Background: To evaluate the clinical efficacy of personalized immunomodulatory protocols—specifically Intralipid and Intravenous Immunoglobulin (IVIG)—in a highly refractory cohort of patients with Recurrent Implantation Failure (RIF) and Advanced Maternal Age (AMA).

Methods: A clinical pilot study was conducted involving 15 women (mean age 41.5 ±4.3years) with a history of extensive reproductive failure (mean of 7.3 previous IVF failures; range 1–29). Pre-treatment screening utilized the Embryotoxicity Assay (ETA) and a comprehensive Natural Killer (NK) cell panel (CD3−CD56+, CD3-CD16-CD56+, and NK functional activity. Immunotherapy was individualized based on these specific profiles: Intralipid monotherapy (40.0%, n=6) or combined Intralipid + IVIG (60.0%, n=9).

Results: Despite the highly refractory history, the clinical pregnancy rate (HCG+) was 73.3% (n=11) and the live birth rate was 60.0% (n=9). Overall, 73.3% (n=11) of the cohort exhibited either high NK cytotoxicity (>10%) and/or positive/inhibiting ETA factors. Notably, two sets of twin pregnancies were successfully carried to term in women aged 48 and 49.

Conclusions: Targeted immunotherapy guided by NK cell-panel and ETA diagnostics significantly restores the "immunological window of implantation." These results suggest that for patients with multiple IVF failures, addressing the maternal immune environment is as critical as embryo quality, extending reproductive viability even in older demographics.