Sodium-glucose cotransporter-2 inhibitors and the risk of gout in patients with type 2 diabetes mellitus: A propensity-score-matched, new-user design study with an active comparator using the IQVIA Medical Research Data UK database.

AIM: To conduct a pharmacoepidemiological study to explore the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and gout in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A retrospective open cohort study using the IQVIA Medical Research Data UK database was performed between November 1, 2012 and December 31, 2018, estimating the risk of gout in patients with T2DM who were new users of SGLT2 inhibitors, compared to propensity-score-matched new users of dipeptidyl peptidase-4 (DPP-4) inhibitors. RESULTS: A total of 85 incident cases of gout were recorded over 30 389 person-years of observation in 13 617 new users of SGLT2 inhibitors and 29 426 new users of DPP-4 inhibitors. Crude incidence rates (IRs) per 1000 person-years were 2.90 and 2.47 for new users of SGLT2 inhibitors and DPP-4 inhibitors, respectively. The unadjusted hazard ratio (HR) was 1.18 (95% confidence interval [CI] 0.76-1.83). The adjusted HR was 1.20 (95% CI 0.77-1.86). In the at-treatment analysis, crude IRs per 1000 person-years were found to be 2.68 and 2.53 for SGLT2 inhibitor and DPP-4 inhibitor users, respectively. In the adjusted model, the adjusted HR was 1.3 (95% CI 0.90-2.29). Sensitivity analyses did not change the findings. CONCLUSIONS: In this nationwide study, no difference in the incidence of gout was documented in patients treated with SGLT2 inhibitors compared to DPP-4 inhibitor users. This neutral finding remained consistent in sensitivity analyses.

Polycystic ovary syndrome and risk of adverse obstetric outcomes: a retrospective population-based matched cohort study in England.

BACKGROUND: Polycystic ovary syndrome (PCOS) affects up to one in five women of childbearing age. Observational studies assessing the association between maternal PCOS and adverse obstetric outcomes have reported varying results, depending on patient population, diagnostic criteria for PCOS and covariates accounted for in their analyses. We aimed to assess the risk of obstetric outcomes among a population-based representative cohort of women with PCOS compared to an age-matched cohort of women without PCOS. METHODS: A retrospective cohort study was conducted of pregnancies of women in England aged 15-49 years identified from the Clinical Practice Research Datalink (CPRD) GOLD pregnancy register and linked Hospital Episodes Statistic (HES) data between March 1997 and March 2020. Pregnancies from the register that had a linked HES delivery record were included. Linked CPRD primary care data was used to ascertain maternal PCOS exposure prior to pregnancy. To improve detection of PCOS, in addition to PCOS diagnostic codes, codes for (1) polycystic ovaries or (2) hyperandrogenism and anovulation together were also considered. Sensitivity analysis was limited to only pregnant women with a diagnostic code for PCOS. Primary outcomes ascertained from linked HES data were (1) preterm delivery (gestation < 37 weeks), (2) mode of delivery, (3) high (> 4000 g) or low birthweight (< 2500 g) and (4) stillbirth. Secondary outcomes were (1) very preterm delivery (< 32 weeks), (2) extremely preterm delivery (< 28 weeks), (3) small and (4) large for gestational age. Conditional logistic regression models were performed adjusting for age, ethnicity, deprivation, dysglycaemia, hypertension, thyroid disorders, number of babies born at index pregnancy, and pre-gravid BMI. Multiple imputation was performed for missing outcome data. RESULTS: 27,586 deliveries with maternal PCOS were matched for age (± 1 year) to 110,344 deliveries without PCOS. In the fully adjusted models, maternal PCOS was associated with an increased risk of (1) preterm birth [aOR: 1.11 (95% CI 1.06-1.17)], and (2) emergency caesarean, elective caesarean and instrumental vaginal compared to spontaneous delivery [aOR: 1.10 (1.05-1.15), 1.07 (1.03-1.12) and 1.04 (1.00-1.09), respectively]. There was absence of association with low birthweight, high birthweight and stillbirth. In the sensitivity analysis, the association with preterm birth [aOR: 1.31 (95% CI 1.13-1.52)], emergency caesarean [aOR: 1.15 (95% CI 1.02-1.30)], and elective caesarean [aOR: 1.03 (95% CI 1.02-1.03)] remained. While there was no significant association with any of the secondary outcomes in the primary analysis, in the sensitivity analysis maternal PCOS was associated with increased risk of extremely preterm delivery [aOR: 1.86 (95% CI 1.31-2.65)], and lower risk of small for gestational age babies [aOR: 0.74 (95% CI 0.59-0.94)]. CONCLUSIONS: Maternal PCOS was associated with increased risk of preterm and caesarean delivery. Association with low birthweight may be largely mediated by lower gestational age at birth.

