Menstrual Cycle Irregularity as an Early Biomarker of Post-Acute Sequelae of SARS-CoV-2 Infection in Women of Reproductive Age: A Prospective Cohort Study from a Tertiary Care Center in Nepal

Background Post-Acute Sequelae of SARS-CoV-2 infection (PASC), commonly referred to as Long COVID, manifests across multiple organ systems. Menstrual cycle disruption following SARS-CoV-2 infection has been increasingly reported anecdotally, yet prospective longitudinal data characterizing its onset, patterns, and association with systemic PASC symptom burden remain absent from South Asian clinical literature. This study aimed to characterize the prevalence, nature, and duration of post-COVID menstrual irregularity in a Nepali cohort and evaluate its utility as an early clinical biomarker of PASC. Methods A prospective cohort study was conducted between January 2024 and January 2025 at Kathmandu Medical College and Teaching Hospital (KMCTH) and Tribhuvan University Teaching Hospital (TUTH), Nepal. Women aged 18–45 years with confirmed SARS-CoV-2 infection (RT-PCR positive) and regular pre-infection menstrual cycles (cycle length 21–35 days) were enrolled within two weeks of diagnosis. Participants were followed at 4, 8, 12, and 24 weeks post-infection. The primary outcome was incident menstrual irregularity (cycle length deviation > 7 days from individual baseline, intermenstrual bleeding, or amenorrhoea ≥ 45 days). Secondary outcomes included PASC symptom burden assessed by the modified PASC Symptom Scale (mPASS), self-rated health, and work capacity. Multivariable logistic regression identified independent predictors of menstrual irregularity. Machine learning-based feature importance analysis using a gradient boosting classifier identified which baseline clinical variables most strongly predicted persistent (> 12-week) menstrual disruption. Results Of 214 enrolled women, 198 completed the full 24-week follow-up. Incident menstrual irregularity was observed in 112 participants (56.6%) at the 4-week assessment. Irregularity persisted beyond 12 weeks in 74 participants (37.4%) and beyond 24 weeks in 41 (20.7%). Persistent irregularity at 24 weeks was significantly associated with severe acute-phase illness (OR 3.21, 95% CI 1.74–5.92), elevated CRP at admission > 25 mg/L (OR 2.87, 95% CI 1.51–5.44), and baseline anxiety disorder (OR 2.14, 95% CI 1.08–4.23). In gradient boosting analysis, the top predictors of persistent menstrual disruption were acute illness severity score, serum ferritin at nadir, and baseline BMI. Participants with persistent menstrual irregularity at 12 weeks had significantly higher total PASC symptom burden at 24 weeks compared to those who recovered (mPASS score 14.7 ± 5.2 vs. 7.3 ± 3.8, p < 0.001), suggesting its utility as an early indicator of protracted PASC trajectory. Conclusions Menstrual irregularity is a highly prevalent and clinically significant manifestation of PASC in Nepali women of reproductive age. Its persistence beyond 12 weeks strongly predicts a high systemic PASC symptom burden at six months, positioning it as a practical, low-cost early biomarker for identifying women at risk of protracted Long COVID. Integration of menstrual health assessment into routine post-COVID follow-up protocols is warranted, particularly in resource-constrained settings where comprehensive laboratory workup is limited.