Incidence and Predictors of Mortality Among Preterm Neonates Admitted to Neonatal Intensive Care Units in Comprehensive Specialized Hospitals in Northeast Ethiopia: A Multi-Center Prospective Follow-Up Study

doi:10.21203/rs.3.rs-4712637/v1

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Incidence and Predictors of Mortality Among Preterm Neonates Admitted to Neonatal Intensive Care Units in Comprehensive Specialized Hospitals in Northeast Ethiopia: A Multi-Center Prospective Follow-Up Study

https://doi.org/10.21203/rs.3.rs-4712637/v1

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Background

Despite numerous efforts, preterm mortality remains a significant public health burden in Ethiopia. Therefore, this study aimed to assess the incidence and predictors of preterm mortality among preterm neonates admitted to Comprehensive Specialized Hospitals in Northeast Ethiopia in 2024.

Methods

A multi-center prospective follow-up study conducted at the institutional level involved 356 preterm neonates, selected through consecutive sampling. A Weibull proportional hazards model was fitted to identify predictors of preterm neonatal mortality.

Result

The preterm neonatal mortality rate was 72 per 1,000 person-days of observation. The median time to death was 10 days (IQR = 7–20 days). Predictors of preterm neonatal mortality included young maternal age (15–19 years) [AHR 2.73 (95% CI: 1.3–5.9)], extremely low birth weight [AHR 2.4 (95% CI: 1.24–4.6)], respiratory distress syndrome [AHR 2.3 (95% CI: 1.34–3.8)], early preterm birth [AHR 1.8 (95% CI: 1.1–3)], lack of kangaroo mother care [AHR 2.2 (95% CI: 1.54–3.21)], multiple pregnancy [AHR 2.1 (95% CI: 1.1–4.3)], necrotizing enterocolitis [AHR 1.53 (95% CI: 1.1–2.22)], suboptimal continuous positive airway pressure therapy [AHR 1.43 (95% CI: 1.02–2.02)], and congenital anomalies [AHR 2.3 (95% CI: 1.32–3.9)].

Conclusion

The current study revealed that preterm neonatal mortality significantly exceeds the national average and is unacceptably high, necessitating immediate intervention. This underscores the urgency to improve optimal childbearing age, optimize continuous positive airway pressure therapy, improve kangaroo mother care practices, and enhance the management of necrotizing enterocolitis and respiratory distress syndrome.

Health sciences/Health care

Health sciences/Risk factors

Incidence

preterm mortality

predictors

NICU

Northeast Ethiopia

Preterm births occur when infants are delivered alive before completing 37 weeks of gestation. They are categorized into three groups based on gestational age: extremely preterm (less than 28 weeks), very preterm (28 to less than 32 weeks), and moderate to late preterm [1, 2].

In 2021, roughly 2.3 million neonates passed away, with prematurity accounting for one-third of all neonatal deaths worldwide [3]. Sub-Saharan Africa bore the brunt of preterm fatalities, contributing the majority of these deaths (nearly 600,000 occurring before 32 weeks of gestation) [3, 4]. In Ethiopia alone, 23,100 neonates died due to preterm complications, and 7,900 preterm survivors experienced impairments annually [5]. In Ethiopia alone, 23,100 neonates died due to preterm complications, and 7,900 preterm survivors experienced impairments annually [5].

Consequently, preterm complications cause high neonatal mortality, visual and hearing impairments, learning difficulties, and enduring disabilities. These burdens extend to parents, manifesting as mental health strains and economic challenges [6]. As a result, urgent action is imperative, as 63 countries, including Ethiopia, are projected to fall short of the neonatal mortality target by 2030 [7].

Studies conducted in Ethiopia have identified various predictors of preterm mortality, such as maternal and neonatal sociodemographic factors, obstetric and maternal health utilization-related factors, and factors specific to the newborns themselves [8–13]. Furthermore, there is a lack of kangaroo mother care (KMC), absence of steroid administration, sub-optimal continuous positive airway pressure (CPAP) therapy, and poor adherence to the standard guidelines for antibiotic treatment [14].

Ethiopia has committed to achieving the Sustainable Development Goals (SDGs) aimed at reducing preterm mortality. This commitment includes promoting positive pregnancy experiences, implementing kangaroo mother care (KMC) immediately after birth, utilizing continuous positive airway pressure (CPAP), enhancing neonatal intensive care unit (NICU) services at hospitals, and providing training for qualified care providers [15–18]. Despite these extensive efforts, preterm birth remains the leading cause of neonatal death in Ethiopia [19] and the incidence of preterm mortality ranges from 14.5 to 71.5 per 1000 person-time [20, 21].

