Short-term survival benefit associated with neonatal clinical trial participation: An observational cohort study in The Gambia
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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 (LMICs), 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;2018-2020) or not enrolled due to operational constraints and hence received standard, non-research care. All infants were prospectively followed until in-patient discharge or death. The eKMC trial previously found no important effect of early KMC on all-cause neonatal mortality. For this analysis, in-patient 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 0.53–0.96). This association varied by season, with no evidence of benefit during the dry season (aRR 0.97, 95% CI 0.60-1.58), but a 40% reduction in adjusted mortality risk during the rainy season (aRR 0.60, 95% CI 0.41-0.87)(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.
Key messages
What is already known on this topic
It is widely perceived that patients in low- and middle-income countries (LMICs) may benefit from participation in clinical trials because of additional resources and access to otherwise-unavailable health services.
The magnitude of the trial participation effect on neonatal survival in LMICs has not previously been quantified
What this study adds
This is the first study from an LMIC to quantify an association between participation in an individually randomised neonatal clinical trial and reduced inpatient mortality.
Preterm/low birth weight (LBW) newborns enrolled in the eKMC trial had 29% lower adjusted relative risk of inpatient mortality compared to clinically comparable, non-enrolled infants receiving routine care at the same neonatal unit
The association between trial participation and reduced mortality was observed only during the rainy season (July-October), when mortality rates were highest, suggesting that participation effects may be most important in higher-mortality contexts.
Trial participants received enhanced clinical monitoring and higher-quality small and sick newborn care (SSNC), including continuous pulse oximetry, higher nursing availability, rigorous safety oversight, and access to laboratory diagnostics, especially blood cultures.
These findings demonstrate that preterm/LBW newborns can safely participate in clinical trials in resource-limited settings when essential components of SSNC are in place.
The study identified key elements of SSNC that should be prioritised within health-system strengthening efforts to accelerate progress towards SDG 3.2.
How this study might affect research, practice or policy
Research: These findings provide the first quantifiable estimate of a neonatal trial participation effect in a low-resource, high-mortality hospital setting. This information could improve the accuracy of sample size calculations and interpretation of trial findings, reducing the risk of underpowered studies and research inefficiency. The findings also highlight the ethical importance of measuring and reporting trial participation effects, particularly in settings where research activities may strengthen the quality of routine newborn care and where effects may be greatest during periods of high mortality risk.
Clinical practice: Key components of SSNC that differed between trial participants and non-participants, included continuous monitoring, higher nursing availability, regular safety oversight, and access to microbiological diagnostics. Strengthening these elements within routine care could improve outcomes for preterm/LBW neonates regardless of research participation and especially in highest mortality settings.
Policy: Investments in neonatal monitoring capacity, nursing, safety and clinical governance, and microbiology services should be prioritised within national newborn health strategies to accelerate progress towards SDG3.2. The greater impact observed during the high-mortality rainy season suggests that such investments may yield the largest survival gains in the highest burden, vulnerable global contexts.
