Uncovering the causes and socio-demographic constructs of stillbirths and neonatal deaths in an urban slum of Karachi.

INTRODUCTION: Neonatal deaths and stillbirths are significant public health concerns in Pakistan, with an estimated stillbirth rate of 43 per 1,000 births and a neonatal mortality rate of 46 deaths per 1,000 live births. Limited access to obstetric care, poor health seeking behaviors and lack of quality healthcare are the leading root causes for stillbirths and neonatal deaths. Rehri Goth, a coastal slum in Karachi, faces even greater challenges due to extreme poverty, and inadequate infrastructure. This study aims to investigate the causes and pathways leading to stillbirths and neonatal deaths in Rehri Goth to develop effective maternal and child health interventions. METHODS: A mixed-method cohort study was nested with the implementation of large maternal, neonatal and child health program, captured all stillbirths and neonatal death during the period of May 2014 till June 2018. The Verbal and Social Autopsy (VASA) tool (WHO 2016) was used to collect primary data from all death events to determine the causes as well as the pathways. Interviews were conducted both retrospectively and prospectively with mothers and caregivers. Two trained physicians reviewed the VASA form and the medical records (if available) and coded the cause of death blinded to each other. Descriptive analysis was used to categorize stillbirth and neonatal mortality data into high- and low-mortality clusters, followed by chi-square tests to explore associations between categories, and concluded with a qualitative analysis. RESULTS: Out of 421 events captured, complete VASA interviews were conducted for 317 cases. The leading causes of antepartum stillbirths were pregnancy-induced hypertension (22.4%) and maternal infections (13.4%), while obstructed labor was the primary cause of intrapartum stillbirths (38.3%). Neonatal deaths were primarily caused by perinatal asphyxia (36.1%) and preterm birth complications (27.8%). The qualitative analysis on a subset of 40 death events showed that health system (62.5%) and community factors (37.5%) contributing to adverse outcomes, such as delayed referrals, poor triage systems, suboptimal quality of care, and delayed care-seeking behaviors. CONCLUSION: The study provides an opportunity to understand the causes of stillbirths and neonatal deaths in one of the impoverished slums of Karachi. The data segregation by clusters as well as triangulation with qualitative analysis highlight the needs of evidence-based strategies for maternal and child health interventions in disadvantaged communities.

Newborn weight change and predictors of underweight in the neonatal period in Guinea-Bissau, Nepal, Pakistan and Uganda.

In low- and middle-income countries (LMIC), growth impairment is common; however, the trajectory of growth over the course of the first month has not been well characterised. To describe newborn growth trajectory and predictors of growth impairment, we assessed growth frequently over the first 30 days among infants born ≥2000 g in Guinea-Bissau, Nepal, Pakistan and Uganda. In this cohort of 741 infants, the mean birth weight was 3036 ± 424 g. For 721 (98%) infants, weight loss occurred for a median of 2 days (interquartile range, 1-4) following birth until weight nadir was reached 5.9 ± 4.3% below birth weight. At 30 days of age, the mean weight was 3934 ± 592 g. The prevalence of being underweight at 30 days ranged from 5% in Uganda to 31% in Pakistan. Of those underweight at 30 days of age, 56 (59%) had not been low birth weight (LBW), and 48 (50%) had reached weight nadir subsequent to 4 days of age. Male sex (relative risk [RR] 2.73 [1.58, 3.57]), LBW (RR 6.41 [4.67, 8.81]), maternal primiparity (1.74 [1.20, 2.51]) and reaching weight nadir subsequent to 4 days of age (RR 5.03 [3.46, 7.31]) were highly predictive of being underweight at 30 days of age. In this LMIC cohort, country of birth, male sex, LBW and maternal primiparity increased the risk of impaired growth, as did the modifiable factor of delayed initiation of growth. Interventions tailored to infants with modifiable risk factors could reduce the burden of growth impairment in LMIC.

Community-based asthma assessment in young children: adaptations for a multicentre longitudinal study in South Asia.

