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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 348-354

Study of oxidative stress in common neonatal disorders and evaluation of antioxidant strategies


Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission25-Jul-2013
Date of Acceptance17-Nov-2013
Date of Web Publication31-Aug-2015

Correspondence Address:
Mohamed A El-Shafie
Department of pediatrics, Faculty of Medicine, Menoufia University, Shebin el kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163883

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  Abstract 

Objectives
The aim of this work is to study oxidative stress and the profile of antioxidant mechanisms in common neonatal disorders. These disorders are prematurity, neonatal hyperbilirubinemia, and perinatal asphyxia. This study also aimed to evaluate the effect of treatment of these disorders on oxidative stress.
Background
In a broad sense, oxidative stress may be considered an imbalance between prooxidant and antioxidant forces or between the amount of reactive oxygen species and antioxidant defenses. The term oxygen radical disease of neonatology has been suggested to designate diseases whose pathogenesis includes tissue aggression from free radicals and reactive oxygen species. However, the mechanisms involved are more complex and involve more than oxidative stress; inflammation, infection, and other factors are important in preterm and neonatal diseases such as neonatal hyperbilirubinemia and exposure to perinatal asphyxia.
Materials and methods
Fifty neonates were studied. Clinical assessment, lab detection of antioxidant enzymes (catalase, glutathione perioxidase, and superoxide dismutase) in plasma, and oxidation reaction initiated by free radical products (F8-isoprostane and melanodialdehyde) in plasma at admission to NICU and before discharge were performed. After discharge, 15 neonates were studied as controls (healthy neonates being followed up at the outpatient clinic and matched for sex and postneonatal age). The remaining 35 neonates were divided into three groups: preterm group, hyperbilirubinemia group, and perinatal asphyxia group.
Results
At admission, the plasma level of antioxidant enzymes was insignificantly suppressed in the preterm group, except superoxide dismutase, which was significantly suppressed. The level of antioxidant enzymes was insignificantly higher in neonates with hyperbilirubinemia and significantly suppressed in neonates exposed to perinatal asphyxia; there was no significant difference in the level of oxidation reaction products in preterm and neonatal hyperbilirubinemia groups compared with the controls, but their level was significantly increased in neonates exposed to perinatal asphyxia. Before discharge, preterm patients received a higher concentration of oxygen (in the form of mechanical ventilation), and oxidation reaction products were significantly elevated as in neonates exposed to perinatal asphyxia.
Conclusion
Oxidative stress plays a definite role in the pathogenesis of complications caused by immaturity and neonatal exposure to oxidative stress favoring factors such as oxygen and many life-saving procedures used in the NICU.

Keywords: antioxidant enzymes, free radicals, neonatal jaundice, oxidative stress, preterm


How to cite this article:
Bahbah MH, Deeb MM, Ragab SM, El-Shafie MA. Study of oxidative stress in common neonatal disorders and evaluation of antioxidant strategies. Menoufia Med J 2015;28:348-54

How to cite this URL:
Bahbah MH, Deeb MM, Ragab SM, El-Shafie MA. Study of oxidative stress in common neonatal disorders and evaluation of antioxidant strategies. Menoufia Med J [serial online] 2015 [cited 2020 Apr 6];28:348-54. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/348/163883


  Introduction Top


The neonatal period is a highly vulnerable period for an infant, in whom many of the physiologic adjustments required for extrauterine existence are achieving completion. The high neonatal morbidity and mortality rates can be attributed to the fragility of life during this period. An infant's transition from intrauterine to extrauterine life requires many biochemical and physiologic changes. No longer dependent on maternal circulation through the placenta, the newborn's respiratory system must function for exchange of oxygen and carbon dioxide [1] .

Newborn infants are also dependent on gastrointestinal tract function for absorbing food, renal function for excreting waste and maintaining chemical homeostasis, hepatic function for neutralizing and excreting toxic substances, and a functioning immunologic system for protection against infection. The neonatal cardiovascular and endocrine systems also adapt for self-sufficient functioning. Many of a newborn infant's specific problems are related to poor adaptation because of asphyxia, premature birth, life-threatening congenital anomalies, or the adverse effects of delivery [2] .

