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Objective: To explore potential reasons for differences in preterm neonatal mortality in neonatal intensive care units (NICUs) in India and Pakistan. Design: A prospective observational study, the Project to Understand and Research Stillbirth and Preterms in Southeast Asia (PURPOSe) was conducted July 2018 to February 2020. Setting: Three hospitals in Davangere, India, and a large public hospital in Karachi, Pakistan. Population: Of a total of 3,202 preterm infants enrolled, 1,512 were admitted to a study NICU. Methods: We collected data for neonates, including length of stay, diagnoses, and diagnostic tests. Main outcome measures: Neonatal mortality, tests performed, diagnoses ascertained. Results: For infants of equivalent weights and gestational ages, neonatal mortality in Pakistan was twice that in the Indian NICU. The mean newborn length of stay in Pakistan was 2 days compared with 10 days for India. Fewer diagnostics and other investigations were used to determine neonatal condition or guide treatment in the Pakistani NICU. Because of limited information from testing in Pakistan concerning clinical respiratory distress, respiratory distress syndrome appeared to be over‐diagnosed, whereas other conditions including pneumonia, sepsis, necrotising entercolitis and intraventricular haemorrhage were rarely diagnosed. Conclusion: In the Pakistani site, the limited resources available to the NICU appeared related to a shorter length of stay and decreased diagnostic testing, likely explaining the higher mortality. With improved care, reduction in mortality among preterm neonates should be achievable. [ABSTRACT FROM AUTHOR]

The PURPOSe study was a prospective, observational study conducted in India and Pakistan to determine the cause of death for stillbirths and preterm neonatal deaths, using clinical data together with minimally invasive tissue sampling (MITS) and the histologic and polymerase chain reaction (PCR) evaluation of fetal/neonatal tissues and the placenta. After evaluating all available data, an independent panel chose a maternal, a placental and a fetal/neonatal cause of death. Here, we summarise the major results. Among the most important findings were that most stillbirths were caused by fetal asphyxia, often preceded by placental malperfusion, and clinically associated with pre‐eclampsia, placental abruption and a small‐for‐gestational‐age fetus. The preterm neonatal deaths were primarily caused by birth asphyxia, followed by various infections. An important finding was that many of the preterm neonatal deaths were caused by a nosocomial infection acquired after neonatal intensive care (NICU) admission; the most common organisms were Acinetobacter baumannii, followed by Klebsiella pneumoniae, Escherichia coli/Shigella and Haemophilus influenzae. Group B streptococcus was less commonly present in the placentas or internal organs of the neonatal deaths. [ABSTRACT FROM AUTHOR]

Objective: Group B streptococcus (GBS) has been associated with adverse pregnancy outcomes, but few prospective studies have assessed its prevalence in low‐ and middle‐income country settings. We sought to evaluate the prevalence of GBS by polymerase chain reaction (PCR) in internal organ tissues and placentas of deceased neonates and stillbirths. Design: This was a prospective, observational study. Setting: The study was conducted in hospitals in India and Pakistan. Population: Pregnant women with stillbirths or preterm births were recruited at delivery, as was a group of women with term, live births, to serve as a control group. Methods: A rectovaginal culture was collected from the women in Pakistan to assess GBS carriage. Using PCR, we evaluated GBS in various tissues of stillbirths and deceased neonates and their placentas, as well as the placentas of live‐born preterm and term control infants. Main outcome measures: GBS identified by PCR in various tissues and the placentas; rate of stillbirths and 28‐day neonatal deaths. Results: The most obvious finding from this series of analyses from India and Pakistan was that no matter the country, the condition of the subject, the tissue studied or the methodology used, the prevalence of GBS was low, generally ranging between 3% and 6%. Among the risk factors evaluated, only GBS positivity in primigravidae was increased. Conclusions: GBS diagnosed by PCR was identified in <6% of internal organs of stillbirths and neonatal deaths, and their placentas, and control groups in South Asian sites. This is consistent with other reports from South Asia and is lower than the reported GBS rates from the USA, Europe and Africa. [ABSTRACT FROM AUTHOR]

