Keywords pregnancy - preeclampsia - aspirin - systematic review - meta-analysis
Preeclampsia, which affects 2 to 8% of pregnancies, is a major cause of maternal and
perinatal morbidity and mortality.[1 ]
[2 ] It is usually defined as hypertension and proteinuria that occur at or after 20
weeks' gestation in women with previously normal blood pressure. The disease is considered
to be severe when it is associated with liver damage, thrombocytopenia, fetal growth
restriction (FGR), and symptoms such as headache, visual disturbance, and right upper-quadrant
pain.[3 ] However, published reports use differing criteria for the diagnoses of preeclampsia
and severe preeclampsia. A growing body of evidence suggests that severe and mild
preeclampsia develop from two distinct pathophysiological processes. Women with preterm
preeclampsia are at higher risk of severe preeclampsia and eclampsia, and their adverse
consequences.[4 ]
[5 ]
[6 ]
[7 ]
Bujold et al found that low-dose aspirin initiated at or before 16 weeks' gestation
could prevent ~50% of preeclampsia and 55% of FGR.[8 ] It has been suggested that low-dose acetylsalicylic acid therapy inhibits thromboxane
more than prostacyclin production and thereby protects against vasoconstriction and
pathological blood coagulation in the placenta.[9 ] The use of low-dose aspirin given in early pregnancy has been associated with improvement
of uterine artery blood flow resistance, suggesting a greater remodeling of the spiral
artery.[10 ]
[11 ] Therefore, we hypothesized that low-dose aspirin could be more effective in the
prevention of severe preeclampsia than in the prevention of mild disease. We performed
a systematic review and meta-analysis of randomized controlled trials (RCTs) that
evaluated the benefits of low-dose aspirin prophylaxis started before 16 weeks' gestation
in the prevention of severe preeclampsia.
Methods
Sources
Keywords and MeSH terms “aspirin,” “antiplatelet,” “salicy*,” “ASA,” “pregnancy-complication,”
“hypertens*,” “blood press*,” “*eclamp*,” “PIH,” “toxaemi*,” “IUGR” were combined
for electronic databases search. Relevant citations were extracted from Embase, PubMed,
the Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science from
1965 to October 2011. No language restriction was imposed. All articles were sorted
by the first reviewer (S.R.) for more detailed evaluation. Citation and abstract were
retrieved for the second sort and was reviewed by two reviewers (S.R., E.B.). All
relevant trials were entirely reviewed by the same two reviewers. Other systematic
reviews were used for additional search.[12 ]
[13 ]
[14 ] Quality and integrity of this review were validated with PRISMA (preferred reporting
items) for systematic reviews and meta-analyses.[15 ]
Study Selection
This meta-analysis includes only prospective, randomized, controlled trials. The population
in the studies involved pregnant women at risk of preeclampsia treated with low-dose
aspirin initiated at or before 16 weeks of gestation. No restrictions were applied
to risk criteria for preeclampsia. Low-dose aspirin was defined as 50 to 150 mg of
acetylsalicylic acid daily, alone or in combination with 300 mg of dipyridamole or
less, another antiplatelet agent. The control group had to be allocated to placebo
or no treatment. Studies' qualities were evaluated using Cochrane Handbook Criteria
for judging risk of bias tool, and studies with high risk of bias were considered
for exclusion.[16 ]
Outcomes
The primary outcome was the occurrence of severe or mild preeclampsia. The American
College of Obstetricians and Gynecologist defines preeclampsia as blood pressure of
140 mm Hg systolic or higher or 90 mm Hg diastolic or higher that occurs after 20
weeks of gestation in a woman with previously normal blood pressure plus proteinuria,
defined as urinary excretion of 0.3 g protein or higher in a 24-hour urine specimen.[17 ] Severe preeclampsia is diagnosed if, in addition to the above criteria, one or more
of the following criteria is present: sustained (at least 6 hours) systolic blood
pressure of at least 160 mm Hg, or sustained diastolic blood pressure of at least
110 mm Hg, severe proteinuria 5 g or higher protein in 24 hours, or 3+ on dipstick),
oliguria of less than 500 mL in 24 hours, cerebral or visual disturbances, pulmonary
edema or cyanosis, epigastric or right upper-quadrant pain, impaired liver function,
thrombocytopenia, FGR.[17 ] However, as the definition of severe preeclampsia varies between countries; we accepted
all definitions that we considered similar. When data regarding severe preeclampsia
were not provided, we contacted the corresponding author or first author for additional
information. When not specifically provided, the number of mild preeclampsia was calculated
as the cases of all preeclampsia minus the cases of severe preeclampsia.
