Final Evidence Summary
Low-Dose Aspirin Use for the Prevention of Morbidity and Mortality From Preeclampsia: Preventive Medication
April 08, 2014
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Release Date: April 8, 2014
By 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
The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.
This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
This article was first published in Annals of Internal Medicine on April 8, 2014 (Ann Intern Med 2014; http://www.annals.org). Select for copyright and source information.
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 through 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.
Limitation: 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.
Preeclampsia is a leading cause of maternal death, affecting 2% to 8% of pregnancies globally1, 2. It affected 3.8% of U.S. deliveries in 2010, and the rate of severe preeclampsia has increased over the past 3 decades3. Perinatal mortality is nearly 2 times higher in pregnancies affected by preeclampsia4, with 12% of maternal deaths due to the condition5. Serious illness is more common, with more than one third of serious maternal morbidity and 15% of preterm births related to preeclampsia6, 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 death10, 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 outcomes12. 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 possible13–15. 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 pregnancy16. 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 headaches17, 18, and asthma17, 19–22. Predictive models combining various biomarkers, patient risk factors, and clinical readings hold promise but are not yet sufficiently validated for clinical use10, 23–25.
Previous comprehensive systematic reviews have found antiplatelets (primarily low-dose aspirin) to be beneficial for the prevention of preeclampsia among women at heightened risk26, 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.
Detailed methods are outlined in our full evidence report28. 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?
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) Collaboration27 and a 2007 Cochrane review26. 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.
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 standards29 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 criteria29, which we supplemented with the National Institute for Health and Care Excellence methodology checklists30 and the Newcastle-Ottawa Scale31. 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 analyses32. For dichotomous outcomes, we entered the number of events and nonevents and estimated pooled random-effects risk ratios by using the DerSimonian–Laird method for all outcomes, except those in which fewer than 10% of the participants had the event33, for which we used a fixed-effects Mantel–Haenszel model34. 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 trials35. 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 I2 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 distribution36, 37. We used profile likelihood estimation to conduct sensitivity analyses for the pooled effects because the DerSimonian–Laird method can overestimate CI precision in meta-analysis, particularly when fewer than 10 studies or when smaller studies with few events are pooled38.
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.
Our literature search yielded 525 unique citations. From these, we reviewed the full text of 73 articles. Twenty-three studies (27 articles) met our inclusion criteria (Appendix Figure 2 and Appendix Table 1).
We identified 15 randomized, controlled trials (RCTs) (8 good-quality) that met inclusion criteria for evaluation of maternal and perinatal health benefits from aspirin chemoprevention and 13 RCTs (8 good-quality) reporting preeclampsia incidence with and without low-dose aspirin among women at high risk. We identified 21 studies (14 good-quality) to evaluate maternal, perinatal, and developmental harms with antenatal aspirin use, including all 15 trials in women at high preeclampsia risk. Eighteen trials described adequate randomization, with 2 trials not clearly reporting appropriate allocation concealment39, 40. All RCTs reported valid outcome measures, and all but 1 study reported using identical placebo formulations41. Adherence to treatment was high, with 14 trials reporting adherence of approximately 80% or greater among participants. All but 11 studies reported attrition, which ranged from 3.3% to 20.4%. Seven studies reported no loss to follow-up.
Overall, women included in the trials were young (mean age ranged from 20.3 to 31 years) and predominantly white (assumed from trial country of origin and reported data), although 3 trials42–44 reported majorities of black women in their samples. Only 9 of the 23 studies included in this review reported race or ethnicity40, 42–49. Study details are provided in Appendix Table 2.
None of the trials initiated treatment before 12 weeks of gestation, and 8 trials initiated treatment before 16 weeks. Treatment was often continued until delivery, but 6 trials40, 44, 46, 47, 50, 51 stopped treatment earlier. Daily aspirin doses ranged from 60 to 150 mg, with 1 trial reporting a dose of 0.5 mg/kg of body weight41. Most trials used doses of 60 mg (6 trials42–44, 52–54]) or 100 mg (8 trials[39, 40, 47, 50, 51, 55–57]).
Benefits of Low-Dose Aspirin Treatment
For perinatal death, the fixed-effects pooled estimate from 10 trials in high-risk women40, 44, 46, 49, 52–56, 58 (12,240 participants) suggested a possible reduced risk with low-dose aspirin use (relative risk [RR], 0.81 [95% CI, 0.65 to 1.01]; I2 = 0%), but the result was not statistically significant (Table). Three of the 4 trials with lower mortality in the placebo group had sample sizes of 100 or fewer per group (40, 54, 58). The fourth study was larger (554 participants), used a higher aspirin dose (150 mg), and enrolled women on the basis of abnormal readings on uterine artery ultrasonograms at 22 to 24 weeks of gestation46; the total number of events was 11.
We found evidence of a risk reduction of 14% for preterm birth (<37 weeks of gestation) (RR, 0.86 [CI, 0.76 to 0.98]; I2 = 33.2%) in a meta-analysis of 10 trials with the outcome (11,779 participants) (Figure 1)39, 40, 44, 46, 47, 52–56, 58. There was evidence of a 20% reduction in IUGR (RR, 0.80 [CI, 0.65 to 0.99]; I2 = 36.0%; 13 trials[39, 41, 44, 46, 47, 49, 50, 52–56, 58]; 12,504 participants) (Figure 2). Sensitivity analyses using the profile likelihood method did not change these estimates; however, the upper 95% confidence limits for both were close to the null and the predictive intervals suggested that future studies could shift pooled estimates toward nonsignificance. We also found evidence of small-study effects based on funnel plot asymmetry for preterm birth (Peter test P = 0.048) and IUGR (Peter test P = 0.018).
