Stillbirth Clinical Trial
Official title:
Project to Understand & Research Preterm Pregnancy Outcomes-South Asia (PURPOSe)
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.
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