ROLE OF LOW DOSE ASPIRIN

FOR THE PREVENTION OF PREECLAMPSIA

I Wayan Artana Putra

Maternal Fetal Medicine Division, Department of Obstetrics and Gynecology Faculty of
Medicine, University of Udayana, Prof. Dr. I.G.N.G Ngoerah Hospital

ABSTRACT

Preeclampsia is the main cause of maternal morbidity and can affect fetal

conditions such as inhibition of intrauterine growth, premature birth, placental abruption,

fetal distress, and worstly fetal death in the womb. The trend that exists in the past two

decades has not seen a significant decrease in the incidence of preeclampsia, in contrast

to the incidence of pregnancies with infections that are decreasing. Prevention of

preeclampsia is an effort that is currently being intensively carried out to reduce

morbidity and mortality for pregnant women. Prophylactic administration of low doses

of aspirin (81 mg / day) is recommended in women with a high risk of preeclampsia and

should be started between 12 weeks of gestation to 18 weeks (optimal before 16 weeks).

The use of aspirin during pregnancy has been shown to be safe for both the mother and

the fetus. Treatment with aspirin did not show an increased risk of congenital

malformations and had no negative effect on fetal development or bleeding

complications in the neonatal period.

Key words : Low Dose Aspirin, Pregnancy, Preeclampsia

BACKGROUND factors, while secondary prevention is by
Preeclampsia is a major cause of limiting salt consumption during
maternal morbidity and can affect fetal pregnancy, use of low-dose aspirin,
conditions such as intrauterine growth calcium supplementation at least 1 gram
retardation, premature birth, placental per day. Cause of preeclampsia in pregnant
abruption, fetal distress, and worst of all, women is not known with certainty so that
fetal death in the womb. The prevalence of the primary prevention is to control the
preeclampsia to date has not changed risk factors of preeclampsia. Risk factors

significantly.1 The World Health for preeclampsia include pregnancy at the

Organization (WHO) estimates that cases extremes of maternal age (adolescents and

of preeclampsia are 7 times higher in women older than 40 years old), obesity,

developing countries than in developed preexisting hypertension, diagnosis of

countries. The prevalence of preeclampsia preeclampsia in a previous pregnancy,

in developed countries is 1.3% - 6%, while diabetes or renal disease, nulliparity,

in developing countries it is 1.8% - 18%. multiple gestation, and preexisting

The report shows that the incidence of autoimmune diseases such as

preeclampsia in Indonesia is 128,273 per antiphospholipid antibody syndrome and

year or around 5.3%. The trend in the last systemic lupus erythematosus.2,3
two decades has not seen a significant Early identification of pregnancy
decrease in the incidence of preeclampsia, with preeclampsia is very important by
In contrast, the incidence of pregnancy health workers at the primary health care

with infection is decreasing.1,2 level to prevent morbidity and mortality.

Prevention of preeclampsia is an Screening for the risk of preeclampsia is

effort that is currently being intensively very important for pregnant women from

carried out to reduce morbidity and the beginning of pregnancy. The majority

mortality for pregnant women. The most of prospective studies using maternal

important prevention principle in clinical risk factors to predict preeclampsia

preeclampsia is to carry out primary show relatively low performance, with

prevention and secondary prevention. only about one third of cases predictable.

Primary prevention is by knowing the In recent years, the use of acetylsalicylic

signs and symptoms of the causes of acid or aspirin has been widely reported as

preeclampsia, such as screening for risk a regimen to prevent the onset of

preeclampsia.4 Meta-analyses have shown and moderate risk.2

that the use of early (before the 16th week

of gestation) low-dose aspirin has been
shown to reduce the risk of the incidence Table 1. Classification of
of preeclampsia.5,6
Preeclampsia Risks Assessed at

Antenatal Visit.2
Screening Preeclampsia
High Risk
Several recent studies have
 History of Preeclampsia
found that the combination of maternal
 Multiple Pregnancy
risk factors, biochemical markers and
 Chronic hypertension
ultrasound markers has the potential to
predict cases of preeclampsia with  Diabetes Mellitus type 1 or 2

higher sensitivity and specificity.  Kidney Disease

According to The International  Autoimmune disease (ex. systemic lupus erythematosus,

Federation of Gynecology and antiphospholipid syndrome)
Obstetrics (FIGO), the combination of Moderate Risk
maternal risk factors, mean arterial
 nullipara
pressure (MAP), serum placental
 Obesity (body mass index > 30 kg/m2
growth factor (PlGF), and uterine artery
 History of preeclampsiato mother or sister
pulsatility index (UTPI) is the best
combination that can be used to screen  Age ≥ 35 years old

for preeclampsia.5,6  Patient specific history(pregnancy interval > 10 years)

