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Background: Chronic hypoxemia is a common cause of fetal growth restriction and can have significant effects on the developing fetal lung. Maternal antioxidant treatment in hypoxic pregnancy protects against offspring cardiovascular dysfunction. The effects of antenatal antioxidants on lung development in the chronically hypoxic growth restricted fetus is unknown., Methods: We investigated the effect of maternal daily Vitamin C (200 mg/kg i.v. vs. Saline) for a month in late gestation on molecular markers regulating lung maturation between normoxic normally grown and hypoxic growth-restricted fetal sheep. Chronic fetal hypoxia and fetal growth restriction were induced by exposure to maternal chronic hypoxia (10% O 2 vs. Normoxia=21% O 2 ) from 105-138 d gestation (term=145 d)., Results: The data show a differential effect of antenatal Vitamin C treatment on regulation of genes involved in surfactant maturation, sodium movement and hypoxia signaling. Limited responsiveness to antenatal Vitamin C exposure in the lung of the hypoxic fetus, compared to responsiveness to antenatal Vitamin C in the normoxic fetus, suggests a maximal upregulation of the molecular signaling pathways in response to the chronic hypoxic insult alone., Conclusion: We provide molecular insight into the heterogeneity of antenatal Vitamin C treatment on development of the normoxic and growth restricted hypoxic fetal lung., Impact: The effect of maternal Vitamin C on molecular markers of lung maturation between normoxic normally grown and hypoxic growth restricted fetal sheep was unknown. We show a differential effect of Vitamin C with a greater increase in molecular markers of lung maturation in normoxic compared with hypoxic fetuses. Limited responsiveness in the hypoxic fetal lung is likely due to maximal upregulation by the hypoxic insult alone, thus added exposure to Vitamin C is unable to upregulate the system further. The work highlights the need to understand differential effects of antenatal interventions in healthy and complicated pregnancy, prior to clinical translation., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Very preterm infants often require respiratory support after birth with current recommendations suggesting the use of continuous positive airway pressure (CPAP) of 4-8 cmH 2 O and an initial fraction of inspired oxygen (FiO 2 ) of 0.21-0.3. We have examined the interaction of high and low CPAP and FiO 2 levels on breathing rates and lung aeration in preterm rabbits., Methods: Prematurely delivered rabbits (29/32 days gestation) received CPAP of either 5cmH 2 O (5CPAP; n = 12) or 15 cmH 2 O (15CPAP; n = 14), and a FiO 2 of either 0.3 (5CPAP/0.3, n = 6 or 15CPAP/0.3, n = 7) or 0.6 (5CPAP/0.6, n = 6 or 15CPAP/0.6, n = 7). Breathing rates, lung aeration (functional residual capacity; FRC), lung bulging and air accumulation in the stomach were measured using phase-contrast X-ray imaging., Results: Kittens receiving 0.6 FiO 2 had higher breathing rates (5CPAP/0.6: 32.6±6.4 breaths/min; p = 0.0064 and 15CPAP/0.6: 36.9±3.5breaths/min; p = 0.0010) than 5CPAP/0.3 kittens (11.8±4.1breaths/min). Kittens receiving 15CPAP/0.6 tended to have higher FRC volumes (34.9±4 mL/kg) than kittens receiving 5 cmH 2 O CPAP (5CPAP/0.3: 13.1±6mL/kg; p = 0.0675 and 5CPAP/0.6: 13.5±6 mL/kg; p = 0.1720) and 15CPAP/0.3 (22.5 ± 6.6 mL/kg; p = 0.4245). Lung bulging and air accumulation in the stomach were not different between groups., Conclusion: Preterm rabbits supported with both 15 cmH 2 O CPAP and 0.6 FiO 2 increased spontaneous breathing rates and lung aeration without increasing the risk of air in the stomach or lung bulging., Impact: While current guidelines recommend the use of low CPAP (4-8 cmH 2 O) and low FiO 2 levels (0.21-0.3 FiO 2 ) to support preterm infants at birth, the optimum levels are unknown. This study has shown that 15 cmH 2 O of CPAP and FiO 2 of 0.6 improved lung aeration and breathing in preterm rabbits, compared with a CPAP of 4 cmH 2 O and FiO 2 of 0.3. These results add to the evidence indicating that initial high CPAP and high FiO 2 levels, followed by titration of both, enhance respiratory support for preterm newborns., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Manual tactile stimulation is used to counteract apnea in preterm infants, but it