Category Archives: Neonatal

Doc Talk: Pregnancy at Altitude & What You Need to Know, an Interview with Dr. Javier Gutierrez, MD (OB/GYN)

A man with gray hair in blue hospital scrubs and a white surgical mask hanging tied from his neck smiles widely with bright teeth showing
Dr. Javier Gutierrez

Dr. Gutierrez is originally from Mexico City and attended medical school at Universidad La Salle Medical School. He completed his residency at the University of Miami School of Medicine, Jackson Memorial Hospital and has been Board Certified by the American Board of Obstetrics and Gynecology since 1986. He worked in Mexico City with his father who is also an OBGYN before moving to Summit County in 1998. He says that he dealt with pregnancy at altitude even in Mexico City as a young doctor but now has become even more experienced while practicing at St. Anthony Summit Hospital in Summit County, Colorado. In his career he has delivered more than 7,000 babies.

Gutierrez estimates that about 3% of his patients are visitors to Summit County. Most of these patients are not at full term in their pregnancy and present in the ER with signs of premature labor due to dehydration. Usually, these patients are stabilized and sent to Denver for definitive treatment given St. Anthony Summit Hospital only has a Level 1 nursery (basic newborn care).

The most common conditions that he sees occurring in pregnant women at altitude are pregnancy-induced hypertension (PIH), intrauterine growth restriction (IUGR), and small for gestational age (SGA). Because of this, he says that the main difference of observing pregnancy at altitude is more frequent ultrasounds to monitor the growth of the baby. Luckily, most pregnant women at altitude are very fit and healthy because of the active lifestyle that Summit County encourages. However, some women also have a difficult time restricting their activity level enough to maintain proper growth of the baby. The recommended maximum heart rate during pregnancy is 80% of your maximum heart rate, which can be hard to not exceed in an active pregnant female living at altitude.

Nevertheless, the risk of high altitude pulmonary edema (HAPE), high altitude cerebral edema (HACE), and sleep problems are about the same as in pregnant women not living at altitude. In general, pregnant women past 24 weeks have difficulty sleeping no matter where they live. In addition, if you know you are at high risk for developing HAPE or have a history of HAPE you are just as likely to develop HAPE during your pregnancy as you are not pregnant.

Sleeping with oxygen is recommended and has many benefits for all individuals living at altitude, pregnant women included. However, it likely wouldn’t decrease the number of SGA babies because of the activity level of most individuals as mentioned earlier. A woman’s body increases blood volume, red blood cell count, respiratory rate, and vasodilates blood vessels to accommodate for the growing fetus. This in turn allows the body to compensate well and usually maintain normal oxygen saturation levels at altitude.  But Dr. Gutierrez feels eventually it will be recommended for everyone to sleep with oxygen, most people just don’t want to.

Especially with dehydration, he has seen very high red blood cell concentrations. However, these individuals usually only need rehydration and do not suffer any complications. He has not seen a drastic increase in the number of blood clots in pregnant females at altitude even though they are likely at higher risk. But if a pregnant female who is dehydrated and recently traveled to altitude presents with shortness of breath, he definitely puts HAPE and pulmonary embolism (PE) higher on his list of possible diagnoses than he would not at sea level.

An important and simple recommendation is increasing their fluid intake. At altitude you have more insensible water loss and are likely more physically active, which in turn can lead to faster dehydration causing premature labor. Luckily this complication is easily managed with adequate fluid intake. In addition, if you know you are at high risk for developing HAPE it is recommended that you do not travel to altitude, especially later in your pregnancy.

The baby lives in a hypoxic environment in the womb anyway so there are no known advantages to living at altitude while being pregnant, other than the active and healthy lifestyle Summit County promotes.

