Scientific Foundation Immune Mechanisms Clinical Evidence Our Impact Evolving Guidelines
Scientific & Clinical Evidence

The immunology of reproduction — why it matters, and what the evidence shows

Successful pregnancy is a highly coordinated immunological process — the maternal immune system must recognize and tolerate the semi-allogeneic embryo while regulating tissue remodeling, vascular development, and fetal protection. Despite advances in embryo and endometrial assessment, success rates have plateaued, and immune factors remain one of the most undertapped opportunities to address unexplained reproductive failure.

Pregmune bridges this gap — translating decades of evidence from reproductive immunology, genetics, and maternal–fetal tolerance into a comprehensive, actionable immune assessment.

Review the Evidence →
Scientific Foundation

Three pillars of reproductive immunology

The scientific basis for immune evaluation in fertility care rests on three converging lines of evidence — how the maternal immune system recognizes, regulates, and responds to the embryo.

Maternal–Fetal Immune Recognition (Compatibility)

The degree to which the maternal immune system recognizes the embryo as "self" versus "non-self" — shaped by parental HLA matching and KIR–HLA-C genotype combinations — sets the baseline level of immune recognition the embryo must overcome at implantation.

Immune Regulation & Tolerance (Modulation)

Regulatory mechanisms — chiefly Tregs and the broader Th1/Th2 balance — modulate and dampen the maternal immune reaction to the embryo, actively maintaining the tolerant state required for implantation and ongoing placentation.

Immune Activation & Inflammatory Response

When recognition and regulation are insufficient, the maternal immune system can mount an active response to the embryo — including NK cell cytotoxicity, inflammatory cytokine dominance, and auto- or allo-immune antibody activity — that can impair implantation or pregnancy maintenance.

Key Immune Mechanisms in Reproduction

What IRMA evaluates — and why each marker matters

Each of the following immune mechanisms has been linked to reproductive failure in peer-reviewed literature. IRMA synthesizes all of them into a single, integrated assessment.

NK Cell Cytotoxic Activity
1 marker
Peripheral NK cytotoxicity elevations — assessed by the CD57 assay — have been associated with implantation failure and RPL. Elevated peripheral NK activity is one of the most actionable immune findings in reproductive medicine, with several evidence-based treatment approaches available.
Moffett & Colucci (2014); Seshadri & Sunkara (2014); Quenby et al. (2009)
Th1/Th2 Cytokine Balance
2 markers
Successful implantation requires a shift toward a Th2-dominant uterine environment. Excessive Th1 activity (elevated TNF-α, IFN-γ) creates an inflammatory milieu hostile to implantation. The Th1/Th2 ratio is one of the most-studied and most-actionable immune variables in reproductive medicine, with direct treatment implications.
Ragupathy (2001); Kwak-Kim et al. (2003)
Regulatory T Cells (Tregs)
1 marker
Tregs are critical mediators of maternal immune tolerance to the semi-allogeneic embryo. Treg deficiency has been identified in patients with RPL and recurrent implantation failure (RIF). Treg-expanding therapies — including G-CSF and intralipid — are under active clinical investigation as immune-modulating interventions.
Jasper et al. (2006); Mjösberg et al. (2010); Saito et al. (2010); Moldenhauer et al. (2024)
Autoimmune Antibodies
25 markers
Antiphospholipid antibodies (aPL), antinuclear antibodies (ANA), anti-thyroid antibodies, and anti-sperm antibodies are associated with thrombotic placental pathology, miscarriage, and implantation failure. Antiphospholipid syndrome is among the most evidence-supported immune indications in fertility care, with established treatment protocols.
Empson et al. (2005); Walter et al. (2021); ESHRE RPL Guidelines (2023)
KIR–HLA-C Compatibility
3 markers
KIR receptors on uterine NK cells interact with paternal HLA-C antigens on trophoblasts. Specific KIR/HLA-C combinations — particularly KIR-AA haplotype with C2 ligand — have been shown to impair placentation and increase miscarriage risk. IRMA includes KIR haplotyping and predicted fetal HLA-C content to identify at-risk parental combinations.
Vento-Tormo et al. (Nature 2018); Hiby et al. (2004, 2010)
Thrombophilic Markers
5 markers
Factor V Leiden, prothrombin gene mutations, MTHFR variants, and acquired thrombophilia (including aPL) are associated with thrombotic placental pathology and pregnancy loss. Thrombophilic workup is among the most evidence-based components of RPL evaluation, with anticoagulation therapies demonstrating clinical benefit in selected populations.
Rodger et al. (2016); Rey et al. (2003); ACOG Practice Bulletin #197
HLA Antibodies
18 markers
Partner-specific antibodies — particularly against paternal HLA-C, the primary classical HLA molecule on trophoblast — have been linked to reproductive failure in a subset of RPL and implantation failure patients. Studies show a higher prevalence of HLA-C antibodies in unexplained RPL, some with complement-fixing activity suggestive of antibody-mediated placental injury.
Meuleman et al. (2016); Kolte et al. (2016)
HY Immunity
6 markers
HY immunity refers to maternal immune responses against male-specific antigens encoded on the Y chromosome. Women with secondary recurrent miscarriage following the birth of a boy show lower subsequent live birth rates and a higher prevalence of HLA class II alleles that present HY antigens. Anti-HY antibodies have been linked to recurrent miscarriage and adverse obstetric outcomes.
Nielsen et al. (2009); Christiansen et al. (2010)
Peer-Reviewed Literature

Key Clinical Evidence

A representative selection of the evidence base informing IRMA's biomarker selection and clinical interpretation framework.

