Article

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

September 2011
Paediatric and Perinatal Epidemiology 25(5):413-24

September 2011
25(5):413-24

DOI:10.1111/j.1365-3016.2011.01205.x

Source
PubMed

Authors:

Germaine M. Buck Louis

George Mason University

Enrique Schisterman

Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Buck Louis GM, Schisterman EF, Sweeney AM, Wilcosky TC, Gore‐Langton RE, Lynch CD, Boyd Barr D, Schrader SM, Kim S, Chen Z, Sundaram R, on behalf of the LIFE Study. Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development – the LIFE Study. Paediatric and Perinatal Epidemiology 2011; 25: 413–424. 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.

Sperm epigenetic clock associates with pregnancy outcomes in the general population

Article

May 2022
HUM REPROD

Study question: Is sperm epigenetic aging (SEA) associated with probability of pregnancy among couples in the general population? Summary answer: We observed a 17% lower cumulative probability at 12 months for couples with male partners in the older compared to the younger SEA categories. What is known already: The strong relation between chronological age and DNA methylation profiles has enabled the estimation of biological age as epigenetic 'clock' metrics in most somatic tissue. Such clocks in male germ cells are less developed and lack clinical relevance in terms of their utility to predict reproductive outcomes. Study design, size, duration: This was a population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 and followed for up to 12 months. Participants/materials, setting, methods: Sperm DNA methylation from 379 semen samples was assessed via a beadchip array. A state-of-the-art ensemble machine learning algorithm was employed to predict age from the sperm DNA methylation data. SEA was estimated from clocks derived from individual CpGs (SEACpG) and differentially methylated regions (SEADMR). Probability of pregnancy within 1 year was compared by SEA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates. Main results and the role of chance: Our SEACpG clock had the highest predictive performance with correlation between chronological and predicted age (r = 0.91). In adjusted discrete Cox models, SEACpG was negatively associated with TTP (fecundability odds ratios (FORs)=0.83; 95% CI: 0.76, 0.90; P = 1.2×10-5), indicating a longer TTP with advanced SEACpG. For subsequent birth outcomes, advanced SEACpG was associated with shorter gestational age (n = 192; -2.13 days; 95% CI: -3.67, -0.59; P = 0.007). Current smokers also displayed advanced SEACpG (P < 0.05). Finally, SEACpG showed a strong performance in an independent IVF cohort (n = 173; r = 0.83). SEADMR performance was comparable to SEACpG but with attenuated effect sizes. Limitations, reasons for caution: This prospective cohort study consisted primarily of Caucasian men and women, and thus analysis of large diverse cohorts is necessary to confirm the associations between SEA and couple pregnancy success in other races/ethnicities. Wider implications of the findings: These data suggest that our sperm epigenetic clocks may have utility as a novel biomarker to predict TTP among couples in the general population and underscore the importance of the male partner for reproductive success. Study funding/competing interest(s): This work was funded in part by grants the National Institute of Environmental Health Sciences, National Institutes of Health (R01 ES028298; PI: J.R.P. and P30 ES020957); Robert J. Sokol, MD Endowed Chair of Molecular Obstetrics and Gynecology (J.R.P.); and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contracts N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). S.L.M. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors declare no competing interests. Trial registration number: N/A.

Sperm mitochondrial DNA biomarkers and couple fecundity

Article

Nov 2020
HUM REPROD

Study question: Do sperm mitochondrial DNA measures predict probability of pregnancy among couples in the general population? Summary answer: Those with high sperm mitochondrial DNA copy number (mtDNAcn) had as much as 50% lower odds of cycle-specific pregnancy, and 18% lower probability of pregnancy within 12 months. What is known already: Semen parameters have been found to poorly predict reproductive success yet are the most prevalent diagnostic tool for male infertility. Increased sperm mtDNAcn and mitochondrial DNA deletions (mtDNAdel) have been associated with decreased semen quality and lower odds of fertilization in men seeking fertility treatment. Study design, size, duration: A population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 followed for up to 16 months. Participants/materials, setting, methods: Sperm mtDNAcn and mtDNAdel from 384 semen samples were assessed via triplex probe-based quantitative PCR. Probability of pregnancy within 1 year was compared by mitochondrial DNA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates. Main results and the role of chance: Higher sperm mtDNAcn was associated with lower pregnancy probability within 12 months and longer TTP. In unadjusted comparisons by quartile (Q), those in Q4 had a pregnancy probability of 63.5% (95% CI: 53.1% to 73.1%) compared to 82.3% (95% CI: 73.2% to 89.9%) for Q1 (P = 0.002). Similar results were observed in survival analyses adjusting for covariates to estimate fecundability odds ratios (FORs) comparing mtDNAcn in quartiles. Relative to those in Q1 of mtDNAcn, FORs (95% CI) were for Q2 of 0.78 (0.52 to 1.16), Q3 of 0.65 (0.44 to 0.96) and Q4 of 0.55 (0.37 to 0.81), and this trend of decreasing fecundability with increasing mtDNAcn quartile was statistically significant (FOR per log mtDNAcn = 0.37; P < 0.001). Sperm mtDNAdel was not associated with TTP. Limitations, reasons for caution: This prospective cohort study consisted primarily of Caucasian men and women and thus large diverse cohorts are necessary to confirm the associations between sperm mtDNAcn and couple pregnancy success in other races/ethnicities. Wider implications of the findings: Our results demonstrate that sperm mtDNAcn has utility as a biomarker of male reproductive health and probability of pregnancy success in the general population. Study funding/competing interest(s): This work was funded in part by the National Institute of Environmental Health Sciences, National Institutes of Health (R01-ES028298; PI: J.R.P.) and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contracts N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). The authors declare no competing interests. Trial registration number: N/A.

Compliance with daily, home-based collection of urinary biospecimens in a prospective, preconception cohort

Article

Full-text available

Jun 2019

Background: Exposures in the periconceptional environment may impact fertility and future health. Assessing time-varying exposures during the periconceptional window requires identifying approximate fertile windows around ovulation. In this prospective cohort study, we instructed women in daily cervical fluid observation and interpretation to identify incipient ovulation; they used this information to time daily urine collection for both partners. Timing and completeness of collection were compared to expert review. Methods: One hundred seventy couples planning pregnancy enrolled from community volunteers from 2011 to 2015; women were taught the Peak Day method to identify fertile windows. Both partners collected daily urine specimens from the first day of fertile-quality fluid (estimator of the beginning of fertile window). Men discontinued on the estimated day of ovulation/conception +2 days; women continued through the onset of next menses, or positive pregnancy test at estimated day of ovulation/conception +18 days. We compared dates from samples with participants' fertility charts to determine proportion correctly collected. Also, expert reviewers judged on which days urine should have been collected, determining investigator-identified sampling days. Results: One hundred sixty-nine couples submitted 6,118 urine samples from 284 cycles. Reviewers and participants agreed in 87% of cycles for the date of the beginning of the fertile window ±3 days (65% exact-day agreement); agreement on ovulation date, ±3 days, was 93% (75% exact-day agreement). Five thousand three hundred twenty-nine female samples were expected based on investigator-identified sampling days, and 4,546 were collected, of which 82% were correctly collected on expected days. Fifty-nine percent of male samples were correctly collected relative to investigator-identified sampling days. Conclusions: Intensively-scheduled, biologically-triggered, at-home biospecimen collection can successfully be targeted to the periconceptional window and completed in a longitudinal cohort study.

A Model-Based Approach to Detection Limits in Studying Environmental Exposures and Human Fecundity

Article

Jun 2019

Human exposure to persistent environmental pollutants often results in concentrations with a range of values below the laboratory detection limits. Growing evidence suggests that inadequate handling of concentrations below the limit of detection (LOD) may bias assessment of health effects in relation to environmental exposures. We seek to quantify such bias in models focusing on the day-specific probability of pregnancy during the fertile window and propose a model-based approach to reduce such bias. A multivariate skewed generalized t-distribution constrained by the LOD is assumed for the chemical concentrations, which realistically represents the underlying distribution. A latent variable-based framework is used to model fecundibility, which nonlinearly relates conception probability to chemical concentrations, daily intercourses, and other important covariates. The advantages of the proposed approach include the use of multiple chemical concentrations to aid the estimation of left censored chemical exposures, as well as the model-based feedback mechanism for fecundibility outcome to inform the estimations, and an adequate handling of model uncertainty through a joint modeling framework. A Markov chain Monte Carlo sampling algorithm is developed for implementing the Bayesian computations and the logarithm of pseudo-marginal likelihood measure is used for model choices. We conduct simulation studies to demonstrate the performance of the proposed approach and apply the framework to the Longitudinal Investigation of Fertility and the Environment study which evaluates the effects of exposures to environmental pollutants on the probability of pregnancy. We found that p,p′-DDT is negatively associated with the day-specific probability of pregnancy.

Associations between Sperm Epigenetic Age and Semen Parameters: An Evaluation of Clinical and Non-Clinical Cohorts

Article

Full-text available

Feb 2024
CURR ISSUES MOL BIOL

The well-documented relationship between chronological age and the sperm methylome has allowed for the construction of epigenetic clocks that estimate the biological age of sperm based on DNA methylation, which we previously termed sperm epigenetic age (SEA). Our lab demonstrated that SEA is positively associated with the time taken to achieve pregnancy; however, its relationship with semen parameters is unknown. A total of 379 men from the Longitudinal Investigation of Fertility and Environment (LIFE) study, a non-clinical cohort, and 192 men seeking fertility treatment from the Sperm Environmental Epigenetics and Development Study (SEEDS) were included in the study. Semen analyses were conducted for both cohorts, and SEA was previously generated using a machine learning algorithm and DNA methylation array data. Association analyses were conducted via multivariable linear regression models adjusting for BMI and smoking status. We found that SEA was not associated with standard semen characteristics in SEEDS and LIFE cohorts. However, SEA was significantly associated with higher sperm head length and perimeter, the presence of pyriform and tapered sperm, and lower sperm elongation factor in the LIFE study (p < 0.05). Based on our results, SEA is mostly associated with defects in sperm head morphological factors that are less commonly evaluated during male infertility assessments. SEA shows promise to be an independent biomarker of sperm quality to assess male fecundity.

Does Older Age Modify Associations between Endocrine Disrupting Chemicals and Fecundability?

Article

Full-text available

Jun 2022
Int J Environ Res Publ Health

Urinary concentrations of several endocrine disrupting chemicals, including phthalate metabolites, bisphenol A (BPA), and benzophenone (BP)-type ultraviolet (UV) filters, have been associated with a longer time-to-pregnancy (TTP). Potential modification of these associations by couple’s age has not been studied. TTP was defined as the number of prospectively observed menstrual cycles a couple attempted pregnancy until the occurrence of a human chorionic gonadotropic-detected pregnancy. Urinary concentrations of two BP-type UV filters and three phthalate metabolites were measured at baseline. Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated for each chemical adjusting for age, body mass index, serum cotinine, creatinine, and accounting for right censoring and left truncation. Models evaluated effect modification between EDC concentrations and TTP by partner’s age, dichotomized at 35 years. Separate models were run for male and female partners. No significant effect modification was observed for any EDC for either partner, but data were suggestive of a longer TTP among females aged ³35 years, particularly for BP-2 (FOR = 0.61, 95% CI 0.36, 1.05) and 4-hydroxybenzophenone (FOR = 0.71, 95% CI: 0.46, 1.09) reflecting 39% and 29% reductions in fecundability, respectively. We saw no evidence of effect modification by couples’ age on associations between TTP and urinary phthalate or BPA metabolite concentrations. Across the EDCs we examined, we found little evidence that age modifies TTP-exposure associations.

Analyzing Highly Correlated Chemical Toxicants Associated with Time to Pregnancy Using Discrete Survival Frailty Modeling Via Elastic Net

Preprint

Full-text available

Dec 2021

Understanding the association between mixtures of environmental toxicants and time-to-pregnancy (TTP) is an important scientific question as sufficient evidence has emerged about the impact of individual toxicants on reproductive health and that individuals are exposed to a whole host of toxicants rather than an individual toxicant. Assessing mixtures of chemicals effects on TTP poses significant statistical challenges, namely (i) TTP being a discrete survival outcome, typically subject to left truncation and right censoring, (ii) chemical exposures being strongly correlated, (iii) accounting for some chemicals that bind to lipids, (iv) non-linear effects of some chemicals, and (v) high percentage concentration below the limit of detection (LOD) for some chemicals. We propose a discrete frailty modeling framework (named Discnet) that allows selection of correlated exposures while addressing the issues mentioned above. Discnet is shown to have better and stable FN and FP rates compared to alternative methods in various simulation settings. We did a detailed analysis of the LIFE Study, pertaining to polychlorinated biphenyls and time-to-pregnancy and found that older females, female exposure to cotinine (smoking), DDT conferred a delay in getting pregnant, which was consistent across prior sensitivity analyses to account for LOD as well as non-linear associations.

Metal(loid)s and human semen quality: The LIFE Study

Article

Oct 2021

Multiple studies have demonstrated a global population-wide decline in semen quality, with sperm concentrations having fallen 50% over the past 50 years. Several metal and metalloid ("metal(loid)") compounds are known to have testicular toxicity, raising concerns about their contribution to rising infertility. In the male reproductive tract, metal(loid)s can reduce semen quality and disturb function both directly, by inducing tissue damage, and indirectly, by disrupting hormone production and secretion. This study assessed associations between 15 creatinine-adjusted metal(loid)s and 7 measures of semen quality among 413 reproductive-aged men recruited from 16 U.S. counties between 2005-2009. Multi-metal(loid) multivariable linear regression models estimated associations between semen quality endpoints and urinary concentrations of chromium, cobalt, copper, molybdenum, selenium, zinc, antimony, arsenic, barium, cadmium, lead, thallium, tin, tungsten, and uranium. LASSO regression was employed to select model variables and account for multicollinearity of the metal(loid)s. A positive association was observed between tin and sperm morphology (β = 4.92 p = 0.045). Chromium (β = 1.87, p = 0.003) and copper (β= -1.30, p = 0.028) were positively and negatively associated with total sperm count, respectively. With respect to DNA fragmentation, cadmium (β = 12.73, p = 0.036) was positively associated and chromium was negatively associated (β = -5.08, p = 0.001). In this cohort of U.S. population-based men, there was evidence of both positive and negative associations between specific metal(loid)s and semen quality. Additional research is needed to determine interactions between metal(loid)s within a mixture, consistent with typical human exposure, and identify sperm effects resulting from cumulative metal(loid) exposures.