One of the most challenging cases Dr. Gutierrez has treated was severe maternal respiratory distress during early third trimester due to HAPE. The most definitive treatment was to transport her to a lower altitude, however, they had to stabilize the mother enough to be able to transfer her and her baby. In addition, Summit County does not have a high level nursery to take care of a very premature baby even if they were able to deliver the baby safely to take stress off the mother’s body. He said it was a delicate balance trying to determine what was best and safest for both the mother and the baby.

Bailie Holst is a second-year Physician Assistant student at Red Rocks Community College in Arvada, CO. Bailie was born in Longmont, Colorado and spent her life in Northern Colorado until moving to Minneapolis, Minnesota for her undergraduate studies at the University of Minnesota. She also spent her life traveling throughout the country competing in gymnastics competitions and eventually earning a full-ride athletic scholarship for gymnastics to the University of Minnesota. She finished her gymnastics career and graduated with a Bachelor’s degree in Physiology in 2017. Prior to PA school she worked as a medical assistant in a sports medicine and rehabilitation office in Colorado for two years. In her free time, Bailie now enjoys golfing, traveling, spending time with family, and playing with her brand-new puppy.

Maternal Intermittent Hypoxia and the Effect on Adult Respiratory Control and the Gut Microbiome in Male Offspring

On Friday, June 4th, I had the pleasure of attending the, online, Fifth Annual Center for Physiological Genomics of Low Oxygen (CPLGO) Summit. There were many great presentations that I had the opportunity to watch, including the presentation of Dr. Christine Ebert-Santos’ study looking at nighttime pulse oximetry in participants living at high altitude for longer than one year. The presentation this post will discuss is about research conducted at the University of Florida by Dr. Tracy Baker, PhD. This presentation was particularly of interest because it looks at hypoxia in relationship to Obstructive Sleep Apnea (OSA). OSA occurs when patency of the upper airway is compromised and air is inhibited from passing, leading to hypopnea and obstructive apneas1. Hypopnea are episodes of greater than 30% decrease in air flow that lasts ≥ 10 seconds with continued respiratory effort1. Obstructive apnea is a total stop in airflow that lasts ≥ 10 seconds with chest and abdominal efforts to continue breathing1. Patients with OSA have a higher apnea-hypopnea index (AHI) at altitude than at sea level, meaning that their time with decreased oxygenation while sleeping is increased at higher altitude2. Additionally, patients living at altitude with mild or moderate sleep apnea may have a false negative sleep apnea result when having a sleep study performed at sea level, which means that patients who have OSA at altitude will not show signs of sleep apnea at sea level, therefore missing the diagnosis on sleep study2.

Currently, it is understood that the effects of hypoxia secondary to sleep apnea takes a toll on the body over time. Patients often experience snoring and daytime sleepiness in addition to other symptoms or changes to the body that may not be as easily recognizable, such as living in an increased inflammatory state1,3. Further, it is well known that an adverse maternal environment during pregnancy can lead to long term fetal complications3. Combining these two concepts, Dr. Baker wanted to further investigate the adverse effects of hypoxia due to maternal sleep apnea to get a better understanding of the subsequent consequences this deprived oxygen state has on mothers and their offspring. The hypothesis of this study was: Intermittent hypoxia during pregnancy has detrimental and long-lasting consequences on offspring neural function.

To test this hypothesis, Dr. Baker and her team exposed pregnant rats to intermittent hypoxia during days 10-21 of gestation. OSA was modeled from hypoxia episodes, but not the sleep fragmentation that accompanies the disease. It is understood that both components of sleep apnea, hypoxia and sleep fragmentation, would have their own influence on the offspring. The rats were put into a chamber and delivered 15 episodes of hypoxia per hour, as people can experience up to 10-20 episodes of apnea per hour during pregnancy, in increments of 90 seconds with 90 seconds of normoxia in between. During hypoxic episodes, oxygen levels were brought down to 10% and oxygen saturation was reliably reduced to 85% with adequate re-saturation during episodes of normoxia. Control rats were exposed to normoxia, 21% oxygen “on and off”, to control for and take into consideration confounding factors such as air flow within the chamber. While in labor, the rats were then removed from the chamber to give birth in a normal environment. The baby rats, or pups, were never exposed to hypoxia after they were born. Lastly, the pups were followed into adulthood to monitor for long term effects.3

