A Prospective Study of Causes of Illness and Death in Preterm Infants in Ethiopia: The SIP Study Protocol.

BACKGROUND: With nearly 15 million annual preterm births globally, preterm birth is the most common cause of neonatal death. Forty to 60 % of neonatal deaths are directly or indirectly associated with preterm mortality. As countries aim to meet the Sustainable Development Goals to reduce neonatal mortality, significant reductions in preterm mortality are needed. This study aims to identify the common causes of preterm illness and their contribution to preterm mortality in low-resource settings. This article will describe the methods used to undertake the study. METHODS: This is a prospective, multi-centre, descriptive clinical study. Socio-demographic, obstetric, and maternal factors, and clinical and laboratory findings will be documented. The major causes of preterm mortality will be identified using clinical, laboratory, imaging, and autopsy methods and use the national Ethiopian guidelines on management of preterm infants including required investigations to reach final diagnoses. The study will document the clinical and management protocols followed in these settings. The approach consists of clinical examinations and monitoring, laboratory investigations, and determination of primary and contributory causes of mortality through both clinical means and by post-mortem examinations. An independent panel of experts will validate the primary and contributory causes of mortality. To obtain the estimated sample size of 5000 preterm births, the study will be undertaken in five hospitals in three regions of Ethiopia, which are geographically distributed across the country. All preterm infants who are either born or transferred to these hospitals will be eligible for the study. Three methods (last menstrual period, physical examination using the New Ballard Score, and ultrasound) will be used to determine gestational age. All clinical procedures will be conducted per hospital protocol and informed consent will be taken from parents or caretakers prior to their participation in the study as well as for autopsy if the infant dies. DISCUSSION: This study will determine the major causes of death and illness among hospitalized preterm infants in a low-resource setting. The result will inform policy makers and implementers of areas that can be prioritized in order to contribute to a significant reduction in neonatal mortality.

Antenatal Steroid Utilization in Ethiopia.

Background. Administration of antenatal corticosteroids to pregnant mothers is one of the most effective interventions to decrease preterm neonatal mortality. In this study we assessed antenatal steroid utilization by the mother and its effect on preterm babies. Method. Two years prospective, multicenter, observational study was conducted in selected hospitals of Ethiopia. Significance of the study outcomes was tested by chi-square and binary logistic regression. Result. Out of 4919 participants, 1575 preterm babies whose gestational ages were below 35 weeks were included in the study. Use of antenatal dexamethasone was 37.5% among study participants. The risk of early onset neonatal sepsis 235 (40.4%) was higher in preterm babies whose mother took antenatal dexamethasone (P-value .002) than those who did not. Conclusion. Antenatal dexamethasone use in our study was comparable with other low and middle-income countries. Risk of early onset neonatal sepsis was higher among infants whose mother took antenatal dexamethasone.

Incidence and associated factors of extrauterine growth restriction (EUGR) in preterm infants, a cross-sectional study in selected NICUs in Ethiopia.

BACKGROUND: Preterm infants have high risk of developing growth restriction and long-term complications. Enteral feeding is often delayed in neonatal intensive care units (NICUs) for the fear of feeding intolerance and the associated necrotising enterocolitis, and recent advances in nutritional support are unavailable in low-income countries. OBJECTIVE: The aim of this study was to assess the incidence and associated factors of extrauterine growth restriction (EUGR) among preterm infants in selected NICUs in Ethiopia. METHOD: This was a cross-sectional study involving a subgroup analysis of preterm infants admitted to hospitals, from a multicentre descriptive study of cause of illness and death in preterm infants in Ethiopia, conducted from 2016 to 2018. EUGR was defined as weight at discharge Z-scores <-1.29 for corrected age. Clinical profiles of the infants were analysed for associated factors. SPSS V.23 software was used for analysis with a significance level of 5% and 95% CI. RESULT: From 436 preterm infants included in the analysis, 223 (51%) were male, 224 (51.4%) very low birth weight (VLBW) and 185 (42.4%) small for gestational age (SGA). The mean (SD) of weight for corrected age Z-score at the time of discharge was -2.5 (1.1). The incidence of EUGR was 86.2%. Infants who were SGA, VLBW and longer hospital stay over 21 days had increased risk of growth restriction (p-value<0.01). SGA infants had a 15-fold higher risk of developing EUGR at the time of discharge from hospital than those who were appropriate or large for gestational age (OR (95% CI)=15.2 (4.6 to 50.1). CONCLUSION: The majority of the infants had EUGR at the time of discharge from the hospital, which indicates suboptimal nutrition. Revision of national guidelines for preterm infants feeding and improvement in clinical practice is highly required.

