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Clinical Influence of Nonadherence With Prophylactic Aspirin

in Preventing Preeclampsia in High-Risk Pregnancies
Renuka Shanmugalingam, XiaoSuo Wang, Penelope Motum, Ian Fulcher,
Gaksoo Lee, Roshika Kumar, Annemarie Hennessy, and Angela Makris
Ahead of Print • Publication Date (Web): 02 Mar 2020
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 Original Article

Clinical Influence of Nonadherence With Prophylactic

Aspirin in Preventing Preeclampsia in High-Risk
Pregnancies
A Multicenter, Prospective, Observational Cohort Study
Renuka Shanmugalingam, XiaoSuo Wang, Penelope Motum, Ian Fulcher, Gaksoo Lee,
Roshika Kumar, Annemarie Hennessy, Angela Makris

See Editorial, pp 941–942

Abstract—Aspirin nonadherence and its associated increase in cardiovascular and cerebrovascular events is well described;
however, the prevalence of aspirin nonadherence among high-risk pregnant women at risk of preeclampsia and its influence
on clinical outcomes remains unclear. Our study examined the prevalence of aspirin nonadherence and resistance among
high-risk pregnant women quantitatively (platelet function analyzer 100 and plasma salicylic acid) and clinical outcomes
relative to adherence. High-risk pregnant women were recruited across 3 centers in the South West Sydney Local Health
District. Simultaneous clinic data, blood sample, and self-reported adherence assessment were prospectively collected at
4-week intervals from 12 to 36 weeks of gestation. Nonadherence was defined as normal platelet function analyzer 100
and nondetectable plasma salicylic acid in <90% of time points. Value of <90% is based on current data. Two hundred
twenty women were recruited over 25 months. No woman was aspirin resistant, and 63 (44%) women demonstrated
inadequate adherence. Women with inadequate adherence had higher incidence of early-onset preeclampsia (17% versus
2%; odds ratio [OR], 1.9 [95% CI, 1.1–8.7]; P=0.04), late-onset preeclampsia (41% versus 5%; OR, 4.2 [95% CI,
1.4–19.8]; P=0.04), intrauterine growth restriction (29% versus 5%; OR, 5.8; [95% CI, 1.2–8.3]; P=0.001), preterm
delivery (27% versus 10%; OR, 5.2 [95% CI, 1.5–8.7]; P=0.008), and higher likelihood of increase in antihypertensives
Downloaded from http://ahajournals.org by on March 4, 2020

antenatally (60% versus 10%; OR, 4.6 [95% CI, 1.2–10.5]; P=0.003). Kaplan-Meier analysis demonstrated lower
incidence of premature delivery in the ≥90% adherent group (HR, 0.3 [95% CI, 0.2–0.5]; P<0.001).Kappa coefficient
agreement between qualitative and quantitative assessment of adherence was moderate (κ=0.48; SE=0.029; P<0.0001).
Our data demonstrates that aspirin is an effective prophylactic agent with an absolute risk reduction of 51% (number
needed to treat, 2) when adherence is ≥90%, compared with women with inadequate adherence. Women who were <90%
adherent had higher rates of preeclampsia, intrauterine growth restriction, preterm delivery, and increase in antenatal
antihypertensive requirements. Self-reported adherence does not accurately reflect actual adherence.  (Hypertension.
2020;75:00-00. DOI: 10.1161/HYPERTENSIONAHA.119.14107.) Online Data Supplement •
Key Words: aspirin ◼ humans ◼ preeclampsia ◼ records ◼ self-report

A spirin nonresponsiveness or resistance refers to a lack of

antiplatelet action or desired clinical effect with the use
of aspirin.1 Multiple factors such as platelet turnover, dose of
aspirin, and patient’s weight have been shown to contribute to
aspirin nonresponsiveness in the nonobstetric population.1,2
Nonobstetric cardiology studies have demonstrated a higher
incidence of morbidity and mortality associated with aspirin
nonresponsiveness resulting in further studies examining the
incidence of aspirin nonresponsiveness.3,4 Subsequent stud-
ies have attributed ≤50% of aspirin nonresponsiveness to in-
adequate adherence, suggesting inadequate adherence is the
strongest confounder in nonresponsiveness.5,6
The use of aspirin in preventing preeclampsia, intrau-
terine growth restriction (IUGR), and preterm delivery has
been examined for over 40 years; however, its prophylactic
role remains controversial because of conflicting outcomes.7–9

