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A meta-analysis of low-dose aspirin for prevention of preeclampsia
NA Trivedi
Department of Pharmacology, Medical College, Baroda, Gujarat, India
Correspondence Address:
N A Trivedi
Department of Pharmacology, Medical College, Baroda, Gujarat
India
Abstract
Background : Low-dose aspirin (LDA) is widely used for prevention of preeclampsia. However, conflicting results have been obtained from various studies. Aim: The aim of our study was to evaluate the effect of LDA in prevention of preeclampsia in high-risk and low-risk women. Materials and Methods : A total of 19 randomized control trials were identified using PUBMED search engine and Cochrane Clinical Trial register. The study population was divided into high-risk and low-risk groups. The effect measured was incidence of preeclampsia in women taking either LDA or placebo where the relative risk (RR) and the 95% confidence interval (CI) were calculated for both groups. Results : A total of 28237 women were studied, out of which 16550 were in the low-risk group while 11687 were in the high-risk group. The overall incidence of preeclampsia was 7.4%. With the aspirin group it was 6.9% while in the placebo group it was 7.8%. In the high-risk group there was 21% reduction in the risk of preeclampsia associated with the use of aspirin (RR 0.79, 95% CI 0.65-0.97). However, LDA is not effective in reducing the risk in low-risk population (RR 0.86, 95% CI 0.64-1.17). Conclusion: LDA has a small effect in the prevention of preeclampsia in women considered to be at high risk for the disease. However, it is not effective in reducing the risk in the low-risk group.
How to cite this article:
Trivedi N A. A meta-analysis of low-dose aspirin for prevention of preeclampsia.J Postgrad Med 2011;57:91-95
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How to cite this URL:
Trivedi N A. A meta-analysis of low-dose aspirin for prevention of preeclampsia. J Postgrad Med [serial online] 2011 [cited 2023 May 28 ];57:91-95
Available from: https://www.jpgmonline.com/text.asp?2011/57/2/91/81858 |
Full Text
Introduction
Preeclampsia is a multi-system disorder of pregnancy, which is characterized by new onset hypertension (systolic and diastolic blood pressure of ≥140 and 90 mm Hg, respectively) and proteinuria (protein excretion of ≥300 mg in a 24-h urine collection, or a dipstick of ≥2+), that develops after 20 weeks of gestation in previously normotensive women. [1],[2]
Preeclampsia occurs in 2-5% of pregnancies in the Occident, but it complicates up to 10% of pregnancies in the developing countries, where emergency care is often inadequate or lacking.
The cause of preeclampsia remains unknown, however, the hypothesis that preeclampsia is associated with a relative deficiency of intravascular production of prostacyclin (a vasodilator) and excessive production of thromboxane (a vasoconstricting prostaglandin synthesized by aggregated platelets) [3],[4],[5] has led to multiple trials testing antiplatelet agents such as low-dose aspirin (LDA) for prevention of preeclampsia. However, controversial results have been reported, with a few trials exhibiting compelling results; however, many of the largest trials to date failed to confirm any real benefit of LDA in preventing preeclampsia. [6] Additionally, it is not clear whether LDA is beneficial only for women at high risk of developing preeclampsia, rather than also for women at low risk.
Based on this controversial background, this meta-analysis was planned to evaluate the benefit of LDA in prevention of preeclampsia.
Materials and Methods
Data source
Studies were identified using electronic databases such as MEDLINE and other data at the National Library of Medicine was accessed using the PUBMED search engine as well as Cochrane Clinical Trial Register.
Only randomized double-blind prospective observational studies comparing LDA with placebo for prevention of preeclampsia published from 1985 to March 2009 were included.
Data selection
Each trial was individually analyzed and included in our study if it matched our inclusion criteria. Only randomized controlled trials in 'English' language were included. Wherever necessary, the author of the manuscript was contacted and necessary information was obtained. Trials giving incomplete information were excluded from the study. Studies including aspirin in combination with other drugs, e.g. dipyridamol, Ca + channel blocker, etc. were also excluded.
The study population was divided into two subgroups: (a) Women at high risk for developing preeclampsia (b) women at low risk.
