Laurie Lesher

A Randomised Trial to Evaluate the Effects of Low‐dose Aspirin in Gestation and Reproduction: Design and Baseline Characteristics

BACKGROUND Low-dose aspirin (LDA) has been proposed to improve pregnancy outcomes in couples experiencing recurrent pregnancy loss. However, results from studies of LDA on pregnancy outcomes have been inconsistent, perhaps because most studies evaluated LDA-initiated post-conception. The purpose of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial was to determine whether preconception-initiated LDA improves livebirth rates in women with one to two prior losses. METHODS We performed a multicentre, block randomised, double-blind, placebo-controlled trial. Study participants were recruited using community-based advertisements and physician referral to four university medical centres in the US (2006-12). Eligible women were aged 18-40 years actively trying to conceive, with one to two prior losses. Participants were randomised to receive daily LDA (81 mg/day) or a matching placebo, and all were provided with daily 400-mcg folic acid. Follow-up continued for ≤6 menstrual cycles while attempting to conceive. For those who conceived, treatment was continued until 36 weeks gestation. The primary outcome was the cumulative livebirth rate over the trial period. RESULTS There were 1228 women randomised (615 LDA, 613 placebo). Participants had a mean age of 28.7, were mostly white (95%), well educated (86% more than high school education), and employed (75%) with a household income >

Complications and safety of preconception low-dose aspirin among women with prior pregnancy losses

100 000 annually (40%). The characteristics of those in the treatment and placebo arms were well balanced. CONCLUSIONS We describe the study design, recruitment, data collection, and baseline characteristics of participants enrolled in EAGeR, which aimed to determine the effect of LDA on livebirth and other pregnancy outcomes in these women.

Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss

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.

Low-Dose Aspirin and Sporadic Anovulation in the EAGeR Randomized Trial

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION 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. TRIAL REGISTRATION ClinicalTrials.gov NCT00467363. FUNDING Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

Recruitment for longitudinal, randomised pregnancy trials initiated preconception: lessons from the effects of aspirin in gestation and reproduction trial.

Context Among women with a single, recent pregnancy loss, daily preconception low-dose aspirin (LDA) increased the live birth rate with no effect on pregnancy loss. Ovulation is a potential mechanism underlying this effect. Objective We estimated the effect of LDA on the per-cycle risk of anovulation among eumenorrheic women. Design Multicenter, randomized, double-blind, placebo-controlled trial of daily LDA on reproductive outcomes. Preconception follow-up lasted 1 to 6 menstrual cycles (ClinicalTrials.gov, NCT00467363). Setting Four US medical centers during 2007 to 2011. Patients or Other Participants Healthy women (n = 1214), age 18 to 40, were attempting pregnancy, had regular menstrual cycles (21 to 42 days), and had a history of 1 to 2 documented pregnancy losses, ≤2 live births, and no infertility. All participants completed at least 1 menstrual cycle of follow-up; none withdrew due to adverse events. Intervention Aspirin (81 mg) daily for 1 to 6 menstrual cycles. Main Outcome Measure Per-cycle risk of anovulation, defined as the absence of both a positive spot-urine pregnancy test and a luteinizing hormone (LH) peak (2.5-fold increase in daily urinary LH). Hypothesis formulation preceded data collection. Results Among 4340 cycles, LDA was not associated with anovulation (LDA: 13.4%, placebo: 11.1%; risk ratio = 1.16, 95% confidence interval, 0.88 to 1.52). Results were similar among women with a single, recent loss. Conclusions Daily LDA had no effect on anovulation among women with a history of 1 to 2 pregnancy losses. LDA may affect fertility via other pathways, and these warrant further study.

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

BACKGROUND 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. METHODS Provider/clinic and community-based outreach strategies were utilised, and the recruitment rate and costs of methods were assessed. RESULTS A screening questionnaire was completed by 5485 women; 42.4% (n = 2323) screened were initially eligible, of whom 50.7% (n = 1228) were randomised. Provider/clinic-based recruitment yielded the highest number eligible of those screened (30.1%) and also the most randomised participants overall (40.3%). The next highest yield came from direct mail and brochures/flyers at 13.1% and 12.5% of women randomised, respectively. However, direct mailings cost

Recent attempted and actual weight change in relation to pregnancy loss: a prospective cohort study

720 per participant randomised. Other than word of mouth, provider/clinic-based recruitment was the most cost effective method, costing an average of

Class III Obese Women's Preferences and Concerns for Cesarean Skin Incision: A Multicenter Survey

60 per randomised participant. Web-based recruitment yielded 4.7% of participants at a cost of

Shorter Time to Pregnancy With Increasing Preconception Carotene Concentrations Among Women With 1–2 Previous Pregnancy Losses

278 per randomised participant. CONCLUSIONS Provider and clinic-based recruitment was the most effective and cost-efficient method of recruitment in a preconception intervention study of reproduction among women.

Process Improvement For Inter-Institutional Research Contracting

Pregnancy loss occurs in up to 30% of conceptions. Women who have had a pregnancy loss are at increased risk for having another loss or adverse pregnancy event. Because aspirin can improve blood flow and reduce inflammation in the reproductive organs, preconception-initiated low-dose aspirin might positively affect pregnancy outcomes. The aim of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial was to assess whether daily treatment with low-dose aspirin, initiated before conception, would improve the rate of live birth in women who had 1 or 2 prior