Immune System Remodelling by Prenatal Betamethasone: Effects on β-Cells and Type 1 Diabetes

Perna-Barrull, David; Gieras, Anna; Rodríguez-Fernández, Silvia; Vives-Pi, Marta

doi:10.3389/fendo.2020.00540

Cited by 8 publications

(5 citation statements)

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“…In fact, antenatal glucocorticoids have an important impact on immune system ontogeny [ 22 ] and modify the T cell receptor repertoire, as we demonstrated in NOD mice [ 17 ]. Our recent results also showed betamethasone effects on β -cell growth, metabolism, and immunogenicity [ 19 ]. Additional effects of glucocorticoids are epigenetic modifications [ 33 ] which could affect both the developing immune system and the β -cells.…”

Section: Discussionmentioning

confidence: 88%

“…Specifically, synthetic glucocorticoids, most often betamethasone, are routinely administered to women at risk of preterm delivery between 24 and 34 weeks of gestation to accelerate lung maturation and reduce the severity of respiratory distress syndrome, therefore improving the survival rates of premature infants. Recent studies in experimental models of T1D show that prenatal betamethasone affects the two main players in this disease, the immune system and the pancreatic β -cells, and that corticosteroid-related changes may have long-term consequences in the offspring [ 17 – 19 ]. Since both the immune system and the pancreatic islets are still developing until birth, glucocorticoid exposure [ 20 ] may affect islet function [ 21 ] and T1D susceptibility.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal Betamethasone Exposure and its Impact on Pediatric Type 1 Diabetes Mellitus: A Preliminary Study in a Spanish Cohort

Perna-Barrull

Murillo

Real

et al. 2022

Journal of Diabetes Research

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Background. Betamethasone, a glucocorticoid used to induce lung maturation when there is a risk of preterm delivery, can affect the immune system maturation and type 1 diabetes (T1D) incidence in the progeny. It has been described that prenatal betamethasone protects offspring from experimental T1D development. The main aim of this study was to evaluate the possible association between betamethasone prenatal exposure and T1D in humans. Research Design and Methods. A retrospective case-control study with a total of 945 children, including 471 patients with T1D and 474 healthy siblings, was performed. Participants were volunteers from the Germans Trias i Pujol Hospital and DiabetesCero Foundation. Parents of children enrolled in the study completed a questionnaire that included questions about weeks of gestation, preterm delivery risk, weight at birth, and prenatal betamethasone exposure of their children. Multiple logistic regression was used to detect the association between betamethasone exposure and T1D. Results. We compared T1D prevalence between subjects prenatally exposed or unexposed to betamethasone. The percent of children with T1D in the exposed group was 37.5% (21 of 56), and in the unexposed group was 49.52% (410 of 828) ( p = 0.139 ). The percentage of betamethasone-treated subjects with T1D in the preterm group (18.05%, 13 of 72) was significantly higher than that found in the control group (12.5%, 9 of 72) ( p = 0.003 ). The odds ratio for T1D associated with betamethasone in the univariate logistic regression was 0.59 (95% confidence interval, 0.33; 1.03 [ p = 0.062 ]) and in the multivariate logistic regression was 0.83 (95% confidence interval, 0.45; 1.52 [ p = 0.389 ]). Conclusions. The results demonstrate that the prenatal exposure to betamethasone does not increase T1D susceptibility, and may even be associated with a trend towards decreased risk of developing the disease. These preliminary findings require further prospective studies with clinical data to confirm betamethasone exposure effect on T1D risk.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Prenatal Betamethasone Exposure and its Impact on Pediatric Type 1 Diabetes Mellitus: A Preliminary Study in a Spanish Cohort

Perna-Barrull

Murillo

Real

et al. 2022

Journal of Diabetes Research

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“…ACS are also potent suppressors of inflammatory responses in the newborn during the first days after birth (Kemp et al, 2016). Following ACS treatment, immune cells in babies, especially neutrophils and macrophages, tend to demarginate from vascular wall and transiently reduce the production of cytokines (i.e., interlutin-6 (IL-6), IL-10 and tumor necrosis factor alpha (TNF-α)), chemokines and reactive oxygen species (ROS) (Fay et al, 2016;Holm et al, 2017;Perna-Barrull et al, 2020). Animal studies have demonstrated those molecules, especially IL-6 and TNF-α, are involved in sensitizing the developing retinal blood vessels to injuries such as oxygen changes, and cause subsequent neovascularization (Tremblay et al, 2013;Hong et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Beyond Fetal Immunity: A Systematic Review and Meta-Analysis of the Association Between Antenatal Corticosteroids and Retinopathy of Prematurity

Zeng

Lei

et al. 2022

Front. Pharmacol.

