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Immunogenetic Determinants of Preeclampsia and Related Pregnancy Disorders

A Systematic Review

From the Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Center for Perinatal, Pediatric & Environmental Epidemiology, Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut.

Objective: We sought to systematically review the impact of immunogenetic factors, specifically human leukocyte antigen (HLA) allele frequencies, maternal homozygosity, couple sharing, and maternal-fetal sharing, on the risk of preeclampsia and intrauterine growth restriction.

Data Sources: A computerized search of PubMed databases from 1975 to 2003 was performed with the terms "preeclampsia," "eclampsia," "intrauterine growth restriction," and "human leukocyte antigens" and limited to studies of human subjects in English. No restrictions were placed on study design. All bibliographies were cross-referenced to identify additional pertinent studies.

Methods of Study Selection: Titles and abstracts were reviewed carefully. Observational and basic science research studies were selected if their main objective was to assess the relationship of any aspect of HLA genotypes with preeclampsia and related disorders of pregnancy.

Tabulation, Integration, and Results: Data were abstracted and tabulated from 22 original research studies. Meta-analytic techniques were not performed owing to variations in disease and exposure definitions as well as research methodologies. Studies that examined maternal, paternal, and fetal HLA allele frequencies, maternal homozygosity, and couple sharing yielded inconsistent results. Although the cumulative evidence points to the HLA-DR locus (particularly DR4) as a correlate of preeclampsia, it remains unclear whether any specific HLA allele, haplotype, or susceptibility gene in linkage disequilibrium with the HLA region is responsible. Although genetic evidence is suggestive of gene-gene interaction between mother and fetus, few studies have evaluated the influence of maternal-fetal HLA sharing.

Conclusion: In the early 1990s, HLA genotypes were dismissed as possible etiologic factors for preeclampsia, based on studies that are heterogeneous with respect to study design, outcome, and exposure assessment. Many of these studies did not take into account the interactions between maternal, paternal, and infant genotypes. Thus, adequately powered studies designed specifically to assess the effect of maternal-fetal HLA sharing on risk of preeclampsia are needed.