Early pregnancy HbA1c as the first screening test for gestational diabetes: results from three prospective cohorts.

BACKGROUND: More than 90% of gestational diabetes cases are estimated to occur in low-income and middle-income countries (LMICs). Most current guidelines recommend an oral glucose tolerance test (OGTT) at 24-28 weeks of gestation. The OGTT is burdensome, especially in LMICs, resulting in a high proportion of women not being screened. We aimed to develop a simple and effective screening strategy for gestational diabetes. METHODS: STRiDE, a prospective cohort study, was set up in seven centres in south India and seven centres in western Kenya, and included pregnant women aged 18-50 years of age and at less than 16 weeks of gestation (<20 weeks in Kenya), confirmed by dating ultrasound. We assessed the efficacy of early pregnancy HbA1c (venous and capillary point-of-care), either alone or as part of a composite risk score with age, BMI, and family history of diabetes, in predicting gestational diabetes at 24-28 weeks of gestation, in two LMICs (India and Kenya) and in a UK multi-ethnic population from the PRiDE study. A key secondary outcome was to assess whether an early pregnancy composite risk score can reduce the need for OGTTs. Gestational diabetes was diagnosed using current WHO criteria. FINDINGS: Between Feb 15, 2016, Dec 13, 2019, we enrolled 3070 participants in India and 4104 in Kenya. 4320 participants were included from the PRiDE cohort. Gestational diabetes prevalence by OGTT at 24-28 weeks was 19·2% in India, 3·0% in Kenya, and 14·5% in the UK. Early pregnancy HbA1c was independently associated with incidence of gestational diabetes at 24-28 weeks of gestation. Adjusted risk ratios were 1·60 (95% CI 1·19-2·16) in India, 3·49 (2·8-4·34) in Kenya, and 4·72 (3·82-5·82) in the UK. Composite risk score models that combined venous or point-of-care HbA1c with age, BMI, and family history of diabetes best predicted testing positive for gestational diabetes. A population-specific, two-threshold screening strategy of rule-in and rule-out gestational diabetes using early pregnancy composite risk score could reduce the requirement of OGTTs by 50-64%. For the HbA1c-alone model, the thresholds were 5·4% (rule in) and 4·9% (rule out) in India, 6·0% (rule in) and 5·2% (rule out) in Kenya, and 5·6% (rule in) and 5·2% (rule out) in the UK. INTERPRETATION: Early pregnancy HbA1c offers a simple screening test for gestational diabetes, allowing those at highest risk to receive early intervention and greatly reduce the need for OGTTs. This can also be carried out using point-of-care HbA1c in LMICs. FUNDING: UK Medical Research Council and the Indian Department of Biotechnology.

Correction: Prevalence of prediabetes and type 2 diabetes mellitus in south and southeast Asian women with history of gestational diabetes mellitus: Systematic review and meta-analysis.

[This corrects the article DOI: 10.1371/journal.pone.0278919.].

Serum bile acid measurements in women of European and South Asian ethnicity with or without gestational diabetes mellitus: A cohort study.

OBJECTIVE: Investigation of serum bile acid profiles in pregnancies complicated by gestational diabetes mellitus (GDM) in a multi-ethnic cohort of women who are lean or obese. DESIGN: Prospective cohort study. SETTING: UK multicentre study. POPULATION: Fasting serum from participants of European or South Asian self-reported ethnicity from the PRiDE study, between 23 and 31 weeks of gestation. METHODS: Bile acids were measured using ultra-performance liquid chromatography-tandem mass spectrometry. Log-transformed data were analysed using linear regression in STATA/IC 15.0. MAIN OUTCOME MEASURES: Total bile acids (TBAs), C4, fasting glucose and insulin. RESULTS: The TBAs were 1.327-fold (1.105-1.594) increased with GDM in European women (P = 0.003). Women with GDM had 1.162-fold (1.002-1.347) increased levels of the BA synthesis marker C4 (P = 0.047). In South Asian women, obesity (but not GDM) increased TBAs 1.522-fold (1.193-1.942, P = 0.001). Obesity was associated with 1.420-fold (1.185-1.702) increased primary/secondary BA ratio (P < 0.001) related to 1.355-fold (1.140-1.611) increased primary BA concentrations (P = 0.001). TBAs were positively correlated with fasting glucose (P = 0.039) in all women, and with insulin (P = 0.001) and the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (P = 0.001) in women with GDM. CONCLUSIONS: Serum BA homeostasis in late gestation depends on body mass index and GDM in ethnicity-specific ways. This suggests ethnicity-specific aetiologies may contribute to metabolic risk in European and South Asian women, with the relationship between BAs and insulin resistance of greater importance in European women. Further studies into ethnicity-specific precision medicine for GDM are required.

