Lithuanian University of Health Sciences

Faculty of Medicine

Department of Gynaecology and Obstetrics

Title of Master’s Thesis:

Use of Aspirin for pre-eclampsia prevention

Master of Medicine Lithuanian University of Health Sciences

Literature review

Author: Alicia Gimeno Sales

Supervisor: Viktorija Tarasevičienė

TABLE OF CONTENTS

Table of contents…………………………………………………..………2

Summary…………………………………………………………………..3

Acknowledgment………………………………………………………….4

Conflict of interest…………………………………………………………4

Abbreviation……………………………………………………………….5

Terms………………………………………………………………………6

Introduction………………………………………………………………..8

Aim and objectives…………………………..………………………….…9

Literature review………………………………………………………….10

Methods………………………………………………….………..………19

Results………….………………………………………………………….20

Discussion of results……………………………………………………….28

Conclusions.………………………………………………………………..30

References………………………………………………………………….31

2

SUMMARY

Author name: Alicia Gimeno Sales

Research Title: Use of aspirin for pre-eclampsia prevention.

Aim: to study the use of aspirin for preventing pre-eclampsia

Objectives:

1. to review to which risk group of women aspirin is used for the prevention of

preeclampsia;

2. to review from which gestational age aspirin is been prescribed;

3. to review the range of the dosages aspirin is been given for the prevention of

preeclampsia.

Materials and Methods: A comprehensive literature review was performed to detect articles

regarding aspirin use for PE prevention. Databases used were PUBMED/NCBI, ScienceDirect and BMJ

journal using the terms of `preeclampsia´, `aspirin´, `prevention´, `pregnancy´. There were no quality

assessments concerning the included studies.

Conclusions:

1. Aspirin should be offered to women at high risk of PE.

2. The use of LDA has shown to be more effective if it is started before 16 weeks of gestation.

3. Most of the studies concluded that LDA (50-150 mg/d) reduces the risk of PE, severe PE, FGR and

maternal perinatal mortality. It has a dose-response effect, meaning that the efficacy of aspirin

grows as the dose increases.

3

ACKNOWLEDGMENT

The author wants to express her gratitude towards Helena Cifuentes Enríquez de Salamanca for

being such an amazing ``second tutor´´ and to her family for their support along the way.

CONFLICT OF INTEREST

The author reports no conflicts of interest.

4

ABBREVIATIONS

PE: Preeclampsia

LDA: Low-dose aspirin

HT: Hypertension

ACS: Acute coronary syndrome

LDH: lactate dehydrogenase

AST: Aspartate transaminase

ALT: Alanine transaminase

DIC: Disseminated intravascular coagulation

FGR: Fetal growth restriction

PA: Placenta abruption

BMI: Body Mass Index

HO-1: Haem oxygenase-1

CTh: Cystathionine-γ-lyase

CO: Carbon monoxide

H2S: Hydrogen sulfide

PIGF: Placental growth factor

sFlt1: soluble fms-like thyrosine kinase 1

NOS: Nitric oxide synthase

CKD: Chronic kidney disease

DM: Diabetes Mellitus

NK: Natural killers

HLA: Human leukocyte antigen

PIGF: Placental growth factor

PAAP-P: pregnancy-associated plasma protein A

5

TERMS

Gestational age: term used during pregnancy to describe how far along the pregnancy is.

Nulliparous: woman who has never born a child.

HELLP syndrome: A combination of the breakdown of red blood cells (Hemolysis), elevated liver

enzymes (EL), and low platelet count (LP) occurring in pregnancy.

Cerebral palsy: a condition marked by impaired muscle coordination (spastic paralysis) and/or other

disabilities, typically caused by damage to the brain or at birth.

Superimposed preeclampsia: refers to women with chronic hypertension who develop PE.

Thrombocytopenia: A condition in which one has a low platelet account, so called thrombocytes.

Fetal growth restriction: defined as the rate of fetal growth that is below normal in light of the growth

potential of a specific infant as per race and gender of the fetus.

DIC: a serious disorder in which blood clots from throughout the body, blocking small vessels.

Placental abruption: A condition that occurs when the placenta detaches from the wall of the uterus

before delivery.

Placenta hypoxia: Occurs when the placenta is deprived of an adequate sypply of oxygen.

Oxidative stress: It´s defined as a disturbances in the balance between the production of reactive pxygen

species and antioxidant defences.

Antiphopholipid syndrome: It´s a disorder of the immune system that causes an increased risk of blood

clots.

Cytotrophoblast: Is the inner layer of the trophoblast.

Trophoblast: Are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and

develop into a large part of the placenta.

