Consensus Statement: Screening for Early-Onset Preeclampsia and Aspirin Prophylaxis in the US

SUMMARY:

Under the auspices of the Gottesfeld-Hohler Memorial Foundation, a Consensus Statement was developed to address the multiple guidelines regarding screening for early-onset preeclampsia (open access summaries of these recommendations can be found below in ‘Related ObG Topics’). This ‘Think Tank Summary’ was comprised of expert participants, including representatives from ACOG, NICHD, SMFM, AIUM, FMF and ISUOG. The Consensus Statement recognizes that while there are differences regarding approach, there is consensus regarding the importance of screening and use of prophylactic aspirin when appropriate. The authors conclude with the following

…it is strongly advised to identify patients at high risk for preeclampsia at least by the guidelines of ACOG, SMFM, the U.S. Preventative Services Task Force, or the Fetal Medicine Foundation criteria.

Offering prophylactic low-dose aspirin starting in the late first or early second trimester, and close scrutiny of these women throughout pregnancy, may help to avert or mitigate the severe complications for the mother, fetus, and neonate that can result from preeclampsia.

KEY POINTS:

Summary of Professional Recommendations

• USPSTF and ACOG/SMFM
  • Recommend screening for preeclampsia using personal and family history risk factors
  • Support the use of low-dose aspirin (81 mg), optimally beginning early in pregnancy <16 weeks (per ACOG)
• FMF (aligned with ISUOG and FIGO recommendations)
  • Based on results from the ASPRE trial (see summary below in ‘Related ObG Topics’), these organizations recommend combined screening
  • The early-preeclampsia screening algorithm includes
    • Maternal factors (history, demographics, CVD and metabolic profile)
    • Maternal arterial BP (MAP)
    • Placental growth factor (PlGF)
    • Pulsatility index (PI) to assess uterine artery resistance
  • For women at high risk, aspirin should be started early in pregnancy
    • Ideally between 11w0d and 14w6d
    • 150 mg every night until 36 weeks, delivery or preeclampsia is diagnosed
• Several studies have duplicated the success of ASPRE regarding test performance
  • However, the Consensus Statement points out that some other investigators have not demonstrated similar results
  • “Reason for the discrepancy is unclear” but could be due to different populations and/or quality of MAP and ultrasound technique

Review of Aspirin Data

• The Consensus Statement provides a literature review of prophylactic aspirin for the prevention of preeclampsia
• Prophylactic aspirin impacts early-onset and not term preeclampsia
• ASPRE study outcome was preeclampsia diagnosis
• The study did not show an overall difference in rates of preeclampsia but rather preeclampsia that led to delivery <37 weeks
• The above may explain those studies that could not duplicate ASPRE performance | Delivery protocols and standards can vary by region

Dosing

• The Consensus Statement recognizes data to support aspirin doses >100 mg
• Higher dose does not appear to increase maternal risk
• Data regarding potential fetal/newborn risks related to altered platelet function are ‘limited’  

Universal aspirin prophylaxis

• There has been literature suggesting that universal aspirin prophylaxis is the most cost-effective strategy (for study review, see ‘Related ObG Topics’ below)
• Data limited
  • Results are based on modeling and not ‘real world’ usage
  • Complications that would occur in approximately 4 million pregnancies is unknown (although authors acknowledge maternal safety for low-dose aspirin)
  • Compliance rates are not known
• The Consensus Statement calls for further trials

Implementation Considerations

• The Consensus Statement recognizes that the FMF model may detect >80% of early-onset preeclampsia
• However, hurdles related to US implementation include
  • Addition of new expenses
  • Training and availability of sonologists with appropriate skill set for assessment of uterine artery PI
• Aspirin dose
  • “Uncertainty remains regarding optimal dosage (81 vs 162 vs 150)”

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Learn More – Primary Sources:

Gottesfeld-Hohler Memorial Foundation Risk Assessment for Early-Onset Preeclampsia in the United States: Think Tank Summary