Background: Systematic assessment of childhood asthma is challenging in low- and middle-income country (LMIC) settings due to the lack of standardised and validated methodologies. We describe the contextual challenges and adaptation strategies in the implementation of a community-based asthma assessment in four resource-constrained settings in Bangladesh, India, and Pakistan. Method: We followed a group of children of age 6-8 years for 12 months to record their respiratory health outcomes. The study participants were enrolled at four study sites of the 'Aetiology of Neonatal Infection in South Asia (ANISA)' study. We standardised the research methods for the sites, trained field staff for uniform data collection and provided a 'Child Card' to the caregiver to record the illness history of the participants. We visited the children on three different occasions to collect data on respiratory-related illnesses. The lung function of the children was assessed in the outreach clinics using portable spirometers before and after 6-minute exercise, and capillary blood was examined under light microscopes to determine eosinophil levels. Results: We enrolled 1512 children, 95.5% (1476/1512) of them completed the follow-up, and 81.5% (1232/1512) participants attended the lung function assessment tests. Pre- and post-exercise spirometry was performed successfully in 88.6% (1091/1232) and 85.7% (1056/1232) of children who attempted these tests. Limited access to health care services, shortage of skilled human resources, and cultural diversity were the main challenges in adopting uniform procedures across all sites. Designing the study implementation plan based on the local contexts and providing extensive training of the healthcare workers helped us to overcome these challenges. Conclusion: This study can be seen as a large-scale feasibility assessment of applying spirometry and exercise challenge tests in community settings of LMICs and provides confidence to build capacity to evaluate children's respiratory outcomes in future translational research studies.

Nutritional support and prophylaxis of azithromycin for pregnant women to improve birth outcomes in peri-urban slums of Karachi, Pakistan-a protocol of multi-arm assessor-blinded randomized controlled trial (Mumta PW trial).

BACKGROUND: Maternal undernutrition is critical in the etiology of poor perinatal outcomes and accounts for 20% of small-for-gestational-age (SGA) births. High levels of food insecurity, antenatal undernourishment, and childhood undernutrition necessitate the supplementation of fortified balanced energy protein (BEP) during pregnancy in low-income settings especially with scarce literature available in this subject. Hence, this paper extensively covers the protocol of such a trial conducted in an urban slum of Karachi, Pakistan. METHODS: The trial is community-based, open-labelled, four-arm, and randomized controlled that will include parallel group assignments with a 1:1:1:1 allocation ratio in low-income squatter settlements in urban Karachi, Pakistan. All pregnant women (PW), if identified between > 8 and < 19 weeks of gestation based on ultrasound, will be offered routine antenatal care (ANC) counseling and voluntary participation in the trial after written informed consent. A total number of 1836 PW will be enrolled with informed consent and randomly allocated to one of the four arms receiving: (1) ANC counseling only (control group), (2) ANC counseling plus BEP supplement (intervention arm 1), (3) ANC counseling plus BEP supplement plus 2 doses azithromycin (intervention arm 2), or (4) ANC counseling plus BEP supplement plus daily single dose of nicotinamide and choline (intervention arm 3). TRIAL REGISTRATION: ClinicalTrials.gov NCT04012177 . Registered on July 9, 2019.

Feasibility, usability and acceptability of paediatric lung ultrasound among healthcare providers and caregivers for the diagnosis of childhood pneumonia in resource-constrained settings: a qualitative study.

