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Preconception-initiated low-dose aspirin might positively affect pregnancy outcomes, but this possibility has not been adequately assessed. Our aim was to investigate whether low-dose aspirin improved livebirth rates in women with one to two previous pregnancy losses. In this multicentre, block-randomised, double-blind, placebo-controlled trial, women aged 18–40 years who were attempting to become pregnant were recruited from four medical centres in the USA. Participants were stratified by eligibility criteria—the original stratum was restricted to women with one loss at less than 20 weeks' gestation during the previous year, whereas the expanded stratum included women with one to two previous losses, with no restrictions on gestational age or time of loss. Women were block-randomised by centre and eligibility stratum in a 1:1 ratio. Preconception-initiated daily low-dose aspirin (81 mg per day) plus folic acid was compared with placebo plus folic acid for up to six menstrual cycles; for women who conceived, study treatment continued until 36 weeks' gestation. Participants, trial staff, and investigators were masked to the assigned treatment. The primary outcome was livebirth rate, which was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00467363. Overall, 1228 women were recruited and randomly assigned between June 15, 2007, and July 15, 2011, 1078 of whom completed the trial and were included in the analysis (535 in the low-dose aspirin group and 543 in the placebo group). 309 (58%) women in the low-dose aspirin group had livebirths, compared with 286 (53%) in the placebo group (p=0·0984; absolute difference in livebirth rate 5·09% [95% CI −0·84 to 11·02]). Pregnancy loss occurred in 68 (13%) women in the low-dose aspirin group, compared with 65 (12%) women in the placebo group (p=0·7812). In the original stratum, 151 (62%) of 242 women in the low-dose aspirin group had livebirths, compared with 133 (53%) of 250 in the placebo group (p=0·0446; absolute difference in livebirth rate 9·20% [0·51 to 17·89]). In the expanded stratum, 158 (54%) of 293 women in the low-dose aspirin group and 153 (52%) of 293 in the placebo group had livebirths (p=0·7406; absolute difference in livebirth rate 1·71% [−6·37 to 9·79]). Major adverse events were similar between treatment groups. Low-dose aspirin was associated with increased vaginal bleeding, but this adverse event was not associated with pregnancy loss. Preconception-initiated low-dose aspirin was not significantly associated with livebirth or pregnancy loss in women with one to two previous losses. However, higher livebirth rates were seen in women with a single documented loss at less than 20 weeks' gestation during the previous year. Low-dose aspirin is not recommended for the prevention of pregnancy loss. Eunice Kennedy Shriver National Institute of Child Health and Human Development (US National Institutes of Health).

Evolutionary theory suggests that some animal species may experience shifts in their offspring sex ratio in response to maternal health and environmental conditions, and in some unfavorable conditions, females may be less likely to bear sons. Experimental data in both animals and humans indicate that maternal inflammation may disproportionately impact the viability of male conceptuses; however, it is unknown whether other factors associated with both pregnancy and inflammation, such as vitamin D status, are associated with the offspring sex ratio. Here, we show that among 1,228 women attempting pregnancy, preconception 25-hydroxyvitamin D concentrations are positively associated with the live birth of a male infant, with notably stronger associations among women with elevated high sensitivity C-reactive protein, a marker of systemic low-grade inflammation. Our findings suggest that vitamin D may mitigate maternal inflammation that would otherwise be detrimental to the implantation or survival of male conceptuses in utero. Higher vitamin D is associated with improved pregnancy and live birth rates, but its potential role in the human offspring sex ratio in unknown. Here, the authors show that the levels of vitamin D at preconception are positively associated with male live birth, particularly among women presenting inflammatory markers.

Background Cadmium is an endocrine disrupting chemical that affects the hypothalamic-pituitary-gonadal axis. Though evidence suggests its potential role in altering androgen synthesis and metabolic pathways that are characteristic of polycystic ovary syndrome (PCOS), its relation in healthy women of reproductive age is largely unknown. As women with mild sub-clinical features of PCOS who do not meet the diagnostic criteria of PCOS may still experience reduced fecundability, investigating associations between cadmium and PCOS-phenotypes among healthy women may provide unique insight into the reproductive implications for many on the PCOS spectrum. Therefore, the objective of this study was to evaluate associations between cadmium and androgens, anti-Müllerian hormone (AMH), and metabolic markers in women of reproductive age. Methods This was a prospective cohort study of 251 healthy premenopausal women without self-reported PCOS (mean age 27.3 years and BMI 24.1 kg/m 2 ). Cadmium was measured in blood collected at baseline. Reproductive hormones and metabolic markers were measured in fasting serum 8 times per menstrual cycle for 2 cycles. Linear mixed models and Poisson regression with a robust error variance were used to examine associations between cadmium and reproductive hormones and metabolic markers and anovulation, respectively. Results Median (interquartile range) blood cadmium concentrations at baseline were 0.30 (0.19–0.43) µg/L. Higher levels of testosterone (2.2 %, 95 % confidence interval [CI] 0.4, 4.1), sex hormone-binding globulin (2.9 %, 95 % CI 0.5, 5.5), and AMH (7.7 %, 95 % CI 1.1, 14.9) were observed per 0.1 µg/L increase in cadmium concentrations. An 18 % higher probability of a mild PCOS-phenotype (95 % CI 1.06, 1.31), defined by a menstrual cycle being in the highest quartile of cycle-averaged testosterone and AMH levels, was also found per 0.1 µg/L increase in cadmium levels. No associations were observed for insulin and glucose. These findings were consistent even after analyses were restricted to non-smokers or further adjusted for dietary factors to account for potential sources of exposure. Conclusions Overall, among healthy reproductive-aged women, cadmium was associated with endocrine features central to PCOS, but not with metabolic markers. These suggest its potential role in the hormonal milieu associated with PCOS even at low levels of exposure.

