Associations of sleep characteristics with outcomes of IVF/ICSI treatment: a prospective cohort study.

STUDY QUESTION: Are sleep characteristics associated with outcomes of IVF/ICSI treatment? SUMMARY ANSWER: Nocturnal sleep <7 h/night and disturbed sleep are related to impaired oocyte and embryo yield, while longer nocturnal sleep might reduce the chance of a successful pregnancy, and the associations between nocturnal sleep duration and IVF/ICSI outcomes are modified by maternal age and subjective sleep quality. WHAT IS KNOWN ALREADY: Disturbed sleep and circadian rhythm contribute to impaired fecundity in the general population, but the effects of sleep characteristics on IVF/ICSI outcomes are largely unknown. STUDY DESIGN, SIZE, DURATION: This study was conducted among 1276 women undergoing IVF/ICSI treatment between December 2018 and September 2019 based on the Tongji Reproductive and Environmental cohort. Owing to the limited number of multiple cycles, we included only the outcomes of their first IVF/ICSI cycle in the current analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on sleep characteristics were collected via questionnaires on the day of oocyte retrieval. IVF/ICSI outcomes were abstracted from medical records. Quasi-Poisson, quasi-binomial or logistic regression models were used to assess the relations between sleep characteristics and reproductive outcomes after adjusting for relevant confounders. We also performed stratified analyses by subjective sleep quality (good versus poor) and maternal age (≤30 versus >30 years). MAIN RESULTS AND THE ROLE OF CHANCE: Compared with women who slept 7 to <8 h/night, those who slept <7 h/night exhibited decreases in the number of retrieved and mature oocytes of 11.5% (95% CI: -21.3%, -0.48%) and 11.9% (95% CI: -22.4%, -0.03%), respectively. A mid-sleep time (MST) earlier than 2:21 a.m. (<2:21 a.m.) or later than 3:00 a.m. (≥3:00 a.m.) and poor subjective sleep quality were inversely associated with the fertilization rate. Women who had trouble falling asleep more than three times per week had a lower number of mature oocytes (-10.5%, 95% CI: -18.6%, -1.6%), normal fertilized oocytes (-14.8%, 95% CI: -23.7%, -4.8%) and good-quality embryos (-15.1%, 95% CI: -25.4%, -3.5%) than those who had no such trouble. In addition, women who slept 9 to <10 h/night had a lower chance of clinical pregnancy compared to women who slept 7 to <8 h/night (odds ratio = 0.65, 95% CI: 0.44, 0.98). In the stratified analyses, the positive associations of nocturnal sleep duration with the number of good-quality embryos and fertilization rate existed only among the women with poor subjective sleep quality (P for interaction = 0.02 and 0.03, respectively). Additionally, we found that the positive associations of nocturnal sleep duration with implantation or clinical pregnancy only existed among women aged over 30 years (P for interaction = 0.04 and 0.01, respectively). LIMITATIONS, REASONS FOR CAUTION: Sleep characteristics are self-reported, which may lead to misclassification. MST serves as a proxy of chronotype and may be non-differentially misclassified resulting in an underestimate of the association of interest. Measuring sleep characteristics on the day of oocyte retrieval may lead to bias. Chance findings cannot be excluded because of the limited number of women with <7 h or ≥10 h nocturnal sleep and multiple testing. Our results may be biased by other confounders and may not be generalizable to women of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Unhealthy sleep characteristics, including short nocturnal sleep, inappropriate sleep time, poor subjective sleep quality and having trouble falling asleep, may impair oocyte quantity and its potential to mature or be fertilized. Long nocturnal sleep might reduce the chance of clinical pregnancy among infertile females, especially women younger than 30 years old. Prolonged nocturnal sleep duration may be a potential beneficial behavior for improving IVF/ICSI outcomes for women aged over 30 years and women with poor subjective sleep quality, which requires further investigation. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (81771654) and the National Key R&D Program of China (No. 2018YFC1004201). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Associations between drinking water disinfection byproducts and menstrual cycle characteristics: A cross-sectional study among women attending an infertility clinic.

