- Email: [email protected]
Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review
Aspirin for Prevention of Preeclampsia in Women With Historical Risk Factors: A Systematic Review Aravinthan Coomarasamy, MRCOG, Honest Honest, MBChB, Spyros Papaioannou, MRCOG, Harry Gee, MD, FRCOG, and Khalid Saeed Khan, MSc, MRCOG OBJECTIVE: To examine the effectiveness of aspirin in preventing perinatal death and preeclampsia in women with predisposing historical risk factors, such as previous history of preeclampsia, chronic hypertension, diabetes, and renal disease. DATA SOURCES: Searches were conducted in MEDLINE, EMBASE, Cochrane Library, National Research Register, SCISEARCH, and ISI Conference Proceedings without any language restriction, using the following medical subject headings and text words: “aspirin,” “antiplatelet*,” “salicyl*,” “acetylsalicyl*,” “platelet aggregation inhibitors,” “pre-eclamp*,” “preeclamp*,” and “hypertens*.” METHODS OF STUDY SELECTION: We included all randomized trials that evaluated the effectiveness of aspirin compared with placebo or no treatment in women with predisposing historical risk factors and reported clinically relevant perinatal or maternal outcomes. Study selection, quality appraisal, and data extractions were performed independently and in duplicate. TABULATION, INTEGRATION, AND RESULTS: We identified 14 relevant trials, including a total of 12,416 women. Metaanalysis showed a significant benefit of aspirin therapy in reducing perinatal death (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.64, 0.96) and preeclampsia (OR 0.86, 95% CI 0.76, 0.96). Aspirin was also associated with a reduction in rates of spontaneous preterm birth (OR 0.86, 95% CI 0.79, 0.94), and an increase of 215 g in mean birth weight (weighted mean difference 215, 95% CI 90, 341). There was no increase in the risk of placental abruption with aspirin (OR 0.98, 95% CI 0.79, 1.21). Funnel plot analysis indicated that publication and related biases were unlikely (Egger test, P ⴝ .84). From the Education Resource Centre, Birmingham Women’s Hospital, Birmingham, United Kingdom. All contributors to this review, except HH, are employees of the National Health Service of United Kingdom. HH holds a WellBeing Research Fund from the Royal College of Obstetricians and Gynaecologists (United Kingdom). No private or commercial funding was obtained. AC and KSK conceived the review. AC, HH, and SP collected, analyzed, and interpreted the data and drafted the manuscript. KSK and HG made critical revisions. AC and HH are the guarantors for this article.
CONCLUSION: Aspirin reduces the risk of perinatal death and preeclampsia in women with historical risk factors. Given the importance of these outcomes and the safety and low cost of aspirin, aspirin therapy should be considered in women with historical risk factors. (Obstet Gynecol 2003; 101:1319 –32. © 2003 by The American College of Obstetricians and Gynecologists.)
Readily obtainable historical information, such as previous history of preeclampsia,1– 4 history of chronic hypertension,3,5,6 diabetes,3,7 renal disease,8,9 and family history10 of preeclampsia may be used to identify groups of women at high risk for preeclampsia. Such an inexpensive and practical risk identification process, which can be done at the primary care level, assumes significant importance if there were an effective therapy to reduce the risk of preeclampsia and its related complications. There are several randomized trials that assess the effectiveness of aspirin in women with historical risk factors.11–19 However, they generally show a statistically nonsignificant inclination toward benefit, which may be owing to lack of power. A meta-analysis of this group of studies should allow us to generate more precise estimates of effect. We therefore conducted a systematic review and meta-analysis of randomized trials to assess the effectiveness of aspirin in women identified to be at risk from historical risk factors. SOURCES We searched MEDLINE (1966 –2001), EMBASE (1980 –2001), Cochrane Library (2001:3), National Research Register (2001:3), SCISEARCH (1974 –2001), and conference proceedings (ISI Proceedings, 1990 – 2001) for relevant citations. A combination of medical subject headings and text words were used to generate two subsets of citations, one including studies of aspirin (“aspirin,” “antiplatelet*,” “salicyl*,” “acetylsalicyl*,” and “platelet aggregation inhibitors”) and the other studies of preeclampsia (“pre-eclamp*,” “preeclamp*,” and “hypertens*”). These subsets were combined using
VOL. 101, NO. 6, JUNE 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
0029-7844/03/$30.00 doi:10.1016/S0029-7844(03)00169-8
1319
Figure 1. Study selection process for systematic review of aspirin to prevent preeclampsia in women with historical risk factors for preeclampsia. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
“AND” to generate a subset of citations relevant to our research question. The reference lists of all known primary and review articles were examined to identify cited articles not captured by electronic searches. Articles frequently cited were used in the Science Citation Index to identify additional citations. We also made inquiries about unpublished studies to researchers investigating in this field. No language restrictions were placed in any of our searches. STUDY SELECTION Studies were selected if the target population was women with historical risk factors for preeclampsia, the therapeutic intervention was low-dose aspirin (any definition) compared with placebo or no drug treatment, and the studies were of randomized design. The historical
1320
Coomarasamy et al
Aspirin in Historical Risk Factors
risk factors included previous preeclampsia, chronic (preexisting) hypertension, diabetes, renal disease, and extremes of age at conception.3,20,21 The main outcomes were perinatal death and preeclampsia (proteinuric hypertension). However, all studies that reported on any clinically relevant perinatal or maternal outcomes, such as preterm birth, birth weight, and antenatal bleeding or placental abruption, were also included. Studies were selected in a two-stage process. First, the titles and abstracts from the electronic searches were scrutinized by two reviewers independently (AC and HH), and full manuscripts of all citations that were likely to meet the predefined selection criteria were obtained. Second, final inclusion or exclusion decisions were made on examination of the full manuscripts. In cases of duplicate publication, the most recent and complete ver-
OBSTETRICS & GYNECOLOGY
Table 1. Quality of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors Author, year (reference) Beaufils et al, 1985 (11) Benigni et al, 1989 (31) Azar et al, 1990 (abstract) Sureau, 1991 (12) Parazzini et al, 1993 (13) Rogov et al, 1993 (14) Viinikka et al, 1993 (15) August et al, 1994 (abstract) Beroyz et al, 1994 (32) ECPPA, 1996 (33) Gallery et al, 1997 (17) Byaruhanga et al, 1998 (18) Caritis et al, 1998 (19) Volpicelli et al, 1999 (34)
Randomization and concealment “Randomly allocated,” but details of randomization or concealment not given “Patients randomly assigned,” but details of randomization or concealment not given Method of randomization and concealment unreported Centralized telephone randomization; concealment adequate Centralized telephone randomization; concealment adequate “Stratified block randomization,” but details of randomization or concealment not given “Randomly allocated,” but details of randomization not given; concealment adequate “Randomized,” but details of randomization or concealment not given Centralized telephone randomization; concealment adequate Centralized telephone randomization; concealment adequate A series of random numbers were used for randomization; method of concealment unreported Computerized randomization; concealment adequate Centralized computer randomization; concealment adequate “Randomized,” but details of randomization or concealment not given
sions were selected. The assessment of English-language manuscripts was performed independently by two reviewers (AC and HH) and other language manuscripts by people who had command of the language. Any disagreements about inclusion were resolved by consensus or arbitration by a third reviewer (KSK). The selected studies were assessed for methodologic quality by using the components of study design that are related to internal validity.22 Information on the adequacy of randomization, concealment, control, blinding, intention to treat, and follow-up rates was sought. Percentage agreement and statistic were used for analysis of agreement between the reviewers. A minimum acceptable agreement was set at a level of 0.7, as this represents substantial strength of agreement.23 From each study outcome data were abstracted in 2 ⫻ 2 tables. Odds ratios (ORs) from individual studies were pooled
VOL. 101, NO. 6, JUNE 2003
Intention to treat
Blinding
Follow-up (%)
None
Unreported
91
Single
Unreported
⬎95
None
Yes
⬎95
Double
Yes
⬎95
Double
Yes
94
None
Unreported
⬎95
Double
Yes
⬎95
Double
Unreported
Double
Yes
⬎95
Double
Yes
⬎95
Unreported
Yes
90
Double
Unreported
92
Double
Unreported
⬎95
Unreported
Unreported
⬎95
91
using the Peto method.24 However, as there is no clear consensus as to the most appropriate method for metaanalysis,25 we examined the sensitivity of our results to variation in statistical approach by performing metaanalysis using fixed-effects26 and random-effects27 models. Weighted mean difference was calculated for continuous variables using means and standard deviations from individual studies. Heterogeneity of treatment effects was evaluated graphically using forest plot27 and statistically using 2 test.28 Exploration of the causes of heterogeneity was planned using variation in features of the population, intervention, outcome, and study quality. To assess for publication bias, we performed a funnel plot analysis,29 using the Egger test30 to evaluate for asymmetry. All statistical analyzes were performed using Stata 7.0 statistical software (Stata Corp., College Station, TX).
