Exploring Structural Uncertainty in Cost-Effectiveness Modeling of Gestational Diabetes Screening: An Application Example from Norway.

BACKGROUND: Screening pregnant women for gestational diabetes mellitus (GDM) has recently been expanded in Norway, although screening eligibility criteria continue to be debated. We aimed to compare the cost-effectiveness of alternative GDM screening strategies and explored structural uncertainty and the value of future research in determining the most cost-effective eligibility criteria for GDM screening in Norway. DESIGN: We developed a probabilistic decision tree to estimate the total costs and health benefits (i.e., quality-adjusted life-years; QALYs) associated with 4 GDM screening strategies (universal, current guidelines, high-risk, and no screening). We identified the most cost-effective strategy as the strategy with the highest incremental cost-effectiveness ratio below a Norwegian benchmark for cost-effectiveness ($28,400/QALY). We excluded inconclusive evidence on the effects of screening on later maternal type 2 diabetes mellitus (T2DM) in the primary analysis but included this outcome in a secondary analysis using 2 different sources of evidence (i.e., Cochrane or US Preventive Services Task Force). To quantify decision uncertainty, we conducted scenario analysis and value-of-information analyses. RESULTS: Current screening recommendations were considered inefficient in all analyses, while universal screening was most cost-effective in our primary analysis ($26,014/QALY gained) and remained most cost-effective when we assumed a preventive effect of GDM treatment on T2DM. When we assumed no preventive effect, high-risk screening was preferred ($19,115/QALY gained). When we assumed GDM screening does not prevent perinatal death in scenario analysis, all strategies except no screening exceeded the cost-effectiveness benchmark. In most analyses, decision uncertainty was high. CONCLUSIONS: The most cost-effective screening strategy, ranging from no screening to universal screening, depended on the source and inclusion of GDM treatment effects on perinatal death and T2DM. Further research on these long-term outcomes could reduce decision uncertainty. HIGHLIGHTS: This article analyses the cost-effectiveness of 4 alternative gestational diabetes mellitus (GDM) screening strategies in Norway: universal screening, current (broad) screening, high-risk screening, and no screening.The current Norwegian screening recommendations were considered inefficient under all analyses.The most cost-effective screening strategy ranged from no screening to universal screening depending on the source and inclusion of GDM treatment effects on later maternal diabetes and perinatal death.The parameters related to later maternal diabetes and perinatal death accounted for most of the decision uncertainty.

DNA methylation risk score for type 2 diabetes is associated with gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share many pathophysiological factors including genetics, but whether epigenetic marks are shared is unknown. We aimed to test whether a DNA methylation risk score (MRS) for T2DM was associated with GDM across ancestry and GDM criteria. METHODS: In two independent pregnancy cohorts, EPIPREG (n = 480) and EPIDG (n = 32), DNA methylation in peripheral blood leukocytes was measured at a gestational age of 28 ± 2. We constructed an MRS in EPIPREG and EPIDG based on CpG hits from a published epigenome-wide association study (EWAS) of T2DM. RESULTS: With mixed models logistic regression of EPIPREG and EPIDG, MRS for T2DM was associated with GDM: odd ratio (OR)[95% CI]: 1.3 [1.1-1.8], P = 0.002 for the unadjusted model, and 1.4 [1.1-1.7], P = 0.00014 for a model adjusted by age, pre-pregnant BMI, family history of diabetes and smoking status. Also, we found 6 CpGs through a meta-analysis (cg14020176, cg22650271, cg14870271, cg27243685, cg06378491, cg25130381) associated with GDM, and some of their methylation quantitative loci (mQTLs) were related to T2DM and GDM. CONCLUSION: For the first time, we show that DNA methylation marks for T2DM are also associated with GDM, suggesting shared epigenetic mechanisms between GDM and T2DM.

Placental weight, surface area, shape and thickness - Relations with maternal ethnicity and cardio-metabolic factors during pregnancy.

