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For high-risk pregnant people taking aspirin to prevent preterm preeclampsia, stopping it toward the end of the second trimester appeared to maintain efficacy while potentially reducing bleeding risk, a randomized trial showed.

Compared with continuing taking 150-mg aspirin until 36 weeks' gestation, discontinuation at 24-28 weeks yielded a similar incidence of delivery due to preeclampsia before 37 weeks of gestation (1.48% vs 1.73%, for an absolute difference of -0.25%, 95% CI -1.86% to 1.36%) that indicated non-inferiority, reported Manel Mendoza, PhD, of the Vall d'Hebron Barcelona Hospital in Spain, and colleagues.

And, in keeping with the rationale for stopping early to reduce bleeding risk, it resulted in significantly fewer minor antepartum hemorrhage events (7.6% vs 12.3% among controls) and numerically fewer patients with at least one bleeding complication (8.0% vs 12.7%), they stated in .

No cases of placental abruption occurred in the early-stop group compared with three (1.1%) in the control group, which although "not statistically significant, it was considered clinically significant because placental abruption is a severe complication," the researchers said.

"This important study challenges a growing body of evidence trending toward increasingly widespread use of low-dose aspirin in pregnancy," wrote Louise C. Laurent, MD, PhD, of the University of California San Diego, and colleagues in an accompanying .

The idea has been that aspirin would delay onset of preterm preeclampsia so that it wouldn't start until term, when the adverse perinatal and maternal outcomes aren't as high, the researchers noted.

Unexpectedly, there was a trend for lower incidence of preeclampsia with delivery at any gestational age with earlier aspirin discontinuation (8.2% vs 13.3%, P=0.05) in the open-label, non-inferiority trial conducted among 936 pregnant patients in nine maternity hospitals across Spain.

It's possible that, "in pregnant individuals who are no longer at risk of preeclampsia, aspirin during the second half of pregnancy may be detrimental, in the same way that aspirin initiated after 16 weeks of gestation may increase the risk of placental abruption," the researchers wrote. While further study is needed to confirm this hypothesis, the results suggest that "aspirin treatment should be restricted to pregnant individuals at actual high risk of preeclampsia and administered during the shortest possible time."

Most guidelines recommend stopping prophylaxis by term and before onset of labor, when risk of bleeding is greatest in pregnant individuals. But stopping earlier would potentially reduce risk of bleeding complications and pregnancy complications at term while also cutting down on "maternal anxiety, treatment costs, number of visits, ultrasound scans, and iatrogenic interventions in a cohort of healthy pregnant individuals in which more than 95% of cases are actually false-positives and, therefore, are taking a drug unnecessarily," Mendoza's group noted.

However, the study results won't be straightforward for application to a U.S. population, the editorialists cautioned.

Firstly, U.S. practice exclusively uses clinical maternal factors to select women at high risk of preeclampsia for aspirin prophylaxis, Laurent's group pointed out. The trial selected women at high risk of preeclampsia with universal first trimester screening based on uterine artery pulsatility index, mean arterial pressure, and serum pregnancy-associated plasma protein A, and enrolled those whose second-trimester reassessment showed a normal ratio of soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF of 38 or less) between 24 and 28 weeks of gestation.

Incorporating those molecular markers into screening as part of the risk assessment paradigm "would represent a marked change in practice accompanied by a substantial increase in cost," the editorialists wrote.

Nevertheless, those are more accurate screening means, they acknowledged.

In the , an sFlt-1:PlGF ratio of 38 or less had a 99.3% negative predictive value for ruling out preeclampsia in the second or third trimesters among patients with suspected preeclampsia. Data from the showed that high sFlt:PlGF measured between 26 and 28 weeks' gestation predicted 100% of early-onset preeclampsia cases.

"U.S. practitioners and professional societies should reconsider current risk assessment strategies, which are largely based on maternal factors, and evaluate whether incorporation of molecular biomarkers would improve maternal and fetal/neonatal outcomes," Laurent and colleagues wrote.

Another important difference was the trial's use of the 150-mg daily dose of aspirin as recommended by international guidelines. Thus, "low-dose aspirin-related bleeding complications may not be relevant to the U.S. population, where accepted guidelines recommend an aspirin dose of 81-mg daily, which some meta-analyses have found to have similar efficacy to the 150-mg dose in prevention of preeclampsia," Laurent and colleagues noted.

Prior studies have yielded inconsistent evidence on antepartum bleeding risk of low-dose aspirin. "Without an increase in bleeding complications, there is no rationale to recommend discontinuation of low-dose aspirin for preeclampsia prevention prior to delivery," the editorialists pointed out.

Study limitations included the open-label design that might have led to differential symptom reporting; the potential for a nocebo effect of aspirin without use of a placebo in the trial; underpowered comparisons for rarer complications; early termination of the trial due to futility, and the low diversity among participants (92% white).

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