Coomarasamy et al
Aspirin in Historical Risk Factors
1321
Table 2. Study Characteristics of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors Author, year (reference)
Participants
Beaufils et al, Women with chronic 1985 (11) hypertension or several previous pregnancy complications (such as stillbirths and growth restriction)
Period of treatment
Experimental treatment
Comparison
From 3 mo gestation 150 mg aspirin No treatment to delivery and 300 mg dipyridamole
Exclusions: women with secondary hypertension, or known or suspected renal disease Benigni et al, Women with chronic 1989 (31) hypertension, previous history of early-onset (⬍32 weeks) preeclampsia, intrauterine growth restriction, or fetal death due to placental insufficiency
Azar et al, 1990 (abstract)
Sureau, 1991 (12) (trial A included in the review)
From 12 wk to delivery
Exclusions: women with antiphospholipid antibodies Women with previous From 16 wk to early-onset preeclampsia, delivery severe intrauterine growth restriction, or fetal death due to placental insufficiency Women with poor outcome From 15 to 18 wk; during the two previous end of treatment pregnancies, at least one not stated being fetal growth restriction or fetal growth restriction during the one preceding pregnancy
Exclusions included women with twin pregnancy, uterine malformations, renal disease, secondary hypertension, and contraindication to use of aspirin or dipyridamole, or current use of antiinflammatory drugs or anticoagulants Parazzini et al, Women with previous From 16 to 32 wk, 1993 (13) history of pregnancyuntil delivery induced hypertension, preeclampsia, chronic hypertension, nephropathy, growth restriction, current twin pregnancy or age less than 18 or over 40 y
60 mg aspirin
Placebo
100 mg aspirin No treatment and 300 mg dipyridamole
150 mg aspirin Placebo or 150 mg aspirin and 225 mg dipyridamole
Outcomes Preeclampsia (diastolic ⬎ 105 mm Hg; proteinuria ⬎ 1.5 g/day) Pregnancy-induced hypertension (blood pressure ⱖ 140/85 mm Hg) Birth weight Birth weight below 10th centile, and 3rd centile Duration of pregnancy Uric acid and platelet levels Perinatal death Pregnancy-induced hypertension (blood pressure ⬎ 140/90 mm Hg) Duration of pregnancy Birth weight Birth weight below 10th centile Perinatal death
Preeclampsia (undefined) Pregnancy induced hypertension Duration of pregnancy Birth weight Stillborn fetus Preeclampsia (blood pressure ⬎ 140/90 mm Hg; proteinuria undefined) Birth weight Birth weight below 10th centile Cesarean delivery before 34 wk Abruption Perinatal death
50 mg aspirin
No treatment
Preeclampsia (diastolic ⬎ 90 mm Hg; proteinuria undefined) Pregnancy-induced hypertension Birth weight Birth weight below 5th or 10th centile Preterm delivery (below 34 or 37 wk) Perinatal death (continued)
Table 2. Study Characteristics of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors (continued) Author, year (reference)
Rogov et al, 1993 (14)
Participants
Period of treatment
Experimental treatment
Comparison
Outcomes
Exclusions: women with a history of chronic disease (except hypertension, renal disease, or diabetes), allergy to aspirin, or documented fetal malformations Women with chronic From 12 to 19 wk, 125 mg aspirin and No treatment hypertension or until delivery 150–225 mg renal disease dipyridamole
Viinikka et al, 1993 (15)
Women with chronic hypertension or previous history of severe preeclampsia
From 12 to 18 wk, 50 mg aspirin until delivery
August et al, 1994 (abstract)
Women with chronic hypertension or previous severe preeclampsia
From 13 to 15 wk, 100 mg sustaineduntil 37 wk release aspirin
Beroyz et al, Women with a history of From 12 to 32 wk, 60 mg film-coated 1994 (32) preeclampsia or growth until delivery aspirin (subgroup restriction in previous in which pregnancy, chronic women were hypertension, renal recruited disease or other on risk factors, such prophylactic as maternal age, criteria family history, or were multiple pregnancy included in the review)
Preeclampsia Preterm delivery (less than 36 wk) Birth weight less than 2 standard deviations for gestational age Perinatal deaths Placental abruptions Matching placebo Preeclampsia (blood pressure ⬎ 160/120 mm Hg in those with preexisting hypertension, and ⬎ 160/110 mm Hg in those normotensive before pregnancy; proteinuria ⬎ 300 mg in 24 h) Pregnancy-induced hypertension Birth weight Birth weight below 2 standard deviations for gestation Duration of pregnancy Duration of labor Mode of delivery Maternal bleeding time Admission to neonatal intensive care Perinatal deaths Matching placebo Preeclampsia (a rise in systolic ⬎ 30 mm Hg or diastolic ⬎ 15 mm Hg; proteinuria undefined) Duration of pregnancy Growth of restriction (undefined) Placental abruptions Matching placebo Preeclampsia (diastolic ⬎ 90 mm Hg AND proteinuria ⱖ 1⫹) Duration of pregnancy Birth weight Birth weight below 3rd centile Preterm delivery (ⱕ 37 wk) Stillbirth or neonatal death Abruptions and other antenatal bleeds (continued)
VOL. 101, NO. 6, JUNE 2003
Coomarasamy et al
Aspirin in Historical Risk Factors
1323
Table 2. Study Characteristics of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors (continued) Author, year (reference)
ECPPA, 1996 (33)
Participants
Period of treatment
Experimental treatment
Exclusions: women with increased risk of bleeding, asthma, allergy to aspirin, or a high likelihood of immediate delivery Women with previous From 12 to 32 wk, 60 mg filmMatching placebo history of preeclampsia, until delivery coated aspirin chronic hypertension, renal disease, growth restriction, diabetes, or primigravid with other risk factors, such as young or old age
Exclusions: women with increased risk of bleeding, asthma, allergy to aspirin, gastric ulcer, and placenta previa Gallery et al, Women with previous early From 17 to 19 wk, 100 mg aspirin 1997 (17) severe preeclampsia, until 2 wk chronic hypertension, or before planned renal disease delivery Exclusions: women with history of aspirin allergy, aspirin sensitive asthma, pre-existing bleeding disorders, or multiple pregnancies Byaruhanga Women with previous et al, 1998 history of pregnancy(18) induced hypertension, preeclampsia, eclampsia, or chronic hypertension
Caritis et al, 1998 (19)
Comparison
From 20 to 28 wk 75 mg aspirin to 38 wk
Exclusions: women with history of allergy to aspirin, peptic ulcers, bleeding disorders, and chronic pulmonary disease; women who developed preeclampsia before trial entry or were on nonsteroidal antiinflammatory drugs were also excluded Women with previous From 13 to 26 wk, 60 mg aspirin history of preeclampsia, until delivery diabetes, chronic hypertension or multifetal pregnancy
Placebo
Outcomes
Preeclampsia (diastolic ⬎ 90 mm Hg; proteinuria undefined) Birth weight Birth weight below 3rd centile Preterm delivery (below 37 wk) Perinatal death Maternal bleeding (including abruption) Fetal bleeding (including intraventricular hemorrhage)
Systolic ⬎ 140 mm Hg; diastolic ⬎ 90 mm Hg Urinary protein ⬎ 300 mg/d Birth weight ⬍ 2500 g Duration of pregnancy Delivery before 37 wk Serum uric acid levels Perinatal death Antepartum hemorrhage
Matching placebo Preeclampsia (hypertension– undefined; proteinuria ⬎ 1⫹ or ⱖ 300 mg/L) Birth weight Birth weight below 10th centile Duration of pregnancy Preterm delivery (⬍ 37 wk) Perinatal death Admission to neonatal unit Blood loss ⬎ 500 mL
Matching placebo Preeclampsia (systolic ⱖ 140 mm Hg or diastolic ⱖ 90 mm Hg AND proteinuria ⱖ 2⫹ or ⬎ 300 mg in 24 h, or platelets count ⬍ 100,000 per mm3) Birth weight below 10th centile (continued)
1324
Coomarasamy et al
Aspirin in Historical Risk Factors
OBSTETRICS & GYNECOLOGY
Table 2. Study Characteristics of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors (continued) Author, year (reference)
Participants
Period of treatment
Exclusions: women with multifetal pregnancy AND diabetes, chronic hypertension, or proteinuria; current history of proteinuria or preeclampsia Volpicelli et al, Women with previous From 18 to 26 wk 1999 (34) history of severe preeclampsia, or chronic hypertension
Experimental treatment
Comparison
50 mg aspirin Placebo
Outcomes Preterm delivery (⬍ 37 wk) Neonatal intraventricular hemorrhage Neonatal bleeding Perinatal death Abruption Postpartum bleeding Preeclampsia (undefined)
Figure 2. Meta-analysis of randomized trials evaluating the effectiveness of aspirin to prevent perinatal death in women with historical risk factors for preeclampsia. The results were not heterogeneous (212 ⫽ 10.61, P ⫽ .56). CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
VOL. 101, NO. 6, JUNE 2003
Coomarasamy et al
Aspirin in Historical Risk Factors
1325
Figure 3. Meta-analysis of randomized trials evaluating the effectiveness of aspirin to prevent preeclampsia in women with historical risk factors. The results were not heterogeneous (212 ⫽ 10.85, P ⫽ .54). CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
