Dose of Aspirin To Prevent Preterm Preeclampsia in

PLOS ONE
RESEARCH ARTICLE
Dose of aspirin to prevent preterm

preeclampsia in women with moderate or
high-risk factors: A systematic review and
meta-analysis
Rachel Van Doorn ID1☯, Narmin Mukhtarova ID2☯, Ian P. Flyke1, Michael Lasarev ID3‡,
KyungMann Kim3‡, Charles H. Hennekens4, Kara K. Hoppe ID2*
1 University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States
a1111111111
of America, 2 Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of
a1111111111 Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America,
a1111111111 3 Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin, United
a1111111111 States of America, 4 Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton,
a1111111111 Florida, United States of America
☯ These authors contributed equally to this work.

‡ These authors also contributed equally to this work.
* [email protected]
OPEN ACCESS
Citation: Van Doorn R, Mukhtarova N, Flyke IP,

Lasarev M, Kim K, Hennekens CH, et al. (2021)
Abstract
Dose of aspirin to prevent preterm preeclampsia in
women with moderate or high-risk factors: A
systematic review and meta-analysis. PLoS ONE
Objective
16(3): e0247782. https://doi.org/10.1371/journal.
pone.0247782 To evaluate the effect of aspirin dose on the incidence of all gestational age preeclampsia
Editor: Kazumichi Fujioka, Kobe University and preterm preeclampsia.
Graduate School of Medicine School of Medicine,
JAPAN
Data sources
Received: November 4, 2020
Electronic databases (Cochrane, PubMed, Scopus, ClinicalTrials.gov and the Web of Sci-
Accepted: February 14, 2021
ence) were searched for articles published between January 1985 and March 2019 with no
Published: March 9, 2021
language restrictions.
Copyright: © 2021 Van Doorn et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which Methods
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
We followed the PRIMSA guidelines and utilized Covidence software. Articles were
author and source are credited. screened by 2 independent reviewers, with discrepancies settled by an independent 3rd
Data Availability Statement: All relevant data are
party. Study selection criteria were randomized trials comparing aspirin for prevention of all
within the paper and its Supporting Information gestational age and preterm preeclampsia to placebo or no antiplatelet treatment in women
files. aged 15–55 years with moderate or high-risk factors according to the list of risk factors from
Funding: This project was funded by the UnityPoint American College of Obstetricians and Gynecologists and United States Preventive Ser-
Health-Meriter Foundation and the University of vices Task Force guidelines. The quality of trials was assessed using the Cochrane risk of
Wisconsin Department of Obstetrics & Gynecology
bias tool. The data were pooled using a random-effects meta-analysis comparing aspirin at
intramural departmental funding. This work was
also partially supported by the Clinical and doses of <81, 81, 100, and 150 mg. Pre-specified outcomes were all gestational age and
Translational Science Award (CTSA) program, preterm preeclampsia.
PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 1 / 18

PLOS ONE Aspirin dose and preeclampsia prevention: Meta-analysis
through National Institutes of Health National Results