INTRODUCTION: A better understanding of the determinants of placental growth is needed. Our primary aim was to explore associations between maternal ethnic origin and cardio-metabolic factors during pregnancy, and placental weight, surface area, shape and thickness. METHODS: A multi-ethnic population-based cohort study of 474 pregnant women examined at mean 15 and 28 weeks' gestation. Placentas were inspected after birth by a placental pathologist. Outcome measures were trimmed placental weight and three uncorrelated placental components; surface area, shape (oval vs round) and thickness, created through a principal components analysis. Multivariate linear regression models were used to explore the associations with maternal factors. RESULTS: Compared with ethnic European women, mothers with South- and East Asian ethnicity had placentas with lower weight (-51 g (95% CI: 75, -27) and -55 g (-95, -14) respectively), primarily due to a smaller surface area. The association between South Asian ethnicity and placental surface area was still significant after adjusting for maternal characteristics and cardio-metabolic factors. Fat mass index in early pregnancy was associated with higher placental weight and thickness. Placental surface area was positively associated with mid-gestational increases in fat mass, fasting glucose and triglycerides and with the 2-h glucose value at the 28 week oral glucose tolerance test, and inversely with a mid-gestational increase in HDL-cholesterol. DISCUSSION: Mid-gestational changes in fat mass, glucose, triglycerides and cholesterol were associated with, but only partly explained ethnic differences in placental surface area, while maternal fat mass in early pregnancy was associated with placental thickness.

Employing fasting plasma glucose to safely limit the use of oral glucose tolerance tests in pregnancy: a pooled analysis of four Norwegian studies.

Background/objective: There is no international consensus about the optimal approach to screening and diagnosis of gestational diabetes mellitus (GDM). Fasting plasma glucose (FPG) has been proposed as an alternative universal screening test to simplify the diagnosis of GDM. We investigate the ability of the FPG to predict a 2-hour glucose value below the cut-off for GDM, thereby "ruling out" the necessity of a full OGTT and assess the proportion of GDM-related complications associated with the identified FPG level. Materials and methods: This study included secondary data from four Norwegian pregnancy cohorts (2002-2013), encompassing 2960 women universally screened with late mid-pregnancy 75g OGTT measuring FPG and 2-hour glucose. For a range of FPG thresholds, we calculated sensitivity to predict elevated 2-hour glucose, number of OGTTs needed and percentage of GDM cases missed, applying modified World Health Organization (WHO) 2013 criteria (2013WHO) and 2017 Norwegian criteria (2017Norwegian). We analyzed pregnancy outcomes for women above and below our selected threshold. Results: The prevalence of GDM was 16.6% (2013WHO) and 10.1% (2017Norwegian). A FPG threshold of 4.7 mmol/L had a sensitivity of 76% (2013WHO) and 80% (2017Norwegian) for detecting elevated 2-hour glucose, with few missed GDM cases (2.0% of those ruled out and 7.5% of all GDM cases for 2013WHO, and 1.1% of those ruled out and 7% of all GDM cases for 2017Norwegian). When excluding women with FPG <4.7mmol/l and those with GDM based on FPG, only 24% (2013WHO) and 29% (2017Norwegian) would require OGTT. Women with FPG <4.7mmol/l, including missed GDM cases, had low risk of large-for-gestational-age newborns, cesarean section and operative vaginal delivery. Conclusion: A FPG threshold of 4.7mmol/l as a first step when screening for GDM could potentially eliminate the need for OGTT in 70-77% of pregnancies. Women with FPG below this threshold appear to carry low risk of GDM-associated adverse pregnancy outcomes.

Cohort profile update: the Norwegian STORK Groruddalen (STORK G) pregnancy and birth cohort-the role of ethnicity and causal pathways for obesity, type 2 diabetes, cardiovascular disease and other health issues.

