Introduction: Immunological dysregulation plays a central role in recurrent early pregnancy loss (REPL) and implantation failure. However, empirical immunotherapy remains controversial. Stratification of patients by immune phenotype may enable targeted, personalised treatment and improve reproductive outcomes.

Objective: To develop and evaluate a phenotype-guided algorithm selecting optimal immunotherapy according to specific immune abnormalities.

Design: A comparative study assessing the efficacy of 4 immunotherapeutic approaches in couples with REPL. Inclusion criteria: Group 1: Couples with two or more implantation failures or miscarriages before 20 weeks. Couples receiving lymphocyte immunotherapy (LIT) (n=80/223). Group 2: Women planning IVF with antiphospholipid antibodies (APA) or diagnosed chronic endometritis (CE) via IHC or HS. Intravenous immunoglobulin therapy (IVIG) (n=131) Group 3: Women aged 18-45 with two or more reproductive failures (miscarriages before 12 weeks or failed IVF). Third-generation lipid emulsion (LET) therapy (n=140/251). Group 4 Personalized immunoadsorption in ANA-positive women with autoimmune-associated recurrent pregnancy loss and implantation failure (n=3/10).

Methods: LET was administered as an empirical immunotherapy during preconception preparation at 20% concentration, dosed at 6 ml/kg monthly for two months. Patients with confirmed antiphospholipid antibodies (APА) and/or chronic endometritis (CE) received IVIG (100 mg × 3 doses), while LIT was administered intradermally over two consecutive cycles and during early pregnancy at 5–6 and/or 8–9 weeks. Suspensions of 5×10⁶–100×10⁶ leukocyte cells were injected into the subscapular region across 6–8 points (0.3 ml per injection). Selective immunoadsorption was performed as five weekly 2-hour procedures. ANA levels were reassessed after the 3rd and 5th sessions.

Results: 1) Of the 48 women who underwent LIT, 64.5% had recurrent miscarriages. Within 12 months, 87% became pregnant, with 45.2% giving birth to healthy full-term babies and 29% having ongoing pregnancies beyond 13 weeks. Among 17 patients with primary infertility and IVF implantation failures, pregnancy occurred in 35.3%, with 50% resulting in live births and 33.3% in ongoing pregnancies. Immunological analysis showed a reduction in NK cells (5.14%) and NKT cells (0.52%), along with decreased NK cell activation markers (CD107a).

 2) IVIG Therapy: In patients with antiphospholipid antibodies, pregnancy rates after IVIG prior to IVF reached 96.6% compared to 63.8% in patients with chronic endometritis (p=0.001). Clinical and demographic characteristics were comparable between groups.

 3) LET: Patients treated with lipid emulsion therapy exhibited significant reductions in NK cells (1.63-fold, p=0.0041) and NKT cells (1.29-fold, p=0.0498), with spontaneous NK cell activation (CD107a) decreasing 2.07-fold (p=0.0498). Induced NK cell activation increased slightly (0.83-fold, p=0.53). Clinical pregnancy occurred twice as frequently in treated patients (56.41%) compared to untreated ones. 

Conclusions: Immune-phenotype–guided therapy was associated with normalization of immune parameters and improved reproductive outcomes. Personalised selection of LIT, IVIG, LET, or immunoadsorption represents a rational, targeted strategy for managing autoimmune and inflammatory endotypes of REPL.

Olesya N Bespalova, MD, PhD, DSc (Med Sci), professor is deputy director for research at the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, Saint Petersburg, Russia, and a board-certified obstetrician-gynecologist of the highest qualification category. She is a leading expert in reproductive immunology, pregnancy complications, and translational obstetrics research. Her work focuses on personalized diagnostic and therapeutic approaches for recurrent pregnancy loss, implantation failure, chronic endometritis, and cervical remodeling. She has authored numerous peer-reviewed publications and supervises national research programs and clinical trials. She is recognized as a leader in medical innovation and holds multiple patented inventions and technology developments in reproductive medicine.