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.