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The COVID-19 pandemic dramatically reduced early-life respiratory viral exposures, yet the long-term respiratory consequences for pandemic-born children remain unclear. We aimed to compare respiratory morbidity at age 4 between children born during versus before the pandemic and assess whether atopic risk modifies this association. This single-center birth cohort follow-up study included children born in February-March 2020 (COVID-19 cohort) and pre-pandemic controls born during the same period in 2019. Respiratory outcomes at age 4 were assessed using a structured telephone questionnaire (The International Study of Wheezing in Infants). The primary outcome was composite respiratory morbidity (CRM), defined as use of a short-acting bronchodilator (SABA), inhaled and/or oral corticosteroids, and/or emergency room visits for respiratory symptoms. Of 588 eligible children, 329 (55.9%) completed follow-up (139 COVID-19, 190 controls); baseline characteristics, including atopy prevalence, were comparable between cohorts. CRM during the fourth year of life was significantly more common in the COVID-19 cohort (39.6% vs. 27.4%, p = 0.02). In stratified analyses, CRM was markedly higher among atopic-risk pandemic-born children (atopic subgroup: n = 47 COVID-19, n = 68 controls) (66% vs. 27.9%, p < 0.001), but not among non-atopic children (26.1% vs. 27%). Multivariable logistic regression confirmed a significant COVID-19 cohort × atopy interaction for CRM (OR 5.04, 95% CI 1.83-13.89, p = 0.002), while neither factor alone was independently associated with the outcome.

 Birth during the COVID-19 pandemic was associated with increased preschool respiratory morbidity, particularly among children with atopic risk. These findings suggest that altered early-life microbial exposures may modify respiratory morbidity trajectories according to host atopic susceptibility.

• Children born during the COVID-19 pandemic had fewer respiratory infections and wheezing episodes in infancy due to reduced viral circulation. • Atopic predisposition is among the strongest risk factors for recurrent wheezing and persistent asthma in preschool children.

• Pandemic-born children show significantly higher composite respiratory morbidity at age 4, but exclusively among those with atopic risk (OR 5.04). • Neither pandemic birth nor atopy alone predicts excess morbidity-only their combination does, suggesting host susceptibility shapes long-term respiratory trajectories.