Irregular Cycles, Ovulatory Disorders, and Cardiometabolic Conditions in a US-Based Digital Cohort.

Importance: Polycystic ovary syndrome (PCOS), characterized by irregular menstrual cycles and hyperandrogenism, is a common ovulatory disorder. Having an irregular cycle is a potential marker for cardiometabolic conditions, but data are limited on whether the associations differ by PCOS status or potential interventions. Objective: To evaluate the association of PCOS, time to regularity since menarche (adolescence), and irregular cycles (adulthood) with cardiometabolic conditions. Design, Setting, and Participants: This cross-sectional study used a large, US-based digital cohort of users of the Apple Research application on their iPhone. Eligibility criteria were having ever menstruated, living in the US, being at age of consent of at least 18 years (or 19 years in Alabama and Nebraska or 21 years in Puerto Rico), and being able to communicate in English. Participants were enrolled between November 14, 2019, and December 13, 2022, and completed relevant surveys. Exposures: Self-reported PCOS diagnosis, prolonged time to regularity (not spontaneously establishing regularity within 5 years of menarche), and irregular cycles. Main Outcomes and Measures: The primary outcome was self-reported cardiometabolic conditions, including obesity, prediabetes, type 1 and 2 diabetes, high cholesterol, hypertension, metabolic syndrome, arrhythmia, congestive heart failure, coronary artery disease, heart attack, heart valve disease, stroke, transient ischemic attack (TIA), deep vein thrombosis, and pulmonary embolism measured using descriptive statistics and logistic regression to estimate prevalence odds ratios (PORs) and 95% CIs. Effect modification by lifestyle factors was also estimated. Results: The study sample (N = 60 789) had a mean (SD) age of 34.5 (11.1) years, with 12.3% having PCOS and 26.3% having prolonged time to regularity. Among a subset of 25 399 participants who completed the hormonal symptoms survey, 25.6% reported irregular cycles. In covariate-adjusted logistic regression models, PCOS was associated with a higher prevalence of all metabolic and several cardiovascular conditions, eg, arrhythmia (POR, 1.37; 95% CI, 1.20-1.55), coronary artery disease (POR, 2.92; 95% CI, 1.95-4.29), heart attack (POR, 1.79; 95% CI, 1.23-2.54), and stroke (POR, 1.66; 95% CI, 1.21-2.24). Among participants without PCOS, prolonged time to regularity was associated with type 2 diabetes (POR, 1.24; 95% CI, 1.05-1.46), hypertension (POR, 1.09; 95% CI, 1.01-1.19), arrhythmia (POR, 1.20; 95% CI, 1.06-1.35), and TIA (POR, 1.33; 95% CI, 1.01-1.73), and having irregular cycles was associated with type 2 diabetes (POR, 1.36; 95% CI, 1.08-1.69), high cholesterol (POR, 1.17; 95% CI, 1.05-1.30), arrhythmia (POR, 1.21; 95% CI, 1.02-1.43), and TIA (POR, 1.56; 95% CI, 1.06-2.26). Some of these associations were modified by high vs low body mass index or low vs high physical activity. Conclusions and Relevance: These findings suggest that PCOS and irregular cycles may be independent markers for cardiometabolic conditions. Early screening and intervention among individuals with irregular menstrual cycles may be beneficial.

Genetic association study of Preterm birth and Gestational age in a population-based case-control study in Peru: Genetics of PTB and GA in pregnant women in Peru.

