Child health and living at high altitude
- 1University of Colorado School of Medicine, Department of Pediatrics (Neonatology), Denver, Colorado, USA
- 2Caja Nacional de Salud, Division of Cardiology (Pediatrics), Clínica del Sur and Clínica Alemana, La Paz, Bolivia
- 3Universidad Nacional Mayor de San Marcos and Universidad Peruana Cayetano Heredia, Department of Pediatrics, Instituto de Salud del Niño, Lima, Perú
- Correspondence to Susan Niermeyer, University of Colorado School of Medicine, Department of Pediatrics (Neonatology), The Children’s Hospital, 1056 E. 19th Avenue, B-070, Denver, Colorado 80218-1088, USA;
- Accepted 26 March 2008
- Published Online First 9 December 2008
The health of children born and living at high altitude is shaped not only by the low-oxygen environment, but also by population ancestry and sociocultural determinants. High altitude and the corresponding reduction in oxygen delivery during pregnancy result in lower birth weight with higher elevation. Children living at high elevations are at special risk for hypoxaemia during infancy and during acute lower respiratory infection, symptomatic high-altitude pulmonary hypertension, persistence of fetal vascular connections, and re-entry high-altitude pulmonary oedema. However, child health varies from one population group to another due to genetic adaptation as well as factors such as nutrition, intercurrent infection, exposure to pollutants and toxins, socioeconomic status, and access to medical care. Awareness of the risks uniquely associated with living at high altitude and monitoring of key health indicators can help protect the health of children at high altitude. These considerations should be incorporated into the scaling-up of effective interventions for improving global child health and survival.
Global perspective on children at high altitude
Efforts to improve global child survival have succeeded by targeting conditions which affect large numbers of children and carry a high risk of death or loss of productive life. Much as diarrhoeal disease and acute respiratory infections have responded to a global approach, a similar perspective can be applied to improving the survival and health of children at high altitude. Although geographically dispersed, the aggregate number of children living at high altitude is substantial, and infant and child mortality remain high in many of these regions. Across regions, the challenges to health are similar, based on hypobaric hypoxia, other environmental conditions, and sociocultural vulnerabilities. A review of the public health issues confronting children living at high altitude was conducted by surveying both the medical and demographic literature.
Approximately 12 per cent of the world’s population lives in mountainous areas. Recent data combining census figures with satellite imagery suggest that about three-quarters of a billion people live in mountainous zones.1 Estimates of mountain dwellers living >2500 m range from 70 to 140 million people.1 2 Although regions >2500 m (fig 1) tend to be rural and sparsely settled, notable exceptions occur in the densely populated highlands of sub-Saharan Africa, growing permanent communities around North American resorts, and burgeoning urban areas in South America. Young families typically inhabit rapidly growing areas. Among the more than 2 million people living in El Alto and La Paz, Bolivia at altitudes between 3600 and 4000 m, 46% are ⩽19 years.3
High-altitude areas present a complex ecology incorporating not only the physical environment, but also elements of population ancestry, socioeconomic factors, and access to medical care.4 Hypoxia often occurs in conjunction with wide variation in diurnal or seasonal temperatures and intense solar radiation. The harsh, often barren terrain in mountainous areas is home to a multitude of indigenous populations. Notable among these are large groups of Tibetans in the Himalayas, Aymara and Quechua in the Andes, and the Amhara of the Semien Mountains in Africa. Among these groups exist differing patterns of genetic adaptation to high-altitude hypoxia, such as increased blood flow and oxygen delivery versus increased erythrocytosis.5 6 7 Agricultural livelihood in the mountains of developing countries is constrained by the limitations of climate, soil and slope, and most families rely on livestock herding and cultivation of a staple grain. With a narrow range of foods and the nutritional content of foods reflecting local conditions, children are especially vulnerable to food insecurity and micronutrient deficiencies. Access to medical care in mountainous zones is often poor, not only due to lack of primary healthcare facilities and professionals, but also because of long distances from homes to roads.1
Estimates of mortality during childhood and the perinatal period are elevated in many developing countries and countries in transition that have a significant proportion of their populations at high altitude. Table 1 presents mortality statistics for several countries with an estimated >20% of the population residing at high altitude.8 Although rates do vary regionally, and determinants such as poverty, women’s status, armed conflict and political commitment to health account for much of the variation, the fact remains that rates for the major indicators of child and maternal mortality are elevated. Within countries, mortality has been demonstrated to rise with increasing elevation. Data from Peru and Bolivia show this trend for neonatal, infant, and under-5-years mortality.9 10 11 12 Respiratory problems account for the majority of neonatal and infant deaths in this region.13 14
The challenges to infants and children include several universal issues that take on special dimensions at high altitude; these include low birth weight, poor growth and nutritional deficiencies, and respiratory infections. In addition, infants and children at high altitude face a variety of conditions that directly reflect the effect of chronic hypoxia on the developing cardiopulmonary system; these include hypoxaemia during infancy, persistence of fetal shunts, symptomatic high-altitude pulmonary hypertension (SHAPH), and re-ascent high-altitude pulmonary oedema (HAPE). Several lines of evidence also raise concern for cognitive development under conditions of intermittent or relative chronic hypoxia, though direct data are limited.
