Yu Zhang1, Vicente Mustieles2, Paige L Williams3, Blair J Wylie4, Irene Souter5, Antonia M Calafat6, Melina Demokritou7, Alexandria Lee8, Stylianos Vagios5, Russ Hauser1, Carmen Messerlian9. 1. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 2. University of Granada, Center for Biomedical Research (CIBM), Spain; Instituto de Investigación Biosanitaria Ibs GRANADA, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 18100, Spain. 3. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 4. Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, MA, USA. 5. Massachusetts General Hospital Fertility Center, Harvard Medical School, Boston, MA, USA; Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA. 6. National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA. 7. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 8. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 9. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Massachusetts General Hospital Fertility Center, Harvard Medical School, Boston, MA, USA; Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: cmesser@hsph.harvard.edu.
Abstract
BACKGROUND: Parental preconception exposure to select phenols and phthalates was previously associated with increased risk of preterm birth in single chemical analyses. However, the joint effect of phenol and phthalate mixtures on preterm birth is unknown. METHODS: We included 384 female and 211 male (203 couples) participants seeking infertility treatment in the Environment and Reproductive Health (EARTH) Study who gave birth to 384 singleton infants between 2005 and 2018. Mean preconception urinary concentrations of bisphenol A (BPA), parabens, and eleven phthalate biomarkers, including di(2-ethylhexyl) phthalate (DEHP) metabolites, were examined. We used principal component analysis (PCA) with log-Poisson regression and Probit Bayesian Kernel Machine Regression (BKMR) with hierarchical variable selection to examine maternal and paternal phenol and phthalate mixtures in relation to preterm birth. Couple-based BKMR model was fit to assess couples' joint mixtures in relation to preterm birth. RESULTS: PCA identified the same four factors for maternal and paternal preconception mixtures. Each unit increase in PCA scores of maternal (adjusted Risk Ratio (aRR): 1.36, 95%CI: 1.00, 1.84) and paternal (aRR: 1.47, 95%CI: 0.90, 2.42) preconception DEHP-BPA factor was positively associated with preterm birth. Maternal and paternal BKMR models consistently presented the DEHP-BPA factor with the highest group Posterior Inclusion Probability (PIP). BKMR models further showed that maternal preconception BPA and mono(2-ethyl-5-hydroxyhexyl) phthalate, and paternal preconception mono(2-ethylhexyl) phthalate were positively associated with preterm birth when the remaining mixture components were held at their median concentrations. Couple-based BKMR models showed a similar relative contribution of paternal (PIP: 61%) and maternal (PIP: 77%) preconception mixtures on preterm birth. We found a positive joint effect on preterm birth across increasing quantiles of couples' total mixture concentrations. CONCLUSION: In this prospective cohort of subfertile couples, maternal BPA and DEHP, and paternal DEHP exposure before conception were positively associated with preterm birth. Both parental windows jointly contributed to the outcome. These results suggest that preterm birth may be a couple-based pregnancy outcome.
BACKGROUND: Parental preconception exposure to select phenols and phthalates was previously associated with increased risk of preterm birth in single chemical analyses. However, the joint effect of phenol and phthalate mixtures on preterm birth is unknown. METHODS: We included 384 female and 211 male (203 couples) participants seeking infertility treatment in the Environment and Reproductive Health (EARTH) Study who gave birth to 384 singleton infants between 2005 and 2018. Mean preconception urinary concentrations of bisphenol A (BPA), parabens, and eleven phthalate biomarkers, including di(2-ethylhexyl) phthalate (DEHP) metabolites, were examined. We used principal component analysis (PCA) with log-Poisson regression and Probit Bayesian Kernel Machine Regression (BKMR) with hierarchical variable selection to examine maternal and paternal phenol and phthalate mixtures in relation to preterm birth. Couple-based BKMR model was fit to assess couples' joint mixtures in relation to preterm birth. RESULTS: PCA identified the same four factors for maternal and paternal preconception mixtures. Each unit increase in PCA scores of maternal (adjusted Risk Ratio (aRR): 1.36, 95%CI: 1.00, 1.84) and paternal (aRR: 1.47, 95%CI: 0.90, 2.42) preconception DEHP-BPA factor was positively associated with preterm birth. Maternal and paternal BKMR models consistently presented the DEHP-BPA factor with the highest group Posterior Inclusion Probability (PIP). BKMR models further showed that maternal preconception BPA and mono(2-ethyl-5-hydroxyhexyl) phthalate, and paternal preconception mono(2-ethylhexyl) phthalate were positively associated with preterm birth when the remaining mixture components were held at their median concentrations. Couple-based BKMR models showed a similar relative contribution of paternal (PIP: 61%) and maternal (PIP: 77%) preconception mixtures on preterm birth. We found a positive joint effect on preterm birth across increasing quantiles of couples' total mixture concentrations. CONCLUSION: In this prospective cohort of subfertile couples, maternal BPA and DEHP, and paternal DEHP exposure before conception were positively associated with preterm birth. Both parental windows jointly contributed to the outcome. These results suggest that preterm birth may be a couple-based pregnancy outcome.
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