Study protocol for economic evaluation of probiotic intervention for prevention of neonatal sepsis in 0-2-month old low-birth weight infants in India: the ProSPoNS trial

Introduction: The ProSPoNS trial is a multicentre, double-blind, placebo-controlled trial to evaluate the role of probiotics in prevention of neonatal sepsis. The present protocol describes the data and methodology for the cost utility of the probiotic intervention alongside the controlled trial. Methods and analysis: A societal perspective will be adopted in the economic evaluation. Direct medical and non-medical costs associated with neonatal sepsis and its treatment would be ascertained in both the intervention and the control arm. Intervention costs will be facilitated through primary data collection and programme budgetary records. Treatment cost for neonatal sepsis and associated conditions will be accessed from Indian national costing database estimating healthcare system costs. A cost–utility design will be employed with outcome as incremental cost per disability-adjusted life year averted. Considering a time-horizon of 6 months, trial estimates will be extrapolated to model the cost and consequences among high-risk neonatal population in India. A discount rate of 3% will be used. Impact of uncertainties present in analysis will be addressed through both deterministic and probabilistic sensitivity analysis. Ethics and dissemination: Has been obtained from EC of the six participating sites (MGIMS Wardha, KEM Pune, JIPMER Puducherry, AIPH, Bhubaneswar, LHMC New Delhi, SMC Meerut) as well as from the ERC of LSTM, UK. A peer-reviewed article will be published after completion of the study. Findings will be disseminated to the community of the study sites, with academic bodies and policymakers. Registration: The protocol has been approved by the regulatory authority (Central Drugs Standards Control Organisation; CDSCO) in India (CT-NOC No. CT/NOC/17/2019 dated 1 March 2019). The ProSPoNS trial is registered at the Clinical Trial Registry of India (CTRI). Registered on 16 May 2019. Trial registration number: CTRI/2019/05/019197; Clinical Trial Registry

WHO global vaccine safety multi-country collaboration project on safety in pregnancy: Assessing the level of diagnostic certainty using standardized case definitions for perinatal and neonatal outcomes and maternal immunization.

Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1-3 of BC diagnostic certainty). Over a one-year period (2019-2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies

Operational lessons learned in conducting an international study on pharmacovigilance in pregnancy in resource-constrained settings: The WHO Global Vaccine safety Multi-Country collaboration project.

The WHO Global Vaccine Safety Multi-Country Collaboration study on safety in pregnancy aims to estimate the minimum detectable risk for selected perinatal and neonatal outcomes and assess the applicability of standardized case definitions for study outcomes and maternal immunization in low- and middle-income countries (LMICs). This paper documents the operational lessons learned from the study. A prospective observational study was conducted across 21 hospitals in seven countries. All births occurring at sites were screened to identify select perinatal and neonatal outcomes from May 2019 to August 2020. Up to 100 cases per outcome were recruited to assess the applicability of standardized case definitions. A multi-pronged study quality assurance plan was implemented. The impact of the COVID-19 pandemic on site functioning and project implementation was also assessed. Multi-layered ethics and administrative approvals, limited clinical documentation, difficulty in identifying outcomes requiring in-hospital follow-up, and poor quality internet connectivity emerged as important barriers to study implementation. Use of electronic platforms, application of a rigorous quality assurance plan with frequent interaction between the central and site teams helped improve data quality. The COVID-19 pandemic disrupted data collection for up to 6 weeks in some sites. Our study succeeded in establishing an international hospital-based surveillance network for evaluating perinatal and neonatal outcomes using common study protocol and procedures in geographically diverse sites with differing levels of infrastructure, clinical and health-utilization practices. The enhanced surveillance capacity of participating sites shall help support future pharmacovigilance efforts for pregnancy interventions

Estimating baseline rates of adverse perinatal and neonatal outcomes using a facility-based surveillance approach: A prospective observational study from the WHO Global Vaccine Safety Multi-Country Collaboration on safety in pregnancy.

BACKGROUND: Most perinatal and neonatal deaths occur in low- and middle-income countries (LMICs), yet, quality data on burden of adverse outcomes of pregnancy is limited in such countries. METHODS: A network of 21 maternity units, across seven countries, undertook surveillance for low birthweight, preterm birth, small for gestational age (SGA), stillbirths, congenital microcephaly, in-hospital neonatal deaths, and neonatal infections in a cohort of over 85,000 births from May 2019 - August 2020. For each outcome, site-specific rates per 1,000 livebirths (or per 1,000 total births for stillbirth) and 95% confidence intervals (CI) were calculated. Descriptive sensitivity analysis was conducted to gain insight regarding underreporting of four outcomes at 16 sites. FINDINGS: Estimated rates varied across countries and sites, ranging between 43·3-329·5 and 21·4-276·6/1000 livebirths for low birthweight and preterm birth respectively and 11·8-81/1,000 livebirths for SGA. No cases of congenital microcephaly were reported by three sites while the highest estimated rate was 13/1,000 livebirths. Neonatal infection and neonatal death rates varied between 1·8-73 and 0-59·9/1000 livebirths respectively while stillbirth rates ranged between 0-57·1/1000 total births across study sites. Results from the sensitivity analysis confirmed the underreporting of congenital microcephaly and SGA in our study. INTERPRETATION: Our study establishes site-specific baseline rates for important adverse perinatal and neonatal outcomes and addresses a critical evidence gap towards improved monitoring of benefits and risks of emerging pregnancy and neonatal interventions. FUNDING: The study was sponsored by the World Health Organization with funding from the Bill and Melinda Gates Foundation

Association of meteorological parameters with intussusception in children aged under 2 years: results from a multisite bidirectional surveillance over 7 years in India

Objectives The study aimed to document the association between intussusception in Indian children and meteorological parameters and examine regional variations.Design A bidirectional (retrospective and prospective) surveillance between July 2010 and September 2017.Setting At 20 hospitals in India, retrospective case record review during July 2010 and March 2016 and prospective surveillance during April 2016 and September 2017 were performed.Participants 2161 children aged 2–24 months with first intussusception episode were included.Interventions The monthly mean meteorological parameters (temperature, sunshine, rainfall, humidity and wind speed) for the study sites were collected.Methods The association between monthly intussusception cases and meteorological parameters was examined at pooled, regional and site levels using Pearson (r) and Spearman’s rank-order (ρ) correlation, factorial analysis of variance, and Poisson regression or negative binomial regression analyses.Results The intussusception cases were highest in summer and lowest in autumn seasons. Pearson correlation analysis showed that temperature (r=0.056; p<0.05), wind speed (r=0.134; p<0.01) and humidity (r=0.075; p<0.01) were associated with monthly intussusception cases. Spearman’s rank-order correlation analysis found that temperature (ρ=0.049; p<0.05), wind speed (ρ=0.096; p<0.01) and sunshine (ρ=0.051; p<0.05) were associated with monthly intussusception cases. Poisson regression analysis resulted that monthly intussusception case was associated with rising temperature (North region, p<0.01 and East region, p<0.05), sunshine (North region, p<0.01), humidity (East region, p<0.01) and wind speed (East region, p<0.01). Factorial analysis of variance revealed a significant seasonal difference in intussusception cases for pooled level (p<0.05), 2–6 months age group (p<0.05) and North region (p<0.01). Significant differences in intussusception cases between summer and autumn seasons were observed for pooled (p<0.01), children aged 2–6 months (p<0.05) and 7–12 months (p<0.05).Conclusions Significant correlations between intussusception cases and temperature, humidity, and wind speed were observed at pooled and regional level in India. A peak in summer months was noted, which may be used for prediction, early detection and referral for appropriate management of intussusception