Prenatal serum screening for Down syndrome and neural tube defects in the United States: Changes in utilization patterns from 2012 to 2020

Objective To compile current usage of serum-based prenatal screening for Down syndrome in the United States and compare it with results from a similar 2011/2012 survey. Setting The College of American Pathologists maternal screening proficiency testing survey includes a supplemental question on the first of three yearly distributions. Methods Information regarding tests offered and the monthly number of pregnancies tested for US-based laboratories were reviewed. Results were stratified by size of laboratory, tests offered, and pregnancies tested. Findings were compared to an earlier survey. Results Fifty-six laboratories reported they will have screened 1,131,336 pregnancies in 2020. Of these, 36% are screened by stand-alone first trimester testing, 48% by stand-alone second trimester testing, and 16% using tests that integrate results from both trimesters. Eighty percent of all serum screens were provided by the five laboratories that performed the most screens (at least 50,000). These five performed similar proportions of first or second trimester screens (42.2% and 41.8%, respectively). Compared to eight years earlier, there are now 54% fewer laboratories. Pregnancies screened using the first trimester, second trimester, and integrated protocols were lower by 27%, 69%, and 72%, respectively. The serum screening activity in the US showed a 62% decrease from 2012 levels. During 2012–2020, the number of cell-free DNA tests increased from negligible to 1,492,332. Conclusions Maternal serum screening for common aneuploidies has changed significantly in eight years with fewer laboratories, a shift toward larger laboratories and a 2.5-fold reduction in pregnancies tested, likely due to the introduction of cell-free DNA screening.

The Relationship between Prenatal Diagnosis Indications and Abnormal Chromosomal Karyotypes: A retrospective cohort of 4646 cases in Beijing from 2012-2019

Background and Objective: Chromosomal abnormalities are genetic disorders caused by abnormal chromosome number or structure and can endanger multiple organs, morphology, and function of the systems. This study aims to investigate the relationship between prenatal diagnosis indications and abnormal karyotypes to improve prenatal screening. Methods: The karyotype analyses were carried out on 4646 pregnant women with prenatal diagnosis indications referred to the first medical center of Chinese PLA General Hospital from 2012 to 2019. The incidence, distribution, and statistical features of chromosomal abnormality of different prenatal diagnosis indications were analyzed, and the relationships with the prenatal diagnosis indications were assessed. Results: A total of 351 fetal chromosomal abnormalities were detected in 4646 karyotypes analysis, with an incidence of 7.6%. The chromosomal abnormality incidence in the single indication group, two indications group, and three indications group was respectively 5.8%, 16.1%, and 70.0%, indicating a statistically significant difference (p<0.05). Advanced maternal age (AMA), high-risk maternal serum screening (MSS), and noninvasive prenatal DNA testing (NIPT) were the important indications for predicting abnormal karyotype. The number of prenatal diagnosis indications was highly correlated with fetal chromosomal abnormalities. The overall incidence of chromosomal abnormalities showed a tendency to increase with age. The incidence of Trisomy 21 was 3.2%, accounting for 42.5% of all chromosomal abnormalities, and the incidence tended to increase with maternal age. Conclusion: Prenatal karyotype analysis of pregnant women with prenatal diagnosis indications can effectively prevent the birth of defective children. AMA, MSS and NIPT were the important indications for predicting abnormal karyotype. In addition, the number of prenatal diagnosis indications is high correlated with chromosomal abnormalities.

Investigation on combined copy number variation sequencing and cytogenetic karyotyping for prenatal diagnosis

