Prepregnancy plant-based diets and risk of hypertensive disorders of pregnancy.

BACKGROUND: Plant-based diets have been associated with a lower risk of cardiovascular disease in nonpregnant adults, but specific evidence for their effects on risk of hypertensive disorders of pregnancy is scarce. OBJECTIVE: This study aimed to evaluate the prospective association between adherence to plant-based diets before pregnancy and the risk for hypertensive disorders of pregnancy. We hypothesized that women with higher adherence to plant-based diets would have a lower risk for hypertensive disorders of pregnancy. STUDY DESIGN: We followed 11,459 parous women (16,780 singleton pregnancies) without chronic diseases, a history of preeclampsia, and cancers who participated in the Nurses' Health Study II (1991-2009), which was a prospective cohort study. Diet was assessed every 4 years using a validated food frequency questionnaire from which we calculated the plant-based diet index (higher score indicates higher adherence) to evaluate the health associations of plant-based diets among participants while accounting for the quality of plant-based foods. Participants self-reported hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension. We estimated the relative risk of hypertensive disorders of pregnancy in relation to plant-based diet index adherence in quintiles using generalized estimating equations log-binomial regression while adjusting for potential confounders and accounting for repeated pregnancies for the same woman. RESULTS: The mean (standard deviation) age at first in-study pregnancy was 35 (4) years. A total of 1033 cases of hypertensive disorders of pregnancy, including 482 cases of preeclampsia (2.9%) and 551 cases of gestational hypertension (3.3%) were reported. Women in the highest quintile of plant-based diet index were significantly associated with a lower risk for hypertensive disorders of pregnancy than women in the lowest quintile (relative risk, 0.76; 95% confidence interval, 0.62-0.93). There was an inverse dose-response relationship between plant-based diet index and risk for hypertensive disorders of pregnancy. The multivariable-adjusted relative risk (95% confidence interval) of hypertensive disorders of pregnancy for women in increasing quintiles of plant-based diet index were 1 (ref), 0.93 (0.78-1.12), 0.86 (0.72-1.03), 0.84 (0.69-1.03), and 0.76 (0.62-0.93) with a significant linear trend across quintiles (P trend=.005). This association was slightly stronger for gestational hypertension (relative risk, 0.77; 95% confidence interval, 0.60-0.99) than for preeclampsia (relative risk, 0.80; 95% confidence interval, 0.61-1.04). Mediation analysis suggested that body mass index evaluation for dietary assessment and pregnancy explained 39% (95% confidence interval, 15%-70%]) of the relation between plant-based diet index and hypertensive disorders of pregnancy and 48% (95% confidence interval, 12%-86%]) of the relation between plant-based diet index and gestational hypertension. CONCLUSION: Higher adherence to plant-based diets was associated with a lower risk of developing hypertensive disorders of pregnancy. Much of the benefit seems to be related to improved weight control.

The associations between pre-conception urinary phthalate concentrations, the serum metabolome, and live birth among women undergoing assisted reproduction.

BACKGROUND: Phthalates are ubiquitous endocrine disruptors. Past studies have shown an association between higher preconception urinary concentrations of phthalate metabolites and lower fertility in women; however, the biological mechanisms remain unclear. Our exploratory study aimed to understand the metabolites and pathways associated with maternal preconception phthalate exposure and examine if any may underline the association between phthalate exposure and live birth using untargeted metabolomics. METHODS: Participants (n = 183) were part of the Environment and Reproductive Health (EARTH) study, a prospective cohort that followed women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital Fertility Center (2005-2016). On the same day, women provided a serum sample during controlled ovarian stimulation, which was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns, and a urine sample, which was analyzed for 11 phthalate metabolites using targeted approaches. We used multivariable generalized linear models to identified metabolic features associated with urinary phthalate metabolite concentrations and live birth, followed by enriched pathway analysis. We then used a meet-in-the-middle approach to identify overlapping pathways and features. RESULTS: Metabolic pathway enrichment analysis revealed 43 pathways in the C18 negative and 32 pathways in the HILIC positive columns that were significantly associated (p < 0.05) with at least one of the 11 urinary phthalate metabolites or molar sum of di-2-ethylhexyl phthalate metabolites. Lipid, amino acid, and carbohydrate metabolism were the most common pathways associated with phthalate exposure. Five pathways, tryptophan metabolism, tyrosine metabolism, biopterin metabolism, carnitine shuttle, and vitamin B6 metabolism, were also identified as being associated with at least one phthalate metabolite and live birth following IVF. CONCLUSION: Our study provides further insight into the metabolites and metabolomics pathways, including amino acid, lipid, and vitamin metabolism that may underlie the observed associations between phthalate exposures and lower fertility in women.

Associations of maternal and paternal preconception and maternal pregnancy urinary phthalate biomarker and bisphenol A concentrations with offspring autistic behaviors: The PEACE study.