Disinfection byproducts (DBPs) have been shown to alter ovarian steroidogenesis and cause estrous cyclicity disturbance and prolongation in experimental studies, however human studies are lacking. We aimed to evaluate the cross-sectional associations between drinking water DBPs and menstrual cycle characteristics. A total of 1078 women attending an infertility clinic in Wuhan, China were included between December 2018 and January 2020. Characteristics of menstrual cycle were collected by questionnaires. Concentrations of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were measured in urine as biomarkers of drinking water DBPs. Multivariate logistic and linear regression models were used to evaluate the associations between urinary DCAA and TCAA concentrations and menstrual cycle characteristics. Higher urinary DCAA concentrations were associated with increased odds ratios (ORs) of irregular menstrual cycle (OR = 1.80; 95% CI: 0.97, 3.33 for the highest vs. lowest quartile; P for trend = 0.05) and long menstrual cycle (OR = 1.62; 95% CI: 0.97, 2.70 for the highest vs. lowest quartile; P for trend = 0.06), as well as prolonged variation in cycle length (ß = 1.27 days; 95% CI: -0.11, 2.66 for the highest vs. lowest quartile; P for trend = 0.04). Higher urinary TCAA concentrations were associated with prolonged bleeding duration (ß = 0.23 days; 95% CI: -0.06, 0.51 for the highest vs. lowest quartile; P for trend = 0.07). These results suggest that exposure to drinking water DBPs is associated with menstrual cycle disturbances. These findings are warranted to confirm in other studies.

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.

Maternal preconception phthalate metabolite concentrations in follicular fluid and neonatal birth weight conceived by women undergoing in vitro fertilization.

Exposure to phthalates during gestation has been associated with decreased birth weight among offspring. However, the associations between preconception phthalate metabolites in follicular fluid (FF) and offspring birth weight among women undergoing in vitro fertilization (IVF) remain largely unknown. Here, we explored the associations between preconception phthalate metabolite concentrations in FF and the birth weights of singletons and twins among women undergoing IVF. We recruited 147 female participants who gave birth to 90 singletons and 57 twin infants at the Reproductive Medicine Center, Tongji Hospital, Wuhan, between November and December 2016. Each participant was asked to complete a questionnaire at the time of recruitment and provide a FF sample on the day of oocyte retrieval. The FF concentrations of eight phthalate metabolites were determined using high-performance liquid chromatography and tandem mass spectrometry. Birth outcomes were abstracted from medical records. The associations between phthalate metabolites in FF and birth weights of the singleton and twin groups were evaluated using generalized linear models (GLMs). We found that birth weight in the twin group had negative dose-response associations with maternal preconception monobenzyl phthalate (MBzP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) in FF (both P for trends < 0.05) and that birth weight in the singleton group had positive dose-response associations with monoethyl phthalate (MEP) and mono(2-ethyl-5 hydroxyhexyl) phthalate (MEHHP) in FF (both P for trends < 0.05). These associations persisted when we modeled as continuous variables. In addition, we observed male-specific association between decreased twin birth weight and MEOHP and MBzP and a female-specific associations between increased singleton birth weight and MEP, MEHHP and the sum of di(2-ethylhexyl) phthalate (∑DEHP) (all P for interactions < 0.05). Preconception phthalate metabolites in maternal FF may affect the birth weights of both singleton and twin newborns.

Phthalate metabolites and biomarkers of oxidative stress in the follicular fluid of women undergoing in vitro fertilization.

Epidemiological studies have suggested that phthalate exposures were associated with adverse reproductive outcomes, such as low oocyte yield and reduced embryo quality, but the underlying mechanisms remained largely unknown. Oxidative stress may be a potential contributor to phthalate-induced adverse reproductive outcomes. To explore the associations between phthalate exposure and levels of oxidative stress among women seeking in vitro fertilization (IVF), we measured the concentrations of eight phthalate metabolites and biomarkers of oxidative stress, including 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and total antioxidant capacity (TAC), in follicular fluid (FF) samples collected from 332 women. Multivariable linear regression models were used to assess the associations between phthalate metabolites and biomarkers of oxidative stress in FF samples. The concentrations of most tested phthalate metabolites were positively associated with the 8-OHdG levels. The metabolites of di-(2-ethylhexyl) phthalate (DEHP) were inversely associated with the TAC levels. The concentrations of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) were positively associated with the MDA levels. Our results revealed a positive association between phthalate metabolites and oxidative stress levels in FF, while more toxicological and epidemiological studies are required to confirm our findings.

