Incidence and Predictors of Mortality Among

Neonates with Perinatal Asphyxia, Northwest

Ethiopia, 2021: An Institution Based Retrospective
Cohort Study.
Aster Tadesse Shibabaw (  [email protected] )
Debre Markos University
Getaneh Mulualem Belay
University of Gondar
Bogale Kassahun Desta
University of Gondar
Fasil Wagnew Shiferaw
Debre Markos
Ayenew Molla Lakew
University of Gondar

Research

Keywords: Mortality, Predictors, Perinatal asphyxia, Neonates

Posted Date: October 29th, 2021

DOI: https://doi.org/10.21203/rs.3.rs-1013476/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License.
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Abstract
Background: - Perinatal asphyxia is the third leading cause of neonatal mortality globally, which usually
happens within the first week of life. Therefore, evidence-based estimation of neonatal mortality is a
cornerstone for tracking progress towards child survival goal and identifying priority areas to improve
progress towards eliminating preventable deaths due to perinatal asphyxia.

Objective: To assess incidence and predictors of mortality among neonates with perinatal asphyxia
admitted to the neonatal intensive care unit of Debre Markos Comprehensive Specialized Hospital, 2021.

Methods: An institutional-based retrospective follow-up study was conducted among 402 neonates with
perinatal asphyxia (PNA) admitted to the neonatal intensive care unit (NICU) of Debre Markos
Comprehensive Specialized Hospital from January 1st, 2018 to the 30th of December, 2020. A simple
random sampling technique was used to select the estimated sample. Data were entered using Epi data
Version 4.6.0.0 and analyzed using Stata Version 14. The Kaplan–Meier and log-rank test were used to
estimate and compare the survival time. Both the bi-variable and multivariable Weibull regression models
were fitted to identify predictors of mortality. Finally, the Hazard ratio with a 95%CI was computed, and
variables with p-values <0.05 were considered as statistically significant predictors of mortality.

Results: A total of 125 (31.09%) neonates died during the follow-up period. The overall incidence rate of
mortality was found to be 53.49 per 1000 neonate-days of observations (95%CI: 44.89-63.74). Neonatal
sepsis (AHR=2.13;95%CI: 1.38-3.27), preterm birth (AHR= 3.42 95%CI; 2.13- 5.48), Hypoxic Ischemic
Encephalopathy stage II (AHR=6.65 95%CI: 2.57-17.26), and III (AHR=16.8 95%CI; 6.28- 44.9), Antepartum
hemorrhage (AHR=2;95%CI: 1.13-3.92), the induced onset of labor (AHR=3.90;95%CI; 1.83-8.27), and post-
partum hemorrhage (AHR=2.12;95%CI: 1.32-3.38) were significant predictors of mortality among
neonates with perinatal asphyxia.

Conclusion: The study found that the overall incidence rate of mortality among neonates with PNA
remains high. Neonatal sepsis, Hypoxic-ischemic encephalopathy stage II and III, preterm birth,
antepartum hemorrhage, postpartum hemorrhage and induced onset of labor were independent
predictors of mortality. Therefore, early anticipating high-risk pregnancies and newborns with the
respective intervention could reduce neonatal due to perinatal asphyxia.

Background
According to the World Health Organization (WHO), Perinatal asphyxia is defined as the failure to initiate
and sustain breathing at birth (1). It results in progressively marked impairment of gas exchange and
subsequently leads to metabolic acidosis, and multi-organ system dysfunction (brain damage, heart,
lungs, gut, kidneys (2–4). Appearance Pulse Grimacing Activity and Respiration (APGAR) score is still an
important universally accepted tool for prenatal asphyxia diagnosis and its severity and is assessed
mostly in the 1st and 5th minutes of life with scores eight to ten: normal, four to seven: moderate, and
between zero and three: severe perinatal asphyxia (5).
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Globally, perinatal asphyxia is the major cause of neonatal mortality and morbidity. According to 2014,
WHO report, between 4 and 9 million newborns develop birth asphyxia each year. Among these, around
1.2 million newborns died during the neonatal period. Moreover, at least a similar number of neonates
develop severe consequences, such as developmental delay, epilepsy, cerebral palsy, and 42 million
disability-adjusted life years (6–8). Indeed, it is a responsible factor for 24% of all neonatal deaths and
11% of deaths of children under 5 years of age (4, 9). Approximately, three-fourths (75%) of such deaths
happen on the first day and less than 2% after 72 hours of birth (10).

