|Year : 2016 | Volume
| Issue : 2 | Page : 95-102
Interleukin-1β in perinatal asphyxia
El-Sayed A Wagdy, Ebrahim T Hasan, Eassa A Eman
Neonatal Intensive Care Unit, Department of Pediatrics, Benha Teaching Hospital, Benha, Egypt
|Date of Submission||09-Aug-2015|
|Date of Acceptance||17-May-2016|
|Date of Web Publication||1-Mar-2017|
El-Sayed A Wagdy
MD Pediatrics, Mansoura University, Benha Teaching Hospital, Benha 5432
Source of Support: None, Conflict of Interest: None
Perinatal asphyxia is a common cause of neonatal morbidity and mortality. Inflammatory cascades are involved in the pathogenesis of ischemic brain injury during asphyxia, which is mediated by cytokines such as interleukin-1β (IL-1β).
We determined IL-1β in cases with perinatal hypoxia to evaluate its role in the pathogenesis of this condition and its relation to the development of complications, which may be reflected on its management.
This is a case–control study.
Patients and methods
The patient group included 31 full-term newborn infants diagnosed as having perinatal asphyxia who were selected from the Neonatal Intensive Care Unit in Benha Teaching Hospital. The control group included 16 full-term newborns with no natal or postnatal complications who were selected from the well baby care unit. IL-1β and C-reactive protein (CRP) were measured by the ELISA technique (highly sensitive CRP). Erythrocyte sedimentation rate (ESR) was performed by the Wintrobe method.
Results were analyzed and compared with 16 controls using SPSS 20.
IL-1β was significantly higher in asphyxia cases compared with controls. In addition, it was significantly higher in cases with seizure, systemic organ failure, and in cases who developed cerebral palsy (CP) compared with those without seizure, organ failure, and CP. IL-1β correlated positively with encephalopathy stages. It showed no relation to gestational age, sex, weight, hematological data, or CRP.
We conclude that the level of IL-1β is high in cases with perinatal asphyxia. Cases with seizure, organ failure, and neurological sequelae had higher levels. It correlates positively with encephalopathy stages without relation to hematological parameters or CRP.
Keywords: cytokines, interleukin-1β, perinatal asphyxia
|How to cite this article:|
Wagdy ESA, Hasan ET, Eman EA. Interleukin-1β in perinatal asphyxia. Benha Med J 2016;33:95-102
| Introduction and objective|| |
Perinatal asphyxia is a common cause of neonatal morbidity and mortality in the neonatal intensive care unit, and it is a cause of long-term neurologic disabilities among survivors . Hypoxic–ischemic encephalopathy (HIE) is a neurologic syndrome that frequently accompanies perinatal asphyxia .
It is estimated that 2–4/1000 full-term neonates suffer asphyxia at or shortly before birth. Approximately 15–33% of infants developing HIE die during the neonatal period, and 25% of the survivors exhibit permanent neuropsychological deficits ,.
There is evidence supporting the involvement of the inflammatory cascade in the pathogenesis of ischemic brain injury. Inflammation triggered by ischemia of the central nervous system (CNS) is characterized by polymorph nuclear cell recruitment, requiring the expression of specific adhesion molecules and chemotactic factors, and it is followed by monocytes and microglial activation .
Cytokines are substances produced by the cells of the immune system to mediate the inflammatory and immunological responses . Some reports described a significant role of cytokines in CNS health and diseases , and others described deleterious effects in hypoxia–ischemia and inflammation .
Some of the cytokines studied in neonatal asphyxia are tumor necrosis factor-α (TNF-α), interferon-γ, and interleukin 6 (IL-6)  and interleukin 18 (IL-18) , which are the proinflammatory cytokines that have been studied frequently in term, preterm, and mixed populations. Most, but not all, of these studies have found elevated levels of these mediators in newborns with evidence of perinatal brain damage compared with controls .
