Results
Among women enrolled in the SCRN study, 384 stillbirth cases that had chromosomal microarray and fetal structural malformation assessments were included in the present analysis. 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.
The most common organ system-specific fetal structural malformations were cardiac defects, followed by craniofacial and skeletal defects, and hydrops. The proportion of cases with fetal structural malformations (any anomaly) was higher among those with abnormal CNVs compared with those with normal CNVs (46.7% vs. 19.6%; p-value<0.001;Figure 1 and Table S1 ). We also found organ system-specific associations with abnormal CNVs. For example, the proportions of cases with cardiac, craniofacial and skeletal defects that had abnormal CNVs were higher than those that had normal CNVs (26.3% vs. 4.3%; p-value<0.001, 21.8% vs. 2.3%; p-value<0.001, and 19.2% vs. 4.0%; p=0.005, respectively). Hydrops, cystic hygroma and gastrointestinal defects were more common when abnormal CNVs were present, but in relatively smaller proportions (all p-values<0.05). Malformations categorized as ‘other anomaly’, umbilical cord abnormalities, central nervous system, thorax and genitourinary defects were not different in their proportions of abnormal CNVs in comparison to those in the normal CNVs group. The proportion of stillborn fetuses with normal CNVs that had any fetal structural malformation was lower than the proportion of those with normal CNVs and had no fetal structural malformation (70.3% vs 89.4%, p-value<0.001; Table S2 ). A pathogenic deletion of 1q21.1 involving 46 genes, including a known CHD1L gene, and a duplication of 21q22.13 involving 4 genes (SIM2 , CLDN14 ,CHAF1B , HLCS ) were associated with a skeletal and cardiac defect, respectively (Table 1 ).