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中华妇幼临床医学杂志(电子版) ›› 2021, Vol. 17 ›› Issue (04) : 410 -419. doi: 10.3877/cma.j.issn.1673-5250.2021.04.006

论著

广西地区50 975例孕妇无创产前筛查分析
雷亚琴, 赖允丽, 易赏, 许富本, 唐燕青, 黄小珊, 易坚, 丘小霞†()   
  • 收稿日期:2020-12-28 修回日期:2021-06-11 出版日期:2021-08-01
  • 通信作者: 丘小霞

Analysis of non-invasive prenatal screening in 50 975 pregnant women in Guangxi region

Yaqin Lei, Yunli Lai, Shang Yi, Fuben Xu, Yanqing Tang, Xiaoshan Huang, Jian Yi, Xiaoxia Qiu†()   

  • Received:2020-12-28 Revised:2021-06-11 Published:2021-08-01
  • Corresponding author: Xiaoxia Qiu
  • Supported by:
    Research Program of Health Department of Guangxi Zhuang Autonomous Region(Z20200601); Guangxi Special Fund for Scientific Base and Talent(GKAD17129016)
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雷亚琴, 赖允丽, 易赏, 许富本, 唐燕青, 黄小珊, 易坚, 丘小霞. 广西地区50 975例孕妇无创产前筛查分析[J]. 中华妇幼临床医学杂志(电子版), 2021, 17(04): 410-419.

Yaqin Lei, Yunli Lai, Shang Yi, Fuben Xu, Yanqing Tang, Xiaoshan Huang, Jian Yi, Xiaoxia Qiu. Analysis of non-invasive prenatal screening in 50 975 pregnant women in Guangxi region[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2021, 17(04): 410-419.

目的

探讨无创产前筛查(NIPS)在胎儿染色体非整倍体异常(CAA)及全基因组拷贝数变异(CNV)筛查中的临床应用价值。

方法

选择2018年1月至2019年12月，广西壮族自治区60余家医疗机构采集血液样本后送至本院完成NIPS的50 975例单胎孕妇为研究对象。其分娩年龄为13~54岁，高龄孕妇(分娩时年龄≥35岁)为17 216例(33.77%)，血样标本采集时，孕龄为10~36孕周。根据血清学筛查结果、孕妇年龄、妊娠史/家族史，将其分为高风险组[n＝22 852，血清学筛查结果高风险(+)、高龄孕妇(+)、不良孕产史/家族史者纳入(+)，至少满足其中一项者]，中风险组[n＝4 584，血清学筛查结果中风险/临界风险(+)、胎儿超声检查软指标异常(+)，至少满足二者之一者]和低风险组(n＝23 539，无上述风险因素者)。对于NIPS提示高风险者，采用介入性产前诊断，进行胎儿G显带染色体核型分析及染色体微阵列分析(CMA)。本研究经广西壮族自治区妇幼保健院伦理委员会批准(审批文号：桂妇保院医伦审[2020]9-2号)。

结果

①50 975例接受NIPS孕妇中，702例NIPS筛查结果显示高风险，高风险率为1.38%。其中21-、18-、13-三体高风险率分别为0.34%(175/50 975)、0.13%(67/50 975)和0.12%(63/50 975)，性染色体非整倍体异常(SCA)高风险率为0.40%(205/50 975)，罕见染色体数目异常(RCA)高风险率为0.19%(96/50 975)，基因组拷贝数变异(CNV)高风险率为0.19%(96/50 975)。②在702例NIPS高风险者中，对555例(79.06%)孕妇进行胎儿染色体核型分析和(或)CMA，93例(16.76%)拒绝进行产前诊断，42例(7.57%)因为流产或已引产而未进行产前诊断，NIPS结果为高风险孕妇的失访率为1.71%(12/702)。555例接受介入性产前诊断的胎儿中，271例阴性胎儿的NIPS和介入性产前诊断结果基本一致，284例假阳性中，16例胎儿的介入性产前诊断结果为染色体异常，但与NIPS高风险结果不一致。③21-三体、18-三体、13-三体、SCA、RCA和CNV的阳性预测值分别为85.09%(137/161)、57.14%(28/49)、16.67%(9/54)、42.31%(66/156)、5.56%(4/72)和42.86%(27/63)。④16例经介入性产前诊断未检测到NIPS所提示的高风险结果，却检测到其他异常结果。其中，4例21-三体高风险胎儿中，3例检测到CNV，1例为21号染色体复杂的结构变异；1例18-三体高风险胎儿中，染色体核型分析结果提示为21-三体；2例13-三体高风险胎儿中，1例为染色体结构变异的嵌合体，另1例为CNV；3例SCA高风险和2例RCA高风险胎儿中，均检测到其他染色体的CNV；4例CNV高风险胎儿中，1例检测到47，XYY，3例为其他染色体的CNV异常。

结论

NIPS对于21-、18-、13-三体等常见CAA的筛查具有较高临床实际应用价值。NIPS对于性染色体单体、RCA及CNV的筛查阳性预测值偏低，但是结合产前超声等相关检查，可为遗传咨询和进一步介入性产前诊断提供依据。

关键词: 产前诊断, 无创产前筛查, 核型分析, 染色体微阵列分析, 罕见染色体数目异常, DNA拷贝数异常, 性染色体, 染色体结构, 孕妇
Objective

To investigate the clinical performance of non-invasive prenatal testing (NIPS) in the detection of chromosome aneuploidies and genome-wide copy number variation (CNV).