The identified risk factors can

assist in assessing the risk of pregnancy
at the initial antenatal visit. Based on the
results of research and the latest
international guidelines, the PNPK of
Preeclampsia published by POGI
divides the major risk factors for
preeclampsia into two, namely high risk
The presence of one high risk factor or the
presence of two or more moderate risk
factors can be used to assist in guiding the
prophylactic administration of aspirin
which is effective in reducing the risk of
preeclampsia. Uterine artery Doppler
ultrasound is a non-invasive method to
detect changes in the early stages of
decreased uteroplacental circulation. On
this examination it can be seen clearly the
direction of flow in the uterine, arcuate,
radial and spiral arteries around the Figure 1.Normal uterine artery Doppler
trophoblast tissue, so that various indices waves in the first trimester14
can be measured as needed.3,4
Several research data showed that
In a normal pregnancy, the
the mean uterine artery PI in early-onset
systolic/diastolic ratio (S/D), pulsatility
severe preeclampsia and normotensive
index (PI) and resistance index (RI) will
pregnancy showed significant differences.
decrease after 24-26 weeks of gestation,
Aardema et al (2004) conducted a Doppler
until a steady picture is achieved, namely a
examination to determine PI in 531
high and almost flat diastolic velocity
nulliparous women at 22 weeks of
picture. . The uterine artery waveform in
gestation, the results showed that there was
the first trimester of pregnancy has a
a significant difference between pregnant
diastolic notch that disappears after 24
women with preeclampsia or hypertension
weeks of gestation.The appearance of a
with uncomplicated pregnancies, where
high impedance in the resistance index (RI
the PI results were found to be increased in
> 0.58) of uterine arteries at 16-24 weeks
pregnant women with early preeclampsia
of gestation which is sometimes
in pregnancy followed by poor pregnancy
accompanied by notching at the beginning
outcome before 35 weeks.15 Soares et al
of diastole indicates high uterine artery
(2007) conducted a study to determine the
resistance due to vasoconstriction of
relationship between uterine artery
uteroplacental blood vessels.If this
Doppler examination results in the first
curvature persists and the S/D, PI, RI
trimester of pregnancy. Uterine artery
values remain high after 24-26 weeks of
Doppler examination is performed at ll-14
gestation, it means that the pressure at the
weeks of gestation in singleton pregnant
end of the uterine arteries is elevated,
women at the University of St. George's
which usually accompanies preeclampsia
Fetomaternal Unit in London. Soares
or restricted fetal growth. 7,8,14
found the mean PI in preeclampsia before
34 weeks was 1.56 while in preeclampsia
after 34 weeks it was 1.42 with a standard
deviation of 0.24.16
The findings of this study are
consistent with previous studies where
high uterine artery resistance in early-onset
severe preeclampsia is associated with the abnormalities of nitric oxide (NO) and
pathogenesis of preeclampsia itself, lipid metabolism.5 In hypertension in
namely the presence of abnormal pregnancy, trophoblast cell invasion
trophoblast invasion in the spiral arteries does not occur in the muscle layer of the
and changes in blood flow in the spiral arteries and surrounding tissues.
subplacental arteries. Whereas in The spiral muscle layer remains rigid
normotensive pregnancies it is associated and hard so that the lumen of the spiral
with normal uterine Doppler artery arteries does not allow distension and
velocimetry images because there is no vasodilation, as a result, the spiral
disruption of placental blood flow. 17
arteries are relatively vasoconstricted,
and spiral artery remodeling fails,
resulting in decreased uteroplacental
blood flow, and placental hypoxia and

ischemia..5,6
Incident of placental ischemia
that causes clinical symptoms of
preeclampsia is related to the production
Figure 1. Abnormal Uterine Artery of placental factors that enter the
Doppler View With Notch. 14
maternal circulation, so that this is what
Spiral Artery Abnormal Changes causes endothelial cell dysfunction. The
placenta produces a protein, soluble
In normal pregnancy, trophoblast
fms-like tyrosine kinase 1 (sFIt-1). This
invasion occurs into the muscle layer of
protein works by binding to receptors
the spiral arteries, which causes
for vascular endothelial growth factor
degeneration of the muscle layer
(VEGF) and placental like growth factor
resulting in dilatation of the spiral
(PLGF). If the levels of these proteins
arteries. Several theories are thought to
increase in the maternal circulation, then
be related to the incidence of
the levels of free VEGF and PLFG will
preeclampsia, such as placental
decrease. This causes endothelial cell
ischemia, generalized vasospasm,
dysfunction. Usually, sFIt-1 levels are
abnormal hemostasis followed by
elevated in maternal serum and placenta
activation of the coagulation system,
in preeclamptic pregnancies than in
vascular endothelial damage,
normal pregnancies. Increased levels of
sFIt-1 have also been reported to be occurs before 34 weeks of gestation and
associated with the degree of disease late onset preeclampsia that occurs at 34

