Does Chromosomal Microarray Analysis (CMA) have an advantage over karyotype analysis in cases of a fetus with multiple anomalies or fetal demise?

Chromosomal Microarray Analysis vs Karyotype in Fetuses with Multiple Anomalies or Fetal Demise

Chromosomal microarray analysis (CMA) has significant advantages over traditional karyotyping in cases of fetuses with multiple anomalies or fetal demise, offering higher detection rates of clinically significant genetic abnormalities and not requiring viable dividing cells.

Advantages of CMA in Fetal Multiple Anomalies

CMA offers several important advantages over traditional karyotyping when evaluating fetuses with multiple anomalies:

• Higher resolution for detecting copy number variants (CNVs) that are too small to be seen on standard karyotype
• Ability to identify submicroscopic deletions and duplications that may explain the fetal phenotype
• Increased diagnostic yield of 4-10% over conventional karyotyping in early-onset fetal growth restriction without structural malformations 1

The Society for Maternal-Fetal Medicine (SMFM) specifically recommends:

• Women should be offered prenatal diagnostic testing with CMA when unexplained isolated fetal growth restriction (FGR) is diagnosed at <32 weeks gestation 1
• CMA should be offered when FGR is detected with fetal malformation, polyhydramnios, or both, regardless of gestational age 1

Advantages of CMA in Fetal Demise

CMA has particular advantages in cases of fetal demise:

• Does not require viable dividing cells, making it more practical for genetic analysis after fetal death 2
• Provides results even when traditional cell culture for karyotyping fails
• Offers a quicker turnaround time compared to traditional karyotyping 3

Detection Rates and Diagnostic Yield

The diagnostic yield of CMA varies based on clinical presentation:

• In fetuses with multiple anomalies: 7.7% incremental yield over karyotype 2
• In fetuses with isolated anomalies: 3.1% incremental yield over karyotype 2
• Overall detection rate in terminated pregnancies due to abnormal ultrasound findings: 23.9% 2

Limitations of CMA

Despite its advantages, clinicians should be aware of CMA's limitations:

• Cannot detect balanced chromosomal rearrangements (translocations or inversions) 1
• Cannot differentiate free trisomies from unbalanced Robertsonian translocations 1
• May miss some marker chromosomes depending on size and composition 1
• Some forms of microarray cannot detect triploidy 1
• May detect variants of uncertain significance requiring parental testing 3, 4

Clinical Algorithm for Genetic Testing in Fetal Anomalies/Demise

1. For fetuses with multiple anomalies:

   • First-line test: CMA (higher diagnostic yield)
   • Consider karyotype if rapid results needed or common aneuploidy suspected

2. For fetal demise cases:

   • First-line test: CMA (does not require viable cells)
   • Add karyotype only if balanced rearrangements are specifically suspected

3. For isolated anomalies:

   • Consider CMA if anomaly is associated with known microdeletion/microduplication syndromes
   • Consider conventional karyotype if common aneuploidy is suspected

Important Considerations

• Parental samples should be available when possible to aid in interpretation of rare copy number variants 1
• Appropriate genetic counseling should be provided before and after testing to explain potential findings and their implications 1
• Follow-up is recommended in cases of chromosome imbalance identified by CMA, including parental evaluation and clinical genetic evaluation 1

In summary, CMA offers significant diagnostic advantages over karyotype in both fetal multiple anomalies and fetal demise cases, with the ability to detect clinically relevant genetic abnormalities that would be missed by conventional karyotyping.