Despite documented studies on the incidence, time to death, and predictors of prematurity in Ethiopia [8–13], many were retrospective, conducted in single institutions, lacked comprehensive inclusion of maternal sociodemographic factors, and did not consistently record birth weight and vital signs at the end of follow-up. Furthermore, unlike previous studies, the current study utilized a parametric survival model.

Therefore, this study aimed to assess the incidence and predictors of preterm mortality among preterm neonates admitted to NICUs in Comprehensive Specialized Hospitals in northeastern Ethiopia. Consequently, it provides recommendations for stakeholders, thereby assisting local hospital managers, care providers, and various institutions in implementing identified predictors to enhance the quality of hospital care for preterm survival. Ultimately, this will help reduce preterm mortality.

Study design, period, and setting

A multi-center prospective follow-up study was conducted at comprehensive specialized hospitals in the eastern Amhara regions of northeastern Ethiopia from February 3 to May 31, 2024. There are three comprehensive specialized hospitals in the northeastern Ethiopia and cater to approximately 15 million residents.The Neonatal Intensive Care Units (NICUs) in the comprehensive specialized hospitals of northeastern Ethiopia currently employ 102 nurses, 14 pediatric and child health specialists, and over 20 general practitioners. On average, each hospital NICU has 33 beds, treats around 203 pretrm newborns per month in NICU, maintains a nurse-patient ratio of 1:4, and a physician-patient ratio of 1:9 in the NICU.

Study population

Consecutively selected preterm neonates were admitted to the NICU from February to May 2024 at comprehensive specialized hospitals in northeastern Ethiopia.

Eligibility criteria

Preterm babies who were admitted from February to May 2024 and has completed data were included.However, those preterm newborns who have incomplete maternal and newborn data were excluded.

Sample size determination

The sample size was determined using the Schoenfeld formula in STATA statistical program version 17, considering the following assumptions: a hazard ratio of the covariates, a variability (SD) of 0.5, a probability of event (death), a margin of error of 5%, a 95% confidence interval to achieve 80% power, and a 10% non-response rate. Moreover, from prior studies, the authors used the following covariates as references: Perinatal Asphyxia (PNA) [13], respiratory distress syndrome (RDS) [13], Kangaroo Mother Care (KMC) [13], dehydration [11], gestational age [8], and Antepartum Hemorrhage (APH) [11]. Based on the Schoenfeld formula, the required sample sizes were 101 for PNA, 135 for RDS, 121 for KMC, 64 for dehydration, 49 for APH, and 356 for gestational age. According to the principle of selecting the covariate with the maximum sample size, gestational age, which required a sample size of 356, was used as the final sample size.

Sampling techniques and procedures

Of the total three comprehensive specialized hospitals in northeastern Ethiopia that have NICU services, all of them were involved, namely: Dessie Comprehensive Specialized Hospital, Woldiya Comprehensive Specialized Hospital, and Debrebrehan Comprehensive Specialized Hospital. The total preterm admissions in the last six months were 750 (Dessie = 285, Woldiya = 250, and Debrebrehan = 215). The required number of subjects were then proportionally allocated to each selected hospital based on their population size. Finally, the preterm neonates were obtained using a consecutive sampling technique, and the required sample size was achieved in each hospital consecutively.

Outcome variables

Incidence of premature newborn

Independent variables

Maternal socio demographic-related predictors; (residence, maternal age, educational status, marital status and occupation).

Maternal obstetrical and medical predictors include multiple pregnancies, Preterm premature rupture of membrane (PPROM), mode of delivery, preeclampsia, placental abruption, antenatal care follow-up, steroid administration, hypertension, diabetes mellitus, human immunodeficiency virus, and sepsis.

Preterm-related predictors include age at admission, sex, weight, gestational age, and weight for gestational age; preterm admission diagnosis; and new problems diagnosed during follow-up (APGAR score, diagnosis at admission, and new medical problems during follow-up).

Preterm management-related predictors include antibiotics, feeding, CPAP, kangaroo mother care (KMC), and type of KMC.

Operational definitions

Neonatal sepsis is diagnosed as if the neonates have at least more than one of the following clinical features: inability to breastfeed, convulsions, movement only when stimulated, unconsciousness, fast breathing rate (60 breaths per minute), body temperature greater than 37.5 ^oc or < 35.5 ^oc, tachycardia (> 160 bit/minutes) or bradycardia (< 100 bit/minutes), and desaturation (< 90% oxygen saturation). Furthermore, at least two hematological criteria for abnormality exist, such as a total leukocyte count < 5,000 or > 12,000 cells/µl and a platelet count < 150x103 or > 450x103 cells/µl [17].

