Aspirin to prevent preeclampsia: When to start and how much to give?

Empirical use of aspirin to prevent myocardial infarction dates back to 1950.¹ It would take another 20 years for Sir John Vane to describe aspirin’s primary mechanism of action, inhibition of cyclooxygenase, for which he shared a Nobel Prize.² In 1975 aspirin’s inhibitory effect on platelet-induced arterial thrombosis was described by Weiss and associates.³ Later studies showed that this antithrombotic property was mediated by inhibition of the synthesis of platelet thromboxane A2 (TXA2), a potent platelet aggregator and vasoconstrictor.

Drawing on these anti-platelet effects, in 1978 Dr Bob Goodlin and colleagues were the first to report the use of aspirin to prevent preeclampsia.⁴ They treated a thrombocytopenic patient with a history of recurrent early–onset severe preeclampsia using high doses of aspirin starting at 15 weeks, and reported that she delivered a live-born, although growth-restricted, infant at 34 weeks gestation. Eleven years later, Schiff and colleagues conducted the first randomized, placebo-controlled clinical trial of low-dose aspirin for the prevention of preeclampsia in high-risk women.⁵ The authors screened 791 high-risk pregnant women with a rollover test at 28 to 29 weeks gestation. Among 65 patients with a positive test, 34 were randomized to a daily dose of 100 mg of aspirin and 31 to placebo. They reported a substantially lower incidence of preeclampsia among aspirin recipients (2.9% vs 22.6%; P = 0.019) and noted that treated patients had decreased ratios of serum TXA2 to prostacyclin (PGI2), a platelet aggregation inhibitor and vasodilator. Several other small studies yielded similar results.^6,7

It seemed we were on the cusp of a potential cure for this ancient, though poorly understood, scourge of mothers and babies. However, as so often happens in the era of evidenced-based medicine, subsequent studies yielded marginal or contradictory results, leaving clinicians confused and discouraged.

A brief history of randomized trials of aspirin to prevent preeclampsia

In 1993, the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units reported the effects of low-dose aspirin on the occurrence of preeclampsia in normotensive nulliparous women.⁸ Patients were randomized at 13 to 26 weeks to either 60 mg of aspirin per day (n=1485) or placebo (n=1500). The authors noted a modest reduction in the occurrence of preeclampsia in the aspirin group (4.6%) compared with placebo (6.3%) (relative risk [RR] of 0.7; 95% CI: 0.6 to 1.0). Greater relative reductions were observed among patients with initially elevated systolic pressures. However, they observed no significant differences in birth weight, the incidence of fetal growth restriction (FGR) or either maternal or neonatal bleeding episodes, and the occurrence of placental abruption was slightly higher in aspirin recipients (1.3% vs 0.4%).

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Subsequently, Subtil and colleagues conducted a large multicenter, randomized, double-blinded placebo-controlled trial of aspirin (100 mg) vs placebo beginning at 14 to 20 weeks among more than over 3000 nulliparous women.⁹ They found no differences in the incidence of preeclampsia between treated and control patients (1.7% vs 1.6%; RR 1.08; 95% CI: 0.64-1.83). Moreover, no differences were found in the occurrence of hypertension, HELLP (hemolysis, elevated liver enzyme levels, and low platelet levels) syndrome, placental abruption, perinatal deaths, or FGR, and, of concern, mothers receiving aspirin had a significantly higher rate of hemorrhage.

By 2007, more than 32,000 pregnant women at varying risk for preeclampsia had been enrolled in 31 randomized control trials (RCTs) testing the efficacy of various doses of aspirin or other antiplatelet agents (eg, dipyridamole) initiated at differing gestational ages for the prevention of preeclampsia. A meta-analysis of these studies found that antiplatelet agents conferred a modest reduction in preeclampsia (RR 0.90; 95% CI: 0.84-0.97), and preterm births (PTB) before 34 weeks (RR 0.90; 95% CI: 0.83-0.98), but had no effect on stillbirth, FGR, or maternal or fetal bleeding.¹⁰ In 2014, after pooling all available studies, many of which were small and of lower quality, the US Preventive Services Task Force (USPSTF) concluded that aspirin was associated with absolute risk reductions in preeclampsia of 2% to 5% (RR 0.76; 95% CI: 0.62 to 0.95), as well as 1% to 5% reductions in FGR (RR 0.80; 95% CI: 0.65 to 0.99), and 2% to 4% reductions in PTB (RR 0.86; 95% CI: 0.76 to 0.98).¹¹ The USPSTF ultimately recommended low-dose aspirin as a preventive medication after 12 weeks gestation in women who had 1 or more high-risk factor(s) and consideration of such treatment in patients with “several” moderate-risk factors (see Table).¹² No specific dosage was recommended but use of 81 mg tablets was considered “reasonable” and a wide gestational age range (12 to 28 weeks) was provided for initiating therapy.

