ACOG/SMFM Professional Guidance on the Role of NIPT as a First Tier Screening Test
The ACOG/SMFM practice bulletin that addresses prenatal screening for fetal chromosomal anomalies clearly states that both aneuploidy screening and diagnostic testing “should be discussed and offered to all patients regardless of maternal age or risk for chromosomal abnormality”
Aneuploidy screening
Serum screening with or without NT ultrasound or
cfDNA screening
Diagnostic testing (CVS or amniocentesis)
Notes
Standard serum screening remains a first-line option along with cell-free DNA screening, also known as noninvasive prenatal testing (NIPT), because additional chromosomal and single gene defects may be picked up with NT and performance may be more comparable to NIPT if the higher NIPT test failure rates are considered
While younger women may have a higher risk for fetal microdeletion syndromes than aneuploidy, ACOG does not recommend NIPT for microdeletions | Women who want information regarding microdeletions should be offered microarray testing using CVS or amniocentesis
What Is NIPT?
NIPT is a blood test that utilizes cell-free DNA technology (cfDNA) to predict the risk for fetal genetic disorders during pregnancy. In 2011, NIPT was introduced as a screen for T21 (trisomy 21 or Down syndrome). Today, NIPT cover the most common aneuploidies (T21, T13 and T18), as well as sex chromosomes and may also include some microdeletions and single gene genetic disorders
How Does It Work?
DNA fragments (outside of cells) can be found floating in the blood of all individuals
In every pregnant woman, there are fragments from
Her own DNA
Fragments of placental DNA (generally thought to derive from the outer cytotrophoblast rather than the inner mesenchymal layer)
A maternal blood sample is obtained ≥10 weeks (with some labs offering testing beginning at 9 weeks) of pregnancy
Usually performed at 11 to 13 weeks
Fetal Fraction
The percentage of fetal DNA found in maternal blood is known as the fetal fraction | Typical range 3 to 13% of maternal cfDNA
The fetal fraction is critical to the success of NIPT | Minimum required approximately 2 to 4%
Sensitivity drops with lower fetal fraction and if too low, test failure will result
Technologies
Generally, NIPT utilizes next generation sequencing and bioinformatics algorithms to interrogate DNA fragments that have been extracted from maternal samples
SNP-based: Bioinformatic algorithms combine risk from individual targeted single nucleotide polymorphisms (SNPs) to differentiate maternal from placental DNA fragments
SNP is the only analysis that can report on zygosity and individual fetal fractions in the case of twins (dependent on laboratory)
Quantification method: Bioinformatic algorithms determine the amount of DNA from chromosomal regions of interest | E.g. if too much chromosome 21 DNA is detected, then a ‘screen positive’ result for T21 will be generated
What Disorders Are Included?
T13, T18 and T21
Most effective at screening for T21
Chromosomes X and Y (fetal sex usually available)
Sex chromosome conditions (depending on the lab)
Monosomy X (Turner syndrome)
47,XXX (Triple X syndrome)
47,XXY (Klinefelter syndrome)
47,XYY (Jacob’s syndrome)
Microdeletions (also known as copy number variants or CNVs) are available with more extensive panels | CNVs occur in 0.4% of pregnancies and are not related to maternal age
22q11.2 deletion syndrome (DiGeorge syndrome) | 1,3000 to 1,4000 live births | May be more prevalent prenatally and cases may be missed at birth (see ‘Related ObG Topics)
1p36 deletion syndrome | 1 in 5,000 to 1 in 10,000 live births
4p16.3 deletion syndrome (Wolf-Hirschhorn syndrome) | 1 in 50,000 live births
5p15.2 deletion syndrome (Cri du Chat syndrome) | 1 in 20,000 to 1 in 50,000 live births
15q11.2 deletion syndrome (Angelman syndrome/Prader-Willi syndrome) |1 in 12,000 to 20,000 (AS) | 1 in 10,000 to 30,000 (PWS)
SYNOPSIS:
NIPT is a screening test only and not diagnostic. Cell-free DNA (cfDNA) is also commonly used with an understanding that the DNA is derived from placenta and not the fetus. NIPT utilizes next generation sequencing and bioinformatics algorithms to look at the DNA fragments in the mother and fetus, as a way of determining the likelihood of certain genetic conditions in the fetus. While there are multiple panels available, there is consensus regarding the clinical utility of NIPS screening for T13, T18 and T21. Patient education, especially around the concept of positive predictive value (PPV) is a priority. Calculator tools are available from professional societies (see ‘Learn More – Primary Sources’ below) or ideally laboratories should be able to provide obstetric professionals with real world test performance results.