Respiratory distress syndrome (RDS): is diagnosed as if the neonates have at least more than two of the following clinical features: grunting, flaring, retraction, and tachypnea, cyanosis, and oxygen saturation less than 90% [17].

Sub-optimal CPAP therapy is operationalized as the presence of one of the following issues: improper equipment uses, such as incorrect CPAP settings; lack of staff training and protocols; inadequate monitoring and maintenance; or resource limitations, such as insufficient CPAP devices or accessories [17].

Censored

preterm neonates who left the follow up without event (transferred to another institution, left against medical advice, discharged and preterm stays more than 28 days) [11].

Death

preterm neonate who died during the follow-up within 28 days after birth and had death summary [11].

Time to death

is the number of days it takes from NICU admission until which the preterm will die during the follow up within 28 days after births [11].

Medical disorders in the neonate

All recorded medical diagnoses for the premature neonates were obtained from their medical records. In this study, all diagnoses were taken from the treating physicians (who were not part of the study team). For example, if a physician diagnosed apnea and documented it on the neonate’s medical chart, the research team recorded that the neonate had apnea until the condition improved. This means that data collectors did not diagnose the neonates themselves.

Data collection method and procedure

The data extraction checklist, developed and adapted from national technical guidance for maternal and prenatal death surveillance and response, along with various literature sources [8–13, 22–24], was meticulously structured and pretested in English. Data collection involved direct face-to-face interviews with mothers and the use of an observational checklist. Socio-demographic and specific obstetric variables were obtained through direct face-to-face interviews with mothers of newborns. Additionally, an observational checklist was used to collect data on obstetric and delivery-related variables, essential neonatal characteristics, clinical and diagnostic features, preterm management and complications, and prematurity outcomes. Information was extracted from the neonatal charts and through daily follow-ups.

The data collection team comprised three neonatal nurses and two supervisors (each holding an MSc in pediatric nursing). The checklist was pretested on 5% of preterm babies admitted to the NICU at Dessie Comprehensive Specialized Hospital, leading to subsequent revisions. The tool's reliability was confirmed with a Cronbach's alpha of 0.83. Data collectors and supervisors received two days of training, and supervisors ensured the completeness of the data during the collection process.

Data analysis

The collected data was coded, entered, and cleaned using EpiData version 4.6, then exported to STATA version 17 for analysis. Descriptive and inferential statistics were utilized to present the data. Descriptive statistics, such as frequency and percentage, were used, while inferential statistics, such as the hazard ratio, were computed to determine predictors of prematurity mortality.

The hazard assumption was verified using a log-log plot and the log-rank test, indicating both graphical and statistical survival differences between variable categories. Moreover, Kaplan-Meier failure curve analysis was used to depict the pattern of death and compare survival curves among different categories. Finally, the Schoenfeld residual test (global test) was used to assess the goodness of fit of the model (Supplementary file 1).

For model comparison, log-likelihood ratio tests, Akaike Information Criteria (AIC), and Bayesian Information Criterion (BIC) values were evaluated. The model with the highest log-likelihood, the lowest AIC, and the lowest BIC was selected as the best fit. Based on these criteria, the Weibull proportional hazard model was chosen over the other models due to its higher log-likelihood (-236.6392) and lower AIC (485.2785) and BIC (507.9629) values (supplementary file 2).

Bivariable Weibull proportional hazard regression analysis was conducted, and variables with a p-value < 0.25 in the bivariable analyses were considered eligible for inclusion in the final multivariable analysis to identify predictors of time to death. The hazard ratio with a 95% confidence interval was calculated for the significant predictive variables, and statistical significance was defined as P < 0.05. Moreover, multicollinearity was assessed using the variance inflation factor (VIF), which ranged from 1.45 to 4.78, indicating low multicollinearity. Moreover, the overall goodness of fit was evaluated using the Schoenfeld residual test (global tests) (χ² = 12.42, p-value = 0.456), indicating a good fit for the model since the test was not statistically significant.

Ethical Approval and Consent to Participate

The study protocol was evaluated and approved by Wollo University College of Medicine and Health science research and community service committee with reference No_(WU/CMHS/20/317/2024) and ethical clearance was obtained. Additionally, before commencing the study, permission letters were obtained from each hospital manager and the quality assurance department. Written informed consent was obtained from each preterm baby's mother. Moreover, this study was conducted in compliance with the Declaration of Helsinki. Study participants were clearly informed about their right to withdraw at any stage of the study. Anonymous data were obtained and the confidentiality of participants information was secured. Moreover, subject confidentiality and any special data security requirements were maintained and assured through the use of codes instead of participants' names.

