Recruitment for longitudinal, randomised pregnancy trials initiated preconception: lessons from the effects of aspirin in gestation and reproduction trial.
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SUBMITTER: Lesher LL
PROVIDER: S-EPMC6194508 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
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Recruitment for longitudinal, randomised pregnancy trials initiated preconception: lessons from the effects of aspirin in gestation and reproduction trial.
Lesher Laurie L LL Matyas Rebecca A RA Sjaarda Lindsey A LA Newman Sarah L SL Silver Robert M RM Galai Noya N Hovey Kathleen M KM Wactawski-Wende Jean J Emerick Leah L Lynch Anne M AM Mead Betsy B Townsend Janet M JM Perkins Neil J NJ Mumford Sunni L SL Stanford Joseph J Schisterman Enrique F EF
Paediatric and perinatal epidemiology 20150214 2
<h4>Background</h4>Recruitment into large, preconception randomised clinical trials (RCT) is challenging. We describe clinic and community-based preconception recruitment strategies for the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and highlight approaches that were and were not successful. This longitudinal RCT was conducted at four major sites in the US. Eligible women had one to two prior pregnancy losses and were actively trying to become pregnant.<h4>Methods</h4>Provide ...[more]
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Project description:ObjectiveThe objective was to determine the effect of preconception-initiated daily low-dose aspirin (LDA; 81 mg/day) treatment on time to pregnancy in women with a history of pregnancy loss.DesignThis was a multicenter, block-randomized, double-blind, placebo-controlled trial. Participants were block-randomized by center and eligibility stratum.SettingThe study was conducted at four U.S.A. medical centers (2007-2012).ParticipantsParticipants women aged 18-40 years actively attempting pregnancy, stratified by eligibility criteria: the "original" stratum, women with one loss <20 weeks' gestation during the previous year; and the "expanded" stratum, women with one or two previous losses of any gestational age regardless of time since loss.InterventionDaily LDA was compared with matching placebo for up to six menstrual cycles of attempting pregnancy.Main outcome measureTime to hCG detected pregnancy and clinically confirmed pregnancy, analyzed by intention-to-treat, was measured.ResultsOf the 1228 women randomly assigned to LDA (n = 615) or placebo (n = 613), 410 (67%) women receiving LDA achieved pregnancy compared to 382 (63%) receiving placebo, corresponding to a fecundability odds ratio (FOR) of 1.14 (95% CI: 0.97, 1.33). Among women in the original stratum (n = 541), LDA was associated with increased fecundability compared to placebo (FOR: 1.28; 95%CI: 1.02, 1.62).ConclusionsPreconception-initiated LDA treatment resulted in a nonsignificant increase in fecundability of 14% in women with a history of 1-2 pregnancy losses, and a significant increase of 28% in women with a history of only one pregnancy loss of <20 weeks' gestation in the preceding year. Preconception-initiated LDA may increase fecundability in certain women with a recent early pregnancy loss.
| S-EPMC4422888 | biostudies-literature
Project description:ObjectiveTo evaluate if antimüllerian hormone (AMH) is associated with pregnancy loss.DesignProspective cohort study within a block-randomized, double-blind, placebo-controlled trial of low-dose aspirin.SettingNot applicable.Patient(s)Women (n = 1,228) were of ages 18-40 years with a history of one to two pregnancy losses and were actively attempting pregnancy without fertility treatment.Intervention(s)Not applicable.Main outcome measure(s)Pregnancy loss.Result(s)Relative risks (and 95% confidence interval [CIs]) of human chorionic gonadotropin (hCG)-detected and clinical pregnancy loss were assessed with the use of log binomial models with robust variance and inverse probability weights adjusted for age, race, body mass index, income, trial treatment assignment, parity, number of previous losses, and time since most recent loss. AMH levels were defined as: low (<1.00 ng/mL; n = 124), normal (referent; 1.00-3.5 ng/mL; n = 595), and high (>3.5 ng/mL; n = 483). Of the 1,202 women with baseline AMH data, 19 (17.3%) with low AMH experienced a clinical loss, compared with 61 (11.4%) with normal AMH and 50 (11.8%) with high AMH levels. Low or high AMH levels, compared with normal AMH, were not associated with clinical loss. Results for hCG-detected pregnancy loss mirrored those of clinical loss.Conclusion(s)AMH values were not associated with hCG-detected or clinical pregnancy loss in unassisted conceptions in women with a history of one to two previous losses. Our data do not support routine AMH testing for prediction of pregnancy loss.Clinical trial registration numberNCT00467363.
