in progress

Draft Recommendation Statement

Aspirin Use to Prevent Morbidity and Mortality From Preeclampsia: Preventive Medication

February 23, 2021

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.

This topic is being updated. Please use the link(s) below to see the latest documents available.
  • Update in Progress for Aspirin Use to Prevent Morbidity and Mortality From Preeclampsia: Preventive Medication

Recommendation Summary

Population Recommendation Grade
Pregnant persons at high risk for preeclampsia The USPSTF recommends the use of low-dose aspirin (81 mg/day) as preventive medication after 12 weeks of gestation in persons who are at high risk for preeclampsia. See the "Practice Considerations" section for information on high risk and dose. B

Additional Information

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Related Resources
  • Aspirin Use for the Prevention of Morbidity and Mortality From Preeclampsia (Consumer Guide): Draft Recommendation | Link to File

Full Recommendation:

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.

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Preeclampsia is one of the most serious health problems affecting pregnancy. It is a multisystem inflammatory syndrome that is often progressive but has an unclear etiology. Worldwide, preeclampsia is the second most common cause of maternal morbidity and mortality. It is a complication in approximately 4% of pregnancies in the United States and contributes to both maternal and infant morbidity and mortality. Preeclampsia also accounts for 6% of preterm births and 19% of medically indicated preterm births in the United States.1

There are racial/ethnic disparities in the prevalence of and mortality from preeclampsia. Non-Hispanic Black women are at greater risk for developing preeclampsia than other women and bear a greater burden of maternal and infant morbidity and perinatal mortality. In the United States, the rate of maternal death from preeclampsia is higher in non-Hispanic Black women than in non-Hispanic White women. Disparities in risk factors for preeclampsia, access to early prenatal care, and obstetric interventions may account for some of the differences in prevalence and clinical outcomes.1

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Persons with type 1 or type 2 diabetes mellitus, chronic hypertension, renal disease, or autoimmune disease are at highest risk for preeclampsia. Additional conditions that place a person at high risk for preeclampsia include multifetal gestation or a history of preeclampsia and related serious complications in a previous pregnancy. Other risk factors for preeclampsia include high prepregnancy body mass index, family history of preeclampsia, advanced maternal age (≥35 years), and race (Black) (Table 1).1

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The USPSTF concludes with moderate certainty that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, small gestational age/intrauterine growth restriction (SGA/IUGR), and perinatal mortality in pregnant persons at high risk for preeclampsia.

See Table 2 for more information on the USPSTF recommendation rationale and assessment. For more details on the methods the USPSTF uses to determine the net benefit, see the USPSTF Procedure Manual.2

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Patient Population Under Consideration

This recommendation applies to pregnant persons who are at high risk for preeclampsia and who have no prior adverse effects with or contraindications to low-dose aspirin. 

Definitions

Preeclampsia is a disease defined by hypertension (defined as office-based blood pressure ≥140/90 mm Hg on two separate occasions during the second half of pregnancy [>20 weeks]) accompanied by proteinuria. Proteinuria is defined as a 24-hour urine collection containing greater than 300 mg protein, a single voided urine protein/creatinine ratio of 0.3 or greater, or a urine dipstick reading of 2+ (used only if other quantitative methods are not available). In the absence of proteinuria, preeclampsia is diagnosed as hypertension with any of the following: thrombocytopenia, impaired liver function, renal insufficiency, pulmonary edema, or cerebral or visual disturbances.3 

Assessment of Risk

Risk factors of preeclampsia can be categorized into those obtained by medical history, clinical examination, laboratory tests, and imaging. Most clinicians use medical history to identify pregnant persons at increased risk. Predictive models that combine risk factors to identify pregnant persons at risk for preeclampsia, such as serum biomarkers, uterine artery Doppler ultrasonography, and clinical history and measures, have been developed. However, there is limited evidence from external validation and implementation studies to demonstrate sufficient accuracy of predictive models for clinical use.1, 4

Although clinical risk assessments were not systematically reviewed for this recommendation, a pragmatic approach is described in Table 1. This approach may help to identify a patient population with an absolute risk for preeclampsia of at least 8%, which is consistent with the lowest preeclampsia incidence observed in control groups in studies reviewed by the USPSTF.1 Pregnant persons with one or more high-risk factors should receive low-dose aspirin. Pregnant persons with two or more moderate-risk factors may also benefit from low-dose aspirin (Table 1), but the evidence is less certain for this approach. Clinicians should use clinical judgment in assessing the risk for preeclampsia and discuss the benefits and harms of low-dose aspirin use with their patients.

