The mean residual life (MRL) function is an important and attractive alternative to the hazard function for characterizing the distribution of a time-to-event variable. In this article, we study the modeling and inference of a family of generalized MRL models for right-censored survival data with censoring indicators missing at random. To estimate the model parameters, augmented inverse probability weighted estimating equation approaches are developed, in which the non-missingness probability and the conditional probability of an uncensored observation are estimated by parametric methods or nonparametric kernel smoothing techniques. Asymptotic properties of the proposed estimators are established and finite sample performance is evaluated by extensive simulation studies. An application to brain cancer data is presented to illustrate the proposed methods.

Eastern Europe continues to have the highest rates of cancer of the uterine cervix (CUC) and human papillomavirus (HPV) infection in Europe. Aim: The aim of this study was to investigate CUC trends in Bulgaria in the context of a lack of a population-based screening program and a demographic crisis. Methodology: This was a retrospective study of 7861 CUC patients who were registered in the Bulgarian National Cancer Registry (BNCR) between 2013 and 2020 and followed up with until March 2022. We used descriptive statistics and modeling to assess temporal trends in new CUC incidence rates and identify factors associated with survival. Results: Bulgaria’s population has decreased by 11.5% between 2011 and 2021. The CUC incidence rate decreased from 29.5/100,000 in 2013 to 23.2/100,000 in 2020 but remains very high. The proportion of patients diagnosed in earlier stages of CUC has decreased over time. Up to 19% of patients with CUC in Bulgaria are diagnosed between the age of 35 and 44 years. The median survival was 101.5 months, with some improvement in later years (adjusted HR = 0.83 for 2017–2020). Conclusions: In countries with well-established population-based screening, CUC is nowadays considered a rare disease. However, it is not considered rare in Bulgaria. Population-based screening starting at an earlier age is the fastest way to improve outcomes.

Introduction/Background The study included 50 patients diagnosed with endometrial cancer (EC) stage I-II. The age of these patients, on average, was 49.1 ± 12.1 years and ranged from 54 to 86 years. Methodology The tumor DNA was extracted from mapped formalin-fixed, paraffin-embedded tissue sections to provide tumor samples for the assays (figure 1). The methylation status of the MLH1 gene was determined using the Methylation Specific Polymerase Chain Reaction (MS-PCR) method and specific primers for both unmethylated and methylated fragments. Results The frequency of MLH1 promoter methylation was 20.0% and was determined in 10 patients. The frequency of tumors with MLH1 promoter methylation increases during menopause, reaching 30.0% at the age of 50–59 years and 50, 0% of cases at 60–69 years and decreases in the age periods 70–79 years, reaching 20.0%.The analysis of the obtained results showed that in patients with EC, the presence of MLH1 epimutation was significantly higher in stage I of the disease. The presence of MLH1 epimutation was observed in 22.0% of patients with stage I EC and only in 2 stage II patients. The results of the analysis of overall survival in patients, according to the presence of MLH1 epimutation, showed that 71% of women with MLH1 epimutation and 92.5% without MLH1 epimutation survived at 3 years. Conclusion MLH1 promoter methylation analysis would play a valuable role as a clinical biomarker.

Introduction/Background Modern methods of studying DNA structure, including cluster analysis, make it possible to determine the genetic profile of tumors. Methodology The prospective study was performed on 50 patients with EC in stages I and II. The study design includes the description of the first stage of the study, marked by the evaluation of clinical-morphological features and the second stage marked by research of genetic features: determination of c.389G> A (p.R130Q) PTEN gene mutation. Results The rate of the presence of the c.389G> A (p.R130Q) PTEN gene mutation is shown in all 4 subgroups of recurrence risk of patients with EC. The median survival time of patients with c.389G> A (p.R130Q) PTEN mutation was 15.7 ± 1.89 (95% CI [11.3–20.5]) months (95% CI 7–7 months), which did not differs (F = 0.005; p = 0.943) from mean time to progression in patients without mutations – 16.0 ± 3.97 (95% CI [12.0–28.0]) (figure 1). $$MISSING OR BAD GRAPHIC SPECIFICATION (2C128DE7-E0AB-4E14-ADC4–2A80097FE4FA) $$ Thus, the median survival time of patients in the low-risk group was 13.5 ± 3.37 (95% CI [9.0–18.0]) months, differing significantly from that in patients high risk – 15.8 ± 3.34 (95% CI [10.5–23.0]) months (F = 16.2; p = 0.891). Our research showed that group risk did not have an impact on the survival time of patients with PTEN mutation, this suggested that c.389G> A (p.R130Q) PTEN gene mutation may be regarded as a powerful prognostic factor for decreased survival time in patients with EC. Conclusion This study showed that c.389G> A (p.R130Q) PTEN genetic mutation is strongly correlated with poor prognosis in EC patients. This may indicate that c.389G> A (p.R130Q) PTEN genetic mutation could be regarded as an important factor in the pathogenesis of EC. However, this finding is derived from small data in observational study, hence well conducted high-quality randomized trials are warranted.

