The Interview
Medscape: Why did you decide do this meta-analysis of the effects of low-dose aspirin prophylaxis in pregnancy with perinatal mortality as the primary endpoint? There have been several meta-analyses of data from trials that looked at the effect of aspirin in preventing preeclampsia, including 2 comprehensive analyses reported in 2007[2,3] and an updated meta-analysis by your own group.[4,5] If aspirin has convincingly been shown to reduce preeclampsia, preterm delivery, and severe adverse outcomes, wouldn't we expect these positive effects to extend to perinatal death?
Dr. Bujold: Yes, we were expecting that the positive effects of aspirin extend to perinatal death, but there is a difference between expectations and evidences. Moreover, since the last update of our meta-analysis,[5] 4 additional randomized trials of aspirin in pregnant women have been published, so we were able to include those in our latest analysis.[6,7,8,9]
Our new meta-analysis included all adverse outcomes -- preeclampsia, intrauterine growth restriction, severe preeclampsia, and perinatal death. We also looked at other outstanding questions, such as whether the dose of aspirin and the criteria for patient inclusion had a differential effect. We found that the results did not differ from what we had previously published in 2010[5] -- that is, when aspirin is given in early pregnancy, when placentation occurs, it reduces the risk for all the adverse outcomes related to abnormal placentation: perinatal death, preeclampsia, and intrauterine growth restriction.
Medscape: You found an advantage in giving aspirin before 16 weeks compared with at 16 weeks or thereafter, but the majority of the trials in the meta-analysis, including the largest ones, started aspirin therapy after 16 weeks. Another limitation of your analysis must have been that none of the trials were designed to look at perinatal death as an outcome. Did this make the comparison between early and later treatment more difficult to analyze?
Dr. Bujold: Of the 42 trials that evaluated aspirin in pregnancy, only 12 of them started aspirin therapy at or before 16 weeks in all participants. The problem with the early trials, even earlier meta-analyses, was that they did not consider the time when aspirin should be given. However, more recently, we and others found that aspirin improves placentation, and such improvement decreases the risk for preeclampsia or any other problem related to the placenta disorders. Placental invasion of the uterus occurs usually between 8 and 16 weeks, so if you your goal is to improve placental invasion, you need to give it before or at that time.
Another problem we had was that several trials did not report perinatal death or were too small to evaluate it. However, as we reported, we found that the effect of low-dose aspirin started at 16 weeks of gestation or earlier was significant and homogeneous and remained significant after exclusion of the trials at high risk for bias.
Medscape: Among the perinatal deaths reported, 65% were attributed to placental-mediated complications of pregnancy (preeclampsia, fetal growth restriction, or placental abruption). What about the other deaths?
Dr. Bujold: Placental impairment is one of the most important causes of perinatal death, but there are many other causes not related to the placenta, so of course, aspirin will not prevent overall mortality. The best study would have been to look at the placenta of in all cases of perinatal deaths, but this was not done in any of the studies.
Medscape: Your analysis didn't show any difference according to aspirin dose.
Dr. Bujold: You are right. However, our meta-analysis did not have the power to give a definitive answer regarding aspirin dosage.
Medscape: The dose range of aspirin used in the studies included in your meta-analysis was quite wide, from 50 to 150 mg. Although your conclusion that low-dose aspirin should be offered to high-risk women did not mention a specific dose or range, would you nowadays recommend a specific dose or dose range? There are already some guidelines, for example those from the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom[10] and the World Health Organization,[11] that recommend 75 mg as the daily dose for women at high risk for preeclampsia.
Dr. Bujold: In fact, 75-80 mg seems to be the right dosage for about two thirds of the women. There have been 4 studies that looked at the effect of dosage,[12,13,14,15] and they reported that approximately two thirds of the women will respond to 75-80 mg. Probably one third will need higher dosages up to 160 mg.
My own opinion is that all high-risk pregnant women should receive 75-80 mg and be assessed for aspirin resistance, which is a test that can be done quite easily in most hospitals, and if we find that a woman is resistant to 75-80 mg, we need to increase the dose.
Medscape: What about women at moderate risk? Would you recommend aspirin in pregnancy in these women?
Dr. Bujold: NICE recommends that aspirin 75 mg be given not only to women at high risk, but also women with 2 or more factors indicating moderate risk, including first pregnancy, age older than 40 years, pregnancy interval greater than 10 years, body mass index (BMI) 35 kg/m2 or greater at first visit, family history of preeclampsia, or multiple pregnancy.[10] A recent study showed that if you treat women with all those risk factors, you would treat up to 46% of pregnant women in the population.[16] In several developed countries, many women combined nulliparity and high BMI or hypertension, so following this recommendation you would treat a lot of women for the small numbers who would really need it.