ESHRE RPL Guidelines (2023)
Clinical Guideline
Updated European Society of Human Reproduction and Embryology guidelines explicitly acknowledge immune mechanisms in recurrent pregnancy loss — including NK cell activity, antiphospholipid syndrome, and alloimmune factors — as clinically relevant areas of investigation.
European Society of Human Reproduction and Embryology, 2023
KIR/HLA-C Interaction Effects on Miscarriage Rates
Basic Science
Study demonstrating that maternal killer-cell immunoglobulin-like receptor (KIR) genotypes, in combination with parental HLA-C genotypes, are associated with recurrent miscarriage. Mothers with the KIR-AA haplotype combined with paternal/fetal HLA-C2 show a significantly increased risk of recurrent miscarriage, establishing a genetic basis for reproductive immune incompatibility at the maternal-fetal interface.
Hiby et al., Human Reproduction, 2008
NK Cells in Recurrent Pregnancy Loss
Systematic Review
Systematic review of 18 studies examining peripheral and uterine NK cell populations in women with RPL compared to controls. Found significantly elevated NK cell levels in the RPL population, supporting peripheral NK cytotoxicity as a relevant clinical biomarker for immune-mediated pregnancy loss.
Seshadri & Sunkara, Human Reproduction Update, 2014
Th1/Th2 in IVF Failure
Clinical Study
Clinical study demonstrating significantly elevated intracellular Th1 cytokine expression (TNF-α, IFN-γ) relative to Th2 cytokines in women with recurrent spontaneous abortion and in infertile women with multiple implantation failures after IVF/ET, compared to women with normal pregnancy. Supports Th1 dominance as a clinically actionable immune mechanism in implantation failure and pregnancy loss.
Ng et al., American Journal of Reproductive Immunology, 2002
Prevention of recurrent miscarriage for women with antiphospholipid syndrome
Systematic Review
Cochrane systematic review confirming that combined anticoagulation therapy (heparin plus aspirin) significantly reduces pregnancy loss in women with antiphospholipid syndrome — establishing aPL as one of the most evidence-backed immune targets in RPL with established treatment benefit.
Empson et al., Cochrane Database of Systematic Reviews, 2005
ACOG Practice Bulletin #197 — Thrombophilia in Pregnancy
Clinical Guideline
ACOG guidelines recommend evaluation for inherited thrombophilias — including Factor V Leiden, prothrombin gene mutation, and antiphospholipid antibodies — in women with a history of recurrent pregnancy loss, establishing the clinical standard for thrombophilic immune evaluation in this population.
American College of Obstetricians and Gynecologists, 2018 (reaffirmed 2025)
HLA-C Antibodies & Antibody-Mediated Rejection in RPL
Basic Science
Case-control study finding HLA-C-specific antibodies significantly more often in women with recurrent miscarriage than in those with uneventful pregnancy, with a higher proportion showing complement-fixing activity — consistent with antibody-mediated rejection as a contributor to RPL. Related work links HY-restricting HLA class II alleles to poorer long-term reproductive outcomes after a firstborn boy.
Meuleman et al., Journal of Reproductive Immunology, 2016; Kolte et al., American Journal of Reproductive Immunology, 2016
HY Immunity & Secondary Recurrent Miscarriage
Basic Science
Maternal carriage of HY-restricting HLA class II alleles is associated with a reduced live birth rate and increased risk of obstetric complications in patients with secondary recurrent miscarriage following a firstborn boy. Companion work shows H-Y antibody titers are elevated in these patients and associated with a low male:female ratio among subsequent live births — supporting a pathogenic role for maternal anti-HY immune responses.
Nielsen et al., Human Molecular Genetics, 2009; Christiansen et al., Journal of Reproductive Immunology, 2010
Regulatory T Cells in Implantation
Review
Review establishing that an active state of maternal immune tolerance, mediated by CD4+ regulatory T cells (Tregs), is essential for embryo implantation and a sustainable pregnancy. Insufficient Treg numbers or function are implicated in idiopathic infertility and recurrent miscarriage, as well as later-onset complications such as preeclampsia and fetal growth restriction.
Robertson, Care & Moldenhauer, Journal of Clinical Investigation, 2018 (PubMed)
Integrated Immune-Genetic Testing & IVF Outcomes
Pregmune RWE
Center-level comparative analysis found that integrating comprehensive genetic and immune testing (via IRMA) with personalized immune-modulating therapy was associated with an increase in live birth rate from 52% (SART 2021 benchmark) to 60% overall (+8%, p=0.10). The benefit was concentrated in women of advanced maternal age: ages 38–42 improved from 34% to 62% (+27%, p=0.002), and ages 43–53 improved from 9% to 50% (+41%, p=0.003), while outcomes for ages 26–37 were comparable to benchmark.
Mansouri-Attia, Vidali, Menarde & Glassner, ASRI Annual Meeting, May 2026
Improved Outcomes of FET with an Immune Modulation Protocol in RPL/RIF
Pregmune RWE
Case-control study of women with recurrent pregnancy loss and/or recurrent implantation failure undergoing single-euploid-embryo frozen embryo transfer. Patients who received an individualized immune-modulation protocol guided by comprehensive immune profiling (via Pregmune) achieved a substantially higher clinical pregnancy rate than those who did not (75% vs. 25%, p<0.05), with no biochemical pregnancies or first-trimester miscarriages in the profiled group, versus 12.5% each in the comparison group.
Haroun, Mansouri-Attia, Mouanness & Merhi, Rejuvenating Fertility Center, Fertility and Sterility, 2025
Pregmune Real-World Evidence

