Background: To evaluate vitamin B12 and folate status in pregnancy and their relationship with maternal obesity, gestational diabetes mellitus (GDM), and offspring birthweight. Methods: A retrospective case-control study of 344 women (143 GDM, 201 no-GDM) attending a district general hospital and that had B12 and folate levels measured in the early 3rd trimester was performed. Maternal history including early pregnancy body mass index (BMI) and neonatal data (birthweight, sex, and gestational age) was recorded for all subjects. Results: 26% of the cohort had B12 levels <150 pmol/L (32% vs. 22% in the two groups respectively, p < 0.05) while 1.5% were folate deficient. After adjusting for confounders, 1st trimester BMI was negatively associated with 3rd trimester B12 levels. Women with B12 insufficiency had higher odds of obesity and GDM (aOR (95% CI) 2.40 (1.31, 4.40), p = 0.004, and 2.59 (1.35, 4.98), p = 0.004, respectively), although the latter was partly mediated by BMI. In women without GDM, the lowest quartile of B12 and highest quartile of folate had significantly higher adjusted risk of fetal macrosomia (RR 5.3 (1.26, 21.91), p = 0.02 and 4.99 (1.15, 21.62), p = 0.03 respectively). Conclusion: This is the first study from the UK to show that maternal B12 levels are associated with BMI, risk of GDM, and additionally may have an independent effect on macrosomia. Due to the increasing burden of maternal obesity and GDM, longitudinal studies with B12 measurements in early pregnancy are needed to explore this link.

BackgroundMetformin, a standard therapy in type 2 diabetes, reduces vitamin B12 levels. Studies linking low vitamin B12 levels and cardiovascular disease are equivocal and suggest improving B12 levels may help in primary prevention. The role of vitamin B12 deficiency on cardiovascular risk factors, especially in type 2 diabetes has not been explored. The aim of this study is to investigate whether vitamin B12 deficiency in type 2 diabetes patients is associated with cardiovascular risk factors in two different ethnic groups in UK and India.MethodsType 2 diabetes patients from two secondary care diabetic centres (Europeans - UK and Indians - India) were studied. Serum vitamin B12, folate and biochemical parameters were measured.ResultsThe prevalence rates of vitamin B12 deficiency (<191 ng/L) were 27% and 12% in Europeans and Indians, respectively and higher in metformin treated type 2 diabetes patients. In linear regression analysis, after adjusting for all likely confounding factors, vitamin B12 independently associated with triglycerides in both the populations and cholesterol/HDL ratio in Indians. Logistic regression showed type 2 diabetes patients with vitamin B12 deficiency were at significantly higher odds of having coexisting coronary artery disease (CAD) in Europeans with similar but non-significant trend in Indians, after adjusting for all likely confounding factors.ConclusionsThe prevalence of vitamin B12 deficiency is common in type 2 diabetes patients and is associated with adverse lipid parameters. Type 2 diabetes management guidelines should include the recommendation for regular testing for B12 levels, especially for those on metformin.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-014-0129-4) contains supplementary material, which is available to authorized users.

Aims/hypothesis The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B12 and low/high folate levels may contribute to GDM risk, but there is conflicting evidence. Our aim is to assess the relationships of early pregnancy vitamin B12 and folate levels with the risk of GDM status at 26–28 weeks of gestation. Methods This was a prospective, multi-centre, multi-ethnic cohort study (n = 4746) in the UK. Participants who were eligible to be selectively screened as per the National Institute for Health and Care Excellence (NICE) criteria were included in the study. Results GDM prevalence was 12.5% by NICE and 14.7% by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Folate deficiency (1.3%) was rare but B12 insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B12 levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26–28 weeks. B12 was negatively associated with fasting plasma glucose (1 SD: −0.06 mmol/l; 95% CI −0.04, −0.08; p < 0.0001) and 2 h plasma glucose levels (−0.07 mmol/l; 95% CI −0.02, −0.12; p = 0.004). Higher B12 was associated with 14.4% lower RR of IADPSG-GDM (0.856; 95% CI 0.786, 0.933; p = 0.0004) after adjusting for key confounders (age, parity, smoking status, ethnicity, family history, household income and folate status). Approximately half of this association was mediated through BMI. Folate was positively associated with 2 h plasma glucose levels (0.08 mmol/l; 95% CI 0.04, 0.13; p = 0.0005) but its relationship with fasting plasma glucose was U-shaped (quadratic β: 0.011; p = 0.05). Higher folate was associated with 11% higher RR of IADPSG-GDM (adjusted RR 1.11; 95% CI 1.036, 1.182; p = 0.002) (age, parity, smoking status, ethnicity, family history, household income and B12 status). Although no interactions were observed for B12 and folate (as continuous variables) with glucose levels and GDM risk, a low B12–high folate combination was associated with higher blood glucose level and risk of IADPSG-GDM (adjusted RR 1.742; 95% CI 1.226, 2.437; p = 0.003). Conclusions/interpretation B12 insufficiency and folate excess were common in early pregnancy. Low B12 and high folate levels in early pregnancy were associated with small but statistically significant changes in maternal blood glucose level and higher RR of GDM. Our findings warrant additional studies on the role of unmetabolised folic acid in glucose metabolism and investigating the effect of optimising early pregnancy or pre-conception B12 and folate levels on subsequent hyperglycaemia. Trial registration: ClinicalTrials.gov NCT03008824. Graphical abstract

