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Study Question: Are children who were conceived with infertility treatment at an increased risk of developing asthma and atopic conditions?, Summary Answer: Infertility treatment is associated with an elevated risk of asthma and atopic conditions in early and middle childhood, even after adjustment for parental asthma and atopy., What Is Known Already: Asthma and atopic conditions are prevalent in childhood. The development of these conditions may be linked to early life exposures, including the use of infertility treatments., Study Design, Size, Duration: Upstate KIDS is a prospective cohort study of singletons and multiples born between 2008 and 2010. A total of 5034 mothers and 6171 children were enrolled and followed up until 2019, and 2056 children participated in the middle childhood follow-up., Participants/materials, Setting, Methods: Women reported the fertility agents used to become pregnant on a baseline questionnaire. Treatment was categorized as ART (∼22%) use, ovulation induction via oral/injectable medications with or without IUI (OI/IUI, ∼20%), or no treatment (∼58%). Outcomes were assessed by maternal report on questionnaires in early (up to age 3 years, prevalence 9-28%) and middle (7-9 years, prevalence 10-16%) childhood. Weighted Poisson regression models with robust standard errors were used to analyze the risk of atopic outcomes in relation to infertility treatment exposure., Main Results and the Role of Chance: Compared to children conceived without treatment, children conceived with any infertility treatment were at an increased risk of persistent wheeze by age 3 years (relative risk (RR): 1.66; 95% CI: 1.17, 2.33) with adjustments for parental atopy among other risk factors. Around 7-9 years, children conceived with treatment were more likely to have current asthma (RR: 1.30; 95% CI: 0.98, 1.71), eczema (RR: 1.77; 95% CI: 1.25, 2.49) or be prescribed allergy-related medications (RR: 1.45; 95% CI: 1.06, 1.99). Similar effect sizes were found when examining associations by treatment type (i.e. ART versus OI/IUI)., Limitations, Reasons for Caution: Childhood outcomes were based on maternal report and are subject to potential misclassification. There was attrition in this study, which limits the precision of our measures of association., Wider Implications of the Findings: Though future research is needed to clarify the mechanisms involved, our findings support that both ART and OI/IUI influences the development of asthma and atopic conditions in the offspring from an early age., Study Funding/competing Interest(s): This work was supported by the National Institutes of Health's Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C, #HHSN275201400013C, #HHSN275201300026I/27500004, #HHSN275201300023I/27500017). The authors have no relevant conflicts of interest to disclose., Trial Registration Number: N/A., (Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology 2022. This work is written by US Government employees and is in the public domain in the US.)

Background: Preterm birth is associated with lower neurocognitive performance. However, whether children's neurodevelopment improves with longer gestations within the full-term range (37-41 weeks) is unclear. Given the high rate of obstetric intervention in the USA, it is critical to determine whether long-term outcomes differ for children delivered at each week of term., Methods: This secondary analysis included 39 199 live-born singleton children of women who were admitted to the hospital in spontaneous labour from the US Collaborative Perinatal Project (1959-76). At each week of term gestation, we evaluated development at 8 months using the Bayley Scales of Infant Development, 4 years using the Stanford-Binet IQ (SBIQ) domains and 7 years using the Wechsler Intelligence Scales for Children (WISC) and Wide-Range Achievement Tests (WRAT)., Results: Children's neurocognitive performance improved with each week of gestation from 37 weeks, peaking at 40 or 41 weeks. Relative to those delivered at 40 weeks, children had lower neurocognitive scores at 37 and 38 weeks for all assessments except SBIQ and WISC Performance IQ. Children delivered at 39 weeks had lower Bayley Mental (β = -1.18; confidence interval -1.77, -0.58) and Psychomotor (β = -1.18; confidence interval -1.90, -0.46) scores. Results were similar for within-family analyses comparing siblings, with the addition of lower WRAT scores at 39 weeks., Conclusions: The improvement in development scores across assessment periods indicates that each week up to 40 or 41 weeks of gestation is important for short- and long-term cognitive development, suggesting 40-41 weeks may be the ideal delivery window for optimal neurodevelopmental outcomes., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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.

