Publications by authors named "Margaret A Adgent"

21 Publications

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

J Clin Endocrinol Metab 2021 Aug;106(9):2635-2645

Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

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.
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http://dx.doi.org/10.1210/clinem/dgab354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372659PMC
August 2021

Gestational diabetes and childhood asthma in a racially diverse US pregnancy cohort.

Pediatr Allergy Immunol 2021 08 7;32(6):1190-1196. Epub 2021 May 7.

Division of General Pediatrics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Childhood asthma is a common chronic disease that likely has prenatal origins. Gestational diabetes alters maternal physiology and may influence fetal risk for childhood-onset disease. However, the association between gestational diabetes and child asthma is not well characterized.

Objective: To investigate the association between gestational diabetes and wheeze/asthma at approximately 4 years of age in a racially diverse US cohort.

Methods: We studied mother-child dyads enrolled prenatally in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study. Gestational diabetes was determined by medical chart review. At approximately 4 years of age, we assessed child respiratory outcomes including parent report of physician-diagnosed asthma (ever), current wheeze (symptoms within the past 12 months), and current asthma (physician diagnosis and/or medication or symptoms within the past 12 months). We used the modified Poisson regression to assess associations between gestational diabetes and child respiratory outcomes, adjusting for maternal age, race, prenatal smoking, pre-pregnancy body mass index, parity, asthma history, socioeconomic status, and infant sex.

Results: Among 1107 women, 66% were African American/Black. Six percent (n = 62) had gestational diabetes documented during pregnancy. Gestational diabetes was associated with increased risk of physician-diagnosed asthma (adjusted risk ratio (RR) [95% Confidence Interval]: 2.13 [1.35, 3.38]; prevalence: 14%), current wheeze (RR: 1.85 [1.23, 2.78]; prevalence: 19%), and current asthma (RR: 2.01 [1.30, 3.10]; prevalence: 16%).

Conclusions: Gestational diabetes was associated with increased risk of asthma and wheeze outcomes. Additional studies are needed to elucidate modifiable pathways underlying this association.
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http://dx.doi.org/10.1111/pai.13523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328913PMC
August 2021

Developing a Standardized and Reusable Method to Link Distributed Health Plan Databases to the National Death Index: Methods Development Study Protocol.

JMIR Res Protoc 2020 Nov 2;9(11):e21811. Epub 2020 Nov 2.

Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, United States.

Background: Certain medications may increase the risk of death or death from specific causes (eg, sudden cardiac death), but these risks may not be identified in premarket randomized trials. Having the capacity to examine death in postmarket safety surveillance activities is important to the US Food and Drug Administration's (FDA) mission to protect public health. Distributed networks of electronic health plan databases used by the FDA to conduct multicenter research or medical product safety surveillance studies often do not systematically include death or cause-of-death information.

Objective: This study aims to develop reusable, generalizable methods for linking multiple health plan databases with the Centers for Disease Control and Prevention's National Death Index Plus (NDI+) data.

Methods: We will develop efficient administrative workflows to facilitate multicenter institutional review board (IRB) review and approval within a distributed network of 6 health plans. The study will create a distributed NDI+ linkage process that avoids sharing of identifiable patient information between health plans or with a central coordinating center. We will develop standardized criteria for selecting and retaining NDI+ matches and methods for harmonizing linked information across multiple health plans. We will test our processes within a use case comprising users and nonusers of antiarrhythmic medications.

Results: We will use the linked health plan and NDI+ data sets to estimate the incidences and incidence rates of mortality and specific causes of death within the study use case and compare the results with reported estimates. These comparisons provide an opportunity to assess the performance of the developed NDI+ linkage approach and lessons for future studies requiring NDI+ linkage in distributed database settings. This study is approved by the IRB at Harvard Pilgrim Health Care in Boston, MA. Results will be presented to the FDA at academic conferences and published in peer-reviewed journals.

Conclusions: This study will develop and test a reusable distributed NDI+ linkage approach with the goal of providing tested NDI+ linkage methods for use in future studies within distributed data networks. Having standardized and reusable methods for systematically obtaining death and cause-of-death information from NDI+ would enhance the FDA's ability to assess mortality-related safety questions in the postmarket, real-world setting.

International Registered Report Identifier (irrid): DERR1-10.2196/21811.
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http://dx.doi.org/10.2196/21811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669437PMC
November 2020

A combined cohort analysis of prenatal exposure to phthalate mixtures and childhood asthma.

