Familial aggregation of stillbirth: a pedigree analysis of a matched
case control study
Abstract
Objective To determine if stillbirth aggregates in families and quantify
its familial risk using extended pedigrees. Design State-wide matched
case-control study. Setting Utah, United States. Population Stillbirth
cases (n=9 404) and live-birth controls (18 808) between 1978 and 2019.
Methods Using the Utah Population Database, a population‐based
genealogical resource linked with state fetal death and birth records,
we identified high-risk pedigrees with excess familial aggregation of
stillbirth using the Familial Standardized Incidence Ratio (FSIR).
Stillbirth odds ratio (OR) for first-degree relatives (FDR),
second-degree relatives (SDR), and third-degree relatives (TDR) of
parents with a stillbirth and live-birth were estimated using logistic
regression models. Results We identified 390 high-risk pedigrees with
evidence for excess familial aggregation (FSIR≥2.00 and
P-value<0.05). FDRs, SDRs and TDRs of affected parents had
1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold
(95% CI: 1.11-1.33), and 1.15-fold (95% CI: 1.08-1.21) higher
stillbirth odds compared to FDRs, SDRs and TDRs of unaffected parents,
respectively. Parental sex-specific analyses showed male FDRs, SDRs and
TDRs of affected fathers had 1.22-fold (95% CI: 1.02-1.47), 1.38-fold
(95% CI: 1.17-1.62), 1.17-fold (95% CI: 1.05-1.30) higher stillbirth
odds compared to those of unaffected fathers, respectively. FDRs, SDRs
and TDRs of affected mothers had 1.12-fold (95% CI: 0.98-1.28),
1.09-fold (95% CI: 0.96-1.24), and 1.15-fold (95% CI: 1.06-1.24)
higher stillbirth odds compared with those of unaffected mothers,
respectively. Conclusions We provide evidence for familial aggregation
of stillbirth. Our findings warrant investigation into genes associated
with stillbirth and underscore the need to design large-scale studies to
determine its genetic architecture.