ACOG敦促改变先兆子痫的诊断和治疗

美国妇产医师协会(ACOG)日前发布了妊娠期高血压临床指南，强调在新发高血压患者中不应继续将蛋白尿视为诊断先兆子痫的关键标准。

ACOG表示，血小板计数下降、肾功能不全、严重头痛、心肺功能受损和肝功能损伤，与蛋白尿同等重要。在妊娠20周或以后，在新发高血压的同时出现上述症状中的任何一种，即足以确立先兆子痫的诊断，即使患者并无蛋白尿。

该指南作者之一、ACOG前主席、密西西比大学医学中心母胎医学部主任James N. Martin博士指出：“临床医生们青睐确切的数字，但有时候数字会误导我们。”对产妇死亡率的审查显示，等待蛋白尿出现可导致干预延迟或漏诊，因为并不是所有先兆子痫患者都会出现蛋白尿。

这部新指南将替代2002年ACOG实践公报(Obstet. Gynecol. 2002;99:159-67)。除了修订诊断标准和精确定义疾病严重程度指标之外，作者们还试图解决一些重要的治疗挑战：本已患有高血压疾病的患者发生先兆子痫；有和无严重症状的先兆子痫患者的引产时机；皮质激素的使用；产后先兆子痫的识别与治疗。

本指南的确强调了一个明确的数字，对于临床医生而言应该是有用的：建议无严重特征的先兆子痫女性患者在妊娠37周时分娩。Martin博士指出，在妊娠37周时分娩的建议在很大程度上是基于2009年一项荷兰临床试验。在该试验中，756名女性被随机分配到妊娠36~37周引产组或期待疗法等待分娩组。结果显示，妊娠37周时引产的受试者仅有31%发生不良结局，而采用期待疗法者有44%发生不良结局。

这部指南将先兆子痫分为有和无严重特征两类，但反对使用“轻度先兆子痫”的说法，认为这种说法具有误导性。“任何形式的先兆子痫都不应被轻描淡写称‘轻度’。”

新指南不仅将蛋白尿的地位下调为先兆子痫的重要诊断标准(而不再是关键标准)，而且不再将蛋白尿视为判断先兆子痫严重程度或决定是否引产的重要指标，原因是尿蛋白量并不能预测母体或胎儿的结局。

胎儿生长受限曾被认为是诊断重度先兆子痫的主要标准之一，现在不再被用于先兆子痫的诊断，而是被视为先兆子痫患者分娩的指征。先兆子痫患者的胎儿极小（小于第5百分位）与脐带血流异常有关。

该指南强调，先兆子痫有可能在分娩后才首次出现，或者在产后进一步恶化而不是改善。对所有产后患者进行有关出院后新发先兆子痫或症状加重的教育是明智的做法，这有助于使接手的医生提高警惕和及时给予治疗以防止问题出现。

新指南在预防方面着墨不多。未建议采用维生素C和E预防先兆子痫，但建议对发生早产重度先兆子痫的患者从孕早期末开始使用小剂量阿司匹林。

“我们真正需要的是生物标志物。” Martin博士补充道，尽管胎盘生长因子和其他潜在早期标志物的相关研究结果令人鼓舞，但还没有任何生物标志物能够在临床上常规使用。

新指南的部分作者报告称存在利益冲突。George Bakris博士承认与武田、CVRx等公司有关联；John Barton博士承认与Alere和Beckman Coulter有关联。AnanthKarumanchi博士承认与Beckman Coulter、罗氏等公司有关联。BahaSibai博士承认与Alere有关联。其余作者均表示无相关利益冲突。

专家点评：新指南可简化治疗

马里兰大学母胎医学系主任Ahmet A. Baschat博士评论指出，ACOG妊娠期高血压工作者的这篇报告标志着与以前的诊治标准划清界限。首先，先兆子痫的诊断不再要求有蛋白尿，因为蛋白尿特异性不强，也可能与慢性高血压有关。工作组将母体肝、肾、肺和脑等终末器官疾病纳入了诊断标准，即使没有蛋白尿也可诊断先兆子痫。


