Short-term survival benefit associated with neonatal clinical trial participation: An observational cohort study in The Gambia

Background Trial participation effect, defined as a change in clinical outcomes associated with trial enrolment regardless of allocation, is understudied in neonatal trials in low- and middle income countries (LMIC), despite its importance for trial design, interpretation, and research ethics. This study aimed to quantify the trial participation effect and explore potential ways by which research participation may influence neonatal survival. Methods This observational cohort study included neonates weighing <2Kg and aged <24h who were admitted to a Gambian referral hospital and either enrolled in a clinical trial comparing early versus later KMC (eKMC trial;2018 to 2020) or not enrolled due to operational constraints and hence received standard, non research care. All infants were prospectively followed until inpatient discharge or death. The eKMC trial previously found no important effect of early KMC on all cause neonatal mortality. For this analysis, inpatient mortality rates were compared using a generalised linear model, adjusting for baseline differences in participant characteristics. Prospectively collected data on small and sick newborn care readiness and delivery during the trial period were used to explore how trial participation may have influenced survival. Results A total of 545 neonates were included: 279 enrolled in the trial and 266 not enrolled, predominantly due to the absence of an available caregiver. Baseline characteristics were similar between groups, although differences were seen in twin status, place of birth, and age at admission. Trial participation was associated with an absolute reduction in inpatient mortality of 6.3% (22.6% (63/279) among enrolled versus 28.9% (77/266) among non enrolled) and a relative reduction of 29% (aRR 0.71, 95% CI 0.53 to 0.96). This association varied by season, with no evidence of benefit during the dry season (aRR 0.97, 95% CI 0.60 to 1.58), but a 40% reduction in adjusted mortality risk during the rainy season (aRR 0.60, 95% CI 0.41 to 0.87)(Interaction test: p=0.086). Trial participants had access to laboratory diagnostics and received more intensive clinical monitoring, including higher staffing ratios, continuous pulse oximetry, structured education of carers on neonatal danger signs, and enhanced scrutiny of clinical management compared to neonates receiving routine care. Conclusion Trial participation was associated with a substantial reduction in inpatient mortality, suggesting that participation effects should be considered when designing, interpreting, and reporting neonatal clinical trials in LMIC settings. The association was evident only during the rainy season. The participation effect may have been mediated by increased clinical oversight and monitoring, additional nursing support, and access to diagnostic investigations, all of which should be prioritised within routine care to accelerate progress towards SDG neonatal survival targets.