Consistent with reduced rates of preterm birth and IUGR, treatment was associated with an average birthweight increase of 130 g (CI, 36.22 to 223.33 g; I2 = 60.0%; P = 0.010), with moderate heterogeneity among studies (data not shown). There also was a 24% reduction in preeclampsia (RR, 0.76 [CI, 0.62 to 0.95]) with aspirin treatment (13 trials; 12,184 participants) (Figure 3). Heterogeneity of preeclampsia incidence was moderate (I2 = 40.5%; P = 0.064), and there was evidence of small-study effects (Peter test P = 0.028).
We did not find evidence in prespecified stratified comparisons that the timing of aspirin administration (<16 weeks) or the dosage had different effects. The estimated risk reduction was greater in studies using more than 75 mg of aspirin (RR, 0.58 [CI, 0.36 to 0.95]) than in those using less than 75 mg (RR, 0.85 [CI, 0.68 to 1.05]), but the difference in the effect size was not significant. Analysis of the effect of dosage also was confounded by unequal distribution of sample sizes in different dosage categories because both of the large studies used doses of 60 mg44, 53.
Harms of Aspirin Treatment
We found no evidence of perinatal mortality harms from low-dose aspirin exposure during pregnancy, even with the addition of average-risk study populations to the fixed-effects model (RR, 0.92 [CI, 0.76 to 1.11]; I2 = 0%; P = 0.65) (Table and Appendix Figure 3). Eleven trials (23,332 participants) reported on placental abruption (6 in women at increased preeclampsia risk [39, 44, 46, 53, 56, 58] and 5 in women at low or average risk [42, 43, 48, 51, 59]) (Appendix Figure 4). Results of fixed-effects meta-analysis suggested possible increases in abruption but were not statistically significant (RR, 1.17 [CI, 0.93 to 1.48]) (Table). Studies were somewhat heterogeneous (I2 = 36.4%; P = 0.138). The pooled placental abruption estimate from studies of women at elevated preeclampsia risk (RR, 1.12 [CI, 0.86 to 1.46]; I2 = 50.1%; P = 0.135) was similar to the estimate among women at all risk levels. No significant harm of perinatal death or abruption was found, but low event rates and studies with no events could introduce bias when effects are pooled, thus increasing statistical uncertainty. For perinatal death, however, the nonsignificant estimates and direction of effect support no harm, and possibly a benefit, with low-dose aspirin prophylaxis.
Meta-analysis of 7 trials (outcome reported for 6 trials in women at high preeclampsia risk[39, 44, 46, 53–55] and 3 in women at low or average risk[43, 51, 59]; 22,616 total participants; 2 trials reported no events) indicated no treatment differences in rates of postpartum hemorrhage (RR, 1.02 [CI, 0.96 to 1.09]). We also found no evidence that low-dose aspirin affected mean blood loss; all 5 trials reporting the outcome (41, 43, 49, 52, 58) found either slightly lower mean blood loss or equivalent amounts between study groups. Of the 10 trials reporting on intracranial hemorrhage in neonates39, 43, 44, 47, 49, 51–53, 59, 60, 4 reported no events in either study group (22,457 participants)39, 47, 49, 52. All but 1 trial (44) reported more events in the placebo group. The fixed-effects pooled risk ratio was 0.84 (CI, 0.61 to 1.16), and heterogeneity was low (I2 = 27.1%; P = 0.23) (Appendix Figure 5).
Two observational studies on aspirin use during pregnancy had null findings for the potentially harmful outcomes considered (miscarriage and cryptorchidism)45, 61. Follow-up data from the large CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) trial reported no differences in developmental outcomes of the infants up to age 18 months and no treatment group differences in hospital visits, gross motor development, or height and weight62. Seven trials reported adverse events during the trial40, 41, 46, 47, 49, 50, 53. In most cases, single adverse events were concluded to be unrelated to treatment. Two studies reported women dropping out of treatment because of itching of the throat and epigastric pain41, 46.
Sensitivity analyses using an alternate method for estimating the pooled random effects resulted in similar point estimates and CIs and did not change the statistical significance of our findings for any benefits or harms.
Daily prophylaxis with low-dose aspirin beginning after the first trimester reduced risk for preterm birth by 14% and for IUGR by 20%. The risk reduction of 24% for preeclampsia among high-risk women supports the causal pathway for perinatal health benefits. Our confidence in the magnitude of the pooled result, however, is tempered by evidence of small-study effects and modest findings in the 2 largest trials. Risk reductions closer to 10% for preeclampsia, IUGR, and preterm birth represent a more conservative interpretation of the results.
Although aspirin use in pregnancy does not seem to increase perinatal mortality, whether it prevents this outcome is unclear. Given the rarity of the outcome and the limited number of high-risk women studied, available evidence cannot rule out the possibility of a 20% reduction in perinatal mortality.
Absolute risk reductions were calculated on the basis of event rates in the trial data at 25th- and 75th-percentile incidence levels for the outcome. These were 10% and 23% for preeclampsia, 7% and 24% for IUGR, and 11% and 31% for preterm birth. Treatment was associated with absolute risk reductions of 2% to 5% for preeclampsia, 1% to 5% for IUGR, and 2% to 4% for preterm birth. Although no short-term harms seem to be associated with low-dose aspirin use during pregnancy, the evidence on long-term outcomes for offspring with in utero aspirin exposure is limited. Follow-up data from one large RCT were reassuring62, with no differences in physical or mental development at 18 months.
