Abstract
Objectives
This article investigates the theoretical detection rate of non-invasive prenatal screening (NIPS) and the residual risk of copy-number variations (CNVs) after normal NIPS results, for fetuses with isolated mild increased nuchal translucency (ImiNT), compared to chromosomal microarray analysis (CMA).
Methods
A retrospective analysis was conducted on CMA results in a cohort with ImiNT (2.5 mm or 95th percentile ≤ NT < 3.5 mm). Theoretical detection rates and residual risk values were calculated for four NIPS panels—Basic NIPS-3, Basic NIPS-5, Expanded NIPS (ExpNIPS), and Genome-Wide (GW) NIPS—for common chromosomal aneuploidies and clinically significant CNVs.
Results
In a cohort of 936 fetuses with ImiNT, 44 cases had clinically significant CMA results. Basic NIPS-3 could detect 10 cases (9 trisomy 21 and 1 trisomy 18), leaving a residual risk of 3.63% (1/28). Basic NIPS-5 detected 17 cases, including 7 sex chromosome abnormalities, reducing the residual risk to 2.88% (1/35). ExpNIPS identified 18 cases, adding one microdeletion compared to Basic NIPS-5, with a residual risk of 2.78% (1/36). GW NIPS detected 22 cases, finding 5 additional CNVs > 10 Mb compared to Basic NIPS-5, lowering the residual risk to 2.35% (1/43).
Conclusion
Using NIPS as a substitute for invasive prenatal diagnosis in cases of ImiNT should still be approached with caution. Couples must be ensured to understand the advantages and limitations of both methods. They should also be informed about the residual risk, ranging from 2.35 (1/43) to 3.63% (1/28), even after normal NIPS results. This understanding will help couples make informed decisions.
Keywords: Nuchal translucency, Invasive procedure, Noninvasive prenatal testing, Chromosome abnormality, Residual risk
What does this study add to the clinical work
| For fetuses with isolated mild NT thickening, NIPS testing may still carry a residual risk of chromosomal abnormalities ranging from 2.35% (1/43) to 3.63% (1/28). Therefore, caution should be exercised when considering NIPS as a substitute for invasive prenatal diagnosis in such cases. |
Introduction
Over the past decade, chromosomal microarray analysis (CMA) and non-invasive prenatal screening (NIPS) have become prominent techniques in prenatal care. With its superior resolution, CMA detects submicroscopic chromosomal imbalances that traditional methods cannot, making it the preferred option for pregnancies with abnormal ultrasound findings. NIPS demonstrates significantly higher accuracy than maternal serum screening (MSS) for identifying common chromosomal aneuploidies and poses no risk of obstetric complications unlike invasive testing methods. Consequently, some countries have adopted NIPS as the first-line screening method [1], and it is widely accepted as an alternative to invasive diagnostic procedures [2, 3].
Nuchal Translucency (NT) refers to the temporary accumulation of subcutaneous fluid behind the fetus's neck, often associated with an elevated risk of chromosomal aneuploidy and submicroscopic abnormalities [4]. Although the threshold for increased NT thickness varies by country, most researchers agree that CMA should be used for prenatal diagnosis when NT ≥ 3.5 mm to detect chromosomal abnormalities beyond common trisomy syndromes [5–7]. For pregnancies with increased NT values below 3.5 mm, decision-making is more challenging. According to Chinese guidelines, NIPS should be used cautiously when ultrasound examinations reveal abnormalities. However, for pregnant women with mildly increased NT who refuse invasive testing, NIPS is recommended as the preferred fetal evaluation method [8].
For the screening performance of NIPS, it has been extensively evaluated in large-scale cohort studies [9, 10]. While most studies focus on the positive predictive value and validation of NIPS for fetuses with mild NT thickening, few have addressed the residual risk of (sub)microscopic chromosomal aberrations after detecting common trisomies. This study aims to theoretically assess the residual risk of clinically significant copy-number variations (CNVs) in fetuses with mild NT thickening by comparing NIPS results with CMA data. It also seeks to help genetic counselors and couples make informed decisions between invasive diagnosis and non-invasive screening.