Catalytic site: that portion of an enzyme molecule at which the actual reaction proceeds.

Constitutive enzyme: Enzymes that are produced in constant amounts without regard to the physiological

demand or the concentration of the substrate.

Inducible enzyme: An enzyme that is normally present in minute quantities within a cell, but whose

concentration increases dramatically when a substrate compound is added.

6

Placebo: Is a substance containing no medicatin and prescribed or given to reinforce a patient´s

expectation to get well.

7

INTRODUCTION

Preeclampsia is one of the leading causes of maternal and perinatal morbidity and mortality, usually

characterized by hypertension and proteinuria. Despite high incidence of preeclampsia the

pathophysiological basis of preeclampsia is still not clear and there are a number of mechanisms and

signaling pathways that intertwine [1].

According to Villa et al. “antiplatelet agents, such as aspirin (acetylsalicylic acid), are among the most

promising candidates for prevention of pre-eclampsia” [2]. Atallah et al. point out that for over 30 years,

the role of aspirin in the primary or secondary prevention of preeclampsia has been the subject of

numerous studies and great controversy. The indications for aspirin, its dosage, and gestational age at the

start of aspirin treatment are still debated [3].

Professional associations now recommend the prophylactic use of low-dose aspirin in women who are

considered to be at high risk for preeclampsia [4]. Women should receive low-dose aspirin starting from

<16 weeks’ gestation [5]. Various studies show that effectiveness of aspirin is not only dependent on the

gestational age at initiation of treatment but also on the dose of the drug, but the recommended dose of

aspirin varies and the optimal does remains unclear [5]. Therefore, there is a need to determine the correct

gestational age and the correct dosage of aspirin for risk group women in cases of preeclampsia.

8

AIM AND OBJECTIVES

Aim: To study the use of Aspirin for preventing pre-eclampsia

Objectives:

1. to review to which risk group of women aspirin is used for the prevention of

preeclampsia;

2. to review from which gestational age aspirin is been prescribed;

3. to review the range of the dosages aspirin is been given for the prevention of

preeclampsia.

9

LITERATURE REVIEW

1. Prevalence of preeclampsia, epidemiology and related complications

Pre-eclampsia is a major cause of maternal death worldwide. It is characterized by the onset of new

HT with proteinuria after 20 weeks of gestation [6]. Most preeclampsia occurs in healthy nulliparous

women, in whom the incidence of preeclampsia may be as high as 7.5 percent [7]. Approximately 0.8

percent of pregnancies are complicated by severe preeclampsia [8]. The prevalence of preeclampsia in

developing countries is up to 7 times higher [9].

If preeclampsia is untreated between 2% and 10% of pregnant women may develop eclampsia, most

seizures occur in women with advanced severe preeclampsia. Eclampsia is a tonic, clonic seizure, or coma

during preeclampsia (up to 80 percent of cases) or during HELLP (up to 30 percent of cases). Most

seizures occur in patients with severe preeclampsia but may also occur in patients with mild elevations of

ABP. 17-38-60 percent of cases of eclampsia may be the first sign of preeclampsia. Most seizures occur

prenatal (38-53 percent) but can also occur at birth (18-36 percent) or even after delivery (11-44 percent)

[10].

4-12 percent cases of preeclampsia can be complicated HELLP syndrome. These include H-hemolysis

(elevated levels of bilirubin and lactate dehydrogenase - LDH³600 IU / l), EL- elevated liver enzymes

(AST - aspartate aminotransferase ³70 IU / l, ALT - alanine transaminase ³40 IU / l), LP - low platelet

count (<100 000 / mm3). The syndrome may be complete or incomplete. The majority of women with the

HELLP syndrome have hypertension and proteinuria but the condition may also occur without these.

Typical clinical symptoms of the HELLP syndrome are right upper abdominal quadrant or epigastric pain,

nausea, and vomiting [11].

Neonatal morbidity remains high in cases of preeclampsia. Babies born after such a condition are at

risk of neurological complications (cerebral palsy, mental retardation, sensory and behavioral disorders),

they are more prone to metabolic disorders, and are more prone to diabetes, cardiovascular disease and

arterial hypertension [12]. Studies also show that preeclampsia affects the mother after birth. A woman

faces the increased risk to develop heart, brain or peripheral vascular disease [12], kidney disease [14].

10

2. Preeclampsia features, classification and diagnostic criteria

The typical development of preeclampsia is seen after 20 weeks gestation and prior to 48 h

postpartum. Young et al. state that “the cardinal features of preeclampsia are new-onset hypertension

(defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) and proteinuria

(300 mg or greater in a 24-h urine specimen)” [7].

