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\begin{document}

\title{Familial Risk of Placental Abruption}



\author[1]{Susan Dalton}%
\author[2]{Huong Meeks}%
\author[3]{Alison Fraser}%
\author[3]{Devin Etcitty}%
\author[1]{Tsegaselassie Workalemahu}%
\author[1]{Michael Varner}%
\author[1]{Robert Silver (USA)}%
\affil[1]{The University of Utah Department of Obstetrics and Gynecology}%
\affil[2]{The University of Utah Department of Pediatrics}%
\affil[3]{University of Utah Health Huntsman Cancer Institute}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Objective:} This study aims to estimate the familial risk of
placental abruption using a large population database. \textbf{Design:}
Retrospective familial aggregation study of placental abruption
utilizing a case-control design. \textbf{Population:} The Utah
Population Database is a genealogic database of over 11 million
individuals, which contains medical and demographic information linked
to official records dating back to the 1900s. \textbf{Methods:} Cases of
placental abruption and controls were ascertained from birth
certificates, death certificates, and inpatient medical records.
Controls were matched 3:1 to cases based on age, parity, and number of
relatives in the database. Familial risk of placental abruption was
estimated using generalized linear mixed-effect regression and
conditional logistic regression. \textbf{Main outcome measures:}
Unadjusted and adjusted odds of placental abruption between first-,
second-, and third-degree relatives. \textbf{Results:} Of 1,168,378
pregnancies analyzed in the Utah Population Database, 32,823 cases
(2.8\%) of placental abruption were identified. First-degree relatives
inherit an adjusted odds of placental abruption estimated at 1.18 (95\%
CI: 1.12 -- 1.23) when a family member has had at least one placental
abruption, and 1.38 (95\% CI: 1.17 -- 1.63) with two or more placental
abruptions. The estimated effect is lower for second- and third-degree
relatives. After controlling for clinical risk factors, individuals
inherit an adjusted odds of placental abruption estimated at 1.16 (95\%
CI: 1.03 -- 1.31, \emph{p}=0.014) with a first-degree family history of
placental abruption. The estimates for second- and third-degree
relatives using this method are not statistically significant.
\textbf{Conclusion:} These findings represent an argument for the
inheritance of genetic factors which predispose the occurrence of
placental abruption.%
\end{abstract}%



\sloppy


\textbf{Title:} Familial Risk of Placental Abruption

\textbf{Authors and affiliations:} Susan Dalton,
MD\textsuperscript{1-2}; Huong Meeks, PhD\textsuperscript{3}; Alison
Fraser, MSPH\textsuperscript{4}; Devin Etcitty, BS\textsuperscript{4};
Tsegaselassie Workalemahu, PhD\textsuperscript{1}; Michael Varner,
MD\textsuperscript{1-2}; Robert M. Silver, MD\textsuperscript{1-2}

\textsuperscript{1}Department of Obstetrics and Gynecology, University
of Utah, Salt Lake City, UT 84132, USA

\textsuperscript{2}Women and Newborn Clinical Program, Intermountain
Healthcare, Salt Lake City, UT, 84111 USA

\textsuperscript{3}Department of Pediatrics, University of Utah, Salt
Lake City, UT 84112, USA

\textsuperscript{4}Population Sciences, Huntsman Cancer Institute,
University of Utah, Salt Lake City, UT 84112, USA

\textbf{Corresponding author:}

Susan Dalton, MD

Email: susan.dalton@hsc.utah.edu

Phone (cell): 1-801-856-1657

ORCID ID: 0000-0003-0229-7365

\textbf{Short Title:} Familial Risk of Placental Abruption

\textbf{Word count:} Abstract: 246; Manuscript: 2403

\textbf{Abstract:}

\textbf{Objective:} This study aims to estimate the familial risk of
placental abruption using a large population database.

\textbf{Design:} Retrospective familial aggregation study of placental
abruption utilizing a case-control design.

\textbf{Population:} The Utah Population Database is a genealogic
database of over 11 million individuals, which contains medical and
demographic information linked to official records dating back to the
1900s.