Sociodemographic characteristics

Out of the total sample size of 356 participants, 350 pairs of preterm newborns and their mothers were included in this study. The remaining 6 were excluded due to declined consent, resulting in a response rate of 98.3%. The majority of the mothers fell within the age range of 25–29 years old, accounting for 129 (36.9%) of the participants, with a mean maternal age of 28 years ± 5.6 standard deviation (SD). Furthermore, most of the newborns' mothers resided in urban areas (181, 51.7%), had attained a secondary school education level (130, 37.1%), and were worked as housewives (252, 72%) (Table 1).

Table 1

Sociodemographic Characteristics of Mothers Whose Preterm Newborns Were Admitted to the NICU of Comprehensive Specialized Hospitals in Northeastern Ethiopia, 2024 (n = 350)
Variables	Frequency	percent
Age of mothers	Mean age 28 yrs. ±5.6 SD
15–19 yrs.	15	4.3
20–24 yrs.	76	21.7
25–29 yrs.	129	36.9
30–34 yrs.	67	19.1
≥ 35 yrs.	63	18.0
Residence of mothers
Urban	181	51.7
Rural	169	48.3
Mothers Level of education
Illiterate	89	25.4
primary education	61	17.4
Secondary education	130	37.1
Tertiary education	70	20.0
Occupational status
Housewife	252	72.0
Civil servant	51	14.6
Self-employed	47	13.4

Obstetric, labor, and delivery characteristics of the mothers of preterm neonates

The majority of mothers of preterm newborns, 190 (54.3%), were multiparous; 347 (99.1%) had attended antenatal care visits, with 171 (49.3%) having undergone three ANC visits. Furthermore, a significant number of mothers (132, 37.7%) experienced gestational hypertension, which was considered a leading cause of preterm delivery. This was followed by antepartum hemorrhage (APH) in 36 cases (10.3%), placental abnormalities in 14 cases (4%), and gestational diabetes mellitus (GDM) in 5 cases (1.4%). However, only 18 (5.1%) mothers received dexamethasone for lung maturity, indicating a low rate of administration (Supplementary file 3).

The basic characteristics and clinical features observed upon admission of the premature neonates

Most of the premature newborns were male, comprising 176 (50.3%) of the cases, with a mean age of 2 days (± 3.2 SD) at admission. The majority of these infants were from single gestations (236, 67.4%), and 297 (84.9%) were classified as appropriate for gestational age (AGA). Additionally, 171 (48.9%) were considered mid-preterm (32–34 weeks), and 234 (66.9%) had low birth weight (LBW). Upon admission, the majority of premature neonates 198 (56.6%) exhibited a normal breathing rate; 217 (62.0%) experienced desaturation; 220 (62.9%) were diagnosed with respiratory distress syndrome (RDS); 327 (93.4%) were hypothermic; and 269 (76.9%) were alert. Furthermore, 325 (92.9%) were unable to breastfeed; 232 (66.3%) had reduced movement; 227 (64.9%) did not exhibit hypoglycemia; and 225 (64.3%) did not show signs of jaundice (Table 2).

