Discussion
Our work demonstrates that there is familial aggregation of stillbirth,
implying that a family history of stillbirth imparts increased
stillbirth risk to family members. Stillbirth risk was stronger in the
male relatives of affected pedigrees. Familial aggregation of stillbirth
supports existing data regarding genetic underpinnings of
stillbirth.26Identification of stillbirth
high-risk pedigrees of may lead to improved characterization of these
families, causal genes and extreme phenotypes such as fetal death.
There are limited data on familial aggregation of fetal death. Some of
the difficulty in studying fetal death lies in varying definitions of
miscarriage, fetal death and stillbirth worldwide.17Additionally, many studies have relied on self-reported outcomes or
chart abstraction, increasing the risk of inaccuracies and recall bias.
Accordingly, data regarding early pregnancy loss have been mixed in
regard to a heritable risk of spontaneous abortion or fetal
death.27,28 Recent studies by Woolner and colleagues
investigated familial risk of miscarriage29 or
stillbirth14 in mother-daughter pairs. Both studies
included mothers (pregnancies between 1949-2000) with at least one
daughter (pregnancies between 1965-2016) in Aberdeen, United Kingdom.
The study of miscarriage included 31,565 mother-daughter pairs and the
study of stillbirth included 27,688 mother-daughter pairs. They
demonstrated an increased risk of miscarriage but not stillbirth in
their intergenerational analysis.14,29 This difference
between our results and theirs may be due to several factors. First, an
intergenerational link may have been missed in their work due to the
relative rarity of fetal death ≥24 weeks and limiting the analysis to
mother-daughter pairs. By utilizing the UPDB, we were able to evaluate
multigenerational trends in fetal death as well as both maternal and
paternal lineages. This likely increased our ability to detect a
familial aggregation for this relatively uncommon pregnancy outcome.
Second, they defined miscarriage as fetal death prior to 24 weeks and
stillbirth as fetal death at 24 weeks and greater. This differs from our
definition of stillbirth as fetal death at 20 weeks or greater. Their
study likely captured many fetal death cases (16 – 23 weeks) which
share pathophysiologic characteristics of fetal death at 20 weeks and
beyond.17 Indeed, the median (IQR) gestational age in
weeks among women with high-risk stillbirth FSIR was lower (29
[23-26]) compared with all affected women (39 [38-40]) included
in our study.
By utilizing the stillborn fetus as the proband we were able to assess
both maternal and paternal contributions to the fetal death phenotype.
We demonstrated a stronger risk of stillbirth in male relatives of
affected pedigrees as compared to female descendants. This risk was
further increased if a paternal history of stillbirth was present.
Paternal genes may play a key role
in placentation, a critical process for fetal
development.15 Esplin and colleagues demonstrated the
importance of paternal genetic contribution in preeclampsia, a process
believed to have pathologic placental underpinnings.13The genetic basis for stillbirth
is as yet poorly characterized and our work highlights an opportunity to
explore parental sex-specific differences in stillbirth familial risk.
Our findings demonstrated an elevated risk of stillbirth for parents
with any family history of stillbirth. This risk persisted into TDR,
suggesting that there may be inherited genetic factors that impart an
increased risk of stillbirth that are independent of shared
environmental characteristics. However, gene-environment interactions
are complex and epigenetic modifications as a result of environmental
exposures can be inherited and affect the health outcomes of future
generations.30 Evaluating the inherited pathogenic
genes in these families will improve our understanding of this process.
There are many pathophysiologic mechanisms by which genetic
abnormalities may lead to stillbirth. Genetic changes resulting in
placental insufficiency, severe fetal growth restriction, anatomic
anomalies not readily identified by ultrasound or metabolic derangements
have been proposed as causative or contributory.31Stanley and colleagues performed whole exome sequencing in a large
stillbirth case cohort and identified previously unknown genetic
variants leading to a suspected genetic cause of death in 18% of the
stillbirths in the study cohort.4 They found variants
in genes that are known to be pathogenic in postnatal life but also
variants that are critical for in utero survival that had not yet
been reported in association with stillbirth.4
Our study contributes new data as the largest and most comprehensive
intergenerational study of stillbirth. It is the first to identify
familial aggregation of stillbirth and quantifies stillbirth risk based
on an individual’s family history. Strengths of this work include use of
the Utah Population Database which enabled access to a vast number of
pedigrees. These genealogic records are linked to birth and fetal death
certificates which allowed increased accuracy as compared to patient
surveys.32 The Utah population has been shown to be of
similar genetic diversity to the U.S. population of Northern European
descent and thus may not be generalizable to the general U.S.
population.33 In order to achieve the most rigorous
definition of stillbirth possible within the UPDB, we utilized fetal
death certificates. This strategy limited our identification of proband
stillbirth cases to the era in which fetal death certificates were
available (1978-2019), but allowed use of the most rigorous definition
of stillbirth available in vital statistics data.
Findings reported herein provide the first demonstration of familial
aggregation of stillbirth. Further study of this population to evaluate
pathogenic genetic variants will be an important next step in defining
heritable genetic mutations. Knowledge of risks for stillbirth according
to family history may also improve patient counseling and management.
Establishing key genes involved in stillbirth will hopefully lead to
better diagnostic tools and preventive measures.