High Altitude and Pre-Eclampsia

Human adaptation to hypoxia is an evolutionary change, evidenced by genetic modifications seen in certain populations such as Tibet in Asia, the Andes of the Americas, and Ethiopia in Africa, who thrive at extremely high altitudes. This is done by a process of natural selection, in which those who possess a higher degree of genetic variability are at an advantage over those with limited variability. There was a study that showed statistically similar genotypic and allelic frequencies in sea-level sojourners who undergo acclimatization on the ascent to high altitude and the adapted high altitude natives, particularly in the variants of the genes EDN1 (endothelin 1), ADRB2 (beta-2 adrenergic receptor, surface), ADRB3 (beta-3 adrenergic receptor), eNOS (nitric oxide synthase, endothelial), SCNN1B (sodium channel, non-voltage gated 1 beta subunit), TH (tyrosine hydroxylase) and VEGF (vascular endothelial growth factor) (Tomar et al. 2015).

Pre-eclampsia is the leading worldwide cause of maternal and fetal morbidity and mortality. However, in spite of extensive research, an exact etiology of pre-eclampsia is unknown. The thought is that there may be insufficient adaptation of spiral arterioles or shallow trophoblastic invasion, resulting in reduced uteroplacental blood flow leading to placental hypoxia. In other words, hypoxia may be a contributing factor to pre-eclampsia. This is shown by higher incidences of pre-eclampsia happening in areas of high altitude, along with higher risks of reproductive loss, intrauterine growth restriction, and other pregnancy complications (Zamudio 2007). Therefore, the main question to ask is, can a hypoxia-induced disorder like pre-eclampsia overcome the scarce microenvironment of oxygen deprivation by “acclimatization,” as a rapid form of adaptation?

A study conducted in 2017 evaluated more than 40 genes that are known to be associated with hypoxia for their genetic variability. A total of 36 RNA-seq samples from the amniotic fluid were retrieved from the NCBI. It involved samples of 19 pre-eclamptic preterm births while the controls were from 17 full-term births. The study revealed that the genes that are well-known to be associated with adaptation to high altitude had almost three times higher genetic variability in cases compared to control. In particular, EPAS1 gene showed the highest number of variants, followed by ADAM9 and EGLN1. This suggests there is higher selective pressure on the deprived cells of preeclampsia that leads to a high degree of genetic variability, which reflects their potency to survive the hypoxic microenvironment (Figure 1 and Figure 2).

Furthermore, while cases of preeclampsia were more hypoxic and had the highest number of hypoxic variants, they still had a lower number of adaptive variants (Table 2). This suggests the role of adaptive variants in relieving hypoxic pressure. Interestingly, there was a kind of reciprocal relation between the number of acclimatized variants and the number of hypoxic variants. In the controls, a higher number of acclimatized variants relieved the high pressure and thus resulted in a lower number of hypoxic variants, whereas in preeclamptic cases, the high number of hypoxic variants existed indicating for persistent signal of high selective pressure.

In summary, our human bodies have an incredible ability to shuffle their genes to win newer and better physiological characteristics in extreme conditions such as high altitude and pre-eclampsia. Samples indicate that those who were pre-eclamptic and therefore in hypoxic states, had higher genetic variability than those with normal pregnancies. This shows that the genes strive to alter and change to better fit their environmental conditions driven by the high selective pressure. Although more studies are required to fully understand the mechanisms of genetic variants in high altitude and preeclampsia, identifying these variants can pave the way to new treatment strategies that can help the body to better overcome challenging situations.


Ahmed, S. I., Ibrahim, M. E., & Khalil, E. A. (2017). High altitude and pre-eclampsia: Adaptation or protection. Medical Hypotheses, 104, 128-132. doi:10.1016/j.mehy.2017.05.007

Tomar, A., Malhotra, S., & Sarkar, S. (2015). Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives. BMC Genetics, 16(1). doi:10.1186/s12863-015-0268-y

Zamudio, S. (2007). High-altitude hypoxia and preeclampsia. Frontiers in Bioscience, 12(8-12), 2967. doi:10.2741/2286

Esther Kwag is a second-year Physician Assistant student at the Red Rocks Community College, Colorado. Esther was born in Seoul, South Korea and spent her elementary years there until she moved to Colorado and has been living here since. She graduated from the University of Colorado with B.S. Biology with Cum Laude in 2017. Prior to PA school, she worked as a CNA at a physical rehabilitation facility working primarily with post-operative patients who underwent orthopedic surgeries. Interacting with patients and advocating for healthier lifestyle motivated Esther to further pursue her education in medicine. In her free time, she enjoys spending time with family and friends, reading books, and travelling.