Preterm birth (PTB) is an adverse pregnancy outcome affecting ~15 million pregnancies worldwide. Genetic studies have identified several candidate loci for PTB, but results remain inconclusive and limited to European populations. Thus, we conducted a genome-wide association study (GWAS) of PTB and gestational age at delivery (GA) among 2,212 Peruvian women. PTB cases delivered ≥ 20 weeks' but < 37 weeks' gestation, while controls delivered at term (≥ 37 weeks but < 42 weeks). After imputation (TOPMED) and quality control, we assessed the association of ~6 million SNPs with PTB and GA using multivariable regression models adjusted for maternal age and the first two genetic principal components. In silico functional analysis (FUMA-GWAS) was conducted among top signals detected with an arbitrary P < 1.0×10-5 in each GWAS. We sought to replicate genetic associations with PTB and GA identified in Europeans, and we developed a genetic risk score for GA based on European markers. Mean GA was 30 ± 4 weeks in PTB cases (N=933) and 39 ± 1 in the controls (N=1,279). PTB cases were slightly older and had higher C-sections and vaginal bleeding than controls. No association was identified at genome-wide level. Top suggestive (P < 1.0×10-5) signals were seen at rs13151645 (LINC01182) for PTB, and at rs72824565 (CTNNA2) for GA. Top PTB variants were enriched for biological pathways associated with polyketide, progesterone, steroid hormones, and glycosyl metabolism. Top GA variants were enriched in intronic regions and cancer pathways, and these genes were upregulated in the brain and subcutaneous adipose tissue. In combination with non-genetic risk factors, top SNPs explained 14% and 15% of the phenotypic variance of PTB and GA in our sample, but these results need to be interpreted with caution. Variants in WNT4 associated with GA in Europeans were replicated in our study. The genetic risk score based in European markers, was associated with a 2-day longer GA (R2=0.003, P=0.002) per standard deviation increase in the score in our sample. This genetic association study identified various signals suggestively associated with PTB and GA in a non-European population; they were linked to relevant biological pathways related to the metabolism of progesterone, prostanoid, and steroid hormones, and genes associated with GA were significantly upregulated in relevant tissues for the pathophysiology of PTB based on the in-silico functional analysis. None of these top variants overlapped with signals previously identified for PTB or GA in Europeans.

A Cross-Sectional Investigation of Preadolescent Cardiometabolic Health: Associations with Fitness, Physical Activity, Sedentary Behavior, Nutrition, and Sleep.

BACKGROUND: Cardiometabolic disease (CMD) risk often begins early in life. Healthy lifestyle behaviors can mitigate risk, but the optimal combination of behaviors has not been determined. This cross-sectional study simultaneously examined the associations between lifestyle factors (fitness, activity behaviors, and dietary patterns) and CMD risk in preadolescent children. METHODS: 1480 New Zealand children aged 8-10 years were recruited. Participants included 316 preadolescents (50% female, age: 9.5 ± 1.1 years, BMI: 17.9 ± 3.3 kg/m2). Fitness (cardiorespiratory fitness [CRF], muscular fitness), activity behaviors (physical activity, sedentary, sleep), and dietary patterns were measured. Factor analysis was used to derive a CMD risk score from 13 variables (adiposity, peripheral and central hemodynamics, glycemic control, and blood lipids). RESULTS: Only CRF (ß = -0.45, p < 0.001) and sedentary time (ß = 0.12, p = 0.019) were associated with the CMD risk score in the adjusted multivariable analysis. CRF was found to be nonlinear (VO2 max ≤ ≈42 mL/kg/min associated with higher CMD risk score), and thus a CRF polynomial term was added, which was also associated (ß = 0.19, p < 0.001) with the CMD risk score. Significant associations were not found with sleep or dietary variables. CONCLUSION: The findings indicate that increasing CRF and decreasing sedentary behavior may be important public health targets in preadolescent children.

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.

Association between Ancestry-Specific 6q25 Variants and Breast Cancer Subtypes in Peruvian Women.

BACKGROUND: Breast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with African American/Black or Non-Hispanic White women. An Indigenous American breast cancer-protective germline variant (rs140068132) has been reported near the estrogen receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in H/Ls of high Indigenous American ancestry. METHODS: Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses, including other risk-associated polymorphisms in the region. RESULTS: We replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47-0.59], as well as the lower odds of developing hormone receptor negative (HR-) versus HR+ disease (OR, 0.77; 95% CI, 0.61-0.97). Models, including HER2, showed further heterogeneity with reduced odds for HR+HER2+ (OR, 0.68; 95% CI, 0.51-0.92), HR-HER2+ (OR, 0.63; 95% CI, 0.44-0.90) and HR-HER2- (OR, 0.77; 95% CI, 0.56-1.05) compared with HR+HER2-. Inclusion of other risk-associated variants did not change these observations. CONCLUSIONS: The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR- and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region. IMPACT: These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies.

Mycobacterium tuberculosis Limits Host Glycolysis and IL-1ß by Restriction of PFK-M via MicroRNA-21.

Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1ß (IL-1ß). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function.

Fitness and Fatness Are Both Associated with Cardiometabolic Risk in Preadolescents.

OBJECTIVE: To determine the associations between cardiorespiratory fitness (CRF) and fatness (overweight-obesity) with cardiometabolic disease risk among preadolescent children. STUDY DESIGN: This cross-sectional study recruited 392 children (50% female, 8-10 years of age). Overweight-obesity was classified according to 2007 World Health Organization criteria for body mass index. High CRF was categorized as a maximum oxygen uptake, determined using a shuttle run test, exceeding 35 mL·kg-1·minute-1 in girls and 42 mL·kg-1·minute-1 in boys. Eleven traditional and novel cardiometabolic risk factors were measured including lipids, glucose, glycated hemoglobin, peripheral and central blood pressure, and arterial wave reflection. Factor analysis identified underlying cardiometabolic disease risk factors and a cardiometabolic disease risk summary score. Two-way analysis of covariance determined the associations between CRF and fatness with cardiometabolic disease risk factors. RESULTS: Factor analysis revealed four underlying factors: blood pressure, cholesterol, vascular health, and carbohydrate-metabolism. Only CRF was significantly (P = .001) associated with the blood pressure factor. Only fatness associated with vascular health (P = .010) and carbohydrate metabolism (P = .005) factors. For the cardiometabolic disease risk summary score, there was an interaction effect. High CRF was associated with decreased cardiometabolic disease risk in overweight-obese but not normal weight children (P = .006). Conversely, high fatness was associated with increased cardiometabolic disease risk in low fit but not high fit children (P < .001). CONCLUSIONS: In preadolescent children, CRF and fatness explain different components of cardiometabolic disease risk. However, high CRF may moderate the relationship between fatness and cardiometabolic disease risk. TRIAL REGISTRATION: ACTRN 12614000433606.

Metabolomic markers of antepartum depression and suicidal ideation.

BACKGROUND: Recent analyses have described metabolomic markers for depression and suicidal ideation in non-pregnant adults. We examined the metabolomic profile of antepartum depression and suicidal ideation during mid-pregnancy, a time of high susceptibility to mood disorders. METHODS: We collected fasting blood from 100 pregnant Peruvian women and profiled 307 plasma metabolites using liquid chromatography-mass spectrometry. We used the Patient Health Questionnaire 9 to define antepartum depression (score  ≥ 10) and suicidal ideation (having thoughts that you would be better off dead, or of hurting yourself). Logistic regression was used to calculate odds ratios (ORs). RESULTS: Three triacylglycerol metabolites (C48:5 triacylglycerol [OR = =1.89; 95% confidence interval (CI): 1.14-3.14], C50:6 triacylglycerol [OR = =1.88; 95%CI: 1.13-3.14], C46:4 triacylglycerol [OR = =1.89; 95%CI: 1.11-3.21]) were associated with higher odds of antepartum depression and 4 metabolites (betaine [OR = =0.56; 95%CI:0.33-0.95], citrulline [OR = =0.58; 95%CI: 0.34-0.98], C5 carnitine [OR = =0.59; 95%CI: 0.36-0.99], C5:1 carnitine [OR = =0.59; 95%CI: 0.35-1.00]) with lower odds of antepartum depression. Twenty-six metabolites, including 5-hydroxytryptophan (OR = =0.52; 95%CI: 0.30-0.92), phenylalanine (OR = =0.41; 95%CI: 0.19-0.91), and betaine (OR = =0.53; 95%CI: 0.28-0.99) were associated with lower odds of suicidal ideation. LIMITATIONS: Our cross-sectional study could not determine whether metabolites prospectively predict outcomes. No metabolites remained significant after multiple testing correction; these novel findings should be replicated in a larger sample. CONCLUSIONS: Antepartum suicidal ideation metabolomic markers are similar to markers of depression among non-pregnant adults, and distinct from markers of antepartum depression. Findings suggest that mood disorder in pregnancy shares metabolomic similarities to mood disorder at other times and may further understanding of these conditions' pathophysiology.

Cerebrovascular disease after placental abruption: A population-based prospective cohort study.