Few studies are available regarding interleukin-1β (IL-1β) in perinatal asphyxia with variable nonconclusive results. It appeared to be specific to brain injury, and its cerebrospinal fluid (CSF) concentration is highly predictive of neurological outcomes . Because of the possible role of cytokines in the pathogenesis and sequelae of neonatal asphyxia, we will estimate the level of IL-1β in newborns with perinatal asphyxia.
| Patients and methods|| |
Thirty-one full-term newborn infants diagnosed as having perinatal asphyxia were selected from the Neonatal Intensive Care Unit in Benha Teaching Hospital and were included in the study. Detailed antenatal and natal history, complete physical and neurological examination, and clinical staging of encephalopathy according to Sarnat staging  were performed at 24 h of age for each newborn.
Diagnosis of perinatal asphyxia
Perinatal asphyxia was defined as the presence of at least two of the following conditions:
- Signs of fetal distress (heart rate of <100 beats/min, late decelerations, or an absence of heart rate variability).
- Thick, meconium-stained amniotic fluid and respiratory depression, hypotonia, or bradycardia.
- Apgar score (determined by evaluating the following parameters of the newborn: heart rate, respiratory effort, muscle tone, response to catheter in nostril, and color) of 4 or less at 1 min or of 6 or less at 5 min.
- A need for resuscitation for more than 1 min with positive-pressure ventilation and oxygen immediately after birth.
- Blood pH value of less than 7.20 or a base deficit of at least 12 within the first hour after birth .
Sarnat staging  classified HIE as follows: mild (grade 1), if hyperexcitability or hyperalertness or hyper-reflexia persisted without seizures for at least 24 h after birth; moderate (grade 2), if the infant was lethargic, with hypotonia, weak primitive reflexes, pupil miosis, and seizures; and severe (grade 3), if the infant had apnea, flaccid weakness, frequent seizures, decelerated posture, or coma.
In addition to the neurologic dysfunction arising from HIE, assessment of possible systemic organ dysfunction within the first week was done.
Multiorgan dysfunction was considered during the following instances: if there was a need for pulmonary ventilator dependence or the need for supplemental oxygen for more than 24 h; congestive heart failure not associated with structural heart disease, shock, gut ischemia, or signs of necrotizing enterocolitis; elevated transaminases; prolonged prothrombin time or partial thromboplastin time; thrombocytopenia; evidence of disseminated intravascular coagulation; acute tubular necrosis; or oliguria (<1 ml/kg/h urine flow rates) beyond 24 h .
Exclusion criteria were cases referred from other hospitals, clinical or laboratory evidence of sepsis, metabolic diseases, cardiovascular, pulmonary and CNS anomalies, prematurity to exclude its effect as a cause and association of asphyxia, and postmaturity and intrauterine growth retardation for the same reason .
All the cases have been re-examined at 1 month of age including complete neurological examination and computed tomography scan to determine possible neurological abnormalities and other possible complications.
Sixteen control full-term newborns with no natal or postnatal complications were selected from the well baby care unit.
Laboratory and radiological investigations
Laboratory investigations such as complete blood count, serum electrolytes, C-reactive protein (CRP), blood culture, blood gas analysis, prothrombin time, partial thromboplastin time, serum liver enzymes (serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT)), and serum creatinine were performed. In addition, chest radiograph and transfontanellar ultrasound for suspected cases of asphyxia were performed.
Three milliliters of blood was taken at 24 h of age from both cases and controls and left for 20 min at 37°C. Serum was separated after centrifugation and kept at −20°C until analysis.
Principle of the assay of interleukin-1β
IL-1β was measured by the ELISA technique using a kit provided from Wkea Med Supplies Corp. (Changchun, China). This assay uses an antibody that is specific for human IL-1β coated on 96-well plates.
Standards and samples were pipetted in the wells and IL-1β present in the sample was bound to the wells by the immobilized antibody. The wells were washed, and biotinylated antihuman IL-1β antibody was added. After washing away unbound biotinylated antihuman IL-1β antibody, horseradishperoxidase (HRP)- conjugated streptavidin was pipetted to the wells. After washing again, a tetramethylbenzidine substrate solution was added, and the color developed is proportional to the amount of IL-1β bound.