Our findings are generally consistent with the results of the most recent Cochrane review (26), which included 65 trials (1965 to 2007), and those from the PARIS Collaboration IPD meta-analysis27, which included data from 31 RCTs (32,217 women and 32,819 infants). Our review found similar effect estimates for preeclampsia, IUGR, preterm birth, and perinatal mortality, particularly compared with the PARIS results, despite differences in study inclusion criteria and the fact that our literature search was more recent. The PARIS Collaboration was able to meta-analyze an outcome not consistently available in the published literature27 and found that aspirin treatment reduced the need for assisted ventilation of infants after delivery by 21% (P = 0.01).
Timing and dosage of aspirin treatment had no consistent effect on outcomes. Comparisons of dosage effects when a cut point of 75 mg was used revealed only 1 outcome with a significant difference: The preterm birth benefit was greater in studies using doses of at least 75 mg. Results for these stratified analyses, however, were confounded by study size; both large studies used 60 mg of aspirin. Forest plots sorted by dose did not indicate a dose–response relationship. The absence of convincing evidence for a dosage effect on benefits or harms is consistent with the PARIS Collaboration IPD meta-analysis27 and other recent systematic reviews63, 64. The Cochrane review, however, found greater benefit in studies using more than 75 mg of aspirin26.
Although included trials reported considerable variation in timing of treatment initiation, all started after the first trimester. In terms of cessation, only the large, U.S.-based MFMU (Maternal-Fetal Medicine Units) trial instructed women to stop treatment if preeclampsia developed; most trials instructed women to continue treatment until delivery. We found that initiating aspirin treatment at 12 to 16 weeks conferred no more benefit than starting later, consistent with the PARIS IPD meta-analysis27. However, another recent systematic review reported that starting treatment at no later than 16 weeks was associated with reduced preeclampsia risk64. Because some cases of preeclampsia may result from problems with the process of trophoblastic invasion completed around 16 weeks of gestation, the importance of initiating treatment before or during this process remains a salient research question65.
Estimated effect sizes were modest, but the averted outcomes are considered critical. Preterm birth is the cause of 70% of neonatal mortality and 75% of neonatal morbidity in developed countries66. Preterm neonates have higher rates of intraventricular hemorrhage, respiratory distress, infection, seizures, and rehospitalizations66, 67. Neonates with IUGR, even when born at term, are more likely to have respiratory distress, seizures, sepsis, and long-term disability66–69.
Although we did not find evidence of direct maternal health benefits, preventing preeclampsia could reduce medical intervention in pregnancy and delivery70–73. Preventing poor perinatal health outcomes could also confer quality-of-life benefits. Preeclampsia is associated with poor psychosocial outcomes, the posttraumatic stress syndrome, and postpartum depression74–77. Maternal health and paternal well-being should be considered in addition to perinatal health outcomes given the stress of caring for a preterm infant or a child with long-term health problems. Many studies also have found associations between preeclampsia and long-term cardiovascular health outcomes78, 79. Current estimates suggest a possible doubling or tripling of cardiovascular disease risk among women who have had preeclampsia during any pregnancy80, 81. It is unclear whether common risk factors or a causal relationship account for the association or whether there is a lifetime benefit from preeclampsia prevention.
Methods for determining high risk for preeclampsia varied considerably across trials, resulting in a wide range of preeclampsia incidence in the control groups (8% to 30%). Recent recommendations from the American Congress of Obstetricians and Gynecologists more narrowly defined the high-risk population for aspirin prophylaxis (women with preeclampsia during >1 previous pregnancy or with prior early preterm birth)9. We found no consistent pattern in effect size by incidence of preeclampsia. Tools to assess individual risk for the condition and to identify subgroups most likely to benefit are needed.
Our study has several limitations. We included only fair- to good-quality studies published in English. Some smaller studies had no events for rare outcomes, such as perinatal death and placental abruption, limiting evidence and the ability to summarize effects. The rarity of maternal morbidity and mortality outcomes did not permit their analysis. Observational studies offer hypothesis-generating evidence on long-term effects of aspirin exposure during pregnancy but have limited applicability and serious threats to validity. Those reporting associations between aspirin exposure and fetal or longer-term outcomes commonly lack information on dosage, timing, or regularity of exposure and often ascertain exposure retrospectively. Data from RCTs on women taking low-dose aspirin during pregnancy are more applicable than observational data, but information on long-term harms is sparse. The CLASP trial conducted an 18-month follow-up, but only for a subset of its sample. It was the only good-quality study that provided evidence on longer-term effects (cognition and growth) of in utero, low-dose aspirin exposure.
Cut points for IUGR were not consistently defined. Included studies used definitions ranging from less than the third percentile to less than the 10th percentile of birthweight for gestational age, with the latter definition from the American Congress of Obstetricians and Gynecologists most commonly used82.
Our review identified small-study effects26, 27, 44, with larger studies reporting more modest results. Two large trials provided the bulk of the data for pooled estimates of potential benefit44, 53. Three additional large studies were added for evaluation of harm43, 51, 59. Most of the large trials were national multisite studies43, 44 or international collaborations51, 53 Smaller studies have important merits in terms of the ability to closely monitor study protocols, but small trials with null findings may be more difficult to publish, potentially leading to inflated estimates of a treatment benefit69.
On the basis of the predictive intervals observed for pooled estimates from random-effects models, the distribution of future studies would include nonsignificant or negative trials. Thus, there is some uncertainty about the likely persistence of the observed effects with future research. If lessons from previous studies and the developing understanding of preeclampsia pathophysiology are incorporated, future trials may more accurately identify women at greatest risk and most likely to benefit.
