阿司匹林可提高近期流产女性的活产率

美国Eunice Kennedy Shriver国立儿童健康与人类发展研究所的Enrique F. Schisterman博士在母胎医学会(SMFM)年会上报告，一些曾发生妊娠丢失的女性仅需服用阿司匹林即可提高下次妊娠的活产率。

这项名为EAGeR(阿司匹林对受孕与生殖的影响)的随机试验招募了1,228名已发生1~2次妊娠丢失但未患不孕症并且打算再次受孕的女性。这些受试者被平均分为两组，分别服用小剂量阿司匹林(81 mg/d)或安慰剂，同时补充叶酸，至多进行6个月经周期的治疗，或者假如受孕则至多治疗至孕36周。

结果显示，总体而言，小剂量阿司匹林组女性的活产率有高于安慰剂组的趋势(57.8% vs. 52.7%，P=0.09)。在分层分析中，小剂量阿司匹林与符合妊娠丢失严格标准(在过去1年中曾发生1次孕20周以内的妊娠丢失)的女性活产率绝对值增加9.2%相关(62.4% vs. 53.2%，P=0.04)。换言之，在这一亚组女性中，仅需对11名女性给予小剂量阿司匹林治疗即可增加1例活产。

这一获益主要来源于早期效应。“阿司匹林对受孕过程和早期妊娠维持有影响，而不影响之后的妊娠进程。这也就意味着，阿司匹林有助于女性受孕，而对于已经妊娠较长时间的女性则不再起作用。”

不过，小剂量阿司匹林在仅符合妊娠丢失一般标准(在过去任何时间曾发生1~2次妊娠丢失，但排除符合严格标准者)的亚组女性中并未显示出相同益处(53.9% vs. 52.2%)。

服用小剂量阿司匹林者似乎有更高的轻度阴道出血和轻度胃肠不适发生率，但与妊娠丢失或主要胎儿、新生儿或母亲并发症风险增加无关。

谈及试验背景，Schisterman博士介绍：“我们都知道，炎症和血流异常——尤其是在子宫、子宫内膜、卵巢和胎盘中——是不孕症、妊娠丢失、先兆子痫、早产和小于胎龄儿等的共同特征。因此显而易见的是，理想的治疗应当能减轻炎症和改善血流，而小剂量阿司匹林可能就是符合条件的治疗手段。”

他还补充道，尽管既往很少有在受孕前给予阿司匹林的研究，但有充分理由这样做。“阿司匹林可影响子宫内膜血管形成和胎盘形成。该药有明确的抗炎作用，而对母亲和胎儿的副作用则非常轻微。这是一种安全、易得且廉价的药物，即使在整个妊娠期都服用，费用也仅为2美元。”

这项试验的受试者年龄为18~39岁(平均29岁)，体重指数约为27 kg/m2，符合妊娠丢失严格标准与普通标准的受试者数量几乎对等。

进一步探究符合严格标准者获益的原因，研究者发现，小剂量阿司匹林组女性的妊娠试验结果阳性率高于安慰剂组(70.5% vs. 61.7%，P=0.03)。两组女性在6周后经超声证实怀孕并且最终活产的几率相似。

Schisterman博士报告称无相关利益冲突。

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By: SUSAN LONDON

Some women who have experienced a pregnancy loss can increase their odds of a live birth in the next pregnancy simply by taking aspirin, investigators reported at the Pregnancy Meeting, the annual meeting of the Society for Maternal-Fetal Medicine.

A team led by Enrique F. Schisterman, Ph.D., conducted a randomized trial of 1,228 healthy young women who had had up to two prior pregnancy losses, but did not have infertility and were attempting to conceive again.
 
The women were assigned evenly to take low-dose aspirin (81 mg) or placebo daily, along with folic acid, for up to six menstrual cycles or, if they conceived, up to the 36th week of pregnancy.

Results showed that low-dose aspirin was associated with an absolute 9.2% increase in the rate of live birth among the subset of women who met restricted criteria for pregnancy loss, namely a single pregnancy loss before 20 weeks’ gestation in the past year, reported Dr. Schisterman, who is a senior investigator and chief of the epidemiology branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Rockville, Md.

The benefit was mainly due to early effects. "There was an effect on becoming pregnant and early pregnancy [maintenance], but there were no differences after that," he elaborated. "The implications of that are not only that aspirin will help women become pregnant, but if you start too late, then the effects of aspirin are not there any more."

Analyses in the group with restricted criteria suggested that only about 11 women would need to be treated with low-dose aspirin to achieve one additional live birth.

In contrast, there was no significant benefit of low-dose aspirin among the subset of women who met general criteria for pregnancy loss that required one or two pregnancy losses at any time in the past, but excluded those meeting restricted criteria.

Low-dose aspirin was associated with somewhat higher rates of minor vaginal bleeding and minor gastrointestinal upset, but the drug was not associated with pregnancy loss or with an increased risk of major fetal, neonatal, or maternal complications.

An attendee wondered about the difference between the two subsets of women having differing histories of pregnancy loss, saying, "You would expect more or less the same effect."

Dr. Schisterman maintained that the two groups were not all that similar. "I am not sure I would expect the same result, although when we did some analyses in which we compared those who had a single loss in the restricted stratum to those who had a single loss in the general stratum, we found attenuated but in a similar direction results in the general stratum," he commented. "So it seems that the number of losses is the driving force. But we are still analyzing that data."

Another attendee raised the issue of the timing of the previous pregnancy loss in the subset meeting restricted criteria. "Were you able to identify any influence of the gestational age of the previous loss on the effectiveness of aspirin in the next pregnancy, the randomized pregnancy?" he asked.

"Not yet," Dr. Schisterman replied, noting that all of the losses were fairly early. However, here too, analyses are still ongoing.

Giving some background to the trial, he noted, "We know that inflammation and abnormal blood flow, especially in the uterus, endometrium, ovaries, and placenta, ... are unifying features of outcomes like infertility, pregnancy loss, preeclampsia, preterm delivery, and small for gestational age. So clearly, an ideal therapy that would reduce inflammation and improve blood flow will be the one that we are looking for. Low-dose aspirin could be such a therapy."

The drug has seldom been studied when given in the preconceptional period, but there is a strong rationale for such use, he maintained.

"It impacts endometrial vascularization and placentation. It has very well documented anti-inflammatory effects. It has very few maternal and fetal side effects. It’s safe, widely available, and more importantly, it’s cheap – it costs $2 for the whole pregnancy to treat a woman," he elaborated.

Women enrolled in the trial, known as EAGeR (The Effects of Aspirin in Gestation and Reproduction), were aged 18-39 years. They were roughly evenly split between meeting the restricted criteria and the general criteria for previous pregnancy loss.

On average, the women were 29 years old and had a body mass index of about 27 kg/m2. Most were married and white.

Overall, there was only a trend toward a higher rate of live births in the low-dose aspirin group compared with the placebo group (57.8% vs. 52.7%, P = .09), reported Dr. Schisterman.

In stratified analyses, there was a significant benefit of low-dose aspirin in the subset meeting the restricted pregnancy loss criteria (62.4% vs. 53.2%, P = .04) but not in the subset meeting the general pregnancy loss criteria (53.9% vs. 52.2%).

When the investigators more closely assessed the reason for benefit in the women meeting restricted criteria, they found a higher rate of achieving a positive pregnancy test with low-dose aspirin (70.5% vs. 61.7%, P = .03). Rates of progression thereafter to confirmed pregnancy by ultrasound at 6 weeks and ultimately to live birth were similar for the two treatment groups.

Dr. Schisterman disclosed no relevant conflicts of interest.