In preeclampsia, platelet TXA2 increases significantly, whereas prostacyclin drops sharply. This imbalance is present from 13 weeks of gestation in patients at high risk [
43]. TXA2/PGI2 imbalance can be reversed by 2 weeks of treatment with low-dose aspirin [
44], which inhibits TXA2 secretion, and thus platelet aggregation [
44], without altering secretion of endothelial prostacyclin (PGI2) [
27], thereby favoring systemic vasodilatation.
More recent understanding of the influence of angiogenic factors on placental hemodynamics during pregnancy has led to assessment of the effect of aspirin on the secretion of these factors in the human placenta. In hypoxic conditions, aspirin inhibits the expression of sFlt-1 in human trophoblasts, and thus shows proangiogenic activity [
45]. sFlt-1 is the soluble form of the VEGF receptor, which, in binding to circulating placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF), behaves as a potent anti-angiogenic factor [
46]. sFlt-1 is present at high levels in the circulation of patients with preeclampsia and is responsible for the angiogenic imbalance seen in the pathogenesis of preeclampsia [
46,
47].
4.1 History of the Use of Aspirin
The early 1950s were marked by numerous studies showing that aspirin effectively prevents cardiovascular disease [
48]. The first evidence of the obstetrical efficacy of aspirin was noted in 1985 by Beaufils et al. [
49], in a randomized study of preventive treatment with aspirin in 102 patients at high risk of preeclampsia and/or intrauterine growth restriction [
49]. The prevalence of preeclampsia was significantly reduced in the aspirin group compared with the untreated group (0/48 vs 6/45
p < 0.05). These findings were welcomed by the scientific community, thus starting the golden age of the prevention of placental vascular disease by aspirin. Numerous randomized, double-blind trials subsequently assessed the efficacy of aspirin in these indications, notably in 1991, when the EPREDA trial showed a beneficial effect of aspirin in the secondary prevention of intrauterine growth restriction [
50].
Between 1992 and 2001, prescriptions of aspirin soared and its indications in obstetrical practice multiplied. Numerous studies were published, using aspirin in patients considered as presenting risk factors, with gestational age at inclusion and dosages varying greatly between studies. The effect measured was clearly less than expected. In 1994, an attempt was made in the randomized CLASP trial to harmonize clinical practices and inclusions [
51]. In a subsequent double-blind randomized trial, Caritis et al. found no benefit of the prescription of 60 mg of aspirin from 13–26 weeks of gestation [
52]. However, the indications used by Caritis et al. for the prescription of aspirin were very broad, and covered patients with diabetes before conception, chronic hypertension, multiple pregnancy, and gestational age > 20 weeks at the start of aspirin treatment in over 50% of randomized patients [
49].
The golden age of aspirin treatment for obstetrical indications in daily practice was thus questioned. It was not until 2001 that a meta-analysis of the efficacy of aspirin in the prevention of preeclampsia in high-risk patients [
53] showed that low-dose aspirin (60–160 mg) reduced the risk of preeclampsia by 15% without changing the incidence of intrauterine growth restriction. The significant benefit of the prescription of low-dose aspirin was clearly below that suggested by early studies. Analysis of individual patient data was necessary to define the indications and a group of at-risk patients in the context of relevant medical indications [
53]. A 2007 meta-analysis by Askie et al. [
5], published by Duley et al. [
54] in the Cochrane database, included over 37,000 patients in 59 trials assessing aspirin in primary and secondary prevention [
54]. The analysis showed a significant but modest reduction of 10% [relative risk (RR) 0.90; 95% CI 0.84–0.97] in the risk of preeclampsia, a 10% decrease in the risk of delivery before 34 weeks of gestation (RR 0.90; 95% CI 0.83–0.98), and a 10% reduction in the risk of unfavorable outcome (RR 0.90; 95% CI 0.85–0.96) (Table
1). Askie et al. noted a more marked benefit when aspirin treatment started before 20 weeks of gestation (RR 0.87; 95% CI 0.79–0.96) and when the dosage was ≥ 75 mg/day (RR 0.77; 95% CI 0.61–0.97) [
5]. So, the benefit demonstrated was lost when aspirin was introduced at ≥ 20 weeks of gestation (RR 0.95; 95% CI 0.85–1.06) or at doses ≤ 75 mg (RR 0.95; 95% CI 0.92–0.99) (Table
2) [
5].