In conclusion, our systematic review identified benefits of low-dose aspirin for prevention of preeclampsia and perinatal illness in women at high risk for preeclampsia. Potential rare or long-term harms could not be ruled out, but none were identified. Research is needed to address remaining uncertainties. More primary research is needed to illuminate how preeclampsia arising from different risk factors develops and responds to aspirin. More robust and consistent tools for preeclampsia risk stratification would support future research and clinical practice. Few trials have been conducted among African American women in the United States, who have the greatest disease burden; clinical research focused on this important subpopulation is urgently needed. For women at high risk for preeclampsia, available evidence indicates modest effects but important benefits of daily low-dose aspirin for prevention of the condition and consequent illness.
Source: This article was first published in Annals of Internal Medicine on April 8, 2014 (Ann Intern Med 2014).
Disclaimer: The authors of this article are responsible for its content. Statements in the article should not be construed as endorsements 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.
Potential Conflicts of Interest: 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.
AHRQ Publication No. 14-05207-EF-3
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60. Newnham JP, Godfrey M, Walters BJ, Phillips J, Evans SF. Low dose aspirin for the treatment of fetal growth restriction: a randomized controlled trial. Aust N Z J Obstet Gynaecol. 1995;35:370-4. [PMID: 8717556]
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|Outcome||High Preeclampsia Risk||All Preeclampsia Risk Levels Combined|
|RR (95% CI)||Trials, n||Participants, n||I2, %||P Value||RR (95% CI)||Trials, n||Participants, n||I2, %||P Value|
|Perinatal death†||0.81 (0.65–1.01)||10||12,240||0||0.78||0.92 (0.76–1.11)||14||22,848||0||0.65|
|Placental abruption‡||1.12 (0.86–1.46)||3||12,366||50.1||0.135||1.17 (0.93–1.48)||8||22,988||36.4||0.138|
RR = relative risk.
* Estimated using fixed-effects models because of low event rates.
† In trials of women at high risk, the total number of events and event rate were 310 and 0.0248, respectively. In trials among women at all risk levels, the values were 412 and 0.0177, respectively.
‡ In trials of women at high risk, the total number of events and event rate were 214 and 0.0168, respectively. In trials among women at all risk levels, the values were 276 and 0.0118, respectively.
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.
Figure 1 is a forest plot depicting the relative risk for preterm birth after aspirin prophylaxis and 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.
Figure 2 is a forest plot depicting the relative risk for intrauterine growth restriction (IUGR) after aspirin prophylaxis and 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.
Figure 3 is a forest plot depicting the relative risk for preeclampsia after aspirin prophylaxis.
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.
Appendix Figure 1 is an analytic framework that depicts the three Key Questions described in the Methods section of the report. In general, the figure illustrates how the use of aspirin prophylaxis to prevent preeclampsia and related adverse maternal and fetal health outcomes as well as possible harms.
The diagram excludes 51 RefMan citations that were pulled for background or informational purposes only and were not systematically reviewed.
KQ = key question.
Appendix Figure 2 is a flow chart that summarizes the search and selection of articles. There were 543 citations identified by searching MEDLINE, the Database of Abstracts of Reviews of Effects, PubMed, and the Cochrane Collaboration Registry of Controlled Trials. An additional 62 citations were identified from outside sources such as reference lists and suggestions from peer reviewers. After duplicates were removed, 525 unique citations were screened at the title/abstract stage. The full-text of 73 citations were examined for inclusion for one or more of the three Key Questions. The following number of articles were included for Key Question 1 (n=72), Key Question 2 (n=73), Key Question 3 (n=73).
CLASP = Collaborative Low-dose Aspirin Study in Pregnancy; MFMU = Maternal-Fetal Medicine Units; NR = not reported; PE = preeclampsia; RR = relative risk.
Appendix Figure 3 is a forest plot depicting the relative risk for perinatal mortality after aspirin prophylaxis and 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.
Appendix Figure 5 is a forest plot depicting the relative risk for intracranial fetal bleeding after aspirin prophylaxis and sorted by sample size.
