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Prevention of Preeclampsia and Intrauterine
Growth Restriction With Aspirin Started in
Early Pregnancy
A Meta-Analysis
Emmanuel Bujold, MD, MSc, Stéphanie Roberge, MSc, Yves Lacasse, MD, MSc, Marc Bureau, MD,Franc¸ois Audibert, MD, MSc, Sylvie Marcoux, MD, PhD, Jean-Claude Forest, MD, PhD,and Yves Gigue re, MD, PhD OBJECTIVE: To estimate the effect of low-dose aspirin
TABULATION, INTEGRATION, AND RESULTS: Thirty-
started in early pregnancy on the incidence of pre-
four randomized controlled trials met the inclusion cri-
eclampsia and intrauterine growth restriction (IUGR).
teria, including 27 studies (11,348 women) with follow-up
DATA SOURCES: A systematic review and meta-analysis
for the outcome of preeclampsia. Low-dose aspirin
were performed through electronic database searches
started at 16 weeks or earlier was associated with a
(PubMed, Cochrane, Embase).
significant reduction in preeclampsia (relative risk [RR]
0.47, 95% confidence interval [CI] 0.34 – 0.65, prevalence
METHODS OF STUDY SELECTION: Randomized con-
in 9.3% treated compared with 21.3% control) and IUGR
trolled trials of pregnant women at risk of preeclampsia
(RR 0.44, 95% CI 0.30 – 0.65, 7% treated compared with
who were assigned to receive aspirin or placebo (or no
16.3% control), whereas aspirin started after 16 weeks
treatment) were reviewed. Secondary outcomes in-
was not (preeclampsia: RR 0.81, 95% CI 0.63–1.03, prev-
cluded IUGR, severe preeclampsia and preterm birth.
alence in 7.3% treated compared with 8.1% control;
The effect of aspirin was analyzed as a function of
IUGR: RR 0.98, 95% CI 0.87–1.10, 10.3% treated com-
gestational age at initiation of the intervention (16 weeks
pared with 10.5% control). Low-dose aspirin started at 16
of gestation or less, 16 weeks of gestation or more).
weeks or earlier also was associated with a reduction in
severe preeclampsia (RR 0.09, 95% CI 0.02– 0.37, 0.7%
treated compared with 15.0% control), gestational hyper-
tension (RR 0.62, 95% CI 0.45– 0.84, 16.7% treated com-
From the Department of Obstetrics and Gynecology, Faculty of Medicine, LavalUniversity, Québec, Canada; the Department of Social and Preventive Medicine, pared with 29.7% control), and preterm birth (RR 0.22,
Faculty of Medicine, Laval University, Québec, Canada; Centre de Recherche, 95% CI 0.10 – 0.49, 3.5% treated compared with 16.9%
Centre Hospitalier Universitaire de Québec, Québec, Canada; Centre de control). Of note, all studies for which aspirin had been
Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et Pneumologie, started at 16 weeks or earlier included women identified
Laval University, Québec, Canada; the Department of Obstetrics and Gynecol-ogy, Faculty of Medicine, University of Montreal, Montréal, Québec, Canada; to be at moderate or high risk for preeclampsia.
and the Department of Molecular Biology, Medical Biology and Pathology, CONCLUSION: Low-dose aspirin initiated in early preg-
Faculty of Medicine, Laval University, Québec, Canada. nancy is an efficient method of reducing the incidence of
Dr. Emmanuel Bujold holds a Clinician Scientist Award and Dr. Franc¸ois preeclampsia and IUGR.
Audibert holds a New Investigator Award from the Canadian Institutes of (Obstet Gynecol 2010;116:402–14) Health Research (CIHR). Dr. Yves Gigue re holds a Clinician-Scientist Awardfrom Fonds de la recherche en sante´ du Que´bec (FRSQ). Supported by the Jeanneand Jean-Louis Le´vesque Perinatal Research Chair at Universite´ Laval. Corresponding author: Emmanuel Bujold, MD, MSc, FRCSC, Associate Pro-fessor, Department of Obstetrics and Gynaecology, CRCHUQ, Faculty of Preeclampsia and intrauterine growth restriction (IUGR) are important causes of maternal and Medicine, Universite´ Laval, 2705, boulevard Laurier, Que´bec, QC, Canada perinatal morbidity and mortality.1,2 Preeclampsia G1V 4G2; email: [email protected]. affects about 2–5% of pregnancies and leads to over 100,000 maternal deaths worldwide each year.2 In The authors did not report any potential conflicts of interest. developed countries, it remains responsible for severe 2010 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins. maternal complications such as coagulopathy, renal ISSN: 0029-7844/10 and liver failure, stroke, and maternal death.3 Pre- VOL. 116, NO. 2, PART 1, AUGUST 2010 OBSTETRICS & GYNECOLOGY

eclampsia also is associated with a fourfold increase in (CENTRAL) from 1965 to July 2008. Keywords and the risk of IUGR, which is linked to both short-term MeSH terms were combined to generate lists of studies: and long-term health consequences.4 Those affected "pregn*," "pregnancy," "pregnancy-complication," "aspi- by IUGR are at high risk of obesity, cardiovascular rin," "antiplatelet," "salicy*," "preeclam*," "pre-eclam*," disease, hypertension, and diabetes later in life.5,6 "hypertension," "hypertens*," "blood press*," "PIH," Although the original causes of preeclampsia and "toxaemi*," "toxemi*," "eclamp*." No language restric- IUGR are still unclear, both entities typically are tion was imposed. The search strategy was sorting by a characterized by defective placentation eliciting inad- first reviewer (S.R.) of articles by title for more detailed equate uteroplacental blood perfusion and ischemia.7 evaluation. The second sort was made by two reviewers Normal placentation comprises trophoblast cell inva- (S.R., E.B.) for abstracts categorized as relevant, not sion of the spiral arteries, which results in reversible relevant or possibly relevant. All relevant and possibly changes in the normal arterial wall architecture.8 relevant trials were entirely reviewed, classified, and Physiological trophoblastic invasion of the spiral ar- approved by the same two reviewers. Disagreement was teries develops from 8 weeks of gestation and is resolved by discussion with a third reviewer (M.B.).
