Prenatal Infection by Respiratory Viruses Is Associated with Immunoinflammatory Responses in the Fetus.

Rationale: Respiratory viral infections can be transmitted from pregnant women to their offspring, but frequency, mechanisms, and postnatal outcomes remain unclear. Objectives: The aims of this prospective cohort study were to compare the frequencies of transplacental transmission of respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), analyze the concentrations of inflammatory mediators in maternal and fetal blood, and assess clinical consequences. Methods: We recruited pregnant women who developed upper respiratory infections or tested positive for SARS-CoV-2. Maternal and cord blood samples were collected at delivery. Study questionnaires and electronic medical records were used to document demographic and medical information. Measurements and Main Results: From October 2020 to June 2022, droplet digital PCR was used to test blood mononuclear cells from 103 mother-baby dyads. Twice more newborns in our sample were vertically infected with RSV compared with SARS-CoV-2 (25.2% [26 of 103] vs. 11.9% [12 of 101]; P = 0.019). Multiplex ELISA measured significantly increased concentrations of several inflammatory cytokines and chemokines in maternal and cord blood from newborns, with evidence of viral exposure in utero compared with control dyads. Prenatal infection was associated with significantly lower birth weight and postnatal weight growth. Conclusions: Data suggest a higher frequency of vertical transmission for RSV than SARS-CoV-2. Intrauterine exposure is associated with fetal inflammation driven by soluble inflammatory mediators, with expression profiles dependent on the virus type and affecting the rate of viral transmission. Virus-induced inflammation may have pathological consequences already in the first days of life, as shown by its effects on birth weight and postnatal weight growth.

Sleep apnoea symptoms and sleepiness associate with future diet quality: a prospective analysis in the Bogalusa Heart Study.

Sleep apnoea is a known risk factor for cardiometabolic diseases (CMD), but it is unknown whether sleep apnoea or its symptoms contribute to increased CMD through an association with diet quality. This study assessed the association between sleep apnoea symptoms on future diet quality in the Bogalusa Heart Study (BHS). This prospective study included 445 participants who completed a sleep apnoea questionnaire in 2007-2010 and a FFQ in 2013-2016 (mean follow-up: 5·8 years; age 43·5 years; 34 % male; 71 % White/29 % Black persons). Diet quality was measured with the Alternate Healthy Eating Index (AHEI) 2010, the Healthy Eating Index (HEI) 2015 and the alternate Mediterranean diet score. Adjusted mean differences in dietary patterns by sleep apnoea risk, excessive snoring and daytime sleepiness were estimated with multivariable linear regression. Models included multi-level socio-economic factors, lifestyle and health characteristics including BMI, physical activity and depressive symptoms. Those with high sleep apnoea risk, compared with low, had lower diet quality 5·8 years later (percentage difference in AHEI (95 % CI -2·1 % (-3·5 %, -0·7 %)). Daytime sleepiness was associated with lower diet quality. After adjusting for dietary pattern scores from 2001 to 2002, having high sleep apnoea risk and excessive sleepiness were associated with 1·5 % (P < 0·05) and 3·1 % (P < 0·001) lower future AHEI scores, respectively. These findings suggest that individuals with sleep apnea or excessive sleepiness should be monitored for diet quality and targeted for dietary interventions to improve CMD risk.

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.

Diet quality in young adulthood and sleep at midlife: a prospective analysis in the Bogalusa Heart Study.

