Detection of Anti‐HLA Antibodies in Maternal Blood in the Second Trimester to Identify Patients at Risk of Antibody‐Mediated Maternal Anti‐Fetal Rejection and Spontaneous Preterm Delivery

Abstract

Problem Maternal anti-fetal rejection is a mechanism of disease in spontaneous preterm labor. The objective of this study was to determine whether the presence of human leukocyte antigen (HLA) panel-reactive antibodies (PRA) during the second trimester increases the risk for spontaneous preterm delivery. Methods of Study This longitudinal case-control study included pregnant women with spontaneous preterm deliveries (n=310) and control patients with normal term pregnancies (n=620), matched for maternal age and gravidity. Maternal plasma samples obtained at 14-16, 16-20, 20-24, and 24-28 weeks of gestation were analyzed for HLA Class I and Class II PRA positivity using flow cytometry. The fetal HLA genotype and maternal HLA alloantibody epitope were determined for a subset of patients with positive HLA PRA. Results 1) Patients with spontaneous preterm delivery were more likely to exhibit HLA Class I (adjusted OR=2.54, p<0.0001) and Class II (adjusted OR=1.98, p=0.002) PRA positivity than those delivering at term; 2) HLA Class I PRA positivity for patients with spontaneous preterm delivery between 28-34 weeks (adjusted OR=2.88; p=0.001) and after 34 weeks of gestation (adjusted OR=2.53; p<0.0001) was higher than for those delivering at term; 3) HLA Class II PRA positivity for patients with spontaneous preterm delivery after 34 weeks of gestation was higher than for those delivering at term (adjusted OR=2.04; p=0.002); 4) multiparous women were at higher risk for HLA Class I PRA positivity than nulliparous women (adjusted OR=0.097, p<0.0001 for nulliparity); 5) nulliparous women had a higher rate of HLA Class I PRA positivity with advancing gestational age (p=0.001); and 6) 78% of women whose fetuses were genotyped had allo-antibodies specific against fetal HLA class I antigens. Conclusions Pregnant women with positive HLA class I or class II PRA during the second trimester are at an increased risk for spontaneous preterm delivery due to antibody-mediated maternal anti-fetal rejection.

Immunobiology of Allograft Human Leukocyte Antigens in the New Microenvironment

“…In melanoma patients, detectable levels of sHLA-DR in serum appeared only in the later stage of the disease. The above findings on the increased level of sHLA-DR in sera of patients with ALL were confirmed by Thompson, et al [163], using a double-determinant ELISA with two mAbs. They further compared sHLA-II in the blood of healthy people and of patients who received either an allogeneic or autologous bone-marrow transplant.…”

Increased human leukocyte antigen-G expression at the maternal–fetal interface is associated with preterm birth

“…Other studies have found increased maternal serum HLA class I (classic) antibodies to be associated with spontaneous PTB and fetal inflammatory responses, suggesting a component of maternal-anti-fetal rejection in the pathogenesis of PTB[33,34]. Thus, our finding that non-classic (immuno-tolerant) HLA protein is higher on fetally derived cells from PTB than from term birth suggests that maternal-fetal interactions may jointly contribute to pregnancy tolerance or rejection[33,34].…”

Preterm labor: One syndrome, many causes

“…Chronic chorioamnionitis, the most common placental lesion in late spontaneous preterm birth, which is characterized by maternal T-cell infiltration of the chorion laeve with trophoblast apoptosis, resembles allograft rejection ( 44 ). Maternal sensitization to fetal HLAs is frequently found in patients with chronic chorioamnionitis, and is accompanied by complement deposition in umbilical vein endothelium ( 45, 46 ). A novel form of fetal systemic inflammation characterized by overexpression of T-cell chemokines ( e.g.…”