that occurs.5,6 weeks of gestation or more. Early-onset

preeclampsia is believed to have a strong
This sustained placental ischemia
association with placental dysfunction.
will liberate toxic substances such as
while late-onset preeclampsia is a maternal
cytokines, free radicals in the form of
disease. This causes the risk of early onset
lipid peroxidase in the maternal blood
preeclampsia is closely related to the
circulation and cause oxidative stress, a
occurrence of stunted fetal growth. Early
condition where the number of free
onset preeclampsia is a major contributor
radicals is more dominant than
to maternal and perinatal morbidity and
antioxidants. In the next stage, oxidative
mortality, affecting 2% of pregnancies.7,8
stress that occurs along with the
circulation of toxic substances can During normal pregnancy, there is
stimulate endothelial dysfunction on all a balance between platelet thromboxane
endothelial surfaces of blood vessels in A2 (TXA2) (platelet activator and

the organs of preeclampsia patients.6 vasoconstrictor) and endothelial

prostacyclin. This balance regulates
platelet aggregation and peripheral
vasoreactivity during pregnancy and
maintains good uteroplacental blood

flow.7 In preeclampsia, platelet TXA2

levels are significantly increased, whereas
prostacyclin levels are markedly
decreased. This imbalance appears from 13
weeks of gestation in high-risk patients.
TXA2/PGI2 imbalance can be treated with
low-dose aspirin 6,7

