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• W4289712260 abstract "Antenatal steroid therapy is standard care for women at imminent risk of preterm delivery. When deliveries occur within 7 days of treatment, antenatal steroid therapy reduces the risk of neonatal death and improves preterm outcomes by exerting diverse developmental effects on the fetal organs, in particular the preterm lung and cardiovascular system. There is, however, sizable variability in antenatal steroid treatment efficacy, and an important percentage of fetuses exposed to antenatal steroid therapy do not respond sufficiently to derive benefit. Respiratory distress syndrome, for example, is a central metric of clinical trials to assess antenatal steroid outcomes. In the present analysis, we addressed the concept of antenatal steroid nonresponsiveness, and defined a failed or suboptimal response to antenatal steroids as death or a diagnosis of respiratory distress syndrome following treatment. For deliveries at 24 to 35 weeks’ gestation, the number needed to treat to prevent 1 case of respiratory distress syndrome was 19 (95% confidence interval, 14–28). Reflecting gestation-dependent risk, for deliveries at >34 weeks’ gestation the number needed to treat was 55 (95% confidence interval, 30–304), whereas for elective surgical deliveries at term this number was 106 (95% confidence interval, 61–421).We reviewed data from clinical and animal studies investigating antenatal steroid therapy to highlight the significant incidence of antenatal steroid therapy nonresponsiveness (ie, residual mortality or respiratory distress syndrome after treatment), and the potential mechanisms underpinning this outcome variability. The origins of this variability may be related to both the manner in which the therapy is applied (ie, the treatment regimen itself) and factors specific to the individual (ie, genetic variation, stress, infection). The primary aims of this review were: (1) to emphasize to the obstetrical and neonatal communities the extent of antenatal steroid response variability and its potential impact; (2) to propose approaches by which antenatal steroid therapy may be better applied to improve overall benefit; and (3) to stimulate further research toward the empirical optimization of this important antenatal therapy. Antenatal steroid therapy is standard care for women at imminent risk of preterm delivery. When deliveries occur within 7 days of treatment, antenatal steroid therapy reduces the risk of neonatal death and improves preterm outcomes by exerting diverse developmental effects on the fetal organs, in particular the preterm lung and cardiovascular system. There is, however, sizable variability in antenatal steroid treatment efficacy, and an important percentage of fetuses exposed to antenatal steroid therapy do not respond sufficiently to derive benefit. Respiratory distress syndrome, for example, is a central metric of clinical trials to assess antenatal steroid outcomes. In the present analysis, we addressed the concept of antenatal steroid nonresponsiveness, and defined a failed or suboptimal response to antenatal steroids as death or a diagnosis of respiratory distress syndrome following treatment. For deliveries at 24 to 35 weeks’ gestation, the number needed to treat to prevent 1 case of respiratory distress syndrome was 19 (95% confidence interval, 14–28). Reflecting gestation-dependent risk, for deliveries at >34 weeks’ gestation the number needed to treat was 55 (95% confidence interval, 30–304), whereas for elective surgical deliveries at term this number was 106 (95% confidence interval, 61–421). We reviewed data from clinical and animal studies investigating antenatal steroid therapy to highlight the significant incidence of antenatal steroid therapy nonresponsiveness (ie, residual mortality or respiratory distress syndrome after treatment), and the potential mechanisms underpinning this outcome variability. The origins of this variability may be related to both the manner in which the therapy is applied (ie, the treatment regimen itself) and factors specific to the individual (ie, genetic variation, stress, infection). The primary aims of this review were: (1) to emphasize to the obstetrical and neonatal communities the extent of antenatal steroid response variability and its potential impact; (2) to propose approaches by which antenatal steroid therapy may be better applied to improve overall benefit; and (3) to stimulate further research toward the empirical optimization of this important antenatal therapy. This review examines