Introduction: The partial oxygen pressure in the air decreases with increasing altitude. This study was designed to compare the pulse oxygen saturation (SpO2) among well full-term neonates at different altitudes during their first 2 h after birth and to establish cutoff values of SpO2 identifying hypoxemia between 30 and 120 min after birth. Methods: A multisite prospective cohort study was conducted at five participating hospitals from the Chinese High Altitude Neonatal Medicine Alliance. Healthy full-term infants were recruited and divided into four groups based on the altitude. Preductal SpO2 was recorded at 10 min, 10–30 min, and 30–120 min after birth. The 2.5th percentile of the SpO2 distribution range was considered as the cutoff for identifying hypoxemia at each altitude. Results: A total of 727 infants were eligible for analysis. The SpO2 of neonates at different altitudes increased with the time after birth. A higher altitude was associated with lower SpO2, especially Shangri-La (3,509 m) and Yushu (4,360 m). The cutoff SpO2 for identifying hypoxemia during 30–120 min after birth were 94% in Xishuangbanna (847 m), 92% in Kunming (1,983 m), 89% in Shangri-La (3,509 m), and 83% in Yushu (4,360 m). Conclusion: An increase in altitude, especially Shangri-La (3,509 m) and Yushu (4,360 m), had a significant impact on SpO2 among healthy full-term neonates during their first 2 h of life. Establishing the cutoff value of SpO2 for identifying hypoxemia during the early postnatal period serves to optimize the oxygen therapy at different altitudes.

© 2022 The Author(s). Published by S. Karger AG, Basel

Introduction

Pulse oximetry is a critical tool in guiding the use of supplemental oxygen for sick newborns as it offers a real-time and noninvasive estimation of arterial oxygen saturation cost-effectively. Its routine use can also aid in the identification of infants with clinically unrecognized congenital heart disease [1]. However, the above application depends on the correct knowledge of normal pulse oxygen saturation (SpO2), especially at different altitudes.

At the sea level, for infants with uncompromised and adequate breathing, the SpO2 increases from 50% to 60% in the fetus, surpasses the 90% threshold at 10 min, and then goes above 95% at 15 min after birth [2, 3]. The increase in SpO2 is due to the activation of the lung, the decrease in pulmonary pressure, and the constriction and closure of the ductus arteriosus as the partial oxygen pressure increases, which is negatively correlated with altitude [4, 5]. Lower air pressure at higher altitudes makes it difficult for O2 to diffuse into the vascular system, which may lead to O2 deprivation or hypoxia, known as hypobaric hypoxia [6]. As a result, postnatal transition may differ at high altitudes, and the overall SpO2 of such infants may be lower [7]. However, there are limited data on the SpO2 during first few hours of life in healthy neonates born at high altitudes [8-12].

The primary outcome of the study was to observe the dynamic trend of SpO2 among neonates during their first 2 h of life at different altitudes and to compare the SpO2 values between different altitudes. The secondary outcome was to establish the cutoff values of SpO2 for identifying hypoxemia between 30 and 120 min after birth at these altitudes.

Materials and MethodsStudy Design and Participants

A multisite prospective cohort study was conducted using data from the Chinese High Altitude Neonatal Medicine Alliance (CHANMA) from May 2021 to March 2022. CHANMA was established in 2021 to maintain a standardized clinical database of neonates in high-altitude areas throughout China. Eleven hospitals from three provinces throughout China participated in CHANMA in 2021. As this was primarily an exploratory study, five participating hospitals were chosen based on feasibility and divided into four groups according to the altitude stratum where they were located. One hospital was in Xishuangbanna, Yunnan (847 m); one in Kunming, Yunnan (1,983 m); two in Shangri-La, Yunnan (3,509 m); and one in Yushu, Qinghai (4,360 m). Of those, the hospital in Yushu started to collect data from November 2021.

The study recruited infants with a gestational age between 37 0/7 and 41 6/7 weeks who were born alive and appeared well as defined by (1) normal vital signs (heart rate ranging from 110 to 180 beats/min, respiratory rate ranging from 30 to 60 breaths/min, temperature ranging from 36.5°C to 37.5°C), (2) absence of signs of illness such as respiratory distress, and (3) mothers residing in the study area. The exclusion criteria were as follows: infants were excluded if they (1) were outborn, (2) received supplemental oxygen or assisted ventilation after birth, (3) had meconium-stained amniotic fluid, (4) were admitted for any reason other than observation, and (5) had a major congenital anomaly. The study was approved by the Ethics Committee of Kunming Children’s Hospital, the leading hospital in CHANMA (2021-03-146-K01). Written informed consent was obtained from the legal guardians of the neonates.

Longitudinal Measurement of SpO2

The test was performed by a trained staff in each center, and the infants were breathing room air during all oximetry tests. After delivery, the newborns were placed under a radiant warmer, and subsequently, a pulse oximeter sensor appropriate to the weight of the infant was placed on the infants’ right hand and connected to an oximeter (Comen C60) that had already been turned on. Pulse oximetry reading at the 10th min after birth was recorded. For the oxygen saturation to be considered valid, the oximeter had to track the peripheral pulse for at least 20 s, giving a regular pulse rate and waveform. Since the postnatal transition may take a longer time at high altitudes, the measurements were taken at 10–30 min and 30–120 min after birth. Pulse oximetry results were obtained when the infants were awake and quiet rather than crying or breastfeeding. Data were collected from the CHANMA database.