Aims/hypothesis Gestational diabetes mellitus (GDM) is associated with an increased future risk of obesity in the offspring. Increased adiposity has been observed in the newborns of women with GDM. Our aim was to examine early fetal adiposity in women with GDM. Methods Obstetric and sonographic data was collated for 153 women with GDM and 178 controls from a single centre in Chennai, India. Fetal head circumference (HC), abdominal circumference (AC), femur length (FL) and biparietal diameter (BPD) were recorded at 11, 20 and 32 weeks. Anterior abdominal wall thickness (AAWT) as a marker of abdominal adiposity at 20 and 32 weeks was compared between groups. Adjustments were made for maternal age, BMI, parity, gestational weight gain, fetal sex and gestational age. Results Fetuses of women with GDM had significantly higher AAWT at 20 weeks (β 0.26 [95% CI 0.15, 0.37] mm, p < 0.0001) despite lower measures of HC, FL, BPD and AC. AAWT remained higher in the fetuses of women with GDM at 32 weeks (β 0.48 [0.30, 0.65] mm, p < 0.0001) despite similar measures for HC, FL, BPD and AC between groups. Both groups had similar birthweights at term. There was an independent relationship between fasting plasma glucose levels and AAWT after adjustment as described above. Conclusions/interpretation A 'thin but fat' phenotype signifying a disproportionate increase in adiposity despite smaller or similar lean body mass was observed in the fetuses of mothers with GDM, even at 20 weeks, thus pre-dating the biochemical diagnosis of GDM. Increased AAWT may serve as an early marker of GDM.

Carcinoid heart disease (CHD) is a consequence of valvular fibrosis triggered by vasoactive substances released from neuroendocrine tumours, classically in those with metastatic disease and resulting in tricuspid and pulmonary valve failure. CHD affects one in five patients who have carcinoid syndrome (CS). Valve leaflets become thickened, retracted and immobile, resulting most often in regurgitation that causes right ventricular dilatation and ultimately, right heart failure. The development of CHD heralds a significantly worse prognosis than those patients with CS who do not develop valvular disease. Diagnosis requires a low threshold of suspicion in all patients with CS, since symptoms occur late in the disease process and clinical signs are difficult to elicit. As a result, routine screening is recommended using the biomarker, N-terminal pro-natriuretic peptide, and regular echocardiography is then required for diagnosis and follow-up. There is no direct medical therapy for CHD, but the focus of non-surgical care is to control CS symptoms, reduce tumour load and decrease hormone levels. Valve surgery improves long-term outcome for those with severe disease compared to medical management, although peri-operative mortality remains at between 10 and 20% in experienced centres. Therefore, care needs to be multidisciplinary at all stages, with clear discussion with the patient and between teams to ensure optimum outcome for these often-complex patients.

ObjectiveTo assess serum B12, folate and the associated homocysteine (Hcy) levels among women of childbearing age in the UK and examine their association with dietary intake in relation to the UK Recommended Nutrient Intakes (RNIs) for B12 and folate.DesignCross-sectional study.SettingData from two publicly available National Diet and Nutrition Surveys (NDNS 2000/2001 and 2008/2012) were used. These were population-based surveys of randomly selected samples of adults which were carried out in their households.ParticipantsWomen of childbearing age (aged 19–39 years), representative of the UK population. Those who were pregnant or breastfeeding were excluded.Outcome measuresThe associations between micronutrient intakes and blood levels of B12, folate and Hcy were assessed by correlation and stepwise linear regression. B12 intake was divided into quintiles and plotted against blood B12 and Hcy concentrations to determine the threshold of any associations.Results299 women from the first NDNS cohort had complete intake and biomarker data. The prevalence of serum vitamin B12 (≤150 pmol/L) and serum folate (≤10 nmol/L) deficiency and hyperhomocysteinemia (≥12 µmol/L) was 12.4%, 6.4% and 21.2%, respectively, despite seemingly adequate B12 intakes (median 3.8 μg/day, 96% consumed more than the UK RNI of 1.5 μg/day). B12 concentrations increased across all quintiles of intake with serum levels in quintiles 4 and 5 (median intake 4.9 and 7.1 μg/day, respectively) significantly higher than quintile 1. However, Hcy concentrations levelled off between quintiles 4 and 5. Comparison of micronutrient intake between the two surveys found that folate intake has reduced in the more recent cohort.ConclusionsThe UK RNI for B12 intake should be increased for women of childbearing age with intakes of around 5–7 μg/day likely to be associated with stable biomarker levels. B12 levels should also be measured in women preconceptionally or in early pregnancy given the high rates of deficiency.

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Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.