|Study Citation||Key Question||Reason for Exclusion|
|Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Italian study of aspirin in pregnancy. Lancet. 1993;341:396-400. [PMID: 8094168]||1–3||Study quality|
|Bakhti A, Vaiman D. Prevention of gravidic endothelial hypertension by aspirin treatment administered from the 8th week of gestation. Hypertens Res. 2011;34:1116-20. [PMID: 21881579]||1–3||Geography|
|Benigni A, Gregorini G, Frusca T, Chiabrando C, Ballerini S, Valcamonico A, et al. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. N Engl J Med. 1989;321:357-62. [PMID: 2664523]||2||No relevant outcomes|
|Byaruhanga RN, Chipato T, Rusakaniko S. A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia. Int J Gynaecol Obstet. 1998;60:129-35. [PMID: 9509950]||1–3||Geography|
|Chandiramani M, Seed P, Poston L, Shennan AH. Antiplatelet agents for prevention of pre-eclampsia [Letter]. Lancet. 2007;370:1685; author reply 1685-6. [PMID: 18022031]||1–3||Study design|
|Chiaffarino F, Parazzini F, Paladini D, Acaia B, Ossola W, Marozio L, et al. A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 2004;112:142-4. [PMID: 14746947]||1–3||Study quality|
|Cowchock S, Reece EA. Do low-risk pregnant women with antiphospholipid antibodies need to be treated? Organizing Group of the Antiphospholipid Antibody Treatment Trial. Am J Obstet Gynecol. 1997;176:1099-100. [PMID: 9166175]||1–3||Population (KQs 1 and 2); no relevant outcomes (KQ3)|
|Cruickshank DJ, Robertson AA, Campbell DM, Macgillivray I. Maternal obstetric outcome measures in a randomised controlled study of labetalol in the treatment of hypertension in pregnancy. Hypertens Pregnancy. 1991;b10:333-44.||1–3||Study relevance (other compound or co-treatment)|
|Dasari R, Narang A, Vasishta K, Garewal G. Effect of maternal low dose aspirin on neonatal platelet function. Indian Pediatr. 1998;35:507-11. [PMID: 10216644]||1–3||Geography|
|Davies NJ, Gazvani MR, Farquharson RG, Walkinshaw SA. Low-dose aspirin in the prevention of hypertensive disorders of pregnancy in relatively low-risk nulliparous women. Hypertens Pregnancy. 1995;14:49-55.||1, 2||Population (healthy nulliparous women)|
|Ebrashy A, Ibrahim M, Marzook A, Yousef D. Usefulness of aspirin therapy in high-risk pregnant women with abnormal uterine artery Doppler ultrasound at 14-16 weeks pregnancy: randomized controlled clinical trial. Croat Med J. 2005;46:826-31. [PMID: 16158479]||1–3||Geography|
|Elder MG, de Swiet M, Sullivan M. A randomised trial of low dose aspirin for primiparae in pregnancy (Golding)/Barbados low dose aspirin study in pregnancy (BLASP) (Rotchell et al.) [Letter]. Br J Obstet Gynaecol. 1999;106:180. [PMID: 10426687]||1–3||Study design|
|Gallery EDM, Ross MR, Hawkins M, Leslie G, Györy ÁZ. Low-dose aspirin in high-risk pregnancy? Hypertens Pregnancy. 1997;16:229-38.||2||No relevant outcomes|
|Goffinet F, Bréart G, Uzan S. ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women [Letter]. Br J Obstet Gynaecol. 1996;103:719-20. [PMID: 8688404]||1–3||Geography|
|Golding J. A randomised trial of low dose aspirin for primiparae in pregnancy. The Jamaica Low Dose Aspirin Study Group. Br J Obstet Gynaecol. 1998;105:293-9. [PMID: 9532989]||1–3||Geography|
|Gunawardana L, Zammit S, Lewis G, Gunnell D, Hollis C, Wolke D, et al. Examining the association between maternal analgesic use during pregnancy and risk of psychotic symptoms during adolescence. Schizophr Res. 2011;126:220-5. [PMID: 21146371]||1–3||Study relevance (KQs 1 and 2); study quality (KQ3)|
|Hauth JC, Goldenberg RL, Parker CR Jr, Philips JB 3rd, Copper RL, DuBard MB, et al. Low-dose aspirin therapy to prevent preeclampsia. Am J Obstet Gynecol. 1993;168:1083-91; discussion 1091-3. [PMID: 8475955]||1, 2||Population (healthy nulliparous women)|
|Hermida RC, Ayala DE, Fernández JR, Mojóon A, Alonso I, Silva I, et al. Administration time-dependent effects of aspirin in women at differing risk for preeclampsia. Hypertension. 1999;34:1016-23. [PMID: 10523401]||3||No relevant outcomes|
|Hermida RC, Ayala DE, Iglesias M. Administration time-dependent influence of aspirin on blood pressure in pregnant women. Hypertension. 2003;41:651-6. [PMID: 12623974]||1–3||No relevant outcomes|
|Hernandez RK, Werler MM, Romitti P, Sun L, Anderka M; National Birth Defects Prevention Study. Nonsteroidal antiinflammatory drug use among women and the risk of birth defects. Am J Obstet Gynecol. 2012;206:228.e1-8. [PMID: 22196851]||1–3||No relevant outcomes|
|Jensen MS, Rebordosa C, Thulstrup AM, Toft G, Sørensen HT, Bonde JP, et al. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology. 2010;21:779-85. [PMID: 20805751]||1–3||Study design (KQs 1 and 2); study quality (KQ3)|
|Jensen MS, Henriksen TB, Rebordosa C, Thulstrup AM, Toft G, Sørensen HT, et al. Analgesics during pregnancy and cryptorchidism: additional analyses [Letter]. Epidemiology. 2011;22:610-2. [PMID: 21642784]||1–3||Study design|
|Keim SA, Klebanoff MA. Aspirin use and miscarriage risk. Epidemiology. 2006;17:435-9. [PMID: 16755260]||1, 2||Study design|
