall antioxidant power of samples. values
TAS was determined by a modified Erel’s method, i.e.
a colorimetric test which depends on the production of
hydroxyl radical. The results are expressed in mmol/L23.
We used the principle of spectrophotometric de-
termination of PON1 activity by using paraoxon as
substrate. The sample is mixed with a substrate dis-
solved in a buffer solution, and the product generated
by hydrolysis of the substrate is monitored for a certain
time at a linear rate and defined temperature. The re-
sults are expressed in U/L24.

Statistical analysis Fig. 1. Length of ventilation in premature infants with

Data were presented as mean ± standard deviation and without retinopathy of prematurity (ROP).
(SD). Kolmogorov-Smirnov test was used to verify the *p<0.05 ROP+ vs. ROP-
normality of distribution of parameters. In order to
analyze statistically significant differences in the mean The mean length of mechanical ventilation for in-
values of the examined parameters between the groups, fants with ROP was 14.1±1.31 days. The mean length
Student’s t test was used according to data distribu- of mechanical ventilation for infants without ROP
tion. The existence of statistically significant correla- was 6.1±0.54 days (Fig. 1). Student’s t-test showed a
tions between variables was confirmed using the statistically significant difference in the length of ven-
Spearman nonparametric correlation. A p-value of less tilation for infants with and without ROP. Premature
than 0.05 was considered statistically significant. infants with ROP were ventilated significantly longer
(p<0.05).
Results The values of the pro-oxidant and antioxidant
markers are presented in Table 2. TOS and MDA val-
Overall, 59 patients were included in the study. ues in premature infants with ROP were TOS
ROP was diagnosed in 18 (30.5%) infants, whereas in 60.6±4.88 μmol/L and MDA 1.82 (1.38 to 2.40)
41 (69.5%) infants ophthalmologic findings were cor- μmol/L. In premature infants without ROP, the pro-
rect or they had moderate ROP. oxidant markers were lower: TOS 38.6±3.17 μmol/L
The mean gestational age (GA) and birth weight and MDA 1.33 (1.16 to 1.52) μmol/L. For both pa-
(BW) of preterm infants with and without ROP are rameters, the difference was statistically significant
displayed in Table 1. Student’s t-test showed signifi- (p<0.05).
cant difference in GA and BW between infants with Premature infants that developed ROP had lower
and without ROP. Premature infants with ROP had a values of TAS (1.1±0.64 mmol/L) than infants with-
significantly shorter mean GA (p<0.01) and lower out ROP (1.2±0.69 mmol/L). PON1 activity was
mean BW (p<0.05). higher in infants with ROP (89.6±13.0 U/L) than in