the lack of response to antenatal steroid (ANS) therapy (involving, eg, death or respiratory distress syndrome [RDS]) in preterm infants. We have broadly defined nonresponse as preterm infants being exposed to standard treatment with ANS, but still having mortality and/or RDS. Establishing a definition of ANS nonresponsiveness is challenging given the multitude of organ systems modulated by glucocorticoids and the difficulty in differentiating a cardiovascular benefit from, for example, a lung maturation benefit in the clinical setting. The task is made further challenging because the benefits of ANS therapy are strongly gestational age (GA)–dependent: at 24 to 35 weeks’ gestation, RDS is a useful marker of treatment efficacy; however, at 35 to 37 weeks’ gestation, RDS rates in the untreated population are low, and generally benign indications such as transient tachypnea of the newborn are more relevant. Furthermore, it could be reasonably argued that a preterm infant presenting with any form of RDS may have had much more severe RDS (and perhaps other complications, including brain injury), and may have subsequently developed bronchopulmonary dysplasia (BPD) in the absence of ANS therapy. Similarly, a fetus treated with ANS may die from other preterm birth–related complications, including intrapartum injury or sepsis. Thus, any definition of ANS nonresponsiveness will be imperfect. Our choice of mortality and/or RDS for determining ANS responsiveness is partly pragmatic because these are among the most readily assessed, clinically-relevant treatment outcomes modulated by ANS therapy. However, this selection is also well aligned with the trial data used to inform ANS recommendations. Mortality and RDS are 2 key metrics (either individually or as part of a composite outcome) used in most randomized control trials (RCTs) undertaken to date to test ANS treatment efficacy. These are the same data that are then used by various obstetrical societies and policy agencies (including the National Institutes of Health and the World Health Organization [WHO]) to make and refine clinical recommendations regarding the use of exogenous glucocorticoid treatments in pregnancy. On this basis, we suggest that it is also reasonable to define nonresponsiveness in a similar fashion while acknowledging the inherent limitations of this approach. The cost–benefit assessment for ANS therapy should include the consideration that exogenous glucocorticoids, an agent class with well-established adverse effects on growth and differentiation, are administered to the rapidly developing fetus at poorly optimized, supraphysiological doses.1Jobe A.H. Goldenberg R.L. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks.Am J Obstet Gynecol. 2018; 219: 62-74Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar,2Jobe A.H. Kemp M. Schmidt A. Takahashi T. Newnham J. Milad M. Antenatal corticosteroids: a reappraisal of the drug formulation and dose.Pediatr Res. 2021; 89: 318-325Crossref PubMed Scopus (23) Google Scholar US and Canadian practice guidelines do not mention ANS nonresponders,3Skoll A. Boutin A. Bujold E. et al.No. 364-antenatal corticosteroid therapy for improving neonatal outcomes.J Obstet Gynaecol Can. 2018; 40: 1219-1239Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar,4Committee on Obstetric PracticeCommittee Opinion No. 713: antenatal corticosteroid therapy for fetal maturation.Obstet Gynecol. 2017; 130: e102-e109Crossref PubMed Scopus (242) Google Scholar suggesting that the neonatal and perinatal community may not appreciate the frequency of nonresponse to ANS treatment. Aside from reducing the impetus to further refine this important treatment, the status quo may also result in patients frequently consenting to ANS treatment without being made aware that it may not convey benefit and, in some cases, may increase the risk of harm. ANS nonresponders are a substantial problem given the increasing number and gestational range of pregnancies exposed to ANS.5Bridges J.P. Sudha P. Lipps D. et al.Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function.Am J Physiol Lung Cell Mol Physiol. 2020; 319: L239-L255Crossref PubMed Google Scholar, 6Welch R.A. Recanati M.A. Welch K.C. Shaw M.K. Maternal plasma LPCAT 1 mRNA correlates with lamellar body count.J Perinat Med. 2018; 46: 429-431Crossref PubMed Scopus (6) Google Scholar, 7McLaughlin K.J. Crowther C.A. Walker N. Harding J.E. Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review.Aust N Z J Obstet Gynaecol. 