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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

Authors

  • JoonHo Lee,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
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  • Roberto Romero,

    Corresponding author
    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
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  • Yi Xu,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
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  • Jezid Miranda,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
    2. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
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  • Wonsuk Yoo,

    1. Biostatistics and Epidemiology Division, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
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  • Piya Chaemsaithong,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
    2. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
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  • Juan Pedro Kusanovic,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
    2. Department of Obstetrics and Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
    3. Center for Research and Innovation in Maternal-Fetal Medicine (CIMAF), Sótero del Río Hospital, Santiago, Chile
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  • Tinnakorn Chaiworapongsa,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
    2. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
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  • Adi L. Tarca,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
    2. Department of Computer Science, Wayne State University, Detroit, MI, USA
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  • Steven J. Korzeniewski,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
    2. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
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  • Sonia S. Hassan,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
    2. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
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  • Nandor Gabor Than,

    1. Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
    2. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
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  • Bo Hyun Yoon,

    1. Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
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  • Chong Jai Kim

    Corresponding author
    1. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
    2. Department of Pathology, Wayne State University School of Medicine, Hutzel Women's Hospital, Detroit, MI, USA
    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI, USA
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Correspondence

Chong Jai Kim, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.

E-mail: ckim@amc.seoul.kr;

Roberto Romero, Perinatology Research Branch, NICHD, NIH, DHHS, Hutzel Women's Hospital, 3990 John R St, Detroit, MI 48201, USA.

E-mail: romeror@mail.nih.gov

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, < 0.0001) and class II (adjusted OR = 1.98, = 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; = 0.001) and after 34 weeks of gestation (adjusted OR = 2.53; < 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; = 0.002); (iv) multiparous women were at a higher risk for HLA class I PRA positivity than nulliparous women (adjusted OR = 0.097, < 0.0001 for nulliparity); (v) nulliparous women had a higher rate of HLA class I PRA positivity with advancing gestational age (= 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.

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