Fetal single ventricle journey to first postnatal procedure: a multicentre UK cohort study.

OBJECTIVES: UK single ventricle (SV) palliation outcomes after first postnatal procedure (FPP) are well documented. However, survival determinants from fetal diagnosis to FPP are lacking. To better inform parental-fetal counselling, we examined factors favouring survival at two large UK centres. DESIGN: Retrospective multicentre cohort study. SETTING: Two UK congenital cardiac centres: Leeds and Birmingham. PATIENTS: SV fetal diagnoses from 2015 to 2021. MAIN OUTCOME MEASURES: Survival from fetal diagnosis with intention to treat (ITT) to birth and then FPP. Maternal, fetal and neonatal risk factors were assessed. RESULTS: There were 666 fetal SV diagnoses with 414 (62%) ITT. Of ITT, 381 (92%) were live births and 337 (81%) underwent FPP. Survival (ITT) to FPP was notably reduced for severe Ebstein's 14/22 (63.6%), unbalanced atrioventricular septal defect 32/45 (71%), indeterminate SV 3/4 (75%), mitral atresia 8/10 (80%) and hypoplastic left heart syndrome 127/156 (81.4%). Biventricular pathway was undertaken in five (1%). After multivariable adjustment, prenatal risk factors for mortality were increasing maternal age (OR 1.05, 95% CI 1.0 to 1.1), non-white ethnicity (OR 2.6, 95% CI 1.4 to 4.8), extracardiac anomaly (OR 6.34, 95% CI 1.8 to 22.7) and hydrops (OR 7.39, 95% CI 1.2 to 45.1). Postnatally, prematurity was significantly associated with mortality (OR 6.3, 95% CI 2.3 to 16.8). CONCLUSIONS: Around 20% of ITT fetuses diagnosed with SV will not reach FPP. Risk varies according to the cardiac lesion and is significantly influenced by the presence of an extracardiac anomaly, fetal hydrops, ethnicity, increasing maternal age and gestation at birth. These data highlight the need for fetal preprocedure data to be used in conjunction with procedural outcomes for fetal counselling.

Corticotroph isolation from Pomc-eGFP mice reveals sustained transcriptional dysregulation characterising a mouse model of glucocorticoid-induced suppression of the hypothalamus-pituitary-adrenal axis.

Glucocorticoids (GC) are prescribed for periods > 3 months to 1%-3% of the UK population; 10%-50% of these patients develop hypothalamus-pituitary-adrenal (HPA) axis suppression, which may last over 6 months and is associated with morbidity and mortality. Recovery of the pituitary and hypothalamus is necessary for recovery of adrenal function. We developed a mouse model of dexamethasone (DEX)-induced HPA axis dysfunction aiming to further explore recovery in the pituitary. Adult male wild-type C57BL6/J or Pomc-eGFP transgenic mice were randomly assigned to receive DEX (approximately 0.4 mg kg-1 bodyweight day-1 ) or vehicle via drinking water for 4 weeks following which treatment was withdrawn and tissues were harvested after another 0, 1, and 4 weeks. Corticotrophs were isolated from Pomc-eGFP pituitaries using fluorescence-activated cell sorting, and RNA extracted for RNA-sequencing. DEX treatment suppressed corticosterone production, which remained partially suppressed at least 1 week following DEX withdrawal. In the adrenal, Hsd3b2, Cyp11a1, and Mc2r mRNA levels were significantly reduced at time 0, with Mc2r and Cyp11a1 remaining reduced 1 week following DEX withdrawal. The corticotroph transcriptome was modified by DEX treatment, with some differences between groups persisting 4 weeks following withdrawal. No genes supressed by DEX exhibited ongoing attenuation 1 and 4 weeks following withdrawal, whereas only two genes were upregulated and remained so following withdrawal. A pattern of rebound at 1 and 4 weeks was observed in 14 genes that increased following suppression, and in six genes that were reduced by DEX and then increased. Chronic GC treatment may induce persistent changes in the pituitary that may influence future response to GC treatment or stress.