Parental preconception exposure to phenol and phthalate mixtures and the risk of preterm birth

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.

Keywords: BPA; Couple; DEHP; Preterm; Singleton; Subfertile.

Figure 1.

Univariate dose-response association (estimates and credible intervals) of maternal preconception phenol and phthalate metabolite concentrations on preterm birth estimate, holding all other biomarkers at their median concentrations among 384 mothers in the Environment and Reproductive Health (EARTH) Study, 2005–2018. Note: Bisphenol A (BPA); methylparaben; propylparaben; butylparaben; monoethyl phthalate (MEP); mono-n-butyl phthalate (MBP); mono-isobutyl phthalate (MiBP); monobenzyl phthalate (MBzP); mono(2-ethylhexyl) phthalate (MEHP); mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); mono(2-ethyl-5-oxohexyl) phthalate (MEOHP); mono(2-ethyl-5-carboxypentyl) phthalate (MECPP); mono(3-carboxypropyl) phthalate (MCPP); monocarboxyisooctyl phthalate (MCOP); monocarboxyisononyl phthalate (MCNP); models were adjusted for maternal age (continuous), BMI (continuous), ART (yes/no), smoking (ever/never), education (categorical), race (categorical).

Figure 2.

Univariate dose-response association (estimates and credible intervals) of paternal preconception phenol and phthalate metabolite concentrations on preterm birth estimate, holding all other biomarkers at their median concentrations among 211 fathers in the Environment and Reproductive Health (EARTH) Study, 2005–2018. Note: Bisphenol A (BPA); methylparaben; propylparaben; butylparaben; monoethyl phthalate (MEP); mono-n-butyl phthalate (MBP); mono-isobutyl phthalate (MiBP); monobenzyl phthalate (MBzP); mono(2-ethylhexyl) phthalate (MEHP); mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); mono(2-ethyl-5-oxohexyl) phthalate (MEOHP); mono(2-ethyl-5-carboxypentyl) phthalate (MECPP); mono(3-carboxypropyl) phthalate (MCPP); monocarboxyisooctyl phthalate (MCOP); monocarboxyisononyl phthalate (MCNP); models were adjusted for maternal and paternal age (continuous), maternal and paternal BMI (continuous), maternal and paternal smoking (ever/never), maternal education (categorical), maternal race (categorical), ART (yes/no).

Figure 3.

Univariate dose-response association (estimates and credible intervals) of couples’ preconception phenols and phthalates metabolite concentrations on preterm birth estimate, holding all other biomarkers at their median concentrations among 203 couples in the Environment and Reproductive Health (EARTH) Study, 2005–2018. Note: Bisphenol A (BPA); methylparaben; propylparaben; butylparaben; monoethyl phthalate (MEP); mono-n-butyl phthalate (MBP); mono-isobutyl phthalate (MiBP); monobenzyl phthalate (MBzP); mono(2-ethylhexyl) phthalate (MEHP); mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); mono(2-ethyl-5-oxohexyl) phthalate (MEOHP); mono(2-ethyl-5-carboxypentyl) phthalate (MECPP); mono(3-carboxypropyl) phthalate (MCPP); monocarboxyisooctyl phthalate (MCOP); monocarboxyisononyl phthalate (MCNP);models were adjusted for maternal age (continuous), BMI (continuous), ART (yes/no), smoking (ever/never), education (categorical), race (categorical).

Figure 4.

Cumulative effect (estimates and credible intervals) across per 5^th quantile above and below medians of maternal, paternal and couples’ total preconception mixture on preterm birth estimate in the Environment and Reproductive Health (EARTH) Study, 2005–2018. Note: Maternal model was restricted to women who participated as couples (n=203), paternal model included all fathers (n=211, i.e. 203 who participated as couples and 8 who participated independently), couples model included the 203 couples; reference group is the median concentration of the respective mixture; models for maternal and couples’ mixtures were adjusted for maternal age (continuous), BMI (continuous), ART (yes/no), smoking (ever/never), education (categorical), race (categorical); models for paternal mixtures were adjusted for maternal and paternal age (continuous), maternal and paternal BMI (continuous), maternal and paternal smoking (ever/never), maternal education (categorical), maternal race (categorical), ART (yes/no).