Received September 30, 2019; first decision October 21, 2019; revision accepted December 5, 2019.
From the Department of Renal Medicine (R.S., A.H., A.M.), Women’s Health Initiative Translational Unit, Ingham Institute For Applied Medical
Research (R.S., P.M., G.L., A.H., A.M.), Department of Haematology (P.M.), and Department of Obstetrics and Gynaecology (I.F., G.L., R.K.), South
Western Sydney Local Health District, NSW, Australia; School of Medicine, Western Sydney University, NSW, Australia (R.S., A.H., A.M.); Vascular
Immunology Research Group, Heart Research Institute (R.S., A.H., A.M.); Bosch Mass Spectrometry Facility, Bosch Institute (X.W.), University of
Sydney, NSW, Australia; and South Western Sydney Clinical School, University of New South Wales, Australia (A.M.).
The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.119.14107.
Correspondence to Renuka Shanmugalingam, Department of Renal Medicine, Liverpool Hospital, NSW 2170, Australia. Email renuka.shanmugalingam@
health.nsw.gov.au
© 2020 American Heart Association, Inc.
Hypertension is available at https://www.ahajournals.org/journal/hyp DOI: 10.1161/HYPERTENSIONAHA.119.14107

1
 2  Hypertension   April 2020
Collective data over the years have demonstrated a vari-
able risk reduction of 10% to 68%, which has largely been
attributed to the heterogeneity of these studies.9,10 This het-
erogeneity includes the dose of aspirin used, the gestation
of aspirin initiation, and the method of risk stratification.
While there has been better clarity on these factors in recent
times,11–14 the prevalence of aspirin nonresponsiveness and
aspirin nonadherence among high-risk pregnant women and
its influence on the desired obstetric outcome has not been
adequately and uniformly examined.
A subanalysis of the recent Aspirin versus Placebo in
Pregnancies at High Risk for Preterm Preeclampsia study
demonstrated that high-risk pregnant women with ≥90%
adherence with aspirin therapy achieved better prophy-
lactic effect with greater risk reduction of preeclampsia.15
However, only 37% of obstetric aspirin trials have assessed
adherence to aspirin.16 Even so, aspirin adherence was
poorly defined and nonuniformly assessed in these studies
through semiquantitative, qualitative, or quantitative meth-
ods16 given the lack of a gold standard method for adherence
assessment.17 With the growing evidence on the prevalence
and impact of inadequate adherence with aspirin in the non-
pregnant population, it is important to examine the preva-
lence of inadequate adherence with aspirin among high-risk
pregnant women. Importantly, to also examine the impact of
adherence on obstetric outcomes.
The primary aim of this study was to examine the prev-
alence and degree of adherence to aspirin among high-risk
pregnant women through a 2-point quantitative assessment
Downloaded from http://ahajournals.org by on March 4, 2020
(platelet function analyzer 100 [PFA-100] and plasma sali-
cylic acid [SA] detection) and examine the effect of adher-
ence on obstetric outcomes (Figure S1 in the online-only Data
Supplement). Secondarily, we aimed to examine the obstetric
outcomes within subcategories of inadequate adherence
(<30% versus 31% to 60% versus <90%) with aspirin and
assess the agreement between patient self-reported adherence
(qualitative assessment) and direct biochemical assessment of
adherence (quantitative assessment) with aspirin.
Methods
The authors declare that all supporting data are available within the
article (and its online-only Data Supplement). Additional data that
support the findings of this study are available from the corresponding
author on reasonable request.
Study Protocol
High-risk pregnant women were recruited across 3 high-risk preg-
nancy clinics in the South Western Sydney Local Health District in
NSW, Australia, over 25 months from December 2016 to January
2019. Ethics approval was obtained (South Western Sydney Local
Health District ethics committee [HE 16/184]), and participants
provided written informed consent. Women were assessed as high
risk by their treating clinicians through The National Institute
for Health and Care Excellence clinical guidelines or the Fetal
Medicine Foundation high-risk screening program (Table S1).
Inclusion criteria included (1) risk-stratified high risk for pree-
clampsia by the treating clinician and (2) <20 weeks of gestation
