Clinical UM Guideline

This document addresses cell-free fetal DNA-based prenatal testing (non-invasive prenatal testing [NIPT]) for fetal aneuploidies (including fetal sex chromosome aneuploidies), fetal sex determination, microdeletions, single-gene disorders and twin zygosity.

For additional information, please refer to:

• CG-MED-88 Preimplantation Embryo Biopsy and Genetic Testing
• CG-GENE-13 Genetic Testing for Inherited Diseases
• CG-GENE-10 Chromosomal Microarray Analysis (CMA) for Developmental Delay, Autism Spectrum Disorder, Intellectual Disability and Congenital Anomalies

Note: Genetic counseling should be a component of a decision to perform genetic testing.

Medically Necessary:

Cell-free fetal DNA-based prenatal screening for fetal aneuploidy (trisomy 13, 18, and 21) is considered medically necessary for women with a current single or twin gestation pregnancy.

Cell-free fetal DNA-based prenatal testing for fetal sex determination is considered medically necessary for singleton pregnancies at increased risk of a sex (X)-linked condition or congenital adrenal hyperplasia.

Not Medically Necessary: 

Cell-free fetal DNA-based prenatal screening for fetal aneuploidy (trisomy 13, 18, 21) is considered not medically necessary for individuals not meeting the criteria above, including pregnancies involving 3 or more fetuses.

Cell-free fetal DNA-based prenatal screening for fetal aneuploidy (trisomy 13, 18, and 21) in twin pregnancies is considered not medically necessary when the current pregnancy is affected by fetal demise, vanishing twin, or one or more anomaly detected in one or both of the twins.

Cell-free fetal DNA-based prenatal testing for fetal sex determination is considered not medically necessary for pregnancies without an increased risk of a sex (X)-linked condition or congenital adrenal hyperplasia.

Cell-free fetal DNA-based prenatal testing is considered not medically necessary for all other indications, including testing for microdeletion syndromes, single-gene disorders or to determine twin zygosity.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Fetal aneuploidy testing
When services are Medically Necessary:

When services are Not Medically Necessary:
For the procedure codes listed above for the following diagnosis codes, or when the code describes a procedure designated in the Clinical Indications section as not medically necessary.

Fetal sex determination testing
hen services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure codes listed above when criteria are not met for single gestation pregnancies and for the following diagnoses

Other testing
When services are Not Medically Necessary:

Prenatal Aneuploidy Testing for Trisomy 13, 18 and 21
Noninvasive cell-free fetal DNA-based screening for fetal aneuploidy is considered as an acceptable screening option for fetal aneuploidy (trisomy 13, 18 and 21) in average-risk women carrying a single gestation. The International Society for Prenatal Diagnosis (ISPD) considers cell-free fetal DNA screening as a primary test for all pregnant women an appropriate testing protocol option (Benn, 2015). The European Society of Human Genetics (ESHG) and the American Society of Human Genetics (ASHG) concluded that “NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer” (Dondorp, 2015).

The American College of Obstetricians and Gynecologists (ACOG) provides the following summary with regards to non-invasive screening for fetal aneuploidy:

The wide variety of screening test options, each offering varying levels of information and accuracy, has resulted in the need for complex counseling by the health care provider and complex decision making by the patient. No one screening test is superior to other screening tests in all test characteristics. Each test has relative advantages and disadvantages. It is important that obstetrician–gynecologists and other obstetric care providers be prepared to discuss not only the risk of aneuploidy but also the benefits, risks, and limitations of available screening tests. Screening for aneuploidy should be an informed patient choice, with an underlying foundation of shared decision making that fits the patient’s clinical circumstances, values, interests, and goals” (ACOG, 2016[b])

The American College of Medical Genetics and Genomics (ACMG) issued a strong recommendation for the use of NIPT over traditional methods to screen for fetal trisomies 13, 18, and 21 in pregnant individuals with singleton and twin gestation pregnancies (strong recommendation, high certainty of evidence). The ACMG also affirmed the importance of providing patients with up-to-date, accurate, and balanced information and personalized, patient-centered counseling (Dugan, 2022).

Noninvasive cell-free fetal DNA-based screening for fetal aneuploidy in women with a single gestation pregnancy, is in accordance with generally accepted standards of medical practice. For additional information on cell-free fetal DNA testing for aneuploidy in women with a multiple gestation pregnancy, see section below on “Multiple Gestations”.

Other Aneuploidies
With regard to massively parallel sequencing (MPS), the National Society of Genetic Counselors (NSGC) states that while there are clinical studies demonstrating the ability of MPS to detect abnormalities in chromosomes 13, 18 and 21:

NIPT has not yet been proven efficacious in detecting other chromosomal abnormalities or single-gene disorders. NSGC recommends that pretest counseling for NIPT include information about the disorders that it may detect, its limitations in detecting these conditions, and its unproven role in detecting other conditions (Devers, 2013).

The ESHG and the ASHG released a joint statement advising against the use of cell-free DNA for conditions apart from trisomy 21, trisomy 18, and trisomy 13. According to the ESHG/ASHG:

Depending on targeted or non-targeted analysis and on the level of resolution, NIPT for common autosomal aneuploidies may lead to findings of abnormalities in other chromosomes, including submicroscopic abnormalities. Ideally, there should be a fit between the range of abnormalities for which the screening is offered and accepted and the scope of the test used to find those conditions. Women or couples may otherwise be confronted with outcomes requiring them to make decisions that they were not sufficiently prepared for. These decisions can be especially difficult when conditions are mild or highly variable or when health implications are otherwise uncertain. This is not a new problem: such findings also emerge at follow-up testing after a positive cFTS (see previous section). However, at the NIPT stage, they precede decision making about invasive testing, which may entail putting the pregnancy at risk for confirming findings that not only have a low PPV (because of their low frequency), but that, if confirmed, may still have highly uncertain implications for the health of the future child (Dondorf, 2015).

The ACMG has indicated that noninvasive prenatal screening using cell-free fetal DNA should not be used to screen for autosomal aneuploidies other than those involving chromosomes 13, 18, and 21 (Gregg, 2016).

