Just How Bad Is Missing a Few Preeclampsia Prophylaxis Doses?

Greater aspirin adherence was associated with better preeclampsia prevention in high-risk pregnancies, according to an observational cohort study.

Inadequate adherence, seen in 63 of 145 women prescribed prophylactic aspirin in the study from Australia, was linked to a higher incidence of:

• Early-onset preeclampsia (17% vs 2% with adequate adherence, OR 1.9, 95% CI 1.1-8.7)
• Late-onset preeclampsia (41% vs 5%, OR 4.2, 95% CI 1.4-19.8)
• Intrauterine growth restriction (29% vs 5%, OR 5.8, 95% CI 1.2-8.3)
• Preterm delivery (27% vs 10%, OR 5.2, 95% CI 1.5-8.7)
• Increase in antihypertensive use antenatally (60% vs 10%, OR 4.6, 95% CI 1.2-10.5)

Good aspirin compliance was linked to lower odds of premature delivery — the only treatment for preeclampsia — on Kaplan-Meier analysis (HR 0.3, 95% CI 0.2-0.5), a study team led by Renuka Shanmugalingam, MBBS, of Liverpool Hospital in Australia, reported online in the Hypertension journal.

With an absolute risk reduction of 51% and number needed to treat of just two when adherence is ≥90%, the authors concluded that aspirin is “an effective prophylactic agent” for the prevention of preeclampsia.

“Therefore, suggesting adequate adherence with aspirin is essential and that nonadherence with aspirin among high-risk pregnant women may result in preventable obstetric complications,” they urged.

They acknowledged, however, that aspirin for preeclampsia prophylaxis “remains controversial” because of conflicting data.

A placebo-controlled trial showed in 2017 that aspirin reduced preterm preeclampsia risk in women who were identified as high-risk based on plasma biomarkers and imaging. On the other hand, an older trial had turned up no difference between aspirin or placebo in the incidence of preeclampsia or perinatal outcomes in women with pregestational diabetes, multifetal gestation, chronic hypertension, or prior preeclampsia.

One way to reconcile these differences is by analyzing the patient population that was studied, according to S. Ananth Karumanchi, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues in an accompanying editorial.

“It is clear that preeclampsia is a syndrome with multiple etiological pathways that mediate disease signs and symptoms,” Karumanchi and co-editorialists said, adding that it would make sense that aspirin is useful in preventing the anti-angiogenic subtype of preeclampsia given the medication’s anti-inflammatory properties.

“In addition to considering the clinical heterogeneity of preeclampsia, adherence with prescribed aspirin is yet another plausible reason to explain the difference in prior trial outcomes,” they wrote.

Shanmugalingam and colleagues had recruited 220 high-risk pregnant women from three centers in the South West Sydney Local Health District for the study. Only 145 had analyzable data and were prescribed aspirin for preeclampsia prophylaxis before 16 weeks gestation.

The women in the study averaged age 33, and more than half were white (Middle Eastern, South Asian, and Southeast Asian groups had the greatest minority representation). No patient was found to be aspirin-resistant.

Whether pregnant women stayed on aspirin was probed qualitatively (via questionnaire) and quantitatively (according to platelet function analyzer 100 assays and plasma salicylic acid testing) every 4 weeks during their clinic visits. Adherence was defined by sufficient evidence of aspirin use for at least 90% of time points.

Notably, self-reported adherence only moderately correlated with quantitative (or actual) adherence, the investigators found.

Assays and lab measurements may provide a more objective and accurate assessment of medication adherence, but cost and need for laboratory expertise often hinders use in clinical studies, the authors said.

Their study was limited by variation in aspirin dose prescribed (100 or 150 mg daily) and the exclusion of non-English speakers.

“Before universal adoption of aspirin for all high-risk pregnant women, it is important to note that the potential long-term consequences of aspirin exposure to developing fetuses are unknown. Recent data on long-term follow-up of children exposed to low-dose aspirin in utero demonstrates a modest risk of childhood asthma in China,” according to Karumanchi’s team.

“More studies to critically evaluate long-term safety are needed,” they continued. “A clinical trial in the United States with incorporation of both aspirin adherence measurements, and risk stratification with biomarkers to evaluate aspirin’s effect on prevention of preeclampsia and more importantly improvement of perinatal outcomes is sorely needed.”