What is the recommended prenatal screening test for pregnant women of advanced maternal age or with a family history of genetic disorders, such as Non-Invasive Prenatal Testing (NIPT)?

Non-Invasive Prenatal Testing (NIPT) for Prenatal Screening

All pregnant women, regardless of maternal age or risk status, should be offered NIPT as the preferred screening method for common fetal aneuploidies (trisomies 13,18,21) and sex chromosome abnormalities. 1, 2

Primary Recommendation for All Pregnant Women

The American College of Medical Genetics and Genomics (ACMG) 2023 guidelines establish that NIPT should be made available to all pregnant patients, fundamentally shifting away from the outdated risk-stratified approach that previously limited testing to women of advanced maternal age (≥35 years) or those with specific risk factors. 1

NIPT demonstrates superior performance compared to traditional screening methods:

• Trisomy 21 (Down syndrome): 98.8% detection rate with only 0.04% false-positive rate, compared to traditional first/second trimester screening detection rates of 64-96% 2, 1
• Trisomy 18: 98.83% sensitivity with 0.07% false-positive rate 2
• Trisomy 13: 92.85% sensitivity with 0.04% false-positive rate 2
• Sex chromosome aneuploidies: 99.6% detection rate with 99.8% specificity 2

Specific Populations and Indications

Advanced Maternal Age

For women ≥35 years at delivery (representing approximately 19% of pregnancies), NIPT is particularly valuable as it has substantially reduced the need for invasive diagnostic procedures that were historically offered based on age alone. 1 Studies demonstrate a 31-79% reduction in diagnostic procedures after NIPT implementation. 1

Family History of Genetic Disorders

For families with specific concerns, NIPT can be expanded beyond common trisomies:

• 22q11.2 deletion syndrome screening should be offered to all patients (conditional recommendation), with 52.6% positive predictive value and detection of 10 in 12 cases in prospective studies 1
• Sex chromosome aneuploidy screening is recommended for singleton pregnancies, including Turner syndrome (45,X), Triple X (47,XXX), Klinefelter syndrome (47,XXY), and 47,XYY syndrome 2, 1

Twin Pregnancies

NIPT is medically necessary for twin pregnancies, with screening performance equivalent to singleton pregnancies for trisomy 21 (98.2% sensitivity), though slightly lower for trisomy 18 (90%) and trisomy 13 (80%). 2

Critical Limitations and Contraindications

NIPT should NOT be performed in the following circumstances:

• Vanishing twin syndrome: Affects accuracy of results 2, 3
• Known maternal malignancy: Somatic genomic aberrations can interfere with testing 2
• Very high maternal BMI: May result in low fetal fraction and test failure in up to 50% of cases 3

Understanding Test Results and Follow-Up

Positive Results Require Confirmation

Any positive NIPT result must be confirmed with diagnostic testing (amniocentesis or CVS) before making irreversible pregnancy decisions. 1, 4 NIPT remains a screening test, not diagnostic, with positive predictive values varying by condition:

• Trisomy 21: 50-95% PPV 1, 2
• Trisomy 18: 100% PPV in some cohorts 4
• Sex chromosome abnormalities: 29.5-74.5% PPV depending on specific condition 2

Low Fetal Fraction or "No-Call" Results

Approximately 1% of NIPT samples result in insufficient fetal fraction for analysis. 3 When this occurs:

• Repeat testing provides results in 75-80% of cases 3
• Offer diagnostic testing (amniocentesis) to individuals with persistent no-call results 3
• Consider alternative screening methods for women with high BMI or early gestational age 3
• Recognize that low fetal fraction is associated with higher rates of trisomies 13,18, and triploidy 3

Timing and Practical Considerations

NIPT can be performed any time during gestation (unlike traditional screening requiring specific trimester timing), though fetal fraction is typically lower at very early gestational ages. 1, 3 A single blood draw is required with no ultrasound necessary for the test itself. 1

What NIPT Does NOT Replace

Traditional screening and ultrasound remain important because:

• NIPT does not screen for neural tube defects (requires maternal serum AFP or ultrasound) 1
• Fetal anatomical survey detects structural abnormalities not identified by NIPT 1
• Genome-wide CNV screening has insufficient evidence for routine use due to limited clinical utility and uncertain positive/negative predictive values 1
• Rare autosomal trisomies (RATs) have insufficient evidence for routine screening 1

Essential Counseling Requirements

Pre-test and post-test genetic counseling are integral components of NIPT and should address: 1, 2

• Superior sensitivity compared to traditional methods
• Screening versus diagnostic nature of the test
• Need for confirmatory testing if positive
• Option to opt-out of sex chromosome aneuploidy screening 1
• Implications of findings, particularly for sex chromosome abnormalities where phenotypes vary widely 1

Common Pitfalls to Avoid

• Failing to offer NIPT to all pregnant women regardless of age or risk status - this perpetuates healthcare inequities 1
• Treating positive NIPT results as diagnostic - always confirm with amniocentesis or CVS before pregnancy termination 1, 4
• Not recognizing that adequate fetal fraction (≥4%, ideally ≥8%) is required for reliable results 3
• Assuming NIPT replaces all other prenatal screening - anatomical ultrasound and maternal serum AFP remain important 1