|Kincaid-Smith P, North RA, Fairley KF, Kloss M, Ihle BU. Prevention of pre-eclampsia in high risk women with renal disease: A prospective randomized trial of heparin and dipyridamole. Nephrology. 1995;1:297-300.||1–3||Study relevance (other compound
|Louden KA, Broughton Pipkin F, Symonds EM, Tuohy P, O’Callaghan C, Heptinstall S, et al. A randomized placebo-controlled study of the effect of low dose aspirin on platelet reactivity and serum thromboxane B2 production in non-pregnant women, in normal pregnancy, and in gestational hypertension. Br J Obstet Gynaecol. 1992;99:371-6. [PMID: 1622907]||1, 2||<20 participants|
|Marret S, Marchand L, Kaminski M, Larroque B, Arnaud C, Truffert P, et al; EPIPAGE Study Group. Prenatal low-dose aspirin and neurobehavioral outcomes of children born very preterm. Pediatrics. 2010;125:e29-34. [PMID: 20026499]||1–3||Study design (KQs 1 and 2);
|Michael CA, Walters BNJ. Low-dose aspirin in the prevention of pre-eclampsia: current evaluation. In: Teoh ERS, MacNaughton M, eds. Maternal Physiology and Pathology. Carnforth, United Kingdom: Parthenon; 1992:183-9.||1–3||Study quality|
|Miller EA, Rasmussen SA, Siega-Riz AM, Frías JL, Honein MA; National Birth Defects Prevention Study. Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study. Am J Med Genet C Semin Med Genet. 2010;154C:62-72. [PMID: 20104597]||1–3||Study design (KQs 1 and 2); study quality (KQ3)|
|Newnham JP, Godfrey M, Walters BJ, Phillips J, Evans SF. Low dose aspirin for the treatment of fetal growth restriction: a randomized controlled trial. Aust N Z J Obstet Gynaecol. 1995;35:370-4. [PMID: 8717556]||1, 2||Population|
|Ognjanovic S, Blair C, Spector LG, Robison LL, Roesler M, Ross JA. Analgesic use during pregnancy and risk of infant leukaemia: a Children's Oncology Group study. Br J Cancer. 2011;104:532-6. [PMID: 21157452]||1–3||Study quality|
|Porreco RP, Hickok DE, Williams MA, Krenning C. Low-dose aspirin and hypertension in pregnancy [Letter]. Lancet. 993;341:312.;[PMID: 8093955]||1–3||Study quality|
|Prakalapakorn SG, Rasmussen SA, Lambert SR, Honein MA; National Birth Defects Prevention Study. Assessment of risk factors for infantile cataracts using a case-control study: National Birth Defects Prevention Study, 2000-2004. Ophthalmology. 2010;117:1500-5. [PMID: 20363508]||1–3||Study design (KQs 1 and 2); study quality (KQ3)|
|Rai U, Chakravorty M, Juneja Y. Role of low dose aspirin in PIH. J Obstet Gynaecol India. 1993:883-6.||1–3||Geography|
|Ramaiya C, Mgaya HN. Low dose aspirin in prevention of pregnancy-induced hypertension in primigravidae at the Muhimbili Medical Center, Dar es Salaam. East Afr Med J. 1995;72:690-3. [PMID: 8904056]||1–3||Geography|
|Rivas-Echeverria CA, Echeverria Y, Molina L, Novoa D. Synergic use of aspirin, fish oil and vitamins C and E for the prevention of preeclampsia. Hypertens Pregnancy. 2000;19(Suppl 1):30.||1–3||Geography|
|Roberts JM, Catov JM. Aspirin for pre-eclampsia: compelling data on benefit and risk. Lancet. 2007;369:1765-6. [PMID: 17512047]||1–3||Study design|
|Rogers MS, Fung HY, Hung CY. Calcium and low-dose aspirin prophylaxis in women at high risk of pregnancy-induced hypertension. Hypertens Pregnancy. 1999;18:165-72. [PMID: 10476618]||1–3||Study quality|
|Rotchell YE, Cruickshank JK, Gay MP, Griffiths J, Stewart A, Farrell B, et al. Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomised trial for the prevention of pre-eclampsia and its complications. Br J Obstet Gynaecol. 1998;105:286-92. [PMID: 9532988]||1, 2||Population|
|Roy UK, Pan S. A study of use of low dose aspirin in prevention of pregnancy induced hypertension. J Indian Med Assoc. 1994;92:188-91. [PMID: 7930659]||1–3||Geography|
|Schiff E, Barkai G, Ben-Baruch G, Mashiach S. Low-dose aspirin does not influence the clinical course of women with mild pregnancy-induced hypertension. Obstet Gynecol. 1990;76:742-4.||1–3||Population|
|Schröcksnadel H, Sitte B, Alge A, Steckel-Berger G, Schwegel P, Pastner E, et al. Low-dose aspirin in primigravidae with positive roll-over test. Gynecol Obstet Invest. 1992;34:146-50. [PMID: 1427414]||1–3||Study quality|
|Seki H, Kuromaki K, Takeda S, Kinoshita K, Satoh K. Trial of prophylactic administration of TXA2 synthetase inhibitor, ozagrel hydrochloride, for preeclampsia. Hypertens Pregnancy. 1999;18:157-64. [PMID: 10476617]||1–3||Study relevance (other compound or co-treatment)|
|Shenoy S, Chandrika D, Pisharody R. RCT of low dose aspirin to prevent the progression of pregnancy induced hypertension grade A to B. J Clin Epidemiol. 1999;52(Suppl 1):28S.||1–3||Geography|
|Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D, Rocco L, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1993;329:1213-8. [PMID: 8413387]||1, 2||Population (healthy nulliparous women)|
|de Souza EV, Sass N, Atallah AN, Kular Jr L. Aspirin and calcium to prevent pre eclampsia in chronic hypertension in women with abnormal uterine artery Doppler ultrasound [Abstract]. Hypertens Pregnancy. 2006;25(Suppl 1):152.||1–3||Study relevance|