OBJECTIVES: Paediatric pneumonia burden and mortality are highest in low-income and middle-income countries (LMIC). Paediatric lung ultrasound (LUS) has emerged as a promising diagnostic tool for pneumonia in LMIC. Despite a growing evidence base for LUS use in paediatric pneumonia diagnosis, little is known about its potential for successful implementation in LMIC. Our objectives were to evaluate the feasibility, usability and acceptability of LUS in the diagnosis of paediatric pneumonia. DESIGN: Prospective qualitative study using semistructured interviews SETTING: Two referral hospitals in Mozambique and Pakistan PARTICIPANTS: A total of 21 healthcare providers (HCPs) and 20 caregivers were enrolled. RESULTS: HCPs highlighted themes of limited resource availability for the feasibility of LUS implementation, including perceived high cost of equipment, maintenance demands, time constraints and limited trained staff. HCPs emphasised the importance of policymaker support and caregiver acceptance for long-term success. HCP perspectives of usability highlighted ease of use and integration into existing workflow. HCPs and caregivers had positive attitudes towards LUS with few exceptions. Both HCPs and caregivers emphasised the potential for rapid, improved diagnosis of paediatric respiratory conditions using LUS. CONCLUSIONS: This was the first study to evaluate HCP and caregiver perspectives of paediatric LUS through qualitative analysis. Critical components impacting feasibility, usability and acceptability of LUS for paediatric pneumonia diagnosis in LMIC were identified for initial deployment. Future research should explore LUS sustainability, with a particular focus on quality control, device maintenance and functionality and adoption of the new technology within the health system. This study highlights the need to engage both users and recipients of new technology early in order to adapt future interventions to the local context for successful implementation. TRIAL REGISTRATION NUMBER: NCT03187067.

Performance of lung ultrasound in the diagnosis of pediatric pneumonia in Mozambique and Pakistan.

INTRODUCTION: Improved pneumonia diagnostics are needed in low-resource settings (LRS); lung ultrasound (LUS) is a promising diagnostic technology for pneumonia. The objective was to compare LUS versus chest radiograph (CXR), and among LUS interpreters, to compare expert versus limited training with respect to interrater reliability. METHODS: We conducted a prospective, observational study among children with World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) chest-indrawing pneumonia at two district hospitals in Mozambique and Pakistan, and assessed LUS and CXR examinations. The primary endpoint was interrater reliability between LUS and CXR interpreters for pneumonia diagnosis among children with WHO IMCI chest-indrawing pneumonia. RESULTS: Interrater reliability was excellent for expert LUS interpreters, but poor to moderate for expert CXR interpreters and onsite LUS interpreters with limited training. CONCLUSIONS: Among children with WHO IMCI chest-indrawing pneumonia, expert interpreters may achieve substantially higher interrater reliability for LUS compared to CXR, and LUS showed potential as a preferred reference standard. For point-of-care LUS to be successfully implemented for the diagnosis and management of pneumonia in LRS, the clinical environment and amount of appropriate user training will need to be understood and addressed.

Nutritional support for lactating women with or without azithromycin for infants compared to breastfeeding counseling alone in improving the 6-month growth outcomes among infants of peri-urban slums in Karachi, Pakistan-the protocol for a multiarm assessor-blinded randomized controlled trial (Mumta LW trial).

BACKGROUND: Globally, 45% of under-five deaths are either directly or indirectly attributable to malnutrition, and most of these deaths are in low- and middle-income countries (LMICs). Children are particularly vulnerable in the first 6 months of life. An estimated 4.7 million infants under the age of 6 months are moderately wasted, whereas 3.8 million are severely wasted. Although the children of malnourished women have an increased risk of stunting and wasting, there is little information on this issue. METHODS: This is a community-based, open-label, multiarm randomized controlled trial that will include parallel group assignments with a 1:1:1 allocation ratio in low-income squatter settlements in urban Karachi, Pakistan. The women in the control group (control arm) will receive standard counseling only, whereas the lactating women in the first intervention group (intervention arm 1) will receive two sachets of balanced energy protein (BEP) supplementation per day from enrollment until the infant reaches 6 months of age. The lactating women in the second intervention group (intervention arm 2) will receive the same BEP supplementation as those in intervention arm 1 while their babies will also receive a single stat dose (20 mg/kg orally) of azithromycin at 42 days. The primary outcome will be the relative length velocity from 0 to 6 months by intervention arm. The primary analysis will be intention-to-treat analysis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03564652 . Registered on 21 June 2018.

Recurrence of WHO-defined fast breathing pneumonia among infants, its occurrence and predictors in Pakistan: a nested case-control analysis.