BACKGROUND: Diet and sleep are both established risk factors for cardiometabolic diseases. Prior evidence suggests a potential link between these behaviors, though longitudinal evidence for how diet associates with sleep is scarce. This study aimed to determine the prospective association between diet quality in young adulthood and multiple sleep outcomes at midlife in the Bogalusa Heart Study (BHS). METHODS: This prospective study included 593 BHS subjects with dietary assessment at the 2001-2002 visit and sleep questionnaire responses from the 2013-2016 visit, after an average of 12.7 years (baseline mean age: 36 years, 36% male, 70%/30% White and Black persons). A culturally tailored, validated food frequency questionnaire assessed usual diet. Diet quality was measured with the Alternate Healthy Eating Index (AHEI) 2010, the Healthy Eating Index (HEI) 2015, and the alternate Mediterranean (aMed) dietary score. Robust Poisson regression with log-link function estimated risk ratios (RR) for insomnia symptoms, high sleep apnea score, and having a healthy sleep pattern by quintile and per standard deviation (SD) increase in dietary patterns. Models adjusted for potential confounders including multi-level socioeconomic factors, depression, and body mass index. Trends across quintiles and effect modification by sex, race, and education were tested. RESULTS: Higher diet quality in young adulthood, measured by both AHEI and HEI, was associated with lower probability of having insomnia symptoms at midlife. In the adjusted model, each SD-increase in AHEI (7.8 points; 7% of score range) conferred 15% lower probability of insomnia symptoms at follow-up (RR [95% confidence interval CI]: 0.85 [0.77, 0.93]), those in Q5 of AHEI had 0.54 times the probability as those in Q1 (95% CI: 0.39, 0.75), and there was a significant trend across quintiles (trend p = 0.001). There were no significant associations between young adult diet quality and having a high sleep apnea risk or a healthy sleep pattern at follow-up. CONCLUSIONS: A healthy diet was associated with a lower probability of future insomnia symptoms. If replicated, these findings could have implications for chronic disease prevention strategies incorporating the lifestyle behaviors of sleep and diet.

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.

Maternal Diet and Infant Feeding Practices Are Associated with Variation in the Human Milk Microbiota at 3 Months Postpartum in a Cohort of Women with High Rates of Gestational Glucose Intolerance.

BACKGROUND: Human milk contains a diverse community of bacteria believed to play a role in breast health and inoculation of the infant's gastrointestinal tract. The role of maternal nutrition and infant feeding practices on the human milk microbiota remains poorly understood. OBJECTIVE: Our aim was to explore the associations between maternal diet (delivery to 3 mo postpartum), infant feeding practices, and the microbial composition and predicted function in milk from women with varied metabolic status. METHODS: This was an exploratory analysis of a previously completed prospective cohort study of women with varying degrees of gestational glucose intolerance (NCT01405547). Milk samples (n = 93 mothers) were collected at 3 mo postpartum. Maternal dietary information (validated food-frequency questionnaire) and infant feeding practices (human milk exclusivity, frequency of direct breastfeeding per day) were collected. V4-16S ribosomal RNA gene sequencing (Illumina MiSeq) was conducted to determine microbiota composition. RESULTS: Intake of polyunsaturated fat [ß estimate (SE): 0.036 (0.018), P = 0.047] and fiber from grains [0.027 (0.013), P = 0.048] were positively associated with ɑ-diversity (Shannon index) of human milk. Overall microbial composition of human milk clustered based on human milk exclusivity (weighted UniFrac R2 = 0.034, P = 0.015; Bray-Curtis R2 = 0.041, P = 0.007), frequency of direct breastfeeding per day (Bray-Curtis R2 = 0.057, P = 0.026), and maternal fiber intake from grains (Bray-Curtis R2 = 0.055, P = 0.040). Total fiber, fiber from grains, dietary fat, and infant feeding practices were also associated with a number of differentially abundant taxa. The overall composition of predicted microbial functions was associated with total fiber consumption (Bray-Curtis R2 = 0.067, P = 0.036) and human milk exclusivity (Bray-Curtis R2 = 0.041, P = 0.013). CONCLUSIONS: Maternal consumption of fiber and fat, as well as mother's infant feeding practices, are important determinants of the human milk microbiota. Understanding whether these microbial changes impact an infant's overall health and development requires future study.

Oligosaccharides and Microbiota in Human Milk Are Interrelated at 3 Months Postpartum in a Cohort of Women with a High Prevalence of Gestational Impaired Glucose Tolerance.