However, in view of the mix of negative and positive trials, heterogeneous populations studied, and variable methodological designs employed, controversies were generated about the magnitude of putative benefits, the optimal dose of aspirin to use, and the ideal gestational age at which to start treatment. Answers to these nagging questions were sought in 2 recent studies.

NEXT: What do the 2 studies show?

Results of recent meta-analyses: more clarity but more confusion

Roberge and associates sought to address both dosing and timing questions by performing an exhaustive systematic review and meta-analysis of RCTs comparing aspirin to either placebo or no treatment.¹³ The authors identified 45 relevant trials involving 20,909 pregnant women randomized to 50 to 150 mg of aspirin daily. They stratified analyses according to whether aspirin was initiated at ≤ 16 or >16 weeks gestation. Of note, when aspirin was initiated at ≤ 16 weeks there was both a significant reduction in preeclampsia and a clear dose-response effect (ie, higher aspirin doses had greater efficacy). The latter effect is an important indicator of biological plausibility. When started at 16 weeks, aspirin markedly reduced the occurrence of preeclampsia (RR 0.57; 95% CI: 0.43-0.75), severe preeclampsia (RR of 0.47; 95% CI: 0.26-0.83) and FGR (RR of 0.56; 95% CI: 0.44-0.70). In contrast, when aspirin was initiated at > 16 weeks, beneficial effects, while still observed, were of a lower magnitude for preeclampsia (RR 0.81; 95% CI: 0.66-0.99) and no effects were observed for severe preeclampsia or FGR. In addition, no dose response was observed when treatment was started > 16 weeks. The authors speculated that earlier treatment enhanced placentation while the higher dose exerted a greater antiplatelet turnover effect. Given the anti-inflammatory effects of aspirin and evidence that decidual inflammation may inhibit placentation,^14,15 this thesis also has biological plausibility.

The study by Roberge and associates appeared to explain many of the contradictory results observed in the literature and might have led to a complete re-thinking of preventative strategies for preeclampsia, had it not been for the simultaneous publication of another meta-analysis in the same journal on the same date with conflicting findings. The latter study, by Meher et al, examined individual participant data on 32,217 women and 32,819 babies recruited in 31 RCTs comparing low-dose aspirin or other antiplatelet agents versus either placebo or no treatment.¹⁶ These authors stratified results to initiation of therapy at < 16 weeks versus ≥ 16 weeks. In contrast to Roberge et al, these authors found a lesser overall benefit from aspirin and no significant difference in treatment effects among women randomized at < versus ≥ 16 weeks for preeclampsia (RR 0.90; 95% CI: 0.79-1.03 vs 0.90; 95% CI: 0.83-0.98, respectively). They concluded that, “The effect of low-dose aspirin and other antiplatelet agents on preeclampsia and its complications is consistent, regardless of whether treatment is started before or after 16 weeks gestation.”

Next: Can a patient safety bundle prevent deaths from PE?

Both studies were carefully performed and involved large numbers of subjects. The Meher study had the advantage of using individual participant data which provides a richer source of more standardized data and allows new analyses to be performed amongst different subgroups. On the other hand, the Meher study mixed outcome data from patients treated with aspirin or other antiplatelet agents. In addition, while Roberge and associates compared treatment initiated at ≤ 16 vs > 16 weeks, Meher and colleagues compared treatment begun at < 16 vs ≥ 16 weeks, albeit a slight difference.

Take-Home Message

We can be heartened by the findings of both Meher et al, and Roberge et al, because low-dose aspirin appears to be effective and safe in preventing preeclampsia in at-risk women. Based on our current state of knowledge, I would recommend treating women with any of the USPSTF high-risk factors or those women with 2 or more of the USPSTF moderate-risk factors (see Table) with low-dose aspirin either 81 mg or 122 mg (a tablet and a half) once a day, starting at 12 to 14 weeks.

