Melissa M. Smarr

Urinary Concentrations of Parabens and Other Antimicrobial Chemicals and Their Association with Couples' Fecundity.

Background: Human exposure to parabens and other antimicrobial chemicals is continual and pervasive. The hormone-disrupting properties of these environmental chemicals may adversely affect human reproduction. Objective: We aimed to prospectively assess couples’ urinary concentrations of antimicrobial chemicals in the context of fecundity, measured as time to pregnancy (TTP). Methods: In a prospective cohort of 501 couples, we examined preconception urinary chemical concentrations of parabens, triclosan and triclorcarban in relation to TTP; chemical concentrations were modeled both continuously and in quartiles. Cox’s proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) adjusting for a priori–defined confounders. In light of TTP being a couple-dependent outcome, both partner and couple-based exposure models were analyzed. In all models, FOR estimates < 1.0 denote diminished fecundity (longer TTP). Results: Overall, 347 (69%) couples became pregnant. The highest quartile of female urinary methyl paraben (MP) concentrations relative to the lowest reflected a 34% reduction in fecundity (aFOR = 0.66; 95% CI: 0.45, 0.97) and remained so when accounting for couples’ concentrations (aFOR = 0.63; 95% CI: 0.41, 0.96). Similar associations were observed between ethyl paraben (EP) and couple fecundity for both partner and couple-based models (p-trend = 0.02 and p-trend = 0.05, respectively). No associations were observed with couple fecundity when chemicals were modeled continuously. Conclusions: Higher quartiles of preconception urinary concentrations of MP and EP among female partners were associated with reduced couple fecundity in partner-specific and couple-based exposure models. Citation: Smarr MM, Sundaram R, Honda M, Kannan K, Buck Louis GM. 2016. Urinary concentrations of parabens and other antimicrobial chemicals and their association with couples’ fecundity. Environ Health Perspect 124:730–736; http://dx.doi.org/10.1289/EHP189

Obstetric and Neonatal Risks Among Obese Women Without Chronic Disease.

OBJECTIVE: To investigate whether prepregnancy obesity is associated with adverse pregnancy outcomes among women without chronic disease. METHODS: Singleton deliveries (N=112,309) among mothers without chronic diseases in the Consortium on Safe Labor, a retrospective U.S. cohort, were analyzed using Poisson regression with robust variance estimation. Relative risks and 95% confidence intervals (CIs) estimated perinatal risks in relation to prepregnancy obesity status adjusted for age, race–ethnicity, parity, insurance, smoking and alcohol use during pregnancy, and study site. RESULTS: Obstetric risks were variably (and mostly marginally) increased as body mass index (BMI) category and obesity class increased. In particular, the risk of gestational hypertensive disorders, gestational diabetes, cesarean delivery, and induction increased in a dose–response fashion. For example, the percentage of gestational diabetes among obese class III women was 14.6% in contrast to 2.8% among women with normal BMIs (corresponding relative risks [95% CI] 1.99 [1.86–2.13], 2.94 [2.73–3.18], 3.97 [3.61–4.36], and 5.47 [4.96–6.04] for overweight, obese class I, obese class II, and obese class III women, respectively) compared with women with normal BMIs. Similarly, neonatal risks increased in a dose–response fashion with maternal BMI status including preterm birth at less than 32 weeks of gestation, large for gestational age (LGA), transient tachypnea, sepsis, and intensive care unit admission. The percentage of LGA neonates increased from 7.9% among women with normal BMIs to 17.3% among obese class III women and relative risks increased to 1.52 (1.45–1.58), 1.74 (1.65–1.83), 1.93 (1.79–2.07), and 2.32 (2.14–2.52) as BMI category increased. CONCLUSION: Prepregnancy obesity is associated with increased risks of a wide range of adverse pregnancy and neonatal outcomes among women without chronic diseases.

Endocrine disrupting chemicals and endometriosis.