Table 1
Principal maternal and fetal events—Askie et al. [
5]
Reduction in the risk of preeclampsia | 0.90 (0.84–0.97)* | 167 (104–556) |
Risk of delivery < 34 WG | 0.90 (0.83–0.98)* | 100 (59–500) |
Risk of unfavorable outcome | 0.90 (0.85–0.96)* | 67 (44–167) |
In utero fetal death | 0.91 (0.81–1.03) | – |
Small for gestational age | 0.90 (0.81–1.01) | – |
Table 2
Effect of aspirin according to dosage and gestational age at the start of treatment, according to Askie et al. [
5]
Gestational age < 20 weeks | 0.87 | 0.79–0.96 |
Gestational age ≥ 20 weeks | 0.95 | 0.85–1.06 |
Dose of aspirin ≤ 75 mg | 0.95 | 0.92–0.99 |
Dose of aspirin > 75 mg | 0.77 | 0.61–0.97 |
Caron et al. in 2009 reported a dose-dependent effect of aspirin in pregnant women, thus confirming the association of an optimal dose for the measurement of a real clinical effect [
29].
In view of the large number of patients and the availability of individual patient data in this meta-analysis, it was possible to analyze the efficacy of aspirin in subgroups. Aspirin did not reduce preeclampsia when prescribed because of certain risk factors, like nulliparity, chronic hypertension before pregnancy, diabetes before conception, age > 35 years, twin pregnancies, and history of a small-for-gestational-age infant (Table
3). This meta-analysis is currently the most important because it is the only one performed with individual patient data.
Table 3
Subgroup analysis: risk of preeclampsia Askie et al. [
5]
Nulliparity | 0.90 (0.76–1.08) |
Multiparity with high risk factor | 0.89 (0.81–0.99) |
Hypertension before conception | 0.97 (0.84–1.12) |
Diabetes before conception | 0.76 (0.56–1.04) |
Nephropathy before conception | 0.63 (0.38–1.06) |
History of small-for–gestational-age infant | 1.05 (0.86–1.28) |
Age > 35 years | 1.02 (0.83–1.26) |
Twin pregnancy | 0.85 (0.61–1.18) |
Between 2007 and 2010, a multitude of contradictory studies and controversial conclusions prompted Bujold et al. to publish in 2010 a meta-analysis of 34 double-blind randomized trials measuring the effect of low-dose aspirin on the incidence of preeclampsia and intrauterine growth restriction [
55]. Their findings were in accord with those of Askie et al. [
5], but suggested a greater beneficial effect, especially when aspirin was started before 16 weeks of gestation (RR 0.47; 95% CI 0.34–0.65) in high-risk patients. This effect was no longer significant when the treatment was started after 16 weeks of gestation (RR 0.81; 95% CI 0.65–1.03). In the cohort of Askie et al., the patients who had early treatment mostly received it between 18 and 20 weeks of gestation, which explains the measurement bias referred to by Bujold et al. [
55]. Considering that data are limited because of an inability to place women in the correct gestational age subgroup from relevant trials, Askie conducted an individual data analysis published in 2017. The aim of the study was to assess whether the treatment effects of antiplatelet agents on preeclampsia and its complications vary based on whether treatment is started before or after 16 weeks of gestation [
56]. Their results showed no significant difference in the effects of antiplatelet therapy for women randomized before 16 weeks of gestation (0.90; 95% CI 0.79–1.03) compared with those randomized at or after 16 weeks (0.90; 95% CI 0.83–0.98). The effect of low-dose aspirin on preeclampsia and its complications was consistent, regardless of whether treatment is started before or after 16 weeks of gestation [
56].
As for the risk of intrauterine growth restriction, Bujold et al. [
55] found a risk reduction of 56% in patients at high risk when the treatment was started before 16 weeks of gestation (RR 0.44; 95% CI 0.30–0.65). After 16 weeks, the risk reduction was not significant and virtually nil (RR 0.98; 95% CI 0.87–1.10) [
55]. The problem with meta-analysis without individual patient data is that subgroup analysis may be affected by several biases. Therefore, the most reliable meta-analysis remains the one published by Askie and colleagues.
