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Familial aggregation of stillbirth: a pedigree analysis of a matched case control study
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  • Tsegaselassie Workalemahu,
  • Jessica Page,
  • Huong Meeks,
  • Zhe Yu,
  • Emily Guinto,
  • Alison Fraser,
  • Michael Varner,
  • Lauren Theilen,
  • Aaron Quinlan,
  • Hilary Coon,
  • Daniel Enquobahrie,
  • Cande Ananth (STATS CONSULTS ONLY),
  • Fasil Tekola-Ayele,
  • Lynn Jorde,
  • Robert Silver (USA)
Tsegaselassie Workalemahu
University of Utah Health

Corresponding Author:tsegaselassie.workalemahu@hsc.utah.edu

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Jessica Page
Intermountain Medical Center
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Huong Meeks
University of Utah Health Huntsman Cancer Institute
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Zhe Yu
University of Utah Health Huntsman Cancer Institute
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Emily Guinto
University of Utah Health Huntsman Cancer Institute
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Alison Fraser
University of Utah Health Huntsman Cancer Institute
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Michael Varner
University of Utah Health
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Lauren Theilen
University of Utah Health
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Aaron Quinlan
University of Utah Health
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Hilary Coon
University of Utah Health
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Daniel Enquobahrie
University of Washington
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Cande Ananth (STATS CONSULTS ONLY)
Rutgers Robert Wood Johnson Medical School
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Fasil Tekola-Ayele
Eunice Kennedy Shriver National Institute of Child Health and Human Development
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Lynn Jorde
University of Utah Health
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Robert Silver (USA)
University of Utah Health
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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.
12 Feb 2022Submitted to BJOG: An International Journal of Obstetrics and Gynaecology
15 Feb 2022Submission Checks Completed
15 Feb 2022Assigned to Editor
19 Feb 2022Reviewer(s) Assigned
27 May 2022Review(s) Completed, Editorial Evaluation Pending
08 Jun 2022Editorial Decision: Revise Major
12 Jul 20221st Revision Received
18 Jul 2022Submission Checks Completed
18 Jul 2022Assigned to Editor
18 Jul 2022Review(s) Completed, Editorial Evaluation Pending
08 Aug 2022Editorial Decision: Accept
09 Oct 2022Published in BJOG: An International Journal of Obstetrics & Gynaecology. 10.1111/1471-0528.17301