What is the recommended prenatal diagnosis for Diamond Blackfan anemia and is amniocentesis (amniotic fluid sampling) or chorionic villus sampling (CVS) necessary?

Prenatal Diagnosis for Diamond-Blackfan Anemia

For prenatal diagnosis of Diamond-Blackfan anemia (DBA), amniocentesis is the recommended procedure over chorionic villus sampling (CVS) due to its lower risk profile, though the choice should be guided by the specific genetic mutation and timing considerations.

Diagnostic Options for Diamond-Blackfan Anemia

• Amniocentesis (15-18 weeks gestation) is generally safer than CVS, with lower rates of pregnancy loss (0.25%-0.50% vs 0.5%-1.0% for CVS) and no associated risk of limb deficiencies 1
• CVS (10-12 weeks gestation) provides earlier results but carries higher risks, including potential limb deficiencies at a rate of 0.03%-0.10% 1
• Detailed ultrasound and echocardiography should be performed to look for signs of fetal anemia or hydrops fetalis, which can occur in affected fetuses 2

Genetic Testing Considerations

• DBA is most frequently caused by mutations in genes encoding ribosomal proteins, with approximately 55% being sporadic mutations 3
• DNA-based diagnosis can be performed on samples obtained from either amniocentesis or CVS 4
• For families with known DBA mutations:
  • Direct genetic analysis can be performed on uncultured cells from CVS or cultured amniocytes from amniocentesis 4, 5
  • The time from CVS biopsy to final diagnosis for genetic analysis is approximately 3-4 weeks 4

Risk Assessment and Decision-Making

• If a parent has DBA, prepregnancy counseling is recommended to discuss inheritance risks and diagnostic options 2
• The background risk for major birth defects for women of all ages is approximately 3%, which provides context when considering the added risks of invasive testing 1
• When early diagnosis is critical, CVS may be preferred despite higher risks, as termination in the first trimester carries lower maternal morbidity and mortality than second-trimester procedures 1

Monitoring and Management of Affected Pregnancies

• If prenatal diagnosis confirms DBA, the following are recommended:
  • Serial ultrasound monitoring for signs of fetal anemia or hydrops 2
  • Consideration of cordocentesis (fetal blood sampling) if there are signs of significant anemia 2
  • Possible in utero transfusions if severe anemia is detected 2
  • Planned early delivery if the fetus is significantly affected 2

Emerging Diagnostic Approaches

• Non-invasive prenatal testing through analysis of fetal cells in maternal blood is being developed for single-gene disorders like DBA, though this is not yet standard clinical practice 6
• Rapid whole-exome sequencing (rWES) has demonstrated clinical utility in confirming DBA diagnoses and can be considered when available 7

Important Caveats and Considerations

• Never perform CVS before 10 weeks' gestation due to significantly increased risk of limb deficiencies (0.20% before 10 weeks vs 0.07% at or after 10 weeks) 1
• Amniocentesis cannot be performed until 15-18 weeks, which may limit options if early diagnosis is needed 1
• Patients must understand that genetic testing cannot predict all outcomes, as DBA has a broad range of clinical presentations 5
• The risk of procedure-related miscarriage must be weighed against the benefits of prenatal diagnosis 1