Accepted: 26 June 2023

DOI: 10.1111/1471-0528.17607

RESEARCH ARTICLE

Aspirin delays the onset of hypertensive disorders of pregnancy

among nulliparous pregnant women: A secondary analysis of the
ASPIRIN trial

Avinash Kavi1 | Matthew K. Hoffman2 | Manjunath S. Somannavar1 |

1 1
Mrityunjay C. Metgud | Shivaprasad S. Goudar | Janet Moore | Eleanor Nielsen3 |
3

Norman Goco3 | Elizabeth M. McClure3 | Adrien Lokangaka4 | Antoinette Tshefu4 |

Melissa Bauserman5 | Musaku Mwenechanya6 | Elwyn Chomba6 | Waldemar A. Carlo7 |
Lester Figueroa8 | Nancy F. Krebs9 | Saleem Jessani10 | Sarah Saleem10 |
Robert L. Goldenberg11 | Prabirkumar Das12 | Archana Patel12,13 | Patricia L. Hibberd14 |
Fabian Esamai15 | Sherri Bucher16 | Marion Koso-­Thomas17 | Robert Silver18 |
Richard J. Derman19
1
KLE Academy of Higher Education and Research, Jawaharlal Nehru Medical College, Belagavi, India
2
Christiana Care Health Services, Newark, Delaware, USA
3
RTI International, Durham, North Carolina, USA
4
Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo
5
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
6
University Teaching Hospital, Lusaka, Zambia
7
University of Alabama at Birmingham, Birmingham, Alabama, USA
8
Instituto de Nutrición de Centroamérica y Panamá, Guatemala City, Guatemala
9
University of Colorado School of Medicine, Denver, Colorado, USA
10
Aga Khan University, Karachi, Pakistan
11
Columbia University, New York, New York, USA
12
Lata Medical Research Foundation, Nagpur, India
13
Datta Meghe Institute of Medical Sciences, Sawangi, India
14
Boston University School of Public Health, Boston, Massachusetts, USA
15
Department of Child Health and Paediatrics, Moi University School of Medicine, Eldoret, Kenya
16
School of Medicine, Indiana University, Indianapolis, Indiana, USA
17
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA
18
University of Utah, Salt Lake City, Utah, USA
19
Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Correspondence
Avinash Kavi, Women's and Children's Health Abstract
Research Unit and Department of Community Objective: To assess the impact of low-­dose aspirin (LDA) starting in early preg-
Medicine, Jawaharlal Nehru Medical College,
KLE Academy of Higher Education and nancy on delaying preterm hypertensive disorders of pregnancy.
Research, Belagavi 590010, Karnataka, India. Design: Non-­prespecified secondary analysis of a randomised masked trial of LDA.
Email: dravinashkavi@gmail.com

Trial Registration: The trial was registered with ClinicalTrials.gov NCT02409680, and the Clinical Trials Registry-­India CTRI/2016/05/006970.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.

BJOG. 2023;00:1–10.  wileyonlinelibrary.com/journal/bjo | 1

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2 |    KAVI et al.

Funding information
Eunice Kennedy Shriver National Institute of
Child Health and Human Development, USA
Setting: The study was conducted among women in the Global Network for Women's
and Children's Health's Maternal and Newborn Health Registry (MNHR) clusters, a
prospective, population-­based study in Kenya, Zambia, the Democratic Republic of
the Congo (DRC), Pakistan, India (two sites-­Belagavi and Nagpur) and Guatemala.
Population: Nulliparous singleton pregnancies between 6+0 weeks and 13+6 weeks in
six low-­middle income countries (Democratic Republic of Congo, Guatemala, India,
Kenya, Pakistan, Zambia) enrolled in the ASPIRIN Trial.
Methods: We compared the incidence of HDP at delivery at three gestational age
periods (<28, <34 and <37 weeks) between women who were randomised to aspirin
or placebo. Women were included if they were randomised and had an outcome at or
beyond 20 weeks (Modified Intent to Treat).
Main Outcome Measures: Our primary outcome was pregnancies with HDP as-
sociated with preterm delivery (HDP@delivery) before <28, <34 and <37 weeks.
Secondary outcomes included small for gestational age (SGA) <10th percentile, <5th
percentile, and perinatal mortality.
Results: Among the 11 976 pregnancies, LDA did not significantly lower HDP@delivery
<28 weeks (relative risk [RR] 0.18, 95% confidence interval [CI] 0.02–­1.52); however, it
did lower HDP@delivery <34 weeks (RR 0.37, 95% CI 0.17–­0.81) and HDP@delivery
<37 weeks (RR 0.66, 95% CI 0.49–­0.90). The overall rate of HDP did not differ between
the two groups (RR 1.08, 95% CI 0.94–­1.25). Among those pregnancies who had HDP,
SGA <10th percentile was reduced (RR 0.81, 95% CI 0.67–­0.99), though SGA <5th
percentile was not (RR 0.84, 95% CI 0.64–­1.09). Similarly, perinatal mortality among
pregnancies with HDP occurred less frequently (RR 0.55, 95% CI 0.33–­0.92) in those re-
ceiving LDA. Pregnancies randomised to LDA delivered later with HDP compared with
those receiving placebo (median gestational age 38.5 weeks vs. 37.9 weeks; p = 0.022).
Conclusions: In this secondary analysis of a study of low-­risk nulliparous singleton
pregnancies, early administration of LDA resulted in lower rates of preterm HDP
and delivery before 34 and 37 weeks but not in the overall rate of HDP. These results
suggest that LDA works in part by delaying HDP.

