Preeclampsia: Low-Dose Aspirin May Prevent Poor Outcomes

Laurie Barclay, MD

April 07, 2014

Daily low-dose aspirin starting as early as the second trimester of pregnancy appears to prevent morbidity and mortality from preeclampsia among high-risk women, according to a systematic review published online April 8 in the Annals of Internal Medicine. However, potential rare or long-term harms could not be ruled out.

"Preeclampsia, which is characterized by hypertension and proteinuria during the second half of pregnancy, is a leading cause of maternal and perinatal death," write Jillian T. Henderson, PhD, MPH, from the Kaiser Permanente Center for Health Research in Portland, Oregon, and colleagues.

"Previous comprehensive systematic reviews have found antiplatelets (primarily low-dose aspirin) to be beneficial for the prevention of preeclampsia among women at heightened risk. We conducted this systematic review to support the US Preventive Services Task Force [USPSTF] in updating its 1996 recommendation, which is no longer active."

Poor perinatal health outcomes linked to preeclampsia may result from increased risk for intrauterine growth restriction or preterm delivery. Preeclampsia accounts for more than one third of serious maternal morbidities and 15% of preterm births. Conditions associated with higher risk for preeclampsia include a history of preeclampsia in a previous pregnancy or chronic conditions including diabetes, hypertension, and kidney disease.

The only effective treatment is delivery, which puts the infant at significant risk if gestational age is less than 34 weeks. Prevention of preeclampsia is therefore necessary to improve outcomes.

The investigators systematically reviewed benefits and harms of low-dose aspirin based on a search of MEDLINE, Database of Abstracts of Reviews of Effects, PubMed, and Cochrane Central Register of Controlled Trials (January 2006 - June 2013). They also consulted previous systematic reviews, clinical trial registries, and surveillance searches for large studies from June 2013 to February 2014.

Inclusion criteria were English-language studies of fair or good quality. These included randomized controlled trials (RCTs) evaluating the benefits of low-dose aspirin among women at high preeclampsia risk and RCTs or large cohort studies of harms of low-dose aspirin among women at any level of risk.

Ultimately they included 23 studies, which were examined by 2 reviewers for study quality and data extraction. These were 2 large, multisite RCTs; 13 smaller RCTs of high-risk women (8 of good quality); and 6 RCTs and 2 observational studies of average-risk women to determine harms (7 of good quality).

Aspirin Use Linked to Better Outcomes

Daily low-dose aspirin use after the first trimester was associated with 24% lower rates of preeclampsia and with reductions in adverse preeclampsia outcomes, depending on baseline risk. Absolute risk reductions with aspirin use were 2% to 5% for preeclampsia (relative risk [RR], 0.76; 95% confidence interval [CI], 0.62 - 0.95), 1% to 5% for intrauterine growth restriction (RR, 0.80; 95% CI, 0.65 - 0.99), and 2% to 4% for preterm birth (RR, 0.86; 95% CI, 0.76 - 0.98).

Although the literature review did not detect any significant perinatal or maternal harms, rare harms could not be excluded. Eighteen-month follow-up from the largest trial found no developmental harms, but there were few data regarding long-term outcomes.

Limitations of this systematic review include small-study effects potentially resulting in overestimation of benefits and failure of predictive intervals to achieve statistical significance.

On the basis of these limitations, the reviewers suggest that relative risk reductions closer to 10% for preeclampsia, intrauterine growth restriction, and preterm birth would be a more conservative interpretation of the results.

"Future studies could shift findings toward the null," the reviewers write. "Daily low-dose aspirin beginning as early as the second trimester prevented clinically important health outcomes. No harms were identified, but long-term evidence was limited."

They recommend more primary research to clarify how preeclampsia arising from different risk factors develops and responds to aspirin.

"More robust and consistent tools for preeclampsia risk stratification would support future research and clinical practice," they conclude. "Few trials have been conducted among African American women in the United States, who have the greatest disease burden; clinical research focused on this important subpopulation is urgently needed. For women at high risk for preeclampsia, available evidence indicates modest effects but important benefits of daily low-dose aspirin for prevention of the condition and consequent illness."

The Agency for Healthcare Research and Quality funded this study. Some of the study authors reported having received government or USPSTF contracts.

Ann Intern Med. Published online April 7, 2014.

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