Objective: To evaluate perinatal outcomes in preterm multiple compared with singleton pregnancies in India and Pakistan. Design: Prospective, observational study. Settings: Study hospitals in India and Pakistan. Population: We evaluated 3897 preterm pregnancies. These mothers gave birth to 3615 (92.8%) singleton infants, 267 (6.8%) sets of twins, 14 (0.4%) sets of triplets and one set of quadruplets. Main outcome measures: Neonatal mortality, stillbirth, cause of death. Results: Of the singleton infants, 691 (19.1%) were stillborn and 2924 (80.9%) live born. Of the 534 infants from twin pregnancies, 41 (7.7%) were stillborn and 493 (92.3%) were live born. Of the 267 sets of twins, in 14 cases (5.2%) both were stillborn, in 13 cases (4.8%) one was stillborn and one live born, and in 240 cases (90.0%) both were live born. In both preterm twins and preterm singletons, the three most common causes of death were intrauterine hypoxia, infections acquired prior to birth and infections acquired at or after birth. The preterm twins appeared less likely to have died from intrauterine hypoxia but more likely to have died from infections acquired at or after birth. Respiratory distress syndrome (RDS) was less likely considered by the panel to be the primary cause of death in either the twins (9.6%) or singletons (9.7%). Congenital anomalies were also not often judged to be the cause of death in either the preterm twins 2 (2.4%) or singletons 27 (5.3%). Conclusion: In the PURPOSe study, neonatal mortality rates in preterm twins compared with singletons when evaluated by sex, GA, birthweight and SGA, were generally similar to rates of preterm singleton neonatal mortality in those groups. Thus, the higher rate of mortality in live‐born twin infants is related to the fact that these infants were more likely to be born earlier rather than to any inherent characteristics of the babies themselves. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the usefulness of data to determine cause of stillbirth in India and Pakistan. Design: Prospective, observational study. Settings: Study hospitals in India and Pakistan. Population: 200 fetal deaths with placental evaluation and minimally invasive tissue sampling (MITS) of internal organs and polymerase chain reaction (PCR) test for 75 pathogens. Main outcome measures: Data defined as useful to determine stillbirth causes. Results: Placental pathology was the most useful to determine cause of stillbirth. Comparing placental and fetal weight with standard weights was useful in 44.5% and 48.5%, respectively. Lung histology was useful in 42.5%. Most of the other findings of internal organ histology were only occasionally useful. Signs of abruption, by maternal history or placental evaluation, were always deemed useful. Placenta, brain and cord blood PCR were also useful, but less often than histology. Conclusion: Based on this analysis, maternal clinical history, placental histology and fetal examination were most informative. Comparing the placental and fetal weights with recognised standards was useful in nearly half the cases. Fetal tissue histology and PCR were also informative. Of all the potential tests of MITS‐obtained specimens, we would first recommend histological evaluation of the lungs, and using a multiplex PCR platform would determine pathogens in blood and brain/CSF. We recognise that this approach will not identify some causes, including some genetic and internal organ anomalies, but will confirm most common causes of stillbirth and most of the preventable causes of stillbirth in low‐ and middle‐income countries. [ABSTRACT FROM AUTHOR]

Objective: To examine internal organ tissues and placentas of stillbirths for various pathogens. Design: Prospective, observational study. Settings: Three study hospitals in India and a large maternity hospital in Pakistan. Population: Stillborn infants delivered in a study hospital. Methods: A prospective observational study. Main outcome measures: Organisms identified by pathogen polymerase chain reaction (PCR) in internal organs and placental tissues of stillbirths. Results: Of 2437 stillbirth internal tissues, 8.3% (95% CI 7.2–9.4) were positive. Organisms were most commonly detected in brain (12.3%), cerebrospinal fluid (CSF) (9.5%) and whole blood (8.4%). Ureaplasma urealyticum/parvum was the organism most frequently detected in at least one internal organ (6.4% of stillbirths and 2% of all tissues). Escherichia coli/Shigella was the next most common (4.1% one or more internal organ tissue sample and 1.3% of tissue samples), followed by Staphylococcus aureus in at least one internal organ tissue (1.9% and 0.9% of all tissues). None of the other organisms was found in more than 1.4% of the tissue samples in stillbirths or more than 0.6% of the internal tissues examined. In the placenta tissue, membrane or cord blood combined, 42.8% (95% CI 40.2–45.3) had at least one organism identified, with U. urealyticum/parvum representing the most commonly identified (27.8%). Conclusions: In about 8% of stillbirths, there was evidence of a pathogen in an internal organ. Ureaplasma urealyticum/parvum was the most common organism found in the placenta and in the internal tissues, especially in the fetal brain. [ABSTRACT FROM AUTHOR]

Background We identified pathogens found in internal organs and placentas of deceased preterm infants cared for in hospitals in India and Pakistan. Methods Prospective, observational study conducted in delivery units and neonatal intensive care units. Tissue samples from deceased neonates obtained by minimally invasive tissue sampling and placentas were examined for 73 different pathogens using multiplex polymerase chain reaction (PCR). Results Tissue for pathogen PCR was obtained from liver, lung, brain, blood, cerebrospinal fluid, and placentas from 377 deceased preterm infants. Between 17.6% and 34.1% of each type of tissue had at least 1 organism identified. Organism detection was highest in blood (34.1%), followed by lung (31.1%), liver (23.3%), cerebrospinal fluid (22.3%), and brain (17.6%). A total of 49.7% of the deceased infants had at least 1 organism. Acinetobacter baumannii was in 28.4% of the neonates compared with 14.6% for Klebsiella pneumoniae , 11.9% for Escherichia coli/Shigella , and 11.1% for Haemophilus influenzae. Group B streptococcus was identified in only 1.3% of the neonatal deaths. A. baumannii was rarely found in the placenta and was found more commonly in the internal organs of neonates who died later in the neonatal period. The most common organism found in placentas was Ureaplasma urealyticum in 34% of the samples, with no other organism found in >4% of samples. Conclusions In organ samples from deceased infants in India and Pakistan, evaluated with multiplex pathogen PCR, A. baumannii was the most commonly identified organism. Group B streptococcus was rarely found. A. baumannii was rarely found in the placentas of these deceased neonates. [ABSTRACT FROM AUTHOR]