Changes in Behavior with Increasing Pregnancy Attempt Time: A Prospective Cohort Study

Article

May 2020
EPIDEMIOLOGY

Background: The extent to which couples change their behaviors with increasing pregnancy attempt time is not well documented. Methods: We examined change in selected behaviors over pregnancy attempt time in a North American preconception cohort study. Eligible females were aged 21-45 years and not using fertility treatment. Participants completed baseline and bimonthly follow-up questionnaires for up to 12 months or until pregnancy. Results: Among 3,339 females attempting pregnancy for 0-1 cycles at enrollment, 250 contributed 12 months of follow-up without conceiving. Comparing behaviors at 12 months versus baseline, weighted for loss-to-follow-up, we observed small-to-moderate reductions in mean caffeine intake (-19.5 mg/day, CI: -32.7, -6.37), alcohol intake (-0.85 drinks/week, CI: -1.28, -0.43), marijuana use (-3.89 percentage points, CI: -7.33, 0.46), and vigorous exercise (-0.68 hours/week, CI: -1.05, -0.31), and a large increase in activities to improve conception chances (e.g., ovulation testing) (21.7 percentage points, CI: 14.8, 28.6). There was little change in mean cigarette smoking (-0.27 percentage points, CI: -1.58, 1.04), perceived stress scale score (-0.04 units, CI: -0.77, 0.69), or other factors (e.g., sugar-sweetened soda intake, moderate exercise, intercourse frequency, and multivitamin use), but some heterogeneity within subgroups (e.g., 31% increased and 32% decreased their perceived stress scores by ≥2 units; 14% reduced their smoking but none increased their smoking by ≥5 cigarettes/day). Conclusions: While many behaviors changed with increasing pregnancy attempt time, mean changes tended to be modest for most variables. The largest differences were observed for use of caffeine, alcohol, and marijuana, and methods to improve conception chances.

At‐home sperm testing for epidemiologic studies: Evaluation of the Trak male fertility testing system in an internet‐based preconception cohort

Article

Dec 2019

Background: Semen quality assessment in population-based epidemiologic studies presents logistical and financial challenges due to reliance on centralised laboratory semen analysis. The Trak Male Fertility Testing System is an FDA-cleared and validated at-home test for sperm concentration and semen volume, with a research use only sperm motility test. Here we evaluate the Trak System's overall utility among men participating in Pregnancy Study Online (PRESTO), a web-based study of North American couples planning pregnancy. Methods: US male participants aged ≥21 years with ≤6 months of pregnancy attempt time at study enrolment were invited to participate in the semen testing substudy after completing their baseline questionnaire. Consenting participants received a Trak Engine (battery-powered centrifuge) and two test kits. Participants shared their test results via smartphone images uploaded to online questionnaires. Data were then linked with covariate data from the baseline questionnaire. Results: Of the 688 men invited to participate, 373 (54%) provided consent and 271 (73%) completed at least one semen test result. The distributions of semen volume, sperm concentration, motile sperm concentration, total sperm count, and total motile sperm count were similar to 2010 World Health Organization (WHO) semen parameter data of men in the general population. The overall usability score for the Trak System was 1.4 on a 5-point Likert scale (1 = Very Easy, 5 = Difficult), and 92% of participants believed they performed the test correctly and received an accurate result. Lastly, men with higher motile sperm count were more likely to report feeling "at ease" or "excited" following testing, while men with low motile sperm count were more likely to report feeling "concerned" or "frustrated." Overall, 91% of men reported they would like to test again. Conclusions: The Trak System provides a simple and potentially cost-effective means of measuring important semen parameters and may be useful in population-based epidemiologic fertility studies.

A Bayesian regularized mediation analysis with multiple exposures

Article

Oct 2018

Mediation analysis assesses the effect of study exposures on an outcome both through and around specific mediators. While mediation analysis involving multiple mediators has been addressed in recent literature, the case of multiple exposures has received little attention. With the presence of multiple exposures, we consider regularizations that allow simultaneous effect selection and estimation while stabilizing model fit and accounting for model selection uncertainty. In the framework of linear structural‐equation models, we analytically show that a two‐stage approach regularizing regression coefficients does not guarantee a unimodal posterior distribution and that a product‐of‐coefficient approach regularizing direct and indirect effects tends to penalize excessively. We propose a regularized difference‐of‐coefficient approach that bypasses these limitations. Using the connection between regularizations and Bayesian hierarchical models with Laplace prior, we develop an efficient Markov chain Monte Carlo algorithm for posterior estimation and inference. Through simulations, we show that the proposed approach has better empirical performances compared to some alternatives. The methodology is illustrated using data from two epidemiological studies in human reproduction.

A Bayesian Multi-Dimensional Couple-Based Latent Risk Model with an Application to Infertility

Article

Sep 2018

Motivated by the Longitudinal Investigation of Fertility and the Environment (LIFE) Study that investigated the association between exposure to a large number of environmental pollutants and human reproductive outcomes, we propose a joint latent risk class modeling framework with an interaction between female and male partners of a couple. This formulation introduces a dependence structure between the chemical patterns within a couple and between the chemical patterns and the risk of infertility. The specification of an interaction enables the interplay between the female and male's chemical patterns on the risk of infertility in a parsimonious way. We took a Bayesian perspective to inference and used Markov chain Monte Carlo algorithms to obtain posterior estimates of model parameters. We conducted simulations to examine the performance of the estimation approach. Using the LIFE Study dataset, we found that in addition to the effect of PCB exposures on females, the male partners' PCB exposures play an important role in determining risk of infertility. Further, this risk is subadditive in the sense that there is likely a ceiling effect which limits the probability of infertility when both partners of the couple are at high risk. This article is protected by copyright. All rights reserved

User Embedding Long Short-Term Model Based Fecundity Prediction Model Using Proposed Fecundity Dataset

Article

Full-text available

Feb 2023

Fecundity prediction is a process that helps couples to understand their fertility status. Fecundity prediction as a domain could be supported by developed intelligent models using a computational method and fecundity data. Although fecundity data and models have been proposed, the problem of low data size and dimensionality of the proposed fecundity dataset has been identified due to the data collection approaches used and the problem of using a weak subfertility definition in the development of a User-embedding LSTM-based fecundity prediction model. To solve the identified problems, this study proposed a fecundity dataset by adopting a hybrid data collection approach using the strengths and disregarding the setbacks of existing data collection approaches and then proposed an improved User-embedding LSTM-based fecundity prediction model based on an improved subfertility definition. A large size fecundity dataset was generated and used for the implementation and evaluation of the existing and proposed LSTM-based fecundity prediction models and the proposed model generated better AUC-ROC evaluation results

Design and Methods of the Apple Women’s Health Study: A Digital Longitudinal Cohort Study

Article

Full-text available

Oct 2021
AM J OBSTET GYNECOL

Background Prospective longitudinal cohorts assessing women’s health and gynecologic conditions have been historically limited. Objectives The Apple Women’s Health Study was designed to gain a deeper understanding of the relationship between menstrual cycles, health, and behaviors. This paper describes the design and methods of the ongoing Apple Women’s Health Study and provides demographic characteristics of the first 10,000 participants. Study Design Mobile-application based longitudinal cohort study with survey and sensor-based data. We collected data from 10,000 participants who responded to the demographics survey upon enrollment between November 14, 2019 and May 20, 2020. Participants were asked to complete a monthly follow-up through November 2020. Eligibility criteria include having ever menstruated, installing the Apple Research app on iPhone with iOS version 13.2 or later, living in USA, age of 18 years or older in most states (19 years old in Alabama and Nebraska, 21 years old in Puerto Rico), proficiency in written and spoken English, sole user of an iCloud account or iPhone, and providing informed consent to participate in the study. Results Mean age at enrollment was 33.6 years old (+/- standard deviation 10.3). Race/ethnicity was representative of the US population [69% White/Non-Hispanic (6,910/10,000)], while 51% (5,089/10,000) had a college education or above. Participant geographic distribution included all U.S. states and Puerto Rico. Seventy-two percent (7,223/10,000) reported use of an Apple Watch, and 24.4% (2,438/10,000) consented to sensor-based data collection. For this cohort, 38% (3,490/9,238) did not respond to the Monthly Survey: Menstrual Update after enrollment. At the six-month follow-up there was a 35% (3,099/8,972) response rate to the Monthly Survey: Menstrual Update. 82.7% (8,266/10,000) of the initial cohort and 95.1% (2,948/3,099) of participants who responded to month 6 of the Monthly Survey: Menstrual Update, tracked at least one menstrual cycle via HealthKit. Participants tracked menstrual bleeding days an average of 4.44 (25-75% range: 3 - 6) calendar months during the study period. Non-White participants were slightly more likely to drop out than White participants; those remaining at 6 months were otherwise similar in demographic characteristics to the original enrollment group. Conclusions The first 10,000 participants of the Apple Women’s Health Study were recruited via the Research app and were diverse in race/ethnicity, educational attainment, and economic status, despite all using an Apple iPhone. Future studies within this cohort incorporating this high-dimensional data may facilitate discovery in women’s health in exposure outcome relationships and population-level trends among iPhone users. Retention efforts centered around education, communication, and engagement will be utilized to improve survey response rates, such as the study update feature.

Population Attributable Fractions of Caffeine and Water Pipe on low birth weight: The Bandar-Abbas Population-based Cohort in suburban areas

Preprint

Full-text available

Sep 2021

Background: Low Birth Weight (LBW) poses a major health challenge in low-resource suburban communities. Despite relatively commonality, there is little evidence on the effects of water pipe and dietary caffeine on reproductive outcomes in the Middle-East region. The Bandar Abbas Pregnancy Cohort (BAPC), as a population-based prospective study, has been investigating the effects of lifestyle and environmental factors on maternal wellbeing and child growth and development in suburban communities in the south of Iran. This study used the BAPC data to estimate the attribution of LBW incidence to fully or partially removal of dietary caffeine intake and water pipe smoking during pregnancy. Methods: ‎The present study used data on 861 live singleton pregnancies in the first two BAPC visits (response rate= 95.42%). Water pipe smoking (yes/no) was measured during pregnancy using a structured checklist recommended by the World Health Organization (WHO). Dietary caffeine intake was measured during pregnancy using a structured checklist and categorized into low for 0-99 mg/day, and high for>100 mg/day. LBW (yes/no) was determined using recorded birth weight in infant`s vaccination card. Exposure relative risks were calculated using Modified Poisson regression models. Population Attributable Fractions (PAFs) and Generalized Impact Fractions (GIFs) were calculated on relative risk scale. The prevalence of counter fact was set as 3% for water pipe smokers and 14.9% for intake of >100 mg/day caffeine. Results: The cumulative incidence of LBW was 16.1%. An estimated 19% (95%CI: 6, 30%) and 11% (95%CI: 8, 14%) of LBW were attributed to high intake of dietary caffeine and water pipe smoking, respectively. Reducing the intake of caffeine to less than 100 mg/day or prevalence of water pipe to 3% would prevent 10.7% (95%CI: 6.6, 25.3%) and 5.7% ‎‎(95%CI: ‎5.0, 6.8%) of LBW incidence, respectively. ‎Conclusions: Our findings have provided evidence on quantitative contributions of caffeine and water pipe on LBW using real-world data. Integration of this information into practical action plans to prevent LBW is the next step in our cohort project. Furthermore, to get an overarching picture and in-depth understanding of reproductive effects of caffeine and water pipe, exercising this study`s analytic approach in other contexts is encouraged.

A multi-pollutant assessment of preconception persistent endocrine disrupting chemicals and incident pregnancy loss

Article

Dec 2021
ENVIRON INT

Background A few endocrine disrupting chemicals (EDCs) have been associated with pregnancy loss often as reported by women, though there has been no study of EDC mixtures and pregnancy loss in keeping with the nature of human exposure. Objectives To investigate preconception exposure to a mixture of EDCs to identify important drivers and inform multi-pollutant models of EDCs in relation to incident human gonadrophin chorionic (hCG) pregnancy loss. Methods A cohort of 501 couples were recruited from the general population and prospectively followed until a hCG-confirmed pregnancy or 12 months of trying to become pregnant. Pregnant (n = 344; 69%) women were followed daily through seven weeks post-conception then monthly until delivery. Loss was defined as conversion to negative pregnancy test or a clinical diagnosis. Preconception exposure assessment of EDCs included sixty-three serum chemicals and three blood metals. EDCs were measured using isotope dilution gas chromatography-high resolution mass spectrometry or high-performance liquid chromatography-tandem mass spectrometry, and inductively coupled plasma-mass spectrometry, respectively. Using elastic net variable selection to identify important factors from the exposure mixture, EDC levels and covariates were then included in Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of time-to-pregnancy loss in multi-pollutant models. Results Incidence of hCG pregnancy loss was 28%. Nine EDCs of the sixty-six chemical mixture were associated with pregnancy loss; HRs were elevated for polychlorinated biphenyl 194, 2-(N-methyl-perfluorooctane sulfonamido) acetate, polybrominated diphenyl ether 28, and cadmium, even in sensitivity models adjusting for male partners’ EDC concentrations. In final multivariable multi-pollutant Cox proportional hazard models, female partners’polybrominated diphenyl ether 28 (aHR = 1.16, 95% CI: 1.02, 1.31) and cadmium (aHR = 1.23, 95% CI: 1.07, 1.40) remained associated with hCG pregnancy loss. Female partners’ preconception serum polychlorinated biphenyl 194 and 2-(N-methyl-perfluorooctane sulfonamido) acetate concentrations were consistently inversely associated with loss [(aHR = 0.72, 95% CI: 0.56, 0.92) and (aHR = 0.79, 95% CI: 0.65, 0.95), respectively]. Conclusion Assessing exposure to a mixture of 66 persistent EDCs, females’ preconception concentrations of polybrominated diphenyl ether 28 and cadmium were positively associated with incident hCG pregnancy loss in a cohort of couples from the general population trying for pregnancy.

Population Attributable Fractions of Caffeine and Water Pipe on Low Birth Weight: A Population-Based Prospective Cohort Study in Iran

Preprint

Full-text available

Nov 2020

Background To estimate Population Attributable Fractions (PAFs) and Generalized Impact Fractions (GIFs) for LBW following scenarios to remove or decrease prenatal use of caffeine or water pipe.Methods‎Using data of 861 pregnant women from a population-based prospective cohort study ‎in suburbs of Bandar Abbas city (2016-2018), PAFs and GIFs were calculated based on the relative risk scale. Practical interventional scenarios to reduce the exposure prevalence were developed for calculation of GIFs. ResultsThe cumulative incidence of LBW was 16.1%. An estimated 19% (95%CI: 6, 30%) of LBW neonates was attributed to dietary caffeine intake of > 100 mg/day and 11% (95%CI: 8,14%) to water pipe smoking. Action plans to reduce caffeine intake and water pipe smoking suggested an avoidable burden of LBW cases of approximately 10.7% (95% CI: 6.6, 25.3%) and 5.7% ‎‎(95%CI: ‎5.0, 6.8%), respectively.‎Conclusions Water pipe smoking and excessive consumption of caffeine during pregnancy decreased birth weight. Practical action plans to control water pipe smoking ‎and to prevent excessive intake of ‎caffeine ‎among pregnant women would substantially reduce LBW burden in the south of Iran.

