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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]

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. [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]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 (μgL−1), lead (μgdL−1) and mercury (μgL−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 12months 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM PUBLISHER]

Summary McLain AC, Sundaram R, Cooney MA, Gollenberg AL, Buck Louis GM. Clustering of fecundability within women. Paediatric and Perinatal Epidemiology 2011; 25: 460-465. 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 US 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. [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]

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. [ABSTRACT FROM PUBLISHER]

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 study the association between salivary stress biomarkers and the secondary sex ratio. Design: Prospective, longitudinal cohort study. Setting: Community setting in the United Kingdom. Patient(s): On discontinuation of contraception for purposes of becoming pregnant, 338 women aged 18–40 years with complete data (90%) were followed until pregnant or up to six menstrual cycles. Intervention(s): None. Main Outcome Measure(s): Secondary sex ratio. Result(s): Human chorionic gonadotropin pregnancies were detected in 207 (61%) women of whom 130 (63%) delivered singleton infants with available gender data. The adjusted odds ratio for a male birth was decreased for women in the highest quartile (AOR = 0.26; 95% confidence interval = 0.09, 0.74) of salivary cortisol relative to women in the lowest quartile during cycle 1. An inverse relation was observed between α-amylase and the 2° sex ratio, though not statistically significant. Conclusion(s): Our findings are consistent with a reversal in the 2° sex ratio with increasing preconception salivary cortisol concentrations. This relation suggests that activation of the hypothalamus–pituitary–adrenal axis may have implications in sex allocation and requires further study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 3.60μg/L increase in Mg (P =0.062), and a 27.7% decrease per 0.54μg/L increase in Zn (P =0.114). Findings indicate that Mg and Zn may impact female fecundity, but in varying directions. [Copyright &y& Elsevier]

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]

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. [ABSTRACT FROM AUTHOR]