RESULTS Figure 1 summarizes the process of literature identification and selection. Of the 729 citations identified, 47 were selected during the initial screening (agreement 99%; 0.91), and on examination of the full manuscripts of these 47, 12 articles,11–15,17–19,31–34 and two abstracts (Azar R, Turpin D. Effect of antiplatelet therapy in women at high risk for pregnancy induced hypertension [abstract]. Proceedings of 7th World Congress, International Society for the Study of Hypertension in Pregnancy, Perugia, Italy. Newcastle upon Tyne, United Kingdom: ISSHP, 1990:257) (August P, Helseth G, Edersheim TG, Hutson JM, Druzin M. Sustained release, low-dose aspirin ameliorates but does not prevent preeclampsia (PE) in a high risk population [abstract]. Proceedings of 9th International Congress, International Society for the Study of Hypertension in Pregnancy, Sydney, Australia. Newcastle upon Tyne, United Kingdom: ISSHP, 1994:352), including a total of 12,416 women, were identified to satisfy the selection criteria for
1326
Coomarasamy et al
Aspirin in Historical Risk Factors
our review (agreement 96%; 0.89). The quality and the main characteristics of the included studies are presented in Tables 1 and 2. Pooling of results from these studies showed a significant benefit of aspirin therapy in reducing perinatal death (OR 0.79, 95% confidence interval [CI] 0.64, 0.96, Figure 2) and preeclampsia (OR 0.86, 95% CI 0.76, 0.96, Figure 3). The results were robust to alternative approaches to statistical pooling using either fixed- or random-effects models (results available from authors on request). The results were also found to be homogeneous (P ⫽ .56 for perinatal death and .54 for preeclampsia). We also found a significant reduction in rates of spontaneous preterm births (OR 0.86, 95% CI 0.79, 0.94, Figure 4), and an increase of 215 g in mean birth weight with aspirin use (weighted mean difference 215, 95% CI 90, 341, Figure 5). There was no increase in the risk of abruptions with aspirin treatment (OR 0.98, 95% CI 0.79, 1.21, Figure 6). Although funnel plot analysis was limited because of the small number of studies, it
OBSTETRICS & GYNECOLOGY
Figure 4. Meta-analysis of randomized trials evaluating the effectiveness of aspirin to prevent preterm birth in women with historical risk factors for preeclampsia. The results were not heterogeneous (26 ⫽ 1.54, P ⫽ .96). CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
indicated that publication and related biases were unlikely (Egger test, P ⫽ .84). CONCLUSION Our systematic review shows that low-dose aspirin has a significant effect in reducing the rates of a number of clinically relevant outcomes, including perinatal deaths and preeclampsia, in women with historical risk factors for preeclampsia. The validity of our findings depends on the methodologic rigor of our review and of the component primary studies. We used a prospective protocol and made a concerted effort to find all the evidence. Two independent reviewers assessed study quality and extracted data, and the agreement between the two reviewers was high. The studies we found were generally of good quality, and the results were homogeneous. The results were significant regardless of the statistical approach used for meta-analysis. In addition, there was no evidence of publication and related biases from funnel plot analysis. One potential source of bias in our review was the inclusion of studies without a placebo arm. To address
VOL. 101, NO. 6, JUNE 2003
this, we performed sensitivity analysis, excluding such studies from the analysis (data not shown), and found that the results were consistent with our inferences. We are, therefore, confident that our inferences are robust. The debate about aspirin to prevent preeclampsia has been rekindled by a recent Cochrane review.35,36 It showed a statistically significant reduction in preeclampsia (relative risk [RR] 0.85, 95% CI 0.78, 0.92) and perinatal death (RR 0.86, 95% CI 0.75, 0.98), but it concluded that the clinical significance of this finding was questionable, stating “as the reductions in risk are small to moderate, relatively large numbers of women will need to be treated to prevent a single outcome” (the number of women needed to be treated to prevent one case of preeclampsia was 100, and to prevent one case of perinatal death was 250). This is likely to be because studies including high-risk women who could benefit most from aspirin therapy were pooled together with those including low-risk women. In high-risk women, the baseline risk of preeclampsia and associated complications would be expected to be higher, thus resulting in higher absolute benefit (lower number needed to treat)
Coomarasamy et al
Aspirin in Historical Risk Factors
1327
Figure 5. Meta-analysis of randomized trials assessing neonatal birth weight in women treated with aspirin compared with placebo or no treatment among women with historical risk factors for preeclampsia. As the results were heterogeneous (27 ⫽ 40.85, P ⫽ .01), random-effects model was used for meta-analysis. CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
from aspirin therapy. For example, a recent systematic review of studies exclusively of those women in whom high risk was identified by an abnormal uterine artery Doppler test showed that the average absolute benefit from aspirin therapy to prevent preeclampsia was substantial (number needed to treat was 16, 95% CI 8, 316).37 Our review did not show any evidence of harm from aspirin therapy. This was also confirmed in the Cochrane review.35,36 In particular, there was no increase in placental abruptions, fetal intraventricular hemorrhage, or other neonatal bleeding. However, as randomized trials and systematic reviews of randomized trials may involve patients studied for a short length of time, they are not likely to detect delayed adverse events.38 We therefore supplemented the evidence on harm with a systematic search for large observational studies using the following words and their word variants in MEDLINE (1966 –2001) and EMBASE (1988 –2001) bibliographic databases: “aspirin [adverse effects]” combined with “pregnancy.” Three large cohort studies39 – 41 and
1328
Coomarasamy et al
Aspirin in Historical Risk Factors
one large case– control study42 were identified (Table 3). These observational studies, with more than 96,000 women between them, did not provide any evidence of teratogenicity or long-term adverse effects of aspirin use in pregnancy. The only evidence of harm came from a case– control study that showed evidence of increased risk of miscarriage when nonsteroidal antiinflammatory drugs were started early in gestation, although this risk was not present if the drugs were started after 12 weeks.41 However, no adjustment was made in this study for the indication of nonsteroidal anti-inflammatory use, and this would be expected to introduce substantial bias. This is because women with conditions such as systemic lupus erythematosus and rheumatoid arthritis are more likely to be users of nonsteroidal anti-inflammatory drugs during pregnancy but have an inherently higher risk of miscarriage as a result of the underlying condition rather than the drug itself. Thus, we regard this evidence of association between nonsteroidal drugs and miscarriage as unreliable.
OBSTETRICS & GYNECOLOGY
Figure 6. Meta-analysis of randomized trials evaluating rates of abruptions and other antepartum bleeding with aspirin compared with placebo or no treatment among women with historical risk factors for preeclampsia The results were not heterogeneous (26 ⫽ 4.00, P ⫽ .67). CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
The baseline risks of perinatal death and preeclampsia among the randomized trials, represented by the control event rates, varied substantially between trials. In this situation, calculating average numbers needed to be treated from pooled metaanalysis results can be seriously misleading.43 This is because numbers needed to be treated are sensitive to the levels of baseline risk, and will, therefore, need to be individualized to appropriate baseline risks.44 Consequently, we have given a range of numbers needed to be treated appropriate for various baseline risks for the several outcomes, as examples, in Table 4. When multiple historical risk factors are involved, the numbers needed to be treated would be expected to be even lower. However, these numbers needed to be treated need to be interpreted with caution, as there may have been changes in baseline risks over time, and the CIs around the numbers needed to be treated do not incorporate the uncertainty around the base-
VOL. 101, NO. 6, JUNE 2003
line risks (as these were not reported in most prevalence studies). Based on our findings and the established safety of aspirin, it seems reasonable to recommend aspirin therapy to women who are historically at high risk for preeclampsia, particularly those with multiple risk factors. Those who may benefit include women with previous severe or early-onset preeclampsia, chronic hypertension, severe diabetes, and moderate to severe renal disease (Table 4). Our findings assume particular significance as the diagnosis of historical risk factors for preeclampsia can be made inexpensively (without the need for any laboratory tests) and at the primary care level. This is of critical importance in the developing world, particularly Africa, where preeclampsia is more prevalent, and resources for sophisticated investigations and expensive treatment are not generally available. Further research needs to address the possible cost– benefits of this approach to health care systems and the society.
