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Objective: To determine the association between ovarian reserve biomarkers and future fertility among late reproductive-age women.Design: Cohort study of participants enrolled in Time to Conceive (TTC), a time-to-pregnancy cohort study of the ovarian reserve biomarkers.Setting: Community.Patient(s): Women aged 30-44 years without a history of infertility who provided a blood sample at enrollment in TTC and who agreed to future follow-up.Intervention(s): Not applicable.Main Outcome Measure(s): The primary outcomes were probability of achieving a live birth >3 years after enrollment in TTC, diagnosis of infertility at any time, and time-to-pregnancy in future pregnancy attempts.Result(s): Women with diminished ovarian reserve, defined as those with an antimüllerian hormone (AMH) level <0.7 ng/mL or follicle-stimulating hormone (FSH) level ≥10 mIU/mL, did not have low risk of future live birth (relative risk [RR], 1.32; 95% confidence interval [CI], 0.95-1.83 and RR, 1.28; 95% CI, 0.97-1.70, respectively) compared with women with normal ovarian reserve after adjusting for age at blood draw, race, obesity, use of hormonal contraception, and year of enrollment in original study. Among women in the cohort that attempted to conceive, there was not a significant association between diminished ovarian reserve, as measured by AMH or FSH, and risk of future infertility (RR, 0.65; 95% CI, 0.21-2.07 and RR,1.69; 95% CI, 0.86-3.31, respectively). Similarly, there was no association between AMH and FSH levels and future fecundability (fecundability ratio, 0.97; 95% CI, 0.59, 1.60; and fecundability ration, 0.86; 95% CI, 0.55-1.36, respectively).Conclusion: Diminished ovarian reserve is not associated with reduced future reproductive capacity. Given the lack of association, women should be cautioned regarding use biomarkers of ovarian reserve as predictors of their future reproductive capacity. [ABSTRACT FROM AUTHOR]

Background: Use of menstrual tracking data to understand abnormal bleeding patterns has been limited because of lack of incorporation of key demographic and health characteristics and confirmation of menstrual tracking accuracy.Objective: This study aimed to identify abnormal uterine bleeding patterns and their prevalence and confirm existing and expected associations between abnormal uterine bleeding patterns, demographics, and medical conditions.Study Design: Apple Women's Health Study participants from November 2019 through July 2021 who contributed menstrual tracking data and did not report pregnancy, lactation, use of hormones, or menopause were included in the analysis. Four abnormal uterine bleeding patterns were evaluated: irregular menses, infrequent menses, prolonged menses, and irregular intermenstrual bleeding (spotting). Monthly tracking confirmation using survey responses was used to exclude inaccurate or incomplete digital records. We investigated the prevalence of abnormal uterine bleeding stratified by demographic characteristics and used logistic regression to evaluate the relationship of abnormal uterine bleeding to a number of self-reported medical conditions.Results: There were 18,875 participants who met inclusion criteria, with a mean age of 33 (standard deviation, 8.2) years, mean body mass index of 29.3 (standard deviation, 8.0), and with 68.9% (95% confidence interval, 68.2-69.5) identifying as White, non-Hispanic. Abnormal uterine bleeding was found in 16.4% of participants (n=3103; 95% confidence interval, 15.9-17.0) after accurate tracking was confirmed; 2.9% had irregular menses (95% confidence interval, 2.7-3.1), 8.4% had infrequent menses (95% confidence interval, 8.0-8.8), 2.3% had prolonged menses (95% confidence interval, 2.1-2.5), and 6.1% had spotting (95% confidence interval, 5.7-6.4). Black participants had 33% higher prevalence (prevalence ratio, 1.33; 95% confidence interval, 1.09-1.61) of infrequent menses compared with White, non-Hispanic participants after controlling for age and body mass index. The prevalence of infrequent menses was increased in class 1, 2, and 3 obesity (class 1: body mass index, 30-34.9; prevalence ratio, 1.31; 95% confidence interval, 1.13-1.52; class 2: body mass index, 35-39.9; prevalence