The debate on the indications for aspirin in the prevention of preeclampsia was reopened in 2014 by the US Preventive Services Task Force (USPSTF) evidence review [
57], which was designed to update the 2002 American Congress of Obstetricians and Gynecologists (ACOG) guidelines [
58]. The efficacy of low-dose aspirin in the prevention of preeclampsia in high-risk patients, and in reduction of perinatal adverse events, was reviewed in order to update clinical practices and obstetrical prescriptions [
57]. All trials included in the review exclusively considered the traditional definition of preeclampsia. The recommendations were above all based on the latest meta-analyses, which did not use individual patient data or allow specific study of the effect of aspirin as a function of the risk factors presented by patients (Table
4). However, the recommendations were formulated as a function of these different risk factors and the USPSTF recommended broad prescription of aspirin in patients with a high-risk factor for preeclampsia and in patients with at least two intermediate risk factors.
Table 4
Meta-analysis and effect of aspirin—after Werner et al. [
59]
| 36 | 34,288 | 0.9 (0.84–0.97) |
| 39 | 37,560 | 0.83 (0.77–0.89) |
| 34 | 11,348 | 0.47 (0.34–0.65)a
0.81 (0.63–1.03)b
|
Henderson et al. [ 57, 62] | 23 | 12,184 | 0.76 (0.62–0.95) |
In the ensuing debate, some scientific and obstetrical experts noted that the USPSTF recommendations had moved away from the ACOG guidelines. Sibai et al. [
60] highlighted that platelet inhibitors are advocated in patients with chronic hypertension, chronic nephropathy, or diabetes, a recommendation not made in previous publications or national recommendations [
60]. In parallel, a 2015 socioeconomic study noted that wide-ranging prevention in line with USPSTF recommendations would be more cost-effective in terms of reduced induction of prematurity and maternal morbidity [
59]. The same study showed that the USPSTF recommendations would lead to the use of low-dose aspirin in 27.6% of pregnant women. These recommendations were followed by comments highlighting an unreasonable massive prescription of aspirin [
60].
Current national guidelines on prevention of preeclampsia vary greatly: some are based on targeted indications in secondary prevention in cases of preeclampsia in a previous pregnancy (ACOG in the USA, Société Française de l’Hypertension Artérielle in France), others extend the indications as a function of the patients’ risk factors (NICE, USPSTF, RANZCOG, SOGC). Table
5 summarizes the guidelines of various learned societies.
Table 5
Prescription of low-dose aspirin according to learned societies
France SFHTA CNGOF | Yes | ± | Yes | No | No | No | No | No |
USA USPSTF | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
USA ACOG | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes |
Canada SOGC | Yes | Yes | Yes | Yes | Yes | Yes | ± | ± |
United Kingdom NICE | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Australia New Zealand RANZCOG | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No |
4.2 Early Detection of Preeclampsia
Timely detection of preeclampsia has been a major challenge in perinatal research for over 50 years. In 1947, Kraver et al. attempted to predict the onset of preeclampsia by the cold pressor test or Hines-Brown test, by studying maternal cardiovascular changes following immersion of the hand in ice-cold water [
67]. The last 20 years have seen extensive research on clinical parameters, biophysical markers (Doppler indices), and various early biochemical markers that reflect impaired placentation [
68‐
72]. Numerous tests were subsequently proposed for detection of preeclampsia in the first trimester, but were of insufficient sensitivity and/or gave too many false-positive results for use in clinical practice. In 2007, Plasencia et al. confirmed that Doppler ultrasound before 16 weeks of gestation in the prediction of preeclampsia is of highly questionable utility. For a 10% false-positive rate, Doppler ultrasound had an insufficient detection rate of 41.1% [
73]. Moreover, the PREDO trial tested the effect of aspirin versus placebo in the prediction of preeclampsia in women with abnormal uterine artery Doppler flow velocimetry and no significant difference was found [
74]. The first study that really opened the way to early detection of preeclampsia was published in 2009 by Poon et al. [
75] of the Fetal Medicine Foundation (FMF), who proposed an algorithm for estimation of the risk of preeclampsia on the basis of maternal demographics, medical and obstetrical history, pulsatility index of the uterine arteries, mean blood pressure, and maternal serum levels of PlGF and pregnancy associated plasma protein A (PAPP-A) between 11 and 13 weeks of gestation. This test identified 91% cases of early and severe preeclampsia, with a 10% false-positive rate. In contrast, the test was poorly predictive of moderate preeclampsia and gestational hypertension. The Poon et al. study [
75] was subject to potential bias, notably in the constitution of the control group of the nested case–control analysis, which could have led to overestimation of the efficiency of the algorithm.
