Supplementary Material for: SIGNIFICANCE OF LOW MATERNAL SERUM Β-HCG LEVELS IN THE ASSESSMENT OF THE RISK OF ATYPICAL CHROMOSOMAL ABNORMALITIES

Introduction: The introduction of prenatal cell-free DNA as a screening test has surpassed traditional combined first-trimester screening (cFTS) in the detection of common trisomies. However, its current limitation in detecting only common trisomies is affecting the diagnostic yield for other clinically significant chromosomal abnormalities.
Methods: In efforts to optimize the detection of fetuses with genetic abnormalities, we have analyzed the relationship between the cFTS risk score and biomarkers with atypical chromosomal abnormalities. Furthermore, we have evaluated the impact of prenatal cell-free DNA screening on the detection of chromosomal abnormalities in our population. For these purposes, we performed a retrospective study of 877 singleton pregnancies who underwent chromosomal microarray analysis (CMA) between 2013 to 2020 and for whom first-trimester screening data were available.
Results: The results demonstrated that low levels of free beta human chorionic gonadotropin (β-hCG) (≤ 0.37 MoM) and increased fetal nuchal translucency (NT) (≥ 3.5mm) were statistically associated with the presence of atypical chromosomal abnormalities. In fact, the risk of pathogenic CMA results increased from 6% to 10% when fetal NT was increased and from 6% to 20% when a low serum β-hCG level was detected in the high-risk cFTS group. Moreover, our results showed that altered serum levels of β-hCG can have a substantial impact on the early detection of clinically relevant copy number variants.
Discussion/Conclusion: Traditional cFTS can potentially identify a substantial proportion of atypical chromosomal aberrations, and women with increased NT or low maternal serum β-hCG levels are at increased risk of having pathogenic CMA results. Our results may help clinicians and women decide whether invasive testing or prenatal cell-free DNA screening testing are more appropriate for each situation.

引言：产前游离胎儿DNA（prenatal cell-free DNA）筛查技术在常见三体综合征的检出效能上已超越传统早孕期联合筛查（cFTS）。然而，该技术目前仅能检出常见三体综合征的局限性，正影响其对其他临床意义显著的染色体异常的诊断效能。
方法：为优化遗传异常胎儿的检出效能，本研究分析了早孕期联合筛查风险评分与非典型染色体异常生物标志物之间的关联。此外，本研究还评估了产前游离胎儿DNA筛查在本研究人群中对染色体异常的检出影响。为此，我们对2013年至2020年间接受染色体微阵列分析（CMA）且具备早孕期筛查数据的877例单胎妊娠病例开展了回顾性研究。
结果：研究结果显示，游离β-人绒毛膜促性腺激素（β-hCG）水平降低（≤0.37 中位数倍数（Multiple of the Median，MoM））与胎儿颈项透明层（NT）增厚（≥3.5mm），均与非典型染色体异常存在统计学关联。具体而言，在早孕期联合筛查高风险组中，胎儿NT增厚时致病性染色体微阵列分析结果的风险从6%升至10%，而血清β-hCG水平降低时该风险则从6%升至20%。此外，本研究结果表明，血清β-hCG水平异常可对临床相关拷贝数变异的早期检出产生显著影响。
讨论/结论：传统早孕期联合筛查可检出相当比例的非典型染色体畸变，而颈项透明层增厚或母体血清β-hCG水平降低的孕妇，其致病性染色体微阵列分析结果的风险显著升高。本研究结果可为临床医师及孕妇个体化选择侵入性检查或产前游离胎儿DNA筛查提供参考依据。