Using methylome data to inform exposome-health association studies: An application to the identification of environmental drivers of child body mass index

Article

Full-text available

May 2020
ENVIRON INT

Background The exposome is defined as encompassing all environmental exposures one undergoes from conception onwards. Challenges of the application of this concept to environmental-health association studies include a possibly high false-positive rate. Objectives We aimed to reduce the dimension of the exposome using information from DNA methylation as a way to more efficiently characterize the relation between exposome and child body mass index (BMI). Methods Among 1,173 mother–child pairs from HELIX cohort, 216 exposures (“whole exposome”) were characterized. BMI and DNA methylation from immune cells of peripheral blood were assessed in children at age 6–10 years. A priori reduction of the methylome to preselect BMI-relevant CpGs was performed using biological pathways. We then implemented a tailored Meet-in-the-Middle approach to identify from these CpGs candidate mediators in the exposome-BMI association, using univariate linear regression models corrected for multiple testing: this allowed to point out exposures most likely to be associated with BMI (“reduced exposome”). Associations of this reduced exposome with BMI were finally tested. The approach was compared to an agnostic exposome-wide association study (ExWAS) ignoring the methylome. Results Among the 2284 preselected CpGs (0.6% of the assessed CpGs), 62 were associated with BMI. Four factors (3 postnatal and 1 prenatal) of the exposome were associated with at least one of these CpGs, among which postnatal blood level of copper and PFOS were directly associated with BMI, with respectively positive and negative estimated effects. The agnostic ExWAS identified 18 additional postnatal exposures, including many persistent pollutants, generally unexpectedly associated with decreased BMI. Discussion Our approach incorporating a priori information identified fewer significant associations than an agnostic approach. We hypothesize that this smaller number corresponds to a higher specificity (and possibly lower sensitivity), compared to the agnostic approach. Indeed, the latter cannot distinguish causal relations from reverse causation, e.g. for persistent compounds stored in fat, whose circulating level is influenced by BMI.

Effect of a Home Pregnancy Test Intervention on Cohort Retention and Pregnancy Detection: A Randomized Trial

Article

Mar 2020

We conducted a parallel non-blinded randomized trial to assess whether offering home pregnancy tests (HPT) to preconception cohort study participants influenced cohort retention or pregnancy detection. Pregnancy Study Online (PRESTO) participants were female, aged 21-45 years, attempting pregnancy, and not using fertility treatment. At enrollment (2017-2018), 1,493 participants with ≤6 cycles of attempt time were randomized with 50% probability to receive Clearblue visual HPTs plus the standard protocol (N=720) or the standard protocol (N=773). Women completed bimonthly questionnaires for 12 months or until conception, whichever came first. In intent-to-treat analyses, retention (≥1 follow-ups) was higher in the HPT arm (N=598; 83%) than the standard protocol arm (N=535; 69%) (mean difference=15%, 95% CI: 10%, 19%). Mean time at first pregnancy testing was identical in both arms (2 days before expected menses), as was mean gestational weeks at first positive pregnancy test (4 weeks). Conception was reported by 78% in the HPT arm and 75% in the standard protocol arm. Spontaneous abortion was reported by 21% in the HPT arm (mean gestational weeks=7) and 21% in the standard protocol arm (mean gestational weeks=6). Randomization of HPTs was associated with greater cohort retention, but had little impact on incidence or timing of pregnancy detection.

Urinary phytoestrogens and menstrual cycle length and variability among healthy, eumenorrheic women

Article

Full-text available

Dec 2019

Context Phytoestrogens may influence fecundability, though biological mechanisms remain elusive. Since it is hypothesized that phytoestrogens may act through influencing hormone levels, we investigated associations between phytoestrogens and menstrual cycle length, a proxy for the hormonal milieu, in healthy women attempting pregnancy. Design A population-based prospective cohort of 326 women ages 18-40 with self-reported cycles 21-42 days were followed until pregnancy or for 12 months of attempting pregnancy. Methods Urinary genistein, daidzein, O-desmethylangolensin, equol, enterodiol, and enterolactone were measured upon enrollment. Cycle length was determined from fertility monitors and daily journals. Linear mixed models assessed associations with continuous cycle length and were weighted by the inverse number of observed cycles. Logistic regression models assessed menstrual regularity (standard deviation >75th vs. ≤75th percentile). Models were adjusted for age, BMI, race, creatinine, exercise, supplements, lipids, lead, cadmium, cotinine, parity, alcohol, and other phytoestrogens. Results Individual phytoestrogens were not associated with cycle length, though total phytoestrogens were associated with shorter cycles (-0.042 days, 95% confidence interval [CI] -0.080, -0.003, per 10% increase). Each 1 nmol/L increase in enterolactone (odds ratio [OR] 0.88, 95% CI 0.79, 0.97) and total lignans (OR 0.85, 95% CI 0.76, 0.95) was associated with reduced irregularity, and each 1 nmol/L increase in genistein with irregularity (OR 1.19, 95% CI 1.02, 1.38). Conclusion Phytoestrogens were not meaningfully associated with cycle length, though may be associated with menstrual regularity, among women with self-reported regular cycles. These results highlight differences between isoflavones and lignans and are reassuring for women attempting pregnancy.

Phthalate exposure and female reproductive and developmental outcomes: a systematic review of the human epidemiological evidence

Article

Full-text available

Sep 2019
ENVIRON INT

Objective: We performed a systematic review of the epidemiology literature to identify the female reproductive and developmental effects associated with phthalate exposure. Data sources and study eligibility criteria: Six phthalates were included in the review: di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of female reproductive and developmental effects in humans, and outcomes were selected for full systematic review based on data availability. Study evaluation and synthesis methods: For each outcome, studies were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. Results: The primary outcomes reviewed here are (number of included/excluded studies in parentheses): pubertal development (5/13), time to pregnancy (3/4), preterm birth (8/12), and spontaneous abortion (5/0). Among these outcomes, preterm birth had moderate evidence of a positive association with phthalate exposure (specifically DEHP, DBP, and DEP). Exposure levels for BBP, DIBP, and DINP were generally lower than for the phthalates with an observed effect, which may partially explain the difference due to lower sensitivity. Other phthalate/outcome combinations were considered to have slight or indeterminate evidence of an association. Conclusions and implications of key findings: Overall, these results support that some phthalates may be associated with higher odds of preterm birth in humans, though there is some remaining inconsistency. More evidence is needed on the mechanism and relevant exposure window for this association. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.

Pregnancy Loss and Iodine Status: The LIFE Prospective Cohort Study

Article

Full-text available

Mar 2019

Iodine deficiency in pregnancy is a common problem in the United States and parts of Europe, but whether iodine deficiency is associated with increased pregnancy loss has not been well studied. The LIFE study provided an excellent opportunity to examine the relationship between iodine status and pregnancy loss because women were monitored prospectively to ensure excellent ascertainment of conceptions. The LIFE study, a population-based prospective cohort study, monitored 501 women who had discontinued contraception within two months to become pregnant; 329 became pregnant, had urinary iodine concentrations measured on samples collected at enrollment, and were followed up to determine pregnancy outcomes. Of the 329, 196 had live births (59.5%), 92 (28.0%) had losses, and 41 (12.5%) withdrew or were lost to follow up. Urinary iodine concentrations were in the deficiency range in 59.6% of the participants. The risk of loss, however, was not elevated in the mildly deficient group (hazard ratio 0.69, 95% confidence interval 0.34, 1.38), the moderately deficient group (hazard ratio 0.81, 95% confidence interval 0.43, 1.51), or the severely deficient group (hazard ratio 0.69, 95% confidence interval 0.32, 1.50). Iodine deficiency, even when moderate to severe, was not associated with increased rates of pregnancy loss. This study provides some reassurance that iodine deficiency at levels seen in many developed countries does not increase the risk of pregnancy loss.

Opportunities and challenges for population-based studies investigating the effects of air pollution on pregnancy loss

Article

Feb 2019
FERTIL STERIL

Exposome-wide association study of semen quality: Systematic discovery of endocrine disrupting chemical biomarkers in fertility require large sample sizes

Article

Full-text available

Dec 2018
ENVIRON INT

Objectives: Exposome-wide association studies (EWAS) are a systematic and unbiased way to investigate multiple environmental factors associated with phenotype. We applied EWAS to study semen quality and queried the sample size requirements to detect modest associations in a reproductive cohort. Study design and setting: We conducted 1) a multivariate EWAS of 128 endocrine disrupting chemicals (EDCs) from 15 chemical classes measured in urine/serum relative to 7 semen quality endpoints in a prospective cohort study comprising 473 men and 2) estimated the sample size requirements for EWAS etiologic investigations. Results: None of the EDCs were associated with semen quality endpoints after adjusting for multiple tests. However, several EDCs (e.g., polychlorinated biphenyl congeners 99, 105, 114, and 167) were associated with raw p < 0.05. In a post hoc statistical power analysis with the observed effect sizes, we determined that EWAS research in male fertility will require a mean sample size of 2696 men (1795-3625) to attain a power of 0.8. The average size of four published studies is 201 men. Conclusion: Existing cohort studies with hundreds of participants are underpowered (<0.8) for EWAS-related investigations. Merging cohorts to ensure a sufficient sample size can facilitate the use of EWAS methods for assessing EDC mixtures that impact semen quality.

Phthalate exposure and male reproductive outcomes: A systematic review of the human epidemiological evidence

Article

Full-text available

Dec 2018
ENVIRON INT

Objective We performed a systematic review of the epidemiology literature to identify the male reproductive effects associated with phthalate exposure. Data sources and study eligibility criteria Six phthalates were included in the review: di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of male reproductive effects in humans, and outcomes were selected for full systematic review based on data availability. Study evaluation and synthesis methods For each outcome, studies were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. Results The primary outcomes reviewed here are (number of included/excluded studies in parentheses): anogenital distance (6/1), semen parameters (15/9), time to pregnancy (3/5), testosterone (13/8), timing of pubertal development (5/15), and hypospadias/cryptorchidism (4/10). Looking at the overall hazard, there was robust evidence of an association between DEHP and DBP exposure and male reproductive outcomes; this was based primarily on studies of anogenital distance, semen parameters, and testosterone for DEHP and semen parameters and time to pregnancy for DBP. There was moderate evidence of an association between DINP and BBP exposure and male reproductive outcomes based on testosterone and semen parameters for DINP and semen parameters and time to pregnancy for BBP. DIBP and DEP were considered to have slight evidence of an association. For DIBP, the less conclusive evidence was attributed to a more limited literature base (i.e., fewer studies) and lower exposure levels in the population, decreasing the ability to observe an effect. For DEP, the findings were consistent with experimental animal data that suggest DEP does not haves as strong an anti-androgenic effect as other phthalates. Conclusions and implications of key findings Overall, despite some inconsistencies across phthalates in the specific outcomes associated with exposure, these results support that phthalate exposure at levels seen in human populations may have male reproductive effects, particularly DEHP and DBP. The relative strength of the evidence reflects differing levels of toxicity as well as differences in the range of exposures studied and the number of available studies. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.

Preconception Seminal Plasma Concentrations of Endocrine Disrupting Chemicals in Relation to Semen Quality Parameters among Male Partners Planning for Pregnancy

Article

Jul 2018

Background: Some non-persistent endocrine disruptors (EDCs) are adversely associated with semen quality and few studies have measured those EDCs in seminal plasma. Objective: To find an association between EDCs in seminal plasma and semen quality parameters. Methods: Five chemical classes of non-persistent EDCs were quantified in seminal plasma from 339 male partners who participated in a prospective pregnancy study. Bisphenols, benzophenone UV-filters, antimicrobials and phthalate diesters and their monoester metabolites were measured using high performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Semen samples underwent next day analysis using a standardized protocol for the quantification of 35 endpoints. Linear mixed-effects models of EDCs that were log transformed and rescaled by their standard deviations or dichotomized at the 75th percentile for each exposure and outcomes with covariate adjustment were performed. EDCs in seminal plasma were also assessed relative to clinical reference values of semen quality endpoints using logistic regression or generalized estimating equations. Results: The most consistent findings supporting adverse associations between seminal EDCs and semen quality were observed for some phthalate metabolites. For example, seminal plasma mono-ethyl, mono-n-butyl, mono-2-isobutyl and mono-benzyl phthalate concentrations were associated with decreased odds of having semen volume above clinical reference values (mEP: aOR=0.46; 95%CI= 0.32, 0.66; mBP: aOR=0.40; 95%CI= 0.28, 0.57; miBP: aOR=0.39; 95%CI= 0.27, 0.56), and mBzP: aOR= 0.34; 95%CI= 0.24, 0.49). Conclusions: Environmentally relevant concentrations of specific phthalates in seminal plasma were associated with diminished semen volume, sperm motility, viability, and morphological alterations in sperm heads such that semen volume and sperm viability fall below reference values.

Seafood Intake, Sexual Activity, and Time to Pregnancy

Article

May 2018

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 may 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 (2005-2009) and were followed for up to1 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 time to pregnancy as determined by an in-home pregnancy test. A secondary outcome was sexual intercourse frequency (SIF) as recorded in daily journals. Results Couples where the male and female partners consumed ≥8 seafood servings/cycle had 47% (95% CI 7, 103%) and 60% (95% CI 15, 122%) higher fecundity (shorter TTP) compared to couples with male and female partners who consumed ≤1 seafood serving/cycle, respectively. Couples in which both partners consumed ≥8 seafood servings/cycle had 61% (95% CI 17, 122%) higher fecundity compared to couples consuming less. Male and female partners with the highest seafood intake (≥8 servings/cycle) also had 22% higher SIF. Conclusions Higher male and female seafood intake was associated with higher frequency of sexual intercourse and fecundity among a large prospective cohort of couples attempting pregnancy.

A Population-based Prospective Study to Identify Contributors to Mother and Child Health in Suburban Communities: The Cohort Profile

Article

Full-text available

Mar 2018

Background Following community health assessment Project (CHAP) in suburbs of Bandar Abbas city, health problems in women and children such as pregnancy complications and infant/child impaired growth are highly prevalent. Therefore, the present population-based prospective cohort study investigated the effects of a wide range of modifiable exposures during pregnancy and postpartum on mother and child health. Methods The sample comprised of 1000 pregnant women in their first gestational trimester, who live in the three most socially and economically vulnerable neighborhoods of Bandar Abbas, are under recruitment during Feb 2016–18. Four structured questionnaires are being carried out from pregnancy to 30 d, 6 months, and 12 months postpartum. Biologic and ultrasound results are also gathered through hospital and health center records. The study is currently close to the end of the recruitment phase. Conclusion The results of the interim and final analyses are being translated into applicable preventive action plans aiming to reduce and control modifiable risk factors for ill-health in mothers and children in suburb communities in South of Iran.

Predictors of Sexual Intercourse Frequency Among Couples Trying to Conceive

Article

Mar 2018

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;XX:XXX-XXX.

Biomarkers of preconception stress and the incidence of pregnancy loss

Article

Feb 2018
HUM REPROD

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.