K EY WOR DS
aspirin, hypertensive disorders of pregnancy, low-­and middle-­income countries, nulliparous, preterm

1 | I N T RODUC T ION population, aspirin dosage, gestational age at initiation and

Hypertensive disorders of pregnancy (HDP) remain a primary
contributor to maternal and perinatal death and result in long-­
term health risks for both the mother and child. The risk of
such complications is greater when the disease is severe and of
early onset resulting in preterm birth. Estimates suggest that
HDP is responsible for approximately one-­sixth of all preterm
births, and is frequently associated with fetal growth restric-
tion.1,2 Preterm birth and fetal growth restriction are known to
have lifelong consequences for the child, including a higher risk
of neurodevelopmental delay, respiratory disorders, renal dys-
function, insulin resistance, obesity, hypertension, cardiovas-
cular disease and impaired work capacity.3 Additionally, HDP
results in adverse maternal outcomes; for example, mothers af-
fected by pre-­eclampsia are two to five times more likely to de-
velop cardiovascular diseases including systemic hypertension
and cerebrovascular disease in the future when compared with
women who were not hypertensive during pregnancy.4
Heterogeneous studies have evaluated the possible benefit
of low-­dose aspirin (50–­150 mg/day) in pregnancy to min-
imise the risk of HDP, with large variations in the included
disease definition.5 The synthesis of these studies has resulted
in low-­dose aspirin (LDA) being recommended for the pre-
vention of HDP by various professional society guidelines, e.g.
the World Health Organization (WHO), American College of
Obstetricians and Gynecologists (ACOG) and the National
Institute for Health and Care Excellence (NICE), which have
increasingly broadened the number of women eligible for
LDA.6–­10 Aspirin use in pregnancy may be an ideal interven-
tion because of its wide availability, relative inexpense, and
few (if any) safety concerns for the mother and fetus.11
Nonetheless, the effects of LDA on overall HDP are mod-
est, which may reflect the heterogeneous aetiologies of the dis-
ease. Increasingly, the literature has suggested that early HDP
(<34 weeks) is secondary to a failure to achieve deep placen-
tation while term pre-­eclampsia reflects placental senescence.
Though this distinction in the literature has emerged, few pri-
mary trials and most of the meta-­analyses have not examined
HDP in the framework that the role of LDA is not to prevent all
HDP but rather to delay it. Recently, a non-­prespecified anal-
ysis of the ASPRE trial12 demonstrated that women who were
at high risk for HDP by clinical, ultrasound and biochemical

ASPIRIN DELAYS HYPERTENSIVE DISORDERS IN PREGNANCY
markers randomised to aspirin at 150 mg had a 4.4-­week delay
in delivery with HDP.13 Given that this finding has not been
evaluated in other populations, we undertook this second-
ary analysis to assess the impact of aspirin administration as
compared with placebo on the gestational age (GA) at deliv-
ery in women with HDP in the recently completed ‘Aspirin
Supplementation for Pregnancy Indicated Risk Reduction
In Nulliparous Women (ASPIRIN)’ trial, which randomised
11 976 nulliparous women in six low-­middle income coun-
tries to either LDA (81 mg daily) or identical placebo between
6+0 weeks and 13+6 weeks through 36 weeks' GA of pregnancy.
2 | M ET HODS
We performed a non-­prespecified secondary analysis of the
ASPIRIN trial examining the impact of LDA on the gesta-
tional age at delivery of nulliparous pregnant women with
HDP. The ASPIRIN trial enrolled nulliparous women from
seven community sites in six low-­and middle-­income coun-
tries (LMIC) (two sites in India, and one site each in Pakistan,
Zambia, the Democratic Republic of the Congo (DRC),
Guatemala and Kenya) between March, 2016 and April, 2019.
The trial was led by the Global Network (GN) for Women's
and Children's Health Research (Eunice Kennedy Shriver
National Institute of Child Health and Human Development
[NICHD], Bethesda, MD, USA). Each site enrolled women
from primary healthcare centres and hospital-­based clinics.
The trial protocol has been published previously.14 The study
protocol was approved by the pertinent ethics committees
and regulatory agencies of each participating country and
the ethics committees of the US collaborating institutes and
14 361 Assessed for eligibility
11 976 randomized
5990 allocated to Aspirin
203 excluded
16 ineligible
15 LFU
172 Delivery <20 weeks
mITT 5787
7 HDP status unkown
Analysis population 5780
FIGU R E 1 Consort diagram. HDP, hypertensive disorders of pregnancy; LFU, lost to follow-­up; mITT, modified intention to treat.
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   | 3
that of the RTI International. Written informed consent for
participation in the trial was obtained from the women or
the guardians/parents of minors, by study staff at each site.
Nulliparous pregnant women aged between 18 and 40 years
(minors aged ≥14 years were enrolled when permitted by in-
dividual ethics boards in the DRC, Kenya and Zambia) with a
singleton gestation between 6+0/7 weeks and 13+6/7 weeks with-
out evidence of a fetal anomaly identified by ultrasound were
deemed eligible. Women with a history of allergy or contraindi-
cation to aspirin; previous consumption of aspirin for more than
7 days during the pregnancy; multiple gestations; more than two
first-­trimester losses; any other medical condition that might be
considered a contraindication to inclusion in the study (e.g. di-
abetes and hypertension) were excluded at the discretion of the
investigators.15 Women were also excluded if their blood pres-
sure was >140/90 mm Hg or haemoglobin was <7.0 g/dL at the
time of enrolment. The crown–­rump length and date of the last
menstrual period (LMP) was used to assess the gestational age
with a mobile application in accordance with ACOG guidance.16
Eligible women who gave their consent were randomly as-
signed (1:1) to receive 81 mg of aspirin or placebo until 36 weeks'
gestation as detailed in the primary study. Medication adher-
ence was noted to be high with 84.9% of women taking 90% of
doses as assessed by pill counts.17 Blood pressure was assessed
by field staff who had been trained in the appropriate tech-
nique of taking blood pressures using a standardised blood
pressure cuff at regular intervals: 16–­20 weeks, 28–­30 weeks,
34 weeks, and then every 2 weeks from 34 weeks until delivery.
Our primary outcome was the gestational epoch (<28,
<34 and <37 weeks) at which a pregnancy was delivered with
HDP. Women were classified as having HDP if they devel-
oped BP >140/90 mmHg after 20 weeks' GA on at least two
2385 excluded
1534 did not meet inclusion
criteria
157 declined particpation
694 did not complete screening
Allocation 5986 allocated to Placebo
215 excluded
7 ineligible
10 LFU
178 delivery <20 weeks
Follow Up mITT 5771
7 HDP status unkown
Analysis Analysis population 5764
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4 |    KAVI et al.