Environ Int 2020 10 30;143:105970. Epub 2020 Jul 30.

Department of Occupational and Environmental Health Sciences, Box 357234, University of Washington, Seattle, WA 98195-7234, USA; Department of Pediatrics, Box 356320, University of Washington, Seattle, WA 98195-6320, USA; Seattle Children's Research Institute, 2001 8th Ave, Seattle, WA 98121, USA.

Background: Previous studies of prenatal phthalate exposure and childhood asthma are inconsistent. These studies typically model phthalates as individual, rather than co-occurring, exposures. We investigated whether prenatal phthalates are associated with childhood wheeze and asthma using a mixtures approach.

Methods: We studied dyads from two prenatal cohorts in the ECHO-PATHWAYS consortium: CANDLE, recruited 2006-2011 and TIDES, recruited 2011-2013. Parents reported child respiratory outcomes at age 4-6 years: ever asthma, current wheeze (symptoms in past 12 months) and current asthma (two affirmative responses from ever asthma, recent asthma-specific medication use, and/or current wheeze). We quantified 11 phthalate metabolites in third trimester urine and estimated associations with child respiratory outcomes using weighted quantile sum (WQS) logistic regression, using separate models to estimate protective and adverse associations, adjusting for covariates. We examined effect modification by child sex and maternal asthma.

Results: Of 1481 women, most identified as White (46.6%) or Black (44.6%); 17% reported an asthma history. Prevalence of ever asthma, current wheeze and current asthma in children was 12.3%, 15.8% and 12.3%, respectively. Overall, there was no adverse association with respiratory outcomes. In sex-stratified analyses, boys' phthalate index was adversely associated with all outcomes (e.g., boys' ever asthma: adjusted odds ratio per one quintile increase in WQS phthalate index (AOR): 1.42; 95% confidence interval (CI): 1.08, 1.85, with mono-ethyl phthalate (MEP) weighted highest). Adverse associations were also observed in dyads without maternal asthma history, driven by MEP and mono-butyl phthalate (MBP), but not in those with maternal asthma history. We observed protective associations between the phthalate index and respiratory outcomes in analysis of all participants (e.g., ever asthma: AOR; 95% CI: 0.81; 0.68, 0.96), with di(2-ethylhexyl)phthalate (DEHP) metabolites weighted highest.

Conclusions: Results suggest effect modification by child sex and maternal asthma in associations between prenatal phthalate mixtures and child asthma and wheeze.
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http://dx.doi.org/10.1016/j.envint.2020.105970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708520PMC
October 2020

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

Paediatr Perinat Epidemiol 2021 01 13;35(1):75-82. Epub 2020 Apr 13.

Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.

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.
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http://dx.doi.org/10.1111/ppe.12673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554126PMC
January 2021

Prenatal Omega-3 and Omega-6 Polyunsaturated Fatty Acids and Childhood Atopic Dermatitis.

J Allergy Clin Immunol Pract 2020 03 15;8(3):937-944. Epub 2019 Oct 15.

Division of General Pediatrics, Vanderbilt University Medical Center, Nashville, Tenn; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tenn. Electronic address:

Background: Atopic dermatitis is a common childhood disease, potentially influenced by prenatal nutritional exposures such as polyunsaturated fatty acids (PUFAs).

Objective: In a racially diverse cohort, we hypothesized that childhood atopic dermatitis would be associated with higher prenatal omega-6 (n-6) and lower omega-3 (n-3) PUFAs.

Methods: We included mother-child dyads, births 2006 to 2011, enrolled in the University of Tennessee Health Sciences Center Conditions Affecting Neurocognitive Development in Early Childhood cohort. Primary exposures included second trimester plasma n-3 and n-6 PUFA status and the ratio of the two (n-6:n-3). We assessed child current atopic dermatitis symptoms in the previous 12 months at age approximately 4 to 6 years. We investigated the association between PUFA exposures and atopic dermatitis using multivariable logistic regression, adjusting for potential confounders. We assessed for effect modification by maternal prenatal smoking, atopic disease history, and child sex.

Results: Among 1131 women, 67% were African American and 42% had an atopic disease history; 17% of children had atopic dermatitis. Higher prenatal n-6 PUFAs were associated with increased relative odds of child atopic dermatitis (adjusted odds ratio: 1.25; confidence interval: 1.01-1.54 per interquartile range difference), and interaction models demonstrated that this association was seen in dyads in which the women had a history of atopic disease. Neither prenatal n-3 PUFAs nor n-6:n-3 were associated with child atopic dermatitis.

