Copy number variants and placental abnormalities in stillborn fetuses: a
secondary analysis of the Stillbirth Collaborative Research Network
study
Abstract
Objective To examine the association of DNA copy number variants (CNVs)
with pathologic placental lesions (PPLs) in stillborn fetuses. Design A
secondary analysis of stillbirth cases in the Stillbirth Collaborative
Research Network case-control study. Setting Multicenter, 59 hospitals
in 5 geographic regions in the USA. Population 387 stillbirth cases
(2006-2008). Methods Using standard definitions, PPLs were categorized
by type including maternal and fetal vascular, inflammatory and
immune/idiopathic lesions. Using single-nucleotide polymorphism array,
CNVs of at least 500 kb were detected. CNVs were classified into two
groups: normal, defined as no CNVs>500 kb or benign CNVs,
and abnormal, defined as pathogenic or variants of unknown clinical
significance. Main outcome measures The proportions of abnormal CNVs and
normal CNVs were compared between stillbirth cases with and without PPLs
using the Wald Chi-squared test. Results Of 387 stillborn fetuses, 327
(84.5%) had maternal vascular PPLs and 60 (15.6%) had abnormal CNVs.
Maternal vascular PPLs were more common in stillborn fetuses with
abnormal CNVs compared with those with normal CNVs (81.7% vs. 64.2%;
p=0.008). The proportions of fetal vascular, maternal/fetal
inflammatory, and immune/idiopathic PPLs were similar among stillborn
fetuses with abnormal CNVs compared to those with normal CNVs.
Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned
several genes with known relevant mechanisms. Conclusions Abnormal
placental/fetal CNVs were associated with maternal vascular PPLs in
stillborn fetuses. Findings may provide insight on the mechanisms of
specific genetic abnormalities associated with placental dysfunction and
stillbirth.