Objective: The objective of this study was to investigate the impact of localization of diffuse adenomyosis on reproductive outcomes after frozen embryo transfer (FET). Design: This prospective cohort study was conducted between January 2019 and December 2022. A total of 585 infertile women undergoing the first FET cycle were recruited. Participants/Materials, Setting, Methods: The study population included 368 women with diffuse adenomyosis where 167 women had diffuse adenomyosis of outer myometrium (OM) (group A) and 201 women had diffuse adenomyosis of the junctional zone (JZ) (group B). 217 women with male infertility were taken as controls. Adenomyosis was diagnosed on transvaginal ultrasound using MUSA criteria where diffuse adenomyosis patients with two or more features were included. These patients were further divided based on the localization of adenomyotic lesions in OM or JZ. All the patients underwent FET cycle. Pregnancy outcomes and complications were compared between different groups. Additionally, adenomyosis patients as a whole were compared with the control group. Results: Women with diffuse adenomyosis have similar (p > 0.05) pregnancy rates (36.14% vs. 35.94%), biochemical pregnancy rates (11.27% vs. 3.84%), and clinical pregnancy rates (32.06% vs. 35.02%) but higher miscarriage rates (22.03% vs. 9.21%; OR: 2.79, 95% CI: 1.14–6.79, p = 0.024) and a lower live birth rates (20.65% vs. 29.95%; OR: 0.61, 95% CI: 0.41–0.89, p = 0.011) than women without adenomyosis. However, women with diffuse adenomyotic lesions affecting the JZ (group B) exhibited significantly lower positive pregnancy (26.37% vs. 47.9%; OR: 0.39, 95% CI: 0.25–0.60, p < 0.0001), clinical pregnancy (23.38% vs. 42.51%; OR: 0.41, 95% CI: 0.26–0.65, p = 0.0001), and live birth (16.42% vs. 25.75%; OR: 0.57, 95% CI: 0.34–0.94, p = 0.029) compared to those with adenomyosis of the OM (group A) but comparable (p > 0.05) biochemical pregnancy (11.32% vs. 11.25%) and miscarriage (23.4% vs. 21.13%). Pregnancy complications were comparable between the adenomyosis groups; however, there was a significantly higher incidence of pregnancy complications, particularly gestational hypertension (OR: 6.41, 95% CI: 1.79–22.92, p = 0.0042), IUGR (OR: 9.08, 95% CI: 2.01–40.99, p = 0.0041), and preterm labor (OR: 9.41, 95% CI: 3.09–28.62, p = 0.0001) in adenomyosis patients compared to the controls. Limitations: It is an observational prospective study, and the study included patients with endometriosis as a comorbidity. The population size is limited to ascertain the effect of diffuse adenomyosis on pregnancy complications, particularly between subgroups. Conclusion: This study emphasizes the importance of evaluation and localization of adenomyotic lesions before initiating ART, which can aid in effective counseling and personalized treatment strategies to optimize reproductive outcomes. Pregnant women with adenomyosis should be managed carefully as high-risk pregnancies, considering the possible serious obstetric complications.

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