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Context: Marine long-chain omega-3 fatty acids have been positively related to markers of fecundity in both men and women. However, seafood, their primary food source, can also be a source of toxicants, which could counteract the reproductive benefits., Objective: To examine the relationship of male and female seafood intake with time to pregnancy (TTP)., Design: Our prospective cohort study included 501 couples planning pregnancy, who participated in the Longitudinal Investigation of Fertility and the Environment study (2005 to 2009) and were followed up for ≤1 year or until pregnancy was detected. Seafood intake was collected daily during follow-up in journals., Setting: Couples residing in Michigan and Texas were recruited using population-based sampling frameworks., Main Outcome Measures: The primary outcome was the TTP, determined using an in-home pregnancy test. A secondary outcome was sexual intercourse frequency (SIF) as recorded in the daily journals., Results: Couples with male and female partners who consumed eight or more seafood servings per cycle had 47% (95% CI, 7% to 103%) and 60% (95% CI, 15% to 122%) greater fecundity (shorter TTP) than couples with male and female partners who consumed one or fewer seafood servings per cycle. Couples with both partners consuming eight or more seafood servings per cycle had 61% (95% CI, 17% to 122%) greater fecundity than couples consuming less. Male and female partners with the highest seafood intake (eight or more servings per cycle) also had 22% greater SIF., Conclusions: Greater male and female seafood intake was associated with a higher SIF and fecundity among a large prospective cohort of couples attempting pregnancy.

Background: Human exposure to parabens and other antimicrobial chemicals is continual and pervasive. The hormone-disrupting properties of these environmental chemicals may adversely affect human reproduction., Objective: We aimed to prospectively assess couples' urinary concentrations of antimicrobial chemicals in the context of fecundity, measured as time to pregnancy (TTP)., Methods: In a prospective cohort of 501 couples, we examined preconception urinary chemical concentrations of parabens, triclosan and triclorcarban in relation to TTP; chemical concentrations were modeled both continuously and in quartiles. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) adjusting for a priori -defined confounders. In light of TTP being a couple-dependent outcome, both partner and couple-based exposure models were analyzed. In all models, FOR estimates < 1.0 denote diminished fecundity (longer TTP)., Results: Overall, 347 (69%) couples became pregnant. The highest quartile of female urinary methyl paraben (MP) concentrations relative to the lowest reflected a 34% reduction in fecundity (aFOR = 0.66; 95% CI: 0.45, 0.97) and remained so when accounting for couples' concentrations (aFOR = 0.63; 95% CI: 0.41, 0.96). Similar associations were observed between ethyl paraben (EP) and couple fecundity for both partner and couple-based models ( p -trend = 0.02 and p -trend = 0.05, respectively). No associations were observed with couple fecundity when chemicals were modeled continuously., Conclusions: Higher quartiles of preconception urinary concentrations of MP and EP among female partners were associated with reduced couple fecundity in partner-specific and couple-based exposure models.

Fecundity, the biologic capacity to reproduce, is essential for the health of individuals and is, therefore, fundamental for understanding human health at the population level. Given the absence of a population (bio)marker, fecundity is assessed indirectly by various individual-based (e.g. semen quality, ovulation) or couple-based (e.g. time-to-pregnancy) endpoints. Population monitoring of fecundity is challenging, and often defaults to relying on rates of births (fertility) or adverse outcomes such as genitourinary malformations and reproductive site cancers. In light of reported declines in semen quality and fertility rates in some global regions among other changes, the question as to whether human fecundity is changing needs investigation. We review existing data and novel methodological approaches aimed at answering this question from a transdisciplinary perspective. The existing literature is insufficient for answering this question; we provide an overview of currently available resources and novel methods suitable for delineating temporal patterns in human fecundity in future research., (Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Perfluoroalkyl substances have been associated with changes in menstrual cycle characteristics and fecundity, when modeled separately. However, these outcomes are biologically related, and we evaluate their joint association with exposure to perfluoroalkyl substances., Methods: We recruited 501 couples from Michigan and Texas in 2005-2009 upon their discontinuing contraception and followed them until pregnancy or 12 months of trying. Female partners provided a serum sample on enrollment and completed daily journals on menstruation, intercourse, and pregnancy test results. We measured seven perfluoroalkyl substances in serum using liquid chromatography-tandem mass spectrometry. We assessed the association between perfluoroalkyl substances and menstrual cycle length using accelerated failure time models and between perfluoroalkyl substances and fecundity using a Bayesian joint modeling approach to incorporate cycle length., Results: Menstrual cycles were 3% longer comparing women in the second versus first tertile of perfluorodecanoate (PFDeA; acceleration factor [AF] = 1.03, 95% credible interval [CrI] = [1.00, 1.05]), but 2% shorter for women in the highest versus lowest tertile of perfluorooctanoic acid (PFOA; AF = 0.98, 95% CrI = [0.96, 1.00]). When accounting for cycle length, relevant covariates, and remaining perfluoroalkyl substances, the probability of pregnancy was lower for women in second versus first tertile of perfluorononanoate (PFNA; odds ratio [OR] = 0.6, 95% CrI = [0.4, 1.0]) although not when comparing the highest versus lowest (OR = 0.7, 95% CrI = [0.3, 1.1]) tertile., Conclusions: In this prospective cohort study, we observed associations between two perfluoroalkyl substances and menstrual cycle length changes, and between select perfluoroalkyl substances and diminished fecundity at some (but not all) concentrations. See video abstract at, http://links.lww.com/EDE/B136.