Oxidative stress (OS) results from an imbalance between reducing agents and enzymes involved in the removal of free radicals (FR) and/or reactive oxygen species (ROS). The consequence of OS on fetal structure involves the activation of a complex array of genes involved in inflammation, coagulation, fibrinolysis, cell cycle, and signal transduction. It is now recognized that ROS are important for fertilization and development of embryos [3] .

In moderate quantities and in the presence of good antioxidant capacity, FRs are generated continuously in the organism and are essential for cell aerobic metabolism and fetal growth, but they are toxic when overproduced, resulting in an attack of all classes of biological macromolecules, polysaccharides, nucleic acid, lipids, and proteins [4] .

Hypoxia, hyperoxia, inflammation, Fenton chemistry, endothelial damage, and arachidonic acid cascade are other mechanisms that lead to the formation of highly reactive products. FR reactions lead to DNA damage (fragmentation, apoptosis, base modifications, and strand breaks), to lipid, protein, and polysaccharide oxidation, and as a consequence, FR reactions may induce a wide range of biological toxic effects [5] .

Many factors contribute toward the increased vulnerability of neonates to OS: prematurity, oxygen therapy, deficiency in antioxidant defense, increased susceptibility to infection, and inflammation [6] .

Hypoxic ischemic conditions, which are widely recognized as the major cause of the brain damage and neurologic disability, can activate a number of mechanisms of potential FR generation [7] .

The neonatal brain, with its high concentrations of unsaturated fatty acids, high rate of oxygen consumption, low concentrations of antioxidants, and high content of metals catalyzing FR formation (especially hydroxyl radicals and peroxynitirite) is particularly vulnerable to OS-mediated damage [8] .

Several strategies can be used to combat OS by FR blockade or enhancing antioxidant power. Many antioxidant drugs have been used in clinical and experimental approaches to reduce OS in oxygen-related neonatal disease [9] .

Treatment with oxygen FR inhibitors and scavengers [i.e. superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)] shows several limitations:

  1. Prolonged time to penetrate the blood-brain barrier;
  2. Narrow therapeutic dosage range; and
  3. Protective only if administered many hours before the insult [10] .

  Materials and methods Top


After approval of the Local Institutional Ethical Committee of Menoufiya University Hospital, 50 neonates who were admitted to and being followed up at the Neonatology Unit, pediatric department, Menoufia University Hospitals, were included in this study.

Study design

Oxidative effects are assessed indirectly by determination of the total antioxidant capacity by measuring individual antioxidant enzymes or by determining the stable end products of OS on lipids, proteins, and DNA.

This study included 50 neonates: 35 patients and 15 controls matched for age and sex.

The patient group was subdivided into three groups:

  1. The preterm group, which included 20 preterm infants (who were born before after completion of 37 weeks of gestational age (G.A.)),
  2. The neonatal hyperbilirubinemia group, which included 10 neonates with total and indirect bilirubin level indicative for phototherapy, and
  3. The perinatal asphyxia group GA, which included five neonates exposed to perinatal asphyxia that was confirmed clinically.
All the neonates in both the main groups and subgroups were subjected to the following.

Assessment of history, with a special focus on the following: history of consanguinity, maternal history of previous pregnancy, labor, or abortion, and history of present pregnancy, labor and resuscitation, and history of perinatal and/or postnatal events. A thorough clinical examination was carried out and anthropometric measurements were performed.

The following investigations were performed:

  1. Routine laboratory investigations such as, complete blood picture, indirect and total bilirubin, C-reactive protein, and blood grouping.
  2. Antioxidant profile.
Antioxidant enzymes: GPx in hemolysate, CAT in hemolysate, and SOD in hemolysate.

Oxidation reaction products: Isoprostane metabolite (F-8 isoprostane)in plasma and melanodialdehyde (MDA) in plasma.