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. Linked article: This article is commented on by Evelyn Verheijen, pp. 2001 in this issue. To view this mini commentary visit https://doi.org/10.1111/1471-0528.17245 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Complete diagnostic autopsy (CDA) is considered to be the gold-standard procedure that aids in determination of cause of death in stillbirths and neonatal deaths. However, CDA is not routinely practiced in South Asian countries due to religious beliefs, lack of expertise, and lack of resources. Minimally invasive tissue sampling (MITS) has been recommended as a less mutilating and less expensive alternative to CDA for obtaining tissues for analysis. The present study aims to evaluate the yield of lung tissue and histological findings using MITS as part of a cause of death analysis for stillborns and preterm neonatal deaths. Methods Data were collected during an observational multicenter prospective study called the Project to Understand and Research Preterm birth and Stillbirth (PURPOSe) conducted in India and Pakistan. After obtaining written informed consent from parents, the eligible stillbirths and neonatal deaths were subjected to MITS using a standard protocol. The tissues were obtained from both lungs for histological and microbiological analysis. Results At both sites, a total of 453 stillbirths and 352 neonatal deaths underwent MITS. For stillbirths and neonatal deaths, the yield of lung tissue using MITS was high (92%). Intrauterine fetal distress and respiratory distress syndrome were the leading lung pathologies reported in stillbirths and neonatal deaths, respectively. Conclusions MITS appears to be a reasonable alternative to CDA in obtaining and evaluating lung tissue to inform accurate cause of death analysis in stillbirth and preterm deaths. [ABSTRACT FROM AUTHOR]

Objective: Early detection of specific signs and symptoms to predict severe illness is essential to prevent infant mortality. As a continuation of the results from the multicenter Young Infants Clinical Signs and Symptoms (YICSS) study, we present here the performance of the seven-sign algorithm in 3 age categories (0–6 days, 7–27 days and 28–59 days) in Pakistani infants aged 0–59 days. Results: From September 2003 to November 2004, 2950 infants were enrolled (age group 0–6 days = 1633, 7–27 days = 817, 28–59 days = 500). The common reason for seeking care was umbilical redness or discharge (29.2%) in the 0–6 days group. Older age groups presented with cough (16.9%) in the 7–27 age group and (26.9%) infants in the 28–59 days group. Severe infection/sepsis was the most common primary diagnoses in infants requiring hospitalization across all age groups. The algorithm performed well in every age group, with a sensitivity of 85.9% and specificity of 71.6% in the 0–6 days age group and a sensitivity of 80.5% and specificity of 80.2% in the 28–59 days group; the sensitivity was slightly lower in the 7–27 age group (72.4%) but the specificity remained high (83.1%). [ABSTRACT FROM AUTHOR]

Globally, more than 5 million stillbirths and neonatal deaths occur annually. For many, the cause of death (CoD) is unknown. Minimally invasive tissue sampling (MITS) has been increasingly used in postmortem examinations for ascertaining the CoD in stillbirths and neonates. Our study compared the counseling and consent methods used in MITS projects in five countries in Africa and south Asia. Key informant interviews were conducted with researchers to describe the characteristics and backgrounds of counselors, the environment and timing of consent and perceived facilitators and barriers encountered during the consent process. Counselors at all sites had backgrounds in social science, psychology and counseling or clinical expertise in obstetrics/gynecology or pediatrics. All counsellors received training about techniques for building rapport and offering emotional support to families; training duration and methods differed across sites. Counselling environments varied significantly; some sites allocated a separate room, others counselled families at the bedside or nursing stations. All counsellors had a central role in explaining the MITS procedure to families in their local languages. Most sites did not use visual aids during the process, relying solely on verbal descriptions. In most sites, parents were approached within one hour of death. The time needed for decision making by families varied from a few minutes to 24 h. In most sites, extended family took part in the decision making. Because many parents wanted burial as soon as possible, counsellors ensured that MITS would be conducted promptly after receiving consent. Barriers to consent included decreased comprehension of information due to the emotional and psychological impact of grief. Moreover, having more family members engaged in decision-making increased the complexity of counselling and achieving consensus to consent for the procedure. While each site adapted their approach to fit the context, consistencies and similarities across sites were observed. [ABSTRACT FROM AUTHOR]