BACKGROUND: Environmental chemical exposures in utero may play a role in autism development. While preconception risk factors for autism are increasingly being investigated, little is known about the influence of chemical exposures during the preconception period, particularly for paternal exposures. METHODS: In 195 children from the Preconception Environmental exposures And Childhood health Effects (PEACE) cohort born to parents recruited from a fertility clinic in Boston, Massachusetts between 2004-2017, we quantified concentrations of 11 phthalate metabolites and bisphenol A (BPA) in urine samples collected from mothers and fathers before conception and mothers throughout pregnancy. When children were 6-15 years old, parents completed the Social Responsiveness Scale (SRS) questionnaire assessing autistic behaviors. We used linear mixed effect models to estimate covariate-adjusted associations of phthalate biomarker and BPA concentrations, separately for maternal preconception (n=179), paternal preconception (n=122), and maternal pregnancy (n=177), with SRS T-scores, based on age and gender, in offspring. We used quantile g-computation models for mixture analyses and evaluated modification by selected dietary factors. RESULTS: The mean SRS T-score was 47.7 (±7.4), lower than the normative mean of 50. In adjusted models for individual biomarkers or mixtures, few associations were observed and estimates were generally negative (e.g., lower SRS T-scores) and imprecise. We observed associations of higher mono-isobutyl phthalate (MiBP) concentrations measured in maternal preconception and paternal preconception periods with lower SRS T-scores (ßmaternal_precon = -1.6, 95% CI -2.7; -0.4; ßpaternal_precon = -2.9, 95% CI -4.6; -1.2) for each loge increase. In a subset of participants with maternal preconception nutrition information, we generally observed stronger inverse associations with higher folate and iron intake, particularly for folate intake and MiBP concentrations. CONCLUSIONS: Urinary phthalate biomarker and BPA concentrations during preconception (maternal and paternal) and pregnancy (maternal) were not associated with adverse autistic behaviors in these children. Larger studies are needed to elucidate the observed associations, while considering interactions between maternal nutrition and chemical exposures.

Occupational factors and markers of testicular function among men attending a fertility center.

STUDY QUESTION: Are occupational factors associated with markers of testicular function among men attending a fertility center? SUMMARY ANSWER: Men working non-daytime/rotating shifts and those with physically demanding jobs have higher sperm concentration and total sperm count as well as higher estradiol and total testosterone concentrations. WHAT IS KNOWN ALREADY: Semen quality has declined during recent decades and has been negatively correlated with higher risks of common chronic diseases and mortality, highlighting its public health importance beyond fertility and reproduction. While most of the previous epidemiology literature on male fertility has focused on environmental exposures, dietary factors, and other related variables, little attention has been paid to occupational factors. STUDY DESIGN, SIZE, DURATION: This observational study included 377 men who were male partners in couples seeking infertility treatment at a fertility center, who enrolled in the Environment and Reproductive Health (EARTH) study between 2005 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Self-reported information on lifting/moving heavy objects, typical shift, and physical level of exertion at work was collected from a take-home questionnaire. Semen samples were analyzed following World Health Organization guidelines. Enzyme immunoassays were used to assess reproductive hormone concentrations. Linear regression models were used to evaluate the association between occupational factors and measures of testicular function, while adjusting for covariates such as age, BMI, education, race, smoking, and abstinence time, and accounting for multiple semen samples (mean = 2, min-max = 1-9) in analyses for semen parameters. MAIN RESULTS AND THE ROLE OF CHANCE: Men had a median (interquartile range) age of 36 (33, 39) years and were predominantly Caucasian (87%). Of the men who completed the survey, 12% reported often lifting or moving heavy objects at work, 6% reported heavy physical exertion at work, and 9% reported evening or rotating shifts. Men who reported often lifting or moving heavy objects at work had 46% higher sperm concentrations (P = 0.01) and 44% higher total counts (P = 0.01) compared with men who reported never lifting or moving heavy objects at work. Similar results were found for men working in rotating shifts compared to those in day shifts, as well as for men involved in heavy levels of physical exertion compared to those with light levels at work. We also found that men involved in heavy/moderate levels of physical exertion at work had higher circulating testosterone concentrations compared to those with lighter exertion (adjusted means of 515 and 427 ng/dl, respectively, P = 0.08), and men who often moved/lifted heavy objects at work had higher estradiol concentrations, compared to those who never did (adjusted means of 36.8 and 27.1 pg/ml, respectively, P = 0.07). Men working evening/rotating shifts had 24% higher testosterone (P = 0.04) and 45% higher estradiol concentrations (P = 0.01), compared to men working day shifts. No associations were observed for ejaculated volume, total motility, morphologically normal sperm, or serum FSH and LH concentrations. LIMITATIONS, REASONS FOR CAUTION: Due to our study design which recruited men from couples seeking fertility treatment, it may not be possible to generalize our findings to men from the general population. Also, as is the case of all studies based on self-reported questionnaires, measurement error and misclassification of the exposure are potential concerns. WIDER IMPLICATIONS OF THE FINDINGS: Physically demanding jobs and rotating or evening shift occupations may be associated with higher testicular function in men measured as higher sperm concentrations and counts as well as higher serum testosterone and estradiol levels. Confirmation of these findings in other non-fertility clinic study populations is warranted. STUDY FUNDING/COMPETING INTEREST(S): NIH grants R01ES022955, R01ES009718, R01ES033651, and R01ES000002 from the National Institute of Environmental Health Sciences (NIEHS) and Legacy, Inc. R.A.G. works part time for Legacy, Inc., which provided funds to perform this analysis. There are no other conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Perceived stress and markers of ovarian reserve among subfertile women.

RESEARCH QUESTION: Is self-reported psychological stress associated with markers of ovarian reserve among subfertile women? DESIGN: Observational study of women (n = 520) seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health study between 2005 and 2019. Women completed the short version of the validated PSS4, which assesses psychological stress. Ovarian reserve markers included AFC and circulating serum levels of day-3 FSH, with AMH assessed in a subset of participants (n = 185). RESULTS: Higher total PSS4 scores were negatively associated with AFC and serum AMH levels. Analyses adjusted for age, BMI, race, smoking, education, physical activity and type of infertility diagnosis. Women in the second and third tertiles of stress had lower AFC (13.3, 95% CI 12.7 to 13.8; and 13.5, 95% CI 13.0 to 14.1) compared with women in the lowest tertile of psychological stress score (14.3, 95% CI 13.8 to 14.9, both P < 0.05). Women in the second and third tertiles of total PSS4 scores also had lower mean serum AMH compared with women in the lowest tertile (2.99, 95% CI 2.24 to 3.74), and (2.99 95% CI 2.22 to 3.76) versus (3.94 95% CI 3.23 to 4.64). These associations varied by several socioeconomic factors, and were observed among women who were younger, belonging to minority races, with a college degree or with annual household income less than $100,000. CONCLUSIONS: Higher perceived stress was negatively associated with AFC and serum AMH levels. These associations varied by several socioeconomic factors.