believed to be mostly completed by 16 to 20 weeks of Quality and integrity of this review were validated with gestation.7,9,10 Recent studies have shown that abnor- PRISMA (preferred reporting items for systematic re- mal uterine artery Doppler and serum markers of views and meta-analyses).25 defective placentation can identify women at high riskof preeclampsia and IUGR, as early as the firsttrimester.11,12 Inadequate perfusion and placental ischemia Only prospective, randomized, controlled trials were evoke endothelial dysfunction, with platelet and clot- included. Quasi-randomized trials were excluded.
ting system activation.13,14 Therefore, the hypothesis The selected population was constituted of pregnant that antiplatelet agents might prevent preeclampsia women at risk of preeclampsia. No restrictions were and IUGR held considerable interest for the last 30 applied to risk criteria for preeclampsia but we eval- years.15,16 It was thought that low-dose aspirin could uated the trials according to the prevalence of pre- inhibit thromboxane-mediated vasoconstriction and eclampsia in each study. Women in the treatment thereby protect against vasoconstriction and patho- group had to receive low-dose aspirin (50 to 150 mg logical blood coagulation in the placenta.17,18 Its use of acetylsalicylic acid daily, alone or in combination was expected to prevent failure of physiological spiral with less than 300 mg of dipyridamole, another artery transformation and, thus, the development of antiplatelet agent). The control group had to be preeclampsia and IUGR. However, the results from allocated to placebo or no treatment. Studies were randomized trials are contradictory.16,19,20 Several excluded if more than 20% of women were lost to large, prospective, multicenter studies failed to dem- follow-up or excluded from analysis after randomiza- onstrate the clinical efficacy of low-dose aspirin in tion to prevent possibility of attrition bias.26 Studies preventing preeclampsia.20–23 On the other hand, late with inappropriate allocation concealment, such as initiation of treatment (after 18 to 20 weeks) and the numbered tables or nonsealed envelopes, also were inclusion of low-risk patients may represent potential excluded to prevent the possibility of selection bias.26 reasons for the negative or weakly-positive results The quality of each study was reported.27 obtained. Indeed, we recently found that prophylactic The primary outcome was the occurrence of low-dose aspirin started before 16 weeks of gestation preeclampsia. Secondary outcomes were IUGR, se- in women with abnormal uterine artery Doppler was vere preeclampsia, gestational hypertension, placen- associated with a 50% reduction of preeclampsia.24 tal abruption, preterm birth, low birth weight and In this review, we aim to assess and compare the gestational age at delivery (Table 1). Data were ex- influence of gestational age at the introduction of tracted in duplicate from all included studies by two aspirin therapy on the incidence of preeclampsia and independent reviewers (S.R., M.B.). Each outcome IUGR by performing a systematic review and meta- was stratified according to gestational age at the analysis of all women identified as being at risk of beginning of aspirin treatment: 16 completed weeks of gestation or less, more than 16 weeks. The thresh-old in gestational age was determined a priori on the basis of the physiological evolution of spiral uterine Relevant citations were extracted from Embase, PubMed artery transformation during pregnancy that usually and the Cochrane Central Register of Controlled Trials ends between 16 and 20 weeks of gestation.7,9 VOL. 116, NO. 2, PART 1, AUGUST 2010 Bujold et al
Preeclampsia and IUGR Prevention With Aspirin

Table 1. Definition of Outcomes and Enrollment Characteristics
Chronic or gestational hypertension combined with proteinuria detected after 20 wk of gestation Systolic BP 140 mmHg or higher or diastolic BP 90 mmHg or higher, or both detected after 20 wk of 300 mg of protein or more in a 24-h urine specimen or a positive reaction (⫹1) on a midstream urine Severe preeclampsia Recorded according to the following criteria: severe hypertension (BP of at least 160 mmHg systolic or 110 mmHg diastolic or 105 mmHg diastolic), severe proteinuria (at least 2, 3, or 5 g of protein in24 h or 3⫹ on dipstick), reduced urinary volume (less than 400 to 500 mL in 24 h), neurologicdisturbances such as headache and visual perturbations, upper abdominal pain, pulmonary edema,impaired liver function tests, high serum creatinine, low platelet count Birth weight less than the 10th percentile (IUGR, less than the 10th percentile) or birth weight less than the 5th or birth weight less than the 3rd percentile or reported as small for gestational age (IUGR,any definition) Birth before 37 wk of gestation or, when not available, before 36, 35, or 34 wk of gestation Placental abruption Abruption of the placenta or antepartum hemorrhage Weight of neonate at birth in grams Gestational age at delivery in weeks Population risk of Prevalence of preeclampsia reported in the control group BP, blood pressure; IUGR, intrauterine growth restriction.
Continuous and dichotomous variables were ana- sia being considered at low risk and those with lyzed with Review Manager 5.0.12 software (Cochrane prevalence greater than 7% being considered a mod- IMS, www.cc-ims.net/revman), and SAS 9.1 (SAS Insti- erate-risk or high-risk population for preeclampsia.
tute Inc., Cary, NC) was used to calculate agreement P values less than 0.05 were considered significant.
between reviewers and to compare subgroup relativerisks (RR).28 The analyses included data on all random- ized participants followed up until the end of pregnancy Through our literature search, 773 articles were iden- on an intention-to-treat basis. Within each trial, for tified as potentially eligible, and 337 of them were dichotomous variables, individual RR with 95% confi- deemed to be potentially relevant. Of these, 290 were dence intervals (CIs) was calculated according to the eliminated because they did not follow the inclusion Mantel-Haentszel method to compare the effectiveness criteria (Fig. 1). For this review, 34 trials were ana- of treatment over placebo. RR were pooled according to lyzed, including 27 for primary outcome (preeclamp- DerSimmonian and Laird random effect models.29 For sia), for a total of 11,348 women.20,21,23,35–66 Interre- continuous variables, mean differences were weighted viewer agreement for the second selection of 337 by the inverse of population variance and combined articles was associated with a weighted kappa of 0.88.
according to random effect models and 95% CI. Heter- In addition to electronic searches, other recent meta- ogeneity between studies was analyzed by Higgins' I2.30,31 analyses permitted us to confirm the completeness of The distribution of trials was examined with funnel plots our literature search.16,67–69 All selected articles were and analyzed with Egger test to assess publication bias.32 published between 1985 and 2005 and included par- Sensitivity analysis was performed to evaluate the ro- ticipants from more than 20 countries. Twelve studies bustness of the findings.31,33 report data from women randomized at or before 16 Relative risks of subgroups stratified according to weeks of gestation, and 22 studies report data from gestational age at entry were compared for primary women randomized after 16 weeks of gestation. Table and secondary outcomes using mixed regression 2 shows the characteristics of all included studies, and weighted by the size of each study.34 Finally, analyses Table 3 shows the aggregated quality of the studies were repeated for studies categorized according to (randomization method, blinding, intention-to-treat prevalence in the control group in each study: those and completeness of follow-up) in each subgroup.
