使用硝苯吡啶保胎无益

旧金山——在荷兰进行的一项大型随机、双盲、安慰剂对照研究证实了较早期研究的结果，即对早产停止(arrested preterm labor)的女性采用常规的硝苯吡啶保胎法未见收益。


Deirdre J. Lyell医生

在加州大学主办的产前与产时管理会议上，斯坦福大学母胎医学、妇产科专家Deirdre J. Lyell医生发言指出，早产停止时应该怎么办，这是很多医生都遇到过的难题；调查显示，1/4以上的母胎医学专家常规使用保胎疗法，最常使用的药物就是硝苯吡啶，尽管其有效性仍受到质疑。

荷兰的这项多中心研究涉及406名“卧床保胎”的女性，她们均在24~34孕周时出现早产停止。这些女性被随机分组，接受20 mg硝苯吡啶保胎疗法或安慰剂处置，每4~6 h一次。硝苯吡啶组第35周时分娩，而对照组在35周2天时分娩。两组患者开始治疗后的继续妊娠天数分别为34和33，其复发性早产的发生率相近。硝苯吡啶组和对照组分别有12%和14%的女性发生了主要复合结局中的至少一个组分，主要复合结局包括围产期死亡、慢性肺部疾病、新生儿脓毒病、2级以上脑室内出血、1级以上脑室周围白质软化症或坏死性直结肠炎。总之，该研究结果未显示出主要结局(不良围产期结局的复合终点)上统计学差异。因为对照组不良事件的发生率低于预期，因此不能排除硝苯吡啶的潜在收益。然而，就目前的结果看来，用硝苯吡啶保胎似乎并无益处(JAMA 2013;309:41-7)。另外，本研究也没有证据显示该药能够推迟分娩。

之前有3项随机试验也未发现硝苯吡啶有助于保胎：一项纳入74名美国女性的非盲研究未发现结局上存在差异(Am. J. Obstet. Gynecol. 1999;181:822-7)；伊朗一项纳入73名女性进行的非盲随机研究亦如此(J. Perinat. Med. 2004;32:220-4)；Lyell医生及其合作者此后对68名女性进行了一项双盲、安慰剂对照试验，结果仍为阴性(Obstet. Gynecol. 2008;112:1221-6)。尽管这些都是小规模研究，但均未得出支持使用硝苯吡啶保胎的证据。

硝苯吡啶可产生母体副作用。在一项对比静脉注射硫酸镁与口服硝苯吡啶用于紧急保胎的试验中，硝苯吡啶导致4%的用药女性发生头痛，5%发生呕吐，5%发生低血压，5%发生气短，5%出现嗜睡(Obstet. Gynecol. 2007;110:61-7)。β模拟剂特布他林对母体、胎儿及新生儿产生的副作用更多，2项随机对照试验显示，使用特布他林泵保胎预防复发性早产的疗效并不优于生理盐水。

2008年一项针对母胎医学会827名会员的调查显示，29%常规使用保胎维持疗法，31%会在患者有意愿的情况下使用。在实施保胎维持疗法的会员中，79%首选硝苯吡啶(Obstet. Gynecol. 2008;112:42-7)。在此次会议上对医生、护士、助产士进行的一项非正式在线调查中，6%自称常规使用保胎维持疗法，67%偶尔使用这种方法，26%从不使用这种方法。在Lyell医生发言后再次进行调查，结果显示与会者无一赞成常规使用保胎维持疗法，53%称可能会偶尔使用，47%称不会再使用这种方法。

本研究由荷兰健康调查与发展组织资助。Lyell医生无相关的经济利益冲突。

爱思唯尔版权所有  未经授权请勿转载

By: By SHERRY BOSCHERT, Ob.Gyn. News Digital Network

SAN FRANCISCO – A large randomized, double-blind placebo-controlled study in the Netherlands supports earlier studies that found no benefit from routine maintenance tocolysis using nifedipine in women with arrested preterm labor.

What to do when preterm labor stops is "a million dollar question that many of us have faced," Dr. Deirdre J. Lyell said at a meeting on antepartum and intrapartum management sponsored by the University of California, San Francisco. Surveys suggest that more than a quarter of maternal-fetal medicine specialists routinely use maintenance tocolysis, most often with nifedipine, despite its questionable utility.
 
The Dutch study of 406 women "puts the question to bed," said Dr. Lyell, a maternal-fetal medicine ob.gyn. at Stanford (Calif.) University. She was not involved in the study.

The multicenter trial in these women was underpowered to show a statistically significant difference in its primary outcome – a composite of perinatal adverse outcomes – because of a lower-than-expected rate of adverse events in the control group, so it couldn’t exclude a possible benefit from nifedipine. However, "its use for maintenance tocolysis does not appear beneficial at this time," the investigators wrote (JAMA 2013;309:41-7).

Women in the study had arrested preterm labor at 24-34 weeks’ gestation. They were randomized to maintenance tocolysis with 20 mg nifedipine or placebo every 4-6 hours. Delivery occurred at 35 weeks in the nifedipine group and at 35 weeks and 2 days in the control group. The number of days of pregnancy after starting treatment was 34 and 33, respectively, and the two groups had similar rates of recurrent preterm labor. Twelve percent in the nifedipine group and 14% in the control group developed one of the problems in the primary composite outcome: perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage greater than grade 2, periventricular leukomalacia greater than grade 1, or necrotizing enterocolitis.

"There’s no evidence these medications were able to delay delivery," Dr. Lyell said.

Three previous randomized trials also found no benefit from maintenance tocolysis with nifedipine. One nonblinded study of 74 U.S. women found no difference in outcomes (Am. J. Obstet. Gynecol. 1999;181:822-7). Neither did a nonblinded Iranian study that randomized 73 women but did not report how the randomization was conducted (J. Perinat. Med. 2004;32:220-4). Dr. Lyell and her associates then conducted a double-blind placebo-controlled trial in 68 women, which again was negative (Obstet. Gynecol. 2008;112:1221-6).

These studies were small, "but we still haven’t seen anything robust to say this is something we should do," Dr. Lyell said.

Nifedipine can produce maternal side effects. In a trial comparing intravenous magnesium sulfate with oral nifedipine for acute tocolysis, nifedipine caused headache in 24% of women who received the drug, vomiting in 5%, hypotension in 5%, shortness of breath in 5%, and lethargy in 5% (Obstet. Gynecol. 2007;110:61-7).

Beta-mimetics such as terbutaline have a much longer list of maternal, fetal, and neonatal side effects, and two randomized controlled trials have shown that maintenance tocolysis using a terbutaline pump was not more effective than giving saline to prevent recurrent preterm labor, Dr. Lyell said.

A 2008 survey of 827 members of the Society of Maternal-Fetal Medicine found that 29% routinely use maintenance tocolysis and 31% will use it if the patient desires. Among members who employ maintenance tocolysis, nifedipine was the first choice of 79% (Obstet. Gynecol. 2008;112:42-7).

In an informal electronic survey of the physicians, nurses, and midwives at the meeting, 6% said they routinely use maintenance tocolysis, 67% occasionally use it, and 26% never use it. In a repeat survey after Dr. Lyell’s talk, none favored routine maintenance tocolysis, 53% said they would use it occasionally, and 47% said they would no longer use it.

The Netherlands Organization for Health Research and Development funded the study. Dr. Lyell reported having no relevant financial disclosures.