2003; 43: 101-106Crossref PubMed Scopus (71) Google Scholar There are 2 pharmacologic issues that may be used to frame a discussion of ANS nonresponsiveness: the pharmacokinetics (PK) of the drugs used for ANS therapy, and the pharmacodynamics (PD) that achieve the desired maturational benefits. We now have a reasonable understanding of the PK of the drugs used for ANS therapy (ie, dexamethasone phosphate, betamethasone phosphate, and combined betamethasone phosphate and acetate).8Jobe A.H. Milad M.A. Peppard T. Jusko W.J. Pharmacokinetics and pharmacodynamics of intramuscular and oral betamethasone and dexamethasone in reproductive age women in India.Clin Transl Sci. 2020; 13: 391-399Crossref PubMed Scopus (29) Google Scholar, 9Krzyzanski W. Milad M.A. Jobe A.H. Peppard T. Bies R.R. Jusko W.J. Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women.J Pharmacokinet Pharmacodyn. 2021; 48: 261-272Crossref PubMed Scopus (7) Google Scholar, 10Ke A.B. Milad M.A. Evaluation of maternal drug exposure following the administration of antenatal corticosteroids During late pregnancy using physiologically-based pharmacokinetic modeling.Clin Pharmacol Ther. 2019; 106: 164-173Crossref PubMed Scopus (24) Google Scholar We know much less about the optimal drug exposures needed to reliably cause the desired PD effects: lung maturation and other, difficult to isolate effects of steroids that improve neonatal adaptation, decrease intraventricular hemorrhage (IVH), and decrease death. The magnitude of the clinical problem of ANS nonresponsiveness is detailed in the Table, which lists individual trials and meta-analyses grouped by 10-year eras during which the RCTs were done. In the most recent meta-analysis (2020),13McGoldrick E. Stewart F. Parker R. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2020; 12: CD004454PubMed Google Scholar for single-course treatment, ANS decreased mortality from 5.3% to 4.5% and decreased RDS from 13.2% to 9.9%. Of note, this meta-analysis included trials of late-preterm infants. Although clearly important, the overall magnitude of the effect results in a large amount of residual mortality and RDS. This meta-analysis also included trials of late-preterm pregnancies wherein death, which is not a discriminating outcome with regard to ANS treatment efficacy, is rare. In the McGoldrick et al13McGoldrick E. Stewart F. Parker R. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2020; 12: CD004454PubMed Google Scholar 2020 meta-analysis of 22 trials, the overall number needed to treat for mortality benefit was 38, which means that many fetuses did not benefit from treatment.TableSummary of placebo-controlled trials of antenatal steroids expressed as number needed to treat for benefit or harm for a neonatal death outcomeTrials and analysesNNT for benefitNNT for harmRR (confidence interval)# of trials# of subjectsACT11Althabe F. Belizán J.M. McClure E.M. et al.A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial.Lancet. 2015; 385: 629-639Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar—2931.12 (1.02–1.22)1100,705Action I Trial (WHO)12Oladapo O.T. Vogel J.P. et al.WHO ACTION Trials CollaboratorsAntenatal dexamethasone for early preterm birth in low-resource countries.N Engl J Med. 2020; 383: 2514-2525Crossref PubMed Scopus (47) Google Scholar26—0.84 (0.72–0.97)12823McGoldrick et al13McGoldrick E. Stewart F. Parker R. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2020; 12: CD004454PubMed Google ScholarMeta-analysis of trials from 1970s–2010s (2020)38—0.78 (0.70–0.87)2210,609McGoldrick et al13McGoldrick E. Stewart F. Parker R. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2020; 12: CD004454PubMed Google ScholarTrials in 1970s56—0.83 (0.67–1.04)72743McGoldrick et al13McGoldrick E. Stewart F. Parker R. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2020; 12: CD004454PubMed Google ScholarTrials in 1980s45—0.90 (0.55–1.49)4326McGoldrick et al13McGoldrick E. Stewart F. Parker R. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2020; 12: CD004454PubMed Google ScholarTrials in 1990s19—0.60 (0.4–0.9)5788McGoldrick et al13McGoldrick E. Stewart F. Parker R. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2020; 12: CD004454PubMed Google ScholarTrials in 2000s4—0.46 (0.31–0.66)2270McGoldrick et al13McGoldrick E. Stewart F. Parker R. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2020; 12: CD004454PubMed Google ScholarTrials in 2010s55—0.83 (0.72–0.96)46482Crowther15Roberts D. Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2006; : CD004454PubMed Google ScholarRepeated dose meta-analysis (2019)71aPrimary serious composite outcome.