ratio, 1.25; 95% confidence interval, 1.05-1.49; class 3: body mass index, >40; prevalence ratio, 1.51; 95% confidence interval, 1.21-1.88) after controlling for age and race/ethnicity. Those with class 3 obesity had 18% higher prevalence of abnormal uterine bleeding compared with healthy-weight participants (prevalence ratio, 1.18; 95% confidence interval, 1.02-1.38). Participants with polycystic ovary syndrome had 19% higher prevalence of abnormal uterine bleeding compared with participants without this condition (prevalence ratio, 1.19; 95% confidence interval, 1.08-1.31). Participants with hyperthyroidism (prevalence ratio, 1.34; 95% confidence interval, 1.13-1.59) and hypothyroidism (prevalence ratio, 1.17; 95% confidence interval, 1.05-1.31) had a higher prevalence of abnormal uterine bleeding, as did those reporting endometriosis (prevalence ratio, 1.28; 95% confidence interval, 1.12-1.45), cervical dysplasia (prevalence ratio, 1.20; 95% confidence interval, 1.03-1.39), and fibroids (prevalence ratio, 1.14; 95% confidence interval, 1.00-1.30).Conclusion: In this cohort, abnormal uterine bleeding was present in 16.4% of those with confirmed menstrual tracking. Black or obese participants had increased prevalence of abnormal uterine bleeding. Participants reporting conditions such as polycystic ovary syndrome, thyroid disease, endometriosis, and cervical dysplasia had a higher prevalence of abnormal uterine bleeding. [ABSTRACT FROM AUTHOR]

Local inflammation plays an important role in normal folliculogenesis and ovulation, and conditions of chronic systemic inflammation, such as obesity and polycystic ovarian syndrome, can disrupt normal follicular dynamics. This study aimed to determine the association between systemic inflammation, as measured by C-reactive protein levels, and menstrual cycle length. This study was a secondary analysis using data from Time to Conceive, a prospective time-to-pregnancy cohort study. The association between cycle length and C-reactive protein was analyzed using multivariable linear mixed and marginal models adjusted for age, race, education, body mass index, time since oral contraceptive use, alcohol, smoking, caffeine consumption, and exercise. Time to Conceive enrolled women aged 30 to 44 years with no history of infertility who were attempting to conceive for <3 months. Serum C-reactive protein levels were measured on cycle day 2, 3, or 4. Participants recorded daily menstrual cycle data for ≤4 months. Main outcome measures included menstrual cycle length and follicular and luteal phase lengths. Multivariable analysis included 1409 cycles from 414 women. There was no linear association between C-reactive protein levels and menstrual cycle length. However, compared with <1 mg/L, a C-reactive protein level >10 mg/L was associated with >3 times the odds (adjusted odds ratio, 3.7; 95% confidence interval, 1.67–8.11) of long cycles (defined as ≥35 days). When evaluating follicular phase length, a C-reactive protein level of >10 mg/L was associated both with follicular phases that were 1.7 (95% confidence interval, 0.23–3.09) days longer and with >2 times the odds of a long follicular phase (adjusted odds ratio, 2.2; 95% confidence interval, 1.05–4.74). There is a potential pathophysiological association between systemic inflammation and menstrual cycle changes. Further studies are needed to determine if systemic inflammation alters the menstrual cycle or if long menstrual cycles are a marker for elevated systemic inflammation. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested that emergent events may affect pregnancy planning decisions. However, few have investigated the effect of factors related to the COVID-19 pandemic on pregnancy planning, measured by attempting conception, and how attempting conception status may differ by individual-level factors, such as social status or educational level.Objective: This study aimed to examine the effects of factors related to the COVID-19 pandemic, until March 2021, on attempting conception status and to assess the effect measure modification by educational level and subjective social status.Study Design: We conducted a longitudinal analysis within a subgroup of 21,616 participants in the Apple Women's Health Study who enrolled