separate occasions or were clinically diagnosed during the
delivery hospitalisation.17 All cases were reviewed by a com-
mittee blinded to treatment allocation. As the availability
and routine assessment of proteinuria differed between sites,
this was not included in the definition of HDP.18 Care and
management of women with HDP was at the discretion of
the local care delivery system. Following delivery, we ob-
tained maternal and neonatal outcomes up to 42 days using
the Global Network Maternal Newborn Health Registry.19,20
2.1 | Statistical analyses
To assess the onset of HDP and associated delivery we chose to
examine three gestational age epochs (<28, <34 and <37 weeks).
Data analyses were performed using SAS software (version
9.4) and graphics were produced using ‘R’ (version 4.0.5).
Consistent with the primary study, women who delivered at
≥20 weeks' gestation with known status of HDP were included
in this analysis (modified intent to treat, mITT). Descriptive
statistics of socio-­demographic, obstetric and clinical char-
acteristics of women with HDP were reported by treatment
group. Gestational age at delivery with HDP was compared
visually between treatment and placebo groups using dot plots.
For each of the primary and secondary maternal and fetal
outcomes, relative risks (RR) and 95% confidence intervals
(CI) comparing aspirin with placebo were calculated using
a generalised linear model with a binomial distribution and
log link adjusted for site. If a model did not converge, RR and
95% CI were calculated using Mantel–­Haenszel estimates of
common relative risk stratified by site. In the case of zero cell
counts, a logit estimator of the common relative risk which
adds 0.5 to each cell frequency in the stratum is reported. The
estimated mean difference and 95% CI for gestational age at
delivery was obtained from a generalised linear model adjust-
ing for site and treatment group. Gestational age at delivery
was log-­transformed and the estimates then back-­transformed.
Quantile regression was performed on the subgroup of
women with HDP using a log transformation of GA at de-
livery and including terms for treatment and site. The model
estimates were then back-­transformed and plotted by quan-
tile and treatment group.
3 | R E SU LT S
Among study participants randomised, 11 558 (96.5%) were
included in the mITT analysis; 11 544 (99.9%) with known

TA BL E 1 Maternal characteristics among women with hypertensive disorder of pregnancy.

Treatment group

Characteristics Total Aspirin Placebo

Women with hypertensive disorder of pregnancy, n 677 352 325
Maternal age, mean (SD) 21.9 (3.7) 21.9 (3.7) 21.9 (3.7)
Maternal education, n/N (%)
No formal schooling 102/677 (15.1) 56/352 (15.9) 46/325 (14.2)
1–­6 years of schooling 65/677 (9.6) 32/352 (9.1) 33/325 (10.2)
7–­12 years of schooling 419/677 (61.9) 211/352 (59.9) 208/325 (64.0)
≥13 years of schooling 91/677 (13.4) 53/352 (15.1) 38/325 (11.7)
GA at randomisation, mean (SD) 10.0 (2.0) 10.0 (1.9) 10.0 (2.0)
Haemoglobin at screening, mean (SD) 11.4 (1.6) 11.4 (1.6) 11.3 (1.7)
Height, cm, mean (SD) 151.8 (6.5) 151.8 (6.4) 151.7 (6.6)
Weight, kg, mean (SD) 49.4 (10.0) 49.2 (9.8) 49.6 (10.2)
BMI, mean (SD) 21.5 (4.2) 21.4 (4.1) 21.6 (4.3)
ANC visits, n/N (%)
0 0/677 (0.0) 0/352 (0.0) 0/325 (0.0)
1–­2 21/677 (3.1) 6/352 (1.7) 15/325 (4.6)
3+ 656/677 (96.9) 346/352 (98.3) 310/325 (95.4)
Site, n/N (%)
DRC 2/677 (0.3) 1/352 (0.3) 1/325 (0.3)
Kenya 13/677 (1.9) 5/352 (1.4) 8/325 (2.5)
Zambia 26/677 (3.8) 13/352 (3.7) 13/325 (4.0)
India –­Belagavi 293/677 (43.3) 162/352 (46.0) 131/325 (40.3)
India –­Nagpur 136/677 (20.1) 67/352 (19.0) 69/325 (21.2)
Pakistan 90/677 (13.3) 45/352 (12.8) 45/325 (13.8)
Guatemala 117/677 (17.3) 59/352 (16.8) 58/325 (17.8)
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ASPIRIN DELAYS HYPERTENSIVE DISORDERS IN PREGNANCY    | 5

