ajog.
org
Preventing preeclampsia with aspirin: does
dose or timing matter?
Stephen Tong, PhD; Ben W. Mol, PhD; Susan P. Walker, MD
I n 1978, Goodlin et al1 published a case report in The
Lancet, describing a 31-year-old woman presenting with
thrombocytopenia at 15 weeks gestation. Her obstetric his-
tory had been tumultuous: 2 preterm births with neonatal
demise, both arising from recurrent toxemia. Perhaps with
some alarm, the treating team found her platelet count was
already just 59,000/mL, with further tests conrming pe-
ripheral consumption. To boost her platelet count, they rst
tried heparin for 4 weeks without avail.
They then turned to aspirin. At the rather hefty dose of 600
mg, 3 times a day, her platelet count commenced a slow but
inexorable upward trajectory, eventually doubling after 10
weeks. But there was more. In contrast to her previous ill-
fated pregnancies, she never developed hypertension for the
22 weeks while she was on aspirin. At 32 weeks gestation, the
team ceased the aspirin due to concern it could close the fetal
ductus arteriosus. Almost immediately she deteriorated,
developing severe hypertension and her platelets acutely
plummeted. Aspirin was promptly recommenced and her
platelet count rose once more. She was eventually delivered at
34 weeks gestation, precipitated by fetal heart rate de-
celerations on a nonstress test where a live-born (albeit
growth-restricted) fetus was delivered. This was the rst case
report of aspirin use in pregnancy and it set in train
remarkable momentum, culminating in 3 decades of earnest
clinical trials to determine whether aspirin can prevent pre-
eclampsia. Some 30,000 women have now been randomized
in clinical trials making aspirin easily one of the most
intensely studied drugs in obstetrics.
Drawing on many of these clinical trials, 2 important meta-
analyses have been published on aspirin use in this issue of
the American Journal of Obstetrics and Gynecology. They have
set out to address very specic important clinical questions
that resonate with everyday clinicians: whether the dose and
timing of aspirin commencement matters.
From Mercy Perinatal, Mercy Hospital for Women, and Department of
Obstetrics and Gynecology, University of Melbourne, Mercy Hospital,
Heidelberg, Australia (Drs Tong and Walker); and Robinson Institute,
School of Medicine, University of Adelaide and South Australian Health
and Medical Research Institute, Adelaide, Australia (Dr Mol).
Received Nov. 19, 2016; accepted Dec. 1, 2016.
Dr Mol is a consultant for ObsEva, Geneva.
Corresponding author: Stephen Tong, PhD. stong@unimelb.edu.au
0002-9378/free
2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2016.12.003
Related articles, pages 110, 121, and 141.
Editorials
Bujold et al2 previously published a meta-analysis of
placebo-controlled randomized clinical trials that suggested
starting aspirin 16 weeks gestation is impressively effective in
preventing preeclampsia, while there was no statistically sig-
nicant effect when aspirin was commenced >16 weeks
gestation. Furthermore, they reported starting aspirin 16
weeks gestation also signicantly reduced the risk of related
obstetric complications, such as perinatal death and fetal
growth restriction. The impact of this meta-analysis, and a
subsequent publication by the group in 2013,3 has been
considerable. There are clinical guidelines now recommending
that aspirin is commenced 16 weeks gestation for maximum
preventative impact.4,5 This 16-week threshold has seeped into
the practicing minds of many clinicians across the world.
In this issue of the American Journal of Obstetrics and
Gynecology, the same team has published a new meta-analysis
examining whether the dose of aspirin matters.6 They also
revisited the 16 weeks gestation threshold and updated their
meta-analysis with 3 new trials. Once more, the team found
commencing aspirin 16 weeks gestation was strongly
effective in reducing the risk of preeclampsia (relative risk
[RR] 0.57), while the RR of 0.81 when starting it >16 weeks
remained statistically not signicant.
Importantly, they found a dose-dependent effect where
doses of 100 mg of aspirin seemed more effective than lower
doses. Table 2 of their report6 suggests a stronger effect with
increasing aspirin dose, an effect that is more profound for
severe preeclampsia. In studies that randomized women >16
weeks gestation, this dose-dependent relationship
disappeared.5
Life for the obstetrician-gynecologist at the coalface would
be clean and simple if we could translate this to a crisp,
incontrovertible recommendation to commence 100 mg of
aspirin <16 weeks. However, also published in this edition of
the American Journal of Obstetrics and Gynecology are powerful
conicting data. Meher et al7 performed an individual partic-
ipant data (IPD) meta-analysis using data from the PARIS
(Perinatal Antiplatelet Review of International Studies) study
published almost a decade ago.8 This analysis showed a far
more modest 10% reduction effect of aspirin on the risk of
preeclampsia, and there was no difference in this risk reduction
if aspirin was commenced either <16 or >16 weeks gestation.7
They arrived at the same conclusion for the risk of fetal demise
and delivering a small-for-gestational-age infant: starting
aspirin <16 or >16 weeks gestation made no difference.