OBJECTIVES: Studies in low-income and middle-income countries have shown an adverse association between environmental exposures including poverty. There is little literature from South Asia. We aimed to test the associations between housing, indoor air pollution and children's respiratory health and recurrent fast breathing pneumonia in a poor urban setting in Pakistan. SETTING: Primary health centres in a periurban slum in Karachi, Pakistan. METHODS: Nested matched case-control study within a non-inferiority randomised controlled trial of fast breathing pneumonia (Randomised Trial of Amoxicillin vs Placebo for Pneumonia (RETAPP)) in periurban slums of Karachi, Pakistan. Cases were children aged 2-60 months enrolled in RETAPP with fast breathing pneumonia who presented again with fast breathing between 8 weeks and 12 months after full recovery. Controls, selected in a 2:1 ratio, were age-matched participants who did not represent. Multivariable conditional logistic regression analysis was undertaken to explore associations with potentially modifiable environmental predictors including housing type, indoor air quality, exposure to tobacco smoke, outdoor pollution, household crowding, water and sanitation quality, nutritional status, immunisation completeness, breast feeding and airways hyperactivity. RESULTS: Fast breathing recurred in 151 (3.7%) of children out of the total (4003) enrolled in the trial. Poor-quality housing of either katcha or mixed type strongly predicted recurrence with adjusted matched ORs 2.43 (95% CI 1.02 to 5.80) and 2.44 (1.11 to 5.38), respectively. Poor air quality, cooking fuel, inadequate ventilation, nutritional status, water, sanitation and hygiene (WASH) index, wheeze at first presentation and group of initial trial assignment were not independently predictive of recurrence. CONCLUSION: Poor-quality housing independently predicted recurrence of fast breathing pneumonia. TRIAL REGISTRATION NUMBER: NCT02372461.

A Community-Based Survey on Health-Care Utilization for Pneumonia in Children in Peri-Urban Slums of Karachi, Pakistan.

Pneumonia, as defined by WHO, is a syndromic diagnosis characterized by presence of cough or difficult breathing. Presentation to health-care provider depends on timely identification of signs and symptoms by caretakers. We explored patterns of health-care utilization among caretakers of a randomly selected sample of 1,152 children aged 2-59 months, residing in low-income settlements of Karachi, Pakistan. Information on household demographics, occurrence of pneumonia-specific symptoms, care seeking, air quality, and knowledge regarding preventive measures for pneumonia was collected. Predictors of care seeking were estimated using weighted logistic regression. Prevalence of pneumonia with cough and rapid or difficulty in breathing was found to be 40.8% and 37.1% in infants (2-11 months) and children (12-59 months), respectively. Ninety-five percentage of caretakers sought care, 68.5% privately. Odds ratios (ORs) for independent predictors of care-seeking were as follows: younger age of child (infants compared with children), 3.60 (95% CI = 2.65-4.87); caretaker with primary education compared with none, 3.40 (2.46-4.70); vaccine awareness, 1.65 (1.45-1.87); and breastfeeding awareness, 1.32 (1.13-1.53). Presence of symptoms such as fever OR, 1.51 (1.30-1.76); tachypnea, 1.57 (1.35-1.83); chest indrawing, 2.56 (2.05-3.18); persistent vomiting, 1.69 (1.37-2.09); and recurrent illness, 2.57 (2.23-2.97) were also predictive. There is high health-care utilization for pneumonia with the skewed presentation toward private services. Strategies should be focused on making pneumonia care standardized, efficient and affordable, especially in the private sector.

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.

BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation.

Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial.