Methods

A total of 50 975 serum specimens from singleton pregnant women who received NIPS at the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region from January 2018 to December 2019 were selected into this study. Based on different risk factors, they were divided into 3 groups. Those with serologic screening results of high risk + elderly pregnant women + adverse maternal history/family history were included in high-risk group (n=22 852), those with moderate risk/critical risk of serologic screening and abnormal ultrasound soft indicators were included in moderate-risk group (n=4 584), and those without the above risk factors were included in low-risk group (n=23 539). For those with high risk of NIPS detection, chromosome karyotype analysis and chromosome microarray analysis (CMA) were used for interventional prenatal diagnosis. The study protocol was approved by the Ethics Review Committee of Guangxi Maternal and Child Health Hospital (approval No.[2020]9-2).

Results

① Of 50 975 pregnant women who underwent NIPS, 702 cases showed high risk, with a total positive rate of 1.38%. Among them, the high risk of 21-, 18-and 13-trisomy was 175 cases (0.34%), 67 cases (0.13%) and 63 cases (0.12%), respectively, the high risk of sex chromosome aneuploidy abnormalities (SCA) was 205 cases (0.40%), the high risk of rare chromosome number abnormality (RCA) was 96 (0.19%), and the high risk of copy number variation (CNV) was 96 (0.19%). ②A total of 555 of the 702 positive cases (79.06%) were followed up by karyotyping and (or) CMA, 93 (16.76%) refused confirmatory diagnosis, 42 (7.57%) did not perform prenatal diagnosis because of abortion or induced labor, and 12 (1.71%) lost follow-up. ③The positive predictive values for trisomy 21, trisomy 18, trisomy 13, SCA, RCA, and CNV were 85.09% (137/161), 57.14% (28/49), 16.67% (9/54), 42.31% (66/156), 5.56% (4/72), and 42.86% (27/63), respectively. ④In 16 cases with high risk of NIPS screening, NIPS was not detected by interventional prenatal diagnosis, but other abnormal results were detected. Of the 4 fetuses with high risk of trisomy 21, CNV was detected in 3 and complex structural variation of chromosome 21 was detected in 1. In one case of 18-trisomy high-risk fetus, the karyotype analysis results suggested that it was 21-trisomy. Among the 2 fetuses with 13-trisomy high risk, one was a chimera with chromosome structural variation, and the other was CNV. CNV of other chromosomes was detected in 3 fetuses with high SCA risk and 2 fetuses with high RCA risk. Among the 4 fetuses with high risk of CNV, 47, XYYY were detected in 1 case and other CNV abnormalities were detected in 3 cases.

Conclusions

NIPS has a high clinical value for screening common chromosomal aneuploidies such as 21-, 18-, and 13-trisomies. the positive predictive value of NIPS for screening SCA, RCA and CNV is low, but combined with prenatal ultrasound and other related examination, it can provide a basis for genetic counseling and further prenatal diagnosis.