Effects of treating subclinical hypothyroidism in pregnancy in India: Are we treating too many for little gain? A retrospective cohort study.

OBJECTIVE: To assess the impact of treatment of subclinical hypothyroidism (SCH) on short-term pregnancy outcomes. METHOD: Data from 4526 consecutive women with singleton pregnancies who delivered between January 2015 and December 2017 were analyzed. SCH was defined as a thyroid-stimulating hormone (TSH) level between 2.5 and 10 mU/mL with normal free thyroxine. Of those with SCH, some were treated but others were not. These two groups were compared using χ2 and Student t tests for categorical and continuous variables, respectively. Multiple logistic regression models, adjusted for maternal age, body mass index, parity, gestation at TSH measurement, and gestational diabetes mellitus status, were used to investigate the effect of treatment on pregnancy and neonatal outcomes. RESULTS: In all, 1227 (27.1%) of 4526 women had SCH, of whom 393 (32.0%) were treated. The mean age and body mass index were similar in both groups. The mean gestation at measuring of TSH was 11.7 ± 6.5 weeks. There was no significant difference in pregnancy or neonatal outcomes between the two groups. A sub-group analysis when SCH was defined as TSH 4.0 mU/mL or greater showed a higher rate of large for gestational age and lower rates of low birth weight and small for gestational age in the treated group. CONCLUSIONS: The prevalence of SCH based on the international guidelines threshold is high in India. Treatment of SCH did not show any difference in pregnancy and neonatal outcomes in this study.

Effectiveness of pre-pregnancy lifestyle in preventing gestational diabetes mellitus-a systematic review and meta-analysis of 257,876 pregnancies.

BACKGROUND: Gestational Diabetes Mellitus (GDM) is hyperglycaemia first detected during pregnancy. Globally, GDM affects around 1 in 6 live births (up to 1 in 4 in low- and middle-income countries- LMICs), thus, urgent measures are needed to prevent this public health threat. OBJECTIVE: To determine the effectiveness of pre-pregnancy lifestyle in preventing GDM. METHODS: We searched MEDLINE, Web of science, Embase and Cochrane central register of controlled trials. Randomized control trials (RCTs), case-control studies, and cohort studies that assessed the effect of pre-pregnancy lifestyle (diet and/or physical activity based) in preventing GDM were included. Random effects model was used to calculate odds ratio (OR) with 95% confidence interval. The Cochrane ROB-2 and the Newcastle-Ottawa Scale were used for assessing the risk of bias. The protocol was registered in PROSPERO (ID: CRD42020189574) RESULTS: Database search identified 7935 studies, of which 30 studies with 257,876 pregnancies were included. Meta-analysis of the RCTs (N = 5; n = 2471) in women who received pre-pregnancy lifestyle intervention showed non-significant reduction of the risk of developing GDM (OR 0.76, 95% CI: 0.50-1.17, p = 0.21). Meta-analysis of cohort studies showed that women who were physically active pre-pregnancy (N = 4; n = 23263), those who followed a low carbohydrate/low sugar diet (N = 4; n = 25739) and those women with higher quality diet scores were 29%, 14% and 28% less likely to develop GDM respectively (OR 0.71, 95% CI: 0.57, 0.88, p = 0.002, OR 0.86, 95% CI: 0.68, 1.09, p = 0.22 and OR 0.72, 95% CI 0.60-0.87, p = 0.0006). CONCLUSION: This study highlights that some components of pre-pregnancy lifestyle interventions/exposures such as diet/physical activity-based preparation/counseling, intake of vegetables, fruits, low carbohydrate/low sugar diet, higher quality diet scores and high physical activity can reduce the risk of developing gestational diabetes. Evidence from RCTs globally and the number of studies in LMICs are limited, highlighting the need for carefully designed RCTs that combine the different aspects of the lifestyle and are personalized to achieve better clinical and cost effectiveness.

