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.