•Prenatal exposure to some phenols was previously associated with preterm birth.•Parental preconception exposure and preterm birth risk is understudied.•Maternal preconception BPA and BPS exposure ...increased risk of singleton preterm birth.•Fathers preconception paraben exposure may be associated with preterm birth.•Preconception phenol exposure may be an unrecognized risk factor for preterm birth in subfertile couples.
Phenol exposure during pregnancy has been associated with preterm birth, but the potential effect of preconception exposure in either parent is unknown. There is a growing body of evidence to suggest that the preconception period is a critical window of vulnerability for adverse pregnancy outcomes.
We examined whether maternal and paternal preconception urinary concentrations of select phenols were associated with the risk of preterm birth among couples attending fertility care.
The analysis included 417 female and 229 male participants of the Environment and Reproductive Health (EARTH) Study who gave birth to 418 singleton infants between 2005 and 2018 and for whom we had phenol biomarkers quantified in at least one urine sample collected before conception. Mothers and fathers provided an average of 4 and 3 urine samples during the preconception period, respectively. We calculated the geometric mean of bisphenol A (BPA), bisphenol S (BPS), benzophenone-3, triclosan, and the molar sum of parabens (ΣParabens) urinary concentrations to estimate each participant’s preconception exposure. Risk ratios (RRs) of preterm birth (live birth before 37 completed weeks’ gestation) were estimated using modified Poisson regression models adjusted for covariates.
The mean (SD) gestational age among singletons was 39.3 (1.7) weeks with 8% born preterm. A natural log-unit increase in maternal preconception BPA (RR 1.94; 95% CI: 1.20, 3.14) and BPS (RR 2.42; 95% CI: 1.01, 5.77) concentration was associated with an increased risk of preterm birth. These associations remained after further adjustment for maternal prenatal and paternal preconception biomarker concentrations. Paternal preconception ΣParabens concentrations showed a possible elevated risk of preterm birth (RR 1.36; 95% CI: 0.94, 1.96). No consistent pattern of association was observed for benzophenone-3 or triclosan biomarkers in either parent.
Maternal preconception urinary BPA and BPS concentrations, as well as paternal preconception urinary parabens concentrations were prospectively associated with a higher risk of preterm birth. Subfertile couples’ exposure to select phenols during the preconception period may be an unrecognized risk factor for adverse pregnancy outcomes.
Use of organophosphate flame retardants (PFRs) has increased over the past decade following the phase out of some brominated flame retardants, leading to increased human exposure. We recently ...reported that increasing maternal PFR exposure is associated with poorer pregnancy outcomes among women from a fertility clinic. Because a small epidemiologic study previously reported an inverse association between male PFR exposures and sperm motility, we sought to examine associations of paternal urinary concentrations of PFR metabolites and their partner's pregnancy outcomes.
This analysis included 201 couples enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2005–2015) who provided one or two urine samples per IVF cycle. In both the male and female partner, we measured five urinary PFR metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP) and bis(1-chloro-2-propyl) phosphate (BCIPP) using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). The sum of the molar concentrations of the urinary PFR metabolites was calculated. We used multivariable generalized linear mixed models to evaluate the association of urinary concentrations of paternal PFR metabolites with IVF outcomes, accounting for multiple in vitro fertilization (IVF) cycles per couple. Models were adjusted for year of IVF treatment cycle, primary infertility diagnosis, and maternal urinary PFR metabolites as well as paternal and maternal age, body mass index, and race/ethnicity.
Detection rates were high for paternal urinary concentrations of BDCIPP (84%), DPHP (87%) and ip-PPP (76%) but low for tb-PPP (12%) and zero for BCIPP (0%). We observed a significant 12% decline in the proportion of fertilized oocytes from the first to second quartile of male urinary ΣPFR and a 47% decline in the number of best quality embryos from the first to third quartile of male urinary BDCIPP in our adjusted models. An 8% decline in fertilization was observed for the highest compared to lowest quartile of urinary BDCIPP concentrations (95% CI: 0.01, 0.12, p-trend=0.06).
