INTRODUCTION:Ovarian stimulation (OS) alters the peri-implantation environment and may affect placentation. Therefore, our study aimed to compare placental pathology and PW among singleton live births conceived after IUI with gonadotropins (Gn), oral medications (OM; clomiphene/letrozole), or unstimulated/natural (Nat) cycles. METHODS:Retrospective review of 386 IUI(±OS) singleton live births with placental examination: Gn (n = 222), OM (n = 129), and Nat (n = 35). Outcomes were placental lesions (classified as anatomic, inflammatory, infectious, or vascular) and PW. Generalized estimating equations (GEE) estimated adjusted risk ratios (adjRR) for pathology, adjusted beta (adjβ), for PW, and their respective 95% confidence interval (95%CI), controlling for maternal age, BMI, race, PCOS diagnosis, gestational age at delivery, infant sex, and pregnancy complications (hypertensive disorders and diabetes). Sensitivity analyses included uncomplicated term livebirths and inverse probability weighting (IPW). RESULTS:After multivariable GEE adjustment, OM was associated with higher odds of anatomic abnormalities compared with both Gn and Nat [adjRR (95% CI): 1.15 (1.02, 1.31) and 1.28 (1.05, 1.56), respectively], whereas Gn did not differ compared to Nat. In our sensitivity analyses, adjRR (95%CI) for anatomic lesions remained similarly more prevalent in OM compared to Nat [Uncomplicated: 1.21 (0.96, 1.52); IPW: 1.29 (1.02, 1.63)], while it was not significant compared to Gn [Uncomplicated: 1.09 (0.93, 1.29); IPW: 1.12 (0.97, 1.30)]. Inflammatory, infectious, vascular placental abnormalities, and PW remained comparable between groups in the main analysis and after the same restrictions. CONCLUSION:Among IUI-conceived singleton births with placental evaluation, oral medications were associated with more anatomic placental abnormalities than gonadotropins or natural cycles, whereas PW did not differ by protocol.

Polycystic ovary syndrome (PCOS)/polyendocrine metabolic ovarian syndrome (PMOS) is the most prevalent endocrine disorder in reproductive-age women and is characterized by long-term metabolic consequences. The purpose of this study is to delineate the metabolomic profile in lean and non-lean PMOS patients. Retrospective cross-sectional study includes 4768 premenopausal patients with available body mass index (BMI) and metabolomics information at the Mass General Brigham (MGB) Biobank. The Biobank includes samples collected from 05/2010 to 08/2023 with unique metabolomic biomarkers that encompass key metabolic pathways, including lipids, amino acids, and glycolysis-related metabolites. The main outcome measures were metabolomic profile differences between PMOS (n = 403) and non-PMOS patients (n = 4365). Sub-analyses were performed within normal BMI (< 25 kg/m2), overweight BMI (25–29.9 kg/m2), and obesity BMI (≥ 30 kg/m2) subgroups. PMOS patients were younger (p < 0.001) and had higher BMI (p < 0.001). When considering the total population and adjusting for age, BMI, exercise, metformin, oral contraceptive pills (OCPs), and glucagon like peptide-1 (GLP-1) agonists, PMOS affected the expression of only 1/71 (1.4

