Environmental Phenols and Growth in Infancy: The Infant Feeding and Early Development Study.

CONTEXT: Higher mean and rapid increases in body mass index (BMI) during infancy are associated with subsequent obesity and may be influenced by exposure to endocrine-disrupting chemicals such as phenols. OBJECTIVE: In a prospective US-based cohort conducted 2010-2014, we investigated associations between environmental phenol exposures and BMI in 199 infants. METHODS: We measured seven urinary phenols at ages 6-8 and 12 weeks and assessed BMI z-score at up to 12 study visits between birth and 36 weeks. We examined individual and joint associations of averaged early infancy phenols with level of BMI z-score using mean differences (ß [95% confidence intervals (CI)]) and with BMI z-score trajectories using relative risk ratios (RR [95% CI]). RESULTS: Benzophenone-3, methyl and propyl paraben, and all phenols jointly were positively associated with higher mean BMI z-score (0.07 [-0.05, 0.18], 0.10 [-0.08, 0.27], 0.08 [-0.09, 0.25], 0.17 [-0.08, 0.43], respectively). Relative to a Stable trajectory, benzophenone-3, 2,4-dichlorophenol, 2,5-dichlorophenol, and all phenols jointly were positively associated with risk of a Rapid Increase trajectory (1.46 [0.89, 2.39], 1.33 [0.88, 2.01], 1.66 [1.03, 2.68], 1.41 [0.71, 2.84], respectively). CONCLUSION: Early phenol exposure was associated with a higher mean and rapid increase in BMI z-score across infancy, signaling potential long-term cardiometabolic consequences of exposure.

A comparison of ultrasound-based testis volume with Prader orchidometry and stability of testis size relative to peers from birth to 28 weeks.

BACKGROUND: Testis volume, an indicator of the reproductive development during minipuberty, is commonly measured by Prader orchidometer, despite ultrasound being the gold standard. Data are lacking on the longitudinal relationship between these two measures and on the stability of boys' relative testis size across infancy. OBJECTIVES: To examine the relationship between ultrasound-based and orchidometer-based testis volume measurements and to assess the stability of relative testis size among individual boys in the study. MATERIALS AND METHODS: The Infant Feeding and Early Development study is a longitudinal cohort of healthy infants recruited from hospitals in the Philadelphia area during 2010-2013. We measured testis size from birth to 28 weeks in 147 infants using Prader orchidometry (nine study visits) and ultrasound (five study visits). We modeled testis growth, extracted predicted volumes for each boy on each day of the study, and ranked these volumes from smallest to largest. RESULTS: The average testis volume trajectory exhibited linear growth over the first 16 weeks followed by slower growth and then a plateau. Prader orchidometry overestimated testis size by almost 3-fold, compared to ultrasound. A range of ultrasound volumes corresponded to each bead size (e.g., bead size of 1 cm3 corresponded to an ultrasound-based volume between 0.11 and 0.87 cm3). Infants changed rankings of median of 22 positions (of 147) across the entire 6-month follow-up. Infants' ranks near birth were highly correlated with their ranks at the end of the study. DISCUSSION: Consistent with other studies, we found wide variability in testis size during infancy and that Prader orchidometry overestimates testis size. When compared to ultrasound, orchidometry only crudely estimates testis size in this age group. Ultrasound-based volumes generally showed stability in relative testis size across infancy. CONCLUSION: Accurate measurement of testis size is difficult using orchidometry in infants. This highlights the need for ultrasound for accurate measurement, with a one-time measurement likely sufficient to determine relative testis size across the first 6 months of infancy.

Environmental phenol exposures in 6- to 12-week-old infants: The Infant Feeding and Early Development (IFED) study.

