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. The Study of Illness in Preterms (SIP) was a prospective, multicentre, cross-sectional, observational clinical study done in five hospitals in Ethiopia. The study participants were preterm infants born at or referred within 7 days to the following five hospitals: in northwestern Ethiopia (Gondar University Hospital), in southwestern Ethiopia (Jimma University Hospital), and three hospitals in Addis Ababa (Ghandi Memorial Hospital, St Paul’s Hospital Millennium Medical College, and Tikur Anbessa Hospital). A map of Ethiopia showing the study regions is included in the appendix. All preterm, liveborn infants who were admitted to one of the study hospitals with an estimated gestational age of younger than 37 weeks were screened. The study hospital staff recruited preterm infants who were alive without any lower gestational age limit. Inclusion criteria were as follows: infant born at or transferred to one of the participating study hospitals; gestational age of younger than 37 weeks according to the algorithm using the three methods: ultrasound before 28 weeks of gestation, mother’s report of last menstrual period, and the New Ballard score completed before 7 days of postnatal age; liveborn defined as infant with crying, breathing, or movement after delivery or Apgar of 1 or greater; infant age younger than 7 days at the time of screening; and parental consent given for study participation. Participants were excluded if delivery was a result of an induced abortion or gestational age could not be reliably established using the study criteria. All eligible, liveborn babies were enrolled into the study. Infants who met the criteria were admitted regardless of whether the baby died before admission to the neonatal intensive care unit (NICU) or was discharged home without admission. The study was approved by the institutional review board of each hospital and at the College of Health Sciences of the Addis Ababa University. Written consent for participation in the study was obtained from the parent or legal guardian, with a separate written consent for complete diagnostic autopsy and minimally invasive tissue sampling (MITS), in cases of death. Consent was obtained in English, Amharic, or Oromiffa languages, as appropriate. Confidentiality of the information was maintained. All clinical procedures were done per hospital protocol. An informed consent form was developed for caretakers to read (or be read to them) so that the participants understood the implications of the research. For preterm infants who died, parents or caretakers were asked to complete a separate consent for post-mortem examinations of the whole body or samples of relevant tissue or fluids. The post-mortem examination could be complete diagnostic autopsy or MITS needle biopsy (or both) depending on the consent of parents or caretakers. Details of the protocol for the SIP study have been published elsewhere.14 Data were collected on maternal socioeconomic status, maternal and obstetric history, infant clinical conditions, imaging assessment, and microbiology of blood and cerebrospinal fluid specimens using predefined case report forms. Post-mortem examinations (both complete diagnostic autopsy and MITS) were done with additional consent from the parent or legal guardian. Following additional training, the MITS process was introduced in the second half of the study period. The clinical management of recruited patients followed the national guidelines developed by the Federal Ministry of Health of Ethiopia.15 To establish cause of death for each case, a panel consisting of international and national experts in neonatology, obstetrics, and pathology (including RP, SD, RLG, and HB) met face to face every 6 months and reviewed the deaths. For each death, the available clinical, laboratory, MITS, and autopsy data, including the sequence of clinical events during the infant’s hospital stay, were available to panellists to establish the primary and contributory fetal or neonatal and maternal causes of mortality using a protocol.14 The panel was divided into pairs comprising an Ethiopian and international clinician; each pair established cause of death for a set of cases. Criteria were prospectively defined for the primary cause of death and prioritisation when more than one possible cause was present.16 The panel assigned the primary cause of death using ICD-10.12 The primary or underlying cause of death is the “disease or injury that initiated the train of events leading directly to death, or circumstances of accident or violence which produced the fatal injury”, unlike the immediate cause of death, which was defined as “the disease or complication which directly preceded or directly led to death”. If the two panel members were unable to reach consensus, the case was presented to the full expert panel for adjudication. If insufficient or conflicting information was present, the panel could decide that the cause could not be established with the available data. In addition to the primary fetal or neonatal cause of death, the panel also identified one or more neonatal and maternal conditions that contributed to each death. Gestational age was established using a hierarchy of three methods: ultrasound before 28 weeks of gestation when available, mother’s report of last menstrual period when judged reliable, and the New Ballard Score completed at younger than 7 days of age.13 The so-called best gestational age, which was used for the study purposes to document whether the infant met the criteria of preterm (<37 weeks gestation at delivery) was calculated using the hierarchy: (1) ultrasound at younger than 28 weeks of gestation; (2) ultrasound at more than 28 weeks of gestation with agreement of a reliable last menstrual period or New Ballard Score; (3) reliable last menstrual period and New Ballard Score; (4) if discrepancy between last menstrual period and New Ballard Score was greater than 2 weeks, the last menstrual period date was used; and (5) if no ultrasound and last menstrual period estimate was not reliable, New Ballard Score was used.13 If the infant was more than 37 weeks or if the gestational age could not be established with these methods, the infant was excluded from the study. For follow-up of recruited infants, all hospitalised infants were assessed daily using a standardised tool and those at home were monitored once a week, either through a face-to-face meeting or by telephone. The research nurses and doctors underwent initial training on the case report forms, and their skills were reinforced every 3 months and with on-the-spot assessments. Each hospital team held once a week meetings to discuss and resolve challenges. In the study hospital NICU, infants were evaluated once to twice per day by a research nurse who documented the findings on case report forms. A supervisor monitored the collection of data and biospecimen for laboratory evaluation. Relevant laboratory, radiology, and pathology personnel were informed about the samples sent. Visits to each hospital were done regularly by the investigators to check data quality and provide support as necessary. At each hospital, data were entered twice by different data clerks into study computers using the data management system developed for this study to control for errors. Data were transferred on a regular basis from each hospital's data management computer to the data centre at Addis Ababa University (Addis Ababa, Ethiopia), creating a complete data repository. Data were merged into one master dataset for analysis. Frequency of the findings from complete diagnostic autopsy and MITS was computed with 95% CIs using beta distribution to account for the finite population size.17 The sample size was calculated on the basis of the sample size for comparing proportions of causes of death. Assuming 20% of preterm deaths are due to one of the likely causes of preterm mortality, with a 4% precision and 95% level of confidence, 384 preterm deaths with confirmed cause of mortality were needed. Assuming attrition of 10–20%, and that 50% of participants would refuse to consent to post-mortem examinations, we estimated that between 770 and 960 preterm deaths (mean of 865) were required. With a case fatality rate of preterm admissions of 20%, we estimated that 4325 preterm admissions were required during the study period. Descriptive statistics were done using Stata version 14.2 (2017 package). The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.