Table 2

Basic and Clinical Features of Preterm Newborns During Admission to the NICU of Comprehensive Specialized Hospitals in Northeastern Ethiopia, 2024 (n = 350)
Variables	Death	Censored
Sex of neonates
Male	81(51.6%)	95(49.2%)
Female	76(48.4%)	98(50.8%)
Newborn age during admission
One day	130(82.8%)	152(78.8%)
2–7 days	24(15.2%)	28(14.6%)
8–28 days	3(2%)	13(6.6%)
Number of pregnancies
Single	104(66.2%)	132(68.4%)
Multiple pregnancies	53(33.8%)	61(31.6%)
Appropriateness for Gestational Age
Appropriate for Gestational Age	130(82.8%)	167(86.5%)
Small for Gestational Age	27(17.2%)	26(13.5%)
Gestational age classifications
Early preterm (28-31Weeks)	48(30.6%)	19(9.8%)
Mid preterm (32-34Weeks)	80(51.0%)	91(47.2%)
late preterm(35-36Weeks)	29(18.5%)	83(43.0%)
Newborn birth weight classifications
Extremely LBW (< 1000 gram)	11(7.0%)	1(0.5%)
very LBW (1000–1499 gram)	60(38.2%)	44(22.8%)
LBW (1500–2499 gram)	86(54.8%)	148(76.7%)
Seizure
Yes	6 (3.8%)	7(3.6%)
No	151(96.2%)	186(96.4%)
Respiratory rate
Normal breathing rate	71(45.2%)	127(65.8%)
Fast breathing rate	83(52.9%)	63(32.6%)
Bradypnea	3(1.9%)	3(1.6%)
Oxygen saturation
< 90%	130(82.8%)	87(45.1%)
≥ 90%	27(17.2%)	106(54.9%)
Had Respiratory Distress Syndrome
Yes	137 (87.3%)	83(43.0%)
No	20(12.7%)	110(57.0%)
Heart rate status
Normal heart rate	100 (63.7%)	156 (80.8%)
Tachycardic	53 (33.8%)	35 (18.1%)
Bradycardic	4 (2.5%)	2 (1.0%)
Body temperature
Normal temperature (36.5-37.5⁰c)	3 (1.9%)	14 (7.3%)
Hypothermia (< 36.5⁰c)	151 (96.2%)	176 (91.2%)
Hyperthermia(> 37.5⁰c)	3 (1.9%)	3 (1.6%)
Had lethargy
Yes	53 (33.8%)	28 (14.5%)
No	104 (66.2%)	165 (85.5%)
Reduced movement
Yes	116 (73.9%)	116 (60.1%)
No	41 (26.1%)	77 (39.9%)
Not able to breastfeed
Yes	151(96.2%)	174(90.2%)
No	6(3.8%)	19(9.8%)
Had hypoglycemia
Yes	66(42.0%)	57(29.5%)
No	91(58.0%)	136(70.5%)
Had jaundice
Yes	50(31.8%)	75(38.9%)
No	107(68.2%)	118(61.1%)

Management and Complications of premature neonates

During hospitalization, the majority of premature infants (266, 76%) received NG tube feeding. Additionally, 274 (78.3%) required respiratory support, with 156 (56.7%) receiving intranasal oxygen (INO2). Phototherapy was administered to 117 (33.4%) infants, while 129 (36.9%) underwent kangaroo mother care (KMC). Three hundred thirty-two infants (94.9%) received antibiotics, primarily ampicillin and gentamicin (327, 98.5%), followed by metronidazole (72, 21.7%). Furthermore, among all hospitalized premature neonates, 318 (90.9%) developed early-onset sepsis, and 73 (20.9%) developed neonatal necrotizing enterocolitis (Table 3).

Table 3

Complications and management of Preterm Newborns Admitted to the NICU of Comprehensive Specialized Hospitals in Northeastern Ethiopia, 2024 (n = 350)
Variables	Death	Censored
Developed sepsis
Yes	150(95.5%)	168(87.0%)
No	7(4.5%)	25(13.0%)
Diagnosed perinatal asphyxia
Yes	11(7.0%)	14(7.3%)
No	146 {93.0)	179(92.7%)
Had congenital anomalies
Yes	18 (11.5%)	7(3.6%)
No	139(88.5%)	186(96.4%)
Developed NEC
Yes	51(32.5%)	22(11.4%)
No	106(67.5%)	171(88.6%)
NG tube feeding
Yes	136(86.6%)	130(67.4%)
No	21(13.4%)	63(32.6%)
Had respiratory support
Yes	153(97.5%)	121(62.7%)
No	4(2.5%)	72(37.3%)
Types of respiratory support
CPAP	66(43.1%)	29 (23.8)
INO2	71(46.4%)	85(69.7%)
Both	16 (10.5%)	8 (6.6%)
Had Phototherapy
Yes	50(31.8%)	67 (34.7%)
No	107(68.2%)	126(65.3%)
Had KMC
Yes	6(3.8%)	123(63.7%)
No	151(96.2%)	70(36.3%)
Had radiant warmer care
Yes	156(99.4%)	179(92.7%)
No	1(0.6%)	14 (7.3%)
Had antibiotics management
Yes	157(100.0%)	175(90.7%)
No	0 (0.0%)	18 (9.3%)
Ampicillin and gentamycin	156(99.4%)	171(97.7%)
Ceftazidime and vancomycin	39(24.8%)	31(17.7%)
Metronidazole	50(31.8%)	22 (12.6%)
Maintenance fluid	154(98.7%)	181(99.5%)
Calcium gluconate	34(21.8%)	23(12.6%)
Potassium chloride (KCl)	11(7.1%)	8 (4.4%)
Had blood transfusion	25(16.0%)	16(8.8%)
Lasix	22(14.1%)	11(6.0%)
Phenobarbitone	5(3.2%)	7 (3.8%)
Aminophylline	23(14.7%)	3 (1.6%)

Treatment outcomes of premature neonates

The mean length of hospitalization was 6 days ± (4.5 SD). Among all premature infants, 157 (44.9%) unfortunately passed away, 184 (52.6%) showed improvement, 1(0.2%) refer to other facility, and 8 (2.3%) left against medical advice (Fig. 1).

