Postmortem minimally invasive tissue sampling in communities: exploring perceptions of families, funeral workers, religious and community leaders and healthcare providers from Pakistan.

BACKGROUND: Minimally invasive tissue sampling (MITS) has increasingly been used to improve the diagnosis of disease and identification of the cause of death, particularly in underserved areas. However, there are multiple barriers to accessing those who die within the community, our study aimed to explore the perceptions and insights of community members and healthcare providers regarding the feasibility of implementing MITS in community settings. METHODS: A qualitative exploratory study was conducted. A total of twenty one in-depth interviews were conducted with deceased infants' parents, elders of the family, religious leaders, community leaders, and funeral workers. Focus group discussions were conducted with health care providers (n = 14) in two peri-urban slum areas of Karachi, Pakistan. The duration of this study was from August to October 2020. Data was analyzed using thematic analysis and was coded and merged into categories forming eight major themes. RESULTS: In general, participants viewed minimally invasive tissue sampling (MITS) as beneficial for improving child health, though some had concerns about disrespecting the deceased during sample collection. Misinformation, fear of needles, and medical procedures were major barriers to MITS implementation. To enhance acceptance, community and religious leaders suggested using religious rulings, obtaining parental consent, ensuring confidentiality, and increasing efforts of community engagement. Community healthcare providers, along with funeral workers, recommended providing community members with grief counseling to increase study participation. Besides concerns about sampling interfering with respect for the decease, community members also raised concerns about misinformation. Further, participants provided feedback on the design and appearance of the mobile van used to collect MITS samples from children under the age of five. CONCLUSION: This study is critical for understanding the challenges associated with implementation of community-based MITS sampling in Pakistan. Integrating the use of a mobile van for sample collection, grief counseling along with community engagement sessions and advocacy will help address community-based misinformation and develop community trust.

Birth asphyxia is under-rated as a cause of preterm neonatal mortality in low- and middle-income countries: A prospective, observational study from PURPOSe.

OBJECTIVE: To assess respiratory distress syndrome (RDS) compared with birth asphyxia as the cause of death in preterm newborns, assigned by the neonatal intensive care unit (NICU) physician at the time of death and assigned by a panel with complete obstetric history, placental evaluation, tissue histology and microbiology. DESIGN: Prospective, observational study. SETTINGS: Study NICUs in India and Pakistan. POPULATION: Preterm infants delivered in study facility. METHODS: A total of 410 preterm infants who died in the NICU with cause of death ascertained by the NICU physicians and independently by expert panels. We compared the percentage of cases assigned RDS versus birth asphyxia as cause of death by the physician and the panel. MAIN OUTCOME MEASURES: RDS and birth asphyxia. RESULTS: Of 410 preterm neonatal deaths, the discharging NICU physicians found RDS as a cause of death among 83.2% of the cases, compared with the panel finding RDS in only 51.0%. In the same neonatal deaths, the NICU physicians found birth asphyxia as a cause of death in 14.9% of the deaths, whereas the panels found birth asphyxia in 57.6% of the deaths. The difference was greater in Pakistan were the physicians attributed 89.7% of the deaths to RDS and less than 1% to birth asphyxia whereas the panel attributed 35.6% of the deaths to RDS and 62.7% to birth asphyxia. CONCLUSIONS: NICU physicians who reported cause of death in deceased preterm infants less often attributed the death to birth asphyxia, and instead more often chose RDS, whereas expert panels with more extensive data attributed a greater proportion of deaths to birth asphyxia than did the physicians.

Factors Associated With Parental Acceptance of Minimally Invasive Tissue Sampling to Identify the Causes of Stillbirth and Neonatal Death.

BACKGROUND: Minimally invasive tissue sampling (MITS) is a noninvasive technique used to determine the cause of deaths. Very little is known about the factors that affect MITS acceptance or refusal. We present findings from a prospective study conducted in Southeast Asia on the reasons for accepting or refusing MITS. METHODS: This substudy was conducted in India and Pakistan to determine the acceptability of MITS in women who had a stillbirth or preterm live birth who later died. A formal questionnaire was used to gather observations during the consent for MITS, such as reasons for acceptance or refusal of MITS, as well as which family members were involved in the decision process. RESULTS: In Pakistan, the MITS acceptability forms were completed for 470 of 477 women (98.5%) with an eligible stillbirth for this substudy, and 334 of 337 (99.1%) with an eligible preterm neonatal death. In India, MITS acceptability forms were completed in 219 of 305 women (71.8%) with an eligible stillbirth and 260 of 264 (98.4%) with an eligible preterm neonatal death. In India, the most common reasons for MITS refusal for both stillbirths and preterm neonatal deaths were cultural concerns, while in Pakistan, the most common reason for MITS refusal was a potential delay in the funeral. The primary reason for accepting MITS was that the parents wanted to understand the cause of death. At both sites, fathers, mothers, and relatives, often in consultation, choose whether or not to accept MITS to determine the cause of death in stillbirths and preterm neonatal deaths. CONCLUSIONS: MITS was more commonly accepted in India than in Pakistan. Cultural concerns in India and funeral delays in Pakistan were common reasons for refusal. Parents from both sites were curious to know the cause of stillbirths and preterm neonatal deaths. The father, mother, and relatives were key decision makers for consenting to or declining MITS.

