Neonatal Hyperbilirubinemia at High Altitude
Cynthia Leibson, PhD; Mark Brown, MD; Steve Thibodeau, PhD; David Stevenson, MD; Hendrik Vreman, PhD;
Ron Cohen, MD; Gisela Clemons, PhD; Wayne Callen, MD; Lorna Grindlay Moore, PhD
\s=b\A previous retrospective study
showed an increased frequency of neona-
tal hyperbilirubinemia at high altitude in
Colorado. In a prospective study we found
that 39% of newborns at 3100m altitude vs
16% at 1600 m exhibited hyperbilirubine-
mia, defined as a day 3 serum bilirubin
level of 205 \g=m\mol/L or higher. Increased
bilirubin production at 3100 m vs 1600 m
was shown by increased levels of cor-
rected carboxyhemoglobin. This finding
was supported by increased erythropoie-
tin and bilirubin values in cord blood and
increased hematocrit values at day 3
among infants at 3100 m vs 1600 m. The
sustained elevation in bilirubin for breast-
fed vs formula-fed infants at 1600 m was
observed for both feeding types at 3100 m.
The findings suggested that there is a he-
matologic response to decreased oxygen
availability at high altitude, resulting in
increased bilirubin production accompa-
nied by delayed bilirubin clearance.
(AJDC. 1989;143:983-987)
^\f ofobserved
e
neonatal
an increased frequency
hyperbilirubinemia at
higher (3100 m) compared with lower
(1600 m) altitude in Colorado in a previ¬
'
ous retrospective study. In the pres¬
ent study we compared infants born at
1600 m and 3100 m to determine wheth¬
er this finding could be confirmed pro-
spectively. If so, we sought to determine
the extent to which increased bilirubin
production and/or decreased capacity
Accepted for publication October 31,1988.
From the Department of Anthropology, Univer-
sity of Colorado at Denver (Drs Leibson and
Moore); the Department of Pediatrics, University
of Colorado Health Sciences Center, Denver (Dr
Brown); Children's Hospital, Denver, Colo (Drs
Brown and Thibodeau); Neonatology Metabolism
Laboratory, Stanford University, Palo Alto, Calif
(Drs Stevenson and Vreman); Santa Clara Valley
Medical Center, San Jose, Calif (Dr Cohen); Law-
rence Berkeley Laboratories, Berkeley, Calif (Dr
Clemons); St Vincent Hospital, Leadville, Colo (Dr
Callen); and Cardiovascular Pulmonary Research
Laboratory, University of Colorado Health Sci-
ences Center, Denver (Dr Moore).
Reprint requests to Department of Health Sci-
ences Research, Mayo Clinic, Rochester, MN 55905
(Dr Leibson).
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/19/2015
for clearance were operating at the
higher altitude. We considered that an
understanding of factors responsible for
the increased frequency of hyperbiliru¬
binemia at 3100 m might be informative
as to how the transition from fetal to
neonatal life was influenced by the re¬
duced oxygen availability of high alti¬
tude, as well as to the understanding of
neonatal hyperbilirubinemia generally.
SUBJECTS AND METHODS
Subjects
Subjects born at lower altitudes consisted
of infants born over a study period of 19
nonconsecutive weeks at Children's Hospi¬
tal/St Luke's, Denver, Colo, at an elevation
of 1600 m. Subjects born at higher altitudes
consisted of infants born over a 10-month
period at St Vincent Hospital, Leadville,
Colo, at an elevation of 3100 m. White, sin¬
gleton, fall-term healthy infants whose par¬
ents granted consent were eligible for the
study. Full-term births were defined as ges¬
tational age between 38 and 41 weeks from
The onset of the mother's last menstrual pe¬
riod. Infants were considered healthy when
their 5-minute Apgar score was 8 or higher
and when their newborn course was uncom¬
plicated by respiratory distress, congenital
abnormality, sepsis, or any other conditions
requiring transfer from the low-risk nurs¬
ery. Infants with positive results of either
direct or indirect Coombs' test indicative of
Rh or blood group incompatibility were ex¬
cluded. The parents of two infants at each
altitude declined consent.
A major part of the analysis involved the
comparison of day 3 serum values between
the two altitudes. For some of the 58 eligible
infants at 1600 m and the 45 eligible infants at
3100 m we were unable to obtain a mean
( ± SEM) blood serum value at 72 ± 12 hours
drawn in conjunction with the required phe-
nylketonuria testing, either because of
scheduling conflicts (n 6 at 1600 m; 7 at
= =
3100 m) or insufficient serum sample (n 3 at
=
1600 m; n 7 at 3100 m). Data analysis with
=
these infants, using serum values from day 2
or day 4 and transcutaneous values when no
serum was available, gave the same results
as analysis without these infants. However,
to assure comparability of the study groups,
infants from whom no serum sample was
available at 72 ± 12 hours were excluded from
the final analysis, yielding a sample size of
41 breast-fed and 8 formula-fed infants at
1600 m and 21 breast-fed and 10 formula-fed
infants at 3100 m. Infants at 3100 m received
supplemental 24% 02 before being weaned to
room air (mean, 17 ± 3 hours; range, 2 to 120
hours). Infants at both altitudes were fol¬
lowed up by one of us (C.L.). Study proce¬
dures were approved by the University of
Colorado, St Vincent Hospital, and Chil¬
dren's Hospital Human Subjects Review
Committees.
Relevant information on all infants was
obtained from medical record review, inter¬
view, and measurement and included the fol¬
lowing: (1) maternal characteristics: age,
education, marital status, gravidity, parity,
prenatal events, history of diabetes, history
of smoking, blood type, labor and delivery
complications, method of delivery, and use
and type of obstetric anesthesia; and (2) in¬
fant characteristics: blood type, gestational
age by date and by physical examination,2
Apgar scores at 1 and 5 minutes, birth weight
and length, head circumference, presence or
absence of bruising, feeding type, frequency
of feeds and supplementation, time of first
bowel movement and frequency of bowel
movement, weight at days 1, 3, and 7, length
of hospital stay, and daily exposure to sun¬
light (on a five-point scale ranging from dark
room/no outings to crib by the window/one or
more outings).
Methods
Measurements were obtained on cord
blood samples for levels of plasma bilirubin
erythropoietin and hematocrit values. Heel
capillary blood samples were obtained3 at
72±12 hours (mean, 70.2 ±0.5 hours at
1600 m and 70.2 ± 1.0 hours at 3100 m) for
measurement of serum bilirubin levels, he¬
matocrit values, and carboxyhemoglobin lev¬
els. Samples were analyzed for both total and
conjugated bilirubin according to the modi¬
fied Jendrassik-Grof method4 using a centrif¬
ugal analyzer (Cobas-Bio, Roche Diagnos¬
tics, Nutley, NJ) in the same laboratory at
Children's Hospital. Samples from Denver
infants and day 3 samples from Leadville
infants were stored in the dark at 4°C and
 were analyzed within 12 hours of collection.
Leadville cord samples were stored at
-25°C and were analyzed within 5 days of
collection. Samples kept at 4°C for 12 hours
were compared with a portion of the same
samples stored at 25°C for 5 days and were
found to agree well (mean[ ± SEM] of differ¬
-