Using IVF as a model to investigate human reproduction and pregnancy outcomes, we found that paternal urinary concentrations of BDCIPP were associated with reduced fertilization. In contrast to previously reported findings for the female partners, the paternal urinary PFR metabolites were not associated with the proportion of cycles resulting in successful implantation, clinical pregnancy, and live birth. These results indicate that paternal preconception exposure to TDCIPP may adversely impact successful oocyte fertilization, whereas female preconception exposure to ΣPFRs may be more relevant to adverse pregnancy outcomes.
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•Preconception cohort of couples undergoing IVF as a model of human reproduction•Measured concentrations of urinary organophosphate flame retardant metabolites•No associations were observed for implantation, clinical pregnancy, or live birth.•Fertilization declined with increasing paternal exposure to TDCIPP.
We have previously investigated whether urinary concentrations of bisphenol A (BPA), parabens, and phthalate metabolites were individually associated with reproductive outcomes among women undergoing ...in vitro fertilization (IVF) treatment. However, humans are typically exposed to many man-made chemicals simultaneously. Thus, investigating one chemical at a time may not represent the effect of mixtures.
To investigate whether urinary concentrations of BPA, parabens, and phthalate metabolite mixtures are associated with reproductive outcomes among women undergoing IVF.
This prospective cohort study included 420 women contributing 648 IVF cycles who provided up to two urine samples per cycle prior to oocyte retrieval (N = 1145) between 2006 and 2017 at the Massachusetts General Hospital Fertility Center, and had available urine biomarker data. Urinary concentrations of BPA, parabens, and phthalate metabolites were quantified using isotope-dilution tandem mass spectrometry. Intermediate and clinical end-points of IVF treatments were abstracted from electronic medical records. Principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) were used to identify main patterns of BPA, parabens, and phthalate metabolites concentrations. We used generalized linear mixed models to evaluate the association between PCA-derived factor scores, in quartiles, and IVF outcomes, using random intercepts to account for multiple IVF cycles and adjusting for known confounders. Because of temporal trends in exposure, we conducted a sensitivity analysis restricted to women who underwent IVF cycles in the earlier years of study (2006–2012).
Urinary concentrations of BPA, parabens, and most phthalate metabolites were significantly lower during the second half of the study period (2013–2017) than during the first half (2006–2012). None of the three factors derived from the PCA di(2-ethylhexyl) phthalate (DEHP), non-DEHP, and paraben was associated with IVF outcomes in the main analyses. Similarly, BKRM analyses did not identify any associations of individual urinary concentrations of BPA, paraben and phthalate metabolites with IVF outcomes while accounting for correlation between exposures. However, in sensitivity analyses restricted to women who underwent IVF cycles from 2006 to 2012, where concentrations of most phthalates and phenols were higher, there were decreases in implantation, clinical pregnancy, and live birth across quartiles of the DEHP factor. Specifically, women in the highest quartile of the DEHP factor had, on average, lower probabilities of implantation (−22% p, trend = 0.08), clinical pregnancy (−24% p, trend = 0.14), and live birth (−38% p, trend = 0.06) compared to women in the lowest quartile. Among this group of women, BKMR results did not identify any single contributor driving the decreased probabilities of live birth within the DEHP factor.
We confirmed that women undergoing IVF are concurrently exposed to multiple endocrine disrupting chemicals (EDCs). While we found no overall significant associations, we observed diminished pregnancy success with specific clusters of chemicals among women who underwent IVF cycles in earlier years of study, when urinary concentrations of these EDCs were higher.
•We used novel approaches to evaluate chemical mixtures among women undergoing IVF.•Factor scores reflecting DEHP, non-DEHP, and paraben concentrations were calculated.•These scores did not show associations with reproductive outcomes or live birth.•For IVF cycles before 2012, higher DEHP scores were linked to lower birth rates.
