Inflammatory, Metabolic and Endothelial Biomarkers Before and After Pregnancy Complications.

Women with gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), and preterm birth (PTB) have excess cardiovascular disease compared to those with uncomplicated births, perhaps related to pre-pregnancy inflammation, dysmetabolism or endothelial dysfunction. We included 1238 women in the Coronary Artery Risk Development in Young Adults Study (1985-2011) with 2215 births classified according to outcomes (term, uncomplicated births were the referent). Repeated measures ANOVA estimated pre-pregnancy, post-pregnancy and biomarker change according to pregnancy outcomes, adjusted for confounders. GDM and HDP groups had higher pre-pregnancy hsCRP (+0.37 [0.08, 0.65]; +0.29 [0.04, 0.55] log mg/L), leptin (+0.29 [0.09, 0.50]; +0.37 [0.17, 0.56] log ng/ml), and lower adiponectin (-0.25 [-0.36, -0.13); -0.11 [-0.22, -0.01] log ng/ml) than those with uncomplicated births and these profiles persisted in magnitude post-pregnancy. Controlling for BMI attenuated most profiles, except lower pre-pregnancy adiponectin remained associated with GDM. PTB without HDP or GDM was related to lower pre-pregnancy hsCRP and sICAM-1 (-0.31 [-0.56, -0.06] log mg/L; -0.05 [-0.09, - 0.01] log ng/ml) and a larger leptin increase from pre- to post-pregnancy, (+0.20 [0.02, 0.37] log ng/ml). Pre-pregnancy inflammation and metabolic dysfunction contributed to GDM and HDP, perhaps due to higher BMI. PTB may be related to adverse metabolic changes post-pregnancy, though the unexpected endothelial biomarker profile warrants further study.

Alanine aminotransferase elevation varies by ethnicity among Asian and Pacific Islander children with overweight or obesity.

BACKGROUND: Limited research on alanine aminotransferase (ALT) screening for metabolic dysfunction-associated steatotic liver disease (MASLD) among US Asian/Pacific Islander (PI) children necessitates investigation in this heterogeneous population. OBJECTIVE: Examine ALT elevation among Asian/PI children with overweight or obesity. METHODS: Elevated ALT prevalence (clinical threshold) and association with body mass index ≥85th percentile were compared among 18 402 Asian/PI and 25 376 non-Hispanic White (NHW) children aged 9-17 years using logistic regression. RESULTS: ALT elevation was more prevalent among Asian/PI (vs. NHW) males with overweight (4.0% vs. 2.7%), moderate (7.8% vs. 5.3%) and severe obesity (16.6% vs. 11.5%), and females with moderate (5.1% vs. 3.0%) and severe obesity (10.2% vs. 5.2%). Adjusted odds of elevated ALT were 1.6-fold and ~2-fold higher for Asian/PI (vs. NHW) males and females (with obesity), respectively. Filipino, Chinese and Southeast Asian males had 1.7-2.1-fold higher odds, but Native Hawaiian/PI (NHPI) and South Asian males did not significantly differ (vs. NHW). Filipina and Chinese females with obesity had >2-fold higher odds, Southeast and South Asian females did not differ and NHPI findings were mixed (vs. NHW). CONCLUSION: High elevated ALT prevalence among Asian/PI children with overweight and obesity emphasizes the need for MASLD risk assessment and examination of ethnic subgroups.

Childhood maltreatment and trajectories of cardiometabolic health across the reproductive life span among individuals with a first birth during the Coronary Artery Risk Development in Young Adults Study.