Predictors of phthalate metabolites in urine and follicular fluid and correlations between urine and follicular fluid phthalate metabolite concentrations among women undergoing in vitro fertilization.

BACKGROUND: Phthalate metabolites in follicular fluid (FF) may negatively affect normal folliculogenesis; however, the predictors of phthalate metabolite concentrations in urine and FF and relationships between urine and FF phthalate metabolite concentrations among women undergoing in vitro fertilization (IVF) are poorly understood. OBJECTIVE: To investigate predictors of phthalate metabolites in urine and FF and correlations between urine and FF phthalate metabolite concentrations among women undergoing IVF. METHOD: We recruited 305 women seeking infertility treatment at a reproductive center in Wuhan, China, from October to November 2016. Information regarding demographic characteristics, personal care product use and plastic material contact was obtained through direct interviews. Concentrations of 8 phthalate metabolites in urine and FF samples were measured using high-performance liquid chromatography and tandem mass spectrometry. Associations regarding metabolite concentrations in urine and FF samples were analysed by Spearman's correlation and linear regression. Generalized linear regression was used to examine potential predictors of phthalate metabolite concentrations in urine and FF. RESULTS: Weak to moderate associations between urine and FF samples were found for monoethyl phthalate (MEP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) (correlation coefficient: MEP, 0.350; MEOHP, 0.377); no associations were observed for other metabolites. The predictive powers of urinary metabolite concentrations in determining FF metabolite concentrations were uniformly low, with R2 ≤ 0.113. Body mass index (BMI) and educational level were inversely associated with the urinary concentrations of certain metabolites. Higher household income, intake of bottled drinks within 48 h, and use of shower gel and soap were frequently associated with higher urinary metabolite concentrations. BMI, higher household income and use of disposable plastic cups within 48 h were associated with higher metabolite concentrations in FF. CONCLUSION: Phthalate metabolite concentrations in urine and FF vary according to sociodemographic characteristics and lifestyle factors. Phthalate metabolite concentrations in urine may not be appropriate for estimating ovary phthalate exposure.

Urinary phthalate metabolites in relation to serum anti-Müllerian hormone and inhibin B levels among women from a fertility center: a retrospective analysis.

BACKGROUND: Phthalates, a class of endocrine disruptors, have been demonstrated to accelerate loss of ovarian follicle pool via disrupting folliculogenesis, and lead to diminished ovarian reserve. However, human data are limited. Here, we aimed to examine whether urinary phthalate metabolites are correlated with markers of ovarian reserve among women attending a fertility clinic. METHODS: We measured eight phthalate metabolites in urine samples collected from 415 women seeking infertility treatment at the Reproductive Medicine Center of Tongji Hospital, Wuhan, China. Data on measures of ovarian reserve, as indicated by serum anti-Müllerian hormone (AMH) and inhibin B (INHB) levels, were retrieved retrospectively through electronic medical charts. Multivariate linear models were performed to estimate the associations of urinary phthalate metabolites and serum AMH and INHB. We further explored the potential nonlinearity of the relationships with restricted cubic spline analysis. RESULTS: Overall, we found largely null associations between urinary phthalate metabolites and serum AMH. The multivariable adjusted differences in serum INHB levels comparing the highest quartile of urinary MEHP to the lowest were - 18.29% (95% CI: - 31.89%, - 1.98%; P-trend = 0.04). Women in the second to fourth quartiles of MEOHP had a significant decrease of - 23.74% (95% CI: -35.85%, - 9.24%), - 19.91% (95% CI: -33.30%, - 3.82%) and - 20.23% (95% CI: -34.43%, - 2.96%), respectively, in INHB levels compared to the first quartile. In the spline analysis, we identified a nonlinear relationship between MEOHP exposure and serum INHB. CONCLUSIONS: We provided evidence for a negative association between urinary concentrations of certain phthalate metabolites and serum INHB levels, suggesting an adverse effect of phthalates exposure on growing antral follicles. Whether phthalates exposure at environmentally level will pose a risk for ovarian reserve needs further investigation.