Non-invasive Prenatal Diagnosis of Trisomy 21 by Dosage Ratio of Fetal Chromosome-specific Epigenetic Markers in Maternal Plasma

This study examined the methylation difference in AIRE and RASSF1A between maternal and placental DNA, and the implication of this difference in the identification of free fetal DNA in maternal plasma and in prenatal diagnosis of trisomy 21. Maternal plasma samples were collected from 388 singleton pregnancies, and placental or chorionic villus tissues from 112 of them. Methylation-specific PCR （MSP） and methylation-sensitive restriction enzyme digestion followed by fluorescent quantitative PCR （MSRE ＋ PCR） were employed to detect the maternal-fetal methylation difference in AIRE and RASSF1A. Diagnosis of trisomy 21 was established according to the ratio of fetal-specific AIRE to RASSF1A in maternal plasma. Both methods confirmed that AIRE and RASSF1A were hypomethylated in maternal blood cells but hypermethylated in placental or chorionic villus tissues. Moreover, the differential methylation for each locus could be seen during the whole pregnant period. The positive rates of fetal AIRE and RASSF1A in maternal plasma were found to be 78.1% and 82.1% by MSP and 94.8% and 96.9% by MSRE ＋ PCR. MSRE ＋ PCR was superior to MSP in the identification of fetal-specific hypermethylated sequences （P〈0.05）. Based on the data from 266 euploidy pregnancies, the 95% reference interval of the fetal AIRE/RASSF1A ratio in maternal plasma was 0.33-1.77, which was taken as the reference value for determining the numbers of fetal chromosome 21 in 102 pregnancies. The accu-racy rate in 98 euploidy pregnancies was 96.9% （95/98）. Three of the four trisomy 21 pregnancies were confirmed with this method. It was concluded that hypermethylated AIRE and RASSF1A may serve as fetal-specific markers for the identification of fetal DNA in maternal plasma and may be used for noninvasive prenatal diagnosis of trisomy 21.

Enrichment of Fetal Nucleated Red Blood Cells by Multi-core Magnetic Composite Particles for Non-invasive Prenatal Diagnosis

A novel kind of multi-core magnetic composite particles, the surfaces of which were respectively mo- dified with goat-anti-mouse IgG and antitransferrin receptor（anti-CD71）, was prepared. The fetal nucleated red blood cells（FNRBCs） in the peripheral blood of a gravida were rapidly and effectively enriched and separated by the mo- dified multi-core magnetic composite particles in an external magnetic field. The obtained FNRBCs were used for the identification of the fetal sex by means of fluorescence in situ hybridization（FISH） technique. The results demonstrate that the multi-core magnetic composite particles meet the requirements for the enrichment and speration of FNRBCs with a low concentration and the accuracy of detetion for the diagnosis of fetal sex reached to 95%. Moreover, the obtained FNRBCs were applied to the non-invasive diagnosis of Down syndrome and chromosome 3p21 was de- tected. The above facts indicate that the novel multi-core magnetic composite particles-based method is simple, relia- ble and cost-effective and has opened up vast vistas for the potential application in clinic non-invasive prenatal diag- nosis.

Non-invasive Prenatal Gene Diagnosis: Progress through Cell-free Fetal DNA and RNA in Maternal Plasma and Urine

Non-invasive prenatal gene diagnosis has been developed rapidly in the recent years, and numerous medical researchers are focusing on it. Such techniques could not only achieve prenatal diagnosis accurately, but also prevent tangential illness in fetuses and thus, reduce the incidence of diseases. Moreover, it is non-invasive prenatal gene diagnosis that prevents potential threaten and danger to both mothers and fetuses. Therefore, it is welcomed by clinical gynecologist and obstetrian, researchers of medical genetics, and especially, pregnancies. This review article touches briefly on the advanced development of using cell-free DNA, RNA in maternal plasma and urine for non-invasive prenatal gene diagnosis.

