Purpose: This study explores postpartum depression (PPD) in women who screened negative in mid-pregnancy to assess the impact of the peripartum period on the development of depressive symptoms. Methods: A prospective cohort study was carried out in two facilities in Argentina. The Edinburgh postnatal depression scale (EPDS) scale was applied to pregnant women between weeks 20–24 gestation, and those screening negative (<10) were included in the cohort. Participants were followed up until the 4th week postpartum, when the EPDS was repeated. If positive, a semi-structured clinical interview was applied (MINI) to define the diagnosis. Results: A total of 112 pregnant women were eligible for the follow-up. At the 4th week postpartum, 14 women (12.5%, CI 95% 7.0; 20.1) screened positive using a cutoff point of 10 or more in the EPDS. Of those screened positive in the EPDS, two participants (1.8%, CI 95% 0.2–6.3) had a Major Depressive Disorder. Newborn admission to the Intensive Care Unit, hospitalization of the newborn after discharge, abuse during childbirth, and lack of company during labor were identified as peripartum risk factors. Conclusions: This study reinforces the relevance of women and newborn mental health care during the hospitalization process surrounding peripartum. The women and newborn hospitalization process should be better explored to understand the contribution to PPD and design and test strategies to alleviate the impact of maternal depression.