Male Urinary Biomarkers of Antimicrobial Exposure and Bi-directional Associations with Semen Quality Parameters

Article

Feb 2018
REPROD TOXICOL

The Environment and Reproductive Health (EARTH) Study: A Prospective Preconception Cohort

Article

Full-text available

Feb 2018

Background: The Environment and Reproductive Health (EARTH) Study is an ongoing prospective preconception cohort designed to investigate the impact of environmental, nutritional, and lifestyle factors among both women and men on fertility and pregnancy outcomes. Methods: The EARTH Study recruits women 18 to 45 years and men 18 to 55 years seeking fertility evaluation and treatment at the Massachusetts General Hospital (MGH) Fertility Center, Boston, USA. Women and men are eligible to join either independently or as a couple. Participants are followed from study entry throughout each fertility treatment cycle, once per trimester of pregnancy (for those achieving pregnancy), and up to labor and delivery, or until they discontinue treatment or withdraw from the study. The study collects biological samples, self-reported questionnaire data (including a food frequency questionnaire) and clinically abstracted information. Results: As of June 2017, the study cohort included 799 women and 487 men (447 couples; 40 men joined without female partners). Women were on average 34.7 years old at time of enrolment and predominantly Caucasian (81%), educated (49% have a graduate degree), and nulliparous (83%). Men were on average 36.6 years at baseline and mostly Caucasian (86%) and never-smokers (67%). Conclusions: The EARTH Study is one of the few cohorts designed to examine multiple potentially critical windows of vulnerability, including the paternal and maternal preconception windows and the periconception and prenatal windows in pregnancy. It is also one of the few human studies that has assessed potential interactions between environmental exposures and dietary factors.

Endocrine disrupting chemicals in seminal plasma and couple fecundity

Article

Feb 2018
ENVIRON RES

Growing evidence supports the importance of men's exposure to non-persistent endocrine disruptors (EDCs) and couple fecundability, as measured by time-to-pregnancy (TTP). This evolving literature contrasts with the largely equivocal findings reported for women's exposures and fecundity. While most evidence relies upon urinary concentrations, quantification of EDCs in seminal plasma may be more informative about potential toxicity arising within the testes. We analyzed 5 chemical classes of non-persistent EDCs in seminal plasma for 339 male partners of couples who were recruited prior to conception and who were followed daily until pregnant or after one year of trying. Benzophenones, bisphenols, parabens, and phthalate metabolites and phthalate diesters were measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) except for phthalate diesters, which were analyzed using gas chromatography-mass spectrometry. Cox regression with discrete-time was used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) for each chemical to estimate the probability of pregnancy. While most EDCs were detected in seminal plasma, concentrations were lower than urinary concentrations previously analyzed for the cohort. None of the EDCs were significantly associated with fecundability even after covariate adjustment, though benzophenones consistently yielded FORs <1.0 (ranging from 0.72 to 0.91) in couple-adjusted models suggestive of diminished fecundity (longer TTP). The findings underscore that a range of EDCs can be quantified in seminal plasma, but the lower concentrations may require a large cohort for assessing couple fecundability, as well as the need to consider other fecundity outcomes such as semen quality.

Atmospheric pollution and Human reproduction.

Thesis

Feb 2017

Lise Giorgis-Allemand

A large fraction of the population is exposed to atmospheric pollution, which has known effects on cardiovascular and respiratory mortality and morbidity and probable effect on birthweight and fetal growth. So far, the biological aptitude to conceive for couples -fecundity- and the female markers of fecundity have been seldom studied in relation with this environmental exposure.The aim of this PhD was to quantify the possible association between atmospheric pollution and specific health outcomes related to human reproduction: menstrual cycle characteristics, probability of pregnancy and preterm birth risk. We relied on a population of couples not using any contraceptive method (Observatory of Fecundity in France) and on 13 birth cohorts participating in the European Study of Cohorts for Air Pollution Effects.We observed that higher levels of atmospheric pollutants during the 30 days before the start of a menstrual cycle were associated with longer follicular phase (n=158, β=1.6 days per each increase by 10 µg/m3 in particulate matters with an aerodynamical diameter of less than 10 µm -PM10; 95% confidence interval: 0.3;2.9). In the population recruited in OBSEFF study, we observed a trend for an increased time to pregnancy with short-term NO2 and PM10 levels in an original approach relying on two seldom used study designs focusing on a marker of fecundity in parallel: the prevalent cohort approach (n=468, hazard ratio of pregnancy, HR: 0.69 per each increase by 10 µg/m3 in PM10 during the 70 days before the inclusion, with a 95% CI of 0.43;1.12) and the current duration approach (n=516, median current duration of unprotected intercourse multiplied by 1.29 per each increase by 10 µg/m3 in PM10 during the 70 days before the contraception stop, 95% CI: 0.97;1.70). In the cohorts included in ESCAPE, preterm delivery risk studied by a survival model with time-dependent exposures was not associated with atmospheric pollutants levels during pregnancy (n=46,791, OR=0.97 per each increase by 10 µg/m3 in PM10 during the whole pregnancy, 95% CI 0.87;1.7). We observed an increased risk of preterm birth with higher atmospheric pressure during the first trimester of pregnancy and to some extent with temperature between -5°C and 10°C during the first trimester of pregnancy. We additionally showed that using exposure windows with different durations between cases and non-cases is a source of a bias in preterm birth studies that may impact several studies in the literature.This work demonstrated that using a survival model with time-dependent exposures is crucial to study preterm delivery risk. It appeals for additional research on the possible adverse effects of atmospheric pollution on menstrual cycle and fecundity, as our studies are among the first ones conducted in a general population on those topics.

Delayed conception in women with low-urinary iodine concentrations: A population-based prospective cohort study

Article

Jan 2018
HUM REPROD

Study question: Is iodine deficiency associated with decreased fecundability? Summary answer: Moderate to severe iodine deficiency is associated with a 46% decrease in fecundability. What is known already: Iodine deficiency is common in women of childbearing age but its effect on fecundability has not been investigated. Study design, size, duration: The LIFE Study, a population-based prospective cohort study, enrolled 501 women who had discontinued contraception within 2 months to become pregnant between 2005 and 2009. Participants/materials, setting, methods: Women reported on risk factors for infertility by interview then kept daily journals of relevant information. Women used fertility monitors to time intercourse relative to ovulation then used home digital pregnancy tests to identify pregnancies on the day of expected menstruation. Urine samples for iodine analysis were collected on enrollment. Main results and the role of chance: Samples were in the deficiency range in 44.3% of participants. The group whose iodine-creatinine ratios were below 50 μg/g (moderate to severe deficiency) had a 46% reduction in fecundity (P = 0.028) compared with the group whose iodine-creatinine ratios were in the adequate range: adjusted fecundability odds ratio of becoming pregnant per cycle, 0.54 (95% confidence interval 0.31-0.94). Limitations, reasons for caution: Iodine concentrations vary within individuals over time, so the data must be interpreted by group as we have done; residual confounding is possible. Wider implications of the findings: Significant delays in becoming pregnant occur at iodine concentrations that are common in women in the USA and parts of Europe. Replicating these findings will be important to determine whether improving iodine status could be beneficial in improving fecundability. Study funding/competing interest(s): This study was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA. Contracts N01-HD-3-3355; N01-HD-3-3356; N01-HD-3-3358 and HHSN275201100001l/HHSN27500007. None of the authors has any conflict of interest to declare.

Latent class modeling approaches for studying the effects of chemical mixtures on disease risk

Chapter

Jan 2024

Assessing preconception exposure to environmental chemicals and fecundity: Strategies, challenges, and research priorities

Article

Mar 2024
REPROD TOXICOL

Optimizing Preconception Care and Interventions for Improved Population Health

Article

Dec 2022
FERTIL STERIL

There is growing literature indicating that optimal preconception health is associated with improved reproductive, perinatal, and pediatric outcomes. Given that preconception care is recommended for all individuals planning a pregnancy, medical providers and public health practitioners have a unique opportunity to optimize care and improve health outcomes for reproductive-aged individuals. Knowledge of the determinants of preconception health is important for all types of health professionals, including policy makers. While some evidence-based recommendations have already been implemented, additional research is needed to identify factors associated with favorable health outcomes and to ensure that effective interventions are made in a timely fashion. Given the largely clinical readership of this journal, this piece is primarily focused on clinical care. However, we acknowledge that optimizing preconception health for the entire population at risk of pregnancy requires broadening our strategies to include population-health interventions that consider the larger social systems, structures, and policies that shape individual health outcomes.

Variable selection for discrete survival model with frailty in presence of left truncation and right censoring: Studying association of environmental toxicants on time‐to‐pregnancy

Article

Dec 2022

Understanding the association between mixtures of environmental toxicants and time‐to‐pregnancy (TTP) is an important scientific question as sufficient evidence has emerged about the impact of individual toxicants on reproductive health and that individuals are exposed to a whole host of toxicants rather than an individual toxicant. Assessing mixtures of chemical effects on TTP poses significant statistical challenges, namely (i) TTP being a discrete survival outcome, typically subject to left truncation and right censoring, (ii) chemical exposures being strongly correlated, (iii) appropriate transformation to account for some lipid‐binding chemicals, (iv) non‐linear effects of some chemicals, and (v) high percentage of concentration below the limit of detection (LOD) for some chemicals. We propose a discrete frailty modeling framework (named Discnet) that allows selection of correlated covariates while appropriately addressing the methodological issues mentioned above. Discnet is shown to have better and stable false negative and false positive rates compared to alternative methods in various simulation settings. We did a detailed analysis of the pre‐conception endocrine disrupting chemicals and TTP from the LIFE study and found that older females, female exposure to cotinine (smoking), DDT conferred a delay in getting pregnant, which was consistent across various approaches to account for LOD as well as non‐linear associations.

RISE FOR HEALTH: Rationale and protocol for a prospective cohort study of bladder health in women

Article

Nov 2022
NEUROUROL URODYNAM

Introduction: The spectrum of bladder health and the factors that promote bladder health and prevent lower urinary tract symptoms (LUTS) among women are not well understood. This manuscript describes the rationale, aims, study design, sampling strategy, and data collection for the RISE FOR HEALTH (RISE) study, a novel study of bladder health in women conducted by the Prevention of Lower Urinary Tract Symptom (PLUS) Research Consortium. Methods and results: RISE is a population-based, multicenter, prospective longitudinal cohort study of community-dwelling, English- and Spanish-speaking adult women based in the United States. Its goal is to inform the distribution of bladder health and the individual factors (biologic, behavioral, and psychosocial) and multilevel factors (interpersonal, institutional, community, and societal) that promote bladder health and/or prevent LUTS in women across the life course. Key study development activities included the: (1) development of a conceptual framework and philosophy to guide subsequent activities, (2) creation of a study design and sampling strategy, prioritizing diversity, equity, and inclusion, and (3) selection and development of data collection components. Community members and cross-cultural experts shaped and ensured the appropriateness of all study procedures and materials. RISE participants will be selected by simple random sampling of individuals identified by a marketing database who reside in the 50 counties surrounding nine PLUS clinical research centers. Participants will complete self-administered surveys at baseline (mailed paper or electronic) to capture bladder health and LUTS, knowledge about bladder health, and factors hypothesized to promote bladder health and prevent LUTS. A subset of participants will complete an in-person assessment to augment data with objective measures including urogenital microbiome specimens. Initial longitudinal follow-up is planned at 1 year. Discussion: Findings from RISE will begin to build the necessary evidence base to support much-needed, new bladder health promotion and LUTS prevention interventions in women.

Urinary phthalate metabolites and their mixtures are associated with advanced sperm epigenetic aging in a general population

Article

Aug 2022
ENVIRON RES

Introduction We have recently shown that sperm epigenetic age (SEA), a surrogate measure of biological aging in sperm, is associated with couples’ time-to-pregnancy (TTP). Advanced SEA was also observed among smokers, suggesting its susceptibility to environmental exposures. Therefore, we assessed the association between urinary phthalate metabolites and SEA in male partners of couples planning to conceive among the general population. Method The Longitudinal Investigation of Fertility and the Environment (LIFE) Study was a prospective multi-site and general population cohort study of couples who were interested in becoming pregnant. Among male partners (n = 333), eleven urinary phthalate metabolites were measured and SEA was previously developed using Super Learner ensemble algorithm. Multivariable linear regression was used to evaluate associations of SEA with individual metabolites. Bayesian kernel machine regression (BKMR), quantile g-computation (qgcomp) and weighted quantile sum (WQS) models were used for mixture analyses. Covariates included were BMI, cotinine, race and urinary creatinine. Result In the single metabolite multivariate analyses, nine (82%) phthalate metabolites displayed positive trends with SEA (range: 0.05–0.47 years). Of these metabolites, advanced SEA was significantly associated with interquartile range increases in exposure of three phthalates [MEHHP (β = 0.23, 95% CI: 0.03, 0.43, p = 0.03), MMP (β = 0.24, 95% CI: 0.01, 0.47, p = 0.04), and MiBP (β = 0.47, 95% CI: 0.14, 0.81, p = 0.01)]. Additionally, in BKMR and qgcomp (p = 0.06), but not WQS models, phthalate mixtures showed an overall positive trend with SEA, with MiBP, MMP and MBzP as major drivers of the mixture effects. Conclusion This is the first study that combined single exposure and mixture models to associate male phthalate exposures with advanced epigenetic aging of sperm in men planning to conceive among the general population. Our findings suggest that phthalate exposure may contribute to the acceleration of biological aging of sperm.

Environmental and occupational pesticide exposure and human sperm parameters: A Navigation Guide review

Article

Oct 2021
TOXICOLOGY

Global sperm counts have declined in recent decades, coinciding with the proliferation of endocrine-disrupting chemicals, of which pesticides are some of the most common. Previous systematic reviews of epidemiologic studies published between 1991 through 2013 have reported associations between environmental and occupational pesticide exposure and reduced sperm quality, particularly associations with reduced sperm concentration. This systematic review used the Navigation Guide to critically evaluate the current body of evidence examining sperm quality and pesticide exposure in epidemiological studies. PubMed, Scopus, and Web of Science databases were searched for all English-language articles published after September 2012 until August 2021. Original observational studies that assessed human sperm quality parameters, defined as concentration, motility, morphology, and DNA integrity, and individual-level pesticide exposure were included. The risk of bias for each included study and the strength of evidence were evaluated using the Navigation Guide protocol. Nineteen studies assessing environmental or occupational pesticide exposure and sperm parameters were included. Eighteen studies were cross-sectional studies and one prospective cohort; sample sizes ranged from 42 to 2122 men from 14 different countries. Fifteen (79%) studies found at least one significant association between pesticide exposure and reduced sperm quality. The overall risk of bias across studies was classified as low to moderate. The quality of evidence was determined to be moderate based on systematic evaluation criteria. There were consistent adverse associations between pesticide exposure and sperm motility (63% of studies) and DNA integrity (80% of studies). For sperm concentration and morphology, 42% and 36% of studies found significant negative associations, respectively. The strength of the body of evidence overall was rated as having sufficient evidence of toxicity. Regarding specific sperm endpoints, there was sufficient evidence that pesticides are toxic for sperm motility and DNA integrity; limited evidence of toxicity for sperm concentration; and inadequate evidence of toxicity for sperm morphology. The studies reviewed here showed consistent associations between pesticide exposure and diminished sperm parameters, particularly sperm motility and sperm DNA integrity. These findings are largely consistent with results of previous reviews, which have found significant negative associations between pesticide exposure and sperm quality in 13 of 20 (65%) studies published between 1991 and 2008, and in 14 of 17 (82%) studies published between 2008 and 2012. After thirty years of mounting evidence, actions are needed to reduce pesticide risks to testicular function and male fertility.

Are we ready to establish a causal relationship between air pollution and pregnancy loss?

