by Julia Wu, PA-S

Every newborn I have managed while rotating at Ebert Family Clinic in Frisco, Colorado at 9000′ has needed oxygen supplementation. It is known that at high altitudes, there is a lower oxygen concentration in the air, which poses challenges to our bodies. What exactly happens, and what are the consequences of chronic high-altitude exposure? There are approximately 140 million people that live at high altitudes, defined as at least 2500 meters above sea level, who are affected by chronic hypoxic conditions.¹ In this article, I will focus on how hypoxia — low levels of oxygen in the blood — affects pregnant women, alters fetal to newborn transition and development, and whether cardiorespiratory exercise by mothers during pregnancy can prevent diseases such as high-altitude pulmonary hypertension (HAPH) development in offspring.  

Pulmonary hypertension (PH) is abnormally high blood pressure in the pulmonary arteries. PH is classified into 5 groups based on the cause. High-altitude pulmonary hypertension (HAPH) is Group III PH and defined as mean pulmonary arterial pressure (PAP) ≥25 mm Hg. Chronic high-altitude hypoxia can lead to the development of HAPH, which has adverse effects on the heart from right ventricular wall thickening to reduced cardiac output, and eventual right heart failure and death. HAPH can occur in utero, so it’s imperative to understand how hypoxia affects mothers and their fetuses during and after birth.²

During pregnancy, the fetus doesn’t breathe air and the lungs are not used. The fetus receives all its oxygen and nutrition needs from the mother’s blood, which flows through the blood vessels in the umbilical cord to the placenta and then to the baby.³ Circulating blood bypasses the lungs by flowing in different pathways through openings called shunts that close at birth to allow for adult circulation. In utero, the baby’s lungs fill with a special fluid that helps the lungs grow.⁴ The fluid in the lungs, in combination with naturally thicker pulmonary vascular and pulmonary vessel vasoconstriction from low PO2, causes higher vascular resistance in pulmonary circulation that allows for the diversion of blood away from the lungs through the shunts.² At low altitudes, in the first few days after birth, the high PAP in the lungs drops. The sharp drop in PAP is due to “expansion of the lungs, pulmonary vasodilation from higher PO2, a gradual receding of fluid, a thinning of pulmonary vascular smooth muscle, and… closing of the [shunts]”. This process is known as cardiopulmonary transition. However, at altitude, perinatal hypoxia negatively affects cardiopulmonary transition. The elevated pressures in the pulmonary arteries and vascular resistance persist into early childhood delaying cardiopulmonary transition, which can have developmental consequences such as HAPH and right heart failure, as discussed.

It was discovered that cardiopulmonary transition delay is linked to a high-altitude hypoxia-induced proinflammatory state within the pulmonary vasculature that leads to pulmonary artery remodeling and HAPH. Hypoxia activates or upregulates transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NK-kB), that signals for inflammatory mediators such as hypoxia-inducible factors (HIF). HIF-1a inhibits mammalian target of rapamycin (mTOR). mTOR signaling has an important role in cell metabolism, cell proliferation, and survival, thus inhibiting mTOR prevents “non-proliferative branching and elongation of conducting airways and fluid removal from the lungs,” which contributes to increases in pulmonary vascular resistance and lung development during the cardiopulmonary transition and the onset of newborn gas exchange. ^2,5 HIF also contributes to the uncontrolled proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMC) which is also a crucial contributing factor to pulmonary vessel wall thickening, pulmonary vascular remodeling, and vascular resistance. ⁵ Metabolic studies showed that chronic hypoxia not only increased the expression of these proinflammatory molecules and mediators but also reduced anti-inflammatory products like omega-3 fatty acids.²

Studies have shown that cardiorespiratory exercise reduces proinflammatory markers and increases anti-inflammatory stimulus in healthy and HAPH populations.² However, exercise training is not sufficient to reverse PAH, so we need to prevent HAPH from developing in utero with maternal exercise.  The American College of Obstetrics and Gynecologists (ACOG) recommends resistance training twice a week and moderate-intensity cardiorespiratory training daily for a total of 150 minutes a week. Studies showed that pregnant women who followed this recommendation had a 25% reduced risk of developing conditions like gestational diabetes and hypertension that contribute to compromised uterine blood flow and fetal hypoxic conditions. At low altitudes, exercise by pregnant mothers leads to benefits such as decreased fat mass, leptin, oxidative stress, pulmonary valve defects, aortic valve defects and inflammation, and increased neurogenesis in the fetus. Some animal studies at high altitudes showed that offspring of physically active pregnant rodents also received similar benefits from maternal exercise. The offspring were protected against proinflammatory stressors evidenced by low levels of inflammatory mediators, which protected them against the inflammatory processes that drive pulmonary artery remodeling and pressures that lead to HAPH. Further animal studies should be conducted to further explore the possibilities that maternal exercise can counteract the inflammatory changes and prevent HAPH development in fetus and newborns.

Resources

1. Mirrakhimov AE, Strohl KP. High-altitude Pulmonary Hypertension: an Update on Disease Pathogenesis and Management. The Open Cardiovascular Medicine Journal. 2016; 10: 19-27. doi: 10.2174/1874192401610010019
2. Leslie E, Gibson AL, Gonzalez Bosc LV, Mermier C, Wilson SM, Deyhle MR. Can Maternal Exercise Prevent High-Altitude Pulmonary Hypertension in Children?. High Altitude Medicine & Biology. 2023; 24: 1-6. https://doi.org/10.1089/ham.2022.0098
3. 2023. Blood Circulation in the Fetus and Newborn. Stanford Medicine Children’s Health. https://www.stanfordchildrens.org/en/topic/default?id=blood-circulation-in-the-fetus-and-newborn-90-P02362
4. 2023. Transient tachypnea- newborn. Icahn School of Medicine at Mount Sinai. https://www.mountsinai.org/health-library/diseases-conditions/transient-tachypnea-newborn#:~:text=As%20the%20baby%20grows%20in,start%20removing%20or%20reabsorbing%20it.
5. He S, Zhu T, Fang Z. The Role and Regulation of Pulmonary Artery Smooth Muscle Cell in Pulmonary Hypertension. International Journal of Hypertension. 2020; 2020: 1478291. doi: 10.1155/2020/1478291