Treatment or Intervention

The only treatment for preeclampsia is delivery of the placenta. Evidence demonstrates that aspirin use reduces the risk of preeclampsia in high-risk populations.1, 5-7

Timing and Dosage

Effective dosages of low-dose aspirin range from 60 to 150 mg/day.1 Although studies did not evaluate a dosage of 81 mg/day, low-dose aspirin is available in the United States as 81-mg tablets, which is a reasonable dosage for prophylaxis in pregnant persons at high risk for preeclampsia.

Low-dose aspirin use should be initiated after 12 weeks of gestation (studies most often initiated before 20 weeks of gestation).

Implementation

Risk factors, based on medical history, may help guide clinicians and their patients in the decision to begin aspirin use (Table 1). Pregnant persons with one or more high-risk factors should receive low-dose aspirin. Pregnant persons with two or more moderate-risk factors may also benefit from low-dose aspirin (Table 1), but the evidence is less certain for this approach. Clinicians should use clinical judgment in assessing the risk for preeclampsia and discuss the benefits and harms of low-dose aspirin use with their patients.

Other Related USPSTF Recommendations

The USPSTF has also issued recommendations for numerous conditions in pregnant persons, including screening for preeclampsia8 and folic acid supplementation to prevent neural tube defects.9 Other related USPSTF recommendations are available at https://www.uspreventiveservicestaskforce.org/.

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Scope of Review

The USPSTF commissioned a systematic review1 to evaluate the effectiveness of low-dose aspirin use to prevent preeclampsia. The current review included evidence on the effectiveness of low-dose aspirin in preventing preeclampsia in pregnant persons at increased risk and in decreasing adverse maternal and perinatal health outcomes, as well as assessing the maternal and fetal harms of low-dose aspirin use during pregnancy.

Benefits of Risk Assessment and Preventive Medication

The USPSTF considered 18 randomized, controlled trials (RCTs) (n=15,908) to assess maternal and perinatal health outcomes and 16 RCTs (n=15,767; 10 good-quality) to assess prevention of preeclampsia.1 All trials were placebo-controlled.1 The three largest trials included one conducted in the United States and two large, multinational trials coordinated from the United Kingdom. Fifteen smaller trials were conducted in various developed countries.1, 5, 11, 12

In general, trial participants were young (mean age range, 20.4 to 33.5 years) and white. Only three trials included majority populations of Black women (range, 50% to 72%).1 Studies most often initiated low-dose aspirin before 20 weeks of gestation, but initiation ranged from at 11 to 32 weeks of gestation, and generally continued until delivery or near term. Nulliparous and multiparous participants were combined in most trials. Aspirin dosages ranged from 50 to 150 mg/day, with most trials using 60 mg/day (6 RCTs) or 100 mg/day (8 RCTs).1 Included trials of selected participants at increased risk for preeclampsia used a variety of approaches to identify the study population, because a validated method for identifying women who are at increased risk for preeclampsia is lacking.1 The incidence of preeclampsia in the placebo groups therefore also varied considerably, but the proportion developing preeclampsia were generally 2 to 3 times higher than the average incidence in the United States.

The USPSTF found evidence of a 20% reduction in risk for preterm birth (pooled relative risk [RR], 0.80 [95% CI, 0.67 to 0.95]; 13 studies; I2=49%) among women at increased risk for preeclampsia who received low-dose aspirin (n=13,619). Pooled estimates provided evidence of an 18% reduction in risk for SGA/IUGR (RR, 0.82 [95% CI, 0.68 to 0.99]; 16 studies; I2=41.0%) in women at increased risk for preeclampsia (n=14,385). There was also a 21% reduction in perinatal mortality (pooled RR, 0.79 [95% CI, 0.66 to 0.96]; 11 studies; I2=0%) in women at increased risk for preeclampsia (n=13,860).1 The USPSTF found evidence of a 15% reduction in risk for preeclampsia (pooled RR, 0.85 [95% CI, 0.75 to 0.95]; 16 studies; I2=0%) with low-dose aspirin use in women at increased risk (n=14,093). Maternal complications of preeclampsia (e.g., eclampsia or death) rarely occurred in studies and could not be evaluated.