Comparison of next generation sequencing-based and methylated DNA immunoprecipitation-based approaches for fetal aneuploidy non-invasive prenatal testing

Over the past few years, many researchers have attempted to develop non-invasive prenatal testing methods in order to investigate the genetic status of the fetus. The aim is to avoid invasive procedures such as chorionic villus and amniotic fluid sampling, which result in a significant risk for pregnancy loss. The discovery of cell free fetal DNA circulating in the maternal blood has great potential for the development of non-invasive prenatal testing(NIPT) methodologies. Such strategies have been successfully applied for the determination of the fetal rhesus status and inherited monogenic disease but the field of fetal aneuploidy investigation seems to be more challenging. The main reason for this is that the maternal cell free DNA in the mother's plasma is far more abundant, and because it is identical to half of the corresponding fetal DNA. Approaches developed are mainly based on next generation sequencing(NGS) technologies and epigenetic genetic modifications, such as fetal-maternal DNA differential methylation. At present, genetic services for non-invasive fetal aneuploidy detection are offered using NGS-based approaches but, for reasons that are presented herein, they still serve as screening tests which are not readily accessed by the majority of couples. Here we discuss the limitations of both strategies for NIPT and the future potential of the methods developed.

Antenatal Noninvasive Fetal Electrocardiography:A Literature Review

Fetal heart rate(FHR)monitoring is one of the central parts of obstetric care.Ultrasound-based technologies such as cardiotocography(CTG)remain the most common method for FHR monitoring.The CTG’s limitations,including subjective interpretation,high interobserver variability,and the need for skilled professionals,led to the development of computerized CTG(cCTG).While cCTG demonstrated advantages,its superiority over visual interpretation remains inconclusive.This has prompted the exploration of alternatives like noninvasive fetal electrocardiography(NIFECG).This review explores the landscape of antenatal FHR monitoring and the need for remote FHR monitoring in a patient-centered care model.Additionally,FHR monitoring needs to evolve from the traditional approach to incorporate artificial intelligence and machine learning.The review underscores the importance of aligning fetal monitoring with modern healthcare,leveraging artificial intelligence algorithms for accurate assessments,and enhancing patient engagement.The physiology of FHR variability(FHRV)is explained emphasizing its significance in assessing fetal well-being.Other measures of FHRV and their relevance are described.It delves into the promising realm of NIFECG,detailing its history and recent technological advancements.The potential advantages of NIFECG are objective FHR assessment,beat-to-beat variability,patient comfort,remote prolonged use,and less signal loss with increased maternal body mass index.Despite its promise,challenges such as signal loss must be addressed.The clinical application of NIFECG,its correlation with cCTG measures,and ongoing technological advancements are discussed.In conclusion,this review explores the evolution of antenatal FHR monitoring,emphasizing the potential of NIFECG in providing reliable,home-based monitoring solutions.Future research directions are outlined,urging longitudinal studies and evidence generation to establish NIFECG’s role in enhancing fetal well-being assessments during pregnancy.

Imperative for improvements and international convergence of intrapartum fetal monitoring: A bird's eye view

Intrapartum fetal monitoring has been criticized for the lack of evidence of improvement in fetal outcome despite causing increased operative intervention. Paradoxically, cardiotocography （CTG） has been a major driver for litigation for neonatal neurological injury. This analytical review tries to explore why extensive clinical studies and trials over 50 years have failed to demonstrate or bring about signifcant improvement in intrapartum fetal monitoring. There seems a need for significant reform. International congruence on most aspects of CTG interpretation [defnitions of fetal heart rate （FHR） parameters, CTG recording speed, 3-tier systems, etc .] is highly desirable to facilitate future meaningful clinical studies, evaluation and progress in this field. The FHR changes are non-specific and poor surrogate for fetal well-being. As a compromise for maintaining low false-negative results for fetal acidemia, a high false-positive value may have to be accepted. The need for redefning the place of adjuvant tests of fetal well-being like fetal blood sampling or fetal electrocardiography （ECG） is discussed. The FHR decelerations are often deterministic （center-stage） in CTG interpretation and 3-tier categorization. It is discussed if their scientifc and physiological classifcation （avoiding framing and confirmation biases） may be best based on time relationship to uterine contractions alone. This may provide a more sound foundation which could improve the reliability and further evolution of 3-tier systems. Results of several trials of fetal ECG （STAN） have been inconclusive and a need for a fresh approach or strategy is considered. It is hoped that the long anticipated Computer-aided analysis of CTG will be more objective and reliable （overcome human factors） and will offer valuable support or may eventually replace visual CTG interpretation. In any case, the recording and archiving all CTGs digitally and testing cord blood gases routinely in every delivery would be highly desirable for future research. This would facilitate well designed retrospective studies which can be very informative especially when prospective randomised controlled trials are often diffcult and resource-intensive.