I believe that we should use a screening program such as the one that has been designed by Nicolaides' group at King's College London in the United Kingdom,[17]which recently found that you could identify up to 90% of women who would benefit from aspirin therapy, with a false-positive rate of 9%-10%.[18]
Medscape: How long should women take aspirin in pregnancy? Up until birth? Presumably, it should not be long enough to worry about any side effects, because aspirin has been associated with maternal and fetal bleeding.
Dr. Bujold: According to the trials, there are very few side effects with aspirin; the dosages used are very low. The question that I cannot answer from our meta-analysis is when we should stop aspirin therapy during pregnancy. If we believe that giving it early in pregnancy is important, then we should probably be able to stop earlier than usual, because placentation is typically completed by 20-22 weeks at the latest. That means that women could potentially take aspirin only for about 10 weeks, but no study has evaluated stopping aspirin as early as that.
Some authors and experts have concluded from many trials that aspirin should be continued up to delivery, but if we use dosages greater than 100 mg, women should certainly stop aspirin therapy earlier. Others have proposed, and I agree, that we should probably stop aspirin around 34 weeks until new studies have evaluated the effect of stopping aspirin therapy earlier or later than that.
Medscape: What other studies do you think are needed to fill in the gaps in current guidelines?
Dr. Bujold: A large unpublished trial that used first-trimester multimarker screening to identify women at increased risk for preeclampsia and randomly assigned them to receive low-dose aspirin (75-150 mg) or placebo to determine whether aspirin can reduce the incidence and severity of the disease.[19]
Another trial that really needs to be done will compare several dosages of aspirin, and that is what we are doing right now in Québec. We are comparing aspirin 80 mg with 160 mg in women at high risk for preeclampsia to determine which dose is associated with greater improvement in placental function, as assessed by biochemistry and ultrasonography, as well as pregnancy complications related to placental insufficiency.[20] We are also looking at whether the change is dependent on platelet aggregation as measured by the PFA-100 test used in several Canadian centers.[21]
Medscape: You have suggested that the mechanism by which aspirin may protect against preeclampsia and related conditions is a consequence of an improvement in the transformation of uterine spinal arteries. Could you explain more about this?
Dr. Bujold: The real mechanisms are not well understood, but around 30 years ago, it was observed that women who were taking aspirin for such conditions as lupus or other connective tissue disease were less likely to develop preeclampsia. Since then, several hypotheses have been proposed. Our meta-analyses showed that low-dose aspirin prevents mainly the preterm and severe forms of preeclampsia, those that are typically associated with deep placentation disorders.[22,23,24] So there is indirect evidence that suggests how aspirin improves placentation, but the exact mechanisms are still unclear.
Medscape: Do you think there might be a case for starting aspirin before conception? US investigators involved in the EAGeR trial, who presented their results at the recent Society for Maternal-Fetal Medicine meeting, reported an association between daily aspirin (81 mg) taken before conception and a significant increase in live births among women with a previous pregnancy loss before 20 weeks.[25]
Dr. Bujold: Overall, in the women in the trial, who had 1-2 prior losses, they found no difference in live birth rate between the low-dose aspirin group and the placebo group (57.8% vs 52.7%, respectively). It was only when they did a subgroup analysis that it became significant, with a very slight increase in women with 1 loss before 20 weeks' gestational age. This is not the first trial that looked at the effect of aspirin before conception. Most experts believe that it is not effective, but if it is, the effect is very small, as the EAGeR study results suggest.
Medscape: What would be your summary guideline on aspirin prophylaxis in pregnancy, on the basis of the evidence to date?
Dr. Bujold: According to meta-analyses, women with a history of preeclampsia should receive low-dose aspirin started before 16 weeks, and I agree with the NICE guidelines that say it should be started around 12 weeks. That is the first point and the most important one. The dosage should be at least 75 mg, and if possible, we should probably try to evaluate aspirin resistance.
Right now, there is not enough evidence to give aspirin to all women, nor is there enough evidence to give aspirin to women before conception. I would add that evidence is insufficient to treat all women at moderate risk on the basis of a single factor, such as BMI; we should look at algorithms or nomograms that would combine risk factors. Hopefully, new studies on this will be done.
In the meantime, the use of data from Nicolaides' group on the Fetal Medicine Foundation's online risk calculator and first-trimester ultrasonography in assessment of risk for preeclampsia was recently confirmed in a study from Brazil,[26] and I believe that on the basis of those data, we should strongly consider using those very low-cost programs to identify high-risk women who can then start taking low-dose aspirin early in pregnancy.
Medscape Cardiology © 2013 WebMD, LLC
Cite this: Aspirin in Pregnancy: Beyond Preeclampsia - Medscape - Apr 25, 2013.
