Antihuman leukocyte antigen antibodies and risk of fetal growth restriction

Fetal growth restriction 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 remains unexplained. Chronic inflammatory placental lesions, such as chronic histiocytic intervillositis or massive perivillous fibrin deposition, are associated with fetal growth restriction and have been interpreted as possible manifestations of maternal antifetal rejection mediated by the human leukocyte antigen system. Maternal antihuman leukocyte antigen antibodies have been associated with chronic chorioamnionitis and preterm birth, but their relationship with fetal growth restriction has not been evaluated at the population level.

To assess whether maternal antihuman leukocyte antigen antibody levels are associated with fetal growth restriction and to explore their relationship with obstetric history.

We conducted a retrospective cohort study in women screened for antihuman leukocyte antigen antibodies between 2010 and 2020, using a blood donor cohort. Obstetric history was obtained by questionnaire. Antihuman leukocyte antigen 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.

Among 574 women, 103 (17.9%) reported a history of fetal growth restriction. Fetal growth restriction was more frequent in women with antihuman leukocyte antigen antibody levels ≥1000 than in those with lower levels (22.0% vs 15.3%). Higher antibody levels were independently associated with fetal growth restriction (adjusted odds ratio, 1.57; 95% confidence interval, 1.02-2.41). No association was observed with overall obstetric complications. Antibody levels increased with the number of prior pregnancies (adjusted odds ratio, 3.06; 95% confidence interval, 1.77-5.27) and decreased with time since the last pregnancy (adjusted odds ratio, 0.93; 95% confidence interval, 0.88-0.97).

Higher maternal antihuman leukocyte antigen antibody levels were associated with fetal growth restriction, 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 antihuman leukocyte antigen 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 fetal growth restriction.