Prediction of postpartum prediabetes by machine learning methods in women with gestational diabetes mellitus.

Early onset of type 2 diabetes and cardiovascular disease are common complications for women diagnosed with gestational diabetes. Prediabetes refers to a condition in which blood glucose levels are higher than normal, but not yet high enough to be diagnosed as type 2 diabetes. Currently, there is no accurate way of knowing which women with gestational diabetes are likely to develop postpartum prediabetes. This study aims to predict the risk of postpartum prediabetes in women diagnosed with gestational diabetes. Our sparse logistic regression approach selects only two variables - antenatal fasting glucose at OGTT and HbA1c soon after the diagnosis of GDM - as relevant, but gives an area under the receiver operating characteristic curve of 0.72, outperforming all other methods. We envision this to be a practical solution, which coupled with a targeted follow-up of high-risk women, could yield better cardiometabolic outcomes in women with a history of GDM.

Prevalence of prediabetes and type 2 diabetes mellitus in south and southeast Asian women with history of gestational diabetes mellitus: Systematic review and meta-analysis.

BACKGROUND: The burden of Gestational Diabetes Mellitus (GDM) is very high in south Asia (SA) and southeast Asia (SEA). Thus, there is a need to understand the prevalence and risk factors for developing prediabetes and type 2 diabetes mellitus (T2DM) postpartum, in this high-risk population. AIM: To conduct a systematic review and meta-analysis to estimate the prevalence of prediabetes and T2DM among the women with history of GDM in SA and SEA. METHODS: A comprehensive literature search was performed in the following databases: Medline, EMBASE, Web of Knowledge and CINHAL till December 2021. Studies that had reported greater than six weeks of postpartum follow-up were included. The pooled prevalence of diabetes and prediabetes were estimated by random effects meta-analysis model and I2 statistic was used to assess heterogeneity. RESULTS: Meta-analysis of 13 studies revealed that the prevalence of prediabetes and T2DM in post-GDM women were 25.9% (95%CI 18.94 to 33.51) and 29.9% (95%CI 17.02 to 44.57) respectively. Women with history of GDM from SA and SEA seem to have higher risk of developing T2DM than women without GDM (RR 13.2, 95%CI 9.52 to 18.29, p<0.001). The subgroup analysis showed a rise in the prevalence of T2DM with increasing duration of follow-up. CONCLUSION: The conversion to T2DM and prediabetes is very high among women with history of GDM in SA and SEA. This highlights the need for follow-up of GDM women for early identification of dysglycemia and to plan interventions to prevent/delay the progression to T2DM.

Thromboembolic events and hemorrhagic stroke after mRNA (BNT162b2) and inactivated (CoronaVac) covid-19 vaccination: A self-controlled case series study.

Background: This study aims to evaluate the association between thromboembolic events and hemorrhagic stroke following BNT162b2 and CoronaVac vaccination. Methods: Patients with incident thromboembolic events or hemorrhagic stroke within 28 days of covid-19 vaccination or SARS-CoV-2 positive test during 23 February to 30 September 2021 were included. The incidence per 100,000 covid-19 vaccine doses administered and SARS-CoV-2 test positive cases were estimated. A modified self-controlled case series (SCCS) analysis using the data from the Hong Kong territory-wide electronic health and vaccination records. Seasonal effect was adjusted by month. Findings: A total of 5,526,547 doses of BNT162b2 and 3,146,741 doses of CoronaVac were administered. A total of 334 and 402 thromboembolic events, and 57 and 49 hemorrhagic stroke cases occurred within 28 days after BNT162b2 and CoronaVac vaccination, respectively. The crude incidence of thromboembolic events and hemorrhagic stroke per 100,000 doses administered for both covid-19 vaccines were smaller than that per 100,000 SARS-CoV-2 test positive cases. The modified SCCS detected an increased risk of hemorrhagic stroke in BNT162b2 14-27 days after first dose with adjusted IRR of 2.53 (95% CI 1.48-4.34), and 0-13 days after second dose with adjusted IRR 2.69 (95% CI 1.54-4.69). No statistically significant risk was observed for thromboembolic events for both vaccines. Interpretation: We detected a possible safety signal for hemorrhagic stroke following BNT162b2 vaccination. The incidence of thromboembolic event or hemorrhagic stroke following vaccination is lower than that among SARS-CoV-2 test positive cases; therefore, vaccination against covid-19 remains an important public health intervention. Funding: This study was funded by a research grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (reference COVID19F01).