OBJECTIVE: To test whether abruption during pregnancy is associated with long-term cerebrovascular disease by assessing the incidence and mortality from stroke among women with abruption. METHODS: We designed a population-based prospective cohort study of women who delivered in Denmark from 1978 to 2010. We used data from the National Patient Registry, Causes of Death Registry, and Danish Birth Registry to identify women with abruption, cerebrovascular events, and deaths. The outcomes included deaths resulting from stroke and nonfatal ischemic and hemorrhagic strokes. We fit Cox proportional hazards regression models for stroke outcomes, adjusting for the delivery year, parity, education, and smoking. RESULTS: The median (interquartile range) follow-up in the nonabruption and abruption groups was 15.9 (7.8-23.8) and 16.2 (9.6-23.1) years, respectively, among 828,289 women with 13,231,559 person-years of follow-up. Cerebrovascular mortality rates were 0.8 and 0.5 per 10,000 person-years among women with and without abruption, respectively (hazard ratio [HR] 1.6, 95% confidence interval [CI] 0.9-3.0). Abruption was associated with increased rates of nonfatal ischemic stroke (HR 1.4, 95% CI 1.1-1.7) and hemorrhagic stroke (HR 1.4, 95% CI 1.1-1.9). The association of abruption and stroke was increased with delivery at <34 weeks, when accompanied by ischemic placental disease, and among women with ≥2 abruptions. These associations are less likely to have been affected by unmeasured confounding. CONCLUSION: Abruption is associated with increased risk of cerebrovascular morbidity and mortality. Disruption of the hemostatic system manifesting as ischemia and hemorrhage may indicate shared etiologies between abruption and cerebrovascular complications.

Stress and hair cortisol concentrations from preconception to the third trimester.

Stress is an important and modifiable determinant of health, and its association with hair cortisol concentrations (HCC) during pregnancy remains unclear. We selected a random sample of 97 participants from a cohort of pregnant participants attending prenatal clinics in Lima, Peru. Each provided a hair sample at enrollment (mean gestational age = 13.1 weeks) and again at full-term delivery. Hair samples were segmented to reflect HCC in preconception and each trimester. At enrollment, measures of stress included: difficulty accessing basic goods, educational attainment, exposure to violence, fair or poor general health, perceived stress, and symptoms of depression, general anxiety, and post-traumatic stress disorder. Linear mixed models evaluated the association between each stress measure and absolute and relative changes in HCC. Pearson correlation coefficients (r) assessed correlations between HCC and continuous stress scores. Educational attainment of ≤12 years was associated with higher HCC in preconception and the 1st trimester, and general anxiety with lower preconception HCC. When modeling HCC patterns across the 4 hair segments, an educational attainment of ≤12 years was associated with higher HCC, high perceived stress with lower HCC, and general anxiety with steeper increases in HCC (group by time p value = .02). Only preconception HCC and GAD scores correlated (r = -0.22, p = .04). We observed few associations between stress and HCC. However, those that were seen were generally restricted to the preconception and 1st trimester. Further investigations into the association between stress and changes in HCC across pregnancy are warranted, and should include the preconception where possible.

Adverse obstetric and neonatal outcomes complicated by psychosis among pregnant women in the United States.

BACKGROUND: Adverse obstetric and neonatal outcomes among women with psychosis, particularly affective psychosis, has rarely been studied at the population level. We aimed to assess the risk of adverse obstetric and neonatal outcomes among women with psychosis (schizophrenia, affective psychosis, and other psychoses). METHODS: From the 2007 - 2012 National (Nationwide) Inpatient Sample, 23,507,597 delivery hospitalizations were identified. From the same hospitalization, International Classification of Diseases diagnosis codes were used to identify maternal psychosis and outcomes. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were obtained using logistic regression. RESULTS: The prevalence of psychosis at delivery was 698.76 per 100,000 hospitalizations. After adjusting for sociodemographic characteristics, smoking, alcohol/substance abuse, and pregnancy-related hypertension, women with psychosis were at a heightened risk for cesarean delivery (aOR = 1.26; 95% CI: 1.23 - 1.29), induced labor (aOR = 1.05; 95% CI: 1.02 - 1.09), antepartum hemorrhage (aOR = 1.22; 95% CI: 1.14 - 1.31), placental abruption (aOR = 1.22; 95% CI: 1.13 - 1.32), postpartum hemorrhage (aOR = 1.18; 95% CI: 1.10 - 1.27), premature delivery (aOR = 1.40; 95% CI: 1.36 - 1.46), stillbirth (aOR = 1.37; 95% CI: 1.23 - 1.53), premature rupture of membranes (aOR = 1.22; 95% CI: 1.15 - 1.29), fetal abnormalities (aOR = 1.49; 95% CI: 1.38 - 1.61), poor fetal growth (aOR = 1.26; 95% CI: 1.19 - 1.34), and fetal distress (aOR = 1.14; 95% CI: 1.10 - 1.18). Maternal death during hospitalizations (aOR = 1.00; 95% CI: 0.30 - 3.31) and excessive fetal growth (aOR = 1.06; 95% CI: 0.98 - 1.14) were not statistically significantly associated with psychosis. CONCLUSIONS: Pregnant women with psychosis have elevated risk of several adverse obstetric and neonatal outcomes. Efforts to identify and manage pregnancies complicated by psychosis may contribute to improved outcomes.

