Antioxidants: powering the fight against fetal hypoxia

Hypoxia is a common challenge in fetal development. Short-term acute episodes occur during labour owing to uterine contractions or umbilical cord compression. In response, the fetus prioritizes oxygen and nutrient delivery to the brain, heart and adrenal glands at the expense of other organs, a mechanism known as the fetal brain-sparing response. However, prolonged fetal hypoxia can occur in many conditions, including placental insufficiency, pre-eclampsia, high-altitude pregnancy and fetal congenital heart disease. Chronic hypoxia increases placental and fetal oxidative stress, triggering increased long-term cardiovascular risks in adult offspring, including hypertension and coronary artery disease. Antioxidants could potentially prevent this. However, as reactive oxygen species play a crucial role in the fetal brain-sparing response, excessive antioxidant use could weaken fetal defences against acute hypoxia, increasing the risk of hypoxic-ischaemic encephalopathy. Thus, for clinical use, an antioxidant should protect against programmed cardiovascular disease while preserving fetal brain sparing. This review summarizes preclinical evidence on the efficacy of antioxidants in preventing cardiovascular disease in the offspring of hypoxic pregnancy. We compare their effects on fetal brain sparing, highlighting the ability of the mitochondria-targeted antioxidant MitoQ to protect against programmed cardiovascular disease while preserving fetal brain sparing and outlining steps for clinical translation. This article is part of the discussion meeting issue 'Pregnancy at high altitude: the challenge of hypoxia'.