from November 2019 to March 2021, who met the inclusion criteria, and who responded to the monthly status menstrual update question on attempting conception status (yes or no). Participants reporting hysterectomy, pregnancy, lactation, or menopause were excluded. We used generalized estimating equation methodology to fit logistic regression models that estimate odds ratios and 95% confidence intervals for the association between the proportion of participants attempting conception and the month of response (compared with a prepandemic reference month of February 2020) while accounting for longitudinal correlation and adjusting for age, race and ethnicity, and marital status. We stratified the analysis by social status and educational level.Results: We observed a trend of reduced odds of attempting conception, with an 18% reduction in the odds of attempting conception in August 2020 and October 2020 compared with the prepandemic month of February 2020 (August odds ratio: 0.82 [95% confidence interval, 0.70-0.97]; October odds ratio: 0.82 [95% confidence interval, 0.69-0.97). The participants with lower educational level (no college education) experienced a sustained reduction in the odds of attempting to conceive from June 2020 to March 2021 compared with February 2020, with up to a 24% reduction in the odds of attempting to conceive in October 2020 (odds ratio, 0.76; 95% confidence interval, 0.59-0.96). Among participants that were college educated, we observed an initial reduction in the odds of attempting to conceive starting in July 2020 (odds ratio 0.73; 95% confidence interval, 0.54-0.99) that returned near prepandemic odds. Moreover, we observed a reduction in the odds of attempting to conceive among those with low subjective social status, with a decline in the odds of attempting to conceive beginning in July 2020 (odds ratio, 0.83; 95% confidence interval, 0.63-1.10) and continuing until March 2021 (odds ratio, 0.79; 95% confidence interval, 0.59-1.06), with the greatest reduction in odds in October 2020 (odds ratio, 0.67; 95% confidence interval, 0.50-0.91).Conclusion: Among women in the Apple Women's Health Study cohort, our findings suggested a reduction in the odds of attempting to conceive during the COVID-19 pandemic, until March 2021, particularly among women of lower educational level and lower perceived social status. [ABSTRACT FROM AUTHOR]

Background: Prospective longitudinal cohorts assessing women's health and gynecologic conditions have historically been limited.Objective: The Apple Women's Health Study was designed to gain a deeper understanding of the relationship among menstrual cycles, health, and behavior. This paper describes the design and methods of the ongoing Apple Women's Health Study and provides the demographic characteristics of the first 10,000 participants.Study Design: This was a mobile-application-based longitudinal cohort study involving survey and sensor-based data. We collected the data from 10,000 participants who responded to the demographics survey on enrollment between November 14, 2019 and May 20, 2020. The participants were asked to complete a monthly follow-up through November 2020. The eligibility included installed Apple Research app on their iPhone with iOS version 13.2 or later, were living in the United States, being of age greater than 18 years (19 in Alabama and Nebraska, 21 years old in Puerto Rico), were comfortable in communicating in written and spoken English, were the sole user of an iCloud account or iPhone, and were willing to provide consent to participate in the study.Results: The mean age at enrollment was 33.6 years old (±standard deviation, 10.3). The race and ethnicity was representative of the US population (69% White and Non-Hispanic [6910/10,000]), whereas 51% (5089/10,000) had a college education or above. The participant geographic distribution included all the US states and Puerto Rico. Seventy-two percent (7223/10,000) reported the use of an Apple Watch, and 24.4% (2438/10,000) consented to sensor-based data collection. For this cohort, 38% (3490/9238) did not respond to the Monthly Survey: Menstrual Update after enrollment. At the 6-month follow-up, there was a 35% (3099/8972) response rate to the Monthly Survey: Menstrual Update. 