The association between preconception cannabis use and gestational diabetes mellitus: The Preconception Period Analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: The metabolic changes that ultimately lead to gestational diabetes mellitus (GDM) likely begin before pregnancy. Cannabis use might increase the risk of GDM by increasing appetite or promoting fat deposition and adipogenesis. OBJECTIVES: We aimed to assess the association between preconception cannabis use and GDM incidence. METHODS: We analysed individual-level data from eight prospective cohort studies. We identified the first, or index, pregnancy (lasting ≥20 weeks of gestation with GDM status) after cannabis use. In analyses of pooled individual-level data, we used logistic regression to estimate study-type-specific odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential confounders using random effect meta-analysis to combine study-type-specific ORs and 95% CIs. Stratified analyses assessed potential effect modification by preconception tobacco use and pre-pregnancy body mass index (BMI). RESULTS: Of 17,880 participants with an index pregnancy, 1198 (6.7%) were diagnosed with GDM. Before the index pregnancy, 12.5% of participants used cannabis in the past year. Overall, there was no association between preconception cannabis use in the past year and GDM (OR 0.97, 95% CI 0.79, 1.18). Among participants who never used tobacco, however, those who used cannabis more than weekly had a higher risk of developing GDM than those who did not use cannabis in the past year (OR 2.65, 95% CI 1.15, 6.09). This association was not present among former or current tobacco users. Results were similar across all preconception BMI groups. CONCLUSIONS: In this pooled analysis of preconception cohort studies, preconception cannabis use was associated with a higher risk of developing GDM among individuals who never used tobacco but not among individuals who formerly or currently used tobacco. Future studies with more detailed measurements are needed to investigate the influence of preconception cannabis use on pregnancy complications.

Large-Scale Data Harmonization Across Prospective Studies.

The Preconception Period Analysis of Risks and Exposures Influencing Health and Development (PrePARED) Consortium creates a novel resource for addressing preconception health by merging data from numerous cohort studies. In this paper, we describe our data harmonization methods and results. Individual-level data from 12 prospective studies were pooled. The crosswalk-cataloging-harmonization procedure was used. The index pregnancy was defined as the first postbaseline pregnancy lasting more than 20 weeks. We assessed heterogeneity across studies by comparing preconception characteristics in different types of studies. The pooled data set included 114,762 women, and 25,531 (22%) reported at least 1 pregnancy of more than 20 weeks' gestation during the study period. Babies from the index pregnancies were delivered between 1976 and 2021 (median, 2008), at a mean maternal age of 29.7 (standard deviation, 4.6) years. Before the index pregnancy, 60% of women were nulligravid, 58% had a college degree or more, and 37% were overweight or obese. Other harmonized variables included race/ethnicity, household income, substance use, chronic conditions, and perinatal outcomes. Participants from pregnancy-planning studies had more education and were healthier. The prevalence of preexisting medical conditions did not vary substantially based on whether studies relied on self-reported data. Use of harmonized data presents opportunities to study uncommon preconception risk factors and pregnancy-related events. This harmonization effort laid the groundwork for future analyses and additional data harmonization.

Urinary phenol concentrations and fecundability and early pregnancy loss.