Study Question: What is the relationship between couple's health and fecundity in a preconception cohort?, Summary Answer: Somatic health may impact fecundity in men and women as couples whose male partner had diabetes or whose female partner had two or more medical conditions had a longer time-to-pregnancy (TTP)., What Is Already Known: The impact of somatic health on human fecundity is hypothesized given the reported declines in spermatogenesis and ovulation among individuals with certain medical comorbidities., Study Design, Size, Duration: A population-based prospective cohort study recruiting couples from 16 counties in Michigan and Texas (2005-2009) using sampling frameworks allowing for identification of couples planning pregnancy in the near future. Five hundred and one couples desiring pregnancy and discontinuing contraception were followed-up for 12 months or until a human chorionic gonadotropin pregnancy was detected., Participants/materials, Settings, Methods: In all, 33 (21.4%) female and 41 (26.6%) male partners had medical conditions at baseline., Main Results and the Role of Chance: Couples' medical comorbidity was associated with pregnancy status. Diabetes in either partner was associated with diminished fecundity, as measured by a longer TTP. Specifically, fecundability odds ratios (FORs) were below 1, indicating a longer TTP, for male partners with diabetes (0.35, 95% confidence interval (CI): 0.14-0.86) even in adjusted models (0.35, 95% CI: 0.13-0.88). Female partners with diabetes had comparable reductions in FORs; however, the analyses did not reach statistical significance (0.26, 95% CI: 0.03-1.98). Female partners with two or more medical conditions had a significantly longer TTP compared with women with no health problems (0.36, 95% CI: 0.14-0.92). Importantly, the presence of medical conditions was not associated with sexual frequency. We cannot rule out residual confounding, Type 2 errors for less prevalent medical conditions, or chance findings in light of the multiple comparisons made in the analysis., Limitations, Reasons for Caution: The findings require cautious interpretation given that medical diagnoses are subject to possible reporting errors, although we are unaware of any potential biases that may have been introduced, as participants were unaware of how long it would take to become pregnant upon enrollment., Wider Implications of the Findings: The current report suggests a relationship between male and female diabetes and fecundity, and possibly somatic health more globally. Moreover, while the mechanism is uncertain, if corroborated, our data suggest that early evaluation and treatment may be warranted for diabetics prior to attempting to conceive., Study Funding/competing Interests: Intramural research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract nos. #N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). The authors have no conflicts of interest to declare., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Menstrual cycle length (MCL) has been shown to play an important role in couple fecundity, which is the biologic capacity for reproduction irrespective of pregnancy intentions. However, a comprehensive assessment of its role requires a fecundity model that accounts for male and female attributes and the couple's intercourse pattern relative to the ovulation day. To this end, we employ a Bayesian joint model for MCL and pregnancy. MCLs follow a scale multiplied (accelerated) mixture model with Gaussian and Gumbel components; the pregnancy model includes MCL as a covariate and computes the cycle-specific probability of pregnancy in a menstrual cycle conditional on the pattern of intercourse and no previous fertilization. Day-specific fertilization probability is modeled using natural, cubic splines. We analyze data from the Longitudinal Investigation of Fertility and the Environment Study (the LIFE Study), a couple based prospective pregnancy study, and find a statistically significant quadratic relation between fecundity and menstrual cycle length, after adjustment for intercourse pattern and other attributes, including male semen quality, both partner's age, and active smoking status (determined by baseline cotinine level 100 ng/mL). We compare results to those produced by a more basic model and show the advantages of a more comprehensive approach., (© 2015, The International Biometric Society.)

The analysis of fecundity data is challenging and requires consideration of both highly timed and interrelated biologic processes in the context of essential behaviors such as sexual intercourse during the fertile window. Understanding human fecundity is further complicated by presence of a sterile population, i.e. couples unable to achieve pregnancy. Modeling techniques conducted to date have largely relied upon discrete time-to-pregnancy survival or day-specific probability models to estimate the determinants of time-to-pregnancy or acute effects, respectively. We developed a class of semi-parametric grouped transformation cure models that capture day-level variates purported to affect the cycle-level hazards of conception and, possibly, sterility. Our model's performance is assessed using simulation and longitudinal data from one of the few prospective cohort studies with preconception enrollment of women followed for 12 menstrual cycles at risk for pregnancy., (© The Author(s) 2012.)

Concern has arisen about benzophenone (BP) ultraviolet (UV) radiation filters, given their use in sunscreen and personal-care products and their reported estrogenic and antiandrogenic activity. We recruited 501 couples who were discontinuing use of contraceptives in order to become pregnant for the Longitudinal Investigation of Fertility and the Environment (LIFE) Study (Michigan and Texas, 2005-2009). Couples provided urine specimens and completed daily journals until they either achieved pregnancy or had tried for 12 months. Women used fertility monitors to time sexual intercourse and digital pregnancy tests. Urinary concentrations of 5 UV filters (ng/mL) were determined using triple-quadrupole mass spectrometry: 2,4-dihydroxybenzophenone (also called BP-1); 2,2',4,4'-tetrahydroxybenzophenone (BP-2); 2-hydroxy-4-methoxybenzophenone (BP-3); 2,2'-dihydroxy-4-methoxybenzophenone (BP-8); and 4-hydroxybenzophenone. Fecundability odds ratios were estimated for each UV filter (dichotomized at the 75th percentile) and adjusted for age, creatinine concentration, body mass index (weight (kg)/height (m)(2)), cotinine concentration, season, and site, while accounting for time off contraception. Separate models were fitted for each UV filter and partner; final models included partners' concentrations. Male partners' concentrations of BP-2 and 4-hydroxybenzophenone were associated with reduced fecundity in adjusted models (fecundability odds ratio (FOR) = 0.69 (95% confidence interval (CI): 0.50, 0.95) and FOR = 0.74 (95% CI: 0.54, 1.00), respectively). In models adjusting for both partners' concentrations, male BP-2 concentration remained associated with reduced fecundity (FOR = 0.69, 95% CI: 0.49, 0.97). These data suggest that male exposure to select UV filters may diminish couples' fecundity, resulting in a longer time to pregnancy., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: To assess the relationship between environmental chemicals and couple fecundity or time to pregnancy (TTP)., Design: Prospective cohort., Setting: Communities of targeted populations with reported exposure., Patient(s): 501 couples recruited upon discontinuing contraception to become pregnant, 2005-2009., Intervention(s): None., Main Outcome Measure(s): Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) estimated for each partner's chemical concentrations adjusted for age, body mass index, cotinine, creatinine, and research site while accounting for time off contraception., Result(s): Couples completed interviews and anthropometric assessments and provided the urine specimens for quantification of bisphenol A (BPA) and 14 phthalate metabolites, which were measured using high-performance liquid chromatography with electrospray triple-quadrupole mass spectrometer. Women recorded menstruation and pregnancy test results in daily journals. Couples were evaluated until a positive human-chorionic gonadotropin pregnancy test or 12 cycles without pregnancy. Neither female nor male BPA concentration was associated with TTP (FOR 0.98; 95% CI, 0.86, 1.13 and FOR 1.04; 95% CI, 0.91, 1.18, respectively). Men's urinary concentrations of monomethyl, mono-n-butyl, and monobenzyl phthalates were associated with a longer TTP (FOR 0.80; 95% CI, 0.70, 0.93; FOR 0.82, 95% CI, 0.70, 0.97; and FOR 0.77, 95% CI, 0.65 0.92, respectively)., Conclusion(s): Select male but not female phthalate exposures were associated with an approximately 20% reduction in fecundity, underscoring the importance of assessing both partners' exposure to minimize erroneous conclusions., (Published by Elsevier Inc.)

