The importance of genetic testing for stillbirth and miscarriage

The American College of Obstetricians and Gynecologists (ACOG) notes in Practice Bulletin #102, “Management of Stillbirth”, that stillbirth (a.k.a. intrauterine fetal demise, IUFD, or fetal death) is one of the most common adverse obstetrical outcomes, occurring in approximately 1 in 160 births at ≥20 weeks of gestation. These tragic losses affect approximately 26,000 patients per year in the USA and more than two million patients per year across the globe. Miscarriage (the loss of a pregnancy under 20 weeks) occurs in approximately 15% of clinically recognized pregnancies and up to 50% of all conceptions. Studies have shown that approximately 50-60% of first trimester miscarriages are due to whole chromosome aneuploidy while approximately 5-15% of second-trimester miscarriages and 1-5% of third-trimester losses are due to whole chromosome aneuploidy, depending on the underlying population characteristics.

The study of stillbirth causation and prevention has been hampered by the lack of uniform protocols for evaluating and classifying stillbirths, as well as the decreasing autopsy rates and lack of local medical expertise in perinatal pathology. In most cases, fetal death certificates are completed prior to reviewing the results of any laboratory, genetic or histological investigations and death certificates are rarely amended after the results of these investigations have been reviewed. It may be difficult to assign a cause of death in any given case, and the complicated, sometimes contradictory classification systems that have been published further contribute to difficulties in public health surveillance efforts.

ACOG’s Practice Bulletin also noted that several questions arise during the evaluation of a fetal death: 1: What are the management options for the patient after confirmation of fetal death? 2: What support and counseling services should be offered? 3: What are the laboratory and medical elements of a thorough stillbirth evaluation? 4: Should clinical management be altered in any future pregnancy? In addition, ACOG has noted that ongoing research efforts are important to investigate the best methodologies to study stillbirth and ideally to minimize the frequency and impact of this personal family tragedy.

The Stillbirth Collaborative Research Network (funded by the National Institutes of Health) published data in the New England Journal of Medicine in 2012 (Reddy et al. 367:2185-93) comparing the usefulness of karyotype vs. Single Nucleotide Polymorphism (SNP) microarray in the assessment of 532 stillbirths. The study demonstrated that SNP microarray analysis yielded results more often than did karyotype analysis (87.4% vs. 70.5%) and provided better detection of genetic abnormalities (aneuploidy and pathogenic copy-number variants (8.3% vs. 5.8%); both of which were statistically significant. In addition, microarray analysis identified more genetic abnormalities among the 443 antepartum stillbirths (8.8% vs. 6.5%) and among the 67 stillbirths with structural birth defects (29.9% vs. 19.4%). Compared with karyotyping, microarray analysis provided a relative increase in the diagnosis of chromosomal abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies. In addition, the use of an SNP microarray prevented errors in analysis that can be caused by contaminating maternal DNA. The New Jersey section of ACOG supported legislation in the state of New Jersey in 2014 to help implement a standardized stillbirth management protocol (including the use of SNP microarray) across all maternity hospitals and to help implement appropriate public health system tools and methodologies to reduce the burden of fetal death.

Finally, the recent Stillbirth Prevention Initiative from the Lancet and World Health Organization has noted a number of priority actions listed below that are necessary to increase our knowledge about stillbirth. Clinicians need to be familiar with these guidelines and the associated public health issues and encourage the use of SNP microarray testing in lieu of karyotyping as part of the assessment of fetal death and stillbirths.*

Priority actions include:
• Monitor and address social determination of maternal and fetal wellbeing (e.g., obesity, smoking)
• Address racial disparity
• Fund and implement high-quality perinatal audit and scale up
• Offer all parents high-quality autopsy and placental histopathology
• Fund education and training of perinatal pathologists
• Provide bereavement care training for all care patients
• Fund research on stillbirth prediction including placental and causal pathways
• Eliminate stigma and fatalism
• Revise federal standard fetal death certificate, address obstacles to implementation
• Harmonize state data collection methodologies