Teriparatide Treatment in Patients with Pregnancy- and Lactation-Associated Osteoporosis.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare disease, presenting in most cases with severe back pain due to low energy vertebral fractures (VFs). Our purpose was to assess the effect of teriparatide (TPTD) vs. conventional management on areal bone mineral density (aBMD) and trabecular bone score (TBS) in patients with PLO. A multicenter retrospective cohort study concerning premenopausal women with PLO. Nineteen women were treated with TPTD (20 µg/day) (group A) plus calcium and vitamin D and eight women with calcium and vitamin D only (group B) for up to 24 months. The primary end-point was between group differences in lumbar spine (LS) and total hip (TH) aBMD, and TBS at 12 and 24 months. Patients in group A had sustained a median of 4.0 VFs (3-9) vs. 2.5 VFs (1-10) in group B (p = 0.02). At 12 months, patients on TPTD vs. controls achieved a mean aBMD increase of 20.9  ±  11.9% vs. 6.2  ±  4.8% at the LS (p < 0.001), 10.0  ±  11.6% vs. 5.8  ±  2.8% at the TH (p = 0.43), and 6.7  ±  6.9% vs. 0.9  ±  3.7% in TBS (p = 0.09), respectively. At 24 months, seven patients on TPTD and six controls achieved a mean LS aBMD increase of 32.9  ±  13.4% vs. 12.2  ±  4.2% (p = 0.001). P1NP levels during the first month of TPTD treatment were positively correlated with the 1-year LS aBMD change (r = 0.68, p = 0.03). No new clinical fractures occurred while on-treatment. In patients with PLO, TPTD treatment resulted in significantly greater increases in LS aBMD compared with calcium and vitamin D supplementation at 12 and 24 months.

Sodium-glucose co-transporter-2 inhibitors and susceptibility to COVID-19: A population-based retrospective cohort study.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are widely prescribed in people with type 2 diabetes. We aimed to investigate whether SGLT2 inhibitor prescription is associated with COVID-19, when compared with an active comparator. We performed a propensity-score-matched cohort study with active comparators and a negative control outcome in a large UK-based primary care dataset. Participants prescribed SGLT2 inhibitors (n = 9948) and a comparator group prescribed dipeptidyl peptidase-4 (DPP-4) inhibitors (n = 14 917) were followed up from January 30 to July 27, 2020. The primary outcome was confirmed or clinically suspected COVID-19. The incidence rate of COVID-19 was 19.7/1000 person-years among users of SGLT2 inhibitors and 24.7/1000 person-years among propensity-score-matched users of DPP-4 inhibitors. The adjusted hazard ratio was 0.92 (95% confidence interval 0.66 to 1.29), and there was no evidence of residual confounding in the negative control analysis. We did not observe an increased risk of COVID-19 in primary care amongst those prescribed SGLT2 inhibitors compared to DPP-4 inhibitors, suggesting that clinicians may safely use these agents in the everyday care of people with type 2 diabetes during the COVID-19 pandemic.

Data extraction for epidemiological research (DExtER): a novel tool for automated clinical epidemiology studies.

The use of primary care electronic health records for research is abundant. The benefits gained from utilising such records lies in their size, longitudinal data collection and data quality. However, the use of such data to undertake high quality epidemiological studies, can lead to significant challenges particularly in dealing with misclassification, variation in coding and the significant effort required to pre-process the data in a meaningful format for statistical analysis. In this paper, we describe a methodology to aid with the extraction and processing of such databases, delivered by a novel software programme; the "Data extraction for epidemiological research" (DExtER). The basis of DExtER relies on principles of extract, transform and load processes. The tool initially provides the ability for the healthcare dataset to be extracted, then transformed in a format whereby data is normalised, converted and reformatted. DExtER has a user interface designed to obtain data extracts specific to each research question and observational study design. There are facilities to input the requirements for; eligible study period, definition of exposed and unexposed groups, outcome measures and important baseline covariates. To date the tool has been utilised and validated in a multitude of settings. There have been over 35 peer-reviewed publications using the tool, and DExtER has been implemented as a validated public health surveillance tool for obtaining accurate statistics on epidemiology of key morbidities. Future direction of this work will be the application of the framework to linked as well as international datasets and the development of standardised methods for conducting electronic pre-processing and extraction from datasets for research purposes.

