The ATP-binding cassette proteins ABCB1 and ABCC1 as modulators of glucocorticoid action.

Responses to hormones that act through nuclear receptors are controlled by modulating hormone concentrations not only in the circulation but also within target tissues. The role of enzymes that amplify or reduce local hormone concentrations is well established for glucocorticoid and other lipophilic hormones; moreover, transmembrane transporters have proven critical in determining tissue responses to thyroid hormones. However, there has been less consideration of the role of transmembrane transport for steroid hormones. ATP-binding cassette (ABC) proteins were first shown to influence the accumulation of glucocorticoids in cells almost three decades ago, but observations over the past 10 years suggest that differential transport propensities of both exogenous and endogenous glucocorticoids by ABCB1 and ABCC1 transporters provide a mechanism whereby different tissues are preferentially sensitive to different steroids. This Review summarizes this evidence and the new insights provided for the physiology and pharmacology of glucocorticoid action, including new approaches to glucocorticoid replacement.

Development of type 2 diabetes in women with comorbid gestational diabetes and common mental disorders in the Born in Bradford cohort.

OBJECTIVES: To compare, in a population of women with gestational diabetes mellitus (GDM), the time to diagnosis of Type 2 diabetes in those with and without common mental disorder (CMD) (depression and/or anxiety) during pregnancy. DESIGN AND SETTING: prospective study of the Born in Bradford cohort in Bradford, UK. PARTICIPANTS: 909 women diagnosed with GDM between 2007 and 2010, with linkage to their primary care records until 2017. The exposed population were women with an indicator of CMD during pregnancy in primary care records. The unexposed were those without an indicator. OUTCOME MEASURES: Time to diagnosis of type 2 diabetes as indicated by a diagnosis in primary care records. ANALYSIS: time to event analysis using Cox regression was employed. Multiple imputation by chained equations was implemented to handle missing data. Models were adjusted for maternal age, ethnicity, education, preconception CMD and tobacco smoking during pregnancy. RESULTS: 165 women (18%) were diagnosed with type 2 diabetes over a follow-up period of around 10 years. There was no evidence of an effect of antenatal CMD on the development of type 2 diabetes following GDM (adjusted HR 0.95; 95% CI 0.57 to 1.57). CONCLUSIONS: Women with CMD were not at an increased risk of type 2 diabetes following GDM. This is reassuring for women with these co-morbidities but requires replication in other study populations.

Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in type 2 diabetes: The Edinburgh Type 2 Diabetes Study.

BACKGROUND: Type 2 diabetes (T2D) is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). However, the absolute risk of progression is low. So, it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk-stratification tools are suboptimal and perform worse in people with diabetes. AIMS: To determine whether the addition of complementary biomarker(s) to current NAFLD risk-stratification tools in people with T2D could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC. METHODS: The Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with T2D (n = 1066, age 60-75 at baseline). Cases of cirrhosis and HCC were identified over 11 years of follow-up. Biomarkers were measured at baseline and year 1 and association with incident disease was assessed using logistic regression. RESULTS: Of existing risk-stratification scores tested, the Fibrosis-4 (FIB-4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut-point ≥ 50  µ  g/L) to FIB-4 (cut-point ≥ 1.3) maintained a false negative rate of ≤25% and reduced the number of people incorrectly identified as "high risk" for incident disease by ∼50%. CONCLUSIONS: The addition of hyaluronic acid to FIB-4 reduced the proportion of people inappropriately identified as "high risk" for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with T2D. These findings require a validation in independent cohorts.

Reproductive and metabolic adaptation to multistressor training in women.