Pregnancy loss and risk of cardiovascular disease: the Nurses' Health Study II.

AIMS: The aim of this study was to explore the association of pregnancy loss (PL) with the incidence of cardiovascular disease (CVD) and examine the extent to which this relation is mediated by subsequent metabolic disorders. METHODS AND RESULTS: We followed 95 465 ever-gravid women participating in the Nurses' Health Study II between 1993 and 2017. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of CVD, including coronary heart disease (CHD), and stroke, according to the occurrence of PL. A mediation analysis was conducted to explore the intermediating effect of subsequent type 2 diabetes, hypertension, or hypercholesterolaemia. During 2 205 392 person-years of follow-up (mean 23.10 years), 2225 (2.3%) incident CVD cases were documented. After adjusting for confounding factors, PL was associated with an HR of 1.21 [95% confidence interval (CI) 1.10-1.33] for CVD during follow-up. A similar association was observed for CHD (HR 1.20; 95% CI 1.07-1.35) and stroke (HR 1.23; 95% CI 1.04-1.44). The risk of CVD increased with the number of PLs [HR 1.18 (95% CI 1.06-1.31) for 1 and 1.34 (95% CI 1.13-1.59) for ≥2 times] and was greater for PL occurring early in reproductive lifespan [HR 1.40 (95% CI 1.21-1.62) for age ≤23 years, 1.25 (95% CI 1.09-1.43) for age 24-29 years, and 1.03 (95% CI 0.88-1.19) for age ≥30 years]. Hypertension, hypercholesterolaemia, and type 2 diabetes all explained <1.80% of the association between PL and CVD. CONCLUSION: PL was associated with a greater CVD risk, independently of subsequent development of metabolic disorders.

Association of peripubertal blood lead levels with reproductive hormones and semen parameters in a longitudinal cohort of Russian men.

STUDY QUESTION: Are peripubertal blood lead levels (BLLs) associated with semen parameters and serum reproductive hormones among young Russian men? SUMMARY ANSWER: We observed a suggestion of lower ejaculate volume with higher peripubertal BLL but no associations of BLLs with reproductive hormones measured throughout adolescence or with other sperm parameters measured at adulthood. WHAT IS KNOWN ALREADY: Lead is a known reproductive toxicant and endocrine disruptor. Previous literature has shown associations between high lead exposure and poorer semen quality both in occupationally and environmentally exposed men. However, to our knowledge, no longitudinal studies have explored the association of childhood lead exposure with semen parameters and reproductive hormones in young men. STUDY DESIGN, SIZE, DURATION: The Russian Children's Study is a prospective cohort study that enrolled 516 boys at age 8-9 years in 2003-2005 and followed them annually for 10 years. BLLs were measured at entry and lifestyle and health questionnaires were completed. Reproductive hormones were measured in blood samples collected every 2 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the 516 boys enrolled, 481 had BLLs measured at entry. Of these, 453 had at least one measurement of serum testosterone, follicle stimulating hormone (FSH) or luteinizing hormone (LH) (median = 5 samples per boy) and 223 had semen samples collected ∼10 years after enrolment. Semen assessment included ejaculated volume, sperm concentration, progressive motility and total sperm count, and parameters were categorized using published andrology standards for low semen quality based on sperm count and motility. Linear mixed models were used to examine the associations of log-transformed BLLs (and BLL categories) with reproductive hormones and semen parameters, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 223 young men with peripubertal BLLs and at least one semen sample (total samples = 438), the median (interquartile range) BLL was 3 (2, 5) µg/dl and 27% had BLL ≥5 µg/dl. Overall, 49% of the semen samples fell below reference levels for sperm count and/or motility. Men with peripubertal BLL ≥5 µg/dl had significantly lower ejaculated volume than those with BLL <5 µg/dl (mean = 2.42 vs 2.89 ml, P = 0.02), but this difference was attenuated in adjusted models (mean = 2.60 vs 2.83 ml, P = 0.25). No associations were observed between BLL measured at age 8-9 years and reproductive hormone levels or sperm parameters, including sperm concentration, total count, progressive motility and total progressive motile sperm count, or with the probability of having low semen quality based on sperm count/motility. LIMITATIONS, REASONS FOR CAUTION: Only a subset of the original cohort participated in the semen quality portion of the study, although inverse probability weighting was used to account for possible selection bias. BLLs were only measured at a single time in peripuberty, and other exposure time periods, including later or longer-term childhood exposure, may be more predictive of semen quality. The young men were also exposed to other chemical contaminants before and during pubertal development. WIDER IMPLICATIONS OF THE FINDINGS: While semen volume often receives less attention than other sperm parameters, it is an important component of male fertility. Additional prospective studies covering different exposure windows and including other seminal plasma biomarkers are warranted to explore our finding of potentially lower ejaculated volume with higher BLLs and to confirm the lack of associations for other semen parameters among youth exposed to environmental BLLs. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided through grants R01ES0014370 and P30ES000002 from the National Institute of Environmental Health Sciences, grant R82943701 from the U.S. Environmental Protection Agency, and grant 18-15-00202 from the Russian Science Foundation (O.S and Y.D.). All authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Women's and men's intake of omega-3 fatty acids and their food sources and assisted reproductive technology outcomes.