Ahmet A. Baschat博士

其次，在确立先兆子痫的诊断后，重度的标准不再包含胎儿生长受限，而是着眼于母体的症状。第三，建议先兆子痫患者即使没有严重特征也应当在妊娠37 0/7周时分娩，并特别强调对于产后首日后血压未能恢复正常的女性应调整镇痛治疗。

现在，新发高血压和终末器官受累的女性即可诊断为先兆子痫，并可根据严重程度标准和妊娠期干预阈值决定治疗方案，而不会再因无尿蛋白症状而冒延误治疗的风险。这一重要变化有可能减少因治疗延迟导致的孕产妇死亡。

将胎儿生长受限从重度标准中摘出来也是一个重要变化，这将有助于临床医生根据母体和胎儿各自的严重程度制定个体化的治疗方案。采用脐动脉多普勒超声进行监测，有可能减少医源性早产——导致新生儿不良结局的一个重要原因。

工作组并没有强调孕早期先兆子痫筛查。此时的标化孕妇血压读数是筛查算法的一部分，为临床医生诊断既有的高血压提供了额外的机会，这对于之后诊断先兆子痫非常关键(Hypertension 2008;51:1027-33)。

此外，工作组也没有太强调早期开始小剂量阿司匹林治疗的重要性，原因是在妊娠16周前开始预防的女性获益最大，而胎盘早剥的风险从孕中期开始增加(J. Obstet. Gynaecol. Can. 2009;31:818-26)。这对于那些开展早期风险评估并据此启动小剂量阿司匹林治疗的医院而言非常重要。

“总之，我认为这些变化是明显的进步，增加了先兆子痫诊断特异性，提供了与母体和胎儿结局最相关的严重程度分层。相应的，新指南还能帮助我们权衡疾病严重程度和胎龄，探索简单而明确的治疗途径。”

Baschat博士报告称无相关利益冲突。

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By: JENNIE SMITH, Ob.Gyn. News Digital Network

Proteinuria, or elevated protein in the urine, should no longer be considered the signature criterion besides new-onset hypertension in diagnosing preeclampsia, says the American College of Obstetricians and Gynecologists.

In exhaustive new clinical guidelines on hypertension in pregnancy, ACOG says that equal weight should be given to reduced platelet counts, renal insufficiency, severe headache, heart-lung compromise, and impaired liver function.

Any one of these concurrent with new-onset hypertension at 20 weeks of pregnancy or beyond is enough to establish preeclampsia, even in the absence of proteinuria.

"Clinicians like hard numbers," said Dr. James N. Martin, chief of the division of maternal-fetal medicine at the University of Mississippi Medical Center in Jackson, a past ACOG president, and an author of the guidelines.

"But sometimes we can be misled by them." Reviews of maternal mortality data have shown that waiting for proteinuria to present can result in delayed intervention or missed diagnosis, as not all women with preeclampsia will develop proteinuria.

The new guidelines replace recommendations from a 2002 ACOG Practice Bulletin (Obstet. Gynecol. 2002;99:159-67). In addition to the revised diagnostic recommendations and precisely defined measures to determine severity of disease, they address several important management challenges: preeclampsia on top of an existing hypertensive disorder; timing of induction for preeclampsia with and without severe symptoms; use of corticosteroids; and recognizing and managing preeclampsia in the postpartum period.

The guidelines do emphasize one hard number that should be useful to clinicians: Delivery at 37 weeks is advised for women with preeclampsia without severe features.

Dr. Martin said that the 37-week delivery recommendation was based largely on results from a 2009 trial in Holland in which 756 women were randomized to induction at the 36- to 37-week point or expectant monitoring to await labor; induction at 37 weeks was associated with poor outcomes in only 31% of subjects, compared with 44% of those receiving expectant monitoring.

The guidelines distinguish extensively between preeclampsia with and without severe features, but discourage the use of the phrase "mild preeclampsia," considering it misleading. "Preeclampsia in any form should never be minimized as ‘mild,’ " Dr. Martin said.

Proteinuria, in addition to being downgraded as the signature diagnostic finding in preeclampsia, should no longer be considered as useful in classifying preeclampsia as severe or in deciding whether to induce, the guidelines say, because the amount of protein in the urine has not been shown to predict either maternal or fetal outcomes.