Written consents have been taken from the parents of all the newborns included in this study. The study was also approved from the Research Ethics Committee in General Organization for Teaching Hospital and Institutes in Cairo.
Data were analyzed using SPSS 20 computer program (IBM, Endicott, New York, USA). Data were expressed as mean ± SD for categorized variables. Tests of significance χ2 and T tests and correlation study were performed where appropriate. P value less than 0.05 was considered statistically significant.
| Results|| |
The study included 47 neonates, 31 cases diagnosed as perinatal asphyxia, controls well baby or 16 healthy neonates as control group. No significant differences were found between cases and controls regarding sex, weight, and gestational age (P = 0.917, 0.297, and 0.099, respectively).
Patients’ group showed higher rates of pregnancy complications and cesarean section (CS) delivery compared with the control groups (P = 0.04 and 0.031, respectively) ([Table 1]).
Clinical characteristics of patient group
Among 31 neonates diagnosed as having perinatal asphyxia, 12 cases developed convulsions, whereas 19 did not. According to Sarnat staging of encephalopathy , 10 cases were in stage 1, 15 cases were in stage 2, and six cases were in stage 3. Twenty-three cases did not develop systemic organ failure, two cases developed acute respiratory distress syndrome, one case had gastrointestinal bleeding, one case had intracranial hemorrhage, two cases developed acute renal failure, and two cases had disseminated intravascular coagulation. Sixteen cases survived without sequelae, four cases died, and 11 cases had cerebral palsy (CP) ([Table 2]).
Laboratory parameters of the patients and controls
No significant differences were found between the patient and controls regarding hemoglobin (Hb), hematocrit (Hct), red blood cells (RBCs), white blood cells (WBCs), platelets, and CRP (P = 0.931, 0.735, 0.736, 0.578, 0.97, and 0.825, respectively), whereas significantly higher levels of IL-1β were found in the patients relative to controls (P = 0.000; [Table 3] and [Figure 1]).
Interleukin-1β in relation to clinical data
Subgroup analysis showed that cases with encephalopathy stage 1 and cases with normal outcome had no statistically significant differences in the levels of IL-1β compared with the controls (P = 0.33 and 0.065, respectively; data not shown). Cases who developed convulsions, systemic organ failure, unfavorable outcome (CP), or died showed a higher level of IL-1β compared with cases without convulsions or organ failure and with normal outcome (P = 0.007, 0.003, and 0.000, respectively). When dead cases were excluded, still cases with CP show a significantly higher level of IL-1β compared with those with favorable outcome (P = 0.002; data not shown). Among cases, no sex difference was found regarding IL-1β (P = 0.312; [Table 4]).
No relation was found between IL-1β and gestational age and weight (P = 0.756 and 0.904 respectively); however, a positive correlation was found between IL-1β and encephalopathy stages (P = 0.000; [Table 5] and [Figure 2]).
|Table 5 Interleukin-1β relation to gestational age, weight, Sarnat stages, and laboratory data|
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|Figure 2 Correlation of interleukin-1β (IL-1β) levels with encephalopathy stages.|
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Interleukin-1β in relation to laboratory parameters
IL-1β showed no relation to Hb, Hct, RBCs, platelets, WBCs, and CRP (P = 0.881, 0.795, 0.422, 0.648 and 0.127, respectively; [Table 5]).
| Discussion|| |
In this study, we evaluated serum IL-1β in 31 cases with perinatal asphyxia. These cases were age, sex, and weight matched with 16 newborns selected as controls. However, they showed higher CS delivery and pregnancy complications compared with the controls ([Table 1]). These differences can be explained by the fact that cases of asphyxia are possibly associated with increased possibility of CS delivery and pregnancy complications than control cases .