Building Global Capacity to Conduct Pathology-Based Postmortem Examination: Establishing a New Training Hub for Minimally Invasive Tissue Sampling.

BACKGROUND: Minimally invasive tissue sampling (MITS), an alternative to complete diagnostic autopsy, is a pathology-based postmortem examination that has been validated in low- and middle-income countries (LMICs) and can provide accurate cause of death information when used with other data. The MITS Surveillance Alliance was established in 2017 with the goal to expand MITS globally by increasing training capacity, accessibility, and availability in LMICs. Between January 2019 and May 2020, the MITS Surveillance Alliance convened a multidisciplinary team of technical advisors to attain this goal. METHODS: This article describes the process used to develop criteria and identify an optimal location for a MITS training hub, establish a cadre of LMIC-based trainers, refine standardized MITS sample collection protocols, develop a training program, and release a telepathology platform for quality assessment of MITS histological samples. RESULTS: Results include the creation of a training hub and curriculum, with a total of 9 pathologists and technicians trained as part of the training of the trainers. Those trainers trained 15 participants from seven MITS projects representing 6 LMICs trained in MITS sample collection. The 15 participants have gone on to train more than 50 project-level staff in MITS sample collection. CONCLUSIONS: Lessons learned include an appreciation for using an iterative process for establishing standardized procedures, creating opportunities for all stakeholders to deliver critical feedback, and highlighting the importance of complementing in-person trainings with ongoing technical assistance.

Methodology to Determine Cause of Death for Stillbirths and Neonatal Deaths Using Automated Case Reports and a Cause-of-Death Panel.

BACKGROUND: Review of data from multiple sources is often necessary to determine cause of death for stillbirths and neonatal deaths, especially in low- to middle-income countries (LMICs) where available data may vary. The minimally invasive tissue sampling (MITS) procedure provides granular histologic and microbiologic data that clinical reports and verbal autopsies cannot provide. Expert panel evaluation of data from individual deaths can be resource-intensive but remains essential to accurately infer causes of death. METHODS: The Project to Understand and Research Preterms and Stillbirths in South Asia (PURPOSe) study uses review panels to evaluate causes of death in 2 LMICs. To make the process manageable, a subset of the study variables was selected with professional input and organized into case reports. Case reports include clinical information, laboratory results, fetal or neonatal organ histology and polymerase chain reaction results from tissue obtained by MITS. Panelists evaluated the complete case report forms and then determined the cause of death based on available data. RESULTS: Computerized case reports averaged 2 to 3 pages. Approximately 6 to 8 cases were reviewed and discussed per 1-hour panel meeting. All panelists were provided the same information; missing data were noted. This limited bias between panelists and across meetings. Study teams notably took ownership of data quality. CONCLUSIONS: Standardized case reports for cause-of-death determination panel evaluation improve the efficiency of the review process, clarify available information, and limit bias across panelists, time, and location.

The project to understand and research preterm pregnancy outcomes and stillbirths in South Asia (PURPOSe): a protocol of a prospective, cohort study of causes of mortality among preterm births and stillbirths.

BACKGROUND: In South Asia, where most stillbirths and neonatal deaths occur, much remains unknown about the causes of these deaths. About one-third of neonatal deaths are attributed to prematurity, yet the specific conditions which cause these deaths are often unclear as is the etiology of stillbirths. In low-resource settings, most women are not routinely tested for infections and autopsy is rare. METHODS: This prospective, cohort study will be conducted in hospitals in Davengere, India and Karachi, Pakistan. All women who deliver either a stillbirth or a preterm birth at one of the hospitals will be eligible for enrollment. With consent, the participant and, when applicable, her offspring, will be followed to 28-days post-delivery. A series of research tests will be conducted to determine infection and presence of other conditions which may contribute to the death. In addition, all routine clinical investigations will be documented. For both stillbirths and preterm neonates who die ≤ 28 days, with consent, a standard autopsy as well as minimally invasive tissue sampling will be conducted. Finally, an expert panel will review all available data for stillbirths and neonatal deaths to determine the primary and contributing causes of death using pre-specified guidance. CONCLUSION: This will be among the first studies to prospectively obtain detailed information on causes of stillbirth and preterm neonatal death in low-resource settings in Asia. Determining the primary causes of death will be important to inform strategies most likely to reduce the high mortality rates in South Asia. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03438110 ) Clinical Trial Registry of India ( CTRI/2018/03/012281 ).