—0.92 (0.82–1.04)115893ACT, Antenatal Corticosteroids Trial; NNT, number needed to treat; RR, relative risk; WHO, World Health Organization.Takahashi. Variability in the efficacy of antenatal steroid therapy. Am J Obstet Gynecol 2022.a Primary serious composite outcome. Open table in a new tab ACT, Antenatal Corticosteroids Trial; NNT, number needed to treat; RR, relative risk; WHO, World Health Organization. Takahashi. Variability in the efficacy of antenatal steroid therapy. Am J Obstet Gynecol 2022. A further challenge is that the PD assessment for mortality is not stable with time because mortality is primarily driven by GA at birth. This outcome is greatly affected by improving modern obstetrical and neonatal practices that decrease mortality, such as surfactant treatments, new approaches to respiratory support such as continuous positive airway pressure (CPAP), noninvasive ventilation, better in utero surveillance of the fetus, and better delivery timing. It is also important to note that we seldom know the cause of death with sufficient precision to be able to assess if it possibly could have been prevented by a better ANS response. Causes of death have not been reported in recent studies. The application of repeated ANS courses also serves to identify the significant potential that exists to improve overall outcomes if the issue of nonresponsiveness can be better addressed. Repeated courses should provide maximum benefit and minimize nonresponders. In the individual patient meta-analysis of a repeated course of ANS, the benefit for avoiding a serious outcome (death, severe respiratory disease) was only a 1.4% absolute difference.15Roberts D. Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.Cochrane Database Syst Rev. 2006; : CD004454PubMed Google Scholar The composite adverse outcome still occurred in 11.4% of the population. For the outcome, ANS decreased respiratory support by 4.8%, again an important difference, but in the single-dose group 31% still required respiratory support. Clearly, repeated courses of ANS do not obviate the need for respiratory support. We can also conclude that additional doses of corticosteroids do not solve the nonresponse problem. The recent WHO trial of 4 doses of 6-mg dexamethasone given every 12 hours vs saline placebo performed effectively in well-resourced hospitals in low- and middle-income countries, with death decreased from 23.5% (331/1406) to 19.6% (278/1417), a significant reduction with P<.03.12Oladapo O.T. Vogel J.P. et al.WHO ACTION Trials CollaboratorsAntenatal dexamethasone for early preterm birth in low-resource countries.N Engl J Med. 2020; 383: 2514-2525Crossref PubMed Scopus (47) Google Scholar In another trial (the A∗STEROID study) testing the 2 most commonly used ANS drugs—dexamethasone phosphate (used in the WHO-recommended standard care protocol in low- and middle-income countries) and combined betamethasone phosphate and acetate (as originally trialed by Liggins and Howie16Crowther C.A. Middleton P.F. Voysey M. et al.Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: an individual participant data meta-analysis.PLoS Med. 2019; 16e1002771Crossref Scopus (38) Google Scholar)—there were no differences in death or neurodevelopment at 2 years.17Liggins G.C. Howie R.N. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.Pediatrics. 1972; 50: 515-525Crossref PubMed Google Scholar However, there were also no differences in respiratory support requirements, with 24% having RDS after either ANS therapy. Therefore, approximately 1 in 4 ANS-treated infants still have RDS, and increasing maternofetal plasma steroid concentrations (in this instance by the sole use of dexamethasone phosphate) do not improve outcomes. From these data it can be concluded that administering higher doses of steroids is not a means by which treatment responsiveness may be improved. An additional challenge is that, even when response is achieved, the durability of benefit (the persistence of the described clinical benefit such as a reduction in death, RDS, or IVH) seems to be transient. This is a particular challenge given that the clinical ANS treatment strategy is often to quickly assess a pregnancy in possible preterm labor, administer ANS, and then attempt to determine if the presentation was correctly identified as being preterm labor. Approximately 50% of these women will be briefly observed in-hospital and discharged, and proceed to deliver at term.18Crowther C.A. Ashwood P. Andersen C.C. et al.Maternal intramuscular dexamethasone versus betamethasone before preterm birth (ASTEROID): a multicentre, double-blind, randomised controlled trial.Lancet Child Adolesc Health. 