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\begin{document}

\title{Mini-commentary on ``Familial aggregation of stillbirth: a pedigree
analysis of a matched case control study'' BJOG\_22-0217}



\author[1]{Matthew Shear}%
\affil[1]{UCSF}%


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  \date{May 17, 2024}


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JOURNAL: BJOG

DATE 08\_25\_2022

TITLE: Mini commentary on ``Familial aggregation of stillbirth: a
pedigree analysis of a matched case control study'' BJOG\_22-0217

Author: Matthew A. Shear, MD\textsuperscript{a,b}

Author Affiliations:

\textsuperscript{a} Department of Obstetrics, Gynecology, \&
Reproductive Sciences, University of California, San Francisco

\textsuperscript{b} Division of Medical Genetics, Department of
Pediatrics, University of California, San Francisco

Despite advances in genomics, the underlying cause of many stillbirths
remains elusive. The emotional toll that a stillbirth takes on families,
as well as the providers caring for them, is hard to overstate.
Karyotype may identify a causative aneuploidy or large unbalanced
translocation, but only in about 6\% of stillbirths. Chromosomal
microarray is higher yield, but still only identifies pathogenic copy
number variants in about 10\% of stillbirth cases (Reddy et al. N Engl J
Med. 2012). The addition of exome sequencing to microarray only yielded
a plausible genetic explanation in 15 out of 246 cases, or about 6\%
(Stanley et al. N Engl J Med. 2020). This suggested that non-mendelian
mechanisms may play a significant role in stillbirth (Wojcik et al N.
Engl J Med. 2020), although single gene pathogenic variants are poorly
understood at the fetal level relative to the postnatal setting. The
non-genetic mechanisms underlying stillbirth are also poorly understood
at present, including viral infections, environmental toxins, and
comorbid conditions.

Workalemahu and their colleagues present a unique analysis suggesting
genomic heritability of stillbirth in some families. Using a robust
matched case-control study of over 9000 stillbirths and 390 high-risk
pedigrees from the Utah Population Database, they calculated the
familial standardized incidence ratio and risk of stillbirth among
first, second, and third-degree relatives of the pregnant individuals
who had experienced stillbirth. In their adjusted model, among all
relatives of an individual who experienced stillbirth, there was a
relative risk of stillbirth of 1.1 (95\% CI 1.00-1.22). This study adds
further evidence there are heritable genetic etiologies of stillbirth
not yet fully described.

Many non-genetic contributors to stillbirth risk may also cluster in
families. In the present study, when adjusting for maternal
race/ethnicity, socioeconomic status, and education, the elevations in
stillbirth risk became attenuated, although this may be due to
collinearity among variables used in the model. Health behaviors are
informed through regional and family culture, leading to patterns in
diet, nutrition, and exercise. These patterns contribute to modifiable
health conditions known to impact stillbirth risk, including
hypertension, obesity, diabetes, and smoking status. We also know the
incidence of stillbirth is higher in lower income versus higher income
countries, higher among individuals of lower educational attainment
versus higher education, and higher among African American and Black
individuals compared to White, likely complicated by the impacts of
systemic racism. This is to say nothing of the additional social
determinants of health that may impact families across generations.

As Workalemahu and colleagues note, there is still much unknown about
complex outcomes such as stillbirth. Their findings support that for a
patient with a high-risk pedigree, genomic testing may prove
informative. Future epigenetic and functional studies may help
understand variants at the tissue level, and the impact of comorbidities
on gene expression. Together with fetal genome sequencing, previously
unexplained cases of stillbirth might be solved, improving patient
counseling, and possibly changing clinical management. While genomic
testing offers promise to explain a subset of stillbirths, we should not
neglect the ``non-mendelian'' and non-genetic factors that continue to
play a significant role in stillbirth risk.

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