Background: Critical data gaps remain regarding infertility treatment and child development. We assessed the utility of a birth certificate registry for developing a population cohort aimed at answering such questions., Methods: We utilised the Upstate New York livebirth registry (n = 201,063) to select births conceived with (n = 4024) infertility treatment or exposed infants, who were then frequency-matched by residence to a random sample of infants conceived without (n = 14,455) treatment or unexposed infants, 2008-10. Mothers were recruited at 2-4 months postpartum and queried about their reproductive histories, including infertility treatment for comparison with birth certificate data. Overall, 1297 (32%) mothers of exposed and 3692 of unexposed (26%) infants enrolled., Results: Twins represented 22% of each infant group. The percentage of infants conceived with/without infertility treatment was similar whether derived from the birth registry or maternal report: 71% none, 16% drugs or intrauterine insemination, and 14% assisted reproductive technologies (ART). Concordant reporting between the two data sources was 93% for no treatment, 88% for ART, and 83% for fertility drugs, but differed by plurality. Exposed infants had slightly (P < 0.01) earlier gestations than unexposed infants (38.3 ± 2.8 and 38.7 ± 2.7 weeks, respectively) based upon birth certificates but not maternal report (38.7 ± 2.7 and 38.7 ± 2.9, respectively). Conversely, mean birthweight was comparable using birth certificates (3157 ± 704 and 3194 ± 679 g, respectively), but differed using maternal report (3167 ± 692 and 3224 ± 661, respectively P < 0.05)., Conclusions: The birth certificate registry is a suitable sampling framework as measured by concordance with maternally reported infertility treatment. Future efforts should address the impact of factors associated with discordant reporting on research findings., (© 2014 John Wiley & Sons Ltd.)

Objective: To assess semen parameters and couple fecundity as measured by time to pregnancy (TTP)., Design: Observational prospective cohort with longitudinal measurement of TTP., Setting: Sixteen Michigan/Texas counties., Patient(s): A total of 501 couples discontinuing contraception were followed for 1 year while trying to conceive; 473 men (94%) provided one semen sample, and 80% provided two samples., Intervention(s): None., Main Outcome Measure(s): Using prospectively measured TTP, fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated for 36 individual semen quality parameters accounting for repeated semen samples, time off contraception, abstinence, enrollment site, and couples' ages, body mass indices, and serum cotinine concentrations., Result(s): In adjusted models, semen quality parameters were associated with significantly shorter TTP as measured by FORs >1: percent motility, strict and traditional morphology, sperm head width, elongation factor, and acrosome area. Significantly longer TTPs or FORs <1 were observed for morphologic categories amorphous and round sperm heads and neck/midpiece abnormalities. No semen quality parameters achieved significance when simultaneously modeling all other significant semen parameters and covariates, except for percent coiled tail when adjusting for sperm concentration (FOR 0.99; 95% CI 0.99-1.00). Male age was consistently associated with reduced couple fecundity (FOR 0.96; 95% CI 0.93-0.99), reflecting a longer TTP across all combined models. Female but not male body mass index also conferred a longer TTP (FOR 0.98; 95% CI 0.96-0.99)., Conclusion(s): Several semen measures were significantly associated with TTP when modeled individually but not jointly and in the context of relevant couple-based covariates., (Published by Elsevier Inc.)

Understanding the mechanisms that underlie successful human reproduction and development is an ambitious goal, given the many unique methodological challenges surrounding such study. These challenges are well understood by reproductive and perinatal epidemiologists and include its conditional nature, unobservable yet informative outcomes such as conception, multi-scale missing data, correlated or non-independent outcomes, interval censoring and a hierarchical data structure. Novel methodologies for overcoming these challenges and for answering critical data gaps are needed if we are to better understand the inefficiency that currently characterises human reproduction with the goal of improving population health. The exposome is an emerging paradigm that offers promise for understanding the natural history of human reproduction and development, and its many associated impairments that develop later in child- or adulthood. This novel paradigm recognises the need to identify and measure the totality of environmental (non-genetic) exposures from preconception through sensitive windows, and to identify patterns associated with healthy and adverse outcomes. The exposome accommodates research focusing on unique subpopulations, such as couples undergoing assisted reproductive technologies, so that methodological limitations such as unobservable and conditional outcomes can be better addressed. Reproductive and perinatal epidemiology is uniquely suited for proof-of-concept exposome research, given the intricate relations between fecundity, gravid health and later onset disease and the narrow and interrelated sensitive windows that characterise the conditional nature of human reproduction and development. Bold new conceptual frameworks such as the exposome are needed for designing research that may lead to discovery and improve population health., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To estimate the prevalence of infertility using a current duration approach for comparison with a traditional constructed measure., Design: Cross-sectional survey., Setting: Not applicable., Patient(s): A nationally representative sample of females aged 15-44 years., Intervention(s): None., Main Outcome Measure(s): Infertility prevalence estimated by two approaches: [1] a constructed measure derived from questions on sexual activity, contraception, relationship status, and pregnancy, and [2] a measure based on estimated time to pregnancy derived from the respondents' current duration of pregnancy attempt (i.e., current duration approach). Associations with self-reported descriptive characteristics using weighted logistic regression or parametric survival models for each respective approach., Result(s): Infertility prevalence was approximately twofold higher using the current duration approach (15.5%; 95% confidence interval 8.6%-27.5%) vs. the constructed measure (7.0%; 95% confidence interval 6.2%-7.8%). Both methods identified similar patterns of increasing age, lower education, nulliparity, and history of gynecologic disorders as being associated with measures of impaired fecundity, whereas opposing patterns were seen for racial/ethnic identification and poverty status., Conclusion(s): Infertility prevalence based on a current duration approach was consistent with other US prospective cohort studies with preconception enrollment. These findings underscore the importance of definition and methodologic approach for estimating the prevalence of infertility., (Published by Elsevier Inc.)

Background: Evidence suggesting that persistent environmental pollutants may be reproductive toxicants underscores the need for prospective studies of couples for whom exposures are measured., Objectives: We examined the relationship between selected persistent pollutants and couple fecundity as measured by time to pregnancy., Methods: A cohort of 501 couples who discontinued contraception to become pregnant was prospectively followed for 12 months of trying to conceive or until a human chorionic gonadotrophin (hCG) test confirmed pregnancy. Couples completed daily journals on lifestyle and provided biospecimens for the quantification of 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, 36 polychlorinated biphenyls (PCBs), and 7 perfluorochemicals (PFCs) in serum. Using Cox models for discrete time, we estimated fecundability odds ratios (FORs) and 95% CIs separately for each partner's concentrations adjusting for age, body mass index, serum cotinine, serum lipids (except for PFCs), and study site (Michigan or Texas); sensitivity models were further adjusted for left truncation or time off of contraception (≤ 2 months) before enrollment., Results: The adjusted reduction in fecundability associated with standard deviation increases in log-transformed serum concentrations ranged between 18% and 21% for PCB congeners 118, 167, 209, and perfluorooctane sulfonamide in females; and between 17% and 29% for p,p´-DDE and PCB congeners 138, 156, 157, 167, 170, 172, and 209 in males. The strongest associations were observed for PCB 167 (FOR 0.79; 95% CI: 0.64, 0.97) in females and PCB 138 (FOR = 0.71; 95% CI: 0.52, 0.98) in males., Conclusions: In this couple-based prospective cohort study with preconception enrollment and quantification of exposures in both female and male partners, we observed that a subset of persistent environmental chemicals were associated with reduced fecundity.

