|Year : 2020 | Volume
| Issue : 2 | Page : 98-110
Magnitude, short-term outcomes and risk factors for hypoxic ischemic encephalopathy at abha maternity and children hospital, Abha City, Saudi Arabia and literature review
Raja M Thigha, Ahmad A Alzoani, Mufareh H M. Almazkary, Amal A Khormi, Rania H Albar
Department of Neonatology, Abha Maternity and Children Hospital, Abha, Saudia Arabia
|Date of Submission||03-Feb-2019|
|Date of Decision||07-Jun-2019|
|Date of Acceptance||23-Mar-2020|
|Date of Web Publication||21-Apr-2020|
Dr. Raja M Thigha
Dr. Hassan Albar Maternity and Children Hospital, Abha
Source of Support: None, Conflict of Interest: None
Background: When hypoxia is the cause for neonatal encephalopathy, a clinical syndrome has been described known as hypoxic–ischemic encephalopathy (HIE). Aim of the Study: This study aimed to determine the magnitude of HIE occurrence, its short-term outcomes, and associated risk factors. Literature review was included for comparing our reported findings with other published ones. Methods: A retrospective, case–control study was conducted at “Abha Maternity and Children Hospital” (AMCH) that included all inborn term and late-preterm newborns with the “admission diagnosis” of HIE during 2016–2017. Healthy newborn babies were taken as controls. Data were extracted from neonatal medical files for HIE cases and maternal medical files for the controls. Results: Of 15,790 livebirths, 124 cases had HIE (7.85/1000 livebirths), of whom 3.98/1000 and 3.86/1000 livebirths were staged as mild and moderate-to-severe HIE, respectively. Short-term outcomes for HIE were 14 deaths (11.3%) and 33 cases with seizures (26.6%), which occurred exclusively among moderate–severe HIE cases; 87 cases (70.2%) required positive pressure ventilation, and 45 cases (36.3%) required mechanical ventilation, with significantly higher rate among moderate–severe HIE than mild cases (P < 0.001). By the 7th day of admission, moderate-to-severe HIE cases showed significantly higher rates for both lack of nutritive sucking reflex and respiratory support than mild HIE ones (P = 0.016 and P < 0.001, respectively). Among HIE cases who required cooling, 96.2% were subjected to it within the “therapeutic window” of ≤6 h. Risk factors associated with HIE were urinary tract infection/vaginitis (P = 0.001), late preterm (P = 0.002), meconium stain (P = 0.003), abnormal cardiotocographic tracing (P < 0.001), prolonged second stage of labor (P = 0.001), assisted delivery (P = 0.011), sentinel events (P = 0.027), and low 1-min APGAR scores (P < 0.001). Conclusions: The burden of moderate-to-severe HIE at AMCH is high with an associated high mortality rate. Early identification of high-risk pregnancy with improved antepartum, intrapartum, and neonatal care can reduce occurrence of HIE.
Keywords: Hypoxic–ischemic encephalopathy, newborns, retrospective case–control, risk factors, short-term outcomes
|How to cite this article:|
Thigha RM, Alzoani AA, Almazkary MH, Khormi AA, Albar RH. Magnitude, short-term outcomes and risk factors for hypoxic ischemic encephalopathy at abha maternity and children hospital, Abha City, Saudi Arabia and literature review. J Clin Neonatol 2020;9:98-110
|How to cite this URL:|
Thigha RM, Alzoani AA, Almazkary MH, Khormi AA, Albar RH. Magnitude, short-term outcomes and risk factors for hypoxic ischemic encephalopathy at abha maternity and children hospital, Abha City, Saudi Arabia and literature review. J Clin Neonatol [serial online] 2020 [cited 2020 Aug 10];9:98-110. Available from: http://www.jcnonweb.com/text.asp?2020/9/2/98/283025
| Introduction|| |
Neonatal encephalopathy (NE) is a nonspecific term that describes a clinically defined syndrome of disordered brain function in term and late-preterm newborns within the first few days of life. The term “NE” is simply a clinical description and does not imply assumptions about either pathogenesis. The etiology of NE disorder includes several conditions, e.g., hypoxia, congenital malformation, neurological/or metabolic causes, trauma, and infectivion.
Antepartum or intrapartum hypoxic–ischemic events, e.g., perinatal asphyxia or birth asphyxia, refer to an insult accompanied by decreased oxygen delivery to the fetal brain before or during birth. When hypoxia is the cause for NE and is followed by encephalopathy signs during the first few hours after birth, a clinical syndrome has been described known as hypoxic–ischemic encephalopathy (HIE), i.e., HIE is a subgroup of NE.