OBJECTIVE: Childhood adversity is associated with poor cardiometabolic health in adulthood; little is known about how this relationship evolves through childbearing years for parous individuals. The goal was to estimate differences in cardiometabolic health indicators before, during and after childbearing years by report of childhood maltreatment in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study. METHODS: Including 743 individuals nulliparous at baseline (1985-1986) with one or more pregnancies >20 weeks during follow-up (1986-2022), we fit segmented linear regression models to estimate mean differences between individuals reporting or not reporting childhood maltreatment (physical or emotional) in waist circumference, triglycerides, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, fasting glucose, and body mass index (BMI) prior to, during, and following childbearing years using generalized estimating equations, allowing for interaction between maltreatment and time within each segment, and adjusting for total parity, parental education, and race (Black or white, self-reported). RESULTS: Individuals reporting maltreatment (19%; 141) had a greater waist circumference (post-childbearing: +2.9 cm, 95% CI (0.7, 5.0), higher triglycerides [post-childbearing: +8.1 mg/dL, 95% CI (0.7, 15.6)], and lower HDL cholesterol [post-childbearing: -2.1 mg/dL, 95% CI (-4.7, 0.5)] during all stages compared to those not reporting maltreatment. There were not meaningful differences in blood pressure, fasting glucose, or BMI. Individuals who reported maltreatment did not report faster changes over time. CONCLUSION: Differences in some aspects of cardiometabolic health between individuals reporting versus not reporting childhood maltreatment were sustained across reproductive life stages, suggesting potentially persistent impacts of childhood adversity.

Understanding the role of childhood nurture, abuse, and stability on gestational diabetes in the Coronary Artery Risk Development in Young Adults study (CARDIA).

BACKGROUND: To estimate associations between facets of the maternal childhood family environment with gestational diabetes (GDM) and to test mediation by pre-pregnancy waist circumference. METHODS: We used data from CARDIA, a cohort of individuals aged 18-30 years at baseline (1985-86), followed over 30 years (2016). We included participants with one or more pregnancies ≥ 20 weeks after baseline, without pre-pregnancy diabetes. The primary exposure was the Childhood Family Environment Scale (assessed year 15), including the total score and abuse, nurture, and stability subscales as continuous, separate exposures. The outcome was GDM (self-reported at each visit for each pregnancy). We fit log binomial models with generalized estimating equations to calculate risk ratios (RR) and 95% confidence intervals (CI), adjusting for age at delivery, parity, race (Black or White), and parental education. We used regression models with bootstrapped CIs to test mediation and effect modification by excess abdominal adiposity at the last preconception CARDIA visit (waist circumference ≥ 88 cm). RESULTS: We included 1033 individuals (46% Black) with 1836 pregnancies. 130 pregnancies (7.1%) were complicated by GDM. For each 1 point increase on the abuse subscale (e.g., from "rarely or never" to "some or little of the time") there was a 30% increased risk of GDM (RR: 1.3, 95% CI: 1.0, 1.7). There was evidence of effect modification but not mediation by preconception abdominal adiposity. CONCLUSIONS: A more adverse childhood family environment was associated with increased risk of GDM, with a stronger association among individuals with preconception waist circumference ≥ 88 cm.

Inflammatory Conditions During Pregnancy and Risk of Autism and Other Neurodevelopmental Disorders.

Background: Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy increase the likelihood of autism spectrum disorder (ASD) or other neurodevelopmental disorders (DDs) is not well understood. Methods: We conducted a case-control study among children born in California from 2011 to 2016 to investigate maternal immune-mediated and cardiometabolic conditions during pregnancy and risk of ASD (n = 311) and DDs (n = 1291) compared with children from the general population (n = 967). Data on maternal conditions and covariates were retrieved from electronic health records. Maternal genetic data were used to assess a causal relationship. Results: Using multivariable logistic regression, we found that mothers with asthma were more likely to deliver infants later diagnosed with ASD (odds ratio [OR] = 1.62, 95% CI: 1.15-2.29) or DDs (OR = 1.30, 95% CI: 1.02-1.64). Maternal obesity was also associated with child ASD (OR = 1.51, 95% CI: 1.07-2.13). Mothers with both asthma and extreme obesity had the greatest odds of delivering an infant later diagnosed with ASD (OR = 16.9, 95% CI: 5.13-55.71). These increased ASD odds were observed among female children only. Polygenic risk scores for obesity, asthma, and their combination showed no association with ASD risk. Mendelian randomization did not support a causal relationship between maternal conditions and ASD. Conclusions: Inflammatory conditions during pregnancy are associated with risk for neurodevelopmental disorders in children. These risks do not seem to be due to shared genetic risk; rather, inflammatory conditions may share nongenetic risk factors with neurodevelopmental disorders. Children whose mothers have both asthma and obesity during pregnancy may benefit from earlier screening and intervention.