NRIP1-mutants on ER a -regulated gene transcription using COS-1 cells. Results Hotspot NRIP1 mutations were identified in 5.4% of the samples, and associated with high FIGO-stage, deep myo-metrial infiltration, and positive lymph-node status. However, there was no significant difference in disease-specific survival between patients with mutated and wildtype NRIP1 , and mutation status did not associate with NRIP1 expression levels. Interestingly, reporter assays showed that the repressive effect of wildtype NRIP1 was significantly abolished with NRIP1 mutants. Further, low NRIP1 expression levels were significantly associated with decreased disease-specific survival, high grade, negative ER a status and low BMI. Gene Set Enrichment Analysis revealed an increase in gene sets related to proliferation in NRIP1 mutated tumors. Conclusion The relatively low mutation rate hampers a firm conclusion on the prognostic value of NRIP1 frameshift mutations in endometrioid EC. However, low NRIP1 expression may be a marker of poor prognosis. Our functional investigations demonstrates that frameshift mutated NRIP1 , compared to wildtype NRIP1 , have a significantly reduced corepressor effect on ER a -transcriptional activity, suggesting a possible effect on estrogen signaling.

More than 50% of all gynecologic tumors can be classified as rare (defined as an incidence of ≤6 per 100,000 women) and usually have a poor prognosis owing to delayed diagnosis and treatment. In contrast to almost all other common solid tumors, the treatment of rare gynecologic tumors (RGT) is often based on expert opinion, retrospective studies, or extrapolation from other tumor sites with similar histology, leading to difficulty in developing guidelines for clinical practice. Currently, gynecologic cancer research, due to distinct scientific and technological challenges, is lagging behind. Moreover, the overall efforts for addressing these challenges are fragmented across different European countries and indeed, worldwide. The GYNOCARE, COST Action CA18117 (European Network for Gynecological Rare Cancer Research) programme aims to address these challenges through the creation of a unique network between key stakeholders covering distinct domains from concept to cure: basic research on RGT, biobanking, bridging with industry, and setting up the legal and regulatory requirements for international innovative clinical trials. On this basis, members of this COST Action, (Working Group 1, “Basic and Translational Research on Rare Gynecological Cancer”) have decided to focus their future efforts on the development of new approaches to improve the diagnosis and treatment of RGT. Here, we provide a brief overview of the current state-of-the-art and describe the goals of this COST Action and its future challenges with the aim to stimulate discussion and promote synergy across scientists engaged in the fight against this rare cancer worldwide.

STUDY QUESTION: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?SUMMARY ANSWER: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.WHAT IS KNOWN ALREADY: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.STUDY DESIGN, SIZE, DURATION: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.PARTICIPANTS, SETTING, METHODS: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.MAIN RESULTS AND THE ROLE OF CHANCE: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).LIMITATIONS, REASONS FOR CAUTION: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.WIDER IMPLICATIONS OF THE FINDINGS: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.STUDY FUNDING/COMPETING INTERESTS: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.TRIAL REGISTRATION NUMBER:The trial was registered at ClinicalTrials.gov #NCT00467363.TRIAL REGISTRATION DATE:27 April 2007.DATE OF FIRST PATIENT'S ENROLLMENT:15 June 2007.

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.

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.