Levels of cerebral oxygen are not directly measurable in humans (in vivo), although fetal venous scalp sample may be taken during labor when clinically indicated but not as a routine practice. This has led to the use of indirect clinical markers for hypoxic–ischemic events, such as low APGAR score (AS),, and low cord blood pH,,,, which if present either alone, or in combination with features of encephalopathy, are taken to imply the occurrence of HIE.,
There is a scarcity of national studies on HIE. Therefore, this study aimed to determine the magnitude of HIE occurrence, its short-term outcomes, and associated risk factors among newborns at Abha Maternity and Children Hospital (AMCH), Assir Region, Saudi Arabia, with detailed literature review for interpreting our HIE rate in relation to those of others, taking into consideration different study methodologies, which produced those figures rather than dealing with those figures as absolute values.
| Methods|| |
This study followed a retrospective, case–control research design. It is a hospital record-based review that covered the period from January 2016 to December 2017. The study was conducted at AMCH, which is a referral, tertiary care, and teaching hospital at the southwestern region of the Kingdom of Saudi Arabia.
The inclusion criteria of patients' data were inborn during the study period, term (gestational age [GA] ≥37 weeks) and late preterm (GA ≥34 0/7 up to 36 6/7 weeks) with “admission diagnosis” of HIE. Exclusion criteria were outborn and inborn with admission diagnoses other than HIE, GA <34 weeks, obvious congenital malformation, metabolic disorders, and initial positive blood culture. The rationale for outborn exclusion is to limit the issue of missing information and to improve, to some extent, accuracy of rate calculation.
The AMCH Statistics Department provided the total number of livebirths during the study period. Recruitment of HIE cases was based on the sequence at which HIE cases were identified, i.e., encephalopathy signs following perinatal depression or asphyxia events. To maximize the ascertainment of cases selection and minimize the risk of loss of cases, HIE cases were identified as follows:
- The “NICU admission log book” that belongs to the study period (from January 1, 2016, through December 31, 2017) was manually searched for the “initial diagnosis” of the following clinically related terminology: “birth asphyxia,” “perinatal depression,” or even HIE ± its staging. Neonates' medical file numbers were directly entered into a preformed Excel sheet (which was designed to include all variables of this study). The list was used to retrieve the medical files from the “Medical Records Department”
- As an added guide, those admitted neonates were subjected to neurological examination. Based on the neurological data, if the “admission diagnosis” was HIE secondary to hypoxia after exclusion of other causes of encephalopathy (such as major congenital malformation), HIE staging was assigned using Sarnat and Sarnat, which was used to determine the legibility for “therapeutic hypothermia.”
Variables related to HIE short-term outcomes included HIE severity, mortality, requirement for positive pressure ventilation at birth, mechanical ventilation, seizure (either clinical documentation or use of phenobarbitone as an antiepileptic medication used as an indicator of seizure occurrence), and therapeutic hypothermia for moderate and severe (clinically significant HIE); moreover, on the 7th day of admission, the “Neonatal ICU Flow Sheet” was reviewed for lack of nutritive suckling reflex and need for respiratory support of any form: supplemental oxygen and noninvasive or invasive respiratory support.
Among our NICU admission criteria is the admission of all newborns <34 weeks. Therefore, choosing the control group from the well-baby, facilitated GA matching between the HIE cases and their controls as both groups were ≥34 weeks. For each HIE case, two healthy babies who were delivered within the same study period were randomly selected, using the random number tables.
To assess the role of antepartum, intrapartum, and neonatal risk factors for HIE occurrence, a predesigned Excel sheet was used for HIE cases and for their controls as follows: For control group, the maternal medical files were reviewed to collect data related to HIE risk factors. For HIE cases, the neonatal medical files were reviewed to collect data related to HIE risk factors, in addition to certain neonatal characteristics and short-term outcomes for HIE cases.
Variables were included in this study based on previous studies' findings. The following clinical data were retrospectively collected for both HIE cases and their controls:
- Antepartum-associated risk factors: Maternal age, nationality, gravidity, un-booked at AMCH, maternal comorbidity (diabetes, preeclampsia/hypertension, urinary tract infection (UTI)/vaginitis)
- Intrapartum-associated risk factors: GA, malpresentation, meconium-stained amniotic fluid, premature rupture of membranes (PROM), abnormal cardiotocographic (CTG) findings, labor augmentation, prolonged second stage of labor, placental abnormalities, mode of delivery, instrumental delivery, sentinel event (included antepartum hemorrhage, abruption placentae, ruptured uterus, shoulder dystocia, and cord prolapse)
- Neonate's data: Gender, birth weight, and AS. Based on our hospital's eligibility criteria for “therapeutic hypothermia,” the following cutoff values were selected: pH ≤7, base deficit (BD) ≥16, and AS ≤5 at 10 min.
