For a patient with intra‑uterine fetal demise (absent fetal heartbeat on ultrasound), which specimen is best for chromosomal analysis?

Best Specimen for Chromosomal Analysis in Fetal Demise

Amniotic fluid (Option B) is the best specimen for chromosomal analysis in cases of intrauterine fetal demise, as it provides reliable fetal cells with established protocols for successful culture and karyotyping. 1

Rationale for Amniotic Fluid as First Choice

Amniotic fluid contains fetal cells shed from multiple sources including fetal skin, bladder, gastrointestinal tract, and amnion, making it an excellent and representative source for chromosomal analysis. 1 The American College of Medical Genetics specifically recommends amniotic fluid for chromosomal analysis in stillbirth cases due to its established protocols for specimen handling and processing that maximize diagnostic success. 1

Key Advantages of Amniotic Fluid:

• Can be collected at the time of delivery when fetal demise is diagnosed, allowing for immediate specimen procurement 1
• Allows for successful culture and karyotyping with well-established laboratory protocols 1
• Provides reliable chromosomal analysis without the confounding issues seen with other specimen types 1

Why Other Options Are Less Optimal

Placental Tissue (Option D) - Major Limitations:

• Confined placental mosaicism is a critical problem: placental tissue may show chromosomal abnormalities not present in the fetus, or vice versa, making results unreliable 1
• Fresh placental tissue has significantly lower success rates for chromosomal analysis 1
• Formalin-fixed paraffin-embedded tissue is not accepted by many genetic testing laboratories due to low success rates related to longer fixation periods 2
• Extensive testing of placental tissue is not recommended as it may not be representative of actual fetal chromosomes 1

Umbilical Cord Sampling (Option A):

• While umbilical cord abnormalities are associated with approximately 10.7% of early IUFD cases 3, the cord itself is not the preferred specimen for chromosomal analysis
• No guideline evidence supports umbilical cord as optimal for chromosomal testing in this clinical scenario

Fetal Cord Blood (Option C):

• Blood samples may not be available or viable in cases of fetal demise, particularly if significant time has elapsed 2
• When blood is unavailable, other tissues must be used, but this is not the first-line approach 2

Specimen Collection Best Practices

Critical timing considerations:

• Collect specimens as soon as possible after diagnosis of fetal demise 1
• Document time of collection after death and storage conditions for laboratory acceptance 1

Handling requirements:

• Fresh tissue should be collected in sterile containers 4
• Purple top EDTA tubes should be used for DNA preservation when collecting any blood or tissue samples 4
• Transport fresh tissue on ice or with dry ice if previously frozen 1

Common Pitfalls to Avoid

• Do not rely solely on placental tissue due to confined placental mosaicism, which can lead to false-positive or false-negative results 1
• Avoid specimens like hair, vitreous fluid, synovial fluid, and urine as they yield low amounts of DNA and have high contamination risk 2, 1
• Do not use formalin-fixed tissue as first choice given the significantly lower success rates 2

Additional Testing Considerations

If chromosomal microarray analysis (CMA) is normal but genetic cause is still suspected:

• Exome or genome sequencing may be appropriate depending on clinical indication 4
• Copy number variant (CNV) analysis should be offered along with single-nucleotide variant analysis 4
• A negative genetic test does not exclude a genetic cause for pregnancy loss, as approximately 50% of first trimester miscarriages have chromosomal abnormalities 4