Key words: Prenatal diagnosis, Non-invasive prenatal screening, Karyotyping, Chromosome microarray analysis, Rare chromosome aneuploidies, DNA copy number variations, Sex chromosomes, Chromosome structures, Pregnant women
表1 3组孕妇NIPS情况[例数(%)]
组别 例数 21-三体 18-三体 13-三体 SCA RCA CNV 合计
高风险组 22 852 121(0.53) 48(0.21) 35(0.15) 86(0.38) 46(0.20) 41(0.18) 377(1.65)
  血清学筛查高风险 3 271 16(0.49) 7(0.21) 9(0.28) 13(0.40) 11(0.34) 7(0.21) 63(1.93)
  高龄 17 216 101(0.59) 37(0.21) 22(0.13) 64(0.37) 32(0.19) 31(0.18) 287(1.67)
  不良孕产史/家族史 2 365 4(0.17) 4(0.17) 4(0.17) 9(0.38) 3(0.13) 3(0.13) 27(1.14)
中风险组 4 584 14(0.31) 2(0.04) 5(0.11) 23(0.50) 10(0.22) 6(0.13) 60(1.31)
  血清学筛查中度风险/临界风险 3 233 9(0.28) 1(0.03) 3(0.09) 21(0.65) 9(0.28) 6(0.19) 49(1.52)
  胎儿超声指标异常 1 351 5(0.37) 1(0.07) 2(0.15) 2(0.15) 1(0.07) 0(0) 11(0.81)
低风险组 23 539 40(0.17) 17(0.07) 23(0.10) 96(0.41) 40(0.17) 49(0.21) 265(1.13)
合计 50 975 175(0.34) 67(0.13) 63(0.12) 205(0.40) 96(0.19) 96(0.19) 702(1.38)
表2 NIPS高风险者进一步进行介入性产前诊断的检测结果
染色体异常 NIPS结果为胎儿高风险例数 介入性产前诊断结果 假阳性率(%) 敏感度(%) 特异度(%) 阳性预测值(%)
阳性 假阳性a
常见CAA 305 174 90 0.18 100.0 99.82 65.91
  21-三体 175 137 24 0.05 100.0 99.95 85.09
  18-三体 67 28 21 0.04 100.0 99.96 57.14
  13-三体 63 9 45 0.09 100.0 99.91 16.67
SCA 205 66 90 0.18 100.0 99.82 42.31
  性染色体数量减少 74 12 43 0.09 100.0 99.91 21.82
  性染色体数量增加 69 38 12 0.02 100.0 99.98 76.00
  性染色体其他异常 62 16 35 0.07 100.0 99.93 31.37
RCA 96 4 68 0.14 100.0 99.86 5.56
  1-单体 1 0 1 0.00 — 100.00 0
  2-三体 2 1 1 0.00 100.0 100.00 50.00
  3-三体 7 0 5 0.01 — 99.99 0
  4-三体 2 0 1 0.00 — 100.00 0
  5-单体 1 0 0 0.00 — 100.00 —
  5-三体 2 0 1 0.00 — 100.00 0
  6-单体 1 0 0 0.00 — 100.00 —
  7-三体 16 1 10 0.02 100.0 99.98 9.09
  8-三体 9 0 7 0.01 — 99.99 0
  9-三体 2 1 1 0.00 100.0 100.00 50.00
  10-三体 6 0 5 0.01 — 99.99 0
  11-单体 1 0 1 0.00 — 100.00 0
  11-三体 3 0 2 0.00 — 100.00 0
  12-三体 1 0 1 0.00 — 100.00 0
  14-单体 7 0 5 0.01 — 99.99 0
  14-三体 3 0 3 0.01 — 99.99 0
  15-三体 4 0 4 0.01 — 99.99 0
  16-单体 2 0 1 0.00 — 100.00 0
  16-三体 12 0 11 0.02 — 99.98 0
  17-三体 2 0 2 0.00 — 100.00 0
  20-三体 5 0 3 0.01 — 99.99 0
  22-三体 7 1 3 0.01 100.0 99.99 25.00
CNV   96 27 36 0.07 100.0 99.93 42.86
表3 16例胎儿NIPS与介入性产前诊断结果不一致
病例(No.) 年龄 孕龄 NIPS胎儿染色体核型异常 介入性产前诊断胎儿染色体核型异常 SNP芯片结果 片段大小(Mb) CNV致病性评估
1 36 16 21-三体高风险 未见数目和结构异常 arr[hg19]21q22.3(44585405-45722442)x3 1.14 临床意义不明
2 37 17+3 21-三体高风险 未见数目和结构异常 arr[hg19]7q11.23(72350815-74138121)x1 1.79 致病
3 35 15 21-三体高风险 未见数目和结构异常 arr[hg19]21q21.2(25114738-26305530)x3 1.19 临床意义不明
4 33 18 21-三体高风险 45，Xn，-21[11]/46，Xn，r(21)(p11q22)[183]/46，Xn，dic r(21；21)(p11q22；p11q22)[6] 未见染色体数目和结构异常 — 致病
5 38 18 18-三体高风险 47，XN，+21 未检测 整条 致病
6 30 18+3 13-三体高风险 45，XY，der(13，13)(q10，q10)[41]/45，XY，der(13，20)(q10，q10)[13]/46，XY[18] 未见染色体数目和结构异常 — 致病
7 26 20+5 13-三体高风险 未见数目和结构异常 arr[hg19]16p13.11(15239631-16289532)x3 1.05 可能致病
8 31 18 性染色体数目减少 未见数目和结构异常 arr[hg19]15q21.3(57080418-57495813)x1 0.42 可能致病
9 32 17+5 性染色体异常 未见数目和结构异常 arr[hg19]3q29(195738406-197409600)x1 1.67 致病
10 37 22+6 性染色体异常 46，X，Yqh- arr[hg19]1q21.1(145384225-145755813)x1 0.37 临床意义不明
11 30 17+4 3-三体高风险 未见数目和结构异常 arr[hg19]9q31.1(104939411-106639645)x1 1.70 临床意义不明
12 27 16+6 7-三体高风险 未见数目和结构异常 arr[hg19]2q13(110982530-113100014)x3 2.12 可能致病
13 35 16+5 11号染色体有重复 47，XYY 47，XYY 整条 致病
14 31 15 20号染色体有缺失 未见数目和结构异常 arr[hg19]8p23.1(9783789-10950866)x3 1.17 临床意义不明
15 24 17 16号染色体有重复 未见数目和结构异常 arr[hg19]22q11.21(21062271-21462353)x3 0.4 临床意义不明
16 27 17 16号染色体有重复 未见数目和结构异常 arr[hg19]21q21.1(19563036-20235268)x1 0.67 临床意义不明
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