BACKGROUND: Human milk is a rich source of human milk oligosaccharides (HMOs) and bacteria. It is unclear how these components interact within the breast microenvironment. OBJECTIVES: The objectives were first, to investigate the association between maternal characteristics and HMOs, and second, to assess the association between HMOs and microbial community composition and predicted function in milk from women with high rates of gestational glucose intolerance. METHODS: This was an exploratory analysis of a previously completed prospective cohort study (NCT01405547) where milk samples (n = 107) were collected at 3 mo postpartum. Milk microbiota composition was analyzed by V4-16S ribosomal RNA gene sequencing and HMOs by rapid high-throughput HPLC. Data were stratified and analyzed by maternal secretor status phenotype and associations between HMOs and microbiota were determined using linear regression models (ɑ-diversity), Adonis (B-diversity), Poisson regression models (differential abundance), and general linear models (predicted microbial function). RESULTS: Prepregnancy BMI, race, and frequency of direct breastfeeding, but not gestational glucose intolerance, were found to be significantly associated with a number of HMOs among secretors and non-secretors. Fucosyllacto-N-hexaose was negatively associated with microbial richness (Chao1) among secretors [B-estimate (SE): -9.3 × 102 (3.4 × 102); P = 0.0082] and difucosyllacto-N-hexaose was negatively associated with microbiota diversity (Shannon index) [-1.7 (0.78); P = 0.029] among secretors. Lacto-N-neotetraose (LNnT) was associated with both microbial B-diversity (weighted UniFrac R2 = 0.040, P = 0.036) and KEGG ortholog B-diversity (Bray-Curtis R2 = 0.039, P = 0.043) in secretors. Additionally, difucosyllactose in secretors and disialyllacto-N-hexaose and LNnT in non-secretors were associated with enrichment of predicted microbial genes encoding for metabolism- and infection-related pathways (P-false discovery rate < 0.1). CONCLUSIONS: HMOs are associated with the microbial composition and predicted microbial functions in human milk at 3 mo postpartum. Further research is needed to investigate the role these relations play in maternal and infant health.

Maternal smoking, genetic susceptibility, and birth-to-adulthood body weight.

BACKGROUND: Maternal smoking (MS) is associated with low birthweight (BW) but adult obesity in offspring, however, it remains unknown whether it modifies offspring's genetic susceptibility to obesity on BW, adult body weight, and birth-to-adulthood body weight tracking pattern. METHODS: This study included 246,759 UK Biobank participants with information on MS, BW (kg), adult body weight and BMI (kg/m2). Individual polygenetic score (PGS) was created on the basis of 97 BMI-associated genetic loci. We calculated individual birth-to-adulthood percentile change, and body weight tracking patterns that combined BW levels (<2.5, 2.5-4.0, and ≥4.0 as low, normal and high BW [LBW, NBW, and HBW]) and adulthood obesity status (≥30 as obesity [OB] and <30 as non-obesity [NOB]), including LBW-to-OB, LBW-to-NOB, NBW-to-OB, NBW-to-NOB, HBW-to-OB, and HBW-to-NOB. RESULTS: Participants exposed to MS had a 0.108 kg lower BW (95% CI, -0.114 to -0.102), a 1.418 kg higher adult body weight (95% CI, 1.291-1.545), and a 6.91 greater percentile increase of body weight from birth to adulthood (95% CI, 6.62-7.21), compared with those nonexposed (all P < 0.001). In comparison to participants of NBW-to-NOB, MS was associated with an approximately twofold higher risk of LBW-to-OB (odds ratio [OR] 1.98, 95% CI 1.87-2.10), and a reduced likelihood of HBW-to-NOB (0.85, 95% CI 0.82-0.88). The increases in BW, adult body weight, and birth-to-adulthood percentile change per increment of 10 BMI-PGS were 0.021 vs. 0.012, 2.50 vs. 2.11, and 4.03 vs. 3.55, respectively, for participants exposed vs. nonexposed to MS (all Pinteraction < 0.05). CONCLUSION: Our results indicate that exposure to MS is associated with an increased risk of transition from low BW-to-adulthood obesity, and reduced likelihood of change from high BW-to-normal adult body weight. MS may modify the relation of genetic susceptibility to obesity and body weight in offspring.

Examining the relationship between maternal body size, gestational glucose tolerance status, mode of delivery and ethnicity on human milk microbiota at three months post-partum.