with a prevalence equal or less than 7% of preeclamp- Women were identified at risk for preeclampsia based Bujold et al
Preeclampsia and IUGR Prevention With Aspirin OBSTETRICS & GYNECOLOGY

Potentially relevant citations identified and screened Citations not relevant; excluded Trials retrieved for more detailed evaluation Citations excluded because of inadequate allocation concealment, other publications of same study, no relevant outcomes, not randomized study with aspirin, personal communication, or Trials deemed potentially appropriate for inclusion in the meta-analysis Trials withdrawn:* n=290 Other publications of the same No relevant outcomes: 28Paper retracted: 2Not randomized study with aspirin: 22Use of medication other than Personal communication: 7Allocation concealment inadequate: 8Letters, commentary, editorial: 11Meta-analysis or review: 15Duplicate: 25More than 20% of participants Other reasons: 42 Fig. 1. Selection process. Summary
of selection process for systematic
Trials used in the analysis review of aspirin to prevent pre- eclampsia. *A study could be inmore than one category. †Partial Trials excluded because of an overlap in the gestational age of recruitment data from five trials that reported the results for women recruited at20 weeks of gestation or morewere included in our analysis.
16 or fewer weeks of gestation More than 16 weeks of gestation Bujold. Preeclampsia and IUGR Prevention With Aspirin. ObstetGynecol 2010. on heterogeneous criteria including nulliparity, previ- (mixed regression analysis for comparison between ous history of preeclampsia or other hypertensive subgroups: 16 weeks or less compared with more than disorders, abnormal uterine artery Doppler, among 16 weeks, P⫽.01). A significant decrease of severe preeclampsia, gestational hypertension and preterm The diminution of preeclampsia was significant in birth was also observed in the subgroup of women the subgroup of women who began the intervention who started the intervention at 16 weeks of gestation at 16 weeks of gestation or less (RR 0.47, 95% CI or less (Table 4). Moreover, the mean gestational age 0.34 – 0.65), whereas it was not in the subgroup of at delivery (weighted mean difference 1.4 weeks, 95% women who began the intervention at more than 16 CI 0.4 –2.3 weeks) was greater when aspirin was weeks (RR 0.81, 95% CI 0.63–1.03) (Fig. 2). The started at 16 weeks or less, whereas it was not when difference of treatment's effect on the risk of pre- started at more than 16 weeks (weighted mean differ- eclampsia between the two groups was significant ence 0.0 weeks; 95% CI -0.7 to 0.7 weeks). The rate of VOL. 116, NO. 2, PART 1, AUGUST 2010 Bujold et al
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Table 2. Characteristics of Included Studies
First Author, Year
16 wk of gestation Chronic HTN or previous severe PE ASA 100 mg vs placebo PE, severe PE, Previous early onset PE, severe IUGR, or fetal death due to placental mg vs no treatment Had several previous complicated PE, GH, severe PE, pregnancies or vascular risk factors such as essential HTN (BP higher mg vs no treatment than 160/95 or a family history ofHTN) Benigni, 198939 33 women at Essential HTN or a significant previous ASA 60 mg vs placebo obstetric history 40 women at less Chronic HTN with or without nephropathy or history of severe PE, eclampsia, IUGR, or stillbirth Primiparous women ASA 100 mg vs placebo SGA, BW, GA at Abnormal uterine artery Doppler and PE, severe PE, BW, risk factors for PE and IUGR Family or own history of PIH, PE, ASA 100 mg vs placebo PE, GH, BW, GA chronic HTN, cardiovascular or endocrine problem, spontaneous abortion, multiple pregnancy, orobesity or nulliparous (younger than18 or older than 35) Family or own history of PIH, PE, ASA 100 mg vs placebo IUGR, PTB, AP chronic HTN, cardiovascular orendocrine problem, spontaneousabortion, multiple pregnancy, orobesity or nulliparous (younger than18 or older than 35) HTN in early pregnancy, DBP 90 ASA 100 mg vs placebo PE, GH mmHg or higher or SBP 140 mmHgor higher or a history of severe PE Previous consecutive miscarriage ASA 50 mg vs placebo Anamnestic risk factor with abnormal ASA 0.5 mg/kg/d vs PE, GH, severe PE, IUGR, SGA,BW, GA atbirth History of PE or chronic HTN ASA 75 mg vs placebo PE, GH, severe PE, Caritis, 199821* 2,539 women at Insulin-treated diabetes, chronic HTN, ASA 60 mg vs placebo multiple pregnancy, or previous PE Risks for PE based on history of HTN, ASA 60 mg vs placebo renal disease, AMA, family history,multiple pregnancy, established PE,or IUGR Nulliparous, Hb higher than 13.2 g/dL ASA 75 mg vs placebo PE, severe PE, GH, at 12–19 wk of gestation, DBP lower than 90 mmHg, and no Chronic HTN, primigravidity, diabetes, ASA 60 mg vs placebo renal disease, history of PE or IUGR preterm birth,IUGR, BW,GH, GA atbirth, AP Bujold et al
Preeclampsia and IUGR Prevention With Aspirin OBSTETRICS & GYNECOLOGY

Table 2. Characteristics of Included Studies (continued)
First Author, Year