Similarly, the 2020 ACOG Practice Bulletin on “Screening for Fetal Chromosomal Abnormalities”, provides the following recommendation with regards to testing for aneuploidies other than abnormalities in chromosomes 13, 18 and 21

“In addition to screening for the common aneuploidies, some laboratories offer testing for other aneuploidies such as trisomy 16 and trisomy 22, microdeletion testing, and genome-wide screening of large copy number changes. Nonmosaic fetal trisomy 16 or 22 is associated with a nonviable gestation. Mosaic trisomy 16 and 22 can be associated with fetal survival; however, screening is not recommended because the screening accuracy with regard to detection and the false-positive rate is not established” (Rose, 2020).

At the current time the use of cell-free fetal DNA to screen for aneuploidies other than trisomy 3, 18 and 21 is not considered standard of care in the practicing medical community.

Multiple Gestations
Gil and colleagues (2019) reported on the clinical implementation of cell-free DNA analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancy, and further explored the performance of the test by combining their results with those identified in a systematic review of the literature. The prospective study population included self-referred females and females selected for cell-free DNA testing following routine first-trimester combined screening from a single medical facility in London. EMBASE, MEDLINE, CENTRAL, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform were employed to identify peer-reviewed publications on clinical validation of cell-free DNA for trisomies 13, 18 and 21 in twin pregnancies. By utilizing the authors’ data set of 997 twin pregnancies and those from the literature search which included seven relevant studies, a meta-analysis was conducted. Cell-free DNA correctly identified 16/17 (94.1%) of trisomy 21; 9/10 (90%) of trisomy 18; 1/2 (50%) of trisomy 13 and 962/968 (99.4%) of those with no trisomies. After combining the authors’ data set with those reported in the literature search, a total of 56 trisomy 21 and 3718 non-trisomy 21 twin pregnancies were identified. The pooled detection rate and false-positive rate was 98.2% (95% confidence interval [CI], 83.2-99.8%) and 0.05% (95% CI, 0.01-0.26%), respectively. For the 18 cases of trisomy 18 and the 3143 non-trisomy 18 pregnancies, the pooled detection rate and false-positive rate were 88.9% (95% CI, 64.8-97.2%) and 0.03% (95% CI, 0.00-0.33%), respectively. Of only 3 cases of trisomy 13, 2 (66.7%) were detected by cell-free DNA with a false-positive rate of 0.19%. The authors concluded that the accuracy of cell-free DNA for trisomy 21 in twin pregnancies is similar to reports in singleton pregnancies and is superior to first-trimester combined testing or second-trimester screening using biochemical testing. It is worth noting that the cell-free DNA test was not carried out in the general population but in a mixture of low- and high-risk pregnancies, in which some of the participants had had another screening test before opting for cell-free DNA testing.

ACOG (Rose, 2020) provides the following recommendations regarding screening for fetal chromosomal abnormalities in multiple gestation pregnancies:

• No method of aneuploidy screening that includes a serum sample is as accurate in twin gestations as it is in singleton pregnancies; this information should be incorporated into pretest counseling for patients with multiple gestations.
  (Level B recommendation, based on limited or inconsistent scientific evidence).
• Cell-free DNA screening can be performed in twin gestations. Overall, performance of screening for trisomy 21 by cell-free DNA in twin pregnancies is encouraging, but the total number of reported affected cases is small. Given the small number of affected cases it is difficult to determine an accurate detection rate for trisomy 18 and 13.
  (Level B recommendation, based on limited or inconsistent scientific evidence).
• In multifetal gestations, if a fetal demise, vanishing twin, or anomaly is identified in one fetus, there is a significant risk of an inaccurate test result if serum-based aneuploidy screening or cell-free DNA is used. This information should be reviewed with the patient and diagnostic testing should be offered.
  (Level C recommendation, based primarily on consensus and expert opinion).

In a more recent position statement on cell-free DNA screening for Down syndrome in multiple pregnancies, the ISPD, based on moderate quality evidence, endorses first-trimester cell-free DNA screening for autosomal trisomies (13, 18 and 21) in twin pregnancies. The ISPD also indicates that cell-free DNA-based screening for common trisomies in twins provides higher positive predictive values among twin pregnancies compared with traditional serum and nuchal translucency-based screening in twins, but are associated with test failures (moderate quality evidence) (Palomaki, 2020).

Although rare, false positive test results have been observed and reported in the literature. It is also important to keep in mind that negative cell-free fetal DNA test results do not ensure an unaffected pregnancy. Additionally, a positive cell-free fetal DNA test result for aneuploidy does not determine if the trisomy is due to a translocation, which affects the risk of recurrence. For this reason, individuals with a positive test result should be referred for genetic counseling and should be offered invasive prenatal diagnosis for confirmation of test results.

Fetal Sex Determination
Prenatal fetal sex determination is generally performed for women who are at risk of having a child with a serious genetic disorder affecting a particular sex. This includes women who are carriers of X-linked genetic disorders such as Duchenne muscular dystrophy (DMD) and adrenoleukodystrohy (ALD) and where fetal sexing is employed to guide decisions about invasive testing. Prenatal fetal sex determination may also be performed for carriers of hemophilia, where it can inform management of labor and delivery of confirmed and ‘at risk’ male pregnancies. In addition, fetal sex determination is used for conditions associated with ambiguous development of the external genitalia, such as congenital adrenal hyperplasia (CAH), where treatment with maternal steroids early in pregnancy can reduce the level of virilization in female fetuses. Chorionic villus sampling from 11 weeks or amniocentesis from 15 weeks are invasive options which allow definitive genetic diagnosis, but both techniques carry a 1% risk of miscarriage. Invasive cytogenetic determination is considered the gold standard for ambiguous genitalia, X-linked conditions and singe-gene disorders such as CAH (Devaney, 2011; Heland, 2016; Hill, 2012; Lewis, 2012).

Traditionally, ultrasound has been the method used for fetal sex determination. Several authors have explored the test performance of fetal ultrasound for sex determination with varying results. Fetal sex determination can be performed by ultrasound as early as 11 weeks gestation, although not reliably (Chelli, 2009; Devaney, 2011; Odeh, 2009.