Hypothalamic-pituitary-gonadal (HPG) axis suppression in exercising women can be caused by low energy availability (EA), but the impact of a real-world, multistressor training environment on reproductive and metabolic function is unknown. This study aimed to characterize reproductive and metabolic adaptation in women undertaking basic military training. A prospective cohort study in women undertaking 11-month initial military training (n = 47) was carried out. Dynamic low-dose 1-h gonadotrophin-releasing hormone (GnRH) tests were completed after 0 and 7 mo of training. Urine progesterone was sampled weekly throughout. Body composition (dual X-ray absorptiometry), fasting insulin resistance (homeostatic modeling assessment 2, HOMA2), leptin, sex steroids, anti-Müllerian hormone (AMH), and inhibin B were measured after 0, 7, and 11 mo with an additional assessment of body composition at 3 mo. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses were suppressed after 7 mo (both P < 0.001). Among noncontraceptive users (n = 20), 65% had regular (23-35 days) cycles preenrollment, falling to 24% by 7 mo of training. Of women in whom urine progesterone was measured (n = 24), 87% of cycles showed no evidence of ovulation. There was little change in AMH, LH, and estradiol, although inhibin B and FSH increased (P < 0.05). Fat mass fluctuated during training but at month 11 was unchanged from baseline. Fat-free mass did not change. Visceral adiposity, HOMA2, and leptin increased (all P < 0.001). HPG axis suppression with anovulation occurred in response to training without evidence of low EA. Increased insulin resistance may have contributed to the observed pituitary and ovarian dysfunction. Our findings are likely to represent an adaptive response of reproductive function to the multistressor nature of military training.NEW & NOTEWORTHY We characterized reproductive endocrine adaptation to prolonged arduous multistressor training in women. We identified marked suppression of hypothalamic-pituitary-gonadal (HPG) axis function during training but found no evidence of low energy availability despite high energy requirements. Our findings suggest a complex interplay of psychological and environmental stressors with suppression of the HPG axis via activation of the hypothalamic-pituitary adrenal (HPA) axis. The neuroendocrine impact of nonexercise stressors on the HPG axis during arduous training should be considered.

First and second pregnancy outcomes in women with class III obesity: An observational cohort study.

INTRODUCTION: Class III obesity (BMI ≥ 40 kg/m2) during pregnancy predisposes mother and offspring to a range of adverse pregnancy complications and outcomes. Risk profiles vary between pregnancies and are affected by interpregnancy weight gain. We evaluated the risk of adverse outcomes in women with BMI ≥ 40 kg/m2 in first and second pregnancies, and the impact of interpregnancy weight change on this risk. MATERIALS AND METHODS: Data were extracted for all women with BMI ≥ 40 kg/m2 at first antenatal visit, who completed antenatal and delivery care for first and second pregnancies in NHS Lothian between 1/1/2009-31/12/2018. Multiple pregnancies and recipients of bariatric surgery were excluded. RESULTS: 442 pregnancies among 221 women were included. In first pregnancy, median (interquartile range) weight was 117 kg (108.5-126.7), age 28 years (24-31) and BMI 42 kg/m2 (41.0-44.5), 14.4% had gestational diabetes (GDM), 11.3% had pregnancy-induced hypertension and 44.6% had a post-partum haemorrhage (PPH). 20.8% of babies were large for gestational age (LGA, ≥97% centile at birth). In second pregnancy, women were heavier with a median weight of 119.9 kg (109.0-130.0, p = 0.00) with 19.9% gaining over 10 kg. Women were more likely to develop GDM (21.6%, p = 0.02). Babies were heavier with 40% of babies LGA (p < 0.0001). Interpregnancy weight change had no significant impact on GDM, pregnancy induced hypertension, PPH, perinatal mortality or LGA. CONCLUSIONS: In a population of women with BMI ≥ 40 kg/m2, pregnancy complications are common and risk is higher in second pregnancy. The interpregnancy period is a critical time to engage women in health improvement and weight loss strategies to maximise outcomes for mother and offspring.

Glucagon-Like Peptide 1 Receptor Agonist (GLP1RA) Exposure and Outcomes in Type 2 Diabetes: A Systematic Review of Population-Based Observational Studies.