In Brief OBJECTIVE: To evaluate the association between low-dose aspirin initiated before conception and the risk of preterm birth. METHODS: This was a secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial. Women with a history of pregnancy loss (original stratum: one loss less than 20 weeks of gestation during the previous year; expanded stratum: one or two losses with no restrictions on timing or gestational age of the losses) were randomized to either daily low-dose aspirin (81 mg, n=615) and folic acid or folic acid alone (placebo; n=613). Preterm birth was compared between groups using intent-to-treat analysis. RESULTS: Preterm birth rates were 4.1% (22/535 low-dose aspirin) and 5.7% (31/543 placebo) (relative risk [RR] 0.72, 95% confidence interval [CI] 0.42–1.23); spontaneous preterm birth rates were 1.1% (6/535 low-dose aspirin) and 2.2% (12/543 placebo) (RR 0.51, 95% CI 0.19–1.34); medically indicated preterm birth rates were 2.6% (14/535 low-dose aspirin) and 2.9% (16/543 placebo) (RR 0.89, 95% CI 0.44–1.80). After restriction to confirmed pregnancies using inverse probability weighting, preterm birth rates were 5.7% and 9.0% (RR 0.63, 95% CI 0.37–1.09) and spontaneous preterm birth rates were 1.4% and 3.2% (RR 0.44, 95% CI 0.17–1.18). In confirmed pregnancies in the original stratum, preterm birth occurred in 3.8% and 9.7% of the low-dose aspirin and placebo groups, respectively (RR 0.39, 95% CI 0.16–0.94). CONCLUSION: Preconception low-dose aspirin was not significantly associated with the overall rate of preterm birth. Although the study was underpowered for this secondary analysis, numeric trends in favor of benefit, particularly in the women with a recent, single early pregnancy loss, warrant further investigation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00467363. LEVEL OF EVIDENCE: I Low-dose aspirin should be investigated as a potential agent to reduce the risk of preterm birth.

OBJECTIVE: We sought to assess the relationship between a short interpregnancy interval (IPI) following a pregnancy loss and subsequent live birth and pregnancy outcomes.STUDY DESIGN: A secondary analysis of women enrolled in the Effects of Aspirin in Gestation and Reproduction trial with a human chorionic gonadotropin-positive pregnancy test and whose last reproductive outcome was a loss were included in this analysis (n = 677). IPI was defined as the time between last pregnancy loss and last menstrual period of the current pregnancy and categorized by 3-month intervals. Pregnancy outcomes include live birth, pregnancy loss, and any pregnancy complications. These were compared between IPI groups using multivariate relative risk estimation by Poisson regression.RESULTS: Demographic characteristics were similar between IPI groups. The mean gestational age of prior pregnancy loss was 8.6 +/- 2.8 weeks. The overall live birth rate was 76.5%, with similar live birth rates between those with IPI <= 3 months as compared to IPI > 3 months (adjusted relative risk [aRR], 1.07; 95% confidence interval [CI], 0.98-1.16). Rates were also similar for periimplantation loss (aRR, 0.95; 95% CI, 0.51-1.80), clinically confirmed loss (aRR, 0.75; 95% CI, 0.51-1.10), and any pregnancy complication (aRR, 0.88; 95% CI, 0.71-1.09) for those with IPI <= 3 months as compared to IPI > 3 months.CONCLUSION: Live birth rates and adverse pregnancy outcomes, including pregnancy loss, were not associated with a very short IPI after a prior pregnancy loss. The traditional recommendation to wait at least 3 months after a pregnancy loss before attempting a new pregnancy may not be warranted.

OBJECTIVE: To evaluate the association between low-dose aspirin initiated before conception and the risk of preterm birth. METHODS: This was a secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial. Women with a history of pregnancy loss (original stratum: one loss less than 20 weeks of gestation during the previous year; expanded stratum: one or two losses with no restrictions on timing or gestational age of the losses) were randomized to either daily low-dose aspirin (81 mg, n=615) and folic acid or folic acid alone (placebo; n=613). Preterm birth was compared between groups using intent-to-treat analysis. RESULTS: Preterm birth rates were 4.1% (22/535 low-dose aspirin) and 5.7% (31/543 placebo) (relative risk [RR] 0.72, 95% confidence interval [CI] 0.42–1.23); spontaneous preterm birth rates were 1.1% (6/535 low-dose aspirin) and 2.2% (12/543 placebo) (RR 0.51, 95% CI 0.19–1.34); medically indicated preterm birth rates were 2.6% (14/535 low-dose aspirin) and 2.9% (16/543 placebo) (RR 0.89, 95% CI 0.44–1.80). After restriction to confirmed pregnancies using inverse probability weighting, preterm birth rates were 5.7% and 9.0% (RR 0.63, 95% CI 0.37–1.09) and spontaneous preterm birth rates were 1.4% and 3.2% (RR 0.44, 95% CI 0.17–1.18). In confirmed pregnancies in the original stratum, preterm birth occurred in 3.8% and 9.7% of the low-dose aspirin and placebo groups, respectively (RR 0.39, 95% CI 0.16–0.94). CONCLUSION: Preconception low-dose aspirin was not significantly associated with the overall rate of preterm birth. Although the study was underpowered for this secondary analysis, numeric trends in favor of benefit, particularly in the women with a recent, single early pregnancy loss, warrant further investigation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00467363. LEVEL OF EVIDENCE: I

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.