Quality of Life in Patients With Asymptomatic Primary Hyperparathyroidism After Parathyroidectomy: A 3-Year Longitudinal Study.

OBJECTIVE: Impaired quality of life (QoL) is considered as a nonclassical manifestation of primary hyperparathyroidism (PHPT). This study aimed to detect and compare changes in the QoL of patients with asymptomatic PHPT who had successful curative parathyroidectomy (PTX) 3 months and 3 years after the procedure. METHODS: Patients with diagnosed PHPT were eligible for the study. There were 2 groups: the PTX group, with patients who underwent PTX, and the non-PTX group, with patients who were treated conservatively. QoL was assessed using Pasieka's Parathyroid Assessment of Symptoms Questionnaire (PAS-Q) at baseline, 3 months, and 3 years. RESULTS: Thirty-eight patients were included in the study: 18 in the PTX group and 20 in the non-PTX group. In the PTX group, the mean PAS-Q total score before PTX was 518, which was reduced significantly at the 3-month (P = .003) and 3-year assessments (P = .001). However, in the non-PTX group, the mean PAS-Q total score was 326 at baseline and increased continuously for 3 years (P = .019). At the 3-year evaluation, the mean total score was significantly higher compared to that of the PTX group (P = .021). Finally, there was a positive correlation between total serum calcium and PAS-Q score in the non-PTX group (r = 0.524, P = .018). CONCLUSION: QoL of patients with PHPT improved significantly compared to that in conservative surveillance as early as 3 months after successful, curative PTX, and remained improved for 3 years. This finding strengthens, even more, the hypothesis that PTX contributes to better QoL, suggesting that the derangement of QoL may be considered as an individual indication for surgery.

Correction: Increased risk of ischemic heart disease, hypertension, and type 2 diabetes in women with previous gestational diabetes mellitus, a target group in general practice for preventive interventions: A population-based cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1002488.].

Risk of incident circulatory disease in patients treated for differentiated thyroid carcinoma with no history of cardiovascular disease.

CONTEXT: The incidence of differentiated thyroid cancer (DTC) is increasing, yet the prognosis is favourable and long-term survival is expected. Exogenous TSH suppression has been used for many years to prevent DTC recurrence and may be associated with increased risks of circulatory diseases. DESIGN: Risks of circulatory disease in patients treated for DTC were compared to randomly matched patients without DTC (controls) up to a 1:5 ratio using age, sex, body mass index (BMI) and smoking as the matching parameters in a population-based, open cohort study using The Health Improvement Network. PATIENTS: A total of 3009 patients treated for DTC with no pre-existing cardiovascular disease were identified and matched to 11 303 controls, followed up to median of 5 years. RESULTS: A total of 1259 incident circulatory events were recorded during the observation period. No difference in the risk of ischaemic heart disease (IHD) (adjusted hazards ratio [aHR]: 1.04, 95% CI: 0.80-1.36) or heart failure (HF) (aHR: 1.27, 95% CI: 0.89-1.81) was detected. The risk of atrial fibrillation (AF) and stroke was significantly higher in patients with DTC (aHR: 1.71, 95% CI: 1.36-2.15 and aHR: 1.34, 95% CI: 1.05-1.72, respectively). In a sensitivity analysis limited to newly diagnosed patients with DTC, only the risk of AF was consistently elevated (aHR: 1.86, 95% CI: 1.33-2.60). CONCLUSIONS: The increased risk of AF in patients who have undergone treatment for DTC but without pre-existing CVD may warrant periodic screening for this arrhythmia. Whereas no evidence of increased risk of IHD or HF was observed, the increased risk of stroke/TIA warrants further investigation.

Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort.