The psychometric properties of the 16-item version of the Prodromal Questionnaire (PQ-16) as a screening instrument for perinatal psychosis.

Psychiatric illness can pose serious risks to pregnant and postpartum women and their infants. There is a need for screening tools that can identify women at risk for postpartum psychosis, the most dangerous perinatal psychiatric illness. This study used exploratory factor analysis (EFA) and Rasch item response theory (IRT) models to evaluate the psychometric properties and construct validity of the Spanish language version of the 16-item Prodromal Questionnaire (PQ-16) as a screening tool for psychosis in a population of pregnant Peruvian women. The EFA yielded a four-factor model, which accounted for 44% of the variance. Factor 1, representing "unstable sense of self," accounted for 22.1% of the total variance; factor 2, representing "ideas of reference/paranoia," for 8.4%; factor 3, representing "sensitivity to sensory experiences," accounted for 7.2%; and factor 4, possibly representing negative symptoms, accounted for 6.3%. Rasch IRT analysis found that all of the items fit the model. These findings support the construct validity of the PQ-16 in this pregnant Peruvian population. Also, further research is needed to establish definitive psychiatric diagnoses to determine the predictive power of the PQ-16 as a screening tool.

Dietary intake and urinary metals among pregnant women in the Pacific Northwest.

Pregnancy is a period when the mother and her offspring are susceptible to the toxic effects of metals. We investigated associations of intake of frequently consumed foods with urinary metals concentrations among pregnant women in the Pacific Northwest. We measured urinary cadmium (U-Cd), arsenic (U-As) and molybdenum (U-Mo) concentrations from spot urine samples in early pregnancy (15 weeks of gestation, on average) among 558 women from Seattle and Tacoma, Washington. We assessed periconceptional dietary intake using a semi-quantitative food frequency questionnaire (FFQ). We also determined early pregnancy zinc concentrations in serum. Statistical analyses involved multivariable linear regression models, adjusted for smoking status, age, race/ethnicity, multivitamin and supplement use, education, estimated total energy intake, and gravidity. The geometric mean and range in µg/g creatinine for U-Cd, U-As and U-Mo were 0.29 (0.1-8.2), 18.95 (3-550), and 72.1 (15-467), respectively. U-Cd was positively associated with dietary zinc intake (P-value = 0.004) and serum zinc (P-value<0.001) while it was negatively associated with coffee intake (P-value = 0.03). U-As was positively associated with dietary fish [(Lean fish, fatty fish, shellfish and non-fried fish) (P-values<0.01)], selenium (P-value = 0.004), zinc (P-value = 0.017), vegetables (P-value = 0.004), and low-fat yogurt (P-value = 0.03). Women who reported higher intake of dietary magnesium (Mg)(P-value = 0.04), insoluble fiber (P-value = 0.03), and low-fat yogurt (P-value = 0.04) had higher U-Mo concentrations. Our study suggests that vegetables, fish, fiber and yogurt might be significant dietary sources of metals. Future studies aimed at investigating the risk of exposure to metals from other various food sources among reproductive-age and pregnant women are needed.

Maternal healthy lifestyle during early pregnancy and offspring birthweight: differences by offspring sex.