Statistical Analysis

A descriptive analysis was performed to show the demographic characteristics of the total study population. Categorical variables were described as numbers (percentages), and as numerical variables did not show a normal distribution, the values were described as medians (interquartile range [IQR]). The 2.5th percentile of SpO2 distribution ranges during 30–120 min after birth was considered as the cutoff for identifying hypoxemia at each altitude [13]. The differences in participant characteristics among the four groups at different altitudes were tested using the χ2 test for categorical variables and Kruskal-Wallis test for continuous variables, and the p value was adjusted by the Bonferroni correction for multiple testing.

A two-tailed p value < 0.05 was considered significant. Statistical analysis was performed using SPSS (v24, IBM Corp., New York, NY, USA).

ResultsParticipant Characteristics

A total of 842 full-term neonates were recorded in the CHANMA from May 2021 to March 2022. A total of 115 infants were excluded (shown in Fig. 1), and the remaining 727 infants were eligible for analysis. We present a map of the location of the four groups, their respective altitudes, and the equivalent oxygen fraction in ambient air [14] (shown in Fig. 2). The descriptive characteristics of the recruited infants are presented in Table 1. Briefly, the gestational age of neonates tended to be lower at higher altitudes, and the difference was only significant between Yushu (4,360 m) and Kunming (1,983 m), with a p value of 0.004. There were no significant differences in the other characteristics among the four groups.

Table 1.

Perinatal Characteristics of neonates at different altitude groups

Fig. 1.

Flow chart of study population.

Fig. 2.

Map showing the location of the participating hospitals, as well as their respective altitudes and the equivalent oxygen fraction in ambient air (FiO2). The map was quoted from http://bzdt.ch.mnr.gov.cn/browse.html?picId=%224o28b0625501ad13015501ad2bfc0065%22, No GS(2016)1609.

Dynamic Trend of SpO2 at Different Altitudes within 2 h after Birth

As shown in Figure 3, SpO2 increased with time after birth, and the dynamic trend differed among the different altitudes. In Xishuangbanna (847 m) and Kunming (1,983 m), the dynamic trend of SpO2 was relatively stable, and over 75% of the SpO2 values were consistently higher than 95% during the first 2 h of life. In Shangri-La (3,509 m) and Yushu (4,360 m), the oxygen saturation increased with a high slope. At 10 min of life, the median SpO2 was 81% (IQR 68–89%) in Shangri-La (3,509 m) and 73% (IQR 70–76%) in Yushu (4,360 m). The SpO2 reached 92% (IQR 91–93%) in Shangri-La (3,509 m) and 90% (88–92%) in Yushu (4,360 m) at 30–120 min of life (shown in Table 2).

Table 2.

Preductal SpO2 during first 2 h after birth in different altitude groups

Fig. 3.

Dynamic trend of SpO2 in neonates during first 2 h, stratified by altitude levels. Values were medians (IQR).

Comparing SpO2 between Different Altitudes within 2 h after Birth

The overall distribution of SpO2 from 0 to 120 min after birth at each altitude is presented in Figure 3, which shows that as the altitude increased, SpO2 decreased, especially in Shangri-La (3,509 m) and Yushu (4,360 m). We further compared the SpO2 values between the different altitude groups and found no significant difference in SpO2 measurements between Xishuangbanna (847 m) and Kunming (1,983 m) after 10 min of life. However, SpO2 values were significantly lower in Shangri-La (3,509 m) and Yushu (4,360 m) than in Xishuangbanna (847 m) and Kunming (1,983 m) at all time points (p value < 0.001). The SpO2 value in Yushu (4,360 m) tended to be lower than that in Shangri-La (3,509 m); however, the difference was not significant (shown in Table 2).

Cutoff Values of SpO2 during 30–120 min after Birth at Different Altitudes

The 2.5th percentile of preductal SpO2 ranges during 30–120 min was chosen as the cutoff for identifying hypoxemia at each altitude, which was 94% in Xishuangbanna (847 m), 92% in Kunming (1,983 m), 89% in Shangri-La (3,509 m), and 83% in Yushu (4,360 m), respectively.

Discussion

In this multicenter prospective cohort study, we found that SpO2 measured by pulse oximetry increased with time after birth with varying dynamic trends at different altitudes. The increase in altitude, particularly above 3,500 m, had a significant impact on the measurement of SpO2. The effect is more pronounced in the early neonatal period and probably decreases with time as acclimatization occurs. We further presented cutoff values for identifying hypoxemia during 30–120 min after birth at each altitude level.