PURPOSE: The STORK Groruddalen cohort was set up in 2008 to explore ethnic differences in: (1) maternal health, primarily gestational diabetes (GDM) and related health issues during pregnancy and post partum, and effects of exposures on risk for type 2 diabetes, cardiovascular disease and other health issues, and (2) offspring's growth and body composition, overweight/obesity and effects of early life exposures. PARTICIPANTS: 823 women (74% of invited) were followed from gestational week (GW) 15. Data were collected from 618 fathers. In total, 59% of women and 53% of fathers had origin from non-Western countries. Maternal mean age was 29.9 years (SD 4.9), and body mass index (BMI) 25.3 kg/m2 (4.9). Data were obtained from 772 women (94%) at GW 28, and 662 women (80%) 14 weeks post partum. Eleven years post partum, 385 women (53% of eligible/47% of original cohort) attended, age was 42.0 years (4.8) and BMI 27.1 kg/m2 (5.1). We have data for 783 children at birth, and for 586 at last time point, mean age 8.6 (0.5) years, weight 30.7 (6.8) kg and length 133.9 (6.3) cm. FINDINGS TO DATE: We collected questionnaire data from parents, clinical measurements and blood samples from mothers, and data on children's growth (mid-pregnancy to 8 years). Our biobank includes maternal blood and urine samples, biopsy material from placentas and umbilical venous cord blood. We found several clinically important differences in maternal health, with higher risk in ethnic minority groups for GDM, insulin resistance, vitamin D and iron deficiency, depressive symptoms and physical inactivity. Contrasting patterns of fetal growth and risk of overweight/thinness at preschool age were observed across ethnic groups. Maternal GDM, obesity and high gestational weight gain were associated with children's BMI trajectories. FUTURE PLANS: We will examine the impact of maternal and fetal health and development during pregnancy on long-term outcomes for mothers and offspring. TRIAL REGISTRATION NUMBER: Project title STORK G-2: Women and Risk of Type 2 Diabetes NCT03870724 (ClinicalTrials.gov).

Adverse pregnancy outcomes among women in Norway with gestational diabetes using three diagnostic criteria.

INTRODUCTION: The aim of this study was to examine the risk of adverse perinatal outcomes in women diagnosed with GDM by the World Health Organization (WHO) 1999 criteria, and in those retrospectively identified by the Norwegian-2017 and WHO-2013 criteria but not by WHO-1999 criteria. We also examine the effect of maternal overweight/obesity and ethnicity. MATERIAL AND METHODS: We used pooled data from four Norwegian cohorts (2002-2013), encompassing 2970 mother-child pairs. Results from universally offered 75-g oral glucose tolerance tests measuring fasting plasma glucose (FPG) and 2-hour glucose (2HG) were used to assign women into three diagnostic groups: Diagnosed and treated by WHO-1999 (FPG≥7.0 or (2HG ≥7.8 mmol/L), identified by WHO-2013 (FPG ≥5.1 or 2HG ≥8.5 mmol/L), and identified by Norwegian-2017 criteria (FPG ≥5.3 or 2HG ≥9.0 mmol/L). Perinatal outcomes included large-for-gestational-age (LGA) infants, cesarean section, operative vaginal delivery, preterm birth and preeclampsia. RESULTS: Compared to the non-GDM group, women diagnosed with GDM by either of the three criteria had an increased risk of large-for-gestational-age infants (adjusted odds ratios (OR) 1.7-2.2). Those identified by the WHO-2013 and Norwegian-2017 criteria but not diagnosed and treated by WHO-1999 criteria had an additional increased risk of cesarean section (OR 1.36, 95% CI 1.02,1.83 and 1.44, 95% CI 1.03,2.02, respectively) and operative vaginal delivery (OR 1.35, 95% CI 1.1,1.7 and 1.5, 95% CI 1.1,2.0, respectively). The proportions of LGA neonates and cesarean section were higher for women with GDM in both normal-weight and overweight/obese women. Asians had a lower risk of delivering large-for-gestational-age infants than Europeans applying national birthweight references, but maternal glucose values were similarly positively associated with birthweight in all ethnic groups. CONCLUSIONS: Women who met the WHO-2013 and Norwegian-2017 criteria, but were not diagnosed by the WHO-1999 criteria and therefore not treated, had an increased risk of LGA, cesarean section and operative vaginal delivery compared to women without GDM.

The impact of recommending iron supplements to women with depleted iron stores in early pregnancy on use of supplements, and factors associated with changes in iron status from early pregnancy to postpartum in a multi-ethnic population-based cohort.

