Perioperative Interventions: A Critical Omission in Delivery Mode Research on Neonatal Gene Expression

We extend our commendations to Carpén and colleagues for their pivotal research on neonatal gene expression patterns associated with delivery mode, as published in Acta Paediatrica. Their study compellingly demonstrates that vaginal delivery results in the upregulation of 95 genes involved in stress and immune-response pathways, including NF-κB signalling and cytokine production, thereby highlighting the significant biological impact of labour on neonatal development [1]. This transcriptional signature offers essential insights into the complexities of neonatal immune programming. Nevertheless, as obstetricians, we must underscore a critical limitation inherent in this research: the absence of comprehensive perioperative intervention data. It is well established that pharmacological agents administered during delivery—such as antibiotics and anesthetics—can markedly influence neonatal physiology. For instance, Ye et al. [2] have illustrated that the administration of azithromycin during labour reduces the incidence of maternal sepsis (OR 0.65) without a corresponding decrease in neonatal sepsis, suggesting that exposure to antibiotics may confound observed differences in gene expression. Such pharmacological interventions can modify inflammatory and oxidative stress pathways, potentially obscuring the authentic effects of delivery mechanics. The transcriptional variations observed in genes such as IL1B and TNF likely reflect a confluence of mechanical stress and hormonal influences. This notion is further supported by Liu et al. [3], who found that caesarean delivery is associated with the upregulation of immune genes in cord blood and an increase in inflammatory markers such as TNF-α and IFN-γ, indicating a pro-inflammatory state that may be linked to long-term health risks. Although the protein-level findings in Carpén's study did not achieve statistical significance after correction, they suggest the presence of a regulated inflammatory transition. We advocate for future investigations to incorporate detailed perioperative protocols, a comprehensive understanding of labour characteristics, and the circumstances surrounding emergency caesarean deliveries. By integrating obstetric covariates with multi-omics approaches, we will be better positioned to distinguish labour-specific effects from potential iatrogenic influences, thereby optimising perinatal management strategies. Shu Song: writing – original draft. Xiaomei Zhu: conceptualization, writing – review and editing, supervision. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.