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Low-Dose Aspirin for Prevention of Morbidity and Mortality From Preeclampsia

IN RESPONSE: Dr. Roberge and colleagues suggest that alternate analyses of our data reveal important effects of the timing of initiation of low-dose aspirin therapy for preventing preeclampsia, intrauterine growth restriction, and preterm birth. Unfortunately, meta-analyses of the available evidence are not well-suited for identifying such effects. Many of the included studies enrolled women initiating treatment across a range of gestational ages. Of note, the 2 largest included trials cannot be precisely classified, having enrolled participants beginning at 12 to 13 weeks of gestation, with 49% initiating aspirin therapy before 20 weeks of gestation in the MFMU (Maternal-Fetal Medicine Units) trial (1) and 69% doing so at 20 weeks of gestation or earlier in CLASP (2).We did sensitivity analyses using the stratification of studies suggested by Dr. Roberge and colleagues but used metaregression with the KnappHartung modification, a more conservative test that accounts for small samples. Our results were similar for preterm birth and intrauterine growth restriction but did not significantly differ for preeclampsia between early and late initiation. Our review reported evidence of small-study effects for preterm birth and intrauterine growth restriction, possibly because of publication bias. With the categorization recommended by Dr. Roberge and colleagues, only the small studies would be pooled in the group of women who began therapy before 16 weeks of gestation, heightening the risk for drawing conclusions from a biased subset of the evidence. Confounding was evident in metaregression, because the effects of early initiation lost statistical significance when we controlled for sample size and population risk. Beyond our concerns about small-study effects and confounding, when investigating study-level characteristics to apply to individuals, there is risk of bias due to the ecological fallacy. Within-study results that examine individuals are more likely to be valid. Both of the large studies included in our review reported subgroup analyses, finding no differences in effects using the cut point of 20 weeks of gestation. Moreover, an important individual-patient data meta-analysis done by the Perinatal Antiplatelet Review of International Studies (PARIS) Collaboration was able to categorize patients rather than studies and found no evidence of effect differences by timing of aspirin initiation (3). We continue to believe that current evidence does not support claims of differential effects by timing of aspirin initiation. Our review, a previous Cochrane review (4), and individual patient-data meta-analyses suggest that modest benefits may be obtained with initiation of low-dose aspirin therapy even after 20 weeks of gestation (3). Nonetheless, we wholly support recommendations for well-designed trials to test whether initiation before 16 weeks confers more benefit.