Associations between Phthalate Metabolite Concentrations in Follicular Fluid and Reproductive Outcomes among Women Undergoing in Vitro Fertilization/Intracytoplasmic Sperm Injection Treatment.

BACKGROUND: Phthalates have been reported to impair fertility in various studies. However, evidence exploring the associations between phthalate metabolites in follicular fluid (FF) and reproductive outcomes is lacking. OBJECTIVES: To investigate the associations between phthalate metabolite concentrations in FF and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes among women recruited from a fertility clinic. METHODS: We included 641 women undergoing IVF/ICSI treatment from December 2018 to January 2020. The levels of eight phthalate metabolites, including monoethyl phthalate (MEP), mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), were quantified in FF collected on the oocyte retrieval day. Associations between quartiles of individual phthalate metabolite concentrations and nine IVF/ICSI outcomes, including oocyte yield, mature oocyte number, two distinct pronuclei (2PN) zygote number, fertilization rate, blastocyst formation rate, implantation, clinical pregnancy, miscarriage, and live birth, were estimated with generalized linear models. The effects of phthalate mixtures on IVF/ICSI outcomes were assessed using Bayesian kernel machine regression (BKMR) models. RESULTS: After adjusting for relevant confounders, elevated quartiles of MBzP, MEHHP, and MEHP in FF were inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes (all p for trends <0.10). In comparison with the lowest quartile, the highest quartile of molar sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP) was associated with a reduction of 9.1% [95% confidence interval (CI): -17.1%, -0.37%] and 10.3% (95% CI: -18.8%, -0.94%) in yielded oocyte and mature oocyte numbers, respectively. Furthermore, the BKMR models revealed inverse associations between phthalate mixtures and the numbers of retrieved oocytes and mature oocytes. We generally found null results for implantation, clinical pregnancy, miscarriage, and live birth. DISCUSSION: Certain phthalate metabolites in FF are inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes among women undergoing IVF/ICSI treatment. https://doi.org/10.1289/EHP11998.

Urinary phthalate metabolites and the risk of endometrial polyp: A pilot study from the TREE cohort.

Phthalates, as endocrine disrupting chemicals that can alter the endogenous hormones, may be involved in the incidence of endometrial polyp, a benign hormone-dependent condition. We conducted a pilot case-control study from the Tongji Reproductive and Environmental (TREE) cohort to investigate the associations between phthalate exposures and the risk of endometrial polyp. A total of 40 endometrial polyp patients were matched to 80 controls by age and body mass index in the ratio of 1:2. Two spot urine samples from each subject were quantified for eight phthalate metabolites to enhance exposure assessment. The conditional logistic regression and quantile-based g-computation models were separately used to explore the associations between individual and mixture of urinary phthalate metabolites and the risk of endometrial polyp. After adjusting for covariates, individual chemical analyses showed that urinary monobenzyl phthalate (MBzP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethylhexyl) phthalate (MEHHP) and the sum of di(2-ethylhexyl) phthalate (ΣDEHP) were associated with increased risks of endometrial polyp, with adjusted odds ratios ranging from 2.62 (95% CI: 0.88, 7.84) for MECPP to 6.96 (95% CI: 1.87, 25.87) for ΣDEHP comparing the extreme exposure categories (all P for trends <0.05 or = 0.057). These associations still persisted when these exposures were modeled as continuous variables. Chemical mixture analyses showed that a simultaneous one-quartile increase in concentrations of eight phthalate metabolites was associated with an elevated odds ratio of 3.14 (95% CI: 1.49, 6.60) in endometrial polyp. Our data suggests that exposure to individual benzylbutyl phthalate (BBzP) and DEHP, as well as mixture of phthalates is associated with increased risk of endometrial polyp. This may inform public health recommendations and policies to avoid phthalate exposures for improving female reproductive health.

Anti-müllerian hormone as a predictor for live birth among women undergoing IVF/ICSI in different age groups: an update of systematic review and meta-analysis.

PURPOSE: To update the evidence of anti-müllerian hormone (AMH) as predictive factors for live birth outcome in women undergoing assisted conception and discover the modulating effect of age. METHODS: PubMed, Embase, Medline, and Web of Science were searched for studies published until June 2021. We included studies that measured serum AMH levels and reported the subsequent live birth outcomes. Random effects models and hierarchical summary receiver operating characteristics (HSROC) models were used. The QUADAS-2 checklist was employed to assess the quality of the included studies. RESULTS: We included 27 studies (27,029 women) investigating the relationship between AMH and live birth outcome after assisted conception. The diagnostic odds ratios (DOR) from random effects models were ruled out due to high heterogeneity. Our findings suggested that AMH was associated with live birth. The DOR was 2.21 (95% CI 1.89-2.59), and 2.49 (95% CI 1.26-4.91) for studies on women with unspecified ovarian reserve and women with low ovarian reserve, respectively. The DOR of those with advanced ages was 2.50 (95% CI 1.87-2.60). For younger women, the DOR was 1.41 (95% CI 0.99-2.02). HSROCs showed that AMH had no predictive ability towards live birth in women with diminished ovarian reserve or younger age. Exclusion of Chinese cohorts lowered the heterogeneity. CONCLUSIONS: This study revealed that AMH had better prediction for live birth in advanced-age women. AMH may have implicative predictive value for assisted conception counseling of couples of advanced ages.

Associations between medication use and phthalate metabolites in urine and follicular fluid among women undergoing in vitro fertilization.

BACKGROUND: Phthalates, which are used as excipients of drugs, have been related to adverse reproductive outcomes. However, the relationships between medication use and phthalate exposure among women undergoing in vitro fertilization (IVF) have not been studied. OBJECTIVE: To investigate the associations between the medication intake and phthalate metabolites in urine and follicular fluid (FF). METHOD: Eight phthalate metabolites were measured in urine and FF samples from 274 women undergoing IVF using liquid chromatography-tandem mass spectrometry. Information on recent medication intake was obtained via interview by trained staff. We constructed generalized linear regression models to examine the associations of medication intake with phthalate metabolite concentrations and dose-response relationships between the number of medicines used and metabolite concentrations in two matrices. RESULTS: Four of 10 drugs were used by more than 10% of the participants, including vitamins (23.0%), traditional Chinese medicine (TCM, 22.3%), antioxidants (12.4%) and amoxicillin (10.2%). Participants who had used TCM had 26.0% (95% CI: 0.0, 58.8%), 32.6% (95% CI: 4.2, 68.8%) and 32.3% (95% CI: 2.6, 70.6%) higher urinary mono-n-butyl phthalate (MBP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) concentrations, respectively, than those who had not. Antioxidant intake was associated with a 30.6% (95% CI: -48.5, -6.6%) decrease in the urinary MBP concentration. Compared with non-users, women who reported the use of medicines had 53.2% (95% CI: 2.7, 128.5%) higher concentrations of MMP and a 37.7% (95% CI: -60.7, -1.5%) lower level of MBP in FF, respectively. CONCLUSION: Our data suggest that the intake of some medications may increase phthalate exposure among women undergoing IVF.