BACKGROUND: We aimed to evaluate the impact of recommending supplementation to pregnant women with serum ferritin (SF) < 20 µg/L in early pregnancy on use of supplements, and to explore which factors were associated with changes in iron status by different iron indicators to 14 weeks postpartum. METHODS: A multi-ethnic population-based cohort study of 573 pregnant women examined at mean gestational week (GW) 15 (enrolment), at mean GW 28 and at the postpartum visit (mean 14 weeks after delivery). Women with SF < 20 µg/L at enrolment were recommended 30-50 mg iron supplementation and supplement use was assessed at all visits. Change of SF, soluble transferrin receptor and total body iron from enrolment to postpartum were calculated by subtracting the concentrations at the postpartum visit from that at enrolment. Linear and logistic regression analyses were performed to assess associations between use of supplements in GW 28 and changes in iron status and postpartum iron deficiency/anaemia. Change of iron status was categorized into 'steady low', 'improvement', 'deterioration', and 'steady high' based on SF status at enrolment and postpartum. Multinomial logistic regression analyses were performed to identify factors associated with change of iron status. RESULTS: At enrolment, 44% had SF < 20 µg/L. Among these women (78% non-Western European origin), use of supplements increased from 25% (enrolment) to 65% (GW 28). Use of supplements in GW 28 was associated with improved iron levels by all three indicators (p < 0.05) and with haemoglobin concentration (p < 0.001) from enrolment to postpartum, and with lower odds of postpartum iron deficiency by SF and TBI (p < 0.05). Factors positively associated with 'steady low' were: use of supplements, postpartum haemorrhage, an unhealthy dietary pattern and South Asian ethnicity (p ≤ 0.01 for all); with 'deterioration': postpartum haemorrhage, an unhealthy dietary pattern, primiparity and no use of supplements (p < 0.01 for all), and with 'improvement': use of supplements, multiparity and South Asian ethnicity (p < 0.03 for all). CONCLUSIONS: Both supplement use and iron status improved from enrolment to the postpartum visit among women recommended supplementation. Dietary pattern, use of supplements, ethnicity, parity and postpartum haemorrhage were identified as factors associated with change in iron status.

Epigenome-wide association study of serum folate in maternal peripheral blood leukocytes.

Aim: To perform an epigenome-wide association study (EWAS) of serum folate in maternal blood. Methods: Cross-ancestry (Europeans = 302, South Asians = 161) and ancestry-specific EWAS in the EPIPREG cohort were performed, followed by methyl quantitative trait loci analysis and association with cardiometabolic phenotypes. Replication was attempted using maternal folate intake and blood methylation data from the MoBa study and verified if the findings were significant in a previous EWAS of maternal serum folate in cord blood. Results & conclusion: cg19888088 (cross-ancestry) in EBF3, cg01952260 (Europeans) and cg07077240 (South Asians) in HERC3 were associated with serum folate. cg19888088 and cg01952260 were associated with diastolic blood pressure. cg07077240 was associated with variants in CASC15. The findings were not replicated and were not significant in cord blood.

Seasonal variation in gestational diabetes mellitus among women in Norway: a national population-based study.

OBJECTIVES: Previous research on seasonal variation in the incidence of gestational diabetes mellitus (GDM) has shown inconclusive results. Furthermore, little is known about whether a seasonal variation in GDM might be associated with the maternal country of birth. We examined whether there was seasonal variation in GDM incidence by the maternal country background. DESIGN: National population-based registry study. SETTING AND PARTICIPANTS: We used national population-based data from the Medical Birth Registry of Norway (MBRN), n=1 443 857 (1990-2016) and data from four merged community-based studies (4GDM) with universal screening for GDM, n=2 978 (2002-2013). OUTCOME MEASURES: The association between season of pregnancy onset with incidence of GDM was examined separately in both datasets using logistic regression analyses, stratified by the mother's country background using two broad geographical categories (MBRN: Norwegian and immigrant; 4GDM: European and African/Asian ethnicity). Winter season was used as reference category. RESULTS: The incidence of GDM in MBRN was highest when the pregnancy started during the winter (Norwegian-born: 1.21%; immigrants: 3.32%) and lowest when pregnancy started during the summer for both Norwegian and immigrant women (Norwegian-born: 1.03% (OR 0.85, 95% CI 0.81 to 0.98); immigrants: 2.99% (OR 0.90, 95% CI 0.84 to 0.96)). The 4GDM data showed that women with European ancestry had the highest incidence of GDM when pregnancy started during autumn (10.7%, OR 1.01, 95% CI 0.69 to 1.46) and winter (10.6%), while ethnic African and Asian women had the highest incidence when pregnancy onset was during the summer (15.3%, OR 1.17, 95% CI 0.54 to 2.53). CONCLUSIONS: Based on national population-based data, this study suggests that GDM incidence varies by season in both Norwegian-born and immigrant women. The 4GDM dataset did not show a clear seasonal variation in GDM incidence, possibly due to the relatively small sample. Causes for the seasonal variation in GDM should be explored further.