|Subtil D, Goeusse P, Puech F, Lequien P, Biausque S, Breart G, et al; Essai Régional Aspirine Mèere-Enfant (ERASME) Collaborative Group. Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women: the Essai Régional Aspirine Mère-Enfant study (Part 1). BJOG. 2003;110:475-84. [PMID: 12742332]||1, 2||Population (healthy nulliparous women)|
|Tewari S, Kaushish R, Sharma S, Gulati N. Role of low dose aspirin in prevention of pregnancy induced hypertension. J Indian Med Assoc. 1997;95:43-4, 47. [PMID: 9357241]||1–3||Geography|
|Tulppala M, Marttunen M, Söderstrom-Anttila V, Foudila T, Ailus K, Palosuo T, et al. Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production. Hum Reprod. 1997;12:1567-72. [PMID: 9262298]||1–3||Population|
|Tyler CP, Paneth N, Allred EN, Hirtz D, Kuban K, McElrath T, et al; ELGAN Study Investigators. Brain damage in preterm newborns and maternal medication: the ELGAN Study. Am J Obstet Gynecol. 2012;207:192.e1-9. [PMID: 22939723]||1–3||Population|
|Uzan S, Beaufils M, Breart G, Bazin B, Capitant C, Paris J. Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial. Lancet. 1991;337:1427-31. [PMID: 1675315]||1–3||Study relevance (other compound or co-treatment)|
|Vaseie M. The effect of low-dose acetylsalicylic acid (ASA) on control of hypertension in pregnancy [Abstract]. Hypertens Pregnancy. 2006;25:148.||1–3||Setting|
|Villa PM, Kajantie E, Räikkönen K, Pesonen AK, Hämäläinen E, Vainio M, et al; PREDO Study group. Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials. BJOG. 2013;120:64-74. [PMID: 23126307]||3||No relevant outcomes|
|Wallenburg HC, Dekker GA, Makovitz JW, Rotmans N. Effect of low-dose aspirin on vascular refractoriness in angiotensin-sensitive primigravid women. Am J Obstet Gynecol. 1991;164:1169-73. [PMID: 2035557]||1–3||No relevant outcomes|
|Wang Z, Li W. A prospective randomized placebo-controlled trial of low-dose aspirin for prevention of intra-uterine growth retardation. Chin Med J (Engl). 1996;109:238-42. [PMID: 8758317]||1–3||Geography|
|Werler MM, Mitchell AA, Moore CA, Honein MA; National Birth Defects Prevention Study. Is there epidemiologic evidence to support vascular disruption as a pathogenesis of gastroschisis? Am J Med Genet A. 2009;149A:1399-406. [PMID: 19533769]||1–3||Study design (KQs 1 and 2); study quality (KQ3)|
|Werler MM, Bosco JL, Shapira SK; National Birth Defects Prevention Study. Maternal vasoactive exposures, amniotic bands, and terminal transverse limb defects. Birth Defects Res A Clin Mol Teratol. 2009;85:52-7. [PMID: 19067400]||3||Study quality|
|Wyatt-Ashmead J. Antenatal closure of the ductus arteriosus and hydrops fetalis. Pediatr Dev Pathol. 2011;14:469-74. [PMID: 21985268]||1–3||Study relevance (KQs 1 and 2); study design (KQ3)|
|Zimmermann P, Eiriö V, Koskinen J, Niemi K, Nyman R, Kujansuu E, et al. Effect of low-dose aspirin treatment on vascular resistance in the uterine, uteroplacental, renal and umbilical arteries — A prospective longitudinal study on a high risk population with persistent notch in the uterine arteries. Eur J Ultrasound. 1997;5:17-30.||1–3||Study quality|
KQ = key question.
* Includes studies that were included for a different KQ from the one listed.
|Preeclampsia Risk Criteria||Daily Aspirin
|Time of Starting
|Mean (SD) Age, y||Non-Hispanic
|Ayala et al, 201355||Good||Spain||RCT||350||Receiving medical care at a high-risk unit
Criteria for high risk include family or personal history of PE; chronic HTN; CVD; endocrine, metabolic, or bleeding disease; spontaneous abortion; multiple pregnancy; obesity; and age
|100||12–16 wk; delivery||IG: 30.3 (5.3)
CG: 31.1 (5.2)
|Benigni et al, 198952||Fair||Italy||RCT||33||HTN or obstetric history (fetal death due to placental insufficiency, severe IUGR, or early-onset PE [<32 wk])||60||12 wk; delivery||IG: 31.0 (5)
CG: 32.0 (6)
|Caspi et al, 199456||Good||Israel||RCT||47||Twin pregnancy||100||15–23 wk (mean, 17.7 wk); delivery||IG: 28.8 (4.4)
CG: 27.8 (4.5)
|CLASP, 199453||Good||Argentina, Australia, Belgium, Canada, Germany, Hong Kong, Israel, Malaysia, New Zealand, Russia, Spain, Sweden, the Netherlands, United Arab Emirates, United Kingdom, United States||RCT||9364||Population at risk for PE or IUGR as determined by a clinician; women were considered for prophylactic entry or therapeutic entry
Prophylactic entry: pregnant women with PE or IUGR in previous pregnancy; chronic HTN; renal disease; or such other risk factors as maternal age, family history, or multiple pregnancy
Therapeutic entry: pregnant women with signs or symptoms of PE or IUGR in current pregnancy
|60||12–32 wk; delivery||IG: 28.5 (5.4)
CG: 28.5 (5.5)
|Davies et al, 199548†||Fair||United Kingdom||RCT||122||Population not at elevated risk (healthy nulliparous women); study included for KQ3 only||75||18 wk; delivery||IG: 25.4 (5.5)
CG: 25.4 (4.2)
|Gallery et al, 199740||Fair||Australia||RCT||108||Preexisting chronic HTN, renal disease, or history of PE as determined by patient interview at16 wk of gestation||100||17–19 wk; 2 wk before planned delivery||IG: 29 (23–28)‡
CG: 28 (22–38)‡
