Increase in Sex Chromosomal Aneuploidy Diagnosis since Cell Free DNA Prenatal Screening
Ted Lee, MD, MSc1, Fang Zhang, PhD2, Caleb Nelson, MD, MPH1, Anjali Kaimal, MD, MAS2, Ann Wu, MD, MPH2.
1Boston Children's Hospital, Boston, MA, USA, 2Harvard Pilgrim Health Care Institute, Boston, MA, USA.
BACKGROUND: Cell free DNA (cfDNA) based screening for fetal aneuploidy, commonly referred to as Non-Invasive Prenatal Testing, has resulted in a significant shift in the landscape of prenatal screening. Due to significant improvements in sensitivity and specificity compared to traditional serum and ultrasound based prenatal tests for trisomy 21, 18, and 13, cfDNA has been widely used. An important but optional feature of cfDNA is the ability to characterize sex chromosomes. This information can be used to determine the sex of the baby and screen for sex chromosomal aneuploidy (SCA). Although SCA is the most common chromosomal aneuploidy in humans, the penetrance is highly variable and the positive predictive value of SCA using cfDNA is low (25-52%). Prior studies have demonstrated that approximately half of those undergoing cfDNA choose to characterize sex chromosomes. Survey data demonstrate that those who choose to do so are often unaware of the possibility of SCA diagnosis. It is unknown how adoption of cfDNA has impacted the timing of diagnosis of SCA. We hypothesized that the rate of SCA diagnosis in children 0 to 1 years of age increased significantly compared to SCA diagnosis rates in children 2 to 18 years of age since introduction of cfDNA.
METHODS: Using a commercial, administrative claims database (Clinformatics Data Mart), children 18 years and younger diagnosed with SCA for the first time between January 1, 2008 and March 31, 2020 were identified. The cohort was divided into children 0-1 and 2-18 years of age. The outcomes of interest were quarterly rates of SCA diagnosis per 100,000 members before and after the introduction of cfDNA within the commercial insurance plan (first quarter of 2014). Multiple-group interrupted time series analysis (difference-in-difference) was performed with introduction of cfDNA as the intervention time point.
RESULTS: We identified 370 children 0-1 years of age and 3,058 children 2-18 years of age diagnosed with SCA between 2008 and 2019. Among children 0-1 years of age, the pre and post-cfDNA diagnosis rates of SCA were 4.9 and 13.3 per 100,000 members per quarter, respectively. Among children 2-18 years, the pre and post cfDNA diagnosis rates of SCA were 2.2 and 2.2 per 100,000 members per quarter, respectively. Since the introduction of cfDNA, there was a significant increase in the rate of SCA diagnosis in children 0-1 years of age compared to children 2-18 years of age (p=0.001).
CONCLUSIONS:
Sex Chromosomal Aneuploidy diagnosis has increased in infants since the introduction of cfDNA based screening studies. It is imperative that those undergoing cfDNA prenatal screening understand the complexities of sex chromosomal characterization through formal genetic counseling. 
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