To evaluate the effect of low dose aspirin (LDA) initiated preconceptionally on the risk of preterm birth (PTB, live birth at <37 weeks' gestation). The EAGeR trial was a multi-center, randomized, double-blind, placebo-controlled trial of 1,228 US women conducted in 2006-2012. Women 18 to 40 years old with a history of pregnancy loss trying to conceive were eligible for the study. Participants were stratified based on eligibility criteria: 1) original: women with 1 pregnancy loss at <20 weeks' gestation during the past 12 months; 2) expanded: women with 1-2 prior losses, regardless of gestational length or recency. Participants were block-randomized by study center and stratum to either daily LDA (81 mg, n=615) or an identical looking placebo (n=613). Participants were followed for 6 menstrual cycles or through gestation if they became pregnant. Pregnancy end date was assessed by post-partum interview and medical record review. Gestational age was determined by an ultrasound conducted in early pregnancy for 98% of pregnancies conceived during the study. Approximately 88% (n=1078) of randomized participants completed the study. In the intent-to-treat analysis, PTB risks were: overall, 4.1% (22/535 LDA) and 5.7% (31/543 placebo) (p=0.22); in the original eligibility stratum, 2.9% (7/242 LDA) and 6.4% (16/250 placebo) (p=0.06); and in the expanded stratum, 5.1% (15/293 LDA) and 5.1% (15/293 placebo) (p=1.0). After restriction to confirmed pregnancies, the PTB risks were 5.9% (22/374 LDA) and 9.0% (31/346 placebo) (p=0.12). Using inverse probability weighting to account for different rates of conception by intervention arm, the PTB risks were 3.8% (LDA) and 5.7% (placebo) (p=0.15). Preconception LDA was not significantly associated with the risk of PTB. However, we observed a trend towards lower PTB in the LDA study arm within the confirmed pregnancies and the original eligibility stratum, which warrants further investigation.

Although recent studies suggest that lower AMH is associated with adverse obstetric outcomes like preeclampsia, less is known about an association with preterm birth. The objective was to assess a possible association between preconception AMH levels with preterm. Secondary analysis of a multicenter, block-randomized, double-blind, placebo-controlled clinical trial. 1228 women attempting pregnancy, aged 18–40 years, with one to two prior pregnancy losses and no history of infertility, pelvic inflammatory disease, tubal occlusion, endometriosis, anovulation, uterine abnormality, or polycystic ovarian syndrome were included. Women were randomized to preconception-initiated daily low-dose aspirin or placebo. The primary outcome for this analysis was preterm birth (defined as a living infant born before 37 weeks and 0 days gestation). AMH was assayed using the Gen II ELISA assay (Beckman-Coulter) at the baseline visit before randomization. AMH was clinically categorized and verified by data analysis into low (<1.25 ng/mL), normal (1.25 to 4.0 ng/mL), and high (>4.0 ng/mL). The Mann Whitney test was utilized to evaluate AMH levels by preterm birth status. Relative Risk (RR) and 95% confidence intervals (CIs) for preterm birth by AMH categories were estimated using generalized linear models adjusted for age. Women were followed for up to six menstrual cycles with N=776 (72%) achieving pregnancy and N=51 (9%) with a preterm birth. Women were predominately of white race (95.6%) with a mean age of 28.9 years (standard deviation (SD) 4.7) and body mass index (BMI) of 26.1 (SD 6.5). Mean AMH among women with a preterm birth were 3.4 ng/ml (SD 2.6) compared to women without a preterm birth at 3.6 (2.7) (p=0.81). There were no significant associations between AMH and preterm birth in women with low AMH (<1.25 ng/mL) (RR=0.72, 95% CI 0.30, 1.7) or high AMH (>4.0 ng/mL) (RR=0.78, 95% CI 0.43, 1.4) compared to women with normal AMH levels after adjustment for age. Although AMH has been recently associated with preeclampsia and pregnancy loss, AMH was not associated with preterm birth in women with normal fertility, suggesting that AMH may be a more of a marker of ovarian and reproductive vasculature, thus affecting vascular diseases of pregnancy.