BACKGROUND: Parenteral antibiotic therapy for young infants (aged 0-59 days) with suspected sepsis is sometimes not available or feasible in countries with high neonatal mortality. Outpatient treatment could save lives in such settings. We aimed to assess the equivalence of two simplified antibiotic regimens, comprising fewer injections and oral rather than parenteral administration, compared with a reference treatment for young infants with clinical severe infection. METHODS: We undertook the Simplified Antibiotic Therapy Trial (SATT), a three-arm, randomised, open-label, equivalence trial in five communities in Karachi, Pakistan. We enrolled young infants (aged 0-59 days) who either presented at a primary health-care clinic or were identified by a community health worker with signs of clinical severe infection. We included infants who were not critically ill and whose family refused admission. We randomly assigned infants to either intramuscular procaine benzylpenicillin and gentamicin once a day for 7 days (reference); oral amoxicillin twice daily and intramuscular gentamicin once a day for 7 days; or intramuscular procaine benzylpenicillin and gentamicin once a day for 2 days followed by oral amoxicillin twice daily for 5 days. The primary outcome was treatment failure within 7 days of enrolment and the primary analysis was per protocol. We judged experimental treatments as efficacious as the reference if the upper bound of the 95% CI for the difference in treatment failure was less than 5·0. This trial is registered at ClinicalTrials.gov, number NCT01027429. FINDINGS: Between Jan 1, 2010, and Dec 26, 2013, 2780 infants were deemed eligible for the trial, of whom 2453 (88%) were enrolled. Because of inadequate clinical follow-up or treatment adherence, 2251 infants were included in the per-protocol analysis. 820 infants (747 per protocol) were assigned the reference treatment of procaine benzylpenicillin and gentamicin, 816 (751 per protocol) were allocated amoxicillin and gentamicin, and 817 (753 per protocol) were assigned procaine benzylpenicillin, gentamicin, and amoxicillin. Treatment failure within 7 days of enrolment was reported in 90 (12%) infants who received procaine benzylpenicillin and gentamicin (reference), 76 (10%) of those given amoxicillin and gentamicin (risk difference with reference -1·9, 95% CI -5·1 to 1·3), and 99 (13%) of those treated with procaine benzylpenicillin, gentamicin, and amoxicillin (risk difference with reference 1·1, -2·3 to 4·5). INTERPRETATION: Two simplified antibiotic regimens requiring fewer injections are equivalent to a reference treatment for young infants with signs of clinical severe infection but without signs of critical illness. The use of these simplified regimens has the potential to increase access to treatment for sick young infants who cannot be referred to hospital. FUNDING: The Saving Newborn Lives initiative of Save the Children, through support from the Bill & Melinda Gates, and by WHO and USAID.

Predictors and outcome of tetanus in newborns in slum areas of Karachi City: a case control study.

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.

Simplified antibiotic regimens for the management of clinically diagnosed severe infections in newborns and young infants in first-level facilities in Karachi, Pakistan: study design for an outpatient randomized controlled equivalence trial.

BACKGROUND: Infection in young infants is a major cause of morbidity and mortality in low-middle income countries, with high neonatal mortality rates. Timely case management is lifesaving, but the current standard of hospitalization for parenteral antibiotic therapy is not always feasible. Alternative, simpler antibiotic regimens that could be used in outpatient settings have the potential to save thousands of lives. METHODS: This trial aims to determine whether 2 simplified antibiotic regimens are equivalent to the reference therapy with 7 days of once-daily (OD) intramuscular (IM) procaine penicillin and gentamicin for outpatient management of young infants with clinically presumed systemic bacterial infection treated in primary health-care clinics in 5 communities in Karachi, Pakistan. The reference regimen is close to the current recommendation of the hospital-based intravenous ampicillin and gentamicin therapy for neonatal sepsis. The 2 comparison arms are (1) IM gentamicin OD and oral amoxicillin twice daily for 7 days; and (2) IM penicillin and gentamicin OD for 2 days, followed by oral amoxicillin twice daily for 5 days; 2250 "evaluable" infants will be enrolled. The primary outcome of this trial is treatment failure (death, deterioration or lack of improvement) within 7 days of enrollment. Results are expected by early 2014. DISCUSSION: This trial will determine whether simplified antibiotic regimens with fewer injections in combination with high-dose amoxicillin are equivalent to 7 days of IM procaine penicillin and gentamicin in young infants with clinical severe infection. Results will have program and policy implications in countries with limited access to hospital care and high burden of neonatal deaths.