To editor, Fetal loss remains a major global health issue, with ~2 million stillbirths annually and a substantial burden of miscarriages, particularly in low- and middle-income countries.1 Despite advances in obstetric care, many cases remain unexplained after routine evaluation. Genetic factors are key contributors, especially in early losses, with chromosomal abnormalities (e.g., trisomies, monosomy X, triploidy) accounting for 50%–60% of first-trimester miscarriages and 5%–15% of later losses. Chromosomal microarray (CMA) detects additional copy number variations in 5%–10% of structurally anomalous fetuses with normal karyotypes. Monogenic disorders are increasingly recognized, particularly in recurrent losses and fetuses with structural anomalies. Next-generation sequencing (NGS), including whole-exome (WES) and whole-genome sequencing (WGS), further improves diagnostic yield, identifying variants in 10%–30% of selected cases. However, a diagnostic gap persists. Conventional karyotyping is limited by culture failure and inability to detect submicroscopic changes, while post-mortem samples are often compromised by autolysis, contamination, and DNA degradation. Accurate genetic diagnosis is crucial for recurrence risk assessment, counseling, and future pregnancy planning, while also advancing understanding of fetal development and disease. Post-mortem genetic testing can confirm prenatal findings and refine diagnoses. Optimizing such testing, especially in devitalized tissues, can reduce unexplained fetal deaths and improve evidence-based care. Post-mortem genetic testing in fetuses and newborns should be considered when the cause of death or anomalies cannot be fully explained by conventional investigations, including autopsy and placental examination, and particularly in cases of multiple congenital anomalies, isolated major structural defects, or dysmorphic features suggestive of an underlying genetic syndrome.2 The presence, pattern, and number of structural abnormalities significantly influence the likelihood of a genetic etiology and guide selection of the post-mortem testing modality. In devitalized tissues with compromised DNA quality, careful phenotypic stratification improves cost-effectiveness and maximizes diagnostic yield. Supplementary Table 1, https://links.lww.com/MFM/A130 outlines the relationship between phenotypic patterns and optimal post-mortem genetic strategies. For post-mortem genetic testing in fetuses, optimal tissue selection ensures adequate DNA yield and reduces maternal contamination. The choice depends on gestational age, degree of maceration, and available resources. The goal is to obtain fetal-origin tissue with minimal maternal contamination and preserved DNA integrity. Preferred tissues include fetal skin (thigh or back), skeletal muscle,3 umbilical cord tissues, and placental samples from the fetal side near the cord insertion (Supplementary Fig. 1, https://links.lww.com/MFM/A130), which offer high cellularity and lower maternal contamination risk. Doughty et al.4 evaluated testing modalities and tissue types in 53 cases of fetal/neonatal demise (20 weeks’ gestation to 28 days). Microarray showed the highest success (96.7%), followed by karyotyping (74.1%), FISH (55.6%), and targeted panels (100%, n = 2). Among tissues, pre-delivery amniotic fluid had 100% success, with placenta-only (84.0%) and combined fetal–placental samples (80.8%) outperforming fetal-only tissue (54.5%). Skin (83.3%; especially minimally macerated) and kidney (75.0%) performed well, whereas umbilical cord (57.1%) and liver (25.0%) were less reliable. Post-mortem genetic testing faces significant technical, biological, logistical, and ethical challenges. DNA degradation due to autolysis, especially in delayed delivery or macerated fetuses, often yields poor-quality DNA unsuitable for CMA or NGS.5 Maternal cell contamination, particularly in placental and chorionic villi samples, can cause false-negative or inconclusive results without careful tissue selection. Tissue acquisition is also difficult in early gestations or highly macerated cases, where only contamination-prone samples may be available. Inadvertent formalin fixation compromises DNA quality, limiting advanced molecular testing. While formalin-fixed, paraffin-embedded tissue may allow some targeted testing (e.g., PCR), it is generally unsuitable for genome-wide assays like CMA or WES. Standardized protocols are also lacking across institutions for proper tissue selection, collection, and storage. Even with optimal samples, technical failures may occur. Karyotyping requires viable dividing cells, often unavailable post-mortem. CMA overcomes some of these limitations but requires high-quality DNA. Some anomalies, such as low-level mosaicism or triploidy, may be missed by certain platforms. NGS requires even higher DNA quality and quantity, limiting its use in degraded tissues. Access to post-mortem genetic testing is limited by a lack of specialized fetal pathology services, trained personnel, and coordination between obstetrics, pathology, and genetics teams, leading to missed sampling opportunities. Advanced tests (CMA, WES) are costly, time-consuming, and often not covered, creating inequities—especially in resource-limited settings—and delaying counseling. Ethical challenges, including consent barriers and cultural sensitivities, along with the need for skilled counseling during bereavement, further hinder uptake. Supplementary Table 2, https://links.lww.com/MFM/A130 summarizes the advantages and limitations of various genetic testing methodologies. Supplementary Table 3 and Supplementary Fig. 2, https://links.lww.com/MFM/A130 present practical strategies across stages, from sample collection to analysis, to mitigate these limitations. Fresh, non-fixed tissue is ideal, with skin, skeletal muscle, and umbilical cord preferred due to lower autolysis. In macerated cases, deeper tissues (e.g., liver, spleen) may still yield DNA if properly sampled. Avoiding maternal decidua during placental sampling reduces contamination. Samples should be collected within 24 hours, stored sterile (dry or in saline), and preserved