Efficacy of oral azithromycin in pregnant women living-in low-income neighborhoods with high-risk of reproductive tract infections to prevent preterm birth: study protocol of an individually randomized trial (pPAZI trial)

Background : India contributes to around one-fifth of all preterm births globally. Reproductive tract infections (RTIs), colonization of fetal membranes, and associated maternal inflammatory immune response are recognized as a major trigger associated with preterm birth. Azithromycin is a broad-spectrum macrolide antibiotic with anti-inflammatory properties and is commonly used for symptomatic reproductive tract infections. Evidence from African trials suggests that oral azithromycin in the antenatal period can substantially reduce preterm births in malaria holoendemic settings (where all pregnant women receive antimalarials as standard). It is unclear whether the intervention works in South Asian settings where malaria is not holoendemic. Methods : Using a individually randomized trial design, our primary study objective is to evaluate whether two doses of oral azithromycin (each dose 1 g/day for two consecutive days) compared to control (calcium 500 g/day for two consecutive days) during the antenatal period, i.e., at 20-24 weeks and at 28-32 weeks of gestation in Indian women with high-risk of reproductive tract infections can substantially prevent preterm birth and birth of other small vulnerable infants. The live newborns and their mothers will be followed up till 2 months after birth to estimate the intervention effect on neonatal sepsis, puerperal pyrexia, or sepsis in the mothers, antibiotic use during the first 2 months of birth, cumulative incidence of phenotypic macrolide resistance. Separate independent teams will conduct the intervention delivery and outcome assessment. Discussion : In low-middle income neighborhoods in India around half of the RTIs are often asymptomatic or unreported and contribute to preterm birth. Our approach involves screening pregnant women at-risk of RTI and using azithromycin as a preventive treatment for preterm birth reduction in Indian settings. Additionally, the study will generate data on the intervention effect on child growth, overall antibiotic use, and any concern related to emerging antimicrobial resistance. If the results show a beneficial effect, they could inform policy discussions on the potential use of azithromycin as a preventative treatment for women at risk of RTIs to reduce preterm birth rates. Trial registration : The trial has been registered prospectively in Clinical Trial Registry – India # CTRI/2024/10/075570, registered on 21 October 2024.