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A reflection on the ACOG bulletin on screening of fetal chromosomal abnormalities

A message from the editor: Prof. Joris Vermeesch, Ph.D.

Dear friends, this is the 12th NIPTupdate. It has been my honor to be able to provide you my insights and thougths about NIPT. I hope you have enjoyed this journey with me. Let me know if you enjoy this, whether you have thougths or ideas on topics to be addressed in the future. In addition to blowing a candle and drink a Champaign, I thought I will use this newsletter to reflect on the recently published ACOG practice bulletin on screening of fetal chromosomal abnormalities. More specifically, I will pinpoint the differences between the American College of Obstetrics and Gynaecology recommendations and the current clinical practice in Belgium, the country where I live and work.

In a first recommendation it is suggested that screening (serum screening with or without NT ultrasound or cell-free DNA screening) and diagnostic testing (CVS or amniocentesis) for chromosomal abnormalities should be discussed and offered to all patients early in pregnancy regardless of maternal age or baseline risk. Historically testing was offered only to patients considered to be high risk because of maternal age or personal or family history. However, given the personal nature of prenatal testing decision making as well as the inefficiency of offering testing only to patients at high risk, the current recommendation is that all patients should be offered both screening and diagnostic testing options. In Belgium, where prenatal testing is fully reimbursed, the prenatal screening is offered to all pregnant women. Diagnostic or invasive testing, however, is restricted to positive screening tests, be it by NIPT or by ultrasound abnormalities. The recommendation of offering diagnostic testing to all seems excessive to me: On the one hand, those invasive tests might lead to unnecessary procedural miscarriages (one of the main arguments for the swift implementation of NIPT) and on the other hand diagnostic testing for all would be an unnecessary financial burden on the health care system and in my opinion also for the individual families. A zero risk is impossible and the de novo incidence of microdeletions that might be revealed by microarrays is lower than the de novo mutation rate in potential developmental genes. So, either we move to full prenatal genome screening or we balance the benefits versus risks properly.

Which tests should be offered to the pregnant women? Amongst the different tests available the distinction is made between the screening by serum analytes plus ultrasound and the cfDNA screening. The recommendations state that all pregnant women should be able to choose one of both screening tests and that only one of both should be offered. However, all evidence shows that the positive predictive value and overall test accuracy of cfDNA is higher compared with the serum screening tests. As a consequence, in Belgium the serum screening test is not offered anymore. All prenatal aneuploidy screening is performed by NIPT. Why would one support the use of the serum screen? ACOG mentions that other chromosomal anomalies could lead to aberrant serum screening values and instigate invasive diagnostic testing. That is true. But also performing genome wide cfDNA analyses allows for genome wide fetal aneuploidy detection, which would direct the women to invasive follow up. The authors state that NIPT is not validated for aneuploidy detection other than trisomy 21, 18 and 13. Both our unpublished data, but also several other studies have shown that those aneuploidies can be readily detected, albeit with low positive predictive values. It will be interesting to compare the PPVs of the serum and the genome wide cfDNA screens.

Finally, I want to emphasize that despite these differences, our clinical practice is in line with the other major recommendations: Upon a positive screening test, there is always genetic counseling and the option for an invasive diagnostic test. Second-trimester ultrasound for fetal structural defects is essential. An abnormal ultrasound leads to invasive genetic testing. Patients whose cell-free DNA screening test results are uniterpretable should be informed that test failure is associated with an increased risk of aneuploidy. They should be offered comprehensive ultrasound evaluation and diagnostic testing.