This study was approved by the Research and Ethics Committee at AMCH. Full confidentiality was maintained all throughout the study, and the collected data were exclusively used for research purposes. This study was self-funded by the researchers, and there was no conflict of interest.
Collected data were coded and entered directly into the preformed Excel sheet. Data analysis was carried out using the Statistical Package for the Social Sciences (SPSS, version 23, IBM Company, New York, USA). Descriptive statistics were calculated, (i.e., frequency and percentages for categorical data and mean and standard deviation for quantitative data). Odds ratio (OR), 95% confidence interval (CI), and tests of significance (e.g., χ2 test and unpaired t-test) were applied. To control for confounders, multivariate binary logistic regression analysis was applied to identify risk factors for HIE. P < 0.05 was considered statistically significant.
| Results|| |
A total of 15,790 all live-born infants were delivered during the study period (2016–2017). Of those newborns, 140 were admitted with the initial diagnoses of “birth asphyxia,” “perinatal depression,” or “HIE of any stage.” Only neonates with the “admission diagnosis” of HIE were included in the study, while others (n = 7) were excluded. Moreover, three cases were further excluded for being outborn in addition to six cases with GA <34 weeks. Therefore, the total number of HIE cases included in this study was 124, with an overall HIE rate of 7.84/1000 all livebirths, of whom 3.98/1000, and 3.86/1000 all livebirths were mild and moderate-to-severe HIE, respectively.
Characteristics of mild and moderate-to-severe HIE cases are shown in [Table 1]. The mean age at which HIE cases received therapeutic cooling was 3.1 ± 2.1 h. A total of 52 HIE cases (41.9%) received cooling, mostly within ≤6 h (50, 96.2%), while only two (3.8%) received it after 6 h of age.
Based on the “admission diagnosis,” 49.2% of HIE cases had moderate-to-severe HIE. We studied evidence on diagnostic accuracy according to the following criteria: AS ≤5 at 10 min of birth, at birth pH ≤7, and BD ≥16 mEq/L for predicting moderate-to-severe HIE. [Table 1] shows that their sensitivities were 36.1%, 55.7%, and 55.7%, respectively, and their specificities were 96.8%, 87.3%, and 88.9%, respectively, for predicting moderate–severe HIE, while their positive likelihood ratios (LR+) were 11.2, 4.4, and 5.0, respectively. The posttest probabilities of moderate-to-severe HIE would rise to 91.3, 80.4%, and 82.9%, respectively.
[Table 2] shows that the details of short-term outcomes among HIE cases. The potential antepartum risk factors for HIE are listed in [Table 3]. Of these, young maternal age (<20 years), non-Saudi nationality, un-booking, and maternal morbidity (i.e., hypertension/PET and UTI or vaginitis) were statistically significant (P = 0.041, P = 0.045, P < 0.0001, P < 0.0001, and P < 0.0001, respectively).
|Table 2: Short-term outcomes of hypoxic-ischemic encephalopathy newborns according to their hypoxic-ischemic encephalopathy staging at Abha Maternity and Children Hospital during 2016 and 2017 (n=124)|
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|Table 3: Antepartum risk factors among hypoxic-ischemic encephalopathy cases in comparison to the control group|
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[Table 4] lists the potential intrapartum risk factors for HIE. Noncephalic presentation and delivery augmentation among HIE cases were more than the control ones but did not differ significantly (10.5% and 6.5%, respectively, P = 0.175, and 21% and 14.5%, respectively, P = 0.117). Other potential intrapartum factors occurred significantly more among HIE cases than the control group, i.e., late preterm babies, meconium-stained amniotic fluid, PROM, abnormal CTG tracings, prolonged second stage of labor, placental abnormalities; less normal vaginal deliveries and more instrumental deliveries occurred among HIE cases than the control group; sentinel events occurred more among HIE cases than the control group.
|Table 4: Intrapartum risk factors among hypoxic.ischemic encephalopathy cases in comparison to the control group|
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[Table 5] shows no significant difference between HIE cases and control group according to neonatal gender. However, there were significantly more newborns in the HIE group than the control group with low birth weight (24.2% and 8.5%, respectively, P < 0.0001). Newborns in the HIE group had significantly lower APGAR scores ≤ 7 at 1 and 5 minutes (P < 0.0001 and 0.0004, respectively), while there was no significant difference between both groups regarding AS at 10 min.