The impact of perinatal asphyxia is not restricted at neonatal age but also results in the long-term and
short-term neurodevelopmental sequelae, counting cognitive and engine incapacities which are mostly
untreatable (11, 12). Nearly a quarter of newborns who survived with perinatal asphyxia faced
neurological disorders, such as cerebral palsy, certain neurodevelopment learning disabilities (13), and
post-traumatic stress disorders (14). Moreover, medical-related costs for the treatment of perinatal
asphyxia were high, spent 9.1% of their annual income on acute care (15).

Perinatal asphyxia causes 40% of all early neonatal deaths in Brazil, (16), 20-40% in South Asia (17, 18),
and 4.8-40.6% (19–23) in Indian. In sub-Saharan Africa, the PNA case fatality rate was still high,
accounts for 31 per 1000 live births.

In Ethiopia, neonatal mortality is 30/1000 live birth, depicting an upward trend (24) and Perinatal
asphyxia is the third leading cause of neonatal mortality that accounts for 12.5-35%, followed by preterm
(21.8%), and neonatal sepsis (18.5%) of all mortalities (18.5%) (25–28).

Previous studies conducted on predictors of mortality found maternal age less than 20 years (29, 30),
mothers who did not attend ANC (20, 21, 31), primipara (20, 32), maternal anemia (21), pregnancy-
induced hypertension (30), delivered out of the hospital (33–35), premature rupture of the membrane
(PROM) (20, 30, 32), spontaneous vaginal delivery (29, 33–35), instrumental delivery (23), multiple births
(32), prolonged labour (23, 32), Obstructed labour (30), meconium-stained amniotic (20), preterm birth
(32, 35, 36), low birth weight (35–39), Hypoxic-ischemic encephalopathy (HIE) stage II and III (20, 21, 23,
40), respiratory distress at admission (21, 39), neonatal sepsis (32, 40, 41), hypoglycemia (20), neonatal
anemia (21) and hypothermia (20) were independent predictors of mortality among neonates with
perinatal asphyxia.

Sustainable development goal (SDG) 3 sets a target of reducing neonatal mortality to 12 deaths or less
per 1000 live births and to end all preventable neonatal deaths including PNA (42–44). Despite this,
neonatal mortality increases from time to time in Ethiopia since 2016 (24, 45). Moreover, limited studies
were conducted in the study area to emphasize mortality and its predictor among newborns with
perinatal asphyxia.

Therefore, estimating the incidence and identifying predictors of mortality are cornerstone for tracking
progress towards child survival goal and identifying priority areas to improve progress towards
eliminating preventable deaths due to perinatal asphyxia. Improvement of neonatal survival is a good
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indicator of quality care. Hence, it is important for the health care providers and health care
commissioners to early detection, diagnosis, management and have follow-up care and have also
practical vital value for patients, health care providers, researchers and policy-makers in the Ministry of
Health.

Hence, this study aimed to determine mortality and its predictors among neonates with perinatal
asphyxia admitted in the neonatal intensive care unit of Debre Markos Comprehensive Specialized
Hospital.

Methods
Study design, period and population
A retrospective follow-up study was carried out from April to May, 2021 at Debre Markos compressive
specialized hospital which serves more than 5 million people in its catchment area. Currently, about 100
health centers and 9 district hospitals are available in the catchment area of the referral hospital. The
hospital has a total of 489(282 male, 207 female) clinical staffs. Furthermore, it provides neonatal
intensive care services for critically ill neonates and those who need neonatal care. The NICU has 27
nurses, one pediatrician, and two general practitioners. In addition, the neonatal intensive unit has 28
neonatal beds and 27 maternal beds(46). The source population was all neonates with perinatal
asphyxia admitted to the NICU of Debre Markos comprehensive specialized hospital. The study
population included randomly selected eligible neonates with perinatal asphyxia admitted to NICU of
Debre Markos comprehensive specialized hospital from January 1, 2018, to December 30, 2020.

Inclusion and exclusion criteria

All neonates with perinatal asphyxia admitted to the NICU of Debre Markos comprehensive specialized
hospital from January 1, 2018, to December 30, 2020, who had registration were included. While records
of children whose admission date and discharge date were not recorded, missing of outcome variable
and neonates with major congenital malformation were excluded in the study.
Sample size and sampling technique
Sample size was computed using single proportion formula with the following assumptions: death rate=
38.7% (p=0.387 and q=0.613) (35), 95% confidence level, 5% margin of error. A total of 789 neonates were
admitted to the hospital from January 1/2018 to December 30/ 2020. A sample of 402 neonates with
asphyxia were selected from 789 neonates using random number computer generated method, the
subsequent unique chart numbers from the registration file were extracted.

