Identification of factors associated with stillbirth in the Indian state of Bihar using verbal autopsy: A population-based study

<div><p>Background</p><p>India was estimated to have the largest numbers of stillbirths globally in 2015, and the Indian government has adopted a target of <10 stillbirths per 1,000 births by 2030 through the India Newborn Action Plan (INAP). The objective of this study was to use verbal autopsy interviews to examine factors associated with stillbirth in the Indian state of Bihar and make recommendations for the INAP to better inform the setting of priorities and actions to reduce stillbirths.</p><p>Methods and findings</p><p>Verbal autopsy interviews were conducted for deaths including stillbirths that occurred from January 2011 to March 2014 in a sample of 109,689 households (87.1% participation) in 1,017 clusters representative of the state of Bihar. The Population Health Metrics Research Consortium shortened verbal autopsy questionnaire was used for each interview, and cause of death was assigned using the SmartVA automated algorithm. A stillbirth was defined as a foetal death with a gestation period of ≥28 weeks wherein the foetus did not show any sign of life. We report on the stillbirth epidemiology and present case studies from the qualitative data on the health provider interface that can be used to improve success of improved, skilled care at birth and delivery interventions. The annualised stillbirth incidence was 21.2 (95% CI 19.7 to 22.6) per 1,000 births, with it being higher in the rural areas. A total of 1,132 stillbirths were identified; 686 (62.2%) were boys, 327 (29.7%) were firstborn, and 760 (68.9%) were delivered at a health facility. Of all the stillbirths, 54.5% were estimated to be antepartum. Only 6,161 (55.9%) of the women reported at least 1 antenatal care visit, and 33% of the women reported not consuming the iron folic acid tablets during pregnancy. Significant differences were seen in delivery-related variables and associated maternal conditions based on the place of delivery and type of stillbirth. Only 6.1% of the women reported having undergone a test to rule out syphilis. For 34.2% of the stillbirths, the possible risk factor for stillbirth was unexplained. For the remaining 65.8% of the women who reported at least 1 complication during the last 3 months of pregnancy, maternal conditions including anaemia, fever during labour, and hypertension accounted for most of the complications. Of importance to note is that the maternal conditions overlapped quite significantly with the other possible underlying risk factors for stillbirth. Obstetrics complications and excessive bleeding during delivery contributed to nearly 30% of the cases as a possible risk factor for stillbirth, highlighting the need for better skilled care during delivery. Of the 5 major themes identified in open narratives, 3 were related to healthcare providers—lack of timely attention, poor skills (knowledge or implementation), and reluctance to deliver a dead baby. The case studies document the circumstances that highlight breakdowns in clinical care around the delivery or missed opportunities that can be used for improving the provision of quality skilled care. The main limitation of these data is that stillbirth is defined based on the gestation period and not based on birth weight; however, this is done in several studies from developing country settings in which birthweight is either not available or accurate.</p><p>Conclusions</p><p>To our knowledge, this study is among the few large, population-based assessments of stillbirths using verbal autopsy at the state level in India. These findings provide detailed insight into investigating the possible risk factors for stillbirths, as well as insight into the ground-level changes that are needed within the health system to design and implement effective preventive and intervention policies to reduce the burden of stillbirths. As most of the stillbirths are preventable with high-quality, evidence-based interventions delivered before and during pregnancy and during labour and childbirth, it is imperative that with INAP in place, India aspires to document stillbirths in a systematic and standardised manner to bridge the knowledge gap for appropriate actions to reduce stillbirths. We have made several recommendations based on our study that could further strengthen the INAP approach to improve the quality and quantity of stillbirth data to avoid this needless loss of lives.</p></div

The classification process used to identify antepartum and intrapartum deaths for the stillbirths in the Indian state of Bihar.

<p>*Skin appearance and the baby’s movement were reported as “do not know” for 96 and 116 cases, respectively. For an additional 24 cases, both were reported as “do not know”.</p

Basic descriptive data for births that resulted in a stillbirth between January 2011 and March 2014 in the Indian state of Bihar.

<p>Basic descriptive data for births that resulted in a stillbirth between January 2011 and March 2014 in the Indian state of Bihar.</p

Diagrammatic representation of the data collection process.

<p>Diagrammatic representation of the data collection process.</p

The distribution of the overlap between the various possible risk factors for stillbirth in the Indian state of Bihar.

<p>Each bar denotes a risk factor indicated on the <i>x</i>-axis, and the stacks in each bar denote the overlap with the other risk factors. *Denotes no overlap with another risk factor.</p

Variation in the distribution of delivery-related variables and associated maternal conditions for stillbirths between January 2011 and March 2014 in the Indian state of Bihar.

<p>Twenty-six deliveries that occurred en route to the hospital are included under health facility delivery. Place of delivery was not available for 2 cases.</p

The distribution of select self-reported associated maternal conditions that had resulted in stillbirth and diagnostic tests performed during pregnancy in the Indian state of Bihar.

<p>VDRL test, Venereal Disease Research Laboratory test.</p

Human AAT inhibited cDC maturation and cytokine secretion.

<p>BM cDCs from B6 mice were generated in vitro in the presence of GM-CSF and IL-4 for 4 days with or without hAAT and then stimulated with 0.5 μg/ml LPS or 10μg/ml CpG for an additional 24 hr prior to FACS analysis. (A) CD80, CD86 and I-A^b expression (measured as mean fluorescence intensity, MFI) in B6 DCs stimulated with LPS. (B) TNF-α, IFNI, and IL-1β secretions in supernatants of B6 DCs stimulated with LPS. (C) CD80, CD86 and I-Ab expression in B6 DCs stimulated with CpG. (D) Secretion of TNF-α, IFN-I, IL-1β, and IL-6 by B6 DCs stimulated with CpG. P values of One-Way-ANOVA using Tukey’s post-hoc test are indicated as * P<0.05; ** P<0.01; *** P<0.001, n = 3.</p

<i>In vivo</i> hAAT treatment attenuated BMDCs differentiation and maturation in MRL/lpr mice.

<p>BMDCs from MRL/lpr mice treated with hAAT or PBS for 11 weeks were stimulated with LPS for 24 hrs. (A) Percentages of CD11c⁺ and (B) CD11b⁺CD11c⁺. (C-D) Percentages of CD80⁺ (C) and I-A (D) expressing BMDCs. P values of Student’s <i>t</i>-test are indicated as * P<0.05; ** P<0.01; *** P<0.001.</p

Human AAT treatment attenuated lupus nephritis in MRL/lpr mice.

<p>(A) Proteinuria scores after 9 weeks after hAAT treatment (Mann-Whitney test). (B) Albuminuria levels after 11 weeks of hAAT treatment. *P = 0.0727. (C) Average area of glomeruli (um²). (D) Average number of nuclei per glomerulus. **P<0.01 and***P<0.001 by student’s <i>t</i>-test. (F) Representative PAS-stained kidney sections from control MRL/lpr mice and hAAT treated MRL/lpr mice. All imaged were photographed at the same magnification (20X).</p