子痫前期是妊娠期特有的疾病，可引起多脏器损伤，是孕产妇死亡的主要原因之一[1]。子痫前期患者由于子宫胎盘血管痉挛及胎盘功能障碍，导致脐血流循环不良，严重时可发生脐动脉舒张末期血流缺失或反流（absent or reversed end-diastolic velocity，AREDV）[2]。孕妇发生AREDV与围产儿不良结局密切相关，应尽快终止妊娠。但是在临床工作中，尤其是早发型子痫前期患者出现AREDV时孕周较小，立即终止妊娠将面临早产儿相关风险，继续期待治疗则面临胎儿发生宫内窘迫甚至胎死宫内等风险。本研究通过回顾性分析早发型子痫前期患者的临床资料，分析其发生AREDV的影响因素及围产儿结局，旨在为临床诊疗工作提供依据。
1 对象与方法
1.1 研究对象
纳入2017年1月—2021年9月在西北妇女儿童医院妇产科重症监护室住院的早发型子痫前期单胎孕妇共416例。纳入标准：单胎孕妇；早发型子痫前期孕妇。排除标准：既往有慢性高血压、肝肾功能损伤及心脑血管疾病等基础病者；多胎妊娠者。根据分娩前是否发生AREDV分为AREDV组（58例）和非AREDV组（358例）。参照中华医学会妇产科学分会2020版《妊娠期高血压疾病诊治指南》进行子痫前期的诊断，以在妊娠34周前因子痫前期终止妊娠者定义为早发型子痫前期[3]。
1.2 资料收集
收集患者年龄、子痫前期诊断孕周、入院时收缩压、入院时舒张压、妊娠期增重及分娩前血常规、肝肾功能和24 h尿蛋白定量等孕妇临床资料，以及围产儿结局资料。
1.3 统计学方法
采用SPSS 27.0软件进行统计学分析。符合正态分布的定量资料用均数±标准差（$\bar{x}±s$）表示，组间比较采用t检验；非正态分布的定量资料用中位数和四分位数[M（P25，P75）]表示，组间比较采用Mann-Whitney U检验；定性资料用例数（百分比）表示，组间比较采用卡方检验。应用二分类Logistic回归分析早发型子痫前期孕妇发生AREDV的影响因素。P<0.05为差异有统计学意义。
2 结果
2.1 2组孕妇临床资料比较
2组孕妇子痫前期诊断孕周、血红蛋白水平、血小板分布宽度和丙氨酸转氨酶比较，差异有统计学意义（均P<0.05）；2组年龄、入院收缩压和舒张压、妊娠期增重、白细胞计数、中性粒细胞计数、淋巴细胞计数、血小板计数、血清白蛋白、天冬氨酸转氨酶、尿素氮、肌酐、尿酸和24 h尿蛋白定量比较，差异无统计学意义（均P>0.05）。见表1。
表1 2组孕妇临床资料比较
| 组别 | n | 年龄 （岁） | 诊断孕周（周） | 入院收缩压 （mmHg） | 入院舒张压 （mmHg） | 妊娠期增重 （kg） | 白细胞计数 （×109/L） | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| <28 | 28~29+6 | 30~31+6 | 32~33+6 | |||||||||||||||||||
| 非AREDV组 | 358 | 31.48±4.42 | 75（20.95） | 69（19.27） | 114（31.84） | 100（27.93） | 157.41±19.36 | 102.45±12.03 | 14（10，18） | 9.86±3.23 | ||||||||||||
| AREDV组 | 58 | 30.74±4.46 | 25（43.10） | 18（31.03） | 11（18.97） | 4（6.90） | 156.29±19.48 | 102.62±11.40 | 12（8，16） | 10.54±4.31 | ||||||||||||
| t或Z或χ2 | 1.185 | 25.082 | 0.409 | -0.101 | -1.839 | -1.133 | ||||||||||||||||
| P | 0.237 | <0.001 | 0.683 | 0.920 | 0.066 | 0.261 | ||||||||||||||||
| 组别 | n | 中性粒细胞计数 （×109/L） | 淋巴细胞计数 （×109/L） | 血小板计数 （×109/L） | 血红蛋白（g/L）* | 血小板分布 宽度（%） | 血清白蛋白 （g/L） | |||||||||||||||