Endometriosis is an estrogen dependent gynecologic disease with lasting implications for many womens fertility, somatic health, and overall quality of life. Growing evidence suggests that endocrine disrupting chemicals (EDCs) may be etiologically involved in the development and severity of disease. We weigh the available human evidence focusing on EDCs and endometriosis, restricting to research that has individually quantified chemical concentrations for women, included a comparison group of unaffected women, and used multivariable analytic techniques. Evidence supporting an environmental etiology for endometriosis includes metals/trace elements, dioxins, and other persistent organic pollutants, as well as nonpersistent chemicals, such as benzophenones and phthalates. To address the equivocal findings for various EDCs, future research directions for filling data gaps include [1] use of integrated clinical and population sampling frameworks allowing for incorporation of new diagnostic modalities; [2] the collection of various biologic media, including target tissues for quantifying exposures; [3] study designs that offer various comparison groups to assess potentially shared etiologies with other gynecologic disorders; and [4] novel laboratory and statistical approaches that fully explore all measured EDCs for the assessment of mixtures and low dose effects and the use of directed acyclic graphs and supporting causal analysis for empirically delineating relationships between EDCs and endometriosis.

Racial/ethnic differences in preterm perinatal outcomes.

Background: Racial disparities in preterm birth and infant death have been well documented. Less is known about racial disparities in neonatal morbidities among infants who are born at <37 weeks of gestation. Objective: The purpose of this study was to determine whether the risk for morbidity and death among infants who are born preterm differs by maternal race. Study Design: A retrospective cohort design included medical records from preterm deliveries of 19,325 black, Hispanic, and white women in the Consortium on Safe Labor. Sequentially adjusted Poisson models with generalized estimating equations estimated racial differences in the risk for neonatal morbidities and death, controlling for maternal demographics, health behaviors, and medical history. Sex differences between and within race were examined. Results: Black preterm infants had an elevated risk for perinatal death, but there was no difference in risk for neonatal death across racial groups. Relative to white infants, black infants were significantly more likely to experience sepsis (9.1% vs 13.6%), peri‐ or intraventricular hemorrhage (2.6% vs 3.3%), intracranial hemorrhage (0.6% vs 1.8%), and retinopathy of prematurity (1.0% vs 2.6%). Hispanic and white preterm neonates had similar risk profiles. In general, female infants had lower risk relative to male infants, with white female infants having the lowest prevalence of a composite indicator of perinatal death or any morbidity across all races (30.9%). Differences in maternal demographics, health behaviors, and medical history did little to influence these associations, which were robust to sensitivity analyses of pregnancy complications as potential underlying mechanisms. Conclusion: Preterm infants were at similar risk for neonatal death, regardless of race; however, there were notable racial disparities and sex differences in rare, but serious, adverse neonatal morbidities.

Persistent organic pollutants and pregnancy complications.

We sought to investigate the relationship between maternal preconception exposures to persistent organic pollutants (POPs) and pregnancy complications, gestational diabetes (GDM) and gestational hypertension. Data from 258 (51%) women with human chorionic gonadotropin (hCG) confirmed pregnancies reaching ≥24weeks gestation, from a prospective cohort of 501 couples who discontinued contraception to attempt pregnancy, were analyzed. Preconception concentrations of 9 organochlorine pesticides (OCPs) and 10 polybrominated diphenyl ethers (PBDEs) were quantified in serum. In separate multiple logistic regression models of self-reported physician diagnosed outcomes: GDM (11%) and gestational hypertension (10%), chemicals were natural log-transformed and rescaled by their standard deviation (SD). Models were adjusted for serum lipids, and then adjusted for age, body mass index, race, and smoking. Models were additionally adjusted for the sum of the remaining POPs in each chemical class. Womens serum concentration of PBDE congener 153 (PBDE-153) was positively associated with an increased odds of GDM per SD increase in log-transformed concentration, for unadjusted (OR=1.36, 95%CI: 1.02-1.81), a priori adjusted (OR=1.38, 95% CI: 1.03-1.86) and with the sum of remaining PBDEs (OR=1.79, 95% CI: 1.18, 2.74) models. Our findings suggest that at environmentally relevant concentrations, maternal exposure to POPs prior to conception may contribute to increased chance of developing GDM.