Coomarasamy et al
Aspirin in Historical Risk Factors
1329
Table 3. Observational Studies That Have Evaluated the Potential Harm of Aspirin Use in Pregnancy Author, year (reference)
Study design
Nielsen et al, 2001 (41)
Cohort
Slone et al, 1976 (39)
Cohort
Population and exposure 18,721 pregnancies: 1462 on nonsteroidal antiinflammatory drugs 17,259 on no drugs during pregnancy
50,282 pregnancies: 5128 heavily exposed to aspirin 9736 intermediately exposed to aspirin 35,418 not exposed to aspirin Klebanoff et al, Cohort 19,226 pregnancies: 1988 (40) 10,159 on aspirin 9067 never on aspirin in pregnancy Werler et al, Case–control Cases: 1381 infants with any 1989 (42) structural cardiac defects Controls: 6966 infants with other malformations
Outcome
Comments
No difference in congenital abnormalities between the exposed and non-exposed groups
No difference in malformation rates between the three groups
No difference in mean intelligence quotient at age 4 y No association between cardiac defects and aspirin
An additional case–control study, assessing the risk of miscarriage, was also reported in this article. It found an association between miscarriage and early aspirin use. However, the miscarriage rate was not increased when aspirin was started after 12 wk Controlling for multiple confounders did not change the conclusion
Controlling for multiple socials, demographic and other confounders did not change the conclusion
Table 4. Examples of Numbers of Women Needed to Be Treated With Aspirin to Prevent One Case of Various Outcomes Individualized According to Baseline Risk of Outcome Without Treatment
Outcome Preeclampsia
Perinatal death
Preterm birth
Historical risk factor Previous severe, early-onset (second trimester) preeclampsia Previous severe preeclampsia Previous preeclampsia Chronic hypertension Diabetes Diabetes after the exclusion of nephropathy or chronic hypertension Moderate to severe renal insufficiency Previous severe early onset (second trimester) preeclampsia Previous severe preeclampsia Chronic hypertension Diabetes Moderate to severe renal insufficiency Previous preeclampsia Chronic hypertension Diabetes Moderate to severe renal insufficiency
Baseline risk of the outcome (%) (reference) 65 (1)
Odds ratio (95% CI) 0.86 (0.76, 0.96)
47 (2) 18 (3,4) 25 (3,5,6) 20 (3) 9 (7) 59 (8) 17 (1) 6 (2) 5 (5) 1 (7) 7 (9) 32 (4) 34 (5) 10 (7) 59 (9)
Number needed to be treated (95% CI) 12 (8, 52) 17 (10, 70) 43 (27, 185) 31 (20, 134) 39 (24, 167) 86 (53, 371)
0.79 (0.64, 0.96)
0.86 (0.79, 0.94)
14 (9, 57) 28 (18, 148) 80 (50, 417) 96 (59, 500) 477 (295, 2500) 68 (42, 357) 32 (21, 79) 30 (20, 74) 100 (67, 250) 17 (12, 43)
CI ⫽ confidence interval.
1330
Coomarasamy et al
Aspirin in Historical Risk Factors
OBSTETRICS & GYNECOLOGY
REFERENCES 1. Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis. Am J Obstet Gynecol 1991;165:1408–12. 2. Sibai BM, el Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: Subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 1986;155:1011–6. 3. Caritis S, Sibai B, Hauth J, Lindheimer M, VanDorsten P, Klebanoff M, et al. Predictors of pre-eclampsia in women at high risk. Am J Obstet Gynecol 1998;179:946–51. 4. Hnat MD, Sibai BM, Caritis S, Hauth J, Lindheimer MD, MacPherson C, et al. Perinatal outcome in women with recurrent preeclampsia compared with women who develop preeclampsia as nulliparas. Am J Obstet Gynecol 2002;186:422–6. 5. Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 1994;171:410–6. 6. Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;67:197–205. 7. Garner PR, D’Alton ME, Dudley DK, Huard P, Hardie M. Preeclampsia in diabetic pregnancies. Am J Obstet Gynecol 1990;163:505–8. 8. Cunningham FG, Cox SM, Harstad TW, Mason RA, Pritchard JA. Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 1990;163:453–9. 9. Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or severe renal insufficiency. N Engl J Med 1996;335:226–32. 10. Mogren I, Hogberg U, Winkvist A, Stenlund H. Familial occurrence of preeclampsia. Epidemiology 1999;10: 518–22. 11. Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet 1985;1:840–2. 12. Sureau C. Prevention of perinatal consequences of preeclampsia with low-dose aspirin: Results of the Epreda trial. Eur J Obstet Gynecol Reprod Biol 1991;41:71–3. 13. Parazzini F, Benedetto C, Frusca T, Gregorini G, Bocciolone L, Marozio, et al. Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Lancet 1993;341:396 – 400. 14. Rogov VA, Tareeva IE, Sidorova IS, Androsova SO, Katamadze KT, Nikiforova OV. Acetylsalicylic acid and kurantil in the prevention of pregnancy complications in glomerulonephritis and hypertension [in Russian]. Ter Arkh 1993;65:65–8. 15. Viinikka L, Hartikainen-Sorri A-L, Lumme R, Hiilesmaa V, Ylikorkala O. Low dose aspirin in hypertensive pregnant women: Effect on pregnancy outcome and prostacyclin-thromboxane balance in mother and newborn. Br J Obstet Gynaecol 1993;100:809–15.
VOL. 101, NO. 6, JUNE 2003
16. Goffinet F, Breart G, Uzan S, Atallah A. ECPPA: Randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. Br J Obstet Gynaecol 1996;103:719–20. 17. Gallery EDM, Ross MR, Hawkins M, Leslie G, Gyory AZ. Low-dose aspirin in high-risk pregnancy? Hypertens Pregnancy 1997;16:229–38. 18. Byaruhanga RN, Chipato T, Rusakaniko S. A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia. Int J Gynecol Obstet 1998;60:129–35. 19. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701–5. 20. Dumont A, Merviel P, Berkane N, Gaudet R, Uzan S. Risk factors for pre-eclampsia. Presse Med 1999;28:2189–96. 21. Visser W, Wallenburg HC. Prediction and prevention of pregnancy-induced hypertensive disorders. Baillieres Best Pract Res Clin Obstet Gynaecol 1999;13:131–56. 22. NHS Centre for Reviews and Dissemination. Undertaking systematic reviews of research on effectiveness. CRD’s guidance for carrying out or commissioning reviews. CRD report number 4, (2nd edition). York, United Kingdom: University of York, NHS Centre for Reviews and Dissemination, 2001. 23. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74. 24. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog Cardiovasc Dis 1985; 27:335–71. 25. Thompson SG, Pocock SJ. Can meta-analyses be trusted? Lancet 1991;338:1127–30. 26. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719–48. 27. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. 28. Clarke M, Oxman MD, eds. Investigating heterogeneity. Cochrane reviewers handbook (updated June 2000). Section 8.6. Oxford, United Kingdom: The Cochrane Collaboration, 2000. 29. Light RJ, Pillemer DB. Summing up: The science of reviewing research. Cambridge, Massachusetts: Harvard University Press, 1984. 30. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. 31. Benigni A, Gregorini G, Frusca T, Chiabrando C, Ballerini S, Valcamonico A, et al. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. N Engl J Med 1989;321:357–62.
Coomarasamy et al
Aspirin in Historical Risk Factors
1331
32. Beroyz G, Casale R, Farreiros A, Palermo M, Margulies M, Voto L, et al. 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. 33. ECPPA (Estudo Colaborativo para Prevencao da Preeclampsia com Aspirina) Collaborative Group. ECPPA: Randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. Br J Obstet Gynaecology 1996;103:39–47. 34. Volpicelli T, D’Anto V, Faticato A, Galante L, Civitillo R. Trial prospecticco sull’uso profillatico dell’aspirina in donne gravide ad alto rischio di pre-eclampsia. Gestosi 1999;99:159–60. 35. Knight M, Duley L, Henderson-Smart DJ, King JF. Antiplatelet agents for preventing and treating pre-eclampsia. Cochrane Database Syst Rev 2000;2:CD000492. 36. Duley L, Henderson-Smart D, Knight M, King J. Antiplatelet drugs for prevention of pre-eclampsia and its consequences: Systematic review. BMJ 2001;322:329–33. 37. Coomarasamy A, Papaioannou S, Gee H, Khan KS. Aspirin for the prevention of preeclampsia in women with abnormal uterine artery Doppler: A meta-analysis. Obstet Gynecol 2001;98:861–6. 38. Ernst E, Pittler MH. Assessment of therapeutic safety in systematic reviews: Literature review. BMJ 2001;323:546. 39. Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman
1332
Coomarasamy et al
Aspirin in Historical Risk Factors
40.
41.
42.
43.
44.