Study Question: Is maternal polycystic ovarian syndrome (PCOS) associated with developmental delays in offspring?, Summary Answer: Offspring of mothers with PCOS were at higher risk of failure on the Ages and Stages Questionnaire (ASQ)., What Is Known Already: There is growing evidence that offspring of mothers with PCOS may be at higher risk for developmental disorders due to potential exposure to hyperandrogenism and insulin resistance. Few studies exist regarding maternal PCOS and early childhood development in the USA., Study Design, Size, Duration: The Upstate KIDS Study is a population-based prospective cohort study of infants born between 2008 and 2010 in New York State (excluding New York City), originally designed to study-and finding no impact of-infertility treatment exposure on child development. Children were followed up to 36 months of age. In all, 4453 mothers completed one or more developmental screening instruments for 5388 children (35.5% twins) up to 36 months of age., Participants/materials, Setting, Methods: In our study, 458 mothers (10.3%) reported a healthcare provider's diagnosis of PCOS, as well as the related treatment received, on the baseline study questionnaire. Parents completed the ASQ on their child's development at 4, 8, 12, 18, 24, 30 and 36 months of age to assess fine motor, gross motor, communication, personal-social functioning and problem-solving cognitive domains. We used generalized linear mixed models to estimate odds ratios (OR) between PCOS diagnosis and failures in the ASQ adjusted for maternal age, race, BMI, education, marital status, smoking, alcohol consumption, diabetes, insurance and plurality., Main Results and the Role of Chance: Diagnosis of PCOS was associated with increased risk of the offspring failing the fine motor domain (adjusted odds ratio (aOR) = 1.77; 95% CI: 1.09, 2.89), largely driven by higher risk in female singletons (aOR = 2.23; 1.16, 4.29). Twins of mothers with PCOS had higher risk of failing the communication (aOR = 1.94; 1.19, 3.18) and personal-social functioning (aOR = 1.76; 1.12, 2.77) domains compared to twins born to mothers without PCOS. Compared to offspring of women without PCOS, offspring of women who reported receiving no treatment for their PCOS had a stronger association with failing the ASQ (aOR = 1.68; 0.95, 2.75) than the association among offspring of women who reported PCOS treatment (aOR = 1.16; 0.79, 1.73)., Limitations, Reasons for Caution: Further study is needed to confirm the role of maternal PCOS in early offspring development with provider-validated diagnosis of PCOS., Wider Implications of the Findings: If confirmed, these findings suggest that offspring of women with PCOS may be at increased risk for developmental delay., Study Funding/competing Interest(s): Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275201200005C, #HHSN267200700019C). Authors have no competing interests to declare., Trial Registration Number: Not applicable.

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.

Background: Little is known about the predictors of sexual intercourse frequency (SIF) among couples trying to conceive despite the well-established link between SIF and fecundity., Aim: To evaluate men's and women's demographic, occupational, and lifestyle predictors of SIF among couples., Methods: 469 Couples without a history of infertility participating in the Longitudinal Investigation of Fertility and the Environment Study (2005-2009) were followed up for ≤1 year while trying to conceive. At enrollment, both partners were interviewed about demographic, occupational, lifestyle, and psychological characteristics using standardized questionnaires. Multivariable generalized linear mixed models with Poisson distribution were used to estimate the adjusted percent difference in SIF across exposure categories., Outcomes: SIF was recorded in daily journals and summarized as average SIF/mo., Results: The median (interquartile range) SIF during follow-up was 6 (4-9) acts/mo. For every year increase in age for women and men, SIF decreased by -0.8% (95% CI -2.5 to 1.0%) and -1.7% (95% CI -3.1 to -0.3%). Women with high school education or less and those of non-white race had 34.4% and 16.0% higher SIF, respectively. A similar trend was seen for men's education and race. Only couples where both partners (but not just 1 partner) worked rotating shifts had -39.1% (95% CI -61.0 to -5.0%) lower SIF compared to couples where neither partner worked rotating shifts. Men's (but not women's) exercise was associated with 13.2% (95% CI 1.7-26.0%) higher SIF. Diagnosis of a mood or anxiety disorder in men (but not women) was associated with a 26.0% (95% CI -42.7 to -4.4%) lower SIF. Household income, smoking status, body mass index, night work, alcohol intake, and psychosocial stress were not associated with SIF., Clinical Translation: Even among couples trying to conceive, there was substantial variation in SIF. Both partners' age, education, race, and rotating shift work as well as men's exercise and mental health play an important role in determining SIF., Conclusions: As this was a secondary analysis of an existing study, we lacked information on many pertinent psychological and relationship quality variables and the hormonal status of participants, which could have affected SIF. The unique population-based couple design, however, captured both partners' demographics, occupational characteristics, and lifestyle behaviors in advance of their daily, prospective reporting of SIF, which was a major strength. Important predictors of SIF among couples attempting to conceive include men's exercise and mental health and both partners' age, education, race, and rotating shift work. Gaskins AJ, Sundaram R, Buck Louis GM, et al. Predictors of Sexual Intercourse Frequency Among Couples Trying to Conceive. J Sex Med 2018;15:519-528., (Copyright © 2018 International Society for Sexual Medicine. All rights reserved.)