\textbf{Methods:} Cases of placental abruption and controls were
ascertained from birth certificates, death certificates, and inpatient
medical records. Controls were matched 3:1 to cases based on age,
parity, and number of relatives in the database. Familial risk of
placental abruption was estimated using generalized linear mixed-effect
regression and conditional logistic regression.

\textbf{Main outcome measures:} Unadjusted and adjusted odds of
placental abruption between first-, second-, and third-degree relatives.

\textbf{Results:} Of 1,168,378 pregnancies analyzed in the Utah
Population Database, 32,823 cases (2.8\%) of placental abruption were
identified. First-degree relatives inherit an adjusted odds of placental
abruption estimated at 1.18 (95\% CI: 1.12 -- 1.23) when a family member
has had at least one placental abruption, and 1.38 (95\% CI: 1.17 --
1.63) with two or more placental abruptions. The estimated effect is
lower for second- and third-degree relatives. After controlling for
clinical risk factors, individuals inherit an adjusted odds of placental
abruption estimated at 1.16 (95\% CI: 1.03 -- 1.31, \emph{p} =0.014)
with a first-degree family history of placental abruption. The estimates
for second- and third-degree relatives using this method are not
statistically significant.

\textbf{Conclusion:} These findings represent an argument for the
inheritance of genetic factors which predispose the occurrence of
placental abruption.

\textbf{Funding:} none

\textbf{Key words:} Placental abruption, familial risk analysis,
heritability, adverse pregnancy outcomes

\textbf{Main text:}

\textbf{Funding:} none.

\textbf{Introduction:}

Placental abruption (PA) -- the partial or complete separation of the
placenta before delivery -- occurs in approximately 1-2\% of all
pregnancies and is associated with considerable maternal and perinatal
morbidity and mortality. \textsuperscript{1--3} While the
pathophysiology is uncertain, the leading theory involves acute
vasospasm or thrombosis in small blood vessels at the placental-uterine
interface which leads to hemorrhage. \textsuperscript{4} Significant
abruptions can cause maternal hemodynamic instability, coagulopathies,
and often require surgical management to facilitate delivery. For the
fetus or neonate, abruptions carry a 9-fold increase risk of stillbirth
and are highly associated with perinatal morbidity and mortality,
particularly in the setting of preterm delivery. \textsuperscript{3} PA
is also associated with fetal growth restriction and hypoxic brain
injury, which can lead to long-term pediatric health
consequences.\textsuperscript{5,6} PA is a clinical diagnosis that is
difficult to predict, and in the majority of cases, impossible to
prevent. Although epidemiologic studies have identified risk factors for
PA, such as pre-labor rupture of membranes (PROM), smoking, prior PA,
hypertension, and a history of cesarean delivery, the majority of cases
occur in the absence of risk factors. \textsuperscript{1,7}

Investigation for a genetic contribution underlying PA began after
practitioners noticed a significant recurrence risk for individuals in
subsequent pregnancies as well as a perceived familial heritability in
pedigrees. \textsuperscript{8,9} Initial population-based studies
determined the recurrence risk of PA to be 6-10 times higher for the
same individual and the odds of PA among first degree relatives to be
2-4 times higher than the baseline risk.
\textsuperscript{10,11}Candidate genetic loci related to
trophoblast-like cellular invasion, mitochondrial biosynthesis,
angiogenesis, oxidative stress, and circadian rhythm have been
identified through genome-wide association studies and candidate gene
association studies. \textsuperscript{12--16}An important step towards
the discovery of preventative strategies or therapeutic targets is the
accurate estimation of a person's inherited PA risk as opposed to the
environmental contribution to this disease process. This study aims to
estimate the familial risk of placental abruption using a large,
well-characterized population database.

\textbf{Methods:}

The familial risk of PA was estimated through this retrospective cohort
study using the Utah Population Database (UPDB), which is a genealogic
database of over 11 million individuals spanning up to 17 generations.
The UPDB contains individual-level medical and demographic information,
linked to official statewide birth and death records dating back to the
1900s. \textsuperscript{17} This study was approved by the Institutional
Review Board at the University of Utah and the Utah Resource for Genetic
and Epidemiologic Research, which oversees studies performed using UPDB
data.