The diagnosis might be difficult to confirm due to the fact that a percentage of women present

atypically without one of these cardinal signs. Edema is considered to be a part of the diagnostic triad of

preeclampsia, but Young et al. point out that “edema is too nonspecific to be used for diagnostic purposes

because a majority of pregnant women without preeclampsia develop edema toward the end of their

pregnancies.” [7]. Clinical signs and symptoms are the basis of current criteria for the diagnosis of

preeclampsia [15] but is not always helpful in cases of atypical or superimposed preeclampsia

(preeclampsia superimposed on chronic hypertension or chronic renal disease) [7].

Preeclampsia can be classified as severe and mild according to various clinical and laboratory

findings. These two forms are distinguished by their level of hypertension and proteinuria and by damage

to other organ systems [10]. Severe preeclampsia is diagnosed in patients with at least one of the

following: systolic ABP ≥ 160mmHg or diastolic ABP ≥ 110mmHg measured with a time period of 6h in

between; proteinuria ≥ 5g / 24 h; headache, vision problems, pain in the sternum or in the right rib cage,

elevated liver enzymes, thrombocytopenia (<100 x 109 / l), sudden swelling in the body, pulmonary

edema, hemolysis, elevated serum liver enzymes and thrombocytopenia (HELLP) syndrome, fetal growth

restriction (FGR), disseminated intravascular coagulation (DIC), or placental abruption (PA) [16]. Nausea,

vomiting, general weakness are considered as non-specific possible clinical symptoms of preeclampsia

[17].

Preeclampsia is divided into early (<34 weeks) and late (≥ 34 weeks) [18]. This distinction is

associated with different maternal and fetal outcomes, biochemical markers, heredity and clinical features

[19]. Late preeclampsia is much more common than early and accounts for about 90% of all cases.

However, the prevalence of early severe PE is higher than the prevalence of late severe PE [20].

11

3. Etiology and risk factors of preeclampsia

The exact etiology of preeclampsia is unknown. There are two commonly described theories of pre-

eclampsia: vascular and immune [21]. According to the vascular theory, “the development of pre-

eclampsia stems from abnormal spiral artery modification leading to placental hypoxia, increase in

oxidative stress and aberrant maternal systemic inflammatory responses” [6]. The immune theory

emphasizes that “elevation in maternal systemic inflammation is the cause of pre-eclampsia“[6]. Ahmed &

Ramma analyzed both theories and concluded that pregnancy can be viewed as a car with an accelerator

and brakes, where inflammation, oxidative stress and an imbalance in the angiogenic milieu act as the

‘accelerator’. The ‘braking system’ includes the protective pathways of haem oxygenase 1 (also referred

as Hmox1 or HO-1) and cystathionine-γ-lyase (also known as CSE or Cth), which generate carbon

monoxide (CO) and hydrogen sulfide (H2S) respectively. The failure in these pathways (brakes) results in

the pregnancy going out of control and the system crashing. Therefore, pre-eclampsia can be viewed as an

accelerator–brake defect disorder. Authors conclude that “CO and H2S hold great promise because of their

unique ability to suppress the anti-angiogenic factors sFlt-1 and soluble endoglin as well as to promote

PlGF and endothelial NOS activity“ [6].

Known risk factors for preeclampsia are identified in the literature. Several medical conditions are

associated with increased preeclampsia risk. High-risk women include arterial hypertension, CKD,

insulin-treated DM and who had early onset preeclampsia in their previous pregnancy [22]. Other risk

factors for preeclampsia that are mentioned in scientific research are various autoimmune diseases, anti-

phospholipid syndrome, gestational diabetes [7]. According to Von Dadelszen & Magee, women

diagnosed with periodontitis, urinary tract infections, chlamydiosis, and cytomegalovirus infection are

also more prone to develop preeclampsia [23].

Preeclampsia is also much more common in women who are pregnant for the first time or have a

multiple pregnancy [24]. Risk factors also include a 10-year gap between pregnancies [25]. Greater than

35 or, according to other authors, 40 years of age, a pre-pregnancy BMI of more than 30, and the use of

assisted reproductive technology also increase risk of preeclampsia [24].

Ethnicity and race can also influence preeclampsia: Chinese women have a lower prevalence of

preeclampsia than Caucasians [26]; Pacific Islanders and Filipinos have a higher risk of preeclampsia

12

compared to whites [27]; black and Hispanic women are at higher risk of preeclampsia than white women

[28].

Some risk factors are related to the couple itself and include infertility; donor embryo, sperm or

ovum; repeated miscarriages; the genetical information of the father [29]. Some studies show that men

who fathered one preeclamptic pregnancy had a significantly increased risk of fathering another

preeclamptic pregnancy with a new partner [30].

