Objective: To examine the association between ambient temperature and antral follicle count (AFC), a standard measure of ovarian reserve. Design: Prospective cohort study. Setting: Fertility center at an academic hospital in the northeastern United States. Patient(s): 631 women attending the Massachusetts General Hospital Fertility Center (2005–2015) who participated in the Environment and Reproductive Health Study. Intervention(s): Daily temperature at the women's residential address was estimated for the 90 days before their antral follicle scan using a spatially refined gridded climate data set. We evaluated the associations between temperature and AFC using Poisson regression with robust standard errors, adjusting for relative humidity, fine particulate matter exposure, age, education, smoking status, year and month of AFC, and diagnosis of diminished ovarian reserve and ovulation disorders. Main Outcome Measure(s): Antral follicle count as measured with transvaginal ultrasonography. Result(s): A 1°C increase in average maximum temperature during the 90 days before ovarian reserve testing was associated with a −1.6% (95% confidence interval [CI], −2.8, −0.4) lower AFC. Associations remained negative, but were attenuated, for average maximum temperature exposure in the 30 days (−0.9%, 95% CI, −1.8, 0.1) and 14 days (−0.8%, 95% CI, −1.6, 0.0) before AFC. The negative association between average maximum temperature and AFC was stronger in November through June than during the summer months, suggesting that timing of heat exposure and acclimatization to heat may be important factors to consider in future research. Conclusion(s): Exposure to higher temperatures was associated with lower ovarian reserve. These results raise concern that rising ambient temperatures worldwide may result in accelerated reproductive aging among women.
Background: Higher exposure to traffic-related air pollution (TRAP) is related to lower fertility, with specific adverse effects on the ovary. Folic acid may attenuate these effects. Our goal was to explore the relation of TRAP exposure and supplemental folic acid intake with epigenetic aging and CpG-specific DNA methylation (DNAm) in granulosa cells (GC). Our study included 61 women undergoing ovarian stimulation at a fertility center (2005–2015). DNAm levels were profiled in GC using the Infinium MethylationEPIC BeadChip. TRAP was defined using a spatiotemporal model to estimate residence-based nitrogen dioxide (NO2) exposure. Supplemental folic acid intake was measured with a validated food frequency questionnaire. We used linear regression to evaluate whether NO2 or supplemental folic acid was associated with epigenetic age acceleration according to the Pan-tissue, mural GC, and GrimAge clocks or DNAm across the genome adjusting for potential confounders and accounting for multiple testing with a false discovery rate < 0.1. Results: There were no associations between NO2 or supplemental folic acid intake and epigenetic age acceleration of GC. NO2 and supplemental folic acid were associated with 9 and 11 differentially methylated CpG sites. Among these CpGs, only cg07287107 exhibited a significant interaction (p-value = 0.037). In women with low supplemental folic acid, high NO2 exposure was associated with 1.7% higher DNAm. There was no association between NO2 and DNAm in women with high supplemental folic acid. The genes annotated to the top 250 NO2-associated CpGs were enriched for carbohydrate and protein metabolism, postsynaptic potential and dendrite development, and membrane components and exocytosis. The genes annotated to the top 250 supplemental folic acid-associated CpGs were enriched for estrous cycle, learning, cognition, synaptic organization and transmission, and size and composition of neuronal cell bodies. Conclusions: We found no associations between NO2, supplemental folic acid, and DNAm age acceleration of GC. However, there were 20 differentially methylated CpGs and multiple enriched GO terms associated with both exposures suggesting that differences in GC DNAm could be a plausible mechanism underlying the effects of TRAP and supplemental folic acid on ovarian function.