Background: Pakistan reports the highest stillbirth rate in the world at 43 per thousand births with more than three-quarters occurring in rural areas. The Global Network for Women's and Children's Health maintains a Maternal and Newborn Health Registry (MNHR) in 14 study clusters of district Thatta, Sindh Pakistan. For the last 10 years, the MNHR has recorded a high stillbirths rate with a slow decline. This exploratory study was designed to understand the perspectives of women and traditional birth attendants regarding the high occurrence of stillbirth in Thatta district. Methods: We used an exploratory qualitative study design by conducting in-depth interviews (IDIs) and focus group discussions (FGDs) using semi-structured interview guide with rural women (FGDs = 4; n = 29) and traditional birth attendants (FGDs = 4; n = 14) who were permanent residents of Thatta. In addition, in-depth interviews were conducted with women who had experienced a stillbirth (IDIs = 4). This study presents perceptions and experiences of women and TBAs regarding high rate of stillbirth in Thatta district, Karachi. Results: Women showed reluctance to receive skilled/ standard care when in need due to apprehensions towards operative delivery, poor attitude of skilled health care providers, and poor quality of care as service delivery factors. High cost of care, far distance to facility, lack of transport and need of an escort from the family or village to visit a health facility were additional important factors for not seeking care resulting in stillbirth. The easy availability of unskilled provider in the form of traditional birth attendant is then preferred over a skilled health care provider. TBAs shared their husband or family members restrict them to visit or consult a doctor during pregnancy. According to TBAs after delivering a macerated fetus, women are given herbs to remove infection from woman's body and uterus. Further women are advised to conceive soon so that they get rid of infections. Conclusion: Women of this rural community carry lots of apprehension against skilled medical care and as a result follow traditional practices. Conscious efforts are required to increase the awareness of women to develop positive health seeking behavior during pregnancy, delivery and the post-partum period. Alongside, provision of respectful maternity care needs to be emphasized especially at public health facilities. [ABSTRACT FROM AUTHOR]

Background: Recently, the minimal invasive tissue sampling (MITS) procedure has been developed to support determination of the cause of death as an alternate to conventional autopsy, especially in countries where complete diagnostic autopsy is not routine. To assess the feasibility of implementation of the MITS procedure for a study to determine cause of death in premature births and stillbirths in south Asia, we explored the views and perceptions of parents and religious leaders on the acceptability of MITS. Methods: A qualitative study was conducted at the National Institute of Child Health (NICH) hospital of Karachi, Pakistan. Focus group discussions (FGDs) were conducted with parents of newborns who visited well-baby clinics of the NICH hospital for post-natal check-ups. Key-informant interviews (KIIs) were conducted with religious leaders. Data were analyzed using NVivo 10 software. Results: A total of 13 interviews (FGDs = 8; KIIs = 5) were conducted. Three overarching themes were identified: (I) acceptability of MITS; (II) concerns affecting the implementation of MITS; and (III) religious and cultural perspectives. Participants' acceptance of MITS was based on personal, religious, cultural and social beliefs. Parents widely recognized the need for this procedure in cases where the couple had experienced multiple stillbirths, neonatal deaths and miscarriages. Counseling of parents was considered vital to address emotional concerns of the parents and the family. Religious leaders indicated acceptability of the MITS procedure from a religious perspective and advised that respect for the deceased and consent of the guardians is mandatory when performing MITS. Conclusions: This qualitative study provided a unique opportunity to understand the views of parents and religious leaders towards the use of MITS. Generally, MITS appears to be an acceptable method for identifying the cause of death in neonates and stillbirths, provided that the deceased is respected and buried as soon as possible without any delays and parents are counseled appropriately. Findings from this research are essential in approaching families for consent for MITS. [ABSTRACT FROM AUTHOR]