BACKGROUND: Few studies have examined how maternal body mass index (BMI), mode of delivery and ethnicity affect the microbial composition of human milk and none have examined associations with maternal metabolic status. Given the high prevalence of maternal adiposity and impaired glucose metabolism, we systematically investigated the associations between these maternal factors in women ≥20 years and milk microbial composition and predicted functionality by V4-16S ribosomal RNA gene sequencing (NCT01405547;  https://clinicaltrials.gov/ct2/show/NCT01405547 ). Demographic data, weight, height, and a 3-h oral glucose tolerance test were gathered at 30 (95% CI: 25-33) weeks gestation, and milk samples were collected at 3 months post-partum (n = 113). RESULTS: Multivariable linear regression analyses demonstrated no significant associations between maternal characteristics (maternal BMI [pre-pregnancy, 3 months post-partum], glucose tolerance, mode of delivery and ethnicity) and milk microbiota alpha-diversity; however, pre-pregnancy BMI was associated with human milk microbiota beta-diversity (Bray-Curtis R2 = 0.037). Women with a pre-pregnancy BMI > 30 kg/m2 (obese) had a greater incidence of Bacteroidetes (incidence rate ratio [IRR]: 3.70 [95% CI: 1.61-8.48]) and a reduced incidence of Proteobacteria (0.62 [0.43-0.90]) in their milk, compared to women with an overweight BMI (25.0-29.9 kg/m2) as assessed by multivariable Poisson regression. An increased incidence of Gemella was observed among mothers with gestational diabetes who had an overweight BMI versus healthy range BMI (5.96 [1.85-19.21]). An increased incidence of Gemella was also observed among mothers with impaired glucose tolerance with an obese BMI versus mothers with a healthy range BMI (4.04 [1.63-10.01]). An increased incidence of Brevundimonas (16.70 [5.99-46.57]) was found in the milk of women who underwent an unscheduled C-section versus vaginal delivery. Lastly, functional gene inference demonstrated that pre-pregnancy obesity was associated with an increased abundance of genes encoding for the biosynthesis of secondary metabolites pathway in milk (coefficient = 0.0024, PFDR < 0.1). CONCLUSIONS: Human milk has a diverse microbiota of which its diversity and differential abundance appear associated with maternal BMI, glucose tolerance status, mode of delivery, and ethnicity. Further research is warranted to determine whether this variability in the milk microbiota impacts colonization of the infant gut.

Genetic variants of gestational diabetes mellitus: a study of 112 SNPs among 8722 women in two independent populations.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is a common complication of pregnancy that has substantial short- and long-term adverse health implications for women and their children. However, large-scale studies on genetic risk loci for GDM remain sparse. METHODS: We conducted a case-control study among 2636 women with GDM and 6086 non-GDM control women from the Nurses' Health Study II and the Danish National Birth Cohort. A total of 112 susceptibility genetic variants confirmed by genome-wide association studies for type 2 diabetes were selected and measured. A weighted genetic risk score (GRS) was created based on variants that were significantly associated with risk of GDM after correcting for the false discovery rate. RESULTS: For the first time, we identified eight variants associated with GDM, namely rs7957197 (HNF1A), rs10814916 (GLIS3), rs3802177 (SLC30A8), rs9379084 (RREB1), rs34872471 (TCF7L2), rs7903146 (TCF7L2), rs11787792 (GPSM1) and rs7041847 (GLIS3). In addition, we confirmed three variants, rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs4506565 (TCF7L2), that had previously been significantly associated with GDM risk. Furthermore, compared with participants in the first (lowest) quartile of weighted GRS based on these 11 SNPs, the ORs for GDM were 1.07 (95% CI 0.93, 1.22), 1.23 (95% CI 1.07, 1.41) and 1.53 (95% CI 1.34, 1.74) for participants in the second, third and fourth (highest) quartiles, respectively. The significant positive associations between the weighted GRS and risk of GDM persisted across most of the strata of major risk factors for GDM, including family history of type 2 diabetes, smoking status, BMI and age. CONCLUSIONS/INTERPRETATION: In this large-scale case-control study with women from two independent populations, eight novel GDM SNPs were identified. These findings offer the potential to improve our understanding of the aetiology of GDM, and particularly of biological mechanisms related to beta cell function.

Cross-sectional association between sugar-sweetened beverage intake and cardiometabolic biomarkers in US women.

