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Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.

ABSTRACT: Preconception-initiated low-dose aspirin might positively affect pregnancy outcomes, but this possibility has not been adequately assessed. Our aim was to investigate whether low-dose aspirin improved livebirth rates in women with one to two previous pregnancy losses.In this multicentre, block-randomised, double-blind, placebo-controlled trial, women aged 18-40 years who were attempting to become pregnant were recruited from four medical centres in the USA. Participants were stratified by eligibility criteria--the original stratum was restricted to women with one loss at less than 20 weeks' gestation during the previous year, whereas the expanded stratum included women with one to two previous losses, with no restrictions on gestational age or time of loss. Women were block-randomised by centre and eligibility stratum in a 1:1 ratio. Preconception-initiated daily low-dose aspirin (81 mg per day) plus folic acid was compared with placebo plus folic acid for up to six menstrual cycles; for women who conceived, study treatment continued until 36 weeks' gestation. Participants, trial staff, and investigators were masked to the assigned treatment. The primary outcome was livebirth rate, which was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00467363.Overall, 1228 women were recruited and randomly assigned between June 15, 2007, and July 15, 2011, 1078 of whom completed the trial and were included in the analysis (535 in the low-dose aspirin group and 543 in the placebo group). 309 (58%) women in the low-dose aspirin group had livebirths, compared with 286 (53%) in the placebo group (p=0·0984; absolute difference in livebirth rate 5·09% [95% CI -0·84 to 11·02]). Pregnancy loss occurred in 68 (13%) women in the low-dose aspirin group, compared with 65 (12%) women in the placebo group (p=0·7812). In the original stratum, 151 (62%) of 242 women in the low-dose aspirin group had livebirths, compared with 133 (53%) of 250 in the placebo group (p=0·0446; absolute difference in livebirth rate 9·20% [0·51 to 17·89]). In the expanded stratum, 158 (54%) of 293 women in the low-dose aspirin group and 153 (52%) of 293 in the placebo group had livebirths (p=0·7406; absolute difference in livebirth rate 1·71% [-6·37 to 9·79]). Major adverse events were similar between treatment groups. Low-dose aspirin was associated with increased vaginal bleeding, but this adverse event was not associated with pregnancy loss.Preconception-initiated low-dose aspirin was not significantly associated with livebirth or pregnancy loss in women with one to two previous losses. However, higher livebirth rates were seen in women with a single documented loss at less than 20 weeks' gestation during the previous year. Low-dose aspirin is not recommended for the prevention of pregnancy loss.Eunice Kennedy Shriver National Institute of Child Health and Human Development (US National Institutes of Health).

SUBMITTER: Schisterman EF

PROVIDER: S-EPMC4181666 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.

Schisterman Enrique F EF Silver Robert M RM Lesher Laurie L LL Faraggi David D Wactawski-Wende Jean J Townsend Janet M JM Lynch Anne M AM Perkins Neil J NJ Mumford Sunni L SL Galai Noya N

Lancet (London, England) 20140402 9937

<h4>Background</h4>Preconception-initiated low-dose aspirin might positively affect pregnancy outcomes, but this possibility has not been adequately assessed. Our aim was to investigate whether low-dose aspirin improved livebirth rates in women with one to two previous pregnancy losses.<h4>Methods</h4>In this multicentre, block-randomised, double-blind, placebo-controlled trial, women aged 18-40 years who were attempting to become pregnant were recruited from four medical centres in the USA. Par ...[more]

PMID: 24702835

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Project description:What is the association between daily preconception-initiated low-dose aspirin (LDA) treatment and very early pregnancy losses or euploid (chromosomally normal) losses among women with one to two prior losses?Daily LDA initiated preconception was not associated with the rate or type of pregnancy loss among women with a history of one to two prior pregnancy losses.LDA is often used to treat recurrent pregnancy loss with reductions in pregnancy loss generally only observed among women with antiphospholipid antibodies, and null associations observed among women without antiphospholipid antibodies. We previously evaluated the association between LDA and pregnancy loss overall among women with one to two prior losses in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and found no association, though did not distinguish between potential effects at different stages of pregnancy loss, including implantation failure, or between euploid and aneuploid losses.The EAGeR trial was a multi-site prospective block-randomized double-blind placebo-controlled trial. In total, 1228 women were randomized to daily LDA (81 mg/day) plus folic acid (400 mcg/day), or placebo plus folic acid. Participants were assigned study drug for less than or equal to six menstrual cycles or if they conceived, throughout pregnancy with study drug discontinued at 36 weeks gestation. This analysis includes additional outcome information obtained from chart abstractions after the completion of the trial, as well as testing of stored urine for measurement of hCG and detection of very early pregnancy losses, and karyotyping of the products of conception for assessment of aneuploidy of the losses.Women aged 18-40 with a history of one to two prior losses and actively trying to conceive were randomized (n = 615 LDA and n = 613 placebo) at four clinical centers in the USA (2007-2011). Log-binomial regression was used to estimate risk ratios under the intent-to-treat approach.Daily LDA initiated preconception was not associated with clinically recognized pregnancy losses or implantation failures among women with proved fecundity and a history of one to two prior losses. Specifically, 1088 (88.6%) women completed the trial with 797 having an hCG detected pregnancy (64.9%). Overall there were 133 clinical losses (12.7% LDA versus 11.8% placebo, P = 0.71) and 55 implantation failures (5.2% LDA versus 4.9% placebo, P = 0.89). No differences were found in rate of euploid losses (RR 1.11, 95% confidence interval: 0.99, 1.26).Generalizability of these findings is limited to women with a history of one to two prior losses, and may further be limited to women of white race with higher socioeconomic status as given the rigors of the study protocol participants tended to be white and have higher incomes and more education. We were also missing karyotype information on approximately one-third of the clinically recognized pregnancy losses, which may limit our power to detect effects on euploid losses, though detailed sensitivity analysis showed similar results.Our data do not support the general use of LDA to decrease pregnancy loss and further demonstrate no increased risk of loss for women on LDA treatment.This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). The authors have no conflicts of interest.The trial was registered at ClinicalTrials.gov #NCT00467363.27 April 2007.15 June 2007.