Statistical Analysis
Studies were combined and analyzed with Review Manager 5.0.25 (The Nordic Cochrane
Centre, The Cochrane Collaboration, Copenhagen, Denmark) software. Individual risk
ratios (RRs) were calculated for each study, and pooled for global analysis with 95%
confidence intervals (CIs). Analysis of preeclampsia was divided into severe preeclampsia
and mild preeclampsia. Global RR was calculated according to DerSimonian and Laird
random effect models in case of heterogeneity.[18 ]
[19 ] Heterogeneity between studies was analyzed using the Higgins' I2 .[20 ] The distribution of trials was examined with funnel plots to assess publication
bias.[21 ]
Results
The literature search identified 7941 potentially eligible studies, and 352 were reviewed
([Fig. 1 ]). The inclusion criteria were met by 15 studies but only four were included (392
women) for the final analysis because information on severe and mild preeclampsia
were available. In three studies, women randomized to the control received placebo,[11 ]
[22 ]
[23 ] and in the fourth study, they received no treatment ([Table 1 ]).[24 ]
Table 1
Characteristics of Included Studies
First Author, Year
Gestational Age at Initiation of Treatment (wk)
Participants (n )
Inclusion Criteria
Intervention
Definition of Preeclampsia
Criteria for Severe Preeclampsia
August, 1994[22 ]
13–15
49
Chronic hypertension or previous severe preeclampsia
ASA 100 mg vs placebo
Rise of 30 mm Hg of SBP and 15 mm Hg of DBP with proteinuria and hyperuricemia or
HELLP syndrome
Severe disease necessitating premature delivery
Ebrashy, 2005[24 ]
14–16
136
Abnormal uterine artery Doppler and risk factors for preeclampsia and intrauterine
growth restriction
ASA 75 mg vs no treatment
SBP ≥140 and DBP ≥90 mm Hg with proteinuria >300 mg/d
SBP reached 160 mm Hg, DBP reached 110 mm Hg, proteinuria reached 2 g in 24-h urine
sample, urine output was <500 mL/d, platelet count was <100,000 per mm3 , and liver enzymes were increased
Vainio, 2002[11 ]
12–14
86
Anamnestic risk factor with abnormal uterine Doppler
ASA 0.5 mg/kg/d vs placebo
SBP ≥140 and DBP ≥90 mm Hg with proteinuria ≥300 mg/d
Birth weight <10th percentile
Villa, 2010[23 ]
13–14
121
Anamnestic risk factor with abnormal uterine Doppler (bilateral second-degree uterine
artery notch)
ASA 100 mg vs placebo
BP ≥140/90 in consecutive measurements and proteinuria ≥0.3 g/24 h
BP ≥160 systolic and/or ≥110 diastolic and/or proteinuria ≥5 g/24 h
ASA, acetylsalicylic acid; BP, blood pressure; DBP, diastolic blood pressure; HELLP
syndrome, hemolysis, elevated liver enzymes, and low platelet count; SBP, systolic
blood pressure.
Figure 1 Flow diagram showing the selection process of articles. ASA, acetylsalicylic acid.
Administration of aspirin initiated at or before 16 weeks' gestation was associated
with a significant reduction in the risk of overall preeclampsia (RR: 0.52, 95% CI:
0.38 to 0.76, p < 0.01) and severe preeclampsia, but not mild preeclampsia ([Table 2 ] and [Figs. 2 ] and [3 ]). The eight studies that were not included in the meta-analysis because of unavailable
data regarding severe/mild preeclampsia but where the overall rate of preeclampsia
was reported demonstrated a similar effect of aspirin on preeclampsia (RR: 0.22, 95%
CI 0.10 to 0.46, p < 0.01).[25 ]
[26 ]
[27 ]
[28 ]
[29 ]
[30 ]
[31 ]
[32 ]
Figure 2 Forest plot of the effect of low-dose aspirin initiated at or before 16 weeks' gestation
on the prevalence of severe preeclampsia. ASA, acetylsalicylic acid; CI, confidence
interval; DPI, dots per inch; M-H, Mantel-Haenszel.
Figure 3 Forest plot of the effect of low-dose aspirin initiated at or before 16 weeks' gestation
on the prevalence of mild preeclampsia. ASA, acetylsalicylic acid; CI, confidence
interval; DPI, dots per inch; M-H, Mantel-Haenszel.
