UOG Journal Club: April 2019 Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review 脐动脉和胎儿大脑中动脉多普勒指数 及脑胎盘比的参考范围：系统综述 D. Oros, S. Ruiz-Martinez, E. Staines-Uria, A. Conde-Agudelo, J. Villar, E. Fabre and A. T. Papageorghiou Volume 53, Issue 4, pages 454-464 Journal Club slides prepared by Dr Fiona Brownfoot (UOG Editor for Trainees) Translated by Dr Fangfei Su and Prof. Qingqing Wu, ISUOG China Task Force

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Introduction 介绍 Doppler velocimetry is used to assess small-for-gestational-age (SGA) fetuses at risk of adverse perinatal outcome.多普勒测速应用于评估小于胎龄儿围产儿不良结局的风险。 Doppler abnormalities in the umbilical artery (UA) are related closely to placental disease whilst changes in the fetal middle cerebral artery (MCA) reflect fetal cardiovascular adaptations to hypoxia or blood flow redistribution.脐动脉多普勒异常与胎盘疾病密切相关，胎儿大脑中动脉的变化反映了胎儿心血管对缺氧或血流重新分布的适应性。 The ratio of MCA-PI to UA-PI (cerebroplacental ratio (CPR)) is an independent predictor of fetal compromise, Cesarean section and adverse perinatal outcome.大脑中动脉PI与脐动脉PI比值（脑胎盘比）是胎儿受损、剖宫产和不良围产儿结局的独立预测因子。 UA and MCA Doppler indices and CPR are currently used to modify the scheduling of antepartum surveillance and, in some cases, to time delivery of the compromised fetus.脐动脉和大脑中动脉多普勒指数和脑胎盘比，目前被用于修改产前监测的时间表，在某些情况下，决定分娩受损胎儿的时间。 References ranges for UA, MCA and CPR differ between studies.不同研究中的脐动脉、大脑中动脉和脑胎盘比的参考范围不同。 2

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Aim of the study 学习目的 To evaluate reference ranges for UA and MCA Doppler indices and CPR. Specifically, to assess the methodological quality of studies on which these are based using a set of predefined quality criteria and to estimate the clinical impact of using different reference charts. 评估脐动脉和大脑中动脉多普勒指数和脑胎盘比的参考范围。 具体而言，是使用一组预定义的质量评价标准来评估多个研究所采用的研究方法质量，及使用不同参考范围对临床的影响。 3

Methods 方法 Study design 研究设计 Study selection 研究选择 Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Methods 方法 Study design 研究设计 Systematic review.系统综述 Study selection 研究选择 Studies were identified through a search of MEDLINE, EMBASE, CINAHL and the Web of Science databases, including studies reported from 1954 to December 2016 in English or Spanish.通过搜索MEDLINE，EMBASE，CINAHL和科学数据库进行研究，包括了1954年至2016年12月的英语或西班牙语研究报告。 Included: Observational (cohort or cross-sectional) studies aimed to create reference ranges for UA and MCA Doppler indices and CPR.包括：观察研究（队列或横断面研究）旨在为脐动脉和大脑中动脉多普勒指数和脑胎盘比提供参考范围 Excluded: Case–control studies, studies in which the primary aim was not to construct Doppler reference ranges or they were limited to pregnancies < 20 or > 40 weeks’ gestation.排除：病例对照研究，因为其主要的目的不是为构建多普勒参考范围，或仅限于小于20周或大于40周的妊娠。

Methods 方法 Inclusion criteria 纳入标准 Exclusion criteria 排除标准 Outcomes 结果 Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Methods 方法 Inclusion criteria 纳入标准 Made clear that women at high risk of pregnancy complications were not included and that women with abnormal outcome were excluded, i.e. an effort was made to include as normal an outcome as possible.很明确不包括有妊娠并发症的高风险女性，并排除有异常结局的女性，尽可能将正常结果纳入范围。 Exclusion criteria 排除标准 Multiple pregnancy; fetuses with congenital, structural or chromosomal anomaly; fetal death/stillbirth; women with disorders that may affect fetal growth or Doppler (at least should specify exclusion of women with pre-existing hypertension, diabetes mellitus, renal disease and smokers); pregnancy complications (at least pre-eclampsia, SGA/IUGR, prematurity, diabetes mellitus); delivery prior to 37 weeks. 多胎妊娠；先天性、结构性或染色体异常的胎儿；胎儿死亡或死产；有可能影响胎儿生长或多普勒的妇女（至少应明确排除有高血压、糖尿病、肾病和吸烟者）；妊娠并发症（至少包括先兆子痫、小于胎龄儿/宫内生长受限、早产、糖尿病）；37周前分娩。 Outcomes 结果 To evaluate reference ranges for UA and MCA Doppler indices and CPR. 评估脐动脉和大脑中动脉多普勒指数和脑胎盘比的参考范围 To assess the methodological quality of studies on which these are based. 评估这些所依据的方法学研究质控。