2019; 3: 769-780Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar For RDS outcome, there is a likely period of benefit lasting from 24 hours to 7 days posttreatment, as originally suggested by Liggins16Crowther C.A. Middleton P.F. Voysey M. et al.Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: an individual participant data meta-analysis.PLoS Med. 2019; 16e1002771Crossref Scopus (38) Google Scholar and in the 2006 meta-analysis of Roberts and Dalziel.14Makhija N.K. Tronnes A.A. Dunlap B.S. Schulkin J. Lannon S.M. Antenatal corticosteroid timing: accuracy after the introduction of a rescue course protocol.Am J Obstet Gynecol. 2016; 214: 120.e1-120.e6Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar The rationale for repeated treatment is the assumption that RDS or death can be prevented until 7 days after initial treatment. In IVH meta-analyses, IVH was decreased only in a treatment-to-delivery interval of 24 to 48 hours.14Makhija N.K. Tronnes A.A. Dunlap B.S. Schulkin J. Lannon S.M. Antenatal corticosteroid timing: accuracy after the introduction of a rescue course protocol.Am J Obstet Gynecol. 2016; 214: 120.e1-120.e6Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar These are rough estimates, further confounded by our limited understanding of how ANS decreases IVH and mortality. Potential causes of the variability observed in responses to ANS treatment may be categorized into 2 groups: (1) those related to the treatment given; and (2) those related to patient-specific factors (Figure 1). These could involve abnormalities in glucocorticoid PK between mother and fetus, glucocorticoid receptor (GR) signaling, variable responses of the developing lung cells, or the regulation of GR-modulated targets such as surfactants, which have been shown to play an important role in functional lung maturation. As noted above, the treatment-to-delivery interval is important for ANS treatment efficacy. Although some studies have failed to report a difference in outcome according to treatment interval,19Block M.F. Kling O.R. Crosby W.M. Antenatal glucocorticoid therapy for the prevention of respiratory distress syndrome in the premature infant.Obstet Gynecol. 1977; 50: 186-190PubMed Google Scholar the general consensus is that the optimal delivery window is 1 to 7 days after initial ANS administration.1Jobe A.H. Goldenberg R.L. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks.Am J Obstet Gynecol. 2018; 219: 62-74Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar The GA at which ANS are administered also has a pronounced impact on the magnitude and nature of treatment benefit.1Jobe A.H. Goldenberg R.L. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks.Am J Obstet Gynecol. 2018; 219: 62-74Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Considering their assessment of glucocorticoid efficacy against pretreatment amniotic fluid lecithin–sphingomyelin ratios in 1976, Block et al19Block M.F. Kling O.R. Crosby W.M. Antenatal glucocorticoid therapy for the prevention of respiratory distress syndrome in the premature infant.Obstet Gynecol. 1977; 50: 186-190PubMed Google Scholar concluded that if the fetal lungs are already mature enough to produce surfactant, there is nothing to be gained with ANS treatment. Broadly speaking, deliveries at earlier gestations (<34 weeks) treated with ANS show significant reductions in RDS and neonatal death, whereas the benefits derived from ANS use at later gestations are largely restricted to reduced oxygen use and improvements in transient tachypnea.20Gyamfi-Bannerman C. Thom E.A. Blackwell S.C. et al.Antenatal betamethasone for women at risk for late preterm delivery.N Engl J Med. 2016; 374: 1311-1320Crossref PubMed Scopus (415) Google Scholar Whether protection from these outcomes, which are generally amenable to postnatal management in well-resourced delivery settings, warrants exposure to ANS treatment given even a small risk of deleterious steroid effects, is a topic that deserves further discussion. Insight into the patient-specific role of ANS nonresponsiveness may be gained from the concept of generalized glucocorticoid resistance, defined as a resistance to adrenal suppression following dexamethasone administration,21Vitellius G. Lombes M. Genetics in endocrinology: glucocorticoid resistance syndrome.Eur J Endocrinol. 2020; 182: R15-R27Crossref PubMed Scopus (20) Google Scholar and observed clinically as Cushing’s syndrome. Resistance to treatment with glucocorticoids has also been identified in a range of diseases including asthma, nephrotic syndrome, and adrenal cortex hyperplasia.21Vitellius G. Lombes M. Genetics in endocrinology: glucocorticoid resistance syndrome.Eur J Endocrinol. 