Center for Advancing Translational Sciences
(NCATS), grant UL1TR000427 and the summer Of 1,609 articles screened, 23 randomized trials, which included 32,370 women, fulfilled
research award from the Herman and Gwendolyn the inclusion criteria. In preterm preeclampsia, women assigned at random to 150 mg
Shapiro Foundation and University of Wisconsin experienced a significant 62% reduction in risk of preterm preeclampsia (RR = 0.38;
School of Medicine and Public Health Dean’s Office
Funds (ANL). The funding source had no role in the
95% CI: 0.20–0.72; P = 0.011). Aspirin doses <150 mg produced no significant reduc-
development of the research or the manuscript. tions. The number needed to treat with 150 mg of aspirin was 39 (95% CI: 23–100).
Competing interests: Drs. Van Doorn,
There was a maximum 30% reduction in risk of all gestational age preeclampsia at all
Mukhtarova, Flyke, Lasarev, and Hoppe have no aspirin doses.
disclosures. Professor Kim reports that he serves
as a member of data monitoring committees for
Astellas, AstraZeneca, Actelion, Bayer, Bristol-
Myers Squibb, GlaxoSmithKline, Idorsia, Merck, Conclusions
and Sarepta. He holds no stock in any In this meta-analysis, based on indirect comparisons, aspirin at a dose greater than the cur-
biopharmaceutical or medical device company.
rent, recommended 81 mg was associated with the highest reduction in preterm preeclamp-
Professor Hennekens reports that he serves as an
independent scientist in an advisory role to sia. Our meta-analysis is limited due to the deficiency of homogeneous high evidence data
investigators and sponsors as Chair of data available in the literature to date; however, it may be prudent for clinicians to consider that
monitoring committees for Amgen, British Heart the optimal aspirin dose may be higher than the current guidelines advise. Future research
Foundation, Cadila, Canadian Institutes of Health
Research, DalCor, and Regeneron; to the United
to compare the efficacy aspirin doses greater than 81 mg is recommended.
States (U.S.) Food and Drug Administration, and
UpToDate; receives royalties for authorship or
editorship of 3 textbooks and as co-inventor on
patents for inflammatory markers and
Study registration
cardiovascular disease that are held by Brigham PROSPERO, CRD42019127951 (University of York, UK; http://www.crd.york.ac.uk/
and Women’s Hospital; has an investment PROSPERO/).
management relationship with the West-Bacon
Group within SunTrust Investment Services, which
has discretionary investment Cover Letter with
amended statements authority; does not own any
common or preferred stock in any pharmaceutical
or medical device company. This does not alter our
adherence to PLOS ONE policies on sharing data
Introduction
and materials. Hypertensive disorders of pregnancy are a leading cause of maternal morbidity and mortality
worldwide, accounting for more than 70,000 maternal deaths each year [1]. Of all maternal
deaths, 10–15% are directly associated with preeclampsia and eclampsia [2]. Aspirin is an inex-
pensive and widely available drug that has the potential to safely help pregnant women and
neonates. While randomized trials have investigated the prophylactic use of aspirin in prevent-
ing preeclampsia, the optimal dose remains unclear. Current guidelines endorsed by American
College of Obstetricians and Gynecologists (ACOG) and United States Preventive Services
Task Force (USPSTF) recommend low-dose aspirin prophylaxis in women at high risk of pre-
eclampsia as well as for women with more than one of several moderate risk factors for pre-
eclampsia [3, 4]. More recent trials have investigated the use of aspirin at a higher dose of 150
mg [5]. In one trial, 150 mg of daily aspirin in pregnant women deemed high-risk for develop-
ing preeclampsia, significantly decreased the incidence of preterm preeclampsia when com-
pared to placebo [5]. In a recent systematic review, the authors concluded that aspirin
beginning at or before 16 weeks gestation reduces the incidence of preeclampsia and its
adverse outcomes among pregnant women and neonates [6]. We, therefore, performed a sys-
tematic review and meta-analysis of 23 randomized controlled trials to explore whether aspirin
is effective and, if so, the optimal dose for women with moderate or high-risk factors of pre-
eclampsia. Our primary objective was to determine the effect of aspirin dose on the incidence
of all gestational age and preterm preeclampsia.

Methods
Data sources
This systematic review followed the Preferred Reporting Items for Systematic Reviews and
Meta-analysis (PRIMSA) guidelines utilizing the software, Covidence, and registered as
CRD42019127951 in the PROSPERO database (University of York, UK; http://www.crd.york.
ac.uk/PROSPERO/). Relevant trials were identified through a search of Cochrane Central Reg-
ister of Controlled Trials, PubMed, Scopus, ClinicalTrials.gov and the Web of Science from
January 1985 to March 2019. We did not search prior to 1985 because the first randomized
controlled trial studying antiplatelet therapy as prevention for preeclampsia was published in
April of that year [7]. References of prior systematic reviews were queried for additional stud-
ies. No language restrictions were applied. Medical Subject Heading (MeSH) terms and key-
word included: (((("Hypertension"[MeSH]) OR "Blood Pressure"[MeSH]) OR ("Eclampsia"
[MeSH] OR "Pre-Eclampsia"[MeSH] OR hypertension OR "high blood pressure" OR hbp OR
eclampsia OR pre-eclampsia OR preeclampsia OR "blood pressure")) AND ("Aspirin"[MeSH]
OR "Acetylsalicylic acid" OR aspirin)) AND (pregnan� OR gestation� ). Approval from an insti-
tutional review board was not required for this review.
Study selection
We conducted a systematic review and meta-analysis of randomized controlled trials that stud-
ied the use of aspirin for the prevention of preeclampsia in women aged 15–55 years with any
moderate or high-risk factors of preeclampsia according to the list of risk factors from USPSTF
and ACOG guidelines. Studies that were quasi-randomized, cluster randomized, or not peer-
reviewed were excluded. Trials using a different treatment regimen were similarly excluded.
The primary outcome was the effect of aspirin dose on the incidence of all gestational age pre-
eclampsia and preterm preeclampsia.
The titles and abstracts of the searched articles were independently screened by two review-
ers (R.VD. and I.F.), with discrepancies addressed by the third reviewer (K.H.). The full text of
the selected articles was individually assessed by two reviewers (R.VD. and N.M.) and any con-
flicts were resolved by the third reviewer (K.H.). Once the final 24 articles were selected for
extraction, N.M. and R.VD. extracted relevant data using Covidence software. The software
provides comparison of the two reviewers’ extractions and a consensus spreadsheet which
requires a specific selection of which extracted data between the two reviewers gets included
into the final document. Any disagreement was resolved by the third reviewer K.H. Extracted
data was principally focused on our primary outcome and if available, demographic data,
adverse maternal, and neonatal outcomes were also extracted. A final collation of data was
exported to Microsoft Excel and sent for statistical review and analysis. Of the 24 articles
selected for data extraction, one article reported results as percentage values only. Upon con-
tacting the author for raw data, we did not receive a response. This study was then excluded
making our total 23 articles.
Each of the 23 articles was subjected to a quality and risk of bias assessment within Covi-
dence. The Covidence software has a built-in Cochrane RoB 1.0 risk of bias assessment tool.44
Studies were screened for the following quality measures and bias risks: sequence generation,
allocation concealment, blinding of participants and personnel for all outcomes, blinding of
outcome assessors for all outcomes, incomplete outcome data for all outcomes, selective out-
come reporting, and other sources of bias. Each category previously listed was independently
rated as “High”, “Low”, or “Unclear” by the two reviewers. Covidence’s reports of any discrep-
ancies were subsequently voted on for a final rating.

Risk ratios (RR) quantifying aspirin’s effect relative to placebo were estimated using DerSi-
monian and Laird’s random-effects model, as we anticipated heterogeneity (measured by the
I2 statistic) would be above 50%. Pooled RRs and supporting 95% confidence intervals (CI)
were computed for overall effect of aspirin on two outcomes; all gestational age preeclampsia
and preterm preeclampsia and for studies grouped by aspirin dose 1) at most 81 mg versus
more than 81 mg and 2) less than 81 mg, exactly 81 mg, exactly 100 mg, and exactly 150 mg for
each outcome as well. Publication bias was assessed graphically using contour-enhanced fun-
nel plots [8]. We also conducted a risk difference analyses allowing for a simple additive reduc-
tion in risk of preeclampsia with aspirin dosing, which allowed for an estimation of the
number needed to treat (NNT) to prevent one case of preeclampsia. Analyses were conducted
using Stata version 15.1 (StataCorp LLC, College Station, TX) with the contributed ‘metan’ [9],
‘metabias’ [10], and ‘confunnel’ [11] packages.
Results
The search strategy yielded 1,609 articles. Preliminary screening by two independent reviewers
(R.VD. and I.F.) excluded 24 duplicates. The remaining article titles and abstracts were
screened as well as any new articles published during the time of the search. A total of 1,585
potentially eligible manuscripts were identified. Of these manuscripts, 1,423 were excluded for
not being relevant to our review criteria. The abstract screening was independently performed
by the same reviewers as the initial screen. Lastly, 162 articles went through full-text screening
and of those, 138 were excluded for not meeting our inclusion criteria, not having reliable
translations, or for being duplicates and commentaries. Any disagreements were settled by the
third reviewer (K.H.). Twenty-four articles met the final requirements for inclusion and data
was extracted. One of the final 24 studies was excluded for lack of adequate reported data met-
rics which prevented us from being able to run the proper statistical analyses on their results.
One of the remaining 23 articles was only used in preterm preeclampsia analysis. The complete
flow diagram of study inclusion is presented in Fig 1.
Study characteristics are presented in Table 1. Our primary outcome measures were the
development of preeclampsia as defined by new onset hypertension (systolic blood pressure
�140 mmHg or diastolic blood pressure �90 mmHg on two occasions at least 4 hours apart)
in pregnant women >20 weeks of gestation and proteinuria (�300 mg on 24-hour urine col-
lection, or protein/creatine �0.3 mg/dL, or dipstick reading of 2+), or in absence of protein-
uria, new onset hypertension accompanied by any of the following: thrombocytopenia, renal
insufficiency, pulmonary edema, or impaired liver function [3] and preterm (diagnosed at
<37 weeks of gestation) preeclampsia. All studies were randomized controlled trials and ran-
ged from 30 to 9,309 total participants. Preeclampsia event was reported by 22/23 studies, how-
ever only 11/23 studies reported the specific incidence of preterm preeclampsia.
Results of the bias assessment via the Cochrane Risk of Bias Template are in S1 Fig. None of
the included studies had risk of bias for “other bias”; five had risk of bias for selective reporting;
eight had risk of bias for incomplete outcome data; eight had risk of bias for blinding of out-
come assessment; eight had risk of bias for outcome of blinding participants and personnel;
eight had risk of bias for allocation concealment; nine had risk of bias for random sequence
generation.
In our primary analysis involving all gestational age preeclampsia outcome, there was noted
heterogeneity among studies using at most 81 mg (I2 = 70.5%; p<0.001) but not in the more
than 81 mg group (I2 �0.5%; p = 0.725, Fig 2). When the analysis of all gestational age pre-
eclampsia outcome was grouped by the four aspirin dosing groups, there was heterogeneity
among the studies using at most 81 mg (I2 = 72.6%; p<0.001) but not in the more than 100 mg

Fig 1. PRISMA flow chart: Summary of article search, selection, and exclusion.
https://doi.org/10.1371/journal.pone.0247782.g001
group (I2 = 0.0%; p = 0.617, Fig 3). Among the 11 studies used for the preterm preeclampsia
analysis there was noted heterogeneity among studies using the at most 81 mg (I2 = 62.7%;
p = 0.013) but not in the more than 100 mg group (I2 = <0.0%; p = 0.973, Fig 4). Publication
bias cannot be excluded based on the funnel plot (S2A and S2B Fig).
Effect of aspirin on all gestational age preeclampsia prevention

The meta-analysis of the 22 studies revealed that aspirin regardless of dose brought about a
27% (RR = 0.73; 95% CI: 0.61–0.87; p<0.001) reduction in risk of all gestational age pre-
eclampsia diagnosis compared to placebo (Fig 5).
Of the final 22 studies included, 15 used at most 81 mg of aspirin, one study used exactly 81
mg (the current recommendation according to ACOG and USPSFT guidelines), and 14 other
studies used between 36 and 80 mg of aspirin. Six used exactly 100 mg and one study used 150
mg, the highest studied dose for preeclampsia prevention to date. The two groups (at most 81
mg vs higher) each showed significant reductions in risk of preeclampsia due to aspirin.

Table 1. Characteristics of 23 randomized control trials included in the meta-analysis.

Study N Inclusion Criteria Follow-Up Aspirin Control Gestational Age at Outcome(s)
Completion Entry
Ayala 2013 350 Familial or personal history of either 98.8% 100 mg Placebo 13.5 ± 1.4 weeks Preeclampsia, preterm delivery, IUGR,
[17] GHTN or preeclampsia; CHTN; and stillbirth.
cardiovascular, endocrine, bleeding, or
metabolic disease; personal history of
spontaneous abortion; multiple
pregnancy; obesity; and adolescent or
middle-aged nulliparous pregnancy.
Beroyz 1994 9,309 For prophylactic entry: history of 99.4% 60 mg Placebo 12–32 weeks Development of proteinuric
[18] preeclampsia or IUGR in the previous preeclampsia, estimated duration of
pregnancy, CHTN, renal disease, or pregnancy, birthweight, birthweight
other risk factors as maternal age, <3rd centile for sex and gestational age,
family history, or multiple pregnancy. stillbirth, or neonatal death ascribed to
For therapeutic entry: signs and preeclampsia, maternal hypertension, or
symptoms of preeclampsia or IUGR in IUGR.
the current pregnancy.
Byaruhanga 230 Previous history of PIH, preeclampsia, 92% 75 mg Placebo 20–28 weeks Preeclampsia; perinatal deaths; and
1998 [19] especially that occurring at < 32 weeks newborn birthweight
of gestation, or eclampsia; and pre-
existing CHTN.
Caritis 1998 2539 Pregnant women with pregestational, 98% 60mg Placebo 16–26 weeks Preeclampsia, abruptio placentae,
[20] insulin-treated diabetes mellitus, preterm birth, infants SGA, neonatal
CHTN, multifetal gestations, or intraventricular hemorrhage,
preeclampsia in a previous pregnancy. postpartum hemorrhage, and neonatal
bleeding.
Chiaffarino 35 CHTN with or without nephropathy, 87.5% 100 mg Placebo <14 weeks GHTN, preeclampsia, birthweight, mean
2004 [21] history of severe preeclampsia or gestational age at birth.
eclampsia, history of IUGR, and history
of intrauterine fetal death.
Ebrashy 2005 139 History of preeclampsia or IUGR, 97.8% 75 mg No 14–16 weeks Preterm preeclampsia, preeclampsia,
[22] CHTN, positive family history or treatment IUGR, preterm delivery, Apgar scores,
underlying vascular disorder, maternal maternal bleeding, and newborn weight.
age < 20 or > 40 years and gestational
diabetes mellitus.
ECPPA 1996 970 Pregnant women at higher risk of 96% 60 mg Placebo 12–32 weeks Proteinuric preeclampsia, preterm
[23] preeclampsia according to a number of delivery, IUGR, birthweight, stillbirth
reasons including CHTN, primigravity, and neonatal death; maternal and fetal
diabetes mellitus, renal disease, history bleeding.
of preeclampsia or IUGR or evidence of
their presence in current pregnancy.
Gilani 1994 200 History of PIH, BP � 140/90 mmHg on 100% 75 mg Placebo 14 weeks, or after Preeclampsia, IUGR, GHTN.
[24] at least two consecutive antenatal visits the 1st antenatal
15 days apart, history of preeclampsia visit
or eclampsia.
Golding 1998 6049 All nulliparous residents in the parishes 97% 60 mg Placebo 12–32 weeks GHTN, proteinuric preeclampsia,
[25] of Kingston and St. Andrew in Jamaica. eclampsia, birthweight, preterm delivery,
perinatal mortality.
Haapsamo 456 Women age < 40 years, < 4 previous 22% 100 mg Placebo Pre-pregnancy to PIH, preeclampsia, IUGR, vaginal
2010 [26] ovarian stimulations, no delivery if woman bleeding during pregnancy, gestational
contraindications for aspirin. becomes pregnant. age at delivery, mode of delivery,
birthweight, Apgar score, umbilical pH,
blood loss in delivery.
Hauth 1993 604 Nulliparous, < 28-years-old. 99% 60 mg Placebo 20–22 weeks GHTN, preeclampsia, preterm delivery,
[27] PPROM, mode of delivery, fetal death,
fetal growth retardation, birth weight,
Apgar score.
Herabutya 1348 All normal, nulliparous pregnant 90% 60 mg Placebo 18–24 weeks Preeclampsia, eclampsia, GHTN.
1996 [28] women.
(Continued )