Our Impact

To understand Pregmune's real impact, we analyzed electronic health record data from a single fertility center using Pregmune since 2022 — comparing outcomes to the same center's published SART data. Same clinic, same physicians, same lab and protocols. Data recorded at the source, not self-reported.

+27%
percentage point improvement in pregnancy success for patients aged 38–42, compared to historical SART data [1]
+41%
percentage point improvement in pregnancy success for patients aged 43 and older, using own eggs [1]
+15.4%
percentage point higher pregnancy success rate per embryo transfer in RIF patients with IRMA (40% vs. 24.6% as reported in a global meta-analysis [2]; all ages)
Success rate defined as ongoing pregnancy beyond 11 weeks.
IRMA leads to action, not just information
98% of patients received at least one actionable, physician-guided recommendation across all age groups, including patients over 40. IRMA does not just explain why something may not be working; it helps guide what to do next.
Age-related decline was less steep
Among IRMA-evaluated IVF patients, pregnancy success rates remained stronger with age than historical averages: ~64% at 38–40, ~55% at 41–42, ~50% above 42. Immune-guided care may help reduce the steep drop-off typically seen with age alone.
Greatest impact in patients often told to give up
The greatest improvements were seen in patients 38 and older. Pregmune helps identify modifiable factors even when age is advanced.
Clarity replaces guessing
Many patients labeled "unexplained" have treatable immune, inflammatory, or metabolic contributors. Guidance based on patterns rather than isolated results can change outcomes.
Evolving Medical Guidelines

The field is catching up to the evidence

Major professional societies have progressively acknowledged immune mechanisms in reproductive failure. Here is how the guideline landscape has evolved.

2014
ASRM — Evaluation and Treatment of Recurrent Pregnancy Loss
ASRM guidelines acknowledge antiphospholipid syndrome as one of the most well-established immune causes of RPL and recommend aPL testing as part of the standard RPL evaluation.
ASRM Guideline
2018
ACOG Practice Bulletin #197 — Thrombophilia in Pregnancy
ACOG formally recommends evaluation for inherited thrombophilias — including Factor V Leiden, prothrombin mutation, and antiphospholipid antibodies — in women with recurrent pregnancy loss. Reaffirmed in 2022.
ACOG Standard of Care
2023
ESHRE Recurrent Pregnancy Loss Guidelines (Updated)
Updated ESHRE guidelines explicitly include immune evaluation as clinically relevant in the RPL workup. Notably, the 2023 update is the first to acknowledge a role for immune therapy (IVIG) in select RPL patients.
Landmark Update
Active
ASRM 2026 RPL Committee Opinion & Unexplained Infertility Guidance
ASRM's 2026 RPL Committee Opinion highlights the expanding understanding of reproductive failure beyond genetics and anatomy and ASRM is now actively revising guidelines on unexplained infertility. The field is moving.
In Development
Apply the Evidence

Ready to integrate immune evaluation into your practice?

IRMA translates this evidence base into a single, actionable assessment. Our Medical Affairs team is available to discuss the science and the clinical workflow.

Contact Medical Affairs

Medical Disclaimer

Patients and physicians should always consult with a licensed medical professional before making any clinical decisions, including starting or discontinuing any treatment. Any information provided by Pregmune, including but not limited to the IRMA Report, AIMY Report, test results, risk estimates, supporting documentation, email communications or other related content (collectively, "Pregmune Content"), is intended for informational purposes only. This content is not medical advice and should not be used as a substitute for professional medical evaluation, diagnosis, or treatment. Pregmune Content is not a recommendation for any specific treatment plan, therapy, medication, or course of action. It is designed to support, not replace, the relationship between patients and their qualified healthcare providers. Pregmune does not provide medical care, and its reports and communications should never delay or override clinical judgment.