Erratum to 'Low gestational weight gain (+2.0 to 4.9 kg) for singleton-term gestations associated with favorable perinatal outcomes for all prepregnancy obesity classes' [AJOG Global Reports 3 (2023) 100246].

[This corrects the article DOI: 10.1016/j.xagr.2023.100246.].

Postpartum defects in inflammatory response after gestational diabetes precede progression to type 2 diabetes: a nested case-control study within the SWIFT study.

BACKGROUND: Gestational diabetes (GDM) is a distinctive form of diabetes that first presents in pregnancy. While most women return to normoglycemia after delivery, they are nearly ten times more likely to develop type 2 diabetes than women with uncomplicated pregnancies. Current prevention strategies remain limited due to our incomplete understanding of the early underpinnings of progression. AIM: To comprehensively characterize the postpartum profiles of women shortly after a GDM pregnancy and identify key mechanisms responsible for the progression to overt type 2 diabetes using multi-dimensional approaches. METHODS: We conducted a nested case-control study of 200 women from the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy (SWIFT) to examine biochemical, proteomic, metabolomic, and lipidomic profiles at 6-9 weeks postpartum (baseline) after a GDM pregnancy. At baseline and annually up to two years, SWIFT administered research 2-hour 75-gram oral glucose tolerance tests. Women who developed incident type 2 diabetes within four years of delivery (incident case group, n = 100) were pair-matched by age, race, and pre-pregnancy body mass index to those who remained free of diabetes for at least 8 years (control group, n = 100). Correlation analyses were used to assess and integrate relationships across profiling platforms. RESULTS: At baseline, all 200 women were free of diabetes. The case group was more likely to present with dysglycemia (e.g., impaired fasting glucose levels, glucose tolerance, or both). We also detected differences between groups across all omic platforms. Notably, protein profiles revealed an underlying inflammatory response with perturbations in protease inhibitors, coagulation components, extracellular matrix components, and lipoproteins, whereas metabolite and lipid profiles implicated disturbances in amino acids and triglycerides at individual and class levels with future progression. We identified significant correlations between profile features and fasting plasma insulin levels, but not with fasting glucose levels. Additionally, specific cross-omic relationships, particularly among proteins and lipids, were accentuated or activated in the case group but not the control group. CONCLUSIONS: Overall, we applied orthogonal, complementary profiling techniques to uncover an inflammatory response linked to elevated triglyceride levels shortly after a GDM pregnancy, which is more pronounced in women who progress to overt diabetes.

Low gestational weight gain (+2.0 to 4.9 kg) for singleton-term gestations associated with favorable perinatal outcomes for all prepregnancy obesity classes.