is unknown when this intervention should be applied. We compared an anticipatory to a reactive approach using vibrotactile stimulation to prevent hypoxia induced apneas., Methods: Preterm rabbit kittens were prematurely delivered and randomized to either group. All kittens breathed spontaneously with a positive airway pressure of 8 cmH 2 O while they were imaged using phase contrast X-ray. Irregular breathing (IB) was induced using gradual hypoxia. The anticipatory group received stimulation at the onset of IB and the reactive group if IB transitioned into apnea. Breathing rate (BR), heart rate (HR) and functional residual capacity (FRC) were compared., Results: Anticipatory stimulation significantly reduced apnea incidence and maximum inter-breath intervals and increased BR following IB, compared to reactive stimulation. Recovery in BR but not HR was more likely with anticipatory stimulation, although both BR and HR were significantly higher at 120 s after stimulation onset. FRC values and variability were not different., Conclusions: Anticipated vibrotactile stimulation is more effective in preventing apnea and enhancing breathing when compared to reactive stimulation in preterm rabbits. Stimulation timing is likely to be a key factor in reducing the incidence and duration of apnea., Impact: Anticipated vibrotactile stimulation can prevent apnea and stimulate breathing effort in preterm rabbits. Anticipated vibrotactile stimulation increases the likelihood of breathing rate recovery following hypoxia induced irregular breathing, when compared to reactive stimulation. Automated stimulation in combination with predictive algorithms may improve the treatment of apnea in preterm infants., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Preterm infants are commonly supported with 4-8 cm H 2 O continuous positive airway pressures (CPAP), although higher CPAP levels may improve functional residual capacity (FRC)., Methods: Preterm rabbits delivered at 29/32 days (~26-28 weeks human) gestation received 0, 5, 8, 12, 15 cm H 2 O of CPAP or variable CPAP of 15 to 5 or 15 to 8 cm H 2 O (decreasing ~2 cm H 2 O/min) for up to 10 min after birth., Results: FRC was lower in the 0 (6.8 (1.0-11.2) mL/kg) and 5 (10.1 (1.1-16.8) mL/kg) compared to the 15 (18.8 (10.9-22.4) mL/kg) cm H 2 O groups (p = 0.003). Fewer kittens achieved FRC > 15 mL/kg in the 0 (20%), compared to 8 (36%), 12 (60%) and 15 (73%) cm H 2 O groups (p = 0.008). While breathing rates were not different (p = 0.096), apnoea tended to occur more often with CPAP < 8 cm H 2 O (p = 0.185). CPAP belly and lung bulging rates were similar whereas pneumothoraces were rare. Lowering CPAP from 15 to 5, but not 15 to 8 cm H 2 O, decreased FRC and breathing rates., Conclusion: In all, 15 cm H 2 O of CPAP improved lung aeration and reduced apnoea, but did not increase the risk of lung over-expansion, pneumothorax or CPAP belly immediately after birth. FRC and breathing rates were maintained when CPAP was decreased to 8 cm H 2 O., Impact: Although preterm infants are commonly supported with 4-8 cm H 2 O CPAP at birth, preclinical studies have shown that higher PEEP levels improve lung aeration. In this study, CPAP levels of 15 cm H 2 O improved lung aeration and reduced apnoea in preterm rabbit kittens immediately after birth. In all, 15 cm H 2 O CPAP did not increase the risk of lung over-expansion (indicated by bulging between the ribs), pneumothorax, or CPAP belly. These results can be used when designing future studies on CPAP strategies for preterm infants in the delivery room., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown., Methods: We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105-138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry., Results: Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1, hypoxia signaling genes (HIF-2α, HIF-3α, ADM, and EGLN-3), genes regulating sodium movement (SCNN1-A, SCNN1-B, ATP1-A1, and ATP1-B1), surfactant maturation (SFTP-B and ABCA3), and airway remodeling (ELN). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue., Conclusions: Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy., Impact: Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development. Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth. In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth., (© 2021. The Author(s).)