ISPD New Statement on NIPGS: A Major Sea-Change

The International Society for Prenatal Diagnosis (ISPD) issued an updated statement on prenatal screening for aneuploidy in April 2015. It is radically different than the one they issued only two years ago.

In 2013, soon after noninvasive prenatal genetic screening (NIPGS) entered the commercial market, ISPD’s Aneuploidy Screening Committee issued a rapid response statement with recommendations for incorporating NIPGS into existing prenatal screening protocols. The critical points were:

• NIPGS should be limited in being offered to expectant mothers considered “high-risk,” since the validation studies to that point had been limited to pools of high-risk mothers.
• NIPGS should not replace traditional screening, since traditional screening identifies more conditions and health indicators about the pregnancy than NIPGS does.
• Significantly, the ISPD expressed “a serious concern” about NIPGS due to “the current absence of specific guidelines for quality control and quality assurance for cfDNA screening.”

However, in the 2015 update, the ISPD has reversed course on all three of these points.

Change in recommendations

The new statement recommends that:

• NIPGS is acceptable as a first-tier screening test, which may be offered to all pregnant women, not just those with elevated risk for chromosomal aneuploidies. (Using NIPGS as a second-tier test based on risk assessment from traditional screening is also acceptable.)
• If a woman receives an unambiguous result–negative or positive–from NIPGS, she should not be offered further screening tests for chromosomal aneuploidies. (Women with positive results from any screen should still be offered confirmatory diagnostic testing, such as amniocentesis.)
• Prenatal care providers should use NIPGS labs “that meet national guidelines for quality control and proficiency testing consistent with that available for other molecular tests.”

On the first point, in the 2015 statement there seems to be no acknowledgement of multiple studies showing that conventional screening detects more conditions than NIPGS, and thus may be useful even if NIPGS results are negative. (A summary of one such study, authored by a member of the Committee, may be found here. For a summary of other studies, see Mark’s related post on his blog.)

On the second point, we note that there are still few validation studies of NIPGS in average-risk populations–and in some of these studies, the performance of NIPGS in the “low-risk” population has not been broken out to show how NIPGS actually performs among these low-risk pregnancies.

And on the last point, it is not entirely clear how providers should distinguish labs with good quality control from those without, since the Committee specifically notes that “specific guidelines for quality control and quality assurance for cfDNA screening have not yet been developed.” Nonetheless, while they continue to “recommend the development of specific requirements for cfDNA screening,” the language regarding this continuing lacuna has been considerably softened. The Committee no longer calls this lack of standards a “serious concern” as it did in 2013. We believe, however, that concern on this issue is still warranted, since NIPGS labs are actively pushing against proposed FDA regulations.

It is worth noting two other changes from 2013 to 2015. First, while the 2013 statement concluded with several objections from the ISPD membership (along with responses to these), the 2015 statement simply notes that member comments and accompanying responses are in a supplementary file. We were unable to find this file, as there seems to be no link to it on the ISPD site. And finally, the number of members of the Committee who disclose conflicts of interest has risen considerably: three-quarters of the Committee now report past or present financial connections to NIPGS labs. We recognize that in today’s funding environment, many of those best able to comment on the state of NIPGS have conducted research with support from the NIPGS labs, and that such connections in no way imply that the judgments of these physicians and researchers are compromised. However, this super-majority seems problematic, if for no other reason than that it does not reflect the broader ISPD membership.

We approach this new position statement with caution and await the reaction of the ISPD membership at this year’s annual meeting.