Background: Fetal death is one of the major adverse pregnancy outcomes and is common in low- and middle-income countries. Placental lesions may play an important role in the etiology of fetal and neonatal deaths. Previous research relating placental lesions to fetal death causation was hindered by a lack of agreement on a placental classification scheme. The Amsterdam consensus statement that was published in 2016 focused its attention on malperfusions in the maternal and fetal placental circulations.Objective: This study aimed to investigate the relationships of placental maternal and fetal vascular malperfusions in fetal and neonatal deaths, focusing on the most important maternal clinical conditions in the pathway to fetal and neonatal deaths, such as maternal hypertension, antepartum hemorrhage, and decreased fetal growth.Study Design: This was a prospective, observational cohort study conducted at 2 Asian sites. The data collected included clinical history, gross and histologic evaluations of the placenta, and several other investigations and were used to determine the cause of death. The placenta was evaluated at both sites using the Amsterdam consensus framework. We estimated the risk of placental maternal and fetal vascular malperfusions in fetal and neonatal deaths.Results: Between July 2018 and January 2020 in India and Pakistan, 1633 women with placentas available for the study provided consent. Of these women, 814 had fetal deaths, 618 had preterm live births and subsequent neonatal deaths, and 201 had term live births. The prevalence of maternal vascular malperfusion was higher in the placentas associated with fetal deaths (58.4%) and preterm neonatal deaths (31.1%) than in the placentas associated with term live births (15.4%). Adjusting for site, maternal vascular malperfusion had a relative risk of 3.88 (95% confidence interval, 2.70-5.59) in fetal deaths vs term live births and a relative risk of 2.07 (95% confidence interval, 1.41-3.02) in preterm neonatal deaths vs term live births. Infarcts and distal villous hypoplasia were the most common histologic components of maternal vascular malperfusion. Compared with maternal vascular malperfusion (58.4%), fetal vascular malperfusion was less common in the placentas associated with fetal deaths (19.0%). However, there were higher frequencies of fetal vascular malperfusion in the placentas associated with fetal deaths (19.0%) than in placentas associated with neonatal deaths (8.3%) or term live birth (5.0%). Adjusting for site, fetal vascular malperfusion had a relative risk of 4.09 (95% confidence interval, 2.15-7.75) in fetal deaths vs term live births and a relative risk of 1.77 (95% confidence interval, 0.90-3.49) in preterm neonatal deaths vs term live births. Furthermore, there was a higher incidence of maternal vascular malperfusion in cases of maternal hypertension (71.4%), small for gestational age (69.9%), and antepartum hemorrhage (59.1%) than in cases of fetal deaths with none of these conditions (43.3%). There was no significant difference in the occurrence of fetal vascular malperfusion in the 4 clinical categories.Conclusion: Histologic examination of the placenta, especially for malperfusion disorders, is crucial in elucidating pathways to fetal and neonatal deaths in preterm infants. In particular, focusing on placental maternal and fetal vascular malperfusions during pregnancy is a means to identify fetuses at risk of fetal death and is an important strategy to reduce the risk of fetal death early delivery. We hope that the increased risk of fetal and neonatal deaths in these pregnancies can be reduced by the development of an intervention that reduces the likelihood of developing maternal and fetal vascular malperfusion. [ABSTRACT FROM AUTHOR]

Background: While the relationship between hemoglobin (Hb) concentrations and pregnancy outcomes has been studied often, most reports have focused on a specific Hb cutoff used to define anemia. Fewer studies have evaluated pregnancy outcomes across the entire range of Hb values. Moreover, to date, most studies of the relationship of Hb concentrations to pregnancy outcomes have been done in high-income countries. Thus, we have sought to determine the relationship between the range of maternal Hb concentrations and adverse birth outcomes among South Asian pregnant women. Methods: For this study, we used data collected from two South Asian countries (Pakistan – Sindh Province and two sites in India - Belagavi and Nagpur) in a prospective maternal and newborn health registry study. To assess the association between Hb concentrations and various maternal and fetal outcomes, we classified the Hb concentrations into seven categories. Regression analyses adjusting for multiple potential confounders were performed to assess adverse pregnancy outcomes across the range of Hb concentrations. Findings: Between January 2012 and December 2018, 130,888 pregnant women were enrolled in the South Asian sites had a Hb measurement available, delivered and were included in the analyses. Overall, the mean Hb concentration of pregnant women from the sites was 9.9 g/dL, 10.0 g/dL in the Indian sites and 9.5 g/dL in the Pakistan site. Hb concentrations < 7 g/dL were observed in 6.9% of the pregnant Pakistani women and 0.2% of the Indian women. In both the Pakistani and Indian sites, women with higher parity and women with no formal education had lower Hb concentrations. In the Pakistani site, women > 35 years of age, women with ≥4 children and those who enrolled in the third trimester were more likely to have Hb concentrations of < 7 g/dL but these associations were not found for the Indian sites. When adjusting for potential confounders, for both India and Pakistan, lower Hb concentrations were associated with stillbirth, preterm birth, lower mean birthweight, and increased risk of low birthweight. In the Pakistani site, there was evidence of a U-shaped relationship between Hb concentrations and low birth weight, and neonatal mortality, and in India with hypertensive disease. Interpretation: This study documented the relationship between maternal Hb concentrations and adverse pregnancy outcomes in women from the Pakistani and Indian sites across the range of Hb values. Both low and high Hb concentrations were associated with risk of at least some adverse outcomes. Hence, both low and high values of Hb should be considered risk factors for the mother and fetus. [ABSTRACT FROM AUTHOR]