Nulliparous women with a placental ASA 60 mg vs placebo side uterine artery resistance indexhigher than the 90th centile or adiastolic notch Gallery, 199746 120 women at Preexisting chronic HTN, renal disease, ASA 100 mg vs placebo PTB, SGA, AP or previous early PE Singleton with early IUGR, impaired ASA 100 mg vs placebo PE uteroplacental flow, chronic HTN, orprevious IUGR, stillbirth, or PE Primiparous women ASA 60 mg vs placebo PE, severe PE, GH, BW, GA at birth,PTB, SGA, AP Nulliparous, healthy, singleton ASA 60 mg vs placebo PE, GH, severe PE, Nulliparous women with persistent ASA 75 mg vs placebo abnormal Doppler waveform IUGR, GA atbirth, BW, Nulliparous with abnormal uterine ASA 100 mg vs placebo PE, GH, PTB, Doppler flow at 18 wk (S/D higher than 3.3 or higher than 3 with earlydiastolic notch) IUGR, umbilical artery, Doppler S/D ASA 100 mg vs placebo BW, IUGR, GA at higher than the 95th centile Normotensive, primigravid with MAP 80 or higher and lower than 106 mmHg early in 2nd trimester andMAP higher than 60 All pregnant women without ASA 75 mg vs placebo PE, GH, severe PE, BW, SGA, PTB,AP, GA at birth Twin pregnancy, a history of PE, ASA 100 mg vs placebo PE, GH, severe PE, nulliparity, and a positive rollover test at 28–29 wk of gestation Primigravid women with positive ASA 80 mg vs placebo PE, GH, severe PE, IUGR, BW, GAat birth, PTB Angiotensin II–sensitive primigravid, no ASA 60 mg vs placebo PE, GH, severe PE, history of HTN, cardiovascular or renal disease, DBP lower than 80mmHg Mainly nulliparous with a singleton ASA 75 mg vs placebo pregnancy at high risk for IUGR PTB, GA at birth, Old nulliparous, multiparous with ASA 50 mg vs placebo history of severe PIH, obesity, MAPhigher than 12 kPa, Hb less than 8,PCV more than 0.37 family history ofHTN or PIH Singleton pregnancy and Doppler ASA 150 mg vs placebo PE, severe PE, pulsatility index more than 1.6 (95th Uterine artery bilateral notches on at birth, PTB,IUGR, AP HTN, hypertension; PE, preeclampsia; ASA, acetyl salicylic acid; IUGR, intrauterine growth restriction; AP, abruptio placenta; GH, gestational hypertension; BW, birth weight; GA, gestational age; BP, blood pressure; PTB, preterm birth; SGA, small for gestationalage; PIH, pregnancy-induced hypertension; DBP, diastolic blood pressure; SBP, systolic blood pressure; AMA, advanced maternalage; Hb, hemoglobin concentration; S/D, systolic/diastolic ratio; MAP, mean arterial blood pressure; PCV, packed cell volume.
* Data for these trials could be extracted for more than 20 wk.
VOL. 116, NO. 2, PART 1, AUGUST 2010 Bujold et al
Preeclampsia and IUGR Prevention With Aspirin

Table 3. Aggregated Results for the Quality of the
groups: 16 weeks or less compared with more than 16 34 Studies Included in the Meta-Analysis
weeks, P⬍.001). The increase in mean birth weightwas 196 g (95% CI 107–285 g) when aspirin was More Than 16
started at 16 weeks of gestation or less compared with70 g (95% CI 15–124 g) when aspirin was started at Method of randomization more than 16 weeks.
We found that the heterogeneity within each subgroup was lower than the heterogeneity present in all studies taken together, and it was almost absent in the 16-weeks-or-less subgroup (I2 for preeclampsia: 16 weeks or less 0%, more than 16 weeks 48%, overall 52%; I2 for IUGR: 16 weeks or less 0%, more than 16 weeks 1%, overall 28%). This finding supports the hypothesis that the effect of low-dose aspirin vary with gestational age. Analysis of the funnel plot revealed the possibility of a publication bias because Data are n (%).
small studies showing no benefits are missing (Fig. 4).33This finding is confirmed by the Egger test that placental abruption was not modified by low-dose indicates asymmetry and publication bias that was aspirin in any subgroups.
significant in the 16-weeks-or-less subgroup. Such The reduction of IUGR, defined as birth weight finding suggests a possible overestimation of the size less than the 10th percentile, or based on any defini- effect. Because other variations could exist between tion used by the different studies, was significant only the trials, we performed a sensitivity analysis to in the subgroup of women who started low-dose examine the robustness of our findings (Fig. 5). In this aspirin at 16 weeks of gestation or less (Fig. 3) (mixed analysis, we found a very small amount of variation in regression analysis for comparison between sub- the 16-weeks-or-less subgroup: no significant differ- Table 4. Relative Risk of Outcomes Associated With the Use of Low-Dose Aspirin According to
Gestational Age at Initiation of Intervention
Treated (%)
Controls (%)
RR (95% CI)
0.47 (0.34–0.65)* 0.81 (0.63–1.03) Severe preeclampsia 0.09 (0.02–0.37)* 0.26 (0.05–1.26) Gestational hypertension 0.62 (0.45–0.84)† 0.63 (0.47–0.85)† 0.22 (0.10–0.49)* 0.90 (0.83–0.97)† IUGR (any definition) 0.44 (0.30–0.65)* 0.98 (0.87–1.10) IUGR ([less than the 10th centile) 0.47 (0.30–0.74)† 0.92 (0.78–1.10) Placental abruption 0.62 (0.08–5.03) 1.56 (0.96–2.55) RR, relative risk; CI, confidence interval; NNT, number needed to treat; IUGR, intrauterine growth restriction.
* P⬍.001.
† P⬍.05.
Bujold et al
Preeclampsia and IUGR Prevention With Aspirin OBSTETRICS & GYNECOLOGY

Risk ratio
Risk ratio
Study or subgroup
Events Total
Events Total Weight (%)
M-H, random (95% CI)
M-H, random (95% CI)
1.1 16 or fewer weeks
August 1994
0.63 (0.17–2.33) 0.24 (0.03–2.10) 0.07 (0.00–1.25) 0.54 (0.37–0.78 0.43 (0.12–1.56) 0.20 (0.02–1.66) 0.33 (0.04–3.04) 0.20 (0.05–0.86) Subtotal (95% CI)
Heterogeneity: Tau2=0.00; Chi2=5.45; df=7 (P=.61); I2=0%Test for overall effect: Z=4.57 (P<.001) 1.2 More than 16 weeks
Byaruhanga 1998
0.77 (0.43–1.35) 0.89 (0.70–1.12) 1.11 (0.83–1.49) 0.74 (0.25–2.20) 0.82 (0.44–1.54) 0.87 (0.06–13.02) 1.36 (0.95–1.95) 1.43 (0.27–7.73) 0.29 (0.11–0.79) 0.11 (0.01–0.81) 0.55 (0.17–1.76) 0.27 (0.07–1.02) 0.84 (0.37–1.94) 0.13 (0.02–1.00) Schrocksnadel 1992 0.07 (0.00–1.11) 0.07 (0.00–1.10) 0.95 (0.67–1.35) 2.00 (0.44–9.08) Subtotal (95% CI)
Heterogeneity: Tau2=0.09; Chi2=32.49; df =17 (P=.01); I2=48%Test for overall effect: Z=1.75 (P=.08) Total (95% CI)
Heterogeneity: Tau2=0.12; Chi2=51.55; df =25 (P=.001); I2=52%Test for overall effect: Z=3.19 (P=.001) Favors experimental Favors control Fig. 2. Forest plot of trials studying preeclampsia. Aspirin treatment to prevent preeclampsia according to gestational age at
the initiation of intervention. CI, confidence interval; M-H, Mantel-Haentszel.