BACKGROUND: Previous studies that evaluated low gestational weight gain or weight loss among prepregnancy obesity classes have not determined the amount of gestational weight gain associated with the lowest risk of adverse perinatal outcomes and neonatal morbidity among singleton term births. OBJECTIVE: This study aimed to evaluate the relationship of specific gestational weight gain categories of weight loss, stable weight, and low gain considered below the 2009 Institute of Medicine guidelines to perinatal outcomes and neonatal morbidity for singleton, term live births among prepregnancy obesity classes. STUDY DESIGN: This was a retrospective cohort study of 18,476 women among 3 classes of prepregnancy obesity, based on measured prepregnancy weight, and delivering a live singleton pregnancy at ≥37 weeks of gestation at a Kaiser Permanente Northern California hospital (2009-2012). Variables from electronic medical records included perinatal outcomes, sociodemographics, and measured prepregnancy and delivery weights to calculate total gestational weight gain, used to define 5 gestational weight gain categories: weight loss (<-2.0 kg), stable weight (-2.0 to +1.9 kg), low gain (+2.0 to 4.9 kg), gain within guidelines (+5.0 to 9.1 kg; referent), and gain above guidelines (>9.1 kg). Logistic regression models estimated adjusted odds ratios and 95% confidence intervals of maternal and newborn perinatal outcomes (hypertensive disorders, cesarean delivery, size for gestational age, length of stay, neonatal intensive care unit admission) associated with gestational weight gain categories stratified by prepregnancy obesity classes 1, 2, and 3. RESULTS: Low gain occurred in 8%, 12%, and 13% of women in obesity class 1 (body mass index, 30.0-34.9), class 2 (body mass index, 35.0-39.9), and class 3 (body mass index, ≥40), respectively. Compared with gestational weight gain within Institute of Medicine guidelines, low gain was associated with similar or improved maternal and newborn perinatal outcomes for all obesity classes without increased odds of neonatal intensive care unit admission, neonatal length of stay ≥3 days, or small for gestational age. The percentages of small for gestational age for the low gain category were 4.4%, 3.0%, and 4.3% among prepregnancy obesity classes 1, 2, and 3, respectively, and comparable with the gestational weight gain within the guideline category (P>.05). The adjusted odds ratios of small-for-gestational age were not statistically significant for all obesity classes; class 1 (1.16; 95% confidence interval, 0.79-1.71) , class 2 (1.05; 95% confidence interval 0.58-1.93), and class 3 (2.03; 95% confidence interval 0.97-4.27). CONCLUSION: Lower gestational weight gain of +2.0 to 4.9 kg showed the most favorable perinatal outcomes, without higher small for gestational age or neonatal morbidity for all obesity classes.

metGWAS 1.0: an R workflow for network-driven over-representation analysis between independent metabolomic and meta-genome-wide association studies.

MOTIVATION: The method of genome-wide association studies (GWAS) and metabolomics combined provide an quantitative approach to pinpoint metabolic pathways and genes linked to specific diseases; however, such analyses require both genomics and metabolomics datasets from the same individuals/samples. In most cases, this approach is not feasible due to high costs, lack of technical infrastructure, unavailability of samples, and other factors. Therefore, an unmet need exists for a bioinformatics tool that can identify gene loci-associated polymorphic variants for metabolite alterations seen in disease states using standalone metabolomics. RESULTS: Here, we developed a bioinformatics tool, metGWAS 1.0, that integrates independent GWAS data from the GWAS database and standalone metabolomics data using a network-based systems biology approach to identify novel disease/trait-specific metabolite-gene associations. The tool was evaluated using standalone metabolomics datasets extracted from two metabolomics-GWAS case studies. It discovered both the observed and novel gene loci with known single nucleotide polymorphisms when compared to the original studies. AVAILABILITY AND IMPLEMENTATION: The developed metGWAS 1.0 framework is implemented in an R pipeline and available at: https://github.com/saifurbd28/metGWAS-1.0.

Associations of Physical Activity and Lactation Duration With Cardiometabolic Risk Factors: The CARDIA Study.

BACKGROUND: Physical activity (PA) and lactation benefit cardiometabolic health. OBJECTIVES: The purpose of this study was to describe the joint associations of PA and lactation with cardiometabolic risk. METHODS: We averaged PA across exams and summed lifetime lactation in Black and White parous women in the Coronary Artery Risk Development in Young Adults Study. Categories were created for PA (-PA:

Heterogeneity in Early Postpartum Metabolic Profiles Among Women with GDM Who Progressed to Type 2 Diabetes During 10-Year Follow-Up: The SWIFT Study.

