Gabby Musk

Introduction: Antenatal corticosteroids (ACS) alter the functional trajectory of key fetal organs, including the lung and heart. Although lung effects are well characterized, less is known about impacts on the developing heart. Herein, we aimed to investigate the functional (via ultrasound) and transcriptional (via array and qPCR) impacts of low-dose vs standard clinical ACS dosing on the fetal heart. Methods: Ewes with single fetuses at 114±1d gestation received either: i) a low-dose maternal intravenous bolus and maintenance infusion of betamethasone phosphate to target fetal plasma concentration of 2 ng/ ml for 36h (low-dose group; n=6); ii) two maternal IM injections of 0.25 mg/kg Celestone Chronodose® (1:1 betamethasone phosphate and betamethasone acetate) spaced at 24h replicating a standard clinical protocol (IM group; n=6); or iii) IM saline (control group; n=6). Functional cardiac analysis was performed by ultrasound 8hrs after steroid treatment at maximum fetal steroid exposure. Lambs were surgically delivered 7 days after treatment. Microarray analysis was performed on fetal left ventricle tissue using Ingenuity Pathway Analysis Software at p<0.01 significance. Differentially expressed genes (low-dose or IM group vs. control) were identified by 2-sample t-tests. Changes in differentially expressed genes were confirmed by qPCR (data not shown). Results: Ultrasound studies showed significantly impaired relaxation in mitral and tricuspid valve E/A ratios, consistent with increased peripheral resistance. Microarray analysis revealed: i) low-dose group, 6 transcripts differentially regulated (1 up and 5 down); and ii) IM group, 43 transcripts regulated (4 up and 39 down). There was no predicted modulation of signaling pathways involved in fetal cardiac hypertrophy either group, although three transcripts, GADD45G, PPPARG, and ADIPOQ (associated with myocardial hypertrophy) were differentially expressed in the IM group only (p-value=5.7E-03, 5.1E-03, and 4.9E-03, respectively). Conclusion: A significantly greater number of transcripts including some transcripts associated hypertrophy were differentially regulated in the high-dose IM group relative to control, and in conjunction with acute afterload change. Although preliminary, these data support the observation that higher total and maximal fetal exposures (IM group) may increase lifetime cardiovascular risk.