INTRODUCTION: Glucagon-like peptide 1 receptor agonists (GLP1RAs) are licensed for the treatment of type 2 diabetes (T2D). They have been shown to be safe (from the cardiovascular (CV) perspective) and effective (in terms of glycaemia, and in some cases, reducing CV events) in extensive randomised controlled trials (RCTs). However, there remain concerns regarding the generalisability of these findings (to those ineligible for RCT participation) and about non-CV safety. For effectiveness, population-based pharmacoepidemiology studies can confirm and extend the findings of RCTs findings to broader populations and explore safety, for which RCTs are not usually powered, in more detail. METHOD: We did a pre-planned and registered (PROSPERO registration CRD42020165720) systematic review of population-based studies investigating GLP1RA effectiveness and safety, following Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. RESULTS: A total of 22 studies were identified (including 200,148 participants and 396,457 person-years of follow-up) exploring exposure to GLP1RA class, exenatide and liraglutide (the only individual drugs with treatment effect estimates identified) on mortality, cardiovascular disease (CVD), acute pancreatitis (AP), pancreatic cancer (PC), thyroid cancer (TC), acute renal failure (ARF), diabetic retinopathy (DR), breast cancer (BC) and hypoglycaemia. For CV and mortality outcomes, studies confirmed the associated safety of these drugs. For liraglutide, point estimate (PE) range (PER) major adverse cardiovascular events (MACE) (0.53-0.95) and PER heart failure (0.34-1.22) were similar in direction to the beneficial effect observed in RCTs for MACE but varied widely for heart failure. For safety outcomes, exposure was not associated with AP (PER 0.50-1.17), PC (PER 0.40-1.54), BC (PER 0.90-1.51) or hypoglycaemia (PER 0.59-1.06). Only one study was identified exploring each of TC (no evidence of association, hazard ratio (HR) 1.46, 95% confidence interval (CI) 0.98-2.19), renal outcomes (no evidence of association, HR 0.77, 95% CI 0.42-1.41) and DR (no evidence of association, HR 0.67, 95% CI 0.51-0.90). CONCLUSION: In T2D, GLP1RAs appear safe from the CV perspective and (for liraglutide) may have associated benefit in primary as well as secondary CVD prevention. For non-CV safety, GLP1RA exposure was not associated with an increased risk of AP, PC, BC or hypoglycaemia; the other outcomes had too few studies to draw firm conclusions and should be explored further.

Is there an association between anxiety and depression prior to and during pregnancy and gestational diabetes? An analysis of the Born in Bradford cohort.

BACKGROUND: anxiety and depression are common in women with gestational diabetes but it is not clear whether they are more likely to precede the onset of gestational diabetes or to co-occur with it. Our aims were to compare the strength of association between common mental disorders of anxiety and depression (i) before pregnancy and (ii) during pregnancy in women with and without gestational diabetes. METHODS: the sample comprised 12,239 women with 13,539 pregnancies from the UK's Born in Bradford cohort. Gestational diabetes was diagnosed by oral glucose tolerance test (OGTT). Indicators of common mental disorders were obtained from linked primary care records. Multivariable robust Poisson and logistic regression were employed. Multiple imputation by chained equations was implemented to handle missing data. Models were adjusted for maternal age, ethnicity, education and obstetric complications. Analyses of common mental disorders during pregnancy were additionally adjusted for maternal smoking, pre-pregnancy BMI, multiple pregnancy and common mental disorders prior to pregnancy. RESULTS: there was no evidence for an association between common mental disorders prior to pregnancy and gestational diabetes (adjusted RR 0.96; 95% CI 0.80,1.15) or between gestational diabetes and common mental disorders during pregnancy (adjusted OR 0.91; 95% CI 0.73,1.12). LIMITATIONS: high levels of deprivation and multi-ethnic composition of the cohort may limit generalisability of these findings to other populations. CONCLUSIONS: routine primary care records did not identify an increased risk of gestational diabetes in women with common mental disorders prior to pregnancy or of gestational diabetes in women with common mental disorders during pregnancy.

