母体自身免疫性疾病及应用抗凝药物对血浆游离DNA胎儿分数的影响

Influence of maternal autoimmune diseases and anticoagulants on fetal fraction of maternal plasma cell-free DNA

目的探讨母体自身免疫性疾病和使用抗凝药物对无创产前检测(non-invasive prenatal testing,NIPT)中母血浆游离DNA胎儿分数的影响。方法以2021年3月至2022年7月在南京大学医学院附属鼓楼医院行NIPT的单胎妊娠孕妇建立前瞻性队列,应用不需要聚合酶链反应扩增的平台开展NIPT检测。母体自身免疫性疾病包括抗磷脂综合征、未分化结缔组织病、干燥综合征和系统性红斑狼疮(systemic lupus erythematosus,SLE);抗凝药物包括低分子量肝素(low-molecular-weight heparin,LMWH)及阿司匹林。采用单因素线性回归和多因素线性回归分析NIPT胎儿分数的影响因素。结果进入队列4102例单胎妊娠孕妇,排除使用LMWH或阿司匹林时间不明确、其他自身免疫性疾病、单纯促排卵受孕、NIPT结果真阳性及最终检测失败的病例后,余3948例纳入分析。其中96例合并抗磷脂综合征,35例合并未分化结缔组织病,34例合并干燥综合征,18例合并SLE;108例仅使用LMWH,121例仅使用阿司匹林,113例同时使用LMWH和阿司匹林。单因素回归分析显示,孕妇NIPT采血时体重指数(B=-0.423)、辅助生殖技术受孕(B=-0.803)、男胎(B=-0.458)、合并未分化结缔组织病(B=1.774)和SLE(B=3.467)对胎儿分数有影响(P值均<0.05)。多因素线性回归分析发现NIPT采血时体重指数(B=-0.415),辅助生殖技术受孕(B=-0.585)、男胎(B=-0.322)、合并SLE(B=3.347)及未分化结缔组织病(B=1.336)均对胎儿分数有影响(P值均<0.05)。结论应用不需要聚合酶链反应扩增的平台开展NIPT检测时,孕妇使用LMWH和/或阿司匹林对NIPT中母血浆游离DNA胎儿分数无影响;NIPT中母血浆游离DNA胎儿分数受母体自身免疫性疾病中未分化结缔组织病及SLE的影响。NIPT前咨询时应告知孕妇可能因合并的自身免疫性疾病影响母血浆中游离DNA胎儿分数而影响检测结果。

Objective To investigate the influence of maternal autoimmune diseases and anticoagulants,including low-molecular-weight heparin(LMWH)and aspirin,on the fetal fraction of maternal plasma cell-free DNA of non-invasive prenatal testing(NIPT).Methods A prospective cohort study was conducted on women with singleton pregnancies receiving NIPT in the Nanjing Drum Tower Hospital from March 2021 to July 2022.NIPT was carried out using a polymerase chain reaction(PCR)-free amplification platform.In this study,four types of maternal autoimmune diseases,which were antiphospholipid syndrome,undifferentiated connective tissue disease,Sjögren's syndrome,and systemic lupus erythematosus(SLE),and two anticoagulants,LMWH and aspirin,were studied.Univariate and multivariate linear regression models were used to analyze the factors influencing fetal fraction of maternal plasma cell-free DNA.Results A total of 4102 singleton pregnant women were enrolled in the prospective cohort,and 3948 were finally included after excluding the cases with unclear dosing time of LMWH or aspirin,other autoimmune diseases,conceiving through ovulation induction alone,and having true positive or failed NIPT result.There were 96 cases with antiphospholipid syndrome,35 with undifferentiated connective tissue disease,34 with Sjögren's syndrome,and 18 with SLE.A total of 108 patients only received LMWH treatment,121 only received aspirin treatment,and 113 received both LMWH and aspirin treatment.Univariate linear regression analysis showed that maternal body mass index at blood collection(B=-0.423),conceived by assisted reproductive technology(B=-0.803),male fetus(B=-0.458),undifferentiated connective tissue disease(B=1.774),and SLE(B=3.467)had influence on the fetal fraction(all P<0.05).Multivariate linear regression analysis showed that maternal body mass index at blood collection(B=-0.415),conceived by assisted reproductive technology(B=-0.585),male fetus(B=-0.322),SLE(B=3.347)and undifferentiated connective tissue disease(B=1.336)were factors influencing fetal fraction(all P<0.05).Conclusions Maternal use of LMWH or aspirin does not affect fetal fraction when performing NIPT on a PCR-free amplification platform,but undifferentiated connective tissue disease and SLE are the influencing factors.Therefore,pregnant women should be informed before the NIPT that the fetal fraction of maternal plasma cell-free DNA may be affected by maternal autoimmune diseases.