Results of recent meta-analyses: more clarity but more confusion
Roberge and associates sought to address both dosing and timing questions by performing an exhaustive systematic review and meta-analysis of RCTs comparing aspirin to either placebo or no treatment.13 The authors identified 45 relevant trials involving 20,909 pregnant women randomized to 50 to 150 mg of aspirin daily. They stratified analyses according to whether aspirin was initiated at ≤ 16 or >16 weeks gestation. Of note, when aspirin was initiated at ≤ 16 weeks there was both a significant reduction in preeclampsia and a clear dose-response effect (ie, higher aspirin doses had greater efficacy). The latter effect is an important indicator of biological plausibility. When started at 16 weeks, aspirin markedly reduced the occurrence of preeclampsia (RR 0.57; 95% CI: 0.43-0.75), severe preeclampsia (RR of 0.47; 95% CI: 0.26-0.83) and FGR (RR of 0.56; 95% CI: 0.44-0.70). In contrast, when aspirin was initiated at > 16 weeks, beneficial effects, while still observed, were of a lower magnitude for preeclampsia (RR 0.81; 95% CI: 0.66-0.99) and no effects were observed for severe preeclampsia or FGR. In addition, no dose response was observed when treatment was started > 16 weeks. The authors speculated that earlier treatment enhanced placentation while the higher dose exerted a greater antiplatelet turnover effect. Given the anti-inflammatory effects of aspirin and evidence that decidual inflammation may inhibit placentation,14,15 this thesis also has biological plausibility.
The study by Roberge and associates appeared to explain many of the contradictory results observed in the literature and might have led to a complete re-thinking of preventative strategies for preeclampsia, had it not been for the simultaneous publication of another meta-analysis in the same journal on the same date with conflicting findings. The latter study, by Meher et al, examined individual participant data on 32,217 women and 32,819 babies recruited in 31 RCTs comparing low-dose aspirin or other antiplatelet agents versus either placebo or no treatment.16 These authors stratified results to initiation of therapy at < 16 weeks versus ≥ 16 weeks. In contrast to Roberge et al, these authors found a lesser overall benefit from aspirin and no significant difference in treatment effects among women randomized at < versus ≥ 16 weeks for preeclampsia (RR 0.90; 95% CI: 0.79-1.03 vs 0.90; 95% CI: 0.83-0.98, respectively). They concluded that, “The effect of low-dose aspirin and other antiplatelet agents on preeclampsia and its complications is consistent, regardless of whether treatment is started before or after 16 weeks gestation.”
Both studies were carefully performed and involved large numbers of subjects. The Meher study had the advantage of using individual participant data which provides a richer source of more standardized data and allows new analyses to be performed amongst different subgroups. On the other hand, the Meher study mixed outcome data from patients treated with aspirin or other antiplatelet agents. In addition, while Roberge and associates compared treatment initiated at ≤ 16 vs > 16 weeks, Meher and colleagues compared treatment begun at < 16 vs ≥ 16 weeks, albeit a slight difference.
We can be heartened by the findings of both Meher et al, and Roberge et al, because low-dose aspirin appears to be effective and safe in preventing preeclampsia in at-risk women. Based on our current state of knowledge, I would recommend treating women with any of the USPSTF high-risk factors or those women with 2 or more of the USPSTF moderate-risk factors (see Table) with low-dose aspirin either 81 mg or 122 mg (a tablet and a half) once a day, starting at 12 to 14 weeks.
Clearly, better identification of at-risk pregnant women should allow for more targeted treatment and, potentially, greater public health benefits from aspirin prophylaxis. Thus, our specialty is eagerly awaiting the results of the ASpirin for evidence-based PREeclampsia (ASPRE) prevention study, which uses a battery of biochemical and sonographic screening tests yielding a 75% sensitivity and 10% false-positive rate for the prediction of preeclampsia to allocate at-risk women to 150 mg of aspirin versus placebo from 11-13 to 36 weeks.17 Hopefully, that study will lend further clarity to this confusing but encouraging story.
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