Is a positive Non-Invasive Prenatal Test (NIPT) an indication for a fetal echocardiogram?

Is a Positive NIPT an Indication for Fetal Echocardiography?

A positive Non-Invasive Prenatal Test (NIPT) alone is not a direct indication for fetal echocardiography, but diagnostic testing is recommended as follow-up for any positive NIPT result, which may include fetal echocardiography if cardiac anomalies are suspected. 1

Understanding NIPT and Its Limitations

• NIPT is a screening test, not a diagnostic test. Diagnostic testing is recommended as follow-up for any positive NIPT result 1
• The fetal contribution of cell-free DNA studied by NIPT is of presumed placental origin and may not always be representative of the fetus 1
• Sources of discordant NIPT results include confined placental mosaicism, resorbed or unrecognized twins, maternal chromosomal abnormalities, maternal malignancy, technical issues including low fetal fraction, or statistical errors 1, 2

Follow-Up Protocol for Positive NIPT Results

Recommended Diagnostic Testing

• For positive NIPT results for trisomies 13,18,21, or other aneuploidies, diagnostic testing through amniocentesis or CVS is recommended 1
• Mosaic CVS results should not be considered confirmation of a positive NIPT result; follow-up amniocentesis is recommended 1
• Chromosomal microarray (CMA) is recommended as follow-up testing for any smaller copy-number changes reported as positive by NIPT 1

Role of Ultrasound and Fetal Echocardiography

• Prenatal sonography performed in the midtrimester has historically been used to adjust risk for fetal trisomies by assessing for the presence of "soft markers" 1
• If NIPT indicates reduced risk after the presence of a soft marker on fetal ultrasound, further testing is usually not recommended 1
• For fetuses with abnormal physical examination findings on ultrasound that are consistent with the aneuploidy in question, additional evaluation may be warranted, which could include fetal echocardiography if cardiac anomalies are suspected 1

Special Considerations for Different Chromosomal Abnormalities

Common Trisomies (21,18,13)

• NIPT has high sensitivity and specificity for trisomy 21 (Down syndrome), which is associated with congenital heart defects 3, 4
• Trisomy 18 and 13 are also associated with cardiac anomalies, but NIPT has lower positive predictive values for these conditions 3, 4
• The presence of certain ultrasound findings in conjunction with positive NIPT may increase the likelihood of cardiac defects and warrant fetal echocardiography 5

Sex Chromosome Aneuploidies (SCAs)

• SCAs detected by NIPT have varying positive predictive values: 29.5% for monosomy X (Turner syndrome), 54% for XXX, 74% for XXY, and 74.5% for XYY 1
• Turner syndrome (45,X) is associated with cardiac defects, particularly coarctation of the aorta, which may warrant fetal echocardiography if confirmed by diagnostic testing 1

22q11.2 Deletion Syndrome

• ACMG suggests that NIPT for 22q11.2 deletion syndrome be offered to all patients (conditional recommendation) 1
• 22q11.2 deletion syndrome is associated with conotruncal cardiac defects, and if confirmed by diagnostic testing, fetal echocardiography would be indicated 1

Clinical Approach to Positive NIPT Results

1. Confirm positive NIPT results with diagnostic testing (amniocentesis or CVS) 1
2. If diagnostic testing confirms chromosomal abnormality:
   • Perform detailed ultrasound evaluation 5
   • Consider fetal echocardiography if:
     • The confirmed abnormality is associated with cardiac defects (e.g., trisomy 21,18,13, Turner syndrome, 22q11.2 deletion) 5, 6
     • Ultrasound shows any cardiac or extracardiac anomalies 5
3. If diagnostic testing is declined:
   • Consider detailed ultrasound evaluation, including fetal echocardiography if the suspected abnormality is associated with cardiac defects 1
   • At birth, request genetics consultation and detailed physical examination 1

Pitfalls and Caveats

• Low fetal fraction in NIPT has been associated with a higher than expected rate of certain fetal chromosome disorders, particularly trisomies 13 and 18, and triploidy 2
• NIPT should not be recommended as the sole genetic evaluation for ultrasound anomalies, as both resolution and sensitivity are inferior to conventional karyotyping and microarray analysis 5
• Positive NIPT results must be confirmed using invasive techniques before making decisions about additional testing like fetal echocardiography 1, 7
• The presence of multiple fetuses can affect fetal fraction measurements and potentially lead to false-positive NIPT results 2, 6