It has been noted that smoking prevents the development of preeclampsia [31]. In many cases,

preeclampsia may develop in the absence of known risk factors, suggesting that various factors in the

female body increase the risk of this pregnancy complication [24].

4. Pathogenesis of preeclampsia

Delivery of the placenta remains the only known treatment for this clinical disease, suggesting that

the placenta is the principal contributor to the pathogenesis of preeclampsia. High levels of anti-

angiogenic factors and low levels of pro-angiogenic factors released by the placenta contribute to the

development of the maternal hypertensive syndrome of preeclampsia, which is thought to result from

widespread endothelial dysfunction [7].

13

Figure 1. Abnormal placentation in preeclampsia (Powe, Levine & Karunmanchi, 2011)

As it can be seen in Figure 1, in normal placental development, invasive cytotrophoblasts of fetal

origin invade the maternal spiral arteries, transforming them from small-caliber resistance vessels to high-

caliber capacitance vessels capable of providing placental perfusion adequate to sustain the growing fetus.

During the process of vascular invasion, the cytotrophoblasts differentiate from an epithelial phenotype to

an endothelial phenotype, a process referred to as pseudovasculogenesis, or vascular mimicry (top). In

preeclampsia, cytotrophoblasts fail to adopt an invasive endothelial phenotype. Instead, invasion of the

spiral arteries is shallow, and they remain small-caliber resistance vessels (bottom) [32].

The pathogenesis of preeclampsia is divided into two stages: stage I - inferior placental formation,

stage II - endothelial cell dysfunction. At stage I, there are no clinical signs of pre-eclampsia, so it is called

asymptomatic or preclinical. Clinical signs after onset of stage II include hypertension, proteinuria,

hepatic dysfunction, and coagulation activation [21]. The two-stage model is compiled of two stages:

1. stage I - incomplete spiral artery remodeling in the uterus that contributes to placental

ischemia;

14

2. stage II - release of antiangiogenic factors from the ischemic placenta into the maternal

circulation that contributes to endothelial damage [33].

Figure 2. The pathogenesis of preeclampsia (Young et al., 2010)

During implantation, placental trophoblasts invade the uterus and induce the spiral arteries to

remodel, while obliterating the tunica media of the myometrium´s spiral arteries; this allows the arteries to

accommodate increased blood flow independent of maternal vasomotor changes to nourish the developing

fetus. Part of this remodeling requires that the trophoblasts adopt an endothelial phenotype and its various

adhesion molecules. If this remodeling is impaired, the placenta is likely to be deprived of oxygen, which

leads to a state of relative ischemia and an increase in oxidative stress during states of intermittent

perfusion [33].

As it can be seen in Figure 2, genetic factors, immune abnormalities [natural killer (NK) cell/human

leukocyte antigen (HLA)-C axis], and other factors such as oxidative stress may cause placental

dysfunction, which in turn leads to the release of anti-angiogenic factors [such as soluble fms-like tyrosine

kinase 1 (sFlt1) and soluble endoglin (sEng)] and other inflammatory mediators to induce hypertension,

proteinuria, and other complications of preeclampsia [7].

15

5. Aspirin in the prevention of preeclampsia

According to Ahmed & Ramma, “there are no effective pharmacological agents to treat pre-

eclampsia” and the premature termination of the pregnancy is the only solution [6]. Although maternal

symptoms appear to be largely resolved with the delivery of the baby, some research indicates that pre-

eclampsia is associated with long-term health issues for both mother and baby [34].

Nevertheless, various studies show that antiplatelet agents, such as aspirin (acetylsalicylic acid), are

among the most promising candidates for prevention of pre-eclampsia [2]. Acetylsalicylic acid (aspirin) is

transformed into salicylic acid, which induces the acetylation of a serine at the heart of COX and binds to

its catalytic site, thereby preventing the binding of arachidonic acid. This blocking of the catalytic site of

COX is dose-dependent, stable, covalent, and irreversible. It is mainly responsible for the inhibition of

COX-1, a constitutive enzyme, while there is less inhibition of COX-2, an inducible enzyme. The duration

of action of aspirin depends on the capacity of the cell to resynthesize COX [3]. The mode of action of

aspirin is presented in Figure 3.