Sex-specific differences in fetal-placental signaling are well established. Female (F) fetuses favor glucocorticoid-regulated pathways, enhancing placental reserve but limiting growth. Male (M) fetuses prioritize androgen-driven signaling, promoting growth at the cost of adaptability. In PCOS, an androgen-mediated condition, these adaptations may be exaggerated, potentially altering placental histopathology. We retrospectively reviewed placental pathology data from singleton livebirths (1/2004–4/2022) conceived with FT (n = 1381). PCOS patients (Rotterdam criteria; n = 181) were grouped by fetal sex (M = 90; F = 91). Placental findings were categorized as anatomic, inflammatory, infectious, or vascular by a blinded perinatal pathologist using Amsterdam Workshop Consensus definitions. Comparisons were made using parametric/nonparametric tests. Logistic regression calculated crude and adjusted odds ratios (aOR), controlling for maternal age, BMI, race, gestational age, FT type, and gestational diabetes (GDM). Baseline characteristics of PCOS patients who delivered M vs F fetuses did not differ significantly [age, mean (SD)—M: 32.8 (3.1) vs F: 33.0 (3.8), p = 0.75; BMI— M: 26.2 (5.6) vs F: 26.2 (5.7), p = 0.89; nulliparity, n (%)—M: 67 (74.4%) vs F: 75 (83.3%), p = 0.14; FT—Ovulation Induction /Intrauterine Insemination—M: 40(44%) vs F: 48 (53.3%); In Vitro Fertilization—M: 51 (56%) vs F: 42 (46.7%), p = 0.21; GDM—M: 14 (15.4%) vs F: 8 (8.9%), p = 0.18]. There were no differences in anatomic, infectious, or vascular abnormalities by fetal sex in crude or adjusted models. Inflammatory abnormalities—villitis of unknown etiology, deciduitis, and intervillositis—were more frequent in F placentas on crude analysis [F: 20 (23%) vs M: 9 (9.9%), OR 1.14 (95% CI 1.02–1.27); p = 0.01], but not after adjustment [aOR 1.07 (95% CI 0.91–1.26); p = 0.4]. This study suggests that fetal sex does not significantly impact placental pathology in PCOS pregnancies. These findings provide reassurance that fetal sex differences may not be a major factor in placenta-mediated pregnancy complications in PCOS patients undergoing FT. Further research should explore the potential influence of androgen exposure on placental function and long-term fetal outcomes in this population.

Persistent downward trends in birth rates and semen quality across the globe have understandably raised interest in understanding the key drivers of human fertility. Among these, interest in factors that are potentially modifiable and subject to an important degree of volitional control, such as diet, exercise, or substance use, has been considerable. Unfortunately for those interested in this topic, either to guide their own behavior or to provide medical advice to those seeking care, the level of detail sought is often misaligned with the level of evidence available at any point in time. Further, the very nature of lifestyle factors is such that for some specific questions patients may pose, there will never be an answer that matches the highest standards of evidence-based medicine. Nevertheless, it is possible to outline rational and robust recommendations that simultaneously balance what is known with the outstanding knowledge gaps. This review addressed three broad topics in their relation to human fertility: diet, including the use of dietary supplements, specific foods, and dietary patterns; energy balance, covering the role of weight management and physical activity; and substance use. Throughout, we identified questions for which the state of the literature allows for strong recommendations; questions that remain open today but are answerable, and addressing them is likely to advance the practice of reproductive medicine; and questions that may never be fully answered without this uncertainty being a barrier for robust action.

OBJECTIVE:To evaluate whether maternal intake of sugar-sweetened beverages (SSB) and artificially sweetened beverages (ASB) affects medically assisted reproduction outcomes (MAR). DESIGN:Prospective cohort study. SETTINGS:Fertility centre at an academic hospital. POPULATION:This study includes 612 women who underwent 1572 MAR cycles, including 804 intrauterine insemination (IUI) cycles and 768 in vitro fertilisation (IVF) cycles. METHODS:A 131-item food frequency questionnaire assessed women's pretreatment SSB and ASB intake. MAIN OUTCOME MEASURES:Live birth per treatment cycle was considered the primary outcome. Secondary outcomes included estradiol trigger levels, endometrial thickness, total oocyte yield, fertilisation, implantation, clinical pregnancy, and pregnancy loss probabilities. RESULTS:A total of 112 (18.3%) women did not consume SSB, and 171 (27.9%) did not consume ASB. SSB and ASB intake were unrelated to the likelihood of success in infertility treatment cycles. The adjusted predicted marginal probability (95% CI) of live birth among women in the lowest and highest category of intake of SSBs was 0.41 (0.32, 0.50) and 0.41 (0.34, 0.49) in couples undergoing IVF/ICSI and 0.10 (0.06, 0.17) and 0.11 (0.07, 0.17) in couples undergoing IUI. The corresponding results for the lowest and highest categories of intake of ASB and live birth were 0.40 (0.33, 0.48) and 0.41 (0.33, 0.49) for IVF/ICSI cycles and 0.09 (0.06, 0.15) and 0.08 (0.05, 0.13) for IUI cycles. There were inconsistent associations in secondary analyses focused on intakes of individual beverages. CONCLUSIONS:Our findings suggest that, in couples seeking MAR, women's intake of SSB or ASB is unrelated to the likelihood of success in infertility treatment with IUI or IVF.

