Copy Number Variants and Fetal Growth in Stillbirths.

BACKGROUND: Fetal growth abnormalities are associated with a higher incidence of stillbirth, with small and large for gestational age infants incurring a 3 to 4, and 2 to 3-fold increased risk, respectively. Although clinical risk factors such as diabetes, hypertension, and placental insufficiency have been associated with fetal growth aberrations and stillbirth, the role of underlying genetic etiologies remains uncertain.

OBJECTIVE(S): To assess the relationship between abnormal copy number variants using chromosomal microarray and fetal growth abnormalities in stillbirths.

STUDY DESIGN: A secondary analysis utilizing a cohort study design of stillbirths from the Stillbirth Collaborative Research Network was performed. The exposure was defined as abnormal copy number variants, including aneuploidies, pathogenic copy number variants, and variants of unknown clinical significance. The outcomes were small for gestational age and large for gestational age stillbirths, defined as a birthweight less than the 10th percentile and greater than the 90th percentile for gestational age, respectively.

RESULTS: Among 393 stillbirths with chromosomal microarray and birthweight data, 16% had abnormal copy number variants. The small for gestational age outcome was more common among those with abnormal copy number variants compared to those with a normal microarray (29.5% vs. 16.5%, p=0.038). This finding was consistent after adjusting for clinically important variables. In the final model, only abnormal copy number variants and maternal age remained significantly associated with small for gestational age stillbirths with an aOR of 2.22 (95% CI: 1.12 - 4.18). While large for gestational age stillbirths were more likely to have an abnormal microarray: 6.2% vs 3.3% (p=0.275), with an OR 2.35 (95% CI: 0.70 - 7.90), this finding did not reach statistical significance.

CONCLUSION(S): Genetic abnormalities are more common in the setting of small for gestational age stillborn fetuses. Abnormal copy number variants not detectable by traditional karyotype make up approximately 50% of the genetic abnormalities in this population.