Neonatal Hypoxic-Ischemic Encephalopathy: Single Tertiary Centre Experience

doi:10.21203/rs.3.rs-1723018/v2

Purpose

This study aimed to determine the factors associated with Neonatal hypoxic-ischemic encephalopathy (HIE) and its neurodevelopmental outcomes.

Methods

A case-control study of infants delivered at King Abdulaziz Medical City, Riyadh, Saudi Arabia, was carried out from 2015 to 2019. Newborns with an admission diagnosis of HIE were identified, and controls were matched for the case. The electronic medical records were used to extract the clinical data for each case. The HIE cases were followed for 24 months to determine their neurodevelopmental outcomes.

Results

The sample included 60 infants diagnosed with HIE and 234 infants as controls, primarily males (56%) with mean gestational age of 38 weeks (SD 1.6). According to Sarnat staging, 36% of the HIE cases (22 patients) had stage 2 encephalopathy, while 35% of infants were at stage 3. Children with HIE were twice as likely to be born to mothers with maternal comorbidities, and more likely to have prepartum and intrapartum complications than the control group. The follow-up of neurodevelopmental outcomes at 24 months for the HIE infants indicated no delays in development of gross motor skills (76%), fine motor skills (78%), language skills (67%), and social skills (78%).

Conclusion

Maternal comorbidities and prepartum or intrapartum complications were more prevalent in the HIE group. HIE severity grade can be used as a prognostic, predictive tool for neurodevelopmental outcomes. Neurodevelopment follow up for at least 24 months is necessary to enhance care and rehabilitation of the patients.

hypoxic-ischemic encephalopathy (HIE)

seizure

perinatal asphyxia

Hypoxic-ischemic encephalopathy (HIE) is a combination of clinical and laboratory evidence of acute or subacute brain injury associated with asphyxia in term or near-term newborns [22]. HIE occurs in about 1–8 per 1,000 live births worldwide [8]. It is considered one of the most common causes of permanent damage to the central nervous system, resulting in neonatal death or neurodevelopment disability [5]. Infants with moderate HIE have a 10% risk of fatality, and those who manage to live have a 30% risk of developing disabilities [17]. Infants with severe HIE have a 60% risk of fatality, and nearly all the survivors experience disabilities, including epilepsy and neurodevelopmental impairment, such as cerebral palsy and intellectual disability [15, 9, 6].

Therapeutic hypothermia is the standard treatment for infants ≥ 36 weeks gestational age (GA) with moderate-to-severe hypoxic-ischemic encephalopathy [4, 18, 2, 20]. Hypothermia attenuates the toxicity produced by the initial injury, which normally produces reactive oxygen species, neurotransmitters, inflammatory mediators, and apoptosis [10]. Erythropoietin has also been administered in neonates with perinatal HIE to reduce the risk of brain injury, cerebral palsy, and cognitive impairment; however, the evidence suggesting its role as an adjuvant to hypothermia is limited [11, 19].

Review of the literature revealed numerous studies conducted to identify the risk factors associated with HIE and its outcomes. However, at the national level, few local studies have attempted to explore the nature of HIE in Saudi Arabia. Al Shehri et al. described the risk factors for developing HIE among 57 cases and a similar number of controls [1]. The study identified HIE risk factors that included non-cephalic presentation, antepartum hemorrhage, instrumental delivery, and prolonged second stage of labor [1]. Also noticed, 67% of infants with moderate or severe encephalopathy had seizures [1]. Additional research in Saudi reported a lower number of HIE than other countries and identified similar and additional HIE risk factors of pregnancy-induced hypertension, prolonged second stage of labor, delivery using instruments or emergency caesarean section, and intrauterine growth retardation [7].

Although the previous studies have described the epidemiological features of HIE infants, the evidence related to the neurodevelopmental outcomes of those children is limited. In addition, there is a lack of updated information on HIE epidemiology at the national level. Therefore, this study was designed to describe the clinical characteristics of HIE infants and follow the neurodevelopmental outcomes of neonates with HIE using clinical and imaging biomarkers.