Incidence and time to death in premature neonates

The preterm neonatal mortality rate was 72 per 1,000 (95% CI: 62–81) neonates admitted to the intensive care units due to prematurity in the Comprehensive Specialized Hospitals of northeastern Ethiopia, based on a total of 2179 person-days of observation. The median time to death was 10 days (IQR = 7–20 days) (Fig. 2). The cumulative failure rate of premature neonates at the end of the first, third, seventh, fourteenth, twentieth, and twenty-eighth days was 2.62%, 23.81%, 48.39%, 56.29%, 71.75%, and 71.75%, respectively (supplementary file 4).

Time-to-death comparisons across different categorical variables

The median time to death hazard for preterm neonates with NEC was 7 days (95% CI: 6–20), notably shorter than the median of 17 days observed for preterm neonates without NEC (Fig. 3). The median time to death hazard for premature neonates who did not receive KMC was 6 days (95% CI: 5–7), which was shorter than the median time observed for neonates who received KMC (Fig. 4).

Predictors of premature neonatal mortality

In the multivariable Weibull proportional hazard regression, young maternal age (15–19 years), respiratory distress syndrome (RDS), early preterm birth, extremely low and very low birth weight (LBW), multiple pregnancy, congenital anomalies at birth, lack of kangaroo mother care (KMC), development of necrotizing enterocolitis complications, and suboptimal CPAP therapy were predictors of mortality among neonates born prematurely (Table 4).

Table 4

Predictors of preterm neonatal mortality Admitted to the NICU of Comprehensive Specialized Hospitals in Northeastern Ethiopia, 2024 (n = 350)
Variables	Prematurity outcome		CHR (95% CI)	AHR (95% CI)	P-value
Variables	Death	Censored	CHR (95% CI)	AHR (95% CI)	P-value
Maternal age
15–19 years	11	4	1.98(1.04, 3.78) *	2.73(1.3, 5.9) **	.010
20–24 years	33	43	1.13(.73, 1.74)	1.34(.85, 2.1)	.207
25–29 years	57	72	Reference	Reference	Reference
30–34 years	30	37	1.2(.76, 1.84)	1.3(.76, 2.2)	.337
≥ 35 years	26	37	1.02(.64, 1.63)	1.1(.65, 1.77)	.773
Gestational age
Early preterm	48	19	2.5(1.6, 4.02) *	1.8(1.1, 3) **	.027
Mid preterm	80	91	1.6(1.04, 2.44)	1.54(.98, 2.42)	.057
Late preterm	29	83	Reference	Reference	Reference
Number of gestations
Single	104	132	Reference	Reference	Reference
Multiple (≥ 2)	49	61	2.7(1.34, 5.26) *	2.1(1.1, 4.3) **	.033
Weight classification
Extremely & very LBW	71	45	3.9(2.1, 7.3) *	2.4(1.24, 4.6) **	.009
LBW	86	148	Reference	Reference	Reference
RDS
Yes	137	83	1.96(1.2, 3.3) *	2.3(1.34, 3.8) **	.002
No	20	110	Reference	Reference	Reference
Minor Congenital anomalies
Yes	18	7	2.4(1.44, 3.9) *	2.3(1.32, 3.9) **	.003
No	139	186	Reference	Reference	Reference
Diagnosed NEC
Yes	51	22	1.45(1.04, 2.03) *	1.53(1.1, 2.22) **	.023
No	106	171	Reference	Reference	Reference
Types of respiratory support(n = 274)
CPAP	66	29	1.54(1.1, 2.2) *	1.43(1.02, 2.02) **	.043
INO2	71	85	Reference	Reference	Reference
Both	16	8	1.4(.811, 2.43)	1.44(.83, 2.5)	.099
KMC
Yes	6	123	Reference	Reference	Reference
No	151	70	1.8(1.3, 26) *	2.2(1.54, 3.21) **	.000
Stands for statistical significance in bivariable and * for multivariable Weibull proportional hazard regression analysis

During the follow-up period, preterm neonates born to young mothers (aged 15–19 years) had a nearly threefold higher risk of death (95% CI: 1.3–5.9) compared to preterm neonates born to mothers in the 25–29 age group. Similarly, neonates born early preterm had a nearly two-times higher risk of death (95% CI: 1.1–3.02) compared to neonates born late preterm. Similarly, premature neonates born from multiple pregnancies had twice the risk of death (95% CI: 1.1–4.3) compared to premature neonates born from single gestations. Moreover, premature neonates who experienced respiratory distress syndrome (RDS) had 2.3 times higher risk of death (95% CI: 1.34–3.8) compared to those who did not have RDS. Furthermore, premature neonates born with congenital anomalies had twice the risk of death (95% CI: 1.32–3.9) compared to those born without congenital anomalies. Additionally, premature neonates who received sub-optimal CPAP therapy as respiratory support had 1.43 times the risk of death (95% CI: 1.02–2.02) compared to those who received INO2. Lastly, premature neonates who did not receive KMC had approximately twice the risk of death (95% CI: 1.54–3.21) (Table 4).

