**Background**
Neonatal mortality remains a major contributor to under-five mortality in India, with infections such as sepsis, pneumonia, and meningitis causing more than a quarter of the approximately 1 million neonatal deaths each year. Low-birth-weight (LBW) infants are particularly vulnerable due to immune compromise, accounting for 40%–80% of neonatal deaths worldwide. Currently, no specific preventive interventions for neonatal sepsis exist beyond general measures like hand washing and exclusive breastfeeding. The ProSPoNS trial was designed to evaluate whether daily probiotic supplementation can reduce the incidence of neonatal sepsis in this high-risk group. This protocol describes the accompanying economic evaluation, which aims to determine whether the intervention, if efficacious, is also cost-effective—a critical question for resource allocation in public health programmes.
**Methods**
The economic evaluation adopts a societal perspective and a cost-utility analysis (CUA) design. The primary outcome is the incremental cost per disability-adjusted life year (DALY) averted. The time horizon is 6 months, with trial estimates extrapolated via decision-analytic modelling to the high-risk neonatal population in India. A discount rate of 3% will be applied. Both deterministic and probabilistic sensitivity analyses (PSA; 999 simulations) will be conducted to address uncertainty.
DATA SOURCES INCLUDE
(1) primary data collection from the RCT for demographic data, treatment effects, adverse events, and out-of-pocket (OOP) expenditures; (2) the Indian National Health Systems Costing Database (NHSCD) for healthcare system costs; (3) Global Burden of Disease estimates (2017) for utility/disability weights; and (4) published literature and the Sample Registration System (SRS) for background mortality.
Costs are categorised as direct medical (Vivomixx, home-based postnatal care, illness management, drugs, diagnostics, doctor consultation, bed charges), direct non-medical (travel, informal payments), and indirect (parental wage loss due to hospitalisation). Intervention costs will be obtained from primary data and programme budgetary records. OOP expenditure data will be collected on a subsample of 1998 neonates (333 per site) across all six study sites, calculated with 80% power and 5% significance assuming a mean OOP of ₹2003 (SD ₹3517) and an error margin of 7.5%.
The trial itself is a phase III, multicentre, double-blind, placebo-controlled RCT enrolling 6144 LBW infants (birth weight 1500–2500 g) aged 3–7 days at six sites across India (JIPMER Puducherry, MGIMS Wardha, KEM Pune, AIPH Bhubaneswar, SMC Meerut, LHMC Delhi). Infants are randomised 1:1 to receive 1 mL/day (10 billion CFU/mL) of Vivomixx or placebo for 30 days. Stratified randomisation by birth weight, sex, and study site uses an Interactive Web Response System (IWRS). Trained field workers conduct daily home visits for the first 7 days, then three times weekly until day 30, and weekly thereafter until day 60. They screen for signs of possible serious bacterial infection (PSBI) and refer symptomatic infants to study physicians for examination, blood culture, and sepsis screening. Primary outcomes are (1) sepsis (clinical symptoms plus positive blood culture, or sterile culture with ≥2 abnormal sepsis screen markers: absolute neutrophil count <1500/mm³, TLC <5000/mm³, immature-to-total neutrophil ratio >0.2, CRP >1.2 mg/dL, ESR >15 mm) and (2) PSBI (fever ≥38°C, hypothermia <35.5°C, not feeding well, convulsions, fast breathing ≥60 bpm, severe chest in-drawing, movement only when stimulated or no movement in infants <7 days). Secondary outcomes include clinical severe infection and critical illness.
**Key Results**
As this is a protocol paper describing planned methodology, no results are yet available. The study start date was 15 November 2022 with anticipated completion in December 2023. The economic evaluation will report incremental cost-effectiveness ratios (ICERs) as cost per DALY averted, along with 95% CIs from PSA. A budget impact analysis over 3–5 years and stakeholder consultations with neonatologists, policymakers, programme managers, and patient representatives are also planned.
**Clinical Implications**
If the probiotic intervention proves both efficacious and cost-effective, it could fill a critical gap in neonatal sepsis prevention for LBW infants in India, where no specific preventive intervention currently exists beyond hand hygiene and breastfeeding. The study's societal perspective and modelling approach aim to provide policymakers with robust evidence on whether the intervention should be incorporated into India's Reproductive, Maternal, Newborn, Child Health (RMNCH) programme under the National Health Mission. The authors note that this would be the first study evaluating cost-effectiveness of probiotic use for neonatal sepsis prevention in India, and that the modelling approach addresses limitations of single-RCT data by allowing exploration of scenarios beyond trial conditions and estimation of long-term outcomes.