Non-invasive prenatal diagnosis (NIPD) using cell-free DNA is also being marketed to curious parents-to-be as a means of determining fetal sex for non-medical purposes. Currently, ultrasound examination is the standard non-invasive method of determining fetal sex. Use of NIPD using cell-free DNA for the purposes of sex determination for non-medical reasons is considered not medically necessary as information regarding the sex of the fetus which does not have any clinical impact of the health outcomes of the parent or fetus can be obtained via routine prenatal ultrasound when the intent is to identify fetal anomalies. ACOG acknowledges that some individuals may request cell-free DNA screening in order to obtain fetal sex information earlier than is possible with other methods such as ultrasound evaluation. ACOG recommends that individuals should be counseled regarding the limitations of cell-free DNA screening and advised that cell-free DNA screening also assesses the risk of other trisomies and if that information is not desired, the screening should not be performed (ACOG, 2015).

It is also worth noting, that although NIPD plays an important role in the non-invasive prenatal diagnosis of selected conditions, cell-free fetal DNA-based testing does not eliminate the need for ultrasound studies (Gregg, 2016).

In summary, NIPD for fetal sex determination provides an important alternative to cytogenetic determination (amniocentesis, chorionic villus sampling) and can improve the safety of medical care by reducing the need for invasive fetal diagnostic tests. The overall performance of noninvasive fetal sex determination using maternal blood can be high, provided that the blood sample is taken at a time during pregnancy when sufficient cell-free fetal DNA is present (7 weeks gestation or later). NIPD can feasibly be performed from as early as 7 weeks gestation, has been shown to be more than 99% accurate and, because it is non-invasive, does not carry the risk of miscarriage. Furthermore, NIPD has been estimated to reduce the need for invasive procedures by up to 50%. NIPD using cell-free DNA for sex determination can be useful in the clinical setting for early detection of fetuses at risk for sex-linked disorders which require follow-up testing. When used for fetal sex determination, NIPD offers several advantages over ultrasound and invasive testing. NIPD using cell-free fetal DNA is a reliable non-invasive means to determine fetal sex without incurring the risk of unintended fetal losses that is associated with invasive procedures. NIPD for fetal sex determination is not appropriate when it is performed solely for non-clinical purposes (such as when a fetus with a sex linked genetic defect is not suspected or to provide the parents with the convenience of knowing the gender of the fetus sooner than can be determined by a routine prenatal ultrasound) (ACOG, 2015; Allyse, 2015; Devaney, 2011; Lewis, 2012). It is important that individuals contemplating NIPD are adequately counseled so that they are equipped to make autonomous, informed decisions regarding whether to undergo NIPT and how to understand the results and limitations of such testing (ACOG, 2015; Allyse, 2015; Dondorp, 2015).

Fetal Sex Chromosome Aneuploidy (SCA) Screening
Sex chromosome disorders are part of a group of genetic conditions caused by an aberration in a sex chromosome in which there is missing or extra sex chromosome material. These numerical changes in the chromosomes interfere with normal sexual development. It has been estimated that SCAs occur in one of every 400 live births. The impact of fetal SCA on general health including psychosocial development varies. These aneuploidies are typically diagnosed postnatally with many individuals going undiagnosed until they seek medical care for fertility problems. SCAs are also sometimes diagnosed as a result of invasive karyotype testing of pregnant women at high risk for Down syndrome. NIPT is being explored as a screening tool to identify common sex chromosome aneuploidies including, but not limited to the following:

• Turner Syndrome (monosomy X or 45, X);
• Klinefelter syndrome (47, XXY);
• Jacob syndrome (47, XYY); and
• Triple X syndrome (XXX) (Dondorp, 2015).

Currently, there is less peer-reviewed published evidence on the diagnostic performance of NIPTs for detecting fetal SCAs. Limited data indicate that NIPT has a lower accuracy for SCA than for trisomies 21 and 18. The sensitivity for sex chromosome abnormalities average 91% and have a sensitivity of greater than 99%, however, the values depend on the particular condition identified. The positive and negative predictive values for SCAs are dependent upon the particular condition identified. In general, the positive predictive value ranges from 20-40% for most of these conditions (ACOG, 2015).

The ESHG/ASHG (Dondorp, 2015) recommends against using cell-free DNA to screen for sex chromosomal abnormalities. In support of this recommendation, the authors provide a discussion of the following concerns. There is little information available about women’s preferences about prenatal screening for SCAs and if, when the prenatal screening for SCA have positive results, the women pursue confirmatory invasive testing. Inasmuch as the majority of prenatally identified SCAs do not lead to a termination of the pregnancy, consideration should be given to how active screening for these conditions impacts the children who are subsequently born with a suspected or confirmed SCA diagnosis. On the one hand, prenatal detection of SCAs may enhance the child’s quality of life by allowing early treatment of behavioral and health problems as well as timely fertility preservation. Alternatively, there are concerns about the potentially negative psychological impact (effect on parent-child interaction, self-esteem, and stigmatization) as a result of being born with a diagnosis that otherwise might never have been made in many cases (or only much later as a result of fertility problems). The authors also point out that screening for SCAs by NIPT will make it impossible to avoid providing information about fetal sex to women or couples who might want to use this for aborting fetuses based on gender.

Based on a systematic review of the evidence, the ACMG issued a strong recommendation (based on high certainty of evidence), favoring the use of non-invasive prenatal over traditional methods to screen for fetal sex chromosome aneuploidies in all individuals with a single or twin gestation pregnancy. The systematic review revealed that the screening performance for four common types of SCA (monosomy X, XXX, XXY, and XYY) was high, with the overall detection rate for any SCA being 99.6% (95% CI; 94.8%-100%) and specificity 99.8% (95% CI; 99.7%-99.9%). However, the authors point out that there were differences in PPVs across the different SCAs which ranged from 29.5% to 74.5% and the studies included in the review did not uniformly indicate the type of diagnostic testing used to confirm the SCA. Although the ACMG recommendations provide information on the clinical validity of SCA screening, the guideline does not specifically present evidence demonstrating the clinical utility (improved patient outcomes or change in clinical decision making) of cell-free fetal DNA-based screening for SCA.