DW, Shapiro S. Aspirin and congenital malformations. Lancet 1976;1:1373–5. Klebanoff MA, Berendes HW. Aspirin exposure during the first 20 weeks of gestation and IQ at four years of age. Teratology 1988;37:249–55. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: Population based observational study and case-control study. BMJ 2001;322:266–70. Werler MM, Mitchell AA, Shapiro S. The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects. N Engl J Med 1989;321:1639–42. Smeeth L, Haines A, Ebrahim S. Numbers needed to treat derived from meta-analyses—sometimes informative, usually misleading. BMJ 1999;318:1548–51. Cook RJ, Sackett DL. The number needed to treat: A clinically useful measure of treatment effect. BMJ 1995; 310:452–4.
Address reprint requests to: Aravinthan Coomarasamy, MRCOG, Research Fellow in Evidence-Based Obstetrics, Birmingham Women’s Hospital, Education Resource Center, Metchley Park Road, Birmingham, B15 2TG, United Kingdom; E-mail: [email protected]. Received September 13, 2002. Received in revised form December 4, 2002. Accepted December 12, 2002.
OBSTETRICS & GYNECOLOGY
CONCLUSION: Aspirin reduces the risk of perinatal death and preeclampsia in women with historical risk factors. Given the importance of these outcomes and the safety and low cost of aspirin, aspirin therapy should be considered in women with historical risk factors. (Obstet Gynecol 2003; 101:1319 –32. © 2003 by The American College of Obstetricians and Gynecologists.)
Readily obtainable historical information, such as previous history of preeclampsia,1– 4 history of chronic hypertension,3,5,6 diabetes,3,7 renal disease,8,9 and family history10 of preeclampsia may be used to identify groups of women at high risk for preeclampsia. Such an inexpensive and practical risk identification process, which can be done at the primary care level, assumes significant importance if there were an effective therapy to reduce the risk of preeclampsia and its related complications. There are several randomized trials that assess the effectiveness of aspirin in women with historical risk factors.11–19 However, they generally show a statistically nonsignificant inclination toward benefit, which may be owing to lack of power. A meta-analysis of this group of studies should allow us to generate more precise estimates of effect. We therefore conducted a systematic review and meta-analysis of randomized trials to assess the effectiveness of aspirin in women identified to be at risk from historical risk factors. SOURCES We searched MEDLINE (1966 –2001), EMBASE (1980 –2001), Cochrane Library (2001:3), National Research Register (2001:3), SCISEARCH (1974 –2001), and conference proceedings (ISI Proceedings, 1990 – 2001) for relevant citations. A combination of medical subject headings and text words were used to generate two subsets of citations, one including studies of aspirin (“aspirin,” “antiplatelet*,” “salicyl*,” “acetylsalicyl*,” and “platelet aggregation inhibitors”) and the other studies of preeclampsia (“pre-eclamp*,” “preeclamp*,” and “hypertens*”). These subsets were combined using
VOL. 101, NO. 6, JUNE 2003 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
0029-7844/03/$30.00 doi:10.1016/S0029-7844(03)00169-8
1319
Figure 1. Study selection process for systematic review of aspirin to prevent preeclampsia in women with historical risk factors for preeclampsia. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
“AND” to generate a subset of citations relevant to our research question. The reference lists of all known primary and review articles were examined to identify cited articles not captured by electronic searches. Articles frequently cited were used in the Science Citation Index to identify additional citations. We also made inquiries about unpublished studies to researchers investigating in this field. No language restrictions were placed in any of our searches. STUDY SELECTION Studies were selected if the target population was women with historical risk factors for preeclampsia, the therapeutic intervention was low-dose aspirin (any definition) compared with placebo or no drug treatment, and the studies were of randomized design. The historical
1320
Coomarasamy et al
Aspirin in Historical Risk Factors
risk factors included previous preeclampsia, chronic (preexisting) hypertension, diabetes, renal disease, and extremes of age at conception.3,20,21 The main outcomes were perinatal death and preeclampsia (proteinuric hypertension). However, all studies that reported on any clinically relevant perinatal or maternal outcomes, such as preterm birth, birth weight, and antenatal bleeding or placental abruption, were also included. Studies were selected in a two-stage process. First, the titles and abstracts from the electronic searches were scrutinized by two reviewers independently (AC and HH), and full manuscripts of all citations that were likely to meet the predefined selection criteria were obtained. Second, final inclusion or exclusion decisions were made on examination of the full manuscripts. In cases of duplicate publication, the most recent and complete ver-
OBSTETRICS & GYNECOLOGY
Table 1. Quality of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors Author, year (reference) Beaufils et al, 1985 (11) Benigni et al, 1989 (31) Azar et al, 1990 (abstract) Sureau, 1991 (12) Parazzini et al, 1993 (13) Rogov et al, 1993 (14) Viinikka et al, 1993 (15) August et al, 1994 (abstract) Beroyz et al, 1994 (32) ECPPA, 1996 (33) Gallery et al, 1997 (17) Byaruhanga et al, 1998 (18) Caritis et al, 1998 (19) Volpicelli et al, 1999 (34)
Randomization and concealment “Randomly allocated,” but details of randomization or concealment not given “Patients randomly assigned,” but details of randomization or concealment not given Method of randomization and concealment unreported Centralized telephone randomization; concealment adequate Centralized telephone randomization; concealment adequate “Stratified block randomization,” but details of randomization or concealment not given “Randomly allocated,” but details of randomization not given; concealment adequate “Randomized,” but details of randomization or concealment not given Centralized telephone randomization; concealment adequate Centralized telephone randomization; concealment adequate A series of random numbers were used for randomization; method of concealment unreported Computerized randomization; concealment adequate Centralized computer randomization; concealment adequate “Randomized,” but details of randomization or concealment not given
sions were selected. The assessment of English-language manuscripts was performed independently by two reviewers (AC and HH) and other language manuscripts by people who had command of the language. Any disagreements about inclusion were resolved by consensus or arbitration by a third reviewer (KSK). The selected studies were assessed for methodologic quality by using the components of study design that are related to internal validity.22 Information on the adequacy of randomization, concealment, control, blinding, intention to treat, and follow-up rates was sought. Percentage agreement and statistic were used for analysis of agreement between the reviewers. A minimum acceptable agreement was set at a level of 0.7, as this represents substantial strength of agreement.23 From each study outcome data were abstracted in 2 ⫻ 2 tables. Odds ratios (ORs) from individual studies were pooled
VOL. 101, NO. 6, JUNE 2003
Intention to treat
Blinding
Follow-up (%)
None
Unreported
91
Single
Unreported
⬎95
None
Yes
⬎95
Double
Yes
⬎95
Double
Yes
94
None
Unreported
⬎95
Double
Yes
⬎95
Double
Unreported
Double
Yes
⬎95
Double
Yes
⬎95
Unreported
Yes
90
Double
Unreported
92
Double
Unreported
⬎95
Unreported
Unreported
⬎95
91
using the Peto method.24 However, as there is no clear consensus as to the most appropriate method for metaanalysis,25 we examined the sensitivity of our results to variation in statistical approach by performing metaanalysis using fixed-effects26 and random-effects27 models. Weighted mean difference was calculated for continuous variables using means and standard deviations from individual studies. Heterogeneity of treatment effects was evaluated graphically using forest plot27 and statistically using 2 test.28 Exploration of the causes of heterogeneity was planned using variation in features of the population, intervention, outcome, and study quality. To assess for publication bias, we performed a funnel plot analysis,29 using the Egger test30 to evaluate for asymmetry. All statistical analyzes were performed using Stata 7.0 statistical software (Stata Corp., College Station, TX).
