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Clinical evidence suggests that experiencing pregnancy increases a woman’s risk of knee osteoarthritis, a painful and mobility limiting disease that results from cartilage deterioration. While understanding the underlying causes and the association with pregnancy is complex, the mechanical load on cartilage during walking appears to be important to the initiation and progression of the disease, especially if walking mechanics are abnormal. Pregnancy involves various changes in mechanical factors like mass, center of mass, and joint laxity which are known to progressively change walking mechanics throughout gestation. However, it is unknown if mechanical changes associated with pregnancy, which may be substantial in magnitude but may be limited in duration, can explain the osteoarthritis risk since osteoarthritis is diagnosed later in life. Given that women typically experience pregnancy early in their lifetime and will need healthy knees for decades after they become mothers, this research aimed to model the mechanical consequences of pregnancy on knee joint loading and knee joint health over the lifetime. Specifically, this dissertation sought to (i) determine how pregnancy influences variables like resultant knee joint kinetics, which more directly indicate the load on cartilage over a range of walking speeds (ii) estimate the impact of pregnancy on internal knee joint forces and tibiofemoral cartilage load during walking and (iii) evaluate the isolated effect of altered loading experienced during pregnancy on cartilage degeneration and the risk of knee osteoarthritis throughout a woman's lifetime. Results suggest that (i) 3D knee joint moments over a range of walking speeds are greater in pregnant vs. non-pregnant individuals and knee adduction moments are altered as pregnant women walk faster. Similarly, pregnant women experience greater total knee joint loading and greater medial knee joint loading which results in additional and altered peak strain on knee cartilage with greater walking speed. Finally, the elevated and altered compressive load experienced over one or more pregnancies resulted in a greater cartilage failure probability, with differential effects when women experience multiple pregnancies later in their lifetime. These findings support the notion that the mechanical factors associated with pregnancy significantly alter knee joint loading and mechanical changes may, in part, contribute to the known association between pregnancy and risk for knee osteoarthritis risk over a woman’s lifetime. Further, present-day American mothers who are conceiving at later stages of life compared to previous generations may be more susceptible to knee osteoarthritis. Future investigations are needed to explore effects postpartum and for populations beyond healthy, active pregnant women. Further research could also investigate if biomechanical adjustments could be used as potential interventions to lessen knee joint loading and potentially decrease the risk of knee osteoarthritis among this population.