BackgroundThe COVID-19 pandemic undermined gains in reducing maternal and perinatal mortality in South Africa. The Mphatlalatsane Initiative is a health system intervention to reduce mortality and morbidity in women and newborns to desired levels.ObjectiveOur evaluation aims to determine the effect of various exposures, including the COVID-19 pandemic, and a system-level, complex, patient-centered quality improvement (QI) intervention (the Mphatlalatsane Initiative) on maternal and neonatal health services at 21 selected South African facilities. The objectives are to determine whether Mphatlalatsane reduces the institutional maternal mortality ratio, neonatal mortality rate, and stillbirth rate (objective 1) and improves patients’ experiences (objective 2) and quality of care (objective 3). Objective 4 assesses the contextual and implementation process factors, including the COVID-19 pandemic, that shape Mphatlalatsane uptake and variation.MethodsThis study is an implementation science type 2 hybrid effectiveness, controlled before-and-after design with quantitative and qualitative components. The Mphatlalatsane intervention commenced at the end of 2019. For objective 1, intervention and control facility-level data from the District Health Information System are compared for changes in institutional maternal and neonatal mortality and stillbirth rates and associations with QI, the COVID-19 pandemic, and both. This first analysis includes data from 18 facilities, regardless of their allocation to intervention or comparison, to obtain a general idea of the effect of the COVID-19 pandemic. For objectives 2 to 3, data collectors abstract data from maternal and neonatal records, interview participants, and conduct neonatal facility assessments. For objective 4, interviews, program documentation, surveys, and observations are used to assess how contextual factors at the macro-, meso-, and microlevels explain variation in intervention uptake and outcome. The intervention dose is measured at the microlevel only in the intervention facilities. The study assesses the Mphatlalatsane Initiative from 2020 to 2022.ResultsFrom preliminary analysis, across the 3 provinces, maternal and neonatal deaths increased during the COVID-19 pandemic, whereas stillbirths remained unchanged. Maternal satisfaction with quality of care was >90%. The COVID-19 pandemic severely disrupted the QI teams functioning. However, the QI teams regained their pre–COVID-19 momentum by adapting the QI model, with advisers providing mentoring and support. Variation in adoption at the mesolevel was related to stable and motivated leadership (particularly at the facility level), poor integration into routine processes, and buy-in from senior district managers who were affected by competing priorities. Varying referral and specialist outreach systems, staff availability and development, and service delivery infrastructure are plausible factors in variable outcomes.ConclusionsFew evaluations rigorously evaluated the effect of health system interventions on improving health services and outcomes. Results will inform the scaling up of successful intervention components and strategies to mitigate the effects of the COVID-19 pandemic or similar emerging epidemics on maternal and neonatal mortality.International Registered Report Identifier (IRRID)DERR1-10.2196/42041