For centuries it’s been known that high altitude can affect childbirth.
When Spaniards landed in South America to mine silver in the 16th century, the neonatal mortality rate became such a concern that women reportedly self-exiled to lower-elevation cities to give birth. In Potosí, Bolivia, historical records show that no child born to Spanish parents survived until 53 years after their initial arrival.
Today, modern science is leading researchers, including Colleen Julian, PhD, associate professor of biomedical informatics at the University of Colorado School of Medicine, toward therapies that can improve the health of mothers and their babies living at high altitude.
At high altitude, the partial pressure of atmospheric oxygen declines and can limit sufficient oxygen delivery throughout the body. Reduced oxygenation, or hypoxia, affects numerous molecular signaling cascades and physiological systems in ways that adversely impact reproductive health and pregnancy.
“Working in Bolivia has many scientific advantages and has the added benefit of allowing us to address conditions of profound public health importance for the local community,” says Julian, who regularly travels to cities located in the Andes mountains of South America. “High altitude provides a natural laboratory to study the effects of hypoxia on physiological adaptation to pregnancy and maternal-infant health outcomes. In addition, populations of lowland and highland ancestry live across a wide gradient of altitude, so we can begin to dissect the interactive and independent effects of genes and hypoxia on physiological responses to pregnancy and pregnancy outcomes.”
Clinical observations published in the Journal of Physiology by Julian and a team of researchers, including Bolivian pediatric cardiologist Alexandra Heath-Freudenthal, MD, shows that sildenafil may be a promising candidate drug for treating neonatal pulmonary hypertension, a potentially life-threatening breathing condition that can occur when a baby isn’t able to get enough oxygen during gestation or after birth. The drug, Julian explains, may restore oxygenation, and reduce mortality in newborns born preterm or under circumstances that restrict growth, like altitude.
Maternal health at altitude
Hypertensive disorders of pregnancy, such as preeclampsia, are a leading cause of maternal and infant mortality worldwide and more common at high altitude. In Bolivia, nearly half of the population lives at high altitude, where up to 20% of women are affected by hypertensive disorders during their first pregnancy.
“Despite fetal growth restriction and preeclampsia being two of the main contributors to maternal and infant mortality worldwide, effective therapies for these conditions simply don’t exist,” Julian explains. “The only cure for preeclampsia is early delivery of the baby, which is far from ideal and, depending on the timing, can have devastating consequences for the newborn. This makes it critical to focus research efforts on identifying the mechanisms involved in these conditions, potential therapeutic avenues, and ways to identify high-risk pregnancies as early as possible.”
These conditions also affect mothers living in the United States. In 2022, Julian was part of a team of researchers that found that high-altitude residence in Colorado increased the rate of hypertensive disorders of pregnancy. Their research also showed higher rates of higher blood pressure throughout pregnancy and higher rates of NICU admissions at greater altitudes.
Colleen Julian, PhD, works with a team of researchers in high-altitude Bolivia to better understand the connections between hypoxia and childbirth. Photo courtesy of Colleen Julian.
Both abroad and at home, Julian considers altitude as a tool to better understanding the effects of hypoxia.
“It’s a natural tool for experiment. Hypoxia is a common feature and consequence of fetal growth restriction and preeclampsia regardless of the underlying cause. At high altitude, we can study the role of hypoxia in these conditions without needing to include women who have underlying health issues that increase the risk of these vascular disorders of pregnancy,” she says. “This helps us avoid the impact of confounding disease and isolate the effects of hypoxia as opposed to other factors.”
Treatments for babies
Babies with neonatal pulmonary hypertension exhibit severe hypoxia and increased pulmonary artery pressure, which can contribute to sudden infant death syndrome (SIDS) because severe hypoxia can cause bradycardia, or a dangerous reduction in heart rate.
“There are persistent changes to the structure and function of pulmonary vascular circulation as a result of hypoxia, fetal growth restriction, preeclampsia, or severe pulmonary hypertension after birth,” Julian says.
Researchers believe this has lasting effects. In animal models, research shows that when a mother is exposed to hypoxia, the offspring are more likely to develop pulmonary hypertension at birth and later in life.
This makes it especially important to find ways to treat babies with the condition. Sildenafil could be a favorable option in the future. In clinical observations, Julian and fellow researchers say the drug seems to reduce the duration of oxygen dependence and raises systemic arterial oxygen saturation.
“Our observations provide a strong rationale for further study into the therapeutic potential of this candidate drug in the context of neonatal pulmonary hypertension at high altitude. The next step would be to design a trial to quantitively determine whether it does improve outcomes or reduces the amount of time a baby has to be on oxygen,” Julian says. “With further research, and after establishing risk-to-benefit ratios, we might have another option for these babies at high altitude and be able to give them the opportunity for a better outcome.”