Machine learning prediction of non-attendance to postpartum glucose screening and subsequent risk of type 2 diabetes following gestational diabetes.

OBJECTIVE: The aim of the present study was to identify the factors associated with non-attendance of immediate postpartum glucose test using a machine learning algorithm following gestational diabetes mellitus (GDM) pregnancy. METHOD: A retrospective cohort study of all GDM women (n = 607) for postpartum glucose test due between January 2016 and December 2019 at the George Eliot Hospital NHS Trust, UK. RESULTS: Sixty-five percent of women attended postpartum glucose test. Type 2 diabetes was diagnosed in 2.8% and 21.6% had persistent dysglycaemia at 6-13 weeks post-delivery. Those who did not attend postpartum glucose test seem to be younger, multiparous, obese, and continued to smoke during pregnancy. They also had higher fasting glucose at antenatal oral glucose tolerance test. Our machine learning algorithm predicted postpartum glucose non-attendance with an area under the receiver operating characteristic curve of 0.72. The model could achieve a sensitivity of 70% with 66% specificity at a risk score threshold of 0.46. A total of 233 (38.4%) women attended subsequent glucose test at least once within the first two years of delivery and 24% had dysglycaemia. Compared to women who attended postpartum glucose test, those who did not attend had higher conversion rate to type 2 diabetes (2.5% vs 11.4%; p = 0.005). CONCLUSION: Postpartum screening following GDM is still poor. Women who did not attend postpartum screening appear to have higher metabolic risk and higher conversion to type 2 diabetes by two years post-delivery. Machine learning model can predict women who are unlikely to attend postpartum glucose test using simple antenatal factors. Enhanced, personalised education of these women may improve postpartum glucose screening.

Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus.

Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography-tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11-13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m2 with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m2 (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.

A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.

We propose a modified self-controlled case series (SCCS) method to handle both event-dependent exposures and high event-related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID-19 vaccines. Event-dependence of vaccinations, and high event-related mortality, are likely to arise in other SCCS studies of COVID-19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death.

Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study).

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 ß: 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.

Cord Blood Adipocytokines and Body Composition in Early Childhood: A Systematic Review and Meta-Analysis.

Childhood obesity is a growing epidemic. Early identification of high-risk groups will allow for the development of prevention strategies. Cord blood adipocytokines have been previously examined as biomarkers predicting future obesity. We conducted a systematic review looking at the association between cord blood leptin and adiponectin with adiposity up to 5 years of age. A literature review was performed between January 1994 and August 2020 using two bibliographic databases (Medline/Pubmed and EMBASE) and was registered on PROSPERO (CRD42017069024). Studies using skinfold thickness and direct methods of assessing body composition in full term neonates were considered. Partial correlation and multiple regression models were used to present the results. Meta-analysis was performed, were possible, using a random effects model. Cochran's Q test was used to assess heterogeneity and I2 statistics to calculate the percentage of variation across studies. The potential for publication bias was assessed using funnel plots. Data from 22 studies were retrieved and reviewed by two independent reviewers. Cord blood leptin was positively associated with adiposity at birth (r = 0.487; 95% CI: 0.444, 0.531) but was inversely related to adiposity up to 3 years of age. The association was not sustained at 5 years. There was a weak positive association between adiponectin in cord blood and adiposity at birth (r = 0.201; 95% CI: 0.125, 0.277). No correlation was found between cord blood adiponectin in young children, but data were limited. This review supports that cord blood leptin and adiponectin are associated with adiposity at birth. The results of this study provide insight into the role of adipocytokines at birth on future metabolic health and their potential use as risk stratification tools.

