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

Jillian T. Henderson, PhD, MPH; Evelyn P. Whitlock, MD, MPH; Elizabeth O’Connor, PhD; Caitlyn A. Senger, MPH; Jamie H. Thompson, MPH; and Maya G. Rowland, MPH
[+] Article and Author Information

This article was published online first at www.annals.org on 8 April 2014.


From Kaiser Permanente Northwest, Portland, Oregon.

Note: This review was conducted by the Kaiser Permanente Research Affiliates Evidence-based Practice Center under contract to AHRQ. AHRQ staff provided oversight for the project and assisted in the external review of the companion draft evidence synthesis.

Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by AHRQ or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank the AHRQ staff; members of the USPSTF; James M. Roberts, MD, Lisa M. Askie, MD, Emmanuel Bujold, MD, MSc, Aaron B. Caughey, MD, MPH, Maurice Druzin, MD, Ramon Hermida, PhD, Baha M. Sibai, MD, Helen J. Barr, MD, Yuling Hong, MD, PhD, MSc, Uma M. Reddy, MD, MPH, Caroline Signore, MD, MPH, and Catherine Y. Sprong, MD, for providing expert and federal partner review of the report; and Carrie Patnode, Kevin Lutz, Smyth Lai, and Keshia Bigler at the Kaiser Permanente Center for Health Research.

Financial Support: By contract HHS-290-2012-00015-I, task order 3, from AHRQ.

Disclosures: Dr. Whitlock reports being paid by contract to conduct the systematic review independently for use by the U.S. Preventive Services Task Force. Dr. O’Connor reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Ms. Senger reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Ms. Rowland reports grants from the Agency for Healthcare Research and Quality outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2844.

Requests for Single Reprints: Reprints are available from the AHRQ Web site (www.ahrq.gov).

Current Author Addresses: Drs. Henderson, Whitlock, and O’Connor; Ms. Senger; Ms. Thompson; and Ms. Rowland: Kaiser Permanente Center for Health Research, 3800 North Interstate Avenue, Portland, OR 97227.

Author Contributions: Conception and design: J.T. Henderson, E.P. Whitlock.

Analysis and interpretation of the data: J.T. Henderson, E.P. Whitlock, E. O’Connor, C.A. Senger, J.H. Thompson.

Drafting of the article: J.T. Henderson, E.P. Whitlock.

Critical revision of the article for important intellectual content: J.T. Henderson, E.P. Whitlock, E. O’Connor, C.A. Senger, J.H. Thompson.

Final approval of the article: J.T. Henderson, E.P. Whitlock, E. O’Connor, C.A. Senger, J.H. Thompson, M.G. Rowland.

Provision of study materials or patients: C.A. Senger, J.H. Thompson, M.G. Rowland.

Statistical expertise: E. O’Connor.

Obtaining of funding: E.P. Whitlock.

Administrative, technical, or logistic support: C.A. Senger, J.H. Thompson, M.G. Rowland.

Collection and assembly of data: C.A. Senger, J.H. Thompson, M.G. Rowland.


Ann Intern Med. 2014;160(10):695-703. doi:10.7326/M13-2844
Text Size: A A A

Background: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality.

Purpose: To systematically review benefits and harms of low-dose aspirin for preventing morbidity and mortality from preeclampsia.

Data Sources: MEDLINE, Database of Abstracts of Reviews of Effects, PubMed, and Cochrane Central Register of Controlled Trials (January 2006 to June 2013); previous systematic reviews, clinical trial registries, and surveillance searches for large studies (June 2013 to February 2014).

Study Selection: Randomized, controlled trials (RCTs) to assess benefits among women at high preeclampsia risk and RCTs or large cohort studies of harms among women at any risk level. English-language studies of fair or good quality were included.

Data Extraction: Dual quality assessment and abstraction of studies.

Data Synthesis: Two large, multisite RCTs and 13 smaller RCTs of high-risk women (8 good-quality) were included, in addition to 6 RCTs and 2 observational studies of average-risk women to assess harms (7 good-quality). Depending on baseline risk, aspirin use was associated with absolute risk reductions of 2% to 5% for preeclampsia (relative risk [RR], 0.76 [95% CI, 0.62 to 0.95]), 1% to 5% for intrauterine growth restriction (RR, 0.80 [CI, 0.65 to 0.99]), and 2% to 4% for preterm birth (RR, 0.86 [CI, 0.76 to 0.98]). No significant perinatal or maternal harms were identified, but rare harms could not be ruled out. Evidence on long-term outcomes was sparse, but 18-month follow-up from the largest trial found no developmental harms.