Non-invasive risk scores do not reliably identify future cirrhosis or hepatocellular carcinoma in Type 2 diabetes: The Edinburgh type 2 diabetes study.

BACKGROUND: The incidence of cirrhosis and hepatocellular carcinoma (HCC) is increased in Type 2 diabetes, primarily secondary to non-alcoholic fatty liver disease (NAFLD). European guidelines recommend screening for NAFLD in Type 2 diabetes. American guidelines, while not advocating a screening protocol, suggest using non-invasive markers of fibrosis for risk-stratification and guiding onward referral. AIMS: To test the ability of individual fibrosis scores and the European screening algorithm to predict 11-year incident cirrhosis/HCC in an asymptomatic community cohort of older people with Type 2 diabetes. METHODS: The Edinburgh Type 2 Diabetes Study investigated men and women with Type 2 diabetes (n = 1066, aged 60-75 at baseline). Liver markers were measured at baseline and year 1; steatosis and fibrosis markers were calculated according to independently published calculations. During 11 years of follow-up, cases of cirrhosis and HCC were identified. RESULTS: Forty-three out of 1059 participants with no baseline cirrhosis/HCC developed incident disease. All scores were significantly associated with incident liver disease by odds ratio (P < .05). The ability of the risk-stratification tools to accurately identify those who developed incident cirrhosis/HCC was poor with low-positive predictive values (5-46%) and high false-negative and -positive rates (up to 60% and 77%) respectively. When fibrosis risk scores were used in conjunction with the European algorithm, they performed modestly better than when applied in isolation. CONCLUSIONS: In a cohort with a moderately low incidence of cirrhosis/HCC, existing risk scores did not reliably identify participants at high risk. Better prediction models for cirrhosis/HCC in people with Type 2 diabetes are required.

Morning plasma cortisol as a cardiovascular risk factor: findings from prospective cohort and Mendelian randomization studies.

OBJECTIVE: The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD). DESIGN AND METHODS: Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses). RESULTS: In the two prospective nested case-control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06-1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06-1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98-1.15. CONCLUSIONS: All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.

Predictors of surgical site skin infection and clinical outcome at caesarean section in the very severely obese: A retrospective cohort study.

INTRODUCTION: The optimal surgical approach for caesarean section is uncertain in women with very severe obesity (body mass index (BMI) >40kg/m2). We aimed to assess maternal and surgical predictors of surgical site skin infection (SSSI) in very severely obese women and to undertake an exploratory evaluation of clinical outcomes in women with a supra-panniculus transverse compared to an infra-panniculus transverse skin incision. MATERIAL AND METHODS: Using a retrospective cohort design, case-records were reviewed of very severely obese women with a singleton pregnancy delivered by caesarean between August 2011 and December 2015 (n = 453) in two maternity hospitals in Scotland. Logistic regression analysis was used to determine predictors for SSSI. Outcomes were compared between women who had a supra-panniculus transverse compared to infra-panniculus transverse skin incision. RESULTS: Lower maternal age was predictive of SSSI, with current smoking status and longer wound open times being marginally significant. Maternal BMI, suture method and material demonstrated univariate associations with SSSI but were not independent predictors. Women with a supra-panniculus transverse skin incision were older (32.9 (4.4), vs. 30.6 (5.7), p = 0.002), had higher BMI (49.2 (7.1), vs. 43.3 (3.3), p<0.001), shorter gestation at delivery (days) (267.7 (14.9), vs. 274.8 (14.5), p<0.001) and higher prevalence of gestational diabetes mellitus (42.6% vs. 21.9%, p = 0.002). SSSI rates did not differ between supra-panniculus transverse (13/47; 27.7%) and infra-panniculus transverse (90/406; 22.2%; p = 0.395) skin incisions. CONCLUSION: SSSI rates are high in very severely obese women following caesarean section, regardless of location of skin incision.