Purpose It is thought that total energy intake in women is increased during the luteal versus follicular phase of the menstrual cycle; however, less is understood regarding changes in diet composition (i.e., macro- and micronutrient intakes) across the cycle. The aim of this study was to investigate changes in macronutrient, micronutrient, and food group intakes across phases of the menstrual cycle among healthy women, and to assess whether these patterns differ by ovulatory status. Methods The BioCycle study (2005–2007) was a prospective cohort study of 259 healthy regularly menstruating women age 18–44 who were followed for up to two menstrual cycles. Dietary intake was measured using 24-h dietary recalls, and food cravings were assessed via questionnaire, up to four times per cycle, corresponding to menses, mid-follicular, expected ovulation, and luteal phases. Linear mixed models adjusting for total energy intake were used to evaluate changes across the cycle. Results Total protein ( P  = 0.03), animal protein ( P  = 0.05), and percent of caloric intake from protein ( P  = 0.02) were highest during the mid-luteal phase compared to the peri-ovulatory phase. There were also significant increases in appetite, craving for chocolate, craving for sweets in general, craving for salty flavor, and total craving score during the late luteal phase compared to the menstrual, follicular, and ovulatory phases ( P  < 0.001). Conclusions Our findings suggest an increased intake of protein, and specifically animal protein, as well as an increase in reported food cravings, during the luteal phase of the menstrual cycle independent of ovulatory status. These results highlight a plausible link between macronutrient intake and menstrual cycle phase.

In 575 women with 1–2 prior pregnancy losses; total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were evaluated preconception and throughout pregnancy to evaluate whether previously observed associations between third trimester maternal lipid profile and birthweight outcomes are driven by preconception lipids or lipid changes during pregnancy. Lipid trajectories were compared by pre-pregnancy body mass index (BMI) <25 or ≥25 kg/m 2 ; logistic regression models evaluated preconception lipid concentration and change from preconception to 28 weeks with adjusted odds of large- or small-for-gestational age (LGA or SGA) neonate by BMI group. Preconception lipid concentrations and gestational lipid trajectories varied by BMI group (P < 0.001). Preconception lipids were not associated with LGA or SGA in either group. A 10 mg/dL increase in HDL-C change from preconception to 28 weeks was associated with decreased odds of LGA (odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.46, 0.86) and 10 mg/dL increase in TG change associated with increased odds of LGA (OR = 1.05, 95% CI: 1.01, 1.1) overall. For ≥25 BMI only, 10 mg/dL increase in HDL-C change was associated with decreased SGA odds (OR = 0.35, 95% CI: 0.19, 0.64). Gestational lipid trajectories differed by BMI group and were differentially associated with birthweight outcomes, with HDL-C more strongly associated with healthy birthweight in women with BMI ≥25.

Biomarker assessment plays a critical role in the study and prevention of disease. However, variation in biomarkers attributable to the menstrual cycle in premenopausal women may impair understanding the role of certain biomarkers in disease development and progression. Thus, in light of the recently increasing evidence of menstrual cycle variability in multiple cardiometabolic biomarkers, a reexamination of approaches for appropriately studying and diagnosing cardiovascular disease in premenopausal women is warranted. We reviewed studies (from 1934 through 2012) evaluating changes in cardiometabolic biomarkers across phases of the menstrual cycle, including markers of oxidative stress, lipids, insulin sensitivity, and systemic inflammation. Each was observed to vary significantly during the menstrual cycle. For example, nearly twice as many women had elevated cholesterol levels warranting therapy (≥200 mg/dL) during the follicular phase compared with the luteal phase (14.3% vs. 7.9%), with only 3% having consistently high levels during all phases of the cycle. Similarly, nearly twice as many women were classified as being at an elevated risk of cardiovascular disease (high sensitivity C-reactive protein >3 mg/L) during menses compared with other phases (12.3% vs. 7.4%). Menstrual cycle–associated variability in cardiometabolic biomarkers is an important source of variability that should be accounted for in both research and clinical settings.