| <110 | 110~134 | ≥135 | ||||||||||||||||||||
| 非AREDV组 | 358 | 7.32±4.60 | 2.01±0.89 | 158.32±60.33 | 83（23.31） | 213（59.83） | 60（16.85） | 15.60±3.39 | 27.05±3.87 | |||||||||||||
| AREDV组 | 58 | 6.92±2.98 | 2.02±0.85 | 166.02±59.26 | 8（14.04） | 32（56.14） | 17（29.82） | 14.36±2.85 | 27.25±5.00 | |||||||||||||
| t或Z或χ2 | 0.653 | -0.086 | -0.897 | 6.467 | 2.556 | -0.281 | ||||||||||||||||
| P | 0.514 | 0.931 | 0.370 | 0.039 | 0.011 | 0.779 | ||||||||||||||||
| 组别 | n | 丙氨酸转氨酶 （U/L） | 天冬氨酸转氨酶 （U/L） | 尿素氮 （mmol/L） | 肌酐 （μmol/L） | 尿酸 （μmol/L） | 24 h尿蛋白定量 （mg） | |||||||||||||||
| 非AREDV组 | 358 | 18.20（11.91，31.24） | 26.10（20.00，40.61） | 5.91±4.34 | 68.07±47.87 | 440.90±113.25 | 4 383.20（1 726.59，7 092.82） | |||||||||||||||
| AREDV组 | 58 | 22.78（15.67，36.42） | 29.27（22.17，38.88） | 5.70±2.53 | 63.08±17.11 | 452.78±97.24 | 4 302.52（1 530.68，7 775.65） | |||||||||||||||
| t或Z或χ2 | -2.240 | -1.482 | 0.353 | 0.777 | -0.746 | -0.218 | ||||||||||||||||
| P | 0.025 | 0.138 | 0.725 | 0.438 | 0.456 | 0.829 | ||||||||||||||||
注：* 非AREDV组2例数据缺失，AREDV组1例数据缺失。诊断孕周和血红蛋白用例数（%）表示，妊娠期增重、丙氨酸转氨酶、天冬氨酸转氨酶、24 h尿蛋白定量用M（P25，P75）表示，其余指标用$\bar{x}±s$表示。1 mmHg=0.133 kPa。
2.2 早发型子痫前期孕妇发生AREDV的影响因素分析
以是否发生AREDV为因变量（否=0，是=1），将子痫前期诊断孕周、血红蛋白水平、丙氨酸转氨酶和血小板分布宽度作为自变量进行多因素Logistic回归分析。对年龄进行校正后，结果显示，子痫前期诊断孕周和血红蛋白水平与AREDV的发生相关。诊断子痫前期孕周越早，发生AREDV的风险越高，诊断孕周为28~29+6周的患者发生AREDV的风险是32~33+6周诊断者的6.532倍（95%CI：2.033~20.985，P=0.002），诊断孕周<28周者发生AREDV的风险是32~33+6周诊断者的8.244倍（95%CI：2.631~25.832，P<0.001）。血红蛋白水平升高增加AREDV的发生风险，血红蛋白≥135 g/L的早发型子痫前期患者发生AREDV的风险是血红蛋白正常者（110~134 g/L）的2.438倍（95%CI：1.173~5.065，P=0.017）。见表2。
表2 Logistic回归分析结果
| 变量 | 赋值 | β | SE | Wald χ2 | P | OR | 95%CI |
|---|---|---|---|---|---|---|---|
| 诊断孕周（周） | |||||||
| <28 | 1 | 2.110 | 0.583 | 13.106 | <0.001 | 8.244 | 2.631~25.832 |