Fetal growth restriction, once considered a major criterion to make the diagnosis of severe preeclampsia, is now to be used not for diagnosis of preeclampsia, but for indicated delivery in a patient with preeclampsia who also has an extremely small fetus (less than 5th centile) that is associated with abnormal blood flow findings in the umbilical cord connecting the fetus to the placenta.

The guidelines emphasize that preeclampsia can appear for the first time following delivery, or worsen rather than improve during in the postnatal period.

It is advisable that all postpartum patients become educated about symptoms suggestive of new or worsening preeclampsia after leaving the hospital so that the patient’s doctors can be alerted and treatment begun in time to prevent problems.

On the prevention front, the guidelines have less to recommend. The use of vitamins C and E is not advised in preventing preeclampsia. Low-dose aspirin, however, is recommended starting late in the first trimester for patients who experience preterm severe preeclampsia.

"What we really need are biomarkers," Dr. Martin said, adding that despite encouraging science on placental growth factor and other potential early markers, none is yet ready for routine clinical use.

Some of the guidelines’ coauthors reported financial relationships or potential conflicts of interest. Dr. George Bakris disclosed associations with Takeda, CVRx, and other companies. Dr. John Barton disclosed relationships with Alere and Beckman Coulter. Dr. AnanthKarumanchi disclosed relationships with Beckman Coulter, Roche, and others. Dr. BahaSibai disclosed a relationship with Alere. The remaining task force members said they had no relevant financial disclosures.

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New guidelines can simplify management

The report from the ACOG Task Force on Hypertension in Pregnancy marks an important departure from prior diagnostic and management criteria. Firstly, the diagnosis of preeclampsia no longer requires the presence of proteinuria, which can be relatively nonspecific and may also be associated with chronic hypertension. Rather, the task force includes evidence of maternal hepatic, renal, pulmonary, and cerebral end-organ disease in the diagnostic criteria – even in the absence of proteinuria.

Once the diagnosis of preeclampsia has been established, the severity criteria no longer include fetal growth restriction, but rather focus on maternal symptoms. Thirdly, delivery is suggested for women with preeclampsia at 37 0/7 weeks’ gestation even in the absence of severe features, and special emphasis is placed on modifying analgesic therapy for women who fail to normalize their blood pressure after the first postpartum day.

These changes are based on evidence and partly choice. The choice to recognize nonproteinuric preeclampsia as a diagnostic entity follows in the footsteps of several international bodies.

Now, women with new-onset hypertension and end-organ effects can be diagnosed with preeclampsia, and management can be based on severity criteria and gestational intervention thresholds without any potentially dangerous delay due to the absence of proteinuria. This important change has the potential to decrease maternal mortality that is attributable to delayed intervention.

The second important step is to remove fetal growth restriction as a severity criterion. This offers the advantage to manage maternal and fetal disease independently based on their individual severities.

In the setting of disease-specific surveillance including umbilical artery Doppler ultrasound, this approach has the potential benefit of minimizing iatrogenic prematurity – an important contributor to adverse neonatal outcome.

One choice that the task force did not make is to emphasize the opportunity of first-trimester screening for preeclampsia. Standardized maternal blood pressure readings at this time both are an integral component of screening algorithms and provide additional diagnostic opportunity to document preexisting hypertension – critical for the later diagnosis of preeclampsia (Hypertension 2008;51:1027-33).

In addition, the task force underemphasizes the importance of early initiation of low-dose aspirin, because the benefit is greatest for women initiating prophylaxis prior to 16 weeks, and risks for placental abruption increase with initiation in the second trimester (J. Obstet. Gynaecol. Can. 2009;31:818-26). This is important for those centers that choose to provide an early risk assessment, and based on that, initiate low-dose aspirin.

In summary, I think these changes offer a clear advantage by increasing the diagnostic specificity for preeclampsia and providing severity stratification that bears closer relevance to maternal and neonatal outcome. Accordingly, a simplified but clear management approach can be developed, tailored on the balance of disease severity and gestational age.

Dr. Ahmet A. Baschat is professor of obstetrics, gynecology, and reproductive sciences, and director of maternal fetal medicine and the section of fetal therapy at the University of Maryland in Baltimore. He was asked to comment on the task force report. Dr. Baschat said he had no financial disclosures relevant to the report.