ELSIcon2022 • Panel • May 27, 2022
Tsegaselassie Workalemahu, Sarah Heerboth, Naomi, Riches, Erin Rothwell
Stillbirths account for most perinatal deaths and almost half of them are attributed to an unknown cause.
The United States has one of the highest stillbirth rates among high-income countries and the rates have not significantly changed over the past 20 years. Further, significant racial disparity exists in the occurrence of stillbirths, with rates among non-Hispanic African American mothers at two to three times the rate of non-Hispanic white mothers. Stillbirth is a devastating adverse pregnancy outcome with poorly understood underlying etiology; it also contributes to impaired physical and mental wellbeing of bereaved parents. In addition, parents who have had one stillbirth are at greater risk for another stillbirth and other obstetric complications in subsequent pregnancies, suggesting that genetics plays a role in its etiology. The present clinical practice paradigms in diagnosing pregnancy loss are antenatal testing of high-risk women, ultrasonographic assessment of fetal growth, and/or chromosomal microarray. However, assessments by karyotyping followed by microarray analyses, including current biophysical fetal surveillance and ultrasound fetal growth assessments have low sensitivity/specific and high costs. Genomic sequencing of perinatal autopsy samples is an emerging technique that can provide additional information about causes and future reproductive risks of stillbirth and is being considered as method to identify mutations that are undetectable by microarray and karyotype techniques. Increasing parental participation in perinatal autopsy in general (which includes genomic sequencing, placental histology and autopsy of the maternal fetal unit (includes the placenta)) has been a significant challenge. Current rates (22-34%) for perinatal autopsy are well below the recommended 75% rates. Further, uptake of perinatal autopsies are significant lower for Hispanic women and non-Hispanic Black women compared to non-Hispanic white women, but overall are quite low suggesting the need for better communication and education around the purpose and timing of these clinical examinations. If we are to understand the causes of stillbirth as well as the high rates of disparity between racial groups, improved documentation of the causes of fetal death are needed to guide prevention efforts. A critical barrier to the diagnosis, treatment and prevention of pregnancy loss is the uncertainty regarding the familial risks and the etiologies, i.e. the lack of knowledge of subtle genetic abnormalities (e.g., pathogenic de novo or inherited variants) that are likely causal. While the knowledge gaps remain unfilled, the current diagnostic tests and treatments for pregnancy loss are costly, not fully effective and may increase couples’ anxiety. In the absence of knowledge of familial risks and subtle genetic abnormalities, justifying the pursuit of genetic factors further in future clinical trials and determining their effectiveness as diagnostic biomarkers of pregnancy loss will likely remain difficult. Therefore, to address the existing knowledge gaps, we conducted two sets of analysis to: 1) determine the familial aggregation of stillbirth in the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, and 2) identify mutations in genes relevant for pregnancy loss using whole genome sequencing of paternal, maternal, live-born children and fetal demise DNA samples. Our preliminary findings suggest that stillbirth aggregates in families and relatives of parents with stillbirth had increased stillbirth risk compared with relatives of unaffected parents. Furthermore, we found compound heterozygous variants in genes that are relevant for recurrent pregnancy loss. We also conducted an electronic medical reviews about the rates of stillbirths and documentation of clinical discussions to undergo genetic testing and perinatal autopsies by race across the Intermountain west from 2015-2020. Further, interviews were conducted to gather qualitative data from women who had stillbirth about why they agreed or did not agree to undergo genetic testing and/or perinatal autopsy. In this presentation, we will present novel findings from these studies and discuss the ethical and normative outcomes across these studies related to practice and policy implications for improving documentation of stillbirth risks and reoccurrence by genetic and inheritance risk and race.