Limitations: Benefits may have been overestimated due to small-study effects. Predictive intervals were not statistically significant. Future studies could shift findings toward the null.

Conclusion: Daily low-dose aspirin beginning as early as the second trimester prevented clinically important health outcomes. No harms were identified, but long-term evidence was limited.

Primary Funding Source: Agency for Healthcare Research and Quality.

Figures

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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.

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Grahic Jump Location
Appendix Figure 2.

Summary of evidence search and selection.

The diagram excludes 51 RefMan (Thomson Reuters, Philadelphia, Pennsylvania) citations that were pulled for background or informational purposes only and were not systematically reviewed. KQ = key question.

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Grahic Jump Location
Figure 1.

Pooled analysis of preterm birth from trials of women at risk for preeclampsia, sorted by sample size.

CLASP = Collaborative Low-dose Aspirin Study in Pregnancy; MFMU = Maternal-Fetal Medicine Units; NR = not reported; PE = preeclampsia; RR = relative risk.

* From random-effects analysis.

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Grahic Jump Location
Figure 2.

Pooled analysis of intrauterine growth restriction from trials of women at risk for preeclampsia, sorted by sample size.

CLASP = Collaborative Low-dose Aspirin Study in Pregnancy; MFMU = Maternal-Fetal Medicine Units; NR = not reported; PE = preeclampsia; RR = relative risk.

* From random-effects analysis.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Pooled analysis of preeclampsia from trials of women at risk for preeclampsia, sorted by sample size.

CLASP = Collaborative Low-dose Aspirin Study in Pregnancy; MFMU = Maternal-Fetal Medicine Units; PE = preeclampsia; RR = relative risk.

* From random-effects analysis.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.

Pooled analysis of perinatal mortality from all trials, sorted by sample size.

CLASP = Collaborative Low-dose Aspirin Study in Pregnancy; MFMU = Maternal-Fetal Medicine Units; NR = not reported; PE = preeclampsia; RR = relative risk.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 4.

Pooled analysis of placental abruption from all trials, sorted by sample size.

CLASP = Collaborative Low-dose Aspirin Study in Pregnancy; MFMU = Maternal-Fetal Medicine Units; PE = preeclampsia; RR = relative risk.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 5.

Pooled analysis of intracranial fetal bleeding from all trials, sorted by sample size.

CLASP = Collaborative Low-dose Aspirin Study in Pregnancy; MFMU = Maternal-Fetal Medicine Units; NR = not reported; PE = preeclampsia; RR = relative risk.

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Low-dose aspirin for the prevention of preterm birth, preeclampsia and fetal growth restriction
Posted on April 17, 2014
Stéphanie Roberge, Msc, Suzanne Demers, MD, Emmanuel Bujold, MD, Msc
Department of Social and Preventive medicine & Obstetrics and Gynecology; Université Laval, Québec, Qc, Canada
Conflict of Interest: None Declared
To the Editors,

We read with great interest the review by Henderson et al. who observed that low-dose aspirin reduces the risk of preterm birth, preeclampsia and intra-uterine growth restriction (IUGR).(1) However, we believe that some important details should have been developed before concluding that low-dose aspirin should be started after the 1st trimester. While the authors reported that 8 trials initiated low-dose aspirin treatment before 16 weeks’ gestation, only 5 of them effectively randomized study participants at mean (or median) gestational age before 16 weeks. For example, the CLASP trial initiated randomization at 12 weeks, but some women were randomized as late as 32 weeks’ gestation for mean gestational age of 19.4 weeks at randomization.(2)