Conclusion: In this racially diverse cohort, higher second trimester n-6 PUFAs were associated with atopic dermatitis in children of women with atopy. PUFAs may represent a modifiable risk factor for atopic dermatitis, particularly in individuals with a familial predisposition.
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http://dx.doi.org/10.1016/j.jaip.2019.09.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064417PMC
March 2020

Maternal childhood and lifetime traumatic life events and infant bronchiolitis.

Paediatr Perinat Epidemiol 2019 07 17;33(4):262-270. Epub 2019 Jun 17.

Division of General Pediatrics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Viral bronchiolitis is a common respiratory infection that often affects term, otherwise healthy infants. A small literature suggests maternal stress during pregnancy is associated with bronchiolitis. However, the association between maternal exposure to lifetime traumatic stress, including traumatic events occurring in childhood or throughout the life course, and bronchiolitis has not been studied previously.

Objectives: To investigate the association between maternal exposure to total lifetime and childhood traumatic stress events and infant bronchiolitis.

Methods: We studied mother-infant dyads enrolled in a prospective prenatal cohort, recruited 2006-2011, and Tennessee Medicaid. During pregnancy, we assessed maternal lifetime exposure to types of traumatic events by questionnaire. We captured bronchiolitis diagnoses in term, non-low birthweight infants' first 12 months using linked Medicaid data. In separate models, we assessed the association of maternal lifetime traumatic events (0 to 20 types) and a subset of traumatic events that occurred during childhood (0 to 3: family violence, sexual, and physical abuse) and infant bronchiolitis using multivariable log-binomial models.

Results: Of 629 women, 85% were African American. The median count (interquartile range) of lifetime traumatic events was 3 (2, 5); 42% reported ≥1 childhood traumatic event. Among infants, 22% had a bronchiolitis diagnosis (0 to 2 lifetime traumatic events: 24%; 3 events: 20%; 4 to 5 events: 18%; 6 or more events: 24%). Total maternal lifetime traumatic events were not associated with bronchiolitis in multivariable analyses. For maternal childhood traumatic events, the risk of infant bronchiolitis increased with number of event types reported: adjusted Risk ratios were 1.12 (95% confidence interval [CI] 0.80, 1.59), 1.31 (95% CI 0.83, 2.07), and 2.65 (95% CI 1.45, 4.85) for 1, 2, and 3 events, respectively, vs none.

Conclusions: Infants born to women reporting multiple types of childhood trauma were at higher risk for bronchiolitis. Further research is needed to explore intergenerational effects of traumatic experiences.
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http://dx.doi.org/10.1111/ppe.12559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660418PMC
July 2019

Prenatal vitamin D levels and child wheeze and asthma.

J Matern Fetal Neonatal Med 2021 Feb 2;34(3):323-331. Epub 2019 May 2.

Division of General Pediatrics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.

Maternal vitamin D status during pregnancy may influence lung development and risk of childhood wheeze and asthma. We investigated the relationship between prenatal vitamin D and child asthma in a racially diverse cohort with a high burden of vitamin D insufficiency and child asthma. We included mother-child dyads in the prenatal Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort (2006-2011, Shelby County, Tennessee). Maternal plasma vitamin D [25(OH)D] was measured from second trimester ( = 1091) and delivery specimens ( = 907). At age 4-6 years, we obtained parent report of current child wheeze (symptoms within the past 12 months) and asthma (physician diagnosis and/or medication or symptoms within the past 12 months). We used multivariable logistic regression to assess associations of 25(OH)D and child wheeze/asthma, including an interaction term for maternal race. Median second trimester 25(OH)D levels were 25.1 and 19.1 ng/ml in White ( = 366) and Black women ( = 725), respectively. We detected significant interactions by maternal race for second-trimester plasma 25(OH)D and child current wheeze ( = .014) and asthma ( = .011). Odds of current wheeze and asthma decreased with increasing 25(OH)D in dyads with White mothers and increased in dyads with Black mothers, e.g. adjusted odds ratio (95% confidence interval) for asthma: 0.63 (0.36-1.09) and 1.41 (1.01-1.97) per interquartile range (15-27 ng/ml 25[OH]D) increase, respectively. At delivery, protective associations in White dyads were attenuated. We detected effect modification by maternal race in associations between prenatal 25(OH)D and child wheeze/asthma. Further research in racially diverse populations is needed.
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http://dx.doi.org/10.1080/14767058.2019.1607286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824925PMC
February 2021

Incidental findings during ultrasound of thyroid, breast, testis, uterus and ovary in healthy term neonates.

