Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program

Jiwon Oh¹, Jessie P Buckley^{2

3

4}, Xuan Li², Kennedy K Gachigi³, Kurunthachalam Kannan^{5

6}, Wenjie Lyu^{7

8}, Jennifer L Ames⁹, Emily S Barrett^{10

11}, Theresa M Bastain¹², Carrie V Breton¹², Claudia Buss^{13

14}, Lisa A Croen⁹, Anne L Dunlop¹⁵, Assiamira Ferrara⁹, Akhgar Ghassabian^{7

8

16}, Julie B Herbstman¹⁷, Ixel Hernandez-Castro¹², Irva Hertz-Picciotto^{1

18}, Linda G Kahn^{7

16}, Margaret R Karagas¹⁹, Jordan R Kuiper², Cindy T McEvoy²⁰, John D Meeker²¹, Rachel Morello-Frosch²², Amy M Padula²³, Megan E Romano¹⁹, Sheela Sathyanarayana²⁴, Susan Schantz²⁵, Rebecca J Schmidt^{1

18}, Hyagriv Simhan²⁶, Anne P Starling^{27

28}, Frances A Tylavsky²⁹, Heather E Volk³⁰, Tracey J Woodruff²³, Yeyi Zhu⁹, Deborah H Bennett¹; program collaborators for Environmental influences on Child Health Outcomes

Affiliations

¹ Department of Public Health Sciences, University of California Davis (UC-Davis), Davis, California, USA.
² Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill (UNC-Chapel Hill), Chapel Hill, North Carolina, USA.
⁵ Wadsworth Center, Division of Environmental Health Sciences, New York State Department of Health, Albany, New York, USA.
⁶ Department of Environmental Health Sciences, University at Albany, State University of New York, Albany, New York, USA.
⁷ Department of Pediatrics, New York University (NYU) Grossman School of Medicine, New York, New York, USA.
⁸ Department of Environmental Medicine, NYU Grossman School of Medicine, New York, New York, USA.
⁹ Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
¹⁰ Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey, USA.
¹¹ Environmental and Occupational Health Sciences Institute, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
¹² Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA.
¹³ Department of Medical Psychology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁴ Department of Pediatrics, UC-Irvine School of Medicine, Orange, California, USA.
¹⁵ Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁶ Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA.
¹⁷ Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York, USA.
¹⁸ Medical Investigations of Neurodevelopmental Disorders Institute, UC-Davis, Sacramento, California, USA.
¹⁹ Department of Epidemiology, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire, USA.
²⁰ Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA.
²¹ Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
²² Department of Environmental Science, Policy and Management and School of Public Health, UC-Berkeley, Berkeley, California, USA.
²³ Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA.
²⁴ Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, Washington, USA.
²⁵ Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
²⁶ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
²⁷ Department of Epidemiology, Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, North Carolina, USA.
²⁸ Center for Lifecourse Epidemiology of Adiposity and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
²⁹ Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
³⁰ Department of Mental Health, Johns Hopkins University, Baltimore, Maryland, USA.

PMID: 38262621
PMCID: PMC10805613
DOI: 10.1289/EHP13182

Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program

Jiwon Oh et al. Environ Health Perspect. 2024 Jan.

. 2024 Jan;132(1):17004.

doi: 10.1289/EHP13182. Epub 2024 Jan 24.

Authors

Affiliations

¹ Department of Public Health Sciences, University of California Davis (UC-Davis), Davis, California, USA.
² Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill (UNC-Chapel Hill), Chapel Hill, North Carolina, USA.
⁵ Wadsworth Center, Division of Environmental Health Sciences, New York State Department of Health, Albany, New York, USA.
⁶ Department of Environmental Health Sciences, University at Albany, State University of New York, Albany, New York, USA.
⁷ Department of Pediatrics, New York University (NYU) Grossman School of Medicine, New York, New York, USA.
⁸ Department of Environmental Medicine, NYU Grossman School of Medicine, New York, New York, USA.
⁹ Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
¹⁰ Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey, USA.
¹¹ Environmental and Occupational Health Sciences Institute, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
¹² Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA.
¹³ Department of Medical Psychology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁴ Department of Pediatrics, UC-Irvine School of Medicine, Orange, California, USA.
¹⁵ Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁶ Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA.
¹⁷ Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York, USA.
¹⁸ Medical Investigations of Neurodevelopmental Disorders Institute, UC-Davis, Sacramento, California, USA.
¹⁹ Department of Epidemiology, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire, USA.
²⁰ Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA.
²¹ Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
²² Department of Environmental Science, Policy and Management and School of Public Health, UC-Berkeley, Berkeley, California, USA.
²³ Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA.
²⁴ Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, Washington, USA.
²⁵ Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
²⁶ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
²⁷ Department of Epidemiology, Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, North Carolina, USA.
²⁸ Center for Lifecourse Epidemiology of Adiposity and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
²⁹ Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
³⁰ Department of Mental Health, Johns Hopkins University, Baltimore, Maryland, USA.