GDM is a strong risk factor for progression to T2D after pregnancy. Although both GDM and T2D exhibit heterogeneity, the link between the distinct heterogeneity of GDM and incident T2D has not been established. Herein, we evaluate early postpartum profiles of women with recent GDM who later developed incident T2D using a soft clustering method, followed by the integration of both clinical phenotypic variables and metabolomics to characterize these heterogeneous clusters/groups clinically and their molecular mechanisms. We identified three clusters based on two indices of glucose homeostasis at 6-9 weeks postpartum - HOMA-IR and HOMA-B among women who developed incident T2D during the 12-year follow-up. The clusters were classified as follows: pancreatic beta-cell dysfunction group (cluster-1), insulin resistant group (cluster-3), and a combination of both phenomena (cluster-2) comprising the majority of T2D. We also identified postnatal blood test parameters to distinguish the three clusters for clinical testing. Moreover, we compared these three clusters in their metabolomics profiles at the early stage of the disease to identify the mechanistic insights. A significantly higher concentration of a metabolite at the early stage of a T2D cluster than other clusters indicates its essentiality for the particular disease character. As such, the early-stage characters of T2D cluster-1 pathology include a higher concentration of sphingolipids, acyl-alkyl phosphatidylcholines, lysophosphatidylcholines, and glycine, indicating their essentiality for pancreatic beta-cell function. In contrast, the early-stage characteristics of T2D cluster-3 pathology include a higher concentration of diacyl phosphatidylcholines, acyl-carnitines, isoleucine, and glutamate, indicating their essentiality for insulin actions. Notably, all these biomolecules are found in the T2D cluster-2 with mediocre concentrations, indicating a true nature of a mixed group. In conclusion, we have deconstructed incident T2D heterogeneity and identified three clusters with their clinical testing procedures and molecular mechanisms. This information will aid in adopting proper interventions using a precision medicine approach.

Early Pregnancy Systolic Blood Pressure Patterns Predict Early- and Later-Onset Preeclampsia and Gestational Hypertension Among Ostensibly Low-to-Moderate Risk Groups.

Background Clinical risk factors, a single blood pressure (BP) measurement, current biomarkers, and biophysical parameters can effectively identify risk of early-onset preeclampsia but have limited ability to predict later-onset preeclampsia and gestational hypertension. Clinical BP patterns hold promise to improve early risk stratification for hypertensive disorders of pregnancy. Methods and Results After excluding preexisting hypertension, heart, kidney, or liver disease, or prior preeclampsia, the retrospective cohort (n=249 892) all had systolic BP <140 mm Hg and diastolic BP <90 mm Hg or a single BP elevation ≤20 weeks' gestation, prenatal care at <14 weeks' gestation, and a still or live birth delivery at Kaiser Permanente Northern California hospitals (2009-2019). The sample was randomly split into development (N=174 925; 70%) and validation (n=74 967; 30%) data sets. Predictive performance of multinomial logistic regression models for early-onset (<34 weeks) preeclampsia, later-onset (≥34 weeks) preeclampsia, and gestational hypertension was evaluated in the validation data set. There were 1008 (0.4%), 10 766 (4.3%), and 11 514 (4.6%) patients with early-onset preeclampsia, later-onset preeclampsia, and gestation hypertension, respectively. Models with 6 systolic BP trajectory groups (0-20 weeks' gestation) plus standard clinical risk factors performed substantially better than risk factors alone to predict early- and later-onset preeclampsia and gestational hypertension, with C-statistics (95% CIs) of 0.747 (0.720-0.775), 0.730 (0.722-0.739), and 0.768 (0.761-0.776) versus 0.688 (0.659-0.717), 0.695 (0.686-0.704) and 0.692 (0.683-0.701), respectively, with excellent calibration (Hosmer-Lemeshow P=0.99, 0.99, and 0.74, respectively). Conclusions Early pregnancy BP patterns up to 20 weeks' gestation plus clinical, social, and behavioral factors more accurately discriminate hypertensive disorders of pregnancy risk among low-to-moderate risk pregnancies. Early pregnancy BP trajectories improve risk stratification to reveal higher-risk individuals hidden within ostensibly low-to-moderate risk groups and lower-risk individuals considered at higher risk by US Preventive Services Task Force criteria.

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.

Contribution of social, behavioral, and contextual exposures to Black-White disparities in incident obesity: The CARDIA study.

