What treatment options are available to reduce elevated immune cell ratios, including tumor necrosis factor-alpha (TNF-a):interleukin-10 (IL-10), interferon-gamma (IFN-g):IL-10, natural killer (NK) cell ratio, cluster of differentiation 19 (CD19), and cluster of differentiation 56 (CD56), to improve in vitro fertilization (IVF) outcomes and birth rates in a patient with impaired fertility?

Immunomodulation for Elevated Inflammatory Markers in IVF

The elevated TNF-α:IL-10 and IFN-γ:IL-10 ratios, along with increased NK cell activity and CD19/CD56 levels, should be addressed with intravenous immunoglobulin (IVIg) therapy, as this is the only evidence-based intervention shown to modulate these specific immune parameters and improve IVF outcomes in patients with documented immunologic abnormalities. Cannabis has no established role in reproductive immunology and should be avoided entirely during fertility treatment.

Understanding Your Immune Profile

Your immune parameters indicate a pro-inflammatory state that is unfavorable for implantation:

• Elevated TNF-α:IL-10 ratio (33.6) and IFN-γ:IL-10 ratio (14.6) reflect a Th1-dominant immune response, which is associated with implantation failure 1, 2.
• Elevated NK cell ratios (50:1 at 28.3% and 25:1 at 24.6%) indicate increased NK cell cytotoxicity, which correlates with poor IVF outcomes 3, 4.
• CD19 (17.8%) and CD56 (6.5%) elevations further confirm immune dysregulation associated with reproductive failure 5.

Women with three or more immune deviations have significantly lower implantation rates (21.4% vs 50.9%) and live birth rates (9.5% vs 33.9%) compared to those with 0-1 deviations 3.

Evidence-Based Treatment: IVIg Therapy

IVIg is the only intervention with demonstrated efficacy in modulating aberrant cellular immune parameters in reproductive failure, including elevated NK cell proportions, increased NK cytotoxicity, and elevated Th1:Th2 ratios 1.

Mechanism of Action

• IVIg modulates NK cell activity and reduces cytotoxicity 1.
• It shifts the immune balance from Th1-dominant (TNF-α, IFN-γ) toward Th2-dominant responses necessary for successful implantation 1.
• IVIg reduces pro-inflammatory cytokine production while preserving immune defense against pathogens 1.

Clinical Recommendations

• IVIg therapy is indicated for patients with recurrent pregnancy loss or repeated implantation failure who have documented immunologic disturbances, including elevated NK cell proportions, increased NK cytotoxicity, or elevated Th1:Th2 ratios 1.
• Treatment should be initiated based on your clinic's established cut-off values for these immune parameters 1.

Cannabis: No Role in Reproductive Immunology

Cannabis has no established evidence for reducing inflammatory immune markers or improving IVF outcomes and should be avoided entirely during fertility treatment.

Critical Concerns

• No published guidelines or research studies support cannabis use for modulating TNF-α:IL-10, IFN-γ:IL-10, NK cell activity, or CD19/CD56 levels in the context of reproductive immunology.
• The EULAR guidelines for women's health and assisted reproduction make no mention of cannabis as a therapeutic option 6.
• Smoking cessation is strongly recommended for all patients undergoing fertility treatment, as smoking impairs fertility outcomes 6, 7.

Fertility Preservation Priority

• Any substance that could potentially affect the hypothalamic-pituitary-gonadal axis or have unknown effects on oocyte quality should be avoided when pursuing fertility 6.
• The focus should be on evidence-based interventions with established safety profiles in reproductive medicine 6.

Additional Immune Modulation Strategies

Beyond IVIg, consider these evidence-based approaches:

Lifestyle Modifications

• Weight optimization (BMI <25) if applicable, as obesity impairs immune regulation and fertility 7.
• Smoking cessation if applicable, as smoking worsens immune parameters and reduces IVF success 7.
• Regular physical exercise improves immune balance and fertility outcomes 7.

Monitoring and Timing

• Repeat immune panel testing after IVIg therapy to document normalization of parameters before proceeding with IVF 1.
• Coordinate IVIg administration timing with your reproductive endocrinologist to optimize immune modulation during the implantation window 1.

Autoantibody Screening

• Given the high prevalence of autoantibodies in patients with elevated NK cells and cytokine abnormalities, screening for antiphospholipid antibodies (APA), antinuclear antibodies (ANA), and antithyroid antibodies (ATA) is warranted 5.
• 75.6% of patients with reproductive failure have at least one immunologic abnormality, and multiple abnormalities often coexist 5.

Critical Pitfalls to Avoid

• Do not use empiric immune suppression without documented immune abnormalities, as this can impair necessary immune defense mechanisms 1.
• Avoid testosterone therapy or anabolic steroids entirely, as these suppress fertility through negative feedback on the hypothalamic-pituitary-gonadal axis 7, 8.
• Do not delay fertility treatment while pursuing unproven interventions, as female partner age is the most critical determinant of IVF success 6.

Multidisciplinary Coordination

• Work with a reproductive immunologist experienced in managing immune-mediated implantation failure 1.
• Coordinate care between your reproductive endocrinologist and immunologist to optimize IVIg timing relative to embryo transfer 1.
• Consider genetic counseling if recurrent pregnancy loss has occurred, as chromosomal abnormalities can coexist with immune factors 6.