Evidence from animal studies suggests that exposure to organophosphate flame retardants (PFRs) can disrupt endocrine function and impair embryo development. However, no epidemiologic studies have ...been conducted to evaluate effects on fertility and pregnancy outcomes.
We evaluated associations between urinary concentrations of PFR metabolites and outcomes of
fertilization (IVF) treatment among couples recruited from an academic fertility clinic.
This analysis included 211 women enrolled in the Environment And Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. We measured five urinary PFR metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP), and bis(1-chloro-2-propyl) phosphate (BCIPP) using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). Molar concentrations of the urinary PFR metabolites were summed. We used multivariable generalized linear mixed models to evaluate the association of the PFR metabolites with IVF outcomes, accounting for multiple IVF cycles per woman.
Detection frequencies were high for BDCIPP (87%), DPHP (94%), and ip-PPP (80%), but low for tb-PPP (14%) and BCIPP (0%). We observed decreased success for several IVF outcomes across increasing quartiles of both summed and individual PFR metabolites (DPHP and ip-PPP) in our adjusted multivariable models. Significant declines in adjusted means from the lowest to highest quartile of ΣPFR were observed for the proportion of cycles resulting in successful fertilization (10% decrease), implantation (31%), clinical pregnancy (41%), and live birth (38%).
Using IVF to investigate human reproduction and pregnancy outcomes, we found that concentrations of some urinary PFR metabolites were negatively associated with proportions of successful fertilization, implantation, clinical pregnancy, and live birth. https://doi.org/10.1289/EHP1021.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Abstract
STUDY QUESTION
Which methodological approaches are most appropriate for analyzing IVF data with multiple cycles in the context of a binary outcome?
SUMMARY ANSWER
Both mixed effect models ...and generalized estimating equation (GEE) modeling approaches can account for multiple IVF cycles and may reduce bias over first-cycle only approaches, but CIs were narrowest with cluster-weighted generalized estimating equation models (CWGEE).
WHAT IS KNOWN ALREADY
There is a lack of consensus among investigators regarding how to best incorporate data from multiple cycles and whether to present odds or risks in the analysis of IVF data. Failure to account for correlated outcomes within individuals and informative cluster size may lead to invalid CIs and biased estimates.
STUDY DESIGN, SIZE, DURATION
The Environment and Reproductive Health (EARTH) Study is an ongoing prospective cohort study of subfertile couples conducted at an academic medical center. This cohort was established in 2004 and follows couples seeking treatment for infertility throughout the course of their treatment and pregnancy.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women aged 18–46 years enrolled in the EARTH Study from 2004 to 2017 who initiated at least one IVF cycle were eligible. Cycle initiation was defined as beginning ovulation induction with the intent to progress through an IVF or ICSI cycle. This analysis included 442 women undergoing 642 cycles who met the study inclusion criteria. We compared the results and interpretations of log-binomial and logistic models restricting to the first cycle, as well as mixed effects models, unweighted GEE models, and CWGEE models including all cycles. This analysis was conducted for two distinct exposures: maternal age at cycle initiation, and maternal preconception urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites (previously reported to be associated with a decreased probability of live birth).
MAIN RESULTS AND THE ROLE OF CHANCE
In general, the CIs were widest for mixed effects models and narrowest for CWGEE models. Further, in models evaluating the sum of urinary concentrations of DEHP metabolites (∑DEHP, available for 91% of women), the point estimates were surprisingly different between the first-cycle and multiple-cycle models. We observed significant associations between maternal age and live birth in all models. However, we observed no associations between ∑DEHP and live birth.
LIMITATIONS, REASONS FOR CAUTION
This analysis was limited to an example dataset in which the true effect of any exposure is unknown. While this allows us to observe model performance in the context of real data, future analyses should be conducted within simulated datasets under various assumptions to further evaluate the appropriateness of each approach. In addition, we did not address differential loss to follow-up in our statistical approaches.