Bujold. Preeclampsia and IUGR Prevention With Aspirin. Obstet Gynecol 2010.
ence was found between the trials in regards with the significant decrease in the incidence of preeclampsia, statistical model used, the blinding, the size of the severe preeclampsia, IUGR and preterm birth in trials, the dose of aspirin, and the addition of dipyrid- women identified to be at risk for preeclampsia. Our amole. Of note, only one large trial was included in observations are in complete agreement with previ- this subgroup and it included only women identified ous meta-analyses which demonstrated an overall to be at moderate or high risk for preeclampsia (rate preeclampsia reduction of approximately 20% with of preeclampsia greater than 7% in the control group).
low-dose aspirin started any time during preg-nancy.16,68 The results also concur with the recent retrospective study of Baschat et al who reported that We determined that daily low-dose aspirin initiated first-trimester, low-dose aspirin decreases placental before 16 weeks of gestation was associated with a blood flow resistance and most likely prevents pre- VOL. 116, NO. 2, PART 1, AUGUST 2010 Bujold et al
Preeclampsia and IUGR Prevention With Aspirin Risk ratio
Risk ratio
Study or
subgroup
Events Total
Events Total Weight (%) M-H, random (95% CI)
M-H, random (95% CI)
2.1 16 or fewer weeks
August 1994
0.35 (0.01–8.12) 0.29 (0.10–0.82) 0.31 (0.07–1.33) 0.20 (0.03–1.59) 0.53 (0.29–0.98) 0.50 (0.05–5.34) 0.40 (0.16–1.01) 0.33 (0.04–3.08) Subtotal (95% CI)
Heterogeneity: Tau2=0.00; Chi2=3.06; df=8 (P=.93); I2=0%Test for overall effect: Z=4.10 (P<.001) 2.2 More than 16 weeks
Byaruhanga 1998
0.96 (0.54–1.73) 1.37 (0.98–1.90) 1.05 (0.79–1.40) 1.03 (0.35–3.02) 0.77 (0.49–1.20) 0.89 (0.47–1.69) 1.08 (0.41–2.86) 1.22 (0.62–2.43) 0.96 (0.79–1.16) 0.30 (0.07–1.40) Schrocksnadel 1992 0.43 (0.04–4.40) 0.67 (0.22–2.05) 0.28 (0.08–0.90) 0.90 (0.67–1.22) 2.00 (0.21–19.44) Subtotal (95% CI)
Heterogeneity: Tau2=0.00; Chi2=14.14; df=14 (P=.44); I2=1%Test for overall effect: Z=0.38 (P=.071) Total (95% CI)
Heterogeneity: Tau2=0.03; Chi2=32.12; df=23 (P=.10); I2=28%Test for overall effect: Z=1.92 (P=.06) 0.01 0.1 1 10 100 Favors experimental Favors control Fig. 3. Forest plot of trials studying intrauterine growth restriction. Aspirin treatment to prevent intrauterine growth restriction
according to gestational age at the initiation of intervention. CI, confidence interval; M-H, Mantel-Haentszel.
Bujold. Preeclampsia and IUGR Prevention With Aspirin. Obstet Gynecol 2010.
eclampsia.70 Furthermore, it is also in agreement with randomization was greater than 20 weeks.68 In this a recent randomized trial that showed a lower inci- scenario, the mean gestational age of women re- dence of hypertensive complications with low-dose cruited in the less-than-20-week subgroup was most aspirin given throughout in vitro fertilization treat- likely between 16 and 18 weeks. Taken together, ment and the first trimester of pregnancy in infertile these results suggest that: 1) women at moderate or women.71 The novelty of our study resides in sub- high risk for preeclampsia benefit from daily low-dose group analysis according to gestational age at the aspirin for the prevention of preeclampsia and IUGR, initiation of therapy. In a previous meta-analysis, and 2) the earlier low-dose aspirin is started in preg- Duley et al reported no significant difference in the nancy, the greater the benefits. It remains unclear if incidence of preeclampsia with low-dose aspirin in there is a gestational age threshold beyond which women recruited in studies where mean gestational low-dose aspirin becomes inefficient, and whether or age at randomization was less than 20 weeks com- not pursuing treatment until the end of pregnancy is pared with studies where mean gestational age at Bujold et al
Preeclampsia and IUGR Prevention With Aspirin OBSTETRICS & GYNECOLOGY
16-week-or-less subgroups were mostly small studies,included only those women at moderate or high riskfor preeclampsia, and were more likely to use higher 16 or fewer weeks doses of aspirin. However, the fact that we noted a More than 16 weeks stronger homogeneity in the subgroups (16 weeks or less and more than 16 weeks) suggests a definitive rolefor the gestational age at initiation of the treatment in the effects of low-dose aspirin in prevention of pre-eclampsia and IUGR. The very strong homogeneity in the results between studies included in the 16- 2.0 0.001 0.1 1 10 1,000 weeks-or-less subgroup suggests a real effect in this Fig. 4. Funnel plot of trials studying preeclampsia. Funnel
specific subgroup of women. On the other hand the plot of the risk ratio (RR) against its standard error (SE) funnel plot and the sensitivity analysis suggest a (empty square, 16 weeks or fewer; filled square, more than potential publication bias.