| 28~29+6 | 2 | 1.877 | 0.595 | 9.934 | 0.002 | 6.532 | 2.033~20.985 |
| 30~31+6 | 3 | 0.810 | 0.617 | 1.722 | 0.189 | 2.248 | 0.670~7.536 |
| 血红蛋白（g/L） | |||||||
| <110 | 1 | -0.397 | 0.460 | 0.745 | 0.388 | 0.672 | 0.273~1.656 |
| ≥135 | 2 | 0.891 | 0.373 | 5.702 | 0.017 | 2.438 | 1.173~5.065 |
| 丙氨酸转氨酶（U/L） | 连续型变量 | -0.003 | 0.003 | 1.194 | 0.274 | 0.997 | 0.991~1.002 |
| 血小板分布宽度（%） | 连续型变量 | -0.088 | 0.050 | 3.062 | 0.080 | 0.916 | 0.830~1.011 |
注：诊断孕周和血红蛋白的参照组分别为32~33+6周和110~134 g/L，赋值均为0。
2.3 2组围产儿结局比较
AREDV组胎死宫内发生率和引产率高于非AREDV组（均P<0.001）；2组选择引产的孕妇终止妊娠孕周和胎儿体质量比较差异无统计学意义（均P>0.05）。AREDV组中选择引产的孕妇终止妊娠孕周低于选择救治的孕妇终止妊娠孕周（t=2.116，P=0.039）；AREDV组引产胎儿体质量和积极救治的新生儿出生体质量比较差异无统计学意义（t=0.505，P=0.616）。见表3。
表3 2组围产儿结局比较
| 组别 | n | 胎死宫内 发生率 | 引产 | 救治 | |||||
|---|---|---|---|---|---|---|---|---|---|
| 引产率 | 终止妊娠孕周 （周） | 胎儿体质量 （g） | 1 min Apgar 评分（分） | 新生儿出生 体质量（g） | 终止妊娠 孕周（周） | 新生儿窒息 发生率 | |||
| 非AREDV组 | 358 | 1.96（7/358） | 11.17（40/358） | 27.73±2.56 | 829.25±303.84 | 9.08±1.09 | 1 519.04±375.48 | 31.80±1.53 | 9.97（31/311） |
| AREDV组 | 58 | 12.07（7/58） | 36.21（21/58） | 28.90±2.88 | 1 003.95±519.15 | 8.20±1.71 | 1 060.33±259.53 | 30.26±1.70 | 23.33（7/30） |
| t或χ2 | 12.743 | 24.998 | 1.623 | 1.628 | 2.756 | 8.830 | 5.218 | 3.679 | |
| P | <0.001 | <0.001 | 0.110 | 0.109 | 0.010 | <0.001 | <0.001 | 0.055 | |
注：胎死宫内发生率、引产率和新生儿窒息发生率用%（n/n）表示，其余指标用$\bar{x}±s$表示。
AREDV组有30例孕妇选择救治胎儿，非AREDV组有311例孕妇选择救治胎儿。AREDV组新生儿1 min Apgar评分、新生儿出生体质量和终止妊娠孕周低于非AREDV组（均P<0.05）；2组新生儿窒息发生率比较差异无统计学意义（P>0.05）。见表3。
3 讨论
3.1 子痫前期发病孕周与AREDV的关系
研究表明，并发妊娠期高血压疾病的孕妇的胎儿脐动脉阻力指数（resistance index，RI）、搏动指数（pulsatility index，PI）、收缩期峰值流速与舒张末期血流速度比值（peak systolic velocity/end diastolic velocity，S/D）均高于正常孕妇[4]。子痫前期孕妇由于胎盘血管内皮细胞损伤、胎盘绒毛间质纤维化，造成部分胎盘绒毛小动脉痉挛、水肿或闭塞，导致胎盘血流量明显减少，最终引起子宫-胎盘、胎儿-胎盘的循环障碍，导致脐动脉血流速度异常，严重时可出现AREDV[5]。由于早发型子痫前期的主要发病机制是继发于子宫螺旋动脉重塑不足的子宫、胎儿灌注不良，导致胎盘绒毛梗死、绒毛缺如和血管扩张等灌注不足的表现较其他类型子痫前期严重[6]。而且诊断孕周越小的早发型子痫前期孕妇妊娠并发症发生率越高，围产儿预后越差[7]。本研究发现，在早发型子痫前期孕妇中，子痫前期诊断孕周与胎儿发生AREDV相关，诊断子痫前期孕周越小，AREDV发生风险越高，与上述研究结果一致。诊断孕周<28周和28~29+6周的早发型子痫前期患者发生AREDV的风险分别是32~33+6周诊断者的8.244倍和6.532倍，在临床工作中需要加强对这类患者的宫内监测频率。