Materials and methods
A retrospective study was conducted on 936 pregnant women who underwent invasive prenatal diagnosis and CMA testing at 18–21 weeks of gestation in Fujian Provincial Maternity and Children's Hospital between June 2016 and February 2025. All participants had early pregnancy ultrasounds at 11–13 +6 weeks, including assessment of crown-rump length, NT, cardiac structure, ductus venosus, nasal bone, umbilical artery, choroid plexus cysts, bowel examination, and placental maturity assessments. Visible fetal structural abnormalities were also evaluated by qualified sonographers. Pregnancies with multiple gestations, high maternal serum screening (threshold of 1:270), or abnormal ultrasound findings were excluded. To achieve a more comprehensive sample size, two commonly used NT thresholds of 2.5 mm and the 95th percentile were selected. Cases with isolated NT values ≥ 2.5 mm or ≥ the 95th percentile but < 3.5 mm were included. Cases with NT values of 2.5 mm or the 95th percentile ≤ NT < 3.0 mm were classified as Group A. Cases with NT values of 3.0 mm ≤ NT < 3.5 mm were classified as Group B. CMA analysis was performed using the CytoScan™ 750 K microarray platform (Thermo Fisher Scientific, USA). The data had been re-annotated according to the Human Genome Assembly GRCh37/hg19. Pre-test counseling was provided to all participants, including informed consent regarding the associated risks of the procedure and diagnostic technology involved. According to the guidelines provided by the American College of Medical Genetics, the nature of CNVs was categorized into five groups: pathogenic CNVs, likely pathogenic CNVs, variants of uncertain significance (VOUS), likely benign CNVs, and benign CNVs [11]. We define clinically significant chromosomal variations as aneuploidy, pathogenic CNVs, and likely pathogenic CNVs. CNVs classified as likely benign and VOUS were excluded.
Nowadays, testing institutions and commercial companies offer various NIPS options with different testing scopes. Based on the strategies used in NIPS, we categorize clinically significant detectable chromosomal abnormalities as follows:
Chromosomal abnormalities identifiable via targeted NIPS (Basic NIPS-3): Detects Trisomy 13, Trisomy 18, and Trisomy 21.
Chromosomal abnormalities identifiable via targeted NIPS (Basic NIPS-5): Detects Trisomy 13, Trisomy 18, Trisomy 21, and X/Y sex chromosome aneuploidies (e.g., 47,XXY; 47,XYY; 47,XXX; 48,XXXY; 45,X0).
Chromosomal abnormalities identifiable via expanded NIPS (Expanded NIPS, ExpNIPS): Detects Trisomy 13, Trisomy 18, Trisomy 21, X/Y sex chromosome aneuploidies, and six common microdeletions (> 3 Mb) at 1p36, 2q33.1, 5p15.3-5p15.1, 15q11-13, 22q11.2, and 8q24.11-q24.13.
Large chromosomal segment imbalances > 10 Mb detectable through genome-wide NIPS (Genome-Wide NIPS, GW NIPS).
Submicroscopic structures detectable exclusively through CMA: chromosomal mosaics and copy-number variations (< 10 Mb).
We assume the NIPS detection rate for all patterns is 100%, with no false negatives (NIPS testing was not performed in this cohort). Based on this assumption, we calculate the residual risk of clinically significant CNVs in fetuses with mild NT thickening. Statistical significance was determined through Analysis of Variance (ANOVA) and Chi-squared tests, with P-values less than 0.05 considered statistically significant.
Results
Patient clinical characteristics
This study included 936 cases with isolated mild nuchal translucency (NT) thickening, divided into Group A (525 cases) and Group B (411 cases). Pregnant women were aged 14–34 years (mean 29.76 ± 0.04 years). Amniocentesis was performed at 18 to 21 weeks of gestation (mean 18.76 ± 0.01 weeks).