Background We aimed to evaluate the clinical value of copy number variation-sequencing (CNV-Seq) in combination with cytogenetic karyotyping in prenatal diagnosis. Methods CNV-Seq and cytogenetic karyotyping were performed in parallel for 9452 prenatal samples for comparison of the diagnostic performance of the two methods, and to evaluate the screening performance of maternal age, maternal serum screening, fetal ultrasound scanning and noninvasive prenatal testing (NIPT) for fetal pathogenic copy number variation (CNV). Results Among the 9452 prenatal samples, traditional karyotyping detected 704 cases (7.5%) of abnormal cytogenetic karyotypes, 171 (1.8%) chromosome polymorphism, 20 (0.2%) subtle structural variations, 74 (0.7%) mutual translocation (possibly balanced), 52 (0.6%) without karyotyping results, and 8431 (89.2%) normal cytogenetic karyotypes. Among the 8705 cases with normal karyotype, polymorphism, mutual translocation, or marker chromosome, CNV-Seq detected 63 cases (0.7%) of pathogenic chromosome microdeletion/duplication. Retrospectively, noninvasive prenatal testing (NIPT) had high sensitivity and specificity for the screening of fetal pathogenic CNV, and NIPT combining with maternal age, maternal serum screening or fetal ultrasound scanning, which improved the screening performance. Conclusion The combined application of cytogenetic karyotyping and CNV-Seq significantly improved the detection rate of fetal pathogenic chromosome microdeletion/duplication. NIPT was recommended for the screening of pathogenic chromosome microdeletion/duplication, and NIPT combining with other screening methods further improved the screening performance for pathogenic fetal CNV.

Factors associated with test failure in pregnant women undergoing cell-free DNA-based testing for fetal trisomy

Objective To investigate the factors associated with cell-free DNA test failure, and the optimal subsequent management of these pregnancies. Methods This was a retrospective study of 27,363 singleton pregnancies undergoing cell-free DNA testing. Women with cell-free DNA test failure were divided into a high-risk group and a low-risk group according to their indications. The subsequent management and pregnancy outcomes of these women were followed up. Results The rate of cell-free DNA test failure at the first sampling was 1.49%, and 78.4% of failures were due to a low fetal fraction. Of the 66 women who refused any subsequent management, an adverse pregnancy outcome was seen in 5 cases, all belonging to the high-risk group. Of the 13 low-risk women who chose second-trimester maternal serum screening, all obtained a low-risk maternal serum screening result and an unaffected pregnancy outcome. A redraw was chosen by 171 women, which yielded a result in 75.4% and their pregnancy outcomes were unaffected; 42 women had an uninformative result again and received an amniocentesis. As 158 women had an amniocentesis after the first sampling, this procedure was offered in 200 cases altogether. Abnormal genetic testing results were shown in six (3%, 6/200) cases, all in the high-risk group. Conclusions High-risk pregnant women with cell-free DNA test failure are at increased risk of adverse pregnancy outcomes. A second sampling for cell-free DNA test or maternal serum screening might be suggested to low-risk women. Invasive prenatal diagnosis should be offered to the high-risk patients, especially those with a second cell-free DNA test failure.

Prenatal detection and molecular cytogenetic characterization of 19q13.42 microduplication: three reported cases and literature review

Background Trisomy 19q is a recognizable syndrome and associated with a wide spectrum of clinical phenotypes in clinic. The purpose of this study was to explore the prenatal phenotypes of 19q13.42 duplication, which was rarely reported in clinic. Case presentation Three pregnant women presenting diverse indications for prenatal diagnosis accepted amniocentesis: increased nuchal translucency and fetal pyelic separation (case 2) and high risk of maternal serum screening for Down syndrome (case 1 and case 3). Case 1 and case 2 shared similar duplicated locus in the region of 19q13.42, encompassing part NLRP12 gene. The latter inherited the chromosomal duplication from the mother with normal phenotypes. Case 3 carried a 1.445 Mb duplication in the 19q13.42q13.43 region. It was proposed that evolutionary duplication of NLRP12 gene could have a causative role in autoinflammatory diseases development. The genotype–phenotype correlation depends mainly on the duplicated size and functional genes involved, which is still yet to be determined. All pregnant women chose to continue the pregnancy and delivered healthy children with no apparent abnormalities. Conclusions The 19q13.42 microduplications in our study were the smallest fragments compared to previous literature. Our findings enriched the prenatal phenotypes for this chromosomal microscopic imbalance. It was proposed that long term follow up analysis should be guaranteed till adulthood to determine whether there will be other emerging clinical symptoms and developmental-behavioral disorders for such carriers.