Cross-Ancestry DNA Methylation Marks of Insulin Resistance in Pregnancy: An Integrative Epigenome-Wide Association Study.

Although there are some epigenome-wide association studies (EWAS) of insulin resistance, for most of them authors did not replicate their findings, and most are focused on populations of European ancestry, limiting the generalizability. In the Epigenetics in Pregnancy (EPIPREG; n = 294 Europeans and 162 South Asians) study, we conducted an EWAS of insulin resistance in maternal peripheral blood leukocytes, with replication in the Born in Bradford (n = 879; n = 430 Europeans and 449 South Asians), Methyl Epigenome Network Association (MENA) (n = 320), and Botnia (n = 56) cohorts. In EPIPREG, we identified six CpG sites inversely associated with insulin resistance across ancestry, of which five were replicated in independent cohorts (cg02988288, cg19693031, and cg26974062 in TXNIP; cg06690548 in SLC7A11; and cg04861640 in ZSCAN26). From methylation quantitative trait loci analysis in EPIPREG, we identified gene variants related to all five replicated cross-ancestry CpG sites, which were associated with several cardiometabolic phenotypes. Mediation analyses suggested that the gene variants regulate insulin resistance through DNA methylation. To conclude, our cross-ancestry EWAS identified five CpG sites related to lower insulin resistance.

Insulin and Body Mass Index Decrease Serum Soluble Leptin Receptor Levels in Humans.

CONTEXT: Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. OBJECTIVE: This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. METHODS: We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization. RESULTS: In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (ß [95% CI] -0.19 [-0.21 to -0.17]), body fat (-0.12 [-0.14 to -0.10), and fasting C-peptide (-2.04 [-2.46 to -1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (-0.5 [-0.7 to -0.4] and -0.5 [-0.6 to -0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, -1.72 [-2.86 to -0.58], and -0.20 [-0.36 to -0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. CONCLUSION: BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.

Prevalence of postpartum anaemia and iron deficiency by serum ferritin, soluble transferrin receptor and total body iron, and associations with ethnicity and clinical factors: a Norwegian population-based cohort study.

Worldwide, there are limited data on the prevalence of postpartum anaemia and iron status. The aims of the present study were to assess the prevalence of anaemia and iron deficiency (ID) by three iron indicators 14 weeks postpartum, their relations to haemoglobin (Hb) and associations with ethnicity and clinical factors in a multi-ethnic population. We conducted a population-based cohort study of 573 women followed from early pregnancy. The prevalence of postpartum anaemia (Hb <12·0 g/dl) was 25 %. ID prevalence varied from 39 % by serum ferritin (SF <15 µg/l), to 19 % by soluble transferrin receptor (sTfR >4·4 mg/l) and 22 % by total body iron (TBI < 0 mg/kg). The mean Hb concentration was 12·8 g/dl in women with no ID, 12·6 g/dl in those with ID by SF only and 11·6 g/dl in those with ID by SF, sTfR and TBI. ID by sTfR and TBI defined by the current threshold values probably identified a more severe iron-deficient population compared with ID assessed by SF. Compared with Western Europeans, the prevalence of anaemia was at least the double in ethnic minorities (26-40 % v. 14 %; P < 0·01-0·05), and the prevalence of ID by sTfR and TBI, but not of ID by SF < 15 µg/l, was significantly higher in some minority groups. After adjustment for covariates, only South Asians had lower Hb and higher sTfR concentration. Insufficient iron intake, gestational anaemia or ID, and postpartum haemorrhage were associated with lower postpartum Hb concentration and poorer iron status.

Predictors of Hypertension Development 1 Year After Heart Transplantation.