Table 2
Relative Risk of Severe Preeclampsia and Mild Preeclampsia Associated with the Use
of Low-Dose Aspirin at or Before 16 Weeks' Gestation
Outcomes
Prevalence of the Outcomes (%)
Relative Risk (95% Confidence Intervals)
p Value
I2
Aspirin
Controls
Severe preeclampsia
2.0
12.6
0.22 (0.08, 0.57)
<0.001
0%
Mild preeclampsia
16.9
22.0
0.81 (0.33, 1.96)
0.63
49%
In the included studies, the homogeneity for the reduction in the relative risk of
severe preeclampsia was high (I2 : 0%), whereas the homogeneity for the effect on the relative risk of mild preeclampsia
was moderate (I2 : 49%). Random model was used for both outcomes because heterogeneity between studies
including the same population was present for at least one outcome. Analysis of the
funnel plot was precluded because of the small number of included studies. According
to Cochrane Handbook Criteria for judging risk of bias tool, all studies were judged
to have low or unclear risk of bias.[16 ]
Discussion
The results of this meta-analysis, which includes the results of one additional RCT
to those provided in our previous report,[8 ] is in complete agreement with the results of our previous report demonstrating a
major beneficial effect of early onset, low-dose aspirin in halving the overall risk
of preeclampsia, and this effect was particularly marked in the case of severe preeclampsia
whose relative risk was reduced by ~90%. In contrast, the use of aspirin was not associated
with a significant reduction in the relative risk of mild preeclampsia.
One likely explanation for a high effectiveness of early onset, low-dose aspirin in
the prevention of severe preeclampsia but not of mild disease is that the pathophysiology
of the two conditions is different and only the former is susceptible to the effects
of aspirin. There is supportive evidence from Doppler ultrasound studies that in a
high proportion of cases of severe preeclampsia with associated FGR, unlike cases
of mild disease without FGR, impedance to flow in the uterine arteries is increased.[33 ] Such increased impedance to flow is thought to be a consequence of inadequate trophoblastic
invasion of the maternal spiral arteries and their conversion from narrow muscular
vessels to wide nonmuscular channels.[34 ]
It is possible that early onset, low-dose aspirin improves placentation and, therefore,
reduces the risk of severe preeclampsia. An alternative explanation for our findings
is that in all cases of preeclampsia there is impaired placentation, but a spectrum
of placental impairment is reflected in the severity of the clinical manifestations
of the disease. In this case, the beneficial effect of aspirin on placentation could
actually reduce substantially the risk of those cases that were destined to develop
mild preeclampsia and convert the predestined severe to mild preeclamptic cases.
The main weaknesses of our study are the small number of studies included in the analysis
and the heterogeneity in the definition of severe preeclampsia. Because most of the
studies potentially eligible were completed before 2000, the primary data are no longer
available for accurate classification of severity. This is especially true as current
definitions of severe preeclampsia perform poorly in identifying true incremental
risk of either adverse maternal or adverse perinatal outcomes.[35 ] However, the diagnosis of preeclampsia remains more reliable when combined with
severity criteria, and this could be another reason for our findings because the diagnosis
of mild preeclampsia can be considered more subjective.
Our meta-analysis is also limited by the absence of very large trials. The six largest
trials that evaluated the impact of low-dose aspirin in preeclampsia recruited women
after 16 weeks' gestation.[36 ]
[37 ]
[38 ]
[39 ]
[40 ]
[41 ] The absence of studies showing no beneficial effects in the funnel plot suggests
the possibility of publication bias. Moreover, the small number of studies that reported
the prevalence of severe preeclampsia and/or preterm preeclampsia precludes the interpretation
of funnel plots for those outcomes. However, the great homogeneity of the results
between the studies included in our meta-analysis for severe preeclampsia suggests
a good validity of our findings. Two eligible studies were excluded because they did
not report the cases of mild preeclampsia, preventing the comparison between severe
and mild disease.[26 ]
[27 ] However, adding those studies to the analysis would have only strengthened the association
of low-dose aspirin and risk reduction of severe preeclampsia (six studies, RR: 0.18,
95% CI: 0.08 to 0.41). These two studies were included in the eight studies that did
not differentiate between mild and severe preeclampsia and therefore could explain
the important effect of aspirin found in that subgroup.
Our meta-analysis included studies that recruited women at high risk for preeclampsia
using a wide variety of inclusion criteria, and the majority of the women had a previous
history of preeclampsia. We believe that definitive trials are required to determine
whether low-dose aspirin can prevent the adverse maternal and perinatal consequences
of severe preeclampsia in high-risk women who may be identified through predictive
screening programs.[42 ]
[43 ]
[44 ]
[45 ] Such trials should consider evaluating the role of aspirin resistance combined,
or not, with adjustment of aspirin dosage.[42 ]
[46 ]
[47 ]
[48 ] Based on the current study, such large-scale trials should aim to decrease the risk
of the adverse maternal and perinatal outcomes associated with severe rather than
mild preeclampsia.
In conclusion, our meta-analysis confirms that low-dose aspirin initiated between
7 and 16 weeks' gestation is associated with a significant reduction in severe preeclampsia,
in a population of women identified at high risk for preeclampsia.