16 weeks). This visual evaluation of the funnel plot suggeststhe possibility of publication bias because small studies The clinical implications of our results are impor- showing no benefits are missing, mainly in the 16 weeks or tant. A growing body of evidence suggests that a fewer subgroup (there is no study from the 16 weeks or significant proportion of women at moderate or high fewer subgroup in the right lower quadrant of the graph).
risk for preeclampsia, and mainly early-onset pre- This finding is confirmed by the Egger test (16 weeks orfewer: P⫽.03; more than 16 weeks: P⫽.06).
eclampsia, severe preeclampsia and IUGR, can be Bujold. Preeclampsia and IUGR Prevention With Aspirin. Obstet identified as early as the first trimester of pregnancy Gynecol 2010. by a combination of factors, such as mean arterialblood pressure, body mass index, ethnicity, serum The limitations of our meta-analysis include the biomarkers and uterine artery Doppler.72 Moreover, reduction of power by stratification of the population recent data indicate that 3-dimensional analysis of into subgroups. Such limitations could lead to false- first-trimester placenta could also predict very early negative results. We found that studies within the placental insufficiency.73,74 Therefore, we hypothe-sized that it is possible to identify women at moderateor high risk for preeclampsia or IUGR or both and toprevent these outcomes with low-dose aspirin started in early pregnancy. Issues that should be considered Random effect (9) in future randomized trials should include the optimal dose of aspirin or platelet aggregation tests for dosage adjustments.75,76 Moreover, with the recent publica- tion of a randomized controlled trial showing that Dose of aspirin
80 mg or less daily (4) low-molecular weight heparin can also decrease the 81 mg or more daily (6) recurrence of severe preeclampsia, future studies should compare low-dose aspirin to heparin in high- risk populations.77 Based on the results of this review, current evi- Risk of preeclampsia
dence indicates that low-dose aspirin started in early Moderate to high (8) pregnancy may reduce the incidence of preeclampsia, Trial size
IUGR and preterm birth in women identified at Fewer than 50 cases (8) moderate or high risk for preeclampsia. Of note, 50 or more cases (1) because most studies in the 16-weeks-or-less subgroup were small and included women at high risk for preeclampsia, and because we found a potential pub- Fig. 5. Sensitivity analysis. The sensitivity analysis examines
lication bias, we believe that a large randomized the robustness of the effect on preeclampsia of low-dose controlled trial should be carrying out to validate our aspirin started at 16 weeks of gestation or before. The results. With the development of better tools to spot dotted vertical line corresponds to the combined risk ratio women at high risk for preeclampsia, it will become from the random effects model.
possible to perform randomized trials combining the Bujold. Preeclampsia and IUGR Prevention With Aspirin. ObstetGynecol 2010. tracking of high-risk women early in pregnancy and VOL. 116, NO. 2, PART 1, AUGUST 2010 Bujold et al
Preeclampsia and IUGR Prevention With Aspirin the prevention of preeclampsia and IUGR with low- of Maternal-Fetal Medicine Units. N Engl J Med 1993;329: dose aspirin in early pregnancy.
20. CLASP CL-dASiPCG. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet 1994;343:619 –29.
1. Geographic variation in the incidence of hypertension in 21. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, pregnancy. World Health Organization International Collab- Thom E, et al. Low-dose aspirin to prevent preeclampsia in orative Study of Hypertensive Disorders of Pregnancy. Am J women at high risk. National Institute of Child Health and Obstet Gynecol 1988;158:80 –3.
Human Development Network of Maternal-Fetal Medicine 2. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF.
Units. N Engl J Med 1998;338:701–5.
WHO analysis of causes of maternal death: a systematic 22. Subtil D, Goeusse P, Puech F, Lequien P, Biausque S, Breart G, review. Lancet 2006;367:1066 –74.
et al. Aspirin (100 mg) used for prevention of pre-eclampsia in 3. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet nulliparous women: the Essai Regional Aspirine Mere-Enfant study (Part 1). BJOG 2003;110:475– 84.
4. Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R.
23. Golding J. A randomised trial of low dose aspirin for primip- Preeclampsia and fetal growth. Obstet Gynecol 2000;96: arae in pregnancy. The Jamaica Low Dose Aspirin Study Group. Br J Obstet Gynaecol 1998;105:293–9.
5. Barker DJ. The fetal and infant origins of adult disease. BMJ 24. Bujold E, Morency AM, Roberge S, Lacasse Y, Forest JC, Giguere Y. Acetylsalicylic acid for the prevention of pre- 6. Barker DJ. The developmental origins of chronic adult disease.
eclampsia and intra-uterine growth restriction in women with Acta Paediatr Suppl 2004;93:26 –33.
abnormal uterine artery Doppler: a systematic review andmeta-analysis. J Obstet Gynaecol Can 2009;31:818 –26.
7. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies 25. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred report- complicated by pre-eclampsia and by small-for-gestational age ing items for systematic reviews and meta-analyses: the infants. Br J Obstet Gynaecol 1986;93:1049 –59.
PRISMA statement. PLoS Med 2009;6:e1000097.
8. Brosens I, Robertson WB, Dixon HG. The physiological 26. Juni P, Altman DG, Egger M. Systematic reviews in health response of the vessels of the placental bed to normal preg- care: assessing the quality of controlled clinical trials. BMJ nancy. J Pathol Bacteriol 1967;93:569 –79.
2001;323:42– 6.
9. Pijnenborg R, Dixon G, Robertson WB, Brosens I. Tropho- 27. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical blastic invasion of human decidua from 8 to 18 weeks of evidence of bias. Dimensions of methodological quality asso- pregnancy. Placenta 1980;1:3–19.
ciated with estimates of treatment effects in controlled trials.
JAMA 1995;273:408 –12.
10. De Wolf F, DeWolf-Peeters C, Brosens I, Robertson W. The human placental bed: electron microscopic study of trophop- 28. Landis J, Koch G. The measurement of observer agreement for lastic invasion of spiral arteries. Am J Obstet Gynecol 1980; categorical data. Biometrics 1977;33:159 –74.
137:58 –70.
29. DerSimonian R, Laird N. Meta-analysis in clinical trials.
11. Cnossen JS, Morris RK, ter Riet G, Mol BW, van der Post JA, Control Clin Trials 1986;7:177– 88.
Coomarasamy A, et al. Use of uterine artery Doppler ultra- 30. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring sonography to predict pre-eclampsia and intrauterine growth inconsistency in meta-analyses. BMJ 2003;327:557– 60.
restriction: a systematic review and bivariable meta-analysis.
31. Egger MSG, Phillips AN. Meta-analysis: principles and proce- dures. BMJ 1997;315:1533–7.
12. Salomon L, Benattar C, Audibert F, Fernandez H, Duyme M, 32. Egger M, Davey Smith G, Schneider M, Minder C. Bias in Taieb J, et al. Severe preeclampsia is associated with high meta-analysis detected by a simple, graphical test. BMJ 1997; inhibin A levels and normal leptin levels at 7 and 13 weeks into 315:629 –34.
pregnancy. Am J Obstet Gynecol 2003;189:1517–22.