Data collection procedure

A data extraction format was developed from standardized management protocol for neonates and
reviewing applicable articles to assemble the required individual information. The data extraction format
consists of socio-demographic characteristics of the mother and the newborn (age, religion, residence,
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sex of the newborn, and age at admission), antepartum related variables (ANC follow-up, pregnancy
induced hypertension, Antepartum hemorrhage, Anemia during pregnancy, gestational diabetic mellitus,
Parity, Gestational Hypertension, diabetic mellites, tetanus vaccination, pregnancy screening test (Rh
factor, syphilis screening test, HIV, and Hepatitis), Intra-partum related variables (mode of delivery, place
of delivery, premature rapture of membrane, Malpresentation, postpartum hemorrhage, prolonged labor,
obstructed labor, types of pregnancy, and onset of labor) and neonatal related variables (gestational age,
birth weight, Meconium aspiration syndrome, anemia, clinically diagnosis neonatal sepsis, Hypoxic
ischemic encephalopathy, birth injury, hypothermia, respiratory distress syndrome, Jaundice,
phototherapy, and Random blood sugar). Three experienced nurses were recruited for data collection and
supervision, and two days training was given for them to standardize and agree on the way to review
medical records. The data extraction tool was checked for completeness and consistency using 5%
preliminary reviewed randomly selected charts to maintain data quality assurance.

Data processing and analysis

Data were entered into Epi data Version 4.6 and exported to Stata version 14 statistical software for
further analysis. Descriptive statistics of numeric variables presented in medians with interquartile range
(IQR), categorical variables were presented using frequency tables and percentages. Multicollinearity was
checked between independent variables. The incidence rate of mortality was also calculated for the entire
follow-up by dividing the total number of new cases of PNA to the total person-days of follow-up. The
Kaplan-Meier failure curve was used to estimate survival time. The Log-rank test was used to compare
Survival experiences between independent groups. Proportional hazard assumption was checked by
graphically using the plot of log [- log (survival probability) versus the log of survival time, by interacting
each covariate with time. The Schoenfeld residual global test for the proportionality assumption was
checked, and (p-value =0.7554) finding was used as a suggestive of satisfying assumption. The log-
likelihood and Akaike Information Criteria (AIC) were applied to select the best fitted model, and a model
with minimum AIC value was considered as the best fitted model. As a result Weibull regression model
was selected with AIC=586.39. The goodness of model fitness was also checked using the Cox-Snell
residual test. Variables with P < 0.2 in the bi-variable analyses were potential candidate variables for the
multivariable analysis, and stepwise forward variable selection was done so as to identify eligible
variables using Weibull regression. Variables having p-value ≤0.05 in the multivariable model were
considered to be significantly associated with the outcome. Finally, the crude and adjusted hazard ratio
(HR) with 95% CI was calculated to determine statistical significance level.

Operational definitions
Perinatal asphyxia:- is considered when the 5th minute APGAR score is <7 (21, 47).

Event(death):- Neonate died in the hospital and death summary written on a chart due to PNA (48).

Censored

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newborns with PNA who did not develop the outcome of interest (death) until the end of follow-up period
or lost to follow-up, recovery from illness, discharged against medical advice or transfer out to other
health institutions without knowing the outcome

Survival time

The time in days from admission to the development of outcome variable (Death) within 28 days follow-
up time.

Defaulted- PNA cases that are signed (parents on behalf of their child) against treatment to leave
treatment before cure.

Results
Socio-demographic and admission characteristics
A total of 402 newborns were enrolled into the study. Nearly two-thirds, 260(64.68 %) of neonates were
males. About 340 (84.58%) of neonates were admitted within the first 24 hours immediately after birth.
The median age of mothers was 25 (IQR: 23, 30) years old, and 37.81% were belonged to the age group
of 20-24 years old. Majority, 348 (86.57%) of the respondents were Orthodox Christianity followers, and
nearly two- thirds, 252(62.69) of them were rural resident (Table 1).

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 Table 1
Socio-demographic characteristics of the mother and the newborn admitted
DMCSH from January, 2018 to 30th of December, 2020, Northwest, Ethiopia,
(N=402)
Variables Category Frequency Percent

Sex of the newborn Male 260 64.68

Female 142 35.32

Admission age of the newborn (hr) ≤24hr 340 84.58

>24hr 62 15.42

Maternal 15-19 16 3.98

Age in years 20-24 152 37.81

25-29 132 32.84

30-34 54 13.43

35-49 48 11.94

Religion Orthodox 348 86.57

Protestant 31 7.71

Muslim 23 5.72

Residence Rural 252 62.69

Urban 150 37.31

Antepartum characteristics of the mother

Nearly two-thirds, 262(65.17%) of the participants were primipara and almost all, 387(96.27%) were
attending ANC follow-up. Among these who attend ANC nearly two third 253 (65.37%) had four and
above ANC visit (Table 2).