NIPT Screening Performance
Detection rates
The following detection rates are based on recent meta-analysis (see ‘Learn More -Primary Resources’ below)
T21: >99% detection rate for T21
98% detection rate for T18
99% detection rate for T13
Combined false positive rate of 0.13%
cfDNA is the most sensitive and specific screen for T21, T18 and T13
Sensitivity and specificity are superior to standard screening for T21 and other common aneuploidies
Positive Predictive Value (PPV)
Trisomies
NIPT generally has very high negative predictive values (NPV) | From ages 20 to 45, NPV is >99% (NSGC GSF calculator)
PPV is also generally high but can vary based on age | Lower background risk will lower PPV
PPVs have been reported up to approximately 90% for T21 but tend to be lower for T18, T13 and monosomy X
Abnormal ultrasound will increase PPV
Microdeletions
NIPT for microdeletion syndromes can have high sensitivity and specificity but still have very low PPV because the particular syndrome is a priori so rare | For example
Cri du Chat Syndrome (Using NSGC GSF calculator – see ‘Learn More – Primary Sources’ below)
Even if sensitivity and specificity are both >99%, the chance of a positive results being a true positive (i.e. PPV) is ≤1%
Negative predictive value will generally always be high for a rare disorder
22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome, found in 1 in 3000 to 4000 live births | Appears to be more common prenatally with a prevalence of approximately 1 in 1000 of otherwise normal pregnancies (see ‘Learn More – Related Entries)
PPV in a low risk population (see ‘Learn More – Primary Sources’) has been reported to be approximately 1 in 20 and higher in pregnancies at higher risk (e.g. congenital heart disease consistent with 22q11.2DS)
Note: NIPT is a screening test and not diagnostic | Regardless of PPV, screen positive results require patients be offered invasive diagnostic testing to confirm results
Some women may opt for a cfDNA screen after a positive serum analyte screen instead of an invasive test. This is a valid option for patients who do not want an invasive test
However, patients should be counseled that a cfDNA screen will not give a diagnosis and may delay a formal diagnosis
cfDNA will not identify all babies with chromosomal abnormalities
Residual risk of a chromosomal abnormality after an abnormal traditional screen followed by a normal cfDNA screen is around 2%
Reasons for a False Positive Result
There is a high likelihood that a positive T21 NIPT screen is truly positive (approximately 90%)
However, confirmatory testing is necessary because false positive results are possible
Confined placental mosaicism (since NIPT only looks at the placental DNA)
Vanishing twin that was aneuploid but surviving twin is normal
Maternal condition such as cancer (NIPT results will usually show multiple chromosomal aneuploidies)
Unknown
NIPT Test Failure
Low fetal fraction
BMI: 10% of patients >250 lbs will have a fetal fraction <4% | May be caused by (1) dilutional effect or (2) elevation in maternal DNA due to inflammatory processes
Early Gestational age <9 weeks
Other reasons for no result include
Laboratory failure | IVF pregnancy | Maternal drug exposure to LMWH | Racial background (e.g. Black and South Asian vs white) | Fetal aneuploidy (e.g. T13 or T18 and sex chromosome aneuploidies)
Follow-Up for ‘No Call Result’
Inform patients that there is an increased risk of aneuploidy | Effect may be due to smaller placentas
Offer genetic counseling, detailed ultrasound evaluation and diagnostic testing
Repeat screening “may be considered’
Success rate 75 to 80% (less with high BMI)
Repeat screening is not advised for the following
Ultrasound anomalies present
Later gestational age where further delay may complicate access to reproductive options
Note: It is preferred that the laboratory report the fetal fraction
Single Gene and NIPT
NIPT also has the capability to identify single gene disorders
Ability to identify single gene variants that would likely not be detected with carrier testing
Generally serious autosomal dominant disorders that may be absent in the parents, but pathogenic variants may spontaneously occur in the fetus (de novo) such as Cornelia de Lange syndrome or Achondroplasia
Some of these conditions are associated with advanced paternal age (≥40 at time of conception)
Single gene screening is clinically available, although currently not recommended by ACOG
Note: ACMG provides healthcare professionals with open access ‘ACT Sheets’ to guide next steps following a positive NIPT report (see ‘Learn More – Primary Sources’ below)
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