Risk factors for food insecurity and association with prenatal care utilization among women who took opioids during pregnancy.

Background: Food insecurity during pregnancy is associated with poorer outcomes for both mothers and their newborns. Given the ongoing opioid crisis in the United States, mothers who take opioids during pregnancy may be at particular risk of experiencing food insecurity. Methods: This research utilized data from 254 biological mothers of infants in the Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome (ACT NOW) Outcomes of Babies with Opioid Exposure (OBOE) Study. We examined factors associated with food insecurity among mothers of infants with antenatal opioid exposure and their unexposed (control) counterparts. Chi-square tests and logistic regression were used to compare food insecurity by sociodemographic characteristics, opioid use, prior traumatic experiences, and housing instability. Similar analyses were conducted to examine the relationship between food insecurity during pregnancy and receipt of adequate prenatal care. Results: Overall, 58 (23%) of the mothers screened positive for food insecurity. Food insecurity was more common among mothers who took opioids during pregnancy (28% vs. 14%; p =0.007), had public insurance (25% vs. 8%; p = 0.027), had housing instability (28% vs. 11%, p = 0.002), experienced three or more adverse experiences in their childhood (37% vs. 17%; p < 0.001), and reported physical or emotional abuse during their pregnancy (44% vs. 17%; p < 0.001). Mothers with food insecurity during pregnancy were less likely to have received adequate prenatal care (78% vs. 90%; p = 0.020). This difference remained after controlling for demographic characteristics (AOR (95% CI) = 0.39 (0.16, 1.00), p = 0.049). Conclusions: This study adds to the body of evidence supporting the need for screening and development of interventions to address food insecurity during pregnancy, particularly among mothers of infants with antenatal opioid exposure, for which limited data are available. The findings revealed that food insecurity frequently co-occurs with housing instability and prior trauma, indicating that a multifaceted intervention incorporating principles of trauma-informed health care is needed. Although those with food insecurity are at increased risk for poor pregnancy outcomes, they were less likely to have received adequate prenatal care despite high levels of public insurance coverage among study participants, suggesting additional strategies are needed to address barriers to health care among this population. Trial registration: The Outcomes of Babies with Opioid Exposure (OBOE) Study is registered at Clinical Trials.gov (NCT04149509) (04/11/2019).

A prospective observational study of nurses performing minimally invasive tissue sampling of brain, liver, and lung tissues among deceased neonates and stillbirths in Ethiopia.

Background: With a neonatal mortality rate of 33 per 1,000 live births in 2019, Ethiopia is striving to attain the Sustainable Development Goal target of 12 deaths per 1,000 live births by 2030. A better understanding of the major causes of neonatal mortality is needed to effectively design and implement interventions to achieve this goal. Minimally Invasive Tissue Sampling (MITS), an alternative to conventional autopsy, requires fewer resources and through task-shifting of sample collection from pathologists to nurses, has the potential to support the expansion of pathology-based post-mortem examination and improve mortality data. This paper evaluates the accuracy and adequacy of MITS performed by nurses at a tertiary and general hospital and in the home of the deceased. Methods: Nurses in a tertiary and general hospital in Ethiopia were trained in MITS sample collection on neonatal deaths and stillbirths using standardized protocols. MITS sample collection was performed by both pathologists and nurses in the tertiary hospital and by nurses in the general hospital and home-setting. Agreement in the performance of MITS between pathologists and nurses was calculated for samples collected at the tertiary hospital. Samples collected by nurses in the general hospital and home-setting were evaluated for technical adequacy using preestablished criteria. Results: One hundred thirty-nine MITS were done: 125 in hospitals and 14 inside homes. There was a perfect or almost perfect agreement between the pathologists and the nurses in the tertiary hospital using Gwet's agreement interpretation criteria. The adequacy of MITS samples collected by nurses in the general hospital was more than 72% when compared to the preset criteria. The adequacy of the MITS sampling yield ranged from 87% to 91% on liveborn neonatal deaths and 76% for the liver, right and left lungs and 55% for brain tissues in stillbirths. Conclusions: This study demonstrated that task-shifting MITS sample collection to nurses can be achieved with comparable accuracy and adequacy as pathologists. Our study showed that with standardized training and supportive supervision MITS sample collection can be conducted by nurses in a tertiary, general hospital and, at the home of the deceased. Future studies should validate and expand on this work by evaluating task-shifting of MITS sample collection to nurses within community settings and with larger sample sizes.

The causes of preterm neonatal deaths in India and Pakistan (PURPOSe): a prospective cohort study.