PurposeTo examine associations between objectively measured sleep duration and sleep timing with odds of completion of an in vitro fertilization (IVF) cycle.MethodsThis prospective cohort study enrolled 48 women undergoing IVF at a large tertiary medical center between 2015 and 2017. Sleep was assessed by wrist-worn actigraphy, 1–2 weeks prior to initiation of the IVF cycle. Reproductive and IVF cycle data and demographic and health information were obtained from medical charts. Sleep duration, midpoint, and bedtime were examined in relation to IVF cycle completion using logistic regression models, adjusted for age and anti-Müllerian hormone levels. A sub-analysis excluded women who worked non-day shifts to control for circadian misalignment.ResultsThe median age of all participants was 33 years, with 29% of women >35 years. Ten women had an IVF cycle cancelation prior to embryo transfer. These women had shorter sleep duration, more nocturnal awakenings, lower sleep efficiency, and later sleep timing relative to those who completed their cycle. Longer sleep duration was associated with lower odds of uncompleted IVF cycle (OR = 0.88; 95%CI 0.78, 1.00, per 20-min increment of increased sleep duration). Women with later sleep midpoint and later bedtime had higher odds of uncompleted cycle relative to those with earlier midpoint and earlier bedtime; OR = 1.24; 95%CI 1.09, 1.40 and OR = 1.33; 95%CI 1.17, 1.53 respectively, for 20-min increments. These results were independent of age, anti-Müllerian hormone levels, or sleep duration, and remained significant after exclusion of shift-working women.ConclusionsShorter sleep duration and later sleep timing increase the odds of uncompleted cycles prior to embryo transfer.

There is evidence demonstrating that certain lifestyle factors have a detrimental effect on fertility. Since such factors often coexist, possible synergistic effects merit further investigation. Thus we aimed to examine the cumulative impact of lifestyle factors on in vitro fertilization (IVF) early reproductive treatment outcomes and their interaction with measures of ovarian reserve. By following women who were starting their first fresh IVF cycle in 2 cohorts, the \"Lifestyle study cohort\" (hypothesis generating cohort, n = 242) and the \"UppSTART study\" (validation cohort, n = 432) in Sweden, we identified two significant risk factors acting independently, smoking and BMI, and then further assessed their cumulative effects. Women with both these risk factors had an Incidence Rate Ratio (IRR) of 0.75 [(95% CI 0.61-0.94)] regarding the number of aspirated oocytes compared to women without these risk factors. Concerning the proportion of mature oocytes in relation to the total number of aspirated oocytes, the interaction between BMI and Antral Follicle Count (AFC) was significant (p-value 0.045): the lower the value of AFC, the more harmful the effect of BMI with the outcome. Data shows that there is an individual as well as a cumulative effect of smoking and BMI on the number of aspirated and mature oocytes in fresh IVF treatment cycles. AFC might modify associations between BMI and the proportion of mature oocytes in relation to the total number of aspirated oocytes. These results highlight the importance of lifestyle factors on IVF early reproductive outcomes and provide additional evidence for the importance of preconception guidance for the optimization of IVF cycle outcome.

Background: Metals can interfere with hormonal functioning by binding at the receptor site and through indirect mechanisms; thus, they may be associated with hormonal changes in premenopausal women. Objectives: We examined the associations between cadmium, lead, and mercury, and anovulation and patterns of reproductive hormones [estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone] among 252 premenopausal women 18-44 years of age who were enrolled in the BioCycle Study in Buffalo, New York. Methods: Women were followed for up to two menstrual cycles, with serum samplescollected up to eight times per cycle. Metal concentrations were determined at baseline in whole blood by inductively coupled mass spectroscopy. Marginal structural models with stabilized inverse probability weights and nonlinear mixed models with harmonic terms were used to estimate the effects of cadmium, lead, and mercury on reproductive hormone levels during the menstrual cycle and anovulation. Results: Geometric mean (interquartile range) cadmium, lead, and mercury levels were 0.29 (0.19-0.43) µg/L, 0.93 (0.68-1.20) µg/dL, and 1.03 (0.58-2.10) µg/L, respectively. We observed decreases in mean FSH with increasing cadmium [second vs. first tertile: -10.0%; 95% confidence interval (CI), -17.3% to -2.5%; third vs. first tertile: -8.3%; 95% CI, -16.0% to 0.1%] and increases in mean progesterone with increasing lead level (second vs. first tertile: 7.5%; 95% CI, 0.1-15.4%; third vs. first tertile: 6.8%; 95% CI, -0.8% to 14.9%). Metals were not significantly associated with anovulation. Conclusions: Our findings support the hypothesis that environmentally relevant levels of metals are associated with modest changes in reproductive hormone levels in healthy, premenopausal women.

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.