OBJECTIVE: Previous studies suggest that androgens have a sexually dimorphic impact on metabolic dysfunction. However, the sex-specific link between circulating androgens and risk of type 2 diabetes mellitus (T2DM) has not been examined in a large scale, longitudinal cohort, a task we undertook in this study. DESIGN: A retrospective cohort study in a UK primary care database. PATIENTS: We included men and women with available serum testosterone and sex hormone-binding globulin (SHBG) results. MEASUREMENTS: We categorized serum concentrations according to clinically relevant cut-off points and calculated crude and adjusted T2DM Incidence Rate Ratios (IRRs and aIRRs). RESULTS: Serum testosterone concentrations were available in 70 541 men and 81 889 women; serum SHBG was available in 15 907 men and 42 034 women. In comparison to a reference cohort with serum testosterone ≥20 nmol/L, men with lower serum testosterone had a significantly increased risk of T2DM, with the highest risk in those with serum testosterone <7 nmol/L (aIRR 2.71, 95% CI 2.34-3.14, P < 0.001). In women, the risk of T2DM started to increase significantly when serum testosterone concentrations exceeded 1.5 nmol/L, with the highest risk in women with serum testosterone ≥3.5 nmol/L (aIRR 1.98, 95% CI 1.55-2.52, P < 0.001). These observations were verified in a continuous rather than categorized analysis. The risk of T2DM increased in men and women with serum SHBG <40 and <50 nmol/L, respectively. CONCLUSIONS/INTERPRETATION: In this longitudinal study, we found sexually dimorphic associations between serum testosterone and risk of incident T2DM. Androgen deficiency and excess should be considered important risk factors for diabetes in men and women, respectively.

Correction to: Clinically meaningful and lasting HbA1c improvement rarely occurs after 5 years of type 1 diabetes: an argument for early, targeted and aggressive intervention following diagnosis.

AbstractIn Table 1 the data for age group, sex and Townsend index were incorrectly identified as mean ± SD instead of n (%). The table is corrected here.

Clinically meaningful and lasting HbA1c improvement rarely occurs after 5 years of type 1 diabetes: an argument for early, targeted and aggressive intervention following diagnosis.

AIMS/HYPOTHESIS: Our objectives were to explore whether the phenomenon of HbA1c 'tracking' occurs in individuals with type 1 diabetes, how long after diagnosis does tracking take to stabilise, and whether there is an effect of sex and age at diagnosis on tracking. METHODS: A total of 4525 individuals diagnosed with type 1 diabetes between 1 January 1995 and 1 May 2015 were identified from The Health Improvement Network (THIN) database. Mixed models were applied to assess the variability of HbA1c levels over time with random effects on general practices (primary care units) and individuals within practices. RESULTS: 4525 individuals diagnosed with type 1 diabetes were identified in THIN over the study period. The greatest difference in mean HbA1c measurement (-7.0 [95% CI -8.0, -6.1] mmol/mol [0.6%]) was seen when comparing measurements made immediately after diagnosis (0-1 year since diagnosis) with those at 10 or more years (the reference category). The mean difference in HbA1c for the successive periods compared with 10 or more years after diagnosis declined and was no longer statistically significant after 5 years. In the stratified analysis using sex and age group there was considerable heterogeneity with adult onset type 1 diabetes appearing to track earlier and at a lower mean HbA1c. CONCLUSIONS/INTERPRETATION: In individuals with type 1 diabetes, glycaemic control measured by HbA1c settles onto a long-term 'track' and this occurs on average by 5 years following diagnosis. Age at diagnosis modifies both the rate at which individuals settle into their track and the absolute HbA1c tracking level for the next 10 years.

Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database.