OBJECTIVE: The aim of this study was to quantify the contributions of socioeconomic, psychosocial, behavioral, reproductive, and neighborhood exposures in young adulthood to Black-White differences in incident obesity. METHODS: In the Coronary Artery Risk Development in Young Adults (CARDIA) study, 4488 Black or White adults aged 18 to 30 years without obesity at baseline (1985-1986) were followed over 30 years. Sex-specific Cox proportional hazard models were used to estimate Black-White differences in incident obesity. Models were adjusted for baseline and time-updated indicators. RESULTS: During follow-up, 1777 participants developed obesity. Black women were 1.87 (95% CI: 1.63-2.13) times more likely and Black men were 1.53 (95% CI: 1.32-1.77) times more likely to develop obesity than their White counterparts after adjusting for age, field center, and baseline BMI. Baseline exposures explained 43% of this difference in women and 52% in men. Time-updated exposures explained more of the racial difference in women but less for men, compared with baseline exposures. CONCLUSIONS: Adjusting for these exposures accounted for a substantial but incomplete proportion of racial disparities in incident obesity. Remaining differences may be explained by incomplete capture of the most salient aspects of these exposures or potential variation in the impact of these exposures on obesity by race.

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

The prospective association of hyperandrogenism, oligomenorrhea and polycystic ovary syndrome with incident gestational diabetes: The coronary artery risk development in young adults women's study.

In this 28-year prospective study of 455 women (mean age: 26 years), polycystic ovary syndrome (PCOS) was associated with a 2.6-fold elevated risk of gestational diabetes (GDM). However, hyperandrogenism or oligomenorrhea in the absence of PCOS was not associated with GDM.

Prepregnancy Protein Source and BCAA Intake Are Associated with Gestational Diabetes Mellitus in the CARDIA Study.

Diet quality and protein source are associated with type 2 diabetes, however relationships with GDM are less clear. This study aimed to determine whether prepregnancy diet quality and protein source are associated with gestational diabetes mellitus (GDM). Participants were 1314 Black and White women without diabetes, who had at least one birth during 25 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study. The CARDIA A Priori Diet Quality Score (APDQS) was assessed in the overall cohort at enrollment and again at Year 7. Protein source and branched-chain amino acid (BCAA) intake were assessed only at the Year 7 exam (n = 565). Logistic regression analysis was used to determine associations between prepregnancy dietary factors and GDM. Women who developed GDM (n = 161) were more likely to have prepregnancy obesity and a family history of diabetes (p < 0.05). GDM was not associated with prepregnancy diet quality at enrollment (Year 0) (odds ratio [OR]: 1.01; 95% confidence interval [CI] 0.99, 1.02) or Year 7 (odds ratio [OR]: 0.97; 95% confidence interval [CI] 0.94, 1.00) in an adjusted model. Conversely, BCAA intake (OR:1.59, 95% CI 1.03, 2.43) and animal protein intake (OR: 1.06, 95% CI 1.02, 1.10) as a proportion of total protein intake, were associated with increased odds of GDM, while proportion of plant protein was associated with decreased odds of GDM (OR: 0.95, 95% CI 0.91, 0.99). In conclusion, GDM is strongly associated with source of prepregnancy dietary protein intake but not APDQS in the CARDIA study.

Prolactin and Maternal Metabolism in Women With a Recent GDM Pregnancy and Links to Future T2D: The SWIFT Study.

CONTEXT: Prolactin is a multifaceted hormone known to regulate lactation. In women with gestational diabetes mellitus (GDM) history, intensive lactation has been associated with lower relative risk of future type 2 diabetes (T2D). However, the role of prolactin in T2D development and maternal metabolism in women with a recent GDM pregnancy has not been ascertained. OBJECTIVE: We examined the relationships among prolactin, future T2D risk, and key clinical and metabolic parameters. METHODS: We utilized a prospective GDM research cohort (the SWIFT study) and followed T2D onset by performing 2-hour 75-g research oral glucose tolerance test (OGTT) at study baseline (6-9 weeks postpartum) and again annually for 2 years, and also by retrieving clinical diagnoses of T2D from 2 years through 10 years of follow up from electronic medical records. Targeted metabolomics and lipidomics were applied on fasting plasma samples collected at study baseline from 2-hour 75-g research OGTTs in a nested case-control study (100 future incident T2D cases vs 100 no T2D controls). RESULTS: Decreasing prolactin quartiles were associated with increased future T2D risk (adjusted odds ratio 2.48; 95% CI, 0.81-7.58; P = 0.05). In women who maintained normoglycemia during the 10-year follow-up period, higher prolactin at baseline was associated with higher insulin sensitivity (P = 0.038) and HDL-cholesterol (P = 0.01), but lower BMI (P = 0.001) and leptin (P = 0.002). Remarkably, among women who developed future T2D, prolactin was not correlated with a favorable metabolic status (all P > 0.05). Metabolomics and lipidomics showed that lower circulating prolactin strongly correlated with a T2D-high risk lipid profile, with elevated circulating neutral lipids and lower concentrations of specific phospholipids/sphingolipids. CONCLUSION: In women with recent GDM pregnancy, low circulating prolactin is associated with specific clinical and metabolic parameters and lipid metabolites linked to a high risk of developing T2D.