| S-EPMC4821799 | biostudies-literature
Project description:BackgroundPlatelet activation may play a role in the pathophysiology of placenta-mediated obstetrical complications, as evidenced by the efficacy of aspirin in preventing preeclampsia, but published data regarding the relationship between biomarkers for platelet activation and adverse obstetrical outcomes are sparse. In particular, it is unknown whether prepregnancy biomarkers of platelet activation are associated with adverse pregnancy outcomes.ObjectiveThis study aimed to determine the following: (1) whether maternal plasma concentrations of platelet factor 4 are associated with risk of placenta-mediated adverse obstetrical outcomes, and (2) whether these associations are modified by low-dose aspirin.Study designThis ancillary study included measurement of platelet factor 4 among 1185 of 1228 women of reproductive age enrolled in the Effects of Aspirin in Gestation and Reproduction trial with available plasma samples, with relevant outcomes assessed among 584 women with pregnancies lasting at least 20 weeks' gestation. We measured platelet factor 4 in plasma samples obtained at the prepregnancy study visit (before randomization to low-dose aspirin or placebo), 12 weeks' gestation, and 28 weeks' gestation. The primary outcome was a composite of hypertensive disorders of pregnancy, placental abruption, and small-for-gestational-age infant. We estimated the relative risks (RRs) and 95% confidence intervals (CIs) for the association between platelet factor 4 and the composite and individual outcomes at each time point using log-binomial regression that was weighted to account for potential selection bias and adjusted for age, body mass index, education, income, and smoking. To evaluate the potential effect modification of aspirin, we stratified the analyses by aspirin treatment assignment.ResultsDuring follow-up, 95 women experienced the composite adverse obstetrical outcome, with 57 cases of hypertensive disorders of pregnancy, 35 of small for gestational age, and 6 of placental abruption. Overall, prepregnancy platelet factor 4 was positively associated with the composite outcome (third tertile vs first tertile; relative risk, 2.36; 95% confidence interval, 1.38-4.03) and with hypertensive disorders of pregnancy (third tertile vs first tertile; relative risk, 2.14; 95% confidence interval, 1.08-4.23). In analyses stratified by treatment group, associations were stronger in the placebo group (third tertile vs first tertile; relative risk, 3.36; 95% confidence interval, 1.42-7.93) than in the aspirin group (third tertile vs first tertile; relative risk, 1.78; 95% confidence interval, 0.90-3.50).ConclusionHigh concentrations of platelet factor 4 before pregnancy are associated with increased risk of placenta-mediated adverse pregnancy outcomes, particularly for hypertensive disorders of pregnancy. Aspirin may mitigate the increased risk of these outcomes among women with higher plasma concentrations of preconception platelet factor 4, but low-dose aspirin nonresponders may require higher doses of aspirin or alternate therapies to achieve obstetrical risk reduction.
| S-EPMC7609468 | biostudies-literature
Project description:Several lines of evidence suggest that male embryos may have greater vulnerability than female embryos to disordered inflammation; therefore, antiinflammatory drugs, such as low-dose aspirin (LDA), may alter the sex ratio. Here, we assessed the effect of LDA on male live birth and male offspring, incorporating pregnancy losses (n = 56) via genetic assessment, as part of a parallel-design, block-randomized, placebo-controlled trial of preconception LDA.Participants (615 treated with LDA, 613 treated with placebo) ranged in age from 18 to 40 years of age, with 1 to 2 prior pregnancy losses. We estimated the intention-to-treat (ITT) risk ratio (RR) and 95% CI and assessed interaction with baseline high-sensitivity C-reactive protein (hsCRP) serum concentration - a marker of systemic inflammation.Among the 1,078 women who completed follow-up (535 treated with LDA, 543 treated with placebo), the male live birth ITT RR equaled 1.31 (95% CI: 1.07-1.59). With increasing tertile of hsCRP, the proportion of males at birth decreased in the placebo group, and the effect of LDA on male live birth increased (first tertile: 48% male in LDA vs. 52% in placebo, ITT RR = 0.97, 95% CI: 0.70-1.35; second tertile: 57% male in LDA vs. 43% in placebo, ITT RR = 1.36, 95% CI: 0.98-1.90; third tertile: 53% male in LDA vs. 35% in placebo, ITT RR = 1.70, 95% CI: 1.13-2.57; P interaction = 0.03). Analysis of pregnancy with male offspring yielded similar results.Initiation of LDA prior to conception restored numbers of male live births and pregnancy with male offspring among women with 1 to 2 prior pregnancy losses. Moreover, our data suggest that LDA modulates inflammation that would otherwise reduce the conception or survival of male embryos.ClinicalTrials.gov NCT00467363.Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
| S-EPMC4588294 | biostudies-literature
Project description:BackgroundPreconception-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.MethodsIn 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.FindingsOverall, 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.InterpretationPreconception-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.FundingEunice Kennedy Shriver National Institute of Child Health and Human Development (US National Institutes of Health).
