Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study

Objective To determine whether 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 = 9404) 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 Standardised 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 (affected) and live birth (unaffected) were estimated using logistic regression models. Main outcome measures Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. Results We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR >= 2.00; 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 with 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) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with 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 the genetic architecture of stillbirth.

Automated summary

This study identifies familial aggregation of stillbirth and quantifies its familial risk. It also reveals gender-specific risks associated with affected parents. These findings suggest the need for research on genes related to stillbirth and large-scale studies to determine the genetic architecture of stillbirth.