J Ultrasound 2019 Sep 27;22(3):395-400. Epub 2019 Feb 27.

Department of Radiology, Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA, 19104, USA.

Incidental sonographic findings in thyroid and estrogen-responsive organs have been described in children and adults, but no publications describe incidental findings of these organs in infancy. We describe ultrasound features in thyroid, breast buds, testes, uterus, and ovaries in infants up to 32 weeks old that vary from the expected tissue architecture. Infants described in this paper were enrolled as healthy term neonates in a longitudinal study of normal feeding practices. Radiology reports for ultrasound exams in these infants described a range of findings that are similar to those reported in older populations. Knowledge of these asymptomatic variants occurring in infancy may guide radiologists in interpretation of these findings during clinical exams.
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http://dx.doi.org/10.1007/s40477-019-00365-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704211PMC
September 2019

Soy-based infant formula feeding and menstrual pain in a cohort of women aged 23-35 years.

Hum Reprod 2019 Jan;34(1):148-154

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.

Study Question: Is soy formula feeding during infancy associated with menstrual pain in reproductive-age women?

Summary Answer: Our data suggest that soy formula feeding during infancy is associated with several indicators of severe menstrual pain in reproductive-age women.

What Is Known Already: A prior study observed greater severity of menstrual pain in young women who as infants participated in feeding studies and were assigned to soy-based formula feeding.

Study Design, Size, Duration: We used data from the Study of Environment, Lifestyle & Fibroids (SELF), a cohort of 1696 African-American women ages 23-35 years at enrollment.

Participants/materials, Settings, Methods: Data on infant soy formula feeding was ascertained by self-administered questionnaire for 1553 participants, with 89% of participants receiving assistance from their mothers. Information on menstrual pain indicators was collected by web- and telephone-interview. We estimated the relative risk (RR) and 95% confidence interval (CI) using log-binomial regression, or log-multinomial regression, adjusting for participant age and maternal education.

Main Results And The Role Of Chance: Women ever fed soy formula as infants were more likely than unexposed women to report ever use of hormonal contraception for menstrual pain (RR 1.4, CI: 1.1-1.9) and moderate/severe menstrual discomfort/pain with 'most periods', but not 'every period', during early adulthood (ages 18-22 when not using hormonal contraception) (RR 1.5, CI: 1.1-2.0).

Limitations, Reasons For Caution: We relied on retrospective recall to ascertain infant exposure to soy formula feeding and data on menstrual pain indicators.

Wider Implications Of The Findings: Our observations add to the growing body of literature from animal and human studies on the reproductive health consequences of early-life exposure to soy formula.

Study Funding/competing Interest(s): This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and, in part, by funds allocated for health research by the American Recovery and Reinvestment Act. This research was also supported by grant K99NR017191 (KU). None of the authors has a conflict of interest.

Trial Registration Number: Not applicable.
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http://dx.doi.org/10.1093/humrep/dey303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296212PMC
January 2019

A Longitudinal Study of Estrogen-Responsive Tissues and Hormone Concentrations in Infants Fed Soy Formula.

J Clin Endocrinol Metab 2018 05;103(5):1899-1909

Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Purpose: Chemicals with hormonelike activity, such as estrogenic isoflavones, may perturb human development. Infants exclusively fed soy-based formula are highly exposed to isoflavones, but their physiologic responses remain uncharacterized. Estrogen-responsive postnatal development was compared in infants exclusively fed soy formula, cow-milk formula, and breast milk.

Methods: We enrolled 410 infants born in Philadelphia-area hospitals between 2010 and 2014; 283 were exclusively fed soy formula (n = 102), cow-milk formula (n = 111), or breast milk (n = 70) throughout the study (birth to 28 or 36 weeks for boys and girls, respectively). We repeatedly measured maturation index (MI) in vaginal and urethral epithelial cells using standard cytological methods, uterine volume and breast-bud diameter using ultrasound, and serum estradiol and follicle-stimulating hormone levels. We estimated MI, organ-growth, and hormone trajectories by diet using mixed-effects regression splines.

