Courtney D. Lynch

Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development--the LIFE Study.

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.

Concurrent validity of the parent-completed Ages and Stages Questionnaires, 2nd Ed. with the Bayley Scales of Infant Development II in a low-risk sample

Abstract Background This study assessed the concurrent validity of the Ages and Stages Questionnaire (ASQ) compared with Bayley Scales of Infant Development II (BSID II) amongst children aged 24 months. Methods Data were collected from 53 infants and mothers who participated in the New York State Angler Cohort Child Development Study. Parents completed the 24-month ASQ to assess communication, personal-social, problem-solving ability, and fine and gross motor control. The BSID II was administered by a clinical psychologist at the 24-month home visit for cognitive and psychomotor assessment. The ASQ was scored using age-specific norms of <2 SDs below any domain mean to define failure. A BSID II score of <85 indicated mild or severe delay, while a score of <70 suggested a severe delay. Results Scores on the ASQ communication and personal-social domains were moderately correlated with the BSID II Mental Scale (R= 0.52, P < 0.001; R= 0.45, P < 0.01) and ASQ gross motor with the BSID II Motor Scale (R= 0.46, P < 0.01), whereas ASQ problem-solving and fine motor domains were not significantly correlated with BSID II scores. The ASQ had a sensitivity of 100% and specificity of 87% at 24 months (n= 40) for severely delayed status. Conclusions Results suggest the ASQs provide a simple, valid, and cost-effective method for clinicians and field-based researchers to reduce the number of standardized assessments required to identify developmentally delayed infants at age 24 months. Future studies should further assess the validity of the ASQs in larger, more diverse populations of infants.

Persistent Environmental Pollutants and Couple Fecundity: The LIFE Study

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.

Validity of self-reported time to pregnancy.

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

The association between childhood asthma prevalence and monitored air pollutants in metropolitan areas, United States, 2001―2004

BACKGROUND Air pollution exposure has been linked to adverse respiratory health outcomes among children, primarily in studies of acute exposures that are often in limited geographic areas. We sought to assess the association between chronic outdoor air pollution exposure, as measured by 12-month averages by county, and asthma among children in metropolitan areas across the nation. METHODS Eligible children included those aged 3-17 years residing in US metropolitan areas who were sampled in the 2001-2004 National Health Interview Survey (N=34,073). 12-month average air pollutant levels for sulfur dioxide, nitrogen dioxide, ozone and particulate matter were compiled by county for 2000-2004. Eligible children were linked to pollutant levels for the previous 12 months for their county of residence. Adjusted odds ratios of having current asthma or an asthma attack in the past 12 months were estimated in single pollutant logistic regression models. RESULTS Children in counties with ozone and, to a less consistent degree, particulate matter levels in the highest quartile were more likely to have current asthma and/or a recent asthma attack than children residing in counties with the lowest pollution levels; the adjusted odds for current asthma for the highest quartile of estimated ozone exposure was 1.56 (95% confidence interval [CI]: 1.15, 2.10) and for recent asthma attack 1.38 (95% CI: 0.99, 1.91). No associations were found with sulfur dioxide or nitrogen dioxide levels. CONCLUSION Although the current US standard for ozone is based on short-term exposure, this cross-sectional study suggests that chronic (12-month) exposure to ozone and particles is related to asthma outcomes among children in metropolitan areas throughout the US.

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

STUDY QUESTION Are womens stress levels prospectively associated with fecundity and infertility? SUMMARY ANSWER Higher levels of stress as measured by salivary alpha-amylase are associated with a longer time-to-pregnancy (TTP) and an increased risk of infertility. WHAT IS KNOWN ALREADY Data suggest that stress and reproduction are interrelated; however, the directionality of that association is unclear. STUDY DESIGN, SIZE, DURATION In 2005-2009, we enrolled 501 couples in a prospective cohort study with preconception enrollment at two research sites (Michigan and Texas, USA). Couples were followed for up to 12 months as they tried to conceive and through pregnancy if it occurred. A total of 401 (80%) couples completed the study protocol and 373 (93%) had complete data available for this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Enrolled women collected saliva the morning following enrollment and then the morning following their first observed study menses for the measurement of cortisol and alpha-amylase, which are biomarkers of stress. TTP was measured in cycles. Covariate data were captured on both a baseline questionnaire and daily journals. MAIN RESULTS AND THE ROLE OF CHANCE Among the 401 (80%) women who completed the protocol, 347 (87%) became pregnant and 54 (13%) did not. After adjustment for female age, race, income, and use of alcohol, caffeine and cigarettes while trying to conceive, women in the highest tertile of alpha-amylase exhibited a 29% reduction in fecundity (longer TTP) compared with women in the lowest tertile [fecundability odds ratios (FORs) = 0.71; 95% confidence interval (CI) = (0.51, 1.00); P < 0.05]. This reduction in fecundity translated into a >2-fold increased risk of infertility among these women [relative risk (RR) = 2.07; 95% CI = (1.04, 4.11)]. In contrast, we found no association between salivary cortisol and fecundability. LIMITATIONS, REASONS FOR CAUTION Due to fiscal and logistical concerns, we were unable to collect repeated saliva samples and perceived stress questionnaire data throughout the duration of follow-up. Therefore, we were unable to examine whether stress levels increased as women continued to fail to get pregnant. Our ability to control for potential confounders using time-varying data from the daily journals, however, minimizes residual confounding. WIDER IMPLICATIONS OF THE FINDINGS This is the first US study to demonstrate a prospective association between salivary stress biomarkers and TTP, and the first in the world to observe an association with infertility. 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.