Vitamin B12 deficiency and altered one-carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia.

Vitamin B12 (B12) is a micronutrient essential for one-carbon (1C) metabolism. B12 deficiency disturbs the 1C cycle and alters DNA methylation which is vital for most metabolic processes. Studies show that B12 deficiency may be associated with obesity, insulin resistance and gestational diabetes; and with obesity in child-bearing women. We therefore hypothesised that the associations between B12 deficiency, BMI and the metabolic risk could be mediated through altered 1C metabolites in early pregnancy. We explored these associations in two different early pregnancy cohorts in the UK (cohort 1; n = 244 and cohort 2; n = 60) with anthropometric data at 10-12 weeks and plasma/serum sampling at 16-18 weeks. B12, folate, total homocysteine (tHcy), methionine, MMA, metabolites of 1C metabolism (SAM, SAH) and anthropometry were measured. B12 deficiency (< 150 pmol/l) in early pregnancy was 23% in cohort 1 and 18% in cohort 2. Regression analysis after adjusting for likely confounders showed that B12 was independently and negatively associated with BMI (Cohort 1: ß = - 0.260, 95% CI (- 0.440, - 0.079), p = 0.005, Cohort 2: (ß = - 0.220, 95% CI (- 0.424, - 0.016), p = 0.036) and positively with HDL cholesterol (HDL-C) (ß = 0.442, 95% CI (0.011,0.873), p = 0.045). We found that methionine (ß = - 0.656, 95% CI (- 0.900, - 0.412), p < 0.0001) and SAH (ß = 0.371, 95% CI (0.071, 0.672), p = 0.017) were independently associated with triglycerides. Low B12 status and alteration in metabolites in 1C metabolism are common in UK women in early pregnancy and are independently associated with maternal obesity and dyslipidaemia. Therefore, we suggest B12 monitoring in women during peri-conceptional period and future studies on the pathophysiological relationship between changes in 1C metabolites and its association with maternal and fetal outcomes on larger cohorts. This in turn may offer potential to reduce the metabolic risk in pregnant women and their offspring.

Systematic review with meta-analysis of over 90 000 patients. Does fast-track review diagnose colorectal cancer earlier?

BACKGROUND: National UK data on colorectal cancer (CRC) stage at diagnosis is incomplete. Site-specific fast-track (2-week wait) cancer data are not collected directly by NHS England. Policy making based on these data alone can lead to inaccuracy. AIMS: To review available data on key outcomes (cancer conversion rate and stage at diagnosis) for the UK's lower gastrointestinal 2-week wait pathway. METHODS: A comprehensive literature search was conducted between 2000 and 2017. Primary outcomes were cancer conversion rate and cancer stage at diagnosis. Results were expressed as proportions with 95% CIs. A random effects model was used for meta-analysis; heterogeneity was assessed by I2 . RESULTS: Of 95 papers reviewed, 49 were included in analysis with a total study population of 93,655. Cancer conversion rate was 7.7% (95% CI: 6.9-8.5). The proportion presenting at Dukes A = 11.2% (95% CI 7.4-15.6), B = 36.7% (95% CI 30.8-42.8), C = 35.7% (95% CI: 30.8-40.8) and D = 11.1% (95% CI 7.3-15.5). No colonic pathology was diagnosed in 54.6% (95% CI: 46.2-62.8). CONCLUSIONS: Only 7.7% of patients referred by the 2-week wait pathway were found to have CRC. No beneficial effect on stage at diagnosis was found compared to non-2-week wait referral pathways. Over half of patients had no colonic pathology and detection of adenomas was very low. These results should prompt a reconsideration of the benefits of the 2-week wait pathway in CRC diagnosis and outcomes, with more focus on strategies to improve patient selection.

Reduced GLP-1 Secretion at 30 Minutes After a 75-g Oral Glucose Load Is Observed in Gestational Diabetes Mellitus: A Prospective Cohort Study.