Background: Babies born weighing ≥ 2500 g account for more than 80% of the births in most resource-limited locations and for nearly 50% of the 28-day neonatal deaths. In contrast, in high-resource settings, 28-day neonatal mortality among this group represents only a small fraction of the neonatal deaths. Yet mortality risks for birth weight of ≥ 2500 g is limited. Knowledge regarding the factors associated with mortality in these babies will help in identifying interventions that can reduce mortality. Methods: The Global Network's Maternal Newborn Health Registry (MNHR) is a prospective, population-based observational study that includes all pregnant women and their pregnancy outcomes in defined geographic communities that has been conducted in research sites in six low-middle income countries (India, Pakistan, Democratic Republic of Congo, Guatemala, Kenya and Zambia). Study staff enroll all pregnant women as early as possible during pregnancy and conduct follow-up visits to ascertain delivery and 28-day neonatal outcomes. We analyzed the neonatal mortality rates (NMR) and risk factors for deaths by 28 days among all live-born babies with a birthweight ≥ 2500 g from 2010 to 2018 across the Global Network sites. Results: Babies born in the Global Network sites from 2010 to 2018 with a birthweight ≥ 2500 g accounted for 84.8% of the births and 45.4% of the 28-day neonatal deaths. Among this group, the overall NMR was 13.1/1000 live births. The overall 28-day NMR for ongoing clusters was highest in Pakistan (29.7/1000 live births) and lowest in the Zambian/Kenyan sites (9.3/1000) for ≥ 2500 g infants. ≥ 2500 g NMRs declined for Zambia/Kenya and India. For Pakistan and Guatemala, the NMR remained almost unchanged over the period. The ≥ 2500 g risks related to maternal, delivery and newborn characteristics varied by site. Maternal factors that increased risk and were common for all sites included nulliparity, hypertensive disease, previous stillbirth, maternal death, obstructed labor, severe postpartum hemorrhage, and abnormal fetal presentation. Neonatal characteristics including resuscitation, hospitalization, congenital anomalies and male sex, as well as lower gestational ages and birthweights were also associated with increased mortality. Conclusions: Nearly half of neonatal deaths in the Global Network sites occurred in infants born weighing ≥ 2500 g. The NMR for those infants was 13.1 per 1000 live births, much higher than rates usually seen in high-income countries. The changes in NMR over time varied across the sites. Even among babies born ≥ 2500 g, lower gestational age and birthweight were largely associated with increased risk of mortality. Since many of these deaths should be preventable, attention to preventing mortality in these infants should have an important impact on overall NMR. Trial registration: https://ClinicalTrials.gov Identifier: NCT01073475 [ABSTRACT FROM AUTHOR]

Background: Globally, around 2.6 million neonatal deaths occur world-wide every year and the numbers of stillbirths is almost similar. Pakistan is ranked among the highest countries in the world for neonatal mortality. In 2016, for every 1000 babies born in Pakistan, 46 died before the end of the first month of life. Also, Pakistan had the highest rate of stillbirths (43.1/1000 births) in 2015. To meet sustainable development (SDG) targets of reducing neonatal mortality and stillbirths, it is essential to gain understanding about the causes of neonatal death and stillbirths. In Pakistan, full autopsies are conducted only in medico-legal cases and are very rarely performed to identify a definitive cause of death (CoD) and because of cost and insufficient staff are generally not feasible. Recently, minimally invasive tissue sampling (MITS) has been used to determine CoD in neonates and stillbirths as it addresses some of the socio-cultural and religious barriers to autopsy. However, it is not known how families and communities will perceive this procedure; therefore, exploring family and healthcare professionals' perceptions regarding MITS is essential in determining acceptable and feasible approaches for Pakistan. Methods: The study will employ an exploratory qualitative research design. The study will be conducted at the National Institute of Child Health (NICH) hospital of Karachi. The data collection method will consist of key-informant interviews (KIIs) and focus group discussions (FGDs). FGDs will be conducted with the families and relatives of newborns who are visiting the outpatient department (OPD) and well-baby clinics of NICH hospital. KIIs will be conducted with the NICH - medical director, healthcare providers, professionals involved in proceedings related to death and dying, religious leaders, health sector representatives from the government, public health experts, maternal and child health (MCH) specialists, obstetricians and neonatologists and experts from the bioethics committee. Study data will be analyzed using NVivo 10 software. Discussion: The research will help explore specific cultural, religious and socio-behavioral factors that may increase or decrease the acceptability of MITS for identifying COD in neonates and stillbirths. The findings of the qualitative study will provide a better understanding of parents' and healthcare professionals' attitudes towards the use of MITS on neonatal deaths and stillborns. [ABSTRACT FROM AUTHOR]