Methods 方法 Methodological quality assessment 方法学质量评估 Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Methods 方法 Methodological quality assessment 方法学质量评估 The methodological quality of the full-text versions of eligible studies was assessed independently by the same reviewers and a medical statistician 合格研究的全文方法学质控由同一审稿人和一名医学统计学家独立评估 A list of methodological quality criteria (next 2 slides) was initially developed by one of the authors, modified for use in the setting of Doppler, and agreed by the team not involved in data extraction. 一位作者最初制定了一份方法学质量标准列表（接下来的2页），对其进行了修改以用于设置多普勒，并得到了不参与数据提取团队的同意。 Every study was assessed against each of the criteria within the checklist and was scored as either 0 or 1 if there was a high or low risk of bias, respectively. The overall quality score was defined as the sum of low risk of bias marks, with the range of possible scores being 0 – 24. 每项研究都根据检查表中的每个标准进行评估，如果存在高或低的偏倚风险，则分别得分为0或1.总体质量分数定义为偏倚分数低风险的总和，可能的分数范围是0-24. Multiple regression analysis were performed to assess the association between quality score and study characteristics that were not part of the scoring algorithm.进行多元回归分析以评估质量评分与不属于评分算法的研究特征之间的相关性。

Methods – Risk of bias due to study design 方法-研究设计可能的偏倚风险 Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Methods – Risk of bias due to study design 方法-研究设计可能的偏倚风险 Domain 范围 Low risk of bias 低偏倚风险 High risk of bias 高偏倚风险 Study design 研究设计 Clearly described as either cross-sectional or longitudinal 清楚地描述为横断面或纵向研究 Not reported 未报告 Mixture of cross-sectional and longitudinal data 横断面和纵向研究的混合数据 Population 人群 Women reported as coming from population of low risk of pregnancy complications 女性来自妊娠并发症风险低的人群 Women from unselected population; or selected; or at high risk of pregnancy complications女性来自随意选择的人群；或经选择的；或有妊娠并发症高风险的人群 Prospective data collection 前瞻性数据收集 Prospective study and ultrasound data collected specifically for purpose of constructing charts of fetal Doppler 前瞻性研究和超声数据收集专门用于构建胎儿多普勒图表 Retrospective study, data not collected specifically for purpose of constructing charts of fetal Doppler, or unclear (e.g. use of routinely collected data) 回顾性研究，未专门收集用于构建胎儿多普勒图标的数据或数据不清（例如使用常规收集的数据） Specific scan 特殊扫查 Specific scan for research purposes用于研究目的特殊扫查 Routine scan in context of pregnancy assessment 妊娠评估中的常规扫查 Sample size 样本量 A-priori determination or calculation of sample size and justification 先验确定或计算样本量和理由 Lack of a-priori sample size determination or calculation and justification 缺乏先验样本量的确定或计算和理由 Recruitment period 招募周期 Reported 有报告 Not reported 无报告 Consecutive enrolment 连续入组 Consecutively included patients 连续纳入患者 Did not include patients consecutively 不连续纳入患者 Inclusion/exclusion criteria 纳入/排除标准 Made clear that women at high risk of pregnancy complications were not included and that women with abnormal outcome were excluded, 明确不包括有妊娠并发症高风险的女性，排除有异常结果的女性 Study population included both low- and high-risk pregnancies研究人群包括低风险和高风险妊娠 Method of dating pregnancy 妊娠日期测定方法 Clearly described known LMP and sonogram before 14 weeks’ gestation 孕14周前清楚描述末次月经和超声图像 Not described clearly未清楚描述 Multicenter study 多中心研究 Study performed with more than one center collaborating 多中心合作研究 Performed at only one hospital 仅单中心研究