Importance: Pregnancy intention assessment is a key element of preconception and contraceptive care. The association between a single screening question and the incidence of pregnancy is unknown. Objective: To prospectively evaluate the dynamics of pregnancy intention and pregnancy incidence. Design, Setting, and Participants: This prospective cohort study (the Nurses' Health Study 3) was conducted from June 1, 2010, to April 1, 2022, in 18376 premenopausal, nonpregnant female nurses aged 19 to 44 years. Main Outcomes and Measures: Pregnancy intention and pregnancy status were assessed at baseline and approximately every 3 to 6 months thereafter. Cox proportional hazards regression models were used to estimate the association between pregnancy intention and pregnancy incidence. Results: A total of 18376 premenopausal, nonpregnant women (mean [SD] age, 32.4 [6.5] years) participated in the study. At baseline, 1008 women (5.5%) were trying to conceive, 2452 (13.3%) were contemplating pregnancy within 1 year, and the remaining 14916 (81.2%) were neither trying to conceive nor thought they would be pregnant within 1 year. A total of 1314 pregnancies were documented within 12 months of pregnancy intention assessment. The cumulative incidence of pregnancy was 38.8% in women actively trying to conceive (median [IQR] time to pregnancy, 3.3 [1.5-6.7] months), 27.6% in women contemplating pregnancy (median [IQR] time to pregnancy, 6.7 [4.2-9.3] months), and 1.7% in women neither trying to conceive nor contemplating pregnancy (median [IQR] time to pregnancy, 7.8 [5.2-10.5] months) among those who became pregnant. Women who were actively trying to conceive were 23.1 times (95% CI, 19.5-27.4 times) and women who were contemplating pregnancy were 13.0 times (95% CI, 11.1-15.2 times) more likely to conceive within 12 months than women who were neither attempting nor contemplating pregnancy. Among women contemplating pregnancy at baseline who did not get pregnant during follow up, 18.8% were actively trying and 27.6% were not trying by 12 months. Conversely, only 4.9% of women neither trying to conceive nor contemplating pregnancy within 1 year at baseline changed pregnancy intention during follow up. Conclusions and Relevance: In this cohort study of reproductive-aged nurses in North America, pregnancy intention was highly fluid among women who were contemplating pregnancy but relatively stable among women trying to conceive and women who were neither trying to conceive nor contemplating pregnancy. Pregnancy intention was strongly associated with pregnancy incidence, but the median time to pregnancy points to a relatively short time window to initiate preconception care..
BACKGROUND: Certain symptoms associated with infertility are associated with cardiovascular disease, including menstrual cycle irregularity, early menopause, and obesity; however, few studies have investigated the association between infertility and cardiovascular disease risk. METHODS AND RESULTS: Participants in the NHSII (Nurses’ Health Study II) who reported infertility (12 months of trying to con-ceive without success, including women who subsequently conceived) or who were gravid, with no infertility were followed from 1989 until 2017 for development of incident, physician-diagnosed coronary heart disease (CHD) (myocardial infarction, coronary artery bypass grafting, angioplasty, stent) and stroke. Time-varying Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs and were adjusted a priori for potential confounding variables. Among 103 729 participants, 27.6% reported having ever experienced infertility. Compared with gravid women who had not reported infertility, women with a history of infertility had greater risk of CHD (HR, 1.13 [95% CI, 1.01–1.26]) but not stroke (HR, 0.91 [95% CI, 0.77– 1.07]). The association between history of infertility and CHD was strongest among women who reported infertility at an earlier age (HR for infertility first reported at ≤25 years, 1.26 [95% CI, 1.09–1.46]; HR at 26–30 years, 1.08 [95% CI, 0.93–1.25]; HR at >30 years, 0.91 [95% CI, 0.70–1.19]). When we investigated specific infertility diagnoses, elevated risk of CHD was observed among women whose infertility was attributed to an ovulatory disorder (HR, 1.28 [95% CI, 1.05–1.55]) or endometriosis (HR, 1.42 [95% CI, 1.09–1.85]). CONCLUSIONS: Women with infertility may be at an increased risk of CHD. Risk differed by age at first infertility diagnosis and was restricted to ovulatory-and endometriosis-related infertility.