STUDY QUESTION: Are urinary phenol concentrations of methylparaben, propylparaben, butylparaben, triclosan, benzophenone-3, 2,4-dichlorophenol or 2,5-dichlorophenol associated with fecundability and early pregnancy loss? SUMMARY ANSWER: 2,5-dichlorophenol concentrations were associated with an increased odds of early pregnancy loss, and higher concentrations of butylparaben and triclosan were associated with an increase in fecundability. WHAT IS KNOWN ALREADY: Phenols are chemicals with endocrine-disrupting potential found in everyday products. Despite plausible mechanisms of phenol reproductive toxicity, there are inconsistent results across few epidemiologic studies examining phenol exposure and reproductive function in non-fertility treatment populations. STUDY DESIGN, SIZE, DURATION: Specimens and data were from the North Carolina Early Pregnancy Study prospective cohort of 221 women attempting to conceive naturally from 1982 to 1986. This analysis includes data from 221 participants across 706 menstrual cycles, with 135 live births, 15 clinical miscarriages and 48 early pregnancy losses (before 42 days after the last menstrual period). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants collected daily first-morning urine specimens. For each menstrual cycle, aliquots from three daily specimens across the cycle were pooled within individuals and analyzed for phenol concentrations. To assess sample repeatability, we calculated intraclass correlation coefficients (ICCs) for each phenol. We evaluated associations between phenol concentrations from pooled samples and time to pregnancy using discrete-time logistic regression and generalized estimating equations (GEE), and early pregnancy loss using multivariable logistic regression and GEE. MAIN RESULTS AND THE ROLE OF CHANCE: ICCs for within-person variability across menstrual cycles in pooled phenol concentrations ranged from 0.42 to 0.75. There was an increased odds of early pregnancy loss with 2,5-dichlorophenol concentrations although the CIs were wide (5th vs 1st quintile odds ratio (OR): 4.79; 95% CI: 1.06, 21.59). There was an increased per-cycle odds of conception at higher concentrations of butylparaben (OR: 1.62; 95% CI: 1.08, 2.44) and triclosan (OR: 1.49; 95% CI: 0.99, 2.26) compared to non-detectable concentrations. No associations were observed between these endpoints and concentrations of other phenols examined. LIMITATIONS, REASONS FOR CAUTION: Limitations include the absence of phenol measurements for male partners and a limited sample size, especially for the outcome of early pregnancy loss, which reduced our power to detect associations. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to use repeated pooled measures to summarize phenol exposure and the first to investigate associations with fecundability and early pregnancy loss. Within-person phenol concentration variability underscores the importance of collecting repeated samples for future studies. Exposure misclassification could contribute to differences between the findings of this study and those of other studies, all of which used one urine sample to assess phenol exposure. This study also contributes to the limited literature probing potential associations between environmental exposures and early pregnancy loss, which is a challenging outcome to study as it typically occurs before a pregnancy is clinically recognized. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (award number F31ES030594), the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (project numbers ES103333 and ES103086) and a doctoral fellowship at the Yale School of Public Health. The authors declare they have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Systemic inflammation and menstrual cycle length in a prospective cohort study.

BACKGROUND: 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. OBJECTIVE: This study aimed to determine the association between systemic inflammation, as measured by C-reactive protein levels, and menstrual cycle length. STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: 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.

Abnormal uterine bleeding patterns determined through menstrual tracking among participants in the Apple Women's Health Study.

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.

Toxic metal mixtures in private well water and increased risk for preterm birth in North Carolina.

BACKGROUND: Prenatal exposure to metals in private well water may increase the risk of preterm birth (PTB) (delivery < 37 weeks' gestation). In this study, we estimated associations between arsenic, manganese, lead, cadmium, chromium, copper, and zinc concentrations in private well water and PTB incidence in North Carolina (NC). METHODS: Birth certificates from 2003-2015 (n = 1,329,071) were obtained and pregnancies were assigned exposure using the mean concentration and the percentage of tests above the maximum contaminant level (MCL) for the census tract of each individuals' residence at the time of delivery using the NCWELL database (117,960 well water tests from 1998-2019). We evaluated associations between single metals and PTB using adjusted logistic regression models. Metals mixtures were assessed using quantile-based g-computation. RESULTS: Compared with those in other census tracts, individuals residing in tracts where > 25% of tests exceeded the MCL for lead (aOR 1.10, 95%CI 1.02,1.18) or cadmium (aOR 1.11, 95% CI 1.00,1.23) had an increased odds of PTB. Conversely, those residing in areas with > 25% MCL for zinc (aOR 0.77 (95% CI: 0.56,1.02) and copper (aOR 0.53 (95% CI: 0.13,1.34)) had a reduced odds of PTB. A quartile increase in the concentrations of a mixture of lead, cadmium, and chromium was associated with a small increased odds for PTB (aOR 1.02, 95% CI 1.01, 1.03). This metal mixture effect was most pronounced among American Indian individuals (aOR per quartile increase in all metals: 1.19 (95% CI 1.06,1.34)). CONCLUSIONS: In a large study population of over one million births, lead and cadmium were found to increase the risk of PTB individually and in a mixture, with additional mixtures-related impacts estimated from co-exposure with chromium. This study highlights critical racial and ethnic health disparities in relation to private well water thereby emphasizing the urgent need for improved private well water quality to protect vulnerable populations.