We took peripheral blood samples rather than umbilical cord blood at 24 h of age. Some investigators used umbilical cord blood samples, and others used CSF samples ,. Using umbilical cord blood samples, they depended only on Apgar scoring rather than on clinical assessment of asphyxia after delivery. CSF sampling is not practical for ethical and legal aspects because lumbar puncture is not taken routinely during asphyxia as in cases with meningitis or encephalitis.
Among cytokines, we investigated serum IL-1β in perinatal asphyxia because of its characteristic role in neonatal brain injury; it is expressed at high levels in the CNS during prenatal and postnatal development , but only at low levels in adult CNS .
Cases with asphyxia did not show significant differences from the controls regarding Hb, Hct, RBCs, WBCs, CRP, and platelets (P = 0.931, 0.735, 0.736, 0.578, and 0.825, respectively; [Table 3]). This matching is because we excluded cases with possible sepsis and preterm labor. In contrast to our finding regarding CRP, Shang et al., found that high-sensitivity CRP is higher in asphyxiated neonates compared with healthy controls. They did not exclude cases with sepsis from their study. Sepsis is an important risk factor for asphyxia in neonates . Another explanation is that possibly they took their samples at a time different from ours. CRP in asphyxia was found to be increased gradually and reached its maximum level at the fourth day after birth .
Our cases showed significantly higher IL-1β levels compared with the controls (P = 0.000). Subgroup analysis showed that cases with encephalopathy stage 1 and cases with normal outcome (without CP) had no statistically significant differences compared with those of the controls (P = 0.33 and 0.065 respectively; data not shown). Liu and Feng  found that IL-1β levels were higher in the umbilical and peripheral blood in HIE patients than in the control group. However, they found that umbilical blood samples correlate better with encephalopathy staging and are more predictive of abnormal neurological outcome at 6 and 12 months of age. In a study conducted by Xanthou et al., peripheral blood IL-1β was significantly higher in asphyxia cases compared with controls and higher in severe cases compared with mild cases.
Several studies support the roles of IL-1β in the pathogenesis of brain injury. Induction of hypoxia–ischemia in neonatal rats was associated with increased IL-1β peak at 6 h in the cortex and at 24 h in the hippocampus. This effect was ameliorated 24 h after injecting IL-1Ra 2 h after hypoxic ischemic (HI) injury . Neonatal rats with induced homozygous deletion of IL-1β-converting enzyme (ICE) are resistant to hypoxic insults compared with wild-type mice . ICE is a cysteine protease, which is synthesized by cells of the monocytic lineage. It cleaves inactive pro-IL-β to the active proinflammatory cytokine IL-β  and is a member of a family of proteases or caspases that play distinct and complex roles as mediators of the apoptotic cell death cascade . The mechanism of brain injury is thought to be mediated through increased water content, neutrophil infiltration and adhesion, and induction of apoptosis and astrogliosis .
Serum IL-1β was also significantly higher in cases with convulsions and in cases with unfavorable outcomes (CP and death) compared with those without convulsions or favorable outcomes ([Table 4]). When the cases who died were excluded, CP cases still showed significantly higher levels compared with those with favorable outcome (P = 0.002). Serum IL-1β showed a strong positive correlation with encephalopathy stages (P = 0.000; [Table 5]). Liu and Feng  found that IL-1β levels correlated with adverse outcomes of neonatal HIE. Previous studies revealed an association between infection inflammation outside the CNS and CP in near-terms ,,. In a meta-analysis study conducted by Dammann and O'Shea , it was hypothesized that infection distant to the brain (either maternal or neonatal) can damage the developing brain because of the circulating cytokines, which associate infection and inflammation. Cai et al., found that intracerebral injection of IL-1β in neonatal rats was associated with brain damage. The time course of IL-1β protein levels correlates well with the time course of cell death level and caspase 3 activity observed during HI injury after induction of hypoxia–ischemia in neonatal rats . However, Oygür et al., did not find any significant differences in plasma TNF-α and IL-1β between asphyxiated full-term newborns with good and bad outcomes (CP and death), whereas significant differences were found in CSF samples. The difference from our findings is possibly because of the time of sample collection. They collected samples at 6 h of age, whereas we collected it at 24 h. Previous reports give results similar to ours at a similar time of sampling ,. Previous reports about preterm babies demonstrate lack of relation between IL-1β, CP, and neurodevelopmental delay ,,. It is possible that contribution of asphyxia to CP in preterm babies is minor compared with different risk factors compared with full-term babies. Immaturity of brain cells and blood–brain barrier (BBB) renders other injurious factors more effective compared with asphyxia. There are no available studies to demonstrate differences in susceptibility of the brain in preterm and full-term babies to injurious effects of cytokines. Preterm babies may be less susceptible to the injurious effect of cytokines compared with full-term babies .
