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.

Copy number variants and fetal structural abnormalities in stillborn fetuses: a secondary analysis of the Stillbirth Collaborative Research Network study

“…Among 384 stillbirth cases, 58 (15.1%) had abnormal CNVs and 326 (84.9%) had normal CNVs. As previously described, 10 cases with abnormal CNVs were older, Hispanic, and with any fetal structural malformations in comparison to cases with normal CNVs. Similarly, cases with abnormal CNVs were not different in their proportions from those with normal CNVs in regard to other socio-economic factors, parity, fetal sex, maternal chronic hypertension, preeclampsia, diabetes and gestational diabetes.…”

“…8 Interpreting the pathogenicity of CNVs, however, remains challenging, 6 as limited studies link relevant clinical information to genetic observations in a structured way. Following our recent work on CNVs and placental abnormalities, 10 we used our multicenter setting of stillbirth population to determine specific CNVs associated with fetal structural malformations. We hypothesized that duplicated or deleted pathogenic CNVs in fetal/placental genes are associated with fetal structural malformations.…”

Familial aggregation of stillbirth: A pedigree analysis of a matched case–control study

“…Their study likely captured many fetal death cases (16-23 weeks) which share pathophysiological characteristics of fetal death at ≥20 weeks. 17 Indeed, the median (IQR) gestational age in weeks among women with high-risk stillbirth FSIR was lower (29 [23][24][25][26]) than that in all affected women (39 [38][39][40]) included in our study.…”

“…There are many pathophysiologic mechanisms by which genetic abnormalities may lead to stillbirth. Genetic changes resulting in placental insufficiency, severe fetal growth restriction, anatomic anomalies 37,38 not readily identified by ultrasound and metabolic derangements have been proposed as causative or contributory. 39 Stanley et al 4 performed whole exome sequencing in a large stillbirth case cohort and identified previously unknown genetic variants leading to a suspected genetic cause of death in 18% of the stillbirths in the study cohort.…”

“…The median (IQR) birthweight in grams was 1145 (440-2567) in cases and 3340 (3020-3646) in controls. The median (IQR) gestational ages of cases and controls were 29 (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) and 39 (38)(39)(40) weeks, respectively. The study population was comprised mostly of non-Hispanic white parents (66.0% cases and 73.0% controls).…”