BACKGROUND: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and represents a lifelong metabolic disorder, with increased risk of type 2 diabetes, hypertension, and cardiovascular events. Previous studies have suggested an increased risk of nonalcoholic fatty liver disease (NAFLD) in individuals with PCOS and implicated androgen excess as a potential driver. METHODS AND FINDINGS: We carried out a retrospective longitudinal cohort study utilizing a large primary care database in the United Kingdom, evaluating NAFLD rates in 63,120 women with PCOS and 121,064 age-, body mass index (BMI)-, and location-matched control women registered from January 2000 to May 2016. In 2 independent cohorts, we also determined the rate of NAFLD in women with a measurement of serum testosterone (n = 71,061) and sex hormone-binding globulin (SHBG; n = 49,625). We used multivariate Cox models to estimate the hazard ratio (HR) for NAFLD and found that women with PCOS had an increased rate of NAFLD (HR = 2.23, 95% CI 1.86-2.66, p < 0.001), also after adjusting for BMI or dysglycemia. Serum testosterone >3.0 nmol/L was associated with an increase in NAFLD (HR = 2.30, 95% CI 1.16-4.53, p = 0.017 for 3-3.49 nmol/L and HR = 2.40, 95% CI 1.24-4.66, p = 0.009 for >3.5 nmol/L). Mirroring this finding, SHBG <30 nmol/L was associated with increased NAFLD hazard (HR = 4.75, 95% CI 2.44-9.25, p < 0.001 for 20-29.99 nmol/L and HR = 4.98, 95% CI 2.45-10.11, p < 0.001 for <20 nmol/L). Limitations of this study include its retrospective nature, absence of detailed information on criteria used to diagnosis PCOS and NAFLD, and absence of data on laboratory assays used to measure serum androgens. CONCLUSIONS: We found that women with PCOS have an increased rate of NAFLD. In addition to increased BMI and dysglycemia, androgen excess contributes to the development of NAFLD in women with PCOS. In women with PCOS-related androgen excess, systematic NAFLD screening should be considered.

Increased risk of ischemic heart disease, hypertension, and type 2 diabetes in women with previous gestational diabetes mellitus, a target group in general practice for preventive interventions: A population-based cohort study.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with developing type 2 diabetes, but very few studies have examined its effect on developing cardiovascular disease. METHODS AND FINDINGS: We conducted a retrospective cohort study utilizing a large primary care database in the United Kingdom. From 1 February 1990 to 15 May 2016, 9,118 women diagnosed with GDM were identified and randomly matched with 37,281 control women by age and timing of pregnancy (up to 3 months). Adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were calculated for cardiovascular risk factors and cardiovascular disease. Women with GDM were more likely to develop type 2 diabetes (IRR = 21.96; 95% CI 18.31-26.34) and hypertension (IRR = 1.85; 95% CI 1.59-2.16) after adjusting for age, Townsend (deprivation) quintile, body mass index, and smoking. For ischemic heart disease (IHD), the IRR was 2.78 (95% CI 1.37-5.66), and for cerebrovascular disease 0.95 (95% CI 0.51-1.77; p-value = 0.87), after adjusting for the above covariates and lipid-lowering medication and hypertension at baseline. Follow-up screening for type 2 diabetes and cardiovascular risk factors was poor. Limitations include potential selective documentation of severe GDM for women in primary care, higher surveillance for outcomes in women diagnosed with GDM than control women, and a short median follow-up postpartum period, with a small number of outcomes for IHD and cerebrovascular disease. CONCLUSIONS: Women diagnosed with GDM were at very high risk of developing type 2 diabetes and had a significantly increased incidence of hypertension and IHD. Identifying this group of women in general practice and targeting cardiovascular risk factors could improve long-term outcomes.

Males with prolactinoma are at increased risk of incident cardiovascular disease.

OBJECTIVE: To investigate whether the risk of incident cardiovascular disease (CVD) is increased in patients with prolactinoma. DESIGN: Population-based, retrospective, open-cohort study using The Health Improvement Network (THIN) database. PATIENTS: A total of 2233 patients with prolactinoma and 10 355 matched controls (1:5 ratio) from UK General Practices contributing to THIN were included. Sex, age, body mass index and smoking status were used as matching parameters. The primary outcome was any incident CVD, defined by Read codes suggesting myocardial infarction, angina pectoris, stroke, transient ischaemic attack or heart failure. Sex-specific-adjusted incidence rate ratios (aIRRs) were calculated with Poisson regression, using clinically relevant parameters as model covariates. Sensitivity analyses were performed to check whether a change in the initial assumptions could have an impact on the findings. RESULTS: During the 6-year observation period, the composite CVD outcome was recorded in 54 patients with prolactinoma and 180 "nonexposed" individuals. The incidence rate was 1.8 and 14.8 per 1000 person-years for the females and males with prolactinoma, respectively. The aIRRs for CVD were estimated at 0.99 [95% confidence interval (CI): 0.61-1.61, P = .968)] in female patients and 1.94 (95% CI: 1.29-2.91, P = .001) in male patients. These findings remained robust in sensitivity analyses restricting to patients with documented record of dopamine agonist treatment and those with newly diagnosed prolactinoma. CONCLUSIONS: In contrast to females, men with prolactinoma have increased risk for incident CVD; the aetiology of this gender-specific finding remains to be elucidated.