Stratified comparisons did not show consistent evidence for effect differences related to intervention or population characteristics such as the timing of aspirin initiation (<16 weeks), the dosage of aspirin used, or participant characteristics.1

Harms of Risk Assessment and Preventive Medication

The USPSTF considered 21 RCTs (n=26,757; 14 good-quality, 7 fair-quality) to assess maternal, perinatal, and developmental harms. Studies of average-risk pregnant women (5 trials) were included with trials of women at increased risk (16 trials).1 All trials were placebo-controlled, except one study in which participants in the control group received usual care with no placebo. Harms that were consistently reported across studies were placental abruption, postpartum hemorrhage, and fetal intracranial bleeding.1

Trials did not demonstrate evidence of harms from daily low-dose aspirin use during pregnancy. Bleeding harms were uncommon. Pooled results were not statistically significant for placental abruption (pooled RR, 1.15 [95% CI, 0.76 to 1.72]; I2=25%; 10 trials; n=24,970), postpartum hemorrhage (pooled RR, 1.03 [95% CI, 0.94 to 1.12]; I2=0%; 9 trials; n=23,133), or fetal intracranial bleeding (pooled RR, 0.90 [95% CI, 0.51 to 1.57]; I2=19%; 6 trials; n=23,719).1

The USPSTF found limited evidence on long-term child developmental outcomes in offspring from in utero exposure to low-dose aspirin. Followup data from the largest trial, Collaborative Low-dose Aspirin Study in Pregnancy (CLASP), reported no differences in physical or developmental outcomes (e.g., gross motor development, height, weight, or hospital visits) in infants at age 12 and 18 months.13 No differences were found within a few studies reporting other rare perinatal harms (e.g., congenital anomalies or malformations).1

The USPSTF also did not find a difference in harms by the dosage or timing of aspirin or for specific populations based on limited subgroup comparisons.1

How Does the Evidence Fit With Biological Understanding?

Preeclampsia is a complex, multisystem inflammatory syndrome that can originate from multiple causes. It is believed to evolve from changes in placental development that result in placental ischemia. Poor placental perfusion may produce inflammation and oxidative stress. Preeclampsia may also develop as a result of overactive inflammatory responses to normal placentation. Preexisting inflammatory conditions are also thought to trigger systemic inflammatory and oxidative stress processes. The anti-inflammatory, antiangiogenesis, and antiplatelet properties of low-dose aspirin are believed to account for its preventive effect on preeclampsia.1

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There are several critical evidence gaps. Studies are needed that provide more information on the following.

  • Research is needed on how to improve recognizing pregnant persons who are at increased risk for preeclampsia. Research to further develop and evaluate the effectiveness of risk assessment tools using clinical history alone or combined with clinical testing could help clinicians better identify pregnant persons who could benefit from aspirin as preventive medication.
  • Further research is needed in populations that bear the highest disease burden for preeclampsia, including Black persons. Future trials should recruit adequate numbers of persons from racial/ethnic populations, such as Black persons, to have sufficient power to determine the effectiveness of different aspirin dosages and timing of initiation in the populations that bear the greatest disease burden.
  • Comparative effectiveness trials are needed to identify the specific aspirin protocol (e.g., dosage, timing, continuation, and time of day) that is likely to have the greatest benefit.
  • Studies are needed to more fully understand the populations most likely to benefit from aspirin prophylaxis and what the risk threshold and factors should be used to identify eligible patient populations.
  • Research is needed on aspirin effectiveness for all hypertensive disorders of pregnancy.
  • Research is needed to improve effective and equitable implementation of clinical guidelines for aspirin use in pregnancy.
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The American College of Obstetricians and Gynecologists,14 the World Health Organization,15 and the American Heart Association/American Stroke Association16 all recommend low-dose aspirin use for the prevention of preeclampsia in persons at increased risk.