An inverse relationship between birth weight and altitude has been demonstrated conclusively in several different population groups.6 Lower birth weight results not from prematurity, but instead, from intrauterine growth restriction. While this decrease in birth weight averages around 100 g for every 1000 m of elevation gain >2000 m,15 16 there is notable variation in the magnitude of the effect, with the least reduction in populations that have resided longest at high altitude (fig 2). Thus, among the population groups studied intensively, the birth weight decrement is least in Tibetans, intermediate in Andeans, and greater in Europeans and Han Chinese.6 Fetal growth correlates with maternal oxygen delivery to the fetoplacental unit. The mechanisms vary among individuals and populations, but increased uterine blood flow and preserved oxygen content represent two major strategies.2 Although birth weight is affected by low socioeconomic level across all altitudes, it appears that high altitude acts independently from socioeconomic factors in birth weight reduction.15 16 17 18
Birth weight is a major determinant of infant mortality. Altitude-associated growth restriction contributes to the increased mortality observed in high-altitude regions where medical care is limited. The significance of reduction in birth weight is most evident among infants who are classified as low birth weight (<2500 g). In the immediate postnatal period, these infants have difficulty maintaining body temperature and may have inadequate energy stores to maintain blood glucose. Such factors directly influence mortality and morbidity in the first week of life.19 20 21 22 23 As adults, individuals with small size at birth encounter greater risk for cardiovascular disease, including coronary heart disease, hypertension and stroke, as well as type 2 diabetes mellitus, and obesity.24 Although most data on the fetal and neonatal origins of adult disease come from sea level, data from large population-based investigations are awaited to validate this principle at high altitude.
Childhood growth and nutrient deficiency
Whether at sea level or at high altitude, growth serves as an overall indicator of child health. Although growth restriction is often reported among high-altitude populations, recent studies from South America suggest that slower linear growth relates more to socioeconomic status and the availability of adequate nutrition than to hypoxia.25 26 27 A positive secular trend in height, suggesting better growth with improved living conditions, supports this.28 29 However, the challenges of appetite blunting under hypoxic conditions, symptomatic altitude-associated illness, and acute respiratory infection may all decrease nutritional intake and increase energetic demands, resulting in poor growth.30 31
Malnutrition among children at high altitude results from deficiency of both macronutrients and micronutrients. Chronic food scarcity and protein-energy malnutrition often result in stunting from an early age. A community survey of Tibetan children demonstrated consistently better height-for-age among urban than rural children, but no direct association of stunting with altitude.26 The high-altitude environment uniquely predisposes to micronutrient deficiencies in vitamins A and D, iron and iodine.1 Vitamin A deficiency is most common where consumption of fruits and vegetables is low; it predisposes young children to respiratory and gastrointestinal illness, blindness, and death. Iron deficiency is common worldwide, affecting mostly children and women of childbearing age. Its effects are magnified at high altitude where erythropoietic demands are high and oxygen content of blood is reduced. Anaemia is a risk factor for maternal and neonatal death, as well as impaired neurodevelopment of children.32 Evaluation of iron deficiency at high altitude requires correction of haemoglobin values or measurement of body iron stores. In Bolivia, body iron stores of mothers and their children aged <5 years correlated strongly, and women living >3000 m had significantly reduced iron stores.33 Iodine deficiency is especially prevalent in the Himalayas, where iodine salts have washed away from soils, and iodine-rich foods and supplementation have limited distribution. Iodine deficiency causes mental retardation and low intelligence quotient; severe deficiency can result in cretinism, birth defects and stillbirth.1 34 Where harsh climate dictates that infants and young children are kept inside or completely covered when outside, rickets (vitamin D deficiency) may be prevalent. In the community survey of Tibetan children, 66% had clinical signs of rickets, and vitamin D levels in a subsample confirmed deficiency.26
Acute and chronic respiratory conditions
Acute respiratory infection is a major cause of mortality among children <5 years of age in most of the developing world. Children living at high altitude also face the potentiating factors of environmental hypoxia and indoor air pollution. Hypoxaemia during acute lower respiratory infections (ALRIs) is more frequent in children at high altitude and associated with increased mortality (table 2). Low arterial oxygen saturation (SaO2) on presentation with ALRI has been shown to be a predictor of death in several settings of moderate-to-high altitude.35 36 37 In Kenya at 1670 m, children with SaO2 <90% were over four times more likely to die within the next 5 days.37 Complicating the situation is the finding that clinical signs of ALRI such as tachypnoea, cyanosis, grunting, flaring, and chest retractions are less predictive of hypoxaemia and pneumonia at high than low altitude.36 37 38 39 However, low SaO2 is relatively sensitive and specific for the diagnosis of pneumonia, and supplemental oxygen, guided by pulse oximetry rather than clinical signs, can decrease mortality.35 Definition of optimal threshold for initiation and discontinuation of oxygen supplementation warrants further research.