3.2 血红蛋白水平与AREDV的关系
子痫前期患者由于小血管痉挛、血管内皮损伤和血管渗漏等原因，可出现血液浓缩及红细胞代偿性增加[8]，引起子痫前期孕妇分娩前血红蛋白水平明显高于正常孕妇[9]。随着血红蛋白水平升高，血液黏度增加，导致胎儿-胎盘灌注不良，进而导致胎儿宫内缺氧[10-11]。本研究发现，早发型子痫前期孕妇血红蛋白水平与发生AREDV相关，血红蛋白水平升高可增加AREDV的发生风险。血红蛋白≥135 g/L的早发子痫前期患者发生AREDV的风险是血红蛋白正常患者的2.438倍，提示高血红蛋白水平可能是早发型子痫前期患者发生AREDV的危险因素。另有研究表明，孕妇妊娠中期血红蛋白水平≥140 g/L可增加低出生体质量儿（OR=1.87，95%CI：1.24~2.81）和早产（OR=1.73， 95%CI：1.06~2.83）的发生风险[12]。所以在临床工作中，应重视高血红蛋白水平对早发型子痫前期患者的不良影响，加强此类孕妇的胎儿宫内监测。但高水平血红蛋白的纠正缺乏有效措施，在临床实践中应用硫酸镁解痉、纠正低蛋白血症、控制血压等治疗措施可能缓解血液浓缩状态，进而降低部分患者的血红蛋白水平。
3.3 并发AREDV的早发型子痫前期孕妇的围产儿结局
姚琳等[13]报道1例妊娠23+2周发生AREDV的孕妇期待治疗长达6周后终止妊娠并获得活产。在我院妇产科重症监护室住院的并发AREDV的早发型子痫前期孕妇如无急诊终止妊娠指征，均给予硫酸镁解痉、低分子肝素改善胎盘循环、地塞米松促胎肺成熟及控制血压等综合治疗，同时定期复查胎心监护、超声脐血流等，一旦病情恶化，则及时终止妊娠。AREDV组中选择救治胎儿的孕妇终止妊娠孕周为（30.26±1.70）周，选择引产的孕妇终止妊娠孕周为（28.9±2.88）周，说明当并发AREDV的早发型子痫前期孕妇病情恶化需要终止妊娠时，终止妊娠时的孕周可能是孕妇及家属是否救治胎儿的重要影响因素。瑞典的一项研究表明，分娩前发生脐动脉舒张末期血流缺失的胎儿有9%发生宫内死亡，15%产后死亡，中位终止妊娠孕周为27周，中位出生体质量为650 g[14]。本研究得出相似结果，AREDV组胎死宫内发生率12.07%，引产比例达36.21%，显著高于非AREDV组，说明AREDV与围产儿不良结局相关，在临床工作中必须充分告知围产儿的相关风险，以便孕妇及家属做好心理准备。有研究报道，妊娠29周前分娩且分娩前发生AREDV的极低出生体质量儿在2岁时存在智力发育迟缓[15]，所以还需告知孕妇及家属新生儿远期智力发育迟缓的风险。76.67%选择积极救治的AREDV孕妇分娩后未发生新生儿窒息，即使被引产的胎儿终止妊娠孕周偏小，引产胎儿体质量与被救治的新生儿出生体质量差异并无统计学意义。说明对于发生AREDV的早发型子痫前期孕妇，如果家属救治意愿强烈，在充分告知围产儿近、远期风险的前提下，可以在严密监测下选择期待治疗。
综上所述，对于诊断孕周早、血红蛋白水平高的早发型子痫前期孕妇，需要加强对胎儿的宫内监测，警惕AREDV的发生。如若发生AREDV，胎死宫内、宫内窘迫和新生儿窒息等围产儿不良结局风险可能增加，对于有救治胎儿意愿的患者，可给予解痉、控制血压、促胎肺成熟、低分子肝素抗凝等治疗，严密监测胎心监护、超声脐血流以及观察孕妇的病情变化，适时终止妊娠。本研究存在一定不足：①研究对象收集于妇产科重症监护室，危重孕妇比例偏高，调查结果可能存在一定的偏倚；②本研究为回顾性分析，未能对存活新生儿进行远期随访。未来需要多中心、前瞻性研究进一步分析早发型子痫前期患者发生AREDV的危险因素，也需要对存活新生儿的远期预后进行随访。
参考文献
Pre-eclampsia
[J].
