Background Our objective was to determine whether preconception-initiated low dose aspirin (LDA) improved live birth rates in women with one to two prior pregnancy losses. Methods This multi-center, block-randomized, double-blind, placebo-controlled trial recruited from four medical centers in the US (2006–2012). Women aged 18–40 years attempting pregnancy were stratified by eligibility criteria: “original”: women with one loss <20 weeks’ gestation during the past year; or “expanded”: women with one to two prior losses regardless of gestational length or time of loss. Women were block-randomized (615 LDA, 613 placebo) by center and eligibility stratum. Preconception-initiated daily LDA (81 mg/day) was compared with placebo for up to six menstrual cycles; for those who conceived, study treatment continued until 36 weeks’ gestation. The primary outcome was live birth rate. The trial was registered on ClinicalTrials.gov (#NCT00467363). Findings Overall, 1078 women completed the trial (LDA 535, placebo 543). Live birth rates were 58% (309/535) in women assigned LDA vs. 53% placebo (286/543; risk difference [RD] 5%; 95% confidence interval [CI] −0·8, 11). Pregnancy loss rates were similar between groups (13% [68/535] LDA, 12% [65/543] placebo; p=0·7812). In the original stratum, live birth rates were 62% (151/242) LDA vs. 53% (133/250) placebo (RD 9%; 95% CI 0·5, 18), and in the expanded, 54% (158/293) LDA vs. 52% (153/293) placebo (RD 2%; 95% CI −6, 10). Major adverse events were similar between treatment arms. LDA was associated with increased bleeding per vaginam, but this was not associated with losses. Interpretation Preconception-initiated LDA was not significantly associated with live birth or pregnancy loss among women with one to two prior losses. However, higher live birth rates were observed among women with a single documented loss at <20 weeks’ gestation during the previous year. LDA is not recommended for the prevention of pregnancy loss.

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 live-birth rates in women with 1–2 prior losses. Methods We performed a multicenter, block randomised, double-blind, placebo-controlled trial. Study participants were recruited using community-based advertisements and physician referral to four university medical centers in the US (2006–12). Eligible women were aged 18–40 years actively trying to conceive with 1–2 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 ≤six menstrual cycles while attempting to conceive. For those that conceived, treatment was continued until 36 weeks gestation. The primary outcome was the cumulative live birth rate over the trial period. Results 1228 women were randomised (615 LDA, 613 placebo). Participants had a mean age of 28.7, were mostly white (95%), well educated (86% >high school education), and employed (75%) with a household income >$100,000 annually (40%). 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 live birth and other pregnancy outcomes in these women.

BACKGROUND AND OBJECTIVES: Early diagnosis of cerebral palsy (CP) is critical in obtaining evidence-based interventions when plasticity is greatest. In 2017, international guidelines for early detection of CP were published on the basis of a systematic review of evidence. Our study aim was to reduce the age at CP diagnosis throughout a network of 5 diverse US high-risk infant follow-up programs through consistent implementation of these guidelines. METHODS:The study leveraged plan-do-study-act and Lean methodologies. The primary outcome was age at CP diagnosis. Data were acquired during the corresponding 9-month baseline and quarterly throughout study. Balancing measures were clinic no-show rates and parent perception of the diagnosis visit. Clinic teams conducted strengths, weaknesses, opportunities, and threats analyses, process flow evaluations, standardized assessments training, and parent questionnaires. Performance of a 3-to 4-month clinic visit was a critical process step because it included a Hammersmith Infant Neurologic Examination, a General Movements Assessment, and standardized assessments of motor function. RESULTS:The age at CP diagnosis decreased from a weighted average of 19.5 (95% confidence interval 16.2 to 22.8) to 9.5 months (95% confidence interval 4.5 to 14.6), with P = .008; 3-to 4-month visits per site increased from the median (interquartile range) 14 (5.2-73.7) to 54 (34.5-152.0), with P , .001; and no-show rates were not different. Parent questionnaires revealed positive provider perception with improvement opportunities for information content and understandability.CONCLUSIONS: Large-scale implementation of international guidelines for early detection of CP is feasible in diverse high-risk infant follow-up clinics. The initiative was received positively by families and without adversely affecting clinic operational flow. Additional parent support and education are necessary.

15 June 2007.

PRECIS Low-dose aspirin should be investigated as a potential agent to reduce the risk of preterm birth.

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 multi-center, 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 1–2 pregnancy losses trying to conceive were randomized to daily low-dose aspirin (81 mg, n=615) or placebo (n=613) and were followed for ≤6 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 vs. 447 [73%] placebo, P=0.65), as was the proportion with at least one emergency care visit (104 [17%] low-dose aspirin vs. 99 [16%] placebo, P=0.76). 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% vs. 17%, P=0.02). The distribution of fetal and neonatal complications—which included 3 stillbirths, 3 neonatal deaths and 10 infants with birth defect(s) —was similar between treatment arms. Conclusions Although rare but serious complications due to 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.

alter the sex ratio of pregnancies among women with a history of pregnancy loss, given the sex-dependent embryonic effects of maternal inflammation.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.

Preconception-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.