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 Table 2
Medical and antenatal obstetric characteristics of the mother at
DMCSH from January 1/2018 to December 30/2020, Northwest,
Ethiopia, (N=402)
Variables Category Frequency Percent

Antenatal care Yes 387 96.27

No 15 3.73

No of ANC follow up 1-3 134 34.63

4 and above 253 65.37

Parity Primipara 262 65.17

Multipara 140 33.83

Anemia Yes 92 22.89

No 310 77.11

Hypertension Yes 18 4.48

No 384 95.52

Diabetic mellites Yes 20 5.00

No 382 95.00

Antepartum hemorrhage Yes 32 7.96

No 370 92.04

Postpartum hemorrhage Yes 43 10.70

No 359 89.30

Preeclampsia/eclampsia Yes 53 13.18

No 349 86.82

Gestational diabetes Yes 22 5.47

No 380 94.53

Rh factor Positive 382 95.02

Negative 20 4.98

HIV status Positive 9 2.24

Negative 393 97.76

Hepatitis Positive 5 1.24

Negative 397 98.76

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 Variables Category Frequency Percent

VDRL Positive 8 1.99

Negative 394 98.01

TT vaccination Yes 371 92.79

No 31 7.71

Intrapartum obstetric factors of the mother

As shown on the (Table 3) more than half, 216 (53.73%) of the respondents delivered through
spontaneous vaginal delivery and nearly one-fifths, 79 (19.65) delivered above 18 hrs duration of labor.
Of all 376 (93.53%) labor started with spontaneously.

Table 3: Intrapartum obstetric characteristics of the mother at DMCSH from January 1/2018 to December
31/2020, Northwest, Ethiopia (N=402)

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 Variables Category Frequency Percent

Mode of delivery SVD 216 53.73

CS 91 22.64

Instrumental 95 23.63

Duration of labor ≤18hr 323 80.35

>18hr 79 19.65

Onset of labor Spontaneous 376 93.53

Induced 26 4.73

Types of pregnancy Single 385 95.77

Multiple 17 4.23

Presentation of the fetus Vertex 367 91.29

Non vertex 35 8.71

PROM Yes 71 17.66

No 331 82.34

Obstructed labor Yes 40 9.95

No 362 90.05

Place of delivery Health center 97 24.13

Hospital 305 75.87

PROM= premature rapture of membrane SVD= spontaneous vaginal delivery CS= caesarean section
Clinical characteristics of neonates. The mean gestational age of the newborn was 38.5(±2.6 SD) weeks
and most, 284 (70.65%) neonates’ gestational age belonged to the age group of 37-42 weeks. Nearly two-
thirds, 268(66.67%) of the newborns were had normal birth weight (Table 4).

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 Table 4
Clinical characteristics of the newborn admitted in the NICU of DMCSH from
January 1/2018 to December 31/2020, North West, Ethiopia, (N=402)
Variables Category Frequency Percent

Gestational age Preterm 92 22.89

Term 284 70.65

Post term 26 6.47

Birth weight <2.5kg 134 33.33

≥2.5-2.99kg 260 66.67

4 & above kg 8 2.00

Neonatal sepsis Yes 159 39.55

No 243 60.45

RDS Yes 70 17.41

No 332 82.59

MAS Yes 128 31.84

No 274 68.16

Resuscitation Yes 362 90.05

No 40 9.95

HIE stages I 124 30.85

II 191 47.51

III 87 21.61

Neonatal jaundice Yes 15 3.73

No 387 96.27

Phototherapy Yes 18 4.48

No 384 95.52

Hypothermia Yes 301 74.88

No 101 25.12

Birth injury Yes 62 15.42

No 340 84.58

RDS=Respiratory distress syndrome, MAS= meconium aspiration syndrome

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 Variables Category Frequency Percent

Neonatal anemia Yes 101 25.12

No 301 74.88

Hypoglycemia Yes 5 1.24

No 397 98.76

RDS=Respiratory distress syndrome, MAS= meconium aspiration syndrome

Incidence of mortality
From the total of 402 neonates who were admitted with perinatal asphyxia (PNA) 125(31.09%) (95% CI:
26.74- 35.81) of them developed the event of interest (death). The total neonate-days observation for the
entire follow-up time was 2337 person-days with minimum and maximum follow up time were 1 and 22
days respectively. The overall incidence of mortality was 53.49 per 1000 neonate- days observation
(95%CI: 44.89- 63.74) during the entire follow-up time. The incidence of death at the beginning of 5, 10,
15 and 20 days was 67, 35, 5.84 and 21.7% per 1000-neonate days observation, respectively.