BACKGROUND: Long-chain omega-3 fatty acids and their food sources have garnered interest as a potential nutrient with wide-range health benefits, including fertility. OBJECTIVE: This study aimed to investigate the association of women's and men's intake of omega-3 fatty acids and omega-3 rich-foods with semen quality and outcomes of infertility treatment with assisted reproductive technologies. STUDY DESIGN: Couples presenting to the Massachusetts General Hospital were invited to enroll in a prospective cohort study (2007-2020). Male and female diets were assessed using a validated 131-item food frequency questionnaire. The primary outcomes were implantation, clinical pregnancy, and live birth probabilities. The secondary outcomes included total and clinical pregnancy loss and conventional semen parameters, for males only. We estimated the relationship between intakes of omega-3 fatty acids, nuts, and fish and the probability (95% confidence interval) of study outcomes using generalized linear mixed models to account for repeated treatment cycles per participant while simultaneously adjusting for age, body mass index, smoking status, education, dietary patterns, total energy intake, and male partner diet. RESULTS: A total of 229 couples and 410 assisted reproductive technology cycles were analyzed for primary and secondary outcomes. Of note, 343 men contributing 896 semen samples were included in analyses for semen quality measures. Women's docosahexaenoic acid + eicosapentaenoic acid intake was positively associated with live birth. The multivariable-adjusted probabilities of live birth for women in the bottom and top quartiles of eicosapentaenoic acid + docosahexaenoic acid intake were 0.36 (95% confidence interval, 0.26-0.48) and 0.54 (95% confidence interval, 0.42-0.66) (P trend=.02). Eicosapentaenoic acid + docosahexaenoic acid intake was inversely related to the risk of pregnancy loss, which was 0.53 among women in the lowest quartile of eicosapentaenoic acid + docosahexaenoic acid intake and 0.05 among women in the highest quartile (P trend=.01). Men's intake of total omega-3 fatty acids was positively related to sperm count, concentration, and motility, but unrelated to any assisted reproductive technology outcomes. Similar associations were observed when evaluating the intake of primary food sources of these fatty acids. CONCLUSION: Women's consumption of omega-3 fatty acids and omega-3-rich foods may improve the probability of conception by decreasing the risk of pregnancy loss. In addition, men's intake of omega-3 fatty acids may influence semen quality.

Cesarean delivery and metabolic health and inflammation biomarkers during mid-childhood and early adolescence.

BACKGROUND: We assessed differences in plasma levels of metabolic health and inflammation biomarkers during mid-childhood and early adolescence between children born by cesarean section vs. vaginal delivery. METHODS: Mother-child pairs (N = 942) enrolled during pregnancy in obstetric practices and child follow-up started at birth. Risk biomarkers were assessed in blood samples collected at the mild-childhood (median = 7 years) and early adolescence (median = 13 years) in-person visits. RESULTS: Two hundred and six children (22%) were born by cesarean section. There were no significant differences in biomarker levels between children born by cesarean and children born vaginally in mid-childhood. However, adolescents born by cesarean section had significantly lower adiponectin [% difference (95% confidence interval (CI)) = -11.3 (-18.1, -4.0) µg/mL] compared to vaginal delivery. We also found some suggestion of higher insulin resistance [insulin levels % difference (95% CI) = 11.5 (-0.40, 25.0) µU/mL and HOMA-IR (homeostatic model assessment of insulin resistance) % difference (95% CI) = 9.1 (-2.30, 21.8) U] in adolescents born by cesarean section compared to those born vaginally. CONCLUSIONS: We found suggestive evidence that adolescents born by cesarean section show differences in certain metabolic health biomarkers relative to adolescents born by vaginal delivery. Further studies are needed to reevaluate these associations since the clinical significance of these differences is unclear. IMPACT: Multiple studies show that children born by cesarean section are at higher risk of obesity compared to those born vaginally. It is unclear yet to what extent this elevated risk may extend to a more adverse profile of biomarkers of metabolic health and inflammation. Adolescents born by cesarean section show small differences in adiponectin and insulin relative to adolescents born by vaginal delivery. Adolescents born by cesarean section may be at higher risk to a more adverse profile of biomarkers of metabolic health and inflammation, but the clinical significance of these differences is uncertain.

Associations between mixtures of urinary phthalate metabolite concentrations and oxidative stress biomarkers among couples undergoing fertility treatment.

Phthalate exposure has been associated with adverse reproductive outcomes and oxidative stress is a potential mechanism by which they act. However, few human studies have explored co-exposure confounding or joint effects. Furthermore, most studies examine associations between biomarkers of exposure and oxidative stress from the same urine sample. We investigated single-exposure, co-exposure-adjusted, and joint associations between phthalate metabolites and oxidative stress in the Environment and Reproductive Health (EARTH) study among couples undergoing fertility treatment. We examined cross-sectional associations in both women and men, and longitudinal associations in women. Urine was collected in the follicular phase (women only) and at the time of fertility procedure (women and men), and analyzed for 11 phthalate metabolites. Urine from the time of fertility procedure was analyzed for oxidative stress biomarkers, including free 8-iso-prostaglandin F2α (8-iso-PGF2α), its primary metabolite (2,3-dinor-5,6-dihydro-15-F2t-isoprostane [F2-IsoP-M]), and prostaglandin F2α (PGF2α). Linear mixed effects models were used to estimate single-exposure associations. Bayesian Kernel Machine Regression (BKMR) was used to adjust for co-exposures and to estimate joint effects. Among women, we observed positive associations between all phthalate metabolites and oxidative stress biomarkers in single-exposure models, but there was clear co-exposure confounding. For instance, in a single-exposure model, we estimated a 63% (95% confidence interval: 51, 77) increase in the 8-iso-PGF2α metabolite per interquartile range (IQR) difference in mono-n-butyl phthalate (MBP) versus a 34% (95% credible interval: 12, 60) increase in co-adjusted models. However, several phthalate metabolites remained associated with oxidative stress in co-exposure models, and the joint effects of all exposures were high (e.g., an 114% increase in the 8-iso-PGF2α metabolite per IQR difference in all exposures). Longitudinal results were also attenuated compared to cross-sectional results in women; however, the joint effect of all exposures and the 8-iso-PGF2α metabolite remained positive and statistically significant (11% increase per IQR difference in all exposures, 95% credible interval: 0.2, 23). In men, associations were generally less pronounced, although the joint effect of the mixture on 8-iso-PGF2α was above the null. Because oxidative stress is related to reproductive success among couples seeking fertility treatment, mitigating phthalate exposure should be considered as a potentially beneficial measure.

