Clarifying power‐mediated aerosol effects and enhancing statistical rigour in <i>in utero</i> electronic cigarette exposure research

To the Editor Mills et al. (2025) employed a mouse model of in utero electronic cigarette exposure to systematically track cerebrovascular responses and neurocognitive outcomes across different developmental stages in the offspring. Their study clearly delineates the distinct roles of ‘power/aerosol burden’ versus ‘nicotine’ in vascular and neural outcomes, rendering this design and its conclusions highly valuable for periconceptional exposure research (Mills et al., 2025). We wish to pose a focused question that can be addressed using the existing publicly available data and to offer two specific, actionable suggestions for supplementary analyses. Table 1 indicates that the in-chamber mass concentration under the 30 W condition was substantially higher than that under the 5 W condition (∼917–1346 vs. 163–231 mg/m3), with ACh-induced endothelium-dependent dilation (EDD) exhibiting more pronounced blunting in the 30 W group (Burrage et al., 2021). We suggest conducting an analysis of covariance (ANCOVA) or partial correlation at the group mean level: using the maximum ACh response in each group/age stratum as the dependent variable, ‘power (5 vs. 30 W)’ and ‘nicotine (0 vs. 50 mg/ml)’ as independent variables and in-chamber mass concentration as a covariate while reporting the partial η2 for power and nicotine. If the main effect of power diminishes or disappears after controlling for mass concentration, this would suggest that the mediation chain ‘power → exposure burden → EDD’ more closely approximates the true causal pathway; conversely, persistence of the effect would support further exploration of ‘power-related non-dose mechanisms’ (e.g. heating profiles or thermal degradation products) (Mills et al., 2025). To contextualize within the broader evidence landscape, we provide a concise cross-comparative overview (selective) based on the relevant studies cited in the original article (Mills et al., 2025): These findings align consistently with the results reported in your journal's publication, indicating that aerosol exposure alone – independent of nicotine – can induce offspring vascular dysfunction; thus establishing a quantifiable link between ‘dose (mg/m3) and response’ would facilitate cross-study integration (Aboaziza et al., 2023; Mills et al., 2024). In describing the ‘non-significant effect of nicotine on EDD’, supplementing group differences across age strata with Hedges' g (or 95% confidence intervals for percentage differences) and conducting two one-sided tests for equivalence (TOST) with predefined clinically negligible effect boundaries would provide a more robust interpretation than the conventional null hypothesis significance testing (NHST) framing of ‘non-significance implies no difference’. The article characterizes dilation via ‘changes in initial lumen diameter’; to mitigate potential confounding by structural differences (e.g. wall thickness/lumen diameter influencing Δdiameter), we recommend converting the ACh response to a percentage of the passive maximum diameter and reporting it accordingly (as passive/active myogenic curves were assessed at 12 months, suggesting this information is available). This would strengthen the conclusion of ‘functional endothelial impairment’ over ‘morphological differences’ (Mills et al., 2025). In summary we commend the authors for their meticulous work in periconceptional electronic cigarette exposure research. Their inclusion would further solidify the key conclusions regarding ‘power-related dose-response relationships’ and the ‘equivalence of nicotine to cerebrovascular EDD’. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. Writing – original draft: Y.W., C.L. and Z.L. Writing – review and editing: S.L. and J.H. Beijing Natural Science Foundation (7244290).