Early screening and treatment of gestational diabetes in high-risk women improves maternal and neonatal outcomes: A retrospective clinical audit.

AIMS: Evidence suggests that screening for gestational diabetes (GDM) occurs too late in pregnancy, when changes in glucose metabolism and fetal growth rates can already be detected. In August 2016 NHS Lothian began screening women with risk factors for GDM during early pregnancy (11-13 weeks). We hypothesised that an earlier identification and treatment of dysglycaemia would improve pregnancy outcomes compared to previous standard care. METHODS: We compared management and outcomes for singleton pregnancies with GDM delivering at Royal Infirmary Edinburgh, UK, diagnosed through routine or early screening from 01/01/2015-31/10/2017 (routine screening n = 335, early screening n = 241). RESULTS: Early screening increased the proportion of women diagnosed before 24 weeks' gestation (n = 59/335, 17.6% vs n = 103/241, 42.7%, p < 0.001) but did not change the average monthly rate of diagnosis. Early screening increased the median duration of GDM during pregnancy (71 vs 93 days of gestation, p < 0.001) with no significant changes in the pharmacological management. Early screening improved the primary composite outcome (emergency caesarean section, neonatal hypoglycaemia and macrosomia; n = 138/335, 41.2% vs n = 73/241, 30.3%, adjusted Odds Ratio [95% confidence interval] 0.62 [0.43-0.91]. CONCLUSIONS: There is a role for early screening and management of GDM however it is unclear whether this represents a cost-effective intervention.

Determinants of cortisol during pregnancy - The ABCD cohort.

BACKGROUND: Psychosocial stress during pregnancy has been proposed as a major contributor of glucocorticoid-mediated programming of the fetal hypothalamic-pituitary adrenal (HPA) axis, with later adverse health consequences. However, evidence linking maternal stress to maternal cortisol values during pregnancy is inconclusive. A possible explanation for this is that other maternal factors overshadow any potential effects of stress on cortisol levels. We studied a large cohort of pregnant women with extensive data on pregnancy characteristics to determine the respective contributions of biological, environmental and psychosocial stress factors to cortisol levels in pregnancy. METHODS: We used data from 3039 women from the Amsterdam Born Children and their Development-study cohort. Serum cortisol was measured in blood, collected at the first prenatal visit, at different gestational ages (median=91days, range=40-256days), and at various time points during the day (median=11:45h, range=08:00-18:30h). We assessed associations between maternal serum cortisol in pregnancy and biological factors, lifestyle factors and stress factors, including depression, anxiety, pregnancy-related anxiety, work stress, parenting stress and fatigue. RESULTS: In multivariable analysis, variables that were associated with higher cortisol levels in pregnancy were lower maternal age [1.5nmol/l, 95%CI (0.6-2.4)], being nulliparous [21.5 nmol/l (15.9-27.1)], lower pre-pregnancy body mass index (BMI) [1.3nmol/l (0.3-2.4)], higher C-reactive protein (CRP) [1.0nmol/l (0.4-1.5)], carrying a female fetus [9.2nmol/l (1.8-16.5)], non-smoking [14.2nmol/l (0.6-27.7)], sufficient sleep [8.5nmol/l (0.9-16.1)], and being unemployed [12.7nmol/l (2.2-23.2)]. None of the psychosocial stressors was significantly associated with serum cortisol levels in pregnancy. A total of 32% of all variance in cortisol was explained by gestational age, maternal age, time of day, parity, pre-pregnancy BMI, CRP, fetal sex, smoking behavior, self-reported sleep sufficiency, and employment. CONCLUSIONS: Our data suggest that maternal cortisol during pregnancy is mainly affected by biological and lifestyle factors, but not by psychosocial factors. We suggest that psychosocial stress in pregnancy might program the fetus through other mechanisms than through altering maternal cortisol levels.