at 4°C short-term or −20°C to −80°C for longer storage. Although commonly used for histopathology, formalin causes DNA–protein cross-linking, fragmentation, and chemical modification of nucleic acids, severely hindering PCR and NGS.5,6 Laboratories should coordinate with pathology departments to avoid formalin fixation for planned genetic studies. If histology is required, a split-sampling approach is recommended, with one portion fresh/frozen and another formalin-fixed. A major issue in post-mortem fetal testing is misinterpretation due to maternal DNA contamination.5,6 Detection and reduction strategies include short tandem repeat genotyping to assess contamination and laser capture microdissection to isolate pure fetal cells.7 Bioinformatic filtering may also help distinguish maternal from fetal alleles in WGS/WES datasets.7 In degraded or autolyzed tissue, traditional DNA extraction methods may yield low-quality DNA. Specialized kits for formalin-fixed paraffin-embedded tissues or degraded samples (e.g., Qiagen FFPE kit, Zymo DNA/RNA Shield) can improve extraction.8 Enzymatic digestion may be prolonged to release nucleic acids from fibrotic or necrotic tissue, and carrier RNA can improve recovery in low-yield samples. DNA quantification and quality assessment (A260/280, Qubit) are essential before downstream analysis. Advances include pre-PCR enzymatic repair kits to restore fragmented DNA. Whole-genome amplification can amplify small or degraded samples, allowing for CMA or sequencing. Multiple annealing and looping-based amplification cycles or multiple displacement amplification are preferred for their uniform coverage and low error rates.8 In stillbirths with suspected inherited metabolic disorders, genetic sequencing should be complemented by histopathological and biochemical evaluation. Morphological findings such as hepatic microvesicular steatosis, myocardial or skeletal muscle vacuolization, lipid accumulation, lysosomal storage material, cardiomyopathy, or non-immune hydrops fetalis may indicate metabolic disease.9 In such cases, fresh or frozen liver, muscle, and cardiac tissue should be preserved for enzyme assays, acylcarnitine profiling, organic acid analysis, or metabolomics.9 Integrating histological findings with molecular testing improves diagnostic yield and interpretation, especially for variants of uncertain significance. To ensure informative results, both test selection and tissue choice must be optimized. Amniocentesis is preferred for obtaining fetal DNA, as post-delivery samples often have lower culture success. Nevertheless, if not feasible, alternative specimens (amniotic fluid, placenta, or fetal tissue) collected at delivery can be used.10 These are generally accepted by commercial laboratories. If an autopsy is performed, fetal DNA may also be obtained directly by the pathologist (Supplementary Fig. 1, https://links.lww.com/MFM/A130). The optimal genetic testing strategy in stillbirth should be individualized based on gestational age, phenotype, DNA quality, and resources. When fetal tissue is available, a stepwise genetic testing approach is advised (Supplementary Table 4, https://links.lww.com/MFM/A130). In early losses, where chromosomal aneuploidy predominates, CMA or rapid aneuploidy testing is appropriate as first-line evaluation. CMA has a higher yield than karyotyping. However, because most causes of stillbirth are due to common aneuploidies (trisomy 13, 18, 21; monosomy X), a karyotype with reflex to CMA is recommended. If non-invasive prenatal testing for aneuploidy indicates low risk, direct CMA is reasonable.10 In later losses with anomalies, a stepwise approach beginning with CMA followed by WES/WGS in nondiagnostic cases is recommended. Alternatives such as CNV sequencing may serve as substitutes for CMA in laboratories where validated, particularly for degraded samples. Targeted techniques—FISH or MLPA—may serve as adjuncts. Variant interpretation should follow ACMG guidelines with phenotypic correlation and, ideally, trio analysis.10 Pretest counseling for CMA should address the higher cost, possibility of variants of uncertain significance (1%–2%), detection of adult-onset or low-penetrance conditions, consanguinity, and inability to define the mechanism of aneuploidy (e.g., nondisjunction vs. Robertsonian translocation). If CMA is nondiagnostic, WES or WGS may be considered. Given the complexity of interpretation, genetic counselor involvement is essential in pre- and post-test phases. Additionally, detailed autopsy phenotyping aids the interpretation of sequencing findings. Post-mortem genetic testing is essential for determining the cause of fetal loss, guiding recurrence risk counseling, and informing future pregnancies. However, its yield is limited by tissue degradation, delayed sampling, and suboptimal strategies. Standardized protocols for collection, preservation, and processing, along with integration of advanced techniques (CMA, NGS, WES/WGS), can improve detection even in devitalized tissues. A multidisciplinary approach enhances interpretation and clinical utility. Future efforts should focus on improving DNA recovery, minimally invasive sampling, and evidence-based guidelines to maximize diagnostic yield and support affected families. Funding None. Author Contributions MM: Concept, design, definition of intellectual content, literature search and review, data extraction, data analysis, manuscript preparation, and approval of the final draft. SP: Concept, design, definition of intellectual content, literature search and review, data extraction, approval of the final draft, and correspondence. RM: Concept, design, definition of intellectual content, literature search and review, data extraction, and approval of the final draft. All the authors have contributed substantially to the conception/ design of the work; the acquisition, analysis, and interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Conflict of Interest None. Data Availability Not applicable, as no new data was generated.
No takes yet. Share an insight, caveat, or question.
Mangla et al. (2026) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: