The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ijmf20

Persisting risk factors for preeclampsia among

high-risk pregnancies already using prophylactic
aspirin: a multi-country retrospective investigation

Katherine A. Muldoon, Cheynne McLean, Darine El-Chaár, Daniel J. Corsi,

Natalie Rybak, Amarjargal Dagvadorj, Yanfang Guo, Ruth Rennicks White,
Alysha L. J. Dingwall-Harvey, Laura M. Gaudet, Mark C. Walker, Shi Wu Wen &
the FACT Collaborating Group

To cite this article: Katherine A. Muldoon, Cheynne McLean, Darine El-Chaár, Daniel J. Corsi,
Natalie Rybak, Amarjargal Dagvadorj, Yanfang Guo, Ruth Rennicks White, Alysha L. J. Dingwall-
Harvey, Laura M. Gaudet, Mark C. Walker, Shi Wu Wen & the FACT Collaborating Group
(2023) Persisting risk factors for preeclampsia among high-risk pregnancies already using
prophylactic aspirin: a multi-country retrospective investigation, The Journal of Maternal-Fetal
& Neonatal Medicine, 36:1, 2200879, DOI: 10.1080/14767058.2023.2200879

To link to this article: https://doi.org/10.1080/14767058.2023.2200879

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
2023, VOL. 36, NO. 1, 2200879
https://doi.org/10.1080/14767058.2023.2200879

ORIGINAL ARTICLE

Persisting risk factors for preeclampsia among high-risk pregnancies already

using prophylactic aspirin: a multi-country retrospective investigation
Katherine A. Muldoona , Cheynne McLeana, Darine El-Chaara,b, Daniel J. Corsia,c , Natalie Rybakb,
Amarjargal Dagvadorja, Yanfang Guoa,c, Ruth Rennicks Whitea, Alysha L. J. Dingwall-Harveya,
Laura M. Gaudeta,d, Mark C. Walkera,b, Shi Wu Wena,b and the FACT Collaborating Group
a
OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; bDepartment of
Obstetrics, Gynecology & Newborn Care, University of Ottawa, Ottawa, Ontario, Canada; cBetter Outcomes Registry and Network (BORN),
Ottawa, Ontario, Canada; dQueen’s Perinatal Research Unit, Kingston General Hospital, Department of Obstetrics and Gynecology,
Queens University, Kingston, Ontario, Canada

ABSTRACT ARTICLE HISTORY

Background: Low-dose aspirin is recommended for pregnant individuals at high-risk of develop- Received 25 August 2021
ing preeclampsia, but less is known about those that develop preeclampsia even while using Revised 31 March 2023
prophylactic aspirin for preeclampsia prevention as the best course of treatment. Accepted 4 April 2023
Objectives: The objective of this study is to investigate the risk factors with the highest risk of
KEYWORDS
developing preeclampsia among pregnant individuals already using aspirin from high-risk Preeclampsia; aspirin;
obstetrical centers across five countries. pregnancy; supplementa-
Design: This is a secondary analysis of pregnant individuals from the Folic Acid Clinical Trial tion; clinical trials
(FACT) who were using prophylactic aspirin before 16 weeks gestation. The FACT randomized
control trial took place in 70 high risk obstetrical centers in Canada, United Kingdom, Australia,
Jamaica, and Argentina between 2011–2015. Participants were included if they had any of the
risk factors for preeclampsia: diabetes, chronic hypertension, twin pregnancy, history of pree-
clampsia, and/or obesity (Body Mass Index
35). The outcomes of interest were preeclampsia
and preterm preeclampsia (<37 weeks). Log binomial regressions assessed factors significantly
associated with any preeclampsia or preterm-preeclampsia (<37 weeks) using adjusted risk ratios
(ARR) and 95% confidence intervals (CI).
Results: There were 2296 pregnant individuals with complete information on aspirin included in
this study. At baseline, all patients were at high risk of preeclampsia and were eligible for aspirin
prophylaxis, however, only 660 (28.7%) were taking aspirin. Among the 660 pregnant individuals
taking aspirin, 132 (20%) developed preeclampsia and 60 (9.09%) preterm preeclampsia. Among
pregnant individuals using aspirin, the risks of preeclampsia were highest for twins (ARR:2.62,
95% CI: 1.68–4.11), history of preeclampsia (ARR: 2.42, 95% CI: 1.74–3.38), and hypertension
(ARR:1.92, 95% CI: 1.37–2.69). Similar trends were found for preterm-preeclampsia for twins
(ARR:4.10, 95% CI:2.15–7.82), history of preeclampsia (ARR:2.75, 95% CI:1.62–4.67), and hyperten-
sion (ARR:2.18, 95% CI:1.28–3.72). No significant differences were found for obesity or diabetes.
Conclusion: These findings suggest that individuals with twin pregnancies, a history of pree-
clampsia, or hypertension may not benefit from aspirin to the same extent as those with other
complications such as obesity or diabetes. Careful clinical monitoring for these risks factors is rec-
ommended and future research into the effectiveness in these populations would increase our
understanding of the current best practice of prophylactic aspirin use to prevent preeclampsia.
TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov
NCT01355159

Introduction end-organ dysfunction [2]. Preeclampsia is a significant

Globally, preeclampsia affects 2.1–5.6% of pregnancies source of maternal and fetal morbidity and is the
[1]. Preeclampsia is a progressive, multisystem disorder second most common cause of maternal mortality glo-
of pregnancy characterized by new-onset hypertension bally [2–5]. Short-term consequences of preeclampsia
and proteinuria or hypertension with significant include increased risk of maternal antenatal stroke,

CONTACT Mark C. Walker mwalker@toh.ca Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, 501 Smyth Road,
Box 804, Ottawa, Ontario.
ß 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the
posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 K. A. MULDOON ET AL.
renal or hepatic impairment, pulmonary edema, hema-
tologic dysfunction (including hemolysis and thrombo-
cytopenia), neurologic involvement, intrauterine
growth restriction (IUGR), and preterm delivery [6–8].
Long-term consequences include increased risk of car-
diovascular and cerebrovascular disease for both the
pregnant person and infant, as well as reduced cogni-
tive function and development of sequelae from IUGR
and preterm delivery for infants [6].
While the only definitive treatment for preeclampsia
is delivery, clinical management requires a balance
between minimizing risk to the pregnant person and
the fetal risk of prematurity [3]. Emphasis is placed on
early identification of pregnant individuals at increased
risk of disease development and administration of
prophylactic interventions and managing preexisting
conditions. A Cochrane systematic review was pub-
lished first in 2003 [9] and then updated in 2007 [10]
and 2019 [11] (now currently synthesizing 77 trials)
consistently reporting a 17–19% reduction in the risk
of preeclampsia associated with the use of antiplatelet
agents, concluding that prophylactic use of low-dose
aspirin led to small-to-moderate benefits.
Informed by the current evidence, the World Health
Organization [12], the US Prevention Services Task
Force (USPSTF) [13], and national guidelines for the
management of hypertension in pregnant individuals
in Canada [14], the United Kingdom [15], Australia
[16], and the United States [17] recommend prophy-
lactic use of low-dose aspirin in pregnant individuals
at high risk of developing preeclampsia [4,13,14,18].
From a practical standpoint, low-dose aspirin is effect-
ive, easily administered, affordable, and widely avail-
able in multiple settings, including high, middle, and
low-income countries [19]. High-risk factors for pree-
clampsia that warrant low-dose aspirin treatment
include a previous past history of preeclampsia, multi-
fetal gestation, chronic hypertension, diabetes mellitus,
or certain autoimmune diseases [13]. Additional mod-
erate-risk factors include maternal obesity, maternal
age
35 years, or family history of preeclampsia [13].
Many high-risk pregnant individuals take prophylac-
tic aspirin but still go on to develop preeclampsia. The
objective of this study is to identify the risk factors for
preeclampsia that persist even while using prophylac-
tic aspirin.
Materials and methods
Study context, design and sample
This study is a secondary analysis of data from the
Folic Acid Clinical Trial (FACT). FACT was an multi-
country, multicenter, randomized control trial in 70
high risk obstetrical centers in Canada, United
Kingdom, Australia, Jamaica and Argentina between
2011 and 2015 [21]. FACT investigated the effect of
folic acid on preeclampsia by comparing a placebo
group (up to 1.1 mg dosage of folic acid) to high-dose
folic acid (4.0 to 5.1 mg/day). In brief, the trial was null
and found that high dose folic acid compared to low
dose did not significantly reduce the incidence of pre-
eclampsia among high-risk pregnant individuals.
This current study leverages the large sample of
pregnant individuals at high risk of developing pree-
clampsia enrolled in FACT to observationally investi-
gate patterns of aspirin use. This sample is restricted
to pregnant individuals with complete data on aspirin
use taking any daily dose of aspirin before 16 weeks of
gestation through to delivery. A summary of global
guidelines for aspirin use is available in Appendix 1.
Outcome measures
The primary outcomes of interest were preeclampsia
and preterm preeclampsia (before 37 weeks of com-
pleted gestation). The trial protocol definition of pree-
clampsia was: diastolic blood pressure
90 mm Hg on
two occasions four hours or more apart and protein-
uria (more than þþ on dipstick, or urinary protein

300 mg in 24 h urine collection, or random protein:
creatinine ratio
30 mg protein/mmol) in pregnant
individuals at 20 weeks of gestation or greater, or
diagnosis of HELLP syndrome (hemolysis, elevated
liver enzymes, low platelets) or superimposed pree-
clampsia (history of preexisting hypertension diag-
nosed before pregnancy or before 20 weeks’ gestation
with new proteinuria [20]. The final diagnosis was
adjudicated by a clinical review board.
Demographic and clinical variables
Five risk factors for preeclampsia were investigated
including preexisting chronic hypertension, diabetes
(Type 1 or Type 2), history of preeclampsia, obesity
defined as a Body Mass Index (BMI) over 35 kg/m2,
and twin pregnancy. Documentation of BMI three
months before pregnancy and up to the time of ran-
domization was required as part of study eligibility.
Demographic factors included: country site, mater-
nal ethnicity, marital status, education level, and age.
Age was measured continuously, categorically (<20,
20–29, 30–34,
35 years), and dichotomized to capture
advanced maternal age (
35 years). Obstetrical factors
included parity (nulliparous vs. parous), smoking, or

alcohol use during pregnancy (yes, no, or quit during
pregnancy). Prescriptions and supplements include
folic acid comparing low dose (1.1 mg/day) vs high
dose (4 mg/day), any calcium supplements, and aspirin
use comparing low dose (75–81mg per day) vs high
dose (82–150 mg per day). Only folic acid was adminis-
tered as part of the trial, both calcium and aspirin
were self-reported.
Statistical analyses
All statistical analyses were conducted using SAS soft-
ware (version 9.4). Descriptive statistics included totals
and percentages for categorical variables. Continuous
variables were displayed with medians (med) and
interquartile ranges (IQR).
Bivariable log binomial regressions were built to
investigate the five main risk factors (i.e. chronic
hypertension, diabetes, history of preeclampsia, BMI

35, and twin pregnancy) and identify the factors
with the highest risks of developing preeclampsia
while taking prophylactic aspirin. The multivariable
models included the five risk factors while adjusting
for age, aspirin dose, and country site. In the event
that the model did not converge, the variables were
reviewed, and the final model included factors to min-
imize the Akaike Information Criteria (AIC) of the
model. Estimates include risk ratios (RR), adjusted risk
ratios (ARR), and 95% confidence intervals (CI).
FACT was approved by the Ottawa Health Sciences
Research Ethics Board (2009107), and at all participat-
ing trial sites. FACT was funded by the Canadian
Institutes of Health Research (grants 198801 and
98030).
Results
In FACT, 2464 pregnant individuals were randomized
and 2301 completed the trial. Of these, there were
660 (28.63%) pregnant individuals taking aspirin
and included in this analysis. There were 548 (83.03%)
taking low-dose aspirin and 112 (16.97%) taking high-
dose aspirin. There were 132 cases of term preeclamp-
sia (20.00%) and 60 cases of preterm preeclampsia
(9.09%) (Table 1).
Sample characteristics are presented in Table 2.
There were 311 (47.12%) from Canada, 91 (13.79%)
from Australia, 243 (36.82%) from the United
Kingdom, and 15 (2.27%) from Jamaica/Argentina
(combined to protect small cell sizes). The median age
was 32 years (IQR: 29.00–35.50) and 216 pregnant indi-
viduals (32.73%) were 35 years and older. There were
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3
Table 1. Aspirin Dose and Preeclampsia (n ¼ 660).
Aspirin dose Yes No Total
Preeclampsia
High dose 33 (5.00) 79 (11.97) 112 (16.97)
Low dose 99 (15.00) 449 (68.03) 548 (83.03)
Total 132 (20.00) 528 (80.00) 660 (100)
Preterm preeclampisa
High dose 19 (2.88) 93 (14.09) 112 (16.97)
Low dose 41 (6.21) 507 (76.82) 548 (83.03)
Total 60 (9.09) 600 (90.91) 660 (100)
NB: Percentages are total percentages all divided by 660.
587 (88.94%) who were married/common law and 381
(57.73%) had completed college or university. The
median BMI was 31.25 kg/m2 and 249 (37.73%) had
obesity with a BMI
35. The most common pre-
pregnancy health conditions were a history of pree-
clampsia (44.24%), chronic hypertension (29.39%), and
diabetes (11.36%). There were 191 (28.94%) with mul-
tiple risk factors. All combinations of risk factors are
available in Appendix 2.
In Table 3, the highest incidence of preeclampsia
occurred among the 77 (58.33%) with a previous his-
tory of preeclampsia, 50 (37.88%) with hypertension,
47 (35.61%) with obesity (BMI
35), and 21 (15.91%)
with a twin pregnancy. At the multivariable level, the
adjusted risk ratios of preeclampsia were highest
among pregnant individuals with twin pregnancies
(ARR:2.62, 95% CI: 1.68–4.11), history of preeclampsia
(ARR: 2.42, 95% CI: 1.74–3.38) and hypertension
(ARR:1.92, 95% CI: 1.37–2.69).
In Table 4, the highest incidence of preterm pree-
clampsia was documented among 35 (58.33%) with a
history of preeclampsia, 22 (36.67%) with chronic
hypertension, and 18 (30.00%) with obesity. At the
multivariable level, the full model (five risk factors,
age, and country) did not converge, and the model
was selected based on minimizing the AIC (and only
included chronic hypertension, history of preeclamp-
sia, and twin pregnancy). The highest risk for pree-
clampsia was seen among those with twin
pregnancies (ARR:4.10, 95% CI:2.15–7.82), a history of
preeclampsia (ARR:2.75, 95% CI:1.62–4.67), and chronic
hypertension (ARR:2.18, 95% CI:1.28–3.72).
Discussion
This study has found that among a sample over 600
pregnant individuals using prophylactic aspirin for pre-
eclampsia, 20% went on to develop preeclampsia and
9% preterm preeclampsia. Even while taking aspirin,
those with twin pregnancies, history of preeclampsia,
or chronic hypertension emerged as groups with the
highest risk of developing preeclampsia. There were
4 K. A. MULDOON ET AL.

Table 2. Demographic and pregnancy characteristics of high- Table 2. Continued.

risk pregnancies taking aspirin (n ¼ 660). Variables Total N (%)
Variables Total N (%) Calcium supplement 123 (18.64)
Aspirin Birth outcomes
Low dose (81 mg per day) 548 (83.03) Preeclampsia 132 (20.00)
High dose (>81 mg per day) 112 (16.97) Preterm preeclampsia (<37 weeks gestation) 60 (9.09)
Preexisting Risk Factors for Preeclampsia Preterm birth (<37 weeks gestation) 151 (22.88)
1
Chronic hypertension 194 (29.39) All combinations are available in Appendix 2.
Any diabetes 75 (11.36)
Type 1 diabetes 42 (6.36)
Type 2 diabetes 33 (5.00)
History of preeclampsia 292 (44.24) no significant differences in risk for those with obesity,
BMI
35 249 (37.73) diabetes, country, or age.
Twin pregnancy 79 (11.97)
Multiple risk factors1 191 (28.94) The incidence of both term and preterm pree-
Number of risk factors clampsia found in this study is comparable to those
1 469 (71.06)
2 157 (23.79) identified in other studies with similar at-risk groups.
3 31 (4.70) In a large US trial conducted by the National Institute
4þ <5
Most common combinations
of Child Health and Human Development Network of
Chronic hypertension and BMI
35 66 (10.00) Maternal-Fetal Medicine Units, the incidence of pree-
History of preeclampsia and BMI
35 62 (9.39)
Chronic hypertension and history of preeclampsia 57 (8.64)
clampsia was 18% in high-risk individuals receiving
Demographic aspirin therapy [21]. Recently, a large multicenter, pla-
Country: cebo-controlled trial identified that preterm pree-
Canada 311 (47.12)
Australia 91 (13.79) clampsia occurred in 1.6% of study participants
United Kingdom 243 (36.82) receiving daily low-dose aspirin prophylaxis [22]. The
Jamaica/Argentina 15 (2.27)
Ethnicity: study assessed singleton pregnancies using an algo-
Indigenous/Aboriginal <5 rithm that combined maternal factors with mean arter-
White 548 (83.03)
Black 44 (6.67) ial pressure, uterine-artery pulsatility index, and
Asian 28 (4.24) maternal serum pregnancy-associated plasma protein
Latino/Hispanic 13 (1.97)
Indian/South Asian 20 (3.03) A and placental growth factor to identify pregnant
Declined to answer <5 individuals at high risk for preeclampsia. Given the
Maternal age (years):
<20 6 (0.91) inclusion of multiparous gestation and adherence to
20–29 194 (29.39) clinical risk stratification, it is likely that the incidence
30–34 244 (36.97)

35 216 (32.73) of preterm preeclampsia among high-risk pregnant
Median age (med, IQR) 32 (29.00–35.50) individuals receiving aspirin therapy identified in this
Marital status:
Single 63 (9.55)
current study maybe a more generalizable estimate
Married/common law 587 (88.94) given the broader inclusion criteria [23].
Divorced/separated 10 (1.52) The findings from this study call attention to the
Maternal education level:
High school and below 153 (23.18) sustained risk for preeclampsia and identify clinical risk
College/university not completed 126 (19.09) factors whereby increased clinical monitoring or sup-
College/university completed 381 (57.73)
Maternal BMI (kg/m2): plemental therapy may be indicated. Of interest, many
Median BMI (med, IQR) 31.25 (25.00–37.80) published trials exclude twin pregnancies and our
<18.5 8 (1.21)
18.5–24 156 (23.64) study identified that twin pregnancies had 2 to 4
25–29 137 (20.76) times the risk of developing preeclampsia [22,24,25].
30–34 110 (16.67)

35 249 (37.73) The inclusion of twins and the analyses of twin data
Obstetrical factors can be methodologically complex, however, this study
Parity:
Nulliparous (0) 182 (27.58) highlights the increased risk and supports the import-
Parous (
1) 478 (72.42) ance of including multi-fetal gestation in the clinical
Smoking during pregnancy:
Yes 38 (5.76) evaluation of preeclampsia [26].
No 581 (88.03) A meta-analysis of large cohort studies investigat-
Quit during pregnancy 41 (6.21)
Alcohol intake during pregnancy:
ing the association and relative risk of preeclampsia
Yes 10 (1.52) identified prior preeclampsia and chronic hyperten-
No 497 (75.3)
Quit during pregnancy 153 (23.18)
sion as having the strongest effect [27], followed by
Prescriptions and supplements pre-gestational diabetes and multifetal pregnancy.
Folic acid supplementation: Interestingly, preexisting diabetes was not identified
Low dose (1 mg/day) 320 (48.48)
High dose (4 mg/day) 340 (51.52) in the present study as a significant risk factor for
(continued)
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5

Table 3. Bivariable and Multivariable log binomial regression models for factors associated with preeclampsia among those
treated with prophylactic aspirin (n ¼ 660).
Bivariable Log Binomial
Development of Preeclampsia Regression Multivariable Log Binomial Regressiona
Yes No
N ¼ 132 N ¼ 528 RR ARR
Variables n(%) n(%) (95% CI) p-values (95% CI) p-value
Preexisting Risk Factors for Preeclampsia
Chronic Hypertension 50 (37.88) 144 (27.27) 1.46 (1.07–1.99) .016 1.92 (1.37–2.69) <.001
Diabetes 12 (9.09) 63 (11.93) 0.78 (0.45–1.34) .369 1.24 (0.72–2.11) .212
History of Preeclampsia 77 (58.33) 215 (40.72) 1.76 (1.29–2.41) <.001 2.42 (1.74–3.38) <.001
BMI
35 47 (35.61) 201 (38.07) 0.92 (0.66–1.26) .602 1.26 (0.93–1.69) .135
Twin Pregnancy 21 (15.91) 58 (10.98) 1.39 (0.93–2.08) .108 2.62 (1.68–4.11) <.001
Aspirin dose (high vs low) 33 (5.00) 79 (11.97) 1.63 (1.16–2.29) .005 1.17 (0.44–3.12) .756
Age
35 38 (28.79) 178 (33.71) 0.83 (0.59–1.16) .285 0.80 (0.57–1.11) .184
Country
Canada 60 (45.45) 251(47.54) (ref) – – –
Australia 27 (20.45) 64 (12.12) 2.02 (0.93–4.37) .036 1.36 (0.66–2.79) .402
United Kingdom 40 (30.30) 203 (38.45) 1.80 (1.18–2.76) .072 0.96 (0.47–1.92) .904
Jamaica/Argentina 5 (3.79) 10 (1.89) 1.12 (0.51–2.45) .771 1.42 (0.94–2.16) .100
a
Multivariable model is built based on 5 risk factors (chronic hypertension, diabetes, history or preeclampsia, BMI
35, twin pregnancy) adjusted for
aspirin dose, age and country site.

Table 4. Bivariable and Multivariable log binomial regression models for factors associated with preterm preeclampsia among
those treated with prophylactic aspirin (n ¼ 660).
Bivariable Log Binomial Multivariable Log Binomial
Development of Preterm Preeclampsia Regression Regression
Yes No
N ¼ 60 N ¼ 600 RR ARR
Variables n(%) n(%) (95% CI) p-values (95% CI) p-value
Preexisting Risk Factors for Preeclampsia
Chronic Hypertension 22 (36.67) 172 (28.67) 1.39 (0.84–2.28) .194 2.18 (1.28–3.72) .004
Diabetes 7 (11.67) 68 (11.33) 1.03 (0.48–2.18) .938
History of Preeclampsia 35 (58.33) 257 (42.83) 1.76 (1.08–2.88) .023 2.75 (1.62–4.67) <.001
BMI
35 18 (30.00) 230 (38.33) 0.71 (0.42–1.21) .208
Twin Pregnancy 13 (21.67) 66 (11.00) 2.03 (1.15–3.59) .014 4.10 (2.15–7.82) <.001
Aspirin dose (high vs low) 19 (2.88) 93 (14.09) 2.27 (1.36–3.76) .002
Age
35 16 (26.67) 200 (33.33) 0.75 (0.43–1.29) .298
Country
Canada 27 (45.00) 284 (47.33) (ref)
Australia 15 (25.00) 76 (12.67) 1.89 (1.05–3.41) .032
United Kingdom 17 (28.33) 226 (37.67) 0.81 (0.44–1.44) .468
Jamaica/Argentina <5 14 (2.33) 0.77 (0.11–5.27) .788
a
Multivariable model did not converge, the variables were reviewed, and the final model included factors to minimize the Akaike Information Criteria
(AIC) of the mode.