Factors Associated with the Death of Preterm Babies Admitted to Neonatal Intensive Care Units in Ethiopia: A Prospective, Cross-sectional, and Observational Study.

Aim. To determine the risk factors for death among preterm neonates. Methods and materials. The data set used was derived from a prospective, multi-center, observational clinical study conducted in 5 tertiary hospitals in Ethiopia from July, 2016 to May, 2018. Subjects were infants admitted into neonatal intensive care unit. Results. Risk factors were determined using statistical model developed for this study. The mean gestational age was 32.87 (SD ± 2.42) weeks with a range of 20 to 36 weeks. There were 2667 (70.69%) survivors and 1106 (29.31%) deaths. The significant risk factors for preterm death were low gestational age, low birth weight, being female, feeding problem, no antenatal care visits and vaginal delivery among mothers with higher educational level. Conclusions. The study identified several risk factors for death among preterm neonates. Most of the risk factors are preventable. Thus, it is important to address neonatal and maternal factors identified in this study through appropriate ANC and optimum infant medical care and feeding practices to decrease the high rate of preterm death.

Disparity in Birth Size of Ethiopian Preterm Infants in Comparison to International INTERGROWTH-21st Data.

Background. Patterns of fetal growth are largely influenced by environmental, nutritional, and socioeconomic factors more than differences in populations. The aim of this study was to assess anthropometric measurements of Ethiopian preterm infants at birth and compare the results with the international INTERGROWTH-21st data. Patients and methods. We analyzed anthropometric data on live-born singleton preterm infants enrolled in a hospital-based multicenter study of illness in preterm infants (SIP). Eligible newborns with gestational age of 28-36 weeks were included. Gestational age (GA) and sex-specific mean and standard deviations (SD), 10th, 50th, 90th, centile values for birth weight, length and head circumference (HC) were calculated and compared with INTERGROWTH-21st data. Result. A total of 2763 preterm infants were included in the study, 54% were male. The prevalence of small for GA (SGA) (<10th percentile) and large for GA (LGA) (>90th percentile) were 10.8% and 9.9%, respectively. In all 3 parameters, the mean values of boys were higher than of girls. Birth weight centiles were comparable to international averages at lower GA, then after GA of 32 weeks the 10th, 50th, and 90th centile values were 100-500 g less than the international averages. The head circumference centiles were mostly comparable, and the 90th centile values were greater than the international averages across the GA and in both sexes. Conclusion. The infants' birth weights were smaller at higher GA, which may indicate maternal undernutrition in the third trimester of pregnancy. Strengthening antenatal nutrition counseling and providing nutrition supplementation might improve the birth weight.

Comparison of neonatal outcomes of small for gestational age and appropriate for gestational age preterm infants born at 28-36 weeks of gestation: a multicentre study in Ethiopia.

PURPOSE: The aim of this study was to assess morbidity and mortality pattern of small for gestational age (SGA) preterm infants in comparison to appropriate for gestational age (AGA) preterm infants of similar gestational age. METHOD: We compared neonatal outcomes of 1336, 1:1 matched, singleton SGA and AGA preterm infants based on their gestational age using data from the study 'Causes of Illness and Death of Preterm Infants in Ethiopia (SIP)'. Data were analysed using SPSS V.23. ORs and 95% CIs and χ2 tests were done, p value of <0.05 was considered statistically significant. RESULT: The majority of the infants (1194, 89%) were moderate to late preterm (32-36 weeks of gestation), 763 (57%) were females. Male preterm infants had higher risk of being SGA than female infants (p<0.001). SGA infants had increased risk of hypoglycaemic (OR and 95% CI 1.6 (1.2 to 2.0), necrotising enterocolitis (NEC) 2.3 (1.2 to 4.1), polycythaemia 3.0 (1.6 to 5.4), late-onset neonatal sepsis (LOS) 3.6 (1.1 to 10.9)) and prolonged hospitalisation 2.9 (2.0 to 4.2). The rates of respiratory distress syndrome (RDS), apnoea and mortality were similar in the SGA and AGA groups. CONCLUSION: Neonatal complications such as hypoglycaemic, NEC, LOS, polycythaemia and prolonged hospitalisation are more common in SGA infants, while rates of RDS and mortality are similar in SGA and AGA groups. Early recognition of SGA status, high index of suspicion and screening for complications associated and timely intervention to prevent complications need due consideration.

