Anti-HLA Antibodies and Risk of Fetal Growth Restriction

BACKGROUND: Fetal growth restriction (FGR) is a major cause of stillbirth, neonatal morbidity, and long-term cardiovascular and neurodevelopmental complications. While placental dysfunction is central to many cases, a substantial proportion remain unexplained. Chronic inflammatory placental lesions, such as chronic histiocytic intervillositis or massive perivillous fibrin deposition, are associated with FGR and have been interpreted as possible manifestations of maternal anti-fetal rejection mediated by the human leukocyte antigen (HLA) system. Maternal anti-HLA antibodies have been associated with chronic chorioamnionitis and preterm birth, but their relationship with FGR has not been evaluated at the population level. OBJECTIVE: To assess whether maternal anti-HLA antibody levels are associated with FGR, and to explore their relationship with obstetric history. STUDY DESIGN: We conducted a retrospective cohort study in women screened for anti-HLA antibodies between 2010 and 2020, using a blood donor cohort. Obstetric history was obtained by questionnaire. Anti-HLA antibodies were analyzed as continuous and categorical variables, using a threshold of ≥1000 for higher levels. Multivariable logistic regression models were adjusted for maternal age at pregnancy, body mass index, and number of pregnancies. RESULTS: Among 574 women, 103 (17.9%) reported a history of FGR. FGR was more frequent in women with anti-HLA antibody levels ≥1000 than in those with lower levels (22.0% vs 15.3%). Higher antibody levels were independently associated with FGR (aOR 1.57; 95% CI [1.02-2.41]). No association was observed with overall obstetric complications. Antibody levels increased with the number of prior pregnancies (aOR 3.06; 95% CI [1.77-5.27]) and decreased with time since the last pregnancy (aOR 0.93; 95% CI [0.88-0.97]). CONCLUSION: Higher maternal anti-HLA antibody levels were associated with FGR, supporting the hypothesis that alloimmune mechanisms may contribute to a subset of growth-restricted pregnancies. These results are hypothesis-generating and do not support routine anti-HLA antibody testing in clinical practice at this stage. Further prospective studies are needed to determine whether this pathway could help refine the evaluation of unexplained FGR.