82.7% (8266/10,000) of the initial cohort and 95.1% (2948/3099) of the participants who responded to month 6 of the Monthly Survey: Menstrual Update tracked at least 1 menstrual cycle via HealthKit. The participants tracked their menstrual bleeding days for an average of 4.44 (25%-75%; range, 3-6) calendar months during the study period. Non-White participants were slightly more likely to drop out than White participants; those remaining at 6 months were otherwise similar in demographic characteristics to the original enrollment group.Conclusion: The first 10,000 participants of the Apple Women's Health Study were recruited via the Research app and were diverse in race and ethnicity, educational attainment, and economic status, despite all using an Apple iPhone. Future studies within this cohort incorporating this high-dimensional data may facilitate discovery in women's health in exposure outcome relationships and population-level trends among iPhone users. Retention efforts centered around education, communication, and engagement will be utilized to improve the survey response rates, such as the study update feature. [ABSTRACT FROM AUTHOR]

Abstract: Both delayed gastrointestinal transit and autonomic neuropathy have been documented in patients with diabetes mellitus. The mechanism of neostigmine, an agent that mimics release of acetylcholine from autonomic neurons by prokinetic agents, to contract smooth muscle, despite dysfunctional enteric neural pathways, was determined using isolated ilea from STZ-treated and control guinea pigs. Both bethanechol- and neostigmine-induced contractions were stronger in diabetic ileum. Bethanechol-induced contractions of control but not diabetic ileum were increased by low dose scopolamine suggesting reduced activation of presynaptic muscarinic autoreceptors in diabetic ileum. The muscarinic receptor antagonist 4-DAMP strongly, but the nicotinic receptor antagonist hexamethonium only weakly, reduced neostigmine-induced contractions of control and diabetic ilea. The amount of acetylcholine, inferred from tissue choline content, was increased in diabetic ileum. Nicotinic neural and noncholinergic postjunctional smooth muscle receptors contributed more strongly to neostigmine-induced contractions in diabetic than control ileum. Relaxation of diabetic ileum by exogenous nitric oxide generated from sodium nitroprusside was comparable to control ileum, but smooth muscle relaxation by l-arginine using neuronal nitric oxide synthase to generate nitric oxide was weaker in diabetic ileum with evidence for a role for inducible nitric oxide synthase. Despite autonomic neuropathy, neostigmine strongly contracted ileum from diabetic animals but by a different mechanism including stronger activation of postjunctional muscarinic receptors, greater synaptic acetylcholine, stronger activation of noncholinergic excitatory pathways, and weaker activation of inhibitory pathways. A selective medication targeting a specific neural pathway may more effectively treat disordered gastrointestinal transit in patients with diabetes mellitus. [Copyright &y& Elsevier]

Background: Studies investigating the effects of pain-relieving medication use on conceiving a pregnancy have shown conflicting results. Furthermore, no previous study has examined medication use around ovulation or implantation and the associations with the probability of conception, fecundability.Objective: The objective of the study was to explore the association between fecundability and analgesic use in 3 different menstrual cycle windows (preovulation, periovulation, and implantation) as well as across the entire menstrual cycle.Study Design: We analyzed data from a prospective cohort study of women between 30 and 44 years of age who were trying to conceive naturally from 2008 through 2015. Using daily diaries, medication usage was classified as acetaminophen, aspirin, or nonaspirin nonsteroidal antiinflammatory drug during 4 time periods of interest (preovulatory, periovulatory, and implantation) as well as the overall nonmenstrual bleeding days of the cycle. Menstrual cycles during the prospective attempt to become pregnant were enumerated using daily diary menstrual bleeding information. Conception was defined as a positive