BACKGROUND: Exposure to phenols, endocrine-disrupting chemicals used in personal care and consumer products, is widespread. Data on infant exposures are limited despite heightened sensitivity to endocrine disruption during this developmental period. We aimed to describe distributions and predictors of urinary phenol concentrations among U.S. infants ages 6-12 weeks. METHODS: The Infant Feeding and Early Development (IFED) study is a prospective cohort study of healthy term infants enrolled during 2010-2013 in the Philadelphia region. We measured concentrations of seven phenols in 352 urine samples collected during the 6- or 8- and/or 12-week study visits from 199 infants. We used linear mixed models to estimate associations of maternal, sociodemographic, infant, and sample characteristics with natural-log transformed, creatinine-standardized phenol concentrations and present results as mean percent change from the reference level. RESULTS: Median concentrations (µg/L) were 311 for methylparaben, 10.3 for propylparaben, 3.6 for benzophenone-3, 2.1 for triclosan, 1.0 for 2,5-dichlorophenol, 0.7 for BPA, and 0.3 for 2,4-dichlorophenol. Geometric mean methylparaben concentrations were approximately 10 times higher than published estimates for U.S. children ages 3-5 and 6-11 years, while propylparaben concentrations were 3-4 times higher. Infants of Black mothers had higher concentrations of BPA (83%), methylparaben (121%), propylparaben (218%), and 2,5-dichorophenol (287%) and lower concentrations of benzophenone-3 (-77%) and triclosan (-53%) than infants of White mothers. Triclosan concentrations were higher in breastfed infants (176%) and lower in infants whose mothers had a high school education or less (-62%). Phenol concentrations were generally higher in summer samples. CONCLUSIONS: Widespread exposure to select environmental phenols among this cohort of healthy U.S. infants, including much higher paraben concentrations compared to those reported for U.S. children, supports the importance of expanding population-based biomonitoring programs to infants and toddlers. Future investigation of exposure sources is warranted to identify opportunities to minimize exposures during these sensitive periods of development.

Asking MultiCrit Questions: A Reflexive and Critical Framework to Promote Health Data Equity for the Multiracial Population.

Policy Points Health equity work primarily centers monoracial populations; however, the rapid growth of the Multiracial population and increasingly clear health disparities affecting the people in that population complicate our understanding of racial health equity. Limited resources exist for health researchers and professionals grappling with this complexity, likely contributing to the relative dearth of health literature describing the Multiracial population. We introduce a question-based framework built on core principles from Critical Multiracial Theory (MultiCrit) and Critical Race Public Health Praxis, designed for researchers, clinicians, and policymakers to encourage health data equity for the Multiracial population.

Understanding the roles of state demographics and state policies in epidemiologic studies of maternal-child health disparities.

Disparities in maternal-child health outcomes by race and ethnicity highlight structural differences in the opportunity for optimal health in the United States. Examples of these differences include access to state-level social policies that promote maternal-child health. States vary in their racial and ethnic composition as a result of the complex history of policies and laws related to slavery, Indigenous genocide and relocation, segregation, immigration, and settlement in the United States. States also vary in the social policies they enact. As a result, correlations exist between the demographic makeup of a state's population and the presence or absence of social policies in that state. These correlations become a mechanism by which racial and ethnic disparities in maternal-child health outcomes can operate. In this commentary, we use the example of three labor-related policies actively under consideration at state and federal levels (paid parental leave, paid sick leave, and reasonable accommodations during pregnancy) to demonstrate how correlations between state demographics and presence of these state policies could cause or exacerbate racial and ethnic disparities in maternal-child health outcomes. We conclude with a call for researchers to consider how the geographic distribution of racialized populations and state policies could contribute to maternal-child health disparities.

Early Life Anti-Müllerian Hormone Trajectories in Infant Girls.

BACKGROUND: Minipuberty is a period of increased reproductive axis activity in infancy, but the importance of this period is not well understood, especially in girls. Previous studies reported a peak in hormone concentrations at 3 to 4 months old. Our objective is to describe anti-Müllerian hormone (AMH) trajectories in the context of other minipuberty factors among healthy infant girls using longitudinal measures of AMH. METHODS: The Infant Feeding and Early Development study is a longitudinal cohort study of healthy infants, recruited from hospitals in the Philadelphia area during 2010 to 2013. We measured AMH in 153 girls who contributed 1366 serum samples across 11 study visits over 36 weeks. We also measured follicle stimulating hormone (FSH), estradiol, and ovarian characteristics. We used latent class mixed effects models to cluster trajectories of AMH concentration with age. Using linear mixed models, we estimated FSH and ovarian characteristic trajectories separately by AMH cluster. RESULTS: We classified infants into four clusters that represent patterns of AMH that were high and decreasing (decreasing), had a peak around 12 weeks or 20 weeks (early peak and middle peak), or were consistently low (low). Infants in these clusters differed in their FSH trajectories, timing of estradiol production, and ovarian characteristics. CONCLUSIONS: The AMH clusters identified suggest variation in the timing and the magnitude of the minipuberty response in infant girls. The decreasing and low clusters have not been described previously and should be further evaluated to determine whether they represent an opportunity for the early identification of later reproductive conditions.