Hematologic Profiles of Ethiopian Preterm Infants With Clinical Diagnoses of Early-Onset Sepsis, Perinatal Asphyxia, and Respiratory Distress Syndrome.

Objective. To determine the hematologic profile of preterm infants with regard to different diseases. Methods. A prospective, cross-sectional, observational study, conducted in 5 hospitals in Ethiopia from July 2016 to May 2018. Preterm babies <7 days of age were included and investigated with complete blood counts (CBC) and other investigations, accordingly. Results. Out of 4919 preterms, 3852 (78.3%) were admitted to a newborn intensive care unit, and of these, 68.3% had a CBC performed. The mean values of hemoglobin, white blood cell (WBC) and platelet counts were 17.9 mg/dL; 12 685 cells/mm3, and 159 340 cells/mm3, respectively. Early onset neonatal sepsis (EONS) 1433 (37%), asphyxia 266 (6.9%), and respiratory distress syndrome (RDS) 1738 (45.3%) were common reasons for admission. The WBC count was <5000 cells/mm3 for 8.8%, 9.0%, and 11.1% of neonates with EONS, asphyxia and RDS, respectively. The hemoglobin value was <7 mg/dL for 0.6%, 1.7%, and 0.4% of preterm infants with EONS, asphyxia, and RDS, respectively. The platelet count was <50 000 cells/mm3 for 16.8%, 17.7%, and 19.8% of preterms admitted with a diagnosis of EONS, asphyxia, and RDS, respectively. Conclusion. WBC and platelet counts were the most common to be associated with EONS, asphyxia, and RDS. Further study is recommended to determine the effect of abnormal hematologic profile on the outcome of preterm babies.

Hyperbilirubinemia in Preterm Infants Admitted to Neonatal Intensive Care Units in Ethiopia.

Background. Hyperbilirubinemia is prevalent and protracted in preterm infants. This study assessed the pattern of hyperbilirubinemia in preterm infants in Ethiopia. Methods. This study was part of multi-centered prospective, cross-sectional, observational study that determined causes of death among preterm infants. Jaundice was first identified based on clinical visual assessment. Venous blood was then sent for total and direct serum bilirubin level measurements. For this study, a total serum bilirubin level ≥5 mg/dL was taken as the cutoff point to diagnose hyperbilirubinemia. Based on the bilirubin level and clinical findings, the final diagnoses of hyperbilirubinemia and associated complications were made by the physician. Result. A total of 4919 preterm infants were enrolled into the overall study, and 3852 were admitted to one of the study's newborn intensive care units. Of these, 1779 (46.2%) infants were diagnosed with hyperbilirubinemia. Ten of these (0.6%) developed acute bilirubin encephalopathy. The prevalence of hyperbilirubinemia was 66.7% among the infants who were less than 28 weeks of gestation who survived. Rh incompatibility (P = .002), ABO incompatibility (P = .0001), and sepsis (P = .0001) were significantly associated with hyperbilirubinemia. Perinatal asphyxia (P-value = 0.0001) was negatively associated with hyperbilirubinemia. Conclusion. The prevalence of hyperbilirubinemia in preterm babies admitted to neonatal care units in Ethiopia was high. The major risk factors associated with hyperbilirubinemia in preterm babies in this study were found to be ABO incompatibility, sepsis, and Rh isoimmunization.

Hypothermia in Preterm Newborns: Impact on Survival.

Background. Globally, prematurity is the leading cause of neonatal mortality, and hypothermia is one of its contributing factors. The goal of this study was to determine the association between hypothermia and mortality. Methods. A prospective, multi-center, descriptive clinical study was conducted in 5 hospitals in Ethiopia. Axillary temperatures were taken at the time of admission to the newborn intensive care units (NICU) and followed during the NICU stay. Results. A total of 3852 premature neonates (<37 weeks) were admitted to the NICUs from July 2016 to May 2018. Of these infants, 1109 (28.8%) died and 2991 (79.6%) had hypothermia. Hypothermia was associated with perinatal asphyxia (89.5%), RDS (86.2%), and resuscitation at birth (82.7%). Admission temperatures in preterm newborns were inversely associated with mortality and morbidity. Conclusion. Hypothermia at admission is associated with neonatal mortality in premature neonates in Ethiopia. RDS and perinatal asphyxia were the main factors associated with hypothermia. The very high prevalence and association with mortality warrants quality improvement interventions.