Exposure to indoor air pollution (ie, smoke in households using biomass fuels) further increases the risk for ALRIs in children living at high altitude. Especially in minimally ventilated rooms in cold climates, infants and young children are exposed daily to high concentrations of pollutants over long periods of time as they are tended by their mothers during household cooking.40 Indoor air pollution has been linked also to increased odds of stillbirth as well as reduction in birth weight.41 42 Further studies are needed to quantify the additional risk, determine the reduction in exposure necessary to improve health, and establish the effectiveness of interventions such as improved cooking stoves.
The contribution of sudden infant death syndrome (SIDS) to infant mortality at high altitude remains uncertain. Population-based studies at relatively low altitudes in the USA and Austria have shown a positive association between SIDS rate and elevation.43 44 However, intervention programmes to promote the supine position for sleep and reduce risk factors such as maternal smoking and lack of breastfeeding have proven effective in the same regions.45 Limited ascertainment of causes of infant death continues to hamper collection of accurate statistics in most countries of the developing world.
Altitude-associated cardiopulmonary pathophysiology
Neonatal respiratory distress is a major cause of mortality and morbidity in the first month of life, whether at high or low altitude. The transition from oxygenation via the placenta to oxygenation across the formerly fluid-filled lungs is especially precarious in a low-oxygen environment. Common causes of neonatal respiratory distress, such as surfactant deficiency, congenital pneumonia, aspiration of meconium-stained amniotic fluid, or retained fetal lung fluid can result in significant hypoxaemia and interfere with the postnatal increase in pulmonary blood flow, resulting in persistent pulmonary hypertension of the newborn.
Even in the absence of pulmonary disorders, neonates may experience arterial oxygen desaturation in the first week of life. Studies performed in Lhasa, Tibet at an altitude of 3658 m and Leadville, Colorado, USA at 3100 m show a decline in SaO2 by 1 week, whereas SaO2 gradually rises after birth or remains fairly constant across time at sea level.46 47 Of note, this fall in saturation is less pronounced among the native Tibetan infants in Lhasa than among the Han infants gestated and living at the same altitude; SaO2 averages 90–94% during the first 2 days among Tibetans and 86–92% in the Han. Tibetan infants maintain SaO2 similar to Leadville infants for 4 months (86–90%). Among the Han, SaO2 in quiet sleep declines progressively from 1 week to 4 months, with the mean (SD) saturation in quiet sleep at 4 months being 76% (5%). In the awake state, differences in SaO2 between the two groups are less marked and begin to converge by 4 months. At similar altitudes in Peru (3750 m) and Bolivia (4018 m) mean SaO2 in native Andean (Quechua and Aymara) infants averages 87–88%.38 48 However, at extreme high altitude, SaO2 ranges from 57 to 75% in neonates and 74 to 81% during infancy and childhood.49 50
Evidence for a slow decline in pulmonary artery pressure after birth at high altitude comes from cardiac catheterisation, echocardiographic studies, and electrocardiographic data.51 In extreme high altitude at 4540 m, pulmonary artery pressure remained at systemic levels for up to 72 h after birth, as measured directly at cardiac catheterisation.49 Pulmonary artery pressure fell nearly to sea level normal ranges when supplemental oxygen was administered to the same infants at 72 h. Electrocardiographic studies in normal infants and children at 4540 m in Peru showed continued right ventricular preponderance throughout childhood.52 Electrocardiographic and echocardiographic indices of pulmonary artery pressure have been shown to fall slowly among South American infants living at 3700 m in Peru53 and Bolivia.54 Among older mestizo children resident at 4100 m in Peru, electrocardiographic and echocardiographic measurements fell essentially within normal ranges for sea level; however, these children enjoyed favourable nutritional and socioeconomic conditions, as well as considerable mobility to low altitude.55 56 In general, pulmonary artery pressures in children are higher at greater elevation (lower arterial oxygen pressure) and decrease with increasing age.57
