Low-Dose Aspirin Use for the Prevention of Morbidity and Mortality From Preeclampsia: Preventive Medication -- Pregnant Women Who Are At High Risk for Preeclampsia


General

Grade: B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.

Specific Recommendations

The USPSTF recommends the use of low-dose aspirin (81 mg/d) as preventive medication after 12 weeks of gestation in women who are at high risk for preeclampsia.

Frequency of Service

Use of low-dose aspirin was initiated between 12 and 28 weeks of gestation. Evidence did not suggest additional benefit when use of aspirin was started earlier (12 to 16 weeks) rather than later (≥16 weeks) in pregnancy in women at increased risk for preeclampsia.

Risk Factor Information

No information available.


Clinical

Clinical Considerations

There are no validated methods of identifying women at high risk for preeclampsia on the basis of biomarkers, clinical diagnostic tests, or medical history. Most clinicians use medical history to identify women at high risk. Risk factors, based on medical history, may help guide clinicians and their patients in the decision to begin aspirin use.

Although clinical risk assessments were not systematically reviewed for this recommendation, a pragmatic approach is described in the Table. 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 USPSTF1. Women with 1 or more high-risk factors should receive low-dose aspirin. Women with several moderate-risk factors may also benefit from low-dose aspirin (Table), but the evidence is less certain for this approach. Clinicians should use clinical judgment in assessing the risk for preeclampsia and talk with their patients about the benefits and harms of low-dose aspirin use.

Table. Clinical Risk Assessment for Preeclampsia*

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
Renal disease
Autoimmune disease (systemic lupus erythematous, antiphospholipid syndrome)
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 (African American 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)
Consider low-dose aspirin if the patient has several 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.
Single risk factors that are consistently associated with the greatest risk for preeclampsia. The preeclampsia incidence rate would be approximately ≥8% in a pregnant woman with ≥1 of these risk factors1, 5.
‡ A combination of multiple moderate-risk factors may be used by clinicians to identify women at high risk for preeclampsia. These risk factors are independently associated with moderate risk for preeclampsia, some more consistently than others1.
§ Moderate-risk factors vary in their association with increased risk for preeclampsia.

Assessment of Risk for Adverse Effects

Low-dose aspirin use in women at increased risk for preeclampsia has not been shown to increase the occurrence of placental abruption; postpartum hemorrhage; or fetal harms, such as intracranial bleeding and congenital anomalies.

Use of Preventive Medication

The dosage and timing of initiation of low-dose aspirin varied across studies. However, the beneficial effects and small harms of low-dose aspirin were consistent across dosages and timing of initiation. It was not possible to determine from the evidence whether a specific dosage or timing of aspirin use conferred greater benefit over other dosages or intervals.

Dosage

Low-dose aspirin at dosages between 60 and 150 mg/d reduced the occurrence of preeclampsia, preterm birth, and IUGR in women at increased risk for preeclampsia in several randomized trials 1. The most commonly used dosage was 100 mg/d, but the 2 largest trials contributing to the estimates of benefit used 60 mg/d1, 6, 7. Although studies did not evaluate a dosage of 81 mg/d, low-dose aspirin is available in the United States as 81-mg tablets, which is a reasonable dosage for prophylaxis in women at high risk for preeclampsia.

Timing

Use of low-dose aspirin was initiated between 12 and 28 weeks of gestation. Evidence did not suggest additional benefit when use of aspirin was started earlier (12 to 16 weeks) rather than later (≥16 weeks) in pregnancy in women at increased risk for preeclampsia 1.

Other Considerations

Research Needs and Gaps

Research is needed on the effect of low-dose aspirin on the development of preeclampsia and how the magnitude of response to low-dose aspirin varies with individual or combined risk factors for preeclampsia. Research on how to improve clinicians' ability to identify women at increased risk for preeclampsia, particularly those who would receive the greatest benefit from aspirin as preventive medication, is also needed. Efforts to validate the effectiveness of risk assessment tools using clinical history alone or combined with clinical testing may help clinicians better identify high-risk women who will benefit from aspirin as preventive medication, and help reduce the incidence of preeclampsia and its consequent outcomes.

Further research in populations that bear the highest disease burden for preeclampsia, including African American and nulliparous women, is needed. Multivariable risk prediction models that identify healthy nulliparous women who are likely to develop preeclampsia are in development, but further refinement and validation are needed. Additional research to further assess preeclampsia risk in pregnant women with 1 or more moderate-risk factors is needed. Future trials should recruit adequate numbers of women from racial/ethnic populations that are at disproportionate risk, such as African American women, in order to have sufficient power to determine the effectiveness of different aspirin dosages and timing of initiation in these high-risk groups.

Larger studies investigating aspirin use in the first or early second trimester may improve the evidence base on optimal timing of low-dose aspirin as preventive medication. Other areas of research include optimal therapies that individualize the aspirin dosage and timing of administration (e.g., morning vs. bedtime).

In addition, studies that explore less well-established risk factors that may better identify women at high risk for preeclampsia are needed. Further research should also investigate whether preeclampsia prevention with low-dose aspirin affects women's long-term risk for cardiovascular disease and whether there are benefits to continuing low-dose aspirin after delivery in women with 1 or more high-risk factors.