Associations of prepubertal urinary phthalate metabolite concentrations with pubertal onset among a longitudinal cohort of boys.

BACKGROUND: Although phthalate exposures have been associated with adverse effects on male reproductive health, few studies have explored longitudinal associations with male pubertal development. OBJECTIVES: We examined the association of prepubertal urinary concentrations of phthalate metabolites with age at pubertal onset in a prospective cohort of Russian boys. METHODS: At enrollment at ages 8-9 years, medical history, dietary, and demographic information was collected. At entry and annually, physical examinations and pubertal staging [Genitalia (G), Pubarche (P), and testicular volume (TV, in ml)] were conducted and spot urines were collected. Prepubertal urine samples (defined as either TV = 1, 2 and G = 1, 2 or TV = 3 and G = 1) were pooled for each boy and phthalate metabolite concentrations were quantified using isotope dilution LC-MS/MS at Moscow State University. We measured 15 metabolites including those from anti-androgenic parent phthalates (AAPs) such as di (2-ethylhexyl) (DEHP) and di-isononyl (DiNP) phthalates as well as monobenzyl (MBzP), mono-n-butyl (MnBP), and mono-isobutyl (MiBP) metabolites. We calculated the molar sums of DEHP (∑DEHP), DiNP (∑DiNP), and AAP (∑AAP) metabolites. Separate interval-censored models were used to assess associations of quartiles of prepubertal phthalate metabolites with each pubertal onset indicator, G2+, P2+ and TV > 3 mL, adjusted for covariates and urine specific gravity. RESULTS: 304 boys had 752 prepubertal urine samples (median 2, range: 1-6) for pooling. In adjusted models, higher urinary AAPs were consistently associated with later pubertal onset (P2) with mean shifts ranging from 8.4 to 14.2 months for the highest versus lowest quartiles. Significantly later onset for G2 and TV > 3 mL was observed for higher versus lower quartiles of MiBP, MBzP, ∑DEHP and ∑DiNP. CONCLUSIONS: On average, boys with higher concentrations of prepubertal urinary AAPs had later pubertal onset by six months to over a year. The impact of AAPs on timing of male puberty may be attributable to disruption of androgen-dependent biological pathways.

Self-reported history of comorbidities and markers of ovarian reserve among subfertile women.

PURPOSE: To investigate whether history of comorbidities is associated with markers of ovarian reserve among subfertile women. METHODS: This observational study includes 645 women seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health (EARTH) study (2005-2019). Women completed a comprehensive questionnaire including medical diagnosis of comorbidities. Ovarian reserve markers including antral follicle count (AFC), assessed by transvaginal ultrasound, and circulating serum levels of day 3 FSH and AMH, are assessed by immunoassays. We fit linear regression models to evaluate the association between history of comorbidities and markers of ovarian reserve while adjusting for confounders. RESULTS: Self-reported history of hypertension, cancer, and neurological disorders was negatively associated with AFC in unadjusted models and in adjusted models for age, smoking, physical activity, comorbidity count, and BMI. Adjusted mean AFC (95% CI) was lower among women with history of hypertension, compared to women with no self-reported history of hypertension (11.5 vs 15.6, p value 0.0001). In contrast, day 3 FSH levels were positively related to history of eating disorders in both unadjusted and adjusted models (10.8 vs. 7.43 IU/L, p value ≤ 0.0001). Self-reported history of other comorbidities was unrelated to AFC, day 3 FSH, and AMH levels. CONCLUSIONS: History of hypertension, cancer, and neurological disorders was negatively associated with AFC, and eating disorders were positively related to day 3 FSH levels. The prevention of common comorbidities among women in reproductive age may help increase women's fertility given the declining birth rates and increasing use of assisted reproductive technologies in the past years.

Association of mode of delivery with offspring pubertal development in Project Viva: a prospective pre-birth cohort study in the USA.

