In the United States, stillbirth occurs in 1 in 175 pregnancies representing a significant public health concern and a tragic, life altering event for families. In high resource countries, the most well-defined risk factors for stillbirth include non-Hispanic Black ancestry, nulliparity, prior obstetric history, substance use such as smoking and/or alcohol, conception via assisted reproductive technology (ART), multiple gestations, obesity, single marital status, advanced maternal age, and certain maternal health conditions such as preexisting diabetes or chronic hypertension.1 Additional risk factors are maternal infection, cord issues, placental issues, and a variety of social determinants of health. Although these clinical risk factors are well described, the specific etiology for stillbirth remains unknown in 25% of cases.2 Only 19% of stillbirths may be predicted based on these known risk factors present at the beginning of pregnancy.3 Additionally, these risk factors are not completely independent and some stillbirths may occur due to an overlay of numerous risk factors similar to Sudden Infant Death (SIDS) wherein a ‘triple risk model’ including a genetic predisposition, a critical developmental period, and an additional stressor leads to death.4

Understanding an etiology for each stillbirth is paramount for clinicians and families alike. Clinicians currently struggle to counsel patients about future prevention, recurrence risks, and recommended surveillance despite a “complete” evaluation of a prior loss which very often may actually be incomplete. Even more concerning is the lifelong impact on the psychological well-being of families in the aftermath of a stillbirth, particularly after one that is unexplained. Patients have even reported feeling blamed for stillbirth and this may happen more frequently for non-white patients, further expanding healthcare disparities.5

Having the cause of a stillbirth identified can help families find closure, alleviate guilt and shame, and support decisions about pursuing another pregnancy. Unfortunately, the fetal autopsy, maternal evaluation, placental pathology, and genetic analyses is inconsistent or unavailable across the country despite American College of Obstetrics and Gynecology (ACOG) guidelines indicating their recommendation.1 A further challenge to providing an accurate genetic diagnosis is ensuring that a fetal specimen is obtained and appropriate genetic tests are available and performed.

Advances in technologies beyond the performance of a karyotype now allow an increasing number of families to discover the etiology of their loss. The aim of this commentary is to outline the history, current state, and future of genomics in the evaluation of stillbirth. This will include comparing the varied genetic and genomic technologies currently recommended, the expanding genomic testing options beyond the standard of care in stillbirth, genetic diagnostic challenges, and future directions. Table 1 outlines a summary of the advantages, limitations, and challenges of the genomic tools outlined below.