These clinical and laboratory procedures were performed twice:

  1. At the postnatal age of 2 days or at admission (in the neonatal hyperbilirubinemia group), and then follow-up of patients was performed throughout the entire course of disease, registering all data of patients,
  2. After recovery and just before discharge (to detect the effect of treatment of different neonatal conditions on the oxidant/antioxidant profile). Then, the results of these two steps were statistically analyzed.

  Results Top


Preterm group

This group included 20 preterm infants, 11 males and nine females, mean gestational age 31 ± 1 weeks and mean weight 1.875 ± 0.263 kg, admitted to the NICU because of respiratory complications of prematurity, low birth weight (LBW <2.500 kg), very low birth weight (VLBW <1.500 kg), and inability to initiate feeding. The first step was initiated at 48 h of postnatal age (GP1).

The preterm group (GP) was compared with the control group (G2) in terms of the following: SOD, CAT, and GPx. There were nonsignificant reductions in the levels of the preterm group (GP1) compared with the control group (G2) for CAT and GPx. SOD level was significantly suppressed in the preterm group in comparison with the control group [Table 1] [Table 2] [Table 3].
Table 1 Comparison between clinical laboratory results of the fi rst samples of the control group (G2), the preterm group (GP), the jaundice group (GH), and the perinatal asphyxia group (GA)

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Table 2 Comparison between laboratory results of the second samples of the control group (G2+), the jaundice group (GH+), and the perinatal asphyxia group (GA)

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Table 3 Comparison between laboratory results of the second samples of different preterm groups (GPa+), (GPb+), and (GPc+)

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There was a nonsignificant difference in the plasma level of F-8 isoprostane and MDA between the preterm group (LBW) and the control group.

Before discharge of this group of patients, the second samples were withdrawn. The mean postnatal age was 21 ± 4 days and the mean weight was 1.850 ± 0.545 kg. According to the diagnosis and the main line of treatment, this group was redivided into three subgroups:

  1. GPa: this subgroup included seven patients, four males and three females; their diagnosis was severe respiratory distress syndrome and the main line of treatment was mechanical ventilation, followed by continuous positive airway pressure (CPAP), noninvasive oxygen therapy through a nasal cannula or mask+intravenous fluids, and feeding until discharge, when the mother could breastfeed her child and the infant's weight was greater than 1.800 kg.
  2. GPb: this subgroup included eight patients, five males and three females; their diagnosis was mild to moderate respiratory distress syndrome and the main line of treatment was continuous positive airway pressure CPAP or noninvasive oxygen therapy through a nasal cannula or mask+intravenous fluids, and then feeding until discharge, when the mother could breastfeed her child and the infant's weight was greater than 1.800 kg.
  3. GPc: this subgroup included five patients, two males and three females; their diagnosis was LBW, VLBW with or without mild respiratory distress syndrome (RDS), and the main line of treatment was feeding using a nasogastric tube at first and then oral feeding (they needed minimal oxygen therapy in the early period of admission and this was usually administered in the form of a nasal cannula) until discharge, when the mother could breastfeed her child and the infant's weight was greater than 1.800 kg.
The results of these groups indicated a significant increase in the F 8 isoprostane level in GPa than the other groups, with a reduction of all antioxidant enzymes.

Hyperbilirubinemia group

This group included 10 full-term neonates, five males and five females, mean gestational age 39 ± 1 weeks and postnatal age of 5 ± 2 days and mean weight 3.277 ± 0.446 kg, admitted to the NICU because of neonatal indirect hyperbilirubinemia. These patients had total serum bilirubin that was beyond their specific chart level for initiating photo therapy, with a mean total serum bilirubin of 16.0 ± 1.3 mg/dl. The first step was initiated at admission at mean postnatal age (5 ± 1days) (GP).

There was a nonsignificant increase in the levels of CAT and GPx in the hyperbilirubinemia group (GH) compared with the control group (G2).

