Final Research Plan

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

September 26, 2019

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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The final Research Plan will be used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Report will form the basis of the USPSTF Recommendation Statement on this topic.

The draft Research Plan was available for comment from June 20 until July 23, 2019 at 8:00 p.m., ET.

Figure 1 is the analytic framework that depicts the three Key Questions to be addressed in the systematic review. The figure illustrates how aspirin use my reduce adverse maternal, perinatal, and/or child health outcomes when taken by pregnant persons at an increased risk of preeclampsia (KQ1). Additionally, the figure depicts that aspirin use may prevent preeclampsia among pregnant persons at an increased risk of the condition (KQ2), as well as harms associated with aspirin use for the prevention of preeclampsia during pregnancy (KQ3).

  1. Does aspirin reduce adverse maternal, perinatal, child, or combined health outcomes in pregnant persons at increased risk of preeclampsia?
    1. Does the effectiveness of aspirin for reducing adverse health outcomes vary by subpopulations defined by personal characteristics or preeclampsia risk factors?
  2. Does aspirin prevent preeclampsia in pregnant persons at increased risk for preeclampsia?
    1. Does the effectiveness of aspirin for reducing preeclampsia vary by subpopulations defined by personal characteristics or preeclampsia risk factors?
  3. What are the harms of aspirin use to prevent preeclampsia during pregnancy?
    1. Do the harms of aspirin use to prevent preeclampsia vary by subpopulations defined by personal characteristics or preeclampsia risk factors?

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. Are there new evidence-based approaches for identifying patients at risk for preeclampsia in clinical practice?
  2. How might recent changes to the diagnostic criteria for preeclampsia and for adult hypertension affect the interpretation or applicability of existing evidence?

The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the evidence report. Criteria are overarching as well as specific to each of the key questions (KQs).

Category Included Excluded
Populations KQs 1, 2 (Efficacy): Pregnant persons at increased risk for preeclampsia based on:
  • Personal sociodemographic characteristics
  • Medical history
  • Diagnostic measurements or assays (e.g., uterine artery Doppler, biomarkers)
  • Risk prediction model
KQ 3 (Harms): Pregnant persons, fetuses, infants, and children		 Nonhuman populations; nonpregnant persons; studies that only/exclusively include persons seeking fertility treatment; and other selected nongeneralizable populations

Disease/condition

 Primary prevention of preeclampsia Trials of aspirin aimed at preventing other complications of pregnancy (e.g., stillbirth)
Setting Countries categorized as “very high” on the 2017 Human Development Index (as defined by the United Nations Development Programme) Countries not categorized as “very high” on the 2017 Human Development Index, as there is concern for nutritional deficiencies in developing countries
Interventions Aspirin (≥50 mg) Nonaspirin antiplatelet medications or aspirin combined with other potentially active interventions
Comparisons Placebo or no treatment Any active substance or intervention (e.g., nonaspirin medication, dietary supplements, dietary change, bed rest, or weight loss)
Outcomes Maternal outcomes:
  • Preeclampsia; preeclampsia with severe features
  • Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome
  • Eclampsia, puerperal cerebrovascular disorder, cerebrovascular hemorrhage, edema, or embolus
  • Renal or hepatic injury/failure
  • Pulmonary edema, adult respiratory distress syndrome
  • Disseminated intravascular coagulation
  • Mental health diagnoses or symptoms
  • Maternal mortality
  • Measures of well-being or quality of life

Potential treatment harms:

  • Abruptio placentae
  • Postpartum hemorrhage
  • Gastrointestinal complications (e.g., bleeding ulcer)

Fetal/neonatal/child outcomes:

  • Preterm birth (<37 weeks): late preterm birth (34 to 36 weeks), moderate preterm birth, (32 to 34 weeks), very preterm birth (<32 weeks), or extremely preterm birth (<28 weeks)
  • Mean gestational age
  • Low birth weight
  • Intrauterine growth restriction/small for gestational age (<10th percentile weight for gestational age)
  • Stillbirth or neonatal mortality

Potential treatment harms:

  • Intracranial fetal bleeding
  • Fetal malformations
  • Nonclosure of the ductus arteriosus
  • Chorioamnionitis
  • Child behavioral or developmental problems
  • Length of hospital stay (without indication)
  • Intensive care unit admission
  • Neonatal intensive care unit admission
Study Designs KQs 1, 2 (Efficacy): Randomized, controlled trials; individual participant data meta-analysis of trials

KQ 3 (Harms): Randomized, controlled trials; comparative cohort studies; or individual participant data meta-analysis of trials

 KQs 1, 2 (Efficacy): Nonrandomized controlled trials

KQ 3 (Harms): Editorials, narrative review, commentary, postmarketing surveillance, or case reports
Study Quality Good- and fair-quality studies Poor-quality studies
Language English Languages other than English

The draft Research Plan was posted for public comment on the USPSTF website from June 20 to July 23, 2019. The USPSTF made several minor additions and wording changes to improve the clarity and specificity of the inclusion criteria. The USPSTF included additional clinically important categories to define preeclampsia and preterm birth to more fully represent health outcomes that may be reported in the literature.