HDP status have been included in this analysis (Figure 1).
Maternal characteristics among women with HDP are de-
scribed in Table 1. The baseline characteristics of the study
population across the groups were similar with respect to
age, education, gestational age at randomisation, baseline
haemoglobin and anthropometric measures. More than
95% of the women had 3+ antenatal visits among both the
groups. Overall, the Asian (India and Pakistan) and Central
American (Guatemala) sites differed from the African (DRC,
Kenya and Zambia) sites in the proportion of HDP cases.
In the primary analysis of the ASPIRIN Trial, there was no
difference in the overall rate of HDP between women receiving
LDA and placebo (LDA 6.1% vs. placebo 5.6%; RR 1.08, 95%
CI 0.94–­1.25).17 Women who had been randomised to LDA
and developed HDP were less likely to deliver before 34 weeks
(RR 0.37, 95% CI 0.17–­0.81) or before 37 weeks (RR 0.66, 95%
CI 0.49–­0.90) than were those treated with placebo. Women
randomised to LDA who developed HDP were less likely to
deliver before 28 weeks (RR 0.18, 95% CI 0.02–­1.52) but this
difference did not achieve statistical significance (Table 2).
No differences in other maternal outcomes among women
with HDP receiving LDA were evident with regard to vagi-
nal bleeding, antepartum haemorrhage, postpartum haemor-
rhage and maternal mortality through 42 days post-­delivery.
Assessment of fetal and neonatal outcomes among women
with HDP revealed that the incidence of low birthweight (LBW;
<2500 g) was less among the aspirin group than the placebo
group (RR 0.71, 95% CI 0.57–­0.87). Aspirin use was signifi-
cantly associated with a reduced incidence of extremely LBW
(<1500 g; RR 0.13, 95% CI 0.03–­0.55). Babies born to women
with HDP who received LDA had lower rates of small for gesta-
tional age (SGA) <10th percentile (RR 0.81, 95% CI 0.67–­0.99)
but not <5th percentile (RR 0.84, 95% CI 0.64–­1.09). Fetal losses
and stillbirth were significantly lower among women with
HDP who received LDA as compared with placebo.
The distribution of gestational age at delivery for women
with HDP in the aspirin and placebo groups is shown in the
dot plot (Figure 2). This graph demonstrates that women ran-
domised to LDA who later developed HDP appear to deliver at
a later gestational age than do women who received the placebo.
This suggests that LDA may delay the onset of HDP at delivery.
The mean GA at delivery was higher for women randomised to

TA BL E 2 Primary and secondary outcomes among women with hypertensive disorder of pregnancy.

Treatment group

Characteristics Total Aspirin Placebo RR (95% CI)

