Impact of Using Cow’s Milk Formula During the First Three Postnatal Days and Other Etiological Factors on the Development of Cow’s Milk Protein Allergy

<b>Background/Objectives:</b> Early cow's milk formula (CMF) exposure in the neonatal period has been proposed as a risk factor for cow's milk protein allergy (CMPA), although evidence remains inconsistent. This study evaluated the association between CMF use within the first 72 h and later CMPA. <b>Methods:</b> This retrospective study included 106 CMPA infants and 106 controls. CMPA was diagnosed according to ESPGHAN 2024 guidelines using clinical assessment, a 2-4-week elimination diet, and a supervised oral food challenge. Demographic and feeding data were collected, and logistic regression identified independent predictors. <b>Results:</b> Early CMF exposure was more common in the CMPA group (76% vs. 59%; <i>p</i> = 0.006). Multivariate analysis confirmed early CMF exposure as an independent risk factor (aOR: 2.35; 95% CI: 1.18-4.68). A subgroup with CMF intake limited to the first 72 h followed by exclusive breastfeeding was markedly overrepresented among CMPA cases (47% vs. 12%; <i>p</i> < 0.001). Early CMF exposure did not significantly impact IgE versus non-IgE phenotype distribution. Family history of atopy also remained a strong predictor. <b>Conclusions:</b> Early CMF exposure during the first 72 h and family history of atopy were key risk factors for CMPA. Supporting breastfeeding initiation and avoiding unnecessary early CMF supplementation may help reduce CMPA incidence.