The current study aimed to determine the incidence and predictors of preterm neonatal mortality among premature neonates in the NICUs of comprehensive specialized hospitals in northeastern Ethiopia. The findings revealed that the preterm neonatal mortality rate was unacceptably high, with 72 per 1,000 preterm neonates admitted to intensive care units. This figure aligns with WHO and Lancet reports for low-income countries [1, 3, 6, 25]. Additionally, the result is comparable to findings from northwest Ethiopia, Mizan-Tepi, and the Bench Sheko zone in southwest Ethiopia, where the incidence ranges from 62 to 75 per 1,000 person-time observations [21, 26, 27]. However, it was higher compared to rates in Pakistan and India, Uganda, the national level in Ethiopia, southern Ethiopia, Debre tabor, Addis Ababa, northern Ethiopia, and northwest Ethiopian hospitals such as Felegehiwot and Debre Markos [11–13, 23, 28–33]. These differences might be due to variations in sample size and the number of facilities involved, as many of the aforementioned studies were conducted at single facilities [23, 28, 30, 33]. Additionally, the level of hospitals and the referral burden might contribute to this difference. The current study was conducted exclusively in comprehensive specialized hospitals, whereas the other studies included a mix of lower and higher-level hospitals [29, 31, 32], where the referral burden and critical preterm newborns admission is much lower compared to the current study. Indeed, socioeconomic disparities play a pivotal role in shaping mortality rates across different countries.

Premature neonates born to young mothers (aged 15–19 years) experience a three-fold higher risk of death compared to preterm neonates born to mothers in the 25–29 age group. This aligns with WHO recommendations, which identify mothers who give birth at less than 18 years or greater than 35 years old as being at high risk for preterm birth and mortality [1, 2]. This suggests that intensive health promotion and behavioral change efforts should focus on enhancing the optimal childbearing age, which ultimately and significantly decreases preterm birth and mortality.

Neonates born with early preterm birth and extremely low or very low birth weight (ELBW or VLBW) had a two-fold higher risk of death compared to late preterm and low birth weight neonates, respectively. This finding is consistent with studies conducted in Iran, Brazil, and Rwanda [34–36]. Studies from Tinkur Anbesa Teaching Hospital in central Ethiopia and the Southwest Ethiopia region support this finding [9, 27]. This might be explained by the fact that premature babies have a high body surface area to body weight ratio, low levels of brown fat, and the immaturity of their vital organs, making them prone to various health issues, including RDS, sepsis, NEC, hypoglycemia, and hypothermia [17, 37]. Consequently, this results in higher rates of death.

Premature neonates with RDS had twice the higher risk of death compared to those without RDS. This finding is consistent with studies conducted in Pakistan, India, Iran, Brazil, Uganda, Rwanda, and Ethiopia [29–31, 34–36]. The primary cause of RDS is surfactant insufficiency related to prematurity and lung immaturity [1, 17]. Once preterm babies acquire RDS, they may be at risk of pulmonary hemorrhage, cerebral palsy, susceptibility to infection, and ultimately, multi-organ damage, accelerating their time-to-death threefold [1, 17]. Therefore, early detection and management of pregnancy-related medical complications, administration of ANC corticosteroids, and improvement in optimal oxygen support services are crucial to reduce neonatal deaths related to RDS.

Premature neonates who developed NEC in this study had roughly twice the risk of death compared to those without NEC development. This finding was consistent with studies conducted in China [38] and Ethiopia [31]. Risk factors for NEC development include the lack of ANC corticosteroid administration, non-adherence to standard enteral feeding protocols such as formula feeding, and other factors like PROM, birth asphyxia, and sepsis [17, 21, 37, 39]. Subsequently, NEC can lead to complications such as DIC, intraventricular hemorrhage, and severe sepsis, resulting in early neonatal deaths [17, 37]. This implies the need for significant improvement in NEC prevention through the administration of ANC corticosteroids and adherence to standard feeding practices.