妊娠期高血压疾病患者子宫动脉、脐动脉血流动力学的变化及其临床意义
[J].
妊娠期高血压疾病诊治指南(2020)
[J].
超声测定早孕期子宫动脉数据预测妊娠期高血压的价值评估
[J].
妊娠期高血压孕妇脐血流不同参数对宫内胎儿缺氧、胎儿生长受限的预测价值
[J].
子痫前期:病理生理学和临床意义
[J].
早发子痫前期的胎儿监测
[J].
红细胞压积及白蛋白指标评估子痫前期治疗效果的应用价值研究
[J].
妊娠各期血红蛋白浓度、铁蛋白的变化与不良妊娠结局的关系
[J].
孕晚期血红蛋白水平与妊娠结局的关系
[J].
Maternal hemoglobin associates with preterm delivery and small for gestational age in two Finnish birth cohorts
[J].
To test whether maternal hemoglobin during pregnancy associates with offspring perinatal outcomes in a developed country. Changes in maternal hemoglobin concentration during pregnancy are partly physiological phenomena reflecting alterations of maternal blood volume. Especially hemoglobin measures outside the physiological range may influence maternal health and fetal growth with long-lasting consequences.We studied an unselected sample drawn from two regional birth cohorts born 20 years apart: The Northern Finland Birth Cohorts 1966 and 1986. These are two mother-and-child population-based birth cohorts together comprising 21,710 mothers and their children. After exclusions, the sample size of the current study was 20,554. Concentrations of maternal hemoglobin at first and last antenatal visits were categorized as low (lowest 10%), medium (reference) or high (highest 10%). Multinomial logistic regression analyses for categories of maternal hemoglobin and perinatal outcomes such as preterm delivery and full-term small and large for gestational age were conducted with adjustments for maternal cofactors.Low maternal hemoglobin at early pregnancy associated with decreased risk of full-term small for gestational age (adjusted OR 0.73, 95% CI [0.58, 0.93], p = 0.010). At late pregnancy, low maternal hemoglobin associated with increased risk of preterm delivery (adjusted OR 1.60, 95% CI [1.26, 2.02], p < 0.0005) whereas high maternal hemoglobin associated with increased risk of full-term small for gestational age (adjusted OR 1.29, 95% CI [1.07, 1.56], p = 0.009). Maternal hemoglobin did not show constant association with risk of large for gestational age.The results from this study support evidence that both low and high maternal hemoglobin associate with adverse perinatal outcomes. Low maternal hemoglobin associated with preterm delivery and high with full-term small for gestational age. Association was mainly present when maternal hemoglobin was measured during the third trimester. These results indicate that it is important to monitor both extremes of maternal hemoglobin throughout the pregnancy.Copyright © 2019 Elsevier B.V. All rights reserved.
Maternal hemoglobin levels and neonatal outcomes: the Japan Environment and Children's Study
[J].
胎儿脐动脉舒张期脐血流缺失1例报告并文献复习
[J].