Primary outcomes
Preterm delivery <37 weeks of pregnancya, n/N (%) 138/677 (20.4) 57/352 (16.2) 81/325 (24.9) 0.66 (0.49– ­0.90)
Preterm <34 weeks of pregnancyb, n/N (%) 29/677 (4.3) 8/352 (2.3) 21/325 (6.5) 0.37 (0.17– ­0.81)
c
Preterm <28 weeks of pregnancy , n/N (%) 4/677 (0.6) 0/352 (0.0) 4/325 (1.2) 0.18 (0.02–­1.52)
Maternal outcomes
Antepartum haemorrhageb, n/N (%) 6/677 (0.9) 1/352 (0.3) 5/325 (1.5) 0.16 (0.02–­1.42)
Postpartum haemorrhageb, n/N (%) 18/676 (2.7) 13/352 (3.7) 5/324 (1.5) 2.21 (0.81–­6.06)
Maternal mortality through 42 daysb, n/N 3/677 (443) 1/352 (284) 2/325 (615) 0.54 (0.05– ­6.17)
(Rate/100 000 deliveries)
Mean gestational age at deliveryd (weeks) 38.2 (2.3) 38.5 (1.9)* 37.9 (2.7)* 1.02 (1.01–­1.03)
Fetal outcomes
Small for gestational age, 10th percentilea, n/N (%) 243/638 (38.1) 115/334 (34.4) 128/304 (42.1) 0.81 (0.67– ­0.99)
a
Small for gestational age, 5th percentile , n/N (%) 159/638 (24.9) 77/334 (23.1) 82/304 (27.0) 0.84 (0.64–­1.09)
Perinatal mortalitya, n/N (rate/1000) 54/677 (79.8) 20/352 (56.8) 34/325 (104.6) 0.55 (0.33– ­0.92)
a
Measured birthweight <2500 g , n/N (%) 224/662 (33.8) 98/344 (28.5) 126/318 (39.6) 0.70 (0.57– ­0.87)
Birthweight <2500 ga, n/N (%) 227/670 (33.9) 99/347 (28.5) 128/323 (39.6) 0.71 (0.57– ­0.87)
b
Measured birthweight <1500 g , n/N (%) 16/662 (2.4) 2/344 (0.6) 14/318 (4.4) 0.13 (0.03– ­0.55)
Birth weight <1500 gb, n/N (%) 18/670 (2.7) 3/347 (0.9) 15/323 (4.6) 0.18 (0.05– ­0.61)
a
Fetal loss , n/N (rate/1000) 54/677 (79.8) 20/352 (56.8) 34/325 (104.6) 0.53 (0.31– ­0.90)
Stillbirth (macerated excluded)a, n/N (rate/1000) 19/667 (28.5) 7/349 (20.1) 12/318 (37.7) 0.52 (0.21–­1.29)
a
All stillbirtha , n/N (rate/1000) 29/677 (42.8) 10/352 (28.4) 19/325 (58.5) 0.47 (0.22– ­0.99)
a
Relative risks and 95% confidence intervals are obtained from generalised linear models with a binomial distribution and a log link adjusting for site and treatment group.
b
Mantel–­Haenszel estimates of common relative risks and 95% confidence intervals adjusting for site are reported due to convergence issues with the generalised linear
models.
c
Logit estimates of common relative risks and 95% confidence intervals adjusting for site are reported due to cell counts of zero. The logit estimator adds 0.5 to each cell
frequency in the stratum.
d
Estimated mean difference and 95% confidence interval obtained from generalised linear model adjusting for site and treatment group. GA at delivery was log-­t ransformed
and the estimates then back-­t ransformed.
*
Wilcoxon Ranked Sum test of gestational age at delivery between treatment groups resulted in a p-­value of 0.022.

6 |   
FIGU R E 2 Gestational age at delivery for women with hypertensive disorders of pregnancy by treatment group.
LDA than to placebo (LDA 38.5 weeks vs. placebo 37.9 weeks; RR
1.02, 95% CI 1.01–­1.03). In addition, the overall median GA at
delivery was higher in the LDA group than in the placebo group
(LDA 38.7 weeks vs. placebo 38.4 weeks; p = 0.022). In a post-­hoc
analysis of women with HDP, quantiles of gestational age at de-
livery were observed to be higher in women who received LDA
than in women who did not receive LDA up to the 0.35 quantile
(see Figure 3 for the estimated quantiles in both groups, adjusted
for site). There was no evidence of a difference between these
two groups in quantiles >0.35, suggesting that LDA may benefit
women with HDP who deliver in earlier gestational windows.
Figure 4 depicts the survival analyses for time until
delivery with HDP for both aspirin and placebo groups.
Participants were censored at time of delivery if there is
no HDP. The inset shows the same data on an enlarged y-­
axis. Hazard ratios and 95% CI for HDP comparing aspirin
with placebo within three GA time periods (early preterm,
preterm and term) are calculated using a Cox proportional
hazard model with a time-­varying treatment arm. The prob-
ability of women with HDP delivering at an early GA had a
smaller hazard ratio with later GA at delivery. The hazard
ratios (95% CI) calculated for different GA ranges are as fol-
lows: for 20–­33 weeks, 0.69 (0.49–­0.97); for 34–­36 weeks, 0.81
(0.56–­1.18); for 37–­43 weeks, 1.21 (1.02–­1.44).
4 | DISC US SION
Increasingly, aspirin has been recommended for the pre-
vention of HDP by a number of professional societies.6–­10
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KAVI et al.
However, the use of aspirin for prevention of HDP has been
debated because of contradictory findings among ran-
domised trials,21,22 and enthusiasm has been tempered by
its relatively modest effect on the overall rate of reduction
of HDP (RR 0.90, 95% CI 0.84–­0.97).5 Several studies have
suggested that the efficacy of LDA is contingent on early ini-
tiation and the use of higher doses (100–­150 mg).5,11,23 More
recently, a secondary analysis of the ASPRE trial has sug-
gested that the true benefit of LDA may not be in preventing
HDP but rather in delaying its onset to later gestational ages
at which fetal/neonatal survival is more likely to occur.12,13
4.1 | Main findings
This secondary analysis of the ASPIRIN trial similarly found
that LDA did not decrease the overall rate of HDP at delivery
but rather decreased the rate of HDP early in pregnancy.17
Women who received LDA and developed HDP appeared to
deliver at a later GA as compared with women who received
the placebo, suggesting that LDA may delay the onset of
HDP at delivery. Specifically, we were able to document that
among women with HDP, deliveries before 34 and 37 weeks
were less common and directionally lower, although not sta-
tistically significant before 28 weeks. The lack of statistical
significance before 28 weeks may reflect the small number
of women who developed HDP at those gestational ages.
Additionally, the probability of not having HDP at delivery
was almost the same until 28 weeks GA. After 32 weeks GA,
a dip in the trajectory was observed in the placebo group,