at the time of enrollment. Exclusion criteria included (1) the com-
mencement of aspirin after 16 weeks of gestation, (2) on aspirin
at the time of recruitment, (3) women of non–English-speaking
background, (4) inability to provide written informed consent,
and (5) >20 weeks of gestation at the time of enrollment. Women
were recruited at the commencement of aspirin and were followed
through to the end of their pregnancy. Blood samples and clin-
ical data were collected prospectively at baseline (before the first
dose of aspirin). Subsequently, serial blood samples, clinical data,
and self-reported adherence assessment was conducted at 16, 20,
24, 28, 32, and 36 weeks of gestation. High-risk pregnant women
who were not prescribed aspirin, either due to aspirin intolerance
or delayed presentation (between 16 and 20 weeks of gestation),
followed the same protocol and served as the control high-risk
pregnancy group.
Blood samples were collected via a 21G Vacutainer Push
Button needle (Becton Dickinson and Company USA) into 3×4 mL
VACUETTE K2EDTA tubes (Greiner Bio-One International) and
2×3.8 mL tubes containing 0.38 mL of 0.129 mol/L buffered so-
dium citrate (pH 5.5) for PFA-100 analysis. Samples in 2 of the 3
VACUETTE K2EDTA tubes were centrifuged immediately at 3000
rpm for 10 minutes; plasma was aliquoted (220 µL) and stored at
−80°C until analysis. The third VACUETTE K2EDTA tube and both
sodium citrate tubes were sent to the South Western Sydney pathol-
ogy service at the Liverpool Hospital, NSW, Australia (National
Association of Testing Authorities, Australia accredited), at room
temperature for full blood count and PFA-100 assessment within 4
hours of collection. Investigators did not have access to these results
till after study completion.
Plasma SA Analysis
Plasma SA level was measured by liquid chromatography tandem-
mass spectrometry as we described previously.14 The time of sample
collection in relation to patient-reported time of aspirin ingestion was
noted. Preparation and dose of aspirin was documented at each time
point to verify the expected plasma SA level based on the time/con-
centration curve published previously.14 Investigators did not have
access to these results till study completion.
PFA-100 Analysis
PFA-100 analysis was performed using plasma with a commercial-
ized and clinically validated Dade PFA-100 collagen/epinephrine
and Dade PFA-100 collagen/ADP test cartridges utilizing the meth-
odology specified by the manufacturer, Dade Behring (Düdingen,
Switzerland). Before analysis, the patient’s full blood count was ana-
lyzed to ensure that the hematocrit and platelet count were >28% and
>100×109/L, respectively. Analysis for PFA-100 was not conducted
if these criteria were not met. Validated reference range of 80 to 170
s for PFA-100 (collagen/epinephrine) and 60 to 120 s for PFA-100
(collagen/ADP) was utilized. PFA-100 prolongation in response to
aspirin was defined as a prolonged PFA-100 (collagen/epinephrine)
of >170 s with a normal PFA-100 (collagen/ADP) of <120 s.18
Qualitative Analysis
The qualitative assessment of adherence was done via a question-
naire based on the Simplified Medication Adherence Questionnaire
(Table S2). Women undertook this assessment at each time point. The
investigators (blinded) verbally questioned each woman at each visit.
Aspirin Adherence and Resistance Criteria
A 2-point analysis of PFA-100 and plasma SA was utilized to dif-
ferentiate a lack of PFA-100 prolongation from nonadherence to
aspirin resistance (Figure S1). Biochemical evidence of complete
adherence to aspirin during the pregnancy was defined as an appro-
priate PFA-100 response with detectable plasma SA level in ≥90%
of the time points. The cutoff of ≥90% was based on published lit-
erature.15 Inadequate biochemical evidence of adherence was de-
fined as an appropriate PFA-100 response and detectable plasma
SA level in <90% of the time points. The inadequate adherence
group was further subcategorized into 3 groups of graded biochem-
ical evidence of adherence (<30% adherent, 30%–59% adherent,
and 60%–89% adherent) for subanalysis. Women were defined as
aspirin resistant if there was a lack of an appropriate PFA-100 re-
sponse despite detectable plasma SA levels (Figure S1). Adherence
 Shanmugalingam et al   Aspirin Adherence in the Prevention of Preeclampsia   3