After stratification of the studies according to mean or median gestational age at initiation of low-dose aspirin, we repeated meta-analyses for the 3 main outcomes using the same data collected by the authors. Five trials recruited 854 women at mean gestational age ≤16 weeks and 8 trials recruited 11,330 women at mean gestational age >16 weeks. According to gestational age at initiation of low-dose aspirin, the Mantzel-Hentzel test indicated significant differences in the relative risk of IUGR (0.45, 95% CI: 0.29-0.69 vs 0.94, 95% CI: 0.80-1.12, p=0.002) and preterm birth (0.33, 95% CI: 0.17-0.66 vs 0.91, 95% CI: 0.85-0.97, p=0.004), suggesting greater benefits of low-dose aspirin started ≤16 weeks, with a similar trend for preeclampsia (0.56, 95% CI: 0.37-0.85 vs 0.85, 95% CI: 0.68-1.06, p=0.08). The 4 trials that recruited most of their participants in the 1st trimester (<14 weeks) showed greater and significant reduction of preeclampsia (0.50, 95% CI: 0.31-0.79, p<0.001) than studies that recruited women mainly in the 2nd and 3rd trimesters (0.86, 95% CI: 0.70-1.04, not significant). According to these analyses, initiation of low-dose aspirin at mean gestational age ≤16 weeks is associated with significant reduction of all 3 outcomes of about 50% while low-dose aspirin initiated in the 2nd trimester is not. This is concordant with the findings of our earlier meta-analyses that included a larger number of trials.(3, 4)

We agree that a large randomized trial should be performed to confirm the benefits of low-dose aspirin started in the 1st trimester for the prevention of adverse pregnancy outcomes in high-risk women. On the other hand, the literature shows very slight benefits, if any, of low-dose aspirin initiated after 16 weeks’ gestation. Therefore, we believe that low-dose aspirin should be started at around 12 weeks’ gestation, in agreement with other national society recommendations, and should not be delayed until the 2nd trimester in women identified at high-risk for adverse placenta-mediated outcomes of pregnancy.(5)

References
1. Henderson JT, Whitlock EP, O'Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: A systematic evidence review for the u.S. Preventive services task force. Ann Intern Med. 2014
2. CLASP CL-dASiPCG. Clasp: A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet 1994;343:619-629
3. Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: A meta-analysis. Ultrasound Obstet Gynecol. 2013;41:491-499
4. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguere Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: A meta-analysis. Obstet Gynecol. 2010;116:402-414
5. Nice clinical guideline. National collaborating centre for women’s and children’s health. Commissioned by the national institute for health and clinical excellence. Hypertension in pregnancy: The management of hypertensive disorders during pregnancy . Cg107. Http://guidance.Nice.Org.Uk/cg107. 2012



Author's Response
Posted on July 18, 2014
Jillian T. Henderson, PhD. MPH, Evelyn P. Whitlock, MD, MPH, Elizabeth O'Connor, PhD
Kaiser Permanente
Conflict of Interest: None Declared
In response

Roberge et al. suggest that alternate analyses of our data reveal important effects of the timing of initiation of low-dose aspirin for preventing preeclampsia, IUGR, 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. Importantly, the two largest included trials cannot be precisely classified, having enrolled participants beginning at 12 to 13 weeks, with 49% initiating aspirin before 20 weeks in the MFMU trial (1) and 69% 20 weeks or earlier in the CLASP trial (2). We conducted sensitivity analysis using the stratification of studies suggested by Roberge et al., but used meta-regression with the Knapp Hartung modification, a more conservative test that accounts for small samples. Our results were similar for preterm birth and IUGR, but we did not find a statistically significant difference between early and late initiation for preeclampsia. For preterm birth and IUGR, our article reported evidence of small study effects for these outcomes, possibly owing to publication bias (3). With the categorization recommended by Roberge at al., only the small studies are pooled in the <16 week group, heightening the risk of drawing conclusions from a biased subset of the evidence. Confounding was evident in meta-regression, as early initiation effects 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 20 week gestation cut points. Moreover, an important individual patient data meta-analysis conducted by the PARIS Collaboration was able to categorize patients rather than studies, and found no evidence of effect differences by aspirin timing (4).
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 (5), and individual patient data meta-analysis suggest that modest benefits may be obtained with initiation of low-dose aspirin, even after 20 weeks gestation (4). Nonetheless, we wholly support recommendations for well-designed trials to test whether initiation before 16 weeks confers more benefit.

References
1. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E et al. Low-Dose Aspirin to Prevent Preeclampsia in Women at High Risk. N Engl J Med. 1998;338:701-705. [PMID: 9494145]
2. CLASP: A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia. Lancet. 1994;343:619. [PMID: 7906809]
3. Henderson JT, Whitlock EP, O'Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;160:695-703. [PMID: 1859300 [pii];10.7326/M13-2844 [doi]]
4. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for preventing pre-eclampsia and its complications. Lancet. 2007;369:1791-1798. [PMID: 17512048]
5. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007;CD004659. [PMID: 17443552]


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