Associations Between Preconception Plasma Fatty Acids and Pregnancy Outcomes.

BACKGROUND: Although fatty acids are involved in critical reproductive processes, the relationship between specific fatty acids and fertility is uncertain. We investigated the relationship between preconception plasma fatty acids and pregnancy outcomes. METHODS: We included 1,228 women attempting pregnancy with one to two previous pregnancy losses from the EAGeR trial (2007-2011). Plasma fatty acids were measured at baseline. We used log-binomial regression to assess associations between fatty acids and pregnancy, pregnancy loss, and live birth, adjusting for age, race, smoking, BMI, physical activity, income, parity, treatment arm, and cholesterol. RESULTS: Although total saturated fatty acids (SFAs) were not associated with pregnancy outcomes, 14:0 (myristic acid; relative risk [RR] = 1.10, 95% confidence interval [CI] = 1.02, 1.19, per 0.1% increase) and 20:0 (arachidic acid; RR = 1.05, 95% CI = 1.01, 1.08, per 0.1% increase) were positively associated with live birth. Findings suggested a positive association between total monounsaturated fatty acids (MUFAs) and pregnancy and live birth and an inverse association with loss. Total polyunsaturated fatty acids (PUFAs) were associated with lower probability of pregnancy (RR = 0.97, 95% CI = 0.95, 1.00) and live birth (RR = 0.96, 95% CI = 0.94, 0.99), and increased risk of loss (RR = 1.10, 95% CI = 1.00, 1.20), per 1% increase. Trans fatty acids and n-3 fatty acids were not associated with pregnancy outcomes. CONCLUSIONS: Preconception total plasma MUFAs were positively associated with pregnancy and live birth. PUFAs were inversely associated with pregnancy outcomes. Specific SFAs were associated with a higher probability of live birth. Our results suggest that fatty acids may influence pregnancy outcomes.

Preconception Perceived Stress Is Associated with Reproductive Hormone Levels and Longer Time to Pregnancy.

BACKGROUND: Women who experience pregnancy loss are especially prone to high stress, though the effects of stress on reproductive outcomes in this vulnerable population are unknown. We assessed relationships between perceived stress and hormones, anovulation, and fecundability among women with prior loss. METHODS: One thousand two hundred fourteen women with 1-2 prior losses were followed for ≤6 cycles while attempting pregnancy and completed end-of-cycle stress assessments. For cycles 1 and 2, women also collected daily urine and completed daily perceived stress assessments. We assessed anovulation via. an algorithm based on human chorionic gonadotropin (hCG), pregnanediol-3-glucuronide (PdG), luteinizing hormone (LH), and fertility monitor readings. Pregnancy was determined via. hCG. Adjusted weighted linear mixed models estimated the effect of prospective phase-varying (menses, follicular, periovulatory, and luteal) perceived stress quartiles on estrone-1-glucuronide (E1G), PdG, and LH concentrations. Marginal structural models accounted for time-varying confounding by hormones and lifestyle factors affected by prior stress. Poisson and Cox regression estimated risk ratios and fecundability odds ratios of cycle-varying stress quartiles on anovulation and fecundability. Models were adjusted for age, race, body mass index (BMI), parity, and time-varying caffeine, alcohol, smoking, intercourse, and pelvic pain. RESULTS: Women in the highest versus lowest stress quartile had lower E1G and PdG concentrations, a marginally higher risk of anovulation [1.28; 95% confidence interval (CI) = 1.00, 1.63], and lower fecundability (0.71; 95% CI = 0.55, 0.90). CONCLUSION: Preconception perceived stress appears to adversely affect sex steroid synthesis and time to pregnancy. Mechanisms likely include the effects of stress on ovulatory function, but additional mechanisms, potentially during implantation, may also exist.

A prospective study of physical activity and fecundability in women with a history of pregnancy loss.