BACKGROUND: Hypertension after heart transplantation (HTx) is common. We investigated predictors of and mechanisms for hypertension development during the first year after HTx, with particular attention toward immunosuppressive agents, reinnervation processes, and donor/recipient sex. METHODS: Heart transplant recipients (HTxRs) were consecutively enrolled 7 to 12 wk after surgery and followed prospectively for 12 mo. Ambulatory blood pressure recordings and autonomic cardiovascular control assessments were performed at baseline and follow-up. Possible predictors of posttransplant hypertension development were investigated in bivariate linear regression analyses followed by multiple regression modeling. RESULTS: A total of 50 HTxRs were included; 47 attended the follow-up appointment at 12 mo. Mean systolic and diastolic blood pressure increased significantly during the observational period (systolic blood pressure from 133 to 139 mm Hg, P = 0.007; diastolic blood pressure from 81 to 84 mm Hg, P = 0.005). The blood pressure increment was almost exclusively confined to HTxRs with a female donor heart, doubling the cases of systolic hypertension (from 6 to 13/14; 46% to 93%, P = 0.031) and diastolic hypertension (from 7 to 14/14; 54% to 100%, P = 0.031) in this subgroup. Autonomic cardiovascular control assessments suggested tonically constricted resistance and capacitance vessels in recipients with female donor hearts. Immunosuppressive agents and reinnervation markers were not associated with hypertension development. CONCLUSIONS: Blood pressures increase during the first year after HTx, with female donor sex as a strong predictor of recipient hypertension development. The underlying mechanism seems to be enhanced peripheral vasoconstriction caused by attenuated cardiovascular homeostasis capabilities. Further studies are needed to confirm the results.

Lipid and lipoprotein concentrations during pregnancy and associations with ethnicity.

BACKGROUND: To describe ethnic differences in concentrations of lipids and lipoproteins, and their changes, during pregnancy to postpartum. METHODS: This was a population-based cohort study conducted in primary antenatal care in Norway. The participants (n = 806) were healthy, pregnant women, 59% were ethnic minorities. Outcomes were triglycerides, total cholesterol, HDL- and LDL-cholesterol, analysed from fasting blood samples drawn at gestational age (weeks) 15, 28 and 14 weeks postpartum. We performed linear regression models and linear mixed models to explore the total effect of ethnicity on the outcomes, adjusting for gestational age /week postpartum, maternal age and education. The analyses are corrected for multiple testing using the Bonferroni correction. RESULTS: At gestational age 15, triglyceride concentrations were lower in women of African origin (1.03 mmol/mol (95% CI: 0.90, 1.16)) and higher in women of South Asian (primarily Pakistan and Sri Lanka) origin (1.42 mmol/mol (1.35, 1.49)) and East Asian (primarily Vietnam, Philippines and Thailand) origin (1.58 mmol/mol (1.43, 1.73)) compared with Western Europeans (1.26 mmol/mol (1.20, 1.32)). Women of Asian and African origin had a smaller increase in triglycerides, LDL- and total cholesterol from gestational age 15 to 28. At gestational age 28, LDL-cholesterol levels were lowest among East Asians (3.03 mmol/mol (2.72, 3.34)) compared with Western Europeans (3.62 mmol/mol (3.50, 3.74)). Triglycerides and HDL-cholesterol were lower postpartum than at gestational age 15 in all groups, but the concentration of LDL-cholesterol was higher, except in Africans. South and East Asian women had lower HDL-cholesterol and higher triglycerides postpartum, while African women had lower triglycerides than Western Europeans. CONCLUSION: We found significant differences in the concentrations of lipids and lipoproteins and their changes during pregnancy and the early postpartum period related to ethnic origin.

Identifying women with gestational diabetes based on maternal characteristics: an analysis of four Norwegian prospective studies.

BACKGROUND: There is still no worldwide agreement on the best diagnostic thresholds to define gestational diabetes (GDM) or the optimal approach for identifying women with GDM. Should all pregnant women perform an oral glucose tolerance test (OGTT) or can easily available maternal characteristics, such as age, BMI and ethnicity, indicate which women to test? The aim of this study was to assess the prevalence of GDM by three diagnostic criteria and the predictive accuracy of commonly used risk factors. METHODS: We merged data from four Norwegian cohorts (2002-2013), encompassing 2981 women with complete results from a universally offered OGTT. Prevalences were estimated based on the following diagnostic criteria: 1999WHO (fasting plasma glucose (FPG) ≥7.0 or 2-h glucose ≥7.8 mmol/L), 2013WHO (FPG ≥5.1 or 2-h glucose ≥8.5 mmol/L), and 2017Norwegian (FPG ≥5.3 or 2-h glucose ≥9 mmol/L). Multiple logistic regression models examined associations between GDM and maternal factors. We applied the 2013WHO and 2017Norwegian criteria to evaluate the performance of different thresholds of age and BMI. RESULTS: The prevalence of GDM was 10.7, 16.9 and 10.3%, applying the 1999WHO, 2013WHO, and the 2017Norwegian criteria, respectively, but was higher for women with non-European background when compared to European women (14.5 vs 10.2%, 37.7 vs 13.8% and 27.0 vs 7.8%). While advancing age and elevated BMI increased the risk of GDM, no risk factors, isolated or in combination, could identify more than 80% of women with GDM by the latter two diagnostic criteria, unless at least 70-80% of women were offered an OGTT. Using the 2017Norwegian criteria, the combination "age≥25 years or BMI≥25 kg/m2" achieved the highest sensitivity (96.5%) with an OGTT required for 93% of European women. The predictive accuracy of risk factors for identifying GDM was even lower for non-European women. CONCLUSIONS: The prevalence of GDM was similar using the 1999WHO and 2017Norwegian criteria, but substantially higher with the 2013WHO criteria, in particular for ethnic non-European women. Using clinical risk factors such as age and BMI is a poor pre-diagnostic screening method, as this approach failed to identify a substantial proportion of women with GDM unless at least 70-80% were tested.