Study Type and Population

A case-control study of live-born infants delivered at King Abdulaziz Medical City, Riyadh, Saudi Arabia, was conducted from 2015 to 2019, where a total of 42658 were born. This neonatal intensive care unit (NICU) is a 40-bed, level IV critical care unit that has an average of 800 admissions per annum. Cases of newborns who had been admitted to the neonatal intensive care unit (NICU) with an admission diagnosis of HIE, either as a primary diagnosis or secondary to other causes of encephalopathy, such as major congenital anomalies or metabolic disorders, were identified. The diagnosis of HIE followed the operational definition as per the hospital developmental policies and procedures (DPP 7610-036, 2020) as a clinical syndrome involving a combination of abnormal consciousness, tone, reflexes, feeding, and respiration (and sometimes seizures) in term or near-term newborns. The definition of the condition is based on severe limitation of oxygen and blood flow near the time of birth and is a subset of neonatal encephalopathy, which can result from many different causes, including HIE [13]. We excluded neonates who had been born in other facilities or who had transferred to another hospital after birth, as it was difficult to track their neurodevelopmental-outcome data. For each HIE case, up to four controls were randomly selected from among all the deliveries in the hospital within the same calendar year, and were matched with the HIE cases in terms of gestational age (± 2 weeks) and maternal age (± 5 years).

Study Variables

The hospital’s electronic medical files were used to extract the clinical data for each HIE case and control (i.e., maternal obstetric history, delivery details). The following data were extracted: antepartum-associated risk factors, intrapartum-associated risk factors, and infant characteristics. The antepartum-associated risk factors included maternal age at delivery, maternal comorbidities (e.g., gestational diabetes, hypertension, thyroid disease), and maternal mortality during the delivery. For the intrapartum-associated risk factors, we collected data on the gestational age, mode of delivery (vaginal or C-section), and intrapartum complications and events, including malpresentation, abnormal cardiotocographic findings, presence of fetal decelerations, positive screening for a group B streptococcus test (GBS), meconium-stained amniotic fluid, abruption placentae, ruptured uterus, and abnormality of amniotic fluid. For the neonatal data, data on the following variables were collected: gender, birth weight, Apgar score (at 1, 5, and 10 min), need for and method of resuscitation (including the use of non-invasive or invasive ventilation), presence of congenital anomalies, and length of stay in NICU, if needed.

Neurodevelopmental Outcomes of the HIE Cases

To describe the neurodevelopmental outcomes of the HIE cases in terms of gross motor, fine motor, language, and social skills development, we followed the HIE cases for 24 months after delivery. We obtained data on their encephalopathy severity, mortality, abnormality in imaging modalities, seizures, cerebral palsy, and intellectual and learning disabilities. The encephalopathy severity was assessed and categorized into normal, stage 1, stage 2, and stage 3 based on the modified Sarnat Staging System [16]. Data on the treatment and use of therapeutic hypothermia for moderate and severe HIE were also collected. The research ethics committee approved this study by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (reference number RC19/302/R).

Analysis Plan

Descriptive statistics were used for the study variables. We compared the maternal intrapartum factors and the neonatal characteristics of the HIE cases and the control group using chi square or Fisher’s exact test for the categorical variables and two-sample t-tests for the continuous variables. If not normally distributed, we used the Wilcoxon rank-sum test. Conditional logistic regression models were used to estimate the odds ratio (OR) and the corresponding 95% confidence interval (CI) and p-value for the risk factor of interest. We lumped the factors into three major categories: maternal comorbidity, preterm, and intrapartum. The variable was retained in the final multivariable model if p < 0.05.

Among the HIE cases, we described the fetal complications and outcomes by HIE stage. Associations between the HIE stage and the study variables were examined using Fisher’s exact test for the categorical variables, t-tests for the continuous variables, or the Kruskal-Wallis H test as a nonparametric alternative. Data with p-values less than 0.05 were considered statistically significant. The statistical analyses were performed using the STATA® version 15 software (StataCorp, College Station, TX, USA).

Description of the Study Population

Initially, 313 infants have identified who met the inclusion criteria of the study, then after reviewing the medical files, a total of 60 HIE cases were included in the case groups and 234 infants were included in the controls groups, giving a total of 294 infants included in the final analysis (Fig. 1). Table 1 shows maternal and labor characteristics for the HIE cases included in the analysis and the control cases. The average maternal age for children with and without HIE was similar. The rate of maternal gestational diabetes was significantly higher for children with HIE compared to the control group (26% for HIE compared to 13% for control, p = 0.015), and the presence of polyhydramnios was significantly higher among HIE cases compared to controls (3.1% among HIE cases compared to 0.4% in the control group, p = 0.04). Compared to control infants, the presence of fetal distress during labor for children with HIE also was significantly higher (78% vs. 1.2%, p < 0.001).