Inflammation and Conception in a Prospective Time-to-Pregnancy Cohort.

BACKGROUND: Inflammation may contribute to subfertility but this has not been well-explored in large prospective cohort studies. METHODS: We conducted a prospective 12-month cohort study of time to pregnancy in North Carolina, the Time to Conceive study (2010-2016). Participants were 30-44 years old, without a history of infertility (N = 727). We analyzed blood samples with a high sensitivity assay for C-reactive protein (CRP). Women reported their weight, height, and other covariates. We natural log-transformed CRP and examined it (1) linearly, after exploration using restricted cubic splines and (2) in categories based on American Heart Association criteria. We estimated fecundability ratios (FRs) with log-binomial discrete-time-to-pregnancy models. Separate models included an interaction term with body mass index (BMI). RESULTS: The adjusted estimated FR per natural log-unit increase in CRP level was 0.97 (confidence interval [CI] = 0.91, 1.0). The FR (CI) for high CRP (>10 mg/L) compared with low CRP (<1 mg/L) was 0.78 (0.52, 1.2). Compared with normal-weight women with low CRP, women with obesity and high CRP had lower estimated fecundability, but the confidence interval was wide (FR = 0.63; CI = 0.35, 1.1). There was no pattern in the estimated fecundability across levels of CRP within categories of BMI. CONCLUSIONS: There was no evidence of an association between CRP and fecundability either alone or within levels of BMI. Further studies of CRP and fecundability should include higher levels of CRP and additional markers of inflammation.

Attempts to conceive and the COVID-19 pandemic: data from the Apple Women's Health Study.

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.

Design and methods of the Apple Women's Health Study: a digital longitudinal cohort study.

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.

A prospective study of maternal 25-hydroxyvitamin D (25OHD) in the first trimester of pregnancy and second trimester heavy metal levels.

BACKGROUND: Vitamin D facilitates the absorption of calcium but may also increase absorption of other metals; the literature is conflicting. OBJECTIVE: To examine whether 25OHD in the first trimester of pregnancy was associated with subsequent metals levels in the late second trimester of pregnancy. METHODS: We used data from a sample of women in the LIFECODES pregnancy cohort (N = 381). 25-hydroxyvitamin D (25OHD) was measured with a chemiluminescence immunoassay in plasma samples drawn at 10 weeks of gestation. A panel of 17 metals and elements was measured in urine collected at 26 weeks of gestation. We used linear or logistic regression to estimate associations between 25OHD (dichotomous, linear, and in tertiles) and either urinary metal concentrations or the proportion of samples below the limit of detection, respectively. Multivariable models included urinary specific gravity, age, race/ethnicity, education, body mass index, insurance type, gestational age, and season. RESULTS: After multivariable adjustment, low 25OHD was associated with a 47% increase in lead level, a 60% increase in tin level, and 1.58 times the odds of detectable tungsten. A 10 ng/ml increase in 25OHD was associated with a 12% decrease in tin and an 8% increase in molybdenum. While we had a small sample size, we found some evidence of effect modification by race. Women who reported their race as Black or were classified in the other race category, who also had low 25OHD, had 40% higher thallium than women with higher 25OHD and were more likely to have detectable beryllium and tungsten. These metals were not associated with low 25OHD in women who reported their race as White. Tin and lead were higher in women with low 25OHD in all race groups. DISCUSSION: In total, further research is warranted to determine if vitamin D levels alter metal levels, and to elucidate the shape of the association for each metal across a range of corresponding 25OHD levels, and longitudinally, across pregnancy. This is especially true for pregnant people as exposure to metals during pregnancy has health consequences for the fetus.