Initiation of dapagliflozin and treatment-emergent fractures.

An increase in fracture risk has been reported in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin, possibly mediated by effects induced by all members of the sodium-glucose co-transporter-2 (SGLT2) inhibitor class. It is unclear whether initiation of dapagliflozin is followed by an increase in the risk of fracture; therefore, we performed a population-based, open cohort study (from January 2013 to January 2016) using The Health Improvement Network (THIN). A total of 22 618 people with T2DM (4548 exposed to dapagliflozin and 18 070 receiving standard antidiabetic treatment, matched for age, sex, body mass index and diabetes duration) with no history of fractures at baseline were included. The primary outcome was the occurrence of any fragility fracture (hip, spine, wrist) during the observation period. Risk of any fracture served as a secondary outcome. Adjusted hazard rate ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox regression. A total of 289 fractures (132 fragility fractures) were recorded. No difference in the risk of fragility fracture was detected between participants prescribed dapagliflozin and matched control participants (crude HR 0.90, 95% CI 0.59-1.39, P = .645; adjusted HR 0.87, 95% CI 0.56-1.35, P = .531). Similarly, no difference in the risk of any fracture was detected (adjusted HR 0.89, 95% CI 0.66-1.20; P = .427). Sensitivity analyses limited to the subset of the population at high risk of fracture produced similar results; thus, there was no evidence to suggest an increase in the risk of treatment-emergent fractures in patients with T2DM who initiated treatment with dapagliflozin.

Type 1 diabetes mellitus and risk of incident epilepsy: a population-based, open-cohort study.

AIMS/HYPOTHESIS: The aim of this research was to explore the relationship between incident epilepsy and type 1 diabetes in British participants. METHODS: Using The Health Improvement Network database, we conducted a retrospective, open-cohort study. Patients who were newly diagnosed with type 1 diabetes mellitus at the age of ≤40 years were identified and followed-up from 1 January 1990 to 15 September 2015. These patients, identified as not suffering from epilepsy at the time of diagnosis, were randomly matched with up to four individuals without type 1 diabetes mellitus, based on age, sex and participating general practice. A Cox regression analysis was subsequently performed using Townsend deprivation index, cerebral palsy, head injury and learning disabilities as model covariates. RESULTS: The study population consisted of a total of 24,610 individuals (4922 with type 1 diabetes and 19,688 controls). These individuals were followed up for a mean of 5.4 years (approximately 132,000 person-years of follow up). Patients with type 1 diabetes were significantly more likely to be diagnosed with epilepsy during the observation period compared with controls (crude HR [95% CI]: 3.02 [1.95, 4.69]). The incidence rate was estimated to be 132 and 44 per 100,000 person-years in patients and controls, respectively. This finding persisted after adjusting for model covariates (adjusted HR [95% CI]: 3.01 [1.93, 4.68]) and was also robust to sensitivity analysis, excluding adult-onset type 1 diabetes mellitus. CONCLUSIONS/INTERPRETATION: Patients with type 1 diabetes are at approximately three-times greater risk of developing epilepsy compared with matched controls without type 1 diabetes. This should be considered when investigating seizure-related disorders in patients with type 1 diabetes mellitus.

Levothyroxine liquid solution versus tablet for replacement treatment in hypothyroid patients.

BACKGROUND: Although replacement treatment with L-thyroxine (LT4) seems easy to manage, about one-third of hypothyroid patients show thyroid-stimulating hormone (TSH) values outside the normal range. OBJECTIVES: To explore whether LT4 liquid formulation (monodose vials or drops) affects TSH stability values and to assess its ability to maintain TSH within the normal range compared to tablets. METHODS: A total of 100 hypothyroid patients on replacement treatment with LT4 liquid solution were enrolled (Liquid Group) at a follow-up visit (revisit). The inclusion criteria were 1) treatment for surgical hypothyroidism for at least 2 years or autoimmune hypothyroidism for at least 5 years, 2) normal TSH at the previous visit 12 months before enrollment (baseline visit), and 3) maintenance of the same LT4 dosage during the time interval between the baseline and the follow-up visit. Using the same selection process, we also enrolled 100 hypothyroid patients on replacement treatment with LT4 tablets (Tablet Group). RESULTS: At the follow-up visit, 19 patients of the Tablet Group and 8 patients of the Liquid Group had abnormal TSH values (P = .023). Weekly and daily LT4 dosage per kilogram were higher in Tablet Group (P = .016 and .006, respectively). The magnitude of TSH change from baseline to follow-up visit was greater in the Tablet Group (P<.001). CONCLUSION: The use of LT4 liquid formulation compared to tablet resulted in a significantly higher number of hypothyroid patients who maintained the euthyroid state in a 12-month follow-up period and a reduced variability in TSH values.