For both HIE cases and controls, the majority were male (56%) infants with mean gestational age of 38 weeks (SD 1.6; Table 2). Compared to controls, children with HIE had a significantly higher percentage of maternal rupture of the uterus, meconium-stained amniotic fluid, and nuchal cord (p < .05; Table 2). The Apgar scores for 1, 5, and 10 min were likewise considerably lower among the HIE cases than the controls, with the HIE cases significantly more likely to average 5- and 10-min Apgar scores below 7 (p < .05). Among HIE cases who underwent resuscitation, 77% were intubated. Congenital anomalies were also more common among the HIE cases compare to the control cases (17% vs. 3.4%; p < 0.001).

Clinical and Labor Characteristic Factors Associated with HIE

Univariate analysis for clinical and labor characteristic factors associated with HIE is given in Table 3. Children with HIE were twice as likely to be born to mothers with maternal comorbidities when compared to infants in the control group (unadjusted OR 2.6, 95% CI 1.4-4.9), and this remained unchanged after adjusting for other factors. Similarly, children with HIE were more likely to have prepartum and intrapartum complications than the infants in the control group.

Fetal Complications and Outcomes by HIE Stage

In total, 60 HIE infants were included at the end of follow-up. According to Sarnat staging, 36% of the cases (22 patients) had stage 2 encephalopathy, while 35% of infants were at stage 3. The neurodevelopmental outcomes of the HIE cases are presented in Table 4 for all the HIE cases by HIE severity stage. The most common characteristics among HIE cases included hypotonia (60%), followed by normal muscle tone (28%). Seventy-five percent of all the HIE cases and 89% of the HIE stage 2 cases received therapeutic hypothermia. Imaging abnormality in magnetic resonance imaging (MRI) was more prevalent among the HIE stage 3 patients than among the HIE stage 2 or 1 cases. (Table 4). Moderate and severe encephalopathy occurred in about 7.4% and 6.4% of all the cases, respectively, with seizures occurring in 44% of the cases. Neonatal seizures were found among 49% of the HIE cases (82% were simple, 17% were intractable). Phenobarbital was the most common type of medication used for those HIE cases with neonatal seizures. At discharge, 62% of the HIE cases received treatment on the day of discharge from the hospital. Among all HIE cases, audiology tests were abnormal in eight patients (13.3%), autistic spectrum disorder was present among two patients (3.3%), and attention deficit hyperactivity disorder was present in 3.3 % of HIE cases.

Epilepsy was found in 6.6% of the HIE cases, and among those with epilepsy, three (75%) patients had simple epilepsy (two patients received levetiracetam, while the other received valproic acid) and one patient had intractable epilepsy (received Levetiracetam and topiramate). Of the HIE cases, 28% of patients had first EEG background information in their medical file, in which 56% of the HIE cases had standard first EEG background and 40% had abnormal first EEG background. Among those patients, nine cases (30%) had epileptiform activity in the first EEG, and five (16%) had a burst suppression pattern. Seven cases (41%) had last EEG pattern in which four (23%) had abnormal epileptiform activity and none had burst suppression pattern.

The follow-up of neurodevelopmental outcomes at 24 months for the 55 HIE infants who had completed the record is shown in Table 5. In total,42 infants (76%) had no delay in gross motor skills development, while six infants (10%) had mild to severe delay in gross motor skills development. Most of those who had mild to severe delay in gross motor skills development had HIE stage 3. Similarly, 78% of the 55 HIE infants had no delay in fine motor development, whereas seven (12%) had severe fine motor skills developmental delay and all of them were HIE stage 3. For language skills, 67% of the total HIE cases had no delay of language skills, whereas 12% had severe delays. For the social skills development, 78% had no delay in this skill development, while 14% had severe social developmental delays, of which more than 54% had stage 3 HIE.

In this study we aimed to identify the risk factors for HIE and to describe the clinical and neurological outcomes of infant diagnosed with HIE. Intrapartum risk factors including placenta abruption, rupture of the uterus, meconium-stained amniotic fluid, and nuchal cord and lower Apgar score were all significantly more prevalent among the HIE cases. For the neurodevelopmental outcomes at age 24 months, two-thirds of the HIE cases had a mild delay in gross motor skills development, of which the majority had no delay in fine motor, language, and social skills development, respectively.