Women at high risk for preeclampsia were identified as those who had previous history of the disease, essential hypertension, positive family history or underlying vascular disorder, maternal age <20 years or >40 years, and gestational diabetes mellitus. In other studies, women at high risk for preeclampsia were identified by positive tests such as those for Doppler ultrasonography, the rollover test, or the angiotensin II sensitivity test.
Low-risk group: Women at low risk for preeclampsia were considered to be those without any risk factor or any of the positive predictive tests described above.
LDA was defined as a dose of aspirin given in the range of 40-160 mg/day.
The main outcome of interest to our analysis was the incidence of preeclampsia in women who had received LDA in comparison to those who had taken placebo.
The secondary outcomes of interest were risk of preterm delivery and development of intrauterine growth restriction (IUGR). Here, preterm delivery is defined as <259 days or <37 weeks from the first day of the last menstrual period and IUGR was diagnosed when the fetal weight was below the 10 th percentile for gestational age and also when the neonatal birth weight fell below the 10 th percentile.
The statistical analysis was performed by CMA (Comprehensive meta-analysis) Version 2 software and the effect was estimated by calculating the relative risk (RR) and the 95% confidence interval (CI); a DerSimonian random-effects model was used.
Results
The search "Aspirin AND Prevention of Preeclampsia" with Limit "RCTs" and "English" retrieved 63 articles, out of which 19 Randomized Controlled Trials (RCTs) involving 28237 women were included in the study. Out of these 14116 were prescribed LDA while 14121 were prescribed placebo for prevention of preeclampsia.
The dose of aspirin used in the study ranged from 50-150 mg/ day. Three studies used 50 mg/day, 10 studies used 60 mg/day, four studies used 75 mg/day while one study each used 100 and 150 mg/day [Table 1] and [Table 2].{Table 1}{Table 2}
Average maternal age was 20-25 years and gestational age of entry varied from 7-32 weeks [Table 1] and [Table 2].
The overall incidence of preeclampsia was 7.4%. In the LDA group it was 6.9% while in the placebo group it was 7.8%.
A total of five trials [7],[8],[9],[10],[11] involving 16550 women were included in the low-risk group, wherein 8262 women were treated with LDA while 8288 were treated with placebo.
The overall incidence of preeclampsia in this group was 4.4% (4.3% in the LDA-treated group and 4.4% in the placebo-treated group). Treatment with LDA failed to produce a significant reduction in the risk of preeclampsia with RR 0.86 (95% 0.64-1.1) and Number Needed to Treat (NNT) is 200 [Figure 1].{Figure 1}
A total of 14 trials [12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] involving 11687 patients were included in the high-risk group, wherein 5854 patients were treated with LDA and 5833 were treated with placebo. The overall incidence of preeclampsia was 11.7% (10.7% in the LDA-treated group and 12.5% in the placebo-treated group). Overall there was 21% reduction in the risk of preeclampsia associated with the use of LDA (RR 0.79, 95% CI 0.65-0.97) NNT 19 [Figure 2].{Figure 2}
Although different doses of aspirin were used in each trial, there was no correlation between the dose of aspirin and prevention of preeclampsia (correlation coefficient r = 0.13 95% CI −0.34-0.55, P = 0.58) [Figure 3].{Figure 3}
In the high-risk group there was an overall 11% reduction in the risk of IUGR with the use of LDA with RR 0.89 (95% CI 0.0.76-1.03) and NNT 143, however, these results were statistically not significant.
LDA failed to produce significant reduction in the risk of IUGR in the low-risk group.
There was an overall 8% reduction in the risk of preterm delivery with the use of LDA with RR 0.92 (95% CI 0.85, 1.0) and NNT 143.
However, in the high-risk group there was 16% reduction in the risk of preterm delivery with RR 0.84 (95% CI 0.71, 0.99) and NNT 27. In the low-risk group there was only 2% reduction in the risk of preterm delivery with the use of LDA with RR 0.98 (95% CI 0.90, 1.07).
Overall, nine trials reported a 6% reduction in the risk of reported death (stillbirth and neonatal death) with the use of LDA with RR 0.94 (95% CI 0.75-1.1). However, this difference was statistically not significant.