Exposure to phthalates is common and difficult to avoid. However, intake of long-chain n-3 polyunsaturated fatty acids (n3PUFAs) may ameliorate negative effects on ovarian reserve by exposure to phthalates as both are involved in key processes of ovarian function. Among 139 women attending a fertility center in the Environment and Reproductive Health (EARTH) Study (2004-2017), we evaluated whether associations between urinary phthalate biomarkers and antral follicle count (AFC) were modified by tertiles of serum α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We used Poisson regression (for individual phthalate biomarkers) and quantile Q-computation (for mixtures) models adjusted for age, body mass index, prior smoking, number of urine samples and urinary specific gravity. We found that serum EPA + DHA levels modified the negative association of urinary phthalate biomarkers mixture with mean AFC (P for interaction = 0.23); sum of di(2-ethylhexyl) phthalate metabolites (∑DEHP) had the strongest effect modification (P interaction = 0.01). Specifically, phthalate biomarkers mixture and ∑DEHP were inversely related with AFC only among women in the low (P trend = 0.03 and < 0.001, respectively) and middle (P trend = 0.07 and 0.002) tertiles of serum EPA + DHA, but not among women in the high tertile (P trend = 0.56 and 0.93). No effect modifications were found by serum ALA. These findings suggest certain serum n3PUFAs may attenuate effects of phthalate exposure on ovarian reserve marker. Such interaction points toward select n3PUFAs as key modifiers of phthalate toxicity on ovarian health with potential implications for other women's reproductive health endpoints.

OBJECTIVE:To investigate the effect of supraphysiologic estradiol levels during ovarian stimulation on placental pathology among singleton livebirths conceived with in vitro fertilization (IVF) and fresh embryo transfer. DESIGN:Retrospective cohort study. SUBJECTS:Six hundred twenty six IVF-conceived singleton livebirths with associated placental pathology. EXPOSURE:Two separate analyses were performed, using the ≥75th (2588.75pg/mL), and ≥ 90th (3120.5 pg/mL) estradiol percentile as cut-offs. Livebirths were categorized as below or above the estradiol cut-off at time of trigger, and placental abnormalities were compared between groups. MAIN OUTCOME MEASURES:Placental pathology (abnormalities classified as: anatomic, vascular, infectious, and inflammatory). RESULTS:Mean (SD) age and body mass index were 35.2 (4.0) years and 24.8 (4.5) kg/m2. Most patients were identified as White (n = 482, 77.0%), and the most common infertility diagnosis was male factor (n = 178, 28.9%). Using the 75th percentile as estradiol cut-off, unadjusted rates of placental abnormalities did not differ between the two groups (anatomic: 63.7% vs. 65.9%; vascular: 72.0% vs. 66.1%; infectious:33.1% vs. 32%; and inflammatory: 14.6% vs. 20%, for ≥75th vs. <75th percentile, respectively). Adjusted risk ratio (adjRR) (95% confidence interval [CI]) was calculated to account for possible confounding factors (maternal age, body mass index, infertility diagnosis, stimulation protocol, gestational age at delivery, and infant sex). AdjRR (95% CI) did not show significant differences between groups in risk of anatomic or infectious abnormalities. In patients with estradiol levels ≥75th percentile, the risk of vascular abnormalities was higher vs. patients in the <75th percentile group (adjRR [95% CI] 1.14 [1.00-1.29]). Among patients with estradiol levels ≥75th percentile, the risk of inflammatory abnormalities was lower vs. patients in the <75th percentile group (adjRR [95% CI] 0.62 [0.38-0.99]). When using the 90th percentile as the cut-off, no significant differences were noted between groups in rates of anatomic, vascular, infectious, or inflammatory abnormalities (65.1% vs. 65.4%; 76.2% vs. 66.6%; 34.9% vs. 32%; and 15.9% vs. 19%, for ≥90th vs. <90th percentile, respectively). AdjRR (95% CI) did not show significant differences between groups in risk of anatomic, infectious, or inflammatory abnormalities. However, risk for vascular abnormalities was higher among patients with estradiol ≥90th vs. <90th percentile (adjRR [95% CI]: 1.19 [1.01-1.39]). CONCLUSION:Our study did not reveal clinically increased risks of placental abnormalities. Higher serum estradiol during IVF was associated with a marginally higher risk for vascular placental abnormalities.