Serum omega-3 and omega-6 fatty acid concentrations and natural fertility.

STUDY QUESTION: Are serum omega-3 and omega-6 essential fatty acid concentrations associated with the probability of conceiving? SUMMARY ANSWER: There is no strong association between serum concentrations of omega-3 and omega-6 fatty acids and the probability of conceiving naturally. WHAT IS KNOWN ALREADY: Omega-3 and omega-6 fatty acid serum concentrations have been shown to play an important role in reproduction in animal models, while conflicting results have been reported in human studies of infertile women. It is unknown to what extent omega fatty acid serum concentrations impact natural fertility. STUDY DESIGN, SIZE, DURATION: A nested, case-control study was conducted consisting of 200 participants [fertile: conceived within 3 cycles of attempt (n = 50), subfertile: conceived within 4 and 12 cycles of attempt (n = 100) and infertile: did not conceive within 12 cycles of attempt (n = 50)] randomly selected from the Time to Conceive cohort, a prospective time-to-pregnancy study (2008 to 2015). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the Time to Conceive study, women aged 30-44 years who were trying to conceive for <3 months and had no history of infertility were recruited and followed until the end of their pregnancy or ~1 year of pregnancy attempt. For this study, serum collected early in the woman's pregnancy attempt was analysed for anti-Müllerian hormone (AMH) and omega-3 and omega-6 fatty acid concentrations by liquid chromatography-mass spectrometry. The primary outcome was a positive home pregnancy test. The secondary outcomes were miscarriage and serum AMH level. A discrete-time Cox proportional hazards model was used to estimate the fecundability ratio. The odds ratios for miscarriage were calculated using logistic regression. The association between serum omega fatty acid concentrations and AMH level (natural log transformed) was analysed using Pearson's Correlation. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 200 women provided 1321 cycles for analysis.Mean omega-3, omega-6 and omega-6:omega-3 ratios did not significantly differ between the fertile, subfertile and infertile groups. There were no associations (all fecundability ratios ~1.0) between pregnancy and individual omega-3 fatty acid concentrations, including alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid, or omega-6 fatty acids, including linoleic acid (LA), dihommo-gamma linolenic acid and arachidonic acid. There was no significant association between any individual omega fatty acid serum concentration and the age-adjusted odds of miscarriage. No association was found between any serum omega fatty acid concentration and AMH. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the sample size. Omega-3 and omega-6 fatty acid concentrations were derived from serum provided at a single timepoint in the first cycle of enrollment. Serum concentrations may therefore not be representative of all critical timepoints in the menstrual cycle or throughout their attempts to conceive. Additionally, women enrolled in this study were 30 years of age and older, and therefore the findings may not apply to younger women. WIDER IMPLICATIONS OF THE FINDINGS: These data would suggest that omega-3 and omega-6 serum levels are not associated with natural fertility or risk of miscarriage. However, due to the above-mentioned limitations, future investigation is still needed to determine whether omega-3 fatty acid supplementation may benefit women planning to conceive naturally. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Division of Reproductive Endocrinology and Infertility at the University of North Carolina at Chapel Hill, by the NIH/NICHD (R21 HD060229-01 and R01 HD067683-01) and, in part, by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01ES103333). Dr. Jukic received vitamin D supplements for a research study from Theralogix, Inc. The authors have no other conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Analgesic use at ovulation and implantation and human fertility.

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.