Overall failure Function (survivorship function)

The overall Kaplan- Meier failure function showed that the probability of death among neonates with PNA
was increased during the follow-up period. During the first day of admission 13% probability of death was
observed. The cumulative probability of death at the end of 5, 10, 15 and 20 days was 0.27, 0.38, 0.39,
and 0.44 respectively and the least probability death 0.44 was observed at the end of 28 days follow-up
time (Figure 2)

Comparison of Survivorship Functions for different

categorical variables
The test of equality for survival distribution for different categories of variables were performed with
Kaplan-Meier and the log-rank test. In general, the pattern that one group survivorship function lying
above another group showed that the upper curve had a better probability of survival compared to the
lower curve. On the other hand, the probability of death was high among the lower groups described by
Kaplan-Meier survival curve. Furthermore, the log-rank test confirmed the observed difference seen on the
KM graph statistical difference or not.

In the current study, newborns who faced HIE stage III has lower survival time compared with stage II and
I, and newborns who developed HIE stage II were lower survival time compared to stage I. Moreover,
neonates without sepsis have favorable survival probability than those neonates with sepsis. This study
also revealed that neonates born from mothers who hadn’t PPH at admission had better probability of
survival compared with those mothers faced PPH.. Furthermore, neonates born from mothers who had

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antepartum hemorrhage (APH) had better probability of survival compared with newborns born from
mothers who did not face APH among neonates admitted with PNA. Thesedifferences were statistically
significant with p value < 0.001 in log rank test (Figure 3)

Model comparison
After the proportional hazard assumption was checked, both semi-parametric and parametric
proportional hazard models were fitted to estimate the survival time to death and identify its predictors
among neonates with perinatal asphyxia. As shown in figure 3 model Comparession was checked
graphically.

Besides, Model Comparession was checked statistically by using information criteria (AIC, BIC) and log-
likelihood to select the most parsimonious models for the data set. Based on this, the Weibull regression
with the AIC= 586.39 model was best fitted model (Table 5).

Table 5
Summary of model comparison among the Cox proportional hazard
model, parametric Cox- Regression models using AIC and LR criteria
Model Baseline Hazard Log-likelihood AIC

Cox regression Unspecific -602.86 1257.72

Weibull regression Weibull -265.19 586.39

Exponential Exponential -266.64 587.29

Gompertz Gompertz -265.66 587.32

Predictors of mortality among neonates with perinatal

asphyxia
In the Bi-variable Weibull regression analysis, age of the mother, parity, postpartum hemorrhage,
preeclampsia or eclampsia, antepartum hemorrhage, chronic diabetes mellites, chronic hypertension,
maternal anemia, other pregnancy related complications like (abortion, placenta previa…), duration of
labor, presentation, onset of labor number of pregnancy, onset of labor ,birth weight, gestational age,
neonatal sepsis, respiratory distress syndrome, Meconium aspiration syndrome, phototherapy, birth injury,
neonatal anemia, hypothermia and HIE status were significant predictors of mortality with P- value less
0.2. However, in the multivariable Weibull regression analysis, prematurity, neonatal sepsis, Antepartum
hemorrhage, induced onset of labor, postpartum hemorrhage and HIE stage II and III were significant
predictors of mortality among neonates admitted with PNA with p value <0.005.

After adjusting for other variables neonates born from mothers who faced postpartum hemorrhage (PPH)
during delivery increased the hazard of death by two times than mothers without PPH (AHR=2.12; 95%CI:
1.32-3.38). Induced onset of labor was also independent predictor of mortality among neonates with
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PNA, which increased the hazard of death nearly four times more likely compared with spontaneous
onset (AHR=3.90; 95%CI; 1.83- 8.27) by keeping other variables constant. In addition to this neonate born
from mothers with current pregnancy complicated with antepartum hemorrhage (APH) increased the
hazard of death by two folds (AHR=2.10; 95%CI: 1.13-3.92) among neonates with PNA compared with
newborns born from mothers without APH. Moreover, neonatal sepsis was independent predictor of
death, which increased the hazard of death among newborns with PNA two times (AHR=2.13; 95%CI:
1.38-3.27) compared with newborns without neonatal sepsis holding other variables constant. Preterm
birth increases the hazard of death by more than three times than neonates delivered within 37-42 weeks
of gestational age (AHR= 3.42; 95%CI: 2.13-5.48) by keeping other variables constant. Besides, HIE stage
II and stage III were strong predictors of death, which increased the hazard of death by seven and nearly
17- times more likely with (AHR=6.65; 95%CI: 2.57-7.26), and (AHR=16.8; 95%CI; 6.28 -44.9) compared to
HIE stage I respectively holding other variables constant (Table 6).