Cases of PA and controls were ascertained from birth certificates (1939
-- 2020), maternal death certificates (1904 -- 2020), and fetal death
certificates (1978 -- 2020), inpatient medical records, and
International Classification of Diseases (ICD) codes (1996 -- 2020) from
the University of Utah Health Sciences Center. While PA can occur at any
time point in pregnancy, this diagnosis is often confirmed at the time
of delivery and more mild cases of placental abruption are often missed
on official medical records. Diagnosing PA antepartum is challenging
because of the poor sensitivity of ultrasound imaging and uncertainty on
the clinicians' part to confirm the diagnosis prior to delivery.
Frequently, a suspected diagnosis of PA will be based on recurrent
antepartum bleeding in the absence of a more obvious explanation.
Therefore, many cases are not captured within our data sources. For this
reason, we included ``antepartum bleeding'' in the case definition.
Pregnancies affected by placenta previa, multifetal gestations, cases
with inadequate demographic information allowing pedigree linkage, or
cases that were listed as gestational carriers were excluded. Controls
were 3:1 matched to cases based on age, parity, number of eligible
female relatives in the UPDB, and availability of eligible first-degree
relatives (FDRs), second-degree relatives (SDRs), or third-degree
relatives (TDRs) for analyses.

Statistical analysis included relatives of all PA cases and controls.
Demographic and clinical variables were compared using Pearson's
Chi-squared test for categorical variables and Wilcoxon rank sum test
for continuous variables. Clinical variables described were restricted
to the index pregnancy, i.e., the pregnancy affected by PA, for cases.
Familial risk of PA was estimated using generalized linear mixed-effect
regression for FDRs, SDRs, and TDRs, clustering around cases and
controls to account for non-independence of observations within
families. The analysis included all cases and controls with at least one
eligible relative in the UPDB. Family members of controls were used as
the reference group in all analyses. Variables adjusted for in the
primary analysis included age, year of pregnancy, race, ethnicity,
education level, and parity. A stratified analysis was performed
estimating familial risk of PA stratified by the number of pregnancies
affected by placental abruption (at least 1 vs. 2 or more vs. 0). A
sensitivity analysis was performed excluding cases coded as ``antepartum
bleeding,'' which excluded 50.4\% of cases.

A secondary analysis was performed, which included cases and controls
with available data in the medical record to adjust for clinical risk
factors. This analysis was performed using an alternative familial risk
statistical method, referred to as an ``ego-driven'' familial analysis
as opposed to ``relative-driven''. Ego-driven familial risk analyses
estimate the risk of PA for a case and control depending on whether a
family member was affected. The method allows for adjusting for
important clinical risk factors and medical comorbidities because they
are only required to be available for the case or control, as opposed to
all the relatives in the analysis. Familial risk of PA using this method
was estimated using conditional logistic regression, adjusting for all
demographic characteristics and potentially confounding clinical risk
factors complicating the pregnancy affected by PA. These risk factors
included smoking, drug use, diabetes, uterine anomaly, hypertension, or
pre-labor rupture of membranes (PROM) complicating the pregnancy
affected by PA, and a history of cesarean delivery in prior pregnancies.
Maternal drug use was noted to be co-linear with smoking and was not
adjusted for in multivariable analysis. Clinical risk factors were
selected based on prior published work evaluating risk factors for
PA\textsuperscript{1,5,7,8} and our univariate analyses. Statistical
analyses were carried out using R version 4.2.2 {[}R Core Team, Vienna,
Austria{]}.\textsuperscript{18}