Figure 3. Mode of action of aspirin (Atallah et al., 2017)

16

S.Roberge et al. observe that studies investigating the dosage of aspirin dose on the prevention of

preeclampsia shows mixed results. Recommendations suggest that women identified as being at high risk

for PE should receive low-dos aspirin starting from <16 weeks’ gestation [5]. Duley et al. state that

Administering low-dose aspirin to pregnant women led to small-to-moderate benefits, including

reductions in pre-eclampsia [35]. A study by S.Roberge et al. included a total of 20,909 pregnant women

randomized to between 50-150 mg of aspirin daily. When aspirin was initiated at 16 weeks, there was a

significant reduction and a dose-response effect for the prevention of preeclampsia and severe

preeclampsia. This study showed that in high-risk women the effect of aspirin for the prevention of PE and

severe PE is dose-dependent and optimal when initiated 16 weeks of gestation [5]. Dose dependence is

pointed out by other authors. For example, Atallah et al. state that aspirin should be administered once a

day in the evening at low doses ranging from 80 to 150 mg because the efficacy of aspirin grows as the

dose increases [3].

The time of gestation also influences the outcomes of aspirin in cases of preeclampsia but similarly

studies show mixed results. Meher et al. performed a meta-analysis of individual participant data

including 32,217 women. The results showed that the effect of low-dose aspirin and other antiplatelet

agents on preeclampsia and its complications is consistent, regardless of whether treatment is started

before or after 16 weeks’ gestation. Therefore, women at an increased risk of preeclampsia should be

offered antiplatelet therapy, regardless of whether they are first seen before or after 16 weeks’ gestation

[36]. Administering aspirin at an earlier time of gestation shows no influence. A study by Chaemsaithong

et al. showed that the administration of low-dose aspirin at <11 weeks’ gestation in women at high risk

does not decrease the risk of preeclampsia, gestational hypertension, any hypertensive disorder of

pregnancy, and fetal growth restriction [37]. Administering aspirin at a later time of gestation shows

ambiguous results. Moore et al. state that Aspirin initiated <17w0d reduces the risk for late-onset

preeclampsia by 29% supporting the practice of early initiation of aspirin in high-risk women [38].

Roberge et al. state that low-dose aspirin initiated at >16 weeks’ gestation has a modest or no impact on

the risk of preeclampsia, severe preeclampsia [5]. Tong et al. suggest that it is still beneficial to start

aspirin even if commenced >16 weeks’ gestation. As to the magnitude of the risk reduction, the risk of

preeclampsia is reduced by about 10% if aspirin is commenced >16 weeks’ gestation [39].

17

Studies that analyze the effect of aspirin using a placebo also show mixed results. According to Villa

et al. no statistically significant effect of aspirin in preventing pre-eclampsia in high-risk women [2]. But a

study performed by Rolnik et al. in which 1776 women attended with singleton pregnancies who were at

high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to

14 weeks of gestation until 36 weeks of gestation. The results show that treatment with low-dose aspirin in

women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo

[4].

It should be noted that aspirin can reduce intrauterine growth restriction, preterm birth, and neonatal

death. Bartsch et al. conclude that aspirin “effectively reduces the risk of PE and its related adverse

perinatal outcomes, including intrauterine growth restriction, preterm birth, and neonatal death” but only

when initiated between 12 to 16 weeks gestation [40]. Therefore authors see aspirin as a highly attractive

agent for the prevention of maternal and perinatal morbidity worldwide due to it being cheap, available

worldwide and easy to administrate [40]. Cui et al. present a similar opinion stating that low-dose aspirin

also significantly reduced the risk of maternal and neonatal adverse outcomes such as preterm birth, SGA

and others [41].

18

METHODS

A comprehensive literature search was performed to identify articles regarding the use of aspirin

preventing PE. The review started with a specific search of articles in September 2019 and on the

databases PUBMED/NCBI, ScienceDirect and BMJ journal using the terms: `preeclampsia´, `aspirin´,

`prevention´, `pregnancy´.

70% of selected articles are less than 10 years old. All articles selected were written in English language

with no geographical exclusion. The search continued until February 2020 and the collected articles were

continuously revaluated for their relevance regarding the aim and objective of this paper. For the articles

that were deemed eligible the full text was obtained and examined to see if they were relevant or not.

There were no quality assessments concerning the included studies. A total of 41 articles were used for

writing this paper.

19

RESULTS

A total of 9 studies were selected in order to answer the questions of to which group of woman aspirin is

given, from which gestational age is recommended to administer aspirin and which range in the dosage of

aspirin should be given.

Table 1: Summary of the studies reviewed.

Nr. Study Year Design Methods N

woman

1 Villa P.M. et

al.

2012 Randomized,

Double blinded,

placebo-

controlled trial.

Participants randomized to either start

with LDA (100mg/d) or placebo.

Interval 12+0 weeks to 13+6 weeks of

gestation.

From the randomized trial, a meta-

analysis was conducted. Date from the

trial and data from 346 women with

abnormal uterine artery Doppler was

included.