Next, data from the gestational induced hypoxia (GIH) offspring and the control rat offspring (GNX) was compared. The GIH offspring showed no evidence for obesity and no difference in the volume of fat pads from shortly after birth to 12 weeks, as they had the same trajectory as the GNX offspring. There was also no difference between gestational length, number of pups, pup retrieval time, or pup survival between the two groups. To evaluate effects of gestational hypoxia on breathing, the adult offspring were placed in a plethysmography chamber. A plethysmography chamber measures changes in volume in the body to assess how much air is in the lungs when breathing. The rats were given one-hour to acclimate in the chamber and ventilation was then measured over the following three hours. Of the two groups, male GIH offspring had a significantly increased number of spontaneous apneas per hour compared to male and female GNX offspring and female GIH offspring, who had no change in the number of apneic episodes. Apneic episodes are defined as a pause in breathing that lasts longer than the duration of two breaths. Spontaneous apneic episodes are episodes of apnea with no apparent trigger on plethysmography signal. Approximately 60% of GIH male offspring had spontaneous apnea out of the 95% confidence interval, suggesting gestational intermittent hypoxia altered the phenotype in the male offspring. Again, this was not a congruent finding in GIH females.3

An additional factor to be considered in this scenario is respiratory plasticity, which is the body’s ability to help animals adapt to life changing circumstances, such as hypoxia and sleep apnea. A body’s ability to have respiratory plasticity is suggestive of a healthy neural system because breathing is an automatic and rhythmic function of the brain stem. Ultimately, the respiratory system you are born with is not the one you will die with. Recurrent central apnea can promote respiratory plasticity. Dr. Baker’s team further investigated whether the GIH rats had an altered adaptive response to conditions that alter the body’s natural response to breathing, which in this case is recurrent central apnea. Her team mechanically ventilated adult offspring that were vagalized, paralyzed, and urethane anesthetized to study neural control of breathing independent from the process of ventilation, and data was recorded via phrenic neurograms. A neural apnea was caused by lowering PaCO2 levels lower than the level for breathing and was then stopped by raising PaCO2 back to baseline levels. Recurrent neural apneas triggered plasticity mechanisms to make it harder to elicit the next apnea. Data showed adult male GIH offspring have impaired responses to recurrent reductions in respiratory neural activity and did not express plasticity following a triggered central apnea episode. Like prior results, female GIH offspring did not have this same neural plasticity impairment as the males, showing no elevations in spontaneous apnea and intact compensatory plasticity triggered by central apneas.3

Further, adult offspring were assessed for increased inflammation. To no surprise, GIH males had increased basal neuroinflammation. Although both male and female GIH offspring had increased inflammatory markers, the females were able to suppress the inflammation by an unknown mechanism that the male GIH offspring could not. Adult offspring of GIH and GNX groups were exposed to bacterial lipopolysaccharide (LPS), which confirmed that the GIH males mounted a greater inflammatory response compared to the other offspring, suggesting these males have an altered inflammation response. In the central nervous system (CNS), microglia are innate immune cells that can produce inflammatory cytokines and comprise 5-10% of CNS cells. Dr. Baker’s team pharmacologically depleted these cells in the adult offspring by administering the drug PLX3397 for seven days. This resulted in a stark reduction of microglia by 86%. The GIH male offspring with depleted microglia were able to regain compensatory plasticity triggered by recurrent central apneas. Three days after stopping PX3397, the microglia came back and expanded. When the microglia repopulated, there was restoration of the impaired plasticity phenotype in GIH males.3