BACKGROUND:The ovarian reserve is established in utero, and therefore may be influenced by parental characteristics such as tobacco smoking. However, the epidemiologic literature on parental smoking and adult antral follicle count (AFC) remains conflicted. RESEARCH DESIGN AND METHODS:Our study included 631 women enrolled in the Environment and Reproductive Health (EARTH) study, a prospective cohort at an academic fertility center between 2005 and 2019. Exposure was assessed by women self-reporting their mother's and father's overall and pregnancy specific smoking status. Outcome was assessed via AFC measured using transvaginal ultrasonography day 3 of an unstimulated menstrual cycle or progesterone withdrawal bleed. Adjusted multivariable Poisson regression with robust standard errors was used to estimate associations between participant maternal and paternal smoking exposure and AFC. RESULTS:The women in our study were mostly ≥35 years (55 %), never smokers (74 %), college-educated (92 %), White (84 %), and US born (76 %). The median AFC was 13.5 (interquartile range: 8-18). History of maternal smoking was not associated with AFC (ever vs never smoker: 1.3 %, 95 % CI: 8.4 %, 6.4 %) nor was maternal smoking during pregnancy (smoked during pregnancy vs. never smoker: 4.6 %, 95 % CI: 7.6 %, 18.4 %). History of paternal smoking was associated with lower AFC (ever vs never: 9.9 %; 95 % CI: 16.3 %, -2.9 %). Participants who reported that both their parents were ever smokers averaged 10.9 % lower AFC (95 % CI: 18.6 %, -2.5 %) compared to participants whose parents never smoked. CONCLUSION:Paternal smoking, including time periods outside the pregnancy window, may negatively influence the long-term ovarian development and function in female offspring. TRIAL REGISTRATION NUMBER:NCT00011713.

Objective: To study whether self-reported psychological stress was associated with impaired semen parameters and reproductive hormones. Design: An observational study including men aged 18-55 years who attended the Massachusetts General Hospital Fertility Clinic. Subjects: A total of 718 men who attended the clinic provided semen and serum blood samples and completed the short version of the Cohen Perceived Stress Scale (PSS-4). Exposure: Scores from completed the short version of the PSS-4 were used to quantify perceived psychological stress. Main Outcome Measures: The World Health Organization semen analysis parameters, including ejaculate volume, sperm count, concentration, motility, and morphology, were ascertained. Further analysis of sperm DNA damage was performed using the Comet Assay. Serum concentrations of luteinizing hormone, follicle stimulating hormone, prolactin, inhibin, testosterone, and estrogen were measured. Linear regression models were used to evaluate associations between self-reported stress and testicular function outcomes, adjusting for age, body mass index, abstinence time, year of semen sample collection, and time to blood sampling. Parameters with skewed distributions were natural log-transformed for analysis where appropriate to minimize the influence of outliers. Results: Compared with the lowest quartile of PSS-4 scores, men in the highest had significantly lower adjusted mean total sperm count, 118 mil/ejaculate (95% confidence interval [CI]: 101-139) vs. 153 mil/ejaculate (95% CI: 133-175) and lower adjusted mean normal morphology count, 5.97 mil/ejaculate (95% CI: 4.73-7.55) vs. 9.13 mil/ejaculate (95% CI: 7.43-11.0). Higher perceived stress showed consistent trends with lower mean levels of sperm concentration, total motile count, percentage of normal sperm morphology, and number of cells with high DNA damage in adjusted models. No associations were observed between self-reported stress and other outcomes of sperm DNA damage and reproductive hormone concentrations. Conclusion: Greater perceived stress was negatively associated with certain semen quality parameters and spermatic cell DNA damage, whereas no associations were found for additional markers of sperm DNA damage or reproductive hormone levels. (Fertil Steril (R) 2025;124:62-70. (c) 2025 by American Society for Reproductive Medicine.) El resumen est & aacute; disponible en Espa & ntilde;ol al final del art & iacute;culo.