Cohort profile: Epigenetics in Pregnancy (EPIPREG) - population-based sample of European and South Asian pregnant women with epigenome-wide DNA methylation (850k) in peripheral blood leukocytes.

Pregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mother's and child's health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring. This cohort profile paper aims to present our sample with genetic and epigenetic data and invite researchers with similar cohorts to collaborative projects, such as replication of ours or their results and meta-analysis. In EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28±1 in Europeans (n = 312) and South Asians (n = 168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC BeadChip (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n = 30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In the offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age. We have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed good agreement with bisulfite pyrosequencing. We plan to study associations between DNA methylation and cardiometabolic traits and outcomes.

Thyroid Function During Pregnancy in A Multiethnic Population in Norway.

CONTEXT: Ethnic differences in thyroid function during pregnancy have been reported. However, it is unclear if this is equally valid across ethnic groups within multiethnic populations. OBJECTIVE: We aimed to assess ethnic differences in thyrotropin (TSH) and free thyroxine (FT4), and the prevalence of thyroid dysfunction and thyroid autoimmunity during pregnancy. METHODS: In a population-based cohort of 785 pregnant women in Oslo, Norway, TSH, FT4, and thyroid peroxidase antibodies (TPO Abs) were measured twice: at gestational week (GW) 15 and 28, and urine iodine concentration at GW 15. Associations were assessed using multivariate linear regression. RESULTS: We found ethnic differences in TSH levels at both time points, but not for fT4. South Asians had 0.42 mU/L (95% CI, 0.20-0.64) higher TSH than Europeans in GW 15. This difference persisted after adjusting for covariates (including TPO Ab positivity and iodine status), and increased further as pregnancy progressed. In contrast, East Asians had the lowest TSH. No new cases of overt hypothyroidism were detected in early pregnancy, but subclinical hypothyroidism was found in 6.6% among all, highest in South Asians (14.2%). Hyperthyroidism early in pregnancy was observed in 3.7% (almost all subclinical), highest in East Asians (11.9%). The prevalence of TPO Ab positivity was 4%, highest in South Asians (8%). CONCLUSION: In a multiethnic population of presumably healthy women, we found ethnic variations in TSH but not FT4 levels throughout pregnancy. South Asians had higher TSH and more subclinical hypothyroidism, not explained by their higher prevalence of TPO Ab positivity. Larger studies are needed to define ethnic- and trimester-specific reference ranges in pregnancy.

Childhood vascular phenotypes have differing associations with prenatal and postnatal growth.

OBJECTIVE: In children aged 8--9 years, we examined the associations of linear and abdominal circumference growth during critical stages of prenatal and postnatal development with six vascular measurements commonly used as early markers of atherosclerosis and later cardiovascular disease (CVD) risk. METHODS: In 724 children from the UK Southampton Women's Survey mother--offspring cohort, offspring length/height and abdominal circumference measurements were collected at 10 ages between 11 weeks' gestation and age 8--9 years. Using residual growth modelling and linear regression, we examined the independent associations between growth and detailed vascular measures made at 8--9 years. RESULTS: Postnatal linear and abdominal circumference growth were associated with higher childhood SBP and carotid--femoral pulse wave velocity, whereas prenatal growth was not. For example, 1SD faster abdominal circumference gain between ages 3 and 6 years was associated with 2.27 [95% confidence interval (CI): 1.56--2.98] mmHg higher SBP. In contrast, faster abdominal circumference gain before 19 weeks' gestation was associated with greater carotid intima--media thickness [0.009 mm (0.004--0.015) per 1SD larger 19-week abdominal circumference), whereas later growth was not. We found no strong associations between prenatal or postnatal growth and DBP or measures of endothelial function. CONCLUSION: Higher postnatal linear growth and adiposity gain are related to higher SBP and carotid--femoral pulse wave velocity in childhood. In contrast, faster growth in early gestation is associated with greater childhood carotid intima--media thickness, perhaps resulting from subtle changes in vascular structure that reflect physiological adaptations rather than subclinical atherosclerosis.

Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers.

BACKGROUND: Chronic fatigue syndrome (CFS) is defined according to subjective symptoms only, and several conflicting case definition exist. Previous research has discovered certain biological alterations. The aim of the present study was to explore possible subgroups based on biological markers within a widely defined cohort of adolescent CFS patients and investigate to what extent eventual subgroups are associated with other variables. METHODS: The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) has previously performed detailed investigation of immunological, autonomic, neuroendocrine, cognitive and sensory processing functions in an adolescent group of CFS patients recruited according to wide diagnostic criteria. In the present study, hierarchical cluster analyses (Ward's method) were performed using representative variables from all these domains. Associations between clusters and constitutional factors (including candidate genetic markers), diagnostic criteria, subjective symptoms and prognosis were explored by standard statistical methods. RESULTS: A total of 116 patients (26.7% males, mean age 15.4 years) were included. The final cluster analyses revealed six clusters labelled pain tolerant & good cognitions, restored HPA dynamics, orthostatic intolerance, low-grade inflammation, pain intolerant & poor cognitions, and high vagal (parasympathetic) activity, respectively. There was substantial overlap between clusters. The pain intolerant & poor cognitions-cluster was associated with low functional abilities and quality of life, and adherence to the Canada 2003 diagnostic criteria for CFS. No other statistically significant cluster associations were discovered. CONCLUSION: Within a widely defined cohort of adolescent CFS patients, clusters could be delineated, but no distinct subgroups could be identified. Associations between clusters and constitutional factors, subjective symptoms and prognosis were scarce. These results question the clinical usefulness of searching for CFS subgroups, as well as the validity of the most "narrow" CFS diagnostic criteria. TRIAL REGISTRATION: Clinical Trials NCT01040429.

Maternal Glucose and LDL-Cholesterol Levels Are Related to Placental Leptin Gene Methylation, and, Together With Nutritional Factors, Largely Explain a Higher Methylation Level Among Ethnic South Asians.

Background: Leptin, mainly secreted by fat cells, plays a core role in the regulation of appetite and body weight, and has been proposed as a mediator of metabolic programming. During pregnancy leptin is also secreted by the placenta, as well as being a key regulatory cytokine for the development, homeostatic regulation and nutrient transport within the placenta. South Asians have a high burden of type 2 diabetes, partly attributed to a "thin-fat-phenotype". Objective: Our aim was to investigate how maternal ethnicity, adiposity and glucose- and lipid/cholesterol levels in pregnancy are related to placental leptin gene (LEP) DNA methylation. Methods: We performed DNA methylation analyses of 13 placental LEP CpG sites in 40 ethnic Europeans and 40 ethnic South Asians participating in the STORK-Groruddalen cohort. Results: South Asian ethnicity and gestational diabetes (GDM) were associated with higher placental LEP methylation. The largest ethnic difference was found for CpG11 [5.8% (95% CI: 2.4, 9.2), p<0.001], and the strongest associations with GDM was seen for CpG5 [5.2% (1.4, 9.0), p=0.008]. Higher maternal LDL-cholesterol was associated with lower placental LEP methylation, in particular for CpG11 [-3.6% (-5.5, -1.4) per one mmol/L increase in LDL, p<0.001]. After adjustments, including for nutritional factors involved in the one-carbon-metabolism cycle (vitamin D, B12 and folate levels), ethnic differences in placental LEP methylation were strongly attenuated, while associations with glucose and LDL-cholesterol persisted. Conclusions: Maternal glucose and lipid metabolism is related to placental LEP methylation, whilst metabolic and nutritional factors largely explain a higher methylation level among ethnic South Asians.