Dynamic Changes in DNA Methylation Occur during the First Year of Life in Preterm Infants.

BACKGROUND: Preterm birth associates with a substantially increased risk of later cardiovascular disease and neurodevelopmental disorders. Understanding underlying mechanisms will facilitate the development of screening and intervention strategies to reduce disease risk. Changes in DNA methylation have been proposed as one mechanism linking the early environment with later disease risk. We tested the hypothesis that preterm birth associates with altered DNA methylation in genes encoding insulin-like growth factor 2 (IGF2) and FK506-binding protein 5 (FKBP5), which appear particularly vulnerable to early life adversity. METHODS: Fifty preterm infants were seen and assessed at birth, term equivalent age, 3 months and 1-year corrected ages; 40 term infants were seen at birth, 3 months and 1 year. Saliva was collected for DNA extraction at birth, term, and 1 year. Pyrosequencing of bisulfite-converted DNA was performed to measure DNA methylation at specific CpG sites within the IGF2 and FKBP5 loci. RESULTS: Weight and head circumference was reduced in preterm infants at all time points. Preterm infants had a higher percentage body fat at term-corrected age, but this difference was not persistent. DNA methylation at the differentially methylated region (DMR) of IGF2 (IGF2DMR2) and FKBP5 was lower in preterm infants at birth- and term-corrected age compared to term infants at birth. IGF2DMR2 and FKBP5 methylation was related to birthweight SD score in preterm infants. Among preterm infants, social deprivation was an independent contributor toward reducing DNA methylation at IGF2DMR2 at birth- and term-corrected age and maternal smoking was associated with reduced DNA methylation at FKBP5 at birth. There were no persistent differences in DNA methylation at 1 year of age. CONCLUSION: Changes in DNA methylation were identified at key regions of IGF2/H19 and FKBP5 in preterm infants in early life. Potential contributing factors include maternal smoking and social deprivation. However, these changes did not persist at 1 year of age and further longitudinal studies are required to determine any associations between altered DNA methylation in the perinatal period of individuals born preterm and their long-term health.

ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.

The aim of treatment in congenital adrenal hyperplasia is to suppress excess adrenal androgens while achieving physiological glucocorticoid replacement. However, current glucocorticoid replacement regimes are inadequate because doses sufficient to suppress excess androgens almost invariably induce adverse metabolic effects. Although both cortisol and corticosterone are glucocorticoids that circulate in human plasma, any physiological role for corticosterone has been neglected. In the brain, the adenosine 5'-triphosphate-binding cassette transporter ABCB1 exports cortisol but not corticosterone. Conversely, ABCC1 exports corticosterone but not cortisol. We show that ABCC1, but not ABCB1, is expressed in human adipose and that ABCC1 inhibition increases intracellular corticosterone, but not cortisol, and induces glucocorticoid-responsive gene transcription in human adipocytes. Both C57Bl/6 mice treated with the ABCC1 inhibitor probenecid and FVB mice with deletion of Abcc1 accumulated more corticosterone than cortisol in adipose after adrenalectomy and corticosteroid infusion. This accumulation was sufficient to increase glucocorticoid-responsive adipose transcript expression. In human adipose tissue, tissue corticosterone concentrations were consistently low, and ABCC1 mRNA was up-regulated in obesity. To test the hypothesis that corticosterone effectively suppresses adrenocorticotropic hormone (ACTH) without the metabolic adverse effects of cortisol, we infused cortisol or corticosterone in patients with Addison's disease. ACTH suppression was similar, but subcutaneous adipose transcripts of glucocorticoid-responsive genes were higher after infusion with cortisol rather than with corticosterone. These data indicate that corticosterone may be a metabolically favorable alternative to cortisol for glucocorticoid replacement therapy when ACTH suppression is desirable, as in congenital adrenal hyperplasia, and justify development of a pharmaceutical preparation.

Decreased maternal hypothalamic-pituitary-adrenal axis activity in very severely obese pregnancy: Associations with birthweight and gestation at delivery.