SpO2 values vary within the first few hours after birth [15]. For neonates from Xishuangbanna (847 m) and Kunming (1,983 m), SpO2 was already over 95% at 10 min after birth, which is consistent with previous studies [8-10]. While for neonates from Shangri-La (3,509 m) and Yushu (4,360 m), SpO2 increased with a high slope within 2 h of life, the values remained significantly lower than those in Xishuangbanna (847 m) or Kunming (1,983 m). However, there are only limited studies on SpO2 values during the early periods of neonates living at altitudes above 3,500 m. Hurtado et al. [12] briefly reported that in Cusco, Peru (3,400 m), SpO2 increased from 72.59% (SD 9.84) in the first minute to 87.46% (SD 3.60) in the 15th minute. Gonzales et al. [11] recorded SpO2 in 39 term neonates from Cerro de Pasco (4,340 m), and the results showed that SpO2 increased from 45.08% (SD 2.47) in the first minute to 87.56% (SD 1.19) at 30 min of life in term neonates. Along with the current study, it is reasonable to presume that the increase in altitude, especially above 3,500 m, had a significant impact on the measurement of SpO2.

Our results further showed that SpO2 values below 95%, the cutoff for identifying hypoxemia at sea level [5, 16, 17], were found in normal local neonates in high-altitude areas, especially above 3,500 m. In Shangri-La (3,509 m) and Yushu (4,360 m), although oxygen saturation increased with a high slope, there were still over 75% of well neonates who had SpO2 below 95% between 30 and 120 min after birth, which can be partially explained by high altitude adaptations [18]. Generations of human inhabitation at high altitudes have led to complex physiological and genetic adaptations, including but not limited to an increase in alveolar ventilation, optimized blood flow to tissues, secretion of erythropoietin hormone, and expression/activation of an array of genes [6, 19, 20], all of which are designed to maintain an adequate oxygen balance in these neonates at high altitudes. It is also suggested that in high-altitude areas, using sea level cutoff thresholds might misclassify a large proportion of healthy neonates as having hypoxemia, resulting in excess oxygen exposure and hyperoxia. As a result, for healthy neonates living at high altitudes, the aim of oxygen management should not be based on normal values at sea level but should aim to achieve an adjusted normal SpO2 for that setting.

Since the increase in altitude had a significant impact on the SpO2 [19, 21], a clearer definition of the lower limit of normal SpO2 among neonates in high-altitude areas would enable protocols for oxygen therapy to be adapted to local conditions and enable appropriate application of resources. In a systemic review, Subhi et al. [18] suggested that for children aged 1 week to 12 years living at altitudes above 2,500 m, an SpO2 threshold of less than 85% was more appropriate to be considered as hypoxemia. Unfortunately, relevant data to establish thresholds for neonates during the first few hours of life at high altitudes are scarce. To the best of our knowledge, this is the first study to cover a wide range of altitude level, and we further presented cutoff values for identifying hypoxemia between 30 and 120 min after birth at different altitude levels, which might contribute to a better quality of oxygen therapy.

In this study, we presented the SpO2 values of healthy full-term neonates during the first 2 h of life at altitudes ranging from 847 m to 4,360 m for the first time and provided the cutoff values for identifying hypoxemia between 30 and 120 min after birth at each altitude level. However, this study has some limitations. First, some perinatal information such as the mother’s disease state, prenatal monitoring data, and the reason for cesarean section was unavailable from the current database. Second, we cannot provide long-term follow-up data to determine whether the lower SpO2 values at higher altitudes are sufficient for those infants to thrive just like their peers at sea level. Third, the dynamic trend of SpO2 after 2 h of life was unavailable. Despite this being an exploratory study, further prospective studies with long-term follow-up data are needed to confirm the optimal normal range of SpO2 at high altitudes, especially above 3,500 m.

Conclusions

In summary, the increase in altitude, especially Shangri-La (3,509 m) and Yushu (4,360 m), had a significant impact on SpO2 in healthy full-term neonates during their first 2 h of life. Establishing the SpO2 reference intervals in the first few hours of life in high-altitude areas will serve to optimize oxygen therapy.

Acknowledgments

We would like to thank the midwives and colleagues in the participating hospitals of CHANMA for their excellent technical assistance, Professor Weili Yan (Children’s Hospital of Fudan University, Shanghai, China) for her help in preparation of the manuscript, Peng Shi for his statistical advice, and Xinran Dong for her help with data visualization.

Statement of Ethics

This study was approved by the Ethics Committee of Kunming children’s hospital (2021-03-146-K01). Written informed consent was obtained from the legal guardians of the neonates.

Conflict of Interest Statement

The authors declare no competing financial interests or any conflicts of interest in relation to the work described.

Funding Sources

This study is funded by the Zhou Wenhao Expert Workstation in Yunnan Province (No. 2019IC052). The funding organization did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author Contributions

Yangfang Li, Bi Ze, Tiesong Zhang, Xiaomei Liu, and Jin Gao supervised the data collection and drafted and revised the manuscript. Hui Mao, Mingcai Qin, Yinzhen Lai, Suo nan ba jiu, and Guoyun Li designed the instruments, collected data, and analyzed the data for the work. Kun Du, Zhangbin Yu, and Wenhao Zhou designed the study, coordinated the data collection, and critically reviewed the manuscript.

Data Availability Statement

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from Dr. Li Yangfang.

This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.