Extent of absent end-diastolic flow in umbilical artery and outcome of pregnancy
[J].To investigate if the extent of absent end-diastolic flow (AEDF) on umbilical artery (UA) Doppler velocimetry predicts pregnancy outcome.This was a retrospective observational study based on data from 25 000 Doppler examinations of UA flow performed between 1998 and 2017 at the Blood Flow Laboratory, Level III Perinatal Center, Lund, Sweden. All pregnancies with AEDF in the UA were identified, and the duration of AEDF as a proportion of the total duration of the cardiac cycle (T /T ratio) was measured in digital images of the Doppler spectrum recorded at the last examination showing AEDF before delivery. Clinical data on pregnancies and neonatal outcomes were extracted from the regional perinatal database and the hospital patient records. The predictive performance of the T /T ratio for intrauterine death and any (intrauterine or postnatal) death was assessed.A total of 170 fetuses (122 (72%) singletons and 48 (28%) twins) were included in the study. Median gestational age at birth was 189.5 days (range, 163-279 days) (i.e. 27 + 0 weeks (range, 23 + 2 to 39 + 6 weeks)), birth weight was 650 g (range, 320-3326 g) and deviation from expected birth weight (standard deviation score) was -2.975 (range, -6.38 to 0.69). There were 15 (9%) intrauterine and 26 (15%) postnatal deaths. The principal outcome variables and their relationship with Doppler velocimetry results did not differ significantly between singletons and twins, giving a rationale for using the T /T ratio in the total study group. Mean T /T ratio was 0.42 ± 0.08 and 0.34 ± 0.08 in stillborn and liveborn fetuses, respectively (P = 0.002). For fetuses examined before 30 weeks' gestation, a T /T ratio cut-off of 0.30 predicted intrauterine death with 92% sensitivity and a negative predictive value (NPV) of 98% (area under receiver-operating-characteristics curve (AUC), 0.74) and predicted any death with 83% sensitivity and a NPV of 85% (AUC, 0.66).In fetuses with AEDF in the UA, duration of absent flow for at least 30% of the total cardiac cycle length might predict the risk of fetal demise, even when assessed before 30 weeks' gestation. This finding is particularly relevant to growth-restricted fetuses. After evaluation in further studies, the extent of AEDF might facilitate obstetric decision-making in very preterm growth-restricted fetuses. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.© 2020 International Society of Ultrasound in Obstetrics and Gynecology.
Two-year neurological outcome of very-low-birth-weight children with prenatal absent or reversed end-diastolic flow velocity in the umbilical artery
[J].The aim of this study was to investigate the 2-year neurological outcome of very-low-birth-weight (VLBW) children who had abnormal umbilical blood flow velocity prenatally.We performed a prospective collection of infants prenatally diagnosed with abnormal umbilical blood flow velocity at a tertiary referral center from January 1, 2001 to September 30, 2005. VLBW children with prenatal absent or reversed end-diastolic flow velocity (AREDV) in the umbilical artery were investigated and compared with two similar demographic control groups of VLBW children without AREDV: one group with fetal growth restriction and the other without it. A follow-up study at 2 years of age for Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) of the Bayley Scales among the three groups was analyzed.Twenty-four VLBW children were identified to have AREDV prenatally, of whom four died during the neonatal period. After 2 years, five children were lost to follow-up and 15 were rescued, of whom 11 had absent end-diastolic velocity and four reversed end-diastolic velocity. We compared the remaining 15 children with the two control groups [28 children in the matched control group with intrauterine fetal growth restriction (IUGR), and 38 children in the matched control group without IUGR], and no significant differences were found in MDI (p = 0.938) and PDI (p = 0.496) scores at 2 years of age. However, we also surveyed the children with a gestational age of ≤ 29 weeks and found a significant difference in MDI scores (p = 0.048), but not in PDI scores (p = 0.219), among the three groups.VLBW children delivered earlier than 29 gestational weeks with abnormal umbilical blood flow velocity prenatally have greater mental developmental delay at 2 years of age.Copyright © 2013. Published by Elsevier B.V.