At the time of this review, no direct comparative evidence was identified that demonstrated cell-free fetal DNA-based screening for SCA resulted in a change in clinical management. It is unclear what effect cell-free DNA-based screening for sex chromosome aneuploidies will have on net health outcomes.

Microdeletion Syndromes
NIPT using cell-free DNA is being researched as a tool to screen for microdeletions. Microdeletions (also referred to as submicroscopic deletions) are chromosomal deletions that are too small to be detected by conventional cytogenetic methods or microscopy. Microdeletions, in conjunction with microduplications, are collectively known as copy number variations (CNVs). CNVs can lead to disease development when the change in copy number of a dose-sensitive gene or genes disturbs the ability of the gene(s) to function and effects the volume of protein produced.

Several genomic disorders associated with microdeletion have been identified. Microdeletion syndromes have distinctive and, in many cases, serious clinical features, including cardiac anomalies, immune deficiency, palatal defects, and cognitive delay. While some microdeletions are inherited, other occur de novo. Microdeletion syndromes include, but are not limited to the following:

• DiGeorge syndrome (22q deletion);
• Shprintzen syndrome (22q11 deletion syndrome);
• Prader-Willi/Angelman syndromes (15q11.2 deletion);
• Cri-du-chat syndrome (5p deletion);
• Wolf-Hirschhorn syndrome (4p deletion); and
• 1p36 deletion syndrome.

The joint position statement of the ESHG and the Social Issues Committee of the ASHG recommends against NIPT-based screening for chromosomal microdeletion syndromes and states the following:

Concerns have been raised that this expansion of the screening offer is based on proof of principle rather than validation studies, and that with the rarity of most of these microdeletion syndromes, the PPV is expected to be low. Multiple false positives as a result of screening for microdeletions will undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. Depending on the resolution used for expanded NIPT, more of the recently identified smaller microdeletion (and duplication) syndromes may also be detected. Many of these are associated with generally milder phenotypes, whereas some may even be present in healthy individuals. With higher resolutions, variants may also be found of which the clinical significance is still unknown. Screening for these conditions and subsequent follow-up testing (also of the parents) will lead to information and counseling challenges, as well as burdening pregnant women or couples with difficult decision making (Dondorp, 2015).

The ACOG Committee Opinion on the use of cell-free DNA screening for fetal aneuploidy states the following:

Microdeletion syndromes occur sporadically or are due to other genetic mechanisms. Screening for these microdeletions has not been validated in clinical studies and the true sensitivity and specificity of this screening test is uncertain. Routine cell-free DNA screening for microdeletion syndromes should not be performed (ACOG, 2015).

The 2022 recommendation from ACMG does not recommend using cell-free DNA for routine screening of the general population for chromosomal microdeletion syndromes at this time due to insufficient evidence and undetermined clinical utility (Dugan, 2022).

The clinical implications of prenatal testing for microdeletions are not clearly defined. It has not yet been determined whether prenatal diagnosis is appropriate given the inherent complexity of accurately predicting the phenotype for the numerous of microdeletion syndromes.

Single-gene Disorders
NIPT has not yet been proven efficacious in detecting other chromosomal abnormalities or single-gene disorders. NSGC recommends that pretest counseling for NIPT include information about the disorders that it may detect, its limitations in detecting these conditions, and its unproven role in detecting other conditions (Devers, 2013).

With regards to the use of cell-free fetal DNA for singe-gene disorders, ACOG’s Practice Advisory on Cell-free DNA to Screen for Single-Gene Disorders contains the following guidance:

The continued innovation in cell-free technology combined with the desire for a maternal blood test to predict the risk for fetal genetic disorders during a pregnancy has broadened the application of cell-free DNA screening beyond aneuploidy to single-gene disorders. Examples of single-gene disorders include various skeletal dysplasias, sickle cell disease and cystic fibrosis. Although this technology is available clinically and marketed as a single-gene disorder prenatal screening option for obstetric care providers to consider in their practice, often in presence of advanced paternal age, there has not been sufficient data to provide information regarding accuracy and positive and negative predictive value in the general population. For this reason, single-gene cell-free DNA screening is not currently recommended in pregnancy (ACOG, 2019).

Zygosity
Prenatal testing for twin zygosity using cell-free fetal DNA is being explored as a tool to inform decisions about early surveillance for twin-to-twin transfusion syndrome and other monochorionic twin-related abnormalities.

Leung et al. (2013) reported the results of a study that assessed the ability of cell-free fetal DNA to provide an individualized assessment of trisomies in twins, as well as fetal fraction and zygosity. MPS was conducted on 11 singleton pregnancies and 8 twin pregnancies, (6 of which had euploid twins, and 2 of which were known to have 1 aneuploid twin). With regards to the zygosity results, zygosity was determined using an algorithm to analyze the ratio of fetal-specific allele to major allele for specific loci. For identical twins it is supposed that the fetal fraction calculated would be the same across all loci, but for fraternal twins, the fetal fraction would vary across various loci. Using this information, the algorithm correctly categorized 4 twin pregnancies as identical, and the other 2 twin pregnancies as fraternal. The authors concluded that noninvasive prenatal assessment of fetal chromosomal aneuploidy for twin pregnancies can be achieved with the use of massively parallel sequencing of cell-free DNA in maternal blood.

In another study, Qu and colleagues (2013) explored the use of MPS of maternal plasma DNA for the noninvasive prenatal assessment of the zygosities of twin pregnancies. Researchers recruited a total of eight twin pregnancies, including four dichorionic diamniotic twins, three monochorionic diamniotic twins, and one monochorionic monoamniotic. Maternal peripheral blood samples were collected on a single occasion between 19 and 30 weeks of gestation prior to any invasive obstetrics procedures. At the time of delivery, cord blood was collected separately from each twin. Microarray genotyping was used to evaluate the cell-free fetal DNA, and regions of DNA heterozygosity were evaluated within each sample. Slight regional variation was anticipated for identical twins, while greater variation was expected for fraternal twins. This method correctly identified the monozygotic and dizygotic twin pregnancies, and in dizygotic twins could determine the contribution of each twin to the fetal fraction.

