Preterm birth is a major cause of child mortality and morbidity, most of which occurs in south-east Asia and sub-Saharan Africa. To date few neonatal cause of death studies, especially in low- and middle-income countries have determined the specific causes of preterm death, instead attributing all neonatal deaths of infants born at less than 37 weeks to prematurity. Infections are responsible for a large proportion of these deaths but because of complexity and costs associated with testing, little is known about the prevalence of infection-related deaths in preterm infants or the specific pathogens associated with mortality.

The primary objective of this study is to determine the cause of deaths among preterm births and stillbirths. Secondary outcomes include determining the specific pathogens responsible for infection-related deaths, potential preventability of these deaths and interventions which may reduce mortality. One site in India and one in Pakistan will include a total sample size of 700 (350 stillbirths and 350 preterm neonatal deaths) for 1,400 cases to be included in the cause of death analyses. All women who deliver a preterm birth or a stillbirth at the study hospitals will be eligible for inclusion. Among those who consent, an obstetric history, clinical obstetric and (if applicable) neonatal care will be collected as well as research investigations including ultrasound, x-ray, microbiology and minimally invasive tissue sampling and autopsy will be collected.

This study will align with other efforts to determine cause of death among infants and children and ultimately the results will inform future interventions to reduce neonatal mortality and stillbirth. The researchers emphasize that this study, with its focus on preterm neonatal mortality and stillbirth, will provide information not available elsewhere.

Neonatal mortality is common in South Asia and sub-Saharan Africa with rates as high as 40 to 50 per 1,000 live births in some countries compared to rates as low as 2 per 1,000 live births in Scandinavia. Worldwide, at least 2.6 million neonatal deaths occur annually, with more than one-third attributed directly to preterm birth. Globally, the risk of death from preterm birth is highest in south Asia and sub-Saharan Africa. Although the mortality rates are often higher in Africa, numerically, more infants die in south Asia. Preterm neonates die from prematurity-related complications such as respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH), and conditions not specifically caused by prematurity such as asphyxia, infection, and congenital anomalies. However, few cause of death studies-especially in low-resource settings in low and middle-income countries (LMIC)-have determined the specific causes of preterm death, instead attributing all neonatal deaths of infants <37 weeks to prematurity. Furthermore, little is known about the causes of death among stillbirths in preterm births in LMIC and especially the specific types of infections associated with stillbirth.

One of the important goals of international organizations is to reduce neonatal mortality in LMIC, with recent efforts highlighting the importance of reducing neonatal mortality in preterm infants. One impeding factor is lack of knowledge about the medical conditions that cause neonatal mortality in preterm infants and the circumstances under which these babies die. It is crucial not only to know the major medical, infectious and pathological causes, but also the sequence of events that led to the death. Answers to these questions are important not only to understand the cause of death in preterm infants, but also to propose effective treatments to reduce the neonatal deaths in live-born preterm infants.

Less is known about the causes of stillbirth than neonatal mortality in LMIC and Asia specifically. Stillbirth rates are also highest in south Asia and sub-Saharan Africa, with rates as high as 40-50/1,000 births compared to 2-3/1,000 in Scandinavia. The highest reported rates of stillbirth occur in Pakistan. In most countries, the stillbirth rates are equivalent to or greater than the neonatal mortality rates with about 3 million third trimester stillbirths occurring yearly. In high-income countries (HIC), 50% of the stillbirths occur prior to 28 weeks and fully 80% occur prior to term. The percent of stillbirths occurring in the preterm period in LMIC is unknown, but probably lower than the HIC rate of 80%, likely in the range of 50%. Thus, the researchers estimate that most the perinatal mortality in LMIC occurs in infants born preterm.

Stillbirths are caused by a variety of maternal and fetal conditions, including placental abruption, obstructed labor, preeclampsia, placental malfunction, infection, congenital anomalies and cord complications, conditions that also contribute to neonatal mortality. The distribution of these causes and the sequence of events leading to the stillbirth in LMIC are generally unknown. One study suggests that when assessing preterm birth, the true picture of preterm birth may be obscured if stillbirth is excluded. In this cross-sectional study of 29 countries, researchers found that inclusion of stillbirths substantially increased the preterm birth rate in all countries. The degree of change was particularly large in LMIC, with the preterm birth rate increasing by 18% when stillbirths were included. Thus, because of the substantial overlap in etiology between preterm neonatal deaths and preterm stillbirths, and the large contribution of stillbirths to the preterm birth rate, the researchers believe that it would be appropriate to evaluate cause of death in all preterm deaths whether live- or stillborn.

For both neonatal deaths and stillbirths, infectious causes of death are often not identified and have largely been under-reported in low-resource settings where both logistics and technology may limit investigations into infections. From a literature review of epidemiological studies and case reports, the list of pathogens potentially causing a stillbirth or neonatal death likely extends to over 100 organisms. Since the identification of pathogens responsible for fetal or neonatal death may not be obtained from blood cultures alone, the identification process becomes more complicated with testing required of specific tissues such as the placenta, and fetal or neonatal organs, often with molecular assays.

In many areas in Asia, most deliveries now occur in health facilities. Despite the dramatic increase in hospital deliveries in the last decade in this region, little reduction in neonatal mortality or stillbirth has been realized. Thus, the Asian study will augment other efforts through examination of the specific causes of preterm neonatal deaths in Asia, and expand understanding of the contribution of preterm birth to perinatal mortality through inclusion of stillbirths. Determining the main causes and risk factors for perinatal mortality will ultimately inform potential strategies to reduce the high neonatal mortality and stillbirth rates currently seen in south Asia. This is a prospective, observational study aimed to better understand causes of stillbirths and neonatal deaths among preterm livebirths in Karachi, Pakistan, and Davengere, India.

Inclusion Criteria:

• Women in labor and delivery with imminent preterm delivery and/or stillbirth

Exclusion Criteria:

• Induced (medical) abortion
• Unable to determine the gestational age at delivery
• Gestational age < 20 weeks at delivery

The study will be conducted at hospitals identified in Karachi, Pakistan and in Davangere, India. All women who deliver a stillbirth and/or who deliver preterm at a study hospital will be screened for study eligibility.