33. Sterne JA, Egger M, Smith GD. Systematic reviews in health 13. Redman CW, Bonnar J, Beilin L. Early platelet consumption in care: investigating and dealing with publication and other pre-eclampsia. Br Med J 1978;1:467–9.
biases in meta-analysis. BMJ 2001;323:101–5.
14. Janes SL, Kyle PM, Redman C, Goodall AH. Flow cytometric 34. Borenstein M, Hedges LV, Higgins JP, Rothstein HR, editors.
detection of activated platelets in pregnant women prior to the Introduction to meta-analysis. West Sussex (UK): Wiley; 2009.
development of pre-eclampsia. Thromb Haemost 1995;74:1059 – 63.
35. August P, Helseth G, Edersheim T, Hutson J, Druzin M.
Sustained relase, low-dose aspirin ameliorates but does not 15. Masotti G, Galanti G, Poggesi L, Abbate R, Neri Serneri GG.
prevent preeclampsia (PE) in a high risk population. Proceed- Differential inhibition of prostacyclin production and platelet ings of the 9th International Congress, International Society for aggregation by aspirin. Lancet 1979;2:1213–7.
the Study of Hypertension March 15–18, 1994, Sydney, Aus- 16. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Anti- tralia. Hypertension in Pregnancy. p. 72.
platelet agents for prevention of pre-eclampsia: a meta-analysis 36. Dasari R, Narang A, Vasishta K, Garewal G. Effect of maternal of individual patient data. Lancet 2007;369:1791– 8.
low dose aspirin on neonatal platelet function. Indian Pediatr 17. Thorp JA, Walsh SW, Brath PC. Low-dose aspirin inhibits thromboxane, but not prostacyclin, production by human 37. Azar R TD. Effect of antiplatelet therapy in women at high risk placental arteries. Am J Obstet Gynecol 1988;159:1381– 4.
for pregnancy-induced hypertension. Proceedings of 7th 18. Aspirin and pre-eclampsia. Lancet 1986;1:328 –9.
World Congress of Hypertension in Pregnancy. October 1990, 19. Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D, Perugia, Italy. p. 257.
Rocco L, et al. Prevention of preeclampsia with low-dose 38. Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of aspirin in healthy, nulliparous pregnant women. The National pre-eclampsia by early antiplatelet therapy. Lancet 1985;1: Institute of Child Health and Human Development Network Bujold et al
Preeclampsia and IUGR Prevention With Aspirin OBSTETRICS & GYNECOLOGY
39. Benigni A, Gregorini G, Frusca T, Chiabrando C, Ballerini S, 54. Newnham JP GM, Walters BJN, Philips J, Evans SF. Low dose Valcamonico A, et al. Effect of low-dose aspirin on fetal and aspirin for the treatment of fetal growth restriction: a random- maternal generation of thromboxane by platelets in women at ised controlled trial. Aust NZ J Obstet Gynaecol 1995;35: risk for pregnancy-induced hypertension. N Engl J Med 1989; 321:357– 62.
55. Rogers MS, Fung HY, Hung CY. Calcium and low-dose 40. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, aspirin prophylaxis in women at high risk of pregnancy- Thom E, et al. Low-dose aspirin to prevent preeclampsia in induced hypertension. Hypert Pregn 1999;18:165–72.
women at high risk. National Institute of Child Health andHuman Development Network of Maternal-Fetal Medicine 56. Rotchell YE, Cruickshank JK, Gay MP, Griffiths J, Stewart A, Units. N Engl J Med 1998;338:701–5.
Farrell B, et al. Barbados Low Dose Aspirin Study in Preg-nancy (BLASP): a randomised trial for the prevention of 41. Chiaffarino F, Parazzini F, Paladini D, Acaia B, Ossola W, pre-eclampsia and its complications. Br J Obstet Gynaecol Marozio L, et al. A small randomised trial of low-dose aspirinin women at high risk of pre-eclampsia. Eur J Obstet Gynecol 1998;105:286 –92.
Reprod Biol 2004;112:142– 4.
57. Schiff E, Peleg E, Goldenberg M, Rosenthal T, Ruppin E, 42. Davies NJ GM, Farquharson RG,Walkinshaw SA. Low-dose Tamarkin M, et al. The use of aspirin to prevent pregnancy- aspirin in the prevention of hypertensive disorders of preg- induced hypertension and lower the ratio of thromboxane A2 nancy in relatively low-risk nulliparous women. Hypertension to prostacyclin in relatively high risk pregnancies. N Engl in Pregnancy 1995;14:49 –55.
J Med 1989;321:351– 6.
43. Ebrashy A, Ibrahim M, Marzook A, Yousef D. Usefulness of 58. Schrocksnadel HSB, Alge A, Stechel-Berger G, Schwegel P, aspirin therapy in high-risk pregnant women with abnormal Pastner E, et al. Low-dose aspirin in primigravidae with uterine artery Doppler ultrasound at 14 –16 weeks pregnancy: positive rollover test. Gynecol Obstet Invest 1992;34:146 –50.
randomized controlled clinical trial. Croat Med J 2005;46: 59. Tulppala M, Marttunen M, Soderstrom-Anttila V, Foudila T, Ailus K, Palosuo T, et al. Low-dose aspirin in prevention of 44. ECPPA. ECPPA: randomised trial of low dose aspirin for the miscarriage in women with unexplained or autoimmune prevention of maternal and fetal complications in high risk related recurrent miscarriage: effect on prostacyclin and pregnant women. ECPPA (Estudo Colaborativo para Preven- thromboxane A2 production. Hum Reprod 1997;12:1567–72.
cao da Pre-eclampsia com Aspirina) Collaborative Group. Br JObstet Gynaecol 1996;103:39 – 47.
60. Vainio M, Kujansuu E, Iso-Mustajarvi M, Maenpaa J. Low dose acetylsalicylic acid in prevention of pregnancy-induced 45. Ferrier C NR, Kincaid-Smith P. Low dose aspirin delays the hypertension and intrauterine growth retardation in women onset of pre-eclampsia in pregnancies with abnormal uteropla- with bilateral uterine artery notches. Br J Obstet Gynecol cental circulation. Proceedings of the 10th World Congress ofthe International Society for the Study of Hypertension in Pregnancy, August 4 – 8, 1996, Seattle, WA. p. 151.