STUDY QUESTION: Is cesarean delivery associated with earlier offspring pubertal development? SUMMARY ANSWER: We identified that boys born by cesarean delivery developed puberty earlier, evidenced by an earlier age at peak height velocity and earlier attainment of puberty score > 1, than boys born by vaginal delivery. WHAT IS KNOWN ALREADY: Cesarean delivery is posited to have long-term effects on health outcomes. However, few studies have examined whether mode of delivery is related to pubertal development. STUDY DESIGN, SIZE, DURATION: Prospective pre-birth cohort study consisting of 1485 mother-child pairs enrolled during pregnancy from obstetric practices and followed up until early adolescence (median age 12.9 years). Participant inclusion required data on mode of delivery and at least one measure of pubertal development. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants are children from the Project Viva study. We abstracted information on delivery mode from electronic medical records from children followed since birth (1999-2002) and examined the following markers of pubertal development: age at peak height velocity (APHV); age at menarche (girls only); parent-reported pubertal development score; and child-reported pictograph Tanner pubic hair staging. We used multivariable regression models to examine associations of delivery mode with these four pubertal indices, adjusting for the following confounders: demographic and socioeconomic factors; maternal height, pre-pregnancy BMI, total gestational weight gain, pregnancy conditions, parity, and maternal age at menarche; paternal height and BMI; gestational age at delivery and birthweight-for-gestational-age z-score. MAIN RESULTS AND THE ROLE OF CHANCE: In this study, 23.2% of children were born by cesarean delivery. Girls had an earlier APHV, had a higher pubertal score throughout childhood and in early adolescence, and were more likely to attain puberty score >1 and Tanner pubic hair Stage >1 earlier compared to boys. Mean (SD) age at menarche in girls was 12.4 (1.0) years. Boys born by cesarean delivery had significantly earlier APHV (ß -0.23 years; 95% CI -0.40, -0.05) and higher risk of earlier attainment of puberty score > 1 (hazard ratio 1.09; 95% CI 1.01, 1.19) than boys born by vaginal delivery, after adjusting for confounders. These associations were not mediated by pre-pubertal BMI and were similar for planned (no labor) and unplanned (labor) cesarean delivery. No associations were observed between delivery mode and time to attain Tanner pubic hair Stage > 1 in boys. In girls, mode of delivery was not associated with any of the measured pubertal development markers. LIMITATIONS, REASONS FOR CAUTION: This study used, as secondary outcomes, parent- and child-reported measures of pubertal development, which may be more prone to error and misclassification than information collected by trained observers or physicians during clinical examinations. The findings may also not be generalizable to populations from different settings, because all participants lived in one geographic area, were well educated, and had health care. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide support for cesarean delivery as a potential indicator of identifying children who are likely to experience earlier pubertal development; however, more studies are needed to confirm or refute these observations. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by grants from the National Institutes of Health. The authors have no financial relationships or competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Substantial Weight Gain in Adulthood Is Associated with Lower Probability of Live Birth Following Assisted Reproduction.

BACKGROUND: Overweight and obesity among women have been associated with lower success of assisted reproduction technologies (ARTs). However, the relation of adolescent body weight and adult weight change to ART outcomes is not well understood. OBJECTIVE: Our objective was to evaluate the associations of female BMI (in kg/m2) at 18 y and weight change from 18 y to current age with ART outcomes. METHODS: We included 486 women in a prospective cohort at the Massachusetts General Hospital Fertility Center (2004-2018) who underwent 863 ART cycles. At study entry, height and weight were measured by research personnel. Women recalled their weight at 18 y. Restricted cubic splines were used to evaluate the associations between BMI at 18 y and weight change since 18 y and ART outcomes adjusting for age, race, education, smoking, and height and accounting for the correlated cycles within women. RESULTS: Women had a median (range) BMI of 20.6 (14.8 to 36.4) at 18 y and 23.3 (16.1 to 45.8) at study entry. The median (range) weight change since 18 y was 7.4 kg (-12.1 to 60.1 kg). There was no association between BMI at 18 y and clinical ART outcomes. Long-term weight change had a nonlinear association with live birth such that higher weight gain since 18 y (particularly ≥15 kg) and weight loss were both associated with lower odds of live birth. The negative association between weight change and live birth was stronger in women ≥22.5 kg/m2 at 18 y such that each 10-kg increase was associated with a 30% (6%, 48%) lower odds of live birth. CONCLUSIONS: Weight gain in adulthood is negatively associated with ART success, particularly among women who were heavier at 18 y. These results add to the growing literature supporting the benefits of preventing weight gain in adulthood on female fertility.

Identifying windows of susceptibility to endocrine disrupting chemicals in relation to gestational weight gain among pregnant women attending a fertility clinic.

BACKGROUND: Exposure to endocrine disrupting chemicals (EDC), such as phthalates and phenols, during pregnancy may be associated with excessive gestational weight gain (GWG), an important predictor of future health of the mother and the offspring. There is however a paucity of literature examining this association, and no study has accounted for the complex nature of EDCs exposure as a time-varying mixture of chemicals. OBJECTIVE: We examined the association between trimester-specific EDCs mixture and GWG in pregnant women attending a fertility clinic, to identify windows of susceptibility to such exposures, and assess the individual contribution of each chemical over pregnancy. METHODS: We included 243 pregnant women from the Environment and Reproductive Health (EARTH) Study, who provided up to 3 urine samples (one per trimester), and with available data on GWG. Urinary concentrations of 7 phthalate metabolites, bisphenol A, and 2 parabens, corrected for specific gravity, were included in the analysis. The association between trimester-specific EDCs mixture and GWG was evaluated using multiple regression models - categorizing exposures into concentration quartiles- and with Bayesian Kernel Machine Regression (BKMR), while adjusting for potential confounders. Hierarchical BKMR (hBKMR) was used to account for the time-varying nature of chemical concentrations over pregnancy, identifying the most important trimester and most important EDC within each trimester. RESULTS: During 1st trimester, higher GWG was observed at higher sum of metabolites of di (2-ethylhexyl) phthalate (ΣDEHP) from both multiple regression (e.g. comparing the 4th quartile with the 1st: ß = 2.36 kg, 95% CI: 0.47, 5.19) and BKMR. During 2nd and 3rd trimesters, positive associations with mono-n-butyl phthalate and propylparaben, and negative with ΣDEHP and methylparaben were observed. When evaluating exposures as a time-varying mixture with hBKMR, 1st trimester was the most important exposure window when evaluating prenatal urinary EDCs in relation to GWG. Within the 1st trimester, urinary ΣDEHP, mono-isobutyl phthalate and propylparaben had the highest contribution in the positive association between the mixture and GWG. CONCLUSION: We observed positive associations between urinary EDCs during pregnancy, especially DEHP metabolites, and GWG. Our results suggest the 1st trimester of pregnancy as the time window of highest susceptibility to the effects of EDCs on GWG, with potential indication for the design of public health interventions, informing prevention strategies for reducing sources of exposure at specific time points.