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Background: Retinopathy of prematurity (ROP) is a major cause of childhood blindness. Antenatal corticosteroids (ACS) exposure is known to ameliorate the risk of and mortality of neonatal morbidities. However, the effect of ACS on ROP development is currently unknown. We conducted a meta-analysis with up-to-date evidence to assess the association between ACS exposure and the development of ROP in at-risk preterm infants.Methods: PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library were systematically searched from inception to May 2021, supplemented with manual search from reference lists. Studies with a control group reporting ROP rate in ACS-exposed infants were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated utilizing a random-effects model. The Newcastle-Ottawa Scale was used for assessment of risk of bias in the included studies. Meta-regressions were performed to explore the predictive role of confounders for between-study variance.Results: A total of 63 studies, involving 196,264 infants, were included. Meta-analysis showed ACS exposure was not associated with ROP occurrence (uOR 0.92, 95% CI 0.80–1.07; aOR 0.87, 95% CI 0.7–1.08). Results from extremely immature subgroups revealed significant reduced risks of ROP occurrence in ACS-exposed infants. ACS exposure was associated with significantly lower odds of ROP progression in adjusted analysis (aOR 0.48, 95% CI 0.26–0.89) instead of unadjusted analysis (uOR 0.86, 95% CI 0.68–1.08). Meta-regression showed birth weight and patent ductus arteriosus of the cohort were associated with ROP occurrence, sample size and study design strongly associated with ROP progression in ACS-exposed infants.Conclusion: ACS treatment may decrease, but not prevent, the severity of ROP. Findings from severe ROP should be interpreted with caution owing to limited studies and the possibility of false-positive results. Considering the particular benefits in extremely immature infants, we recommend routine usage of ACS in mothers with threatened delivery to this particular birth cohort to prevent ROP occurrence. Future studies adjusting for major confounders are warranted to mitigate risk of bias in such observational evidence.

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“…Preterm birth has previously been associated with increased risk of developing type 1 diabetes [26]. The higher risk of type 1 diabetes in preterm born children may be explained by reduced insulin sensitivity [40], gut dysbiosis [41], exposure to antenatal corticosteroids [42] and rapid weight gain in infancy [24] due to catch up growth [43]. Preterm children with CAs had a reduced risk of type 1 diabetes compared with children with CAs born at term, which was of borderline signi cance.…”

Section: Discussionmentioning

confidence: 99%

Prescriptions for insulin and insulin analogues in children with and without major congenital anomalies: A data linkage cohort study across six European regions

Given

Morris

Garne

et al. 2022

Preprint

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Purpose: Are children with major congenital anomalies more likely to develop type 1 diabetes, as indicated by prescriptions for insulin, than children without congenital anomalies? The aim of this study is to evaluate prescription rates of insulin/insulin analogues in children aged 0-9 years with and without major congenital anomalies.Methods: A EUROlinkCAT data linkage cohort study, involving six population-based congenital anomaly registries in five countries. Data on children with major congenital anomalies (60,662) and children without congenital anomalies (1,722,912), the reference group, were linked to prescription records. Birth cohort and gestational age were examined.Results: The mean follow-up for all children was 6.2 years. In children with congenital anomalies aged 0-3 years, 0.04 per 100 child-years (95% CIs 0.01-0.07) had >1 prescription for insulin/insulin analogues compared with 0.03 (95% CIs 0.01-0.06) in reference children, increasing ten-fold by age 8-9 years. The risk of >1 prescription for insulin/insulin analogues aged 0-9 years in children with non-chromosomal anomalies (RR 0.92, 95% CI 0.84-1.00) was similar to that of reference children. However, children with chromosomal anomalies (RR 2.37, 95% CI 1.91-2.96), and specifically children with Down syndrome (RR 3.44, 95% CIs 2.70-4.37), Down syndrome with congenital heart defects (RR 3.86, 95% CIs 2.88-5.16) and Down syndrome without congenital heart defects (RR 2.78, 95% CIs 1.82-4.27), had a significantly increased risk of >1 prescription for insulin/insulin analogues aged 0-9 years compared to reference children. Female children had a reduced risk of >1 prescription aged 0-9 years compared with male children (RR 0.76, 95% CI 0.64-0.90 for children with congenital anomalies and RR 0.90, 95% CI 0.87-0.93 for reference children). Children without congenital anomalies born preterm (<37 weeks) were more likely to have >1 insulin/insulin analogue prescription compared to term births (RR 1.28, 95% CIs 1.20-1.36). Conclusions: This is the first population-based study using a standardised methodology across multiple countries. Males, children without congenital anomalies born preterm and those with chromosomal anomalies had an increased risk of being prescribed insulin/insulin analogues. These results will help clinicians to identify which congenital anomalies are associated with an increased risk of developing type 1 diabetes and allow them to reassure families of children who have non-chromosomal anomalies that their risk is similar to that of the general population.

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Immune System Remodelling by Prenatal Betamethasone: Effects on β-Cells and Type 1 Diabetes

Cited by 8 publications

References 86 publications

Prenatal Betamethasone Exposure and its Impact on Pediatric Type 1 Diabetes Mellitus: A Preliminary Study in a Spanish Cohort

Prenatal Betamethasone Exposure and its Impact on Pediatric Type 1 Diabetes Mellitus: A Preliminary Study in a Spanish Cohort

Beyond Fetal Immunity: A Systematic Review and Meta-Analysis of the Association Between Antenatal Corticosteroids and Retinopathy of Prematurity

Prescriptions for insulin and insulin analogues in children with and without major congenital anomalies: A data linkage cohort study across six European regions

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