Genetic Testing Options for Missed Miscarriage Tissue from D&C
The primary genetic test to perform on tissue from a D&C for missed miscarriage is chromosomal microarray analysis (CMA), which can identify chromosomal abnormalities in approximately 50% of first trimester losses and provides results even when tissue culture fails. 1, 2
Primary Testing Modality
Chromosomal Microarray Analysis (CMA)
- CMA using single nucleotide polymorphism (SNP) microarray or array comparative genomic hybridization (aCGH) is the preferred first-line test because it detects both aneuploidy and copy number variants without requiring cell culture 1, 2
- This 24-chromosome microarray analysis identifies a definite cause in approximately 67% of recurrent pregnancy loss cases 3
- CMA has higher success rates than traditional karyotyping because it can analyze DNA directly from tissue without requiring viable cells for culture 1
Alternative and Complementary Testing Options
Traditional Cytogenetic Karyotyping
- Conventional karyotyping requires viable cells and tissue culture, which has higher failure rates (10-40%) compared to CMA 1
- Should be offered on pregnancy tissue of the third and subsequent miscarriage(s) and in any second trimester miscarriage 4
- Fresh tissue or cultured cells such as fibroblasts are more successful in yielding results than formalin-fixed tissue 5
Exome or Genome Sequencing
- Exome or genome sequencing may be appropriate depending on clinical indication, particularly when CMA is normal but there is suspicion of a genetic cause 5
- Gene panels followed by reflex exome/genome sequencing can be considered in specific circumstances 5
Copy Number Variant (CNV) Analysis
- CNV analysis should be offered along with single-nucleotide variant (SNV) analysis, as many genes can have copy number variants that may be missed with SNV analysis alone 5
Mitochondrial Genome Analysis
- Mitochondrial genome analysis should be considered in addition to nuclear genome analysis in appropriate cases 5
Specimen Collection and Handling Considerations
Optimal Sample Types
- Fresh tissue collected in sterile containers is ideal for genetic testing 5
- Purple top EDTA tubes for DNA preservation should be used when collecting blood or tissue samples 5
- Formalin-fixed paraffin-embedded tissue can be used but has lower success rates due to DNA degradation 5
Samples to Avoid
- Hair, vitreous fluid, synovial fluid, and urine are not good candidates due to low DNA yield and contamination risk 5
Clinical Context and Timing
When to Test
- Cytogenetic analysis should be offered on the third and subsequent miscarriage(s) 4
- Testing after the second miscarriage combined with standard recurrent pregnancy loss workup identifies a cause in over 90% of cases 2, 3
- Any second trimester miscarriage warrants genetic testing 4
Cost-Effectiveness
- Initial 24-chromosome microarray analysis on miscarriage tissue results in 50% cost savings compared to performing full recurrent pregnancy loss workup first 3
- This approach reduces unnecessary testing in patients whose losses are explained by chromosomal abnormalities 3
Important Caveats
Maternal Cell Contamination
- Maternal cell contamination can occur and lead to false-negative results, requiring careful laboratory interpretation 3
- Sample collection technique and timing affect contamination risk 5
Test Limitations
- A negative genetic test does not exclude a genetic cause for pregnancy loss 5
- Approximately 50% of first trimester miscarriages have chromosomal abnormalities, meaning half will have normal genetic testing 1, 3