Table 1. (Continued)

Completion Entry
Morris 1996 102 Nulliparous women with abnormal 98% 100 mg Placebo 17–19 weeks Fetal growth restriction, PIH,
[29] uteroplacental resistance (S/D > 3.3 or preeclampsia, preterm delivery, perinatal
in the presence of an ipsilateral early death.
diastolic notch, an S/D > 3.0 on uterine
artery Doppler assessment) at 18 weeks
of gestation.
Odibo 2015 30 Singleton pregnancy under-going 56.6% 81 mg Placebo 11+0–13+6 weeks Preeclampsia, GHTN, SGA, preterm
[30] ultrasound examination at 11+0 to13+6 birth, stillbirth, antepartum hemorrhage,
weeks and at high risk for preeclampsia neonatal death, NICU admission,
by: CHTN, history of preeclampsia, miscarriage.
diabetes, BMI > 30 kg/m2, bilateral
uterine artery notches, low PAPP-A.
Parazzini 920 Prophylactic criteria: age under 18 or 94% 50 mg No 16–32 weeks Outcome of pregnancy (induced
1993 [31] over 40 years; mild or moderate CHTN, Treatment abortion, spontaneous abortion,
nephropathy with normal renal delivery), birthweight, duration of
function and normal blood pressure, gestation, PIH, mode of delivery, NICU
history of PIH with or without admission, GHTN, IUGR.
proteinuria developing at > 32 weeks of
pregnancy, history of IUGR, and
current twin pregnancy. Therapeutic
criteria: PIH or early signs of IUGR.
Rolnik 2017 1,620 An age of 18 years or more, singleton 91% 150 mg Placebo 11–14 weeks Preterm preeclampsia at < 37 weeks of
[32] pregnancy, live fetus at the time that gestation, adverse outcomes of
scanning was performed and a high risk pregnancy at < 34 weeks, < 37 weeks,
(>1 in 100) for preterm preeclampsia and � 37 weeks of gestation
according to the screening algorithm. (preeclampsia, GHTN, SGA, miscarriage
or stillbirth, abruption, spontaneous
delivery); death and neonatal
complications; neonatal therapy; and
poor fetal growth (birthweight < 3rd, 5th,
or 10th percentil
Rotchell 1998 3,641 All pregnant women attending 99% 75 mg Placebo 12–32 weeks Proteinuric preeclampsia, other PIH,
[33] antenatal clinic between 12–32 weeks of pregnancy duration, birthweight,
gestation. stillbirths and neonatal deaths, major
neonatal events.
Subtil 2003 3,294 Nulliparous women between 14 and 20 99% 100 mg Placebo 14–20 weeks Preeclampsia with proteinuria.
[34] weeks of gestation.
Talari 2014 80 History of preeclampsia, CHTN, 70% 80 mg Placebo 12–16 weeks Preeclampsia, IUGR, prematurity, mode
[35] positive family history of underlying of delivery, birthweight, and Apgar
vascular disorder, gestational diabetes scores.
mellitus, or maternal age < 20 years
or > 40 years.
Tewari 1997 50 History of CHTN or GHTN, positive 70% 50 mg No 28–30 weeks GHTN, preterm birth, mean
[36] rollover test (ROT) at 28–30 weeks of treatment birthweight.
gestation.
Vainio 2002 86 History of CHTN, familial risk of 95.5% 0.5 mg/ Placebo 12–14 weeks PIH, duration of pregnancy, birthweight
[37] preeclampsia (mother or sister), kga and IUGR, induction of labor,
gestational diabetes mellitus, maternal spontaneous delivery, C-section,
age < 20 or > 40 years, history of postpartum hemorrhage, other fetal
preeclampsia, IUGR, or previous outcomes.
intrauterine death. Constant bilateral
diastolic notch in the uterine arteries at
12 to 14 weeks of gestation on Doppler
ultrasound examination.
(Continued )

Table 1. (Continued)