STUDY QUESTION: Is physical activity (PA) associated with fecundability in women with a history of prior pregnancy loss? SUMMARY ANSWER: Higher fecundability was related to walking among overweight/obese women and to vigorous PA in women overall. WHAT IS KNOWN ALREADY: PA may influence fecundability through altered endocrine function. Studies evaluating this association have primarily utilized Internet-based recruitment and self-report for pregnancy assessment and have yielded conflicting results. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a multisite, randomized controlled trial of preconception-initiated low-dose aspirin. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy women (n = 1214), aged 18-40 and with 1-2 prior pregnancy losses, were recruited from four US medical centers. Participants were followed for up to six menstrual cycles while attempting pregnancy and through pregnancy for those who became pregnant. Time to hCG detected pregnancy was assessed using discrete-time Cox proportional hazard models to estimate fecundability odds ratios (FOR) adjusted for covariates, accounting for left truncation and right censoring. MAIN RESULTS AND THE ROLE OF CHANCE: The association of walking with fecundability varied significantly by BMI (P-interaction = 0.01). Among overweight/obese women, walking ≥10 min at a time was related to improved fecundability (FOR = 1.82, 95% CI: 1.19, 2.77). In adjusted models, women reporting >4 h/wk of vigorous activity had significantly higher fecundability (FOR = 1.69, 95% CI: 1.24, 2.31) compared to no vigorous activity. Associations of vigorous activity with fecundability were not significantly different by BMI (P-interaction = 0.9). Moderate activity, sitting, and International Physical Activity Questionnaire (IPAQ) categories were not associated with fecundability overall or in BMI-stratified analyses. LIMITATIONS, REASONS FOR CAUTION: Some misclassification of PA levels as determined by the short form of the IPAQ is likely to have occurred, and may have led to non-differential misclassification of exposure in our study. Information on diet and change in BMI was not collected and may have contributed to some residual confounding in our results. The generalizability of our results may be limited as our population consisted of women with a history of one or two pregnancy losses. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide positive evidence for the benefits of PA in women attempting pregnancy, especially for walking among those with higher BMI. Further study is necessary to clarify possible mechanisms through which walking and vigorous activity might affect time-to-pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors report no conflicts of interest in this work. TRIAL REGISTRATION NUMBER: #NCT00467363.

Prevalence and Contributors to Low-grade Inflammation in Three U.S. Populations of Reproductive Age Women.

BACKGROUND: Inflammation, measured by high-sensitivity C-reactive protein (hsCRP), is linked to adverse reproductive outcomes. However, prevalence and predictors of low-grade inflammation are poorly understood among reproductive age women. Therefore, the current aim was to characterize: (i) the prevalence of elevated hsCRP and (ii) whether the association of various demographic, anthropometric, life style, and metabolic characteristics with higher hsCRP varies across populations of reproductive age women with varying risk profiles for adverse reproductive outcomes. METHODS: Bivariate analysis of characteristics among women ages 18-40 having hsCRP <2.0 vs. ≥2.0 mg/L in the BioCycle Study (N = 259), the Effects of Aspirin in Gestation and Reproduction Trial (EAGeR) (N = 1228), and the National Health and Nutrition Examination Survey (NHANES; N = 2173) were conducted. Multivariable regression analysis estimated the association of all characteristics to hsCRP within each cohort. RESULTS: Prevalence of hsCRP≥2 mg/L ranged from 20 to 40%. Age, BMI, waist circumference, blood pressure, lipids, glucose, and insulin were frequently higher in women with hsCRP ≥2 mg/L. In multivariable models, however, only adiposity (BMI, waist circumference) was independently associated with hsCRP within all three cohorts. Some variables showed cohort-specific associations with higher hsCRP: white race (EAGeR), higher fasting glucose (BioCycle), and lesser education and employment (NHANES). The total characteristics explained 28-46% of the variation in hsCRP across the three cohorts. CONCLUSIONS: Low-grade inflammation was common, including among predominantly non-obese women, affecting from 20 to 40% of reproductive age women. Given the potential to reduce inflammation through inexpensive, widely available therapies, examination of the impact of chronic inflammation on reproductive and pregnancy outcomes, as well as preventive interventions, are now needed.