The Exposome Research Paradigm: an Opportunity to Understand the Environmental Basis for Human Health and Disease

Purpose of ReviewThis paper presents an overview of the exposome research paradigm with particular application to understanding human reproduction and development and its implications for health across a lifespan.Recent FindingsThe exposome research paradigm has generated considerable discussion about its feasibility and utility for delineating the impact of environmental exposures on human health. Early initiatives are underway, including smaller proof-of-principle studies and larger concerted efforts. Despite the notable challenges underlying the exposome paradigm, analytic techniques are being developed to handle its untargeted approach and correlated and multi-level or hierarchical data structures such initiatives generate, while considering multiple comparisons. The relatively short intervals for critical and sensitive windows of human reproduction and development seem well suited for exposome research and may revolutionize our understanding of later onset diseases.SummaryEarly initiatives suggest that the exposome paradigm is feasible, but its utility remains to be established with applications to population human health research.

Is human fecundity changing? A discussion of research and data gaps precluding us from having an answer

Fecundity, the biologic capacity to reproduce, is essential for the health of individuals and is, therefore, fundamental for understanding human health at the population level. Given the absence of a population (bio)marker, fecundity is assessed indirectly by various individual-based (e.g. semen quality, ovulation) or couple-based (e.g. time-to-pregnancy) endpoints. Population monitoring of fecundity is challenging, and often defaults to relying on rates of births (fertility) or adverse outcomes such as genitourinary malformations and reproductive site cancers. In light of reported declines in semen quality and fertility rates in some global regions among other changes, the question as to whether human fecundity is changing needs investigation. We review existing data and novel methodological approaches aimed at answering this question from a transdisciplinary perspective. The existing literature is insufficient for answering this question; we provide an overview of currently available resources and novel methods suitable for delineating temporal patterns in human fecundity in future research.

Proximity to major roadways and prospectively-measured time-to-pregnancy and infertility

We aimed to study the potential impact of proximity to major roadways on time-to-pregnancy and infertility in couples attempting pregnancy in the Longitudinal Investigation of Fertility and Environment (LIFE) study (2005-2009), a population-based, prospective cohort study. Couples attempting pregnancy (n=500) were enrolled and followed prospectively until pregnancy or 12months of trying and 393 couples (78%) had complete data and full follow-up. Time-to-pregnancy was based on a standard protocol using fertility monitors, tracking estrone-3-glucuonide and luteinizing hormone, and pregnancy test kits to detect human chorionic gonadotropin (hCG). The fecundability odds ratio (FOR) and 95% confidence interval (CI) were estimated using proportional odds models. Infertility was defined as 12months of trying to conceive without an hCG pregnancy and the relative risk (RR) and 95% CI were estimated with log-binomial regression. Final models were adjusted for age, parity, study site, and salivary alpha-amylase, a stress marker. Infertile couples (53/393; 14%) tended to live closer to major roadways on average than fertile couples (689m vs. 843m, respectively) but the difference was not statistically significant. The likelihood of pregnancy was increased 3% for every 200m further away the couples residence was from a major roadway (FOR=1.03; CI=1.01-1.06). Infertility also appeared elevated at moderate distances compared to 1000m or greater, but estimates lacked precision. Our findings suggest that proximity to major roadways may be related to reductions in fecundity. Prospective data from larger populations is warranted to corroborate these findings.