The Preconception Period analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. OBJECTIVES: The consortium will investigate the effects of preconception exposures on four sets of outcomes: (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. POPULATION: A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. DESIGN: The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. METHODS: Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. PRELIMINARY RESULTS: Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women's health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. CONCLUSIONS: The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.

Association of urinary concentrations of phthalate metabolites and bisphenol A with early pregnancy endpoints.

BACKGROUND: Phthalates and bisphenol A (BPA) are environmental contaminants that may affect early embryonic development. OBJECTIVE: To assess the association between phthalate metabolites and BPA with early pregnancy endpoints in a cohort of women followed from before conception. METHODS: We quantified 11 phthalate metabolites and BPA in 137 conception cycles from naturally conceived clinical pregnancies. Phthalate metabolites and BPA concentrations were measured in a pooled sample of three daily morning urine specimens. Daily urinary hormone measurements had previously been used to define ovulation, implantation, and corpus luteum rescue. We assessed associations between conception cycle exposures (phthalate biomarkers and BPA) and 1) time from ovulation to implantation; 2) type of corpus luteum rescue (timing and pattern of rise in progesterone: early, late, or no rise); and 3) rate of initial rise in hCG. RESULTS: Mono(3-carboxypropyl) phthalate (MCPP) and mono-isobutyl phthalate (MiBP) were associated with earlier implantation (6-8 days vs. 9 days (the most commonly observed); per natural log-unit, OR (95% CI) = 2.8 (1.2, 6.7) and OR (CI) = 2.1 (1.2, 3.7), respectively). Monoethyl phthalate (MEP) was associated with later implantation (10-12 days vs. 9 days); OR (CI) = 1.5 (1.0, 2.1). Compared with implantation on day 9, BPA was significantly associated with both earlier and later implantation (OR=2.2 for both). Women with concentrations above the median of monobenzyl phthalate (MBzP) (p = 0.04) or above the median of the molar sum of four di(2-ethylhexyl) phthalate metabolites (∑DEHP) (p = 0.08) had a slower initial rise in hCG. Increasing MCPP was associated with an increased odds of a late rise rescue (OR (CI) = 2.9 (1.0, 8.5); late rise vs. early rise), while increasing MEP was associated with a no rise rescue (OR (CI) = 1.6 (0.9, 2.8); no rise vs. early rise). CONCLUSIONS: The reported associations varied in their direction of effect, some potentially protective, others adverse. This may reflect the complexity with which these potential endocrine disrupting chemicals can be acting, but chance findings are also possible. Given that women continue to be exposed to these compounds (or their precursors), continued research on the effects they may have on pregnancy is warranted.

Association of urinary concentrations of early pregnancy phthalate metabolites and bisphenol A with length of gestation.

BACKGROUND: Environmental exposure to phthalates and bisphenol A (BPA) may have endocrine disrupting effects that alter length of gestation. We assessed the association between the urinary concentrations of 11 phthalate metabolites and BPA with length of gestation in a cohort of women followed from before conception with daily 1st-morning urinary hormone measures that identified day of implantation. METHODS: Pre-implantation and post-implantation urinary phthalate metabolites and BPA concentrations were measured in pooled urine samples designed to limit single-measure variability due to the likely episodic nature of these exposures and the short half-life of these compounds. We estimated associations between these exposure biomarkers early in pregnancy with length of gestation from implantation to spontaneous birth. Cox proportional hazards models were used to estimate the hazard of birth among 125 naturally-conceived, singleton live births with censoring for medical interventions that artificially shortened pregnancy. RESULTS: Higher concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (a metabolite of di (2-ethylhexyl) phthalate (DEHP)) during the pre-implantation window were associated with reduced probability of birth, i.e., longer gestations (hazard ratio (HR): 0.55, 95% CI: 0.35, 0.86; p = 0.01). The HR for the molar sum of the four DEHP metabolites measured showed a similar association (HR: 0.67, 95% CI: 0.43, 1.05). Higher concentrations of mono (3-carboxypropyl) phthalate (MCPP), a non-specific metabolite of several high molecular-weight phthalates, measured post-implantation were associated with increased risk of earlier birth, i.e. shorter length of gestation, HR: 1.59, CI: 1.02, 2.49. CONCLUSIONS: Early gestational exposure to DEHP and possibly other high-molecular weight phthalates, (as reflected by urinary MCPP concentrations) may influence the length of pregnancy. Such effects could have consequences for neonatal and maternal health.