\textbf{Results:}

We analyzed 1,168,378 pregnancies in the UPDB and identified 32,823
cases (2.8\%) of PA over the years 1939 -- 2020 after excluding for
missing data or ineligible pedigrees. Relatives included in the primary
analysis were 313,823 FDRs, 559,116 SDRs, and 1,242,936 TDRs (Fig. 1).
16,542 (50.4\%) of these cases were identified by the term ``antepartum
bleeding'' without a known diagnosis of placenta previa. The majority of
cases were identified based on birth certificate data (83.7\%), with the
remaining cases identified from medical records (13.4\%), fetal death
certificates (2.3\%) and maternal death certificates (0.5\%).
Individuals affected by PA were more likely to smoke (8.6\% vs.
6.4\%,\emph{p} -value \textless{}0.001), use drugs (1.2\% vs.
0.5\%,\emph{p} -value \textless{}0.001), have pre-gestational diabetes
(0.4\% vs. 0.3\%, \emph{p} -value \textless{}0.001), hypertension (7.5\%
vs. 5.6\%, \emph{p} -value \textless{}0.001), or a uterine anomaly
(0.2\% vs. 0.1\%, \emph{p} -value \textless{}0.001), experience PROM
(4.3\% vs. 1.3\%, \emph{p} -value \textless{}0.001), have less than a
high school education (8.7\% vs. 6.1\%, \emph{p} -value
\textless{}0.001) and were more likely to be Hispanic (9.5\% vs. 8.2\%,
\emph{p} -value \textless{}0.001) and less likely to be White (95.1\%
vs. 96.0\%,\emph{p} -value \textless{}0.001). See Table 1 for full
details.

Table 2 represents results from the primary PA familial risk analysis.
PA appears to be heritable, with a statistically significant risk
transmitted to FDRs and SDRs. FDRs inherit an increased odds of PA with
an aOR 1.18 (95\% CI: 1.12 -- 1.23, \emph{p} \textless{}0.001). SDRs
also inherit an increased odds of PA with an aOR 1.09 (95\% CI: 1.06 --
1.13, \emph{p} \textless{}0.001). TDRs do not appear to inherit a
significant PA risk with an aOR 1.01 (95\% CI: 0.99 -- 1.03,\emph{p}
=0.428). When stratified by number of pregnancies affected by PA, FDRs
of cases with two or more PAs inherit a more significant odds of PA with
aOR 1.38 (95\% CI: 1.17 -- 1.63, \emph{p} \textless{}0.001). The
measures of association are also higher for SDRs and TDRs when their
family member was affected by two or more PAs, with the estimation for
SDRs nearing statistical significance (Fig. 2). Through a sensitivity
analysis in which cases of PA obtained by the code ``antepartum
bleeding'' were removed, the risk inherited by FDRs increased to an aOR
1.20 (95\% CI: 1.12 -- 1.27, \emph{p} \textless{}0.001), while the risk
for SDRs was similar at an aOR 1.09 (95\% CI: 1.05 -- 1.14,
\emph{p}\textless{}0.001). The association for TDRs did not reach
statistical significance (Table 3). All relative-driven familial risk
analyses were adjusted for by available demographic variables for
relatives: age, year of pregnancy, race, ethnicity, education level, and
parity.

For the ego-driven subgroup analysis, we analyzed 1,168,378 pregnancies
in the UPDB and identified 53,072 cases (4.5\%) of PA matched to 159,124
controls over the years 1939 -- 2020 after excluding for missing data
(Fig. S1). The majority of cases were identified based on birth
certificate data (82.2\%), with the remaining cases identified from
medical records (14.9\%), fetal death certificates (2.5\%) and maternal
death certificates (0.4\%). Demographic differences between cases and
controls were similar to the relative-driven method. See Table S1 for
full details. Table 4 depicts clinical risk factors with estimated
adjusted odds ratios associated with PA. Of these, PROM was most highly
associated with PA with an OR 2.18 (95\% CI: 1.80 -- 2.64,
\emph{p}\textless{}0.001). The presence of a uterine anomaly was also
highly associated with PA with an OR 2.17 (95\% CI: 1.18 --
3.97,\emph{p} =0.004).

Table 5 represents the results of the ego-driven familial risk analysis
adjusting for demographic and potentially confounding clinical
variables. If an individual has a first-degree family history of PA,
their odds of developing PA is estimated at an aOR 1.16 (95\% CI: 1.03
-- 1.31, \emph{p} =0.014). Using this alternative method of analysis,
the odds estimated for an individual with second- and third-degree
relatives affected by PA is not statistically significant.

\textbf{Discussion:}

\textbf{Main findings:}

Placental abruption (PA) occurs in 1-2\% of pregnancies and incurs
considerable maternal and perinatal morbidity and mortality. While the
majority of research underlying the causes of PA has been directed at
evaluating environmental risk factors (e.g. PROM, smoking, prior PA,
hypertension, history of cesarean delivery), recent studies have
assessed genetic causes. \textsuperscript{8--16} A pivotal step in the
distinction between environmental and genetic causes for PA is the
estimation of familial risk in a population. We estimated 18-20\% as the
inherited odds for PA in FDRs, and 9\% and 0-1\% respectively, for SDRs
and TDRs. We noted an elevated odds of PA for all degrees of relation
for the highest risk individuals, or individuals who experienced two or
more PAs.