Norwitz and colleagues (2019) analyzed maternal plasma cell-free DNA samples from twin pregnancies in a prospective blinded study to evaluate a single-nucleotide polymorphism (SNP)-based NIPT for zygosity, fetal sex, and aneuploidy. Zygosity was assessed by looking for either one or two fetal genome complements, fetal sex was assessed by evaluating Y-chromosome loci, and aneuploidy was evaluated through SNP ratios. Zygosity was correctly forecasted in 100% of cases (93/93; 95% CI, 96.1%-100%). Individual fetal sex for both twins was also predicted with 100% accuracy (102/102; 95% weighted CI, 95.2%-100%). Every case with copy number truth were also correctly identified. Researchers calculated the dizygotic aneuploidy sensitivity to be 100% (10/10; 95% CI, 69.2%-100%), and overall specificity was 100% (96/96; 95% weighted CI, 94.8%-100%). The mean fetal fraction (FF) of monozygotic twins (n=43) was 13.0% (standard deviation (SD), 4.5%); for dizygotic twins (n=79), the mean lower fetal fraction was 6.5% (SD, 3.1%) and the mean higher fetal fraction was 8.1% (SD, 3.5%). The authors concluded SNP-based NIPT for zygosity is of value in those instances when chorionicity is uncertain or anomalies are identified. Limitations of this study include but are not necessarily limited to the use of different methods to confirm zygosity and a lack of information on timing of the index test.

Currently there is insufficient evidence to support the use of NIPT for twin zygosity. Additional studies that confirm the clinical validity of the test are needed as well as prospective studies that demonstrate how the data provided by the test impacts clinical management or results in improved patient outcomes.

Genetic Counseling
While several organizations have emphasized the importance of genetic counseling for individuals undergoing cell-free DNA testing, some authors have cautioned that due in part to the sheer volume of the pregnant individuals, the rapid uptake of maternal plasma cell-free DNA-based screening, and the exploration of cell-free DNA testing for other indications, there are not enough resources to make this practical for the general pregnancy population (Kloza, 2015; Meredith, 2016; Piechan, 2016). In order to assist healthcare professionals facilitate informed decision-making, Sachs and colleagues (2015) have provided a summary of the key points to be included in discussions with patients who are considering NIPT. Genetic counseling for individuals undergoing fetal aneuploidy screening is likely to include information on several key points, including but not necessarily limited to the following:

• Fetal aneuploidy screening is optional and can be declined;
• The types of conditions that may be detected by screening;
• The performance of the screening test (eg, sensitivity, false positive rate, false negative rate and test failure rate); and
• Abnormal screening results should be confirmed before considering pregnancy termination.

Individuals with positive non-invasive cell-free DNA screening results should undergo confirmatory diagnostic prenatal testing (such as amniocentesis or chorionic villus sampling) (ACOG, 2015; ACOG, 2016; ACOG, 2020; Gregg, 2016; Dugan, 2022).

Laboratory Developed Tests
There are currently several commercially available laboratory developed tests which analyze circulating cell-free DNA to identify increased representation of various chromosomes. These tests include but are not necessarily limited to the following:

• The MaterniT21^® Test (Sequenom Center for Molecular Medicine, Grand Rapids, MI), utilizes MPS to identify an increased representation of chromosome 21.
• The MaterniT21^® Plus Test (Sequenom Center for Molecular Medicine, Grand Rapids, MI), utilizes MPS to identify an increased representation of chromosomes 21, 18 and 13 and fetal sex aneuploidies and microdeletions.
• The VisibiliT^™ (Sequenom Center for Molecular Medicine, Grand Rapids, MI), uses maternal age, fetal fraction, and the relative amount of chromosomal material for chromosomes 21 and 18 to generate a personalized risk score for common fetal trisomies, such as Down syndrome and Edwards syndrome. The test is intended for women with single gestation pregnancy at low risk.
• The verifi^® Prenatal Test (Illumina, Inc., San Diego, CA), utilizes MPS to identify an increased representation of chromosomes 21, 18, and13. Verinata Health, Inc. also offers testing for Monosomy X (Turner Syndrome) as an additional option to the verifi prenatal test.
• The Harmony^™ Prenatal Test (Ariosa Diagnostics, San Jose, CA), employs directed analysis of cell-free DNA fragments. This test couples DANSR and a proprietary algorithm, FORTE™, to selectively analyze cell-free DNA in maternal blood for trisomy 21, 18, 13 and microdeletions.
• The Panorama^™ Test (Natera, San Carlos, CA), is a single-nucleotide polymorphism-based test which screens and provides a personalized risk score for fetal chromosomal abnormalities such as Trisomy 13, 18, 21, certain sex chromosome abnormalities, triploidy and microdeletions.
• While most if not all laboratories currently offer cell-free DNA screening for aneuploidy include trisomies 13, 18 and 21 as part of a standard panel, the approach to sex chromosomes and other chromosome abnormalities vary. Some laboratories offer routine microdeletion, sex chromosome and rare trisomy (for example trisomy 22 or trisomy 16) assessment, whereas others require that sex chromosome and other assessments be specifically requested in order for those results to be reported (ACOG, 2015).

Adrenal cortex: The outer layer of the adrenal gland(s).

Aneuploidy: A condition where there are either fewer or more than the normal number of chromosomes present in cells of a person's body.

Camptodactyly: Permanently closed (flexed) fingers.

Chorionic villus sampling: A prenatal test to detect birth defects which involves retrieval and examination of tissue from the chorionic villi (placenta).

Circulating cell-free fetal DNA (ccffDNA): The result of the breakdown of fetal cells (mostly placental) which clears from the maternal system within hours.

Euploidy: The state of having a balanced set of chromosomes.

Fetal fraction: A measurement of the amount of cell-free DNA material in the maternal blood that is of fetal origin.

Holoprosencephaly: Failure of the forebrain to divide into lobes or hemispheres.

Hypotonia: Weak muscle tone.

Microcephaly: A small head.