Few studies have evaluated the relationships between intake of sugar-sweetened beverages (SSB) and intermediate biomarkers of cardiometabolic risk. Associations between artificially sweetened beverages (ASB) and fruit juice with cardiometabolic biomarkers are also unclear. We investigated habitual SSB, ASB and fruit juice intake in relation to biomarkers of hepatic function, lipid metabolism, inflammation and glucose metabolism. We analysed cross-sectional data from 8492 participants in the Nurses' Health Study who were free of diabetes and CVD. Multivariate linear regression was used to assess the associations of SSB, ASB and fruit juice intake with concentrations of fetuin-A, alanine transaminase, γ-glutamyl transferase, TAG, HDL-cholesterol, LDL-cholesterol, total cholesterol, C-reactive protein (CRP), intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1, adiponectin, insulin and HbA1c as well as total cholesterol:HDL-cholesterol ratio. More frequent intake of SSB was significantly associated with higher concentrations of fetuin-A, TAG, CRP, ICAM-1, adiponectin and insulin, a higher total cholesterol:HDL-cholesterol ratio, and a lower concentration of HDL-cholesterol (P trend ranges from <0·0001 to 0·04) after adjusting for demographic, medical, dietary and lifestyle variables. ASB intake was marginally associated with increased concentrations of CRP (P trend=0·04) and adiponectin (P trend=0·01). Fruit juice intake was associated with increased concentrations of TAG and HbA1c and a lower concentration of adiponectin (P trend ranges from <0·0001 to 0·01). In conclusion, habitual intake of SSB was associated with adverse levels of multiple cardiometabolic biomarkers. Associations between ASB and fruit juice with cardiometabolic risk markers warrant further exploration.

Weight History and All-Cause and Cause-Specific Mortality in Three Prospective Cohort Studies.

BACKGROUND: The relationship between body mass index (BMI) and mortality is controversial. OBJECTIVE: To investigate the relationship between maximum BMI over 16 years and subsequent mortality. DESIGN: 3 prospective cohort studies. SETTING: Nurses' Health Study I and II and Health Professionals Follow-Up Study. PARTICIPANTS: 225 072 men and women with 32 571 deaths observed over a mean of 12.3 years of follow-up. MEASUREMENTS: Maximum BMI over 16 years of weight history and all-cause and cause-specific mortality. RESULTS: Maximum BMIs in the overweight (25.0 to 29.9 kg/m2) (multivariate hazard ratio [HR], 1.06 [95% CI, 1.03 to 1.08]), obese I (30.0 to 34.9 kg/m2) (HR, 1.24 [CI, 1.20 to 1.29]), and obese II (≥35.0 kg/m2) (HR, 1.73 [CI, 1.66 to 1.80]) categories were associated with increases in risk for all-cause death. The pattern of excess risk with a maximum BMI above normal weight was maintained across strata defined by smoking status, sex, and age, but the excess was greatest among those younger than 70 years and never-smokers. In contrast, a significant inverse association between overweight and mortality (HR, 0.96 [CI, 0.94 to 0.99]) was observed when BMI was defined using a single baseline measurement. Maximum overweight was also associated with increased cause-specific mortality, including death from cardiovascular disease and coronary heart disease. LIMITATION: Residual confounding and misclassification. CONCLUSION: The paradoxical association between overweight and mortality is reversed in analyses incorporating weight history. Maximum BMI may be a useful metric to minimize reverse causation bias associated with a single baseline BMI assessment. PRIMARY FUNDING SOURCE: National Institutes of Health.

High Fiber and Low Starch Intakes Are Associated with Circulating Intermediate Biomarkers of Type 2 Diabetes among Women.