Measurement of Vitamin D for Epidemiologic and Clinical Research: Shining Light on a Complex Decision.

Vitamin D is a fat-soluble vitamin that is synthesized in the skin with exposure to sunlight or is ingested from dietary supplements or food. There has been a dramatic increase in research on vitamin D, linking it with health outcomes as varied as reproductive function, infection, cardiovascular disease, and cancer. The study of vitamin D has generated much excitement, partly because there is an ideal intervention: Low levels may be common and can be remedied with widely available supplements. Determination of vitamin D status is complex and has advanced dramatically in the past 5 years. In this paper, we begin by describing important considerations for measurement of total 25-hydroxyvitamin D (25(OH)D), the biomarker traditionally assessed in epidemiologic studies. While 25(OH)D remains the most commonly measured biomarker, emerging evidence suggests that other related analytes may contribute to the characterization of an individual's vitamin D status (e.g., vitamin D-binding protein, bioavailable and free 25(OH)D, the C-3 epimer of 25(OH)D, 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D). The measurement of these analytes is also complex, and there are important considerations for deciding whether their measurement is warranted in new research studies. Herein we discuss these issues and provide the reader with an up-to-date synthesis of research on vitamin D measurement options and considerations.

25-Hydroxyvitamin D and Long Menstrual Cycles in a Prospective Cohort Study.

BACKGROUND: Vitamin D insufficiency is associated with subfertility and prolonged estrus cycles in animals, but humans have not been well studied. METHODS: A prospective time-to-pregnancy study, Time to Conceive (2010-2015), collected up to 4 months of daily diary data. Participants were healthy, late reproductive-aged women in North Carolina who were attempting pregnancy. We examined menstrual cycle length as a continuous variable and in categories: long (35+ days) and short (≤25 days). Follicular phase length and luteal phase length were categorized as long (18+ days) or short (≤10 days). We estimated associations between those lengths and serum 25-hydroxyvitamin D (25[OH]D) using linear mixed models and marginal models. RESULTS: There were 1,278 menstrual cycles from 446 women of whom 5% were vitamin D deficient (25[OH]D, <20 ng/ml), 69% were between 20 and 39 ng/ml, and 26% were 40 ng/ml or higher. There was a dose-response association between vitamin D levels and cycle length. Compared with the highest 25(OH)D level (≥40 ng/ml), 25(OH)D deficiency was associated with almost three times the odds of long cycles (adjusted odds ratio [aOR] = 2.8 [95% confidence interval (CI) = 1.0, 7.5]). The aOR was 1.9 (1.1, 3.5) for 20 to <30 ng/ml. The probability of a long follicular phase and the probability of a short luteal phase both increased with decreasing 25(OH)D. CONCLUSIONS: Lower levels of 25(OH)D are associated with longer follicular phase and an overall longer menstrual cycle. Our results are consistent with other evidence supporting vitamin D's role in the reproductive axis, which may have broader implications for reproductive success.

Long-term Recall of Pregnancy-related Events.