61. Wallenburg HC, Dekker GA, Makovitz JW, Rotmans P.
46. Gallery EDM, Ross MR, Hawkins M, Leslie G, Gyo¨ry AZ.
Low-dose aspirin prevents pregnancy-induced hypertension Low-dose aspirin in high-risk pregnancy. Hypertens Preg- and pre-eclampsia in angiotensin-sensitive primigravidae. Lan- nancy 1997;16:229 –38.
47. Grab D, Paulus WE, Erdmann M, Terinde R, Oberhoffer R, 62. Wang Z, Li W. A prospective randomized placebo-controlled Lang D, et al. Effects of low-dose aspirin on uterine and fetal trial of low-dose aspirin for prevention of intra-uterine growth blood flow during pregnancy: results of a randomized, place- retardation. Chin Med J (Engl) 1996;109:238 – 42.
bo-controlled, double-blind trial. Ultrasound Obstet Gynecol 63. Wu J, Yang W, Shen W, He Y. Small dosage aspirin in the 2000;15:19 –27.
prevention of hypertension of pregnancy. Acta AcademiaeMe- 48. Hauth JC, Goldenberg RL, Parker CR Jr, Philips JB, 3rd, dicinae Suzhou 1996;16:551–3.
Copper RL, DuBard MB, et al. Low-dose aspirin therapy toprevent preeclampsia. Am J Obstet Gynecol 1993;168: 64. Yu CK, Papageorghiou AT, Parra M, Palma Dias R, Nico- laides KH. Randomized controlled trial using low-dose aspirinin the prevention of pre-eclampsia in women with abnormal 49. Hermida RC, Ayala DE, Fernandez JR, Mojon A, Alonso I, uterine artery Doppler at 23 weeks' gestation. Ultrasound Silva I, et al. Administration time-dependent effects of aspirin Obstet Gynecol 2003;22:233–9.
in women at differing risk for preeclampsia. Hypertension1999;34:1016 –23.
65. Zimmermann P, Eirio V, Koskinen J, Niemi K, Nyman R, Kujansuu E, et al. Effect of low dose aspirin treatment on 50. Hermida RC, Ayala DE, Iglesias M, Mojon A, Silva I, Ucieda R, et al. Time-dependent effects of low-dose aspirin adminis- vascular resistance in the uterine, uteroplacental, renal and tration on blood pressure in pregnant women. Hypertension umbilical arteries - a prospective longitudinal study on a high 1997;30:589 –95.
risk population with persistent notch in the uterine arteries.
Euro J Ultrasound 1997;5:17–30.
51. McParland P, Pearce JM, Chamberlain GV. Doppler ultra- sound and aspirin in recognition and prevention of pregnancy- 66. Byaruhanga RN, Chipato T, Rusakaniko S. A randomized induced hypertension. Lancet 1990;335:1552–5.
controlled trial of low-dose aspirin in women at risk frompre-eclampsia. Int J Gynaecol Obstet 1998;60:129 –35.
52. Michael CA, Walters BNJ. Low-dose aspirin in the prevention of pre-eclampsia: current evaluation. In: Teoh ES, Ratnam SS, 67. Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan KS.
Macnaughton MC, editors. Maternal physiology and pathol- Aspirin for prevention of preeclampsia in women with histor- ogy. The current status of gynaecology and obstetrics series.
ical risk factors: a systematic review. Obstet Gynecol 2003;101: Carnforth (UK): Parthenon Publishing Group Limited; 1992.
68. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet 53. Morris JM FR, Ellwood DA, Cook C, Devonald KJ. A agents for preventing pre-eclampsia and its complications. The randomized controlled trial of aspirin in patients with abnor- Cochrane Database of Systematic Reviews 2007, Issue 2. Art.
mal uterine artery blood flow. Obstet Gynecol 1996;87:74 – 8.
No.: CD004659. DOI: 10.1002/14651858.CD004659.pub2.
VOL. 116, NO. 2, PART 1, AUGUST 2010 Bujold et al
Preeclampsia and IUGR Prevention With Aspirin 69. Ruano R, Fontes RS, Zugaib M. Prevention of preeclampsia early placental insufficiency. J Obstet Gynaecol Can 2009; with low-dose aspirin – a systematic review and meta-analysis 31:1144 – 8.
of the main randomized controlled trials. Clinics (Sao Paulo) 74. Rizzo G, Capponi A, Pietrolucci ME, Capece A, Arduini D.
First-trimester placental volume and vascularization measured 70. Baschat AA, Poon LY, Blitzer M, Nicolaides KH, Harman C.
by 3-dimensional power Doppler sonography in pregnancies Impact of 1st trimester aspirin on population pervalence of with low serum pregnancy-associated plasma protein a levels.
preeclampsia. Ultrasound Obstet Gynecol 2009;34:14.
J Ultrasound Med 2009;28:1615–22.
71. Lambers MJ, Groeneveld E, Hoozemans DA, Schats R, Hom- 75. Dumont A, Flahault A, Beaufils M, Verdy E, Uzan S. Effect of burg R, Lambalk CB, et al. Lower incidence of hypertensive aspirin in pregnant women is dependent on increase in bleed- complications during pregnancy in patients treated with low- ing time. Am J Obstet Gynecol 1999;180:135– 40.
dose aspirin during in vitro fertilization and early pregnancy.
76. Caron N, Rivard GE, Michon N, Morin F, Pilon D, Moutquin Hum Reprod 2009;24:2447–50.
JM, et al. Low-dose ASA response using the PFA-100 in 72. Poon LC, Stratieva V, Piras S, Piri S, Nicolaides KH. Hyper- women with high-risk pregnancy. J Obstet Gynaecol Can tensive disorders in pregnancy: combined screening by uterine artery Doppler, blood pressure and serum PAPP-A at 11–13 77. Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, weeks. Prenat Diagn 2010;30:216 –23.
et al. Dalteparin for the prevention of recurrence of placental- 73. Bujold E, Effendi M, Girard M, Gouin K, Forest JC, mediated complications of pregnancy in women without Couturier B, et al. reproducibility of first trimester three- thrombophilia: a pilot randomized controlled trial. J Thromb dimensional placental measurements in the evaluation of Haemost 2009;7:58 – 64.
Bujold et al
Preeclampsia and IUGR Prevention With Aspirin OBSTETRICS & GYNECOLOGY

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