With use of the ego-driven familial analysis, known clinical risk
factors such as PROM, smoking, and hypertension were adjusted for, which
diminished the estimated increased odds of PA for an individual towards
the null (16\% vs. 20\% with the relative-driven analysis). We see that
these environmental risk factors outweigh genetic heritability at the
second- and third-degree relation level as those estimations were not
statistically significant.

\textbf{Strengths and limitations:}

Our study is unique in its size and breadth, including over one million
individuals, stretching as far back as 1939. The size of the study
allowed us to calculate a precise estimate for the familial risk of PA.
While the UPDB allows for population-level results, we were able to
collect data at the individual level using birth and death certificates
as well as electronic medical records. This allowed for careful
inclusion of cases, stratification of separate pregnancies for each
individual, and the ability to address confounding environmental and
clinical risk factors. We used a novel alternative method for evaluating
heritability, the ``ego-driven'' risk analysis, which allowed for
adjustment of clinical confounders as well as evaluating familial risk
using the relatives as the study population rather than the individual.
One limitation to generalizability is that our cohort arises from a
population of individuals living in a single state in the US. While the
state's current population resulted from a smaller founder population in
the 1800s, recent genetic investigations have revealed a similar
proportion of genetic heterogeneity to the rest of the US
population.\textsuperscript{19} The inclusion of all cases of PA in
research is often limited by under-reporting and reliance on the
subjective judgement of health care professionals. We attempted to
mitigate this limitation by including cases of ``antepartum bleeding''
while excluding placenta previa in our case definition. While there
might be causes of antepartum bleeding independent of PA, like cervical
or vaginal bleeding, PA is the most common leading cause of vaginal
bleeding throughout pregnancy.\textsuperscript{1,7} Our results revealed
a trend towards the null with the inclusion of ``antepartum bleeding'':
from 20\% estimated heritability to 18\%. While we attempted to adjust
for all known risk factors for PA in our heritability analyses, one
possible confounding factor includes shared environments in family
pedigrees, which could have led to an overestimation in our risk.

\textbf{Interpretation:}

The genetics of PA is difficult to study given the clinical ambiguity of
the diagnosis and research towards this realm has been limited.
Acknowledging the inherent limitations of population-based studies, the
ability to evaluate a large cohort of people with multiple pregnancies
is valuable in estimating an individuals' inherited risk of PA. We
estimated 18-20\% as the inherited increase in odds for PA in FDRs,
which is similar to the results of a smaller study performed in Norway.
Rasmussen et. al (2009) performed a population-based study including
greater than 160,000 families and estimated the heritability among FDRs
to be 16\%. \textsuperscript{10} Our estimates for SDRs and TDRs, 9\%
and 0-1\% respectively, reveal a strong argument for the presence of
genetic changes shared among relatives with declining heritability for
more distantly related individuals in a pedigree. At the third-degree
level, the estimated heritability is equivalent to the suspected
baseline risk of PA in the US population of 1-2\%.\textsuperscript{1--3}
An elevated odds of PA was estimated for the highest risk individuals,
or individuals who experienced two or more PAs, which further supports
the hypothesis that shared genetic changes may predispose to PA
occurrence. After adjusting for possibly confounding clinical risk
factors with the ego-driven familial analyses, the effect estimates were
noted to be lower than those without considering these risk factors,
which raises the suspicion of shared environments among family members.

\textbf{Conclusion:}

This study offers a precise estimate of the familial risk for placental
abruption, an obstetric complication previously associated with
predominantly environmental risk factors. This research advances our
understanding of genetic predisposition to adverse outcomes associated
with placental dysfunction and will further advance our goal of
discovering preventative and therapeutic targets in the future.