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.)

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., (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.)

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., (Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

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.)

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., (Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

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.)

New cervical cancer screening guidelines in the US and many European countries recommend that women get tested for human papillomavirus (HPV). To inform decisions about screening intervals, we calculate the increase in precancer/cancer risk per year of continued HPV infection. However, both time to onset of precancer/cancer and time to HPV clearance are interval-censored, and onset of precancer/cancer strongly informatively censors HPV clearance. We analyze this bivariate informatively interval-censored data by developing a novel joint model for time to clearance of HPV and time to precancer/cancer using shared random-effects, where the estimated mean duration of each woman's HPV infection is a covariate in the submodel for time to precancer/cancer. The model was fit to data on 9,553 HPV-positive/Pap-negative women undergoing cervical cancer screening at Kaiser Permanente Northern California, data that were pivotal to the development of US screening guidelines. We compare the implications for screening intervals of this joint model to those from population-average marginal models of precancer/cancer risk. In particular, after 2 years the marginal population-average precancer/cancer risk was 5%, suggesting a 2-year interval to control population-average risk at 5%. In contrast, the joint model reveals that almost all women exceeding 5% individual risk in 2 years also exceeded 5% in 1 year, suggesting that a 1-year interval is better to control individual risk at 5%. The example suggests that sophisticated risk models capable of predicting individual risk may have different implications than population-average risk models that are currently used for informing medical guideline development.

We consider the joint modelling, analysis and prediction of a longitudinal binary process and a discrete time-to-event outcome. We consider data from a prospective pregnancy study, which provides day level information regarding the behaviour of couples attempting to conceive. Reproductive epidemiologists are particularly interested in developing a model for individualized predictions of time to pregnancy (TTP). A couple's intercourse behaviour should be an integral part of such a model and is one of the main focuses of the paper. In our motivating data, the intercourse observations are a long series of binary data with a periodic probability of success and the amount of available intercourse data is a function of both the menstrual cycle length and TTP. Moreover, these variables are dependent and observed on different, and nested, timescales (TTP is measured in menstrual cycles whereas intercourse is measured on days within a menstrual cycle) further complicating its analysis. Here, we propose a semiparametric shared parameter model for the joint modelling of the binary longitudinal data (intercourse behaviour) and the discrete survival outcome (TTP). Further, we develop couple-based dynamic predictions for the intercourse profiles, which in turn are used to assess the risk for subfertility (i.e. TTP longer than six menstrual cycles).

Prospective pregnancy studies are a valuable source of longitudinal data on menstrual cycle length. However, care is needed when making inferences of such renewal processes. For example, accounting for the sampling plan is necessary for unbiased estimation of the menstrual cycle length distribution for the study population. If couples can enroll when they learn of the study as opposed to waiting for the start of a new menstrual cycle, then due to length-bias, the enrollment cycle will be stochastically larger than the general run of cycles, a typical property of prevalent cohort studies. Furthermore, the probability of enrollment can depend on the length of time since a woman's last menstrual period (a backward recurrence time), resulting in selection effects. We focus on accounting for length-bias and selection effects in the likelihood for enrollment menstrual cycle length, using a recursive two-stage approach wherein we first estimate the probability of enrollment as a function of the backward recurrence time and then use it in a likelihood with sampling weights that account for length-bias and selection effects. To broaden the applicability of our methods, we augment our model to incorporate a couple-specific random effect and time-independent covariate. A simulation study quantifies performance for two scenarios of enrollment probability when proper account is taken of sampling plan features. In addition, we estimate the probability of enrollment and the distribution of menstrual cycle length for the study population of the Longitudinal Investigation of Fertility and the Environment Study., (Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

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.)