2020; 182: R15-R27Crossref PubMed Scopus (20) Google Scholar,22Vitellius G. Trabado S. Hoeffel C. et al.Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study.Eur J Endocrinol. 2018; 178: 411-423Crossref PubMed Scopus (30) Google Scholar Given the involvement of glucocorticoid resistance in other diseases, it is reasonable to argue that resistance to glucocorticoid signaling may similarly play a role in the efficacy of ANS therapy. Indeed, in light of data linking GR polymorphisms with differential preterm outcomes,21Vitellius G. Lombes M. Genetics in endocrinology: glucocorticoid resistance syndrome.Eur J Endocrinol. 2020; 182: R15-R27Crossref PubMed Scopus (20) Google Scholar, 22Vitellius G. Trabado S. Hoeffel C. et al.Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study.Eur J Endocrinol. 2018; 178: 411-423Crossref PubMed Scopus (30) Google Scholar, 23Baas E.M. Romijn M. van der Pal S.M. et al.No association between glucocorticoid receptor polymorphisms and long-term respiratory outcome after very preterm birth.Endocrine. 2021; 73: 226-229Crossref PubMed Scopus (1) Google Scholar, 24Bertalan R. Patocs A. Vasarhelyi B. et al.Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene.J Steroid Biochem Mol Biol. 2008; 111: 91-94Crossref PubMed Scopus (16) Google Scholar, 25Schreiner C. Schreiner F. Härtel C. et al.Glucocorticoid receptor gene variants and neonatal outcome in very-low-birth-weight preterm infants.Neonatology. 2017; 111: 22-29Crossref PubMed Scopus (5) Google Scholar and the persistence of RDS in ANS-treated infants, it is not inconceivable that some forms of RDS may eventually be categorized as glucocorticoid-sensitive and glucocorticoid-resistant. The molecular mechanisms involved in glucocorticoid signaling and regulation are both complex and incompletely understood.26Cain D.W. Cidlowski J.A. Immune regulation by glucocorticoids.Nat Rev Immunol. 2017; 17: 233-247Crossref PubMed Scopus (734) Google Scholar,27Oakley R.H. Cidlowski J.A. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease.J Allergy Clin Immunol. 2013; 132: 1033-1044Abstract Full Text Full Text PDF PubMed Scopus (600) Google Scholar ANS function primarily via their interaction with and activation of the GR (NR3C1). Free (dephosphorylated) betamethasone and dexamethasone bind with high affinity to the ligand-binding domain of the GR in the cytoplasm. GR–glucocorticoid complexes translocate to the nucleus where they exert transcriptional activation and suppression.27Oakley R.H. Cidlowski J.A. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease.J Allergy Clin Immunol. 2013; 132: 1033-1044Abstract Full Text Full Text PDF PubMed Scopus (600) Google Scholar There are several different GR isoforms, of which GRα and GRβ are the primary examples. GRα is the isoform predominantly involved in glucocorticoid signaling. The role of GRβ is still not fully understood; it lacks a ligand-binding domain, making it unable to bind glucocorticoids or transduce GR-activated signaling. It can, however, dimerize with GRα, and is believed to predominantly exert a negative regulatory effect on GRα activity via the formation of GRα–GRβ dimers.27Oakley R.H. Cidlowski J.A. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease.J Allergy Clin Immunol. 2013; 132: 1033-1044Abstract Full Text Full Text PDF PubMed Scopus (600) Google Scholar,28Ramos-Ramírez P. Tliba O. Glucocorticoid receptor β (GRβ): beyond its dominant-negative function.Int J Mol Sci. 2021; 22: 3649Crossref PubMed Scopus (16) Google Scholar Potential pregnancy-associated candidates for dysregulation of GR signaling, and thus ANS resistance in the setting of ANS therapy, include: stress,29Cohen S. Janicki-Deverts D. Doyle W.J. et al.Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk.Proc Natl Acad Sci U S A. 2012; 109: 5995-5999Crossref PubMed Scopus (731) Google Scholar GR mutations resulting in loss or reduction in function,21Vitellius G. Lombes M. Genetics in endocrinology: glucocorticoid resistance syndrome.Eur J Endocrinol. 2020; 182: R15-R27Crossref PubMed Scopus (20) Google Scholar,22Vitellius G. Trabado S. 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• W4289712260 date "2022-11-01" @default.
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• W4289712260 title "The complex challenge of antenatal steroid therapy nonresponsiveness" @default.
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