To get a better understanding of what could be driving the persistent microglial inflammation in the GIH males, the gut-brain-axis was assessed. In human literature, it is suggested that sleep apnea is associated with gut dysbiosis. Investigating this link, feces was collected from the rats which showed diversity in the bacterial species present in GIH males compared to GIH females and both sexes of the GNX group. Dr. Mangalam looked at the GI bacteria shift and determined the gut microbiomes were comprised of two main phyla of bacteria, Bacteroidetes and Firmicutes. GIH males had increased Bacteroidetes and decreased Firmicutes compared to the other offspring. Initially unsure of this significance, Dr. Mangalam deduced that the decreased bacteria in the GIH male microbiome produce a short string fatty acid called butyrate. Once produced, this fatty acid stimulates the release of neuropeptides and serotonin, which are up taken by the portal vein. From there, butyrate enters the blood circulation and crosses the blood brain barrier (BBB), stimulating active receptors on the vagus nerve. Butyrate supports plasticity in the brain and reduces inflammation.3

This leads to the final question: can the neural plasticity deficit be rescued by decreasing neuroinflammation by supplementing male GIH offspring with butyrate? GIH male rats were supplemented with eight doses of 2mg/kg of Tributyrin over 22 days, which is converted into butyrate3. Upon creating central apnea in the GIH males treated with Tributyrin, it was found that their respiratory plasticity was fully rescued3. So, what does this mean?

Simply, this means gestational intermittent hypoxia has sex-specific, long-lasting effects on adult offspring physiology. This is shown by: 1) gut dysbiosis in male offspring, 2) increased central apneas during sleep with impaired respiratory plasticity, 3) enhanced basal inflammation of microglia in male offspring with increased inflammatory response upon provocation, and 4) microglial depletion or butyrate supplementation repaired deficits in respiratory plasticity.3

The research conducted by Dr. Baker’s team opens additional research opportunities regarding effects of hypoxia on vulnerable populations, such as pregnant mothers and their offspring. The findings from this study can be retested and built upon as research continues to be done. Although this research was not conducted at altitude, it is still interesting and pertinent to the altitude community, as hypoxia and OSA are common problems at altitude. This study contributes important knowledge to the science and medical community; however, more research will need to be done to confirm and fully understand the adverse effects of hypoxia during pregnancy. Further, more information is needed to understand how effects of gestational hypoxia can be applied to populations experiencing hypoxia secondary to living at altitude in a low oxygen environment.

References:

  1. Guilleminault C, Zupancic M. Sleep Disorders Medicine. Third Edition. Philadelphia, PA. Saunders. 2017. pp: 319-339.
  2. Patz D, Spoon M, Corbin R, et al. The effect of altitude descent on obstructive sleep apnea. CHEST. 2006; 130(6): 1744-1750. Doi: https://doi.org/10.1378/chest.130.6.1744
  3. Baker T. CoBAD: Maternal Intermittent Hypoxia and the Effect on Adult Respiratory Control and the Gut Microbiome in Male Offspring. Oral presentation at: the Fifth Annual Center for Physiological Genomics of Low Oxygen (CPLGO) Summit; June 4th, 2021; online.

Amanda Smith is a second year PA student at Drexel University in Philadelphia, Pennsylvania. Amanda was raised in the “sweetest place on Earth”, Hershey, Pennsylvania. She obtained her B.S. in Health Science with a double minor in Creative Writing and Community Health at Hofstra University on Long Island. Between obtaining her undergraduate and graduate degrees, Amanda worked as an Emergency Department scribe, pediatric nurse aide, and as a lead research coordinator in Neurosurgery/Neuro-Oncology at the Penn State Hershey Neuroscience Institute. Amanda loves to travel and was able to incorporate her love for traveling and medicine by traveling across the country for clinical rotations, rotating at sites in New York, California, Pennsylvania, and Colorado, with her next destination in Alaska!