through the qualitative assessment was defined as a negative re- Table 1.  Characteristics of Participating High-Risk Pregnant Women
sponse to questions 2 and 3 in the qualitative questionnaire in ≥90%
Aspirin Group Nonaspirin
of the time points.
Characteristics (n=145) Group (n=42) P Value
Obstetric Outcome Criteria Age, y* 32 (±4.3) 31 (±5.2) 0.4
The obstetric end points examined were preeclampsia, early-onset Primigravity 25 (17%) 8 (19%) 0.8
preeclampsia, late-onset preeclampsia, gestational hypertension,
preterm delivery, and IUGR (calculated based on validated New Prepregnancy BMI of ≥30 62 (43%) 24 (57%) 0.1
South Wales population-based birth percentile chart19) as defined Multifetal pregnancy 6 (4%) 1 (2%) 0.7
by current guidelines and antenatal antihypertensive requirements
(Table S3).20,21 Secondary education only 16 (11%) 5 (12%) 0.8
Smoking in pregnancy 8 (6%) 3 (7%) 0.6
Statistical Analysis Ethnicity 0.2
Sample size was calculated based on the assumption that the untreated
high-risk pregnant population has a preeclampsia risk rate of 40%  White 74 (51%) 20 (48%)
and that aspirin-treated high-risk pregnant women will have a 50%  Middle Eastern 24 (17%) 6 (14%)
reduction in preeclampsia risk compared with the untreated group.
Thus, ≈60 women in each group (aspirin and nonaspirin) would be  South Asian 22 (15%) 5 (12%)
needed to have 80% power. The target recruitment number was in-  South East Asian 14 (10%) 4 (10%)
flated to 145 in the aspirin group (220 women in total) to allow for a
predicted 20% dropout in both groups and a high prevalence (50%)  African 6 (4%) 3 (6%)
of inadequate adherence.  Polynesians 3 (2%) 4 (10%)
Unadjusted χ2 analysis was used to examine for difference be-
tween characteristics and obstetric outcomes. An adjusted analysis  Australian Aboriginals† 2 (1%) 0
using a binary logistic regression analysis (stepwise backward) was Indication for aspirin in pregnancy‡
undertaken to assess group differences (expressed as the odds ratio
[OR] and 95% CI). Repeated measures ANOVA was used to exam-  Chronic hypertension 82 (57%) 28 (67%) 0.1
ine differences between average systolic blood pressure and dias-  Previous preeclampsia 69 (48%) 11 (26%) 0.1
tolic blood pressure over time and between groups. Comparison of
outcomes in women with varying degree of intermittent adherence  Renal disease 34 (23%) 7 (17%) 0.4
with nonaspirin control group was done through a Pearson χ2 anal-  Type 1 or 2 diabetes mellitus 12 (8%) 3 (7%) 0.8
ysis. A Kaplan-Meier analysis was undertaken to assess pregnancy
continuation (survival) between the ≥90% adherent group and  Based on first trimester (FMF) 
8 (6%) 0 0.3
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<90% adherent group. Agreement between self-reported and bio- Screening only†§
chemical adherence was assessed with a Cohen kappa coefficient.  Systemic lupus erythematosus 4 (3%) 1 (2%) 0.7
P of <0.05 was considered significant. IBMSPSSv25 was utilized
for data analysis. BMI indicates body mass index; FMF, Fetal Medicine Foundation; MAP,
mean arterial pressure; PAPP-A, pregnancy-associated plasma protein A; PI,
pulsatility index; and PlGF, placental growth factor.
Results *Mean with SD (±SD).
A total of 220 high-risk women were recruited, and data from †Analysis based on Fisher exact test.
187 women were available for analysis (Figure 1; Table 1). Of ‡Added percentages exceed 100% as some women had >1 medical
the 187 high-risk women, 145 were prescribed aspirin by their condition.
§FMF first trimester screening was done in private screening units based on
treating clinician based on center-specific practice: 104 (72%)
a combined multiple of the median algorithm of maternal MAP, uterine artery PI,
on 100 mg of aspirin and 41 (28%) on 150 mg of aspirin. and maternal serum PlGF and PAPP-A with a cutoff of 1:100.