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1. Henderson JT, Vesco KK, Senger CA, Thomas RG, Redmond N. Aspirin Use to Prevent Preeclampsia and Related Morbidity and Mortality: An Evidence Update for the U.S. Preventive Services Task Force. Evidence Synthesis No. 205. AHRQ Publication No. 21-05274-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2021.
2. U.S. Preventive Services Task Force. Procedure Manual. https://uspreventiveservicestaskforce.org/uspstf/procedure-manual. Accessed February 10, 2021.
3. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 202: gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133(1):e1-e25.
4. Henderson JT, Thompson JH, Burda BU, et al. Preeclampsia screening: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2017;317(16):1668-1683.
5. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613-622.
6. Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007;2:CD004659.
7. Askie LM, Duley L, Henderson-Smart DJ, et al. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575):1791-1798.
8. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al. Screening for preeclampsia: US Preventive Services Task Force recommendation statement. JAMA. 2017;317(16):1661-1667.
9. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al. Folic acid supplementation for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement. JAMA. 2017;317(2):183-189.
10. U.S. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(11):819-26.
11. Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med. 1998;338(11):701-705.
12. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994;343(8898):619-629.
13. Low dose aspirin in pregnancy and early childhood development: follow up of the Collaborative Low dose Aspirin Study in Pregnancy. CLASP Collaborative Group. Br J Obstet Gynaecol. 1995;102:861-868.
14. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 743: low-dose aspirin use during pregnancy. Obstet Gynecol. 2018;132(1):e44-e52.
15. World Health Organization. WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. https://www.who.int/reproductivehealth/publications/maternal_perinatal_health/9789241548335/en/. Accessed February 8, 2021.
16. Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(5):1545-1588.

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Risk Level Risk Factors Recommendation

High

  • History of preeclampsia, especially when accompanied by an adverse outcome
  • Multifetal gestation
  • Chronic hypertension
  • Type 1 or 2 diabetes mellitus
  • Renal disease
  • Autoimmune disease (i.e., systemic lupus erythematous, antiphospholipid syndrome)
  • Combinations of multiple moderate-risk factors
Recommend low-dose aspirin if the patient has ≥1 of these high-risk factors

Moderate

  • Nulliparity
  • Obesity (body mass index >30 kg/m2)
  • Family history of preeclampsia (mother or sister)
  • Sociodemographic characteristics (Black race, low socioeconomic status)
  • Age ≥35 years
  • Personal history factors (e.g., low birthweight or small for gestational age, previous adverse pregnancy outcome, >10-year pregnancy interval)
Recommend low-dose aspirin if the patient has ≥2 moderate-risk factors

Consider low-dose aspirin if the patient has one of these moderate-risk factors§

Low Previous uncomplicated full-term delivery Do not recommend low-dose aspirin

* Includes only risk factors that can be obtained from the patient medical history. Clinical measures, such as uterine artery Doppler ultrasonography, are not included.
† Includes single risk factors that are consistently associated with the greatest risk for preeclampsia. Preeclampsia incidence would likely be ≥8% in a population of pregnant individuals who have ≥1 of these risk factors.
These risk factors are independently associated with moderate risk for preeclampsia, some more consistently than others. A combination of multiple moderate-risk factors may place a pregnant person at higher risk for preeclampsia.
§Moderate-risk factors vary in their association with increased risk for preeclampsia.

 

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RationaleAssessment
Benefits of preventive medication
  • There is adequate evidence of a reduction in risk for preterm birth, SGA/IUGR, and perinatal mortality in persons at increased risk for preeclampsia who received low-dose aspirin, thus demonstrating substantial benefit.
  • There is also adequate evidence that use of low-dose aspirin in pregnant persons at increased risk for preeclampsia reduces risk for preeclampsia which leads to improved maternal and perinatal outcomes, demonstrating substantial benefit.
Harms of preventive medicationThere is adequate evidence to bound the harms of low-dose aspirin as no greater than small based on the absence of evidence of harms associated with daily aspirin use.
USPSTF assessmentThe USPSTF concludes with moderate certainty that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, SGA/IUGR, and perinatal mortality in persons at high risk for preeclampsia.

Abbreviations: IUGR=intrauterine growth restriction; SGA=small for gestational age; USPSTF=U.S. Preventive Services Task Force.

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