Reduced cardiovascular risks in women with endometriosis or polycystic ovary syndrome carrying a common functional IGF1R variant.

STUDY QUESTION: Is the increased future cardiovascular risk seen in women with endometriosis or polycystic ovary syndrome (PCOS) mitigated by functional insulin-like growth factor-1 receptor (IGF1R) single-nucleotide polymorphism (SNP) rs2016347 as previously shown in women with hypertensive disorders of pregnancy? SUMMARY ANSWER: This cohort study found that women with endometriosis or PCOS who carry a T allele of IGF1R SNP rs2016347 had a reduced future risk of developing cardiovascular disease (CVD) and associated risk factors, with risk reduction dependent on cohort era. WHAT IS KNOWN ALREADY: Women with endometriosis or PCOS have been shown to have an increased future risk of CVD and associated risk factors with limited predictive ability. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study took place in the Nurses' Health Study 2 (NHS2), which enrolled 116 430 participants in 1989 who were followed through 2015. The study population was analyzed in its entirety, and subdivided into entry (pre-1989) and after entry (post-1989) exposure cohorts. All NHS2 participants were eligible for inclusion in the study, 9599 (8.2%) were excluded for missing covariates. PARTICIPANTS/MATERIALS, SETTING, METHODS: The NHS2 enrolled female registered nurses from 14 different states who ranged in age from 25 to 42 years at study entry. Data were collected from entry and biennial questionnaires, and analysis conducted from November 2020 to June 2021. Cox proportional hazard models were used to assess risk of CVD, hypertension (HTN), hypercholesterolemia (HC) and type 2 diabetes, both with and without genotyping for rs2016347. MAIN RESULTS AND THE ROLE OF CHANCE: While women without endometriosis or PCOS, as a whole, demonstrated no impact of genotype on risk in either cohort, women with endometriosis carrying a T allele had a lower risk of CVD (hazard ratio (HR), 0.48; 95% CI, 0.27-0.86, P = 0.02) and HTN (HR, 0.80; 95% CI, 0.66-0.97, P = 0.03) in the pre-1989 cohort, while those in the post-1989 cohort had a decrease in risk for HC (HR, 0.76; 95% CI, 0.62-0.94, P = 0.01). Women with PCOS in the post-1989 cohort showed a significant protective impact of the T allele on HTN (HR, 0.44; 95% CI, 0.27-0.73, P = 0.002) and HC (HR, 0.62; 95% CI, 0.40-0.95, P = 0.03). LIMITATIONS, REASONS FOR CAUTION: Data on specific endometriosis lesion locations or disease stage, as well as on PCOS phenotypes were lacking. In addition, data on systemic medical treatments beyond the use of oral contraceptives were missing, and these treatments may have confounded the results. WIDER IMPLICATIONS OF THE FINDINGS: These findings implicate systemic dysregulation of the insulin-like growth factor-1 axis in the development of HTN, HC and clinical CVD in endometriosis and PCOS, suggesting a common underlying pathogenetic mechanism. STUDY FUNDING/COMPETING INTEREST(S): The NHS2 infrastructure for questionnaire data collection was supported by National Institute of Health (NIH) grant U01CA176726. This work was also supported in part by NIH and National Cancer Institute grant U24CA210990; as well, research effort and publication costs were supported by the Elizabeth MA Stevens donor funds provided to the Buck Institute for Research on Aging. The authors declare they have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.