ences in 19 samples, 0.34 ± 1.37 pmol/L; not

significant). So that two infants at 1600 m and
one infant at 3100 m who underwent photo¬
therapy outside of 72 ± 12 hours were not
excluded, the last available bilirubin value
before phototherapy was used for these
infants.
For nine of the infants in the higher-alti¬
tude group, we were unable to collect suffi¬
cient serum for bilirubin analysis by the mod¬
ified Jendrassik-Grof method, and total
bilirubin values were determined using the
ultramicro spectral method5 (American Opti¬ Fig 1.—Distributions of serum bilirubin val¬
ues at 72 ± 12 hours in infants at altitudes of
cal Bilirubinometer, Southbridge, Mass).
3100 m and 1600 m. Shaded areas indicate
Spectral values were converted to the equiv¬ formula-fed infants. Fig 2.—Median transcutaneous bilirubin val¬
alent Jendrassik-Grof value with a linear re¬ ues in breast-fed (top) and formula-fed (bot¬
gression equation determined from 28 sepa¬ tom) infants at altitudes of 3100 m (breast-fed
rate newborn samples analyzed with both the infants, =
21; formula-fed infants, =
10)
Jendrassik-Grof (y) and spectral methods (x) Statistical Analysis and 1600 m (breast-fed infants, =
41 ; formu¬
la-fed infants, =
8).
(2/ 0.944x + 17;
=
.000; Sy,x 8.8; 95%
= =

