Main findings
We observed an overall rising prevalence of CA, particularly in trisomy 21, SCA, and microdeletion/microduplication from 2014 to 2020 in Zhejiang Province, China. However, the prevalence of CA in live births has remained stable over time. Aneuploidies and SCA were strongly associated with maternal age, with the risk increasing by 3–5 times in women aged ≥ 35 years compared with those aged 25–29 years. Upward trends with a sharp increase in the detection proportions of CA before 22 GW, particularly at trisomy 21, were observed. Relatively, trisomy 21 and SCA had higher detection rates than microdeletion/microduplication. Overall, 88.3% of the pregnancies with CA were terminated.
Interpretations
In our study, the upward trends in CA prevalence and changes in maternal characteristics may reflect the rapid advancement of prenatal screening and improved maternal awareness over the study period in Zhejiang Province, China, as well as changes in maternal characteristics. The first- and second-trimester screening protocols, whether integrated, sequential, or contingent, provides a high detection rate [22]. Although NIPT is regarded as a second-tier cost-efficient screening method in Zhejiang, it was reported to have ahigh sensitivity for trisomy 21 (94–100%) and trisomy 18 (over 80%) [23]. The introduction of NIPT may have contributed to the increasing prenatal screening rate, especially given its efficiency and safety. Most importantly, the beginning of the universal two-child birth policy and guidelines on NIPT were implemented by the Chinese government in 2016 [10, 24]. The comprehensive factors may partially explain the obvious increase in maternal age-related CA, as the association between aneuploidies and advanced maternal age has been well established [25,26,27]. Strengthening health education and genetic counseling in outpatient services also promotes the uptake of screening among women.
Comparing the overall CA prevalence worldwide is difficult due to differences in inclusion criteria. Trisomy 21, trisomy 18, and trisomy 13 comprised the largest proportion of CA cases in our study, which was consistent with the previous findings in Europe and research in other regions in China [2, 28]. EUROCAT reported an overall prevalence of 25.01 per 10,000 births for trisomy 21, 6.34/10,000 births for trisomy 18, and 2.33/10,000 births for trisomy 13 between 2013 and 2019 [2], while the United States reported a prevalence of 15 per 10,000 live births for trisomy 21 [29]. Both studies reported higher rates than the detected prevalence in our study, whereas Japan reported a similar overall prevalence (approximately 10.5/10,000 births) of trisomy 21 [30]. This disparity possibly may have resulted from the differences in maternal characteristics, surveillance systems, and screening programs. For example, in Eastern Ireland, over 30% of women studied were aged ≥ 35 years, giving a prevalence of 35.7 per 10,000 births for trisomy 21 [31], whereas in our study, women of advanced age accounted for only 13% of the participants. However, our screening program showed a satisfactory performance, with a prenatal diagnosis rate of approximately 70% for trisomy 21 before 22 GW, which is comparable with the results from Norway [32].
The prevalence of SCA is estimated to be 20–40 per 10,000 births [33], most of which are diagnosed during adolescence. According to our surveillance system, the detected prevalence of SCA was approximately 7 per 10,000 births in 2020, which was consistent with a previous study from Denmark that reported a prevalence of 172 in 275,037 pregnancies [34] based on a similar screening program. A population-based cohort study in Australia also recorded an annual prenatal prevalence of SCA of 4.4 per 10,000 births between 1986 and 2016 [35]. Combined first-trimester screening is an effective tool for detecting autosomal aneuploidies, but not for SCA. The overall positive predictive value (PPV) for SCA using NIPT was about 40–55% [36,37,38,39], whereas that for special types (e.g., 47 XXX or 47 XXY) was found to be over 80% [36], resulting in a rise in prenatal detection. Early diagnosis of SCA promotes medical-care and special education, as individuals with SCA are associated with a higher risk of comorbidity, neurocognitive deficits, and lower socioeconomic status [7].