Completion Entry
Viinikka 1993 197 Women at increased risk for developing 95% 50 mg Placebo 12–18 weeks Fetal weight, proteinuria > 300 mg/day,
[38] preeclampsia: blood pressure before exacerbation of pre-existing
pregnancy > 140/90 mmHg, or severe hypertension (usually > 160/120
preeclampsia in prior pregnancy. mmHg) necessitating the initiation of
antihypertensive therapy.
Villa 2013 121 Women with one or more risk factors 79.6% 100 mg Placebo 12+0–13+6 weeks Preeclampsia, GHTN, birthweight
[39] for preeclampsia, such as: age < 20 + days standard deviation score, SGA, length of
or > 40 years, obesity (BMI > 30 kg/ gestation.
m2), CHTN, and others.
GHTN, gestational hypertension; CHTN, chronic hypertension; IUGR, intrauterine growth retardation; PIH, pregnancy-induced hypertension; SGA, small for
gestational age; PPROM, preterm premature rapture of membranes; S/D, systolic-diastolic ratio; PAPP-A, pregnancy-associated plasma protein A; BMI, body mass
index; NICU, neonatal intensive care unit.
a
Daily dose of aspirin was 35–37 mg at the randomization and adjusted at a follow up visit if the weight of the woman exceeded the initial weight by at least 10%.
https://doi.org/10.1371/journal.pone.0247782.t001
Aspirin at most 81 mg demonstrated a 29% reduction (RR = 0.71; 95% CI: 0.56–0.89;
p = 0.003) while at more than 81 mg, a 25% reduction (RR = 0.75; 95% CI: 0.60–0.93,
p = 0.009) in preeclampsia diagnosis (Fig 2). Analyses were also conducted using the risk dif-
ference to quantify the effect of aspirin on reduction of preeclampsia (S3 Fig). On this scale,
the lower dose of aspirin showed a significant reduction in preeclampsia risk (p = 0.007) while
more than 81 mg doses produced a nonsignificant effect (p = 0.115). Those given at most 81
mg saw a 2.6 percentage point (ppt) reduction in risk (95% CI: 0.7–4.4 ppt reduction). This
translated to having to treat 38 (95% CI: 23–143) women with lower-dose aspirin to avoid one
case of preeclampsia.
The studies accounting for all gestational age preeclampsia outcomes were grouped into the
four levels determined by the aspirin doses less than 81 mg, 81 mg, 100 mg, and 150 mg. There
was no evidence that exactly 81 mg of aspirin had an effect (RR = 0.88; 95% CI: 0.21–3.66;
p = 0.855), and the effect for 100 mg not significant (RR = 0.78; 95% CI: 0.57–1.06; p = 0.113).
At the lower and upper ends, there was evidence that aspirin reduces risk and the effect at both
extremes was similar, approximately a 28% reduction in risk (RR = 0.70; 95% CI: 0.55–0.89;
p = 0.003 and RR = 0.72; 95% CI: 0.54–0.98; p = 0.034; Fig 3). Conclusions were similar when
effects are conveyed as simple (additive) reductions in risk: exactly 81 mg and 100 mg each
failed to show a robust effect (p = 0.855 and 0.223, respectively), while the lower dose (36–80
mg, p = 0.007; 2.6 (95% CI: 0.7–4.5) ppt reduction) and highest dose (150mg, p = 0.032; 3.2
(95% CI: 0.3–6.1) ppt reduction) each demonstrated protective effects from aspirin (S4 Fig).
Those lowest/highest doses correspond to NNT values of 38 (95% CI: 22–143) and 31 (95% CI:
16–333).
Effect of aspirin on prevention of preterm preeclampsia

Eleven of the 23 studies presented data of preterm preeclampsia outcome. The meta-analysis
of the overall effect of aspirin on preterm preeclampsia prevention revealed that aspirin is
related to a 30% (RR = 0.70; 95% CI: 0.53–0.92; p = 0.011) reduction in risk of preterm pre-
eclampsia compared to placebo (Fig 6).
When grouped according to aspirin dose at most 81 mg (eight studies) and more that 81
mg (three studies), the analysis revealed an insignificant effect of aspirin at most 81 mg
(RR = 0.78; 95% CI: 0.58–1.05; p = 0.107), while at more than 81 mg (above currently recom-
mended according to ACOG and USPSFT guidelines) the effect of aspirin was significant and

Fig 2. Forest plot of the effect of aspirin on the all gestational age preeclampsia outcome stratified by two groups of aspirin doses: At most 81
mg and more than 81 mg. RR, risk ratio; CI, confidence interval. Black diamond indicates the weight of each study; blue diamond indicates the
overall effect of pooled sample; horizontal line indicates 95% confidence interval; solid vertical line indicates no effect.
demonstrated 54% (RR = 0.46; 95% CI: 0.28–0.74) reduction in risk of preterm preeclampsia
compared to placebo (Fig 7).
Furthermore, studies were grouped according to the four levels of aspirin dose: seven at the
low end (36–80 mg), one at exactly 81 mg, two at exactly 100 mg, and one at exactly 150 mg.
None of the doses/dose groups that were below 150 mg showed a significant reduction in risk
of preterm preeclampsia. The single Rolnik [2017] study demonstrated a convincingly signifi-
cant risk reduction of 62% (RR = 0.38; 95% CI: 0.20–0.72; p = 0.011) for aspirin compared to
placebo (Fig 4). These results should be interpreted with caution considering that the Rolnik
study at 150 mg is only a single value providing data for statistical analysis. These same 4
groups of studies, when expressed as risk differences (S5 Fig), showed evidence of protection
at the low end (36–80 mg; p = 0.045; 2.4 (95% CI: 0.1–4.6 ppt reduction) and at the highest
dose (150 mg; p = 0.002; 2.6 (95% CI: 1.0–4.3 ppt reduction), but not for 81 mg or 100 mg
(p = 0.855 and 0.187, respectively). The NNT for 36–80 mg is estimated to be 42 (95% CI: 22–
1000) and 39 (95% CI: 23–100) for the 150 mg dose.