home pregnancy test. Discrete time fecundability models were used to estimate the fecundability ratio and 95% confidence interval in each of the 4 time windows of interest and for each pain reliever (aspirin use, nonaspirin nonsteroidal antiinflammatory drug use, acetaminophen) compared with no medication use after adjustment for several covariates including age, race, education, body mass index, alcohol and caffeine use, frequency of intercourse, and a history of migraines or uterine fibroids.Results: Medication use was infrequent in the 858 women and 2366 cycles in this analysis. Use of nonaspirin nonsteroidal antiinflammatory drugs or acetaminophen was not associated with fecundability in any of the time windows of interest. Although the sample size was small, aspirin use during the implantation window was associated with increased fecundability (adjusted fecundability ratio [confidence interval]: 2.05 [1.23-3.41]). This association remained when limiting the analysis to cycles with minimal missing data or when adjusting for gravidity. None of the other medications were associated with fecundability.Conclusion: Aspirin use around implantation was associated with increased fecundability. These results expand previous literature to suggest the following: (1) implantation may be an important target for the effects of aspirin on conception and (2) aspirin may be beneficial, regardless of pregnancy loss history. These observations should be tested with a clinical trial. [ABSTRACT FROM AUTHOR]

To examine the association between serum 25-hydroxyvitamin D [25(OH)D] levels and ovarian reserve as measured using antimüllerian hormone (AMH) levels. Cross-sectional study. Detroit, Michigan area. Data were obtained from a prospective cohort of self-identified Black or African American women aged 23–35 years at the time of enrollment (N = 1,593), who had no prior diagnosis of polycystic ovary syndrome, were not currently pregnant, and were not missing AMH or 25(OH)D level measures. Serum 25(OH)D. The serum AMH level was the main outcome. Linear regression was used to examine the associations between categorical 25(OH)D levels (<12, 12–<20, 20–<30, and ≥30 ng/mL) and continuous natural log-transformed AMH levels. Associations between 25(OH)D and high (upper 10th percentile: >7.8 ng/mL) or low AMH (<0.7 ng/mL) levels were estimated with logistic regression. Models were adjusted for age, age-squared, body mass index (kg/m2), hormonal contraceptive use, smoking, and exercise. The 25(OH)D levels were low; 70% of participants were below 20 ng/mL. In fully adjusted models, compared with 25(OH)D levels <12 ng/mL, those with 25(OH)D levels of 12–<20, 20–<30, and ≥30 ng/mL had an AMH level that was 7% (95% confidence interval [CI]: −4, 20), 7% {95% CI: −6, 22}, or 11% {95% CI: −7, 34} higher, respectively. Moreover, these groups had lower odds of having low AMH levels (odds ratio [95% CI]: 0.63 {0.40, 0.99}, 0.60 {0.34, 1.07}, and 0.76 {0.35, 1.65}, respectively), and the highest category of 25(OH)D levels had higher odds of having high AMH levels (odds ratio [95% CI]: 1.42 {0.74, 2.72}). Exclusion of participants with either irregular cycles or very high AMH (>25 ng/mL) levels did not alter the associations. Taken together, these results indicate that higher levels of 25(OH)D are associated with slightly higher AMH levels, lower odds of low AMH levels, and higher odds of high AMH levels. This evidence is weak, however, because only a small percentage of participants had high 25(OH)D levels. Future studies should examine populations with a wide distribution of 25(OH)D levels (both high and low), with a clinical trial design, or with longitudinal measures of both 25(OH)D and AMH levels. [ABSTRACT FROM AUTHOR]