Among the 936 CMA results, 44 were clinically significant: 25 in Group A and 19 in Group B (P = 1.000). Of these, 10 cases could theoretically be detected by Basic NIPS-3: 3 Trisomy 21 cases in Group A (3/25, 12.0%) and 7 cases in Group B (7/19, 36.8%), including 6 Trisomy 21 and 1 Trisomy 18 (P = 0.074 between groups). A total of 8 sex chromosome aneuploidy abnormalities were identified in the cohort, with 7 cases theoretically detectable by Basic NIPS-5 and Expanded NIPS, including 6 cases in Group A and 1 case in Group B. The remaining 1 case, a mosaic sex chromosome abnormality (47,XXX/45,X), could not be detected. Eight common microdeletions in the 15q11.2 region were found; only 1 deletion exceeding 3 Mb was theoretically detectable by Expanded NIPS. The deletion fragments in the remaining 7 cases were all smaller than the minimum detectable fragment size. Among the remaining 14 copy-number variations, cases such as 2q32.2q37.3 duplication (51.5 Mb) (with concurrent 9p24.3p24.2 microdeletion, 4.3 Mb), 3q22.1q29 duplication (64.2 Mb), 4p16.3p15.1 deletion (34 Mb), 18p11.32p11.21 duplication (13.8 Mb), and Yq11.21q11.23 deletion (15 Mb) (with Xp22.33 or Yp11.32 microdeletion, 1.8 Mb) could theoretically be detected by GW NIPS. The remaining 9 copy-number variations (< 10 Mb) could only be detected by CMA. Tables 1 and 2 summarize the theoretical detection rates and calculated residual risks of common NIPS models for clinically significant CMA results. Table 1 specifically outlines the theoretical detection possibilities of common NIPS models for clinically significant CMA results.
Table 1.
Microarray test results with clinical significance and their theoretical detection probabilities in various types of NIPS
| NT | CMA result | n | Basic NIPS-3 | Basic NIPS-5 | ExpNIPS | GW NIPS |
|---|---|---|---|---|---|---|
| Group A (2.5 mm or 95th ≤ NT < 3.0 mm) | Trisomy 21 | 3 | √ | √ | √ | √ |
| 47,XXY | 3 | – | √ | √ | √ | |
| 47,XXX | 2 | – | √ | √ | √ | |
| 48,XXXY | 1 | – | √ | √ | √ | |
| Mosaic 47,XXX/45,X (18%) | 1 | – | – | – | – | |
| 1q21.1q21.2 microduplication (1.4 Mb) | 1 | – | – | – | – | |
| 2q32.2q37.3 duplication (51.5 Mb) + 9p24.3p24.2 microdeletion (4.3 Mb) | 1 | – | – | – | √ | |
| 3q22.1q29 duplication (64.2 Mb) | 1 | – | – | – | √ | |
| 15q11.2 microdeletion (0.507 Mb ~ 0.512 Mb) | 4 | – | – | – | – | |
| 16p11.2 microduplication (0.611 Mb/0.673 Mb) | 2 | – | – | – | – | |
| 16p13.11 microduplication (0.791 Mb/1.6 Mb) | 2 | – | – | – | – | |
| Xp21.2p21.1 microdeletion (0.345 Mb) | 1 | – | – | – | – | |
| Xp22.33 or Yp11.3 2 microdeletion (0.694 Mb) | 1 | – | – | – | – | |
| Yq11.21q11.23 deletion (15 Mb) + Xp22.33 or Yp11.32 microdeletion (1.8 Mb) | 1 | – | – | – | √ | |
| Yq11.222q11.223 deletion (5.6 Mb) | 1 | – | – | – | – | |
| Group B (3.0 mm ≤ NT < 3.5 mm) | Trisomy 21 | 6 | √ | √ | √ | √ |
| Trisomy 18 | 1 | √ | √ | √ | √ | |
| 48,XXYY | 1 | – | √ | √ | √ | |
| 1q21.1q21.2 microdeletion (1.29 Mb/2.2 Mb) | 2 | – | – | – | – | |
| 4p16.3p15.1 deletion (34 Mb) | 1 | – | – | – | √ | |
| 13q12.12 microdeletion (1.4 Mb) | 1 | – | – | – | – | |
| 15q11.2 microdeletion (0.312 Mb ~ 0.512 Mb) | 3 | – | – | – | – | |
| 15q11.2q13.1 deletion (6.16 Mb) | 1 | – | – | – | – | |
| 15q13.3 microdeletion (0.49 Mb) | 1 | – | – | – | – | |
| 18p11.32p11.21 duplication (13.8 Mb) | 1 | – | – | – | √ | |
| Xq28 microduplication (0.266 Mb) | 1 | – | – | – | – |
Table 2.