Objective: To assess the association between self-reported measures of stress, anxiety, depression, and related constructs and fecundity., Design: Prospective cohort study of women trying to conceive., Setting: United Kingdom., Patient(s): Three hundred thirty-nine women aged 18-40 years who were attempting to conceive., Intervention(s): Completed daily diaries for up to six cycles or until pregnancy was detected. For each cycle, stress biomarkers were measured and psychosocial questionnaires were completed., Main Outcome Measures(s): Fecundability odds ratios (FORs) and 95% confidence intervals were calculated using discrete time survival methods, and the day-specific probabilities of pregnancy were calculated using Bayesian statistical techniques., Result(s): Among the 339 women, 207 (61%) became pregnant during the study, 69 (20%) did not become pregnant, and 63 (19%) withdrew. After controlling for maternal age, parity, months trying to conceive before enrollment, smoking, caffeine use, and frequency of intercourse, we found no association between most psychosocial measures and FORs or the day-specific probabilities of pregnancy save for an increased FOR for women reporting higher versus lower levels of social support., Conclusion(s): Self-reported psychosocial stress, anxiety, and depression were not associated with fecundity. Any adverse effect of stress or psychological disturbance on fecundity does not appear to be detectable via the questionnaires administered., (Copyright © 2012 American Society for Reproductive Medicine. All rights reserved.)

Menstrual cycle patterns are often used as indicators of female fecundity and are associated with hormonally dependent diseases such as breast cancer. A question of considerable interest is in identifying menstrual cycle patterns, and their association with fecundity. A source of data for addressing this question is prospective pregnancy studies that collect detailed information on reproductive aged women. However, methodological challenges exist in ascertaining the association between these two processes as the number of longitudinally measured menstrual cycles is relatively small and informatively censored by time to pregnancy (TTP), as well as the cycle length distribution being highly skewed. We propose a joint modeling approach with a mixed effects dispersion model for the menstrual cycle lengths and a discrete survival model for TTP to address this question. This allows us to assess the effect of important characteristics of menstrual cycle that are associated with fecundity. We are also able to assess the effect of fecundity predictors such as age at menarche, age, and parity on both these processes. An advantage of the proposed approach is the prediction of the TTP, thus allowing us to study the efficacy of menstrual cycle characteristics in predicting fecundity. We analyze two prospective pregnancy studies to illustrate our proposed method by building a model based on the Oxford Conception Study, and predicting for the New York State Angler Cohort Prospective Pregnancy Study. Our analysis has relevant findings for assessing fecundity., (© 2012, The International Biometric Society.)

The effect of heavy metals at environmentally relevant concentrations on couple fecundity has received limited study despite ubiquitous exposure. In 2005-2009, couples (n=501) desiring pregnancy and discontinuing contraception were recruited and asked to complete interviews and to provide blood specimens for the quantification of cadmium (μg L(-1)), lead (μg dL(-1)) and mercury (μg L(-1)) using inductively coupled plasma-mass spectrometry. Couples completed daily journals on lifestyle and intercourse along with menstruation and pregnancy testing for women. Couples were followed for 12 months or until pregnant. Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated adjusting for age, body mass index, cotinine, and serum lipids in relation to female then male exposures. FORs <1 denote a longer time to pregnancy. In adjusted models, reduced FORs were observed for both female cadmium (0.78; 95% CI 0.63-0.97) and male lead (0.85; 95% CI 0.73-0.98) concentrations. When jointly modeling couples' exposures, only male lead concentration significantly reduced the FOR (0.82; 95% CI 0.68, 0.97), though the FOR remained <1 for female cadmium (0.80; 95% CI 0.64, 1.00). This prospective couple based cohort with longitudinal capture of time to pregnancy is suggestive of cadmium and lead's reproductive toxicity at environmentally relevant concentrations., (Published by Elsevier Ltd.)

Understanding conception probabilities is important not only for helping couples to achieve pregnancy but also in identifying acute or chronic reproductive toxicants that affect the highly timed and interrelated processes underlying hormonal profiles, ovulation, libido, and conception during menstrual cycles. Currently, 2 statistical approaches are available for estimating conception probabilities depending upon the research question and extent of data collection during the menstrual cycle: a survival approach when interested in modeling time-to-pregnancy (TTP) in relation to women or couples' purported exposure(s), or a hierarchical Bayesian approach when one is interested in modeling day-specific conception probabilities during the estimated fertile window. We propose a biologically valid discrete survival model that unifies the above 2 approaches while relaxing some assumptions that may not be consistent with human reproduction or behavior. This approach combines both the survival and the hierarchical models allowing investigators to obtain the distribution of TTP and day-specific probabilities during the fertile window in a single model. Our model allows for the consideration of covariate effects at both the cycle and the daily level while accounting for daily variation in conception. We conduct extensive simulations and utilize the New York State Angler Prospective Pregnancy Cohort Study to illustrate our approach. We also provide the code to implement the model in R software in the supplemental section of the supplementary material available at Biostatistics online.

Adverse pregnancy outcomes have long been observed to cluster within women resulting in the inclusion of past reproductive history in clinical assessments and perinatal scoring systems. However, limited study has focused on the clustering of fecundability as measured by time to pregnancy (TTP), despite growing evidence suggestive of a possible association with adverse pregnancy outcomes known to cluster within women. We sought to empirically evaluate the clustering of conception delay, and TTP more globally, in one of the few existing prospective pregnancy cohort studies that captured women's successive pregnancies. The study cohort comprised 544 women who contributed 1119 pregnancies in the U.S. Collaborative Perinatal Project. We used a discrete Cox frailty model to estimate the degree and significance of within-woman clustering of TTP. Women with an initial conception delay (TTP > 6 months) were older, less educated and had higher body mass indices than women not experiencing delays (TTP ≤ 6 months). Our analysis indicates that there is significant within-woman clustering of TTP (variance of the frailty = 0.80, [95% confidence interval 0.49, 1.11]) after adjusting for baseline maternal age, body mass index and education level. Similar to many other reproductive and perinatal outcomes, our findings suggest that TTP clusters within women. Identifying exposures or behaviours that affect TTP may offer strategies for reducing conception delay in future pregnancy attempts., (Published 2011. This article is a US Government work and is in the public domain in the USA.)