PURPOSE: Individual maternal lifestyle factors during pregnancy have been associated with offspring birthweight; however, associations of combined lifestyle factors with birthweight and potential differences by offspring sex have not been examined. MATERIALS AND METHODS: Participants (N = 2924) were identified from a pregnancy cohort in Washington state. Lifestyle factors during early pregnancy were dichotomized based on Alternate Healthy Eating Index score ≥62, leisure time physical activity (LTPA) ≥ 150 min/week, not smoking during pregnancy and Perceived Stress Scale score ≤3, then combined into a lifestyle score (0-4). Regression models were run overall and stratified by offspring sex, prepregnancy overweight/obese (BMI ≥25 kg/m2) and prepregnancy LTPA. RESULTS: Overall, 20% of participants had healthy diet, 95% were nonsmokers, 55% had low stress levels, and 66% were physically active. Lifestyle score was not associated with birthweight (ß = 3.3 g; 95% CI: -14.5, 21.0); however, associations differed by offspring sex (p = .009). For each unit increase in lifestyle score, there was a suggested 22.4 g higher birthweight (95% CI: -2.7, 47.6) among males and 14.6 g lower birthweight (95% CI: -39.9, 10.7) among females. Prepregnancy BMI and LTPA did not modify associations. CONCLUSIONS: Healthy lifestyle score in early pregnancy may be associated with greater birthweight among male offspring, but lower birthweight among female offspring.

MicroRNA-21 Limits Uptake of Listeria monocytogenes by Macrophages to Reduce the Intracellular Niche and Control Infection.

MiRNAs are important post-transcriptional regulators of gene expression. MiRNA expression is a crucial part of host responses to bacterial infection, however there is limited knowledge of their impact on the outcome of infections. We investigated the influence of miR-21 on macrophage responses during infection with Listeria monocytogenes, which establishes an intracellular niche within macrophages. MiR-21 is induced following infection of bone marrow-derived macrophages (BMDMs) with Listeria. MiR-21-/- macrophages display an increased bacterial burden with Listeria at 30 min and 2 h post-infection. This phenotype was reversed by the addition of synthetic miR-21 mimics to the system. To assess the immune response of wildtype (WT) and miR-21-/- macrophages, BMDMs were treated with bacterial LPS or infected with Listeria. There was no difference in IL-10 and IL-6 between WT and miR-21-/- BMDMs in response to LPS or Listeria. TNF-α was increased in miR-21-/- BMDMs stimulated with LPS or Listeria compared to WT macrophages. We next assessed the production of nitric oxide (NO), a key bactericidal factor in Listeria infection. There was no significant difference in NO production between WT and miR-21-/- cells, indicating that the increased bacterial burden may not be due to impaired killing. As the increased bacterial load was observed early following infection (30 min), we questioned whether this is due to differences in uptake of Listeria by WT and miR-21-/- macrophages. We show that miR-21-deficiency enhances uptake of FITC-dextran and FITC-Escherichia coli bioparticles by macrophages. The previously observed Listeria burden phenotype was ablated by pre-treatment of cells with the actin polymerization inhibitor cytochalasin-D. From analysis of miR-21 targets, we selected the pro-phagocytic regulators myristoylated alanine-rich C-kinase substrate (MARCKS) and Ras homolog gene family, member B (RhoB) for further investigation. MARCKS and RhoB are increased in miR-21-/- BMDMs, correlating with increased uptake of Listeria. Finally, intra-peritoneal infection of mice with Listeria led to increased bacterial burden in livers of miR-21-/- mice compared to WT mice. These findings suggest a possible role for miR-21 in regulation of phagocytosis during infection, potentially by repression of MARCKS and RhoB, thus serving to limit the availability of the intracellular niche of pathogens like L. monocytogenes.

Healthy Lifestyle During Early Pregnancy and Risk of Gestational Diabetes Mellitus.