Outdoor air pollution and anti-Müllerian hormone concentrations in the Sister Study.

BACKGROUND: Anti-Müllerian hormone (AMH) concentrations are a marker of ovarian reserve and are indicative of a woman's reproductive lifespan. Exposure to tobacco smoke has been associated with lower AMH concentrations; however, less is known about the association between ambient air pollution and ovarian reserve. METHODS: For 883 premenopausal Sister Study participants recruited between 2003 and 2009 in the United States, adult residential annual average concentrations of PM2.5, PM10, and NO2 were estimated using validated universal kriging models incorporating land-use regression. We estimated the distance in meters to the nearest major road for both adult enrollment and childhood residences. Serum AMH was measured using an ultrasensitive ELISA assay. Samples with AMH concentrations below the detection limit were analyzed using a picoAMH ELISA assay. Multivariable-adjusted linear regression was used to estimate the percent change in AMH in relation to ambient residential air pollution, categorized in quartiles and per interquartile range increase, and distance to a major roadway. RESULTS: Overall, we observed little to no evidence of associations between AMH and air pollution concentrations or proximity to roadways. Women in the highest quartile of NO2 exposure, a traffic-related pollutant, had higher estimated AMH concentrations (Q4 vs. Q1, 42.9%; 95% CI = -3.4, 111.4) compared with the lowest quartile. However, lower mean AMH concentrations were observed for women living closer to a major roadway (<50 m to nearest roadway vs. ≥200 m = -32.9%; 95% CI = -56.1, 2.6). CONCLUSIONS: We saw little consistent evidence to support an association between outdoor air pollution and diminished ovarian reserve in US women ages 35-54.

Prevalence of Hirsutism Among Reproductive-Aged African American Women.

Background: Hirsutism is the most common clinical symptom of hyperandrogenism, but racial and ethnic-specific thresholds have not been established. Our objective was to characterize hirsutism using self-report of hair growth in a large sample of African American women. Materials and Methods: The Study of Environment, Lifestyle, and Fibroids is a prospective community-based cohort study of African American women (23-34 at recruitment). A total of 1568 participants received the modified Ferriman-Gallwey (mFG) pictorial assessment and were asked if they were ever bothered by excess hair. We estimated the prevalence of hirsutism (mFG score ≥8) and associations of acne, polycystic ovary syndrome (PCOS), and menstrual cycle characteristics with hirsutism. We also explored hirsutism defined by the 95th percentile of scores in our cohort (mFG = 11) and a newly recommended criterion, mFG = 4. Results: We could determine hirsutism status in 1556 women. Thirty-seven percent reported being bothered by excess hair, and 10% met the mFG criterion for hirsutism. History of severe facial acne was positively associated with hirsutism (prevalence ratio: 1.90; 95% confidence interval [CI]: 1.30-2.76), as was physician-diagnosed PCOS (2.22, 95% CI: 1.30-3.81). Women with irregular menstrual cycles were also more likely to report hirsutism (1.78, 95% CI: 1.00-3.18). Results were similar using mFG ≥11 and attenuated using mFG ≥4. Conclusions: Hirsutism prevalence was 10% in this community sample of African American women and was associated with PCOS, severe acne, and irregular menstrual cycles suggesting this represented hirsutism caused by hyperandrogenism. Ethnically diverse, population-based studies assessing the association between mFG score and androgen levels are needed to better understand the hirsutism threshold as a clinical marker of hyperandrogenism.

Reproductive Hormone Concentrations and Associated Anatomical Responses: Does Soy Formula Affect Minipuberty in Boys?