Persistence of the patent foramen ovale (PFO) and persistently patent ductus arteriosus (PDA), both characteristic of the fetal circulatory pattern, have been observed in several populations at high altitude. In a population-based survey of school-aged children on the Tibetan plateau, both PDA and PFO were noted to increase in prevalence with altitude. At 2260 m the combined prevalence was 2.2% (all in Han residents); and at 4500 m the combined prevalence was 5.2%, occurring in both Han and Tibetan residents.58 This compares to a combined prevalence in sea-level surveys of <0.04%.58 An echocardiographic survey of 326 children aged 2 months to 19 years in Tintaya, Peru (4000 m) identified five children with structural cardiac abnormalities, three of which (two PFO/atrial septal defect, PDA) were potentially referable to development at high altitude. The comparatively low incidence in this South American population may reflect genetic admixture, outmigration and access to medical care.59
SHAPH is another condition unique to children living at high elevations. This clinical entity has been described in North American, South American, and Asian populations at high altitude, although the nomenclature has been variable and somewhat confusing, including “primary pulmonary hypertension in children living at high altitude”, “cardiac insufficiency of the nursling”, “paediatric high-altitude heart disease”, and “subacute infantile mountain sickness”.60 61 62 63 Underlying all of these entities is the common pathophysiology of pulmonary hypertension accompanied by muscularisation of pulmonary arteries and arterioles and resulting in hypertrophy and dilation of the right ventricle with ultimate right-sided congestive heart failure.63 The clinical characteristics include cyanosis or pallor, fatigue, irritability and dyspnoea. Poor feeding results in suboptimal growth. On physical exam, the second heart sound may be increased and there may or may not be a cardiac murmur of tricuspid regurgitation. In more advanced cases, hepatomegaly and oedema may offer a clue to the right-sided congestive heart failure. The typical radiograph is remarkable for consistent cardiomegaly and prominence of the pulmonary outflow tract. Infiltrates are variable and hepatomegaly may be notable on chest radiographs as well as the physical exam. Clinical diagnosis requires a high index of suspicion, as the presenting signs may be subtle. Confirmation of the diagnosis can be obtained through electrocardiogram, echocardiography and cardiac catheterisation. The typical electrocardiographic pattern shows increased QRS duration and right deviation of the QRS axis. Voltage of the S-wave is decreased in V1 and increased in V6, and there may be an upright T-wave in V1. Echocardiography often shows septal flattening as an anatomic correlate of increased right-sided pressures, and a quantifiable tricuspid regurgitation jet, permitting calculation of pulmonary artery pressures using the modified Bernoulli equation. Right ventricular hypertrophy, right atrial dilation, and persistence of PFO and PDA may also be noted. Although diagnosis is usually made on the basis of echocardiography, cardiac catheterisation may reveal unsuspected shunts and malformations and provide information on therapeutic response to oxygen and pulmonary vasodilators.