ASPIRIN DELAYS HYPERTENSIVE DISORDERS IN PREGNANCY
FIGU R E 3 Estimated quantile of gestational age at delivery for women with hypertensive disorders of pregnancy by treatment arm for each quantile.
whereas at 40 weeks GA, the probability of delivery with
HDP increased in the aspirin group. The calculated hazard
ratios for early preterm birth were lower than for late pre-
term and term deliveries.
Similarly, the incidence of LBW, extreme LBW, fetal loss
and stillbirths were significantly lower among women who
received LDA than women who received placebo among the
pregnancies complicated by HDP. Maternal outcomes such
as antepartum haemorrhage, postpartum haemorrhage and
vaginal bleeding did not differ between the two groups.
4.2 | Interpretation
Initiating LDA in low-­ r isk nulliparous singleton preg-
nancies early in gestation (6+0 –­13+6 weeks) resulted in
extending the gestational age at delivery among women
who developed HDP. Similarly, the risk of perinatal mor-
tality and SGA <10th percentile are reduced. These find-
ings are consistent with other trials.12,21,22 Specifically, the
finding that HDP women who received LDA tended to
deliver at a later GA compared with women who received
the placebo, is also consistent with a secondary analysis
14710528, 0, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17607 by Nat Prov Indonesia, Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
   | 7
of the ASPRE trial that randomised women at high-­r isk
for pre-­eclampsia to LDA 150 mg or placebo, and found
that the overall rate of HDP was not lowered but rather
delayed to later gestational ages.12,13 It is interesting to
note that the risk reduction of preterm delivery <34 weeks
among women with HDP in this analysis (RR 0.37, 95%
CI 0.17–­0.81) was nearly identical to the risk reduction
reported in the ASPRE trial (RR 0.38, 95% CI 0.20–­0.70)
despite a lower dose of aspirin being used.12 The risk of
postpartum haemorrhage was not significantly increased
but was higher among women with HDP receiving LDA.
This increased risk has been reported in randomised tri-
als targeting high-­r isk populations12,24 and among stud-
ies evaluating universal aspirin prophylaxis in low-­risk
populations. 25,26
4.3 | Strengths and limitations
The strength of this investigation includes the large number
of women who were recruited with negligible loss to follow-
­up, use of a placebo and masked ascertainment of the pri-
mary outcome. It should be remembered that these results

8 |   
FIGU R E 4 Survival plot of hypertensive disorder of pregnancy by treatment group.
do not negate the results of the primary study, which was
designed to examine the impact of LDA on preterm birth.
This was a non-­prespecified analysis and in the primary
paper study we did not explicitly ascertain whether HDP re-
sulted in iatrogenic preterm delivery. Additionally, we had
limited power to examine the outcome of HDP associated
with preterm delivery before 28 weeks, a group that is partic-
ularly at risk for perinatal mortality in LMICs.
5 | C ONC LUSION
Women randomised to LDA were less likely to have HDP
at delivery before 34 and 37 weeks. Similarly, SGA <10th
percentile and perinatal mortality occurs less frequently
in those receiving LDA. This suggests that LDA improves
pregnancy outcomes by delaying the onset of HDP, thereby
extending the gestational age at delivery.
AU T HOR C ON T R I BU T ION S
MKH, SSG, RJD, NG, JM, EMMcC, MK-­ T and RS de-
signed the study. AK, MSS, MCM, SSG, AL, AT, MB, MM,
EC, WAC, LF, NFK, SJ, SS, RLG, PD, AP, PLH, FE and SB
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KAVI et al.
collected data and oversaw the trial at each centre. MKH,
SSG, RJD, NG, JM, EMMcC, RS and MK-­T provided over-
all trial oversight. JM and EN statistically analysed the data.
AK and MKH wrote the first draft of the paper. All authors
reviewed and contributed to the article.
AC K N O​W L E​D G E​M E N T S
We thank the women who participated in this study. We
appreciate the field study staff (registry administrators,
home visit research assistants, laboratory technicians and
community health workers) and the Global Network Sites
Investigators for their valuable contributions.
F U N DI N G I N F OR M AT ION
Eunice Kennedy Shriver National Institute of Child Health
and Human Development, USA.
C ON F L IC T OF I N T E R E S T S TAT E M E N T
None declared.
DATA AVA I L A BI L I T Y S TAT E M E N T
Deidentified participant data from the study will be avail-
able at the National Institute of Child Health and Human