Endocrine disrupting chemicals in seminal plasma and couple fecundity

&NA; Growing evidence supports the importance of mens 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 womens 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. HighlightsNon‐persistent endocrine disruptors were detected and quantified in seminal plasma.Concentrations were lower in seminal plasma than in urine.Benzophenones were associated with reduced fecundability, but not significantly.Bi‐directional associations for other endocrine disruptors, but not significant. Abbreviations: BP‐1: 2,4‐dihydroxybenzophenone; BP‐2: 2,2′,4,4′‐tetrahydroxybenzophenone; BP‐3: 2‐hydroxy‐4‐methoxybenzophenone; BP‐8: 2,2′‐dihydroxy‐4‐methoxybenzophenone; 4‐OH‐BP: 4‐hydroxybenzophenone; BPA: bisphenol A;; BPF: bisphenol F;; BPS: bisphenol S; BuP: butyl‐paraben; BzBP: benzyl butyl phthalate; BzP: benzyl‐paraben; CI: confidence interval; DBP: di‐n‐butyl phthalate; DCHP: dicyclohexyl phthalate; DEHP: di(2‐ethylhexyl) phthalate; DEP: diethyl phthalate; DIBP: diisobutyl phthalate; DMP: dimethyl phthalate; DNHP: di‐n‐hexyl phthalate; DOP: di‐n‐octyl phthalate;; EDC: endocrine disrupting chemicals; EtP: ethyl‐paraben; FOR: fecundability odds ratio; HeP: heptyl‐paraben; 4‐HB: 4‐hydroxybenzoic acid; 3,4‐DHB: 3,4‐dihydroxybenzoic acid; MnBP: mono‐n‐butyl phthalate; MBzP: mono‐benzyl phthalate; MCHP: mono‐cyclohexyl phthalate; MCMHP: mono‐[(2‐carboxymethyl) hexyl] phthalate; MCPP: mono‐(3‐carboxypropyl) phthalate; MIDP: mono‐(8‐methyl‐1‐nonyl) phthalate; MECPP: mono‐(2‐ethyl‐5‐carboxypentyl) phthalate; MEHHP: mono‐(2‐ethyl‐5‐hydroxyhexyl) phthalate; MEOHP: mono‐(2‐ethyl‐5‐oxohexyl) phthalate; MEP: mono‐ethyl phthalate; MeP: methyl‐paraben; MHxP: mono‐hexyl phthalate; MIBP: mono‐2‐isobutyl phthalate; MINP: mono‐isononyl phthalate; MMP: mono‐methyl phthalate; MOP: mono‐octyl phthalate; PrP: propyl‐paraben; TCC: triclocarban; TCS: triclosan; TTP: time‐to‐pregnancy.

Male urinary paracetamol and semen quality

The endocrine‐disrupting properties of paracetamol have been previously demonstrated in rodent studies of abnormal sperm morphology and diminished testosterone production, in addition to epidemiologic studies of diminished couple fecundity. In this study, we examined the relationship between paracetamol and its metabolite p‐aminophenol quantified in a single spot urine and semen quality among 501 male partners of couples planning for pregnancy. Men provided a urine specimen and two fresh semen samples collected approximately one month apart and underwent 24‐h analysis for 35 semen quality parameters. Paracetamol and p‐aminophenol were quantified in urine by ultra‐high‐performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry. The relationship between natural‐log‐transformed urinary paracetamol and p‐aminophenol rescaled by their standard deviation and 21 Box‐Cox‐transformed, 14 non‐transformed semen parameters was assessed using linear mixed‐effects models. The median concentrations (IQR) of urinary paracetamol and p‐aminophenol were 15.5 ng/mL (5.44, 73.5) and 978 ng/mL (500, 1596), respectively. Following adjustment for creatinine and age, a 1‐standard deviation increase in log‐transformed urinary paracetamol was associated with a reduction in beat cross‐frequency and an increase in DNA fragmentation [β (95% CI): −0.59 Hz (−1.16, −0.03) and 0.05% (0.01, 0.09), respectively]. These findings were corroborated in models of categorical chemical concentrations; higher concentrations of paracetamol remained associated with reduced beat cross‐frequency and increased DNA fragmentation. A 1‐standard deviation increase in log‐transformed urinary p‐aminophenol was associated with a reduction in sperm head area [β (95% CI): −0.1 μm2 (−0.18, −0.02) and width −0.02 μm (−0.04, −0.01)]. However, only the association with sperm head area remained statistically significant in models of p‐aminophenol quartiles. Our findings suggest that adult male urinary paracetamol is associated with sperm motility and DNA fragmentation, while the metabolite, p‐aminophenol, is predominantly associated with sperm head morphometry.