Article

Full-text available

May 2019

Individual Differences in Maternal, Marital, Parenting and Child Outcomes Following Perinatal Loss: A Longitudinal Study

Article

Mar 2019

Objective: To examine the impact of past perinatal loss on mothers and children in a community sample and to consider maternal race and adult attachment status as moderators. Background: Prior perinatal loss has been shown to impact subsequent maternal parenting and child outcomes, but findings have been inconsistent particularly in minority mothers and samples not chosen due to perinatal loss history. Methods: Participants were 204 first-time mothers from a longitudinal study about predictors of sensitivity. Mothers completed the Adult Attachment Interview prenatally and reported on depressive symptoms and marital satisfaction prenatally and at 6 months and 1 year postpartum. Maternal sensitivity was observed at 6 months and 1 year, and infant-mother attachment security was assessed via the Strange Situation when children were 1 year old. Mothers reported on their reproductive history and current attitudes about the target child during the preschool period. Results: Fifty-eight (28.43%) mothers had a history of prior perinatal loss. Between group analysis revealed no differences based on perinatal loss and no moderation by maternal race or adult attachment. However, within the loss group, mothers who experienced losses later in the gestational period had less positive feelings about parenting and their children had less secure attachments to them; and mothers who had more perinatal losses had higher depressive symptoms at 1 year postpartum and less positive attitudes about parenting independent of race and SES. Conclusion: In the circumstance of multiple and later perinatal losses maternal well-being and child outcomes may be negatively impacted.

Impact of ambient PM2.5 on adverse birth outcome and potential molecular mechanism

Article

Mar 2019

PM2.5 (particulate matter ≤2.5 µm in aerodynamic diameter) refers to atmospheric particulate matter (PM) with an aerodynamic diameter of equal and less than 2.5 µm that tends to be suspended for long periods of time and travel over long distances in both outdoor and indoor atmospheres. PM2.5, along with the toxic compounds attached on it, may cause a wide range of disorders. The fetus is considered to be highly susceptible to a variety of toxicants including atmospheric pollutants such as PM2.5 through prenatal exposure. To better understand the relationship between maternal exposure to PM2.5 and adverse birth outcomes for reproduction and fetus development, we studied the published data on this issue including case-control studies, cohort studies and meta-analyses studies, and summarized the basic impact of ambient particulate matter on adverse birth outcomes. Research evidence indicates that PM2.5 has a potential to induce low birth weight (LBW), preterm birth (PTB), and stillbirth. A further in-depth analysis shows that oxidative stress, DNA methylation, mitochondrial DNA (mtDNA) content alteration, and endocrine disruptions may all play an important role in PM2.5 induced adverse effects to pregnant women and fetuses. In addition, PM2.5 exposure can cause male reproductive toxicity, leading to associated adverse pregnancy outcomes.

A weighted kernel machine regression approach to environmental pollutants and infertility

Article

Oct 2018

In epidemiological studies of environmental pollutants in relation to human infertility, it is common that concentrations of a large number of exposures are collected in both male and female partners. Such a couple‐based study poses some new challenges in statistical analysis, especially when the effect of the totality of these chemical mixtures is of interest, because these exposures may have complex nonlinear and nonadditive relationships with the infertility outcome. Kernel machine regression, as a nonparametric regression method, can be applied to model such effects, while accounting for the highly correlated structure within and across exposures. However, it does not consider the partner‐specific structure in these study data, which may lead to suboptimal estimation for the effects of environmental exposures. To overcome this limitation, we developed a weighted kernel machine regression method (wKRM) to model the joint effect of partner‐specific exposures, in which a linear weight procedure is used to combine the female and male partners' exposure concentrations. The proposed wKRM is not only able to reduce the number of analyzed exposures but also provide an overall importance index of female and male partners' exposures in the risk of infertility. Simulation studies demonstrate good performance of the wKRM in both estimating the joint effects of exposures and fitting the infertility outcome. Application of the proposed method to a prospective infertility study suggests that the male partner's exposure to polychlorinated biphenyls might contribute more toward infertility than the female partner's.

Polybrominated diphenyl ethers and incident pregnancy loss: The LIFE Study

Article

Sep 2018

Background: Polybrominated diphenyl ethers (PBDEs) have not been studied in relation to incident pregnancy loss in human populations, despite their ubiquitous exposure and purported reproductive toxicity. Objectives: To investigate the association between preconception serum PBDE concentrations and incident pregnancy loss. Methods: A preconception cohort of 501 couples was followed while trying to become pregnant, and for whom serum concentrations of 10 PBDE congeners were measured using gas chromatography-high resolution mass spectrometry. Pregnancy was prospectively identified as a positive home pregnancy test on the day of expected menstruation. Incident pregnancy loss was defined for 344 singleton pregnancies as a conversion to a negative home pregnancy test, menses, or clinical diagnosis depending upon gestational age. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for individual and summed PBDEs and incident pregnancy loss, adjusting for relevant covariates and male partners' information. In sensitivity analyses, inverse probability weighting was used to account for couples not becoming pregnant and, thereby, not at risk for loss. Results: The incidence of prospectively observed pregnancy loss was 28%, and the serum concentrations of PBDE congeners in females were consistently associated with a higher hazard of incident pregnancy loss. Specifically, statistically significant hazard ratios (HRs) for incident pregnancy loss were observed for lower brominated PBDE congeners: 17 (HR 1.23; CI: 1.07-1.42), 28 (HR 1.25; CI: 1.03-1.52), 66 (HR 1.23; CI: 1.07-1.42), and homolog triBDE (HR: 1.25; CI: 1.05-1.49). Findings were robust to various model specifications explored in sensitivity analyses. Conclusions: Maternal preconception serum concentrations of specific PBDE congeners may increase the hazard of incident pregnancy.

Toward Capturing the Exposome: Exposure Biomarker Variability and Co-Exposure Patterns in the Shared Environment

Article

Full-text available

Jul 2018

Many factors affect the variation in the exposome and we examined the influence of shared household and partner’s sex in relation to the variation in 128 endocrine disrupting chemical (EDC) exposures among couples. In a cohort comprising 501 couples trying for pregnancy, we measured 128 (13 chemical classes) persistent and non-persistent EDCs and estimated 1) sex-specific differences; 2) variance explained by shared household; and 3) Spearman's rank correlation coefficients (rs) for females, males, and couples’ exposures. Sex was correlated with 8 EDCs including polyfluoroalkyl substances (PFASs) (p < 0.05). Shared household explained 43% and 41% of the total variance for PFASs and blood metals, respectively, but less than 20% for the remaining 11 EDC classes. Co-exposure patterns of the exposome were similar between females and males, with within-class rs higher for persistent than for non-persistent chemicals. Median rss of polybrominated compounds and urine metalloids were 0.45 and 0.09, respectively, for females (0.41 and 0.08 for males; 0.21 and 0.04 for couples). Individual, rather than shared environment, could be a major factor influencing the co-variation of 128 markers of the exposome. Correlations between exposures are lower in couples than in individual partners and have important analytical and sampling implications for epidemiological study.

Reduced fecundity in HIV-positive women

Article

Mar 2018
HUM REPROD

Study question: Is HIV associated with increased time to pregnancy (TTP)? Summary answer: HIV-positive women who discontinue a contraceptive method to become pregnant have increased TTP, particularly among those who likely do not know their status. What is known already: HIV-positive women have fewer children on average than their HIV-negative counterparts due to both behavioral and biological factors. There is a need to better describe and quantify fecundity patterns associated with HIV in the general population. Study design, size, duration: This cross-sectional study was based on data from 12 Demographic and Health Surveys (DHSs) conducted between 2003 and 2013 in 11 African countries. All studies collected dried blood spot samples for HIV testing and included a retrospective calendar module that recorded women's monthly reproductive status in the 5 years preceding the survey. TTP was measured among 3181 women discontinuing a contraceptive method within 2 years of the survey in order to become pregnant. Participants/materials, setting, methods: We use Cox proportional hazard models for discrete survival data to model TTP and estimate fecundability odds ratios (FOR) and 95% CIs for the 12-month period following contraceptive discontinuation. In addition to employing a binary measure of HIV status, we also develop an additional explanatory measure that combines HIV status with information on whether respondents had ever been tested for HIV and received their results (which proxies for knowledge of HIV status) to reduce the threat of confounding from behavioral changes following an HIV diagnosis. Main results and the role of chance: In our sample, 10.3% of women were HIV-positive, and a little more than half (51.8%) of women received test results and likely knew their status. Over a 12-month observation period, HIV-positive women had a 25% average reduction in fecundity compared to HIV-negative women [adjusted FOR (aFOR) = 0.75 (0.62-0.92)] after adjusting for confounders. The 12-month fecundity patterns differed by women's likely knowledge of their status such that results were primarily driven by HIV-positive women who likely did not know their status. Moreover, reductions in fecundity attributable to HIV were not uniform over time. Among women who were still trying for pregnancy after 3 unsuccessful months, HIV-positive women had half the odds of becoming pregnant compared to HIV-negative women [aFOR = 0.50 (0.35-0.71)]. Conversely, there were no significant differences in FORs between HIV-negative and HIV-positive women in the first 3 months. Limitations reasons for caution: Because dried blood spot samples for HIV testing were collected at the time of the survey but reproductive calendar data were collected retrospectively, it is possible that we introduced misclassification bias, as we have no knowledge if the acquisition of HIV occurred before or after pregnancy attempt. Wider implications of the findings: As life expectancy and quality health status improve due to earlier initiation of antiretroviral (ARV) treatment in HIV-positive women, there has been growing awareness that services should also address the fertility desires of HIV-positive women who want children. These findings indicate that if a pregnancy does not occur after 3 months of attempting pregnancy, HIV-positive women and HIV-discordant couples should request access to HIV and reproductive pre-pregnancy counseling and health assessments. Study funding/competing interest(s): A.G. was supported by the National Institutes of Health (contract T32-HD007275) during the study. During the conceptualization, data collection and analysis time frame, S.vdP. was supported by WHO/RHR/HRP Special Program in Reproductive Health and Research, Geneva, Switzerland, and HRP (the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction). The authors have no conflicts of interest to declare.

Ambient air pollution and semen quality

Article

Feb 2018
ENVIRON RES

Background: Ambient air pollution is associated with systemic increases in oxidative stress, to which sperm are particularly sensitive. Although decrements in semen quality represent a key mechanism for impaired fecundability, prior research has not established a clear association between air pollution and semen quality. To address this, we evaluated the association between ambient air pollution and semen quality among men with moderate air pollution exposure. Methods: Of 501 couples in the LIFE study, 467 male partners provided one or more semen samples. Average residential exposure to criteria air pollutants and fine particle constituents in the 72 days before ejaculation was estimated using modified Community Multiscale Air Quality models. Generalized estimating equation models estimated the association between air pollutants and semen quality parameters (volume, count, percent hypo-osmotic swollen, motility, sperm head, morphology and sperm chromatin parameters). Models adjusted for age, body mass index, smoking and season. Results: Most associations between air pollutants and semen parameters were small. However, associations were observed for an interquartile increase in fine particulates ≤2.5 µm and decreased sperm head size, including -0.22 (95% CI -0.34, -0.11) µm2for area, -0.06 (95% CI -0.09, -0.03) µm for length and -0.09 (95% CI -0.19, -0.06) µm for perimeter. Fine particulates were also associated with 1.03 (95% CI 0.40, 1.66) greater percent sperm head with acrosome. Conclusions: Air pollution exposure was not associated with semen quality, except for sperm head parameters. Moderate levels of ambient air pollution may not be a major contributor to semen quality.

Gluckman PD, Hanson MA, Buklijas T.. A conceptual framework for the developmental origins of health and disease. J Dev Origin Health Dis 1: 6-18

Article

Full-text available

Feb 2010

In the last decades, the developmental origins of health and disease (DOHaD) have emerged as a vigorous field combining experimental, clinical, epidemiological and public health research. Its goal is to understand how events in early life shape later morbidity risk, especially of non-communicable chronic diseases. As these diseases become the major cause of morbidity and mortality worldwide, research arising from DOHaD is likely to gain significance to public health and economic development. But action may be hindered by the lack of a firm mechanistic explanation and of a conceptual basis, especially regarding the evolutionary significance of the DOHaD phenomenon. In this article, we provide a succinct historical review of the research into the relationship between development and later disease, consider the evolutionary and developmental significance and discuss the underlying mechanisms of the DOHaD phenomenon. DOHaD should be viewed as a part of a broader biological mechanism of plasticity by which organisms, in response to cues such as nutrition or hormones, adapt their phenotype to environment. These responses may be divided into those for immediate benefit and those aimed at prediction of a future environment: disease occurs in the mismatch between predicted and realized future. The likely mechanisms that enable plasticity involve epigenetic processes, affecting the expression of genes associated with regulatory pathways. There is now evidence that epigenetic marks may be inherited and so contribute to non-genomic heritable disease risk. We end by discussing the global significance of the DOHaD phenomenon and its potential applications for public health purposes.

The ovarian dysgenesis syndrome

Article

Full-text available

Feb 2011

New thinking has arisen about the origin of adult onset diseases stemming from a collective body of evidence commonly referred to as the developmental origins of health and disease. This conceptual paradigm posits that certain adult onset diseases arise during critical or sensitive windows of human development or even transgenerationally. The testicular dysgenesis hypothesis (TDS) postulates an in utero origin for adverse male reproductive outcomes, and is an excellent example of the early origins of the paradigm. Despite similarities in the development of the male and female reproductive tracks, noticeably absent is a collective body of evidence focusing on the plausibility of an early origin for gynecologic outcomes and later onset of adult diseases. Using the TDS paradigm, we synthesized the available literature relative to the ovarian dysgenesis syndrome (ODS), which we define as alterations in ovarian structure or function that may manifest as fecundity impairments, gynecologic disorders, gravid diseases or later onset adult diseases. We evaluated environmental exposures, particularly the role of endocrine disrupting chemicals, in relation to these outcomes, and found evidence (although fragmented) consistent with an in utero origin of gynecologic outcomes, which in turn is associated with later onset of adult diseases. The findings are interpreted within the ODS paradigm while delineating methodological challenges and future research opportunities designed to answer critical data gaps regarding the origin of fecundity, gravid health and chronic diseases affecting the female population.

Timing Clinic Visits to Phases of the Menstrual Cycle by Using a Fertility Monitor: The BioCycle Study

Article

Full-text available

Nov 2008

Planning study visits during specific menstrual cycle phases is important if the exposure or outcome is influenced by hormonal variation. However, hormone profiles differ across cycles and across women. The value of using fertility monitors to time clinic visits was evaluated in the BioCycle Study (2005–2007). Women aged 18–44 years (mean, 27.4) with self-reported menstrual cycle lengths of 21–35 days were recruited in Buffalo, New York, for 2 cycles (n = 250). Participants were provided with home fertility monitors that measured urinary estrone-3-glucuronide and luteinizing hormone (LH). The women were instructed to visit the clinic for a blood draw when the monitor indicated an LH surge. The monitor recorded a surge during 76% of the first cycles and 78% of the second cycles. Scheduling visits by using set cycle days or algorithms based on cycle length, such as a midcycle window or a window determined by assuming a fixed luteal phase length, would be simpler. However, even with perfect attendance in a 3-day window, these methods would have performed poorly, capturing the monitor-detected LH surge only 37%–57% of the time. Fertility monitors appear to be useful in timing clinic visits in a compliant population with flexible schedules.