Methods – Risk of bias due to reporting and statistical methods研究方法——报告和统计方法导致的偏倚风险 Domain Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Domain范围 Low risk of bias低偏倚风险 High risk of bias高偏倚风险 Perinatal outcome 围生结局 Collected and reported prospectively 前瞻性收集和报告 Not reported 未报告 Gestational age range胎龄范围 Reported已报告 Ultrasound machines and probe type used 使用的超声机和探头型号 Clearly specified 明确规定 Not clearly specified 未明确规定 Reported sonographers 报告的超声医师 Number of sonographers reported 报告超声医师的数量 Sonographer experience 超声工作经验 Experienced or specifically trained sonographers clearly reported 明确报告了有经验或受过专门训练的超声医师 Blinded measurements 盲法 Sonographers were blinded 超声医师盲法 Ultrasound quality control measures 超声质控措施 Should include the following: assessment of intraobserver variability; assessment of interobserver variability; image review; image scoring; image storage 应包括以下内容：对观察者自身差异的评估；观察者间差异的评估；图像回顾；图像评分；图像存储 Does not contain quality control measures 不包含质控措施 Protocol 研究计划 Study described sufficient and unambiguous details of measurement techniques used for fetal Doppler parameters 研究充分且明确的描述了用于胎儿多普勒参数测量的细节 Not described sufficiently and unambiguous details of measurement未充分和明确描述测量细节 Number of measurements taken for each Doppler variable 每个多普勒变量的测量次数 At least three measures per fetus per scan 对此扫查至少对胎儿进行三次测量 Single measure or not specified 一次测量或未规定 Angle correction 角度校正 Not clearly specified 为明确规定 Statistical methods 统计学方法 Clearly described and identified 明确描述和确定 Not clearly described and identified未明确描述和确定 Report of mean and SD of each measurement and sample size for each week of gestation 报告各孕周每个测量的平均值，标准差和样本量 Presented in a table or clearly described 在表格中展现或清楚描述 Not presented in a table or not clearly described 未在表格中呈现或清楚描述 Report of regression equations for mean (and SD if relevant) for each measurement 每次测量的平均值回归方程报告（如相关，还有标准差） Reported 已报告 Scatter diagram 散点图 Study included Doppler chart with mean and SD or centiles (at least 5th, 50th and 95th centiles) 研究包括平均值和标准差或百分位数的多普勒图标（至少第5.50和95百分位数） Doppler charts not included 未包含多普勒图表

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Results结果 引用回顾n=2902 标题/摘要筛选后排除 先兆子痫 宫内生长受限 结果预测 除脐动脉或大脑中动脉之外的血管 心功能研究 英语或西班牙语外的其他语言 妊娠期用药研究 研究母体指征 多普勒在胎儿畸形时的应用 双胎 胎盘研究 其他 A total of 38 studies from 22 countries met the inclusion criteria and were included in the final analysis. 共有来自22个国家的38个研究符合纳入标准，并进行最后分析 The median sample size of participating women was 206 (range, 13–2323; interquartile range (IQR), 70.75–675.25).参与女性的样本量中位数为206（范围13-2323；四分位数间距70.75–675.25） The median number of ultrasound examinations was 400 (range, 60–2323; IQR, 183.5–952). 超声检查的中位数为400（范围60-2323；四分位数间距183.5–952） The earliest included study was published in 1987 and the latest in 2016.最早的研究发表于1987年，最晚的发表于2016年。 *** The baseline characteristics table is now in the supp file which I don’t have access to. 检索出版物 全文评估后排除 综述中包含的研究

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Results结果 Data collection was prospective in 34 studies, but in only 19 studies was data collection explicitly for research purposes. 有34项研究是前瞻性收集数据，但只有19项研究明确数据收集用于研究目的。 Low-risk pregnancies were included in 22 (57.9%) studies. 有22项研究（57.9%）包含了低风险妊娠 Dopplers reported:多普勒报告 -UA and MCA Doppler reference ranges were reported in 30 and 19 studies, respectively. 脐动脉和大脑中动脉多普勒参考范围分别在30和19项研究中提出 -11 studies reported reference ranges for both UA and MCA. 有11项研究同时包含了脐动脉和大脑中动脉参考范围 -4 studies reported reference ranges for CPR.有4项研究包含了脑胎盘比参考范围 -PI was reported in 31 studies. 31项研究报道了搏动指数PI -Resistance index in 22 studies. 22项研究报道了阻力指数RI -Systolic-diastolic ratio in 21 studies. 21项研究包含了收缩舒张比 An equation for the mean and SD was reported in 23 of 38 studies, whereas printed charts of the median and centile curves were seen in 25 publications. 38项中的23项研究报道了平均值和标准差的方程，而在25篇文章中有中位数表和百分位数曲线图