Preterm neonates treated with sub-optimal CPAP therapy had roughly twice the higher risk of death than those treated with INO2 in the current study. This result aligns with findings from studies conducted in Pakistan, India, Uganda [29, 30], and in public hospitals in northeastern Ethiopia [39]. The possible explanation in our context could be sub-optimal CPAP therapy, such as resource limitations and the use of locally made CPAP equipment, often constructed from cut water container plastic. During routine care operations, these items may become contaminated, inadvertently exposing newborns to sepsis and ultimately shortening their time to death. This implies that sub-optimal CPAP therapy needs improvement through better resource allocation, either by enhancing local technologies or ensuring an adequate supply of CPAP devices and accessories to meet the needs of the NICU.

In the current study, premature neonates who did not receive KMC had twice the risk of death compared to those who received KMC. These results are consistent with findings from Pakistan, India, Uganda, and public hospitals in Addis Ababa, Ethiopia [11, 29, 30]. The possible explanation is that KMC encourages early breastfeeding and exposes the baby to the mother's protective microbiome, reducing the risk of infections, particularly necrotizing enterocolitis [17]. Furthermore, KMC decreases the incidence of respiratory distress syndrome (RDS), hypothermia, and hypoglycemia [17, 37]. Without KMC, premature newborns are more likely to die due to the aforementioned complications [17]. This implies that enhancing KMC practices is crucial for reducing neonatal mortality.

Strength and limitation of the study

The authors employed a prospective follow-up study design, using a multi-center approach with extensive geographical coverage to ensure representative data. However, diagnostic subjectivity, the possibility of medical record errors, and service-related factors besides CPAP therapy as predictors of mortality were not controlled.

Conclusion and recommendations

In the current study, the incidence of preterm neonatal mortality significantly exceeds the national average and is unacceptably high, necessitating immediate intervention. Factors contributing to this high mortality rate include young maternal age (15–19 years), respiratory distress syndrome (RDS), early preterm birth, extremely low and very low birth weight, multiple gestations, minor congenital anomalies at birth, lack of kangaroo mother care (KMC), development of necrotizing enterocolitis, and sub-optimal CPAP therapy. This highlights the urgent need to optimize childbearing age and enhance the clinical competence of NICU staff in managing prematurity. This includes ensuring optimal CPAP therapy, kangaroo mother care (KMC), and necrotizing enterocolitis (NEC) management through on-site continuous professional development (CPD) training and mentorship. Additionally, the practice of administering antenatal corticosteroids must be significantly improved to reduce preterm neonatal deaths related to respiratory distress syndrome (RDS) and NEC.

AHR, Adjusted Hazard Ratio; CHR, Crude Hazard Ratio; CPAP, continuous positive airway pressure; ELBW, extremely low birth weight; KMC, kangaroo mother care; NEC, necrotizing enterocolitis; RDS, respiratory distress syndrome.

Ethical Approval and Consent to Participate

Consent for publication

Not applicable

Availability of data and materials

All data generated or analyzed during this study are included in this manuscript and its Supplementary Information files.

Competing interests

The authors declare that there are no conflicts of interest.

Funding

There is no financial funding available for this study, except for administrative support from Wollo University.

Author’s contribution

All authors contributed to the preparation of the manuscript. TAB conceived and designed the research, performed the analysis, and SMT and YSE served as an advisor in proposal and thesis writing. EBW, FSB, MAW, and YAY prepared the initial draft of the manuscript, while MAB revised the final drafts. All authors reviewed and approved the final manuscript for publication.

Acknowledgments

The authors express gratitude to the Dessie, Woldiya, and Debrebrehan Comprehensive specialized hospitals for their support. We also extend our appreciation to the study participants, data collectors, and supervisors for generously contributing their time and information to this study.

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Incidence and Predictors of Mortality Among Preterm Neonates Admitted to Neonatal Intensive Care Units in Comprehensive Specialized Hospitals in Northeast Ethiopia: A Multi-Center Prospective Follow-Up Study

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Abstract

Background

Methods

Result

Conclusion

Figures

Introduction

Materials and Methods

Study design, period, and setting

Study population

Eligibility criteria

Sample size determination

Sampling techniques and procedures

Outcome variables

Independent variables

Operational definitions

Data collection method and procedure

Data analysis

Results

Sociodemographic characteristics

Obstetric, labor, and delivery characteristics of the mothers of preterm neonates

The basic characteristics and clinical features observed upon admission of the premature neonates

Management and Complications of premature neonates

Treatment outcomes of premature neonates

Incidence and time to death in premature neonates

Time-to-death comparisons across different categorical variables

Predictors of premature neonatal mortality

Discussion

Strength and limitation of the study

Conclusion and recommendations

Abbreviations

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References

Additional Declarations

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