Lithuanian University of Health Sciences Faculty of Medicine

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

TABLE OF CONTENTS

Aim and objectives………..……….…9

SUMMARY

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

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

ABBREVIATIONS

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

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.

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].

AIM AND OBJECTIVES

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;

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].

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.}

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].

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

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:

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].

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.

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].

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].

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´.

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)

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)

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).

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).

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.

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

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

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

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:

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.

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.

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.

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.

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