BACKGROUND: Carbohydrate quality has been consistently related to the risk of type 2 diabetes (T2D). However, limited information is available about the effect of carbohydrate quality on biomarkers related to T2D. OBJECTIVE: We examined the associations of carbohydrate quality measures (CQMs) including carbohydrate intake; starch intake; glycemic index; glycemic load; total, cereal, fruit, and vegetable fiber intakes; and different combinations of these nutrients with plasma concentrations of adiponectin, C-reactive protein (CRP), and glycated hemoglobin (HbA1c). METHODS: This is a cross-sectional analysis of 2458 diabetes-free women, ages 43-70 y, in the Nurses Health Study. CQMs were estimated from food-frequency questionnaires, and averages from 1984, 1986, and 1990 were used. Plasma biomarkers were collected in 1990. Multiple linear regression models were used to assess the associations between CQMs and biomarkers. RESULTS: After age, body mass index, lifestyle, and dietary variables were adjusted, 1) total fiber intake was positively associated with adiponectin (P-trend = 0.004); 2) cereal fiber intake was positively associated with adiponectin and inversely associated with CRP, and fruit fiber intake was negatively associated with HbA1c concentrations (all P-trend < 0.03); 3) starch intake was inversely associated with adiponectin (P-trend = 0.02); 4) a higher glycemic index was associated with lower adiponectin and higher HbA1c (both P-trend < 0.05); 5) a higher carbohydrate-to-total fiber intake ratio was associated with lower adiponectin (P-trend = 0.005); 6) a higher starch-to-total fiber intake ratio was associated with lower adiponectin and higher HbA1c (both P-trend < 0.05); and 7) a higher starch-to-cereal fiber intake ratio was associated with lower adiponectin (P-trend = 0.002). CONCLUSIONS: A greater fiber intake and a lower starch-to-fiber intake ratio are favorably associated with adiponectin and HbA1c, but only cereal fiber intake was associated with CRP in women. Further research is warranted to understand the potential mechanism of these associations in early progression of T2D.

Contribution of the Nurses' Health Studies to Uncovering Risk Factors for Type 2 Diabetes: Diet, Lifestyle, Biomarkers, and Genetics.

OBJECTIVES: To review the contribution of the Nurses' Health Study (NHS) and the NHS II to addressing hypotheses regarding risk factors for type 2 diabetes. METHODS: We carried out a narrative review of 1976 to 2016 NHS and NHS II publications. RESULTS: The NHS and NHS II have uncovered important roles in type 2 diabetes for individual nutrients, foods, dietary patterns, and physical activity independent of excess body weight. Up to 90% of type 2 diabetes cases are potentially preventable if individuals follow a healthy diet and lifestyle. The NHS investigations have also identified novel biomarkers for diabetes, including adipokines, inflammatory cytokines, nutrition metabolites, and environmental pollutants, offering new insights into the pathophysiology of the disease. Global collaborative efforts have uncovered many common genetic variants associated with type 2 diabetes and improved our understanding of gene-environment interactions. Continued efforts to identify epigenetic, metagenomic, and metabolomic risk factors for type 2 diabetes have the potential to reveal new pathways and improve prediction and prevention. CONCLUSIONS: Over the past several decades, the NHS and NHS II have made major contributions to public health recommendations and strategies designed to reduce the global burden of diabetes.

Long-term risk of type 2 diabetes mellitus in relation to BMI and weight change among women with a history of gestational diabetes mellitus: a prospective cohort study.

AIMS/HYPOTHESIS: Women with a history of gestational diabetes mellitus (GDM) are advised to control their weight after pregnancy. We aimed to examine how adiposity and weight change influence the long-term risk of developing type 2 diabetes after GDM. METHODS: We included 1,695 women who had incident GDM between 1991 and 2001, as part of the Diabetes & Women's Health study, and followed them until the return of the 2009 questionnaire. Body weight and incident type 2 diabetic cases were reported biennially. We defined baseline as the questionnaire period when women reported an incident GDM pregnancy. We estimated HRs and 95% CIs using Cox proportional hazards models. RESULTS: We documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. The adjusted HRs of type 2 diabetes associated with each 1 kg/m(2) increase in BMI were 1.16 (95% CI 1.12, 1.19) for baseline BMI and 1.16 (95% CI 1.13, 1.20) for most recent BMI. Moreover, each 5 kg increment of weight gain after GDM development was associated with a 27% higher risk of type 2 diabetes (adjusted HR 1.27; 95% CI 1.04, 1.54). Jointly, women who had a BMI ≥30.0 kg/m(2) at baseline and gained ≥5 kg after GDM had an adjusted HR of 43.19 (95% CI 13.60, 137.11), compared with women who had a BMI <25.0 kg/m(2) at baseline and gained <5 kg after GDM. CONCLUSIONS/INTERPRETATION: Baseline BMI, most recent BMI and weight gain after GDM were significantly and positively associated with risk of progression from GDM to type 2 diabetes.

