What is the optimal prenatal testing protocol for Down syndrome?

Last week, both the American College of Medical Genetics and Genomics and the International Society for Prenatal Diagnosis (ISPD) issued position statements on the latest developments in prenatal testing for Down syndrome. I selected highlights here. In this post, I cover what the ISPD statement claims is “optimal” for prenatal testing for Down syndrome. With the first letter of ISPD standing for “International,” that frames the scope of the ISPD statement. Being an international organization, when it takes a position, it recognizes that there is wide diversity in the availability and reliability of prenatal testing on a global scale. The same can be said here in the United States: there is great disparity from metropolitan to rural settings and regionally for what type of testing is available and how reliable the testing is.

Therefore, when reviewing the following, “optimal” means just that: when all conditions are at their best, here is what the ISPD recognizes as optimal for Down syndrome prenatal testing. Further, “optimal,” in the ISPD’s usage, is when testing should be available and which type of testing has the greatest reliability for detecting Down syndrome with the lowest false positives. Figure 1 attempts to graphically represent ISPD’s protocol of optimal testing, but reading the list below provides the better understanding.

Fig. 1 ISPD optimal prenatal testing protocol for Down syndrome

Here is what ISPD recognizes as the optimal prenatal testing protocol for Down syndrome:

1. Nuchal translucency (NT) test at 11-13 weeks combined with serum markers.
   [ISPD states that 12 weeks is the optimal time for NT testing. ISPD further recognizes that NT is a useful indicator beyond just testing for Down syndrome–e.g. cardiac defects–and says it should be made available separate-and-apart from screening and diagnostic testing for Down syndrome].
2. Offer first trimester (1T) ultrasound (UT) for other soft markers if provider has been validated to perform such testing, e.g. absence of fetal nose bone, tricuspid regurgitation.
3. Contingent test: if Step 1 returns borderline risks, then have Step 2 at a specialist center.
4. Quad test if patient first presents at or after 14 weeks. Though Quad test can be done between 14-21 weeks, ISPD recognizes that 15-19 weeks is optimal for also open neural tube screening.
5. Combine options Step 1 and Step 4 in stepwise or contingent testing provided all screening test data is included in final risk assessment. Only make available integrated screening when CVS is not available.
   [Stepwise/contingent is where Step 1 results are reported and then an offer is made to conduct second trimester (2T) quad testing where the results will then be combined; integrated is where Step 1 is performed but results are not reported until 2T test results are returned. Because Integrated has the highest detection rate, ACOG recommends that “ideally” it should be offered, but it has been criticized on the basis of disrespecting a mother’s right to know because it does not report Step 1 results].
6. Contingent 2T UT to modify risks for Step 1, 4, or 5 results; i.e. like Step 3, if Steps 1, 4, or 5 return borderline risks, have a second trimester “anomaly scan” performed at 18-23 weeks at a validated center.
   [ISPD further notes that 2T UT, on its own, is “not a very effective screening test.”].
7. Non-Invasive Prenatal Screening (NIPS) for high risk women
   [“High risk” is a result from Steps 1-6, or based on maternal age, UT abnormality suggestive of Down syndrome, family history with Down syndrome/aneuploidy, history of previous pregnancy with Down syndrome/aneuploidy].

Step 7 of the ISPD statement is consistent with the previously released guidelines from ACOG and NSGC, i.e. NIPS should be offered only to high-risk patients. ISPD makes clear that maternal age alone is insufficient to assess fetal Down syndrome risk other than advanced maternal age being an indicator of high risk for purposes of offering NIPS. Like every other professional guideline, ISPD states that NIPS is NOT a replacement for amniocentesis or CVS, and only amnio or CVS can provide a definitive diagnosis of Down syndrome.

Furthermore, consistent with ACOG’s emphasis on prenatal testing needing to be the result of an independent, voluntary informed choice by the patient, ISPD similarly emphasizes the need for prenatal testing to be a personal, independent decision by the patient. This section from the ISPD statement is quoted in full because it addresses the need for counseling prior to accepting testing and when delivering results:

Prior to undergoing prenatal screening, women should be given information on the screening process and be provided with an opportunity to discuss this with a health professional before making a personal decision to accept or decline screening. Whenever possible, the results from more than one screening approach in the same pregnancy should be combined into an accurate unified risk assessment. Following the screening, results should be explained in the context of the hazards and benefits of definitive diagnosis through amniocentesis and CVS.

Information must be provided through non-directive counseling. Each woman should make her own determination as to whether she wishes to receive screening and diagnostic services. Respect for ethical and cultural values, sensitivities and the decisions made by each patient are of key importance in the provision of prenatal testing services. 

The ISPD position statement has a much broader scope than the other professional organizations who have issued statements in the past six months. Unlike ACOG, NSGC, and ACMG, the ISPD statement seeks to address all prenatal testing for Down syndrome, not just NIPS. The ISPD position statement supercedes its previous statements on prenatal testing for aneuploidy and NIPS.

A few weeks ago, I was asked whether there is an on-line resource that simply lists what prenatal testing is available for Down syndrome. Turns out there are several. The headline, the content, and Figure 1 for this post should be taken for what they are: a report on what the ISPD states is the optimal protocol for prenatal testing for Down syndrome. Put another way, this is not me saying what is the optimal method for prenatal testing for Down syndrome.

In future posts, I look forward to reporting on what the ISPD has to say specifically about NIPS, and what the ISPD noticeably does not address and how that silence justifies a significant question about its statement on prenatal testing for Down syndrome: “WHY?”

I’d like to hear your thoughts about the ISPD statement on prenatal testing for Down syndrome. Do you think ISPD’s testing protocol is “optimal?” What has been your experience and would the ISPD protocol have improved it?