Highlights
- Evidence suggests a significant association between higher maternal anti-HLA antibody levels (≥1000 MFI) and an increased risk of fetal growth restriction (aOR 1.57).
- The alloimmune hypothesis posits that FGR may, in some cases, represent a form of maternal anti-fetal rejection similar to organ transplant rejection.
- Maternal sensitization to fetal human leukocyte antigens (HLA) increases with the number of prior pregnancies but wanes over time.
- Current findings are hypothesis-generating; routine anti-HLA screening in low-risk or unexplained FGR is not yet recommended for clinical practice.
Background: The Challenge of Unexplained Fetal Growth Restriction
Fetal growth restriction (FGR), characterized by the failure of a fetus to reach its biological growth potential, remains one of the most significant challenges in modern obstetrics. It is a leading cause of stillbirth, neonatal morbidity, and long-term sequelae including neurodevelopmental delays and adult-onset metabolic and cardiovascular diseases. While the etiology of FGR is often attributed to maternal factors (e.g., hypertension, malnutrition), fetal factors (e.g., aneuploidy), or placental factors (e.g., abnormal placentation), a substantial proportion of cases remain idiopathic.
Recent advances in placental pathology have identified specific inflammatory lesions associated with severe FGR, such as chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). These lesions are histologically characterized by an influx of maternal immune cells into the intervillous space, suggesting a breakdown of maternal-fetal tolerance. This has led to the emerging hypothesis that FGR may be a manifestation of maternal anti-fetal rejection, mediated by the human leukocyte antigen (HLA) system.
Key Content: Evidence for Alloimmune-Mediated FGR
The Role of the HLA System in Pregnancy
Pregnancy is a unique immunological state where the maternal immune system must tolerate semi-allogeneic fetal tissue. The placenta plays a critical role in this tolerance; extravillous trophoblasts express a unique repertoire of HLA molecules (HLA-C, HLA-E, and HLA-G) while lacking highly polymorphic classical Class I (HLA-A, HLA-B) and Class II molecules. However, maternal sensitization to paternal HLA molecules can occur through prior pregnancies, miscarriages, or blood transfusions, leading to the development of anti-HLA antibodies.
Association Between Anti-HLA Antibodies and FGR
In a retrospective cohort study by Hannoun et al. (2026), researchers evaluated 574 women to determine the link between maternal anti-HLA antibody titers and obstetric outcomes. The study utilized a blood donor cohort screened for antibodies between 2010 and 2020. The primary findings revealed that FGR was significantly more prevalent in women with high anti-HLA antibody levels (threshold ≥1000 MFI) compared to those with lower levels (22.0% vs. 15.3%).
Adjusted multivariable logistic regression confirmed that higher antibody levels were independently associated with FGR (adjusted Odds Ratio [aOR] 1.57; 95% CI 1.02-2.41). Interestingly, this association was specific to FGR; no significant correlation was found with other general obstetric complications, suggesting that the alloimmune response may specifically target the mechanisms of nutrient and oxygen exchange at the placental interface.
Impact of Obstetric History on Antibody Levels
The study also elucidated the dynamics of HLA sensitization. Consistent with immunological principles, the risk of harboring high anti-HLA titers increased with parity. Women with a history of multiple pregnancies showed a three-fold higher risk of elevated antibodies (aOR 3.06). Conversely, the antibody levels showed a progressive decline over time following the last pregnancy (aOR 0.93 per year), indicating that the “alloimmune memory” may diminish, potentially influencing the risk profile of subsequent pregnancies depending on the inter-pregnancy interval.
Mechanistic Insights: From Antibodies to Placental Lesions
The transition from circulating antibodies to clinical FGR is thought to be mediated by chronic inflammatory placental lesions. Chronic chorioamnionitis and chronic villitis of unknown etiology (VUE) have previously been linked to maternal anti-HLA antibodies. These conditions involve the infiltration of maternal T-cells into fetal tissues. The presence of anti-HLA antibodies may act as a biomarker for a broader state of maternal-fetal dysregulation, or they may directly contribute to placental damage via complement activation and recruitment of inflammatory cells (monocytes and macrophages) to the intervillous space, as seen in CHI.
Expert Commentary: Clinical Implications and Limitations
The findings by Hannoun et al. provide compelling evidence for the “rejection” model of pregnancy complications. However, the study’s retrospective nature and the use of a blood donor population—who may be healthier than the general obstetric population—warrant cautious interpretation. Furthermore, the presence of anti-HLA antibodies is common in multiparous women who experience completely healthy pregnancies, suggesting that antibodies alone are not sufficient to cause FGR. The pathogenicity likely depends on the specific HLA targets (e.g., antibodies directed against fetal HLA-C), the antibody titer, and the maternal-fetal HLA compatibility (the “mismatch” load).
From a clinical perspective, these results are not yet sufficient to justify routine anti-HLA testing in prenatal care. However, for patients with a history of recurrent, unexplained FGR or those with known placental inflammatory lesions in previous pregnancies, anti-HLA screening could eventually provide diagnostic clarity. If the alloimmune pathway is confirmed, future therapeutic interventions might involve immunomodulatory agents such as aspirin, hydroxychloroquine, or even intravenous immunoglobulin (IVIG), which are currently under investigation for related conditions like CHI.
Conclusion: Shifting the Paradigm in FGR Management
The identification of maternal anti-HLA antibodies as an independent risk factor for fetal growth restriction marks a significant shift from purely vascular models of placental insufficiency toward a more nuanced, immunological understanding of gestational pathology. While further prospective, longitudinal studies are required to validate these findings and establish clinical thresholds, the current evidence reinforces the hypothesis that a subset of FGR cases is fundamentally an alloimmune phenomenon. Refining our ability to identify these cases could lead to personalized management strategies for one of the most recalcitrant conditions in maternal-fetal medicine.
References
- Hannoun P, Verdoux M, Jollet I, Taupin JL, Zuber J, Bonneaudeau B, Brossard P, Thévenin S, Grimaldi L, Benachi A, Lafarge X. Anti-HLA Antibodies and Risk of Fetal Growth Restriction. American journal of obstetrics and gynecology. 2026-05-29. PMID: 42217663.
- Redline RW. Villitis of unknown etiology: non-specific marker or specific genetic disease? Pathology. 2007;39(1):2-11. PMID: 17365818.
- Reuwer PJ, et al. Chronic villitis: a review of the literature and its association with fetal growth restriction. Eur J Obstet Gynecol Reprod Biol. 1985.