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Project description:ObjectiveTo estimate the association between physical activity and risk of subclinical and clinical pregnancy loss among women with a history of pregnancy loss.DesignProspective cohort study as a secondary analysis of the Effects of Aspirin in Gestation and Reproduction randomized controlled trial of preconception-initiated low-dose aspirin among women with one or two prior pregnancy losses.SettingFour U.S. clinical centers, 2007-2011.Patient(s)Women with confirmed pregnancy (n = 785) as determined from hCG testing in longitudinally collected biospecimens.Main outcome measure(s)Subclinical loss of pregnancy detected only by hCG testing and clinically recognized loss.Result(s)Among 785 women (mean [SD] age, 28.7 [4.6] years) with an hCG-confirmed pregnancy, 188 (23.9%) experienced pregnancy loss. In multivariable models adjusted for confounders, compared with the first tertile of physical activity (median = 7.7 metabolic equivalent of task hours/week), there was a roughly twofold higher risk of subclinical loss in the second (risk ratio = 2.06; 95% confidence interval, 1.03-4.14) and third tertiles (risk ratio = 1.92; 95% confidence interval, 0.94-3.90), with median metabolic equivalent of task hours/week of 27.8 and 95.7, respectively. No relations were observed between physical activity and clinically recognized loss.Conclusion(s)Risk related to physical activity is different for pregnancy failure close to the time of implantation compared with that for later, clinical pregnancy loss. Higher physical activity levels were associated with an elevated risk of subclinical loss (i.e., pregnancies detected only by hCG, n = 55); however, no relationship was observed with clinically recognized loss. Further work is required to confirm these findings, assess generalizability to women without prior losses, and evaluate mechanisms.Ethical approvalEach participating center's Institutional Review Board approved the study, and participants provided written informed consent. The trial was registered on ClinicalTrials.gov (NCT00467363), and a Data Safety and Monitoring Board provided oversight.
| S-EPMC7994027 | biostudies-literature
Project description:ObjectiveTo evaluate complications and safety of preconception low-dose aspirin in 1,228 U.S. women (2007-2011).MethodsEvaluation 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.ResultsThe 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.ConclusionAlthough 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.
| S-EPMC4805457 | biostudies-literature
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.
| S-EPMC4755442 | biostudies-literature
Project description:Growth Hormone (GH) has been considered as a therapeutic option to increase the number of growing follicles during Assisted Reproductive Technology (ART) for more than 30 years. In this review the biological rationale for therapeutic GH usage is explained through evidence in animal models, aiming to put this into a clinical context. First, we explain the GH-Insulin like Growth Factor (IGF)-1-gonadal axis and its role in reproduction. Evidence suggests that GH can stimulate the secretion of IGF1 not only in the liver but also in the peripheral target structures, including the ovary. Moreover, IGF-1 can be secreted locally under the influence of stimuli other than GH. In the case of the ovary, steroid hormones, gonadotropins or the combination of both seems to be involved. Even more interesting, the ovary itself can secret GH locally and exert a paracrine action modulating the intracellular signaling pathway of GH, i.e., not by the systemic pathway where GH binds to the extracellular domain of the GH receptor. Finally, these aspects from animal models are put into clinical perspective by discussing results and shortcomings of studies and meta-analyses in order to put forth the state-of-the-art rationale for therapeutic GH usage in modern ART.
| S-EPMC6607366 | biostudies-literature
Project description:ObjectiveThis study aimed to examine whether prenatal low-dose aspirin (LDA) therapy affects risk of cesarean versus vaginal delivery.Study designThis study is a secondary analysis of the randomized clinical effects of aspirin in gestation and reproduction (EAGeR) trial. Women received 81-mg daily aspirin or placebo from preconception to 36 weeks of gestation. Mode of delivery and obstetric complications were abstracted from records. Log-binomial regression models estimated relative risk (RR) of cesarean versus vaginal delivery. Data were analyzed among the total preconception cohort, as well as restricted to women who had a live birth.ResultsAmong 1,228 women, 597 had a live birth. In the intent-to-treat analysis, preconception-initiated LDA was not associated with risk of cesarean (RR = 1.02; 95% confidence interval [CI]: 0.98-1.07) compared with placebo. Findings were similar in just women with a live birth and when accounting prior cesarean delivery and parity.ConclusionPreconception-initiated daily LDA was not associated with mode of delivery among women with one to two prior losses.Key points· Aspirin was not associated with risk of cesarean section.. · Aspirin was not associated with mode of delivery.. · No increased risk of bleeding with use of aspirin..
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