ObjectiveObstetricians often recommend waiting 3mo after a pregnancy loss before attempting to conceive. However, there are no data to support this empiric recommendation. Our objective was to compare pregnancy outcomes in women conceiving prior to and after 3mo following a loss.Study DesignSecondary analysis of women enrolled in the EAGeR trial with a positive pregnancy test. The EAGeR trial (2006-2012) was a randomized, multi-center, double-blind, placebo-controlled trial of preconception low dose aspirin or placebo in women with 1-2 prior losses. All women were actively trying to conceive. Pregnancy was confirmed by a 6.5wk ultrasound. Interpregnancy interval (IPI) was defined as the time between prior documented loss and LMP of the confirmed pregnancy and categorized by 3mo intervals. We compared demographic and reproductive history characteristics by IPI group using exact chi-square tests and ANOVA. Success of pregnancy and live birth between IPI groups was compared using multivariate logistic regression adjusting for age, race, and BMI.Results724 women had a confirmed pregnancy. Demographic characteristics were similar between groups except that women with a longer IPI tended to be older, non-white, and with higher BMI. Number of prior pregnancy losses was similar among IPI groups. There were no significant differences in odds for a confirmed pregnancy between women with an IPI of 0-3mo vs >3mo (94.8% vs 93.2%; adjusted OR [aOR], 1.3; 95% confidence interval [CI], 0.7-2.7), pregnancy loss (14.2% vs 18.1%; aOR, 0.80; 95% CI, 0.5-1.3), or live birth (82.6% vs 76.9%; aOR, 1.4; 95% CI ,0.9-2.1). Similarly, there were no significant differences between 3mo interval IPI groups and those with an IPI of 0-3mo (Table 1).ConclusionTabled 1*Multivariate logistic regression adjusting for age, race, and BMI. Open table in a new tab ObjectiveObstetricians often recommend waiting 3mo after a pregnancy loss before attempting to conceive. However, there are no data to support this empiric recommendation. Our objective was to compare pregnancy outcomes in women conceiving prior to and after 3mo following a loss. Obstetricians often recommend waiting 3mo after a pregnancy loss before attempting to conceive. However, there are no data to support this empiric recommendation. Our objective was to compare pregnancy outcomes in women conceiving prior to and after 3mo following a loss. Study DesignSecondary analysis of women enrolled in the EAGeR trial with a positive pregnancy test. The EAGeR trial (2006-2012) was a randomized, multi-center, double-blind, placebo-controlled trial of preconception low dose aspirin or placebo in women with 1-2 prior losses. All women were actively trying to conceive. Pregnancy was confirmed by a 6.5wk ultrasound. Interpregnancy interval (IPI) was defined as the time between prior documented loss and LMP of the confirmed pregnancy and categorized by 3mo intervals. We compared demographic and reproductive history characteristics by IPI group using exact chi-square tests and ANOVA. Success of pregnancy and live birth between IPI groups was compared using multivariate logistic regression adjusting for age, race, and BMI. Secondary analysis of women enrolled in the EAGeR trial with a positive pregnancy test. The EAGeR trial (2006-2012) was a randomized, multi-center, double-blind, placebo-controlled trial of preconception low dose aspirin or placebo in women with 1-2 prior losses. All women were actively trying to conceive. Pregnancy was confirmed by a 6.5wk ultrasound. Interpregnancy interval (IPI) was defined as the time between prior documented loss and LMP of the confirmed pregnancy and categorized by 3mo intervals. We compared demographic and reproductive history characteristics by IPI group using exact chi-square tests and ANOVA. Success of pregnancy and live birth between IPI groups was compared using multivariate logistic regression adjusting for age, race, and BMI. Results724 women had a confirmed pregnancy. Demographic characteristics were similar between groups except that women with a longer IPI tended to be older, non-white, and with higher BMI. Number of prior pregnancy losses was similar among IPI groups. There were no significant differences in odds for a confirmed pregnancy between women with an IPI of 0-3mo vs >3mo (94.8% vs 93.2%; adjusted OR [aOR], 1.3; 95% confidence interval [CI], 0.7-2.7), pregnancy loss (14.2% vs 18.1%; aOR, 0.80; 95% CI, 0.5-1.3), or live birth (82.6% vs 76.9%; aOR, 1.4; 95% CI ,0.9-2.1). Similarly, there were no significant differences between 3mo interval IPI groups and those with an IPI of 0-3mo (Table 1). 724 women had a confirmed pregnancy. Demographic characteristics were similar between groups except that women with a longer IPI tended to be older, non-white, and with higher BMI. Number of prior pregnancy losses was similar among IPI groups. There were no significant differences in odds for a confirmed pregnancy between women with an IPI of 0-3mo vs >3mo (94.8% vs 93.2%; adjusted OR [aOR], 1.3; 95% confidence interval [CI], 0.7-2.7), pregnancy loss (14.2% vs 18.1%; aOR, 0.80; 95% CI, 0.5-1.3), or live birth (82.6% vs 76.9%; aOR, 1.4; 95% CI ,0.9-2.1). Similarly, there were no significant differences between 3mo interval IPI groups and those with an IPI of 0-3mo (Table 1). ConclusionTabled 1*Multivariate logistic regression adjusting for age, race, and BMI. Open table in a new tab *Multivariate logistic regression adjusting for age, race, and BMI.