Figure 3. Organ Dysfunction in

ASPIRIN
Preeclampsia.6
Aspirin or acetylsalicylic acid is an
Preeclampsia is divided into two irreversible inhibitor of the platelet
subtypes based on the time of onset of the cyclooxygenase (COX)-1 enzyme, which
disease, early onset preeclampsia that acts to suppress the formation of TXA2, a
potent activator of vasoconstriction and
platelet aggregation. Aspirin can interfere
with platelet aggregation by irreversibly
inactivating the platelet cyclooxygenase
(COX) enzyme. The presence of TXA2
activation can be mediated through COX-
1. Aspirin is able to inhibit COX-1, so it
can improve the balance of thromboxane
A2/prostacyclin. COX-2 is also involved
in increased sensitivity to angiotensin II,
immune system activation, and increased
oxidative stress during preeclampsia.
However, aspirin has anticoagulant
and anti-inflammatory properties that
contribute to the mechanism of action in
preventing preeclampsia. When given at
the beginning of the second trimester (<16
weeks gestation) low-dose aspirin works to
inhibit platelet aggregation and promote
vasodilation. This pharmacologic
mechanism results in increased blood flow
to the uterus and placenta. Debate over
indications of aspirin in the prevention of
preeclampsia was discussed again in 2014
by the US Preventive Services Task Force
(USPSTF), it aims to update the guidelines
of the American Congress of Obstetricians
and Gynecologists (ACOG) 2002.7,8
Efficacy of administering low-dose aspirin
in the prevention of preeclampsia in high-
risk patients and in reducing perinatal
adverse events revisited to update clinical
practice guidelines and prescribing in
obstetrics. The recommendations are based
primarily on a recent meta-analysis. The
USPSTF recommends that prophylactic
low-dose aspirin should be considered for
women with more than one of several
moderate risk factors for preeclampsia.8,9
Based on Pedoman Nasional
Pelayanan Kedokteran (PNPK)
“Diagnosis dan Tatalaksana
Preeklampsia” published by the
Indonesian Obstetrics and Gynecology
Association (POGI), several conclusions
were obtained in the use of aspirin,
namely:2
1. The use of low-dose aspirin for pri
mary prevention is associated with
a reduced risk of preeclampsia, pre
term delivery, fetal or neonatal dea
th and small infants during pregna
ncy, while for secondary preventio
n it is associated with a reduced ris
k of preeclampsia, preterm deliver
y <37 weeks, and birth weight <25
00. g.
2. Preventive effect of aspirin was
more pronounced in the high-risk
group.
3. There are no data showing any diff
erence between aspirin administrat
ion before and after 20 weeks.
4. Administration of high-dose aspiri
n is better at reducing the risk of p
reeclampsia, but the resulting risk
is also higher.
Based on these conclusions, POGI
recommends the use of aspirin in
the following patients:2
1. The use of low-dose aspirin
(75mg/day) is recommended for
the prevention of preeclampsia in
women with high risk (Level evid
ence II, Grade A major in the mother and unrelated to t
recommendation).
2. Low-dose apirin should be
started to be used before 20 weeks
gestational age (Level evidence II
I, Grade C recommendation).
The Aspirin for Evidence-Base
d Preeclampsia Prevention (ASPRE) st
udy was a double-blind randomized pl
acebo-controlled trial, which identified
patients at high risk of preeclampsia at
11-14 weeks of gestation using a scree
ning test by the Fetal Medicine Founda
tion (FMF). Then, comparisons were
made between aspirin (150 mg per day
at bedtime) and placebo in patients defi
ned as high risk, from 11-14 weeks of
gestation to 36 weeks. The results of th
is study showed a significant reduction
of 62% in the incidence of premature p
reeclampsia.4,5
The use of aspirin during pregnancy ha
s been shown to be safe for both mothe
r and fetus. Treatment with aspirin has
not been shown to increase the risk of
congenital malformations and has no n
egative effects on fetal development or
bleeding complications in the neonatal
period.12 Although side effects such a
s vaginal bleeding and gastrointestinal
symptoms are reported to be small in
about 10% of patients, there is no evid
ence of an increased risk of bleeding.
he incidence of placental abruption. 4
Concerns regarding premature closure
of the fetal arterial canal have never b
een confirmed and reported.
Research conducted by Rachmi (2
016) examined the effect of giving aspirin
125 mg/day, namely 500 mg Acetosal tabl
ets divided into four parts (available at the
puskesmas) on decreasing uterine artery va
scular resistance in pregnant women. Ultra
sound Doppler velocimetry of abnormal ut
erine arteries at gestational age of 16 -24 w
eeks.9 The results showed that ultrasound
doppler velocimetry of the uterine arteries
after giving aspirin 125 mg/day for 4 week
s in pregnant women. The results obtained
were 76 subjects with uterine artery Doppl
er ultrasound which became normal and 23
subjects remained with abnormal ultrasoun
d results (20 level I and 3 pregnant women
level III). This study showed that low-dose
aspirin could significantly reduce uterine a
rtery resistance, with p=0.0001 (p<0,05) a