A conversation with Dr. Chris on neonatal oxygen levels at elevations 9000’ and above

My name is Austin Ethridge, I am a physician assistant student from Red Rocks Community College PA program who has been fortunate enough to have completed my pediatric rotation with Dr. Chris in Frisco, Colorado, this month. Dr. Chris has extensive experience providing care to the pediatric residents of Summit County, having established her practice here in 2000, following 20 years as a pediatrician on Saipan, in the Northern Mariana Islands, southeast of Japan. She has a unique perspective on high altitude health, having transitioned from sea level to the 8000′ and above elevations unique to Summit County. Since moving here, she has been advocating for more in-depth medical research regarding the needs specific to these high-altitude communities. We are here in her office today at the Ebert Family Clinic to discuss neonatal oxygen use in Summit County.

Dr. Chris, based on your experience, why do neonates need oxygen at a higher elevation? Is it because they need to acclimate?

Yes, that’s basically it, and smaller lung size at birth.

Yes, that’s what I read. Basically, the maternal physiology compensates for the higher altitude. When the infant is born, their lung size and physiology need to catch up to the altitude.

Based on your practice, when do you place neonates on oxygen?

Usually at 89% or below, but you see, that’s just it. Many parents ask why their children need to be on oxygen when neither themselves nor their siblings were on oxygen. One of the primary reasons that this has become more of an issue is the less invasive methods of measuring oxygen saturation in the blood. Before the 1990s, the only time to measure oxygen saturation in a newborn was if a concern for illness or pulmonary problems existed, which was completed by obtaining an arterial blood gas, a very invasive procedure. Do you know at what oxygen saturation level we begin to detect cyanosis in neonates?

Around75%, which means before the pulse oximeter used today, we had no idea if the infant’s oxygen saturation was in the 80s! Now that we have the pulse oximeter, we have access to so much more information. And this is why it is essential to determine the normal oxygen levels for these infants at higher elevations.

Does this include cyanosis or blue discoloration of the hands and feet, or is it just central as in the face and chest?

The blue discoloration of legs and arms do not count; this is very common and not concerning, only the discoloration of the trunk and face.

Yes, based on the articles that I have been reading while I have been here, there are not many studies that reflect normal oxygen saturation in neonates at a higher elevation. Most of the articles that I did find determined that newborn oxygen saturation is lower at elevations of around 6000’, with average values within the range of 89-96% SpO2 compared to greater than 97% at sea level. However, there could be a significant difference between 9000’-10000’ feet and the 6000’ in these studies.1-3

That is exactly right, and that is why I want to do a study here in Summit County to determine the average oxygen saturation at these altitudes.

On average, how many newborns do you place on oxygen in Summit County?

About 40% of newborns are placed on oxygen due to low oxygen levels at birth, and I would say that less than 5% will still need oxygen after their two-week visit; however, this rate may be higher in those that live at elevations of 10,000′ or greater. In general, studies have observed that the lowest oxygen levels tend to occur around the 4th day of life and then improve from this point onward. What is the main complication that we are worried about in infants that have low oxygen levels?

Pulmonary hypertension. At birth, when the fetal circulation is shunted back through the lungs, the pulmonary pressure decreases to allow this to happen. If the oxygen levels are too low, the vessels in the lungs may not dilate enough, and this could lead to elevated pulmonary pressures. I read an interesting study that found increased pulmonary pressures in Tibet children as measured by ECHO cardiogram until the age of 14. These pressures were noted to increase with increasing elevation but to decrease with increasing age. Generally, by the age of 14, the pulmonary pressures had normalized; the authors considered this to be a normal physiological response. However, it is worth noting that these children in the study came from generations of individuals that have always lived at these altitudes.4-5

That is correct. That is the difference between adaptation and acclimatization. Many of the children that live up here are acclimatized, meaning that their bodies have adapted on a physiological level, but their genetics remain the same. However, adaptation is observed in many families that have lived at high elevations for generations; in these instances, the changes have occurred at the genetic level.

