Introduction
Stillbirth is common worldwide with rates exceeding the neonatal and infant death rates in many high-income countries.1This is driven in part by a large number of unexplained stillbirths. In a well characterized cohort of stillbirth cases (fetal death at ≥20 weeks’ gestation) in the U.S., approximately 24% of stillbirths remained unexplained following thorough, standardized evaluation.2 The identification of stillbirths due to genetic abnormalities has improved with advancing genomic technologies. The addition of microarray improved the diagnostic yield from 6.5% to 8.8% as compared to karyotype.3 Moreover, 8.5% of stillbirth cases with a normal chromosomal microarray had a probable molecular genetic diagnosis attributable to Mendelian disorders discovered on whole exome sequencing.4 The combined results of karyotype, microarray and whole exome sequencing identified a potential genetic cause of death in 18% of stillbirth cases.4 These observations highlight the possibility of a heritable component in the genesis of stillbirth.
Adverse pregnancy outcomes, particularly ischemic placental disease (preeclampsia, placental abruption and small for gestational age) and preterm birth, aggregate in families.5–13 These data suggest that there are genetic underpinnings for many adverse pregnancy outcomes. However, data regarding an inherited genetic risk for stillbirth are limited. One study evaluated mother-daughter pairs and did not find an inherited predisposition for stillbirth.14 Given that there are both maternal and paternal contributions to the fetal genotype, investigation into broader pedigrees may reveal important insights to understand the extent to which genes may affect stillbirth risk.15 Thus, we sought to investigate whether stillbirth aggregates in families and, if so, to quantify the risk of stillbirth for parents with family history in extended pedigrees.