Clearly, better identification of at-risk pregnant women should allow for more targeted treatment and, potentially, greater public health benefits from aspirin prophylaxis. Thus, our specialty is eagerly awaiting the results of the ASpirin for evidence-based PREeclampsia (ASPRE) prevention study, which uses a battery of biochemical and sonographic screening tests yielding a 75% sensitivity and 10% false-positive rate for the prediction of preeclampsia to allocate at-risk women to 150 mg of aspirin versus placebo from 11-13 to 36 weeks.¹⁷ Hopefully, that study will lend further clarity to this confusing but encouraging story.

References

1. Craven LL. Acetylsalicylic acid: possible preventive of coronary thrombosis. Ann West Med Surg. 1950;4:95–99. PMID: 15403207

2. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231: 232–235 PMID: 5284360

3. Weiss HJ, Tschopp TB, Baumgartner HR. Impaired interaction [adhesion-aggregation] of platelets with the subendothelium in storage-pool disease and after aspirin ingestion. A comparison with von Willebrand’s disease. N Engl J Med. 1975;293:619–623. PMID: 1080251

4. Goodlin RC, Haesslein HO, Fleming J. Aspirin for the treatment of recurrent toxaemia.  Lancet. 1978 Jul 1;2(8079):51. No abstract available. PMID: 78253

5. Schiff E, Peleg E, Goldenberg M, et al. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. N Engl J Med. 1989 Aug 10;321(6):351-356. PMID: 2664522

6. Benigni A, Gregorini G, Frusca T, et al. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. N Engl J Med. 1989 Aug 10;321(6):357-362. PMID: 2664523

7. Beaufils M, Uzan S, Donsimoni R, et al. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet. 1985 Apr 13;1(8433):840-842. PMID: 2858710

8. Sibai BM, Caritis SN, Thom E, Klebanoff M, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1993 Oct 21;329(17):1213-1218. PMID: 8413387

9. Subtil D, Goeusse P, Puech F, et al. Essai Régional Aspirine Mère-Enfant (ERASME) Collaborative Group. Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women: the Essai Régional Aspirine Mère-Enfant study (Part 1). BJOG. 2003 May;110(5):475-84. PMID: 12742332

10. Askie LM, Duley L, Henderson-Smart DJ, et al. PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007 May 26;369(9575):1791-1798. Review. PMID: 17512048

11. Henderson JT, Whitlock EP, O’Connor E, et al. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014 May 20;160(10):695-703. doi: 10.7326/M13-2844. Review. PMID: 24711050

12. US Preventive Services Task Force. Final Recommendation Statement: Low-Dose Aspirin Use for the Prevention of Morbidity and Mortality From Preeclampsia: Preventive Medication. Available at: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/low-dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-medication. Accessed May 16, 2017.

13. Roberge S, Nicolaides K, Demers S, et al. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2017 Feb;216(2):110-120.e6. doi: 10.1016/j.ajog.2016.09.076. Epub 2016 Sep 15. Review. PMID: 27640943

14. Lockwood CJ, Yen CF, Basar M, Kayisli UA, et al. Preeclampsia-related inflammatory cytokines regulate interleukin-6 expression in human decidual cells. Am J Pathol. 2008 Jun;172(6):1571-1579. doi: 10.2353/ajpath.2008.070629. Epub 2008 May 8. PMID: 18467705

15. Lockwood CJ, Huang SJ, Chen CP, et al. Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia. Am J Pathol. 2013 Sep;183(3):841-856. doi: 10.1016/j.ajpath.2013.05.029. Erratum in: Am J Pathol. 2013 Nov;183(5):1698. PMID: 23973270

16. Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia: an individual participant data meta-analysis. Am J Obstet Gynecol. 2017 Feb;216(2):121-128.e2. doi: 10.1016/j.ajog.2016.10.016. Epub 2016 Nov 1. Review. PMID: 27810551

17. O’Gorman N, Wright D, Rolnik DL, et al. Study protocol for the randomised controlled trial: combined multimarker screening and randomised patient treatment with ASpirin for evidence-based PREeclampsia prevention (ASPRE). BMJ Open. 2016 Jun 28;6(6):e011801. doi: 10.1136/bmjopen-2016-011801. PMID: 27354081