152

2 Rolnik D.E. et

al

2017 Double-blinded,

Placebo-

controlled trial.

A total of 798 woman received aspirin

(150mg/d) and 822 woman placebo

from 11 to 14 until 36 weeks of

gestation.

1776

3 Roberge S. et

al

2017 Randomized

control trials,

Systematic

review,

Meta-analysis.

Impact of LDA (50-150mg/d)

according to gestational age at

initiation of aspirin (≤16 and >16

weeks)

20.909

20

In the following tables, results and interpretation of the results according to the objectives are going to be

exposed and explained.

4 Duley L. et al. 2019 Systematic

review.

Comparison of administering

antiplatelet agents with either placebo

or no antiplatelet agent.

40,249

5 Meher S.,

Duley L.,

Hunter K.,

Askie L.

2017 Meta-analysis Outcomes of administering LDA or

other antiplatelet agents before or after

16 weeks of gestation.

32,217

6 Chaemsaithon

g P. et al.

2019 Systemic review,

Meta-analysis.

Effect of LDA initiated before 11

weeks of gestation.

1426

7 Moore G.S. et

al.

2015 Secondary

analysis of

MFMU control

trial.

Effect of LDA in the prevention of PE

when starting it before 17w0d of

gestation in high risk woman.

523

8 Bartsch E. et

al.

2015 Experimental

study

Presenting 2 objective approaches to

determine the minimum absolute risk

for PE at which Aspirin prevention is

justified: Minimum control event rate

(CERmin) and Minimum event rate for

treatment (MERT)

9 Cui, Y., Zhu,

B., & Zheng,

F.

2018 Systemic review,

Meta-analysis.

EfficacyofLDAwhenstartedbefore16

weeksofgestaAon.

3.168

21

Table 2: Gestational age and outcomes.

Author Results Interpretation of the results

Meher S.,

Duley L.,

Effect of antiplatelet therapy given before or after

or at 16 weeks of gestation:

PE, relative risk, 0,90, (95% confidence interval,

0,79-1,03):

For <16w, relative risk 0,90 (95% confidence

interval, 0,83-0,98).

For ≥16w (interaction test, P=0,98)

According to the results,

antiplatelet agents reduce the risk

of preeclampsia. There is no

statistical different whether if it is

started before or after 16 weeks

of gestation.

Every women at high risk should

be recommended to start with the

antiplatelet therapy.

Chaemsai

thong P.

et al.

Significant results regarding administration of

LDA to high risk woman, started before 11 weeks

of gestation:

To prevent PE, relative risk 0,52 (95% confidence

interval, 0,23-1,17, P=0,115).

To prevent preterm delivery, relative risk 0,52

(95% confidence interval, 0,27-0,97, P=0.040).

The early administration of LDA

showed no significant impact to

decrease the risk of pre-eclampsia

in women at high risk. However,

it could decrease the risk of

preterm delivery in women at

high risk if it´s administered early

in the pregnancy.

22

Moore

G.S. et

al.

LDA (60 mg/d) or placebo was given to high risk

women prior 17w of gestation. Primary outcomes

was PE at any time of pregnancy; secondary

outcome were early PE (<34w), late PE (>34w),

SGA and composite (early PE or SGA).

Subgroups were CHTN, DM and history of PE in a

previous pregnancy.

Significant results: Primary outcomes:

PE at any time using aspiring or placebo 22,26%

vs 27,52% (P=0,164) respectively.

Significant results: Secondary outcomes:

Late PE using aspirin 17,36% and using placebo

24,42% (P=0,047).

Significant results: subgroups:

CHTN, late PE. Using aspirin 18,28% and using

placebo 31,18% (P=0.041).

History of PE, SGA. Using aspirin 6,41% and

using placebo 14,71% (P=0.1).

From the results we can

conclude:

1.Given aspirin or placebo to

primary outcomes of PE at any

time of the pregnancy shows no

significant differences.

2.Looking at secondary

outcomes, only the rate of late PE

was significant reduced by the

use of aspirin.

3.Subgroup: CHTN. Only has a

significant importance reducing

the risk of late PE.

4.Subgroup: History of PE. The

risk of SGA was reduced

significantly but the difference

did not reach the significance

(P=0,086).

According the results exposed,

we can conclude that it could be

beneficial the use of LDA before

17w of gestation in high risk

women specially those suffering

from CHTN.

23

Table 3: Aspirin dosage.

Cui, Y.,

Zhu, B.,

& Zheng,

F

LDA at ≤16w was associated with a significant

reduction (33%) in the relative risk ratio (RR=0,68,

95% confidence interval, CI=0,57-0,80, P<0.0001)

regardless the time of delivery.