Previous studies have examined the maternal and neonatal factors associated with increased risk of HIE [8, 14]. In our study, maternal comorbidity, such as gestational diabetes, was high among mothers who had a child with HIE compared to the control group which is consistent with previous studies. Prior research evidence supports that infants whose mothers had comorbidities were twice more likely to have HIE than infants whose mothers had no comorbidity [14]. Although maternal hypertension has been identified as a common risk factor for HIE in previous research [19], our study failed to demonstrate a significant association (p = 0.42).

The HIE cases were found to have a significant risk for the prepartum complication/event of fetal distress during labor compared to the control group (78% vs. 1.2%), such as polyhydramnios (3.1% vs.0.4%), for example. However, with regard to other prepartum complications/events, such as positive screening for GBS, breech presentation, and oligohydramnios, the HIE cases only showed higher percentages than the controls without demonstrating statistical significance (p > 0.05). The lack of association between non-cephalic presentation and risk of HIE that was shown in our study was surprising (5% vs. 2.5%). This contrasts with the findings of the study conducted in Abha City (southwestern Saudi Arabia) in 2005 [1].

Demographically, most of the HIE cases were male, which was significantly different from the control group (p = 0.03), and overall acute intrapartum events were also more prevalent in the HIE cases compared to the controls. Placenta abruption, rupture of the uterus, meconium-stained amniotic fluid, and nuchal cord were all significantly more prevalent among the HIE cases (p < 0.05). The Apgar scores for 1, 5, and 10 min were likewise significantly lower among the HIE cases than among the controls. The HIE cases were significantly more likely to have an average 5- and 10-min Apgar score below 7. Among all the HIE cases who underwent resuscitation, 77% were intubated, 95% required bag valve mask ventilation and positive pressure ventilation, only nine patients had cardiac message, and two patients received epinephrine. These results are similar to those of another local study conducted in 2005, which found the following significant risk factors: mode of delivery, antepartum hemorrhage, low Apgar score, and low birth weight [7]. Congenital anomalies and dysmorphism were also more common among the HIE cases, compared to cases in the control group (17% vs. 3.4; 13% vs. 0; p < 0.001).

The most sensitive and specific imaging technique for examining infants with suspected hypoxic-ischemic brain injury is MRI [3, 21]. Brain MRI was classified in this study as the last recommendation pattern of HIE [12](Fig. 3). Abnormality in MRI was more prevalent among the HIE stage 3 cases than among the HIE stage 2 or 1 cases. Watershed predominant followed by global, white matter, and basal ganglia or thalamus lesion were all significantly more prevalent among the HIE cases (p < 0.001). Although abnormal brain CT was also more common among the HIE cases than among the controls, we failed to demonstrate a significant association (p = 0.17). The results of the other investigations, including genetic and metabolic workup, such as ammonia, plasma amino acid, neonatal screening, karyotyping, microarray, and whole exam sequence also were not found to be significantly associated with HIE. Seventy-five percent of all the HIE cases and 89% of the HIE stage 3 cases received therapeutic hypothermia. In most of these cases (68%), erythropoietin was also given. This included 84% with HIE stage 3 cases and 72% with HIE stage 2 cases.

The outcomes were more prevalent in the HIE stage 3 cases than in stage 1 and 2. The outcomes included intellectual disability, learning disability, autism spectrum disorder, attention deficit hyperactivity disorder, cerebral palsy, and epilepsy. Outcomes of cerebral palsy and epilepsy were significant among the HIE stage 3 cases (p < 0.02). Cerebral palsy cases accounted for 6.3% of all HIE grade 3 cases, with the majority having quadriplegia type, a single case having diplegia cerebral palsy type, and other types (hemiplegia or monoplegia) not mentioned in any patients. Abnormal muscle tone was found in 42 infants with HIE, and the majority (60%) having hypotonia.

For the neurodevelopmental outcomes, which included gross motor, fine motor, language, and social skills at 24 months of follow up, only 24% of the HIE cases had delay in gross motor skills development and 22%, 33%, and 22% had delay in fine motor, language, and social skills development, respectively. The majority of the HIE stage 3 cases had a severe delay in all the four neurodevelopmental-outcome domains, particularly evident in language skills development, although all of developmental skills demonstrated a significant association with the severity of HIE (p < 0.05).

