A case report recently published in the American Journal of Reproductive Immunology described a link between excessive maternal-paternal HLA compatibility and recurrent second-trimester euploid pregnancy losses despite immunotherapy, highlighting alloimmune mechanisms in recurrent pregnancy loss (RPL).
Specific HLA types can indirectly cause fetal and neonatal alloimmune thrombozytopenia (FNAIT) by acting as immune triggers that help the mother’s immune system recognize HPA-1a as foreign, initiating the production of anti-HPA-1a antibodies.
Learn more about FNAIT causes and risk factors
A patient with RPL experienced multiple second-trimester losses of fetuses with normal chromosomes, with HLA typing revealing allele sharing across four of five loci between the patient and her partner, aligning with impaired maternal-fetal immune tolerance despite treatments like intravenous immunoglobulin and corticosteroids.
RPL affects 1%–3% of women, with up to half unexplained after standard evaluations, and implicates alloimmune factors that impair placentation. RPL’s causes often involve alloimmune mechanisms, such as excessive HLA compatibility disrupting maternal recognition and tolerance of the semi-allogeneic fetus, alongside other factors, including genetics, thrombophilias, and infections.
Current treatments for suspected immune-mediated RPL include empiric immunotherapy (e.g., intravenous immunoglobulin, corticosteroids, hydroxychloroquine, aspirin, low-molecular-weight heparin, progesterone), though evidence is limited and outcomes vary, as seen in this case’s failure.
Current evidence includes meta-analyses indicating increased odds of HLA-B and HLA-DR sharing in RPL patients compared to controls, supporting the role of reduced immunogenetic diversity in compromising tolerance.
“A comprehensive meta-analysis found that patients with recurrent miscarriage have increased odds of sharing HLA-B and HLA-DR alleles (compared to controls), supporting that excessive HLA compatibility may compromise maternal immune recognition and maternal tolerance induction toward the fetal-placental unit,” the authors wrote.
The authors aimed to investigate the potential role of excessive maternal-paternal HLA compatibility in impairing maternal-fetal immune tolerance, leading to recurrent euploid pregnancy loss, by conducting a narrative review of alloimmune mechanisms, including classical and non-classical HLA pathways and KIR-HLA interactions, while using a representative clinical case of recurrent second-trimester losses despite immunotherapy to illustrate and contextualize these concepts.
The methods involved a narrative review of existing literature on alloimmune factors in recurrent pregnancy loss, focusing on HLA sharing and related immune interactions, combined with a detailed description of a single clinical case where the patient underwent extensive evaluations, including HLA typing.
Outcomes revealed that despite treatments like intravenous immunoglobulin, corticosteroids, hydroxychloroquine, progesterone, aspirin, and low-molecular-weight heparin, the patient had multiple euploid fetal losses, with HLA analysis showing sharing across four of five loci, consistent with disrupted trophoblast-immune signaling and tolerance.
Improvements could include incorporating multiple case studies or a cohort for broader generalizability, prospective monitoring to track immune markers over time, and randomized controlled trials to assess targeted immunotherapies more rigorously.
“Excessive maternal–paternal HLA compatibility may contribute to recurrent euploid pregnancy loss through disruption of maternal–fetal immune tolerance. This case-based review underscores the need for individualized immunologic assessment and further research into targeted therapies for alloimmune-mediated reproductive failure,” the authors concluded.
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