The authors consequently subdivided the results

into 2 groups: preterm and term PE.

Only for preterm PE the use of LDA before 16w

had a significant reduction (65%) in the relative

risk (RR=0,35, confidence interval 95%,

CI=0,13-0,94) but not for term PE (RR=1,01, 95%

confidence interval CI0,60-1,70).

According to the results, we can

conclude that the use of LDA

prior 16 weeks of gestation has a

significant reduction of the risk

of preterm preeclampsia .

Author Results Interpretation of the results

Villa P.M.

et al

PREDO trial results: showed any reduction in the

risk of:

PE (RR= 0,7, 95%, CI 0,3-1,7).

Gestational HT (RR=1,6, 95%, CI 0,6-4,2).

Early PE (RR=0,2, 95%, CI=0,03-2,1).

Severe PE (RR=0,4, 95%, CI=0,1-1,3).

Meta-analysis results:

Reduction in the risk of PE (RR=0,6, 95%,

CI=0,4-0,8)

Reduction in the risk of severe PE (RR=0,3, 95%,

CI=0,1-0,7)

According to the results of the

PREDO trial, we could

conclude that larger studies

were needed in order to

observed the efficacy of the

use of LDA.

The meta-analysis concluded

that LDA started prior 16

weeks of gestation reduces the

risk of both PE and severe

preeclampsia.

24

Rolnik D.E.

et al.

Participants were divided into 2 group: 798 aspirin

group and 822 placebo group. The results were the

following:

Preterm PE occurred in 1,6% of the aspirin group.

Preterm PE occurred in 4.3% of the placebo group.

(RR=0,38, 95%, CI=0,20-0,74, P=0,004).

From the study, we can

conclude that LDA given to

high risk women for preterm

PE resulted in a lower

incidence than placebo group.

Duley L. et

al.

The present meta-analysis was composed with a

total of 77 trials. Aspirin was given from 50mg to

150mg in the large trials.

Results were:

LDA reduced the risk of proteinuric

preeclampsia by 18% (36,716 women, 60 trials,

RR 0,82, 95% CI o,77-0,88).

Reduction of 9% the risk for preterm birth

(<37w) (35,212 women, 47 trials, RR 0,91, 95%

CI 0,87- 0,95).

Reduction by 14% in fetal deaths, neonatal

deaths or death before hospital discharge

(35,391 babies, 52 trials, RR 0,85, 95% CI 0,76-

0,95).

Slightly reduces the risk of SGA (35,761 babies,

50 trials, RR 0,84, 95% CI 0,76- 0,92).

Reduction in the risk pregnancies with severe

outcomes (17,382 women, 13 trials, RR 0,90, 95%

CI 0,85- 0,96).

Slightly increased postpartum haemorrhage

>500 mL (23,769, 19 trials, RR 1,06, 95% CI

1.00-1.12).

From the present large meta-

analysis, we could conclude

that LDA aspirin is a safe

agent to prevent PE. Serious

outcomes were absent after its

usage during pregnancy and

only a slightly increased in

postpartum haemorrhage was

observed.

We also could conclude that

aspirin has a beneficial effect

in the mother and in the baby.

It reduces the risk of PE,

preterm birth and SGA. It also

reduces the risk of fetal death,

neonatal death and death

before hospital discharge. And

decreases the risk of

pregnancies with serious

adverse outcome.

25

Bartsch E.

et al.

According to approaches the author objectively

determines the minimum absolute risk for Peat

which ASA prophylaxis is justified.

First approach is known as CERmin (Minimum

Control Event Rate).

The equation which they present is the following:

CERmin= TER + [DC/QALYs gained x $50000]

*TER: Treatment event rate

*DC: Direct cost of the treatment for one patient

*QALYs gained: number of quality adjusted life

years gained by avoiding one target event.

The author assumes a DC of ASA of $10 per

pregnancy.

Under the reality that ASA is cheap, the author saw

that the TER very closely approximated to CERmin

for even a small QALYs gain.

If ASA would be an expensive drug, the

availability of this drug would be reserved for few

women.

Second approach is known as MERT (Minimum

Event Rate for Treatment).

The equation presented is the following:

MERT= 1/ (NNPT x RRR)

*NNPT: Number needed to treat

*RRR: Relative risk ratio

As it was expected, the MERT is highest when

NNPT is lowest. But also the MERT declines by

increasing the RRR (indicating a greater efficacy

of aspirin).

From this scientific research,

few conclusions had been

made.

First of all, due the efficacy of

aspirin preventing PE, it´s

given to women that may not

need to take antiplatelet drugs.