The influence of fine particulate matter on the association between residential greenness and ovarian reserve.

BACKGROUND: Natural vegetation, or greenness, is thought to improve health through its ability to buffer and reduce harmful environmental exposures as well as relieve stress, promote physical activity, restore attention, and increase social cohesion. In concert, these effects could help mitigate the detrimental effects of air pollution on reproductive aging in women. METHODS: Our analysis included 565 women attending the Massachusetts General Hospital Fertility Center (2004-2014) who had a measured antral follicle count (AFC), a marker of ovarian reserve. We calculated peak residential greenness in the year prior to AFC using 250 m2 normalized difference vegetation index (NDVI) from the Terra and Aqua satellites operated by the United States National Aeronautics and Space Administration. Validated spatiotemporal models estimated daily residential exposure to particulate matter <2.5 µm (PM2.5) for the 3 months prior to AFC. Poisson regression models with robust standard errors were used to estimate the association between peak greenness, average PM2.5 exposure, and AFC adjusted for age, BMI, smoking status, education, year, and season. RESULTS: Women in our study had a mean age of 35.2 years with a standard deviation (SD) of 4.3 years (min: 20 years, max: 45 years). The peak residential NDVI ranged from 0.07 to 0.92 with a SD of 0.18. There was no statistically significant association between peak residential greenness and AFC; however, higher exposure to PM2.5 was associated with lower AFC (-6.2% per 2 µg/m3 [1 SD increase] 95% CI -11.8, -0.3). There was a significant interaction between exposure to PM2.5 and peak greenness on AFC (P-interaction: 0.03). Among women with an average PM2.5 exposure of 7 µg/m3, a SD increase in residential peak greenness was associated with a 5.6% (95% CI -0.4, 12.0) higher AFC. Conversely, among women with a PM2.5 exposure of 12 µg/m3, a SD increase in residential peak greenness was associated with a 5.8% (95% CI -13.1, 2.1) lower AFC. CONCLUSIONS: Residing in an area with high levels of greenness may slow reproductive aging in women only when exposure to PM2.5 is low.

Reproductive outcomes associated with flame retardants among couples seeking fertility treatment: A paternal perspective.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) have been phased out of production for nearly a decade yet are still frequently detected in serum of U.S. adults. PBDE concentrations have been associated with adverse reproductive outcomes and laboratory studies suggest hydroxylated-BDEs (OH-BDEs) may act as endocrine disruptors. We set out to assess the joint effects of paternal and maternal serum PBDE concentrations on in vitro fertilization (IVF) outcomes and the association between paternal serum OH-BDE concentrations and IVF outcomes. METHODS: This analysis included 189 couples (contributing 285 IVF cycles) recruited between 2006 and 2016 from a longitudinal cohort based at Massachusetts General Hospital Fertility Center who completed at least one IVF cycle and had an available blood sample at study entry. Congeners (47, 99, 100, 153, and 154) and OH-BDEs (3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49) were quantified in serum. Log-transformed PBDEs and OH-BDEs were modeled in quartiles for associations with IVF outcomes using multivariable generalized mixed models and cluster weighted generalized estimating equations. RESULTS: Lipid-adjusted concentrations of PBDEs and OH-BDEs were higher in females than in male partners. There were no clear patterns of increases in risk of adverse IVF outcomes associated with PBDEs and OH-BDEs. However, some decreases in associations with IVF outcomes were observed in isolated quartiles. CONCLUSIONS: Our assessment of couple level exposure is unique and highlights the importance of including male and female exposures in the assessment of the influence of environmental toxicants on pregnancy outcomes.

Men's dietary patterns in relation to infertility treatment outcomes among couples undergoing in vitro fertilization.

PURPOSE(S): To evaluate the relationship of men's dietary patterns with outcomes of in vitro fertilization (IVF). METHODS: This is a prospective cohort study including 231 couples with 407 IVF cycles, presented at an academic fertility center from April 2007 to April 2018. We assessed diet with a validated food frequency questionnaire and identified Dietary Pattern 1 and Dietary Pattern 2 using principal component analysis. We evaluated adjusted probability of IVF outcomes across the quartiles of the adherence to two dietary patterns by generalized linear mixed models. RESULTS: Men had a median age of 36.8 years and BMI of 26.9 kg/m2. Women's median age and BMI were 35.0 years and 23.1 kg/m2, respectively. Adherence to Dietary Pattern 1 (rPearson=0.44) and Dietary Pattern 2 (rPearson=0.54) was positively correlated within couples. Adherence to Dietary Pattern 1 was positively associated with sperm concentration. A 1-unit increase in this pattern was associated with a 13.33 (0.71-25.96) million/mL higher sperm concentration. However, neither Dietary Pattern 1 nor Dietary Pattern 2 was associated with fertilization, implantation, clinical pregnancy, or live birth probabilities. CONCLUSIONS: Data-derived dietary patterns were associated with semen quality but unrelated to the probability of successful IVF outcomes.

Exploring reproductive associations of serum polybrominated diphenyl ether and hydroxylated brominated diphenyl ether concentrations among women undergoing in vitro fertilization.

