What conditions are screened by non‑invasive prenatal testing (NIPT) performed on maternal blood after 10 weeks gestation?

What Tests Consist of NIPT

Non-invasive prenatal testing (NIPT) screens for common fetal chromosomal abnormalities by analyzing cell-free DNA in maternal blood, primarily detecting trisomies 21,18, and 13, sex chromosome aneuploidies, and optionally 22q11.2 deletion syndrome.

Core Screening Components

Common Autosomal Trisomies (Standard)

• Trisomy 21 (Down syndrome) is detected with 98.8% sensitivity and 0.04% false-positive rate 1
• Trisomy 18 (Edwards syndrome) is detected with 98.83% sensitivity and 0.07% false-positive rate 1
• Trisomy 13 (Patau syndrome) is detected with 92.85% sensitivity and 0.04% false-positive rate 1

These three conditions represent the primary screening targets that all NIPT platforms assess 1, 2.

Sex Chromosome Aneuploidies (Routinely Offered)

NIPT screens for four common sex chromosome abnormalities with overall 99.6% detection rate and 99.8% specificity 1:

• Monosomy X (Turner syndrome, 45,X) with PPV of 29.5% 1
• XXX (Triple X syndrome) with PPV of 54% 1
• XXY (Klinefelter syndrome) with PPV of 74% 1
• XYY syndrome with PPV of 74.5% 1

Patients can opt out of sex chromosome aneuploidy screening, as this represents a unique capability of NIPT not available through traditional screening 1. The lower PPV for monosomy X reflects higher rates of placental mosaicism and maternal mosaicism that would not be detected through amniocentesis 1.

Fetal Sex Determination

• Fetal sex can be determined after 9-10 weeks gestation when 10-15% of cell-free DNA is of placental origin 3
• This is particularly valuable for pregnancies at risk for X-linked genetic disorders 3

Optional Screening Components

22q11.2 Deletion Syndrome (Conditional Recommendation)

• ACMG suggests offering NIPT for 22q11.2 deletion syndrome to all patients based on moderate certainty of evidence 1
• This is the most common pathogenic microdeletion identified prenatally, with prevalence of 1 in 990 to 1 in 2148 1
• Detection rate is 10 in 12 cases (83%) with PPV of 52.6% using updated algorithms 1
• This screening should be discussed in the context of shared decision-making 1

Other Microdeletion Syndromes (Not Routinely Recommended)

Some laboratories offer targeted screening for additional microdeletion syndromes beyond 22q11.2, but ACMG does not recommend genome-wide CNV screening due to limited clinical utility, uncertainties regarding PPV and NPV, and lack of clinical validation 1.

Critical Timing and Technical Requirements

Gestational Age Window

• NIPT should be performed after 10 weeks gestation when fetal fraction reaches 10-15% of total cell-free DNA 1, 3
• Testing can be performed any time during gestation once this threshold is met 1
• Earlier testing (6-9 weeks) has been explored but is not standard practice due to insufficient fetal fraction 4

Fetal Fraction Requirements

• Minimum fetal fraction of approximately 4% is required for reliable results 5
• Approximately 1% of samples result in "no-call" results, most commonly due to insufficient fetal fraction 3, 5
• High maternal BMI is strongly associated with low fetal fraction, with test failure in up to 20% of women with high BMI 3, 5

What NIPT Does NOT Screen For

NIPT cannot replace ultrasound for detection of structural anomalies and does not screen for neural tube defects 3. The test is limited to chromosomal abnormalities detectable through cell-free DNA analysis 6.

Rare autosomal trisomies (RATs) involving chromosomes other than 13,18,21, X, or Y are not routinely reported, as there is insufficient evidence to recommend screening for these conditions 1.

Important Caveats

NIPT is a Screening Test, Not Diagnostic

• All positive NIPT results require confirmation with invasive diagnostic testing (amniocentesis or CVS) 1, 3, 7
• PPV varies by condition and maternal age, ranging from 29.5% for monosomy X to 91.8% for trisomy 21 1

Factors That May Interfere With Results

• Vanishing twin gestation may affect interpretation, though ACMG does not recommend withholding NIPT in this scenario 1
• Known maternal malignancy is a relative contraindication due to somatic genomic aberrations in cancerous cells 1
• Confined placental mosaicism can lead to discordant results between NIPT and fetal karyotype 1, 5

Twin Pregnancies

NIPT demonstrates equivalent screening performance in twin pregnancies compared to singletons for trisomy 21 (98.2% sensitivity, 99.9% specificity), though fewer studies exist 1. Sex chromosome aneuploidy screening is limited or unavailable in twins depending on technology and chorionicity 1.