• DOI:10.7326/M13-2844
• Corpus ID: 33835367

Low-Dose Aspirin for Prevention of Morbidity and Mortality From Preeclampsia: A Systematic Evidence Review for the U.S. Preventive Services Task Force

@article{Henderson2014LowDoseAF,
  title={Low-Dose Aspirin for Prevention of Morbidity and Mortality From Preeclampsia: A Systematic Evidence Review for the U.S. Preventive Services Task Force},
  author={Jillian T. Henderson and Evelyn P. Whitlock and Elizabeth A. O’Connor and Caitlyn A. Senger and Jamie H. Thompson and Maya G Rowland},
  journal={Annals of Internal Medicine},
  year={2014},
  volume={160},
  pages={695-703}
}

• J. Henderson, E. Whitlock, +3 authors Maya G Rowland
• Published 20 May 2014
• Medicine
• Annals of Internal Medicine

Preeclampsia is a leading cause of maternal death, affecting 2% to 8% of pregnancies globally (1, 2). It affected 3.8% of U.S. deliveries in 2010, and the rate of severe preeclampsia has increased over the past 3 decades (3). Perinatal mortality is nearly 2 times higher in pregnancies affected by preeclampsia (4), with 12% of maternal deaths due to the condition (5). Serious illness is more common, with more than one third of serious maternal morbidity and 15% of preterm births related to preeclampsia (6, 7). Preeclampsia is defined as hypertension (blood pressure 140/90 mm Hg) and proteinuria (presence of 0.3 g of protein in a 24-hour period) observed during the second half of pregnancy (>20 weeks of gestation) (8, 9). It is also classified as having severe features with any of the following: blood pressure above 160/110 mm Hg, thrombocytopenia, impaired liver function, renal insufficiency, pulmonary edema, or cerebral or visual disturbances (9). Preeclampsia with or without severe features can evolve rapidly into eclampsia or the hemolysis, elevated liver enzymes, and low platelets syndrome, sometimes leading to systemic complications and maternal death (10, 11). Poor perinatal health outcomes are associated with preeclampsia, primarily due to increased risk for intrauterine growth restriction (IUGR) or medically initiated preterm delivery. Once preeclampsia develops, the only effective treatment is delivery, with serious neonatal harms when remote from term (<34 weeks of gestation). Current understanding of preeclampsia pathophysiology suggests that it may be a collection of syndromes with different precipitating factors and outcomes (12). Early in pregnancy, aberrations in placental development can result in placental ischemia and release of inflammatory and oxidative stress factors into the maternal bloodstream. In addition, even with normal placentation, preexisting hypertension, diabetes, and other inflammatory conditions (such as lupus) may activate systemic inflammatory and oxidative stress processes, as can twin or higher-order pregnancies. Accurate prediction of who will develop preeclampsia and have serious complications is not currently possible (1315). The most consistent predictors of high risk are previous preeclampsia, certain medical conditions (diabetes, chronic hypertension, renal disease, autoimmune diseases, and the antiphospholipid syndrome), and multifetal pregnancy (16). Moderately elevated risk for preeclampsia is associated with nulliparity (first birth), advanced maternal age (40 years), between-pregnancy interval of more than 10 years, high body mass index (35 kg/m2), and family history of preeclampsia (mother or sister). Risk factors with less consistent evidence include changes in paternity between pregnancies, history of migraine headaches (17, 18), and asthma (17, 1922). Predictive models combining various biomarkers, patient risk factors, and clinical readings hold promise but are not yet sufficiently validated for clinical use (10, 2325). Previous comprehensive systematic reviews have found antiplatelets (primarily low-dose aspirin) to be beneficial for the prevention of preeclampsia among women at heightened risk (26, 27). We conducted this systematic review to support the U.S. Preventive Services Task Force (USPSTF) in updating its 1996 recommendation, which is no longer active. Methods Detailed methods are outlined in our full evidence report (28). This review addressed 3 key questions (Appendix Figure 1). First, is low-dose aspirin effective for reducing adverse maternal and perinatal health outcomes among women at increased risk for preeclampsia? Second, is low-dose aspirin effective for preventing preeclampsia among women at increased risk for the condition? Third, are there harms to the woman and fetus associated with aspirin use during pregnancy? Appendix Figure 1. Analytic framework and key questions. ARDS = acute respiratory distress syndrome; HELLP = hemolysis, elevated liver enzymes, and low platelets. *Abbreviated list of health outcomes. See Appendix Table 2 for a full list. Data Sources and Searches In addition to considering all studies from the previous USPSTF review, we performed a comprehensive search of MEDLINE, PubMed, the Database of Abstracts of Reviews of Effects, and the Cochrane Central Register of Controlled Trials for studies published between January 2006 and 1 June 2013. We also examined the reference lists from existing systematic reviews to identify potentially eligible studies, including an individual-patient data (IPD) meta-analysis published