This is all very perplexing. How can we possibly reconcile
these opposing ndings? The methodology of the IPD meta-
analysis ensures that clinical characteristics of all individual
patients from different studies are available for analysis. The
use of IPD meta-analysis has several advantages over the use of
FEBRUARY 2017 American Journal of Obstetrics & Gynecology 95
Editorials
aggregate data: more up-to-date information can be included
than was available at the time of the original trials publication;
analyses across studies are standardized; results of previously
missing or poorly reported outcomes are incorporated; and
clinical decisions can be personalized by assessing different
treatment effects for subgroups, ensuring the optimal dose,
timing, and delivery method of the interventions can be
studied.9 Meher et al7 also reached more statistical powerethey
examined data from 9241 women to derive the RR of pre-
eclampsia if aspirin was commenced <16 weeks and data from
21,429 women to calculate the RR of preeclampsia if aspirin
was started >16 weeks. In contrast, Roberge et al6 included
5130 participants who started aspirin 16 weeks and 15,779
participants who started aspirin >16 weeks.
Apart from this increase in statistical power, the study of
Meher et al7 is more protected against publication bias that may
be present in the study by Roberge et al6 (see their funnel plot
[Figure 4, A] and the accompanying statistical analysis6).
Also, it should be noted that there have been no clinical
trials that have randomized women to starting aspirin <16
weeks gestation vs afterwards. Thus, there is no evidence
addressing this question in direct comparisons: both meta-
analyses have examined data generated from clinical trials,
drawing their conclusions from indirect comparisons.
Turning to the possible biological mechanism of action
does not really help us make our minds up whether aspirin
will work better, if started earlier in pregnancy. The enthu-
siasts believing aspirin works better if commenced early
might refer to the long-standing belief that aspirin somehow
facilitates early placental embedding,10 a process that is in fact
poorly understood but is likely to be complete by 16 weeks
gestation. However, aspirin also increases prostacyclin
(vasodilator) and may also decrease endothelial (blood vessel)
dysfunction,11 actions that could make it effective in pre-
venting clinical preeclampsia well >20 weeks gestation.
So here we are in 2017, >23 trials and 30,000 women later,
still debating what to do. With the available evidence, clini-
cians on the ground need pragmatic advice that is useful for
day-to-day care. We suggest the following. Firstly, the dose-
response data in the report of Roberge et al6 for the
outcome of severe preeclampsia look pretty convincing and
suggest that the aspirin dose to prevent preeclampsia should
not be <100 mg. Until this is assessed in an IPD or head-to-
head comparative studies, clinicians should prescribe aspirin
at dose of at least 100 mg. Secondly, while both reports
concur that commencing aspirin <16 weeks gestation has
preventative effects, the IPD of Meher et al7 representing
>21,000 women suggest it is still benecial to start aspirin
even if commenced >16 weeks gestation. As to the magni-
tude of the risk reduction, the risk of preeclampsia is reduced
by about 10% if aspirin is commenced >16 weeks gestation.
It is tricky to decide what we should say is the risk reduction
if it is started <16 weeks gestation. The IPD approach of
Meher et al7 with a signicantly larger sample size may be
arguably more robust than the meta-analysis of Roberge
et al.6 Therefore, advising patients that aspirin reduces the
96 American Journal of Obstetrics & Gynecology FEBRUARY 2017
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risk of preeclampsia by 10% is probably closer to the truth
based on the current evidence.
Our responsibility does not end here. As researchers, we
must design studies that address the knowledge gaps. The
PARIS IPD meta-analysis has published a reanalysis of its data
10 years after its conception, but the IPD has not been
updated. The hypothesis that an earlier start is benecial and
a high dose is better should be tested in trials directly
comparing an early vs later start. We note with anticipation
that the Aspirin for Evidence-based Preeclampsia Prevention
Trial is due to report its ndings soon.12 It is a study where
nearly 30,000 women are being screened in the rst trimester
for their risk of developing preeclampsia. Around 1700
identied as high risk are then randomized to aspirin or
placebo. The quality and independence of systematic reviews
can be improved by complying with guidelines such as those
recommended by the Institutes of Medicine, and by following
transparent protocols.13,14 Finally, we appeal to clinicians on
the ground to contribute to studies as part of their routine
practice. Currently, the costs of trial are in the millions
and one of the main drivers is difcult recruitment, a
responsibility that rests with all of us.