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 Table 6
Bivariable and multivariable Weibull regression analysis for predictors death among neonates with
perinatal asphyxia admitted at DMCSH from 2018-2020, North West, Ethiopia, December January 1/2018
to December 31/2020 (N=402)
Variables Category Status CHR;(95%CI) AHR;(95%CI)

Event Censored

Phototherapy Yes 9 9 1.58(0.80- 3.11) 0.66(0.30-1.43)

No 116 268 1 1

Age of the mother 15-19 7 9 1.54 (0 .69 3.41) 0.58(0 .21-1.61)

20-24 45 107 1 1

25-29 34 98 0.76 (0.49-1.19) 0.70(0.40-1.23)

30-34 15 39 1.02(0.57- 1.84) 1.73(0 .80- 3.75)

above 35 24 24 2.12(1.29-3.48) 1.61(0 .77- 3.38)

Parity Multipara 51 89 1.44 (1.01-2.05) 0.84 (0.48-1.48)

Primi para 74 188 1 1

Maternal anemia Yes 38 54 1.70(1.16- 2.49) 1.05 (0 .64-1.72)

No 87 223 1 1

Hypertension Yes 13 5 4.00 (2.26-7.17) 1.27 (0 .62- 2.62)

No 112 272 1 1

PPH Yes 30 13 3.49(2.31- 5.26) 2.12(1.32-3.38) **

NO 95 264

APH Yes 19 13 2.64(1.62- 4.30) 2.10 (1.23-3.92) *

No 106 264 1 1

Pre/eclampsia Yes 25 28 1.62(1.04-2.51) 0.73 (0.42-1.26)

No 100 249 1 1

Diabetes mellites Yes 12 8 3.47 (1.90- 6.31) 1.25 (0.60-2.60)

No 113 269 1 1

Duration of labor >18hr 35 44 1.82(1.23- 2.69) 1.35 (0.86-2.14)

≤18hr 90 233 1 1

APH= Antepartum hemorrhage, PPH= Postpartum hemorrhage, RDS= respiratory distress syndrome,
HIE= hypoxia ischemic encephalopathy and MAS= Meconium Aspiration Syndrome
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 Types of Multiple 9 8 2.51(1.27- 4.97) 1.41 (0.61-3.27)
Pregnancy Single 116 269 1 1

Onset of labor Induced 11 15 1.72(0.93- 3.20) 3.90 (1.83-8.27) ***

Spontaneous 114 262 1 1

Presentation Non- Vertex 14 21 1.65(0.95-2.88) 1.78 (0.93-3.42)

Vertex 111 256 1 1

Gestational Preterm 73 19 7.86(5.44-11.37) 3.42 (2.13-5.48) ***

Age(week) Term 48 236 1 1

Post term 4 22 0.82(0.30- 2.28) 0.52 (0.17-1.56)

Term 44 240 1 1

Sepsis Yes 87 72 4.17(2.85-6.11) 2.13 (1.38-3.27) **

No 38 205 1

MAS Yes 49 79 1.33(0 .93- 1.90) 1.22 (0.80-1.84)

No 76 198 1 1

RDS Yes 38 32 2.40 (1.64- 3.50) 1.07 (0.68-1.68)

No 87 245 1 1

Neonatal Anemia Yes 51 50 2.45(1.71- 3.50) 1.26 (0.82-1.93)

No 74 227 1 1

HIE I 5 119 1 1

II 47 144 5.9(2.35-14.85) 6.65 (2.57-17.26) ***

III 73 14 34.5(13.9-85.44) 16.8(6.28 -44.9) ***

Birth injury Yes 24 38 1.46(0 .93-2.27) 1.06 (0.62-1.80)

No 101 239 1 1

Hypothermia Yes 103 198 1.55(0.98- 2.46) 0.63 (0.37-1.05)

No 22 79 1 1

APH= Antepartum hemorrhage, PPH= Postpartum hemorrhage, RDS= respiratory distress syndrome,
HIE= hypoxia ischemic encephalopathy and MAS= Meconium Aspiration Syndrome
NB: *** Significant (P-value < 0.001), ** significant (p-value<0.005), * significant (p<0.05)

Discussion
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Among 402 neonates under the follow up, 125 (31.09%) died during the follow-up period. The overall
incidence of mortality was 53.5 deaths per 1000 neonate-days observation with (95%CI: 44.89- 63.74).
This finding is higher than a study conducted in Brazil 0.95-1.38/1000 live birth (29), 0.65-0.81/1000 live
birth in 2017 (16), and 9.7/1000 live birth in Southern Nepal (32). This marked difference might be
attributed to a number of factors such as source population of the study participants was live birth, while
the currents study was PNA, another possible justifying may be due to a study area was population
based. On the other hand, the current study was intuitional based.