|Grab et al, 200057||Fair||Germany||RCT||43||Current IUGR; impaired uteroplacental blood flow; chronic HTN; or history of PE, stillbirth, or growth restriction||100||18 wk; 38 wk||NR||NR||NR||Yes|
|Hauth et al, 199342†||Good||United States||RCT||606||Population not at elevated risk (healthy nulliparous women); study included for KQ3 only||60||23 wk; delivery||IG: 20.3 (2.6)
CG: 20.4 (2.7)
|Hermida et al, 199739||Good||Spain||RCT||100||Treatment at high-risk unit of hospital (reasons included family or personal history of gestational HTN, PE, or chronic HTN; cardiovascular, endocrine, bleeding, or metabolic disease; and personal history of spontaneous abortion, multiple pregnancy, obesity, or adolescent or middle-aged nulliparous pregnancy [<18 or >35 y])||100||12–16 wk; delivery||IG: 30.3 (0.9)
CG: 30.1 (0.8)
|Jensen et al, 201061†||Good||Denmark||Cohort||47.400||Population not at elevated risk (all children born to women who were pregnant between 1996 and 2002 were enrolled); study included for KQ3 only||NR||Anytime during pregnancy||All children were aged 18 mo at follow-up||NR||Primiparous: Unexposed: 48.2
|Keim and Klebanoff, 200645†||Good||United States||Case–control||3129||Population not at elevated risk (early fetal loss in previous pregnancy); study included for KQ3 only||NR||Anytime during pregnancy||Case patients: 26.9 (6.5)
Control participants: 25.2 (5.7)
|Case patients: 62.0
Control participants: 66.0
|McParland et al, 199049||Fair||United Kingdom||RCT||106||Persistent abnormal Doppler flow velocity waveforms at 24 wk of gestation (measured twice)||75||24 wk; delivery||IG: 25.6 (4.2)
CG: 26.5 (5.1)
|MFMU, 199844||Good||United States||RCT||2539||Medical history that placed women in 1 of 4 high-risk groups: women with DM, those with chronic HTN, those with MGs, and those with previous PE
Women with DM could also have HTN (but were analyzed with the DM group), but those with MGs were excluded if they also had DM or HTN
|60||13–26 wk; delivery or development of PE||DM: 26.0 (6)
HTN: 30.0 (6)
MG: 25.0 (6)
PE: 25.0 (5)
|Total n = 668||Yes|
|Newnham et al,199560†||Good||Australia||RCT||51||Population not at risk for PE (at risk for IUGR); study included for KQ3 only||100||28–36 wk; delivery||IG: 26.8 (7.2)
CG: 28.6 (6.2)
|Rotchell et al, 199859†||Good||Barbados||RCT||3647||Population not at elevated risk (healthy women without contraindication for aspirin therapy); study included for KQ3 only||75||12–32 wk; delivery||NR§||NR||Primigravid: IG: 44.0
|Schiff et al, 198947||Good||Israel||RCT||65||≥1 of the following: nulliparity, twin gestation, history of PE, or positive rollover test result||100||28 or 29 wk; 38 wk||IG: 27.1 (6.1)
CG: 27.6 (5.7)
|Sibai et al, 199343†||Good||United States||RCT||3135||Population not at elevated risk (healthy nulliparous women); study included for KQ3 only||60||13–25 wk; delivery||IG: 20 (4.0)
CG: 21 (5.0)
|Subtil et al, 200351†||Good||France, Belgium||RCT||3294||Population not at elevated risk (healthy nulliparous women); study included for KQ3 only||100||14–20 wk; 34 wk||IG: 24.7 (4.4)
CG: 24.6 (4.4)
|Vainio et al, 200241||Fair||Finland||RCT||90||Bilateral diastolic notch identified by transvaginal Doppler ultrasonography and risk for PE or IUGR as determined by medical history||0.5 per kg of body weight||12–14 wk; not clearly specified||IG: 30.6 (6.3)
CG: 30.0 (5.9)
|Viinikka et al, 199358||Fair||Finland||RCT||208||Diagnosis of arterial HTN (BP >140/90 mm Hg without treatment before pregnancy) or history of severe PE||50||15–16 wk; delivery||IG: 33.2 (4.9)
CG: 32.7 (5.4)
|NR||IG: 25.2 CG:
|Villa et al, 201350||Fair||Finland||RCT||152||Age, BMI >30 kg/m2, chronic HTN, the Sjögren syndrome or lupus, history of gestational diabetes, PE, small for gestational age, fetus mortus, and second-degree diastolic notch present at 120/7 through 136/7 wk of gestation||100||12–13 wk; 35 wk or delivery||IG: 30.8 (5.3)
CG: 31.0 (5.1)
|Wallenburg et al, 198654||Good||The Netherlands RCT||RCT||46||Angiotensin II sensitivity determined by blood test||60||26 wk; delivery||IG: 23.0 (17–38)ǁ
CG: 25.0 (19–36)ǁ
|Yu et al, 200346||Good||Brazil, Chile, South Africa, United Kingdom||RCT||560||Women with mean PI >1.6 and early diastolic notching of uterine arteries identified by transvaginal color Doppler ultrasonography||150||22–24 wk; 35 wk¶||IG: 29 (23–33)**
CG: 29 (24–33)**
BMI = body mass index; BP = blood pressure; CG = control group; CLASP = Collaborative Low-dose Aspirin Study in Pregnancy; CVD = cardiovascular disease; DM = diabetes mellitus; HTN = hypertension; IG = intervention group; IUGR = intrauterine growth restriction; KQ = key question; MFMU = Maternal-Fetal Medicine Units; MG = multifetal gestation; NR = not reported; PE = preeclampsia; PI = pulsatility index; RCT = randomized, controlled trial.
† Included for analysis of KQ3 (harms only) and not in a high-risk population.
‡ Mean (range).
§ Authors reported that 24% of patients in each group were aged <20 y, 55% in each group were aged 20 to 29 y, 20% in each group were aged 30 to 39 y, and 1% in each group were aged >40 y.
ǁ Median (range).
** Median (interquartile range).