In the past decade and a half, the pace of discoveries in the
eld of preeclampsia have accelerated and this has led to some
new drug possibilities that could prove effective to treat or
prevent preeclampsia. The line of proposed new drugs are an
eclectic mixesildenal,15 esomeprazole,16 metformin,17 and
even pravastatin.18,19 There may be others. Thus, it is possible
that in coming years a drug will be proven in clinical trials to
be clearly better than aspirin at preventing preeclampsia and
other major complications. Lets hope soethat could nally
draw to a close the circular debates over the timing, dose,
and the effectiveness of aspirin. -
REFERENCES
1. Goodlin RC, Haesslein HO, Fleming J. Aspirin for the treatment of
recurrent toxemia. Lancet 1978;2:51.
2. Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and
intrauterine growth restriction with aspirin started in early pregnancy: a
meta-analysis. Obstet Gynecol 2010;116:402-14.
3. Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of
perinatal death and adverse perinatal outcome using low-dose aspirin: a
meta-analysis. Ultrasound Obstet Gynecol 2013;41:491-9.
4. Tranquilli AL, Dekker G, Magee L, et al. The classication, diagnosis
and management of the hypertensive disorders of pregnancy: a revised
statement from the ISSHP. Pregnancy Hypertens 2014;4:97-104.
5. Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P. SOGC Hy-
pertension Guideline Committee. Diagnosis, evaluation, and manage-
ment of the hypertensive disorders of pregnancy: executive summary.
J Obstet Gynaecol Can 2014;36:575-6.
6. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The
role of aspirin dose on the prevention of preeclampsia and fetal growth
restriction: systematic review and meta-analysis. Am J Obstet Gynecol
2017;216:110-20.e1-6.
7. 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;216:121-8.
8. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA.
PARIS Collaborative Group. Antiplatelet agents for prevention of
ajog.org
pre-eclampsia: a meta-analysis of individual patient data. Lancet
2007;369:1791-8.
9. Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual
participant data: rationale, conduct, and reporting. BMJ 2010;340:c221.
10. Merviel P, Carbillon L, Challier JC, Rabreau M, Beauls M, Uzan S.
Pathophysiology of preeclampsia: links with implantation disorders. Eur J
Obstet Gynecol Reprod Biol 2004;115:134-47.
11. Vainio M, Riutta A, Koivisto AM, Maenpaa J. Prostacyclin,
thromboxane A and the effect of low-dose ASA in pregnancies at high
risk for hypertensive disorders. Acta Obstet Gynecol Scand 2004;83:
1119-23.
12. OGorman N, Wright D, Rolnik DL, Nicolaides KH, Poon LC. Study
protocol for the randomized controlled trial: combined multimarker
screening and randomized patient treatment with ASpirin for evidence-
based PREeclampsia prevention (ASPRE). BMJ Open 2016;6:
e011801.
13. Institute of Medicine. Finding what works in health care: standards for
systematic reviews. Washington (DC): National Academies Press; 2011.
14. Moher D, Shamseer L, Clarke M, et al; PRISMA-P Group. Preferred
reporting items for systematic review and meta-analysis protocols
(PRISMA-P) 2015 statement. Syst Rev 2015;4:1.
Editorials
15. Trapani A Jr, Goncalves LF, Trapani TF, Vieira S, Pires M, Pires MM.
Perinatal and hemodynamic evaluation of sildenal citrate for
preeclampsia treatment: a randomized controlled trial. Obstet Gynecol
2016;128:253-9.
16. Cluver CA, Walker SP, Mol BW, et al. Double blind, randomized,
placebo-controlled trial to evaluate the efcacy of esomeprazole to treat
early onset pre-eclampsia (PIE trial): a study protocol. BMJ Open 2015;5:
e008211.
17. Brownfoot FC, Hastie R, Hannan NJ, et al. Metformin as a prevention
and treatment for preeclampsia: effects on soluble fms-like tyrosine ki-
nase 1 and soluble endoglin secretion and endothelial dysfunction. Am J
Obstet Gynecol 2016;214:356.e1-15.
18. Brownfoot FC, Tong S, Hannan NJ, et al. Effects of pravastatin on
human placenta, endothelium, and women with severe preeclampsia.
Hypertension 2015;66:687-97.
19. Costantine MM, Cleary K, Hebert MF, et al; Eunice Kennedy Shriver
National Institute of Child Health and Human Development Obstetric-
Fetal Pharmacology Research Units Network. Safety and pharmacoki-
netics of pravastatin used for the prevention of preeclampsia in high-risk
pregnant women: a pilot randomized controlled trial. Am J Obstet
Gynecol 2016;214:720.e1-17.
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