Life-course comorbidity patterns and integrated prediction of postpartum depression, multimorbidity, and symptom progression

Perinatal depression (PD) is common and disabling, yet its longitudinal comorbidity patterns and predictability remain poorly understood. This study leveraged 8,804 women with delivery records in the All of Us cohort, including 438 with clinically diagnosed postpartum depression (PPD), to characterize multimorbidity trajectories and develop integrated prediction models. Comorbidities were grouped into 38 conditions across psychiatric, autoimmune, metabolic, neurological/pain, and reproductive/gynecological categories and examined both cross-sectionally and in monthly time bins from 250 months before to 500 months after delivery. Latent class analysis identified three pre- and post-delivery multimorbidity profiles and transitions between classes, while polygenic risk scores for depression and obstetric, clinical and socioeconomic variables were combined in machine learning models to predict PPD, post-delivery class membership, and symptom worsening among initially low-burden women. PPD cases showed higher odds of several psychiatric, autoimmune, and metabolic conditions and a tendency toward greater post-delivery comorbidity accumulation, particularly among women who were healthy pre-pregnancy. Multimorbidity profiles based on latent classes captured clinically meaningful risk gradients, and transition analyses revealed that incident PPD in previously healthy women marked a shift toward more symptomatic post-delivery profiles. Machine learning models achieved moderate discrimination for PPD and comorbidity outcomes and highlighted the importance of genetic liability, obstetric complications, and socioeconomic disadvantage, but low positive predictive values limit clinical implementation. These findings position PPD as a critical event in women's psychiatric, cardiometabolic, and pain-related health trajectories and support life-course, multimorbidity-informed screening and prevention strategies that extend beyond the traditional postpartum period.