ASPIRIN DELAYS HYPERTENSIVE DISORDERS IN PREGNANCY
Development data repository (N-­DASH): https://dash.nichd.
nih.gov/. Data sharing will be accessed and governed accord-
ing to the procedures and policies of N-­DASH.
E T H IC S S TAT E M E N T
The ASPIRIN study protocol was approved by the ethics
review committees of the sites and partner institutions, viz.
Institutional Review Boards of Thomas Jefferson University
Office of Human Research Institutional Review Board,
Philadelphia, PA, USA (Control #16F.320); Jawaharlal Nehru
Medical College (JNMC), Institutional Ethics Committee
on Human Subjects Research, Belagavi, India; (MDC/
IECHSR/2016-­ 17/A-­72) and Karnataka State Health &
Family Welfare Society, Bangalore, India; University of North
Carolina at Chapel Hill, Chapel Hill, NC, USA (No. 15-­
1780); Kinshasa School of Public Health (KSPH) of Public
Health Ethics Committee, Kinshasa, Democratic Republic
of Congo (ESP/CE/082/2015); University of Alabama
Institutional Review Board for Human Use, Birmingham,
AL, USA (F150611007); University of Zambia Biomedical
Research Ethics Committee, Lusaka, Zambia (No. 007-­
08-­15); University of Colorado Denver Anschutz Medical
Campus Multiple Institutional Review Board, Aurora, CO,
USA (COMIRB Protocol 15–­1625); Institute for Nutrition in
Central America and Panama (INCAP), School of Medicine
Ethics Committee, Guatemala City, Guatemala, (Universidad
Francisco Marroquín) (CE-­FM/UFM-­055-­15); Columbia
University Human Research Protection Office Institutional
Review Boards, New York, NY, USA (IRB-­AAAP5506); Aga
Khan University (AKU) Ethics Review Committee, Karachi,
Pakistan (3562-­CHS-­ERC-­15); Boston University, Office of
the Institutional Review Board, Boston, MA, USA (H-­35466);
Lata Medical Research Foundation, Research Ethics Review
Committee, Nagpur, India (RPC #21); Indiana University
School of Medicine, Office of Research Administration,
Indianapolis, IN, USA (1507246903R001); Moi University
School of Medicine Institutional Research and Ethics
Committee, Eldoret, Kenya (IREC/2015/81 Approval No.
0001429); RTI International, Research Triangle Park, North
Carolina Office of Research Protection Institutional Review
Board, Durham, NC, USA (12940-­7). An independent data-­
monitoring committee appointed by the NICHD reviewed
the study protocol and progress. The trial was registered
with ClinicalTrials.gov NCT02409680, and the Clinical Trials
Registry-­India CTRI/2016/05/006970. Written informed con-
sent was obtained from all participants in the ASPIRIN study.
ORC I D
Avinash Kavi https://orcid.org/0000-0002-2176-4697
Matthew K. Hoffman https://orcid.
org/0000-0002-2927-8693
Manjunath S. Somannavar https://orcid.
org/0000-0002-8871-5072
Mrityunjay C. Metgud https://orcid.
org/0000-0002-0844-8569
Shivaprasad S. Goudar https://orcid.
org/0000-0002-8680-7053
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   | 9
Elizabeth M. McClure https://orcid.
org/0000-0001-8659-5444
Archana Patel https://orcid.org/0000-0002-2558-7421
R EFER ENCES
1. Duley L. The global impact of pre-­eclampsia and eclampsia. Semin
Perinatol. 2009;33:130–­7.
2. Stevens W, Shih T, Incerti D, Ton TGN, Lee HC, Peneva D, et al.
Short-­term costs of preeclampsia to the United States health care sys-
tem. Am J Obstet Gynecol. 2017;217:237–­248.e16.
3. Moster D, Lie RT, Markestad T. Long-­term medical and social conse-
quences of preterm birth. N Engl J Med. 2008;359:262–­73.
4. Wu P, Haththotuwa R, Kwok CS, Babu A, Kotronias RA, Rushton
C, et al. Preeclampsia and future cardiovascular health: a system-
atic review and meta-­ a nalysis. Circ Cardiovasc Qual Outcomes.
2017;10(2):e003497. https://doi.org/10.1161/CIRCO​U TCOM​ES.116.​
003497
5. Askie LM, Duley L, Henderson-­ Smart DJ, Stewart LA, PARIS
Collaborative Group. Antiplatelet agents for prevention of pre-­
eclampsia: a meta-­analysis of individual patient data. Lancet. 2007;369:​
1791–­8.
6. World Health Organization. WHO recommendations for preven-
tion and treatment of pre-­eclampsia and eclampsia. Geneva: WHO;
2011 [cited 2023 Mar 7]. Available from: http://apps.who.int/iris/bitst​
ream/10665/​4 4703/​1/97892​41548​335_eng.pdf
7. American College of Obstetricians and Gynecologists. Hypertension
in pregnancy. Washington: American College of Obstetricians and
Gynecologists; 2013 [cited 2023 Mar 5]. Available from: http://www.
acog.org/Resou​rces-­A nd-­Publi​catio​ns/Task-­Force​-­a nd-­Work-­Group​
-­Repor​ts/Hyper​tensi​on-­in-­Pregn​a ncy
8. ACOG Committee opinion no. 743 summary: low-­dose aspirin use
during pregnancy. Obstet Gynecol. 2018;132(1):254–­6. https://doi.
org/10.1097/AOG.00000​0 0000​0 02709
9. National Institute for Health and Care Excellence. Hypertension in
pregnancy: quality standard. Manchester: NICE; 2013 [cited 2023
Mar 8]. Available from: https://www.nice.org.uk/guida ​nce/qs35/
resou​rces/hyper​tensi​on-­in-­pregn​a ncy-­20986​07923141
10. Poon LC, Shennan A, Hyett JA, Kapur A, Hadar E, Divakar H, et al.
The International Federation of Gynecology and Obstetrics (FIGO)
initiative on pre-­ eclampsia: a pragmatic guide for first-­ t rimester
screening and prevention. Int J Gynaecol Obstet. 2019;145(Suppl
1):1–­33. https://doi.org/10.1002/ijgo.12802; Erratum in: Int J Gynaecol
Obstet. 2019;146(3):390–­1.
11. Chavarria ME, Lara-­Gonzalez L, Gonzalez-­Gleason A, Garcia-­Paleta
Y, Vital-­Reyes VS, Reyes A. Prostacyclin/thromboxane early changes
in pregnancies that are complicated by preeclampsia. Am J Obstet
Gynecol. 2003;188(4):986–­92.
12. Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco
Matallana C, et al. Aspirin versus placebo in pregnancies at high risk
for preterm preeclampsia. N Engl J Med. 2017;377(7):613–­22.
13. Wright D, Nicolaides KH. Aspirin delays the development of pre-
eclampsia. Am J Obstet Gynecol. 2019;220(6):580.e1–­580.e6.
14. Hoffman MK, Goudar SS, Kodkany BS, Goco N, Koso-­Thomas M,
Miodovnik M, et al. A description of the methods of the aspirin sup-
plementation for pregnancy indicated risk reduction in nulliparas
(ASPIRIN) study. BMC Pregnancy Childbirth. 2017;17(1):135.
15. Henderson J, Whitlock E, O'Connor E, Senger C, Thompson J,
Rowland M. Low-­dose aspirin for the prevention of morbidity and
mortality from pre-­ eclampsia. A systematic evidence review for
the US Preventive Services Task Force. Evidence syntheses, no. 112.
Rockville: Agency for Healthcare Research and Quality; 2014.
16. Smith GCS, Shah I, Pell JP, Crossley JA, Dobbie R. Maternal obesity in
early pregnancy and risk of spontaneous and elective preterm deliver-
ies: a retrospective cohort study. Am J Public Health. 2007;97:157–­62.
17. Hoffman MK, Goudar SS, Kodkany BK, Metgud M, Somannavar
M, Okitawutshu J, et al. Low-­dose aspirin for the prevention of
preterm delivery in nulliparous women with a singleton pregnancy
 14710528, 0, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17607 by Nat Prov Indonesia, Wiley Online Library on [13/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 |    KAVI et al.