There was a nonsignificant difference in the plasma level of MDA and F-8 isoprostane between the hyperbilirubinemia group (GH) and the control group.

There was a nonsignificant difference between the levels of CAT and GPx in the hyperbilirubinemia group (GH+) compared with the control group (G2+).

There was a nonsignificant difference in the plasma level of MDA and F-8 isoprostane between the hyperbilirubinemia group (GH+) and the control group (G2+). There was a nonsignificant increase in the plasma level of MDA between the hyperbilirubinemia group (GH+) and the control group (G2+).

Perinatal asphyxia group

This group included five full-term neonates, four males and one female, mean gestational age 39 ± 1weeks and mean weight 3.136 ± 0.391 kg, admitted to the NICU because of exposure to perinatal asphyxia. The first step was initiated at 48 h of postnatal age (GA).

All patients in this group were diagnosed with sarnat 1 (mild encephalopathy). Before discharging this group of patients, the second set of samples was withdrawn (GA+). The mean postnatal age was 7 ± 2 days and the mean weight was 2.970 ± 0.280 kg.

There were nonsignificant reductions in CAT and GPx and SOD level in this group compared with the control group.

There was a significant increase in the plasma level of F-8 isoprostane and MDA between the GA group and the control group (G2).

Results of the second sample of G2+ and GA+

There was an insignificant statistical relation between the levels of SOD, GPx, and CAT in the two groups.

There was a significant increase in the plasma level of F-8 isoprostane and MDA between the GA+ group and the control group (G2+).


  Discussion Top


Preterm group

The preterm group (GP) was compared with the control group (G2) for the following: SOD, CAT, and GPx. There were nonsignificant reductions in the levels of CAT and GPx in the preterm group (GP1) compared with the control group (G2). SOD level was significantly suppressed in the preterm group in comparison with the control group.

There was a nonsignificant difference in the plasma level of F-8 isoprostane and MDA between the preterm group (LBW) and the control group.

Trindade and Rugolo [11] and Trindade [10] obtained similar results: a decrease in the level of antioxidant enzymes and increased susceptibility to OS in preterm infants compared with healthy full-term infants shortly after birth.

This can be explained as it is now believed that antioxidant enzyme capacity usually develops late in the third trimester. Thus, it is very obvious that preterm neonates will have less antioxidant capacity when compared with healthy full-term neonates as reported by Vento et al. [12] and Trindade and Rugolo [11] . Thus, this group of neonates is at an increased risk for OS.

Before discharging this group of patients, the second set of samples was withdrawn.

The results of these groups indicated a significant increase in the F 8 isoprostane level in GPa than the other groups, with a reduction of all antioxidant enzymes. The GPa group was the only group that was exposed to the highest O 2 levels and pressures as they were mechanically ventilated and subjected to many life-saving procedures, which led to the development of OS in this group more than in the other groups. Vento et al. [12] and Volpe [13] reported almost identical results, but Vento et al. [12] also measured isofuran metabolites in urine, which was increased, also indicating more OS.

Hyperbilirubinemia group

There was a nonsignificant increase in the levels of CAT and GPx in the hyperbilirubinemia group (GH) compared with the control group (G2).

There was a nonsignificant difference in the plasma level of MDA and F-8 isoprostane between the hyperbilirubinemia group (GH) and the control group.

These results indicate that OS in this group is minimal and the insignificant increase in antioxidant enzymes has been explained in the literature. Wiedemann et al. [14] found a direct relationship between the total antioxidant status of newborn plasma and bilirubin concentrations in both preterm and term infants. They also reported that exchange transfusion, by reducing the serum bilirubin concentration, decreases plasma antioxidant capacity.

The nontoxic form of bilirubin (biliverdin) is considered as indirect antioxidant enzyme inducer as according to the study by Comporti et al. [15] and Wiedemann et al. [14] .

Therefore, OS may be not encountered in cases of neonatal jaundice, Comporti et al. [15] .

