Urinary Phthalate Metabolite Concentrations and Reproductive Outcomes among Women Undergoing in Vitro Fertilization: Results from the EARTH Study

Abstract

Background:Evidence from both animal and human studies suggests that exposure to phthalates may be associated with adverse female reproductive outcomes.Objective:We evaluated the associations between urinary concentrations of phthalate metabolites and outcomes of assisted reproductive technologies (ART).Methods:This analysis included 256 women enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2004–2012) who provided one to two urine samples per cycle before oocyte retrieval. We measured 11 urinary phthalate metabolites [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-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monoethyl phthalate (MEP), monocarboxyisooctyl phthalate (MCOP), monocarboxyisononyl phthalate (MCNP), and mono(3-carboxypropyl) phthalate (MCPP)]. We used generalized linear mixed models to evaluate the association of urinary phthalate metabolites with in vitro fertilization (IVF) outcomes, accounting for multiple IVF cycles per woman.Results:In multivariate models, women in the highest as compared with lowest quartile of MEHP, MEHHP, MEOHP, MECPP, ΣDEHP (MEHP + MEHHP + MEOHP + MECPP), and MCNP had lower oocyte yield. Similarly, the number of mature (MII) oocytes retrieved was lower in the highest versus lowest quartile for these same phthalate metabolites. The adjusted differences (95% CI) in proportion of cycles resulting in clinical pregnancy and live birth between women in the fourth versus first quartile of ΣDEHP were –0.19 (–0.29, –0.08) and –0.19 (–0.28, –0.08), respectively, and there was also a lower proportion of cycles resulting in clinical pregnancy and live birth for individual DEHP metabolites.Conclusions:Urinary concentrations of DEHP metabolites were inversely associated with oocyte yield, clinical pregnancy, and live birth following ART.Citation:Hauser R, Gaskins AJ, Souter I, Smith KW, Dodge LE, Ehrlich S, Meeker JD, Calafat AM, Williams PL, for the EARTH Study Team. 2016. Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study. Environ Health Perspect 124:831–839; http://dx.doi.org/10.1289/ehp.1509760

Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility center

“…We previously reported that urinary DEHP concentrations were negatively associated with oocyte yield (Hauser et al 2015) and therefore, the negative association between urinary MHiNCH concentrations and total oocyte yield could be partially driven by DEHP exposure. As expected, urinary MHiNCH and DEHP metabolite concentrations were moderately correlated (r=0.65, p=0.03).…”

“…Because of their widespread use, their urinary metabolites are generally detected in the U.S., European, and Canadian general populations (Dewalque et al 2014, Saravanabhavan et al 2013, Schutze et al 2014, Tefre de Renzy-Martin et al 2014, Zota et al 2014). Because of their potential adverse effects on human health (Braun et al 2013, Dodge et al 2015, Hauser et al 2015, Messerlian et al 2016, Miodovnik et al 2014), the use of certain phthalates in diverse products have been banned (or banned from use in high amounts) in the European Union (EU 2005), Canada (Canada 2012), and in the U.S. by the Consumer Product Safety Commission (CPSC 2008). Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer, was introduced commercially in 2002 as a safer alternative to ortho-phthalate esters because of a more favorable toxicological profile (EFSA 2006, SCENIHR 2015).…”

“…We recently published that urinary concentrations of the metabolites of di-(2-ethylhexyl) phthalate (DEHP), the most common PVC phthalate plasticizer (Hauser and Calafat 2005) were negatively associated with oocyte yield, clinical pregnancy and live birth among women following in vitro fertilization (IVF) treatments in an academic fertility clinic in Boston, MA (Hauser et al 2015). In the current study, we explored the associations between urinary concentrations of DINCH metabolites on IVF outcomes in a subsample of women from the same study cohort with urinary concentrations of DINCH measured.…”

Parental contributions to early embryo development: influences of urinary phthalate and phthalate alternatives among couples undergoing IVF treatment

“…Studies from the Environmental and Reproductive Health (EARTH) have reported that male partner preconception urinary concentrations of select phthalate metabolites were associated with decreased odds of implantation and live birth among couples seeking fertility treatment, while female partner phthalate metabolite concentrations were associated with lower mature and overall oocyte yield as well as decreased probability of clinical pregnancy and live birth; however, no associations were observed with embryo quality at the cleavage stage (Day 3) (Dodge et al, 2015;Hauser et al, 2016). These results suggest that parental contributions to early life development may appear after Day 3, the cleavage stage, when the embryo transitions away from maternal control and zygotic genome activation occurs.…”

Low-Level Prenatal Toxin Exposures and Breastfeeding Duration: A Prospective Cohort Study

“…Higher exposures to phthalates have been associated with decreased anogenital distance (Braun et al 2013), diminished oocyte yield for in-vitro fertilization (Hauser 2015), decreased maternal thyroid levels (Boas et al 2012) and increased prenatal blood pressure and pregnancy-induced hypertensive diseases (Werner et al 2015). Phthalates are metabolized and excreted in the urine.…”