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ISPD Position Statement on Noninvasive Prenatal Testing Calls for Greater Nuance


NEW YORK – A new position statement on noninvasive prenatal testing to screen for fetal chromosomal conditions from the International Society for Prenatal Diagnosis (ISPD) calls for greater context in considering when to offer such screening, compared to guidelines published by the American College of Medical Genetics and Genomics (ACMG).

The statement, published earlier this month in Prenatal Diagnosis, is not a clinical practice guideline. It lays out the consensus opinion of the ISPD board on the current state of knowledge and clinical practice of prenatal screening and updates the former one, which the organization issued in 2015.

The ISPD pointed out that the body of published research in the noninvasive prenatal testing (NIPT) field has "exploded" since its prior statement, demanding that recommendations evolve. Issues that have seen considerable change since 2015, the authors wrote, include the comparative performance of NIPT to traditional screening methods, confusion about false positive results, and concerns over missed opportunities to detect atypical chromosome conditions, as well as ethical and cost-effectiveness concerns.

The ISPD also noted that its statement — written by researchers from Australia, the US, China, the UK, Belgium, and Mexico on behalf of the organization's board — is meant to apply to high-income settings, where prenatal aneuploidy screening is considered an established part of antenatal care.

Several of the ISPD's positions differ from recommendations made by ACMG, whose own most recent practice guidelines were published last December.

The differences largely revolve around the scope of testing for common autosomal aneuploidies, sex chromosome conditions, and 22q11 deletion syndrome.

The ACMG, for instance, recommends that noninvasive prenatal screening (NIPS) be offered to all pregnant women as a primary screen for the three most common trisomies, whereas the ISPD mentions that, while it is "the most accurate screening test for the common autosomal aneuploidies (trisomies 21, 13 and 18) in unselected singleton populations," factors such as health policies will influence decisions and implementation models and should therefore be taken into account.

A spokesperson for the ISPD said that the use of "NIPS" versus "NIPT" was equivalent with respect to the two statements.

Susan Klugman, president of the ACMG, praised the ISPD statement for examining numerous aspects of prenatal cell-free DNA screening and for including thoughts on the role of ultrasound in prenatal screening, which remains particularly useful for identifying fetal structural anomalies, incorrect dating, multiple gestation, or nonviable pregnancy prior to NIPT.

"The ISPD statement aligns well with the ACMG’s evidence-based guideline published in 2022 after our initial systemic evidence base review on this topic," Klugman said.

Similar to its recommendations for common aneuploidy screening, the ACMG recommended NIPS to screen for sex chromosome aneuploidy (SCA) and for 22q11.2 deletion syndrome for all pregnant women, although the organization did note that its recommendation for 22q11.2 deletion syndrome was a conditional recommendation, based on moderate evidence certainty.

With regard to SCA screening, the ISPD said that it should be offered with specific pretest counseling and consent, noting that such screening is explicitly prohibited in certain countries.

In addressing the moderate certainty of 22q11.2 deletion testing, the ISPD pointed out that two studies in particular appeared to have informed the ACMG's recommendation.

One study analyzed the cost-benefit ratio of 22q11.2 screening and had been conducted only in the US, the ISPD said, and the same cost-benefit ratio did not necessarily translate to other healthcare systems outside the US.

The second study comprised the only prospective study of 22q11.2 syndrome to date with confirmatory postnatal testing of all cases, including those with a low chance result. This study, the ISPD wrote, found a relatively high frequency of 22q11.2 deletion that may not reflect the syndrome's true prevalence in the general population.

Klugman noted that the ACMG agrees with the ISPD that further studies into microdeletion/microduplication syndromes are needed to provide more information.

With respect to offering NIPS for both SCA and microdeletion/microduplication syndromes, the ISPD specified consideration of societal, economic, cultural, and ethical factors when deciding whether or not to offer it.

Lisa Hui, a clinical leader of Australia's Genomics Health Futures Mission and a member of the ISPD's board of directors, commented that the ISPD felt concern that the ACMG's recommendations to offer NIPS for sex chromosome conditions and 22q11.2 deletion syndrome to all women would pressure clinicians to provide such options, rather than tailoring their practices to adapt to local conditions and to individual patients' needs.

"Pre- and post-test counselling for these conditions is more complex than for the common autosomal aneuploidies and requires expertise that may not be available in all settings," she said. "Not only is NIPS less accurate for these conditions than for the common autosomal aneuploidies, providing prognostic information during pregnancy is complicated by [their] wide phenotypic variation."

"It would not be responsible to implement population-based screening for these conditions without ensuring that clinicians have sufficient skills for accurate post-test counselling and clinical management," she added.

Vanessa Olsen, a Palo Alto, California-based Ob/Gyn who performs prenatal screening and testing in her own practice, noted that healthcare economics and other factors not directly related to patient care are not something that physicians are necessarily trained to consider when making patient management decisions.

"Physicians can be more sensitive when cost directly impacts their patients, for example, [when] ordering a generic drug rather than the brand name," she said. "However, when we are talking about big picture healthcare system costs, many physicians are not as thoughtful."

The ISPD statement also noted that differences between technological platforms used throughout NIPT challenge attempts to generalize performance from one assay to another.

"Pretest information should be tailored to the platform being used, and healthcare professionals should be aware of what is being offered through the differing technologies," the ISPD wrote.

The ISPD concluded that "the clinical utility of NIPT for the detection of subchromosomal rearrangements, including microdeletion and duplication syndromes, [rare autosomal trisomies], and other adverse pregnancy outcomes is still emerging, and further research is required prior to widespread clinical implementation."

Both the ACMG and ISPD, said Klugman, "recommend pre- and post-test counseling for any pregnant individual undergoing genetic screening or testing."

Additionally, the ACMG recently published a separate statement advocating for changing the term "noninvasive prenatal screening" to "prenatal cell-free DNA screening," due to the resemblance that the acronym NIPS has to an ethnic slur for Japanese people.