Fig 3. Forest plot of the effect of aspirin on the all gestational age preeclampsia outcome stratified by four groups of aspirin dose: 36–80 mg, 81 mg, 100 mg, and
150 mg. RR, risk ratio; CI, confidence interval. Black diamond indicates the weight of each study; blue diamond indicates the overall effect of pooled sample; horizontal
line indicates 95% confidence interval; solid vertical line indicates no effect.
Discussion
All aspirin doses less than 150 mg were ineffective in reducing preterm preeclampsia; however,
there was a 62% reduction in risk using 150 mg (RR = 0.38; 95% CI: 0.20–0.72; P = 0.011). The
NNT using 150 mg for preterm preeclampsia prevention is 39 (95% CI: 23–100). Dividing the
aspirin doses into four groups demonstrated that only less than 81 mg and the 150 mg groups
had a significant reduction in risk of all gestational age preeclampsia which was approximately
28% at each end. The NNT using less than 81 mg and 150 mg was 38 (95% CI: 22–143) and 31

Fig 4. Forest plot of the effect of aspirin on the preterm preeclampsia outcome stratified by four groups of aspirin doses: 36–80 mg, 81 mg, 100 mg, and 150 mg. RR,
risk ratio; CI, confidence interval. Black diamond indicates the weight of each study; blue diamond indicates the overall effect of pooled sample; horizontal line indicates
95% confidence interval; solid vertical line indicates no effect.
(95%CI: 16–333), respectively for preeclampsia prevention at all gestational ages. Again, with
the 150 mg being only a single study, it is important to acknowledge that there is a need for
more RCTs using 150 mg dosing to increase the statistical power of these conclusions.
Strengths of our review include the number of studies we analyzed compared to other sys-
tematic reviews performed on this topic. The last systematic review in February 2018 included
10 studies; we added 13 more randomized controlled trials [6]. We aimed to define a specific
dose of aspirin to employ as prevention for preeclampsia versus the current standard of 81 mg,
or the generally used and non-specific term: “low-dose aspirin”. Limitations to our review
include the potential risk of bias among the articles included, despite our risk assessment and
quality measure of each study. We cannot confidently know that all biases were excluded in
the methodologic approach to each study that we included in our review. Our percentage
point (ppt) risk reduction analysis with the following NNT calculation is limited based on the

Fig 5. Forest plot of the effect of all aspirin doses on the all gestational age preeclampsia outcome. RR, risk ratio; CI, confidence interval. Black diamond indicates the
weight of each study; blue diamond indicates the overall effect of pooled sample; horizontal line indicates 95% confidence interval; solid vertical line indicates no effect.
heterogeneity of the pooled data and should be interpreted cautiously. Our analysis is limited
to the congruency among the studies included. Differing outcome measures, cohorts of
women, and how each study reported results defined how and what amount of data we could
extract. Especially the difference in the gestational age of aspirin therapy initiation in the stud-
ies included into this meta-analysis needs to be acknowledged. There is limited data on the
optimal aspirin dosing, specifically, of 81 mg compared to 150 mg. This warrants further ran-
domized controlled trials to validate our findings. We recommend future conduction of ran-
domized control trials comparing the efficacy of the daily dosage of 81 mg vs 150 mg aspirin.
Analysis of the efficacy of increasing the clinically used dose of aspirin from 81 mg to 150 mg
on short and long-term maternal and neonatal outcomes is needed and also recommended.
Since the first evidence of aspirin for reducing the risk of preeclampsia in 1985, many stud-
ies have attempted to determine the effect with controversial results. Aspirin dosage remains a
topic of debate [12, 13]; however, it is believed there is a dose dependent response.

Fig 6. Forest plot of the effect of all aspirin doses on the preterm preeclampsia outcome. RR, risk ratio; CI, confidence interval. Black diamond indicates the
weight of each study; blue diamond indicates the overall effect of pooled sample; horizontal line indicates 95% confidence interval; solid vertical line indicates no
effect.
Currently in the United States, it is recommended in high-risk and considered in moder-

ate-risk women to initiate aspirin prior to 16 weeks and take 81 mg daily until delivery [3, 4,
14]. The USPSTF states that universal aspirin prophylaxis for preeclampsia would save $365
million dollars in direct healthcare costs annually [15]. At best, we interpret all women with
moderate or high-risk factors may have approximately a 30% reduction in preeclampsia if they
initiate 81 mg of aspirin. When acknowledging the impact of a diagnosis of preterm pre-
eclampsia, this reduction is not sufficient. Our analysis suggests that aspirin doses less than
150 mg may not be reducing the risk of preterm preeclampsia sufficiently. Our results indicate
a dose of 150 mg may provide up to 62% reduction of preterm preeclampsia.
The effect of aspirin on COX-dependent prostaglandin synthesis is dose dependent. At
lower dosages (less than 100 mg/day) aspirin irreversibly acetylates COX-1, resulting in
decreased platelet synthesis of thromboxane-A2 without affecting vascular wall production of
prostacyclin, which improves the thromboxane-A2/prostacyclin balance in favor of prostacy-
clin [12, 13]. At higher doses, aspirin inhibits both COX-1 and COX-2; 1) effectively blocking
all prostaglandin production and 2) blocking COX-2 decreases sensitivity to angiotensin II,
decreases the activation of the immune system, and decreases oxidative stress. High dose aspi-
rin may be the best option allowing for restoration of the angiogenic balance and improvement
in vascular function associated with preeclampsia [16]. Aspirin at low doses has good maternal