Brief Report: Cesarean Delivery and Subsequent Fecundability.

BACKGROUND: Studies have shown that cesarean delivery is associated with fewer subsequent births relative to vaginal delivery, but it is unclear whether confounding by pregnancy intention or indication for surgery explained these results. We evaluated the association between cesarean delivery and subsequent fecundability among 910 primiparous women after singleton live birth. METHODS: In a cohort of Danish women planning pregnancy (2007-2012), obstetrical history was obtained via registry linkage; time-to-pregnancy and covariate data were collected via questionnaire. Fecundability ratios (FRs) and 95% confidence intervals (CIs) were adjusted for potential confounders. RESULTS: Relative to spontaneous vaginal delivery, emergency cesarean delivery with cephalic presentation showed little association with fecundability (FR = 1.0, 95% CI = 0.83, 1.3), but cesarean delivery with breech presentation (FR = 0.72, 95% CI = 0.53, 0.97) and planned cesarean delivery with cephalic presentation (FR = 0.51, 95% CI = 0.25, 1.0) were associated with reduced fecundability. CONCLUSIONS: The cesarean-fecundability association varied by previous fetal presentation and emergency status.

Serum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women.

BACKGROUND: Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in women's reproductive health. OBJECTIVE: The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. METHODS: The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (α-tocopherol, γ-tocopherol, retinol, lutein, lycopene, and ß-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5-8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. RESULTS: Serum antioxidant concentrations varied across the menstrual cycle. Retinol and α-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: -0.06 mIU/mL; 95% CI: -0.09, -0.03 mIU/mL). The ratio of α- to γ-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06). CONCLUSIONS: These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress.

History of uterine leiomyomata and incidence of breast cancer.

PURPOSE: Uterine leiomyomata (UL), benign tumors of the myometrium, are influenced by sex steroid hormones. A history of UL diagnosis has been associated with a higher risk of uterine malignancies. The relation between UL and breast cancer, another hormonally responsive cancer, has not been studied. METHODS: We investigated the association between self-reported physician-diagnosed UL and incidence of breast cancer in the Black Women's Health Study, a prospective cohort study. We followed 57,747 participants without a history of breast cancer from 1995 to 2013. UL diagnoses were reported at baseline and biennially. Breast cancer was reported on biennial questionnaires and confirmed by pathology data from medical records or cancer registries. Cox regression was used to derive incidence rate ratios (IRRs) and 95 % confidence intervals (CI) and adjust for potential confounders. RESULTS: There were 2,276 incident cases of breast cancer (1,699 invasive, 394 in situ, and 183 unknown) during 879,672 person-years of follow-up. The multivariable IRR for the overall association between history of UL and breast cancer incidence was 0.99 (95 % CI 0.90-1.08), with similar results for ER + (IRR = 1.03) and ER - breast cancer (IRR = 1.05). IRRs for early diagnosis of UL (before age 30) were slightly above 1.0, with IRRs of 1.14 (95 % CI 0.99-1.31) for overall breast cancer, 1.14 (95 % CI 0.93-1.40) for ER + breast cancer, and 1.20 (95 % CI 0.89-1.61) for ER - breast cancer. IRRs for early diagnosis of UL were elevated for breast cancer diagnosed before 40 years of age (IRR = 1.39, 95 % CI 0.97-1.99) and premenopausal breast cancer (IRR = 1.26, 95 % CI 1.01-1.58). No consistent patterns in risk were observed across estrogen receptor subtypes, and IRRs did not differ appreciably within strata of BMI, female hormone use, mammography recency, or family history of breast cancer. CONCLUSIONS: The present study of US black women suggests that a history of UL diagnosis is unrelated to the incidence of breast cancer overall. The positive associations observed for early diagnosed UL with breast cancer before age 40 and with premenopausal breast cancer require confirmation in future studies.