Previous studies have found associations between individual healthy behaviors and reduced risk of gestational diabetes mellitus (GDM); however, the association of composite healthy lifestyle during pregnancy with GDM has not been examined. Participants in the Omega Study (n = 3,005), a pregnancy cohort study conducted in Washington State (1996-2008), reported information on diet, physical activity, smoking, and stress during early pregnancy. Lifestyle components were dichotomized into healthy/unhealthy and then combined into a total lifestyle score (range, 0-4). Regression models were used to determine relative risk of GDM (n = 140 cases) in relation to healthy lifestyle. Twenty percent of participants had a healthy diet, 66% were physically active, 95% were nonsmokers, and 55% had low stress. Each 1-point increase in lifestyle score was associated with a 21% lower risk of GDM (95% confidence interval: 0.65, 0.96) after adjustment for age, race, and nulliparity. Adjustment for prepregnancy body mass index, prepregnancy physical activity, and prepregnancy smoking attenuated the associations slightly. Associations were similar in normal-weight and overweight/obese women. In this study, a composite measure of healthy lifestyle during early pregnancy was associated with substantially lower GDM risk. Public health messaging and interventions promoting multiple aspects of a healthy lifestyle during early pregnancy should be considered for GDM prevention.

Maternal pre-pregnancy body mass index and circulating microRNAs in pregnancy.

BACKGROUND: Maternal pre-pregnancy overweight and obese status has been associated with a number of pregnancy complications and adverse offspring outcomes. Mechanisms for observed associations, however, are largely unknown. We investigated associations of pre-pregnancy body mass index with early-mid pregnancy epigenetic biomarkers, circulating microRNAs. METHODS: Peripheral blood was collected from participants (16-27 weeks gestation) of two multi-racial pregnancy cohorts, the Omega Study and the Pregnancy Outcomes and Community Health Study. Plasma miRNA expression was characterised using epigenome-wide (319 miRNAs) profiling among 20 pregnant women in each cohort. Cohort-specific linear regression models that included the predictor (pre-pregnancy body mass index), the outcome (microRNA expression), and adjustment factors (maternal age, gestational age at blood collection, and race) were fit. RESULTS: Expression of 27 miRNAs was positively associated with pre-pregnancy body mass index in both cohorts (p-values <0.05). A number of these differentially expressed miRNAs have previously been associated with adipogenesis (e.g. let-7d*, miR-103-2*, -130b, -146b-5-p, -29c, and -26b). Identified miRNAs as well as their experimentally validated targets participate in pathways that involve organismal injury, reproductive system disease, connective tissue disorders, cancer, cellular development, growth and proliferation. CONCLUSION: Pre-pregnancy body mass index is associated with circulating miRNAs in early-mid pregnancy.

Early pregnancy vitamin D status and risk of preeclampsia.

BACKGROUND: Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia. METHODS: We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia. RESULTS: Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10-0.96). Differential expression of 348 vitamin D-associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity. CONCLUSIONS: Vitamin D supplementation initiated in weeks 10-18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00920621. FUNDING: Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Associations of self-reported and objectively measured sleep disturbances with depression among primary caregivers of children with disabilities.

OBJECTIVE: The objective of this study was to determine the association between sleep and depression using both self-reported (subjective) and actigraphic (objective) sleep traits. METHODS: A cross-sectional study was conducted among 175 female primary caregivers of children with disabilities receiving care at a rehabilitation center in Punta Arenas, Chile. The eight-item Patient Health Questionnaire was used to ascertain participants' depression status. The Pittsburgh Sleep Quality Index was used to define subjective, or perceived, sleep quality. Wrist-worn actigraph monitors, worn for seven consecutive nights, were used to characterize objective sleep quality and disturbances. Interviewer-administered questionnaires were used to collect information on sociodemographic and lifestyle factors. Linear regression models were fit using continuous sleep parameters as the dependent variables and depression status as the independent variable. Multivariable models were adjusted for body mass index, marital status, smoking status, education level, and children's disabilities. RESULTS: Using an eight-item Patient Health Questionnaire score ≥10, 26.3% of participants presented with depression. Depressed women were more likely to self-report overall poorer (subjective) sleep compared to non-depressed women; however, differences in sleep were not consistently noted using actigraphic (objective) sleep traits. Among the depressed, both sleep duration and total time in bed were significantly underestimated. In multivariable models, depression was negatively associated with sleep duration using both subjective (ß=-0.71, standard error [SE] =0.25; P=0.006) and objective sleep (ß=-0.42, SE =0.19; P=0.026). CONCLUSION: The association between sleep and depression differed comparing subjective and objective methods of assessment. Research strategies allowing for the integration of both perceived and objective measures of sleep traits are encouraged.