WIDER IMPLICATIONS OF THE FINDINGS
The use of CWGEE models should be more widely considered in the analysis of IVF data with multiple cycles per woman. The CWGEE approach is computationally simple, addresses non-ignorable (informative) cluster size, and is robust against mis-specification of the underlying covariance structure. Among the methods compared in this analysis, CWGEE models generally yielded the narrowest CIs, possibly indicating the most precise estimates. We also stress the importance of estimating risks rather than odds in the analysis of IVF data.
STUDY FUNDING/COMPETING INTEREST(s)
The project was funded by Grants (R01ES022955, R01ES009718, and P30ES000002) from the National Institutes of Health. None of the authors has any conflicts of interest to declare.
Smoking exposure during adulthood can disrupt oocyte development in women, contributing to infertility and possibly adverse birth outcomes. Some of these effects may be reflected in epigenome ...profiles in granulosa cells (GCs) in human follicular fluid. We compared the epigenetic modifications throughout the genome in GCs from women who were former (N = 15) versus never smokers (N = 44) undergoing assisted reproductive technologies (ART). This study included 59 women undergoing ART. Smoking history including time since quitting was determined by questionnaire. GCs were collected during oocyte retrieval and DNA methylation (DNAm) levels were profiled using the Infinium MethylationEPIC BeadChip. We performed an epigenome-wide association study with robust linear models, regressing DNAm level at individual loci on smoking status, adjusting for age, ovarian stimulation protocol, and three surrogate variables. We performed differentially methylated regions (DMRs) analysis and over-representation analysis of the identified CpGs and corresponding gene set. 81 CpGs were differentially methylated among former smokers compared to never smokers (FDR < 0.05). We identified 2 significant DMRs (KCNQ1 and RHBDD2). The former smoking-associated genes were enriched in oxytocin signaling, adrenergic signaling in cardiomyocytes, platelet activation, axon guidance, and chemokine signaling pathway. These epigenetic variations have been associated with inflammatory responses, reproductive outcomes, cancer development, neurodevelopmental disorder, and cardiometabolic health. Secondarily, we examined the relationships between time since quitting and DNAm at significant CpGs. We observed three CpGs in negative associations with the length of quitting smoking (p < 0.05), which were cg04254052 (KCNIP1), cg22875371 (OGDHL), and cg27289628 (LOC148145), while one in positive association, which was cg13487862 (PLXNB1). As a pilot study, we demonstrated epigenetic modifications associated with former smoking in GCs. The study is informative to potential biological pathways underlying the documented association between smoking and female infertility and biomarker discovery for smoking-associated reproductive outcomes.
Abstract
STUDY QUESTION
Are urinary phthalate metabolites associated with reduced antral follicle growth among women in an infertility setting?
SUMMARY ANSWER
Higher urinary concentrations of ...di(2-ethylhexyl) phthalate (DEHP) metabolites were associated with significant decreases in antral follicle count (AFC) among women seeking infertility care.
WHAT IS KNOWN ALREADY
Experimental animal studies show that DEHP accelerates primordial follicle recruitment and inhibits antral follicle growth. Whether phthalates also reduce the growing antral follicle pool in humans remains unknown.
STUDY DESIGN, SIZE, DURATION
We examined the association between urinary phthalate metabolites and AFC using prospective data from 215 females recruited between 2004 and 2012 in the Environment and Reproductive Health (EARTH) study.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We quantified the urinary concentrations of 11 phthalate metabolites. We estimated the geometric mean for all urine samples provided prior to unstimulated day 3 AFC assessment for each woman. We evaluated the association of AFC with ∑DEHP (molar sum of four DEHP metabolites) and individual phthalate metabolites using Poisson regression, adjusting for age, BMI and smoking.