by the Perinatal Antiplatelet Review of International Studies (PARIS) Collaboration (27) and a 2007 Cochrane review (26). We searched ClinicalTrials.gov for ongoing trials (May 2013). Between the last search date and this publication, we actively monitored published literature for potentially important new trials or other large observational studies directly relevant to our key questions; none were identified. Study Selection Two investigators independently reviewed abstracts and full-text articles for inclusion according to predetermined criteria. We resolved discrepancies through consensus with a third investigator. To evaluate benefits of aspirin prophylaxis, we included any study that used a risk selection approach aimed at achieving a sample of women at high risk for preeclampsia. The trials could define risk on the basis of medical history, pregnancy characteristics, or clinical measurements known to be associated with risk for the condition. Although preeclampsia occurs more often in first births than in subsequent ones, prevalence rates are relatively low (approximately 4%) compared with other high-risk groups. Because aspirin treatment based only on this risk factor has not been supported, trials with nulliparity as the sole risk factor were not included for evaluation of benefits. We used broader inclusion criteria to identify possible harms of aspirin exposure during pregnancy. The trials of women at high risk were combined with trials of women at low or average risk exposed to daily low-dose aspirin. Large prospective observational studies were also included to assess harms but were not included in pooled analyses. We included interventions that compared patients receiving 50 to 150 mg of aspirin with a placebo or no treatment group and excluded studies of nonaspirin antiplatelet medications or aspirin combined with another active substance. We also excluded studies that we rated as poor-quality on the basis of the USPSTF quality rating standards (29) and studies not published in English. Data Extraction and Quality Assessment Two investigators critically appraised all included studies independently using the USPSTF's design-specific criteria (29), which we supplemented with the National Institute for Health and Care Excellence methodology checklists (30) and the Newcastle-Ottawa Scale (31). According to the USPSTF criteria, a good-quality study met all prespecified standards. A fair-quality study did not meet (or it was unclear whether it met) at least 1 criterion, but it also had no known limitation that could invalidate its results. A poor-quality study had a single fatal flaw or multiple important limitations that could seriously bias its results. Discrepancies were resolved through discussion of identified limitations and consultation with a third investigator, if necessary. One investigator extracted study details and results, and a second investigator reviewed the abstracted information. Data Synthesis and Analysis We used the metan procedure in Stata, version 11.2 (StataCorp, College Station, Texas), for all reported meta-analyses and the metaan procedure for sensitivity analyses (32). For dichotomous outcomes, we entered the number of events and nonevents and estimated pooled random-effects risk ratios by using the DerSimonianLaird method for all outcomes, except those in which fewer than 10% of the participants had the event (33), for which we used a fixed-effects MantelHaenszel model (34). We also included prediction intervals in forest plots of random-effects models, which provided an estimate of where the effect size from 95% of newly conducted trials would fall, assuming that the between-study variability in the included trials held for new trials (35). The prediction intervals are shown on the forest plots by the horizontal lines that extend from the diamond representing the 95% CI of the pooled estimate. Potential sources of heterogeneity in effect size by aspirin timing, dosage, and preeclampsia risk determination were identified a priori and explored using meta regression and visual inspection of sorted forest plots. We used the I 2 and chi-square statistics to assess statistical heterogeneity. To evaluate small-study effects, we examined funnel plots and used the Begg or Peter test depending on the outcome distribution (36, 37). We used profile likelihood estimation to conduct sensitivity analyses for the pooled effects because the DerSimonianLaird method can overestimate CI precision in meta-analysis, particularly when fewer than 10 studies or when smaller studies with few events are pooled (38). Role of the Funding Source This study was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Members of the USPSTF and the AHRQ medical officer assisted in the development of the review's scope. Approval from AHRQ was required before the manuscript could be submitted for publication, but the authors are solely responsible for its content and the decision to submit it for publication. Results Our literature search yielded 544 unique citations. From these, we reviewed the full text of 75 articles. Twenty-three studies (27 articles) met our inclusion criteria (Appendix Figure 2 and Appendix Table 1). Appendix Figure 2. Summary of evidence search and selection. The diagram excludes 51 RefMan (Thomson Reuters, Philadelph