Dietary factors and luteal phase deficiency in healthy eumenorrheic women.

STUDY QUESTION: Are prospectively assessed dietary factors, including overall diet quality, macronutrients and micronutrients, associated with luteal phase deficiency (LPD) in healthy reproductive aged women with regular menstrual cycles? SUMMARY ANSWER: Mediterranean Diet Score (MDS), fiber and isoflavone intake were positively associated with LPD while selenium was negatively associated with LPD after adjusting for age, percentage body fat and total energy intake. WHAT IS KNOWN ALREADY: LPD may increase the risk of infertility and early miscarriage. Prior research has shown positive associations between LPD and low energy availability, either through high dietary restraint alone or in conjunction with high energy expenditure via exercise, but few studies with adequate sample sizes have been conducted investigating dietary factors and LPD among healthy, eumenorrheic women. STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) prospectively enrolled 259 women from Western New York state, USA, and followed them for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-44 years, with self-reported BMI between 18 and 35 kg/m(2) and cycle lengths between 21 and 35 days, were included in the study. Participants completed baseline questionnaires, four 24-h dietary recalls per cycle and daily diaries capturing vigorous exercise, perceived stress and sleep; they also provided up to eight fasting serum samples during clinic visits timed to specific phases of the menstrual cycle using a fertility monitor. Cycles were included for this analysis if the peak serum luteal progesterone was >1 ng/ml and a urine or serum LH surge was detected. Associations between prospectively assessed diet quality, macronutrients and micronutrients and LPD (defined as luteal duration <10 days) were evaluated using generalized linear models adjusting for age, percentage body fat and total energy intake. MAIN RESULTS AND THE ROLE OF CHANCE: LPD occurred in 41 (8.9%) of the 463 cycles from 246 women in the final analysis. After adjusting for age, percentage body fat and total energy intake, LPD was positively associated with MDS, adjusted odds ratio (aOR): 1.70 (95% confidence interval [CI]: 1.17, 2.48), P = 0.01. In separate macro- and micronutrient adjusted models, increased fiber and isoflavone intake showed modest positive associations with LPD: fiber (per g), aOR: 1.10 (95% CI: 0.99, 1.23), P = 0.07; and isoflavones (per 10 mg), aOR: 1.38 (95% CI: 0.99, 1.92), P = 0.06. In contrast, selenium (per 10 mcg) was inversely associated with LPD, aOR: 0.80 (95% CI: 0.65, 0.97), P = 0.03. Additional adjustments for relevant lifestyle factors including vigorous exercise, perceived stress and sleep did not appreciably alter estimates. LIMITATIONS, REASONS FOR CAUTION: The number of LPD cycles was limited, and thus these findings are exploratory. We relied on participant self-report of their medical history to apply exclusion criteria; it is possible that we admitted to the study women with a gynecologic or medical disease who were unaware of their diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that diet quality may be associated with LPD among healthy eumenorrheic women. As LPD may contribute to infertility and early miscarriage, further research is warranted to elucidate how dietary factors, such as MDS, may influence LPD. The inverse association we found with selenium is supported by previous research and deserves further investigation to determine whether this finding has pathophysiologic and therapeutic implications. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No competing interests declared.

Maternal Recall Error in Retrospectively Reported Time-to-Pregnancy: an Assessment and Bias Analysis.