Background: Women are at greater risk than men of developing chronic inflammatory conditions and “long COVID.” However, few gynecologic health risk factors for long COVID-19 have been identified. Endometriosis is a common gynecologic disorder associated with chronic inflammation, immune dysregulation, and comorbid presentation with autoimmune and clotting disorders, all of which are pathophysiological mechanisms proposed for long COVID-19. Therefore, we hypothesized that women with a history of endometriosis may be at greater risk of developing long COVID-19. Objective: This study aimed to investigate the association between history of endometriosis before SARS-CoV-2 infection and risk of long COVID-19. Study Design: We followed 46,579 women from 2 ongoing prospective cohort studies—the Nurses’ Health Study II and the Nurses’ Health Study 3—who participated in a series of COVID-19-related surveys administered from April 2020 to November 2022. Laparoscopic diagnosis of endometriosis was documented prospectively in main cohort questionnaires before the pandemic (1993–2020) with high validity. SARS-CoV-2 infection (confirmed by antigen, polymerase chain reaction, or antibody test) and long-term COVID-19 symptoms (≥4 weeks) defined by the Centers for Disease Control and Prevention were self-reported during follow-up. Among individuals with SARS-CoV-2 infection, we fit Poisson regression models to assess the associations between endometriosis and risk of long COVID-19 symptoms, with adjustment for potential confounding variables (demographics, body mass index, smoking status, history of infertility, and history of chronic diseases). Results: Among 3650 women in our sample with self-reported SARS-CoV-2 infections during follow-up, 386 (10.6%) had a history of endometriosis with laparoscopic confirmation, and 1598 (43.8%) reported experiencing long COVID-19 symptoms. Most women were non-Hispanic White (95.4%), with a median age of 59 years (interquartile range, 44–65). Women with a history of laparoscopically-confirmed endometriosis had a 22% greater risk of developing long COVID-19 (adjusted risk ratio, 1.22; 95% confidence interval, 1.05–1.42) compared with those who had never been diagnosed with endometriosis. The association was stronger when we defined long COVID-19 as having symptoms for ≥8 weeks (risk ratio, 1.28; 95% confidence interval, 1.09–1.50). We observed no statistically significant differences in the relationship between endometriosis and long COVID-19 by age, infertility history, or comorbidity with uterine fibroids, although there was a suggestive trend indicating that the association may be stronger in women aged <50 years (<50 years: risk ratio, 1.37; 95% confidence interval, 1.00–1.88; ≥50 years: risk ratio, 1.19; 95% confidence interval, 1.01–1.41). Among persons who developed long COVID-19, women with endometriosis reported on average 1 additional long-term symptom compared with women without endometriosis. Conclusion: Our findings suggest that those with a history of endometriosis may be at modestly increased risk for long COVID-19. Healthcare providers should be aware of endometriosis history when treating patients for signs of persisting symptoms after SARS-CoV-2 infection. Future studies should investigate the potential biological pathways underlying these associations.
by
Yu-Han Chiu;
Raj P Fadadu;
Audrey Gaskins;
Sheryl L Rifas-Shiman;
Hannah E Laue;
Kelle H Moley;
Marie-France Hivert;
Andrea Baccarelli;
Emily Oken;
Jorge E Chavarro;
Andres Cardenas
Maternal fat intake during pregnancy affects fetal growth, but mechanisms underlying this relationship are unclear. We performed an exploratory study of the associations of fat consumption during pregnancy with cord blood DNA methylation of the insulin-like growth factor 2 (IGF2) and H19 genes. We used data from 96 uncomplicated full-term pregnancies of mothers of whom majority had normal body mass index (BMI) (66%) in Project Viva, a prospective pre-birth cohort. We assessed maternal diet with validated food frequency questionnaires during the first and second trimesters and measured DNA methylation in segments of the IGF2- and H19-differentially methylated regions (DMRs) by pyrosequencing DNA extracted from umbilical cord blood samples. Mean (SD) age was 32.8 (4.1) years and prepregnancy BMI was 24.0 (4.4) kg/m2. Mean DNA methylation was 56.3% (3.9%) for IGF2-DMR and 44.6% (1.9%) for H19-DMR. Greater first trimester intake of omega-6 polyunsaturated fat (effect per 1% of calories at the expense of carbohydrates) was associated with lower DNA methylation of IGF2-DMR (−1.2%; 95% confidence interval [CI]: −2.2%, −0.2%) and higher DNA methylation at H19-DMR (0.8%; 95% CI: 0.3%, 1.3%). On the other hand, greater first trimester intake of omega-3 polyunsaturated fat was associated with lower DNA methylation of the H19-DMR (−4.3%; 95% CI: −7.9%, −0.8%). We did not find significant associations of IGF2 and H19 methylation with IGF2 cord blood levels. Our findings suggest that early prenatal fat intake (omega-3, omega-6, and saturated fatty acids) may influence DNA methylation at the IGF2 and H19 locus, which could impact fetal development and long-term health.