Detection rates of non-invasive prenatal screening models and residual risk of chromosomal abnormalities
| Subgroup | n | CMA | Basic NIPS-3 | Basic NIPS-5 | ExpNIPS | GW NIPS | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| P + LP n(%) | P + LP n(%) | Residual rate (%)(1 in) | P + LP n(%) | Residual rate (%)(1 in) | P + LPn(%) | Residual rate (%)(1 in) | P + LP n(%) | Residual rate (%)(1 in) | ||
| 2.5 mm or 95th ≤ NT < 3.0 mm | 525 | 25 (4.76) | 3 (0.57) | 4.19 (24) | 9 (1.71) | 3.05 (33) | 9 (1.71) | 3.05 (33) | 12 (2.29) | 2.48 (40) |
| 3.0 mm ≤ NT < 3.5 mm | 411 | 19 (4.62) | 7 (1.70) | 2.92 (34) | 8 (1.95) | 2.68 (37) | 9 (2.19) | 2.43 (41) | 10 (2.43) | 2.19 (46) |
| Total | 936 | 44 (4.70) | 10 (1.07) | 3.63 (28) | 17 (1.82) | 2.88 (35) | 18 (1.92) | 2.78 (36) | 22 (2.35) | 2.35 (43) |
P pathogenic CNVs; LP likely pathogenic CNVs
We designed four NIPS scenarios to represent four common NIPS patterns. Assuming that all abnormalities within the theoretical detection range could be identified without false negatives, we compared these results with those of CMA to calculate the residual risk for each NIPS pattern. After excluding abnormalities detectable by Basic NIPS-3, the residual risk relative to CMA detection was 3.63% (1/28), ranging from 4.19% (1/24) in Group A to 2.92% (1/34) in Group B (P = 0.411). Excluding abnormalities detectable by Basic NIPS-5 (common autosomal trisomies and sex chromosome abnormalities) further reduced the residual risk to 2.88% (1/35), varying from 3.05% (1/33) in Group A to 2.68% (1/37) in Group B (P = 0.894). Including common microdeletions lowered the residual risk to 2.78% (1/36). When detection of common microdeletions was included, the residual risk was reduced to 2.78% (1/36). The residual risk in Group A remained unchanged, while in Group B, after excluding one case of a 15q11.2q13.1 deletion (6.16 Mb), the residual risk dropped to 2.43% (1/41). There was no significant difference between the two groups (P = 0.722). Finally, after excluding five additional abnormalities larger than 10 Mb, the theoretical residual risk following GW NIPS detection was approximately 2.35% (1/43), ranging from 2.48% (1/40) in Group A to 2.19% (1/46) in Group B (P = 0.947). No statistically significant differences were observed in the detection rate or residual risk between the two subgroups. Table 2 summarizes abnormal detection rates and residual risks for each NIPS pattern compared with CMA.
Discussion
The discovery and development of cell-free fetal DNA (cffDNA) and the enhanced accuracy of fetal chromosomal abnormalities screening using next-generation sequencing have paved the way for ultrasound-based aneuploidy screening [12, 13]. Several esteemed organizations, including the Society for Maternal–Fetal Medicine (SMFM), American College of Obstetricians and Gynecologists (ACOG), International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), National Institute for Health and Nursing Excellence, National Institute for Health and Care Excellence, as well as the Society of Obstetricians and Gynaecologists of Canada, have issued recommendations regarding assessing aneuploidy risk using soft indicators [14–17]. The 2021 SMFM Consult Series advises that, for pregnant women with negative NIPS and isolated thickened nuchal fold or absent/hypoplastic nasal bone, no additional aneuploidy evaluation is recommended. Although this series primarily focuses on evaluating and managing ultrasound soft markers in the second trimester without providing clear guidance on managing thickened NT in early trimesters, it is evident that the significance of ultrasound soft markers has evolved with the introduction of non-invasive screening using cffDNA [12].
Currently, it is acknowledged that NT thickening refers to the fetal nuchal translucency thickness reaching or exceeding 3.5 mm. At this stage, prenatal diagnosis becomes necessary for the fetus and additional chromosomal microarray (CMA) testing is recommended to identify and rule out potential chromosomal aberrations (approximately 7%) and submicroscopic variations (4%) [18]. Different countries establish varying thresholds for the NT values that trigger invasive examinations. Many countries still adhere to a cut-off value of 2.5 mm or the 95th percentile value of nuchal translucency (NT) for assessing risks associated with chromosome abnormalities [19–21]. Therefore, for fetuses exhibiting a mild increase in nuchal translucency (NT) thickness (ranging from 2.5 mm or the 95th percentile value to 3.4 mm), risk assessment for aneuploidy remains necessary. Options may involve invasive prenatal diagnosis or NIPS.
