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 of 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: (i) 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; (ii) HLA class I PRA positivity for patients with spontaneous preterm delivery between 28 and 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; (iii) 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); (iv) multiparous women were at a higher risk for HLA class I PRA positivity than nulliparous women (adjusted OR = 0.097, P < 0.0001 for nulliparity); (v) nulliparous women had a higher rate of HLA class I PRA positivity with advancing gestational age (P = 0.001); and (vi) 78% of women whose fetuses were genotyped had alloantibodies specific against fetal HLA class I antigens.

Conclusion: Pregnant women with positive HLA class I or class II PRA during the second trimester are at an increased risk of spontaneous preterm delivery due to antibody-mediated maternal anti-fetal rejection.

Keywords: Flow cytometry; preterm birth; rejection; transplantation.

Figure 1. HLA PRA in maternal plasma

(A) HLA class I and class II PRA positive rates in normal term delivery and spontaneous preterm delivery cases, (B) HLA class I PRA positive rate according to gestational age at delivery. HLA, human leukocyte antigen; PRA, panel-reactive antibody; TD, normal term delivery; sPTD, spontaneous preterm delivery; extreme sPTD, delivered before 28 + 0 weeks of gestation; moderate sPTD, delivered between 28 + 0-33 + 6 weeks of gestation; late sPTD, delivered between 34 + 0-36 + 6 weeks of gestation.

Figure 2. Illustration of effect modification between parity and case status over time

The likelihood of a HLA PRA class I > 10% elevating among women with spontaneous preterm delivery compared to women with normal term delivery over time differed significantly by parity in multiparous women with spontaneous preterm delivery, exhibiting the greatest risk relative to nulliparous women over time. TD, normal term delivery; sPTD, spontaneous preterm delivery; OR, odds ratio.