Updated recommendation for people at high and moderate risk

Low-dose aspirin should be used as preventive medication for pre-eclampsia after 12 weeks of gestation in women who are at high risk for the pregnancy complication, according to the U.S. Preventive Services Task Force (USPSTF).

The “B” grade guideline, updated from 2014, sets the aspirin dose at 81 mg/day, and supports the aspirin regimen in patients who have one or more of multiple high-risk factors, including multifetal gestation, chronic hypertension, pre-gestational diabetes, and a “[h]istory of pre-eclampsia, especially when accompanied by an adverse outcome,” wrote Karina W. Davidson, PhD, MASc, of the Feinstein Institutes for Medical Research in New York City. Moderate risk factors include obesity, ages ≥35, low income, and nulliparity.

The prevention of pre-eclampsia is “something in pregnancy management that we’ve been seeking for a long time,” said task force member Aaron B. Caughey, MD, PhD, of the Oregon Health & Science University in Portland, in a JAMA interview.

However, USPSTF stressed in JAMA that they “do not recommend low-dose aspirin” for people with “[p]rior uncomplicated term delivery and absence of risk factors.”

In a JAMA Patient Page, Jill Jin, MD, MPH, of Northwestern Medicine in Chicago, explained that other risk factors for pre-eclampsia are “diabetes before pregnancy, chronic kidney disease, some autoimmune diseases… Prevention of pre-eclampsia is important because once it occurs, the only cure is to deliver the infant.”

And the condition can prove challenging to catch, noted Angela R. Jones, MD, of HMH Jersey Shore University Medical Center in Tinton Falls, New Jersey. “I see pre-eclampsia all the time [and] I see it kind of as my nemesis… pre-eclampsia is like the great pretender,” she said in a 2020 podcast. “It can present atypically. I’ve seen patients not have it and then, boom, all of a sudden, they develop it. I’ve seen patients that were stable with [pre-eclampsia] and then… in a matter of hours, it goes to severe.”

In terms of the potential mechanism of action for low-dose prophylactic aspirin, it “causes decreased production of the hormone thromboxane A2, which is thought to increase the risk of pre-eclampsia,” Nana Ama Ankumah, MD, of the McGovern Medical School at UTHealth in Houston, told UTHealth News.

The current recommended timing of once daily after 12 weeks’ gestation is in keeping with real-world practice. “Typically, we initiate low-dose aspirin… between 12 weeks and 28 weeks of gestation. Optimally, you want to… start the aspirin before 16 weeks,” Jones said. The American College of Obstetricians and Gynecologists, as well as the Society of Maternal-Fetal Medicine, call for 81 mg/d prophylaxis for those at high risk of pre-eclampsia, with the ideal start time of 16 weeks, and maintained daily until delivery.

Joo Teoh, MD, MBBCh, of Genea Hollywood Fertility in Perth, Australia, acknowledged that he supports the use of low-dose aspirin as a prophylactic for pre-eclampsia, but emphasized that “nothing is without side effects. Aspirin is known to make someone more prone to bleeding, [but] there are no reports of aspirin including bleeding in pregnancy… Aspirin is good for the longer term for the placenta to be healthier; the placenta architecture, how it’s formed, to have a better pregnancy outcome,” he said in a 2020 YouTube presentation.

Indeed, the JAMA evidence report of 21 trials on daily use of low-dose aspirin indicated that “no greater risk of placental abruption, postpartum hemorrhage, or fetal intracranial bleeding was identified among participants treated with aspirin compared with those who were not,” according to Jillian T. Henderson, PhD, MPH, Kaiser Permanente Evidence-based Practice Center, Center for Health Research, Kaiser Permanente Northwest, in Portland, Oregon, and co-authors.

Specifically, they found no significant associations of aspirin use with risk of postpartum hemorrhage (pooled relative risk 1.03, 95% CI 0.94 to 1.12) and other bleeding-related harms, or with rare perinatal or longer-term harms. The absolute risk reductions for pre-eclampsia tied to aspirin use ranged from −1% to −6% across larger trials (n>300), but were greater in smaller trials, while for perinatal mortality, absolute risk reductions were at a low of 0.5% to a high of 1.1% in the three largest trials.