Non-invasive prenatal molecular detection of a fetal point mutation for congenital adrenal hyperplasia using co-amplification at lower denaturation temperature PCR

Conventional prenatal diagnosis relies on invasive chorionic biopsy or amniocentesis, which increases the risk of miscarriage, and is undertaken at 11-20 weeks gestation.1 The discovery of cell-free fetal DNA in maternal plasma has, however, offered a new strategy for non-invasive prenatal diagnosis.2 Cell-free fetal DNA in maternal plasma has been used for the determination of fetal gender3 and RHD status4 as well as testing certain monogenic diseases such as 13-thalassemia5 and cystic fibrosis.6 However,

全程胎心监护

目的 :探讨全程胎心率监护的价值。方法 :对 15 0例产妇进行全程胎心率监护 ,分析胎心率图形与羊水性状 ,新生儿出生后 1min Apgar评分及分娩方式的关系。结果 :胎心率图形 :异常组 4 2例中羊水污染 2 7例 ,正常组 10 8例中羊水污染 17例 ,有明显升高 (χ2 =8.4 7,P<0 .0 0 5 ) ;新生儿出生后 1min Apgar评分≤ 7分 :异常组 10例 ,正常组 2例 ,有明显升高 (χ2 =19.80 ,P<0 .0 0 5 ) ;分娩方式 :异常组顺产 15例 ,正常组 81例 ,两者比较有显著差异 (χ2 =2 0 .2 6 ,P<0 .0 0 5 )。结论 :全程监护有利于筛选胎儿宫内窘迫 ,便于临床掌握分娩时机与选择分娩方式。

胎儿心电图联合超声心动图检测对胎儿期前收缩判别的意义

【目的】联合应用胎儿心电图与超声心动图检测，以提高胎儿期前收缩的诊断率。【方法】通过产前胎心听诊和（或）胎心率监护筛查出胎儿心律失常的病例，将胎儿一心电图（FECG）及胎儿超声心动图（FUCG）诊断为胎儿期前收缩者纳入本研究，评价两种检测方法的一致性及其对胎儿期前收缩诊断的灵敏度和特异度。【结果】FECG发现期前收缩占胎儿心律失常36.8％，FUCG发现期前收缩占胎儿心律失常35．5％，两种检测方法的一致性为0．972；FECG联合FUCG判断室上性期前收缩的灵敏度和特异度分别为95．95％、89．17％，判断室性期前收缩灵敏度和特异度分别为93．55％、96．50％。【结论】FECG与FUCG判定胎儿期前收缩有很好的一致性；对期前收缩性质的判断，采用FECG联合FUCG检测可弥补其相互不足，提高胎儿期前收缩判断准确度。

胎心监护仪与彩色多普勒超声对胎儿窘迫的诊断效能评价

目的:分析胎儿窘迫诊断使用胎心监护仪与彩色多普勒超声诊断效能。方法:分析在医院产检并分娩的278例产妇妊娠资料,所有产妇产前均行超声检查,分娩时接受胎心监护。所有新生儿根据产后检测脐动脉血pH值分为窘迫组(pH值<7.1,125例)和正常组(pH值≥7.1,153例),比较两组孕妇胎心异常、脐动脉血流动力学情况,并以pH值<7.1为标准,评价胎心监护与超声诊断效能。结果:正常组胎心异常发生率(19.61%)显著低于窘迫组(85.60%),其差异有统计学意义(x2=119.86,P<0.05);窘迫组产妇舒张末期血流速度(EDV)和收缩期最大流速(PSV)显著低于正常组,其差异有统计学意义(t=9.94,t=5.55;P<0.05),阻力指数(RI)、搏动指数(PI)以及舒张压血流峰速比值(S/D)显著高于正常组,其差异有统计学意义(t=10.10,t=11.23,t=12.81;P<0.05)。超声诊断窘迫组宫内窘迫灵敏度、特异度、准确率高于胎心监护方式,但两种方式间诊断效能差异无统计学意义(x2=2.57,x2=0.24,x2=2.44;P>0.05);联合方式诊断窘迫组宫内窘迫灵敏度、特异度、准确率高于胎心监护和超声,其灵敏度和准确率与胎心监护和超声诊断方式之间比较差异显著(x2=14.99,x2=14.83,x2=4.85,x2=5.77;P<0.05)。结论:胎心监护仪与彩色多普勒超声从不同方面诊胎心监护超声断胎儿窘迫,两者联合诊断效能更佳。

