The Genetic Approach to Stillbirth: A Systematic Review

Abstract

ABSTRACT Stillbirth represents a significant burden to individuals and families and has a great variety of causes, but much is still unknown about the underlying etiologies. The overall contribution of genetic abnormalities to stillbirth is not well known; this study was designed to evaluate known genetic causes of unexplained stillbirths, as well as understand the current position and future direction for using genetic and genomic testing in this field. This study was a systematic review of literature published between 1953 and 2020 on genetic testing and stillbirth. Inclusion criteria for studies were human cases, details and specific data on cohorts that included proportion of unexplained fetal deaths, and data on genetic testing and the subsequent results. Exclusion criteria were pregnancy loss before 22 weeks of gestation, focus on known causes of stillbirth, focus on fetal pathology or abnormalities, investigating neonatal death, genetic testing in populations with congenital anomalies or suspected specific syndromes, and those without details on genetic testing. The final review included 9 studies, 1 comparing karyotyping and chromosomal microarray analysis (CMA); 1 comparing karyotyping, CMA, and quantitative fluorescence–polymerase chain reaction; 2 with CMA only; and 5 with exome sequencing data. The studies that examined only CMA found 1 case of copy number variants (CNVs) in 24 cases and 31 CNVs in 96 cases. The largest study included here analyzed 532 stillbirths and compared CMA and karyotyping. Chromosomal microarray analysis showed a higher rate of detection of CNVs, increasing from 5.8% to 8.3% (P = 0.007) when compared with karyotype analysis. One challenge presented by this topic is that some disorders that could contribute to unexplained stillbirth are typically diagnosed when symptoms appear later in life and so are not usually associated with stillbirth or the risk of stillbirth. One example of this could be cardiac rhythm anomalies or other rare genetic variants that lead to stillbirth when appearing in a particular variation. One study included a cohort of unexplained stillbirth after postmortem examination that excluded obvious causes. Genetic analysis showed that several cases carried a variant that was functionally disruptive that may have contributed to stillbirth, but several additional cases that were functionally normal. Genetic variations relating to unexplained stillbirth are a broad and largely unexplored topic. Genetics play a vital role in clinical exploration and treatment of many disorders and in diagnosing causes of fetal mortality and morbidity. This review shows that genetic testing for stillbirth varies greatly according to test availability and guidelines of use, with some tests showing greater diagnostic yield than others. Although these studies incorporated large cohorts of unexplained stillbirths, genetic analysis identified potential causes for only a small percentage. Future research is needed to explain potential genetic causes for stillbirth.