无创产前DNA检测技术在筛查妊娠双胎染色体异常中的应用研究

Application of noninvasive prenatal genetic testing in screening for chromosome abnormalities in pregnant twins

目的探究并分析无创产前DNA检测技术在筛查妊娠双胎染色体异常中的应用价值。方法选取2022年12月—2023年12月期间在周口市妇幼保健院接受无创产前DNA检测技术筛查的双胎妊娠孕妇200例作为此次研究对象,抽取研究对象外周血液样本并进行前瞻性研究,对研究对象的无创产前DNA检测检测结果提示为低风险的197例妊娠双胎孕妇进行随访,记录年龄、孕周以及绒毛膜性、妊娠方式及无创产前DNA检测结果、临床核型、分娩方式、妊娠结局、检测结果、T21高风险病例及不适用人群。结果(1)无创产前DNA检测结果显示妊娠双胎染色体异常的有3例,21-三体高风险(T21)、18-三体高风险(T18)和微缺失各1例,且3例阳性检出者均接受了羊水穿刺,穿刺结果显示有1例为真阳性,染色体异常类型为微缺失,其余2例为假阳性。研究后,无创产前DNA检测筛查妊娠双胎染色体异常的联合阳性预测值(PPV)为33.33%(1/3)。(2)在无创产前DNA检测筛查中,微缺失的联合阳性预测值为100%(1/1)。(3)随访结果分析:显示双胎妊娠染色体异常阳性的孕妇选择减胎手术,另2例经证实为假阳性的孕妇未做其他干预,足月妊娠后分娩,且娩出的新生儿表型均无异常。对无创产前DNA检测结果提示为低风险的197例妊娠双胎孕妇进行随访。结果显示:分娩正常表型双胞胎的足月妊娠孕妇189例,占比95.94%(189/197);不良妊娠结局:2例早产,2例低体重儿,1例脐疝,1例多囊肾,共6例,占比3.05%(6/197),但未有智力障碍、染色体异常容貌等不良妊娠结局;另2例流产,占比1.02%(2/197)。(4)分析无创产前DNA检测假阳性结果的原因:相关研究表明,导致此技术在妊娠双胎染色体异常筛查时出现假阳性的主要原因包括母体肿瘤、染色体拷贝数变异以及限制性胎盘嵌合等。(5)21-三体高风险(T21)、18-三体高风险(T18)和13-三体高风险各1例,通过染色体核型检查过后显示双胎之一为T21;剩余197例孕妇检测结果呈低风险,且染色体核型均未发生异常表现,经无创产前DNA检测结果分析:ART阳性率为3.16,假阳性率为1.05,其敏感度为100%,特异度为99%,检出率100%;血清学筛查(1∶1000~1∶270)阳性率为1.10%,敏感度、特异度、检出率均为100%;年龄≥35岁阳性率为7.69,敏感度、特异度、检出率均为100%。无漏诊病例,T18、T13暂未出现阳性病例,T21均正确识别检测。因此,若无创产前DNA检测的筛查结果与羊水穿刺结果不一致时,还需要医务工作者对孕妇及家属做好安抚和解释工作,还应结合其他检测结果合理引导染色体异常高风险孕妇进行羊水穿刺检验,以便进一步明确有无异常。结论作为一种筛查技术,无创产前DNA检测在妊娠双胎染色体异常时的阳性预测值有限,筛查的效果不够理想,在妊娠双胎染色体异常筛查中还需慎重选择此技术。

Objective To explore and analyze the application value of noninvasive prenatal genetic testing technology in screening for chromosome abnormalities in pregnant twins.Methods From December 2022 to December 2023,200 pregnant women with twin pregnancies who received non-invasive prenatal genetic testing screening in our hospital were selected as subjects of this study.Peripheral blood samples of the subjects were collected and prospective studies were conducted.Age,gestational age,chorionic sex,pregnancy mode and non-invasive prenatal genetic test results,clinical karyotype,delivery mode and pregnancy outcome were recorded and analyzed.Results(1)The results of noninvasive prenatal genetic testing showed that there were 3 cases of chromosome abnormality in pregnancy twins,1 case of trisomy 21-high risk(T21),1 case of trisomy 18-high risk(T18)and 1 case of microdeletion each.The 3 cases of positive detection received amniotic fluid puncture,and the puncture results confirmed that 1 case was true positive,the type of chromosomal abnormality was microdeletion,and the other 2 cases were confirmed as false positive.It was calculated that the combined positive predictive value(PPV)of noninvasive prenatal genetic testing to screen for chromosome abnormalities in pregnancy twins was 33.33%(1/3).(2)The combined positive predictive value of non-invasive prenatal genetic testing screening for microdeletions was 100%(1/1).(3)Analysis of follow-up results:the pregnant women who were confirmed to be true positive for chromosome abnormality in twin pregnancy chose reduction surgery after communication,and the two pregnant women who were confirmed to be false positive did not do other intervention,and gave birth after full-term pregnancy,and the newborn phenotype was not abnormal.A total of 189 pregnant women,95.94%(189/197),with full-term pregnancy and delivery of twins with obvious normal phenotype were followed up for 197 pregnant women with low risk due to non-invasive prenatal genetic testing results.There were 6 cases of adverse pregnancy outcomes,accounting for 3.05%(6/197),but none of the 6 cases of adverse pregnancy outcomes showed any characteristic intellectual impairment or chromosomal abnormalities(details of adverse pregnancy outcomes:2 premature births,2 low birth weight infants,1 umbilical hernia,1 polycystic kidney).There were also 2 cases of abortion,accounting for 1.02%(2/197).(4)Analysis of the causes of false positive results of noninvasive prenatal genetic testing:relevant studies have shown that the main causes of false positive results in the screening of pregnant twins with this technology include maternal tumors,chromosome copy number variation and restrictive placental mosaism.(5)One case of trisomy 21-high risk(T21),one case of trisomy 18-high risk(T18)and one case of trisomy 13-high risk,and one of the twins was T21 after chromosome karyotype examination;The remaining 197 pregnant women showed low risk and no abnormal karyotype.The results of non-invasive prenatal genetic testing showed that the positive rate of ART was 3.16,the false positive rate was 1.05,the sensitivity was 100%,the specificity was 99% and the detection rate was 100%.Serological screening(1∶1000~1∶270)positive rate was 1.10%,sensitivity,specificity and detection rate were 100%;The positive rate of age≥35 years old was 7.69,and the sensitivity,specificity and detection rate were 100%.There were no missed cases,no positive cases in T18 and T13,and T21 were correctly identified and tested.Therefore,if the screening results of non-invasive prenatal genetic testing are inconsistent with the results of amniocentesis,medical workers should also do a good job of pacification and explanation for pregnant women and their families,and it should also be combined with other test results to reasonably guide pregnant women at high risk of chromosome abnormalities to perform amniocentesis to further clarify whether there are abnormalities.Conclusion As a screening technique,the positive predictive value of noninvasive prenatal genetic testing in pregnant twins with chromosome abnormalities is limited,and the screening effect is not ideal,and this technique should be carefully selected in the screening of pregnant twins with chromosome abnormalities.