Prevention and management of type 2 diabetes: dietary components and nutritional strategies.

In the past couple of decades, evidence from prospective observational studies and clinical trials has converged to support the importance of individual nutrients, foods, and dietary patterns in the prevention and management of type 2 diabetes. The quality of dietary fats and carbohydrates consumed is more crucial than is the quantity of these macronutrients. Diets rich in wholegrains, fruits, vegetables, legumes, and nuts; moderate in alcohol consumption; and lower in refined grains, red or processed meats, and sugar-sweetened beverages have been shown to reduce the risk of diabetes and improve glycaemic control and blood lipids in patients with diabetes. With an emphasis on overall diet quality, several dietary patterns such as Mediterranean, low glycaemic index, moderately low carbohydrate, and vegetarian diets can be tailored to personal and cultural food preferences and appropriate calorie needs for weight control and diabetes prevention and management. Although much progress has been made in development and implementation of evidence-based nutrition recommendations in developed countries, concerted worldwide efforts and policies are warranted to alleviate regional disparities.

Joint association between birth weight at term and later life adherence to a healthy lifestyle with risk of hypertension: a prospective cohort study.

BACKGROUND: Low birth weight and unhealthy lifestyles in adulthood have been independently associated with an elevated risk of hypertension. However, no study has examined the joint effects of these factors on incidence of hypertension. METHODS: We followed 52,114 women from the Nurses' Health Study II without hypercholesterolemia, diabetes, cardiovascular disease, cancer, prehypertension, and hypertension at baseline (1991-2011). Women born preterm, of a multiple pregnancy, or who were missing birth weight data were excluded. Unhealthy adulthood lifestyle was defined by compiling status scores of body mass index, physical activity, alcohol consumption, the Dietary Approaches to Stop Hypertension diet, and the use of non-narcotic analgesics. RESULTS: We documented 12,588 incident cases of hypertension during 20 years of follow-up. The risk of hypertension associated with a combination of low birth weight at term and unhealthy lifestyle factors (RR, 1.95; 95 % CI, 1.83-2.07) was more than the addition of the risk associated with each individual factor, indicating a significant interaction on an additive scale (P interaction <0.001). The proportions of the association attributable to lower term birth weight alone, unhealthy lifestyle alone, and their joint effect were 23.9 % (95 % CI, 16.6-31.2), 63.7 % (95 % CI, 60.4-66.9), and 12.5 % (95 % CI, 9.87-15.0), respectively. The population-attributable-risk for the combined adulthood unhealthy lifestyle and low birth weight at term was 66.3 % (95 % CI, 56.9-74.0). CONCLUSION: The majority of cases of hypertension could be prevented by the adoption of a healthier lifestyle, though some cases may depend on simultaneous improvement of both prenatal and postnatal factors.

Association between alcohol consumption and plasma fetuin-A and its contribution to incident type 2 diabetes in women.

AIMS/HYPOTHESIS: The benefits of moderate alcohol consumption for type 2 diabetes have been postulated to involve a mechanism of improved insulin sensitivity. Fetuin-A, which is known to inhibit insulin signalling, has emerged as a biomarker for diabetes risk. Alcohol consumption may influence circulating fetuin-A concentrations and subsequently diabetes risk by altering the insulin signal. We therefore hypothesised that moderate alcohol consumption would be associated with lower fetuin-A concentration and that fetuin-A would partly explain the association between alcohol consumption and incident type 2 diabetes. METHODS: Among diabetes-free female participants in the Nurses' Health Study (n = 1,331), multiple linear regression was conducted to assess the association between alcohol consumption and plasma fetuin-A. Least-squares means (lsmeans) of fetuin-A were estimated in categories of alcohol consumption (0, 0.1-4.9, 5-14.9 and ≥ 15 g/day). The proportion of alcohol consumption and diabetes association explained by baseline fetuin-A was assessed in 470 matched incident diabetes case-control pairs with follow-up 2000-2006. RESULTS: Higher alcohol consumption was associated with lower plasma fetuin-A (p for trend = 0.009): lsmean ± SE 476.5 ± 5.9 µg/ml for abstainers, 468.9 ± 5.2 µg/ml for 0.1-4.9 g/day consumers, 455.9 ± 7.0 µg/ml for 5.0-14.9 g/day consumers, and 450.0 ± 9.4 µg/ml for ≥ 15.0 g/day consumers. Fetuin-A and fasting insulin explained 18.4% and 54.8%, respectively, of the inverse association between alcohol consumption and diabetes after multiple adjustment (both p for contribution <0.04). CONCLUSIONS/INTERPRETATION: Moderate alcohol consumption is associated with lower plasma fetuin-A in diabetes-free women. Fetuin-A and insulin explain a significant proportion of the association between alcohol consumption and incident type 2 diabetes. Further studies are needed to examine potential biological mechanisms underlying this association.