Coomarasamy et al
Aspirin in Historical Risk Factors
1321
Table 2. Study Characteristics of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors Author, year (reference)
Participants
Beaufils et al, Women with chronic 1985 (11) hypertension or several previous pregnancy complications (such as stillbirths and growth restriction)
Period of treatment
Experimental treatment
Comparison
From 3 mo gestation 150 mg aspirin No treatment to delivery and 300 mg dipyridamole
Exclusions: women with secondary hypertension, or known or suspected renal disease Benigni et al, Women with chronic 1989 (31) hypertension, previous history of early-onset (⬍32 weeks) preeclampsia, intrauterine growth restriction, or fetal death due to placental insufficiency
Azar et al, 1990 (abstract)
Sureau, 1991 (12) (trial A included in the review)
From 12 wk to delivery
Exclusions: women with antiphospholipid antibodies Women with previous From 16 wk to early-onset preeclampsia, delivery severe intrauterine growth restriction, or fetal death due to placental insufficiency Women with poor outcome From 15 to 18 wk; during the two previous end of treatment pregnancies, at least one not stated being fetal growth restriction or fetal growth restriction during the one preceding pregnancy
Exclusions included women with twin pregnancy, uterine malformations, renal disease, secondary hypertension, and contraindication to use of aspirin or dipyridamole, or current use of antiinflammatory drugs or anticoagulants Parazzini et al, Women with previous From 16 to 32 wk, 1993 (13) history of pregnancyuntil delivery induced hypertension, preeclampsia, chronic hypertension, nephropathy, growth restriction, current twin pregnancy or age less than 18 or over 40 y
60 mg aspirin
Placebo
100 mg aspirin No treatment and 300 mg dipyridamole
150 mg aspirin Placebo or 150 mg aspirin and 225 mg dipyridamole
Outcomes Preeclampsia (diastolic ⬎ 105 mm Hg; proteinuria ⬎ 1.5 g/day) Pregnancy-induced hypertension (blood pressure ⱖ 140/85 mm Hg) Birth weight Birth weight below 10th centile, and 3rd centile Duration of pregnancy Uric acid and platelet levels Perinatal death Pregnancy-induced hypertension (blood pressure ⬎ 140/90 mm Hg) Duration of pregnancy Birth weight Birth weight below 10th centile Perinatal death
Preeclampsia (undefined) Pregnancy induced hypertension Duration of pregnancy Birth weight Stillborn fetus Preeclampsia (blood pressure ⬎ 140/90 mm Hg; proteinuria undefined) Birth weight Birth weight below 10th centile Cesarean delivery before 34 wk Abruption Perinatal death
50 mg aspirin
No treatment
Preeclampsia (diastolic ⬎ 90 mm Hg; proteinuria undefined) Pregnancy-induced hypertension Birth weight Birth weight below 5th or 10th centile Preterm delivery (below 34 or 37 wk) Perinatal death (continued)
Table 2. Study Characteristics of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors (continued) Author, year (reference)
Rogov et al, 1993 (14)
Participants
Period of treatment
Experimental treatment
Comparison
Outcomes
Exclusions: women with a history of chronic disease (except hypertension, renal disease, or diabetes), allergy to aspirin, or documented fetal malformations Women with chronic From 12 to 19 wk, 125 mg aspirin and No treatment hypertension or until delivery 150–225 mg renal disease dipyridamole
Viinikka et al, 1993 (15)
Women with chronic hypertension or previous history of severe preeclampsia
From 12 to 18 wk, 50 mg aspirin until delivery
August et al, 1994 (abstract)
Women with chronic hypertension or previous severe preeclampsia
From 13 to 15 wk, 100 mg sustaineduntil 37 wk release aspirin
Beroyz et al, Women with a history of From 12 to 32 wk, 60 mg film-coated 1994 (32) preeclampsia or growth until delivery aspirin (subgroup restriction in previous in which pregnancy, chronic women were hypertension, renal recruited disease or other on risk factors, such prophylactic as maternal age, criteria family history, or were multiple pregnancy included in the review)
Preeclampsia Preterm delivery (less than 36 wk) Birth weight less than 2 standard deviations for gestational age Perinatal deaths Placental abruptions Matching placebo Preeclampsia (blood pressure ⬎ 160/120 mm Hg in those with preexisting hypertension, and ⬎ 160/110 mm Hg in those normotensive before pregnancy; proteinuria ⬎ 300 mg in 24 h) Pregnancy-induced hypertension Birth weight Birth weight below 2 standard deviations for gestation Duration of pregnancy Duration of labor Mode of delivery Maternal bleeding time Admission to neonatal intensive care Perinatal deaths Matching placebo Preeclampsia (a rise in systolic ⬎ 30 mm Hg or diastolic ⬎ 15 mm Hg; proteinuria undefined) Duration of pregnancy Growth of restriction (undefined) Placental abruptions Matching placebo Preeclampsia (diastolic ⬎ 90 mm Hg AND proteinuria ⱖ 1⫹) Duration of pregnancy Birth weight Birth weight below 3rd centile Preterm delivery (ⱕ 37 wk) Stillbirth or neonatal death Abruptions and other antenatal bleeds (continued)
VOL. 101, NO. 6, JUNE 2003
Coomarasamy et al
Aspirin in Historical Risk Factors
1323
Table 2. Study Characteristics of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors (continued) Author, year (reference)
ECPPA, 1996 (33)
Participants
Period of treatment
Experimental treatment
Exclusions: women with increased risk of bleeding, asthma, allergy to aspirin, or a high likelihood of immediate delivery Women with previous From 12 to 32 wk, 60 mg filmMatching placebo history of preeclampsia, until delivery coated aspirin chronic hypertension, renal disease, growth restriction, diabetes, or primigravid with other risk factors, such as young or old age
Exclusions: women with increased risk of bleeding, asthma, allergy to aspirin, gastric ulcer, and placenta previa Gallery et al, Women with previous early From 17 to 19 wk, 100 mg aspirin 1997 (17) severe preeclampsia, until 2 wk chronic hypertension, or before planned renal disease delivery Exclusions: women with history of aspirin allergy, aspirin sensitive asthma, pre-existing bleeding disorders, or multiple pregnancies Byaruhanga Women with previous et al, 1998 history of pregnancy(18) induced hypertension, preeclampsia, eclampsia, or chronic hypertension
Caritis et al, 1998 (19)
Comparison
From 20 to 28 wk 75 mg aspirin to 38 wk
Exclusions: women with history of allergy to aspirin, peptic ulcers, bleeding disorders, and chronic pulmonary disease; women who developed preeclampsia before trial entry or were on nonsteroidal antiinflammatory drugs were also excluded Women with previous From 13 to 26 wk, 60 mg aspirin history of preeclampsia, until delivery diabetes, chronic hypertension or multifetal pregnancy
Placebo
Outcomes
Preeclampsia (diastolic ⬎ 90 mm Hg; proteinuria undefined) Birth weight Birth weight below 3rd centile Preterm delivery (below 37 wk) Perinatal death Maternal bleeding (including abruption) Fetal bleeding (including intraventricular hemorrhage)
Systolic ⬎ 140 mm Hg; diastolic ⬎ 90 mm Hg Urinary protein ⬎ 300 mg/d Birth weight ⬍ 2500 g Duration of pregnancy Delivery before 37 wk Serum uric acid levels Perinatal death Antepartum hemorrhage
Matching placebo Preeclampsia (hypertension– undefined; proteinuria ⬎ 1⫹ or ⱖ 300 mg/L) Birth weight Birth weight below 10th centile Duration of pregnancy Preterm delivery (⬍ 37 wk) Perinatal death Admission to neonatal unit Blood loss ⬎ 500 mL
Matching placebo Preeclampsia (systolic ⱖ 140 mm Hg or diastolic ⱖ 90 mm Hg AND proteinuria ⱖ 2⫹ or ⬎ 300 mg in 24 h, or platelets count ⬍ 100,000 per mm3) Birth weight below 10th centile (continued)
1324
Coomarasamy et al
Aspirin in Historical Risk Factors
OBSTETRICS & GYNECOLOGY
Table 2. Study Characteristics of the Trials Included in the Systematic Review of Aspirin in the Prevention of Preeclampsia in Women With Historical Risk Factors (continued) Author, year (reference)
Participants
Period of treatment
Exclusions: women with multifetal pregnancy AND diabetes, chronic hypertension, or proteinuria; current history of proteinuria or preeclampsia Volpicelli et al, Women with previous From 18 to 26 wk 1999 (34) history of severe preeclampsia, or chronic hypertension
Experimental treatment
Comparison
50 mg aspirin Placebo
Outcomes Preterm delivery (⬍ 37 wk) Neonatal intraventricular hemorrhage Neonatal bleeding Perinatal death Abruption Postpartum bleeding Preeclampsia (undefined)
Figure 2. Meta-analysis of randomized trials evaluating the effectiveness of aspirin to prevent perinatal death in women with historical risk factors for preeclampsia. The results were not heterogeneous (212 ⫽ 10.61, P ⫽ .56). CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
VOL. 101, NO. 6, JUNE 2003
Coomarasamy et al
Aspirin in Historical Risk Factors
1325
Figure 3. Meta-analysis of randomized trials evaluating the effectiveness of aspirin to prevent preeclampsia in women with historical risk factors. The results were not heterogeneous (212 ⫽ 10.85, P ⫽ .54). CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