非产时完整母胎动态心电图监测对胎儿窘迫的预测价值

目的:探讨非产时完整母胎动态心电图监测对胎儿窘迫的预测价值。方法:收集2018年1月-2019年10月本院产前检查并住院分娩的孕妇106例临床资料,根据孕妇是否具有高危因素分为高危组(n=50)与低危组(n=56),根据是否为可疑胎儿窘迫分为可疑窘迫组(n=38)与正常组(n=68)。监测并比较各组的非产时Holter参数[胎儿心率基线值(BFHR)、胎儿心率加速次数(LA)、胎儿心率短变异(STV)、胎儿心率低变异周期所占比例(PELV)、胎儿心率高变异周期所占比例(PEHV)、加速力(AC)、减速力(DC)、AC/DC]。结果:高危组与低危组的BFHR、LA、STV、PEHV、AC、DC、AC/DC值比较无差异(P>0.05),PELV高危组高于低危组(P<0.05)。可疑窘迫组与正常组的BFHR、AC、DC、AC/DC值比较无差异(P>0.05);LA、STV、PEHV可疑窘迫组低于正常组,PELV高于正常组(P<0.05)。ROC曲线分析显示,LA(AUC 0.813,95%CI 0.602~0.941)、STV(AUC 0.736,95%CI 0.518~0.893)、PELV(AUC 0.660,95%CI 0.449~0.832)、PEHV(AUC 0.660,95%CI 0.440~0.839),敏感性分别为91.7%、83.3%、84.6%、50.0%,特异性分别为75.0%、58.3%、46.2%、83.3%。Holter参数结合新生儿脐动脉血气指标预测新生儿窒息实际发生有较好的敏感性(78.6%)及特异性(96.2%)。结论:非产时完整母胎Holter监测对胎儿窘迫有一定预测价值,但与高危妊娠不良妊娠结局的关系未明确。

孕妇心电监护可穿戴装备的研究现状与发展趋势

基于非侵入型小型医疗监护可穿戴设备和围产期孕妇心电监护问题,文章介绍了目前国内外孕妇心电监护可穿戴装备的研究现状,以及现有的和正在研究开发的非侵入型孕妇心电监护装备、小型非服装类、服装类孕妇心电监护装备的最新研究进展。并针对目前孕妇心电监护服装研发过程中,传感技术的实现和服装功能性设计要求的两大难点进行了梳理和分析研究。研究表明:心电监护服装与皮肤之间的日常动态作用的关系、适应围产期孕妇腹围变化的服装可调节性、传感器稳定性、传感器位置与织物结构电路的关系,以及传感原件与服装结合的加工技术等,将成为服装类孕妇心电监护可穿戴装备发展重点及需要解决的关键问题。

1000例胎儿心电图监测分析

应用ＲＭ─６０００型多道生理记录仪经孕妇腹壁测试１０００例胎儿心电图，成功率为９１．６％。孕２１～２５周组成功率最高，为９９．２％。获得一套腹壁胎儿心电图的参数。发现异常胎儿心电图３０例，为临床提供了重要参考。胎儿心电图测试方法简便，对母儿均无任何损害，是围生期胎儿监护的一种有效方法。

Two factors affecting the success rate of the second non-invasive prenatal screening after initial no-call result: experience from a single tertiary center in China