Figure 1.  Recruitment of high-risk pregnant women. *Due to difficulty in
attending research follow-up appointments.
Primary Outcomes
Of the 145 high-risk women who were prescribed aspirin,
82 (56%) were found to be adherent with aspirin and 63
(44%) were found to have inadequate adherence (adherence
at <90% of time points) based on quantitative assessment
of adherence (Figure S1). No woman was found to have
biochemical features of aspirin resistance. Logistic regres-
sion analysis of patient characteristics between the <90%
and ≥90% adherent groups demonstrated a higher number
of women with secondary-level education only (24% versus
13%; adjusted OR in the <90% adherent group, 2.9 [95%
CI, 1.8–5.6]; P=0.005) and a lower number of women with
previous preeclampsia (24% versus 55%; adjusted OR in
the <90% adherent group, 0.4 [95% CI, 0.1–07]; P=0.01) in
the <90% aspirin adherent group compared with the ≥90%
adherent group (Table 2).
 4  Hypertension   April 2020

Table 2.  Comparison of Characteristics Between Women in ≥90% Aspirin Adherent Group to <90% Aspirin Adherent Group

Unadjusted Analysis Adjusted Analysis

<90% Adherent ≥90% Adherent
Characteristics (n=63) (n=82) OR 95% CI P Value OR 95% CI P Value
Age, y* 33.5 (±5.8) 32.5 (±5.6) 0.3
Primigravity 11 (17%) 14 (17%) 1.3 0.3–5.5 0.7
Prepregnancy BMI of ≥30 28 (44%) 34 (41%) 1.1 0.5–2.2 0.7
Multifetal pregnancy 1 (2%) 6 (7%) 0.2† 0.1–0.7 0.02
Previous preeclampsia 15 (24%) 45 (55%) 0.3† 0.2–0.8 0.03 0.4 0.1–0.7 0.01
Pregnancy via assisted reproductive 3 (5%) 11 (13%) 0.4† 0.1–0.8 0.03
therapy
Family history of preeclampsia 5 (8%) 8 (10%) 0.7 0.2–2.5 0.7
Secondary-level education only 15 (24%) 11 (13%) 2.5† 1.3–4.9 0.02 2.9 1.8–5.6 0.005
Smoking in pregnancy 4 (6%) 4 (9%) 0.8 0.2–3.2 0.7
Ethnicity 0.9 0.4–8.2 0.2
 White 35 (55%) 40 (50%)
 Middle Eastern 8 (13%) 15 (18%)
 South Asian 12 (19%) 10 (12%)
 South East Asian 3 (5%) 11 (13%)
 African 2 (3%) 4 (5%)
 Polynesians 1 (2%) 2 (2%)
 Australian Aboriginals 2 (3%) 0 (%)
Preexisting medical conditions†
 Chronic hypertension 38 (60%) 44 (54%) 0.8 0.4–1.5 0.4
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 Renal disease 13 (21%) 21 (26%) 1.3 0.6–2.3 0.4

 Type 1 or 2 diabetes mellitus 5 (8%) 7 (9%) 1.1 0.3–3.6 0.8
 Systemic lupus erythematosus 2 (3%) 2 (2%) 1.0 0.3–5.0 0.9
BMI indicates body mass index; and OR, odds ratio.
*t test analysis of mean with SD (±SD).
†Some women had >1 medical condition. Binary logistic regression analysis (stepwise backward) was adjusted for age, primigravidity, multifetal pregnancy, previous
preeclampsia, pregnancy via assisted reproductive therapy, secondary-level education only, smoking in pregnancy, and preexisting medical conditions.

Logistic regression analysis of obstetric outcomes demon- Secondary Outcomes

strated that women in the <90% aspirin adherent group had
a significantly higher incidence of early-onset preeclampsia
(17% versus 2%; adjusted OR in <90% adherent group, 1.9
[95% CI, 1.1–8.7]; P=0.04), late-onset preeclampsia (41%
versus 5%; adjusted OR in <90% adherent group, 4.2 [95% CI,
1.4–19.8]; P=0.04), IUGR (29% versus 5%; adjusted OR in
<90% adherent group, 5.8 [95% CI, 1.2–8.3]; P=0.001),preterm
delivery (27% versus 10%; adjusted OR in <90% adherent
group, 5.2 [95% CI, 1.5–8.7]; P=0.008), higher antihyperten-
sive requirements (60% versus 10%; adjusted OR in <90% ad-
herent group, 4.6 [95% CI, 1.2–10.5]; P=0.003), and reduced
likelihood of decrease in antihypertensive agents (5% versus
30%; adjusted OR in <90% adherent group, 0.2 [95% CI, 0.1–
0.8]; P=0.04; Table 3). Women in the <90% adherent group
also had higher average systolic blood pressure (126.5±11.8
versus 115.3±12.1; P<0.001) and diastolic blood pressure
(78.4±8.5 versus 71.1±4.3; P<0.001; Table 3). Kaplan-Meier
analysis demonstrated significant lower incidence of prema-
ture delivery and a longer pregnancy duration in the ≥90% ad-
herent group (HR, 0.3 [95% CI, 0.2–0.5]; P<0.001; Figure 2).
Obstetric outcomes were reassessed compared with the con-
trol group (nonprescribed aspirin group) with adherence as an
ordinal (<30% versus 31%–60% versus 61%–89% adherence)
rather than a dichotomous variable. Analysis comparing the
4 groups did not demonstrate any difference in the examined
obstetric outcomes (Table 4).
A κ-coefficient agreement analysis between self-reported
aspirin adherence (qualitative assessment) of ≥90% and bi-
ochemically observed aspirin adherence (quantitative assess-
ment) of ≥90% showed only moderate agreement with κ=0.48
(SE=0.029; P<0.0001).
Discussion
The finding of our study demonstrates that aspirin is an effec-
tive prophylactic agent in the prevention of preeclampsia, with
an absolute risk reduction of 51% (number needed to treat, 2)
in high-risk women who were ≥90% adherent with aspirin in
comparison to women who were <90% adherent. Women who
were adherent at <90% of the time points had a 79% higher
rate of preeclampsia, 92% higher rate of IUGR, 82% higher
 Shanmugalingam et al   Aspirin Adherence in the Prevention of Preeclampsia   5

Table 3.  Comparison of Obstetric Outcome Between ≥90% Aspirin Adherent and <90% Aspirin Adherent Groups