Background: Stillbirth rates remain high, especially in low and middle-income countries, where rates are 25 per 1000, ten-fold higher than in high-income countries. The United Nations' Every Newborn Action Plan has set a goal of 12 stillbirths per 1000 births by 2030 for all countries. Methods: From a population-based pregnancy outcome registry, including data from 2010 to 2016 from two sites each in Africa (Zambia and Kenya) and India (Nagpur and Belagavi), as well as sites in Pakistan and Guatemala, we evaluated the stillbirth rates and rates of annual decline as well as risk factors for 427,111 births of which 12,181 were stillbirths. Results: The mean stillbirth rates for the sites were 21.3 per 1000 births for Africa, 25.3 per 1000 births for India, 56.9 per 1000 births for Pakistan and 19.9 per 1000 births for Guatemala. From 2010 to 2016, across all sites, the mean stillbirth rate declined from 31.7 per 1000 births to 26.4 per 1000 births for an average annual decline of 3.0%. Risk factors for stillbirth were similar across the sites and included maternal age < 20 years and age > 35 years. Compared to parity 1–2, zero parity and parity > 3 were both associated with increased stillbirth risk and compared to women with any prenatal care, women with no prenatal care had significantly increased risk of stillbirth in all sites. Conclusions: At the current rates of decline, stillbirth rates in these sites will not reach the Every Newborn Action Plan goal of 12 per 1000 births by 2030. More attention to the risk factors and treating the causes of stillbirths will be required to reach the Every Newborn Action Plan goal of stillbirth reduction. Trial registration: NCT01073475. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Objective: To assess the diagnostic accuracy of postnatal foot length (FL) measurements as a proxy to identify low birth weight (LBW) for frontline healthcare workers in rural Sindh Province, Pakistan., Design: A community-based cross-sectional study., Setting: This study was conducted in the catchment area of Global Network's Maternal and Newborn Health Registry, Thatta, Sindh Province, Pakistan, from January to June 2023., Participants: Singleton live births irrespective of gestational age at birth., Reference Standard: Birth weight was measured using calibrated digital weighing scales in grams based on the average of three readings with minimal clothing., Index Test: FL was measured within 48 hours of birth using a rigid transparent plastic ruler in centimetres based on the average of three measurements., Primary Outcome: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), receiver operating characteristics curve and area under the curve with 95% CI were calculated. Euclidean distance was used to identify the cutoff of FL to identify LBW. A simple linear equation was created to predict the birth weight., Results: Out of 336 analysed newborns, 179 (53.3%) were male and 157 (46.7%) were female. The median birth weight was 2801 g (IQR: 2465-3057), of whom 88 (26.2%) were LBW. The median foot length was 7.9 cm (IQR: 7.6-8.1). For identifying LBW, the foot length cutoff was ≤7.6 cm with 90.3% sensitivity, 81.8% specificity, 63.8% PPV and 96.0% NPV. A FL of 7.6 cm predicted birth weight of 2459.4 g., Conclusion: Postnatal FL cutoff of ≤7.6 cm has adequate predictive value served as a simple, low-cost and reliable method to identify LBW for frontline healthcare providers in the rural settings of Thatta without calibrated weighing scales to triage LBW newborns in need of higher-level care., Trial Registration Number: NCT05515211., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: Reliable methods for identifying prematurity and low birth weight (LBW) are crucial to ending preventable deaths in newborns. This study explored healthcare providers' (HCPs) knowledge, practice, perceived barriers in assessing gestational age and birth weight and their referral methods for preterm and LBW infants. The study additionally assessed the potential of using a mobile app for the identification and referral decision of preterm and LBW., Methods: This qualitative descriptive study was conducted in Thatta District, Sindh, Pakistan. Participants, including doctors, nurses, lady health visitors, and midwives, were purposefully selected from a district headquarter hospital, and private providers in the catchment area of Global Network's Maternal and Newborn Health Registry (MNHR). Interviews were conducted using an interview guide after obtaining written informed consent. Audio recordings of the interviews were transcribed and analyzed using NVIVO® software with an inductive approach., Results: The HCPs had extensive knowledge about antenatal and postnatal methods for assessing gestational age. They expressed a preference for antenatal ultrasound due to the perceived accuracy, though accept practical barriers including workload, machine malfunctions, and cost. Postnatal assessment using the Ballard score was only undertaken sparingly due to insufficient training and subjectivity. All HCPs preferred electronic weighing scales for birth weight Barriers encountered included weighing scale calibration and battery issues. There was variation in the definition of prematurity and LBW, leading to delays in referral. Limited resources, inadequate education, and negative parent past experiences were barriers to referral. Foot length measurements were not currently being used. While mobile apps are felt to have potential, unreliable electricity supply and internet connectivity are barriers., Conclusion: The HCPs in this study were knowledgeable in terms of potential tools, but acknowledged the logistical and parental barriers to implementation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tikmani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Stillbirth rates are high and represent a substantial proportion of the under-5 mortality in low and middle-income countries (LMIC). In LMIC, where nearly 98% of stillbirths worldwide occur, few population-based studies have documented cause of stillbirths or the trends in rate of stillbirth over time., Methods: We undertook a prospective, population-based multi-country research study of all pregnant women in defined geographic areas across 7 sites in low-resource settings (Kenya, Zambia, Democratic Republic of Congo, India, Pakistan, and Guatemala). Staff collected demographic and health care characteristics with outcomes obtained at delivery. Cause of stillbirth was assigned by algorithm., Results: From 2010 through 2018, 573,148 women were enrolled with delivery data obtained. Of the 552,547 births that reached 500 g or 20 weeks gestation, 15,604 were stillbirths; a rate of 28.2 stillbirths per 1000 births. The stillbirth rates were 19.3 in the Guatemala site, 23.8 in the African sites, and 33.3 in the Asian sites. Specifically, stillbirth rates were highest in the Pakistan site, which also documented a substantial decrease in stillbirth rates over the study period, from 56.0 per 1000 (95% CI 51.0, 61.0) in 2010 to 44.4 per 1000 (95% CI 39.1, 49.7) in 2018. The Nagpur, India site also documented a substantial decrease in stillbirths from 32.5 (95% CI 29.0, 36.1) to 16.9 (95% CI 13.9, 19.9) per 1000 in 2018; however, other sites had only small declines in stillbirth over the same period. Women who were less educated and older as well as those with less access to antenatal care and with vaginal assisted delivery were at increased risk of stillbirth. The major fetal causes of stillbirth were birth asphyxia (44.0% of stillbirths) and infectious causes (22.2%). The maternal conditions that were observed among those with stillbirth were obstructed or prolonged labor, antepartum hemorrhage and maternal infections., Conclusions: Over the study period, stillbirth rates have remained relatively high across all sites. With the exceptions of the Pakistan and Nagpur sites, Global Network sites did not observe substantial changes in their stillbirth rates. Women who were less educated and had less access to antenatal and obstetric care remained at the highest burden of stillbirth., Study Registration: Clinicaltrials.gov (ID# NCT01073475).