Maternal subclinical hypothyroidsm and gestational diabetes mellitus: a meta-analysis.

OBJECTIVE: The association between subclinical hypothyroidism (SCH) and gestational diabetes mellitus (GDM) is controversial. This review evaluates whether the risk of GDM is different in pregnant women with SCH compared to euthyroid pregnant women. METHODS: A computerized search of the MEDLINE and EMBASE databases was conducted from their inceptions to July 2013 and was complemented with the perusal of the reference sections of the retrieved articles. Prespecified criteria were applied to assess eligibility, and standard meta-analytic methodology was employed for evidence synthesis. RESULTS: Six cohort studies, reporting data on 35,350 pregnant women (1,216 women with SCH), were identified. The risk of GDM in pregnant women with SCH was found to be substantially higher compared to euthyroid pregnant women (5 studies, pooled unadjusted odds ratio [OR]: 1.35, 95% confidence interval [CI]: 1.05-1.75, I2: 41%, Harbord test P = .44). Similarly, the risk of GDM was estimated to be significantly higher in pregnant women with SCH when using adjusted estimates (3 studies, pooled adjusted OR: 1.39, 95% CI: 1.07-1.79, I2: 0%). Neither finding remained significant in sensitivity analyses. CONCLUSION: A modestly increased risk of GDM might be present in pregnant women with SCH compared to euthyroid pregnant women. Assuming a 5% baseline risk of GDM and that SCH increases the risk of GDM by 50% (in odds) compared to a euthyroid population, then there would be 1 extra case of GDM in every 43 pregnant women with SCH. This preliminary finding warrants further investigation.

Thyroid cancer after in vitro fertilization: a retrospective, non-consecutive case-series analysis.

Although a firm association between fertility treatment and thyroid cancer has not been established, the widespread use of IVF, as a substantial reservoir of subclinical thyroid cancer disease and evidence suggesting an estrogen-dependent behavior may render thyroid cancer patients after IVF a distinct subpopulation of particular interest. Thus, a retrospective, non-consecutive case-series analysis of patients with history of thyroid cancer after in vitro fertilization was conducted. Twelve female patients with thyroid cancer who had previously undergone IVF treatment were identified within the cohort of thyroid cancer patients followed in our institution. All cases of thyroid cancer were papillary thyroid carcinoma (PTC) on histology and median tumor size (25th and 75th percentile) was 12 mm (7 and 17 mm). Thyroid cancer was diagnosed after a median of 4 years (2 and 6 years) from the last IVF cycle and at the time of diagnosis lymph node metastases were present in five patients (42%) and distant metastases where seen in four of them. Collectively, these data suggest that an aggressive pattern of PTC might be present in this distinct subpopulation. This preliminary observation may be explained, at least in part, by the delay in the diagnosis.

Association of TSH concentrations and thyroid autoimmunity with IVF outcome in women with TSH concentrations within normal adult range.

BACKGROUND/AIMS: This study aimed to evaluate the association of thyroid-stimulating hormone (TSH) concentrations and presence of thyroid autoimmunity (TAI) with the live birth rate in euthyroid women undergoing in vitro fertilization (IVF). METHODS: This study of retrospective design included 158 euthyroid women (TSH 0.5-4.5 µIU/ml) who underwent IVF from January 2006 to December 2010. Thyroid parameters were measured on day 3 of the previous nontreatment cycle. Women were subgrouped and analyzed according to their TSH concentrations (low: 0.5-2.5 vs. high: 2.6-4.5 µIU/ml) and TAI (present vs. absent). RESULTS: No difference in the live birth rate was found between the TSH (low: 34.2% vs. high: 36.8%, p = 0.763) or TAI (present: 26.7% vs. absent: 34.3%, p = 0.568) subgroups. CONCLUSION: This study found no evidence that increased TSH concentrations or the presence of TAI determined before IVF affect the live birth rate in euthyroid women. A better insight into the role of thyroid function during application of IVF is needed.