460 Acta Clin Croat, Vol. 57, No. 3, 2018

Lidija Banjac et al. Pro-oxidants and antioxidants in retinopathy of prematurity

Table 2. Pro-oxidant and antioxidant parameters measuring TAS and PON1 activity. Nowadays, these
in patients with and without retinopathy of prematurity markers can be measured by simple and sensitive
(ROP) methods.
All infants included in the study (N=59) were
ROP+ ROP-
Parameter p screened for ROP. Timing of the first ROP screening
(n=18) (n=41)
examination was also at 33rd pmw. Laser photocoagu-
TOS (μmol/L) 60.6±4.88 38.6±3.17 p<0.05
lation was used in 18 (30.5%) infants.
1.82 1.33
MDA (μmol/L)* p<0.05 According to our results, premature infants with
(1.32-2.40) (1.16-1.52)
ROP had a significantly lower BW, shorter GA (Table
TAS (mmol/L) 1.1±0.64 1.2±0.69 p=0.55
1) and longer duration of mechanical ventilation (pro-
PON1 (U/L) 89.6±13.01 60.3±7.24 p=0.15
longed oxygen exposure) (Fig. 1).
TOS = total oxidant status; MDA = malondialdehyde; TAS = total Studies also confirmed strong connection between
antioxidant status; PON1 = paraoxonase 1; data expressed as mean
± standard deviation; *data expressed as median values (interquar-
short GA, low BW, mechanical ventilation and ROP.
tile range); continuous variables were compared using Student’s It has been reported that premature infants on pro-
t test longed ventilation have more chances for development
of ROP12,25,26.
Table 3. Correlation among antioxidative parameters We found a statistically significant difference in
and gestational age, body weight and malondialdehyde TOS values between infants with and without ROP.
(oxidative stress marker) Infants with ROP had significantly higher values of
TOS (Table 2).
TAS PON1
Parameter Studies confirm that vasoconstriction in the retina
(μmol/L) (U/L)
is an early response to oxygen that can lead to vaso-
Gestational age (weeks) +0.42* /
obliteration, neovascularization, and retinal traction
Birth weight (g) +0.55* /
Malondialdehyde (μmol/L) / +0.292** (ROP). Disturbance in the equilibrium of oxidant and
antioxidant status initiates an inflammatory process in
Spearman’s coefficient ρ; TAS = total oxidative status; PON1 = retinal tissue leading to development of ROP12,27.
paraoxonase 1 activity; *p<0.05; **p<0.001
As shown in Table 2, MDA was also significantly
higher in infants with ROP. According to our results,
those without ROP (60.3±7.24 U/L). There was no serum concentration of MDA is a good marker of oxi-
significant difference between the groups (p=0.55; dative stress and a ROP predictor.
p=0.15). Studies have shown that elevated levels of serum
Spearman’s nonparametric correlation showed sig- MDA were associated with adverse respiratory and
nificant positive correlation between TAS values and ophthalmologic outcome in very-low-birth-weight in-
GA, and between TAS and BW (Table 3). We also fants14. Infants exposed to higher oxidative stress (pre-
found significant positive correlation between PON1 mature infants, newborns from cesarean section) have
activity and MDA (Table 3). a higher level of MDA28,29. Also, significant oxidative
stress can be easily assessed by measuring urinary
Discussion and Conclusion MDA levels30. The concentrations of MDA were not
predictors of bronchopulmonary dysplasia/death31.
Newborns, especially premature ones, are at an in- In the present study, we did not find a statistically
creased risk of damage mediated by oxidative stress. In significant difference in TAS values and PON1 activ-
the present study, we investigated parameters of oxida- ity between the groups. TAS values were lower in in-
tive stress (pro-oxidants and antioxidants) in prema- fants with ROP, while the values of PON1 activity
ture infants at 33rd pmw (onset of ROP 2 phase) in were even higher in infants with ROP (Table 2).
order to understand the significance of these parame- Studies confirm that inadequate TAS is associated
ters in the pathogenesis of ROP. with development of various pathologic conditions in-
Pro-oxidants were assessed by measuring TOS and cluding hypoxic injury and ROP32. Decreased mater-
serum MDA. Antioxidant protection was estimated by nal serum PON1 levels may also have a role in preterm

Acta Clin Croat, Vol. 57, No. 3, 2018 461

Lidija Banjac et al. Pro-oxidants and antioxidants in retinopathy of prematurity

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tioxidant in preventing oxidation of low-density lipo-
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proteins34. GE. Natural history of retinopathy of prematurity in infants
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significantly with the development of ROP. Our re- 2010;128(10):1289-94, https://doi.org/10.1001/archophthal-
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Acknowledgment
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Sažetak

PRO-OKSIDANSI I ANTIOKSIDANSI U PREMATURNOJ RETINOPATIJI

L. Banjac, G. Banjac, J. Kotur-Stevuljević, V. Spasojević-Kalimanovska, T. Gojković,

N. Bogavac-Stanojević, Z. Jelić-Ivanović i G. Banjac

Nedonoščad je osobito osjetljiva na oksidacijski stres koji uzrokuje bolesti poput prematurne retinopatije (PR). Oksida-
cijski stres je neravnoteža između proizvodnje pro-oksidansa i sposobnosti tijela za detoksikaciju njihovih štetnih učinaka
antioksidansima. Druga, proliferacijska faza PR započinje oko 33. postmenstrualnog tjedna (pmt). Svrha našega istraživanja
bila je procijeniti pro-oksidacijski/antioksidacijski status u nedonoščadi u 33. pmt. U istraživanju je sudjelovalo 59 nedo-
noščadi. PR je klasificirana prema Međunarodnoj klasifikaciji PR. Totalni oksidacijski status (TOS), totalni antioksidacijski
status (TAS), malondialdehid (MDA) i paraoksonaza 1 (PON1) određeni su spektrofotometrijski. Vrijednosti pro-oksidansa
TOS i MDA u nedonoščadi s PR bile su značajno više nego u nedonoščadi bez PR (p<0,05 za oba). Nije bilo značajne razlike
u vrijednostima TAS i PON1 između nedonoščadi s PR i bez PR. Naše istraživanje je pokazalo da razina pro-oksidansa
značajno korelira s razvojem PR, ali nije potvrdilo značajnu razliku u razini antioksidansa između skupina. Prema našim
rezultatima TOS i MDA dobri su pokazatelji oksidacijskog stresa, dok su TAS i PON1 nepouzdani u procjeni antioksidacij-
ske zaštite.
Ključne riječi: Reaktivni spojevi kisika; Antioksidansi; Retinopatija nedonoščadi; Nedonošče; Oksidacijski stres

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