Previous studies have demonstrated that NIPS effectively reduces the residual risk of RA in high-risk fetuses [22]. Fetal aneuploidy can be assessed by NIPS as early as 12 weeks of gestation, avoiding complications from invasive prenatal diagnosis. However, despite its proven high detection efficiency for common aneuploidy abnormalities, NIPS may still leave residual risks for other chromosomal abnormalities that fall outside its technical capabilities. The aim of this study is to theoretically evaluate the residual risk of other chromosomal aberrations after NIPS screening, compared with CMA detection technology, in the context of evaluating fetuses with isolated mild thickening of NT.
In our study, based on the CMA results of 936 fetuses with isolated NT thickening, we found that Basic NIPS-3, Basic NIPS-5, Expanded NIPS, and even GW NIPS would miss 77.3%, 61.4%, 59.1%, and 50.0% of clinically significant CMA findings, respectively, which aligns with the literature reports from large-sample cohort studies by I. MAYA et al. [23]. In fetuses with NT value of 2.5 mm or 95th ≤ NT < 3.0 mm, the residual risk of CMA findings after normal NIPS results ranged from 2.48 (1/40) to 4.19% (1/24), while in fetuses with NT value of 3.0 mm ≤ NT < 3.5 mm, the residual risk ranged from 2.19 (1/46) to 2.92% (1/34). No statistically significant difference was observed between these two groups. However, this residual risk is substantially higher than the threshold for invasive testing recommended in this country (1:270), prompting obstetricians and genetic counselors to reconsider the utility of NIPS in evaluating aneuploidy in fetuses with mild increased NT thickening.
Although the emergence of GW NIPS and Expanded NIPS has enabled the detection of large fragment deletions and submicroscopic copy-number abnormalities, both methods have inherent limitations. For instance, GW NIPS is limited in detecting CNV fragments smaller than 10 Mb. In our study, 47.7% of CNV fragments were below this threshold, rendering them undetectable by GW NIPS. Despite advancements in technology improving the resolution of GW NIPS, its current limitations mean that minor CNVs will continue to be missed during the detection process in the near future. The Expanded NIPS mode specifically targets six common microdeletions with fragment sizes greater than 3 Mb. Among these, only one type (15q11-13) was detected by CMA, with a total of eight cases identified. Of these eight cases, only one [a 15q11.2q13.1 deletion (6.16 Mb)] met the minimum detection threshold of 3 Mb for Expanded NIPS and was therefore detectable. The remaining seven cases had fragment sizes smaller than 1 Mb and thus fell below the detection limit of Expanded NIPS.
In this study, the detection rate of 15q11.2 microdeletion in cases of NT thickening was 0.86% (1/117), which aligns with the literature reports ranging from 0.57 to 1.27% [24]. Expanded NIPS detected only one common microdeletion for three reasons: (1) expanded NIPS has limitations in detecting copy-number fragments smaller than 3 Mb, making deletions below this threshold undetectable; (2) so-called "common" microdeletions are not as frequent as their name suggests, and their actual incidence rates are relatively low. For instance, a 1p36 deletion syndrome incidence in live-born infants is approximately 1 in 5000 [25], and 5p15.3-5p15.1 locus is even rarer, occurring in approximately 1 in 15,000 to 1 in 50,000 pregnancies [26]; (3) common microdeletions associated with NT thickening primarily include 15q11.2 microdeletion, 16p11.2 microduplication, and 22q11.2 microduplication [27, 28]. The detection rate of other microdeletions in fetuses with NT thickening remains low. As a consequence, Expanded NIPS has not significantly reduced residual risk compared to 5-NIPS. Due to the low prevalence of detected diseases, the positive predictive value is also low. Currently, no international society endorses screening for these genetic syndromes [23].