Objective: To assess salivary stress biomarkers (cortisol and α-amylase) and female fecundity., Design: Prospective cohort design., Setting: United Kingdom., Patient(s): 274 women aged 18 to 40 years who were attempting pregnancy., Intervention(s): Observation for six cycles or until pregnancy: women collected basal saliva samples on day 6 of each cycle, and used fertility monitors to identify ovulation and pregnancy test kits for pregnancy detection., Main Outcome Measure(s): Salivary cortisol (μg/dL) and α-amylase (U/mL) concentration measurements; fecundity measured by time-to-pregnancy and the probability of pregnancy during the fertile window as estimated from discrete-time survival and Bayesian modeling techniques, respectively., Result(s): Alpha-amylase but not cortisol concentrations were negatively associated with fecundity in the first cycle (fecundity odds ratio=0.85; 95% confidence interval 0.67, 1.09) after adjusting for the couples' ages, intercourse frequency, and alcohol consumption. Statistically significant reductions in the probability of conception across the fertile window during the first cycle attempting pregnancy were observed for women whose salivary concentrations of α-amylase were in the upper quartiles in comparison with women in the lower quartiles (highest posterior density: -0.284; 95% interval -0.540, -0.029)., Conclusion(s): Stress significantly reduced the probability of conception each day during the fertile window, possibly exerting its effect through the sympathetic medullar pathway., (Published by Elsevier Inc.)

Trace exposures to metals may affect female reproductive health. To assess the relation between trace concentrations of blood metals and female fecundity, 99 non-pregnant women discontinuing contraception for the purpose of becoming pregnant were prospectively followed. Participants completed a baseline interview and daily diaries until pregnant, or up to 12 menstrual cycles at risk for pregnancy; home pregnancy test kits were used. For 80 women, whole blood specimens were analyzed for arsenic, cadmium, lead, magnesium, nickel, selenium and zinc using inductively coupled plasma mass spectrometry (ICP-MS). Time to pregnancy was estimated using Cox proportional hazards models for discrete time. Metal concentrations were generally within population reference intervals. Adjusted models suggest a 51.5% increase in the probability for pregnancy per 3.60 μg/L increase in Mg (P=0.062), and a 27.7% decrease per 0.54 μg/L increase in Zn (P=0.114). Findings indicate that Mg and Zn may impact female fecundity, but in varying directions., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Human fecundability is defined as the probability of conception during a menstrual cycle among couples at risk for pregnancy. It is highly relevant for understanding human reproduction and represents a series of highly interrelated and timed processes. The statistical literature has recognized the need to incorporate both biological and behavioral factors (Barrett and Marshall, 1969; Dunson and Stanford, 2005) when modeling conception probabilities, given that intercourse during the fertile window is a necessary but not sufficient criterion for conception. The heterogeneity of behaviors such as the timing and frequency of intercourse in a menstrual cycle needs to be considered when estimating conception. Here we propose a joint model of intercourse behavior and human fecundability through a classic conception probability model and a structural equation model (SEM) to accommodate intercourse during the menstrual cycle. The SEM part of the proposed model allows the dependency between intercourse behaviors on consecutive days in a menstrual cycle to vary across days. Consequently, the proposed model can accommodate not only a broad variety of intercourse patterns and dependency structures but also general covariate effects. Finally, we present a detailed analysis of the New York State Angler Cohort Prospective Pregnancy Study to illustrate the proposed methodology.

Background: The reliability of retrospective time to pregnancy (TTP) has been established, but its validity has been assessed in only 1 study, which had a short follow-up., Methods: Ninety-nine women enrolled a decade earlier in a prospective TTP study were queried by means of mailed questionnaires about the duration of time they had required to become pregnant. Their responses were compared with their earlier data from daily diaries (gold standard)., Results: One-third of women could not recall their earlier TTP either in menstrual cycles or calendar months. Only 17%-19% of women recalled their TTP exactly. Agreement increased to 41%-51%, 65%-72%, and 72%-77% when defined as +/-1, +/-2, and +/-3 months, respectively. Women with longer observed TTPs or previous pregnancies were more likely to under-report their TTP., Conclusions: The findings raise questions about the commonly assumed validity of self-reported TTP. Recalled TTP may introduce error when estimating fecundability or classifying couples' fecundity status.

ObjectiveTo identify frequently reported prescription medications and supplements among couples planning pregnancy because there is a lack of descriptive information on these agents in women and men who are trying to conceive.MethodsFive hundred one couples enrolled in the Longitudinal Study of Infertility and the Environment, which took place between 2005 and 2009. Participants reported prescription medications as well as prescription and over-the-counter supplements used through interviews at study enrollment and through daily dairies during the 12-month follow-up. We identified prescription medications and supplements prospectively reported by ≥1% of women and men at baseline and from daily journal information grouped into 3-month preconception follow-up intervals while couples tried for pregnancy.ResultsThe 5 most reported prescription medications among women were levothyroxine (5.8%), cetirizine (2.6%), fluticasone (2.4%), escitalopram (1.8%), and fluoxetine (1.8%) and for men were lisinopril (2.0%), mometasone (2.0%), fexofenadine (1.8%), atorvastatin (1.6%), and montelukast (1.6%). The most reported supplements were multivitamins (63.3%, 43.5%) and fish oil (13.2%, 9.4%) for women and men, respectively, and prenatal vitamins (22.0%) for women. For women during the first 3 months of follow-up, prenatal vitamins (6.0%) and antibiotics (1.2%-2.6%) were among the most frequently started medications. During the next 3 months, clomiphene (4.5%) was the most frequently initiated medication.ConclusionsCouples trying for pregnancy reported a variety of prescription medications and supplements, and they differed by gender. Preconception guidance should address medication and supplement use to avoid potential exposures associated with adverse reproductive and perinatal outcomes.