MAIN RESULTS AND THE ROLE OF CHANCE
We observed significant decreases in mean AFC for all higher quartiles of ∑DEHP as compared with the lowest quartile. Compared with women in the first quartile of ∑DEHP, women in the second, third and fourth quartiles had a −24% (95% confidence interval (CI): −32%, −16%), −19% (95% CI: −27%, −9%), and −14% (95% CI: −23%, −5%) decrease in mean AFC. The absolute mean AFC in the first quartile was 14.2 follicles (95% CI: 13.2, 15.2) compared with 10.7 follicles (95% CI: 9.9, 11.6) in the second quartile. We observed similar trends among the four individual DEHP metabolites. There was no consistent change in AFC among the remaining phthalate metabolite concentrations evaluated.
LIMITATIONS, REASONS FOR CAUTION
We demonstrated a negative association between DEHP and a well-established marker of ovarian reserve among a subfertile population. However these findings may not be generalizable to women without fertility concerns, and we cannot rule out co-exposure to other chemicals.
WIDER IMPLICATIONS OF THE FINDINGS
Environmental chemicals that inhibit the size of the growing antral follicle pool can impair fertility and reduce fecundity. This study suggests evidence in need of further investigation on the impact of phthalates on the human oocyte and follicular development.
STUDY FUNDING/COMPETING INTERESTS
Work supported by grants ES009718, ES022955, ES000002, and T32ES007069 from the National Institute of Environmental Health Sciences (NIEHS) and grant T32 DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). C.M. was supported by a post-doctoral training award from the Canadian Institutes of Health Research. There are no competing interests to declare.
Bisphenol S (BPS) was introduced in the market as a potentially safer alternative to bisphenol A (BPA). However, there are limited studies on health effects of BPS and no epidemiologic studies on its ...relationship with male reproductive health outcomes, specifically semen quality.
To investigate predictors of urinary BPS concentrations and its association with semen parameters among men attending a fertility center.
This cross-sectional analysis included 158 men of couples seeking fertility treatment (2011–2017) contributing 338 paired semen and urine samples. At the time of sample collection, men completed a questionnaire on self-reported use of household products and food intake within the previous 24 h. Urinary concentrations of BPA, BPS and bisphenol F were quantified using isotope-dilution tandem mass spectrometry. Semen samples were analyzed following WHO guidelines. Multivariable mixed models were used to investigate predictors of urinary BPS concentrations and to evaluate associations between urinary BPS concentrations and semen parameters, using random intercept to account for correlation in outcomes across multiple observations per man and adjusting for abstinence time, specific gravity, age, body mass index (BMI), year of sample collection and BPA concentrations. Analyses were also stratified by BMI (≥25 vs <25 kg/m2).
Median (IQR) urinary BPS concentration was 0.30 (0.20, 0.90) μg/L, and 76% of samples had detectable (>0.1 μg/L) concentrations. Self-reported fabric softener and paint/solvent use as well as intake of beef and cheese within 24 h before urine collection were positively associated with BPS concentrations. Men with higher BPS concentrations also had significantly higher BMI. Lower semen parameters were found among men with detectable BPS concentrations, compared to men with non-detectable BPS 2.66 vs. 2.91 mL for volume (p = 0.03), 30.7 vs. 38.3 mil/mL for concentration (p = 0.03), 76.8 vs. 90.0 mil for total count (p = 0.09), 43.7 vs. 47.0% for motility (p = 0.06), and 5.42 vs. 6.77% for morphologically normal sperm (p = 0.24). Some associations of BPS with lower semen parameters were only found among men with a BMI ≥ 25 kg/m2.
We identified dietary and lifestyle factors associated with BPS exposure, suggesting potential avenues for reducing exposures. We also observed negative associations between BPS and semen parameters, especially among overweight and obese men.
•BPS was detected in 76% of the urine samples.•Urinary BPS was positively associated to use of fabric softener and paint/solvent as well as intake of beef and cheese.•Urinary BPS was associated with lower semen parameters, and some associations were only observed in overweight/obese men.
Preconceptional folate and vitamin B-12 have been linked to beneficial reproductive outcomes in both natural pregnancies and those after assisted reproductive technology (ART) treatment.