Association of Age at Menarche with Inflammation and Glucose Metabolism Biomarkers in U.S. Adult Women: NHANES 1999-2018.

CONTEXT: Early age at menarche (AAM) is a risk factor for type 2 diabetes later in life, but the pathogenic pathways that confer increased risk remain unknown. OBJECTIVE: We examined the associations between AAM and inflammatory and glucose metabolism biomarkers among U.S. adult women who were free of diabetes. METHODS: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2018, 19,228 women over 20 years old who were free of self-reported cancer and diabetes were included in this cross-sectional analysis. AAM was the self-reported age at first menstruation. CRP, fasting glucose, fasting insulin, and ferritin levels were measured as biomarkers of inflammation and glucose metabolism in adult blood samples using latex-enhanced nephelometry, enzymatic, and immunoassay methods. Multiple linear regression was used to relate AAM to the biomarkers. RESULTS: The median age at the time of blood sample collection was 44 years (IQR, 33-62). After age adjustment, there was an association between a lower AAM and higher CRP (P-trend=0.006); fasting glucose (P-trend<0.0001); fasting insulin (P-trend <0.0001); and ferritin (p-trend<0.0001). These remained significant after additional adjustment for demographic, reproductive, lifestyle, and adiposity variables, except for ferritin. Smoking modified the effect of AAM on CRP (p-interaction = 0.014), fasting insulin (p-interaction <0.001), and fasting glucose (p-interaction<0.001). In stratified analysis, the observed associations became more pronounced in non-smokers, while they were attenuated to non-significance in active smokers. CONCLUSION: Earlier age at menarche is associated with an unfavorable inflammatory and glucose metabolic biomarker profile in a nationally representative sample of adult women free of diabetes, especially among non-smokers.

Lifetime Duration of Breastfeeding and Cardiovascular Risk in Women With Type 2 Diabetes or a History of Gestational Diabetes: Findings From Two Large Prospective Cohorts.

OBJECTIVE: Breastfeeding duration is inversely associated with risks of cardiovascular disease (CVD) and type 2 diabetes in parous women. However, the association among women at high risk, including women with type 2 diabetes or gestational diabetes mellitus (GDM) is unclear. RESEARCH DESIGN AND METHODS: We included 15,146 parous women with type 2 diabetes from the Nurses' Health Study I and II (NHS, NHS II) and 4,537 women with a history of GDM from NHS II. Participants reported history of breastfeeding via follow-up questionnaires. Incident CVD by 2017 comprised stroke or coronary heart disease (CHD) (myocardial infarction, coronary revascularization). Adjusted hazard ratios (aHRs) and 95% CIs were estimated using Cox models. RESULTS: We documented 1,159 incident CVD cases among women with type 2 diabetes in both cohorts during 188,874 person-years of follow-up and 132 incident CVD cases among women with a GDM history during 100,218 person-years of follow-up. Longer lifetime duration of breastfeeding was significantly associated with lower CVD risk among women with type 2 diabetes, with pooled aHR of 0.68 (95% CI 0.54-0.85) for >18 months versus 0 months and 0.94 (0.91-0.98) per 6-month increment in breastfeeding. Similar associations were observed with CHD (pooled aHR 0.93 [0.88-0.97]) but not with stroke (0.96 [0.91-1.02]) per 6-month increment in breastfeeding. Among women with GDM history, >18 months versus 0 months of breastfeeding was associated with an aHR of 0.49 (0.28-0.86) for total CVD. CONCLUSIONS: Longer duration of breastfeeding was associated with lower risk of CVD in women with type 2 diabetes or GDM.