CONTEXT: Soy formula feeding is common in infancy and is a source of high exposure to phytoestrogens, documented to influence vaginal cytology in female infants. Its influence on minipuberty in males has not been established. OBJECTIVE: To assess the association between infant feeding practice and longitudinally measured reproductive hormones and hormone-responsive tissues in infant boys. METHODS: The Infant Feeding and Early Development study was a prospective cohort of maternal-infant dyads requiring exclusive soy formula, cow milk formula, or breast milk feeding during study follow-up. In the 147 infant boy participants, serum testosterone, luteinizing hormone, stretched penile length, anogenital distance, and testis volume were longitudinally assessed from birth to 28 weeks. We examined feeding-group differences in age trajectories for these outcomes using mixed-effects regression splines. RESULTS: Median serum testosterone was at pubertal levels at 2 weeks (176 ng/dL [quartiles: 124, 232]) and remained in this range until 12 weeks in all feeding groups. We did not observe differences in trajectories of hormone concentrations or anatomical measures between boys fed soy formula (n = 55) and boys fed cow milk formula (n = 54). Compared with breastfed boys (n = 38), soy formula-fed boys had a more rapid increase in penile length (P = .004) and slower initial lengthening of anogenital distance (P = .03), but no differences in hormone trajectories. CONCLUSION: Reproductive hormone concentrations and anatomical responses followed similar trajectories in soy and cow milk formula-fed infant boys. Our findings suggest that these measures of early male reproductive development do not respond to phytoestrogen exposure during infancy.

Douching or Perineal Talc Use and Prevalent Fibroids in Young African American Women.

Background: Black women are at an increased risk of developing fibroids, but the cause is unclear. Douching and perineal talc use are common lifestyle exposures among Black women, and may be risk factors for fibroid development. Materials and Methods: This cross-sectional study consisted of Black women 23-35 years of age in the metropolitan Detroit area (n = 1693) without prior diagnoses of fibroids and intact uteri. Main exposures were ever douching (yes/no) and any perineal talc use (ever/never). Main outcomes were prevalent fibroids at baseline (yes/no) and total fibroid volume at baseline (no fibroids/

Characterization of ovarian development in girls from birth to 9 months.

BACKGROUND: The minipuberty of infancy is a period of increased reproductive axis activity. Changes in reproductive hormone concentrations and organ size occur during this period, but longitudinal changes have not been well described. OBJECTIVES: The objective of this study was to characterize ovarian growth trajectories and ovarian follicle development during the first 9 months of life in a large longitudinal cohort of healthy girls. METHODS: Data from the Infant Feeding and Early Development Study, a longitudinal cohort study of oestrogen-responsive outcomes in healthy infants, were used to estimate ovarian growth trajectories and describe the presence of ovarian antral follicles in girls 0-9 months old. Ovarian ultrasound evaluations were performed on the infants within 72 hours of birth (newborn visit) and at 4, 8, 16, 24, and 32 weeks of age. Mixed-effects regression splines were used to characterize changes in ovarian volume during infancy and assess the association between the presence of ovarian follicles at the newborn visit and ovarian growth. RESULTS: This analysis included 163 girls with two or more ovarian ultrasounds in the study. Results from the estimated overall ovarian growth trajectory show that ovarian volume increases more than sixfold during the first 16 weeks after birth and then remains relatively stable in the later weeks of infancy. Among girls with observable ovaries at the newborn visit (n = 133), girls with at least one visible ovarian follicle showed more rapid initial ovarian growth compared with girls without visible follicles. CONCLUSIONS: Infant ovarian volume increased to a peak at 16 weeks, which was influenced by the number and size of developing follicles. This research contributes to future development of reference ranges for postnatal ovarian growth in healthy, term infants.

Improving Diversity and Promoting Inclusion in the Society for Epidemiologic Research Through Choice of Conference Location.

Scientific conferences provide attendees opportunities to network, share research, learn new skills and ideas, and initiate collaborations. Conference attendance is especially important for students and early-career researchers who are establishing their research careers or looking for jobs. However, attending conferences can be expensive, and the high cost of conference attendance might hit students and early-career researchers the hardest. According to a new member survey from the Society for Epidemiologic Research, early-career members are more racially and ethnically diverse than senior members, meaning that reducing financial barriers to conference participation might be an important consideration for increasing diversity among conference attendees. In this commentary, we discuss how choice of conference location-choosing less expensive cities nearer to more Society for Epidemiologic Research members-could reduce financial and other barriers to conference attendance for all members and improve diversity and inclusion in the Society.