Study Question: Are biomarkers of preconception stress associated with pregnancy loss?Summary Answer: Preconception stress, as measured by basal salivary cortisol and alpha-amylase concentrations, is not associated with pregnancy loss.What Is Known Already: Many studies, most of which have been retrospective, have identified an association between stressful life events and perceived stress and miscarriage.Study Design, Size, Duration: A prospective pregnancy study with preconception enrollment was conducted between 2005 and 2009. Among the 344 women who became pregnant during the Longitudinal Investigation of Fertility and the Environment (LIFE) study, 337 (98%) had salivary biomarker data for analysis.Participants/materials, Setting, Methods: Couples planning pregnancy were followed for up to 12 months as they tried to become pregnant and through pregnancy if it occurred. Participating women collected a basal saliva sample on the morning following enrollment and a second on the morning following their next menses to measure cortisol and alpha-amylase, biomarkers of stress. Women used home pregnancy tests on the day of expected menses. A pregnancy loss was defined as a negative pregnancy test following a positive pregnancy test, the onset of menses, or for pregnancies that survived to clinical recognition, recognition of the loss by a healthcare provider.Main Results and the Role Of Chance: Among the 337 couples, the median age of female and male partners was 29 and 31 years, respectively. Most of the women were non-Hispanic white (83%) and highly educated. There were 97 pregnancy losses reported among the 337 pregnancies. The median gestational age at loss was 6 weeks 5 days with only two losses occurring in the second trimester. Using Cox proportional hazards models, we found no clear pattern of association between two preconceptional biomarkers of stress (salivary cortisol and alpha-amylase concentrations) modeled both continuously or in tertiles and incident pregnancy loss after adjustment for confounders.Limitations Reasons For Caution: Our prior work suggests that women enrolled in the LIFE Study had lower stress levels than women in the general population. Owing to concerns regarding participant burden, we were unable to collect serial saliva measurements, which would have allowed us to examine the association between stress in early pregnancy and pregnancy loss. Further, with regard to the measurement of perceived stress, the Cohen's Perceived Stress Scale was only administered at baseline. While every attempt was made to ensure diversity in the cohort, non-Hispanic white women were over-represented, therefore it is possible that the results might not be generalizable to all women.Wider Implications Of the Findings: In one of the largest studies in the USA to prospectively capture data on the incidence of early pregnancy loss, we found no clear association between two biomarkers of preconception stress (measured in saliva) and pregnancy loss.Study Funding/competing Interest(s): This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Study Question: Is couples' body compositions associated with reduced fecundity as measured by a longer time-to-pregnancy (TTP)?Summary Answer: Couples whose BMI are within obese class II (≥35 kg/m2) have a longer TTP in comparison to leaner (BMI < 25 kg/m2) couples, observed only when both partner's BMI was jointly modeled.What Is Known Already: Extremes of BMI have been associated with a longer TTP and with less successful assisted reproductive technology (ART) outcomes. To our knowledge, the association between measured adiposity in both partners of the couple and prospectively measured TTP has not been investigated despite pregnancy being a couple-dependent outcome.Study Design, Size, Duration: Prospective cohort with preconception recruitment of 501 couples trying for pregnancy and recruited from 16 counties in Michigan and Texas between 2005 and 2009. Couples were followed daily for up to a year of trying or until a hCG pregnancy.Participants/materials, Setting, Methods: In-home standardized anthropometric assessment of couples upon enrollment included measured height and weight using calibrated stadiometers and scales, and measured waist and hip circumferences. Discrete-time Cox regression was used to estimate fecundability odds ratios (FORs) and 95% CIs, controlling for potential confounders including age, number of days of vigorous physical activity, serum cotinine concentration, race, education, free cholesterol levels for each partner in partner-specific models and for both partners in couple-based models as well as average acts of intercourse per menstrual cycle and menstrual cycle regularity.Main Results and the Role Of Chance: Neither male nor female partner's BMI was associated with TTP when modeled individually. However, obese class II (BMIs ≥ 35.0 kg/m2) couples experienced a reduction in fecundability in both unadjusted (FOR = 0.45; 95% CI: 0.23, 0.89) and adjusted analyses (aFOR = 0.41; 95% CI: 0.17, 0.98) resulting in a longer TTP in comparison to couples with normal BMI (<25 kg/m2). Female partners' waist circumference ≥88.6 cm was associated with a significant reduction in fecundability in the unadjusted model (FOR = 0.64; 95% CI: 0.48, 0.86) but not in the adjusted model (aFOR = 0.77; 95% CI: 0.55, 1.08) in comparison to females with a smaller (<80 cm) circumference.Limitations, Reasons For Caution: BMI and waist circumference are proxy measures of body composition and residual confounding cannot be eliminated. Findings may not be generalizable to clinical populations.Wider Implications Of the Findings: This is the first cohort study known to us with preconception enrollment of couples who underwent standardized anthropometric assessment and for whom TTP was prospectively measured. The findings underscore the importance of considering both partners' body composition for fecundity outcomes and preconception guidance.Study Funding/competing Interest(s): Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts #N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). The authors have no competing interests.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

We aimed to study the potential impact of proximity to major roadways on time-to-pregnancy and infertility in couples attempting pregnancy in the Longitudinal Investigation of Fertility and Environment (LIFE) study (2005–2009), a population-based, prospective cohort study. Couples attempting pregnancy (n = 500) were enrolled and followed prospectively until pregnancy or 12 months of trying and 393 couples (78%) had complete data and full follow-up. Time-to-pregnancy was based on a standard protocol using fertility monitors, tracking estrone-3-glucuonide and luteinizing hormone, and pregnancy test kits to detect human chorionic gonadotropin (hCG). The fecundability odds ratio (FOR) and 95% confidence interval (CI) were estimated using proportional odds models. Infertility was defined as 12 months of trying to conceive without an hCG pregnancy and the relative risk (RR) and 95% CI were estimated with log-binomial regression. Final models were adjusted for age, parity, study site, and salivary alpha-amylase, a stress marker. Infertile couples (53/393; 14%) tended to live closer to major roadways on average than fertile couples (689 m vs. 843 m, respectively) but the difference was not statistically significant. The likelihood of pregnancy was increased 3% for every 200 m further away the couples residence was from a major roadway (FOR = 1.03; CI = 1.01–1.06). Infertility also appeared elevated at moderate distances compared to 1000 m or greater, but estimates lacked precision. Our findings suggest that proximity to major roadways may be related to reductions in fecundity. Prospective data from larger populations is warranted to corroborate these findings. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies suggest female smoking increases time-to-pregnancy (TTP), a couple-dependent reproductive outcome, while associations with male smoking are more ambiguous. Furthermore, despite small increases in smokeless tobacco use in the United States, no prior study has evaluated TTP among smokeless tobacco users.Methods: Using population-based sampling in 16 counties in Michigan and Texas, 501 couples discontinuing contraception to become pregnant were followed until positive pregnancy test or 12 months of trying. Participants were interviewed on lifetime and current cigarette, cigar, and chew/snuff (smokeless) use and provided blood samples for quantification of heavy metals and cotinine. Fecundability odds ratios (FORs) and 95% confidence intervals (95% CIs) were estimated, adjusted for demographics/lifestyle. FORs less than 1 reflect longer TTP.Results: Eleven percentage of females and 15% of males smoked cigarettes. Among men, 14% smoked cigars, 9% used snuff, and 2% used chew. Compared with never tobacco users, male (FOR: 0.41, 95% CI: 0.24, 0.68) and female (FOR: 0.53, 95% CI: 0.33, 0.85) smoking were individually associated with longer TTP; males' smoking remained significant (FOR: 0.46, 95% CI: 0.27, 0.79) when modeling partners together. Cadmium levels were higher in smokers than smokeless tobacco and never users; adjusting for cadmium attenuated the cigarette-TTP association, particularly among women. TTP was shorter among smokeless tobacco users relative to smokers (FOR: 2.86, 95% CI: 1.47, 5.57).Conclusions: Compared with never users, smokeless tobacco did not alter TTP in our cohort; however, TTP was shorter compared with smokers. We observed longer TTP in male and female smokers; cadmium may partially contribute.Implications: Both partners' preconception smoking contributed to longer TTP, highlighting the importance of both partners' lifestyles in healthy reproduction and underscores the need for couple-based preconception guidance. The male's contribution is a new finding. Higher cadmium levels may partially contribute to longer TTP in smokers, particularly among females. Though we do not observe longer TTP among a small sample of smokeless tobacco users compared with never tobacco users, we observe shorter TTP compared with smokers. Further work is needed to more thoroughly delineate the relationship between smokeless tobacco use and TTP and possible mechanisms of tobacco use's effects on reproduction. [ABSTRACT FROM AUTHOR]

