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Evaluation of prenatal cfDNA screening for trisomies 13, 18, and 21 in California, 2022-2024

Prenatal Genetics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction:
The California Prenatal Screening Program (CA PNS), administered by the Genetic Disease Screening Program (GDSP), offers prenatal screening for chromosomal aneuploidies and neural tube defects to all pregnant individuals in California, with participation being voluntary. On September 19, 2022, it transitioned from traditional biochemical screening of multiple serum analytes with or without measurement of nuchal translucency to prenatal cell-free DNA (cfDNA) screening for the chromosomal aneuploidies trisomy 13, 18, and 21. The shift from biochemical screening was motivated by a trend in prenatal screening toward cfDNA, due to its precision for certain trisomies and patient-centered benefits. This study examined the results and positive predictive values of CA PNS’s cfDNA screening for these trisomies as well as uptake rates for various follow-up services statewide.

 

Methods:
This descriptive cohort study included all pregnancies participating in the CA PNS Program from September 19, 2022 through March 31, 2024. Information on maternal characteristics, maternal blood specimen collection, prenatal cfDNA screening results (including fetal fraction data), and follow-up services provided through the CA PNS Program were collected and reported to the GDSP via SIS 2.0, a secure, web-based screening information system for clinical data management.

Results:
The CA PNS Program enrolled 338,234 pregnant individuals during the study period. The cfDNA screen positive rate was 0.09% (N=298) for trisomy 13, 0.14% (N=482) for trisomy 18, and 0.42% (N=1,432) for trisomy 21, for an overall screen positive rate of 0.65%. This was lower than the overall screen positive rate of approximately 3% prior to September 19, 2022, when the program used biochemical methodologies to screen for trisomies 18 and 21 only. The CA PNS Program observed a low fetal fraction rate of 1.77% (N=5,987) at the time of the first maternal blood draw. Of those with an initial low fetal fraction result, most (79%, N=4,702) had a redraw test, which reduced the final low fetal fraction rate to 0.67% (N=2,281). A total of 2,747 participants with a positive cfDNA screen or low fetal fraction result elected to receive follow-up services at a state-approved Prenatal Diagnosis Center (PDC) through the CA PNS Program. Genetic counseling was offered to all participants at the PDC visit, and the uptake rate was 100%. The uptake rate of second trimester ultrasound was 96% (N=1,829 out of 1,905). However, for participants eligible for chorionic villus sampling (CVS) or amniocentesis based on gestational age, the uptake rate for CVS was 56.88% (N=401 out of 705) and for amniocentesis was 39.21% (N=689 out of 1,757). Participants with positive cfDNA results were much more likely to undergo CVS or amniocentesis than those with low fetal fraction results, with uptake rates of 60.80% vs. 7.69% for CVS and 59.59% vs. 15.87% for amniocentesis, respectively. The overall positive predictive value for the three trisomies was 76.5% among prenatal cfDNA screen positives that had confirmatory diagnostic testing. The specific positive predictive values were 30.89% for trisomy 13, 59.36% for trisomy 18, and 90.46% for trisomy 21, compared to the previous PPV of approximately 8% for trisomy 18 and 5% for trisomy 21 on biochemical prenatal screening. The PNS Program detected aneuploidy for trisomy 13 or 18 in 4 out of 132 (3.03%) participants with low fetal fraction result who elected to undergo confirmatory diagnostic testing.

 

Conclusion:
Compared to previous biochemical prenatal screening, the CA PNS Program identified an estimated 9000 fewer false positives using cfDNA methodology, due to the lower screen positive rate and the higher positive predictive value of this new approach.  

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