Polychlorinated biphenyl serum concentrations, lifestyle and time-to-pregnancy

BACKGROUND Consumption of fish contaminated with polychlorinated biphenyls (PCBs) and prenatal PCB serum concentrations have been associated with a longer time-to-pregnancy (TTP). However, the relationship between preconception serum PCBs concentrations and TTP has not been previously studied. METHODS Eighty-three women (contributing 442 menstrual cycles) planning pregnancies completed daily diaries regarding menstruation, intercourse, home pregnancy test results, and reported use of alcohol and cigarettes. TTP denoted the number of observed menstrual cycles required for pregnancy. Preconception blood specimens underwent toxicologic analysis for 76 PCB congeners via gas chromatography with electron capture; serum lipids were quantified with enzymatic methods. A priori, PCB congeners were summed into a total and three groupings-estrogenic, anti-estrogenic and other-and entered into discrete analogs of Cox models with time-varying covariates to estimate fecundability odds ratios (FOR) and corresponding 95% confidence intervals (CIs). RESULTS Estrogenic and anti-estrogenic PCB concentrations (ng/g serum) conferred reduced FORs in fully adjusted models (0.32; 95% CI 0.03, 3.90 and 0.01: 95% CI < 0.00, 1.99, respectively). Reduced FORs (0.96) were observed for alcohol consumption standardized to a 28-day menstrual cycle in the same adjusted model (FOR = 0.96; 95% CI 0.93, 1.00). CONCLUSIONS These data suggest that environmental exposures including those amenable to change, such as alcohol consumption, may impact female fecundity. The findings are sensitive to model specification and PCB groupings, underscoring the need to further assess the impact of chemical mixtures on sensitive reproductive outcomes, such as TTP, especially in the context of lifestyle factors which are amenable to change, thereby improving reproductive health.

Analysis of repeated pregnancy outcomes

Women tend to repeat reproductive outcomes, with past history of an adverse outcome being associated with an approximate two-fold increase in subsequent risk. These observations support the need for statistical designs and analyses that address this clustering. Failure to do so may mask effects, result in inaccurate variance estimators, produce biased or inefficient estimates of exposure effects. We review and evaluate basic analytic approaches for analysing reproductive outcomes, including ignoring reproductive history, treating it as a covariate or avoiding the clustering problem by analysing only one pregnancy per woman, and contrast these to more modern approaches such as generalized estimating equations with robust standard errors and mixed models with various correlation structures. We illustrate the issues by analysing a sample from the Collaborative Perinatal Project dataset, demonstrating how the statistical model impacts summary statistics and inferences when assessing etiologic determinants of birth weight.

Maternal smoking and birth weight : Interaction with parity and mother's own in utero exposure to smoking

Background: Few studies have reported interactions between maternal smoking and other maternal characteristics and exposures. We examined maternal smoking in a cohort study for which data from 3 generations were available to examine maternal characteristics and exposures from a life-course perspective. Methods: We had data from 3 generations: women enrolled in the U.S. Collaborative Perinatal Project (CPP) between 1959 and 1965 at the Baltimore site (G1); daughters (G2) of those G1 mothers who were followed to ages 27–33 years in the Pathways to Adulthood study; and children (G3) born to the G2 women who provided pregnancy and birth information during the Pathways study. These data allowed examination of exposures that occurred to the mother during her childhood and in utero. Results: We found evidence of a 3-way interaction effect on birth weight for maternal smoking in pregnancy, maternal exposure to smoking in utero (grandmaternal smoking), and maternal parity. Maternal smoking reduced birth weight in 3 of the subgroups, with the size of the effect on birth weight moderated by parity and the mothers own in utero exposure to smoking. Conclusions: A mothers prenatal exposure to smoke may affect the birth weight of her offspring. This effect would be consistent with both the accumulation-of-risk and the fetal-programming hypotheses.

Are increased levels of self-reported psychosocial stress, anxiety, and depression associated with fecundity?

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