Objective: To determine the association between antimüllerian hormone (AMH), a measure of ovarian reserve, and miscarriage among naturally conceived pregnancies.Design: Prospective cohort study.Setting: Not applicable.Patient(s): Women (n = 533), between 30 and 44 years of age with no known history of infertility, polycystic ovarian syndrome, or endometriosis who conceived naturally.Intervention(s): None.Main Outcome Measure(s): Miscarriage, defined as an intrauterine pregnancy loss before 20 weeks' gestation.Result(s): After adjusting for maternal age, race, history of recurrent miscarriage, and obesity, risk of miscarriage decreased as AMH increased (risk ratio per unit increase in natural log of AMH = 0.83; 95% confidence interval [CI], 0.73, 0.94). Women with severely diminished ovarian reserve (AMH ≤ 0.4 ng/mL) miscarried at over twice the rate of women with an AMH ≥ 1 ng/mL (hazard ratio, 2.3; 95% CI, 1.3, 4.3).Conclusion(s): AMH levels are inversely associated with the risk of miscarriage. Women with severely diminished ovarian reserve are at an increased risk of miscarriage. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between serum 25-hydroxyvitamin D [25(OH)D] and menstrual cycle length and regularity.Design: Community-based, cross-sectional study of serum 25(OH)D (adjusted for seasonal differences in timing of blood draw) and menstrual cycle length. Women aged 23-34 years reported their gynecologic history. Menstrual cycles were described with four independent categories (normal, short, long, irregular). We used polytomous logistic regression to estimate the association between a doubling of seasonally adjusted 25(OH)D and the odds of each cycle category.Setting: Not applicable.Patient(s): A total of 1,102 African American women.Intervention(s): Not applicable.Main Outcome Measure(s): Self-reported menstrual cycle length over the previous 12 months, excluding women who were using cycle-regulating medications over the entire year. Women who reported that their cycles were "too irregular to estimate" were classified as having irregular cycles. A typical cycle length of <27 days was considered "short," >34 days was "long," and 27-34 days was "normal."Result(s): The median 25(OH)D level was 14.7 ng/mL (interquartile range, 10.9-19.6 ng/mL). A doubling of 25(OH)D was associated with half the odds of having long menstrual cycles: adjusted odds ratio (aOR) 0.54, 95% confidence interval (CI) 0.32-0.89. 25-Hydroxyvitamin D was not associated with the occurrence of short (aOR 1.03, 95% CI 0.82-1.29) or irregular (aOR 1.46, 95% CI 0.88-2.41) menstrual cycles. Results were robust to several sensitivity analyses.Conclusion(s): These findings suggest that vitamin D status may influence the menstrual cycle and play a role in ovarian function. Further investigation of 25(OH)D and ovarian hormones, and prospective studies of 25(OH)D and cycle length, are needed. [ABSTRACT FROM AUTHOR]

Objective: To provide female age-related estimates of fecundity and incidence of infertility by history of prior pregnancy among women 30-44 years of age.Design: Prospective, time-to-pregnancy cohort study.Setting: Not applicable.Patient(s): Women, between 30 and 44 years of age, attempting to conceive for ≤3 months, and no known history of infertility, polycystic ovarian syndrome (PCOS), or endometriosis.Intervention(s): Not applicable.Main Outcome Measure(s): Fecundability and incidence of infertility.Result(s): Compared to women aged 30-31 years, fecundability was reduced by 14% in women 34-35 years of age (fecundability ratio [FR] 0.86, 95% confidence interval [CI] 0.68-1.08), 19% in women 36-37 years of age (FR 0.81, 95% CI 0.60-1.08, 30% in women 38-39 years of age (FR 0.70, 95% CI 0.48-1.01), 53% in women 40-41 years of age (FR 0.47, 95% CI 0.28-0.78), and 59% in women 42-44 years of age (FR 0.39, 95% CI 0.16-0.93). Fecundability did not differ between women aged 30-31 years and 32-33 years. In general, fecundability and cumulative probability of pregnancy was lower for women who had never had a prior pregnancy.Conclusion(s): Women experience a significant reduction in fecundity and increase in the probability of infertility in their late thirties. At any age >30 years, women who have never conceived have a lower probability of achieving a pregnancy.Clinical Trial Registration Number: NCT01028365. [ABSTRACT FROM AUTHOR]

• Digital cohort of 125,104 menstrual cycles from 17,427 participants within the US. • Modest seasonal variation of menstrual cycle length from June 2020 to July 2022. • Shorter cycles (<1/5 day) in May–Aug and Sept–Dec compared to Jan–April. • Younger participants <35°N and >40°N with PCOS had strongest seasonal trends. • No seasonal patterns in cycle lengths were found for participants above age 40. [ABSTRACT FROM AUTHOR]