BACKGROUND: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. METHOD: Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. RESULTS: Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation). CONCLUSION: In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy.

Health Behaviours during Pregnancy in Women with Very Severe Obesity.

The health behaviours of pregnant women with very severe obesity are not known, though these women are at high risk of pregnancy complications. We carried out a prospective case-control study including 148 very severely obese (BMI >40 kg/m²) and 93 lean (BMI <25 kg/m²) pregnant women. Diet, physical activity, smoking, alcohol and folic acid consumption were assessed by questionnaire in early and late (16 and 28 weeks gestation) pregnancy. Circulating levels of iron, vitamin B12 and folate and other essential trace elements and minerals were measured in a subset at each time point. The findings biochemically confirmed that very severely obese women consumed diets that were energy-rich but poor in essential micronutrients. A third of all women met physical activity recommendations for pregnancy. A third of very severely obese women and two thirds of lean women took folic acid supplements prior to pregnancy. Very severely obese women were more likely to smoke but less likely to drink alcohol than lean women (all p < 0.05). Women with very severe obesity have low self-reported intakes and circulating levels of essential micronutrients in pregnancy and few follow current recommendations for pregnancy nutrition and lifestyle. These high-risk women represent a group to target for education about health behaviours prior to and during pregnancy.

Maternal Obesity During Pregnancy Associates With Premature Mortality and Major Cardiovascular Events in Later Life.

One in 5 pregnant women is obese but the impact on later health is unknown. We aimed to determine whether maternal obesity during pregnancy associates with increased premature mortality and later life major cardiovascular events. Maternity records of women who gave birth to their first child between 1950 and 1976 (n=18 873) from the Aberdeen Maternity and Neonatal databank were linked to the National Register of Deaths, Scotland and Scottish Morbidity Record. The effect of maternal obesity at first antenatal visit on death and hospital admissions for cardiovascular events was tested using time-to-event analysis with Cox proportional hazard regression to compare outcomes of mothers in underweight, overweight, or obese body mass index (BMI) categories compared with normal BMI. Median follow-up was at 73 years. All-cause mortality was increased in women who were obese during pregnancy (BMI>30 kg/m(2)) versus normal BMI after adjustment for socioeconomic status, smoking, gestation at BMI measurement, preeclampsia, and low birth weight (hazard ratio, 1.35; 95% confidence interval, 1.02-1.77). In adjusted models, overweight and obese mothers had increased risk of hospital admission for a cardiovascular event (1.16; 1.06-1.27 and 1.26; 1.01-1.57) compared with normal BMI mothers. Adjustment for parity largely unchanged the hazard ratios (mortality: 1.43, 1.09-1.88; cardiovascular events overweight: 1.17, 1.07-1.29; and obese: 1.30, 1.04-1.62). In conclusion, maternal obesity is associated with increased risk of premature death and cardiovascular disease. Pregnancy and early postpartum could represent an opportunity for interventions to identify obesity and reduce its adverse consequences.

Sex-Differences in the Metabolic Health of Offspring of Parents with Diabetes: A Record-Linkage Study.