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

Article

Full-text available

Oct 2008
HUM REPROD

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. 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). 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). 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.

Chemical Interaction: Enhancement and Inhibition of Clastogenicity

Article

Full-text available

Nov 1993

Wagida A. Anwar

Most environmental exposures involve concurrent or sequential exposure to multiple chemicals in air, water, and food. Interactive effects in carcinogenesis have been described for certain combinations of agents. They are described in terms of enhancement or inhibition of carcinogenesis. Enhancement effects have been documented for cigarette smoking in combination with exposure to asbestos, radon, alcohol, or other exposures. A variety of inhibitors of carcinogenesis have also been described. They are classified into agents preventing formation of carcinogens; blocking agents; and suppressing agents. Assessment of risk from exposure to multiple agents can be derived either from epidemiological studies in relation to actual exposure or from laboratory studies after controlled exposure to different agents. Prediction of how toxic components of mixtures will interact should be based on an understanding of the mechanisms of such interactions. Compounds may interact chemically, yielding new toxic components or causing a change in the biological availability of the existing components or metabolites. In humans, great individual variability in response is to be expected because of genetic heterogeneity or acquired host susceptibility factors. Interaction is thus a key component in the risk assessment process. In this paper, the definition of interaction and the theoretical basis for different types of interaction in cancer causation are reviewed. Epidemiological and experimental studies showing interactive effects of two chemical carcinogens are also presented.

A prospective study of psychosocial stress and fertility in women

Article

Full-text available

Nov 1997

The objective of this study was to compare average stress levels during the month of conception to those of previous infertile months. We postulated that stress level during the actual month of conception would be lower than that during previous non-conception cycles. Thirteen normal women from the general community, who were attempting pregnancy, kept daily records of coital activity and basal body temperature, and twice a month completed self-administered questionnaires and provided a 12 h overnight urine sample. On average, women reported significantly more favourable mood states on standard psychometric tests, during the month of conception than during the previous non-conception cycles. In addition, they felt significantly less 'hassled' during the month of conception. However, mean urinary hormone excretion of adrenaline, noradrenaline and cortisol did not significantly differ between conception and non-conception cycles and there was little relationship between the psychological measures of mood state and excretion of adrenaline and cortisol. There was no evidence of increased coital frequency during the month of conception when mood states were improved, suggesting that stress effects on libido were unlikely to account for the findings. The results support the conclusion that psychosocial stress influences fertility in females but as yet mechanisms remain unclear.

The Effect of Pregnancy Intention on Child Development

Article

Full-text available

Mar 2000

In this paper, we use data from the National Longitudinal Survey of Youth to investigate the empirical link between unintended pregnancy and child health and development. An important contribution of our study is the use of information on siblings to control for unmeasured factors that may confound estimates of the effect of pregnancy intentions on infant and child outcomes. Results from our study indicate that unwanted pregnancy is associated with prenatal and postpartum maternal behaviors that adversely affect infant and child health, but that unwanted pregnancy has little association with birth weight and child cognitive outcomes. Estimates of the association between unwanted pregnancy and maternal behaviors were greatly reduced after controls for unmeasured family background were included in the model. Our results also indicate that there are no significant differences in maternal behaviors or child outcomes between mistimed and wanted pregnancies.

Identifying Critical Windows of Exposure for Children's Health

Article

Full-text available

Jul 2000

Several authors have considered the importance of exposure timing and how this affects the outcomes observed, but no one has systematically compiled preconceptional, prenatal, and postnatal developmental exposures and subsequent outcomes. Efforts were undertaken to examine the information available and to evaluate implications for risk assessment for several areas: a) respiratory and immune systems, b) reproductive system, c) nervous system, d) cardiovascular system, endocrine system, and general growth, and e) cancer. Major conclusions from a workshop on "Critical Windows of Exposure for Children's Health" included a) broad windows of sensitivity can be identified for many systems but detailed information is limited; b) cross-species comparisons of dose to target tissue and better data on the exposure-dose-outcome continuum are needed; c) increased interaction among scientific disciplines can further understanding by using laboratory animal results in designing epidemiological studies and human data to suggest specific laboratory studies on mechanisms and agent-target interactions; and d) thus far, only limited attention has been given to peripubertal/adolescent exposures, adult consequences of developmental exposures, and genome-environment interactions. More specific information on developmental windows will improve risk assessment by identifying the most sensitive window(s) for evaluation of dose-response relationships and exposure, evaluation of biological plausibility of research findings in humans, and comparison of data across species. In public health and risk management, information on critical windows may help identify especially susceptible subgroups for specific interventions. Images Figure 3

Prevalence of selected maternal behaviors and experiences, Pregnancy Risk Assessment Monitoring System (PRAMS)

Article

Jan 1999

The women and their pregnancies

Article

Jan 1972

Sensitive Windows of Human Reproduction and Development

Article

Feb 2011

Germaine M. Buck Louis

Successful human reproduction and development is dependent upon men and women undergoing a series of highly interrelated and conditional biologic processes, many of which delineate critical or sensitive windows of human development. This chapter provides an overview of six sensitive windows including folliculogenesis, spermatogenesis and steriodogenesis, menstruation, ovulation and the fertile window, implantation window, and the intrauterine environment. Understanding the biology of these sensitive windows has methodologic implications for study design and the timing of data and biospecimens collection, particularly when attempting to identify fecundity determinants or reproductive and/or developmental toxicants. Sensitive windows are highly relevant for assessing the early origins of health and disease including the elucidation of epigenetic mechanisms that impact human reproduction and development across the lifespan and, possibly, across generations.

The Best Intentions: Unintended Pregnancy and the Well-Being of Children and Families

Article

Jan 1998

Experts estimate that nearly 60 percent of all U.S. pregnancies--and 81 percent of pregnancies among adolescents--are unintended. Yet the topic of preventing these unintended pregnancies has long been treated gingerly because of personal sensitivities and public controversies, especially the angry debate over abortion. Additionally, child welfare advocates long have overlooked the connection between pregnancy planning and the improved well-being of families and communities that results when children are wanted. Now, current issues--health care and welfare reform, and the new international focus on population--are drawing attention to the consequences of unintended pregnancy. In this climate The Best Intentions offers a timely exploration of family planning issues from a distinguished panel of experts. This committee sheds much-needed light on the questions and controversies surrounding unintended pregnancy. The book offers specific recommendations to put the United States on par with other developed nations in terms of contraceptive attitudes and policies, and it considers the effectiveness of over 20 pregnancy prevention programs. The Best Intentions explores problematic definitions--"unintended" versus "unwanted" versus "mistimed"--and presents data on pregnancy rates and trends. The book also summarizes the health and social consequences of unintended pregnancies, for both men and women, and for the children they bear. Why does unintended pregnancy occur? In discussions of "reasons behind the rates," the book examines Americans' ambivalence about sexuality and the many other social, cultural, religious, and economic factors that affect our approach to contraception. The committee explores the complicated web of peer pressure, life aspirations, and notions of romance that shape an individual's decisions about sex, contraception, and pregnancy. And the book looks at such practical issues as the attitudes of doctors toward birth control and the place of contraception in both health insurance and "managed care." The Best Intentions offers frank discussion, synthesis of data, and policy recommendations on one of today's most sensitive social topics. This book will be important to policymakers, health and social service personnel, foundation executives, opinion leaders, researchers, and concerned individuals. May

Unintended Pregnancy and the Well-Being of Children and Families

Article

Nov 1995

Sarah S. Brown

The Absorption of Tritium-Labelled Prostaglandin E 1 from the Vagina of Non-Pregnant Women

Article

Feb 1968
ACTA OBSTET GYN SCAN

Tritium labelled prostaglandin E1 was deposited for 6 hours in the posterior fornix of 7 normally menstruating volunteers who were without any signs of infection. 10-25% of the radio activity administered was recovered in the urine within 24-32 hours. The application of a cervical cup to the cervix failed to influence the absorption which was estimated to be 20-50%. The physiological significance of this absorption remains uncertain. No conclusion can be drawn from this investigation regarding the absorption rate during this period since elimination through the kidney is so slow.

Anthropometric Standardization Reference Manual Abridged Edition

Article

Aug 1992

This abridged version of the "Anthropometric Standardisation Reference Manual" contains the heart of the original manual - complete procedures for 45 anthropometric measurements. Its style enables it to be used as a supplemental text for courses in fitness assessment and exercise prescription, kinanthropometry, body composition, nutrition, and exercise physiology. It can also be used as a reference for exercise scientists. For each of the 45 measurements included in this abridged edition, readers will find complete information on the recommended technique for making the measurement, the purpose and uses for the measurement, the literature on which the measurement technique is based, and the reliability of the measurement.

Unintended pregnancy in the United States, 2001

Article

Sep 2005
CONTRACEPTION

Litter-based methods in developmental toxicity risk assessment

Article

Mar 2000

Developmental toxicity experiments are designed to assess potential adverse effects of drugs and other exposures on developing fetuses from pregnant dams. Extrapolation to humans is a very difficult problem. An important issue here is whether risk assessment should be based on the fetus or the litter level. In this paper, fetus and litter-based risks that properly account for cluster size are defined and compared for the beta-binomial model and a conditional model for clustered binary data. It is shown how the hierarchical structure of non-viable implants and viable but malformed offspring can be incorporated. Risks based on a joint model for death/resorption and malformation are contrasted with risks based on an adverse event defined as either death/resorption or malformation. The estimation of safe exposure levels for all risk types is discussed and it is shown how estimation of the cluster size distribution affects variance estimation. The methods are applied to data collected under the National Toxicology Program and in large sample simulations.

A follow-up study of environmental and biologic determinants of fertility among 430 Danish first-pregnancy planners: Design and methods

Article

Feb 1998
REPROD TOXICOL

This paper presents design and methods of a follow-up study of fecundability (defined as the probability of conception during one menstrual cycle) in first-pregnancy planners. We recruited 430 couples by postal letter among 52,255 members of four trade unions. Couples without earlier reproductive experience were enrolled when they discontinued contraception and were followed in six complete menstrual cycles or until a pregnancy was recognized. Data included daily recordings of coitus and menstrual bleeding. Blood, semen, and urine specimens were collected to assess endocrine profile, semen quality, occult embryonal loss, and occupational exposures. Information was obtained about 1661 menstrual cycles (94% of expected). The proportion of couples obtaining a clinical pregnancy during 6 months of follow-up was 65%, and the average probability to obtain a pregnancy across all cycles was 16% (95% CI 14–18%). Among all conceptions the proportion of early embryonal loss was 17% (95% CI 12–22%). This study demonstrates the feasibility of a prospective study of fertility and that the established study base can provide useful information on environmental risk to subfertility.

Sociodemographic aspects of human susceptibility to toxic chemicals: Do class and race matter for realistic risk assessment?

Article

Dec 1997
ENVIRON TOXICOL PHAR

K Sexton

Susceptibility is well-recognized as a potentially important aspect of health risk assessment, particularly for groups such as pregnant women and their fetuses, infants, children, the elderly, and the infirm, that are known or suspected to be more vulnerable to environmental insults. More recently, it has become apparent that economically disadvantaged groups are likely to be systematically both more exposed and more susceptible to environmental pollution. This article reviews the reasons why low-income communities and many racial minorities are at an increased risk because they are more susceptible to the adverse health effects of toxic chemicals. The scientific challenges of quantifying the magnitude of environmental health risks for these groups are discussed, emphasizing ramifications for risk assessment and risk management decisions. Problems incorporating susceptibility into risk-based decision making are identified, and specific actions are recommended to address these deficiencies.

Natural family planning. I. The peak symptom and estimated time of ovulation

Article

Dec 1978
OBSTET GYNECOL

The observation of the "Peak" mucus symptom in women using the ovulation method of natural family planning has been correlated with the estimated time of ovulation, as evaluated by indirect hormonal parameters. In 65 cycles of the 73 studied in 24 patients, there was hormonal confirmation of ovulation; in eight cycles, anovulation or luteal dysfunction was suspected. In the 65 normal cycles, 64 exhibited a Peak symptom. In those cycles, ovulation was estimated to occur from 3 days before to 3 days after the Peak symptom with a mean of 0.31 days before the Peak symptom. In 95.4% of these cycles, ovulation was estimated to occur from 2 days before to 2 days after the Peak symptom. The variation between cycles of the same patient ranged from 0 to 4 days with a mean of 1.8 days. The beginning of the mucus symptom preceded the estimated time of ovulation by an average of 5.9 days.

Evaluation of Recruitment Strategies for Prospective Studies of Spontaneous Abortion

Article

Jan 1990
J Occup Med

The examination of spontaneous abortions may offer a sensitive index to potential adverse health effects due to environmental exposures. However, difficulties in ascertaining spontaneous abortions on a population basis, as well as problems in recruiting unselected women into studies of this nature, have severely limited the use of this end point in environmental epidemiology studies. The current research assesses the feasibility of recruiting a representative sample of women into a prospective pregnancy study. Four protocols varying in intensity of data collection were offered to the participants. Fifty-two percent of the eligible women agreed to participate. Seventy-four percent chose the most intensive protocol level. Overall compliance for urine collection and questionnaire completion were 80% and 81%, respectively. Four pregnancies were observed, which was the expected number for the study area during this time frame, suggesting that the majority of pregnancies occurring within a population could be ascertained with this approach.

Reporting accuracy among mothers of malformed and nonmalformed infants

Article

Mar 1989
AM J EPIDEMIOL

The potential for recall bias in case-control studies is a common concern. The authors assessed whether recall bias was present in exposure information reported at postpartum interview by mothers of malformed and nonmalformed infants who delivered at Brigham and Women's Hospital, Boston, during 1984. Accuracy of exposure reporting was measured by comparing interview data with exposure information documented during pregnancy in obstetric records. The authors' measure of recall bias, relative sensitivity (RS), is the ratio of exposure-reporting accuracy for mothers of malformed infants to that of mothers of nonmalformed infants. Relative sensitivity estimates that are greater than 1.0 indicate that mothers of malformed infants are more accurate reporters than mothers of nonmalformed infants. Relative sensitivity was estimated for eight exposure factors: antibiotic or antifungal drug use (RS = 1.2), urinary tract or yeast infection (RS = 2.7), history of infertility (RS = 1.4), use of birth control after conception (RS = 7.6), elective abortion history (RS = 1.1), any over-the-counter drug use (RS = 1.0), spotting or bleeding (RS = 1.2), and nausea or vomiting (RS = 0.8) These data suggest the presence of recall bias for some exposure factors. The authors advise the use of malformed controls to reduce potential recall bias in case-control studies of selected malformations and many etiologic factors.