Unadjusted Analysis Adjusted Analysis

<90% Adherent ≥90% Adherent
Obstetric Outcomes (n=63) (n=82) OR 95% CI P Value OR 95% CI P Value
Preeclampsia 37 (58%) 6 (7%) 18.5 6.8–28.5 <0.001 2.3 1.2–11.6 0.03
 Early-onset preeclampsia 11 (17%) 2 (2%) 8.5 1.8–15.6 0.02 1.9 1.1–8.7 0.04
 Late-onset preeclampsia 26 (41%) 4 (5%) 13.7 4.6–32.2 <0.001 4.2 1.4–19.8 0.04
Gestational hypertension 3 (5%) 3 (4%) 0.8 0.1–5.3 0.8
Preterm delivery (before 37 wk of 17 (27%) 8 (10%) 3.2 1.4–9.5 0.006 5.2 1.5–8.7 0.008
gestation)
IUGR 18 (29%) 4 (5%) 5.2 1.4–9.4 0.008 5.8 1.2–8.3 0.001
Increase in antihypertensive agents 38 (60%) 8 (10%) 14.5 5.8–24.2 <0.001 4.6 1.2–10.5 0.003
Decrease in antihypertensive agents 3 (5%) 25 (30%) 0.1 0.01–0.3 <0.001 0.2 0.1–0.8 0.04
Average systolic BP* 126.5 (±11.8) 115.3 (±12.1) <0.001
Average diastolic BP* 78.4 (±8.5) 71.1 (±4.3) <0.001
BP indicates blood pressure; IUGR, intrauterine growth restriction; and OR, odds ratio.
*Repeated measures ANOVA of means with SD (±SD). Binary logistic regression analysis (stepwise backward) was adjusted for preeclampsia, gestational hypertension,
preterm delivery, IUGR, and increase and decrease in antihypertensive agents.

rate of delivering before 37 weeks of gestation, and increase
in antihypertensive requirements in pregnancy compared with
high-risk women who were ≥90% adherent. Women who
were ≥90% adherent with aspirin were also 6× more likely to
have a reduction in their antihypertensive agents antenatally.
Our data also showed that a graded adherence did not affect
clinical outcome. This is in keeping with current data15 that the
prophylactic benefit of aspirin is most evident in women who
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P=0.02), and IUGR (5% versus 21%; P<0.001) among
high-risk pregnant women who were aspirin adherent in
comparison to high-risk pregnant women who were not on
aspirin (Table S4).
Nonadherence with medication in pregnancy is reported
to occur in 40% to 60% of women and is associated with
a higher rate of preventable maternal and fetal complica-
tions.23,24 Studies examining maternal use of chronic main-