Maternal diabetes in pregnancy affects offspring health. The impact of parental diabetes on offspring health is unclear. We investigated the impact of parental diabetes on the metabolic-health of adult-offspring who did not themselves have diabetes. Data from the Generation Scotland: Scottish Family Health Study, a population-based family cohort, were record-linked to subjects' own diabetes medical records. From F0-parents, we identified F1-offspring of: mothers with diabetes (OMD, n = 409), fathers with diabetes (OFD, n = 468), no parent with diabetes (ONoPD, n = 2489). Metabolic syndrome, body, biochemical measurements and blood-pressures were compared between F1-offspring groups by sex. A higher proportion of female OMD had metabolic syndrome than female OFD or ONoPD (P<0.0001). In female offspring, predictors of metabolic syndrome were: having a mother with diabetes (OR = 1.78, CI 1.03-3.07, [reference ONoPD]), body mass index (BMI, OR = 1.21, CI 1.13-1.30) and age (OR = 1.03, CI 1.01-1.06). In male offspring, predictors of metabolic syndrome were: BMI (OR = 1.18, CI 1.09-1.29) and percent body-fat (OR = 1.12, CI 1.05-1.19). In both sexes, OMD had higher blood-pressures than OFD (P<0.0001). In females, OMD had higher glucose (P<0.0001) and percent body-fat (P<0.0001) compared with OFD or ONoPD. OMD and OFD both had increased waist-measurements (P<0.0001), BMI (P<0.0001) and percent body-fat (P<0.0001) compared with ONoPD. Female OMD and OFD had lower HDL-cholesterol levels (P<0.0001) than female ONoPD. Parental diabetes is associated with higher offspring-BMI and body-fat. In female offspring, maternal diabetes increased the odds of metabolic syndrome, even after adjusting for BMI. Further investigations are required to determine the mechanisms involved.

Screening and management of gestational diabetes mellitus in Scottish obstetric units: a national survey.

BACKGROUND AND AIMS: The last study of screening practices for gestational diabetes (GDM) in the UK concluded that a lack of consensus about screening was due to a lack of clinical guidelines. We aimed to determine current practices in Scotland since new guidelines recommended that diagnosis should be made at a lower level of hyperglycaemia. METHOD AND RESULTS: An online questionnaire designed to investigate the screening and management of GDM was distributed to all maternity units in Scotland managing women with GDM (n = 15) for completion by relevant clinical team members. The response rate was 100%. Considerable variation in clinical practice existed between units. Thirteen units (86.7%) had adopted the lower glucose tolerance values for diagnosis of GDM (fasting ≥5.1 mmol/L; 2-h ≥8.5 mmol/L) recommended by the Scottish Intercollegiate Guidelines Network in 2010. Available data from units using this guideline (n = 3) revealed a significant increase in the percentage of women diagnosed with GDM between 2010 and 2012 (2010: 1.28%, 2012: 2.54%; p < 0.0001). CONCLUSION: Despite provision of clinical guidelines, there are still inconsistencies in screening and management of GDM in Scotland. If a similar increase in the prevalence of GDM is experienced across Scotland, there will be major implications for health care provision and resource allocation.

Unhealthy lifestyle in early psychoses: the role of life stress and the hypothalamic-pituitary-adrenal axis.

An unhealthy lifestyle is thought to contribute to the metabolic syndrome in subjects with psychoses. In the present study we aimed to study whether life stress or cortisol measures may influence dietary patterns in subjects with early stages of psychoses. We studied 81 subjects with early psychoses (65 subjects with a psychotic disorder [PD] and <5 years of illness; 16 subjects at risk for psychosis [high-risk, HR]) and a control group of 25 healthy subjects (HS). Dietary habits were examined by a dietician, who registered food intake (24h recall). Physical activity was assessed by validated questionnaire. Life stress was assessed with Holmes-Rahe Social Readjustment Scale. Fasting morning salivary and plasma cortisol levels were determined. We found that PD and HR reported an unhealthier lifestyle with more smoking, reduced physical activity and poorer dietary habits. HR reported increased intake of calories and saturated fatty acids and reduced protein consumption, when compared to HS. Life stress was a predictor of these adverse behaviours, although we found opposite associations in HR and PD. Life stress was associated with increased intake of refined sugar in PD and decreased intake in HR and HS. Salivary cortisol was related to increased intake of saturated fat only in HR subjects, but cortisol levels in plasma or saliva were not associated with other dietary habits or obesity measures (BMI, waist circumference). Our study suggests that unhealthy diet in early psychoses is influenced by stress, but our data do not support this effect being mediated by hypercortisolism. Future preventive interventions in psychosis may target dietary habits, particularly for those who are at risk for psychosis.