|Table 5: Neonatal hypoxic-ischemic encephalopathy risk factors among hypoxic-ischemic encephalopathy cases compared with those in the control|
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After controlling for confounders by applying multivariate binary logistic regression analysis, the statistically significant risk factors for HIE were limited to UTI/vaginitis (P = 0.001), late preterm (P = 0.002), meconium-stained amniotic fluid (P = 0.003), abnormal CTG findings (P < 0.001), prolonged second stage of labor (P = 0.001), assisted delivery (P = 0.011), sentinel events (P = 0.027), and AS at 1 min (P < 0.001), as shown in [Table 6].
|Table 6: Binary logistic regression model for the association of potential antepartum/intrapartum/neonatal risk factors for the occurrence of hypoxic-ischemic encephalopathy at Abha Maternity and Children's Hospital|
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| Discussion|| |
The HIE rate in our study, being 7.84/1000 all livebirths, varies widely when compared to the reported HIE incidence in the national and international studies [Table 7]. This figure is in relative accordance with other reported national figures in Saudi Arabia,, significantly lower than internationally cited studies from: Nepal, Nigeria, India, Tanzania, Uganda, and significantly higher than other internationally cited studies from: Sweden,, London,, Malaysian, Italy, Iceland, Spain, and South Africa, as shown in [Table 7] and [Figure 1].
|Table 7: Case definition in cited studies and associated hypoxic-ischemic encephalopathy/birth asphyxia/perinatal asphyxia estimated rate|
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|Figure 1: Hypoxic–ischemic encephalopathy rates (per 1000) as reported by local studies and international population-based studies and international hospital-based studies compared with our study|
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We found it an opportunity to compare, over time,, our HIE rate of 7.84/1000 with the previously published study of AlShehri and Eid of 4.9/1000 all livebirths. Both studies were carried out in Abha City, but the hospital setting itself was changed to a new one. The comparison might be misleading in terms of concluding that the situation is getting worse over time, this unlikely to be so. It can be argued that the detection rate of HIE cases in the current setting is increased over time, considering the positive changes in our clinical setting, higher qualification of the current staff, mandating NRP for all neonatology staff, introduction of active cooling as a therapeutic modality which was not available during AlShehri and Eid study. This contributed largely to the increase in both clinical awareness and scrutiny in examining those cases in more detail to determine their eligibility for cooling.
One might argue that developed countries are better in terms of HIE occurrence in comparison to our setting. This might be acceptable if published studies settings were comparable. By reviewing in detail cited literatures, variations were found in studies' set-up and design, HIE case definition, and HIE rate estimations. If this reviews' findings were taken into consideration while interpreting our HIE rate figure in relation to others, the comparison will be fair as it is taking into consideration the different study methodology which produced those figures rather than dealing with those figures as absolute values.
Variations in cited studies' setup
Study's setup was either population-based or, as our study, hospital-based ones [Table 7]. Hospital-based studies tend to be conducted in referral centers. Therefore, due to referral bias, hospital-based incidence figures tend to be higher than population-based results. While our study excluded outborn newborns, referral bias is still likely to be present, to some extent, because of continued antenatal referrals of complicated pregnancies whose newborns are counted as inborn with the possibility of greater risk of HIE occurrence. Moreover, among hospital-based studies that reported HIE rate lower than ours, apart from the studies by García-Alix et al. and Padayachee and Ballot, most of them were before 2005 [Table 7].,,,,,, There is again a possibility of increasing detection rate over time.
Variations in cited studies' design
As other cited studies,,, our study is retrospective case–control one, where being retrospective might make it prone to information bias. Other study designs were used [Table 7].
Variations in hypoxic–ischemic encephalopathy case definition
By reviewing all cited studies, it was found that no sets of two investigators used the same HIE case definition, i.e., there was lack of agreement on what hypoxia/asphyxia is. As shown in [Table 7], cited studies used a single or different combination of clinical, laboratory, or perinatal events were used as a surrogate clinical marker for hypoxic-ischemic encephalopathy case definition.