Fig 7. Forest plot of the effect aspirin on the preterm preeclampsia outcome stratified by two groups of aspirin doses: At most 81 mg and more
than 81 mg. RR, risk ratio; CI, confidence interval. Black diamond indicates the weight of each study; blue diamond indicates the overall effect of
pooled sample; horizontal line indicates 95% confidence interval; solid vertical line indicates no effect.
and fetal safety profiles; however, doses over 100 mg have not been adequately studied. Based
on our study, increasing the standard dose of aspirin to 150 mg would provide a substantial
reduction in preterm preeclampsia. However, future studies are needed to confirm the mecha-
nism leading to an increased reduction of preterm preeclampsia by use of higher doses of aspi-
rin. In addition, while a higher dosage appears to be the most effective dose for preterm
preeclampsia prevention, future studies should validate we are not compromising safety of the
mother and baby.
Despite this being based on a single study, our review demonstrated a significant reduction
in preterm preeclampsia with 150 mg aspirin compared to all other dosages. We did not find
significant differences in risk reduction of preeclampsia at 81 mg in comparison to the other
dosages. Randomized trials that compare higher doses of aspirin to 81mg are necessary to
complete the totality of evidence.
Supporting information
S1 Checklist. PRISMA 2009 checklist.
(DOCX)

S1 Fig. Risk of bias assessment according to the Cochrane Collaboration Template.

(TIF)
S2 Fig. Funnel plot of publication bias. A: All gestational age preeclampsia; B: Preterm pre-
eclampsia.
(TIF)
S3 Fig. Forest plot of the risk difference between aspirin and placebo for all gestational age
preeclampsia outcome stratified by two groups of aspirin doses: At most 81 mg and more
than 81 mg.
(TIF)
S4 Fig. Forest plot of the risk difference between aspiring and placebo for all gestational
age preeclampsia outcome stratified by four groups of aspirin doses: 36–80 mg, 81 mg, 100
mg, and 150 mg.
(TIF)
S5 Fig. Forest plot of the risk difference between aspirin and placebo for preterm pre-
eclampsia outcome.
(TIF)
Acknowledgments
We are thankful to Robert Kohler and Mary Hitchcock who were our librarians at University
of Wisconsin-Madison.
Author Contributions
Conceptualization: Rachel Van Doorn, Narmin Mukhtarova, Ian P. Flyke, Charles H. Henne-
kens, Kara K. Hoppe.
Data curation: Rachel Van Doorn, Narmin Mukhtarova, Ian P. Flyke, Michael Lasarev,
KyungMann Kim, Kara K. Hoppe.
Formal analysis: Michael Lasarev, KyungMann Kim.
Funding acquisition: Kara K. Hoppe.
Investigation: Rachel Van Doorn, Narmin Mukhtarova, Ian P. Flyke, Kara K. Hoppe.
Methodology: Michael Lasarev, KyungMann Kim, Charles H. Hennekens, Kara K. Hoppe.
Project administration: Rachel Van Doorn, Narmin Mukhtarova, Kara K. Hoppe.
Resources: Michael Lasarev, KyungMann Kim, Kara K. Hoppe.
Software: Michael Lasarev, KyungMann Kim, Kara K. Hoppe.
Supervision: Kara K. Hoppe.
Visualization: Michael Lasarev, KyungMann Kim.
Writing – original draft: Rachel Van Doorn, Narmin Mukhtarova, Charles H. Hennekens,
Kara K. Hoppe.
Writing – review & editing: Michael Lasarev, KyungMann Kim, Charles H. Hennekens, Kara
K. Hoppe.

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Dose of aspirin to prevent preterm

☯ These authors contributed equally to this work.

Citation: Van Doorn R, Mukhtarova N, Flyke IP,

PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 1 / 18

through National Institutes of Health National Results

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PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 4 / 18

Effect of aspirin on all gestational age preeclampsia prevention

PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 5 / 18

Table 1. Characteristics of 23 randomized control trials included in the meta-analysis.

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Study N Inclusion Criteria Follow-Up Aspirin Control Gestational Age at Outcome(s)

PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 7 / 18

Study N Inclusion Criteria Follow-Up Aspirin Control Gestational Age at Outcome(s)

Effect of aspirin on prevention of preterm preeclampsia

PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 8 / 18

PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 9 / 18

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PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 12 / 18

Currently in the United States, it is recommended in high-risk and considered in moder-

PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 13 / 18

PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 14 / 18

S1 Fig. Risk of bias assessment according to the Cochrane Collaboration Template.

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PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 16 / 18

20. Caspi E, Raziel A, Sherman D, Arieli S, Bukovski I, Weinraub Z. Prevention of Pregnancy-Induced

PLOS ONE | https://doi.org/10.1371/journal.pone.0247782 March 9, 2021 17 / 18

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