Background:One inevitable shortcoming of non-invasive prenatal screening(NIPS)/cell-free DNA(cfDNA)sequencing is the uninterpretable(“no-call”)result,which is mainly caused by an insufficient fetal fraction.This study was performed to investigate the factors associated with a successful second NIPS in these cases and determine the optimal management for women with initial no-call results.Methods:We retrospectively analyzed the data of women who underwent NIPS with initial no-call results due to an insufficient fetal fraction from 2017 to 2019 in our center.We compared these women's maternal and pregnancy information with the data of women who had attained a successful second NIPS result and women who had received no-call results for a second time.Results:Among the 33,684 women who underwent NIPS,137 with a no-call result underwent a retest.Comparison between the 87(63.50%)women with a successful retest and the other 50(36.50%)women showed a significant difference in both the initial fetal fraction and maternal body mass index(BMI),whereas the other factors showed no significant differences.In addition,with an initial fetal fraction of<2.00%,the retest success rate was very limited.Conclusions:We identified two major factors associated with a successful NIPS retest:the initial fetal fraction and the maternal BMI.These findings suggest the need for specialized management for this subset of women and would be instructional for the counseling for these women.

Management of Cardiac Pacemakers in a Pregnant Patient

Introduction: Despite the increasing use of permanent cardiac pacemakers in a younger patient population, there are little data related to pregnancy. We present our experience in managing a pregnant patient with a pre-existing pacemaker and review the existing literature to establish management guidelines. Case: A 27-year-old G1 P0 presented for prenatal care in the first trimester of pregnancy. She had a past medical history of bradycardia, hypotension and syncope that required dual chamber cardiac pacemaker placement 6 years earlier, and one episode of left upper extremity venous thrombosis related to replacement of the pacemaker wire 4 years earlier. In the early second trimester, the patient began experiencing light-headedness and breathlessness with exertion. The rate settings of the pacemaker were increased with resolution of the patient’s symptoms. The patient underwent primary cesarean section at 39 weeks gestation with delivery of a healthy term infant. Preoperative anesthesia consultation was obtained. The postoperative course was uneventful. Pre-pregnancy pacemaker settings were re-established after the postpartum period. Discussion: The current literature on managing pregnant patients with pre-existing pacemakers is quite limited. Such patients require a multidisciplinary approach to care. Normal physiologic changes in pregnancy may necessitate rate adjustments. Other than routine thromboprophylaxis, no other anticoagulation is needed. Route of delivery is generally based on obstetric indications. During surgery consider using bipolar electrocautery in place of unipolar electrocautery, to reduce electromagnetic interference. Also, the placement of the grounding pad should be as far away from the pacemaker as possible. It should be anticipated that the patient will return to her baseline cardiac status postpartum and therefore pacemaker settings can be adjusted accordingly.

胎儿先天性长QT综合征的产前诊断进展

先天性长QT综合征是一种遗传性心脏复极障碍相关的疾病,是导致胎儿和新生儿死亡的重要原因之一。但由于胎儿心电图获取困难,长QT综合征难以产前诊断。随着技术的进步,近年来不断有研究探索提高长QT综合征产前诊断率的方法,如胎儿心磁图、无创胎儿心电图和超声心动图。本文综述这些方法产前诊断长QT综合征的研究进展。

腹电式动态胎儿监护仪的临床应用研究

目的评价腹电式动态胎儿监护仪的有效性和安全性。方法于2022年9月至2022年12月在北京大学第三医院和北京大学人民医院招募130例妊娠晚期孕妇,采用腹电式动态胎儿监护仪和传统胎心监护仪分别进行监护,比较两组胎心数据一致性、胎心监护图形临床判读结果符合率、宫缩信号的一致性、母体心率一致性数据点,以及腹电式动态胎儿监护仪与多普勒胎儿监护仪的一致性、连续性及完整性。结果130例孕妇中,因器械缺陷等因素剔除15例(11.54%,15/130)。129例全分析集(full analysis set,FAS)中,平均胎心数据一致性占比为95.18%(95%CI:94.21%~96.15%);符合方案集(per protocol set,PPS)中,平均胎心数据一致性占比为95.15%(95%CI:94.18%~96.12%)。FAS和PPS中,胎心监护图形判读符合率的平均值分别为78.26%和78.76%(95%CI:70.29%~86.23%;70.78%~86.74%);两种监护仪器械平均宫缩信号的一致性分别为80.00%vs 80.00%(95%CI:74%~87%;73%~87%);母体心率一致性占比平均分别为98.46%和98.45%(95%CI为96.73%~100.18%;96.71%~100.19%)。使用设备(3±1)d内患者无局部皮肤皮损或过敏反应等不良事件。结论与传统的多普勒胎儿监护仪比较,腹电式动态胎儿监护仪有效性高,安全可靠,可实现24 h长时间胎儿监护,可以有效判断胎儿宫内情况。