PMID: 38262621
PMCID: PMC10805613
DOI: 10.1289/EHP13182

Erratum in

Erratum: "Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program".
Oh J, Buckley JP, Li X, Gachigi KK, Kannan K, Lyu W, Ames JL, Barrett ES, Bastain TM, Breton CV, Buss C, Croen LA, Dunlop AL, Ferrara A, Ghassabian A, Herbstman JB, Hernandez-Castro I, Hertz-Picciotto I, Kahn LG, Karagas MR, Kuiper JR, McEvoy CT, Meeker JD, Morello-Frosch R, Padula AM, Romano ME, Sathyanarayana S, Schantz S, Schmidt RJ, Simhan H, Starling AP, Tylavsky FA, Volk HE, Woodruff TJ, Zhu Y, Bennett DH; and program collaborators for Environmental influences on Child Health Outcomes. Oh J, et al. Environ Health Perspect. 2024 Apr;132(4):49003. doi: 10.1289/EHP14968. Epub 2024 Apr 10. Environ Health Perspect. 2024. PMID: 38598327 Free PMC article. No abstract available.

Abstract

Background: Widespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results.

Objectives: We conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex.

Methods: We included 6,646 pregnant participants from 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program. Nine OPE biomarkers were quantified in maternal urine samples collected primarily during the second and third trimester and modeled as $\log_{2}$ -transformed continuous, categorized (high/low/nondetect), or dichotomous (detect/nondetect) variables depending on detection frequency. We used covariate-adjusted linear, logistic, and multinomial regression with generalized estimating equations, accounting for cohort-level clustering, to estimate associations of OPE biomarkers with gestational length and birth weight outcomes. Secondarily, we assessed effect modification by sex.

Results: Three OPE biomarkers [diphenyl phosphate (DPHP), a composite of dibutyl phosphate and di-isobutyl phosphate (DBUP/DIBP), and bis(1,3-dichloro-2-propyl) phosphate] were detected in $> 85 %$ of participants. In adjusted models, DBUP/DIBP [odds ratio (OR) per $doubling = 1.07$ ; 95% confidence interval (CI): 1.02, 1.12] and bis(butoxyethyl) phosphate (OR for high vs. $nondetect = 1.25$ ; 95% CI: 1.06, 1.46), but not other OPE biomarkers, were associated with higher odds of preterm birth. We observed effect modification by sex for associations of DPHP and high bis(2-chloroethyl) phosphate with completed gestational weeks and odds of preterm birth, with adverse associations among females. In addition, newborns of mothers with detectable bis(1-chloro-2-propyl) phosphate, bis(2-methylphenyl) phosphate, and dipropyl phosphate had higher birth weight-for-gestational-age $z$ -scores ( $β$ for detect vs. $nondetect = 0.04 - 0.07$ ); other chemicals showed null associations.

Discussion: In the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182.