RESULTS Figure 1 summarizes the process of literature identification and selection. Of the 729 citations identified, 47 were selected during the initial screening (agreement 99%; 0.91), and on examination of the full manuscripts of these 47, 12 articles,11–15,17–19,31–34 and two abstracts (Azar R, Turpin D. Effect of antiplatelet therapy in women at high risk for pregnancy induced hypertension [abstract]. Proceedings of 7th World Congress, International Society for the Study of Hypertension in Pregnancy, Perugia, Italy. Newcastle upon Tyne, United Kingdom: ISSHP, 1990:257) (August P, Helseth G, Edersheim TG, Hutson JM, Druzin M. Sustained release, low-dose aspirin ameliorates but does not prevent preeclampsia (PE) in a high risk population [abstract]. Proceedings of 9th International Congress, International Society for the Study of Hypertension in Pregnancy, Sydney, Australia. Newcastle upon Tyne, United Kingdom: ISSHP, 1994:352), including a total of 12,416 women, were identified to satisfy the selection criteria for
1326
Coomarasamy et al
Aspirin in Historical Risk Factors
our review (agreement 96%; 0.89). The quality and the main characteristics of the included studies are presented in Tables 1 and 2. Pooling of results from these studies showed a significant benefit of aspirin therapy in reducing perinatal death (OR 0.79, 95% confidence interval [CI] 0.64, 0.96, Figure 2) and preeclampsia (OR 0.86, 95% CI 0.76, 0.96, Figure 3). The results were robust to alternative approaches to statistical pooling using either fixed- or random-effects models (results available from authors on request). The results were also found to be homogeneous (P ⫽ .56 for perinatal death and .54 for preeclampsia). We also found a significant reduction in rates of spontaneous preterm births (OR 0.86, 95% CI 0.79, 0.94, Figure 4), and an increase of 215 g in mean birth weight with aspirin use (weighted mean difference 215, 95% CI 90, 341, Figure 5). There was no increase in the risk of abruptions with aspirin treatment (OR 0.98, 95% CI 0.79, 1.21, Figure 6). Although funnel plot analysis was limited because of the small number of studies, it
OBSTETRICS & GYNECOLOGY
Figure 4. Meta-analysis of randomized trials evaluating the effectiveness of aspirin to prevent preterm birth in women with historical risk factors for preeclampsia. The results were not heterogeneous (26 ⫽ 1.54, P ⫽ .96). CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
indicated that publication and related biases were unlikely (Egger test, P ⫽ .84). CONCLUSION Our systematic review shows that low-dose aspirin has a significant effect in reducing the rates of a number of clinically relevant outcomes, including perinatal deaths and preeclampsia, in women with historical risk factors for preeclampsia. The validity of our findings depends on the methodologic rigor of our review and of the component primary studies. We used a prospective protocol and made a concerted effort to find all the evidence. Two independent reviewers assessed study quality and extracted data, and the agreement between the two reviewers was high. The studies we found were generally of good quality, and the results were homogeneous. The results were significant regardless of the statistical approach used for meta-analysis. In addition, there was no evidence of publication and related biases from funnel plot analysis. One potential source of bias in our review was the inclusion of studies without a placebo arm. To address
VOL. 101, NO. 6, JUNE 2003
this, we performed sensitivity analysis, excluding such studies from the analysis (data not shown), and found that the results were consistent with our inferences. We are, therefore, confident that our inferences are robust. The debate about aspirin to prevent preeclampsia has been rekindled by a recent Cochrane review.35,36 It showed a statistically significant reduction in preeclampsia (relative risk [RR] 0.85, 95% CI 0.78, 0.92) and perinatal death (RR 0.86, 95% CI 0.75, 0.98), but it concluded that the clinical significance of this finding was questionable, stating “as the reductions in risk are small to moderate, relatively large numbers of women will need to be treated to prevent a single outcome” (the number of women needed to be treated to prevent one case of preeclampsia was 100, and to prevent one case of perinatal death was 250). This is likely to be because studies including high-risk women who could benefit most from aspirin therapy were pooled together with those including low-risk women. In high-risk women, the baseline risk of preeclampsia and associated complications would be expected to be higher, thus resulting in higher absolute benefit (lower number needed to treat)
Coomarasamy et al
Aspirin in Historical Risk Factors
1327
Figure 5. Meta-analysis of randomized trials assessing neonatal birth weight in women treated with aspirin compared with placebo or no treatment among women with historical risk factors for preeclampsia. As the results were heterogeneous (27 ⫽ 40.85, P ⫽ .01), random-effects model was used for meta-analysis. CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
from aspirin therapy. For example, a recent systematic review of studies exclusively of those women in whom high risk was identified by an abnormal uterine artery Doppler test showed that the average absolute benefit from aspirin therapy to prevent preeclampsia was substantial (number needed to treat was 16, 95% CI 8, 316).37 Our review did not show any evidence of harm from aspirin therapy. This was also confirmed in the Cochrane review.35,36 In particular, there was no increase in placental abruptions, fetal intraventricular hemorrhage, or other neonatal bleeding. However, as randomized trials and systematic reviews of randomized trials may involve patients studied for a short length of time, they are not likely to detect delayed adverse events.38 We therefore supplemented the evidence on harm with a systematic search for large observational studies using the following words and their word variants in MEDLINE (1966 –2001) and EMBASE (1988 –2001) bibliographic databases: “aspirin [adverse effects]” combined with “pregnancy.” Three large cohort studies39 – 41 and
1328
Coomarasamy et al
Aspirin in Historical Risk Factors
one large case– control study42 were identified (Table 3). These observational studies, with more than 96,000 women between them, did not provide any evidence of teratogenicity or long-term adverse effects of aspirin use in pregnancy. The only evidence of harm came from a case– control study that showed evidence of increased risk of miscarriage when nonsteroidal antiinflammatory drugs were started early in gestation, although this risk was not present if the drugs were started after 12 weeks.41 However, no adjustment was made in this study for the indication of nonsteroidal anti-inflammatory use, and this would be expected to introduce substantial bias. This is because women with conditions such as systemic lupus erythematosus and rheumatoid arthritis are more likely to be users of nonsteroidal anti-inflammatory drugs during pregnancy but have an inherently higher risk of miscarriage as a result of the underlying condition rather than the drug itself. Thus, we regard this evidence of association between nonsteroidal drugs and miscarriage as unreliable.
OBSTETRICS & GYNECOLOGY
Figure 6. Meta-analysis of randomized trials evaluating rates of abruptions and other antepartum bleeding with aspirin compared with placebo or no treatment among women with historical risk factors for preeclampsia The results were not heterogeneous (26 ⫽ 4.00, P ⫽ .67). CI ⫽ confidence interval. Coomarasamy. Aspirin in Historical Risk Factors. Obstet Gynecol 2003.
The baseline risks of perinatal death and preeclampsia among the randomized trials, represented by the control event rates, varied substantially between trials. In this situation, calculating average numbers needed to be treated from pooled metaanalysis results can be seriously misleading.43 This is because numbers needed to be treated are sensitive to the levels of baseline risk, and will, therefore, need to be individualized to appropriate baseline risks.44 Consequently, we have given a range of numbers needed to be treated appropriate for various baseline risks for the several outcomes, as examples, in Table 4. When multiple historical risk factors are involved, the numbers needed to be treated would be expected to be even lower. However, these numbers needed to be treated need to be interpreted with caution, as there may have been changes in baseline risks over time, and the CIs around the numbers needed to be treated do not incorporate the uncertainty around the base-
VOL. 101, NO. 6, JUNE 2003
line risks (as these were not reported in most prevalence studies). Based on our findings and the established safety of aspirin, it seems reasonable to recommend aspirin therapy to women who are historically at high risk for preeclampsia, particularly those with multiple risk factors. Those who may benefit include women with previous severe or early-onset preeclampsia, chronic hypertension, severe diabetes, and moderate to severe renal disease (Table 4). Our findings assume particular significance as the diagnosis of historical risk factors for preeclampsia can be made inexpensively (without the need for any laboratory tests) and at the primary care level. This is of critical importance in the developing world, particularly Africa, where preeclampsia is more prevalent, and resources for sophisticated investigations and expensive treatment are not generally available. Further research needs to address the possible cost– benefits of this approach to health care systems and the society.
