Chlamydia trachomatis infection screening to prevent preterm birth in Botswana: protocol for the HERA individually randomized controlled trial

Background Preterm birth is a leading cause of under-five mortality globally, rates remain intractable, and identifying modifiable risk factors is a global priority. Chlamydia trachomatis (CT) is a common and curable sexually transmitted infection (STI) that has been consistently associated with increased risk of preterm birth. However, in most low- and middle-income countries, antenatal care relies on syndromic management, missing most infections, which are asymptomatic. Individually randomized evidence evaluating the impact of antenatal CT infection screening and treatment on preterm birth is limited. The Healthy Expectancy through Routine Antenatal STI Screening (HERA) Trial aims to address this gap. Methods HERA is a prospective, individually randomized controlled trial that will enrol 2,000 pregnant women attending antenatal clinics in Gaborone, Botswana, and surrounding towns and villages. Eligibility criteria include: ≥15 years of age, ≤20 weeks’ gestation, first antenatal care (ANC) visit, and asymptomatic for CT infection (per standard of care screening at first ANC exam). Participants will be randomized 1:1 to standard-of-care (syndromic management) or intervention (standard-of-care plus CT and Neisseria gonorrhoeae (NG) infection screening and treatment if positive at first antenatal visit and in the third trimester). The primary outcome is preterm birth ( < 37 weeks 0 days gestation). Gestational age will be determined using menstrual dating if confirmed by ultrasound, or ultrasound alone if menstrual dating and ultrasound are not consistent. Secondary outcomes include low birth weight, very preterm birth, spontaneous preterm birth, and hypertensive disorders of pregnancy. Generalized Estimating Equations regression models will be used to estimate intervention effects. An integrated economic evaluation will assess costs, cost-effectiveness (cost per disability-adjusted life year averted), and budget impact. Discussion The HERA Trial will provide needed evidence on the effectiveness and economic value of antenatal CT infection screening and treatment among asymptomatic pregnant women. By focusing on women who are missed by syndromic management, the study is well positioned to inform national policy in Botswana and contribute to global guidelines on antenatal STI screening, particularly as affordable diagnostic technologies become more accessible. Ultimately, this work has the potential to improve maternal and neonatal outcomes through more effective STI detection and management during pregnancy. Trial registration This trial is registered with ClinicalTrials.gov (Identifier NCT07458802 Registered on: March 4, 2026)