nd is effective for reducing abnormal uter
ine artery resistance in pregnant women a
ged 16-24 weeks. 9,11
A recent meta-analysis report by
Van Doorn et al (2021) evaluated the
effect of aspirin dose on the incidence of
preeclampsia at all ages and preeclampsia.
In premature preeclampsia, women who
were randomly assigned to a dose of 150
mg had a significantly reduced risk of
preeclampsia by 62% (RR = 0.38; 95% CI:
0.20-0.72; P = 0.011). Aspirin doses <150
mg did not result in a significant reduction
in the risk of preeclampsia. The number
needed to treat (NNT) 150 mg aspirin was
reported as 39 (95% CI: 23-100). There is
a maximum 30% reduction in the risk of
preeclampsia at all gestational ages at all
aspirin doses.13
CONCLUSION
Preeclampsia is one of the main
causes of maternal and perinatal morbidity
and mortality. Early diagnosis during
routine antenatal and natal examinations
and prompt and appropriate management
are very important to prevent morbidity
and mortality. Screening is carried out on
every pregnant woman to find out whether
it is included in the criteria for high risk or
moderate risk of preeclampsia. The use of
low-dose aspirin has been widely reported
as a preventive measure in patients at high
risk of preeclampsia. The use of aspirin
during pregnancy has been shown to be
safe for both mother and fetus. The US
Preventive Services Task Force (USPSTF)
and ACOG recommend low-dose aspirin
(81 mg/day) for women at high risk of
preeclampsia and should be started
between 12 weeks and 28 weeks of
gestation (optimally before 16 weeks) and
continued daily until delivery. Recent
studies published aspirin at a dose of 150
mg / day can reduce the incidence of early-
onset preeclampsia by more than 50%.
REFERENCES
1. . Fox R, Kitt J, Leeson P, Aye CYL, L
ewandowski AJ. Preeclampsia: risk fa
ctors, diagnosis, management, and th
e cardiovascular impact on the offspri
ng. J Clin Med. 2019;8(10):16
25.
2. Obstetri P, Indonesia G. Panduan Nas
ional Pelayanan Kedokteran (PNPK) t
entang Preeklampsia. Jakarta Perkum
pulan Obstet dan Ginekol Indones. 2
015
3. Mayrink J, Costa ML, Cecatti JG. Pre
eclampsia in 2018: revisiting concepts,
physiopathology, and prediction. Sci
World J. 2018;2018.
4. Rolnik DL, Wright D, Poon LC, O’Go
rman N, Syngelaki A, de Paco Matall
ana C, et al. Aspirin versus placebo in
pregnancies at high risk for preterm pr
 eeclampsia. N Engl J Med. 2017;377
(7):613–22.
5. Sumulyo G, Iswari WA, Pardede TU,
Darus F, Puspitasari B, Santana S, et a
l. Diagnosis dan Tatalaksana Preekla
mpsia Berat Tidak Tergantung Protein
uria. Cermin Dunia Kedokteran
2017;44(8):576–9. http://www.cdkj
ournal.com/index.php/CDK/article/vie
w/742/505.
6. Gabbe SG, Niebyl JR, Simpson JL, L
andon MB, Galan HL, Jauniaux ERM,
et al. Obstetrics: normal and problem
pregnancies e-book. Elsevier Health
Sciences; 2016.
7. Abdelaziz HK, Saad M, Pothineni NV
K, Megaly M, Potluri R, Saleh M, et a
l. Aspirin for primary prevention of c
ardiovascular events. J Am Coll Cardi
ol. 2019;73(23):2915–29.
8. Atallah A, Lecarpentier E, Goffinet F,
Doret-Dion M, Gaucherand P, Tsatsa
ris V.Aspirinfor prevention of
preeclampsia.Drugs. 2017;77(17):
1819–31.
9. Kim J, Lee K-S, Kim J-H, Lee D-K, P
ark M, Choi S, et al. Aspirin prevents
TNF-α-induced endothelial cell dysfu
nction by regulating the NF-κb- depe
ndent mir-155/enos pathway: Role of
a mir-155/enos axis in preeclampsia.
Free Radic Biol Med. 2017;
104:185–98.
10. Li C, Raikwar NS, Santillan MK, Sant
illan DA, Thomas CP. Aspirin inhibits
expression of sflt1 from human cytot
rophoblasts induced by hypoxia, via c
yclo-oxygenase 1. Placenta.
2015;36(4):446–53.
11. Vieillefosse S, Guibourdenche J, Atal
lah A, Haddad B, Fournier T, Tsatsaris
V, et al. Predictive and prognostic fact
ors of preeclampsia: interest of plgf a
nd sflt-1. J Gynecol Obstet Biol Repr
od (Paris). 2016;45(9):999–1008.
12. Gynecologists AC of O and. ACOG C
ommittee Opinion No. 743. Low-dose
aspirin use during pregnancy.
Obs Gynecol. 2018;132(1):e44–
52.
13. Lin L, Zhu Y, Li B, Yang H. Low-dos
e aspirin in the prevention of pre- ecla
mpsia in China (APPEC study): proto
col for a multicentre randomized cont
rolled trial. Trials. 2018 Dec;
19(1):1-7
14. Guedes-Martins, L. et al. (2014) ‘Inter
nal iliac and uterine arteries Doppler u
ltrasound in the assessment of normot
ensive and chronic hypertensive pregn
ant women’, Scientific Reports 2014 4 :
1, 4(1), pp. 1–8. doi: 10.1038/srep037
85.
15. Aardema MW, Saro, M Lander, Ooste
rhof, Aarnoudse. Second Trimester Do
ppler Ultrasound Screening of The Ut
erine Arteries Differentiates between
Subsequent Normal and Poor Outcom
 es of Hypertensive Pregnancy: Two D
ifferent Pathophysiological Entities. C
linical Science 2004; 106: 377 -382
16. Soares S, Fratelli N, Prefumo F, Bhide
A, Thilaganathan B. First-trimester ute
rine artery Doppler and Spontaneous p
reterm delivery. Ultrasound Obstetri
Gynecology 2007;29: 146-149
17. Melchiorre K, Wormald B, Leslie K,
Bhide A, Thilaganathan B. First-trime
ster uterine artery Doppler indices in t
erm and preterm preeclampsia. Ultras
ound Obstetri Gynecology 2008;32: 1
33-137