The relation of cytokines to seizures has been studied in literature. In genetic studies, homozygosity for the IL-1β-511 allele 2, which is suggested to be an inducer of IL-1β, was over-represented in temporal lobe epilepsy patients with hippocampal sclerosis and increased risk of febrile convulsions ,.
Despite the presence of contradicting reports, this contradiction can be explained by different prevalences of the allele in different ethnicities. In experimental modes, intrahippocampal application of IL-1 has proconvulsant actions  and the intravenous administration of IL-1Ra exhibited significant reduction of status epilepticus intensity in the rat . In one study on neonatal seizures, IL-1Ra was continuously inactivated, and it dropped to significantly lower levels in the seizure group compared with the control group . Lack of consistent induction of IL-1Ra in response to the epileptogenic environment was suggested to be characteristic of neonatal seizures . The mechanism of seizures in perinatal hypoxia is that it is caused by cytokines in addition to direct brain injury, as mentioned before . In addition, cytokines including IL-1β cause changes in the functional properties of the BBB . This causes BBB failure , which induces brain cell damage and neuronal hyperexcitability and consequently seizures .
Some authors utilized the role of IL-1β in the pathogenesis of brain injury during perinatal asphyxia in management modalities of this condition . They supposed a beneficial thereby using adjunct blockade of IL-1β as a means to minimize the neurotoxic effect associated with HIE in a similar manner to anti IL-1β thereby in cryopyrin associated periodic fever syndrome. As mentioned before, ICE is a member of the caspase family proteases, which is involved in the apoptotic cell death cascade and brain injury in perinatal hypoxia. Treatment with several general caspase inhibitors was found to be neuroprotective in adult rat and mouse models of reversible focal cerebral ischemia .
Other cytokines that have been studied in perinatal asphyxia included TNF-α and IL-6. Both cytokines appeared to have dual action (neurotoxic and neuroprotective effects) ,. This apparent contradicting action needs detailed and comprehensive investigations before starting trial of both cytokines (IL-6 and TNF-α) in thereby of perinatal asphyxia. There is no available up-to-date study proving a neuroprotective role of IL-1β in asphyxia. This increases the value of IL-1β-targeted therapy, as mentioned before.
There are some limitations to our study: we did not follow-up the infants at older ages (6–12 months) to properly evaluate the neurological outcome and subsequent developmental delay. Relatively small number of cases and subgroups limit extensive statistical study. Further study is required with larger number of cases and with longer time of follow-up (may extend to years) for further study and analysis of the relation of different cytokines to the pathogenesis and outcome of perinatal asphyxia.
| Conclusion|| |
We investigated IL-1β in full-term newborns with perinatal asphyxia. Cases with asphyxia showed higher level of IL-1β compared with controls. Cases who developed convulsions, systemic organ failure, and poor outcome had higher values compared with those without convulsions, systemic organ failure, and those who survived without sequelae. IL-1β correlated positively with encephalopathy stages.
Financial support and sponsorship
Conflicts of interest
We thank all staffs in NICU Benha Teaching Hospital for their cooperation in completing this work. None of the authors has any conflicts of interest to declare.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]