Results: Maternal demographics did not differ between cow-milk-fed and soy-fed infants but did differ between formula-fed and breastfed infants. Vaginal-cell MI trended higher (P = 0.01) and uterine volume decreased more slowly (P = 0.01) in soy-fed girls compared with cow-milk-fed girls; however, their trajectories of breast-bud diameter and hormone concentrations did not differ. We observed no significant differences between boys fed cow-milk vs soy formula; estradiol was not detectable. Breastfed infants differed from soy-formula-fed infants in vaginal-cell MI, uterine volume, and girls' estradiol and boys' breast-bud diameter trajectories.

Conclusions: Relative to girls fed cow-milk formula, those fed soy formula demonstrated tissue- and organ-level developmental trajectories consistent with response to exogenous estrogen exposure. Studies are needed to further evaluate the effects of soy on child development.
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http://dx.doi.org/10.1210/jc.2017-02249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456922PMC
May 2018

Size of testes, ovaries, uterus and breast buds by ultrasound in healthy full-term neonates ages 0-3 days.

Pediatr Radiol 2016 Dec 31;46(13):1837-1847. Epub 2016 Aug 31.

Department of Radiology, The Children's Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadelphia, PA, 19104, USA.

Background: Hormonally sensitive organs in the neonate can change size within days of birth as circulating maternal estrogen wanes. Although several reports document the size of these organs through infancy, few focus attention on the near-birth period. Clinical and research evaluation of hormonal and genitourinary disorders would benefit from reference size standards.

Objective: We describe the size of the uterus, ovaries, testes and breast buds in healthy term neonates.

Materials And Methods: As part of the Infant Feeding and Early Development (IFED) study, we sonographically measured the largest diameter of these organs in sagittal, transverse and anterior-posterior planes for 194 female and 204 male newborns up to 3 days old. We calculated mean, median and percentiles for longest axis length and for volume calculated from measured diameters. We evaluated size differences by laterality, gender and race and compared our observations against published values.

Results: Mean length and mean volume were as follows: uterus, 4.2 cm and 10.0 cm; ovary, 1.0 cm and 0.2 cm; testis, 1.1 cm and 0.3 cm (0.4 cm Lambert volume); female breast bud, 1.2 cm and 0.7 cm; male breast bud, 1.1 cm and 0.6 cm. Breast buds were larger in females than males. Laterality differences were typically below the precision of clinical measurement. No significant race differences were detected.

Conclusion: Using data from our large cohort together with published values, we provide guidelines for evaluating the size of reproductive organs within the first 3 days of age. Discrepancies between our results and published values are likely attributable to technique.
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http://dx.doi.org/10.1007/s00247-016-3681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744487PMC
December 2016

Environmental factors, epigenetics, and developmental origin of reproductive disorders.

Reprod Toxicol 2017 03 12;68:85-104. Epub 2016 Jul 12.

Reproductive Medicine Group, Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States. Electronic address:

Sex-specific differentiation, development, and function of the reproductive system are largely dependent on steroid hormones. For this reason, developmental exposure to estrogenic and anti-androgenic endocrine disrupting chemicals (EDCs) is associated with reproductive dysfunction in adulthood. Human data in support of "Developmental Origins of Health and Disease" (DOHaD) comes from multigenerational studies on offspring of diethylstilbestrol-exposed mothers/grandmothers. Animal data indicate that ovarian reserve, female cycling, adult uterine abnormalities, sperm quality, prostate disease, and mating behavior are susceptible to DOHaD effects induced by EDCs such as bisphenol A, genistein, diethylstilbestrol, p,p'-dichlorodiphenyl-dichloroethylene, phthalates, and polyaromatic hydrocarbons. Mechanisms underlying these EDC effects include direct mimicry of sex steroids or morphogens and interference with epigenomic sculpting during cell and tissue differentiation. Exposure to EDCs is associated with abnormal DNA methylation and other epigenetic modifications, as well as altered expression of genes important for development and function of reproductive tissues. Here we review the literature exploring the connections between developmental exposure to EDCs and adult reproductive dysfunction, and the mechanisms underlying these effects.
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http://dx.doi.org/10.1016/j.reprotox.2016.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233640PMC
March 2017

Triclosan and prescription antibiotic exposures and enterolactone production in adults.

Environ Res 2015 Oct 23;142:66-71. Epub 2015 Jun 23.

Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, P.O. Box 12233 Research Triangle Park, NC 27709, USA.