BACKGROUND: Epidemiologic studies of fecundability often use retrospectively measured time-to-pregnancy (TTP), thereby introducing potential for recall error. Little is known about how recall error affects the bias and precision of the fecundability odds ratio (FOR) in such studies. METHODS: Using data from the Danish Snart-Gravid Study (2007-12), we quantified error for TTP recalled in the first trimester of pregnancy relative to prospectively measured TTP among 421 women who enrolled at the start of their pregnancy attempt and became pregnant within 12 months. We defined recall error as retrospectively measured TTP minus prospectively measured TTP. Using linear regression, we assessed mean differences in recall error by maternal characteristics. We evaluated the resulting bias in the FOR and 95% confidence interval (CI) using simulation analyses that compared corrected and uncorrected retrospectively measured TTP values. RESULTS: Recall error (mean = -0.11 months, 95% CI -0.25, 0.04) was not appreciably associated with maternal age, gravidity, or recent oral contraceptive use. Women with TTP > 2 months were more likely to underestimate their TTP than women with TTP ≤ 2 months (unadjusted mean difference in error: -0.40 months, 95% CI -0.71, -0.09). FORs of recent oral contraceptive use calculated from prospectively measured, retrospectively measured, and corrected TTPs were 0.82 (95% CI 0.67, 0.99), 0.74 (95% CI 0.61, 0.90), and 0.77 (95% CI 0.62, 0.96), respectively. CONCLUSIONS: Recall error was small on average among pregnancy planners who became pregnant within 12 months. Recall error biased the FOR of recent oral contraceptive use away from the null by 10%. Quantitative bias analysis of the FOR can help researchers quantify the bias from recall error.

Predictors of recall certainty of dates of analgesic medication use in pregnancy.

PURPOSE: Recalled dates of medication use are difficult to validate, particularly for over-the-counter (OTC) medications. We evaluated mothers' recall certainty as an approximation of the accuracy of their recalled exposures. METHODS: We used data from the Slone Epidemiology Center Birth Defects Study collected by retrospective interview of women about pregnancy medication use. For each medication reported, women were asked to report the dates of their use and how certain they were of their reported dates. For this analysis, 32,107 reports from 14,577 analgesic users were categorized as "high" or "low" recall certainty if they considered a reported date as exact or estimated, respectively. Patterns of analgesic use, maternal demographics, and health behaviors were explored as predictors of high recall certainty of dates of analgesic use. We used log-binomial regression with the generalized estimating equations extension to account for multiple reports per subject in estimating prevalence ratios (PR) and 95% confidence intervals. RESULTS: Relative to episodes of short-term routine use (≥4 times/week for ≤30 days), high recall certainty was more likely for episodes of a single dose (prescription PR = 1.92 (1.61, 2.27); OTC PR = 3.65 (3.03, 4.40)) and less likely for episodes of occasional use (prescription PR = 0.10 (0.05, 0.18); OTC PR = 0.65 (0.53, 0.79)). The association of chronic routine use with high recall certainty was inverse among prescription analgesics and positive among OTC analgesics (prescription PR = 0.56 (0.40, 0.80); OTC PR = 2.46 (1.92, 3.42)). CONCLUSIONS: Some characteristics that were associated with recall accuracy in previous studies were also associated with recall certainty in this study.

African ancestry and genetic risk for uterine leiomyomata.

Rates of uterine leiomyomata (UL) are 2-3 times higher in African Americans than in European Americans. It is unclear whether inherited factors explain the ethnic disparity. To investigate the presence of risk alleles for UL that are highly differentiated in frequency between African Americans and European Americans, the authors conducted an admixture-based genome-wide scan of 2,453 UL cases confirmed by ultrasound or surgery in the Black Women's Health Study (1997-2009), a national prospective cohort study. Controls (n = 2,102) were women who did not report a UL diagnosis through 2009. Mean percentage of European ancestry was significantly lower among cases (20.00%) than among controls (21.63%; age-adjusted mean difference = -1.76%, 95% confidence interval: -2.40, -1.12; P < 0.0001), and the association was stronger in younger cases. Admixture analyses showed suggestive evidence of association at chromosomes 2, 4, and 10. The authors also genotyped a dense set of tag single nucleotide polymorphisms at different loci associated with UL in Japanese women but failed to replicate the associations. This suggests that genetic variation for UL differs in populations with and without African ancestry. The admixture findings further indicate that no single highly differentiated locus is responsible for the ethnic disparity in UL, raising the possibility that multiple variants jointly contribute to the higher incidence of UL in African Americans.

