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.

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.

Evaluation of the risk of cardiovascular events with clarithromycin using both propensity score and self-controlled study designs.

AIM: Some previous studies suggest a long term association between clarithromycin use and cardiovascular events. This study investigates this association for clarithromycin given as part of Helicobacter pylori treatment (HPT). METHODS: Our source population was the Clinical Practice Research Datalink (CPRD), a UK primary care database. We conducted a self-controlled case series (SCCS), a case-time-control study (CTC) and a propensity score adjusted cohort study comparing the rate of cardiovascular events in the 3 years after exposure to HPT containing clarithromycin with exposure to clarithromycin free HPT. Outcomes were first incident diagnosis of myocardial infarction (MI), arrhythmia and stroke. For the cohort analysis we included secondary outcomes all cause and cardiovascular mortality. RESULTS: Twenty-eight thousand five hundred and fifty-two patients were included in the cohort. The incidence rate ratio of first MI within 1 year of exposure to HPT containing clarithromycin was 1.07 (95% CI 0.85, 1.34, P = 0.58) and within 90 days was 1.43 (95% CI 0.99, 2.09 P = 0.057) in the SCCS analysis. CTC and cohort results were consistent with these findings. CONCLUSIONS: There was some evidence for a short term association for first MI but none for a long term association for any outcome.

Flexible modelling of vaccine effect in self-controlled case series models.

The self-controlled case series (SCCS) method, commonly used to investigate the safety of vaccines, requires information on cases only and automatically controls all age-independent multiplicative confounders, while allowing for an age-dependent baseline incidence. Currently, the SCCS method represents the time-varying exposures using step functions with pre-determined cut points. A less prescriptive approach may be beneficial when the shape of the relative risk function associated with exposure is not known a priori, especially when exposure effects can be long-lasting. We therefore propose to model exposure effects using flexible smooth functions. Specifically, we used a linear combination of cubic M-splines which, in addition to giving plausible shapes, avoids the integral in the log-likelihood function of the SCCS model. The methods, though developed specifically for vaccines, are applicable more widely. Simulations showed that the new approach generally performs better than the step function method. We applied the new method to two data sets, on febrile convulsion and exposure to MMR vaccine, and on fractures and thiazolidinedione use.

Self-controlled case series method with smooth age effect.

The self-controlled case series method, commonly used to investigate potential associations between vaccines and adverse events, requires information on cases only and automatically controls all age-independent multiplicative confounders while allowing for an age-dependent baseline incidence. In the parametric version of the method, we modelled the age-specific relative incidence by using a piecewise constant function, whereas in the semiparametric version, we left it unspecified. However, mis-specification of age groups in the parametric version can lead to biassed estimates of exposure effect, and the semiparametric approach runs into computational problems when the number of cases in the study is moderately large. We, thus, propose to use a penalized likelihood approach where the age effect is modelled using splines. We use a linear combination of cubic M-splines to approximate the age-specific relative incidence and integrated splines for the cumulative relative incidence. We conducted a simulation study to evaluate the performance of the new approach and its efficiency relative to the parametric and semiparametric approaches. Results show that the new approach performs equivalently to the existing methods when the sample size is small and works well for large data sets. We applied the new spline-based approach to data on febrile convulsions and paediatric vaccines. Co

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.

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.].

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.

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.

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.

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).

Cardiovascular outcomes associated with use of clarithromycin: population based study.

STUDY QUESTION: What is the association between clarithromycin use and cardiovascular outcomes? METHODS: In this population based study the authors compared cardiovascular outcomes in adults aged 18 or more receiving oral clarithromycin or amoxicillin during 2005-09 in Hong Kong. Based on age within five years, sex, and calendar year at use, each clarithromycin user was matched to one or two amoxicillin users. The cohort analysis included patients who received clarithromycin (n=108,988) or amoxicillin (n=217,793). The self controlled case series and case crossover analysis included those who received Helicobacter pylori eradication treatment containing clarithromycin. The primary outcome was myocardial infarction. Secondary outcomes were all cause, cardiac, or non-cardiac mortality, arrhythmia, and stroke. STUDY ANSWER AND LIMITATIONS: The propensity score adjusted rate ratio of myocardial infarction 14 days after the start of antibiotic treatment was 3.66 (95% confidence interval 2.82 to 4.76) comparing clarithromycin use (132 events, rate 44.4 per 1000 person years) with amoxicillin use (149 events, 19.2 per 1000 person years), but no long term increased risk was observed. Similarly, rate ratios of secondary outcomes increased significantly only with current use of clarithromycin versus amoxicillin, except for stroke. In the self controlled case analysis, there was an association between current use of H pylori eradication treatment containing clarithromycin and cardiovascular events. The risk returned to baseline after treatment had ended. The case crossover analysis also showed an increased risk of cardiovascular events during current use of H pylori eradication treatment containing clarithromycin. The adjusted absolute risk difference for current use of clarithromycin versus amoxicillin was 1.90 excess myocardial infarction events (95% confidence interval 1.30 to 2.68) per 1000 patients. WHAT THIS STUDY ADDS: Current use of clarithromycin was associated with an increased risk of myocardial infarction, arrhythmia, and cardiac mortality short term but no association with long term cardiovascular risks among the Hong Kong population. FUNDING, COMPETING INTERESTS, DATA SHARING: ID was funded by grants from the Medical Research Council for this project. LS was funded by a grant from the Wellcome Trust. The authors have no competing interests. No additional data are available.