Glucagon-like peptide 1 (GLP-1) levels may be reduced in type 2 diabetes, but whether a similar impairment exists in gestational diabetes mellitus (GDM) has not been established. We studied this in a prospective cohort study of pregnant women (n = 144) during oral glucose tolerance test (OGTT). GLP-1, glucose, and insulin were sampled at 30-min intervals during a 2-h 75-g OGTT, and indices of insulin secretion and sensitivity were calculated. In a nested case-control study, women with GDM (n = 19) had 12% lower total GLP-1 secretion area under the curve (AUC) compared with control subjects matched for age, ethnicity, and gestational age (n = 19), selected from within the lowest quartile of glucose120 min values in our cohort. GDM had lower GLP-1 response in the first 30 min (19% lower GLP-130 min and 17% lower AUC0-30 min) after adjustment for possible confounders. Their glucose levels began to diverge at 30 min of the OGTT with increasing insulin levels, and by 120 min, their insulin levels were three times higher. In a secondary cohort of 57 women that included "high-normal" glucose120 min values, low GLP-1 AUC0-30 min was independently associated with lower indices of insulin secretion and sensitivity. In conclusion, we have observed that women with GDM have lower GLP-1 response at 30 min of an OGTT and hyperglycemia at 120 min despite significant hyperinsulinemia.

Effectiveness of live attenuated influenza vaccine in preventing amoxicillin prescribing in preschool children: a self-controlled case series study.

Objectives: To determine the effectiveness of live attenuated influenza vaccine (LAIV) in reducing amoxicillin prescribing in preschool children in primary care. Patients and methods: We used The Health Improvement Network (THIN), a large primary care database from the United Kingdom. We included children aged 2 to 4 years old at the start of either the 2013/14 or the 2014/15 winter season, with at least one amoxicillin prescription between September and May, irrespective of LAIV vaccination status. We used the self-controlled case series method to estimate influenza vaccine effectiveness (VE). Results: The total study sample included 33 137 children from 378 general practices during the two winter seasons. Of these children, 43.4% with at least one amoxicillin prescription had been vaccinated. The rate of amoxicillin prescribing was significantly reduced during periods of influenza vaccine immunity. The associated VE for amoxicillin prescribing was 12.8% (95% CI 6.9%, 18.3%) in 2013/14 and 14.5% (9.6%, 19.2%) in 2014/15. Given a VE of 14.5%, we estimated that amoxicillin prescribing could have been reduced by 5.6% if LAIV uptake in children aged 2-4 years increased to 50% in the 2014/15 winter season. Conclusions: Influenza vaccination of young children may contribute to a reduction in the prescribing of amoxicillin, one of the most commonly prescribed antibiotics in primary care. Further studies are required to confirm the size of the effect.

Investigating the assumptions of the self-controlled case series method.

We describe some simple techniques for investigating 2 key assumptions of the self-controlled case series (SCCS) method, namely, that events do not influence subsequent exposures and that events do not influence the length of observation periods. For each assumption, we propose some simple tests based on the standard SCCS model, along with associated graphical displays. The methods also enable the user to investigate the robustness of the results obtained using the standard SCCS model to failure of assumptions. The proposed methods are investigated by simulations and applied to data on measles, mumps and rubella vaccine, and antipsychotics.

Spline-based self-controlled case series method.

The self-controlled case series (SCCS) method is an alternative to study designs such as cohort and case control methods and is used to investigate potential associations between the timing of vaccine or other drug exposures and adverse events. It requires information only on cases, individuals who have experienced the adverse event at least once, and automatically controls all fixed confounding variables that could modify the true association between exposure and adverse event. Time-varying confounders such as age, on the other hand, are not automatically controlled and must be allowed for explicitly. The original SCCS method used step functions to represent risk periods (windows of exposed time) and age effects. Hence, exposure risk periods and/or age groups have to be prespecified a priori, but a poor choice of group boundaries may lead to biased estimates. In this paper, we propose a nonparametric SCCS method in which both age and exposure effects are represented by spline functions at the same time. To avoid a numerical integration of the product of these two spline functions in the likelihood function of the SCCS method, we defined the first, second, and third integrals of I-splines based on the definition of integrals of M-splines. Simulation studies showed that the new method performs well. This new method is applied to data on pediatric vaccines. Copyright © 2017 John Wiley & Sons, Ltd.