Myo-inositol and clomiphene with sildenafil are associated with improved pregnancy outcomes in women with infertility

ImportanceFemale infertility affects approximately one in six couples worldwide and disproportionately impacts women aged 30–42 years, yet evidence on which interventions improve clinically meaningful outcomes (live birth and safety) is heterogeneous.ObjectiveThe aim of this study was to synthesize evidence on interventions that restore or improve fertility in women aged 30–42 years, grouped by etiology.Evidence reviewWe conducted a PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses)-compliant systematic review (PROSPERO CRD420251109428). PubMed and Scopus were searched for English/Spanish studies (1 January 2020 to 31 July 2025). Eligible designs were randomized trials and non-randomized interventional and observational studies. We aligned outcomes to the infertility core outcome set, prioritizing live birth per woman, then ongoing/clinical pregnancy and prespecified safety endpoints. Risk of bias used RoB 2 [randomized controlled trials (RCTs)], ROBINS-I (non-randomized), and JBI (observational). When pooling was not feasible, we applied SwiM (Synthesis Without Meta-analysis) and summarized by etiology and intervention class.FindingsA total of 21 studies met inclusion criteria for synthesis, and two additional randomized protocols were summarized narratively (23 records tracked overall). Interventions spanned hormonal therapies, assisted reproductive technologies (ART) strategies, surgical procedures, lifestyle and psychosocial programs, and investigational adjuncts. Across etiologies, several interventions were associated with improved pregnancy-related outcomes—such as myo-inositol, clomiphene with sildenafil, selected luteal support regimens, structured stress management, and specific ART strategies—whereas live-birth effects were supported by only moderate-certainty evidence, limited by small samples, heterogeneity, and indirectness. Diagnostic and prognostic approaches (e.g., serum progesterone profiling, BAP-EB receptivity assay, and endometrial T-bet/GATA3 ratio) showed predictive value but no therapeutic effect. Safety reporting was limited; few studies reported ovarian hyperstimulation syndrome, multiple gestation, or neonatal outcomes, and patient-reported outcomes were seldom assessed.Conclusions and relevanceFor women aged 30–42 years, established hormonal and ART strategies improve pregnancy outcomes; however, certainty for live birth and safety remains limited. Clinical care should prioritize standard therapies and shared decision-making, acknowledging evidence gaps. Future trials must center on live birth, adopt standardized core outcomes, and consistently report maternal–neonatal safety.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420251109428.