Other Approaches to Prevention

The USPSTF recommends that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 µg) of folic acid. More information is available at www.uspreventiveservicestaskforce.org.

Update of Previous USPSTF Recommendation

In 1996, the USPSTF concluded that evidence was insufficient to recommend for or against the routine use of aspirin for the prevention of preeclampsia or IUGR. Although a significant reduction in risk for preterm birth suggested benefits for infants, there was inadequate evidence that aspirin provided benefits for women at increased risk for preeclampsia. In addition, the studies available at that time indicated that aspirin use was associated with risk for placental abruption. As a result, the USPSTF concluded that the evidence was insufficient to assess the balance of benefits and harms of aspirin use to prevent preeclampsia in pregnant women at increased risk for preeclampsia9.

This recommendation updates the 1996 recommendation. It differs from the previous recommendation in that new evidence on the effectiveness and harms of low-dose aspirin on maternal and perinatal health outcomes now allows the USPSTF to recommend its use in women at high risk for preeclampsia. This recommendation also differs from the 1996 recommendation in that it discusses defining "high preeclampsia risk" in pregnant women in more detail.


Rationale

Rationale

Importance

Preeclampsia is one of the most serious health problems affecting pregnant women. It is a complication in 2% to 8% of pregnancies worldwide and contributes to both maternal and infant morbidity and mortality. Preeclampsia also accounts for 15% of preterm births in the United States1. The disorder is defined by the onset of hypertension (blood pressure ≥140/90 mm Hg) and proteinuria (≥0.3 g of protein in the urine within a 24-hour period) during the second half of pregnancy (>20 weeks). In the absence of proteinuria, preeclampsia is classified as hypertension with any of the following: thrombocytopenia, impaired liver function, renal insufficiency, pulmonary edema, or cerebral or visual disturbances2.

Recognition of Risk Status

Important risk factors for preeclampsia include history of preeclampsia (including early-onset preeclampsia), intrauterine growth restriction (IUGR), or preterm birth; placental abruption or fetal death; maternal comorbid conditions (including type 1 or 2 pregestational diabetes, chronic hypertension, renal disease, and autoimmune diseases); and multifetal gestation1.

Predictive models that combine risk factors to identify women at risk for preeclampsia, such as serum biomarkers, uterine artery Doppler ultrasonography, and clinical history and measures, are in development3, 4. None have yet shown sufficient accuracy for clinical use.

Benefits of Preventive Medication

The USPSTF found adequate evidence of a reduction in risk for preeclampsia, preterm birth, and IUGR in women at increased risk for preeclampsia who received low-dose aspirin, thus demonstrating substantial benefit.

Low-dose aspirin (range, 60 to 150 mg/d) reduced the risk for preeclampsia by 24% in clinical trials and reduced the risk for preterm birth by 14% and IUGR by 20%.

Harms of Preventive Medication

The USPSTF found adequate evidence that low-dose aspirin as preventive medication does not increase the risk for placental abruption, postpartum hemorrhage, or fetal intracranial bleeding. In a meta-analysis of randomized, controlled trials (RCTs) and observational studies of women at low/average or increased risk for preeclampsia, there was no significantly increased risk for these adverse events. In addition, there was no difference in the risk for placental abruption by aspirin dosage.

The USPSTF also found adequate evidence that low-dose aspirin as preventive medication in women at increased risk for preeclampsia does not increase the risk for perinatal mortality.

Evidence on long-term outcomes in offspring exposed in utero to low-dose aspirin is limited, but no developmental harms were identified by 18 months of age in the one study reviewed.

The USPSTF concludes that the harms of low-dose aspirin in pregnancy are no greater than small.

USPSTF Assessment

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, and IUGR in women at high risk for preeclampsia.


Others

Recommendations of OthersThe American College of Obstetricians and Gynecologists recommends initiating use of low-dose aspirin (60 to 80 mg/d) during the late first trimester to prevent preeclampsia in women with a medical history of early-onset preeclampsia and preterm delivery (<34 weeks) or history of preeclampsia in more than 1 previous pregnancy2. The World Health Organization recommends the use of low-dose aspirin (75 mg/d) starting as early as 12 to 20 weeks of gestation for high-risk women (i.e., those with a history of preeclampsia, diabetes, chronic hypertension, renal or autoimmune disease, or multifetal pregnancies). It states that there is limited evidence regarding the benefits of low-dose aspirin in other subgroups of high-risk women15. The National Institute for Health and Clinical Excellence recommends that women at high risk for preeclampsia (i.e., women with a history of hypertension in a previous pregnancy, chronic kidney disease, autoimmune disease, type 1 or 2 diabetes, or chronic hypertension) take 75 mg/d of aspirin from 12 weeks until delivery. It recommends the same for women with more than 1 moderate-risk factor (first pregnancy, age ≥40 years, pregnancy interval >10 years, body mass index ≥35 kg/m2, family history of preeclampsia, or multifetal pregnancies)16. The American Heart Association and the American Stroke Association recommend that women with chronic primary or secondary hypertension or previous pregnancy-related hypertension take low-dose aspirin from 12 weeks until delivery17. The American Academy of Family Physicians recommends low-dose aspirin (81 mg/d) after 12 weeks of gestation in women who are at high risk for preeclampsia18.


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