are ≥90% adherent with aspirin. Therefore, suggesting ade-
quate adherence with aspirin is essential and that nonadher-
ence with aspirin among high-risk pregnant women may result
in preventable obstetric complications. No woman in our
study demonstrated biochemical features of aspirin resistance.
The evidence for the use of prophylactic aspirin in the
prevention of preeclampsia among high-risk women con-
tinues to strengthen.8,13,22 In keeping with the current data,
a subanalysis of our data in comparing the obstetric out-
comes of high-risk women who were adequately adherent
with aspirin against high-risk women who were not on as-
pirin demonstrated a lower rate of early-onset preeclampsia
(2% versus 7%; P=0.04), late- onset preeclampsia (5%
versus 29%; P<0.01), preterm delivery (8% versus 26%;
Figure 2.  Kaplan-Meier survival curve of duration of pregnancy between
≥90% aspirin adherent group, <90% aspirin adherent group, and
nonaspirin group of high-risk pregnant women. HR indicates hazard ratio.
tenance therapy have demonstrated a nonadherence rate of
50% to 60% and was found to be associated with accidental
omission and women’s concerns of teratogenic effects of
medications,23,25 with women often overestimating the te-
ratogenic effect of medications.26 Sociodemographic data
suggest that women who are younger and of higher educa-
tion level are more likely to be adherent with medications
in pregnancy27,28; however, these studies have been confined
to a single demographic. Our data consisted of women of
multiethnic background and demonstrated that women who
have had previous preeclampsia had a higher rate of ≥90%
adherence while women with secondary-level education
only had a lower rate of ≥90% adherence with aspirin. This
suggests that previous adverse pregnancy outcome and
education level played a role in women’s adherence with
aspirin in pregnancy. The investigators of this study also
examined the patient-reported factors that influenced ad-
herence with aspirin in this cohort of women. This mixed
method study demonstrated that the patient’s relationship
with healthcare providers, pill burden, and accidental omis-
sion played a role with aspirin adherence in pregnancy
(manuscript under review).
Despite the high prevalence of nonadherence with medi-
cations in pregnancy, it remains largely unrecognized and
underreported. The lack or difficulty in establishing a gold
standard assessment of medication adherence is a key fac-
tor.17 A systemic review of methods used to assess adherence
in pregnancy demonstrated a significant variation in meth-
ods utilized with self-reported adherence being the most
 6  Hypertension   April 2020
Table 4.  Comparison of Obstetric Outcome Between Varying Degrees of Aspirin Adherence With Nonaspirin High-Risk Pregnant Control Group
<30% Adherent 31%–60% Adherent
Obstetric outcomes (n=31) (n=10)
Preeclampsia 20 (65%)
 Early-onset preeclampsia 7 (23%)
 Late-onset preeclampsia 13 (42%)
Gestational hypertension 1 (3%)
Preterm delivery (before 37 wk of gestation) 9 (29%)
IUGR 9 (29%)
Increase in antihypertensive agents 18 (58%)
Decrease in antihypertensive agents 1 (3%)
IUGR indicates intrauterine growth restriction.
commonly used method.29 Reported adherence with medi-
cations was found to be higher (≤88%) with self-reporting
compared with semiqualitative methods such as pill count
and pharmacy claims (28%–32% adherence). This suggests
that self-reported adherence in pregnancy is likely con-
founded by inaccurate reporting because of dishonesty or
recall bias.29 Similarly, only 37% of aspirin obstetric stud-
ies have assessed adherence. Even so, the methods used
were variable and poorly defined with 42% of studies uti-
lizing qualitative assessment (self-reported adherence), 48%
of studies utilizing semiquantitative methods (pill count or
inspection), and 10% of studies utilized quantitative meth-
ods.16 Quantitative methods of adherence with aspirin utilize
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markers of platelet aggregation, such as PFA-100, platelet
multiplate analysis, thromboxane A2, and plasma detection
of aspirin or its active metabolite SA. These methods pro-
vide a more objective and accurate assessment of direct ad-
herence; however, its cost and need for laboratory expertise
often hinders its use in clinical studies.
Our study utilized a commercialized, clinically avail-
able PFA-100 assay and laboratory-based plasma SA
detection with a sensitive liquid chromatography tandem-
mass spectrometry method 14 for a 2-point quantitative
assessment in addition to a 4-point, Simplified Medication
Adherence Questionnaire–based, qualitative, self-reported
assessment of adherence with aspirin for comparison of
both methods. Direct measure adherence with plasma
aspirin level was not used because of its short half-life
of 15 minutes. 30 We derived the qualitative assessment
questionnaire based on the clinically validated Simplified
Medication Adherence Questionnaire 31 that has been used
in obstetric studies. 32 κ-Coefficient of agreement between
both methods used was only moderate at 0.48, indicating
that self-reported adherence poorly represents actual ad-
herence with aspirin. In our study, assessment of adher-
ence to aspirin with both quantitative methods (PFA-100
and liquid chromatography–mass spectrometry for plasma
SA) suggests that PFA-100 alone may be adequate within
its limitations for quantitative assessment of adherence to
aspirin (Tables S5 and S6). This test is also readily avail-
able with a reasonable turnaround time in most institutions
61%–89% Adherent No Aspirin
(n=22) (n=42) P Value
5 (50%) 12 (55%) 15 (36%) 0.1
2 (20%) 3 (14%) 3 (7%) 0.1
3 (30%) 9 (41%) 12 (29%) 0.2
1 (10%) 1 (5%) 6 (14%) 0.1
3 (30%) 5 (23%) 9 (21%) 0.3
3 (30%) 6 (27%) 9 (21%) 0.2
6 (60%) 14 (63%) 23 (55%) 0.7
1 (10%) 1 (5%) 2 (5%) 0.1
and may serve as a role for pragmatically assessing adher-
ence in clinical practice. However, further analysis on the
cost-effectiveness on routine PFA-100 assessment for the
purpose of adherence assessment will be beneficial.
This study is novel in assessing for obstetric outcomes in a
multicenter, demographically diverse cohort of high-risk preg-
nant women based on quantitative assessment of adherence
with aspirin. Additionally, this study also assessed the clinical