The proportion 31.09% was relatively comparable with studies reported from Nigeria 31% (31), Congo
28.5% (49), India 26%(23). The finding of this study was higher than the studies reported in Nigeria 18%
(34), 14.7% (39), and 23% (30),Tanzania 23% (50), South Africa 13.3%(33), India 4.8%(19) and 10% (20).
On the other hand, this finding was lower than the studies conducted at India 40.6(21) and Nigeria 38.7%
(35). This may be due to the fact that other studies included only outborn newborns; while in this study
participants were both inborn and outborn newborns. Therefore, including outborn overestimated death
rate. Moreover, The discrepancy might be variation in different studies was due to different operational
definitions for birth asphyxia and adopted by different researchers (30, 33, 34, 39, 50). Moreover, this high
death emanated from the poor neonatal resuscitation skills, the lack of resuscitative equipment, lack of
skilled manpower in neonatal resuscitation at birth and delay in transporting the asphyxiated newborn to
a higher health facilities (51, 52).

Neonatal sepsis at the time of admission significantly increased the hazard of death among neonates
with PNA. This finding was supported by the studies conducted in developed and developing countries
(32, 38, 40, 41, 50). The possible reason might be associated with neonatal sepsis causes
hypothermia/fever, poor feeding, hypotension respiratory distress, shock, multi-organ failure, and
meningitis. Besides, poor quality of care and treatment delay also the major gaps of developing counties
including Ethiopia. Moreover, the unnecessary overuse of antibiotics can increase the chances of severe
candidiasis and multi-drug resistant organisms (53–56). These collectively resulted to have high
mortality due to sepsis among neonates with PNA. This study implied that there is a clear gap in the
management and prevention of sepsis. This finding emphasizes the need to improve the quality of care
in health facilities, in particular, we strongly believe that achieving a high-quality intrapartum and
postnatal care is required to improve neonatal health.

Preterm neonates with PNA increased the hazard of death compared to full-term births. This was in
accordance with the studies conducted in Nigeria and South Asian (30, 32, 35). Higher risk of mortality
among premature neonates could be explained by different factors, like newborns with GA less than 37
weeks (preterm) were higher risk to develop complications, such as, infections, hypothermia, and
hypoglycemia due to limited number of immunoglobulins at birth. Another possible explanation may be
due to lack of feasible, cost-effective care, such as breastfeeding support, basic care for infections and
breathing difficulties were practiced in developing counties like Ethiopia (57, 58). Given these factors are
the most common causes of morbidity and mortality in neonates with PNA (59–61). This implies that

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anticipating high-risk newborn babies and taking combined approaches to reduce the death of such
physiologically and anatomically vulnerable neonates are needed (62, 63)

In the current study, hypoxic ischemic encephalopathy (HIE) stage II and III were strong (leading)
independent predictors of death, that stage II and III increase the hazard of death by seven times and 17-
fold respectively compared with stage I by holding another variables constant. This finding is supported
by the studies conducted in Nigeria (22, 31, 34, 39), South Africa (33) and India(20, 21, 23). The possible
reason might be once HIE stage II and III occur, they result in poor feeding, seizure, brain damage, and
multiorgan dysfunction. In addition, due to lack of feasible, cost-effective care like therapeutic
hypothermia, supportive management of seizure and adequate resuscitation in developing countries
including Ethiopia (51, 64). Besides, the probability that infants with the greatest hypoxic‑ischemic brain
damage will benefit least by any specific intervention (65, 66).

The collectively increased death among neonates with PNA who faced HIE Stage II and III during
admission. This study implies that more attention should be focused on the early assessment of high-risk
mothers and newborns and timely referral to the tertiary care center. Moreover, adequate resuscitation,
therapeutic hypothermia, supportive management of seizure and fluid balance is essential in ensuring
optimal outcomes (67).

In the current study, induced onset of labor increases the hazard of death by nearly four times compared
with spontaneous onset by adjusting effects of other variables. This may be associated with induced
labor was indicted for high-risk mothers like (Preeclampsia, eclampsia, gestational hypertension…),
intrauterine growth restriction, and post -term pregnancy (68–71). As well, induction increases the greater
risk for instrumental birth, postpartum hemorrhage, affects the natural process of pregnancy and labour
and increases hospitalization for maternal as well as newborn. These collectively increase the risk of
death among newborns with PNA (72–75).