Neonatal seizure was found in almost half of the HIE cases, with the majority having simple seizure, which was most often treated with Phenobarbital. Only 38% of HIE cases with neonatal seizure were discharged without any antiepileptic medication. Epilepsy was found in 6.6% of the HIE cases, with the majority having simple seizure, which required only one medication. Levetriacetam was the most frequently used medication among HIE cases with epilepsy, followed by the use of valporic acid. EEG was performed in only 28% of the HIE cases, in which abnormal background was frequently reported in first EEG. In addition on initial EEG, epilptiform activity was found in 9 patients, and burst suppression pattern (Fig. 2) found in only 5 patients. In comparison, on the last EEG, only 23% had an abnormal result, which included abnormal epileptiform activity.

Moderate and severe encephalopathy occurred in about 7.4% and 6.4% of all the HIE cases, respectively, with Epilepsy occurring in 44% of the cases. In the aforementioned study conducted in Abha City in 2005 [1], moderate or severe encephalopathy occurred in about 63% of all the HIE cases, with seizures occurring in 67% of them. This current study was able to identify significant prenatal/antenatal and perinatal factors associated with encephalopathy that were more comprehensive and detailed than those found in the other Western Asian studies, especially the other local studies conducted in Saudi Arabia.

This study had several limitations. First, the data were obtained from a single center, limiting potential generalizability of the findings of this study, and highlighting the importance of establishing a national registry of HIE cases. The benefits of such registry would be great in terms of improving the care of newborns with HIE through identifying the risk factors and examining the most effective management plans. The second limitation of this study was related to potential effect of the presence of unmeasured confounders between cases and controls, which can underestimate or overestimate the associated risk. Finally, the completeness of the obstetric, neonatal, and neurologists’ records from which the study data were extracted or obtained may affect the validity of the results. As such, given these limitations, the interpretation of the findings should be done with caution.

Maternal comorbidities and prepartum or intrapartum fetal complications were more prevalent in the HIE group than in the control group. These findings support the importance of applying strict preventive measures, particularly for high-risk pregnancies. The HIE severity grade can be used as a prognostic predictive tool for the neurodevelopmental outcomes, especially in gross motor skills. Neurodevelopmental follow up for at least 24 months is necessary to enhance the care and rehabilitation of the patients, after which the recommendations can be offered.

HIE: hypoxic-ischemic encephalopathy; GA: gestational age; NICU: neonatal intensive care unit; DPP: developmental policies and procedures; GBS: group B streptococcus test; OR: odds ratio; CI: confidence interval; MRI: magnetic resonance imaging; EEG: Electroencephalography.

Ethics approval and consent to participate

The research ethics committee approved this study by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (reference number RC19/302/R).

All methods were carried out in accordance with relevant guidelines and regulations or declaration of helsinki.

The need for informed consent was waived by the ethics committee/Institutional Review Board of King Abdullah International Medical Research Center (KAIMRC), because of the retrospective nature of the study.

Consent for publication: The need for informed consent was waived by the ethics committee/Institutional Review Board of King Abdullah International Medical Research Center (KAIMRC), because of the retrospective nature of the study.
Availability of data and material: all data are collected anonymously and securely saved in hospital records system.

Dr. Mohammed A. Almuqbil (Principal Investigator) could be contacted for any required data or information.
Competing interests: None.
Funding: None.
Authors' contributions:

JA: Data curation; Software; Supervision; Validation; original draft writing; review & editing.

MAA: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; original draft writing - review & editing.

NA: Data curation; Software; Validation; Writing - review & editing.

DB: Data curation; Supervision; Validation; Writing - review & editing.

WA: Data curation; Supervision; Validation; Writing - review & editing.

AA: Data curation; Supervision; Validation; Writing - review & editing.

MTA: Data curation; Supervision; Validation; Writing - review & editing.

FO: Conceptualization; Data curation; Formal analysis; Methodology; Project administration; Software; Supervision; Validation; Visualization; review & editing.

SA: Conceptualization; Data curation; Project administration; Supervision; Validation; Visualization; review & editing.
Acknowledgements: None.