Evaluation of Methods for the Prospective Identification of Early Fetal Losses in Environmental Epidemiology Studies

Article

May 1988
AM J EPIDEMIOL

A major problem in the epidemiologic investigation of early fetal losses has been incomplete or biased ascertainment. In order to assess early fetal losses more accurately, one must first develop a simple method to identify early pregnancy. This study, conducted at the University of Pittsburgh from October 1985 through October 1986, has developed such a method through the use of monoclonal antibody urine pregnancy testing kits. A total of 88 volunteers collected urine samples beginning on the seventh postovulatory day and continued until either menses occurred or a serum radioimmunoassay pregnancy test was performed on day 16. If pregnancy was diagnosed, all of the participants' urine specimens from that menstrual cycle were analyzed by five monoclonal antibody tests. A total of 34 pregnancies were diagnosed, six (18%) of which resulted in early fetal losses. Pregnancy was first detectable between eight and 18 days postovulation. The mean time to the first positive test was 14 days for all five kits. The results indicate that it is possible to diagnose early pregnancy with urine testing and that this method is likely to prove acceptable for use in large-scale prospective studies.

Incidence of Early Loss of Pregnancy

Article

Aug 1988

We studied the risk of early loss of pregnancy by collecting daily urine specimens from 221 healthy women who were attempting to conceive. Urinary concentrations of human chorionic gonadotropin (hCG) were measured for a total of 707 menstrual cycles with use of an immunoradiometric assay that is able to detect hCG levels as low as 0.01 ng per milliliter, with virtually 100 percent specificity for hCG in the presence of luteinizing hormone. Our criterion for early pregnancy--an hCG level above 0.025 ng per milliliter on three consecutive days--was determined after we compared the hCG levels in the study group with the levels in a comparable group of 28 women who had undergone sterilization by tubal ligation. We identified 198 pregnancies by an increase in the hCG level near the expected time of implantation. Of these, 22 percent ended before pregnancy was detected clinically. Most of these early pregnancy losses would not have been detectable by the less sensitive assays for hCG used in earlier studies. The total rate of pregnancy loss after implantation, including clinically recognized spontaneous abortions, was 31 percent. Most of the 40 women with unrecognized early pregnancy losses had normal fertility, since 95 percent of them subsequently became clinically pregnant within two years.

A Prospective Study of the Relation Between Smoking and Fertility

Article

Jul 1988

A prospective study of fertility was conducted from 1977 to 1982. Analysis of the relation between cigarette smoking and occurrence of a pregnancy was performed on 1887 couples. The actuarial pregnancy rate was 82.9% at the end of a year. Cigarette smoking by both members of the couple was found to be related to decreased fertility when this factorwas considered alone. But after including all the confounding covariates in a Cox semi-proportional hazards model for survival data, no relationship remained between cigarette smoking and fertility. Odds ratios were respectively 0.86 (95% confidence interval: 0.63, 1.19) and 0.99 (0.85, 1.14) for women smoking and men smoking. This could suggest that the relationship found by other authors might be at least partly explained by a relation between cigarette smoking and other factors related to fertility.

Fetal loss after implantation. A prospective study

Article

Oct 1980

The incidence of post-implantation pregnancy loss in 197 women was determined prospectively. The diagnosis of pregnancy was based on the detection of human chorionic gonadotropin in the urine during the luteal phase of each menstrual cycle. There were 152 conceptions in the 623 cycles studied with a pregnancy loss rate of 43%. 14 of the pregnancies ended in clinically recognised spontaneous abortions and in 50 the sole evidence of pregnancy was an increased concentration of urinary hCG. The maximum conception rate achieved was 36% in the first cycle after removal of an intra uterine device.

Absorption from the Vagina

Article

Feb 1983

Methods and results are reviewed of research on the permeability of the vagina to a wide variety of compounds including steroids prostaglandins (PGs) antimicrobials proteins antigens and hormones nonoxynol-9 methadone and inorganic compounds. Although the literature indicates that the vagina is capable of absorbing a wide variety of organic and inorganic compounds quantitative data on the extent of absorption are often lacking. Most steroids were readily absorbed and their bioavailability after intravaginal instillation was greater than after oral administration because of a reduced first-pass effect. Natural and synthetic PGs were absorbed; the extent of absorption ranged from 10-43% of the dose. Penicillin and sulfanilamide exhibited extremely variable absorption from the vagina. In most women neither econazole miconazole nor clotrimazole were effectively absorbed. In 1943 it was demonstrated that proteins could be absorbed from the vagina. Data on human absorption of nonoxynol-9 are indirect but are consistent with absorption. Methadone povidone-iodine and potassium permanganate have also been shown to be absorbed through the vagina. The stage of the reproductive cycle may alter the extent of vaginal absorption but this has been clearly demonstrated for only 1 substance in the rat.

A prospective study of the preselection of the sex of offspring by timing intercourse relative to ovulation

Article

Jul 1984
FERTIL STERIL

The relationship between the sex of offspring and the time interval between coitus and ovulation/fertilization has been prospectively investigated in 33 pregnancies using the rise in luteinizing hormone in the early morning urine, the peak cervical mucus symptom, and the shift in basal body temperature as indicators for ovulation. Reference to the peak cervical mucus symptom showed a significant association of conception of a male child with longer intervals (greater than 2 days) between coitus and fertilization (P less than 0.03). However, while a similar trend for male conceptions was evident when the duration of sperm survival was determined by reference to each of the other two indicators of ovulation, the relationship was not significant. The results clearly refute the theory that intercourse close to ovulation favors male conceptions. While the findings are consistent with the contrary theory, it may be premature to conclude that a male child is more likely to be conceived if coitus takes place several days before ovulation.

A Global Measure of Perceived Stress

Article

Jan 1984

This paper presents evidence from three samples, two of college students and one of participants in a community smoking-cessation program, for the reliability and validity of a 14-item instrument, the Perceived Stress Scale (PSS), designed to measure the degree to which situations in one's life are appraised as stressful. The PSS showed adequate reliability and, as predicted, was correlated with life-event scores, depressive and physical symptomatology, utilization of health services, social anxiety, and smoking-reduction maintenance. In all comparisons, the PSS was a better predictor of the outcome in question than were life-event scores. When compared to a depressive symptomatology scale, the PSS was found to measure a different and independently predictive construct. Additional data indicate adequate reliability and validity of a four-item version of the PSS for telephone interviews. The PSS is suggested for examining the role of nonspecific appraised stress in the etiology of disease and behavioral disorders and as an outcome measure of experienced levels of stress.

Infertility and early pregnancy loss

Article

Jun 1995
AM J OBSTET GYNECOL

We describe the epidemiologic characteristics of conception, including subclinical early pregnancy loss, in a population of healthy women volunteers who had heterogeneous fertility experiences, and we describe the conception experience of women within this group who had evidence of impaired fertility. This was a prospective observational study of a cohort of women employed in two semiconductor manufacturing facilities. A total of 148 volunteers completed interviews and daily diaries and collected daily urine specimens for an average of 7 months. Conception, including subclinical losses and clinical pregnancies, was determined with a highly sensitive and specific assay for urinary human chorionic gonadotropin, and ovulation was determined with assays of urinary ovarian steroid hormones. There were 679 menstrual cycles at risk for pregnancy contributed by 124 (84%) of the 148 women. Women with evidence of subfertility before or during the study period had a rate of early pregnancy loss of 70% compared with 21% in women without fertility problems (relative risk 2.6, 95% confidence interval 1.8 to 3.8). The risk of pregnancy loss associated with subfertility increased with age and remained the same in women treated with clomiphene citrate. These results suggest that subfertile women have increased subclinical pregnancy losses regardless of fertility treatment and that the association between reduced fertility and advancing age may be related, in part, to early subclinical pregnancy loss.

Psychosocial factors, female fertility and pregnancy: a prospective study — Part I: Fertility

Article

Jul 1994

The aim of the study was to determine prospectively whether psychosocial, personality-related or stress factors have influence on fertility. Initially 191 healthy nulliparas without a history of infertility who were planning to have children were studied gynecologically and by psychiatric examination. Life changes and changes in psychosocial stress were monitored throughout the study period of 6 months at regular intervals. The following factors turned out to be associated with higher than average fertility in the final follow-up sample of 180 women: looking younger than one's actual age, no fluctuation in body weight before pregnancy, low consumption of coffee, low score of psychosomatic symptoms, being the youngest sibling, low number of negative life changes, younger than spouse, having phobic traits, and customarily religious. There was no clearcut association between low fertility and deviations in personality factors.

An evaluative process for assessing human reproductive and developmental toxicity of agents

Article

Feb 1995
REPROD TOXICOL

Prospective assessment of fecundability of female semiconductor workers

Article

Dec 2010

To investigate a possible effect of reduced fecundability (probability of conception per menstrual cycle) among women who fabricate silicon wafers, 152 fabrication-room (fab) and 251 nonfab workers were followed for an average of five menstrual cycles. Daily urine samples were analyzed to confirm clinical spontaneous abortions (SABs) and early fetal losses (EFLs). Adjusted fecundability odds ratios (FRs) for fab workers ranged from 0.59 to 0.72 (p = 0.09-0.28 vs. nonfab). For clinical pregnancies only, the adjusted FR ranged from 0.43-0.50 (p = 0.04-0.09 vs. nonfab). This lower fecundability was most pronounced among dopants and thin-film workers [adjusted FR = 0.61, 95% confidence interval (CI) = 0.27-1.40 for all pregnancies; adjusted FR = 0.22, 95% CI = 0.05-0.96 for clinical pregnancies] and in workers exposed to ethylene-based glycol ethers (adjusted FR = 0.37, 95% CI = 0.11-1.19).

A prospective study of early pregnancy loss

Article

Feb 1996

The New York State Early Pregnancy Detection Study was a prospective study of early pregnancy loss, between implantation and menses, in 217 women attempting to become pregnant during 1989–1992. Women collected urine samples on three consecutive mornings during the late luteal phase of their menstrual cycle, for up to 12 cycles, contributing samples for 1253 menstrual cycles. Urinary human chorionic gonadotrophin (HCG), measured using an immunoradiometric assay, was the biomarker for pregnancy. We observed a range of early pregnancy loss (EPL) rates, from a low estimate of 11.0% to a high estimate of 26.9%, depending on the definition used and the subgroup analysed. Based on a definition of 3 days of HCG concentration > 4.00 pmol/1, 2 days 3=533 pmol/1 or the last, day of HCG 2 = 6.67 pmol/1, we identified 115 positive cycles; 95 cycles were clinically confirmed pregnancies and 20 cycles were EPL, giving an EPL rate of 17.4% [95% confidence interval (CI) 11.0-25.6]. In addition, we observed an EPL rate of 19.5% (95% CI 113-30.1) for samples collected within a 15 day window around menses, and a rate of 203% (95% CI 113-32.2) for samples limited to the first three menstrual cycles. Because studies use urine collection schemes other than daily sampling, the definition of pregnancy will be crucial in defining EPL.

Estimates of human fertility and pregnancy loss

Article

Apr 1996
FERTIL STERIL

To examine the fertility and pregnancy wastage rates in a group of presumably fertile couples. Prospective observational study of 200 couples desiring to achieve pregnancy over 12 menstrual cycles coupled with pregnancy outcome follow-up. A university-based obstetrics and gynecological center. Personal interviews and questionnaires were used to screen couples for entry into the study. Couples were counseled to have intercourse centered on predicted day of ovulation. Phase 1 included the first three cycles in which women collected daily morning urine samples, underwent midcycle postcoital tests, and, if late for their menses, presented for serum hCG testing. Phase 2 encompassed the next nine cycles in which women were contacted monthly by phone and underwent serum hCG testing if menses was delayed. Urine samples from cycles in which clinical (serum hCG) pregnancy did not occur underwent sensitive hCG testing to detect occult pregnancies. Pregnancies were followed until delivery to ascertain outcome. Eighty-two percent of the 200 couples followed for the entire study period conceived. The maximal fertility rate was approximately 30% per cycle in the first two cycles. This rate quickly tapered over the remainder of the study. Pregnancy wastage during phase 1 accounted for 31% of the pregnancies detected. Forty-one percent (15/36) of these losses were seen only by urine hCG testing and were categorized as occult. Eleven of these same patients later achieved clinically recognized conceptions during the study. These results support the concept that the efficiency of human reproduction is maximum at approximately 30% per cycle. A very significant number of these pregnancies end in spontaneous abortion. In addition, pregnancy loss before missed menses occurs in a significant proportion of women.

Comparison of Two Question Sequences for Assessing Pregnancy Intentions

Article

Jun 1997
AM J EPIDEMIOL

Unintended pregnancies can have serious health, social, and economic consequences. Such pregnancies may be unwanted (a baby is not wanted at any time) or mistimed, yet wanted (a baby is wanted eventually). Intended pregnancies are those conceived when desired. Reproductive health survey respondents' understanding of these concepts and validity of survey results may be affected by question order and wording. Using a randomized crossover design, National Survey of Family Growth (NSFG) and Demographic and Health Survey (DHS) intendedness questions were asked in a 1993 survey of Arizona women aged 18-44 years. Of 2,352 ever-pregnant respondents, 25% gave discordant responses to DHS and NSFG questions about the most recent pregnancy. Age, marital status, household income, education, parity, time since pregnancy, and outcome of pregnancy were significantly predictive of discordant responses. DHS and NSFG questions yielded similar prevalence estimates of intendedness and wantedness; but young, unmarried respondents gave more "mistimed" responses on whichever question was asked later. Classifying pregnancies as intended, mistimed, or unwanted may be a problem for women who have not decided on lifetime reproductive preferences. Approaches to improving survey validity include addressing ambivalence, clarifying the definition of "unwanted," and, for young, unmarried women, not attempting to classify unintended pregnancies as mistimed or unwanted.

Recruitment, retention and characteristics of women in a prospective study of preconceptional risks to reproductive outcomes: Experience of the Diana Project

Article

Aug 1997

Preterm delivery, low birthweight, and intrauterine growth retardation are common and recalcitrant problems in many countries. Although much remains to be learned, we know particularly little about the relationships between preconceptional and early pregnancy exposures and these and other reproductive outcomes. The study presented here was primarily designed to investigate the relationships between nutritional exposures measured before and during pregnancy and reproductive outcomes. This paper describes methods used to recruit the required 1000 preconceptional women from the collaborating health maintenance organisation (HMO) and the retention of participants in this time-intensive study. The results presented demonstrate that an adequate completion rate (66.3%), and a remarkably representative sample of women that poses few threats to the study's validity, can be obtained by population-based recruitment of women from an HMO.

Hormone measures in finger‐prick blood spot samples: New field methods for reproductive endocrinology

Article

Sep 1997

Comparative endocrine studies have notably advanced understanding of ecological factors that contribute to variation in human reproductive function. Such research has relied on methodological advances that permit hormone determinations in samples that are easily and safely collected, stored, and transported, most recently on measurement of steroids in saliva. This report seeks to further expand the scope of endocrine research by demonstrating the value of blood spot samples collected by finger prick. As a sampling strategy, finger-prick blood spot collection offers the advantages of short collection time, low invasiveness, repeatability, absence of postcollection processing, low biohazard risk, and ease of sample storage and transport. We document good sample stability and present sensitive assay methods for a range of steroids and proteins (FSH, LH, PRL, T, E2, DHEAS, androstenedione, cortisol, SHGB) in blood spots that require sample volumes of 3-12 microliters and display good reliability, specificity, precision, accuracy, and convertibility of results to plasma/serum equivalent concentrations. Laboratory evaluation was augmented by a feasibility study at a remote site in Papua New Guinea that confirmed validity and stability of blood spot collections under field conditions. Research applications of blood spot sampling are illustrated with a series of studies, including cross-sectional surveys for developmental and life span endocrinology, a longitudinal, population-based developmental epidemiologic study of puberty, and serial sampling in a dynamic study of neuroendocrine response to suckling. We conclude that the sampling features and wide range of measurable biomolecules of blood spots do constitute a methodological advance for endocrine research.