Increasingly, uneven pulmonary vasoconstriction, exaggerated vasoreactivity to hypoxia, and pulmonary hypertension are being recognised as circumstances underlying HAPE.64 65 PFO also has been observed to be more common among HAPE-susceptible than HAPE-resistant adult mountaineers.66 In children resident at high altitude, the characteristics of HAPE differ somewhat from the circumstances of occurrence in adults. Among high-altitude residents, children are more likely than adults to develop re-entry HAPE, pulmonary oedema occurring upon return from low altitude to the high altitude of residence.67 HAPE in children is associated, as well, with antecedent viral infections, trisomy 21 and underlying congenital cardiovascular malformations, such as unilateral absence of the pulmonary artery.68 69 70 71
Cognitive development during infancy and childhood at high altitude is an area of growing concern, but relatively limited research data.72 Newborn infants from a mestizo population at extreme high altitude in Cerro de Pasco, Peru (4300 m) showed less visual and auditory orientation, less activity and motor maturity, and less self-quieting on the Brazelton Neonatal Behavioral Assessment Scale as compared with matched sea level controls.73 However, a study of older infants and children aged between 2 months and 2 years at somewhat lower altitude (3780 m in Puno, Peru) showed no deficit in early motor development.74 The infants in Puno were significantly better grown at birth, with mean birth weight 3260 g versus 2824 g in the group from Cerro de Pasco.75 At sea level, chronic fetal hypoxia correlates with lower intelligence quotient values. Data from over 19 000 children in the US national Collaborative Perinatal Study showed that maternal gestational anaemia, hypotension, hypertension, and fetal growth retardation resulted in lower scores on the Wechsler Intelligence Scale at 7 years, when results were controlled for maternal IQ and socioeconomic status.76 Intrauterine growth restriction, fetal mortality and gestational hypertension are common complications of pregnancy among Bolivian women living >3600 m in La Paz, suggesting that chronic fetal hypoxia may affect incompletely adapted populations living at high altitude.77 Exposure to chronic or intermittent hypoxia during childhood may also contribute to adverse cognitive effects. Among children with cyanotic heart disease and sleep-disordered breathing, well-designed studies have identified negative effects on development, behaviour and academic achievement.78 Although it might be argued that these two groups may have intrinsic abnormalities affecting cognitive development, the saturation levels encountered are analogous to those at high altitude. Finally, exposures to carbon monoxide from biomass combustion and heavy metals associated with mining activity pose specific threats to normal development in mountain environments.32 Future studies will require sophisticated methodology to take into account the influences of genetic adaptation on physiology, cultural and ethnic behaviour, and environmental factors on development at high altitude.
Health monitoring at high altitude
Effective interventions for further reducing unnecessary deaths of children at a global level are in place and scaling-up is now imperative. Children resident at high altitude face a unique set of sociocultural and physiological challenges to health. Recognition of these crucial factors that impact child health at high altitude – low birth weight, suboptimal growth and malnutrition, acute respiratory infection, hypoxaemia during infancy, SHAPH, and high-altitude pulmonary oedema – must be integrated into a system of monitoring for children resident there. Beginning at birth, weight should be assessed for adequacy with respect to gestational age and with respect to the defined value of 2500 g, below which infants are classified as low birth weight. Monitoring of SaO2 in the first 1–2 weeks of life should be considered to detect significant desaturation associated with clinical signs of fussiness, sleep disturbance and poor feeding. Descent may be advisable for symptomatic infants where ambulatory oxygen supplementation is not feasible. Growth should be monitored frequently to detect the impact of intercurrent illnesses or cardiopulmonary conditions as well as undernutrition. Especially in areas of restricted food supply, evidence of specific micronutrient deficiency should be sought, and programmes of individual or community supplementation considered.79 80 Routine health visits should focus also on detection of persistent cardiac shunts, such as PFO and PDA. Prompt recognition of acute respiratory infections, both by clinical signs and use of pulse oximetry to quantitate SaO2, should be followed by appropriate use of supplemental oxygen to decrease mortality.81 Among children presenting with signs of pneumonia or recurrent respiratory complaints, as well as failure to thrive, there should also be a high index of suspicion for SHAPH. Confirmation of the diagnosis should be sought with chest radiograph, electrocardiogram, and echocardiography if possible.
Though the health of infants and children is an important goal in and of itself, the conditions experienced during development, especially during neonatal life and infancy, likely have lifelong impact for the individual. Much as conditions of intrauterine life that lead to low birth weight now are well recognised to predispose to development of cardiovascular disorders in adulthood, persistent pulmonary hypertension of the newborn has been linked to exaggerated pulmonary vasoreactivity among young adults upon exposure to hypobaric hypoxia at high altitude.82 Chronic perinatal hypoxia affects the chemoreceptor pathway, delaying the maturation and decreasing the ultimate ventilatory sensitivity to hypoxia achieved in experimental animals.83 84 Gender differences also exist, with progesterone enhancing hypoxic ventilatory response and testosterone depressing respiration in neonatal rats raised at high altitude.85 Such interactions between steroid hormones and ambient hypoxia in the development of respiratory control may help explain the blunted hypoxic ventilatory response and the male preponderance of chronic mountain sickness.86 Thus, to assure the health of the individual both as a child and as an adult, the challenges of growing up at high altitude deserve attention from the medical community.