ASPRE Trial: A Combined Risk Algorithm and Use of Aspirin to Prevent Preterm Preeclampsia

BACKGROUND AND PURPOSE:

• Multiple studies have demonstrated beneficial effects of low dose aspirin for prevention of preeclampsia
• ACOG supports the key USPSTF findings and recommends considering the use of low dose aspirin (81 mg/day) between 12 and 28 weeks’ gestation in women with known clinical risk factors including
  • History of preeclampsia, especially if accompanied by an adverse outcome
  • Multifetal gestation
  • Chronic hypertension
  • Diabetes (Type 1 or Type 2)
  • Renal disease
  • Autoimmune disease (for example, systematic lupus erythematosus, antiphospholipid syndrome)
• An alternative Bayesian risk algorithm that combines multiple clinical, biochemical and fetal sonographic (functional) findings at 11 to 13 weeks has been well studied an appears to have superior performance characteristics when compared to clinical factors alone
  • Applicable to general pregnant population, not just high risk
• Previous studies have found that (1) starting aspirin ≤ 16 weeks provides greater preventative benefit; (2) prevention is limited to preterm preeclampsia; (3) there is a positive dose-dependent benefit effect beyond 81 mg/day; (4) taking aspirin in the evening may be beneficial
• Purpose: The goal of the Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial (Rolnik, NEJM 2017) was to determine if 150 mg of aspirin at night could reduce the incidence of preterm preeclampsia in women identified at high risk using the combined Bayesian model approach

METHODS:

Randomized, double-blind, placebo-controlled trial (RCT)

• Population: Women undergoing their routine prenatal visit at 11 weeks 0 days through 13 weeks 6 days
• Screening tool: Bayesian risk algorithm which assesses the following factors
  • Age
  • Weight and height (BMI)
  • Racial/ethnic origin (white, Afro-Caribbean, South Asian, East Asian, and mixed)
  • Medical History
    • Chronic hypertension
    • Systemic lupus erythematosus or antiphospholipid syndrome
    • Diabetes mellitus type 1 or 2
  • Mode of conception – spontaneous vs. assisted
  • Obstetrical history
    • Parity ( ≥ 24 weeks)
    • Previous preeclampsia
    • Gestational age and weight at delivery in the last pregnancy
    • Interval since last pregnancy
  • Family history of preeclampsia in the patient’s mother
  • Biomarkers
    • Mean arterial pressure (MAP)
    • Uterine artery pulsatility index (UtA-PI)
    • Pregnancy associated plasma protein-A (PAPP-A)
    • Placental growth factor (PlGF)
• Intervention:  150 mg dose/day of aspirin or placebo from 11 to 14 weeks until 36 weeks
  • 2971 women out of 26,941 women (11.0%) were ‘screen positive’ for risk of preterm preeclampsia
  • Following exclusion, withdrawal and loss to follow up, 798 participants remained in the aspirin group and 822 in the placebo group

RESULTS:

Delivery with preeclampsia < 37 weeks:  Definition of preeclampsia based on International Society for the Study of Hypertension in Pregnancy criteria

• 1.6% in the aspirin group had preterm preeclampsia vs. 4.3% in the placebo group (odds ratio 0.38; 95% CI 0.20 to 0.74; P=0.004)

Secondary Outcomes:  Such as abruption, stillbirth, miscarriage, neonatal morbidity and mortality

• No statistical differences found but study not powered to draw definitive conclusions

Adverse Events: Including maternal, fetal and neonatal

• No statistical differences between groups overall, including anemia, vaginal, nasal and other bleeding

CONCLUSION:

• Aspirin did not reduce the incidence of term preeclampsia
• In singleton pregnancies, using a combined Bayesian risk assessment tool, 150 mg of aspirin nightly from 11-14 weeks until 36 weeks led to a 62% reduction in the rate of preterm preeclampsia compared to placebo

Learn More – Primary Sources:

Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

Competing risks model in screening for preeclampsia by maternal characteristics and medical history

Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks’ gestation