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Figures

Figure 1 is a set of twenty error bar graphs. The first five graphs on the left are titled Preterm, plotting odds ratio (95 percent confidence interval), ranging from 0.8 to 1.2 in increments of 0.2; 0.8 to 1.2 in increments of 0.2; 0.4 to 1.6 in increments of 0.6; 0.2 to 1.8 in increments of 0.8; and 0.5 to 1.5 in increments of 0.5 (y-axis) across diphenyl phosphate; composite of dibutyl phosphate and di-isobutyl phosphate; low and high bis(2-chloroethyl) phosphate; low and high bis(butoxyethyl) phosphate; and low and high bis(1-chloro-2-propyl) phosphate (x-axis) for all, female, and male. The next five graphs are titled early-term, plotting odds ratio (95 percent confidence interval), ranging from 0.8 to 1.2 in increments of 0.2; 0.8 to 1.2 in increments of 0.2; 0.6 to 1.4 in increments of 0.4; 0.5 to 1.5 in increments of 0.5; and 0.4 to 1.6 in increments of 0.6 (y-axis) across diphenyl phosphate; composite of dibutyl phosphate and di-isobutyl phosphate; low and high bis(2-chloroethyl) phosphate; low and high bis(butoxyethyl) phosphate; and low and high bis(1-chloro-2-propyl) phosphate (x-axis) for all, female, and male. The next five graphs are titled gestational age, plotting lowercase beta (95 percent confidence interval), ranging from negative 0.07 to 0.07 in increments of 0.07; negative 0.09 to 0.09 in increments of 0.09; negative 0.3 to 0.3 in increments of 0.3; negative 0.3 to 0.3 in increments of 0.3; negative 0.3 to 0.3 in increments of 0.3 (y-axis) across diphenyl phosphate; composite of dibutyl phosphate and di-isobutyl phosphate; low and high bis(2-chloroethyl) phosphate; low and high bis(butoxyethyl) phosphate; and low and high bis(1-chloro-2-propyl) phosphate (x-axis) for all, female, and male. The next five graphs are titled birth weight for gestational age, plotting lowercase beta (95 percent confidence interval), ranging from negative 0.07 to 0.07 in increments of 0.07; negative 0.06 to 0.06 in increments of 0.06; negative 0.2 to 0.2 in increments of 0.2; negative 0.2 to 0.2 in increments of 0.2; and negative 0.2 to 0.2 in increments of 0.2 (y-axis) across diphenyl phosphate; composite of dibutyl phosphate and di-isobutyl phosphate; low and high bis(2-chloroethyl) phosphate; low and high bis(butoxyethyl) phosphate; and low and high bis(1-chloro-2-propyl) phosphate (x-axis) for all, female, and male. — **Figure 1.**
Associations of DPHP, DBUP/DIBP, BCETP, BBOEP, and BCPP with preterm ( $lowercase italic n equals 449$ ) and early-term ( $lowercase italic n equals 1,436$ ), compared with full-term birth ( $lowercase italic n equals 3,947$ ), gestational age (in weeks) ( $lowercase italic n equals 6,646$ ), and BW-GA $z$ -score ( $lowercase italic n equals 6,646$ ) among all newborns in the ECHO cohorts, and stratified by child’s sex (females: $lowercase italic n equals 3,250$ , males: $lowercase italic n equals 3,396$ ). Point estimates indicate regression coefficients or odds ratios (ORs), and error bars indicate 95% confidence intervals (CIs). Regression models were adjusted for maternal race/ethnicity, maternal age at delivery, maternal education, maternal marital status, maternal prepregnancy BMI, maternal smoking during pregnancy, parity, child’s sex, and sample collection season and year. Sample size of each birth outcome by child’s sex is presented in Table 2, and numeric data regarding regression coefficients, ORs, 95% CIs, and $p$ -values for main effects and interaction terms between child’s sex and OPE biomarkers are presented in Tables 4, 5, S7, and S8. Note: BBOEP, bis(butoxyethyl) phosphate; BCETP, bis(2-chloroethyl) phosphate; BCPP, bis(1-chloro-2-propyl) phosphate; BMI, body mass index; BW-GA, birth weight for gestational age; DBUP/DIBP, composite of dibutyl phosphate and di-isobutyl phosphate; DPHP, diphenyl phosphate; ECHO, Environmental influences on Child Health Outcomes.

See this image and copyright information in PMC

References

1. Blum A, Behl M, Birnbaum LS, Diamond ML, Phillips A, Singla V, et al. . 2019. Organophosphate ester flame retardants: are they a regrettable substitution for polybrominated diphenyl ethers? Environ Sci Technol Lett 6(11):638–649, PMID: , 10.1021/acs.estlett.9b00582. - DOI - PMC - PubMed
1. Liu Y, Gong S, Ye L, Li J, Liu C, Chen D, et al. . 2021. Organophosphate (OP) diesters and a review of sources, chemical properties, environmental occurrence, adverse effects, and future directions. Environ Int 155:106691, PMID: , 10.1016/j.envint.2021.106691. - DOI - PubMed
1. Yang Y, Chen P, Ma S, Lu S, Yu Y, An T. 2022. A critical review of human internal exposure and the health risks of organophosphate ester flame retardants and their metabolites. Crit Rev Environ Sci Technol 52(9):1528–1560, 10.1080/10643389.2020.1859307. - DOI
1. Wei GL, Li DQ, Zhuo MN, Liao YS, Xie ZY, Guo TL, et al. . 2015. Organophosphorus flame retardants and plasticizers: sources, occurrence, toxicity and human exposure. Environ Pollut 196:29–46, PMID: , 10.1016/j.envpol.2014.09.012. - DOI - PubMed
1. Saillenfait AM, Ndaw S, Robert A, Sabaté JP. 2018. Recent biomonitoring reports on phosphate ester flame retardants: a short review. Arch Toxicol 92(9):2749–2778, PMID: , 10.1007/s00204-018-2275-z. - DOI - PubMed

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Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program

Affiliations

Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program

Authors

Affiliations

Erratum in

Abstract

Figures

References

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