Background: The gut microbiome plays an important role in the development of disease. The composition of the microbiome is influenced by factors such as mode of delivery at birth, diet and antibiotic use, yet the influence of environmental chemical exposures is largely unknown. The antimicrobial compound triclosan, found in many personal care products and widely detected in human urine, is an environmental exposure for which systemic microbiotic effects may be of particular interest. To investigate the relationship between triclosan and gut microflora, we assessed the association between triclosan and enterolactone, an intestinal metabolite that is produced via bacterial transformation of dietary lignans (seeds, nuts) and has known susceptibility to oral antibiotics.

Methods: We examined urinary triclosan and enterolactone for 2005-2008 U.S. National Health and Nutrition Examination Survey subjects, aged ≥20 years (n=3041). We also examined the association between prescription antibiotic use and enterolactone to confirm its susceptibility to changes in bacterial composition of the body. Associations between natural log-transformed enterolactone and (1) detected vs. not detected (<2.3 ng/mL) triclosan, (2) triclosan quintiles (Q1-Q5), and (3) any vs. no antibiotics were estimated with multiple linear regression, adjusting for sex, age, race, body mass index, poverty income ratio, education, fiber intake, bowel movement frequency, cotinine and creatinine (n=2441).

Results: Triclosan was detected in 80% of subjects (range: <2.3-3620 ng/mL), while enterolactone was detected in >99% of subjects (range: <0.1-122,000 ng/mL). After adjustment, enterolactone was not associated with triclosan (detect vs. non-detect: β= 0.07 (95% CI: -0.15, 0.30); Q5 (≥104.5 ng/mL) vs. Q1 (none): β= 0.06 (95% CI: -0.21, 0.34)). In sex-stratified analyses, triclosan was associated with higher enterolactone in women (detect vs. non-detect: β= 0.31 (95% CI: -0.07, 0.70), but not men β= -0.18 (95% CI: -0.47, 0.11). However, any antibiotic use (n=112), as compared to no antibiotic use, was associated with significantly lower enterolactone (β=-0.78 (95%CI: -1.22, -0.36)), with no sex-specific effects. This association was driven by inverse associations with the following antibiotic classes: macrolide derivatives, quinolones, sulfonamides, and lincomycin derivatives.

Conclusions: Antibiotics, but not triclosan, are negatively associated with urinary enterolactone. Antibiotics may reduce enterolactone by killing certain gut bacteria. At levels detected in the U.S., triclosan does not appear to be acting similarly, despite broad antimicrobial properties. Additional study of determinants of triclosan exposure and enterolactone production may be needed to better understand positive associations among women.
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http://dx.doi.org/10.1016/j.envres.2015.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609256PMC
October 2015

Brominated flame retardants in breast milk and behavioural and cognitive development at 36 months.

Paediatr Perinat Epidemiol 2014 Jan 19;28(1):48-57. Epub 2013 Aug 19.

National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Background: Polybrominated diphenyl ethers (PBDEs) are persistent flame retardants found in the environment, in household dust, and in humans. Breast feeding is a prominent route of exposure in infancy. PBDEs adversely affect neurodevelopment in animals. Here, we estimate associations between PBDEs in breast milk and behaviour and cognitive skills in children at 36 months of age.

Methods: We prospectively studied 304 mothers and their children. We measured PBDEs in breast milk collected at 3 months postpartum. At 36 months, we measured child behaviour with the parent-rated Behavioral Assessment System for Children 2 (n = 192), and cognitive skills with the Mullen Scales of Early Learning (n = 184). We analysed data with robust regression.

Results: We detected BDE-28, -47, -99, -100, and -153 in >70% of milk samples. For each congener, the highest quartile of breast milk PBDE concentration, vs. the lowest, was associated with more anxious behaviour, after confounder adjustment. Select congeners were associated with increased withdrawal (BDE-28) and improved activity of daily living skills (BDE-153). Cognitive skills tended to be positively associated with PBDEs, especially language and fine motor skills. However, most estimates were imprecise.

Conclusions: Here, lactational PBDE exposure was modestly and imprecisely associated with anxiety and withdrawal, but was also associated with improved adaptive and cognitive skills. Positive factors associated with breast feeding may have mitigated some of the hypothesised adverse neurodevelopmental outcomes associated with PBDEs. Further research is needed to inform our understanding of PBDE neurotoxicity and how sources of exposure might confound neurodevelopmental studies.
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http://dx.doi.org/10.1111/ppe.12078DOI Listing
January 2014

Urogenital epithelial cells as simple markers of estrogen response in infants: methods and applications.

PLoS One 2013 16;8(10):e77061. Epub 2013 Oct 16.

Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, North Carolina, United States of America.

Exposure to estrogen-mimicking chemicals during critical periods of development, such as infancy, may have adverse effects. However, these effects can be difficult to characterize in most epidemiologic studies. For example, growth of reproductive organs may be susceptible to estrogenic chemicals, but measuring it requires skilled ultrasound examination; timing of pubertal onset may be altered, but observing it requires long-term follow up. To address the need for a simple marker of response to estrogenic exposures in infants, we propose a novel application of a classic marker of estrogen response in adult women: cytological evaluation of urogenital epithelial cells. In this cross-sectional study of 34 female and 41 male infants, we demonstrate that epithelial cells can be obtained from swabs of the vaginal introitus (females) and urethral meatus (males), as well as from spun urine, and that these cells respond to differential estrogenic conditions, as indicated by the relative abundance of the superficial epithelial cell type. To model varying estrogen exposure, we sampled from infants who were either newborn (highly exposed to maternal estrogens), or 12 weeks old (12 W) (negligibly exposed to estrogen). Newborns had a higher percentage of superficial cells (%S), as compared to 12 W (mean ± standard error: 8.3 ± 1.8 vs. 0.9 ± 0.2) (p < 0.01), consistent with an estrogen response. This difference in %S from newborn to 12 W was observed similarly for swab (-7.6 ± 1.7) and urine (-7.3 ± 2.6) specimens and for males (-9.6 ± 2.9) and females (-5.2 ± 2.1). Examination of urogenital epithelial cells can successfully demonstrate estrogen response in both sexes, using cell specimens collected from either swab or urine sampling. In future studies, this simple, non-invasive method may be applied to assess whether estrogen-mimicking chemicals produce an estrogenic response in infants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077061PLOS
August 2014

Desferrioxamine inhibits protein tyrosine nitration: mechanisms and implications.

Free Radic Biol Med 2012 Aug 15;53(4):951-61. Epub 2012 Jun 15.

Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Tissues are exposed to exogenous and endogenous nitrogen dioxide ((·)NO(2)), which is the terminal agent in protein tyrosine nitration. Besides iron chelation, the hydroxamic acid (HA) desferrioxamine (DFO) shows multiple functionalities including nitration inhibition. To investigate mechanisms whereby DFO affects 3-nitrotyrosine (3-NT) formation, we utilized gas-phase (·)NO(2) exposures, to limit introduction of other reactive species, and a lung surface model wherein red cell membranes (RCM) were immobilized under a defined aqueous film. When RCM were exposed to ()NO(2) covered by +/- DFO: (i) DFO inhibited 3-NT formation more effectively than other HA and non-HA chelators; (ii) 3-NT inhibition occurred at very low[DFO] for prolonged times; and (iii) 3-NT formation was iron independent but inhibition required DFO present. DFO poorly reacted with (·)NO(2) compared to ascorbate, assessed via (·)NO(2) reactive absorption and aqueous-phase oxidation rates, yet limited 3-NT formation at far lower concentrations. DFO also inhibited nitration under aqueous bulk-phase conditions, and inhibited 3-NT generated by active myeloperoxidase "bound" to RCM. Per the above and kinetic analyses suggesting preferential DFO versus (·)NO(2) reaction within membranes, we conclude that DFO inhibits 3-NT formation predominantly by facile repair of the tyrosyl radical intermediate, which prevents (·)NO(2) addition, and thus nitration, and potentially influences biochemical functionalities.
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http://dx.doi.org/10.1016/j.freeradbiomed.2012.06.003DOI Listing
August 2012

Early-life soy exposure and age at menarche.

Paediatr Perinat Epidemiol 2012 Mar 16;26(2):163-75. Epub 2011 Dec 16.

Department of Epidemiology, Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, NC, USA.

