Diabetes, medical comorbidities and couple fecundity.

What is the relationship between couple's health and fecundity in a preconception cohort? 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). The impact of somatic health on human fecundity is hypothesized given the reported declines in spermatogenesis and ovulation among individuals with certain medical comorbidities. 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. In all, 33 (21.4%) female and 41 (26.6%) male partners had medical conditions at baseline. 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. 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. 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. 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.

Eisenberg ML ，Sundaram R ，Maisog J ，Buck Louis GM ... -  《-》

Couples' body composition and time-to-pregnancy.

Is couples' body compositions associated with reduced fecundity as measured by a longer time-to-pregnancy (TTP)? 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. 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. 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. 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. 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. BMI and waist circumference are proxy measures of body composition and residual confounding cannot be eliminated. Findings may not be generalizable to clinical populations. 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. 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. N/A.

Sundaram R ，Mumford SL ，Buck Louis GM 《-》

Urinary paracetamol and time-to-pregnancy.

Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)? Higher urinary paracetamol concentrations among male partners were associated with a longer TTP. 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. 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. 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. 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. 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. 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. 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.

Smarr MM ，Grantz KL ，Sundaram R ，Maisog JM ，Honda M ，Kannan K ，Buck Louis GM ... -  《-》

Successive time to pregnancy among women experiencing pregnancy loss.

Is time to pregnancy (TTP) similar across successive pregnancy attempts among women experiencing pregnancy loss? TTP after a loss may be longer compared with TTP before a loss. Two pregnancy cohort studies have reported that TTP is similar across pregnancy attempts in fertile women. However, this has not been investigated among women experiencing pregnancy losses. Data for this analysis come from the Longitudinal Investigation of Fertility and the Environment Study, a population-based, preconception cohort of couples attempting pregnancy. During 2005-2009, recruitment was targeted to 16 counties in Michigan and Texas with reported exposures to persistent environmental chemicals. A total of 501 couples were recruited and followed for up to 12 months of pregnancy attempts allowing for continued participation of women with pregnancy losses until censoring. We assessed TTP among 70 couples recruited upon discontinuing contraception for purposes of becoming pregnant and experiencing ≥1 prospectively observed pregnancy losses during 12 months of trying. There were 61 couples who contributed two pregnancy attempts and 9 who contributed three. Women were instructed in the use of urine-based home fertility monitors to time intercourse relative to ovulation and recorded their bleeding patterns in daily journals. TTP was defined as the number of menstrual cycles taken to achieve pregnancy. Women were also instructed in the use of home digital pregnancy tests and asked to begin pregnancy testing on the day of expected menses. Women recorded the results of their pregnancy tests in a daily journal with a single positive pregnancy test result indicating an hCG-confirmed pregnancy. Pregnancy losses were ascertained from a subsequent recorded negative pregnancy test or clinically confirmed loss. We estimated fecundability odds ratios (FORs) comparing subsequent to first TTP using discrete Cox models with robust standard errors, accounting for cycles off contraception before study entry and adjusting for maternal age, body mass index, reproductive history and time-varying cigarette, alcohol and caffeine usage while trying. The mean female age was 30.3 ± 4.3 years; 21% had a prior pregnancy loss before study entry. Of the second and third attempts, 59 and 43%, respectively, were longer compared with the first attempt. FORs <1 suggest reduced fecundability or a longer TTP when comparing the second with the first attempt (0.42, 95% confidence interval (CI): 0.28, 0.65), and similarly for the third relative to the first attempt (0.64, 95% CI: 0.18, 2.36). TTP in the second attempt was a median of 1 cycle longer (interquartile range: 0, 3 cycles) compared with TTP in the first attempt. As this is the first study to investigate successive TTP exclusively among women experiencing pregnancy loss, our findings await corroboration since most losses occurred early in gestation. As such, the generalizability of our findings for all pregnancy losses awaits further research. We also had limited power to detect a reduction in fecundability for the third compared with first pregnancy attempt. Unlike fertile women, TTP in women experiencing early pregnancy losses may trend towards longer subsequent attempts. If the findings are corroborated, women experiencing losses may benefit from counselling regarding trying times. This research 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 and NOH-HD-3-3358). K.J.S. was supported by an Intramural Research Training Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research. The authors have no conflicts of interest to declare.

Sapra KJ ，McLain AC ，Maisog JM ，Sundaram R ，Buck Louis GM ... -  《-》

Preconception stress increases the risk of infertility: results from a couple-based prospective cohort study--the LIFE study.

Lynch CD ，Sundaram R ，Maisog JM ，Sweeney AM ，Buck Louis GM ... -  《-》