A prospective study of dairy intake and risk of uterine leiomyomata.

Rates of uterine leiomyomata are 2-3 times higher among black women than white women. Dietary factors that differ in prevalence between these populations that could contribute to the disparity include dairy intake. During 1997-2007, the authors followed 22,120 premenopausal US Black Women's Health Study participants to assess dairy intake in relation to uterine leiomyomata risk. Because soy may be substituted for dairy, the effect of soy intake was also evaluated. Diet was estimated by using food frequency questionnaires in 1995 and 2001. Incidence rate ratios and 95% confidence intervals were estimated with Cox regression. There were 5,871 incident cases of uterine leiomyomata diagnosed by ultrasound (n = 3,964) or surgery (n = 1,907). Multivariable incidence rate ratios comparing 1, 2, 3, and > or =4 servings/day with <1 serving/day of total dairy were 0.94 (95% confidence interval (CI): 0.88, 1.00), 0.87 (95% CI: 0.78, 0.98), 0.84 (95% CI: 0.70, 1.01), and 0.70 (95% CI: 0.58, 0.86), respectively (P-trend <0.001). Incidence rate ratios comparing the highest (> or =2 servings/day) with the lowest (<1 serving/week) intake categories were 0.81 (95% CI: 0.66, 0.99) for high-fat dairy, 0.80 (95% CI: 0.70, 0.91) for low-fat dairy, and 0.78 (95% CI: 0.68, 0.89) for milk. Soy intake was unrelated to uterine leiomyomata risk. This large prospective study of black women provides the first epidemiologic evidence of reduced uterine leiomyomata risk associated with dairy consumption.

C-Reactive protein in relation to fecundability and anovulation among eumenorrheic women.

OBJECTIVE: To assess systemic inflammation in relation to fecundability and anovulation. DESIGN: Prospective cohort study among participants in the Effects of Aspirin in Gestation and Reproduction trial who were assigned to the placebo. SETTING: Academic medical centers. PATIENT(S): Healthy eumenorrheic women (n = 572), 18-40 years of age, with one or two pregnancy losses, attempting spontaneous pregnancy. INTERVENTION(S): Baseline serum high-sensitivity C-reactive protein (hsCRP) values <10 mg/L were categorized into tertiles. MAIN OUTCOME MEASURE(S): Discrete Cox proportional hazards models estimated the fecundability odds ratio (FOR) and 95% confidence interval (CI) and adjusted for potential confounders. Log-binomial regression estimated the risk ratio (RR) and 95% CI of anovulation. The algorithm to define anovulation used data on urinary concentrations of hCG, pregnanediol-3-glucuronide, and LH as well as fertility monitor readings. RESULT(S): Higher hsCRP was associated with reduced fecundability but not with an increased risk of anovulation. CONCLUSION(S): Among healthy women attempting pregnancy after one or two pregnancy losses, we found preliminary evidence that systemic inflammation is associated with reduced fecundability, but not independently from adiposity. Sporadic anovulation did not appear to drive this association. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00467363.

Low-Dose Aspirin and Sporadic Anovulation in the EAGeR Randomized 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 Restores Diminished Pregnancy and Live Birth Rates in Women With Low-Grade Inflammation: A Secondary Analysis of a Randomized Trial.