Several other studies in large prospective cohorts subsequently focused on algorithms predictive of preeclampsia, but the results were disappointing [
68‐
71]. Oliveira et al. [
76,
77] in 2014 also discussed the limited external validity of these different tests, calling into question their application to the general population [
76,
77]. The performance of the algorithms in the new population was indeed significantly poorer than in the original population. The sensitivity of the test proposed by Poon et al., initially given as 95%, was 52% in the at-risk population tested by Oliveira et al. [
76,
77]. The FMF algorithm is, however, the most studied and its performance in a population of 35,948 patients was in line with the findings of Poon et al. [
75]. The estimated area under the curve of the test was 0.907, with 89% sensitivity, and a 10% false-positive rate in the prediction of early preeclampsia [
78].
4.3 The ASPRE (Aspirin for Evidence-Based PREeclampsia Prevention) Trial
To study the use of the FMF algorithm in clinical practice, the ASPRE trial was designed to propose aspirin as a treatment for primary prevention of preeclampsia in all patients considered to be at high risk following first-trimester combined screening. This multicenter, double-blind, randomized, placebo-controlled trial evaluated the effect of prophylactic low-dose aspirin administered in the first trimester of pregnancy on the incidence of delivery with preeclampsia before 37 weeks of gestation in patients at high risk. The secondary objectives were to study the effects of aspirin on the incidence of early (delivery before 34 weeks of gestation) preeclampsia, the incidence of intrauterine growth restriction, fetal death, perinatal death, admission to neonatal intensive care, a composite measure of neonatal morbidity and mortality and placental abruption [
79].
The risk cut-off used in this study was 1/100, which corresponds to about 10% of pregnant women. Patients considered at high risk were randomized to either a group given aspirin (150 mg per day, taken at bedtime) or a group given a placebo. Treatment was started in the first trimester (between 11 and 14 weeks of gestation) and continued to 36 weeks of gestation [
79].
Testing was offered to 26,941 pregnant women, 2641 of whom were at high risk of preeclampsia and eligible for inclusion. Among the patients included, 1776 were randomized to aspirin or a placebo. The occurrence of preterm preeclampsia (< 37 weeks) was significantly reduced by aspirin (0.38; 95% CI 0.20–0.74;
p = 0.004). Preterm preeclampsia occurred in 13 of 798 participants (1.6%) in the aspirin group, as compared with 35 of 822 (4.3%) in the placebo group [
79]. The effect of preeclampsia was more pronounced in nulliparous women (OR 0.27; 95% CI 0.11–0.65). There was no significant difference in the incidence of preeclampsia after 37 weeks (OR 0.95. 95% CI 0.57–1.57), small for gestational age with or without preeclampsia, placental abruption and spontaneous delivery with or without preeclampsia [
79]. Moreover, there was no difference in the incidence of preterm preeclampsia in multiparous women with or without a history of preeclampsia (OR 0.5; 95% CI 0.08–3.09 and 0.79; 95% CI 0.22–2.88, respectively). In this study, the dose of 150 mg of aspirin per day was selected on the basis of previous evidence of a dose-dependent benefit [
80]. Inclusion criteria contained a high risk (> 1 in 100) for preterm preeclampsia according to the screening algorithm. Interestingly, the incidence seemed to be significantly reduced only in women with an estimated risk for preterm preeclampsia ranging between 1 in 10.1 and 1 in 50 (OR 0.33; 95% CI 0.13–0.84) [
79]. Further studies considering this threshold (> 1 in 50) may refine the estimated high risk of preterm preeclampsia.
This study raises several questions. Is screening of preeclampsia based on the FMF algorithm more effective than current national guidelines (NICE, ACOG, etc.)? This question is the subject of an ongoing study in the UK (SPREE study) [
81]. Meanwhile, the results from the ASPRE study suggest that a large number of patients need to be screened in order to avoid one case of preeclampsia [
82]. In the ASPRE study, 25,797 patients were included and 630 developed preeclampsia. Aspirin was associated with a reduction of 21 cases of preterm preeclampsia. Therefore, to avoid one case of preterm preeclampsia, 1228 patients must be screened and nearly 10% of the population must be treated with aspirin. A medical economics study is also needed to evaluate the cost effectiveness of such prevention. We believe that more data are needed before implementing first-trimester screening of preeclampsia in real practice and before modification of national guidelines.