Pregnant women often prefer NIPS when facing a slight increase in NT, wishing to avoid the procedure-related risk of pregnancy loss [29]. First, due to the international criteria for NT thickening values and invasive prenatal diagnosis, as well as the small but non-zero risk of miscarriage associated with invasive prenatal diagnosis [4], Second, this is related to women’s cognitive status. Although many women understand common trisomy syndromes, their knowledge of other rare aneuploidies and CNVs detectable through invasive prenatal diagnosis and CMA is limited. Third, even after receiving reassuring NIPS results in the first trimester, some women may choose subsequent imaging to monitor fetal development. If fetal anatomical variations are found during the second or third trimester, the need for invasive prenatal diagnostic procedures and CMA should be evaluated. However, even if the fetus is regularly monitored through imaging examinations in strict compliance with the established protocols throughout the entire pregnancy, not all copy-number abnormalities can be detected by these methods. The likelihood of detecting such abnormalities during the second trimester or later depends, in part, on the size of the CNVs and the specific chromosomes involved. For example, the incidence of pathogenic CNVs differs between structurally normal and abnormal fetuses, and CNVs linked to late-onset conditions do not always correlate with fetal malformations [30]. Some local governments have incorporated NIPS into public health initiatives, providing it free of charge to pregnant women with maternity insurance. Among pregnant women with elevated NT values, a significant proportion hope to obtain a negative result via NIPS before proceeding to invasive procedures and amniocentesis diagnosis to alleviate anxiety and stress [31]. However, it is important to note that in the general pregnant population, the risk of submicroscopic chromosomal abnormalities exceeds that of Down syndrome/common trisomy syndromes [32, 33], which aligns with our findings (26/18). Therefore, it is crucial for pregnant women to fully understand the residual risk associated with NIPS when undergoing this test.
Our study has several limitations that need to be considered. We do not delve into the sensitivity and specificity of NIPS but rather focus on determining its potential application for screening chromosomal abnormalities in fetuses with isolated thickened NT. Theoretically, it is assumed that the detection rate could reach 100%, thus eliminating false-negative results. However, it is undeniable that this scenario could result in an underestimation of the calculated residual risk. Additionally, it is important to note that NIPS detects cells derived from the fetal placenta rather than directly from the fetus itself. Moreover, the article does not discuss the risk of restrictive placental mosaicism, which occurs in 2% of cases and may lead to inconsistency with true fetal outcomes. Furthermore, due to patients being given a choice between karyotype analysis and SNP testing, not all patients with relevant sole indications were included in this study resulting in a limited sample size. Finally, pregnant women with a gestational age of over 12 weeks are eligible for NIPS testing, whereas the samples in this study underwent invasive prenatal diagnosis between 18 and 21 weeks. Consequently, during earlier stages of pregnancy, pregnancy termination or miscarriage due to abnormal NIPS results or other unknown factors may also influence the calculation of residual CMA risk. These concerns will be further explored in future studies. Collecting a larger cohort of samples for analysis and integrating combined detection of NIPS and CMA will contribute to refining and substantiating the experimental findings of this study.
Conclusion
The use of NIPS for assessing aneuploidy in fetuses with isolated mild NT thickening carries a risk of missing clinically significant CNVs ranging from 2.35 (1/43) to 3.63% (1/28). This residual risk is influenced by the methodology and resolution of NIPS. Consequently, caution is advised when considering NIPS as an alternative to invasive prenatal diagnosis for pregnant women with slightly increased NT measurements during chromosomal aneuploidy assessment. Obstetricians and genetic counselors should fully inform pregnant women with mild nuchal translucency (NT) thickening that even low-risk results from non-invasive prenatal screening (NIPS) do not rule out clinically significant copy-number variations (CNVs). They should also provide the latest data on miscarriage risks with invasive procedures and mention the availability of invasive prenatal chromosomal microarray analysis (CMA). This helps couples make informed decisions about whether to proceed with invasive testing or continue with NIPS.
Author contributions
LS, LX, and XW conceived the study, carried out the assays, and prepared the original draft; HH and WZ carried out the laboratory tests; YL conducted a statistical analysis of the data; XX, LZ, and CM polished the article. All authors contributed to the article and approved the submitted version. The authors would like to thank all the patients and research staff for their participation.
Funding
This work was funded by Startup Fund for scientific research, Fujian Medical University (Grant No. 2022QH1186).
Data availability
No datasets were generated or analyzed during the current study.
Declarations
Conflict of interest
The authors declare no competing interests.
Ethical approval
This study was approved by the Ethics Committee of Fujian Provincial Maternity and Children's Hospital and conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all pregnant women and their families.
Consent for publication
Not applicable.
Footnotes
Publisher's Note
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Contributor Information
Liangpu Xu, Email: kuaicanbao_2011@163.com.
Xiaoqing Wu, Email: Wuxiaoqing013@126.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analyzed during the current study.