Micrognathia: A small jaw.

Monosomy: The absence of one chromosome of the usual pair to (two) chromosomes.

Monosomy X: A congenital disorder caused by the absence of one X sex chromosome (the individual has only one X sex chromosome rather than the usual pair [either two Xs or one X and one Y sex chromosome]); also called Turner syndrome and monosomy XO.

Myelin: The fatty covering that insulates nerves in the spinal cord and brain.

NIPT: Non-invasive prenatal test.

Pectus carinatum: An unusual shaped chest.

Polydactyly: Extra fingers or toes.

Robertsonian translocations: Chromosomal rearrangement in humans that occurs in five acrocentric (long and short arm) chromosome pairs (13, 14, 15, 21, and 22). These translocations are also called “whole-arm” or centric-fusion translocations. During a Robertsonian translocation, the chromosomes break at their centromeres and the long arms fuse to form a single chromosome with a single centromere. The short arms also join, but usually contain nonessential genes and are usually lost within a few cell divisions.

Rocker-bottom feet: A rigid flatfoot deformity.

Sex chromosome aneuploidy: A group of genetic conditions caused by an abnormal sex chromosome aberration in which there is missing or extra sex chromosome material.

Trisomy: The presence of three chromosomes, rather than the usual pair of (two) chromosomes.

Trisomy X: A congenital disorder caused by having an extra copy of chromosome X; also called Triple X syndrome.

Trisomy 13: A congenital disorder caused by having an extra copy of chromosome 13; also called Patau syndrome.

Trisomy 18: A congenital disorder caused by having an extra copy of chromosome 18; also called Edwards syndrome.

Trisomy 21: A congenital disorder caused by having an extra copy of chromosome 21; also called Down syndrome.

Vanishing twin: A fetus in a multi-gestation pregnancy which spontaneously dies in utero during early pregnancy.

Virilization: The development of male physical characteristics (such as body hair, deep voice and muscle bulk) in a female or at an unusually early age in a boy, typically due to excess androgen production.

Zygosity: The genetic identity of each twin in the pregnancy.

Peer Reviewed Publications:

1. Anderson CL, Brown CE. Fetal chromosomal abnormalities: antenatal screening and diagnosis. Am Fam Physician. 2009; 79(2):117-123.
2. Ashoor G, Syngelaki A, Wagner M, et al. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012; 206(4):322.e1-e5.
3. Ashoor G, Syngelaki A, Wang E, et al. Trisomy 13 detection in the first trimester of pregnancy using a chromosome-selective cell-free DNA method. Ultrasound Obstet Gynecol. 2013; 41(1):21-25.
4. Bianchi DW, Parker RL, Wentworth J, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014; 370(9):799-808.
5. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012; 119(5):890-901.
6. Bodurtha J, Strauss JF 3rd. Genomics and perinatal care. N Engl J Med. 2012; 366(1):64-73.
7. Canick JA, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. 2012; 32(8):730-734.
8. Chelli D, Methni A, Dimassi K, et al. Fetal sex assignment by first trimester ultrasound: a Tunisian experience. Prenat Diagn. 2009; 29(12):1145-1148.
9. Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011; 342:c7401.
10. Chiu RW, Cantor CR, Lo YM. Non-invasive prenatal diagnosis by single molecule counting technologies. Trends Genet. 2009; 25(7):324-331.
11. Chiu RW, Chan KC, Gao Y, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci U S A. 2008; 105(51):20458-20463.
12. Chiu RW, Sun H, Akolekar R, et al. Maternal plasma DNA analysis with massively parallel sequencing by ligation for noninvasive prenatal diagnosis of trisomy 21. Clin Chem. 2010; 56(3):459-463.
13. Cunniff C, Hudgins L. Prenatal genetic screening and diagnosis for pediatricians. Curr Opin Pediatr. 2010; 22(6):809-813.
14. Dan S, Wang W, Ren J, et al. Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors. Prenat Diagn. 2012; 32(13):1225-1232.
15. Devaney SA, Palomaki GE, Scott JA, Bianchi DW. Noninvasive fetal sex determination using cell-free fetal DNA: a systematic review and meta-analysis. JAMA. 2011; 306(6):627-636.
16. Driscoll DA, Gross S. Clinical practice. Prenatal screening for aneuploidy. N Engl J Med. 2009; 360(24):2556-2662.
17. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011; 204(3): 205.e1-205.e11.
18. Fan HC, Blumenfeld YJ, Chitkara U, et al. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci. 2008; 105(42):16266-16271.
19. Finning K, Martin P, Summers J, et al. Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study. BMJ. 2008; 336(7648):816-818.
20. Gil M, Galeva S, Jani J, et al. Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of the Fetal Medicine Foundation results and meta-analysis. Ultrasound Obstet Gynecol. 2019; 53(6):734-742.
21. Gil MM, Quezada MS, Bregant B, et al. Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies. Ultrasound Obstet Gynecol. 2013; 42(1):34-40.
22. Gil MM, Quezada MS, Revello R, et al. Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2015; 45(3):249-266.
23. Handley D, Peters DG. Noninvasive prenatal chromosomal aneuploidy detection using plasma cell-free nucleic acid. Expert Rev Obstet Gynecol. 2010; 5(5) 581-590.
24. Harris S, Reed D, Vora NL. Screening for fetal chromosomal and subchromosomal disorders. Semin Fetal Neonatal Med. 2018; 23(2):85-93.
25. Heland S, Hewitt JK, McGillivray G, Walker SP. Preventing female virilisation in congenital adrenal hyperplasia: the controversial role of antenatal dexamethasone. Aust N Z J Obstet Gynaecol. 2016; 56(3):225-232.
26. Hill M, Lewis C, Jenkins L, et al. Implementing noninvasive prenatal fetal sex determination using cell-free fetal DNA in the United Kingdom. Expert Opin Biol Ther. 2012; 12 Suppl 1:S119-126.
27. Kloza EM, Haddow PK, Halliday JV, et al. Evaluation of patient education materials: the example of circulating cell free DNA testing for aneuploidy. J Genet Couns. 2015; 24(2):259-266.
28. Leung TY, Qu JZ, Liao GJ, et al. Noninvasive twin zygosity assessment and aneuploidy detection by maternal plasma DNA sequencing. Prenat Diagn. 2013; 33(7):675-681.
29. Lewis C, Hill M, Skirton H, Chitty LS. Non-invasive prenatal diagnosis for fetal sex determination: benefits and disadvantages from the service users' perspective. Eur J Hum Genet. 2012; 20(11):1127-1133.
30. Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med. 2005; 353(19):2001-2011.
31. Mazloom AR, Dzakula Z, Oeth P, et al. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn. 2013; 33(6):591-597.
32. Meredith S, Kaposy C, Miller VJ, et al. Impact of the increased adoption of prenatal cfDNA screening on non-profit patient advocacy organizations in the United States. Prenat Diagn. 2016; 36(8):714-719.
33. Morris S, Karlsen S, Chung N, et al. Model-based analysis of costs and outcomes of non-invasive prenatal testing for down’s syndrome using cell free fetal DNA in the UK national health service. PLoS One. 2014; 9(4):e93559.
34. Nicolaides KH, Syngelaki A, Gil M, et al. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat Diagn. 2013; 33(6):575-579.
35. Norton ME, Brar H, Weiss J, et al. Non-Invasive Chromosomal Evaluation (NICE) study: results of a multicenter, prospective, cohort study for detection of fetal trisomy 18. Am J Obstet Gynecol. 2012; 207(2):137.e1-e8.
36. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015; 372(17):1589-1597.
37. Norwitz ER, McNeill G, Kalyan A, et al. Validation of a single-nucleotide polymorphism-based non-invasive prenatal test in twin gestations: determination of zygosity, individual fetal sex, and fetal aneuploidy. J Clin Med. 2019; 8(7) pii: E937.
38. Odeh M, Granin V, Kais M, et al. Sonographic fetal sex determination. Obstet Gynecol Surv. 2009; 64(1):50-57.
39. Palomaki GE, Deciu C, Kloza EM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. 2012; 14(3):296-305.
40. Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011; 13(11):913-920.
41. Piechan JL, Hines KA, Koller DL, et al. NIPT and informed consent: an assessment of patient understanding of a negative NIPT result. J Genet Couns. 2016; 25(5):1127-1137.
42. Qu JZ, Leung TY, Jiang P et al. Noninvasive prenatal determination of twin zygosity by maternal plasma DNA analysis. Clin Chem. 2013; 59(2):427-435.
43. Quezada MS, Gil MM, Francisco C, et al. Screening for trisomies 21, 18 and 13 cell-free DNA analysis of maternal blood at 10-11 weeks' gestation and the combined test at 11-13 weeks. Ultrasound Obstet Gynecol. 2015; 45(1):36-41.
44. Ramsey KW, Slavin TP, Graham G, et al. Monozygotic twins discordant for trisomy 13. J Perinatol 2012; 32:306–308.
45. Rock KR, Millard S, Seravalli V, et al. Discordant anomalies and karyotype in a monochorionic twin pregnancy: a call for comprehensive genetic evaluation. Ultrasound Obstet Gynecol 2017; 49: 544–545.
46. Sachs A, Blanchard L, Buchanan A, et al. Recommended pre-test counseling points for noninvasive prenatal testing using cell-free DNA: a 2015 perspective. Prenat Diagn. 2015; 35(10):968-971.
47. Samango-Sprouse C, Banjevic M, Ryan A, et al. SNP-based noninvasive prenatal testing detects sex chromosome aneuploidies with high accuracy. Prenat Diagn. 2013; 33(7):643-649.
48. Sayres LC, Allyse M, Norton ME, Cho MK. Cell-free fetal DNA testing: a pilot study of obstetric healthcare provider attitudes toward clinical implementation. Prenat Diagn. 2011; 31(11):1070-1076.
49. Sehnert AJ, Rhees B, Comstock D, et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin Chem. 2011; 57(7):1042-1049.
50. Sparks AB, Struble CA, Wang ET, et al. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012(a); 206(4):319.e1-9.
51. Sparks AB, Wang ET, Struble CA, et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn. 2012(b); 32(1):3-9.
52. Sparks TN, Norton ME, Flessel M, et al. Observed rate of Down syndrome in twin pregnancies. Obstet Gynecol 2016; 128:1127–1133.
53. Wang, JC, Sahoo, T, Schonberg, S, et al. Discordant noninvasive prenatal testing and cytogenetic results: a study of 109 consecutive cases. Genet Med. 2015; 17(3):234-236.
54. Wright CF, Chitty LS. Cell-free fetal DNA and RNA in maternal blood: implications for safer antenatal testing. BMJ. 2009; 339:b2451.
55. Yao H, Jiang F, Hu H et al: Detection of fetal sex chromosome aneuploidy by massively parallel sequencing of maternal plasma DNA: initial experience in a Chinese hospital. Ultrasound Obstet Gynecol 2014; 44(1):17-24.
56. Zamerowski ST, Lumley MA, Arreola RA, et al. Favorable attitudes toward testing for chromosomal abnormalities via analysis of fetal cells in maternal blood. Genet Med. 2001; 3(4):301-309.
57. Zhang H, Gao Y, Jiang F, et al. Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146 958 pregnancies. Ultrasound Obstet Gynecol. 2015; 45(5):530-538.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American College of Obstetricians and Gynecologists (ACOG). ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: Screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007a; 109(1):217-227.
2. American College of Obstetricians and Gynecologists (ACOG). ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders. Obstet Gynecol. 2016a; 127(5):e108-122.
3. American College of Obstetricians and Gynecologists (ACOG). ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 163: Summary: Screening for Fetal Aneuploidy. Obstet Gynecol. 2016b; 127(5):979-981.
4. American College of Obstetricians and Gynecologists (ACOG). Committee opinion no. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012; 120(6):1532-1534.
5. American College of Obstetricians and Gynecologists (ACOG). Practice Advisory: Cell-free DNA to Screen for Single-Gene Disorders. Available at: https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2019/02/cell-free-dna-to-screen-for-single-gene-disorders. Accessed on January 17, 2023.
6. Badeau M, Lindsay C, Blais J, et al. Genomics-based non-invasive prenatal testing for detection of fetal chromosomal aneuploidy in pregnant women. Cochrane Database Syst Rev. 2017 Nov 10;11:CD011767.
7. Benn P, Borell A, Chiu R, et al. Position statement from the Aneuploidy Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn. 2013; 33(7):622-629.
8. Benn P, Borell A, Chiu R, et al. Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn. 2015; 35(8):725-734.
9. Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center (TEC). Noninvasive maternal plasma sequencing-based screening for fetal aneuploidies other than trisomy 21. TEC Assessment Program. Chicago, IL: BCBSA; 2014; 29(7).
10. Devers PL, Cronister A, Ormond KE, et al. Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors. J Genet Couns. 2013; 22(3):291-295.
11. Dondorp W, de Wert G, Bombard Y, et al. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Eur J Hum Genet. 2015; 23(11):1438-1450.
12. Dungan JS, Klugman S, Darilek S, et al. ACMG Board of Directors. Electronic address: documents@acmg.net. Noninvasive prenatal screening (NIPS) for fetal chromosome abnormalities in a general-risk population: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022: S1098-3600(22)01004-8.
13. Gregg AR, Skotko BG, Benkendorf JL, et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genet Med. 2016; 18(10):1056-1065.
14. Guy C, Haji-Sheikhi F, Rowland CM, et al. Prenatal cell-free DNA screening for fetal aneuploidy in pregnant women at average or high risk: Results from a large US clinical laboratory. Mol Genet Genomic Med. 2019; 7(3):e545.
15. Ontario Health Technology Assessment Series. Noninvasive prenatal testing for trisomies 21, 18, and 13, sex chromosome aneuploidies, and microdeletions: a health technology assessment. Ont Health Technol Assess Ser [Internet]. 2019; 19(4):1–166. Available at: https://www.hqontario.ca/Evidence-to-Improve-Care/Health-Technology-Assessment/Reviews-And-Recommendations/Noninvasive-Prenatal-Testing-for-Trisomies-21-18-and-13-Sex-Chromosome-Aneuploidies-and-Microdeletions. Accessed on January 17, 2023.
16. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
17. National Society of Genetic Counselors. Position Statement. Prenatal cell-free DNA screening. 2021. Updated April 23, 2021. Available at Prenatal Cell-Free DNA Screening (nsgc.org). Accessed on January 17, 2023.
18. Palomaki GE, Chiu RWK, Pertile MD, et al. International Society for Prenatal Diagnosis Position Statement: cell free (cf)DNA screening for Down syndrome in multiple pregnancies. Prenat Diagn. 2020 Oct 5. Epub ahead of print.
19. Rose NC, Kaimal AJ, Dugoff L, Norton ME; American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins-Obstetrics; Committee on Genetics; Society for Maternal-Fetal Medicine. Screening for Fetal Chromosomal Abnormalities: ACOG Practice Bulletin, Number 226. Obstet Gynecol. 2020; 136(4):e48-e69.
20. Society for Maternal-Fetal Medicine (SMFM) Publications Committee. #36: Prenatal aneuploidy screening using cell-free DNA. Am J Obstet Gynecol. 2015; 212(6):711-716.
21. Society for Maternal and Fetal Medicine (SMFM). SMFM Statement: Maternal serum cell-free DNA screening in low risk women. 2014. Available at: https://www.smfm.org/publications/157-smfm-statement-maternal-serum-cell-free-dna-screening-in-low-risk-women. Accessed on January 17, 2023.

