Aspirin discontinuation at 24 to 28 weeks noninferior to continuation for preventing preterm preeclampsia
Preeclampsia is a serious multisystem disorder. It is typically characterized by the development of hypertension and proteinuria after 20 weeks of gestation and can be classified according to gestational age at delivery as early-onset preeclampsia (with delivery at <37 weeks of gestation), and term preeclampsia (with delivery at ≥37 weeks of gestation). Complications associated with preeclampsia include preterm birth, fetal growth restriction, placental abruption, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, seizures (eclampsia), and other end organ damage (acute kidney injury, stroke, myocardial infarction, pulmonary edema, retinal detachment, and hepatic dysfunction), especially with onset at earlier gestational ages.
Aspirin has been proven to reduce the incidence of preterm preeclampsia by 62%. Although the exact etiology of preeclampsia is unknown, aspirin inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane. This results in an inhibition of the oxidative stress and inflammation and platelet aggregation, as well as promotes trophoblast invasion, spiral arteries remodeling, and development of chorionic villi, a phenomenon that mainly occurs during the first trimester of pregnancy and is completed by 20 weeks of gestation. This may explain why prevention of preeclampsia with aspirin is most effective when aspirin is initiated between 11 weeks 0 days and 16 weeks 6 days of gestation.
First-trimester preeclampsia screening (11 to 13 weeks of gestation) allows initiation of aspirin (150 mg per day) before 16 weeks of gestation until 36 weeks of gestation. Aspirin may be associated with an increased risk of peripartum bleeding which could be mitigated by discontinuing aspirin earlier. The Detection of False Positives From First-trimester Preeclampsia Screening at the Second-trimester of Pregnancy (StopPRE) Trial was designed to test the hypothesis that discontinuing aspirin in pregnancies at high risk of preterm preeclampsia in the first trimester and with an sFlt-1:PlGF ratio of 38 or less between 24 weeks 0 days and 27 weeks 6 days of gestation is noninferior to prevent preterm preeclampsia as compared with a control group treated with aspirin until 36 weeks of gestation.
Multicenter, open-label, randomized, phase 3, noninferiority trial was conducted in 9 maternity hospitals across Spain. Pregnant individuals (n = 968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n = 473; control: n = 463). Follow-up was until delivery for all participants. Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group). Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%.
Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, −0.25% [95% CI, −1.86% to 1.36%]), indicating noninferiority. Discontinuing aspirin at 24 to 28 weeks of gestation was noninferior to continuing aspirin until 36 weeks of gestation for preventing preterm preeclampsia in individuals who had a high risk of preeclampsia in the first trimester of pregnancy and an sFlt-1:PlGF ratio of 38 or less between 24 and 28 weeks of gestation. In addition, aspirin discontinuation might reduce the risk of minor bleeding complications or pregnancy complications at 37 weeks or more of gestation.
In the present study, aspirin at a dose of 150 mg was used. Because this is one of the highest doses recommended for preventing preeclampsia, discontinuing aspirin in this trial may have led to a significant reduction in severe bleeding complications. However, an association between earlier discontinuation of aspirin treatment and a reduction in rarer bleeding complications, such as placental abruption, maternal intracranial hemorrhage, postpartum hemorrhage, and/or neonatal intraventricular hemorrhage, was not observed. These findings could be due to several reasons; first, this study was not powered enough to assess these rare outcomes and larger studies should be conducted to address this topic, and second, aspirin was discontinued before labor in both groups, thereby reducing the chances of finding differences in the rates of postpartum and neonatal hemorrhages.
In summary, Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio.
Source: Manel Mendoza, PhD; Erika Bonacina, MD; Pablo Garcia-Manau, MD; JAMA. 2023;329(7):542-550. doi:10.1001/jama.2023.0691