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/m(2)) 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/m(2) 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.

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.)

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.

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.

While elevated levels of proinflammatory cytokines are clearly associated with preterm birth, the relation between cytokines and fetal growth is unclear. The authors examined associations between umbilical cord serum cytokine concentrations and risk of small-for-gestational-age (SGA) and preterm birth. This cross-sectional analysis was nested within a National Institute of Child Health and Human Development-University of Alabama population-based cohort study of high-risk prenatal care patients in Jefferson County, Alabama. Patients were enrolled between 1985 and 1988. For 370 singletons, umbilical cord serum concentrations of interferon gamma (IFN-gamma), tumor necrosis factor alpha, and interleukins 12p70, 4, and 10 were determined. Associations between each cytokine and SGA and preterm delivery were evaluated using log binomial regression. Increasing log concentration of tumor necrosis factor alpha was associated with an increased risk of preterm birth (risk ratio (RR) = 2.00, 95% confidence interval (CI): 1.31, 3.06). IFN-gamma was associated with a decreased risk of SGA birth (RR = 0.78, 95% CI: 0.61, 1.01). After stratification for preterm birth status, the association between IFN-gamma concentration and SGA birth was pronounced among preterm babies (RR = 0.56, 95% CI: 0.31, 1.01). The observations regarding IFN-gamma, which is involved in the activation of adaptive immune responses and regulation of trophoblast function, suggest that IFN-gamma levels at birth may be related to fetal growth restriction.

Animal studies indicate that either the fetus or the intrauterine environment, both of which set the pattern for fetal growth, may affect the timing of parturition. The authors examined the association between fetal growth and timing of spontaneous onset of labor in humans among low-risk white US women with singleton pregnancies (1987-1991). They restricted the data to pregnancies which had a reliable date of the last menstrual period, normal fetal growth in the first half of pregnancy, and no history of or current pregnancy complications that might have impaired fetal growth (n = 3,360). Subjects received ultrasound examinations at 15-22 and 31-35 weeks' gestation. Fetal growth was adjusted for parity, fetal sex, and maternal prepregnancy weight and height. Results showed that slower or faster fetal growth in the second half of pregnancy resulted in substantially lower or higher birth weight, respectively. However, fetal growth in the second half of pregnancy, even at extremes (2 standard deviations below or above the mean), did not have a meaningful impact on the timing of parturition; neither did fetal growth acceleration or deceleration in late pregnancy. Thus, in low-risk pregnancies where fetal growth is normal in early gestation, fetal growth in the second half of pregnancy does not affect the timing of normal parturition.

Multistage models are used to describe individuals (or experimental units) moving through a succession of "stages" corresponding to distinct states (e.g., healthy, diseased, diseased with complications, dead). The resulting data can be considered to be a form of multivariate survival data containing information about the transition times and the stages occupied. Traditional survival analysis is the simplest example of a multistage model, where individuals begin in an initial stage (say, alive) and move irreversibly to a second stage (death). In this article, we consider general multistage models with a directed tree structure (progressive models) in which individuals traverse through stages in a possibly non-Markovian manner. We construct nonparametric estimators of stage occupation probabilities and marginal cumulative transition hazards. Empirical calculations of these quantities are not possible due to the lack of complete data. We consider current status information which represents a more severe form of censoring than the commonly used right censoring. Asymptotic validity of our estimators can be justified using consistency results for nonparametric regression estimators. Finite-sample behavior of our estimators is studied by simulation, in which we show that our estimators based on these limited data compare well with those based on complete data. We also apply our method to a real-life data set arising from a cardiovascular diseases study in Taiwan.