Preterm Nutrition and Clinical Outcomes.

Background. In low-income countries, preterm nutrition is often inadequately addressed. The aim of the study was to assess the patterns of feeding and associated clinical outcomes of preterm neonates admitted to neonatal intensive care units in Ethiopia. Method. This was a multicenter, prospective study. Infants' clinical characteristics at birth, daily monitoring of feeding history, and weight measurements were collected. An outcome assessment was completed at 28 days. Result. For this analysis, 2560 infants (53% male) were eligible. The mean (SD) gestational age was 33.1 (2.2) weeks. During the hospital stay the proportion of infants on breast milk only, preterm formula, term formula, and mixed feeding was 58%, 27.4%, 1.6%, and 34.1%, respectively. Delay in enteral feeding was associated with increased risk of death (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.33-2.78; P < .001) and (OR = 5.06, 95% CI = 3.23-7.87; P < .001) for 1 to 3 and 4 to 6 days of delay in enteral feeding, respectively, after adjusting for possible confounders. The length of delay in enteral feeding was associated with increased risk of hypoglycemia (OR = 1.2, 95% CI = 1.1-1.2; P = .005). The mortality rate was lower in hospitals providing preterm formula more often (P = .04). Half of the infants continued losing weight at the time of discharge. Conclusion. Delayed enteral feeding significantly increases the risk of mortality before discharge and hypoglycemia in preterm infants in resource-limited settings. Ensuring adequate nutritional support of preterm infants is highly needed.

Major causes of death in preterm infants in selected hospitals in Ethiopia (SIP): a prospective, cross-sectional, observational study.

BACKGROUND: Neonatal deaths now account for 47% of all deaths in children younger than 5 years globally. More than a third of newborn deaths are due to preterm birth complications, which is the leading cause of death. Understanding the causes and factors contributing to neonatal deaths is needed to identify interventions that will reduce mortality. We aimed to establish the major causes of preterm mortality in preterm infants in the first 28 days of life in Ethiopia. METHODS: We did a prospective, cross-sectional, observational study in five hospitals in Ethiopia. Study participants were preterm infants born in the study hospitals at younger than 37 gestational weeks. Infants whose gestational age could not be reliably estimated and those born as a result of induced abortion were excluded from the study. Data were collected on maternal and obstetric history, clinical maternal and neonatal conditions, and laboratory investigations. For neonates who died of those enrolled, consent was requested from parents for post-mortem examinations (both complete diagnostic autopsy and minimally invasive tissue sampling). An independent panel of experts established the primary and contributory causes of preterm mortality with available data. FINDINGS: Between July 1, 2016, to May 31, 2018, 4919 preterm infants were enrolled in the study and 3852 were admitted to neonatal intensive care units. By 28 days of post-natal age, 1109 (29%) of those admitted to the neonatal intensive care unit died. Complete diagnostic autopsy was done in 441 (40%) and minimally invasive tissue sampling in 126 (11%) of the neonatal intensive care unit deaths. The main primary causes of death in the 1109 infants were established as respiratory distress syndrome (502 [45%]); sepsis, pneumonia and meningitis (combined as neonatal infections; 331 [30%]), and asphyxia (151 [14%]). Hypothermia was the most common contributory cause of preterm mortality (770 [69%]). The highest mortality occurred in infants younger than 28 weeks of gestation (89 [86%] of 104), followed by infants aged 28-31 weeks (512 [54%] of 952), 32-34 weeks (349 [18%] of 1975), and 35-36 weeks (159 [8%] of 1888). INTERPRETATION: Three conditions accounted for 89% of all deaths among preterm infants in Ethiopia. Scale-up interventions are needed to prevent or treat these conditions. Further research is required to develop effective and affordable interventions to prevent and treat the major causes of preterm death. FUNDING: Bill & Melinda Gates Foundation.