Henderson’s group evaluated 23 randomized controlled trials (RCTs) in total (n=26,952) of which 18 were done in women at risk for pre-eclampsia. Aspirin dosages ranged from 50 mg/d to 150 mg/d. They reported that aspirin use was linked with a lower risk of:

  • Pre-eclampsia: pooled relative risk 0.85 (95% CI 0.75-0.95).
  • Perinatal mortality: pooled RR 0.79 (95% CI 0.66-0.96).
  • Preterm birth: pooled RR 0.80 (95% CI 0.67-0.95).
  • Intrauterine growth restriction: pooled RR 0.82 (95% CI 0.68-0.99).

In an accompanying editorial, Jimmy Espinoza, MD, MSc, of the Texas Children’s Hospital Pavilion for Women and Baylor College of Medicine in Houston, pointed out that a “limitation of the systematic review is the lack of stratification between pre-eclampsia occurring preterm (<37 weeks) and at term (≥37 weeks). This is important because an RCT from 2017 that involved 1620 patients demonstrated beneficial effects of low-dose aspirin in the prevention of preterm but not term pre-eclampsia.”

He also stressed that most of the participants in the studies reviewed were White, so “generalizability of the findings to underserved populations such as Black or Hispanic individuals” was limited, although he noted that a 2017 study indicated that, after the release of the 2014 guidelines, recurrent pre-eclampsia rates did drop among Hispanic women.

Task force member Michael Silverstein, MD, MPH, of Boston University, agreed. “It is essential that the health community focus on why the disparities exist and what changes can be made to improve health outcomes for Black people and their babies,” he said in a February 2021 USPSTF Bulletin, when a draft of the recommendation was released. “The Task Force is committed to addressing this disparity and is calling for more research on how best to prevent pre-eclampsia in Black people who are pregnant.”

A 2020 expert review in the American Journal of Obstetrics & Gynecology pointed out that “[w]ell-established clinical risk factors for pre-eclampsia such as obesity, diabetes, and chronic hypertension disproportionately affect non-Hispanic Black, American Indian or Alaskan Native, and Hispanic populations. However, with comparable clinical risk factors for pre-eclampsia among women of different race or ethnic groups, addressing modifiable risk factors has not been found to have the same protective effect for all women.”

Other issues that require clarification are potential dose adjustment “and the long-term benefits and risks for mothers and their infants exposed to low-dose aspirin during pregnancy… If aspirin use during pregnancy reduces the risk for CVD [cardiovascular disease] later in life, this could be construed as evidence that low-dose aspirin use during pregnancy also may prevent the changes that increase the risk for long-term CVD,” Espinoza wrote. However, he cautioned that “a lack of this benefit may indicate that a common risk factor predisposes for both pre-eclampsia and CVD later in life and that aspirin use during pregnancy may not change the natural history of these diseases.”

  1. The U.S. Preventive Services Task Force (USPSTF) recommends the use of low-dose aspirin (81 mg/day) as preventive medication after 12 weeks of gestation in persons who are at high risk for pre-eclampsia.

  2. An evidence report to support the USPSTF recommendation found no significant associations of aspirin use with risk of postpartum hemorrhage and other bleeding-related harms, or with rare perinatal or longer-term harms.

Shalmali Pal, Contributing Writer, BreakingMED™

The USPSTF is funded by the Agency for Healthcare Research and Quality (AHRQ). The evidnce report was funded by AHRQ. USPSTF members reported travel reimbursement and an honorarium for participating in USPSTF meetings.

Henderson and co-authors, as well as Espinoza, reported no relationships relevant to the contents of this paper to disclose.

Jin reported serving as JAMA associate editor.

Cat ID: 41

Topic ID: 83,41,570,730,41,192,925