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Introduction Material and Methods Results Conclusions Evidence suggests that gestational diabetes mellitus (GDM) is associated with subsequent cardiovascular disease; however, it is unclear what impact changes in screening and diagnostic criteria have had on the association of GDM with long‐term outcomes such as cardiovascular disease. The purpose of this study was to determine the association between GDM and subsequent cardiovascular disease during a period of rising gestational diabetes diagnosis in England. Specifically, associations were compared before and after 2008, when national guidelines supporting risk factor‐based screening were introduced.We conducted a cohort study using routinely collected data from the Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study consisted of persons aged 15–45 years with a livebirth or stillbirth between 1998 and 2017 and without a history of cardiovascular disease or pre‐pregnancy diabetes mellitus. Cox proportional hazards models, with propensity score weighting using matching weights, were used to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the association of GDM diagnosis in the first recorded pregnancy with subsequent cardiovascular disease.Among 232 315 individuals, the incidence of cardiovascular disease was 6.6 per 1000 person‐years among those with GDM and 2.2 per 1000 person‐years among those without GDM over a mean follow‐up duration of 5.8 years. The overall aHR, 95% CI was 1.91 (1.41, 2.60). Diagnosis of GDM increased over the study period, from 0.7% in 1998–99 to 5.3% in 2017. The effect size was not markedly different in the years before (1998–2007: adjusted HR 2.05, 95% CI 2.05 1.35, 3.12) and after 2008 (2008–2017: adjusted HR 1.79, 95% CI 1.15, 2.80).There was a strong association of GDM with cardiovascular disease after accounting for social and demographic factors and multiple comorbidities, and this association was present both before and after 2008, when national gestational diabetes screening criteria were established. [ABSTRACT FROM AUTHOR]

Aims: Metformin is increasingly used off‐label as the treatment of gestational diabetes (GDM). Our objective was to determine if metformin versus insulin initiation is associated with the adverse pregnancy outcomes. Materials and Methods: We conducted a retrospective cohort study using data from the Clinical Practice Research Datalink, its pregnancy register, and Hospital Episode Statistics from 1998 to 2018. We included pregnancies of women who initiated metformin or insulin between 20 weeks gestation and pregnancy end. The primary outcome was a composite outcome of large for gestational age (LGA) and macrosomia. The secondary outcomes included small for gestational age (SGA), preterm birth, caesarean delivery, and hypertensive disorders during pregnancy (HDP). Inverse probability weighted‐Cox proportional hazards models were to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CI), comparing those who initiated metformin versus insulin at cohort entry, accounting for baseline covariates. Results: Our cohort included pregnancies of 1297 women initiating metformin and of 895 women initiating insulin. Compared to insulin initiation, metformin initiation was associated with a decreased risk of LGA or macrosomia (HR 0.64, 95% CI 0.49, 0.78), Caesarean delivery (HR 0.83, 95% CI 0.69, 0.98), and preterm birth (HR 0.83, 95% CI 0.58, 1.08). The HRs for HDP and SGA were 0.92 (95% CI 0.57, 1.27) and 1.33 (95% CI 0.67, 2.00), respectively. Conclusions: Our study suggests that, compared to initiating insulin, initiating metformin is associated with decreased risks of adverse pregnancy outcomes among women with GDM. These findings provide important real‐world evidence regarding the use of metformin for GDM. [ABSTRACT FROM AUTHOR]

Background: While the benefits of levothyroxine are well‐established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women. Objective: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data. Methods: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention‐to‐treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non‐users (1:4) on time of diagnosis, gestational week of the first eligible trial and high‐dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). Results: Based on 159,177 eligible person‐trials (5781 women), the matched cohort included 181 initiators and 640 non‐initiators of levothyroxine, with 57 pregnancy losses occurring during follow‐up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid‐stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non‐initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56). Conclusions: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy. [ABSTRACT FROM AUTHOR]

