Antenatal Vitamin C differentially affects lung development in normally grown and growth restricted sheep.

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% O₂ vs. Normoxia=21% O₂) 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.