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Table 1

Maternal and Labor Characteristics for the Hypoxic-Ischemic Encephalopathy Cases and their Matched Controls

Characteristics	All patients (n = 294)	Control (n = 234; 80%)	Cases (n = 60; 20%)	P- value*
Maternal age (mean±SD)	30±5	30±5	31±5	0.13
Maternal comorbidity
Thyroid disease	18 (6.1)	12 (5.1)	6 (10)	0.16
Gestational diabetes	48 (16.3)	32 (13.6)	16 (26.9)	0.015
Hypertension	6 (2.1)	4 (1.7)	2 (3.1)	0.42
Prepartum complications and events
Presence of fetal deceleration	50 (17.0)	3 (1.2)	47 (78.3)	< 0.001
Positive screening for GBS	39 (13.2)	32 (13.6)	7 (11.1)	0.68
Breech presentation	9 (3.1)	6 (2.5)	3 (5.0)	0.32
Polyhydramnios	3 (1.0)	1 (0.4)	2 (3.1)	0.04
Oligohydramnios	4 (1.3)	2 (0.8)	2 (3.1)	0.13
Mode of delivery				< 0.001
Vaginal (spontaneous or induced)	218 (73.8)	198 (84.6)	20 (33.3)
Caesarean section (emergency or elective)	76 (25.8)	36 (15.3)	40 (66.6)

SD,Standrad Devitaion; GBS, positive screening for a group B streptococcus test

*Chi square or Fisher’s exact test was used for the categorical variables and the two-sample t-tests for the age. Cutoff point of 0.05 was used for significant level.

Table 2

Intrapartum-, Postpartum-, and Neonatal-related Characteristics for the Hypoxic-Ischemic Encephalopathy Cases and their Matched Controls

Characteristics	All patients (n = 294)	Control (n = 234; 80%)	Cases (n = 60; 20%)	P-value
Gestational age at delivery; mean (SD)	38.8±1.6	38.9±1.5	38.4±1.9	0.11
Infant characteristics
Male	166 (56.4)	125 (53.4)	41 (68.2)	0.03
Birth weight (kg); mean (SD)	3.13±0.1	3.17±0.47	2.93 (0.61)	0.004
Head circumference (cm); mean (SD)*	34.3±2.5	34.4(1.4)	33.7 (4.9)	0.06
Placenta abruption	10 (3.4)	1 (0.4)	9 (15.0)	< 0.001
Rupture uterus	3 (1.0)	0	3 (3.3)	0.005
Meconium staining	42 (14.0)	22 (9.4)	21 (33.3)	< 0.001
Meconium aspiration	10 (3.4)	0	11 (17.4)	< 0.001
Nuchal cord	29 (9.8)	18 (7.6)	11 (17.4)	0.014
Apgar score; mean (SD)
At 1 min	7.4±2.7	8.6±0.7	2.2±1.6	< 0.001
At 5 min	8.1±1.7	8.9±0.34	5.1±2.1	< 0.001
At 10 min	8.5±1.3	9±1	6.1±1.9	< 0.001
Arterial cord pH; mean (SD)	7.07±0.1	7.2±0.06	7.01±0.15	< 0.001
Resuscitation
Bag valve mask ventilation	60 (20)	0	60 (95.2)	< 0.001
Positive-pressure ventilation	61 (20)	4 (1.7)	57 (95)	< 0.001
Cardiac massage	9 (3.1)	0	9 (15.8)	< 0.01
Bicarbonate given	3 (1.0)	0	3 (4.7)	0.001
Epinephrine	2 (0.6)	0	2 (4.7)	0.005
Intubation	47 (15)	0	47 (77)	< 0.001
Neurological examination abnormality after delivery			27 (54)
Presence of congenital abnormality	19 (6.4)	8 (3.4)	11 (17.4)	< 0.001
Dysmorphism	8 (2.7)	0	8 (13.3)	< 0.001

SD,Standrad Devitaion;GBS, positive screening for a group B streptococcus test

*Chi square or Fisher’s exact test was used for the categorical variables and the two-sample t-tests for the age

Table 3

Clinical and Labor Characteristics/Factors Associated with Hypoxic-Ischemic Encephalopathy Cases Compared to Control Cases

Characteristic	Univariate analysis	Multivariable analysis
Characteristic	Unadjusted OR (95% CI)	Adjusted
Maternal comorbidity disease	2.68 (1.45–4.96)	2.73 (1.11–0.03)
Prepartum complication	25.1 (11.5–55.0)	30.2 (11.8–77.2)
Intrapartum complication	9.82 (5.17–18.6)	13.5 (5.37–34.09)

CI, confidence interval; OR, odds ratio

The significant risk factors were lumped in three categories maternal comorbidity, preterm, and intrapartum complications. Reference group were those who don’t have those factors.