The rising prevalence in microdeletion/microduplication has attracted increased attention, despite having an increased diagnosis rate. Currently, studies on microdeletion/microduplication remains limited, compared to those on aneuplodies or SCAs. Awareness and knowledge about microdeletion/microduplication in healthcare providers are relatively poor, especially for CNVs with uncertain significance. Previous studies about microdeletion/microduplication were mainly carried out in pregnant women with clinical indications, such as advanced maternal age, family history, and abnormal ultrasonographic findings [40], or in specific population with recurrent pregnancy loss [41]. Our study revealed a preliminary data of prevalence of microdeletion/microduplication in the general population. Data from the European congenital anomaly registry reported a prevalence of microdeletions approximately 1.27 per 10,000 between 2000 and 2006 [42], lower than that of in our study. This discrepancy may by explained by different observation periods, different detection resolutions, and reporting thresholds of CNVs. In Europe, all cases with birth defects were followed up for one year after delivery, while we only reported cases diagnosed in the first week after delivery. Furthermore, the threshold of CNVs for microdeletion/microduplication has not yet reached agreement. In Zhejiang Province, we set a backbone resolution of 200 kb and 500 kb for CMA, with increased detection sensitivity; however, the clinical validity should be considered with caution.
The rising detected prevalence of microdeletion/microduplication is mainly attributed to an increase in accumulated knowledge, and universal acceptance of invasive diagnosis after counselling. The procedure-related miscarriage rate following amniocentesis and CVS decreased [43], which is consistent with the risk in women without invasive procedures [44]. CMA technology greatly facilitates the accurate detection of microdeletion/microduplication, and overcomes the disadvantages of conventional karyotypic analysis [45]. The estimated prevalence ranged from one in 1900 births to one in 50,000 births for different types of common MMS [46,47,48], and the prevalence varied dramatically because of different microarray coverage and depth in different laboratories and the allocation of experienced genetic counsellors. The risk for microdeletion and microduplication did not change with increasing maternal age, and some foetuses with microdeletion/microduplication had no apparent structural anomalies. This poses challenges for identification and elucidates the low diagnosis rate before 22 GW. Long-term follow-up is recommended for these infants because possible intellectual disability, autism, and multiple malformations may occur. In addition, our data demonstrated that pathogenic CNVs occurred more frequently on chromosomes 22, 17, 16 and 1, consistent with the a previous study by Chau, et al. [40]. More information about the genotype and phenotype is needed to update the database for better interpretation of variants in future studies.
The prenatal detection rate showed no significant differences between tertiary and district hospitals (Additional file 3: Table S1). Since CA diagnosis must be performed in qualified hospitals in Zhejiang, prenatal diagnosis institutions are reasonably distributed across regions. Early detection makes early termination possible and acceptable, as early abortion is associated with a lower risk of maternal complications [49]. However, the termination of CA is influenced by the legal requirements of different countries [50, 51] and categories of CA. This requires counsellors to have a clear understanding of the pros and cons of prenatal diagnosis methods, patient preferences, and ethical assessments.
Strengths and limitations
Our large sample size and full coverage of the CA subgroups based on the provincial surveillance system indicate that our results are robust. The hospital delivery rate is 100% in Zhejiang Province, therefore, the hospital-based surveillance data are a good reflection of the population. Most previous studies have investigated the ability of current prenatal screening methods and have focused on high-risk or referral populations. Therefore, our longitudinal study provides comprehensive insights into CA and avoided possible selection bias.
This study has several limitations. First, our surveillance system only reported the detected prevalence of abnormalities diagnosed prenatally and within 7 days after delivery, whereas a large proportion of CA were not confirmed until one year after birth or in adolescence/adulthood. Few inversions and translocations were reported by this system, and the prevalence rates of SCA and microdeletion/microduplication were underestimated to some extent. Therefore, these prevalence rates should be interpreted with caution, and further birth-cohort studies with long-term follow-ups are necessary. Second, as our surveillance system was a passive reporting database, we failed to obtain detailed pathogenicity information information for microdeletion/microduplication. Therefore, we focused on the well-known MMS, CNVs < 5 Mb and CNV5-10 Mb, in order to include complete cases. Our sensitivity analysis supported the rising trend of microdeletion and microduplication after dealing with the missing data for variant size.