(ASPIRIN): a randomised, double-­ blind, placebo-­

controlled trial. 24. Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of
Lancet. 2020;395:285–­93. perinatal death and adverse perinatal outcome using low-­dose aspi-
18. Brown MA, Lindheimer MD, de Swiet M, VanAssche A, Moutquin JM. rin: a meta-­a nalysis. Ultrasound Obstet Gynecol. 2013;41:491–­9.
The classification and diagnosis of the hypertensive disorders of preg- 25. Mone F, Mulcahy C, McParland P, Breathnach F, Downey P,
nancy: statement from the international society for the study of hyper- McCormack D, et al. Trial of feasibility and acceptability of routine
tension in pregnancy (ISSHP). Hypertens Pregnancy. 2001;20:IX–­XIV. lowdose aspirin versus early screening test indicated aspirin for pre-­
19. Goudar SS, Carlo WA, McClure EM, Pasha O, Patel A, Esamai F, eclampsia prevention (TEST study): a multicentre randomised con-
et al. The maternal and newborn health registry study of the Global trolled trial. BMJ Open. 2018;8:e022056.
Network for Women's and Children's Health Research. Int J Gynaecol 26. Subtil D, Goeusse P, Puech F, Lequien P, Biausque S, Breart G, et al.
Obstet. 2012;118(3):190–­3. Aspirin (100 mg) used for prevention of pre-­clampsia in nulliparous
20. McClure EM, Garces AL, Hibberd PL, Moore JL, Goudar SS, Saleem women: the Essai Regional Aspirine Mere-­Enfant Study (part 1).
S, et al. The Global Network Maternal Newborn Health Registry: a BJOG. 2003;110:475–­84.
multi-­country, community-­based registry of pregnancy outcomes.
Reprod Health. 2020;17(Suppl 2):184.
21. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E,
et al. Low-­dose aspirin to prevent preeclampsia in women at high risk.
How to cite this article: Kavi A, Hoffman MK,
N Engl J Med. 1998;338:701–­5.
22. CLASP (Collaborative Low-­ dose Aspirin Study in Pregnancy) Somannavar MS, Metgud M, Goudar SS, Moore J,
Collaborative Group. CLASP: a randomised trial of low-­dose aspirin et al. Aspirin delays the onset of hypertensive
for the prevention and treatment of pre-­eclampsia among 9364 preg- disorders of pregnancy among nulliparous pregnant
nant women. Lancet. 1994;343:619–­29. women: A secondary analysis of the ASPIRIN trial.
23. Short VL, Hoffman M, Metgud M, Kavi A, Goudar SS, Okitawutshu
BJOG. 2023;00:1–10. https://doi.org/10.1111/1471-
J, et al. Safety of daily low-­ dose aspirin use during pregnancy
in low-­ income and middle-­ income countries. AJOG Glob Rep. 0528.17607
2021;1(1):100003. https://doi.org/10.1016/j.xagr.2021.100003