1. Centers for Disease Control and Prevention Facts about Down syndrome. Reviewed November 18, 2022. Available at: http://www.cdc.gov/ncbddd/birthdefects/DownSyndrome.html. Accessed on January 17, 2023.
2. National Library of Medicine (NLM). Genetics Home Reference. Down syndrome. Last updated June 1, 2020. Available at: http://ghr.nlm.nih.gov/condition/down-syndrome. Accessed on January 17, 2023.
3. National Library of Medicine (NLM). Genetics Home Reference. Duchenne and Becker muscular dystrophy. Last updated November 1, 2016. Available at: https://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy. Accessed on January 17, 2023.
4. National Library of Medicine (NLM). Genetics Home Reference. Hemophilia. Last updated May 6, 2022. Available at: https://ghr.nlm.nih.gov/condition/hemophilia. Accessed on January 17, 2023.
5. National Library of Medicine (NLM). Genetics Home Reference. Triple X syndrome. Last updated February 28, 2022. Available at: https://ghr.nlm.nih.gov/condition/triple-x-syndrome. Accessed January 17, 2023.
6. National Library of Medicine (NLM). Genetics Home Reference. Trisomy 13. Last updated September 21, 2021. Available at: https://ghr.nlm.nih.gov/condition/trisomy-13. Accessed on January 17, 2023.
7. National Library of Medicine (NLM). Genetics Home Reference. Trisomy 18. Last updated February 16, 2021. Available at: http://ghr.nlm.nih.gov/condition/trisomy-18. Accessed on January 17, 2023.
8. National Library of Medicine (NLM). Genetics Home Reference. Turner syndrome. Last updated October 1, 2017. Available at: http://ghr.nlm.nih.gov/condition/turner-syndrome. Accessed January 17, 2023.
9. National Library of Medicine (NLM). Genetics Home Reference. X-linked adrenoleukodystrophy. Last updated October 26, 2022. Available at: https://ghr.nlm.nih.gov/condition/x-linked-adrenoleukodystrophy#. Accessed on January 17, 2023.

Down syndrome
Fetal sex chromosome aneuploidy
Fetal sex determination
Harmony Prenatal Test
Massively parallel DNA sequencing
MaterniT Genome
MaterniT21
MaterniT21 Plus
Microdeletions
Monosomy X
Monosomy XO
Panorama Prenatal Test
Patau syndrome
Triple X syndrome
Trisomy X
Trisomy 13
Trisomy 18
Trisomy 21
Turner syndrome
verifi Prenatal Test
VisibiliT Prenatal Test

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