The ...objective of the study was to evaluate the associations of serum folate and vitamin B-12 with ART outcomes.
This analysis included a random sample of 100 women (154 ART cycles) participating in a prospective cohort study Environment and Reproductive Health (EARTH) at the Massachusetts General Hospital Fertility Center (2007-2013). Serum folate and vitamin B-12 were measured in blood samples collected between days 3 and 9 of treatment. Generalized estimating equations with adjustment for age, BMI, and race were used to evaluate the association of serum folate and vitamin B-12 with ART outcomes.
Women in the highest quartile of serum folate (>26.3 ng/mL) had 1.62 (95% CI: 0.99, 2.65) times the probability of live birth compared with women in the lowest quartile (<16.6 ng/mL). Women in the highest quartile of serum vitamin B-12 (>701 pg/mL) had 2.04 (95% CI: 1.14, 3.62) times the probability of live birth compared with women in the lowest quartile (<439 pg/mL). Suggestive evidence of an interaction was observed; women with serum folate and vitamin B-12 concentrations greater than the median had 1.92 (95% CI: 1.12, 3.29) times the probability of live birth compared with women with folate and vitamin B-12 concentrations less than or equal to the median. This translated into an adjusted difference in live birth rates of 26% (95% CI: 10%, 48%; P = 0.02).
Higher serum concentrations of folate and vitamin B-12 before ART treatment were associated with higher live birth rates among a population exposed to folic acid fortification. This trial was registered at clinicaltrials.gov as NCT00011713.
•We used PCA and BKMR to evaluate chemical mixtures among men in couples undergoing IVF.•Factor scores reflecting urinary DEHP, non-DEHP/BPA, and paraben were calculated.•Paternal mixtures of DEHP ...metabolites were related to higher infertility treatment failure.•BKMR identified ∑DEHP as the most important contributor to the mixture-outcome association.
Few epidemiologic studies have evaluated the impact of paternal environmental exposures, particularly as mixtures, on couples’ pregnancy outcomes.
We investigated whether mixtures of paternal urinary bisphenol A (BPA), paraben, and phthalates were associated with pregnancy outcomes among couples attending a fertility center.
We included 210 couples undergoing 300 in vitro fertilization (IVF) between 2004 and 2017 in this prospective analysis. We quantified paternal urinary biomarker concentrations in one sample per cycle using isotope-dilution tandem mass spectrometry. We used principal component analysis (PCA) to identify correlations of biomarker concentrations and multivariable Cox proportional hazards models for discrete survival time to estimate the hazard ratios (HRs) and 95% CIs for the associations between PCA-derived factor scores and probability of failing to achieve a live birth. Interactions were also included in the models to examine strength of associations over three vulnerable periods embryo transfer to implantation, implantation to clinical pregnancy, and clinical pregnancy to live birth. Models were adjusted for paternal and maternal ages and body mass indexes, urinary dilution (specific gravity) and year of collection, infertility diagnosis, and other PCA factor scores. Sensitivity analyses with further adjustment for maternal PCA factor scores were performed.
We identified three factors, representing di-2-ethylhexyl phthalate (DEHP) metabolites, BPA and non-DEHP metabolites, and parabens, accounting for 56%, 15% and 10%, respectively, of the total variance explained. An interquartile range (25th and 75th percentiles) increase in the DEHP-related factor score was associated with elevated probability of failing prior to live birth (HR = 1.41, 95% CI: 1.08, 1.81) and the association was stronger between implantation and clinical pregnancy as well as between clinical pregnancy and live birth compared to before implantation. The overall HRs of failure for the BPA/non-DEHP-related and paraben-related factor scores were HR = 1.24 (95% CI: 0.97, 1.59) and HR = 0.99 (95% CI: 0.80, 1.24). We found similar HRs when additionally adjusting for maternal PCA factor scores.
Paternal mixtures of urinary concentrations of DEHP metabolites were related to higher infertility treatment failure.
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