STUDY QUESTION: Are serum concentrations of polybrominated diphenyl ethers (PBDEs) and hydroxylated brominated diphenyl ethers (OH-BDEs) associated with IVF endpoints? SUMMARY ANSWER: Positive associations were observed for BDE153 and several OH-BDEs with IVF endpoints. WHAT IS KNOWN ALREADY: PBDEs have been voluntarily phased out of production in the USA and EU due to their persistence and toxicity to humans and ecosystems. PBDEs have been associated with implantation failure among women undergoing IVF, yet some animal studies suggest greater toxicity from their metabolites, OH-BDEs. STUDY DESIGN, SIZE, DURATION: We evaluated a subset of 215 women (contributing 330 IVF cycles) enrolled between 2005 and 2016 in a longitudinal cohort based at Massachusetts General Hospital Fertility Center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The following PBDEs were quantified: 47, 99, 100, 153 and 154 and the following OH-BDEs: 3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49. Clinical endpoints of IVF treatments were abstracted from electronic medical records. Associations of log-transformed PBDEs and OH-BDEs with IVF outcomes were assessed using multivariable generalized mixed models and cluster weighted generalized estimating equation models adjusted for lipids, age, BMI, race, year of sample collection, IVF protocol and FSH levels. Outcomes were adjusted to represent a percent change in outcome with an increase equal to the magnitude of the difference between the 75th and 25th percentiles for each specific compound (interquartile range (IQR) increase). MAIN RESULTS AND THE ROLE OF CHANCE: Detection frequencies were highest for congeners 47 and 153 (82% ≥ method detection limit (MDL)) and metabolites 3 and 5-OH-BDE47 and 4-OH-BDE49 (92% > MDL). PBDE and OH-BDE geometric mean concentrations declined by up to 80% between participants recruited in 2005 and those recruited in 2016. An IQR increase of BDE153 was associated with an increase in the probability of implantation (relative risk (RR) = 1.26, 95% CI: 1.16, 1.36), clinical pregnancy (RR = 1.32, 95% CI: 1.19, 1.46) and live birth (RR = 1.34; 95% CI: 1.15, 1.54). An IQR increase in 3 and 5-OH-BDE47 was associated with increased probabilities of implantation (RR = 1.52; 95% CI: 1.11, 2.09), clinical pregnancy (RR = 1.66; 95% CI: 1.17, 2.36), and live birth (RR = 1.61; 95% CI: 1.07, 2.40). When models were stratified by race (White (86%)/Other race (14%)), associations remained positive for White women, yet inverse associations were observed for Other race women. An IQR increase in BDE47 was associated with a 46% decreased probability of clinical pregnancy (95% CI: 0.31, 0.95) for Other race women. LIMITATIONS, REASONS FOR CAUTION: Despite the long half-lives of PBDEs and OH-BDEs, exposure misclassification is possible for women who underwent multiple treatment cycles over several months or years. It is also possible another medium, such as follicular fluid would be optimal to characterize exposure. We also tested associations for multiple congeners and metabolites with multiple outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Detections of serum concentrations of PBDEs and OH-BDEs were highest in the early years of the study and suggests that the phase-out of these compounds has contributed to a decrease in exposure. The negative associations found for PBDEs and IVF outcomes among other race women suggests the potential for racial disparity. Potential racial disparities in PBDE exposure and exploration of alternative flame retardants with reproductive health outcomes should be the focus of future investigations. STUDY FUNDING/COMPETING INTEREST(S): Funding for this research was supported by the National Institutes of Environmental Health Sciences (NIEHS) [R01 ES009718, ES022955, ES000002 and 009718T32ES007069]. The authors have no conflicts of interest.

Ambient air pollution and risk of pregnancy loss among women undergoing assisted reproduction.

Accumulating evidence suggests that air pollution increases pregnancy loss; however, most previous studies have focused on case identification from medical records, which may underrepresent early pregnancy losses. Our objective was to investigate the association between acute and chronic exposure to ambient air pollution and time to pregnancy loss among women undergoing assisted reproductive technologies (ART) who are closely followed throughout early pregnancy. We included 275 women (345 human chorionic gonadotropin (hCG)-confirmed pregnancies) undergoing ART at a New England academic fertility center. We estimated daily nitrogen dioxide (NO2), ozone (O3), fine particulate matter <2.5 µm (PM2.5), and black carbon (BC) exposures using validated spatiotemporal models estimated from first positive hCG test until day of failure or live birth. Air pollution exposures were averaged over the past week and the whole pregnancy. Multivariable Cox proportional hazards models were used to estimate the hazards ratio (HR) for pregnancy loss for an interquartile range (IQR) increase in pollutant exposure. We tested for violation of proportional hazards by considering an interaction between time (in days) since positive hCG (<30 days vs. ≥30 days) and air pollution. The incidence of pregnancy loss was 29 per 100 confirmed pregnancies (n = 99). Among pregnancies not resulting in live birth, the median (IQR) time to loss was 21 (11, 30) days following positive hCG. Average past week exposures to NO2, O3, PM2.5, and BC were not associated with time to pregnancy loss. Exposure throughout pregnancy to NO2 was not associated with pregnancy loss; however, there was a statistically significant interaction with time (p-for-interaction<0.001). Specifically, an IQR increase in exposure to NO2 was positively associated with pregnancy loss after 30 days (HR = 1.34, 95% CI: 1.13, 1.58), but not in the first 30 days after positive hCG (HR = 0.83, 95% CI: 0.57, 1.20). Overall pregnancy exposure to O3, PM2.5, and BC were not associated with pregnancy loss regardless of timing. Models evaluating joint effects of all pollutants yielded similar findings. In conclusion, acute and chronic exposure to NO2, O3, PM2.5, and BC were not associated with risk of pregnancy loss; however, higher exposure to NO2 throughout pregnancy was associated with increased risk of loss 30 days after positive hCG. In this cohort, later pregnancy losses appeared more susceptible to the detrimental effects of air pollution exposure.