Though data on maternal bleeding was not assessed uniformly in all the trials, the outcome of six studies indicates a marginal increase in the risk of post partum hemorrhage (PPH) in women taking LDA with RR 1.16 (95% CI, 1.007-1.351). However, this result was statistically not significant.
There was no significant difference in the risk of neonatal bleeding in the treatment and control groups.
Discussion
Our meta-analysis shows that the overall incidence of preeclampsia was 7.4%. In the LDA-treated group it was 6.9% while in the placebo-treated group it was 7.8%.
LDA has a small effect in the prevention of preeclampsia in women considered to be at high risk for the disease (RR = 0.79, NNT 19). However, it is not effective in reducing the risk in the low-risk group.
Moreover, there was overall only marginal reduction (statistically not significant) in the risk of IUGR (11%), and fetal death (6%) even in the high-risk group. However, LDA was slightly more beneficial in reducing the risk of preterm delivery in the high-risk group.
The results of this study are in accordance with those obtained by Duley et al.,[6] and Ruano et al.,[26] which state that LDA produces a marginal benefit in reducing the risk of preeclampsia in the high-risk group with RR 0.83, (95% CI 0.77-0.89) and 0.87 (95% CI 0.79-0.96) respectively. While in the low-risk group it fails to produce any significant advantage.
An important issue in a meta-analysis is the degree of heterogeneity of design of the included studies. Excessive heterogeneity reduces the validity of the approach. On the other hand, although absolute design homogeneity among studies would be ideal and desirable, this is an almost impossible goal to achieve. However, the problem can be avoided by understanding and analyzing the sources of heterogeneity.
The important sources of heterogeneity in this study were:
Differences in aspirin dosage among studies. Aspirin was used in the dose range of 50-150 mg/day in these studies. However, our analysis demonstrates that differences in aspirin dosage did not correlate with the relative risk for preeclampsia [Figure 1].As [Table 2] demonstrates, different inclusion criteria were used in each trial to define women at high risk for preeclampsia. Moreover, in many studies, all these conditions, which may have different pathophysiologies, are mixed together. Therefore, it should be of interest to randomize women according to different risk factors in further trials.The gestational age at the time of entry into the study also varied widely between 7-32 weeks of gestation.
However, a meta-analysis done by Bujold et al., (2010) [27] on pregnant women at moderate to high risk of preeclampsia indicates that when LDA is started at 16 weeks or earlier, it produces a significant reduction in preeclampsia (RR 0.47, 95% CI 0.34-0.65) and IUGR (RR 0.44, 95% CI 0.30-0.65), however, these beneficial effects are lost when LDA is given after 16 weeks of gestation with preeclampsia: RR 0.81, 95% CI 0.63-1.03 and IUGR: RR 0.98, 95% CI 0.87-1.10.
However, the influence of gestational age at entry into the study could not be evaluated here because the timing of aspirin administration varied between the trials and even within the trial.
So, the duration of aspirin administration should be carefully evaluated in all future clinical trials.
Another limitation of the study was that the search was limited to only English literature. Studies showing intervention to be effective are more likely to be published in 'English", while those showing less significant results are more commonly published in language other than English. Any summary of only the English language reports may result in an overestimate of effectiveness due to a language bias.
Considering the high prevalence and associated high maternal and perinatal morbidity/mortality rates, sincere efforts should be made for the prevention of occurrence of preeclampsia. Primary prevention, consisting of averting the occurrence of the disease, requires an understanding of its etiology. As the fundamental problem of misalliance between trophoblast and maternal tissue is not well understood, true etiological intervention has not been possible in preeclampsia. On the other hand, secondary prevention, consisting of at least slowing down the disease process before it becomes clinically apparent, is based on pathophysiological concepts.
LDA has been used as a strategy for secondary prevention of preeclampsia. However, as observed in the present analysis, low-dose aspirin exhibits only a small effect in the prevention of preeclampsia and this benefit is restricted to the high-risk group, showing that we still need to study and better understand the pathophysiology of preeclampsia.
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