Study Question: Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)?Summary Answer: Higher urinary paracetamol concentrations among male partners were associated with a longer TTP.What Is Known Already: Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking.Study Design, Size, Duration: This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005-2009 and residing in Michigan or Texas, USA.Participants/materials, Setting, Methods: Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other.Main Results and the Role Of Chance: Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously.Limitations, Reasons For Caution: Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders.Wider Implications Of the Findings: If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment.Study Funding/competing Interests: This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the relationship between body size, physical activity and semen parameters among male partners of couples attempting to become pregnant? SUMMARY ANSWER Overweight and obesity are associated with a higher prevalence of low ejaculate volume, sperm concentration and total sperm count. WHAT IS KNOWN ALREADY Higher BMI is associated with impaired semen parameters, while increasing waist circumference (WC) is also associated with impaired semen parameters in infertile men. STUDY DESIGN, SIZE, DURATION Data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study were utilized. The LIFE study is a population-based prospective cohort of 501 couples attempting to conceive in two geographic areas (Texas and Michigan, USA) recruited in 2005–2009. Couples were recruited from four counties in Michigan and 12 counties in Texas to ensure a range of environmental exposures and lifestyle characteristics. In person interviews were conducted to ascertain demographic, health and reproductive histories followed by anthropometric assessment. PARTICIPANTS/MATERIALS, SETTING, METHODS We categorized BMI (kg/m2) as <25.0 (underweight and normal), 25.0–29.9 (overweight) 30.0–34.9 (obese, class I) and ≥35 (obese, class II) for analysis. Data were available for analysis in 468 men (93% participation), with a mean ± SD age of 31.8 ± 4.8 years, BMI of 29.8 ± 5.6 kg/m2 and WC of 100.8 ± 14.2 cm. The majority of the cohort (82%) was overweight or obese with 58% reporting physical activity <1 time/week. The median sperm concentration for the men in the cohort was 60.2 M/ml with 8.6% having oligospermia (<15 M/ml). MAIN RESULTS AND THE ROLE OF CHANCE When examining semen parameters, ejaculate volume showed a linear decline with increasing BMI and WC (P < 0.01). Similarly, the total sperm count showed a negative linear association with WC (P < 0.01). No significant relationship was seen between body size (i.e. BMI or WC) and semen concentration, motility, vitality, morphology or DNA fragmentation index. The percentage of men with abnormal volume, concentration and total sperm increased with increasing body size (P < 0.05). No relationship between physical activity and semen parameters was identified. LIMITATIONS, REASONS FOR CAUTION Our cohort was largely overweight and sedentary, which may result in limited external validity, i.e. generalizability. The lack of physical activity did preclude examination of exercise more frequently than once per week, thus our ability to examine more active individuals is limited. WIDER IMPLICATIONS OF THE FINDINGS Body size (as measured by BMI or WC) is negatively associated with semen parameters with little influence of physical activity. Our findings are the first showing a relationship between WC and semen parameters in a sample of men without known infertility. Given the worldwide obesity epidemic, further study of the role of weight loss to improve semen parameters is warranted. STUDY FUNDING/COMPETING INTEREST(S) Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts #N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). There are no competing interests. [ABSTRACT FROM AUTHOR]

The relationship between the environment and human fecundity and fertility remains virtually unstudied from a couple-based perspective in which longitudinal exposure data and biospecimens are captured across sensitive windows. In response, we completed the LIFE Study with methodology that intended to empirically evaluate a priori purported methodological challenges: implementation of population-based sampling frameworks suitable for recruiting couples planning pregnancy; obtaining environmental data across sensitive windows of reproduction and development; home-based biospecimen collection; and development of a data management system for hierarchical exposome data. We used two sampling frameworks (i.e., fish/wildlife licence registry and a direct marketing database) for 16 targeted counties with presumed environmental exposures to persistent organochlorine chemicals to recruit 501 couples planning pregnancies for prospective longitudinal follow-up while trying to conceive and throughout pregnancy. Enrolment rates varied from <1% of the targeted population (n = 424,423) to 42% of eligible couples who were successfully screened; 84% of the targeted population could not be reached, while 36% refused screening. Among enrolled couples, ∼ 85% completed daily journals while trying; 82% of pregnant women completed daily early pregnancy journals, and 80% completed monthly pregnancy journals. All couples provided baseline blood/urine samples; 94% of men provided one or more semen samples and 98% of women provided one or more saliva samples. Women successfully used urinary fertility monitors for identifying ovulation and home pregnancy test kits. Couples can be recruited for preconception cohorts and will comply with intensive data collection across sensitive windows. However, appropriately sized sampling frameworks are critical, given the small percentage of couples contacted found eligible and reportedly planning pregnancy at any point in time. [ABSTRACT FROM AUTHOR]

