According to the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal Fetal Medicine Consensus Update (2020), a stillbirth workup should include:
A trained pathologist should examine the placenta, cord, and membranes to yield the most complete and valuable information.
Providers should conduct a general examination of the stillborn fetus as soon as possible. This exam should include:
ACOG asserts that a fetal autopsy is one of the most useful diagnostic tests in determining the cause of fetal death when following published guidelines for perinatal autopsy.
If a family is uncomfortable with having a complete autopsy, diagnostic information can be obtained through other options such as:
What maternal testing is recommended after a stillbirth?
ACOG advises taking a thorough maternal medical history to obtain information about the following:
2. Maternal History
3. Obstetrical history
4. Current Pregnancy
When possible, original medical records should be obtained with particular attention to accurate fetal dating by the last menstrual period or early ultrasound.
Recommendations regarding additional laboratory workup of the birthing person differ amongst professional society guidelines. Other laboratory testing should include:
Other testing sometimes recommended includes:
ACOG advises taking a thorough maternal medical history to obtain information about the following:
2. Maternal History
3. Obstetrical history
4. Current Pregnancy
When possible, original medical records should be obtained with particular attention to accurate fetal dating by the last menstrual period or early ultrasound.
Recommendations regarding additional laboratory workup of the birthing person differ amongst professional society guidelines. Other laboratory testing should include:
Other testing sometimes recommended includes:
In addition to the autopsy of the fetus and pathology exam of the placenta and umbilical cord, ACOG recommends routine placental testing for Group B Streptococcus, Listeria, Escherichia Coli, and Syphilis.
The ACOG-SMFM Consensus Statement (2020) advises that fetal genetic testing should be performed in all cases of stillbirth after obtaining the necessary parental permission. Professional associations and guidelines recommend chromosomal microarray (CMA) over karyotyping. CMA has improved resolution (10-100 kB) over the 10 Mb achieved with conventional karyotype. The incremental yield of CMA over karyotype is 4% for pathogenic copy number variants (CNVs) and 8% for variants of uncertain significance. The yield is highest in structurally abnormal fetuses.
A second advantage of CMA over karyotype over CMA is that CMA can be performed on non-living tissues in contrast to karyotype, which can only be performed on actively dividing cells. This difference between the two technologies can give providers and families more time to decide what kind of stillbirth evaluation they want and on what timeline.
Whole exome and genome sequencing (WES/WGS), two types of next-generation sequencing (NGS), provide an even higher resolution examination of the fetus's genetic makeup. NGS allows rapid sequencing (or decoding) of large amounts of DNA. While WES/WGS has shown promise in identifying some fetal genetic variations correlated with stillbirth, it is not yet the standard of care for stillbirth evaluation. Insurance companies do not cover the cost of post-mortem WES/WGS testing. Hence, it is only available to families participating in research conducted by researchers such as the Fetal Genetics Consortium.
Over the last ten years, technological and scientific advances in gene sequencing delivered new insight into potential causes of stillbirth. The genetic options for stillbirth testing involve screening for:
Scientists have been able to sequence DNA's nucleic acid building blocks for about 40 years. A karyotype is a laboratory-produced image of a person’s chromosomes isolated from an individual cell and arranged in numerical order. The earliest reviews of stillbirth causes reported that karyotyping provided the most precise picture of possible genetic causes of stillbirth pathology. It was demonstrated that karyotypic abnormalities were detected in 6-13% of stillbirths that had a successful analysis.
There are several drawbacks to using karyotype. A karyotype can only be done on living cells that are actively dividing. A karyotype can not see DNA changes smaller than 5-10 Mb. Newer technology, the chromosomal microarray (CMA), detects DNA gains and losses at 100-200 kb resolution. CMA and other molecular techniques do not require actively dividing cells, meaning results are more easily and successfully collected in stillbirth cases. It has been shown that CMA provides significantly improved pathogenic findings detection in stillbirth cases.
Allowing even greater detection of potential pathogenic findings, the addition of next-generation sequencing (NGS) allows for a more detailed examination of the fetal genome. NGS uses parallel sequencing of multiple small DNA fragments to determine a sequence. NGS is a "high-throughput" technology that allows rapid sequencing (or decoding) of large amounts of DNA. These tests can detect thousands or even hundreds of thousands of genetic variants in a single test run.
The latest versions of NGS are whole exome and whole genome sequencing (WES/WGS). Exons are the portion of DNA that contain instructions for making proteins. All of the exons in a person’s DNA are called the exome. The exome is about 1 percent of a person’s genome. Studying the sequencing of a person’s entire DNA (genome) or only a portion of it (the exome) can provide valuable information about possible genetic mutations responsible for stillbirth.
Whole exome and genome sequencing (WES/WGS) provide the highest possible resolution examination of an individual's genetic makeup, more detailed than chromosomal microarray (CMA). The benefits of exome or genome sequencing after a stillbirth are that many more genetic changes can be identified with whole exome and whole genome sequencing than by sequencing just one or a few genes.
Current research suggests that WGS can detect up to three percent of protein-coding variants missed by exome sequencing. Researchers have already identified several genes and gene regions that may be involved in pregnancy loss. These include genes associated with cardiac arrhythmias (Crotti) and Smith Lemli Opitz (SLO), an inherited metabolic disorder of the cholesterol pathway.
When considering all candidate genes identified in a 2020 study, researchers reported that 8.5 percent of stillbirths with a normal chromosomal microarray (CMA) and without probable maternal or obstetrical causes (such as placental abruption) were probably attributable to single gene disorders.
Compared to postnatal population studies, less is known about what exome and genome sequencing can answer about the causes of stillbirth. Patients need more comprehensive information critical to medical decision-making and future reproductive planning. It is important to note that, at this time, WES/WGS performed postmortem is not covered by insurance. As a result, such valuable answers may only be available to patients through their participation in research studies like that offered through the Fetal Genomics Consortium.
You can refer patients to this study by giving them the website address, helping them fill out the Contact Form on the website, and giving them the Fetal Genetics Consortium contact phone number, or emailing us at info@fetalgenomics.org. Please do not include identifiable information beyond name and contact information.
Please refer your patients to the For Patients part of the FGC website. In the “Find Support” section, we have assembled a list of books, support groups, organizations, and online support to provide comfort, information, and assistance for patients and families impacted by fetal loss, stillbirth, or genetic diagnoses.
If your patient would benefit from talking with our study staff about the Fetal Genomics Consortium and fetal genetic testing, please direct them to this website and the Contact Us page. Medical staff, researchers, and trained genetic counselors can speak with providers and families one-on-one.
We are available to answer your questions and tell you more about our goals.