Background: Air pollution exposure has been linked with diminished fertility. Identifying the metabolic changes induced by periconception air pollution exposure among women could enhance our understanding of the potential biological pathways underlying air pollution's reproductive toxicity. Objective: To identify serum metabolites associated with periconception air pollution exposure and evaluate the extent to which these metabolites mediate the association between air pollution and live birth. Methods: We included 200 women undergoing a fresh assisted reproductive technology (ART) cycle at Massachusetts General Hospital Fertility Center (2005–2015). A serum sample was collected during stimulation, and untargeted metabolic profiling was conducted using liquid chromatography with ultra-high-resolution mass spectrometry. Exposure to nitrogen dioxide (NO2), ozone (O3), fine particulate matter <2.5 µm (PM2.5), and black carbon (BC) was estimated using validated spatiotemporal models. Multivariable linear regression models were used to evaluate the associations between the air pollutants, live birth, and metabolic feature intensities. A meet in the middle approach was used to identify overlapping features and metabolic pathways. Results: From the C18 and HILIC chromatography columns, 10,803 and 12,968 metabolic features were extracted. There were 190 metabolic features and 18 pathways that were significantly associated with both air pollution and live birth (P < 0.05) across chromatography columns. Eight features were confirmed metabolites implicated in amino acid and nutrient metabolism with downstream effects on oxidative stress and inflammation. Six confirmed metabolites fell into two intuitive clusters – “antioxidants” and “oxidants”- which could potentially mediate some of the association between air pollution and lower odds of live birth. Tryptophan and vitamin B3 metabolism were common pathways linking air pollution exposure to decreased probability of live birth. Conclusion: Higher periconception air pollution exposure was associated with metabolites and biologic pathways involved in inflammation and oxidative stress that may mediate the observed associations with lower probability of live birth following ART.
Objective: To investigate the associations between dietary patterns and antral follicle count (AFC), a marker of ovarian reserve. Design: Prospective cohort study. Setting: Fertility center at an academic hospital. Patient(s): A total of 363 women seeking preconception evaluation and infertility care at the Massachusetts General Hospital who participated in the Environment and Reproductive Health Study. Intervention(s): None. At enrollment, women reported diet through a food frequency questionnaire, from which we computed three dietary pattern adherence scores: the Mediterranean diet, the Fertility diet, and the Profertility diet. Main Outcome Measure(s): The AFC was assessed with a transvaginal ultrasound performed on the third day of an unstimulated menstrual cycle or on the third day of a P withdrawal bleed. Result(s): Higher adherence to the three dietary patterns examined were unrelated to AFC. The multivariable adjusted AFC means and 95% confidence intervals for women in the highest compared with the lowest quartile of adherence score were 13.9 (13.0–14.9) and 13.5 (12.6–14.4) for the Mediterranean diet, 14.0 (13.2–14.9) and 13.5 (12.7–14.3) for the Fertility diet, and 12.5 (11.6–13.5) and 13.3 (12.5–14.2) for the Profertility diet. Conclusion(s): Dietary patterns were unrelated to AFC among a cohort of women presenting at a fertility center. Due to the limited and heterogeneous current evidence, it is important to evaluate this association in further studies, and in particular among women from the general population.
Objective: To investigate the effects of oocyte donor and recipient body mass index (BMI) on outcomes of vitrified donor oocyte assisted reproductive technology (ART). Design: Retrospective cohort study. Setting: Private fertility center. Patient(s): A total of 338 oocyte donors and 932 recipients who underwent 1,651 embryo transfer cycles in 2008–2015. Intervention(s): Multivariable log binomial regression models with cluster-weighted generalized estimating equations were used to estimate the adjusted risk ratios. Main Outcome Measure(s): Live birth, defined as the delivery of at least one live-born infant, including all embryo transfer cycles. Secondary outcomes included birth weight and gestational length only among singleton live births. Results: The mean ± SD body mass indexes (BMIs) of donors and recipients were 22.6 ± 2.5 kg/m2 and 24.6 ± 4.8 kg/m2, respectively. There were no significant associations between donor BMI and probability of live birth. Recipients with BMI ≥35 kg/m2 had a significantly higher probability of live birth compared with normal-weight recipients. Among singleton live births, recipients with BMI <18.5 kg/m2 had a lower risk whereas women with BMI ≥35 kg/m2 had a higher risk of delivery in an earlier gestational week compared with normal weight women. Recipients with a BMI ≥35 kg/m2 also had a higher risk of having a low birth weight infant compared with normal-weight women. Conclusions: In the setting of vitrified donor oocyte ART, recipient BMI was positively associated with probability of live birth but negatively associated with gestational length and birth weight among singleton births.