preeclampsia. This may be due to the complex inter-
play between aspirin and glycemic control [28,29], or
that there were fewer people with diabetes in the
trial, or potentially attributed to limited information
on adherence to treatment for diabetes and diet
within the FACT Trial.[30]
Out of all FACT participants, fewer than one-third
were taking a daily dose of aspirin before 16 weeks of
gestation [20]. This raises the question of barriers to
aspirin prescribing patterns, uptake, and adherence.
FACT enrolled participants between 2011–2015, before
several RCTs were published and before clinical guide-
lines recommended low-dose aspirin as an effective
intervention for preeclampsia prophylaxis. Inconsistent
prescribing patterns may be due in part to the division
regarding its efficacy as some studies at the time had
reported no significant effect on the risk of preeclampsia
[31]. Recently published research has provided conflict-
ing evidence regarding the efficacy of aspirin for hyper-
tension and the prevention of preeclampsia [32–34].
Non-adherence with medical therapy is a multifaceted
and complex problem involving patient factors such as
physician preferences, regimen factors, personal, family,
cultural, demographic factors, geographic and socioeco-
nomic barriers to accessing treatment, [35]. In addition
to the multitude of factors that influence medication
adherence in non-pregnant individuals, the unique factor
of concern for potential fetal harm has been identified
as a barrier to medication adherence within the preg-
nant population [35–38].
6 K. A. MULDOON ET AL.
Limitations
A notable strength of this work is the large, inter-
national, multicenter design of the FACT trial, permit-
ting the investigation of preeclampsia risk factors
across five countries. There was high data complete-
ness and the follow-up rate for all participants
was greater than 95% [20]. Limitations include the
potential for measurement bias as aspirin use was self-
reported at follow-up visits. As this is a secondary ana-
lysis from FACT (focused on adherence to folic acid),
there was limited information on the timing and dose
of aspirin. Confounding by indication is possible as
pregnant individuals at high risk for preeclampsia
were the most likely to be placed on aspirin. Further
research can investigate as to whether alterations to
dose and timing of aspirin might mitigate risk.
Conclusions
While aspirin continues to be the best-recommended
course of treatment in the prevention of preeclampsia
among pregnant individuals at high risk, 20% and 9%
still went on to develop preeclampsia and preterm-
preeclampsia, even while taking aspirin. While many
robust studies have proven the protective effect of
aspirin, the literature is becoming divided and this
study highlights that a large percentage of women
still develop preeclampsia, and a continued search for
preventative treatments and symptom management
are still needed in addition to the current recommen-
dations of low-dose aspirin.
Acknowledgements
We thank the participants in FACT, site investigators,
research staff at the participating sites, and staff at the
Ottawa Hospital Research Institute for their support and
hard work. A full list of the FACT Collaborating Group is
available in the supplementary file.
Ethical approval
FACT was approved by the Ottawa Health Sciences Research
Ethics Board (2009107), and at all participating trial sites.
Authors’ Contributions
MCW and SWW designed the FACT trial. KM and CM wrote
the manuscript with assistance from DE-C, DJC, NR, AD, YG,
RRW, AD-H, LG, SWW, MCW. KM with assistance from DJC
carried out the statistical analyses. All authors participated in
the review and critical revisions of the final manuscript.
MCW has primary responsibility for the final content. All
authors read and approved the final manuscript.
Disclosure statement
The authors report no competing interests.
Funding
This study was sponsored by the Ottawa Hospital Research
Institute and funded by the Canadian Institutes of Health
Research (grants 198801 and 98030).
ORCID
Katherine A. Muldoon http://orcid.org/0000-0002-0766-
4294
Daniel J. Corsi http://orcid.org/0000-0001-7063-3354
Data availability statement
With a data sharing agreement, de-identified data, the data
dictionary, and ethics protocol are available.
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