Association of urinary concentrations of early pregnancy phthalate metabolites and bisphenol A with length of gestation.

BACKGROUND: Environmental exposure to phthalates and bisphenol A (BPA) may have endocrine disrupting effects that alter length of gestation. We assessed the association between the urinary concentrations of 11 phthalate metabolites and BPA with length of gestation in a cohort of women followed from before conception with daily 1st-morning urinary hormone measures that identified day of implantation. METHODS: Pre-implantation and post-implantation urinary phthalate metabolites and BPA concentrations were measured in pooled urine samples designed to limit single-measure variability due to the likely episodic nature of these exposures and the short half-life of these compounds. We estimated associations between these exposure biomarkers early in pregnancy with length of gestation from implantation to spontaneous birth. Cox proportional hazards models were used to estimate the hazard of birth among 125 naturally-conceived, singleton live births with censoring for medical interventions that artificially shortened pregnancy. RESULTS: Higher concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (a metabolite of di (2-ethylhexyl) phthalate (DEHP)) during the pre-implantation window were associated with reduced probability of birth, i.e., longer gestations (hazard ratio (HR): 0.55, 95% CI: 0.35, 0.86; p = 0.01). The HR for the molar sum of the four DEHP metabolites measured showed a similar association (HR: 0.67, 95% CI: 0.43, 1.05). Higher concentrations of mono (3-carboxypropyl) phthalate (MCPP), a non-specific metabolite of several high molecular-weight phthalates, measured post-implantation were associated with increased risk of earlier birth, i.e. shorter length of gestation, HR: 1.59, CI: 1.02, 2.49. CONCLUSIONS: Early gestational exposure to DEHP and possibly other high-molecular weight phthalates, (as reflected by urinary MCPP concentrations) may influence the length of pregnancy. Such effects could have consequences for neonatal and maternal health.

Intrauterine, Infant, and Childhood Factors and Ovarian Reserve in Young African American Women.

Background: Ovarian toxic exposures during early development may contribute to reduced ovarian reserve in adulthood. Materials and Methods: We explored a range of intrauterine, infant, and childhood factors in relation to a biomarker of ovarian reserve, anti-Müllerian hormone (AMH) concentrations, in adulthood. We conducted a cross-sectional exploratory study of 1600 African American women 23-35 years of age residing in the Detroit, Michigan metropolitan area, who had serum AMH measurements (Ansh Labs PicoAMH enzyme-linked immunosorbent assay) and no previous polycystic ovarian syndrome diagnosis. Information on 32 intrauterine, infant, and childhood factors was ascertained by self-administered questionnaires, with 87% of participants receiving assistance from mothers. The percent differences in AMH concentrations in relation to early-life factors and 95% confidence intervals (CIs) were estimated using multivariable linear regression, adjusting for age, current hormonal contraceptive use, and body mass index. Results: Of the early-life factors evaluated in this study, two maternal pregnancy factors were associated with lower AMH concentrations in adult participants. Participants whose mothers lived or worked on a farm (vs. neither lived nor worked on a farm) when pregnant with the participant had 42% lower AMH concentrations (95% CI = -62 to -9). Among participants whose mothers lived in Michigan when pregnant with the participant (n = 1238), maternal residence in Detroit for at least a month was associated with 22% lower AMH concentrations (95% CI = -34 to -8) in the participant. Conclusions: Further research is merited to replicate our findings and identify the aspects of maternal farm exposure and Detroit residence that may be associated with lower AMH concentrations.

Association of urinary concentrations of phthalate metabolites and bisphenol A with early pregnancy endpoints.