Context: Inflammation is linked to causes of infertility. Low-dose aspirin (LDA) may improve reproductive success in women with chronic, low-grade inflammation. Objective: To investigate the effect of preconception-initiated LDA on pregnancy rate, pregnancy loss, live birth rate, and inflammation during pregnancy. Design: Stratified secondary analysis of a multicenter, block-randomized, double-blind, placebo-controlled trial. Setting: Four US academic medical centers, 2007 to 2012. Participants: Healthy women aged 18 to 40 years (N = 1228) with one to two prior pregnancy losses actively attempting to conceive. Intervention: Preconception-initiated, daily LDA (81 mg) or matching placebo taken up to six menstrual cycles attempting pregnancy and through 36 weeks' gestation in women who conceived. Main Outcome Measures: Confirmed pregnancy, live birth, and pregnancy loss were compared between LDA and placebo, stratified by tertile of preconception, preintervention serum high-sensitivity C-reactive protein (hsCRP) (low, <0.70 mg/L; middle, 0.70 to <1.95 mg/L; high, ≥1.95 mg/L). Results: Live birth occurred in 55% of women overall. The lowest pregnancy and live birth rates occurred among the highest hsCRP tertile receiving placebo (44% live birth). LDA increased live birth among high-hsCRP women to 59% (relative risk, 1.35; 95% confidence interval, 1.08 to 1.67), similar to rates in the lower and mid-CRP tertiles. LDA did not affect clinical pregnancy or live birth in the low (live birth: 59% LDA, 54% placebo) or midlevel hsCRP tertiles (live birth: 59% LDA, 59% placebo). Conclusions: In women attempting conception with elevated hsCRP and prior pregnancy loss, LDA may increase clinical pregnancy and live birth rates compared with women without inflammation and reduce hsCRP elevation during pregnancy.

Trying to Conceive After an Early Pregnancy Loss: An Assessment on How Long Couples Should Wait.

OBJECTIVE: To compare time to pregnancy and live birth among couples with varying intervals of pregnancy loss date to subsequent trying to conceive date. METHODS: In this secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, 1,083 women aged 18-40 years with one to two prior early losses and whose last pregnancy outcome was a nonectopic or nonmolar loss were included. Participants were actively followed for up to six menstrual cycles and, for women achieving pregnancy, until pregnancy outcome. We calculated intervals as start of trying to conceive date minus pregnancy loss date. Time to pregnancy was defined as start of trying to conceive until subsequent conception. Discrete Cox models, accounting for left truncation and right censoring, estimated fecundability odds ratios (ORs) adjusting for age, race, body mass index, education, and subfertility. Although intervals were assessed prior to randomization and thus reasoned to have no relation with treatment assignment, additional adjustment for treatment was evaluated given that low-dose aspirin was previously shown to be predictive of time to pregnancy. RESULTS: Couples with a 0-3-month interval (n=765 [76.7%]) compared with a greater than 3-month (n=233 [23.4%]) interval were more likely to achieve live birth (53.2% compared with 36.1%) with a significantly shorter time to pregnancy leading to live birth (median [interquartile range] five cycles [three, eight], adjusted fecundability OR 1.71 [95% confidence interval 1.30-2.25]). Additionally adjusting for low-dose aspirin treatment did not appreciably alter estimates. CONCLUSION: Our study supports the hypothesis that there is no physiologic evidence for delaying pregnancy attempt after an early loss.

Serum caffeine and paraxanthine concentrations and menstrual cycle function: correlations with beverage intakes and associations with race, reproductive hormones, and anovulation in the BioCycle Study.

BACKGROUND: Clinicians often recommend limiting caffeine intake while attempting to conceive; however, few studies have evaluated the associations between caffeine exposure and menstrual cycle function, and we are aware of no previous studies assessing biological dose via well-timed serum measurements. OBJECTIVES: We assessed the relation between caffeine and its metabolites and reproductive hormones in a healthy premenopausal cohort and evaluated potential effect modification by race. DESIGN: Participants (n = 259) were followed for ≤2 menstrual cycles and provided fasting blood specimens ≤8 times/cycle. Linear mixed models were used to estimate associations between serum caffeine biomarkers and geometric mean reproductive hormones, whereas Poisson regression was used to assess risk of sporadic anovulation. RESULTS: The highest compared with the lowest serum caffeine tertile was associated with lower total testosterone [27.9 ng/dL (95% CI: 26.7, 29.0 ng/dL) compared with 29.1 ng/dL (95% CI: 27.9, 30.3 ng/dL), respectively] and free testosterone [0.178 ng/mL (95% CI: 0.171, 0.185 ng/dL) compared with 0.186 ng/mL (95% CI: 0.179, 0.194 ng/dL), respectively] after adjustment for age, race, percentage of body fat, daily vigorous exercise, perceived stress, depression, dietary factors, and alcohol intake. The highest tertiles compared with the lowest tertiles of caffeine and paraxanthine were also associated with reduced risk of anovulation [adjusted RRs (aRRs): 0.39 (95% CI: 0.18, 0.87) and 0.40 (95% CI: 0.18, 0.87), respectively]. Additional adjustment for self-reported coffee intake did not alter the reproductive hormone findings and only slightly attenuated the results for serum caffeine and paraxanthine and anovulation. Although reductions in the concentrations of total testosterone and free testosterone and decreased risk of anovulation were greatest in Asian women, there was no indication of effect modification by race. CONCLUSION: Caffeine intake, irrespective of the beverage source, may be associated with reduced testosterone and improved menstrual cycle function in healthy premenopausal women.