孕晚期胎心无应激试验可疑型的长程胎心监护特点

目的研究孕晚期胎心无应激试验（non-stress test，NST）可疑型的长程胎心监护的特点，为NST可疑型的处理提供更加充足的依据。方法研究对象为2014年4月至2015年10月在北京大学第三医院建档且规律产前检查，孕36~40周＋6，单胎头位，无妊娠合并症、或合并甲状腺疾病但甲状腺功能正常、妊娠期糖尿病单纯饮食控制血糖正常等的孕妇。所有研究对象均知情同意后行长程胎心监护。根据NST结果分为NST可疑型组（36例）和NST反应型组（30例）。收集年龄、终止妊娠天数、终止妊娠方式、新生儿窒息率、住院率、超声多普勒脐动脉收缩期最大血流速度与舒张末期血流速度的比值等临床资料，以及通过专门设计的软件分析获得的胎心监护所得数据。采用t检验或χ2检验进行统计学分析。结果2组孕妇年龄、终止妊娠天数、终止妊娠方式、新生儿窒息率比较，差异均无统计学意义（P值均〉0.05）。NST可疑型组胎心率基线高于NST反应型组[（138.05±5.65）与（135.10±5.39）次/min，t=－2.170，P〈0.05]；而NST可疑型组胎心率基线变异值低于NST反应型组[（5.19±1.07）与（6.28±1.15）次/min，t=3.960，P〈0.001]。与NST反应型组比较，NST可疑型组胎心率轻度变异率显著升高[（40.79±9.97）与（51.17±10.84）%]，中度变异率显著降低[（56.57±8.86）与（46.72±10.24）%]，差异均有统计学意义（t值分别为－4.018和4.133，P值均〈0.001）。NST可疑型组的平均胎心加速时长比例和平均单位时间加速面积分别为（37.41±4.60）%和（1.42±0.48） cm2/20 min，均低于NST反应型组[分别为（40.78±4.23）%和（2.03±0.67） cm2/20 min]，差异均有统计学意义（t值分别为3.079和4.359，P值均〈0.05）。结论孕晚期NST可疑型胎儿的长程胎心监护主要表现为胎心基线变异幅度下降、轻度变异率增加和单位时间加速面积减少，但妊娠结局及短期预后与NST反应型胎儿无差异。

对妊娠肝内胆汁淤积症孕妇进行胎儿监护的临床意义

目的 探讨对妊娠肝内胆汁淤积症 (ICP)孕妇进行胎儿监护的临床价值。方法 对 2 0 6例ICP孕妇进行无负荷试验 (NST)和声振刺激试验 (VAS T) ,对其中 5 1例进行宫缩应力试验 (CST)或催产素激惹试验 (OCT) ,15 7例进行超声脐动脉血流分析、12 7例进行胎儿心电图检查。结果 OCT和超声脐血流分析结果异常者的围产儿预后不良的发生率分别为 73 .3 %和 5 0 .0 % ,明显高于正常者的 2 7.8%和 3 3 .0 % ,差异有显著性 (P <0 .0 0 5和P <0 .0 5 )。NST、VAS T和胎儿心电图正常者和异常者的围产儿预后不良发生率无明显差异。结论 OCT和超声脐动脉血流分析对了解ICP孕妇胎盘功能和预测围产儿预后具有较高的临床价值 ;NST和VAS T具有操作简便、价格低廉、对母婴无任何创伤、重复性强等优点 ,可作为了解ICP孕妇胎儿宫内安危的首选监护项目 ;胎儿心电图检查在ICP孕妇伴有其他妊娠合并症时 。