Chemical Mixtures in the Workplace: Research and Practice

Article

Feb 1998

Linda Mccauley

1. Exposures to mixtures of chemicals in occupational settings and in the environment are of increasing concern. No single approach is appropriate for determining the risk associated with exposure to chemical mixtures. 2. The effects of coexposure of chemicals can occur in different stages of metabolism, including uptake, elimination, biotransformation, and binding. 3. Solvents represent the most widespread use of multicomponent mixtures in industry today. Solvents have the ability to inhibit the metabolism of other chemicals. 4. Lifestyle factors such as exercise, alcohol use, smoking, and the use of medications can affect the uptake and metabolism of chemicals. The effects of these factors are of particular significance in interpreting the results of biological monitoring of exposed workers.

Unintended pregnancy in the United States. Fam Plann Perspect, 30, 24-30

Article

Jan 1998
Fam Plann Perspect

Stanley K. Henshaw

Current debates on how to reduce the high U.S. abortion rate often fail to take into account the role of unintended pregnancy, an important determinant of abortion. Data from the 1982, 1988 and 1995 cycles of the National Survey of Family Growth, supplemented by data from other sources, are used to estimate 1994 rates and percentages of unintended birth and pregnancy and the proportion of women who have experienced an unintended birth, an abortion or both. In addition, estimates are made of the proportion of women who will have had an abortion by age 45. Excluding miscarriages, 49% of the pregnancies concluding in 1994 were unintended; 54% of these ended in abortion. Forty-eight percent of women aged 15-44 in 1994 had had at least one unplanned pregnancy sometime in their lives; 28% had had one or more unplanned births, 30% had had one or more abortions and 11% had had both. At 1994 rates, women can expect to have 1.42 unintended pregnancies by the time they are 45, and at 1992 rates, 43% of women will have had an abortion. Between 1987 and 1994, the unintended pregnancy rate declined by 16%, from 54 to 45 per 1,000 women of reproductive age. The proportion of unplanned pregnancies that ended in abortion increased among women aged 20 and older, but decreased among teenagers, who are now more likely than older women to continue their unplanned pregnancies. The unintended pregnancy rate was highest among women who were aged 18-24, unmarried, low-income, black or Hispanic. Rates of unintended pregnancy have declined, probably as a result of higher contraceptive prevalence and use of more effective methods. Efforts to achieve further decreases should focus on reducing risky behavior, promoting the use of effective contraceptive methods and improving the effectiveness with which all methods are used.

Trends in Contraceptive Use in the United States: 1982-1995

Article

Jan 1998
Fam Plann Perspect

Trends in contraceptive use have implications for shifts in pregnancy rates and birthrates and can inform clinical practice of changes in needs for contraceptive methods and services. Information on current contraceptive use was collected from a representative sample of women of reproductive age in the 1995 National Survey of Family Growth (NSFG). This information is compared with similar data from 1982 and 1988 to examine trends in use, both overall and in social and demographic subgroups. The proportion of U.S. women using a contraceptive method rose from 56% in 1982 to 60% in 1988 and 64% in 1995. As in 1982 and 1988, female sterilization, the pill and the male condom were the most widely used methods in 1995. Between 1988 and 1995, the proportion of users relying on the pill decreased from 31% to 27%, while condom use rose from 15% to 20%. The largest decreases in pill use and the largest increases in condom use occurred among never-married women and among black women younger than 25. Reliance on the IUD dropped sharply among Hispanic women, while use of the diaphragm fell among college-educated white women. The decline in pill and diaphragm use and the increase in reliance on condoms suggest that concerns about HIV and other sexually transmitted diseases are changing patterns of method use among unmarried women.

Predicting Maternal Behaviors During Pregnancy: Does Intention Status Matter?

Article

Mar 1998
Fam Plann Perspect

Women's behavior during pregnancy, which can affect the health of their infant, may be influenced by their attitude toward the pregnancy. Multivariate analyses of data from the 1988 National Maternal and Infant Health Survey and the 1988 National Survey of Family Growth were conducted to investigate whether women with unplanned births differ from other women in their pregnancy behavior, independent of their social and demographic characteristics. Women with intended conceptions are more likely than similar women with unintended pregnancies to recognize early signs of pregnancy and to seek out early prenatal care, and somewhat more likely to quit smoking, but they are not more likely than women with comparable social and demographic characteristics to adhere to a recommended schedule of prenatal visits once they begin care, to reduce alcohol intake, or to follow their clinician's advice about taking vitamins and gaining weight. Social and demographic differences in these behaviors are largely unaffected by planning status, indicating that these differences are independently related to pregnancy behaviors. Both the intendedness of a pregnancy and the mother's social and demographic characteristics are important predictors of pregnancy-related behavior.

Accuracy of the Ovulon Fertility Monitor to Predict and Detect Ovulation

Article

Mar 1998
J Nurse Midwifery

The purpose of this pilot study was to correlate the three biologic markers of the Ovulon fertility monitor (a long-term predictive peak about 6 days before ovulation, a short-term predictive peak about 1 day before ovulation, and a nadir at the time of ovulation) with the peak in cervical mucus and the luteinizing hormone (LH) surge in the urine. Ten volunteer subjects (mean age 30.2 years) monitored their cervical-vaginal mucus, the surge of LH in the urine with a home assay test, and their vaginal electrical readings (with Ovulon monitors) on a daily basis for one to four menstrual cycles. In 19 of the 21 cycles that indicated a LH surge, there was a strong positive correlation between the LH surge and the peak of cervical-vaginal mucus (r = 0.96, P < or = .01), and between the LH surge and both the Ovulon nadir and Ovulon short-term predictive peak (r = 0.84, P < or = .01), and a modest positive correlation between the long-term Ovulon predictive peak and the LH surge (r = 0.62, P < or = .01). The time of optimal fertility as determined by the peak in cervical mucus, the LH surge, and the Ovulon was similar. The Ovulon has potential as a reusable device to help women determine their fertile period.

A simple mouthwash method for obtaining genomic DNA in molecular epidemiologic studies

Article

Sep 1998

Genomic DNA for genetic analyses has traditionally been derived from blood samples. With the availability of PCR techniques requiring only minute amounts of DNA and the current demand for high-volume testing, a less invasive, simpler to perform, and cheaper method to obtain DNA is desirable. We developed a method to obtain high-quality genomic DNA from buccal cells that has high acceptability and allows for a large number of PCR assays from a single sample. Sixty subjects vigorously swished 10 ml of undiluted commercial mouthwash in the mouth for 60 s and expelled the liquid into a collection container. DNA was isolated from the buccal cells with a rapid method using proteinase K digestion, phenol-chloroform extraction, and ethanol precipitation. Electrophoretic analysis of the extracted DNA showed detectable levels of high molecular weight genomic DNA in all samples. The DNA yields ranged from 0.2 to 134.0 microg, for an average of 49.7 microg. Using these samples, all 60 subjects were successfully genotyped by PCR-based assays for polymorphisms in the CYP1A1 (MspI and exon 7), CYP2E1 (RsaI), GSTM1, GSTT1, and NQO1 genes, confirming that the quality of DNA isolated from mouthwash samples was sufficient to reliably support PCR amplification. Storage of the (unprocessed) specimens at room temperature or at 37 degrees C for 1 week (temperature conditions that may be encountered when mailing samples) or at -20 degrees C for at least 6 months did not affect the DNA yield or ability to PCR amplify the samples. The results suggest that this mouthwash procedure may be suitable for large community-based studies of genetic susceptibility to disease in which samples can be collected by the participants themselves, mailed back to the study center, and stored for months prior to DNA analysis.

Obesity is a risk factor for early pregnancy loss after IVF or ICSI

Article

Feb 2000

Experience with polycystic ovary syndrome shows that insulin resistance is related to early pregnancy loss. This association was examined by comparing pregnancy outcome in obese and lean women. A cohort of 383 patients conceiving after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was studied. Ovarian stimulation was achieved by GnRHa and FSH or hMG (n=362), by FSH or hMG alone (n=16), or by clomiphene citrate and FSH or hMG (n=5). Luteal phase was supported with progesterone. Pregnancies were defined by >10 IU/l plasma beta-hCG on day 14. Ultrasound scan on week 6 and week 12 confirmed fetal viability. Lean group (body mass index [BMI]<25 kg/m2; n=304) and obese group (BMI > or =25 kg/m2; n=79) were established. Obese patients had fewer oocytes collected (median: 8 vs 10 p=0.03), they had higher abortion rate during the first 6 weeks (22% vs 12%; p=0.03) and lower live-birth rate (63% vs 75%; p=0.04). The relative risk of abortion before week 6 was 1.77 (95% CI: 1.05 to 2.97). Multivariate logistic regression analysis revealed that obesity and low oocyte count were independently associated with spontaneous abortion. In the obese group, low oocyte number was associated with a more profound increase in the risk of abortion than among lean patients. The effect of age, history of past pregnancies, or infertility diagnosis on the probability of miscarriage were not significant. Obesity is an independent risk factor for early pregnancy loss. This risk is, in part, related to the lower number of collected oocytes in obese women.

Semen Quality and Human Fertility: A Prospective Study With Healthy Couples

Article

Jan 2000

Measures of semen quality are used as surrogate measures of male fertility in clinical andrology, reproductive toxicology, epidemiology, and risk assessment. However, only limited data are available to relate those measures to fertility. This prospective study with 210 reproductive-age couples was conducted to provide information on the value of semen quality measures for predicting human male fertility potential and for development of models to estimate the effects of changes in semen quality on fertility in a given population for risk assessment. Couples without known risk factors for infertility and who had discontinued contraception to have a child were accepted. The study followed each couple for up to 12 menstrual cycles while they attempted to conceive and evaluated semen quality measures from multiple ejaculates per man with known abstinence intervals. For each cycle, the day of ovulation was predicted, and the couple was advised to have intercourse multiple times on that day and on the days around it. Among the demographic variables assessed, parity, contraception status prior to entering the study, male education level, and male smoking were associated significantly with 12-cycle pregnancy rate. Several semen quality measures also were associated significantly with pregnancy rate, with percentage morphologically normal sperm by strict criteria and measures involving total number of sperm showing particularly strong associations. Localized regression-smoothing plots of semen quality data against proportion of couples pregnant suggested levels below which fertility declines for several semen quality measures. These results have applications in both clinical andrology and in assessment of risk to male fecundity from environmental or pharmaceutical exposures. In particular, they contribute information on behavior of fertility with varying semen quality and can allow development of models to predict effects on fertility in populations from decrements in semen quality.

Pregnancy Intentions May Not be a Useful Measure for Research on Maternal and Child Health Outcomes

Article

Sep 1999
Fam Plann Perspect

Marjorie R Sable

The findings of three researchers about pregnancy intendedness as a measure for understanding maternal and child health outcomes were evaluated. Studies have linked unintended pregnancy to some behaviors and to negative birth weight. Several issues undermine the validity of intendedness as it is presently measured, such as recall bias implicit in retrospective queries about intention; and pregnancy intention as a complex concept. Moreover, discrepancies between the stated and actual contraceptive practice of women also complicated the issue of intention status. Also, the issue of mistimed versus unwanted pregnancy presented another problem. Thus, intendedness may be too complex to quantify and measure accurately.

A Reminder that Human Behavior Frequently Refuses to Conform to Models Created by Researchers

Article

Sep 1999
Fam Plann Perspect

Kristin Luker

This is a comment on the models created by researchers concerning contraceptive failure and unintended pregnancy. Human behavior refuses to conform to the models due to the occurrence of some unusual events. Thus, the models should be used with caution. Both unintended pregnancies and contraceptive failures are more complex than they appear at first glance. Part of the problem resides in the history of the instrument used to measure unintended pregnancy. Becoming accidentally pregnant presents people the oppressing responsibility of having to decide whether to enter into parenthood or not. The choices about parenthood are problem-filled in this country. As a consequence, the processes that determine the intimate lives of couples and in the culture as a whole should be studied. Otherwise, the industrialized world will have to put up with contraceptive "accidents", while political movements will continually promise to resolve these complexities.

Are All Contraceptive Failures Unintended Pregnancies? Evidence from the 1995 National Survey of Family Growth

Article

Sep 1999
Fam Plann Perspect

The incidence of unintended pregnancy has long been used as a primary indicator of the state of reproductive health. However, the definition--and therefore the measurement--of this indicator has been elusive. Data from the 1995 National Survey of Family Growth (NSFG) were used to compare levels of unintended pregnancy among contraceptive users based on two definitions--the standard definition based on women's reports of contraceptive failure, and the NSFG definition based on pregnancy timing (wanted then, wanted later, or not wanted then or in the future). An attitudinal scale was used to examine women's feelings about their unintended pregnancy. Of pregnancies classified as contraceptive failures under the standard definition, only 68% were unintended pregnancies--94% of those ending in abortion and 60% of those ending in birth. Just 59% of women with a contraceptive failure classified as an unintended pregnancy reported feeling unhappy or very unhappy about their pregnancy, while 90% of those with a failure classified as an intended pregnancy reported being happy or very happy. Measures of wantedness based on women's feelings about their pregnancy may correlate more closely with important pregnancy outcomes than do traditional measures of intendedness.

Evaluation of a Container for Collection and Shipment of Semen With Potential Uses in Population‐Based, Clinical, and Occupational Settings

Article

May 2000

Large, population-based studies of semen quality are encumbered by the logistics and expense of obtaining semen samples from men who live in a variety of locations. A prototype semen collection and transportation kit, the TRANSEM100, can be distributed to study participants and then directly shipped to a central laboratory for analysis. This study was designed to evaluate the ability of male volunteers to correctly use the kit. Thirty volunteers aged 20 to 44 years with no history of diabetes, recent chemotherapy, fertility problems, or vasectomy were recruited through a newspaper advertisement, interviewed to obtain demographic information, and instructed on the use of the kit. Twenty-six of the initial subjects provided at least 1 semen specimen using the kit and returned the specimens by overnight delivery to the laboratory for analysis, 25 completed a follow-up interview on the use of the collection kit, and 20 submitted a second semen sample using the same method. The average volunteer was white, 27.8 years old, and held at least a college degree. Forty percent of the volunteers were married. In general, participants correctly followed the instructions for collecting, packaging, and shipping the semen samples. Volunteers were instructed to collect samples after at least 2, but no more than 7 days of abstinence. For the first and second samples submitted, participants collected semen samples after an average of 3.3 and 3.9 days of abstinence, respectively. Seventeen (65%) of the samples from the first sampling period and 16 (80%) of the samples from the second period were received in the laboratory the day after they had been collected. In summary, the TRANSEM100 may prove to be useful for collecting human semen in field studies. Further testing of this method is warranted to evaluate preservation of sample quality and use of the kit by men among diverse socioeconomic groups.

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

Abstract

No full-text available

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