BACKGROUND: Early-life factors can be associated with future health outcomes and are often measured by maternal recall. METHODS: We used data from the North Carolina Early Pregnancy Study and Follow-up to characterize long-term maternal recall. We used data from the Early Pregnancy Study as the gold standard to evaluate the accuracy of prepregnancy weight, early pregnancy behaviors, symptoms and duration of pregnancy, and child's birthweight reported at follow-up, for 109 women whose study pregnancies had resulted in a live birth. RESULTS: Most (81%) participants reported a prepregnancy weight at follow-up that correctly classified them by BMI category. Women reported experiencing pregnancy symptoms later at follow-up than what they reported in the Early Pregnancy Study. Accuracy of reporting of early pregnancy behaviors varied based on exposure. Overall, women who had abstained from a behavior were more likely to be classified correctly. Sensitivity of reporting was 0.14 for antibiotics, 0.30 for wine, 0.71 for brewed coffee, and 0.82 for vitamins. Most misclassification at follow-up was due to false-negative reporting. Among women who gave birth to singletons, 94% could report their child's correct birthweight within ½ pound and 86% could report duration of pregnancy within 7 days at follow-up. CONCLUSIONS: Self-report of prepregnancy weight, duration of pregnancy, and child's birthweight after almost 30 years was good, whereas self-reported pregnancy-related exposures resulted in higher levels of reporting error. Social desirability appeared to influence women's report of their behaviors at follow-up. Self-reported assessment of confidence in the recalled information was unrelated to accuracy.

Predictors of prenatal care satisfaction among pregnant women in American Samoa.

BACKGROUND: Pregnant women in American Samoa have a high risk of complications due to overweight and obesity. Prenatal care can mitigate the risk, however many women do not seek adequate care during pregnancy. Low utilization of prenatal care may stem from low levels of satisfaction with services offered. Our objective was to identify predictors of prenatal care satisfaction in American Samoa. METHODS: A structured survey was distributed to 165 pregnant women receiving prenatal care at the Lyndon B Johnson Tropical Medical Center, Pago Pago. Women self-reported demographic characteristics, pregnancy history, and satisfaction with prenatal care. Domains of satisfaction were extracted using principal components analysis. Scores were summed across each domain. Linear regression was used to examine associations between maternal characteristics and the summed scores within individual domains and for overall satisfaction. RESULT: Three domains of satisfaction were identified: satisfaction with clinic services, clinic accessibility, and physician interactions. Waiting ≥ 2 h to see the doctor negatively impacted satisfaction with clinic services, clinic accessibility, and overall satisfaction. Living > 20 min from the clinic was associated with lower clinic accessibility, physician interactions, and overall satisfaction. Women who were employed/on maternity leave had lower scores for physician interactions compared with unemployed women/students. Women who did not attend all their appointments had lower overall satisfaction scores. CONCLUSIONS: Satisfaction with clinic services, clinic accessibility and physician interactions are important contributors to prenatal care satisfaction. To improve patient satisfaction prenatal care clinics should focus on making it easier for women to reach clinics, improving waiting times, and increasing time with providers.

Voices: A Conversation with Allen J. Wilcox.

Allen James Wilcox was born on 30 September 1946 in Columbus, OH. He studied medicine at the University of Michigan, graduated in 1973, and after a rotating internship, he completed a master's degree in maternal and child health (1976) and a PhD in epidemiology (1979) at the University of North Carolina in Chapel Hill. After graduation, he went to work at the National Institute of Environmental Health Sciences (NIEHS, one of the US National Institutes of Health) in Durham, NC, where he has spent his career. He developed a research program in reproductive and perinatal epidemiology, a relatively unexplored area at the time. His studies include the early pregnancy study, which documented the extent of subclinical pregnancy loss in humans and established the fertile days of a woman's menstrual cycle. He served as the Chief of the Epidemiology Branch from 1991 to 2001, and as Editor-in-Chief of the journal EPIDEMIOLOGY from 2001 to 2014. His textbook, Fertility and Pregnancy-An Epidemiologic Perspective, was published by Oxford University Press in 2010. He was elected to the American Epidemiological Society in 1989, and served as its president in 2003. He also served as president of the Society of Pediatric and Perinatal Epidemiological Research (1996) and the president of the Society of Epidemiological Research (1998). He holds adjunct teaching appointments at the University of North Carolina, Harvard University, and the University of Bergen (Norway), which awarded him an honorary doctoral degree in 2008.