Project description:OBJECTIVE:To evaluate complications and safety of preconception low-dose aspirin in 1,228 U.S. women (2007-2011). METHODS:Evaluation of the safety of low-dose aspirin in the participants and their fetuses was a planned secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, a multicenter, block-randomized, double-blind, placebo-controlled trial investigating the effect of low-dose aspirin on the incidence of live birth. Women aged 18-40 years with a history of one to two pregnancy losses trying to conceive were randomized to daily low-dose aspirin (81 mg, n=615) or placebo (n=613) and were followed for up to six menstrual cycles or through gestation if they became pregnant. Emergency care visits and possible aspirin-related symptoms were assessed at each study follow-up using standardized safety interviews. In addition, complications for both the participant and her fetus or neonate were captured prospectively using case report forms, interviews conducted during pregnancy and postpartum, and medical records. RESULTS:The proportion of women with at least one possible aspirin-related symptom during the trial was similar between treatment arms (456 [74%] low-dose aspirin compared with 447 [73%] placebo, P=.65) as was the proportion with at least one emergency care visit (104 [17%] low-dose aspirin compared with 99 [16%] placebo, P=.76). Maternal complications were evenly distributed by treatment arm with the exception of vaginal bleeding, which was more commonly reported in the low-dose aspirin arm (22% compared with 17%, P=.02). The distribution of fetal and neonatal complications-which included three stillbirths, three neonatal deaths, and 10 neonates with birth defect(s)-was similar between treatment arms. CONCLUSION:Although rare but serious complications resulting from low-dose aspirin cannot be ruled out, preconception low-dose aspirin appears to be well tolerated by women trying to conceive, women who become pregnant, and by their fetuses and neonates.

Project description:Low socioeconomic status (SES) is associated with adverse pregnancy outcomes and infertility. Low-dose aspirin (LDA) was shown to improve livebirth rates in certain subsets of women, and therefore, may impact pregnancy rates differentially by SES status. Therefore, the aim of the current study was to examine whether daily preconception-initiated LDA affects rates of pregnancy, livebirth, and pregnancy loss differently across strata of socioeconomic status (SES). This is a secondary analysis of The Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial, a multisite, block- randomized, placebo-controlled trial conducted at four U.S. medical centers (n = 1,228, 2007-2012). Women attempting spontaneous conception with a history of pregnancy loss were randomly allocated preconception to 81mg of aspirin + 400mcg of folic acid (n = 615) or placebo + 400mcg of folic acid (n = 613). Study medication was administered for six menstrual cycles or until 36 weeks' gestation if pregnancy was achieved. For this analysis, women were stratified by SES, which included income (low, mid, high) and a combined grouping of education and income (low-low, low-high, high-low, high-high). Log binomial models with robust variance estimated risks of pregnancy, livebirth, and pregnancy loss for LDA versus placebo. LDA increased pregnancy and livebirth rates (RR 1.23, 95% CI: 1.03, 1.45) in the high-income, but not mid- or low-income groups. LDA increased pregnancy rates in both the low education-low income group (RR 1.22, 95% CI: 1.02, 1.46) and the high education-high income group (RR 1.23, 95%CI: 1.06, 1.42), with no effect observed in mid-SES groupings. LDA, a low-cost and widely available treatment, may be particularly beneficial to women at the highest and lowest ends of the socioeconomic spectrum, though underlying mechanisms of this disparity are unclear. Confirming these findings and identifying factors which may modulate the effectiveness of LDA will ultimately facilitate personalized clinical care and improvements in population-level reproductive health. Trial registration number: ClinicalTrials.gov, NCT00467363.

Project description:BackgroundPreterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation.MethodsASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks' gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970.FindingsFrom March 23, 2016 to June 30, 2018, 14?361 women were screened for inclusion and 11?976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks' gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (<34 weeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups.InterpretationIn populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality.FundingEunice Kennedy Shriver National Institute of Child Health and Human Development.

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Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.

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Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.

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