Return to High Altitude after Recovery from Coronavirus Disease 2019

Andrew M. Luks and Colin K. Grissom


Prior to COVID-19, I would hike the beautiful mountains of Colorado known as 14ers, a name given to these mountains for being over 14,000 ft. I, like most high-altitude travelers faced the more common concerns associated with hiking such as acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE). With the increase in high-altitude travel, I wondered if there are any new precautions that we should consider before resuming the activities that we love.

The purpose of this article is to highlight the recommendations for patients who wish to return to high-altitude travel after a COVID infection. Not everyone needs an evaluation after a COVID infection. The recommendations noted in this article are based on the duration and severity of the illness of each individual person.

So, who should receive an evaluation before high-altitude travel?

  1. Individuals with symptoms after 2 weeks of a positive COVID-19 test without hospitalization,
  2. Individuals with symptoms after 2 weeks after hospital discharge,
  3. Anyone who required care in the intensive care unit (ICU), and
  4. Anyone who developed myocarditis or thromboembolic events. The recommendations are to undergo pulse oximetry at rest and with activity, spirometry, lung volumes, and diffusion capacity for carbon monoxide(DLCO), chest imaging, electrocardiography (EKG), B-type natriuretic peptide, high sensitivity cardiac troponin (hsTn), and echocardiography.

It is expected that people with lower oxygen levels (hypoxemia) at rest or with exertion in lower elevations will experience greater hypoxemia with ascent to high altitude. It has been shown that ascent to high altitude causes a decrease in barometric pressure leading to a decrease in ambient and inspired partial pressure of oxygen. The decrease in partial pressure of oxygen in alveoli (PaO2) will trigger vasoconstriction of pulmonary arterioles that slows the rate of oxygen diffusion and activates chemoreceptors that increase minute ventilation from hypoxia. However, it is still unclear whether people with low oxygen levels at low elevations are at greater risk for acute altitude illness after ascent. The recommendation is to monitor pulse oximetry after arrival of high altitude.

Individuals with abnormal lung function tests don’t have to avoid high altitude travel as previous studies have shown that patients with COPD with abnormal lung functions tolerate exposure. Furthermore, in people with mild to severe COVID-19 symptoms, the lung mechanic markers such as forced expiratory volume (FEV1), forced vital capacity (FVC) and total lung capacity (TLC) normalize in up to 150 days of infection.  However, if individuals have severe limitations with exercise capacity, they should monitor their oxygen levels with pulse oximetry after ascent. Reduction in exercise capacity is possible after COVID infection and depends on the severity of the illness. Blokland et al., 2020 has shown that previously intubated individuals had a median VO2 max of 15ml/kg per min (average male 35 to 40 and average female 27 and 30), roughly 57% predicted immediately after hospitalization. 

In acute hypoxia, the heart rate increases, which leads to an increase in cardiac output. Individuals with reduced ventricular function from COVID infection do not have to avoid travel. Previous research has shown that individuals with heart failure can tolerate exercise with hypoxia. Moreover, data has shown that individuals with COVID infection maintain preserved left ventricular function and only 3% show a reduced ejection fraction. Individuals with abnormal EKG rhythms and ischemia should be referred to cardiology.  If high sensitivity troponin was abnormally elevated, this would require evaluation for myocarditis with a cardiac MRI. Knight et al., (2020), found that 45% of patients with unexplained elevations of high-sensitivity troponin were found to have myocarditis during hospitalization. It is still unclear how long these abnormalities will last and how it will affect people.

 A concerning finding on ECHO is pulmonary hypertension, as previous research has shown an increased risk in developing HAPE. A study reported that 10% of patients hospitalized for COVID without mechanical ventilation had right ventricular dysfunction for over 2 months. Several studies reported that 7-10% of individuals may have pulmonary hypertension after COVID infection. A vasodilating drug such as nifedipine can be given prophylactically if pulmonary hypertension is unrelated to left heart dysfunction but nifedipine can worsen hypoxemia.