Background: Tetanus in newborns, is an under-reported public health problem and a major cause of mortality in developing countries. This study aimed to determine the predictors and outcome of tetanus in newborn infants in the slums of Bin-Qasim town, Karachi, Pakistan., Methods: We conducted a case-control study at primary health care centers of slums of Bin-Qasim town, area located adjacent to Bin Qasim seaport in Karachi, from January 2003 to December 2013. Cases were infants aged ≤30 days with tetanus, as defined by the World Health Organization. Controls were newborn infants aged ≤30 days without Tetanus, who were referred for a checkup or minor illnesses. The case to control ratio was 1:2., Results: We analyzed 26 cases and 52 controls. The case fatality was 70.8%. We identified four independent predictors of Tetanus in newborns: maternal education (only religious education with no formal education OR 51.95; 95% CI 3.69-731), maternal non-vaccination (OR 24.55; 95% CI 1.01-131.77), lack of a skilled birth attendant (OR 44.00; 95% CI 2.30-840.99), and delivery at home (OR 11.54; 95% CI 1.01-131.77)., Conclusions: We identified several potentially modifiable socio-demographic risk factors for Tetanus in newborns, including maternal education and immunization status, birth site, and lack of a skilled birth attendant. Prioritization of these risk factors could be useful for planning preventive and cost-effective measures.

Introduction: Retinopathy of prematurity (ROP) is a treatable cause of blindness in neonates. In Pakistan, ROP is often not recognized early because screening and treatment programs are not yet in place in most neonatal units, even in tertiary care hospitals. It is hoped that this report will help inform medical professionals of the magnitude of the problem and help to design appropriate management strategies., Objectives: The aim was to determine the frequency of ROP in premature and very low birth weight (BW) neonates (BW<1500 g and gestational age (GA) <32 weeks)., Study Design: Cross-sectional study., Study Setting: Neonatal intensive care unit (NICU) of a tertiary care hospital in Karachi, Pakistan., Study Duration: From June 2009 to May 2010., Subjects and Methods: Neonates with a Birth weight (BW) <1500 g and Gestational Age (GA) <32 weeks who were admitted to the NICU and received an eye examination, or were referred for a ROP eye examination as an outpatient, were included in the study. GA was estimated from intrauterine ultrasound findings. Neonates with major congenital malformations, syndromes or congenital cataracts or tumors of the eyes, and those that died before the eye examination or did not attend the out patients department for an eye examination, were excluded. The neonatal eye examination was performed by a trained ophthalmologist at 4 or 6 weeks of age., Results: Out of 86 neonates, ROP was identified in nine neonates (10.5%) at the first eye examination. ROP was significantly associated with BW (P = 0.037), GA (P = 0.033), and chronological age (P<0.001)., Conclusions: we identified ROP in 10.5% of neonates at first eye examination. Significant associations between ROP and a GA<32 weeks and a BW<1500 g were also observed.we also stress that serial follow-up of neonates at risk for ROP is important when making a final diagnosis.