Preterm Birth Has Sex-Specific Effects on Autonomic Modulation of Heart Rate Variability in Adult Sheep

Introduction: Globally, 11% of infants are born preterm. In adulthood, individuals born preterm are at increased risk of cardiovascular morbidity and mortality, but the mechanistic basis of this remains unknown. Clinically overt cardiovascular disease may be preceded by altered cardiac autonomic activity characterised by increased sympathetic activity and/or reduced parasympathetic activity. Thus, altered cardiac autonomic activity in survivors of preterm birth may underlie later cardiovascular risk. Objective: To investigate the impact of gestational age on cardiac autonomic activity in juvenile and adult sheep. Methods and Results: Singleton-bearing ewes were randomised antenatally to spontaneous term birth (TC; n=73) or corticosteroid induced preterm birth (PT; n=60). Cardiac autonomic modulation was assessed using heart rate variability analysis in juvenile and adult offspring. Preterm birth in adult males was associated with altered sympathovagal modulation (LFnu: PT 64 +/- 4 vs. TC 49 +/- 4, p<0.05; LogLF/HF: PT 1.8 +/- 0.1 vs. TC 1.5 +/- 0.1, p<0.05) and reduced parasympathetic modulation (LogRMSSD: PT 2.9 +/- 0.2 vs. TC 3.4 +/- 0.1, p<0.05; LogNN50: PT 0.3 +/- 0.4 vs. TC 1.6 +/- 0.4, p<0.05). Within the range of term birth, each one-day increment in gestational age was associated with a decrement in LFnu in juvenile females and with a decrement in LFnu and LF/HF ratio, but an increment in RMSSD and NN50 in adult females. Conclusions: Cardiac autonomic function in adult sheep is affected in a sex-specific manner by gestational age at birth, even within the term range. Altered cardiac autonomic function may contribute to increased later cardiovascular morbidity in those born preterm.