The recommendation for patients who developed myocarditis from a COVID infection is to have an ECHO, Holter monitor, and exercise EKG 3-6 months after illness. Travel can resume after a normal ECHO, no arrhythmias on exercise EKG, and after inflammatory markers (ESR and/or CRP) have normalized. Previous studies suspected that areas with low atmospheric pressures (e.g., high-altitude) that induce hypoxia have increased risk for clot formation. However, this suspicion has never been firmly established; therefore there is no reason to believe that high-altitude will increase the risk for clot formation in individuals who developed an arterial or venous clot from COVID infection.

A few things to consider before planning a high-altitude excursion includes planning to visit areas with access to medical resources or the ability to descend rapidly. If you are new to high altitude, it is recommended to slow the ascent rate. Traveling to high elevations (>4000m) should be avoided until tolerance has developed with moderate elevations (2000-3000m). A more gradual return to physical activity at high altitude is recommended rather than immediate resumption of heavy exertion. As the pandemic subsides and with increase in mountain travel, more research will develop that can better address these risks.

Good news! The Ebert Family Clinic in Frisco, CO provides pulse oximeters for free. So, make sure to visit and grab your pulse oximeter before your next ascent.

Quick Summary of Recommendations

Individuals who require evaluation prior to high-altitude travel:

  1. Individuals who have symptoms after 2 weeks of a positive COVID-19 test without hospitalization
  2. Individuals who have symptoms after 2 weeks after hospital discharge
  3. Any patient who required care in the intensive care unit (ICU)
  4. Any patient who developed myocarditis or thromboembolic events

General recommendations for anyone before high-altitude travel:

  1. Monitor pulse oximetry after arrival of high altitude, and access care or descend if symptoms worsen.
  2. Rest and avoid high-altitude travel for at least 2 weeks after a positive test, and consider a gradually return to physical activity at higher altitudes.
  3. All individuals planning high-altitude travel should be counseled on how to recognize, prevent, and treat the primary forms of acute altitude illness (AMS, HACE, and HAPE)
  4. Limit the extent of planned exertion after ascent and, instead, engage in graded increases in activity that allow the individual to assess performance and avoid overextending themselves.

Reasons to forgo high-altitude travel:

  1. Severely elevated pulmonary artery pressures may be a reason to forego high-altitude travel altogether.
  2. High-altitude travel should likely be avoided while active inflammation is present in myocarditis.
  3. Patients who experienced arterial thromboembolic events due to COVID-19, (e.g. myocardial infarction or stroke) should defer return to high altitude for several months after that event or any associated revascularization procedures.


  1. Andrew M. Luks and Colin K. Grissom. Return to High Altitude After Recovery from Coronavirus Disease 2019. High Altitude Medicine & Biology. http://doi.org/10.1089/ham.2021.0049
  2. Christensen CC, Ryg M, Refvem OK, Skjønsberg OH. Development of severe hypoxaemia in chronic obstructive pulmonary disease patients at 2,438 m (8,000 ft) altitude. Eur Respir J. 2000 Apr;15(4):635-9. doi: 10.1183/09031936.00.15463500. PMID: 10780752.
  3. Blokland IJ, Ilbrink S, Houdijk H, Dijkstra JW, van Bennekom CAM, Fickert R, de Lijster R, Groot FP. Inspanningscapaciteit na beademing vanwege covid-19 [Exercise capacity after mechanical ventilation because of COVID-19: Cardiopulmonary exercise tests in clinical rehabilitation]. Ned Tijdschr Geneeskd. 2020 Oct 29;164:D5253. Dutch. PMID: 33331718.
Image of Jesse Santana, dark brown hair, brown skin, beard and moustache with a stethoscope draped over his white coat, striped, collared shirt and maroon tie.

Jesse Santana is a second-year PA student at Red Rocks Community College in Denver, Colorado. He grew up in Colorado Springs, CO and attended the University of Colorado-Colorado Springs where he earned a bachelor’s in Biology and Psychology. Jesse worked as a Certified Nursing Assistant for two years before pursuing a Master’s in Biomedical Sciences at Regis University in Denver. Shortly after, he coordinated clinical trials in endocrinology and weight loss as a Clinical Research Coordinator at University of Colorado Anschutz Medical Campus. He enjoys hiking Colorado’s 14ers, spending time with family and friends, and camping.