That makes sense; so the data from some of those studies may not directly apply to the population here.

That is correct. Are we worried about brain damage in this setting of low blood oxygen levels?

No, I do not think so.

We are not! In fact, as an example of this: when I was in Saipan, there was a child that had a cyanotic, congenital heart defect that was unable to be repaired for social reasons. This child always appeared blue, and his oxygen saturation would have been very low. He did just fine in terms of development and progress in academics. There were no signs of developmental delay or any other neurological problems at all.

Are there any resources you recommend for parents whose newborn may need to be on oxygen?

Yes, I have a handout that I provide to all families whose infants are on oxygen. (View Dr. Chris’s handout here.)

Are there any red flags or signs that the newborns’ oxygen may not be high enough when they are sent home? Is there anything parents should look out for? I know that you mentioned the oxygen level needs to be as low as 75% before there are any signs of concerning central cyanosis.

No, there really are no clinical signs. A company called Owlet produces a sock for the newborn’s foot that monitors oxygen saturation. I am not sure how accurate this is, but if the parents really want to do something to monitor the oxygen level, this could be a way to do so. It is pretty expensive. On an aside, we are currently in communication with this company regarding future opportunities to conduct research using their product with regards to newborn oxygen saturation at higher elevations, so stay tuned for more developments on this topic.

Are there any risks to starting the infant on oxygen?

No, not at the level that these newborns are sent home on. In premature infants, there is a risk associated with oxygen therapy for eye and lung disease. However, these premature infants are placed on very high flow rates and positive pressures. The damage is actually caused by the pressures of the oxygen being too high. This is not the case for the newborns that we place on oxygen.

Are there any risks to infants or children growing up at high altitude?

Yes, there is some evidence of a very slight increased risk of pulmonary hypertension, but this is very rare.

Thank you so much for taking the time to discuss this, Dr. Chris!

References

  1. Ravert P, Detwiler TL, Dickinson JK. Mean oxygen saturation in well neonates at altitudes between 4498 and 8150 feet. Adv Neonatal Care. 2011 Dec;11(6):412-7. doi: 10.1097/ANC.0b013e3182389348. Erratum in: Adv Neonatal Care. 2012 Feb;12(1):27. PMID: 22123474.
  2. Morgan MC, Maina B, Waiyego M, Mutinda C, Aluvaala J, Maina M, English M. Oxygen saturation ranges for healthy newborns within 24 hours at 1800 m. Arch Dis Child Fetal Neonatal Ed. 2017 May;102(3):F266-F268. doi: 10.1136/archdischild-2016-311813. Epub 2017 Feb 2. PMID: 28154110; PMCID: PMC5474098.
  3. Bakr AF & Habib HS, Normal Values of Pulse Oximetry in Natewborns at High Altitude. Journal of Tropical Pediatrics 2005; 51(3) 170-173.
  4. Qi HY, Ma RY, Jiang LX, et al. Anatomical and hemodynamic evaluations of the heart and pulmonary arterial pressure in healthy children residing at high altitude in China. Int J Cardiol Heart Vasc. 2014;7:158-164. Published 2014 Nov 12. doi:10.1016/j.ijcha.2014.10.015
  5. Remien K, Majmundar SH. Physiology, Fetal Circulation. [Updated 2020 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539710/
  6. Thilo EH, Park-Moore B, Berman ER, Carson BS. Oxygen Saturation by Pulse Oximetry in Healthy Infants at an Altitude of 1610 m (5280 ft): What Is Normal? Am J Dis Child. 1991;145(10):1137–1140. doi:10.1001/archpedi.1991.02160100069025

Austin Ethridge is a second-year physician assistant student at the Red Rocks Community College Physician Assistant Program. Originally from the Colorado front range, Austin attended the University of Northern Colorado where he obtained both a bachelors and masters degree in chemistry prior to attending PA school. In his free time, Austin enjoys spending time with his friends and family, reading, and cycling.