Objective To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 384 stillbirth cases of the SCRN study (2006-2008). Methods FSMs were grouped by anatomic system and specific malformation type (e.g., central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb 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 FSMs using the Wald Chi-squared test. Results The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs compared with those with normal CNVs (46.7% vs. 19.6%; p-value<0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by craniofacial and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g., CHD1L) and a duplication of 21q22.13 involving 4 genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. Conclusion Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counseling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

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.