BACKGROUND:Phthalate exposures are ubiquitous and have been associated with pregnancy complications. Interaction between serum long-chain n-3 polyunsaturated fatty acids (n3PUFA) and phthalate biomarkers is biologically plausible because both can bind to human peroxisome proliferator-activated receptors (PPARs), which are involved in placenta development. However, evidence of this interaction in humans is lacking. OBJECTIVE:This study evaluated whether serum n3PUFA modifies the associations of biomarkers of phthalate exposure on pregnancy outcomes. METHODS:Among 351 women undergoing in vitro fertilization in the Environment and Reproductive Health study (2004-2017), we evaluated the effect modification of eicosapentaenoic acid (EPA) and serum docosahexaenoic acid (DHA) on the association of pregnancy outcomes with the mixture of urinary concentrations of phthalate biomarkers by quantile g-computation. All models were adjusted for age, body mass index, prior smoking, infertility diagnosis, treatment year, and urinary specific gravity. RESULTS:Concentrations of the phthalate biomarkers mixture were associated with higher adjusted probabilities of pregnancy loss and lower estimated probabilities of live birth among women with serum EPA+DHA in the lowest tertile (<2.66% of total fatty acids), but not among women with middle-to-high serum EPA+DHA (p interactions=0.06 and 0.15, respectively). Among women in the lowest tertile of serum EPA+DHA, the adjusted probability [95% confidence interval (CI)] of pregnancy loss for women in the lowest and highest quartile of phthalates mixtures was 5% (95% CI: 2%, 16%) and 44% (95% CI: 23%, 85%), respectively (p trend=0.01). The corresponding estimates were 14% (95% CI: 5%, 41%) and 11% (95% CI: 3%, 42%) among women with serum EPA+DHA in the highest tertile (≥3.78%  of total fatty acids) (p trend=0.81). Similar trends were observed for live birth but not for implantation and clinical pregnancy. CONCLUSIONS:This study suggests adverse effects of phthalate exposure on pregnancy loss and live birth may be attenuated by intakes of n3PUFA. These results, if replicated, could inform clinical practice reducing the burden of infertility by phthalate exposure among the general population and improving pregnancy outcomes among subfertile couples. https://doi.org/10.1289/EHP15942.

Background/Objectives: The aim of this study was to investigate the association between antioxidant intake and antral follicle count (AFC), a marker of ovarian reserve, in women attending a fertility clinic. Methods: We conducted an observational study with 567 women undergoing infertility evaluation at the Massachusetts General Hospital Fertility Center, who were enrolled in the Environment and Reproductive Health (EARTH) study. Participants filled out the lifestyle and health questionnaires and a validated food frequency questionnaire (FFQ) for assessing habitual dietary intake and underwent a transvaginal ultrasound to measure AFC. Intake of nutrients with direct antioxidant capacity (vitamin A, C, and E and carotenoids) and intake of antioxidant food sources were estimated from the FFQ. Adjusted Poisson regression models were fitted to assess the relationships between antioxidants and AFC while adjusting for potential confounders. Non-linearity was assessed with restricted cubic splines. Results: The median (interquartile range) age and AFC of participants were 35.0 (32.0-38.0) years and 13 (9-18), respectively. Our findings revealed a non-linear association between lycopene intake and AFC. There was a positive linear association with the highest AFC among women consuming approximately 6000 mcg/day of lycopene (p for non-linearity = 0.003). An inverse association was observed between retinol intake, predominantly from dairy foods, and AFC among women aged under 35 years (p-trend < 0.001 and 0.01, respectively). Conclusions: Our findings suggest that lycopene intake might influence the ovarian reserve in fertility patients. The observed inverse association with retinol, if confirmed, may reflect biological mechanisms different from oxidative stress. The underlying mechanisms of these associations remain to be elucidated and warrant further investigation.

Background/Objectives: Few studies have investigated the association of dietary glycemic index (GI), glycemic load (GL), and carbohydrate intake with antral follicle count (AFC). This study aimed to investigate the association of total carbohydrate intake and carbohydrate quality, measured by dietary GI and GL, with ovarian reserve assessed by AFC. Methods: This study included 653 females from the Environment And Reproductive Health Study who completed AFC and food frequency questionnaire. Of these, 579 female individuals had a quantifiable AFC in both ovaries and were included in the primary analysis. We estimated average GI and GL for each participant from self-reported intakes of carbohydrate-containing foods and divided participants into tertiles. Poisson regression models were used to quantify the relations of GI, GL, carbohydrates, and AFC while adjusting for potential confounders. Results: Participants had a median age of 35 y. Compared to participants in the lowest tertile of dietary GI, those in the highest tertile had a 6.3% (0.6%, 12.3%) higher AFC (p, trend 0.03) after adjustment for potential confounders. Stratified analyses revealed that the association between GI and AFC was present only among participants who had not undergone infertility evaluations. Conclusions: A higher dietary GI was associated with a higher AFC. Subgroup analyses among individuals who had not had a diagnostic evaluation of infertility before joining the study suggest that high-glycemic carbohydrates may be related to PCOM.