Before discharge of this group of patients, the second set of samples was withdrawn (GH+). There were nonsignificant differences between the levels of CAT and GPx in the hyperbilirubinemia group (GH+) compared with the control group (G2+).

There was a nonsignificant difference in the plasma level of MDA and F-8 isoprostane between the hyperbilirubinemia group (GH+) and the control group (G2+). There was a nonsignificant increase in the plasma level of MDA between the hyperbilirubinemia group (GH+) and the control group (G2+).

This step mainly assesses the effect of phototherapy on the oxidant/antioxidant status of the body.

From these results, it can be concluded that phototherapy exerted no major effect on the oxidant/antioxidant status of the body. Ozture et al. [16] and Aycicek and Erel [17] reported the same result.

Gathwala and Sharama [18] and Kiran [19] reported the same result of elevated MDA, but they attributed this to increased ROS formation as a result of phototherapy as it energizes bilirubin, which acts as a photosensitizer. Thus, they consider phototherapy a factor that favors OS.

Cotario and Brines [20] , Yuksmhel et al. [21] , Pippger et al. [22] ; and Sobaec et al. [23] arrived at the same conclusion.

Perinatal asphyxia group

There was a nonsignificant reduction in CAT and GPx and SOD levels in this group compared with the control group.

This reduction may be attributed to exposure to hypoxia and delivery of a depressed neonate (which resulted in extensive resuscitative measures), which led to a condition of OS that induced depletion of antioxidant enzyme capacity.

This study did not find this significant reduction in the level of antioxidant enzymes mostly because of the small number of patients, and all of the patients only had a manifestation of mild encephalopathy.

There was a significant increase in the plasma level of F-8 isoprostane and MDA in the (GA) group and the control group (G2).

These results indicate a state of excess OS with depressed antioxidant enzymes and increased levels of OS end products. The transition from an intrauterine hypoxic environment to an extrauterine normoxic environment leads to an acute increase in oxygenation, which induces the production of R0S. A total of 5-10% of newly born infants require active resuscitation with supplementary oxygen at birth, and the ideal oxygen concentration for neonatal resuscitation is unclear, which is a major concern [2] . Hypoxic neonates have increased plasma concentrations of lipid peroxidation and oxidation protein products at birth and 7 days later as reported by Vento et al. [12] .

Volpe [13] reported that inadequate scavenging ability of the immature nervous system, characterized by lower SOD and GPx activity, contributes toward the accumulation of H 2 O 2 and subsequent neurotoxicity.

Lackman et al. [24] , Tan et al. [25] , Perlman [26] , and Mishra et al. [27] found a significant reduction in the level of SOD, GPx, and CAT compared with normal healthy neonates.

Results of the second sample of G2+ and GA+

There was an insignificant statistical relation between the levels of SOD, GPx, and CAT between the two groups.

There was a significant increase in the plasma level of F-8 isoprostane and MDA between the GA+ group and the control group (G2+).

These results were not in agreement with the results of Lackman et al. [24] and Tan et al. [25]. These studies had reported increased levels of SOD and GPx in hypoxic neonates who showed recovery.

This may explained by presence of all of our patients in the category of mild encephalopathy.

Other studies have included a larger number of patients and moderate to severe encephalopathy was present, which implied the presence of convulsion and use of phenobarbital, according to the study by Perlman [26] and Volpe [13] .

Phenobarbital is a known enzyme inducer that may explain the increased level of SOD and GPx in these studies, Perlman [26] and Mishra et al. [27]

The process of hypoxic-ischemic brain injury begins with the insult and extends for several hours into the recovery period (reperfusion phase of injury) [13] .


  Conclusion Top


From this study, it can be concluded that the capacity of dealing with OS in preterm neonates is reduced in comparison with healthy full-term neonates, although most of these preterm infants are exposed to major OS because of intense oxygen therapy.

Neither neonatal jaundice nor phototherapy had caused any additional OS. Perinatal asphyxia is a major cause of OS in the neonatal period, and resuscitation and treatment of such neonates has been a main source of OS.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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