Variation in hypoxic–ischemic encephalopathy rate estimations
There were difficulties in interpreting our HIE rate in comparison with other published rates. The first difficulty is related to the numerator and the other one is related to the denominator definitions. Regarding the numerator, most studies included term HIE newborns,,,,,,,,,,, while few included both term and late preterm,, [Table 7]. Our study addressed this gap in knowledge by including both term and late preterm HIE cases. Late preterm are at an increased risk of adverse outcome in comparison to the term ones; this might contribute to inflation in our numerator figure and consequently increases HIE rate. When it comes to the denominator, there is a concern regarding the selection of the correct denominator. The correct denominator should include only those newborns at risk of being in the numerator (at risk of being a case), which by definition for HIE means that they should be all late-preterm and term newborns. In our study, it was difficult to get livebirths data by GA, so the denominator included all livebirths at AMCH. Most studies quoted HIE incidence per 1000 all livebirths,,,,,,,,,,,,,,, and some quoted per 1000 term livebirths.,,,,,,,,
The proportion of clinically significant (moderate–severe) HIE in the present study (49.1%) is comparable to some studies: Airede (45.8%), Simiyu et al. (49.2%), and al-Alfy et al. (51%); lower than Namusoke et al. (56.5%), Bhunia and Saharia (56.9%), Mahar et al. (60.5%), Ellis et al. (63%), Alshehri and Eid (63%), and Itoo et al. (71%); and higher than Selvakumar et al. (45%).
In our study, the overall HIE rate was 7.84/1000 livebirths, of whom 3.85/1000 showed moderate–severe HIE. [Table 7] and [Figure 2] show our moderate–severe HIE rate in comparison to other studies.
|Figure 2: Moderate-to-severe hypoxic–ischemic encephalopathy rates (per 1000) as reported by international population-based studies and international hospital-based studies compared with our study |
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Apart from the risk factor chorioamnionitis (which was excluded), the issue of missing information for the predetermined risk factors assessment was not of a major concern.
The mortality rate in the present study (11.3%) was higher than those reported by Selvakumar et al. (4.8%), Finer et al. (7%), Badawi et al. (9.1%), and Simiyu et al. (9.1%) and lower than Shireen et al. (16%), Itoo et al. (17.1%), Babu et al. (17.8%), Mahar et al. (25%), Namusoke et al. (26%), Bhunia and Saharia (31%), and Ellis et al. (44%).
Therapeutic hypothermia guidelines mandate early identification of clinically significant HIE cases to start cooling within the “therapeutic window” of the 1st 6 h of life.,, Our study reported the mean age at which cooling started was ≈3 h.
Among clinically significant HIE cases, AS ≤5 at 10 min reported moderate-to-large rise in posttest probability, while both pH ≤7 and BD ≥6 reported slight-to-moderate rise in posttest probability, i.e., AS can be used as predictor of clinically significant HIE.
Although it was beyond the scope of the current study to review those retrieved medical files of the surviving and discharged HIE cases for long-term neurodevelopmental outcome as cerebral palsy,,,,,, our reporting, as in other studies,, for the following: presence of seizure, lack of sucking reflex, requirement for oxygen of any form, closely approximates short-term neurological outcome of HIE.
Some antepartum/intrapartum risk factors for HIE are probably universal, such as obstetric emergencies, whereas the contribution of others may vary among populations and over time. In the present study setting, the majority of HIE-associated risk factors were similarly reported in other studies [Table 8].
|Table 8: Reported antepartum, intrapartum, and neonatal risk factors for hypoxic-ischemic encephalopathy occurrence|
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| Conclusions|| |
The rate for HIE at AMCH is 7.85/1000 livebirths. Reported HIE rates vary widely. These variations can be either genuine or due to differences in HIE case definition, studies' set up or design. However, HIE occurrence rate at AMCH is an area for improvement by identifying risk factors in order to understand the causal pathways and to enable the application of preventive strategies at both primary (reduce HIE incidence) and secondary (early HIE detection and timely management) levels. It is important to pay close attention to modifiable risk factors which if tackled appropriately might alter the natural course of HIE and modify the outcome favorably. This can be achieved by implementing long-term programs and team-based training that can optimize appropriate, timely recognition, and management of HIE risk factors; early communication between the caring obstetrician and neonatology staff in case risk factor(s) is/are identified; improve facility for antenatal care; maternal screening for pregnancy-associated morbidity; wise application of augmented and instrumental deliveries; early recognition of intrapartum adverse obstetrical events (such as: fetal distress manifested by abnormal CTG tracing, meconium-stained amniotic fluid, placental and cord abnormalities, and prolonged second stage of labor); early identification of HIE cases and its staging, so as to offer timely cooling of HIE cases within the therapeutic window.
Adding preterm to term HIE cases has important implications at different levels, in particular for the healthcare planner, in planning their strategies for minimizing HIE occurrence, and in identifying the accurate proportion of clinically significant HIE cases that are likely to benefit neurologically from cooling annually.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]