Comment on Francisca de Castro Mendes et al.Jiatao Li 1*, Fusen Chen1*, Tiejuan Shao1,21 College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.2Center for Innovative Basic Research in Autoimmune Diseases in Medicine, Hangzhou, 310053, ChinaJiatao Li，Fusen Chen contributed equally.Jiatao Li，1210812074@qq.comFusen Chen，2641214515@qq.comCorresponding author: Prof. Tiejuan Shao, tiejuanshao@zcmu.edu.cnFunding: Financial support for this research was provided by grants from the research was funded by National Key R&D Program of China (No.2022YFC3501204).Conflict of interest statement: We declared no competing interests.Dear EditorWe read with great interest the article, ” Maternal caffeine intake during pregnancy and the risk of childhood asthma by 10 years of age—Evidence from The Generation XXI birth cohort study,” published in the Pediatr Allergy Immunol [1]. This study provided valuable insights into the significant correlation between caffeine intake during pregnancy and the 10-year development of asthma. Maternal caffeine intake during pregnancy is estimated to be about 93 mg/day, which can decrease the risk of asthma in children by 10 years of age. Nonetheless, we believe several aspects warrant further exploration and discussion.First, we would like to emphasize the importance of P450 1A2 (CYP1A2) genotype information in the relationship between caffeine metabolism and asthma. polymorphic cytochrome CYP1A2 is the main enzyme directly responsible for caffeine metabolism. CYP1A2 can induce excessive production of reactive oxygen species (ROS), causing oxidative stress and inflammatory responses, leading to chronic inflammatory diseases including asthma [2].CYP1A2*1A allele homozygote carriers are caffeine “fast”metabolizers, while CYP1A2*1F variant allele carriers are caffeine“slow”metabolizers. The duration of caffeine exposure caused by genetic metabolic differences may be an important factor between caffeine intake during pregnancy and asthma development by 10 years[3].Second, the confounding effect of birth mode on the conclusion should be considered. In Portugal, the average cesarean section rate from 2013 to 2020 was 29.42% [4]. The study found that the risk of asthma in children born by cesarean section increased by 20%[5]. There is a link between cesarean section and the risk of childhood asthma [6]. Reducing cesarean section can prevent childhood asthma.Third, information on caffeine intake in this study were based on face-to-face interviews with structured questionnaires. While these are validated instruments, outcome measures are particularly vulnerable to performance and detection biases, especially in non-blinded trials. The lack of reliable blinding in the study can lead to a high level of performance bias, this is an important factor leading to a decrease in the quality of evidence. Therefore, in addition to being evaluated by structured questionnaires, caffeine can also be evaluated by both plasma concentrations of caffeine and paraxanthine. These studies will help to provide a more robust and reliable assessment of the efficacy of caffeine.In conclusion, the study of Francisca de Castro Mendes et al. represents a significant progress in the relationship of maternal caffeine intake during pregnancy and asthma development in children. Our comments aim to further improve and strengthen this excellent research.