Antepartum hemorrhage (APH) was increasing the hazard of death among neonates with PNA. This may
be associated with APH increases premature delivery, low birth weight, and fetal growth retardation (76).
Moreover, APH leads neonatal anemia and decreases placental perfusion as well as hypoxia then which
leads to bradycardia, and multiorgan failure (76–79).

Postpartum hemorrhage (PPH) was also independent predictor of neonatal mortality among neonates
admitted with PNA, which increases the hazard of death by two times compared with mother who were
not faced for PPH during delivery. This may be associated with PPH management delays the time for
essential newborn care as well as neonatal resuscitations. Moreover, postpartum hemorrhage is the
leading cause of maternal mortality (80, 81), which also resulted neonatal death. since the survival of the
mother was vital for their child survival (82, 83). This study implies that regular antenatal care, early
detection of high-risk mothers, allowing them to be timely admitted for schedule, availability of blood
banks, and early referral to a higher center to reduce APH and PPH related neonatal death (79, 84, 85).

Page 18/29
Limitation
As the study was based on secondary data, the main limitation could be incomplete medical records. In
this regard, some important predictors, such as maternal nutritional status, mothers’ educational level,
birth interval, and monthly household income were not available from medical recorded data. In addition,
the exact causes of death were not recorded. Thus, we assumed that all causes of the deaths were
related to admission diagnosis. Furthermore, as the study was conducted at hospital, neonatal mortality
might be underestimated because neonates delivered and died at home could be underreported. On the
other hand, since the study included sick neonates, the mortality could be overestimated

Conclusion
The study found that the overall incidence rate of mortality among neonates with PNA remains high.
Neonatal sepsis, HIE II and III, prematurity, postpartum hemorrhage, antepartum hemorrhage, and induced
onset of labor were significant predictors of mortality.

Abbreviations

Page 19/29
 AHR Adjusted Hazard Ratio

AIC Akaike Information Criteria

APGAR Appearance Pulse Grimacing Activity and Respiration

APH Antepartum Hemorrhage

CI Confidence Interval

CPAP Continuous positive airway pressure

DM Diabetic Mellites

DMCSH Debre Markos Comprehensive Specialized Hospital

EDHS Ethiopian Demographic Health Survey

EMDHS Ethiopian Mini Demographic Health Survey

GDM Gestational Diabetic Mellites

HIE Hypoxic Ischemic Encephalopathy

LBW Low Birth Weight

LL Log Likely hood

MAS Meconium Aspiration Syndrome

MUAC Mid Upper Arm Circumference

PNA Perinatal Asphyxia

PPH Postpartum Hemorrhage

PROM Premature Rapture of Membrane

RDS Respiratory Distress Syndrome

VIF Variance Inflation Factor

WHO World Health Organization

Declarations
Ethics approval and consent to participate

The study was carried out after getting approval from the university of Gondar institutional review board
(IRB). Then, data were collected after getting consent from the hospital manager. This study didn’t inflict
or exposes children to unnecessary risk as a result of reviewing their medical records. To maintain
confidentiality, each and every one collected data were coded and locked in a separate room prior to enter

Page 20/29
into the computer. Following entered into the computer all data were protected by password. Names and
unique medical registered numbers (MRN) were not incorporated in the data collection set-up.

Consent for publication

Not applicable

Availability of data and material

Additional file: Data abstraction tool

Data set: The data sets used and/or analyzed during the current study are available from the
corresponding author on reasonable request.

Competing interests

The authors have declared that they have no competing interest.

Authors’ contribution

AT: the conception of the research idea, study design, data collection, analysis and interpretation, and
manuscript write-up. GMB, BKD, AML and FWS: data analysis and interpretation and supervision. All
authors have read and approved the final manuscript.

Funding

Not applicable.

Acknowledgment

The authors would like to acknowledge the University of Gondar, College of Medicine and Health Sciences
for support of this research project. The authors also extend their special thanks to both data collectors
and supervisors

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Figures

Figure 1

Kaplan Meier failure function death among neonates with perinatal asphyxia admitted in the NICU of
DMCSH from January 2018 to December 2020, North, West, Ethiopia, (N=402)

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Figure 2

Kaplan- meier survival function among groups of neonatal sepsis (A), stages of HIE (B), PPH(C) and APH
(D) for neonates with perinatal asphyxia admitted the NICU of DMCSH from 2018-2020, North West,
Ethiopia ,2021.

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Figure 3

Graph of Nelsen -Aalen cumulative hazard function against Cox-Snell residual obtained by fitting (A)
Weibull, (B) Cox, (C) Exponential and (D) Gompertz models for mortality among neonates with perinatal
asphyxia admitted at the NICU of DMCSH from 2018-2020, North West Ethiopia,2021

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