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Results 结果 Overall mean quality score for the included studies was 51.4% (95% CI, 47.1–55.8%). 纳入研究的总体平均质量评分为51.4%（95%可信区间，47.1-55.8%） Quality scores for study design and statistical and reporting methods were 47.4% (95% CI, 42.6–52.1%) and 54.3% (95% CI, 48.8–59.7%), respectively. 研究设计、统计和报告方法的质量评分分别为47.4%（95%CI，42.6-52.1%）和54.3%（95%CI，48.8-59.7%） The overall methodology score was similar for the studies focused on:对于所关注的研究，总体方法学评分相似 -UA (median, 49.0%; range, 20.8 – 70.8%), 脐动脉（中位数，49.0%；范围，20.8-70.8%） -MCA (median, 55.0%; range, 29.1 – 79.1%), 大脑中动脉（中位数，55.0%；范围，29.1-79.1%） -CPR (median, 54.1%; range, 41.6–62.5%).脑胎盘比（中位数，54.1%；范围，41.6-62.5%） Year of publication (P = 0.506), sample size of participating women (P = 0.119), ultrasound examinations (P=0.215), study duration (P=0.251), teaching hospital (P=0.395), number of participating sites (P = 0.278) or number of sonographers (P = 0.447) were not significant predictors of quality score on univariate or multiple regression analysis.发表年份(P = 0.506)，受试女性样本量(P = 0.119)，超声检查(P=0.215)，研究持续时间 (P=0.251), 教学医院(P=0.395),参与单位数(P = 0.278)或超声医师人数 (P = 0.447)不是单因素或多元回归分析质量得分的重要预测因子

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Results 结果 Despite high methodological quality, all studies reported quite variable reference ranges. 尽管方法学质量很高，但所有研究都报道了相当多的参考范围 大脑中动脉-PI 脐动脉-PI 脑胎盘比 孕周

Study limitations研究局限性 Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Discussion讨论 There is considerable heterogeneity in the methodological quality of ultrasound studies aimed at creating reference ranges for UA and MCA Doppler indices and CPR.超声研究 的方法学质量存在相当大的异质性，旨在为脐动脉和大脑中动脉多普勒指数和脑胎盘比建立参考范围 These differences may at least partly explain the differences in reported reference ranges and these may in turn explain some of the discrepancies seen in perinatal research based on Doppler.这些差异至少可以部分解释报告参考范围的差异，而这些差异又可以解释基于 多普勒围产儿研究中发现的一些差异 Even when assessing only those studies with the highest scores of methodological quality, clinical cut-offs varied significantly and could lead to important differences in clinical management, demonstrating that about 40–50% of fetuses may be misclassified by using one chart rather than another. 即使仅评估那些方法学得分最高的研究，临床 临界值也存在显著差异，并可能导致临床管理方面的重要差异，这表明大约40-50%胎儿可能因使用一张图表而不是 另一张而被错误分类。 Study limitations研究局限性 Inclusion of studies published in only the English or Spanish language; it is possible that biological variations might account for differences in Doppler results.仅包括以英语或 西班牙语发表的研究，可以用生物多样性解释多普勒结果的差异。 13

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Conclusion结论 This systematic review has identified many ultrasound studies with poor methodology and reporting of reference ranges for UA and MCA Doppler indices and CPR. 本系统综述已经确定了许多超声研究的方法学较差，并且报道了脐动脉和大脑中动脉多普勒指数和脑胎盘比的参考范围。 These should be taken into account in future studies and we recommend using a checklist of methodological good practices in further studies aimed at creating reference ranges for UA and MCA Doppler parameters and CPR. 在未来的研究中应考虑这些因素，我们建议在进一步研究中使用方法学较好的检查表，目的是为了建立脐动脉和大脑中动脉多普勒参数和脑胎盘比的参考范围。 Our aim was to recommend reference ranges for use in clinical services based on the lowest risk of methodological bias, however, even among these studies there are differences of clinical importance with what is considered normal and what is not; urgent research is needed to reach consensus on this issue or create charts of optimal quality for widespread use. 我们的目的是根据方法学偏倚的最低风险推荐用于临床的参考值范围，然而，即使在这些研究中，在临床重要性上，哪些正常哪些不正常存在差异；现在迫切需要研究的是就这一问题达成一致，或制定最佳质量的图表供广泛使用

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review Oros et al., UOG 2019 Discussion points 讨论点 Given the large variability between studies, perhaps Doppler indices change depending on the population.鉴于研究之间存在较大差异，多普勒指数可能会随着人群的变化而变化 It would be interesting to see whether the different Doppler ranges result in differences in the clinical outcome of the pregnancies. 不同多普勒范围是否会导致妊娠临床结果的差异将是件有趣的事 Do fetal growth differences e.g. macrosomia change the Doppler range?胎儿生长差异，如巨大儿，是否会导致多普勒范围改变呢？ 15