BACKGROUND: Preterm birth remains the major cause of neonatal death worldwide. South Asia contributes disproportionately to deaths among preterm births worldwide, yet few population-based studies have assessed the underlying causes of deaths. Novel evaluations, including histological and bacteriological assessments of placental and fetal tissues, facilitate more precise determination of the underlying causes of preterm deaths. We sought to assess underlying and contributing causes of preterm neonatal deaths in India and Pakistan. METHODS: The project to understand and research preterm pregnancy outcomes and stillbirths in South Asia (PURPOSe) was a prospective cohort study done in three hospitals in Davangere, India, and two hospitals in Karachi, Pakistan. All pregnant females older than 14 years were screened at the time of presentation for delivery, and those with an expected or known preterm birth, defined as less than 37 weeks of gestation, were enrolled. Liveborn neonates with a weight of 1000 g or more who died by 28 days after birth were included in analyses. Placentas were collected and histologically evaluated. In addition, among all neonatal deaths, with consent, minimally invasive tissue sampling was performed for histological analyses. PCR testing was performed to assess microbial pathogens in the placental, blood, and fetal tissues collected. An independent panel reviewed available data, including clinical description of the case and all clinical maternal, fetal, and placental findings, and results of PCR bacteriological investigation and minimally invasive tissue sampling histology, from all eligible preterm neonates to determine the primary and contributing maternal, placental, and neonatal causes of death. FINDINGS: Between July 1, 2018, and March 26, 2020, of the 3470 preterm neonates enrolled, 804 (23%) died by 28 days after birth, and, of those, 615 were eligible and had their cases reviewed by the panel. Primary maternal causes of neonatal death were hypertensive disease (204 [33%] of 615 cases), followed by maternal complication of pregnancy (76 [12%]) and preterm labour (76 [11%]), whereas the primary placental causes were maternal and fetal vascular malperfusion (172 [28%] of 615) and chorioamnionitis, funisitis, or both (149 [26%]). The primary neonatal cause of death was intrauterine hypoxia (212 [34%] of 615) followed by congenital infections (126 [20%]), neonatal infections (122 [20%]), and respiratory distress syndrome (126 [20%]). INTERPRETATION: In south Asia, intrauterine hypoxia and congenital infections were the major causes of neonatal death among preterm babies. Maternal hypertensive disorders and placental disorders, especially maternal and fetal vascular malperfusion and placental abruption, substantially contributed to these deaths. FUNDING: Bill & Melinda Gates Foundation.

The causes of stillbirths in south Asia: results from a prospective study in India and Pakistan (PURPOSe).

BACKGROUND: South Asia contributes more than a third of all global stillbirths, yet the causes remain largely unstudied in this region. New investigations, including novel assessments of placental and fetal tissues, facilitate more precise determination of the underlying causes of stillbirth. We sought to assess underlying and contributing causes of stillbirth from settings in India and Pakistan. METHODS: In this prospective cohort study (PURPOSe), we report the cause of death in stillbirths in hospitals in central India and south Pakistan (Davangere, India [three public and private hospitals] and Karachi, Pakistan [one public maternity and one children's hospital]). Women aged 15 years or older and with a known stillbirth (defined as a pregnancy at 20 or more weeks of gestation with the in-utero death of a fetus) weighing 1000 g or more were included in the study. Maternal clinical factors, placental evaluation, fetal tissue evaluation (from minimally invasive tissue sampling), and PCR for microbial pathogens were used to identify the causes of death. An expert panel reviewed available data for all stillbirths to identify the primary and contributing maternal, placental, and fetal causes of stillbirth. FINDINGS: Between Sept 1, 2018, and Feb 12, 2020, 981 stillborns were included and, of those, 611 were reviewed by the expert panel. The primary maternal causes of stillbirth were hypertensive disease in 221 (36%) of 611 stillbirths, followed by severe anaemia in 66 (11%) stillbirths. The primary placental causes were maternal and fetal vascular malperfusion, in 289 (47%) stillbirths. The primary fetal cause of stillbirth was intrauterine hypoxia, in 437 (72%) stillbirths. We assessed the overlap of main causes and 116 (19%) stillbirths had intrauterine hypoxia, placental malperfusion, and eclampsia or pre-eclampsia indicated as primary causes of death. Infection (including of the placenta, its membranes, and in the fetus) and congenital anomalies also were causative of stillbirth. INTERPRETATION: In south Asia, fetal asphyxia is the major cause of stillbirth. Several placental lesions, especially those associated with maternal and fetal vascular malperfusion and placental abruption, have an important role in asphyxia and fetal death. Maternal hypertension, and especially pre-eclampsia, is often the primary maternal condition associated with this pathway. FUNDING: Bill & Melinda Gates Foundation.