Evaluation and interpretation of Hawthorne and other trial-related effects in Celiac Disease: A systematic review and meta-analysis
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Dorina Pjetraj1, Elena Lionetti1, Alfredo Pulvirenti2
1Department of Pediatrics, Marche Polytechnic University, via Tronto 10/a, Ancona 60126, Italy.
Background And Aims:
The Hawthorne effect describes outcome changes driven by awareness of observation rather than active intervention. In celiac disease (CeD), improvements reported in placebo or control arms suggest that observation may influence objective outcomes. We aimed to analyze the Hawthorne and other trial-related effects in treated CeD, focusing on histological changes of the small intestinal mucosa.
Methods:
We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. PubMed and ClinicalTrials.gov were searched from inception to October 2025 for studies enrolling patients with CeD on a gluten-free diet (GFD) reporting outcomes in placebo or control arms. Outcomes were synthesized qualitatively, and by a random-effects meta-analysis of pooled within-group changes in villous height-crypt depth (Vh/Cd) ratio.
Results:
Ten studies were included in the qualitative synthesis, and three studies (168 participants) provided histological data. Placebo or control groups showed improvements in symptoms, dietary adherence markers, and mucosal morphology. Meta-analysis demonstrated a significant increase in Vh/Cd ratio (median difference +0.25; 95% CI 0.11-0.39; p < 0.001) with low heterogeneity. This improvement suggests significant gluten contamination of the pre-trial GFD.
Conclusions:
In treated CeD, structured monitoring is associated with meaningful histological improvement independent of active intervention, that should be considered when interpreting trial outcomes.