impact of varying degrees of intermittent adherence on ob-
stetric outcome and agreement between quantitative assess-
ment of adherence and self-reported adherence with aspirin.
Limitations of this study include the variation in aspirin
doses. In the aspirin group, 72% of women were on 100 mg
and 28% were on 150 mg of aspirin. This variation is due to
the change in evidence and clinical recommendation during
the period of this observational study.8 There was no crossover
in the dose taken by any woman. Given the small numbers
of women in each subgroup, an analysis to compare obstetric
outcomes between the 2 doses would be underpowered. There
was no significant difference in maternal or fetal complica-
tions with both doses of aspirin (Table S7). This study did
not assess for reliability of semiqualitative method of adher-
ence. Additionally, our study excluded women of non–Eng-
lish-speaking background. This has been shown to influence
adherence with medications in nonobstetric studies,33 and,
therefore, further studies examining the relationship between
language and adherence as assessed by semiqualitative and
quantitative methods in obstetric studies would be beneficial.
Perspectives
Aspirin plays an effective role in the prevention of pree-
clampsia among high-risk women with adherence of ≥90%.
However, the prevalence of inadequate adherence of aspirin
(<90%) is high and is associated with a significantly higher
incidence of preeclampsia, IUGR, and preterm delivery. Our
study demonstrates that self-reported adherence is not a reli-
able method of assessment and a clinically available quanti-
tative method may assist in monitoring adherence. Our study
highlights the need for clinicians to emphasize the signifi-
cance of adherence with aspirin in obstetric clinical studies to
improve the outcomes for women and their babies.
 Shanmugalingam et al   Aspirin Adherence in the Prevention of Preeclampsia   7
Acknowledgments
We would like to thank and acknowledge the women who participat-
ed in this study. We would also like to thank the Department of Renal
Medicine of South West Sydney Local Health District (SWSLHD),
Department of Obstetrics and Gynaecology of SWSLHD, Women’s
Health Initiative Translational Unit, SWSLHD (Women’s Health
Initiative Translational Unit), South Western Sydney Pathology
Service, the Heart Research Institute, PEARLS Foundation, and all
the midwives of SWSLHD for their immeasurable support in con-
ducting this study.
Sources of Funding
This study was supported by the PEARLS Preeclampsia Research
Laboratories, Australia, and Women’s Health Initiative Translational
Unit (Women’s Health Initiative Translational Unit), South West
Sydney Local Health District, NSW, Australia.
Disclosures
None.
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Novelty and Significance
What Is New?
• The obstetric use of aspirin in the prevention of preeclampsia has been
studied over the last 40 years with significant variation in the observed
risk reduction, ranging from 10% to 68% in most recent studies. These
variations have been attributed to the heterogeneity in the studies, which
includes inconsistent dosing, gestation of initiation of aspirin, and meth-
ods used to risk stratify women. While these factors have been better
addressed in more recent studies, the influence of nonadherence with
aspirin remains unclear. We conducted a PubMed search using the terms
“preeclampsia” or “preeclampsia” or “hypertensive disorders of preg-
nancy” or “hypertension in pregnancy” and “aspirin” or “acetylsalicylic
acid” and “adherence” or “compliance” for articles published in English
before June 30, 2019. The search generated 43 items, of which only 3
studies were relevant in examining the prevalence of nonadherence with
aspirin in pregnancy. Of these studies, only 2 studies examined for the
influence of adherence on the desired obstetric outcome (preeclampsia).
Even so, both studies used varying methods of analysis for adherence;
semiqualitative/qualitative method in 1 study and quantitative method
with the use of platelet function analyzer 100 in another. Additionally,
adherence was not uniformly defined in both studies, and, therefore, the
findings in both studies were vastly different. To our knowledge, this is
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the first obstetric aspirin study to utilize both quantitative and qualitative
methods of assessing adherence in addition to comparing the observed
adherence to the desired obstetric outcome comprehensively. Our study
32. Abheiden CN, van ReulerAV, Fuijkschot WW, deVries JI, ThijsA, de Boer MA.
Aspirin adherence during high-risk pregnancies, a questionnaire study.
Pregnancy Hypertens. 2016;6:350–355. doi: 10.1016/j.preghy.2016.08.232
33. Andreae MH, White RS, Chen KY, Nair S, Hall C, Shaparin N. The effect
of initiatives to overcome language barriers and improve attendance: a
cross-sectional analysis of adherence in an inner city chronic pain clinic.
Pain Med. 2017;18:265–274. doi: 10.1093/pm/pnw161
demonstrates that nonadherence with aspirin is high and is associated
with a significantly higher rate of preeclampsia, intrauterine growth re-
striction, and preterm delivery, therefore, highlighting the importance of
emphasizing and assessing for adherence with aspirin among high-risk
pregnant women. Our study demonstrated that qualitative assessment
of adherence, in the form of self-reported adherence, is not reflective of
true adherence with aspirin. Therefore, suggesting that quantitative as-
sessment of adherence is preferable. Our study also compares 2 quanti-
tative methods of assessment, the methodologies of which are described
in detail in this article.
What Is Relevant?
• The evidence, including our study, suggests that aspirin is an effec-
tive prophylactic agent in minimizing the risk of preeclampsia among
high-risk pregnant women. Recent obstetric aspirin meta-analyses have
shown the importance of initiating aspirin before 16 weeks of gesta-
tion, risk stratification method, and need for dose of ≥100 mg. Our study
adhered to these recent findings and demonstrates the additional impor-
tance of adherence at ≥90%.
Summary
The data of our study demonstrate that adequate adherence with
aspirin is essential and nonadherence with aspirin among high-risk
pregnant women may result in preventable obstetric complications.