Aims: The contemporary prescription patterns of antidiabetic drugs following guideline changes recommending metformin as first‐line gestational diabetes (GDM) pharmacotherapy is underexplored. We aimed to examined use of metformin and insulin during pregnancy among women with GDM over 20 years in the United Kingdom. Methods: We conducted a population‐based cohort study using linked data from the Clinical Practice Research Datalink, its pregnancy register and Hospital Episode Statistics from 1998 to 2017. We included pregnancies of women without prior diabetes history who received GDM diagnosis or initiated an antidiabetic drug after 20 weeks gestation. Patient‐level and practice‐level characteristics were compared between metformin initiators and insulin initiators. We described trends of initiating metformin as first‐line treatment and described time to initiation of rescue insulin overall, and by body mass index among metformin initiators. Results: Our cohort included 5633 pregnancies from 5393 women with GDM, of whom 38.9% initiated pharmacotherapy (41% insulin, 59% metformin). Metformin prescriptions (as opposed to insulin) increased substantially, from <5% of pregnancies before 2007 to 42.5% in 2008. Over 85% of pregnancies that were prescribed pharmacotherapy were prescribed metformin as first‐line treatment in 2015. Among metformin initiators, 16% initiated rescue insulin, typically occurring within 40 days of metformin initiation. Choice of GDM pharmacotherapy varied by characteristics, including smoking, obesity, race/ethnicity and general practice regions. Conclusions: Metformin was the most prescribed medication for GDM, with large increases over the past 2 decades. The increasing use of oral‐antidiabetic drugs during pregnancy, consistent with other regions, highlights the need for future studies examining effectiveness and safety of antidiabetic drug use during pregnancy. [ABSTRACT FROM AUTHOR]

Photoperiod/temperature‐sensitive genic male sterility (P/TGMS) is widely applied for improving crop production. Previous investigations using the reversible male sterile (rvms) mutant showed that slow development is a general mechanism for restoring fertility to P/TGMS lines in Arabidopsis. In this work, we isolated a restorer of rvms–2 (res3), as the male sterility of rvms–2 was rescued by res3. Phenotype analysis and molecular cloning show that a point mutation in UPEX1 l in res3 leads to delayed secretion of callase A6 from the tapetum to the locule and tetrad callose wall degradation. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis demonstrated that the tapetal transcription factor ABORTED MICROSPORES directly regulates UPEX1 expression, revealing a pathway for tapetum secretory function. Early degradation of the callose wall in the transgenic line eliminated the fertility restoration effect of res3. The fertility of multiple known P/TGMS lines with pollen wall defects was also restored by res3. We propose that the remnant callose wall may broadly compensate for the pollen wall defects of P/TGMS lines by providing protection for pollen formation. A cellular mechanism is proposed to explain how slow development restores the fertility of P/TGMS lines in Arabidopsis. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests a role for micro RNAs (mi RNAs) in regulating various processes of mammalian postnatal development and aging. To investigate the changes in blood-based mi RNA expression from preterm infants to adulthood, we compared 365 mi RNA expression profiles in a screening set of preterm infants and adults. Approximately one-third of the mi RNAs were constantly expressed from postnatal development to adulthood, another one-third were differentially expressed between preterm infants and adults, and the remaining one-third were not detectable in these two groups. Based on their expression in infants and adults, the mi RNAs were categorized into five classes, and six of the seven mi RNAs chosen from each class except one with age-constant expression were confirmed in a validation set containing infants, children, and adults. Comparing the chromosomal locations of the different mi RNA classes revealed two hot spots: the mi RNA cluster on 14q32.31 exhibited age-constant expression, and the one on 9q22.21 exhibited up-regulation in adults. Furthermore, six mi RNAs detectable in adults were down-regulated in older adults, and four chosen for individual quantification were verified in the validation set. Analysis of the network functions revealed that differentially regulated mi RNAs between infants and adults and mi RNAs that decreased during aging shared two network functions: inflammatory disease and inflammatory response. Four expression patterns existed in the 11 mi RNAs from infancy to adulthood, with a significant transition in ages 9-20 years. Our results provide an overview on the regulation pattern of blood mi RNAs throughout life and the possible biological functions performed by different classes of mi RNAs. [ABSTRACT FROM AUTHOR]