\textbf{Acknowledgements:}

We thank the Pedigree and Population Resource of Huntsman Cancer
Institute, University of Utah (funded in part by the Huntsman Cancer
Foundation) for its role in the ongoing collection, maintenance, and
support of the Utah Population Database (UPDB). We also acknowledge
partial support for the UPDB through grant P30 CA2014 from the National
Cancer Institute, University of Utah and from the University of Utah's
program in Personalized Health and Center for Clinical and Translational
Science, funded by NIH Clinical and Translational Science Awards, the
University of Utah Information Technology Services and Biomedical
Informatics Core for establishing the Master Subject Index between the
Utah Population Database, and the University of Utah Health Sciences
Center and Intermountain Healthcare.

\textbf{Statements and Declarations:}

\textbf{Funding:} The authors declare that no funds, grants, or other
additional support (except for those indirect funding sources listed in
acknowledgements) were received during the preparation of this research
or manuscript.

\textbf{Financial disclosures:} The authors have no relevant financial
or non-financial interests to disclose.

\textbf{Author contributions:} All authors contributed to the study
conception and design. Material preparation, data collection and
analyses were performed by Huong Meeks, Alison Fraser, and Devin
Etcitty. The first draft of the manuscript was written by Susan Dalton
and all authors commented on subsequent versions of the manuscript. All
authors read and approved the final manuscript.

\textbf{Ethics approval \& Informed consent:} Approval was obtained by
the Institutional Review Board at the University of Utah (IRB\#
00012636) and the Utah Resource for Genetic and Epidemiologic Research
(UPDB\# 00000441) before data collection or analyses were begun. This is
a retrospective observational study of de-identified data and written
informed consent of research participants was waived.

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\textbf{Table and Figure headings:}

\textbf{Table 1.} Demographic and clinical characteristics compared
between placental abruption cases and controls. Clinical characteristics
are specific to the pregnancy affected by placental abruption.

\textbf{Table 2.} Results from primary analysis of familial risk of
placental abruption.

*Variables adjusted for include age, year of pregnancy, race, ethnicity,
education level, and parity.

\textbf{Table 3.} Results from sensitivity analysis of familial risk of
placental abruption excluding cases with ``antepartum bleeding''.

*Variables adjusted for include age, year of pregnancy, race, ethnicity,
education level, and parity.

\textbf{Table 4.} Clinical risk factors with estimated odds ratios
associated with placental abruption.

\textbf{Table 5.} Results from subgroup analysis of familial risk of
placental abruption adjusting for demographic and clinical risk factors.

*Demographic variables adjusted for include age, year of pregnancy,
race, ethnicity, education level, and parity. Clinical variables
included smoking, diabetes, uterine anomaly, hypertension, and pre-labor
rupture of membranes (PROM) in the pregnancy affected by placental
abruption, and cesarean delivery in a prior pregnancy.

\textbf{Figures:}

\textbf{Figure 1} Flow chart of included cases and controls and number
of first-, second-, and third-degree relatives available for familial
risk analyses.

\textbf{Figure 2} Results from stratified analysis of familial risk of
placental abruption when estimating odds between cases and controls
stratified by number of pregnancies affected by placental abruption.

\textbf{Supplementary material:}

\textbf{Table S1.} Demographic and clinical characteristics compared
between placental abruption cases and controls for subgroup analysis.
Clinical characteristics are specific to the pregnancy affected by
placental abruption.

\textbf{Figure S1} Flow chart of included cases and controls for
subgroup analysis including clinical risk factors.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Fig1/Fig1}

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\textbf{Hosted file}

\verb`Supplementary Table 1.docx`  available at \url{https://authorea.com/users/460175/articles/649810-familial-risk-of-placental-abruption}

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/460175/articles/649810-familial-risk-of-placental-abruption}

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\verb`Table 2.docx`  available at \url{https://authorea.com/users/460175/articles/649810-familial-risk-of-placental-abruption}

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\verb`Table 3.docx`  available at \url{https://authorea.com/users/460175/articles/649810-familial-risk-of-placental-abruption}

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\verb`Table 4.docx`  available at \url{https://authorea.com/users/460175/articles/649810-familial-risk-of-placental-abruption}

\textbf{Hosted file}

\verb`Table 5.docx`  available at \url{https://authorea.com/users/460175/articles/649810-familial-risk-of-placental-abruption}

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