Coomarasamy et al
Aspirin in Historical Risk Factors
1329
Table 3. Observational Studies That Have Evaluated the Potential Harm of Aspirin Use in Pregnancy Author, year (reference)
Study design
Nielsen et al, 2001 (41)
Cohort
Slone et al, 1976 (39)
Cohort
Population and exposure 18,721 pregnancies: 1462 on nonsteroidal antiinflammatory drugs 17,259 on no drugs during pregnancy
50,282 pregnancies: 5128 heavily exposed to aspirin 9736 intermediately exposed to aspirin 35,418 not exposed to aspirin Klebanoff et al, Cohort 19,226 pregnancies: 1988 (40) 10,159 on aspirin 9067 never on aspirin in pregnancy Werler et al, Case–control Cases: 1381 infants with any 1989 (42) structural cardiac defects Controls: 6966 infants with other malformations
Outcome
Comments
No difference in congenital abnormalities between the exposed and non-exposed groups
No difference in malformation rates between the three groups
No difference in mean intelligence quotient at age 4 y No association between cardiac defects and aspirin
An additional case–control study, assessing the risk of miscarriage, was also reported in this article. It found an association between miscarriage and early aspirin use. However, the miscarriage rate was not increased when aspirin was started after 12 wk Controlling for multiple confounders did not change the conclusion
Controlling for multiple socials, demographic and other confounders did not change the conclusion
Table 4. Examples of Numbers of Women Needed to Be Treated With Aspirin to Prevent One Case of Various Outcomes Individualized According to Baseline Risk of Outcome Without Treatment
Outcome Preeclampsia
Perinatal death
Preterm birth
Historical risk factor Previous severe, early-onset (second trimester) preeclampsia Previous severe preeclampsia Previous preeclampsia Chronic hypertension Diabetes Diabetes after the exclusion of nephropathy or chronic hypertension Moderate to severe renal insufficiency Previous severe early onset (second trimester) preeclampsia Previous severe preeclampsia Chronic hypertension Diabetes Moderate to severe renal insufficiency Previous preeclampsia Chronic hypertension Diabetes Moderate to severe renal insufficiency
Baseline risk of the outcome (%) (reference) 65 (1)
Odds ratio (95% CI) 0.86 (0.76, 0.96)
47 (2) 18 (3,4) 25 (3,5,6) 20 (3) 9 (7) 59 (8) 17 (1) 6 (2) 5 (5) 1 (7) 7 (9) 32 (4) 34 (5) 10 (7) 59 (9)
Number needed to be treated (95% CI) 12 (8, 52) 17 (10, 70) 43 (27, 185) 31 (20, 134) 39 (24, 167) 86 (53, 371)
0.79 (0.64, 0.96)
0.86 (0.79, 0.94)
14 (9, 57) 28 (18, 148) 80 (50, 417) 96 (59, 500) 477 (295, 2500) 68 (42, 357) 32 (21, 79) 30 (20, 74) 100 (67, 250) 17 (12, 43)
CI ⫽ confidence interval.
1330
Coomarasamy et al
Aspirin in Historical Risk Factors
OBSTETRICS & GYNECOLOGY
REFERENCES 1. Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis. Am J Obstet Gynecol 1991;165:1408–12. 2. Sibai BM, el Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: Subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 1986;155:1011–6. 3. Caritis S, Sibai B, Hauth J, Lindheimer M, VanDorsten P, Klebanoff M, et al. Predictors of pre-eclampsia in women at high risk. Am J Obstet Gynecol 1998;179:946–51. 4. Hnat MD, Sibai BM, Caritis S, Hauth J, Lindheimer MD, MacPherson C, et al. Perinatal outcome in women with recurrent preeclampsia compared with women who develop preeclampsia as nulliparas. Am J Obstet Gynecol 2002;186:422–6. 5. Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 1994;171:410–6. 6. Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;67:197–205. 7. Garner PR, D’Alton ME, Dudley DK, Huard P, Hardie M. Preeclampsia in diabetic pregnancies. Am J Obstet Gynecol 1990;163:505–8. 8. Cunningham FG, Cox SM, Harstad TW, Mason RA, Pritchard JA. Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 1990;163:453–9. 9. Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or severe renal insufficiency. N Engl J Med 1996;335:226–32. 10. Mogren I, Hogberg U, Winkvist A, Stenlund H. Familial occurrence of preeclampsia. Epidemiology 1999;10: 518–22. 11. Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet 1985;1:840–2. 12. Sureau C. Prevention of perinatal consequences of preeclampsia with low-dose aspirin: Results of the Epreda trial. Eur J Obstet Gynecol Reprod Biol 1991;41:71–3. 13. Parazzini F, Benedetto C, Frusca T, Gregorini G, Bocciolone L, Marozio, et al. Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Lancet 1993;341:396 – 400. 14. Rogov VA, Tareeva IE, Sidorova IS, Androsova SO, Katamadze KT, Nikiforova OV. Acetylsalicylic acid and kurantil in the prevention of pregnancy complications in glomerulonephritis and hypertension [in Russian]. Ter Arkh 1993;65:65–8. 15. Viinikka L, Hartikainen-Sorri A-L, Lumme R, Hiilesmaa V, Ylikorkala O. Low dose aspirin in hypertensive pregnant women: Effect on pregnancy outcome and prostacyclin-thromboxane balance in mother and newborn. Br J Obstet Gynaecol 1993;100:809–15.
VOL. 101, NO. 6, JUNE 2003
16. Goffinet F, Breart G, Uzan S, Atallah A. ECPPA: Randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. Br J Obstet Gynaecol 1996;103:719–20. 17. Gallery EDM, Ross MR, Hawkins M, Leslie G, Gyory AZ. Low-dose aspirin in high-risk pregnancy? Hypertens Pregnancy 1997;16:229–38. 18. Byaruhanga RN, Chipato T, Rusakaniko S. A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia. Int J Gynecol Obstet 1998;60:129–35. 19. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701–5. 20. Dumont A, Merviel P, Berkane N, Gaudet R, Uzan S. Risk factors for pre-eclampsia. Presse Med 1999;28:2189–96. 21. Visser W, Wallenburg HC. Prediction and prevention of pregnancy-induced hypertensive disorders. Baillieres Best Pract Res Clin Obstet Gynaecol 1999;13:131–56. 22. NHS Centre for Reviews and Dissemination. Undertaking systematic reviews of research on effectiveness. CRD’s guidance for carrying out or commissioning reviews. CRD report number 4, (2nd edition). York, United Kingdom: University of York, NHS Centre for Reviews and Dissemination, 2001. 23. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74. 24. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog Cardiovasc Dis 1985; 27:335–71. 25. Thompson SG, Pocock SJ. Can meta-analyses be trusted? Lancet 1991;338:1127–30. 26. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719–48. 27. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. 28. Clarke M, Oxman MD, eds. Investigating heterogeneity. Cochrane reviewers handbook (updated June 2000). Section 8.6. Oxford, United Kingdom: The Cochrane Collaboration, 2000. 29. Light RJ, Pillemer DB. Summing up: The science of reviewing research. Cambridge, Massachusetts: Harvard University Press, 1984. 30. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. 31. Benigni A, Gregorini G, Frusca T, Chiabrando C, Ballerini S, Valcamonico A, et al. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. N Engl J Med 1989;321:357–62.
Coomarasamy et al
Aspirin in Historical Risk Factors
1331
32. Beroyz G, Casale R, Farreiros A, Palermo M, Margulies M, Voto L, et al. 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. 33. ECPPA (Estudo Colaborativo para Prevencao da Preeclampsia com Aspirina) Collaborative Group. ECPPA: Randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. Br J Obstet Gynaecology 1996;103:39–47. 34. Volpicelli T, D’Anto V, Faticato A, Galante L, Civitillo R. Trial prospecticco sull’uso profillatico dell’aspirina in donne gravide ad alto rischio di pre-eclampsia. Gestosi 1999;99:159–60. 35. Knight M, Duley L, Henderson-Smart DJ, King JF. Antiplatelet agents for preventing and treating pre-eclampsia. Cochrane Database Syst Rev 2000;2:CD000492. 36. Duley L, Henderson-Smart D, Knight M, King J. Antiplatelet drugs for prevention of pre-eclampsia and its consequences: Systematic review. BMJ 2001;322:329–33. 37. Coomarasamy A, Papaioannou S, Gee H, Khan KS. Aspirin for the prevention of preeclampsia in women with abnormal uterine artery Doppler: A meta-analysis. Obstet Gynecol 2001;98:861–6. 38. Ernst E, Pittler MH. Assessment of therapeutic safety in systematic reviews: Literature review. BMJ 2001;323:546. 39. Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman
1332
Coomarasamy et al
Aspirin in Historical Risk Factors
40.
41.
42.
43.
44.
DW, Shapiro S. Aspirin and congenital malformations. Lancet 1976;1:1373–5. Klebanoff MA, Berendes HW. Aspirin exposure during the first 20 weeks of gestation and IQ at four years of age. Teratology 1988;37:249–55. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: Population based observational study and case-control study. BMJ 2001;322:266–70. Werler MM, Mitchell AA, Shapiro S. The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects. N Engl J Med 1989;321:1639–42. Smeeth L, Haines A, Ebrahim S. Numbers needed to treat derived from meta-analyses—sometimes informative, usually misleading. BMJ 1999;318:1548–51. Cook RJ, Sackett DL. The number needed to treat: A clinically useful measure of treatment effect. BMJ 1995; 310:452–4.
Address reprint requests to: Aravinthan Coomarasamy, MRCOG, Research Fellow in Evidence-Based Obstetrics, Birmingham Women’s Hospital, Education Resource Center, Metchley Park Road, Birmingham, B15 2TG, United Kingdom; E-mail: [email protected]. Received September 13, 2002. Received in revised form December 4, 2002. Accepted December 12, 2002.
OBSTETRICS & GYNECOLOGY