Women with a history of pregnancy loss are at increased risk of a subsequent loss and other adverse pregnancy outcomes. The pathophysiologic mechanisms responsible for pregnancy loss are unclear. It is believed that decreased blood flow and increased inflammation may play an important role in pregnancy loss and other adverse pregnancy events. Because aspirin can improve blood flow and reduce inflammation in reproductive organs, it has been hypothesized that giving aspirin to women attempting to conceive might improve pregnancy outcomes. Many health care providers prescribe low-dose preconception aspirin therapy for women who have had a pregnancy loss and who would like to get pregnant again. However, the efficacy of this treatment is unproven. The aim of the EAGeR (Effects of Aspirin in Gestation and Reproduction) trial was to determine whether preconception treatment with low-dose aspirin would reduce the risk of pregnancy loss in women with 1 or 2 previous pregnancy losses. The study was a multicenter, block-randomized, double-blind, placebo-controlled trial conducted in women aged 18 to 40 years with a history of pregnancy loss who were attempting to become pregnant. Participants were recruited from 4 university medical centers in the United States. The original stratum included women who had 1 loss at less than 20 weeks' gestation during the previous year. Because of slow enrollment, the stratum was expanded to include women with 1 to 2 previous losses without any restrictions on gestational age or time of loss. Prior to conception, women were randomized to receive either low-dose aspirin (81 mg/d) plus folic acid or placebo plus folic acid for up to 6 menstrual cycles. Treatment was continued until 36 weeks' gestation for women who became pregnant. Trial staff, investigators, and participants were masked to the assigned treatment. The primary study outcome was live birth rate. Data were analyzed according to intention to treat. Of the 1228 women randomly assigned between 2007 and 2011, 1078 (88%) completed the trial and were included in the analysis (535 in the aspirin group and 543 in the placebo group). A total of 309 women (58%) in the low-dose aspirin group became pregnant and later gave birth, compared with 286 (53%) in the placebo group (absolute difference, 5.09%; 95% confidence interval [CI], -0.84% to 11.02%; P = 0.10). Pregnancy loss occurred in 68 (13%) of the women in the aspirin group and in 65 (12%) of the women in the placebo group (P = 0.78). Among women in the original stratum, who had a single recent pregnancy loss, live births occurred in 62% (151/242) of women in the aspirin group, compared with 53% (133/250) of those in the placebo group; the absolute difference was 9.2%, with a 95% CI of 0.51% to 17.89%, P = 0. 045. In the expanded stratum, however, no significant difference between treatment groups occurred in live birth rates (54% [158/293] in the low-dose aspirin group vs 52% [153/293] in the placebo group; absolute difference, 1.71%; 95% CI, -6.37% to 9.79%; P = 0.74). Major adverse events in both treatment groups were similar. Low-dose aspirin was associated with increased vaginal bleeding, but this was not associated with pregnancy loss. The use of preconception-initiated low-dose aspirin to prevent recurrent pregnancy loss is not supported by these data. Further studies are needed to investigate the apparent increased birth rate among women who had a single well-documented loss at less than 20 weeks' gestation during the previous year.

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 >$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.