Table 4

Outcomes of the Patients with Hypoxic-Ischemic Encephalopathy at the End of Follow-up

		Staging according to Sarnat
	Total Population n = 60 (%)	Stage 1 17 (28.3%)	Stage 2 22 (36.6%)	Stage 3 21 (35%)	P-value
Muscle tone
Normal	18 (29.3)	13 (71.3)	2 (10.0)	3(14.2)
Hypotonia	36 (60.0)	4 (23.5)	19 (86.3)	13 (62.1)
Hypertonia	6 (10.0)	-	1 (4.5)	5 (23.8)
Treatment
Therapeutic hypothermia	45 (75)	8 (47.1)	20 (90.9)	17 (89.4)	< 0.001
Erythropoietin	41(68.3)	9(52.9)	16(72.7)	16(84.2)	0.01
Imaging modularity
Abnormal CT	6 (10)	1 (5.2)	1 (4.5)	3 (15)	0.17
MRI abnormality finding	36 (61)	5 (29.4)	13 (59.1)	17 (98)	0.001
Basal ganglia or thalamus lesion	17(28.3)	3(17.6)	6(27.2)	7(36.8)	0.08
Watershed predominant	26(43.3)	4(23.5)	8(36.3)	13(68.4)	0.03
white-matter predominant	21(35)	2(11.7)	7(31.8)	11(57.8)	0.05
Global	22(36)	3(17.6)	9(40.9)	10(52.6)	0.02
Outcome among those who survived
Intraventricular hemorrhage	10 (15.8)	2 (10.5)	3 (13.6)	5 (25)	0.62
Delayed myelination	2 (3.1)	1 (5.2)	-	1 (5)	0.56
Hypoglycemia encephalopathy	1 (1.5)	-	1 (4.5)	-	0.90
Intellectual disability	2 (3.1)	1 (5)	-	1 (5)	0.80
Learning disability	1 (1.5)	-	-	1 (5)	0.66
Cerebral palsy	4 (6.3)	-	-	4 (20)	0.02
Epilepsy	5 (7.9)	-	-	5 (25)

CT, computerized tomography scan; MRI, Magnetic resonance imaging

*Chi square or Fisher’s exact test was used for the categorical variables

Table 5

Neurodevelopmental Outcome after 24 month Follow-up According to the HIE Staging

	Study population n = 55 (%) Total (%)	Staging according to Sarnat
	Study population n = 55 (%) Total (%)	Stage 1 16 (29.1%)	Stage 2 19 (34.5%)	Stage 3 20 (36.3%)	P-value
Neurodevelopmental outcome after 24 month follow-up
Gross motor skills development					0.03
No delay	42 (76.3)	14 (87.5)	19 (100)	9(45.0)
Mild	2(3.5)	-	-	2(10.5)
Moderate	5 (9.1)	2(12.5)	-	3(15.7)
Severe	6(10.9)	-	-	6(30.0)
Fine motor skills development					0.01
No delay	43 (78.1)	14 (87.5)	19(100)	10 (50.0)
Mild	2(3.6)	-	-	2 (10.0)
Moderate	3 (5.4)	2 (12.5)	-	1(5.6)
Severe	7 (12.7)	-	-	7 (35.0)
Language skills development					0.009
No delay	37 (67.6)	11 (68.7)	16(72.7)	10 (48)
Mild	5 (9.0)	2(12.5)	2(9.1)	1 (5)
Moderate	6 (10.9)	3(18.7)	1(4.5)	2(10.5)
Severe	7 (12.7)	-	-	7 (36.8)
Social skills development					0.01
No delay	43 (78.1)	13(81.2)	19(100)	11 (55.0)
Mild	1 (1.8)	-	-	1 (5.0)
Moderate	3(5.4)	3(18.7)	-	-
Severe	8(14.5)	-	-	8(40.0)

Fisher’s exact test was used for the categorical variables

No competing interests reported.

Neonatal Hypoxic-Ischemic Encephalopathy: Single Tertiary Centre Experience

Status:

Version 2

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Method

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 2