The Significance of Maternal KIR AA Haplotype and Fetal HLA-C2 in Reproductive Medicine

Source: Cuadrado-Torroglosaet al., Maternal-Fetal Compatibility in Recurrent Pregnancy Loss. J Clin Med. 2024 Apr 19;13(8):2379. Upraveno

Maternal KIR AA haplotype and its interaction with fetal HLA-C2 have emerged as important factors influencing reproductive outcomes—particularly in cases of recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), and pregnancy complications such as preeclampsia. According to several studies, this interplay between maternal immune receptors and fetal antigens affects placental development and may guide infertility treatment strategies within IVF.

Biological Mechanism of the KIR–HLA Interaction

At the maternal–fetal interface, complex immune interactions take place in which uterine NK cells (uNK) expressing killer immunoglobulin-like receptors (KIRs) engage with fetal trophoblast cells bearing HLA-C antigens. Key findings include:

• KIR AA haplotype: Characterized by a predominance of inhibitory receptors (notably KIR2DL1) and absence of activating receptors such as KIR2DS1.

• HLA-C2: A subgroup of fetal HLA-C antigens that binds strongly to the inhibitory receptor KIR2DL1.

• Pathogenic interaction: When a KIR AA mother carries an HLA-C2 fetus, excessive inhibition at the uNK–trophoblast interface limits trophoblast invasion and leads to defective placentation. This mechanism is associated with:

  • Up to a 50% higher risk of miscarriage in IVF cycles compared to controls.

  • A 2.4-fold increased risk of preeclampsia—a condition marked by high blood pressure and organ damage (especially renal), often necessitating preterm delivery and carrying increased peripartum risks.

    
    

Elevated incidence of fetal growth restriction, resulting in low birth weight, higher rates of preterm birth, and long-term sequelae such as developmental delays and weakened immunity.

Clinical Data from Reproductive Studies

1. IVF Outcomes

   • Patients with KIR AA receiving a single embryo transfer from donors genotyped HLA-C1/C1 exhibit higher pregnancy rates than those with unknown donor HLA-C status.

   • Higher miscarriage rates are reported after transfers from donors with unknown HLA-C genotype versus HLA-C1/C1 donors.

   • Overall, KIR AA patients undergoing IVF face an increased overall risk of pregnancy loss.

   
   

2. KIR / HLA-C Testing in IVF 

   Based on these observations and clinical trials, implementing KIR–HLA-C genotyping can aid in:

   • Personalized embryo selection: Prioritizing HLA-C1/C1 embryos for KIR AA patients may increase implantation success, reduce miscarriage rates, and lower preeclampsia risk.

   • Donor selection optimization: Choosing oocyte or sperm donors with HLA-C1/C1 for KIR AA recipients avoids the adverse KIR AA–HLA-C2 interaction and can improve pregnancy rates.

Controversies and Technical Limitations

Although most studies endorse KIR–HLA testing and its clinical application, several unresolved issues remain:

• The number of HLA-C2 alleles needed to produce clinically significant adverse effects with KIR AA is unclear.

• The impact of maternal versus paternal HLA-C2 origin on pregnancy outcomes is debated.

• Some reports describe successful pregnancies in KIR AA patients carrying HLA-C2 embryos without any clinical intervention.

• The negative KIR AA–HLA-C2 effect appears more pronounced in European populations than in Asian cohorts.

• Current assays cannot assess the functional expression levels of individual KIR receptors.

Additional modulators—such as IL-15 and TGF-β signaling pathways—may influence KIR receptor activation.

Conclusion

KIR and HLA-C genotyping offers a promising tool for identifying IVF couples at elevated risk of implantation failure and pregnancy complications, especially when maternal KIR AA and fetal HLA-C2 are present. While the evidence supports its clinical relevance, further research is needed to elucidate the underlying mechanisms and optimize its application in personalized reproductive medicine.

We now propose an in-house study at Repromeda aimed at characterizing the frequency of maternal KIR AA haplotype and fetal HLA-C2 among couples with recurrent miscarriages and implantation failures following euploid embryo transfer. Results will be compared to a control group in which embryo transfer led to uncomplicated pregnancies.