Association of Nausea and Vomiting During Pregnancy With Pregnancy Loss: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Nausea and vomiting during pregnancy have been associated with a reduced risk for pregnancy loss. However, most prior studies enrolled women with clinically recognized pregnancies, thereby missing early losses. Objective: To examine the association of nausea and vomiting during pregnancy with pregnancy loss. Design, Setting, and Participants: A randomized clinical trial, Effects of Aspirin in Gestation and Reproduction, enrolled women with 1 or 2 prior pregnancy losses at 4 US clinical centers from June 15, 2007, to July 15, 2011. This secondary analysis was limited to women with a pregnancy confirmed by positive results of a human chorionic gonadotropin (hCG) test. Nausea symptoms were ascertained from daily preconception and pregnancy diaries for gestational weeks 2 to 8. From weeks 12 to 36, participants completed monthly questionnaires summarizing symptoms for the preceding 4 weeks. A week-level variable included nausea only, nausea with vomiting, or neither. Main Outcomes and Measures: Peri-implantation (hCG-detected pregnancy without ultrasonographic evidence) and clinically recognized pregnancy losses. Results: A total of 797 women (mean [SD] age, 28.7 [4.6] years) had an hCG-confirmed pregnancy. Of these, 188 pregnancies (23.6%) ended in loss. At gestational week 2, 73 of 409 women (17.8%) reported nausea without vomiting and 11 of 409 women (2.7%), nausea with vomiting. By week 8, the proportions increased to 254 of 443 women (57.3%) and 118 of 443 women (26.6%), respectively. Hazard ratios (HRs) for nausea (0.50; 95% CI, 0.32-0.80) and nausea with vomiting (0.25; 95% CI, 0.12-0.51) were inversely associated with pregnancy loss. The associations of nausea (HR, 0.59; 95% CI, 0.29-1.20) and nausea with vomiting (HR, 0.51; 95% CI, 0.11-2.25) were similar for peri-implantation losses but were not statistically significant. Nausea (HR, 0.44; 95% CI, 0.26-0.74) and nausea with vomiting (HR, 0.20; 95% CI, 0.09-0.44) were associated with a reduced risk for clinical pregnancy loss. Conclusions and Relevance: Among women with 1 or 2 prior pregnancy losses, nausea and vomiting were common very early in pregnancy and were associated with a reduced risk for pregnancy loss. These findings overcome prior analytic and design limitations and represent the most definitive data available to date indicating the protective association of nausea and vomiting in early pregnancy and the risk for pregnancy loss. Trial Registration: clinicaltrials.gov Identifier: NCT00467363.

Antimüllerian hormone and pregnancy loss from the Effects of Aspirin in Gestation and Reproduction trial.

OBJECTIVE: To evaluate if antimüllerian hormone (AMH) is associated with pregnancy loss. DESIGN: Prospective cohort study within a block-randomized, double-blind, placebo-controlled trial of low-dose aspirin. SETTING: Not 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 NUMBER: NCT00467363.