This study examines the timing of menarche in relation to infant-feeding methods, specifically addressing the potential effects of soy isoflavone exposure through soy-based infant feeding. Subjects were participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers were enrolled during pregnancy and their children have been followed prospectively. Early-life feeding regimes, categorised as primarily breast, early formula, early soy and late soy, were defined using infant-feeding questionnaires administered during infancy. For this analysis, age at menarche was assessed using questionnaires administered approximately annually between ages 8 and 14.5. Eligible subjects were limited to term, singleton, White females. We used Kaplan-Meier survival curves and Cox proportional hazards models to assess age at menarche and risk of menarche over the study period. The present analysis included 2920 girls. Approximately 2% of mothers reported that soy products were introduced into the infant diet at or before 4 months of age (early soy). The median age at menarche [interquartile range (IQR)] in the study sample was 153 months [144-163], approximately 12.8 years. The median age at menarche among early soy-fed girls was 149 months (12.4 years) [IQR, 140-159]. Compared with girls fed non-soy-based infant formula or milk (early formula), early soy-fed girls were at 25% higher risk of menarche throughout the course of follow-up (hazard ratio 1.25 [95% confidence interval 0.92, 1.71]). Our results also suggest that girls fed soy products in early infancy may have an increased risk of menarche specifically in early adolescence. These findings may be the observable manifestation of mild endocrine-disrupting effects of soy isoflavone exposure. However, our study is limited by few soy-exposed subjects and is not designed to assess biological mechanisms. Because soy formula use is common in some populations, this subtle association with menarche warrants more in-depth evaluation in future studies.
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http://dx.doi.org/10.1111/j.1365-3016.2011.01244.xDOI Listing
March 2012

Early-life soy exposure and gender-role play behavior in children.

Environ Health Perspect 2011 Dec 3;119(12):1811-6. Epub 2011 Aug 3.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27709-2233, USA.

Background: Soy-based infant formula contains high levels of isoflavones. These estrogen-like compounds have been shown to induce changes in sexually dimorphic behaviors in animals exposed in early development.

Objective: We examined gender-role play behavior in relation to soy-based and non-soy-based infant feeding methods among children in the Avon Longitudinal Study of Parents and Children.

Methods: We studied 3,664 boys and 3,412 girls. Four exposure categories were created using data from questionnaires administered at 6 and 15 months postpartum: primarily breast, early formula (referent), early soy, and late soy. Gender-role play behavior was assessed using the Pre-School Activities Inventory (PSAI). Associations between infant feeding and PSAI scores at 42 months of age were assessed using linear regression. Post hoc analyses of PSAI scores at 30 and 57 months were also conducted.

Results: Early-infancy soy use was reported for approximately 2% of participants. Mean [95% confidence interval (CI)] PSAI scores at 42 months were 62.3 (62.0, 62.6) and 36.9 (36.6, 37.2) for boys and girls, respectively. After adjustment, early soy (vs. early formula) feeding was associated with higher (less feminine) PSAI scores in girls (β = 2.66; 95% CI: 0.19, 5.12) but was not significantly associated with PSAI scores in boys. The association between soy exposure and PSAI scores in girls was substantially attenuated at 30 and 57 months.

Conclusions: Although not consistent throughout childhood, early-life soy exposure was associated with less female-typical play behavior in girls at 42 months of age. Soy exposure was not significantly associated with play behavior in boys.
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http://dx.doi.org/10.1289/ehp.1103579DOI Listing
December 2011

Environmental tobacco smoke and sudden infant death syndrome: a review.

Birth Defects Res B Dev Reprod Toxicol 2006 Feb;77(1):69-85

ASPH Environmental Public Health Fellow, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460, USA.

Environmental tobacco smoke (ETS), containing the developmental neurotoxicant, nicotine, is a prevalent component of indoor air pollution. Despite a strong association with active maternal smoking and sudden infant death syndrome (SIDS), information on the risk of SIDS due to prenatal and postnatal ETS exposure is relatively inconsistent. This literature review begins with a discussion and critique of existing epidemiologic data pertaining to ETS and SIDS. It then explores the biologic plausibility of this association, with comparison of the known association between active maternal smoking and SIDS, by examining metabolic and placental transfer issues associated with nicotine, and the biologic responses and mechanisms that may follow exposure to nicotine. Evidence indicates that prenatal and postnatal exposures to nicotine do occur from ETS exposure, but that the level of exposure is often substantially less than levels induced by active maternal smoking. Nicotine also has the capacity to concentrate in the fetus, regardless of exposure source. Experimental animal studies show that various doses of nicotine are capable of affecting a neonate's response to hypoxic conditions, a process thought to be related to SIDS outcomes. Mechanisms contributing to deficient hypoxia response include the ability of nicotine to act as a cholinergic stimulant through nicotinic acetylcholine receptor (nAChR) binding. The need for future research to investigate nicotine exposure and effects from non-maternal tobacco smoke sources in mid to late gestation is emphasized, along with a need to discourage smoking around both pregnant women and infants.
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http://dx.doi.org/10.1002/bdrb.20068DOI Listing
February 2006
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