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ABSTRACT & COMMENTARY

Low-dose Aspirin and Preeclampsia

February 1, 2016

By John C. Hobbins, MD

Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Dr. Hobbins reports no financial relationships relevant to this field of study.

SYNOPSIS: A study comparing outcomes before and after offering low-dose aspirin to patients who were deemed to be high risk by a first trimester protocol showed a decrease in preterm birth prior to 34 weeks and a decrease in early-onset preeclampsia.

SOURCE: Park F, et al. Prediction and prevention of early onset preeclampsia: Impact of aspirin after first trimester screening. Ultrasound Obstet Gynecol 2015;46:419-423.

Controversy abounds regarding whether preeclampsia can be prevented with low-dose aspirin (ASA) and, if it does, whether selected high-risk patients or every pregnant patient should be on this medication. An article from Australia by Park et al may shed some light on these issues.1

This “before and after” study, which was conducted between April 2010 and March 2012, identified a group of women who were screened for preeclampsia during the first trimester (the observational group) with an already validated algorithm2 based on demographic history, mean arterial pressure, uterine artery waveform analysis, and pregnancy associated plasma protein A. No treatment was offered to these patients during this time period.

The second (interventional) group was screened between April 2012 and June 2013 using the same first trimester protocol, but those deemed to be at “high risk” (> 2% chance of having early-onset preeclampsia) were offered treatment with a nightly dose of 150 mg ASA up until the 34th week of gestation. The records were then tracked carefully for signs of preeclampsia (elevated blood pressure and proteinuria). Those having elevated blood pressure prior to 20 weeks were labeled as chronic hypertensives.

There were 3066 patients in the observational group (over 24 months) and 2717 patients in the interventional group (over 15 months). When comparing outcomes between the two sequential groups overall (regardless of risk), the only variable showing a significant difference was a decrease in the rate of delivery prior to 34 weeks in the group treated with nightly ASA (0.40% vs 0.04%, P < 0.01). However, when comparing the patients in each group at risk for preeclampsia (301 vs 264), the treated (interventional) group had an incidence of preeclampsia that was almost halved in the observational group (2.36 vs 1.42%, P < 0.01.) Also, the rate of those needing delivery before 34 weeks was significantly lower (3.6% vs 0.38%, P < 0.01) in the interventional group vs the observational group, respectively. There were no significant differences in other variables such as abruption, but there was a trend toward a lower risk of stillbirth (0.29% vs 0.11%) in the group treated with ASA.

COMMENTARY

After initiating a policy of offering low-dose ASA (150 mg) early in pregnancy to patients at risk for preeclampsia, there was a significantly reduced chance of preeclampsia and a significant drop in patients delivering prior to 34 weeks, suggesting that the stronger the predilection for preeclampsia, the stronger the effect of the ASA.

Because of the low prevalence of pre-eclampsia in low-risk patients, it has been hard to prove the benefit of low-dose ASA, and even in the high-risk patients, the results have been inconsistent.3 However, as sometimes happens, individual randomized, controlled trials (RCTs) may not show differences between ASA treatment and control patients, but a cumulative meta-analysis of these studies did detect a difference.4 What does seem clear is that the benefit is greatest if the ASA is initiated at, or prior to, 16 weeks5: ergo, the move to screen in the first trimester.

So why not give everyone ASA? “ASA-for-all” advocates might say that a low chance of benefit has not discouraged, seemingly, every man in the Viagra-taking age group from taking daily low-dose ASA for prevention of adverse cardiovascular events. Well, in the spirit of “do no harm,” there has been a nagging doubt about an increased risk of abruption. This arose from one of the early NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development) network RCTs3 and another later study.6 Other studies, as well as the above study, have not shown a trend toward an increase in abruptions with ASA, but most were not powered to show a difference. The other problem is a potential allergy to the medication, as well as gastric intolerance. Also, it seems like a dubious undertaking to give ASA to a low-risk population where thousands of patients would be treated to prevent one patient from getting preeclampsia. However, for high-risk patients the numbers can make sense. For example, in the above index study,1 the authors stated that for every 296 patients screened, 29 high-risk patients would be earmarked to take ASA to prevent one case of “early” preeclampsia. The drawback, of course, is that, if using their protocol, every patient would need first trimester uterine artery wave form analysis and biochemistry, the former being something that is uncommonly done in the United States.

The before-and-after study design is vulnerable to some criticism, but, despite its shortcomings, the findings were worth doing the retrospective analysis. I do question why the investigators chose 150 mg, rather than the 84 mg dose used most commonly. This “if some is good, more is better” approach certainly did not show that 150 mg was superior to the standard dose, and it leaves us in a quandary now regarding which regimen to follow.

Until new information surfaces, it seems reasonable to identify those at greatest risk by whatever protocol one wishes to use and to treat with low-dose ASA before 16 weeks, and preferably by the end of the first trimester. I’ll continue to use the one tablet, 84 mg dose, at night and will recommend discontinuing it at 34 weeks, because in some hospitals anesthesiologists are reluctant to administer epidurals in patients with ASA on board, and there is no evidence of prophylactic benefit past this point. It must be realized that with uterine artery screening, there is a very high screen positive rate for preeclampsia, compared with second trimester screening, but then one misses the ideal treatment window with the latter approach.

REFERENCES

  1. Park F, et al. Prediction and prevention of early onset preeclampsia: Impact of aspirin after first trimester screening. Ultrasound Obstet Gynecol 2015;46:419-423.
  2. Park F, et al. Clinical evaluation of a first trimester algorithm predicting the risk of hypertensive disease in pregnancy. Aust NZ J Obstet Gynecol 2013;53:532-539.
  3. Caritis S, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701-705.
  4. Askie LM, et al; PARIS Collaborative Group. Antiplatelet agents for prevention of preeclampsia: A meta-analysis of individual patient data. Lancet 2007;369:1791-1798.
  5. Roberge S, et al. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: A systemic review and meta-analysis. Fetal Diagn Ther 2012;31:141-146.
  6. Yu CK, et al; Fetal Medicine Foundation Second Trimester Screening Group. Randomized controlled trial using low dose aspirin in the prevention of preeclampsia in women with abnormal uterine artery Doppler at 23 weeks’ gestation. Ultrasound Obstet Gynecol 2003;22:233-239.