Population Surveillance of Birth Defects: Implications of Temporal Changes in Genetic Diagnosis

Population-based surveillance of birth defects in the United States was instigated by the thalidomide tragedy that occurred in multiple countries worldwide during the 1960s. Women who took the prescription medication thalidomide during pregnancy experienced high rates of miscarriage and stillbirth, or gave birth to children with severe birth defects. This tragedy, and others such as the more recent global Zika virus outbreak of 2015–2016, underscores the vital need for population-based surveillance of birth defects. Such surveillance is crucial for capturing temporal and geographic variations in the occurrence of birth defects that may arise from new teratogenic exposures introduced across time and place, or from known exposures occurring in new or unique settings. As Bergman and colleagues point out in this issue of Paediatric and Perinatal Epidemiology 1, a major challenge of population-based surveillance is accurately distinguishing birth defect cases with a ‘known’ cause—typically genetic in nature—from those with relatively unknown causes. Currently, up to 80% of birth defects are believed to be multifactorial in aetiology, resulting from complex gene–environment interactions 2, 3. Approximately 20% of birth defect cases are attributed to genetic factors, including chromosomal abnormalities—disorders characterized by numerical or structural alterations of one or more chromosomes affecting autosomes, sex chromosomes, or both (e.g., Down syndrome or Turner syndrome)—and single-gene disorders (inherited genetic conditions) 2. For many years, the diagnosis of genetically related birth defects relied on fluorescent in situ hybridization and karyotyping. However, technological advances—particularly next-generation sequencing–based assays such as chromosomal microarrays, whole-genome sequencing (WGS) and whole-exome sequencing (WES)—have greatly advanced prenatal and postnatal diagnosis of genetic birth defects since 2010, advances that also rely on far less invasive DNA sampling approaches. In 2021, the American College of Medical Genetics recommended WES and WGS as first- or second-tier tests (guided by clinical judgement) for patients younger than one year old with one or more birth defects 4. In 2022, the International Society for Prenatal Diagnosis issued a position statement recommending prenatal sequencing for any foetus with one or more major birth defects 5. Similar recommendations have been made by EuroGentest and the European Society for Human Genetics 6. Studies assessing the use of WGS and WES in clinical practice have found that these approaches can reveal a broader spectrum of genetic variants, elucidate the natural history of disorders and expand potential treatment options 7. WGS and WES also demonstrate higher diagnostic yield than microarrays or targeted testing, with yields ranging from 30% to 50% compared with 10%–12% 4, 8. Moreover, WGS and WES can be cost-effective in the United States and Europe when used as first- or second-tier tests, even in public health settings with limited resources 4, 8. Some have even argued for universal genome sequencing of all newborns 9. More than two decades after completion of the Human Genome Project, and with next-generation sequencing now integrated into clinical practice in the United States and Europe for the management of pregnancies and children with birth defects, it is reasonable to ask whether improved and more widely available diagnostic methods have resulted in increased ascertainment of genetic birth defects and higher population prevalence of genetic diagnoses among affected pregnancies. The objectives of the study by Bergman and colleagues 1 were to estimate the proportion of genetic diagnoses among cases with birth defects and to determine whether this proportion changed over time. The underlying rationale is that identifying temporal and geographic changes in genetic diagnoses is essential for effective surveillance of potential “new teratogens” among non-genetic anomalies. The authors used pooled data from the EUROCAT network, a consortium of population-based birth defects surveillance systems in Europe. Founded in 1979, EUROCAT is recognized for its highly standardized protocols and rigorous data quality procedures. Data were pooled from 20 surveillance systems across 14 countries, covering approximately 25% of annual births in Europe (1.5 million births) between 2013 and 2022. Systems using active ascertainment identified cases from all pregnancy outcomes, including live births, foetal deaths at ≥ 20 weeks' gestation and terminations of pregnancy for foetal anomalies at any gestational age. Bergman and colleagues estimated annual changes in the proportion of genetic diagnoses overall, by surveillance system and by defect subgroup, using two-year time periods. They observed only modest increases in the proportion of genetic diagnoses over time: a 1.4% annual percentage change, corresponding to an absolute increase of 3% over the 10-year period. After excluding chromosomal defects, the annual percentage change was only 1.2%. Most surveillance systems reported increasing trends in genetic diagnoses. After excluding chromosomal defects, the highest proportions of genetic diagnoses were observed for aortic atresia/interrupted aortic arch, common arterial truncus and arhinencephaly/holoprosencephaly. In contrast, defects with the lowest proportions of genetic diagnoses included congenital pulmonary airway malformations, biliary atresia, gastroschisis, posterior urethral valves, hypospadias, hip dislocation, conjoined twins, VACTERL association and caudal regression sequence. Bergman and colleagues note an important limitation: the lack of information on which individuals actually underwent genetic testing. This omission is critical because observed proportions are based solely on positive test results from an unknown denominator (i.e., all individuals tested) and may therefore not reflect the true prevalence of genetic diagnoses within surveillance systems. The authors rightly note other important limitations in their study, which included potential differences between countries and registries in factors influencing genetic diagnosis proportions, access to clinical genetic services and implementation of new diagnostic technologies, availability and duration of follow-up for live-born infants, timing of genetic testing, and the observation that registries with longer follow-up tended to report higher proportions of genetic diagnoses. The overall increase in genetic diagnoses over time is consistent with changes in clinical practice reported in the literature, although the magnitude of the increase is smaller than might be expected given current recommendations for next-generation sequencing in prenatal and postnatal care. Adoption of these technologies has been inconsistent within and between countries due to logistical, financial and technical barriers 4. Despite evidence of cost-effectiveness, additional obstacles remain, including shortages of physician geneticists, paediatric genetic counsellors, clinical geneticists and laboratory services in the United States and other countries 4. In the United and other countries States, where access to health care is not universal, insurance coverage for these tests may be limited, and families may lack insurance or be unable to afford out-of-pocket costs. Closely related to the exclusion of genetic defects from routine population-based surveillance estimates is the need to improve understanding of gene–environment interactions in the aetiology of birth defects. The prevailing hypothesis is that many, if not most, birth defects result from the interaction of genetic susceptibility with environmental exposures. As noted more than 15 years ago, ‘… efforts to comprehensively examine the role of common genetic variation and the interaction of these genetic variants with environmental exposures and lifestyle factors in the aetiology of birth defects have been insufficient’ 10. In an era in which genomic screening has become a powerful and increasingly accessible tool, Bergman and colleagues provide a glimpse into what population-level genomic integration may offer for understanding birth defect aetiologies—an understanding that remains limited. Their findings reinforce the need to continue population-based birth defects surveillance so that we are prepared for the next thalidomide-like event, Zika virus outbreak, or Accutane-related disaster. Birth defects surveillance systems not only monitor population trends but also serve as a critical resource for advancing knowledge of the complex aetiologies underlying birth defects. Wendy N. Nembhard: conceptualization, writing – original draft, writing – review and editing. Gary M. Shaw: conceptualization, writing – review and editing. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. This is a linked article to Bergman et al. ‘Genetic Diagnoses Among Congenital Anomaly Cases in Europe: Data From the EUROCAT Network.’ To view this article, visit https://doi.org/10.1111/ppe.70099. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.