BACKGROUND: Phthalates and bisphenol A (BPA) are environmental contaminants that may affect early embryonic development. OBJECTIVE: To assess the association between phthalate metabolites and BPA with early pregnancy endpoints in a cohort of women followed from before conception. METHODS: We quantified 11 phthalate metabolites and BPA in 137 conception cycles from naturally conceived clinical pregnancies. Phthalate metabolites and BPA concentrations were measured in a pooled sample of three daily morning urine specimens. Daily urinary hormone measurements had previously been used to define ovulation, implantation, and corpus luteum rescue. We assessed associations between conception cycle exposures (phthalate biomarkers and BPA) and 1) time from ovulation to implantation; 2) type of corpus luteum rescue (timing and pattern of rise in progesterone: early, late, or no rise); and 3) rate of initial rise in hCG. RESULTS: Mono(3-carboxypropyl) phthalate (MCPP) and mono-isobutyl phthalate (MiBP) were associated with earlier implantation (6-8 days vs. 9 days (the most commonly observed); per natural log-unit, OR (95% CI) = 2.8 (1.2, 6.7) and OR (CI) = 2.1 (1.2, 3.7), respectively). Monoethyl phthalate (MEP) was associated with later implantation (10-12 days vs. 9 days); OR (CI) = 1.5 (1.0, 2.1). Compared with implantation on day 9, BPA was significantly associated with both earlier and later implantation (OR=2.2 for both). Women with concentrations above the median of monobenzyl phthalate (MBzP) (p = 0.04) or above the median of the molar sum of four di(2-ethylhexyl) phthalate metabolites (∑DEHP) (p = 0.08) had a slower initial rise in hCG. Increasing MCPP was associated with an increased odds of a late rise rescue (OR (CI) = 2.9 (1.0, 8.5); late rise vs. early rise), while increasing MEP was associated with a no rise rescue (OR (CI) = 1.6 (0.9, 2.8); no rise vs. early rise). CONCLUSIONS: The reported associations varied in their direction of effect, some potentially protective, others adverse. This may reflect the complexity with which these potential endocrine disrupting chemicals can be acting, but chance findings are also possible. Given that women continue to be exposed to these compounds (or their precursors), continued research on the effects they may have on pregnancy is warranted.

"Research on Infertility: Definition Makes a Difference" Revisited.

In a 1989 paper, Marchbanks et al. (Am J Epidemiol. 1989;130(2):259-267) noted inconsistent definitions of infertility across research and clinical practice and examined differences in prevalence estimates across definitions. Since their study, there have been substantial changes in society, technology, and clinical practice related to female reproductive health. In response, we revisited the original paper using data from a recent study among reproductive-aged women. Internal comparisons across various definitions of infertility were made by assessing how many and which women were classified as infertile, their age at infertility, and the probability of spontaneous pregnancy after infertility. Results were also compared with Marchbanks et al. Black women were more likely to be classified as infertile than white women based on the definition "12 months of unprotected intercourse" (40.1% vs. 33.7%) but less likely by "12 months of attempting pregnancy" (14.3% vs. 21.8%) and "visiting a doctor for help getting pregnant" (8.4% vs. 19.7%). After unprotected intercourse for 12 months, 36.1% of women who were attempting pregnancy spontaneously conceived by 6 months compared with 13.5% of women who were not attempting pregnancy. While our results for most infertility definitions were similar to those of Marchbanks et al., prevalence estimates continued to differ across demographic groups by definition.

Environmental chemicals and preterm birth: Biological mechanisms and the state of the science.

PURPOSE OF REVIEW: Preterm birth is a significant worldwide health problem of uncertain origins. The extant body of literature examining environmental contaminant exposures in relation to preterm birth is extensive but results remain ambiguous for most organic pollutants, metals and metalloids, and air pollutants. In the present review we examine recent epidemiologic studies investigating these associations, and identify recent advances and the state of the science. Additionally, we highlight biological mechanisms of action in the pathway between chemical exposures and preterm birth, including inflammation, oxidative stress, and endocrine disruption, that deserve more attention in this context. RECENT FINDINGS: Important advances have been made in the study of the environment and preterm birth, particularly in regard to exposure assessment methods, exploration of effect modification by co-morbidities and exposures, and in identification of windows of vulnerability during gestation. There is strong evidence for an association between maternal exposure to some persistent pesticides, lead, and fine particulate matter, but data on other contaminants is sparse and only suggestive trends can be noted with the current data. SUMMARY: Beyond replicating current findings, further work must be done to improve understanding of mechanisms underlying the associations observed between environmental chemical exposures and preterm birth. By examining windows of vulnerability, disaggregating preterm birth by phenotypes, and measuring biomarkers of mechanistic pathways in these epidemiologic studies we can improve our ability to detect associations with exposure, provide additional evidence for causality in an observational setting, and identify opportunities for intervention.