The author considers that is

necessary to stablish an

absolute risk ratio at which

prophylaxis is indicated.

The equations could provide to

the physicians more specific

information to detect the right

women in whom ASA

prophylaxis is warrant.

Moreover, the author

suggested that eligible women

need not be at high risk for PE,

but rather, at some modestly

elevated level.

To conclude:

Due to its very low cost,

worldwide availability and

safety profile, antiplatelet

agents seems to be a great

agent for the prevention of PE.

26

Roberge S.

et al.

The following study compares the use of LDA and

its effect if it started before or after 16 weeks of

gestation. Also analyzes the concept of dose-

dependent effect.

Results were:

Preeclampsia < 16w (RR 0,57, 95% CI 0,43- 0,75)

and >16w (RR 0,81, 95% CI 0,66-0,99).

Severe preeclampsia <16w (RR 0,47, 95% CI

0,26- 0,83) and >16w (RR 0,85, 95% CI

0,64-1,14).

FGR <16w (RR 0,56, 95% CI 0,44-0,70) and

>16w (RR 0,95, 95% CI 0,86-1,05).

Dose-response effect: when started <16w (R2 44%,

P=0,036) and >16w (R2 0%, P=0,941).

From the results, we can

conclude that LDA when

started before to 16 weeks of

pregnancies has a significant

reduction in PE and a dose-

response effect, severe

preeclampsia and fetal growth

restriction.

When started after 16 weeks of

gestation, there is a small

reduction in PE and no dose-

response effect. No reduces

the risk of severe PE and fetal

growth restriction.

27

DISCUSSION OF THE RESULTS

It is a certainty that aspirin is one of the most widely used medications for the prevention of

cardiovascular diseases. Due to its properties (anti-platelet formation, anti-inflammatory, analgesic and

anti-pyretic) and its mechanism of action (inhibits the synthesis of prostaglandins by irreversibly

inhibiting COX-1 And COX-2), aspirin manages to neutralice many processes that could be harmful for

the human body.

Due to its very low cost, great availability worldwide and its easy form of administration, aspirin is one of

the most attractive agents for the prevention of maternal and perinatal mortality.

The administration of aspirin in people at high risk for PE is discussed in all studies reviewed in this

paper. According to more recent studies, any women presenting with clinical factors (maternal

characteristics and risk factors, mean ABP), abnormal imaging tests (uterine artery Doppler to determine

the pulsatility of the uterine arteries) and elevated biochemical markers (PIGF and PAAP-A) would be

considered a high risk person.

In order to early detect these group of high-risk women it could be convenient to, first of all, perform

epidemiological studies and cost-benefit studies for the assessment of, second of all, to carry out massive

screening tests on all pregnant women who have few or many risk factors in order to identify high risk

patient early in pregnancy and, consequently, decrease the incidence of PE.

Most articles reviewed in this paper describe that aspirin is beneficial if it is administered before the 16th

weeks of gestation. These results could indicate that aspirin does indeed help the placentation process, a

process which takes place during the first weeks of pregnancy which are the most important weeks in the

development of a good circulation network to the embryo. However, any study indicates the exact moment

when the treatment should begin.

Likewise, there are few data that we have regarding when experts should stop administering aspirin. The

FIGO guidelines March 2019 recommend to stop aspirin at 37 weeks of gestation or 2 weeks before a

planned early delivery. As much as if we use aspirin beyond 37 week of gestation or if we stop

28

administering before 37 week of gestation and its respective benefit or ham, are two uncertain points

nowadays.

Low-dose aspirin has been found to reduce the incidence rate of PE and its benefit is dose-dependent. The

exact dose is yet to be determined, although many authors point to the administration of aspirin at

150mg/d as the most recommended dose and widely used to decrease the incidence rate.

Most studies indicate that LDA is safe for both during pregnancy and the postpartum period and only in

the article published by Duley L. et al. is described that LDA causes a slightly increase percentage of

postpartum bleeding risk of more than 500ml.

By contrast, the use of high-dose aspirin (>500mg/d) has been shown to have a teratogenic effect and,

therefore, due to its poor risk-benefit ratio would be ruled out for the preventive use of PE.

29

CONCLUSIONS

According to the scientific literature, with presented studies, several conclusions can be established:

1. Aspirin should be offered to women at high risk of PE.

2. The use of LDA has shown to be more effective if it is started before 16 weeks of gestation.

3. Most of the studies concluded that LDA (50-150 mg/d) reduces the risk of PE, severe PE, FGR and

maternal perinatal mortality. It has a dose-response effect, meaning that the efficacy of aspirin

grows as the dose increases.

30

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