MikolajczykPrevious research has described variability in menstrual cycle lengths within and across women, though less attention has focused on characterising patterns of bleeding. While clinical definitions for menstrual bleeding are often given in standard textbooks, the validity of conventional definitions has not been empirically evaluated in epidemiological studies. The definition of menstrual bleeding may affect the analysis of time to pregnancy and pregnancy dating that relies upon the last menstrual period. We used daily records of vaginal bleeding from a prospective cohort study that included 74 women trying to become pregnant who reported 430 bleeding episodes. A longitudinal mixture model (PROC TRAJ) was used to classify patterns of bleeding. Among the first 74 bleeding episodes, 15% comprised only days with spotting or light bleeding (possibly representing non-menstrual bleeding given the length of the cycle defined by these bleeding episodes). When all 430 bleeding episodes were analysed, four distinct bleeding patterns emerged: (1) episodic bleeding comprising 1-3 days of spotting (10%), (2) bleeding lasting 3-6 days (40%), (3) bleeding lasting 6-8 days (33%), and (4) bleeding lasting 8-12 days (17%). These findings suggest that non-menstrual bleeding may be relatively common. Considerable variation in menstrual bleeding patterns is evident, and as such is likely to impact fecundity-related endpoints or gestational age estimates that rely upon menstrual cycle dates. The association between bleeding patterns and female fecundity awaits future research. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether children conceived using assisted reproductive technology (ART) or ovulation induction (OI) have greater cardiometabolic risk than children conceived without treatment.Design: Clinical assessments in 2018-2019 in the Upstate KIDS cohort.Setting: Clinical sites in New York.Patient(s): Three hundred thirty-three singletons and 226 twins from 448 families.Intervention(s): Mothers reported their use of fertility treatment and its specific type at baseline and approximately 4 months after delivery. High validity of the self-reported use of ART was previously confirmed. The children were followed up from infancy through 8-10 years of age. A subgroup was invited to participate in clinic visits.Main Outcome Measure(s): The measurements of blood pressure (BP), arterial stiffness using pulse wave velocity, anthropometric measures, and body fat using bioelectrical impedance analysis were performed (n = 559). The levels of plasma lipids, C-reactive protein, and hemoglobin A1c were measured using blood samples obtained from 263 children.Result(s): The average age of the children was 9.4 years at the time of the clinic visits Approximately 39% were conceived using fertility treatment (18% using ART and 21% using OI). Singletons conceived using fertility treatment (any type or using ART or OI specifically) did not statistically differ in systolic or diastolic BP, heart rate, or pulse wave velocity. Singletons conceived using OI were smaller than singletons conceived without treatment, but the average body mass index of the latter was higher (z-score: 0.41 [SD, 1.24]) than the national norms. Twins conceived using either treatment had lower BP than twins conceived without treatment. However, twins conceived using OI had significantly higher arterial stiffness (0.59; 95% CI, 0.03-1.15 m/s), which was attenuated after accounting for maternal BP (0.29; 95% CI, -0.03 to 0.46 m/s). Twins did not significantly differ in size or fat measures across the groups. The mode of conception was not associated with the levels of lipids, C-reactive protein, or glycosylated hemoglobin.Conclusion(s): Clinical measures at the age of 9 years did not indicate greater cardiometabolic risk in children conceived using ART or OI compared with that in children conceived without treatment.Clinical Trial Registration Number: ClinicalTrials.gov #NCT03106493. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment.Design: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment.Setting: New York State (excluding New York City).Patient(s): This analysis included 855 newborns and 152 children at approximately 9 years of age.Intervention(s): None.Main Outcome Measure(s): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted.Result(s): Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction.Conclusion(s): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood. [ABSTRACT FROM AUTHOR]

To evaluate whether underlying infertility and mode of conception are associated with childhood behavioral disorders. Oversampling on fertility treatment exposure using vital records, the Upstate KIDS Study followed 2057 children (of 1754 mothers) from birth to 11 years. Type of fertility treatment and time to pregnancy (TTP) were self-reported. Mothers completed annual questionnaires reporting symptomology, diagnoses, and medications at 7–11 years of age. The information identified children with probable attention-deficit/hyperactivity disorder, anxiety or depression, and conduct or oppositional defiant disorders. We estimated adjusted relative risks (aRR) for disorders by underlying infertility (TTP > 12 months) or treatment exposure groups compared to children born to parents with TTP ≤ 12 months. Children conceived with fertility treatment (34%) did not have an increased risk of attention-deficit/hyperactivity disorder (aRR): 1.21; 95% CI: 0.88, 1.65), or conduct or oppositional defiant disorders (aRR: 1.31; 0.91, 1.86), but did have an increased risk of anxiety or depression (aRR: 1.63; 1.18, 2.24), which remained elevated even after adjusting for parental mood disorders (aRR: 1.40; 0.99, 1.96). Underlying infertility without the use of treatment was also associated with a risk of anxiety or depression (aRR: 1.82; 95% CI: 0.96, 3.43). Underlying infertility or its treatment was not associated with risk of attention-deficit/hyperactivity disorder. Observations of increased anxiety or depression require replication. [ABSTRACT FROM AUTHOR]

Purpose: Given reportedly high clustering but limited validity of retrospectively reported time-to-pregnancy (TTP), we assessed within-woman clustering for retrospectively reported TTPs alone and including gold-standard prospectively observed TTPs among women with 2 or more retrospectively reported and 1 or more prospectively observed TTPs. We further investigated whether past trying times inform future trying time among women with 1 or more retrospectively reported and 1 or more prospectively observed TTPs.Methods: Five hundred one couples attempting pregnancy were prospectively observed until human chorionic gonadotropin pregnancy or 12 months of trying. Women reported TTP for past planned pregnancies. Clustering as measured by the frailty variance was estimated using discrete Cox frailty models, adjusted for age, body mass index, smoking at each attempt. Utility of past attempts to inform future attempts was assessed with discrete Cox models and relative risk regression, adjusted for enrollment age, body mass index, smoking.Results: Seventy-five women with 2 or more prior pregnancies contributed 180 retrospective and 91 prospective TTPs for frailty modeling. Retrospectively reported TTP clustering was high (frailty variance = 0.89) but substantially lower when including prospectively observed TTPs (frailty variance = 0.42). Among 202 women with 1 or more prior pregnancies, past trying times did not inform future trying time.Conclusions: TTP recall rather than TTP may account for clustering. Past trying times may not inform future trying times. [ABSTRACT FROM AUTHOR]

Abstract: An evolving body of evidence suggests an adverse relation between persistent organochlorine pollutants (POPs) and menstruation, though prospective longitudinal measurement of menses is limited and served as the impetus for study. We prospectively assessed the relation between a mixture of persistent organochlorine compounds and menstrual cycle length and duration of bleeding in a cohort of women attempting to become pregnant. Eighty-three (83%) women contributing 447 cycles for analysis provided a blood specimen for the quantification of 76 polychlorinated biphenyls and seven organochlorine pesticides, and completed daily diaries on menstruation until a human chorionic gonadotropin confirmed pregnancy or 12 menstrual cycles without conception. Gas chromatography with electron capture detection was used to quantify concentrations (ngg−1 serum); enzymatic methods were used to quantify serum lipids (mgdL−1). A linear regression model with a mixture distribution was used to identify chemicals grouped by purported biologic activity that significantly affected menstrual cycle length and duration of bleeding adjusting for age at menarche and enrollment, body mass index, and cigarette smoking. A significant 3-d increase in cycle length was observed for women in the highest tertile of estrogenic PCB congeners relative to the lowest tertile (β =3.20; 95% CI 0.36, 6.04). A significant reduction in bleeding (<1d) was observed among women in the highest versus lowest tertile of aromatic fungicide exposure (γ =−0.15; 95% CI −0.29, −0.00). Select POPs were associated with changes in menstruation underscoring the importance of assessing chemical mixtures for female fecundity. [Copyright &y& Elsevier]