confidence interval 0.899, 0.989; 90% pre¬

= Measurements were made in duplicate and
diction interval at xm 180 213).
=
Transcutaneous bilirubin measurements
were made on days 1, 2, 3, 5, 7, and 14 using
the Minolta Jaundice Meter 101 (Air Shields,
Hatboro, Pa). Transcutaneous meter read¬
ings were highly reproducible (mean
[±SEM] of differences between first and
second measurements 0.46 ±0.09 U; not
=
significant). The meter was calibrated at
both lower and higher altitudes by compar¬
ing day 3 transcutaneous and serum bilirubin
the average value was recorded. Comparison
of values between 1600 m and 3100 m was
conducted using unpaired (Student's) t tests,
Mann-Whitney U tests, and 2 tests. Com¬
parison of bilirubin levels obtained from the
same infant at birth and day 3 were per¬
formed using paired t tests. Relationships
between variables were assessed using lin¬
ear regression techniques. Results were con¬
sidered significant when P=s.05. Data are
reported as mean ± SEM.
rubin levels among formula-fed infants
at 3100 m vs 1600 m. Lower bilirubin
values have been reported for infants
whose mothers smoke at least one pack
of cigarettes a day compared with in¬
fants of nonsmoking mothers.9 Compar¬
ison of formula-fed infants of nonsmok¬
ing mothers revealed bilirubin values at
day 3 at 3100 m to be 180 ±24 µ /L
(n 9) vs values at 1600 m of 127 ±31
=

values obtained simultaneously from each in¬ RESULTS µ /L (n 5; not signifcant). When all
=

fant (y 0.9x + 125; r=.94). Six infants

= infants of nonsmoking mothers were
were not available for measurement because Neonatal hyperbilirubinemia, de¬ considered, this difference reached sig¬
they received phototherapy (4 at 1600 m on fined as a serum bilirubin level of 205 nificance (181 ± 12 µ /L at 3100 m vs
days 3, 5, 5, and 5 and 2 infants at 3100 m on µ /L or higher at 72 ± 12 hours after 153 ±11 µ /L at 1600 m; .05). A
=

days 3 and 5). All 6 infants were breast-fed.
Hematocrit values were measured using
the microcentrifuge technique.3 Erythropoi¬
etin level was measured by radioimmunoas-
say.6 Laboratory values for interassay and
birth, occurred in 39% (12/31) of the in¬
fants born at 3100 m, which was more
than twice the 16% (8/49) incidence at
1600 m (Fig 1). The effect of altitude was
most apparent in the comparison of for¬
significant association was found be¬
tween bilirubin values at day 3 and alti¬
tude when adjusted for feeding type,
maternal smoking, supplement, and ca-
put/hematoma(F[l,74] 3.94;P=.05).
=

intra-assay variability for this procedure are

9.7% and 8.4%, respectively. The opportuni¬
ty for carboxyhemoglobin analysis became
available after the study at low altitude was
nearly completed. Carboxyhemoglobin val¬
ues were obtained from 8 of the infants born
at 1600 m and 17 of the infants born at 3100 m.
Samples were analyzed by gas chromatogra¬
phy in the Neonatology Metabolism Labora¬
tory at Stanford University, Palo Alto,
Calif.7 Blood carboxyhemoglobin values
were corrected for ambient carbon monoxide
levels.8 Ambient air samples were collected
at times and locations near where the sam¬
pling for each infant was done and were ana¬
lyzed by gas chromatography.
mula-fed infants; mean day 3 and trans¬
cutaneous bilirubin values for breast¬
fed infants did not differ between
altitudes (Table 1 and Fig 2). However,
the proportion of breast-fed infants at
3100 m with bilirubin levels of 205
µ /L or more at day 3 was 2.8 times
that for breast-fed infants at 1600 m (10
of 21 at 3100 m vs 7 of 41 at 1600 m;
P<.05).
We considered the possibility that
differences in maternal smoking be¬
tween altitudes, while not significant,
contributed to the finding of higher bili-
Cord bilirubin values were signifi¬
cantly elevated in infants at 3100 m com¬
pared with infants at 1600 m (Table 1).
The rise in bilirubin from birth to day 3
measured serially on the same infants
was greater at 3100 m than at 1600 m
(Abilirubin, 154 ± 12 vs 123 ± 10 µ /L;
P<.05). This difference was apparent
when formula-fed but not breast-fed
infants were compared (Fig 2). Serial
transcutaneous measurements indi¬
cated that mean bilirubin values at day 7
for formula-fed infants at 3100 m
(81 ± 23 µ /L; 10) remained signif-
=

Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/19/2015

 icantly elevated above cord blood lev¬ Table 1 .—Comparison of Bilirubin and Hématologie Characteristics at 1600 m and
els, whereas values at day 7 for formula- 3100 m*
fed infants at 1600 m (24 ±12 µ /L;
=
8) had returned to cord blood levels. Altitude
Time of peak bilirubin level did not dif¬
1600 m 3100 m Pt
fer between altitudes. Infants at 3100 m
Total bilirubin, µ /L
exhibited higher carboxyhemoglobin Birth 32 ±2(37) 38 + 2 (23) .01
values, higher hematocrit values at 72 h 149 ±9(49) 178±12 (31) .06
day 3, and increased erythropoietin val¬ Breast-fed 156±10 (41) 178±17 (21) .25
ues compared with infants at 1600 m
Formula-fed 115±20 (8) 180±14 (10) .02
(Table 1). Conjugated bilirubin, µ .
Comparison of subjects at 1600 m and Birth 6±0 (36) 5±1 (21) .52
3100 m for maternal and infant charac¬ 72 h 8±0 (40) 6±1 (11) .003
teristics showed that the study groups Hematocrit
were similar with respect to most risk Birth 0.51+0.01 (28) 0.54 + 0.01 (27) .08
factors for neonatal hyperbilirubine¬ 72 h 0.54 + 0.01 (31) 0.62 ±0.01 (30) .000
mia. Values for selected characteristics, Breast-fed 0.55 + 0.01 (26) 0.62 ±0.01 (21) .000
including all those for which a signifi¬ Formula-fed 0.51 ±0.03 (5) 0.60 ±0.02 (10) .02
cant difference between altitudes was Erythropoietin, In mU/mL
found, are presented in Table 2. As de¬ Birth 3.6±0.1 (30) 4.0 ±0.2 (17) .05
termined from review of maternal his¬ Carboxyhemoglobin, corrected %
Saturation, STPD, % 0.64 + 0.06 (8) 1.17±0.14 (17) .02
tories, none of the mothers were diabet¬ Breast-fed 0.59 + 0.08 (6) 1.17±0.22 (10) .07
ic or exhibited gestational diabetes.
Formula-fed 0.78 ±0.00 (2) 1.16±0.14 (7) .31
COMMENT "Values are givenas mean ± SEM. Numbers in parentheses are sample sizes. In indicates natural
log transformation; STPD, a volume of gas at standard temperature and pressure that contains no water
This prospective study confirmed the vapor.
previous retrospective observation of a tAII values were derived with a two-tailed t test except for those for hematocrit for formula-fed
more than twofold increase in the pro¬ infants, which were derivedby the Mann-Whitney U Test.
portion of infants with serum bilirubin Table 2.-Maternal and Infant Characteristics at 1600 m and 3100 m*
values at day 3 of 205 µ /L or more at
3100 m compared with 1600 m in Colora¬ Altitude
do.1 The increased proportion of neona¬
tal hyperbilirubinemia was supported 1600 m 3100 m
Characteristic (n 49)
=
(n 31)
=

by higher cord blood bilirubin values at Maternal age, y 28±1 26±1

3100 m. Infants at high risk for neonatal
Maternal education, y 14±1 13±1
hyperbilirubinemia (eg, those with posi¬ Prenatal care, No. of visits 10±0 9±1
tive results of Coombs' test indicative of
Gravidity 2.5 ±0.3 2.4 ±0.2
hemolytic disease and those with condi¬ Parity 1.9 + 0.1 1.8 ±0.2
tions requiring transfer from the low-
risk nursery) were excluded; therefore, Gestational age, wk (by dates) 39.9 ±0.2 39.8 ±0.2

the reported figures may represent Gestational age, wk (by examination) 39.7 ±0.2 39.9 ±0.3
minimal estimates of the true frequency Apgar score, 1 min 7.8 ±0.2 7.9 ±0.2
of neonatal hyperbilirubinemia at each Apgar score, 5 min 9.0±0.1 9.2 ±0.1
altitude. Birth weight, g 3301 ±58 3126 ±74
The greater rise in bilirubin values Birth length, cm 50.9 ±0.3 50.9 ±0.4
from birth to day 3, higher mean biliru¬ Head circumference, cm 34.2 ±0.2 33.5±0.2t
bin values, and sustained elevation of Infant weight gain by day 7, % 0.6 + 1.1 1.0+1.8
bilirubin values at 3100 m vs 1600 m Breast-feeding 41/49 21/31
were observed in the comparison of for¬ Supplement (breast-fed only) 20/41 16/21t
mula-fed but not breast-fed infants (Ta¬ Supplements/d (breast-fed only) 0.5±0.1 1.6 ±0.4+
ble 1 and Fig 2). Although an explana¬ Frequency of breast-feeding/d 8.5 ±0.3. 7.1 ±0.4+
tion is not clearly discernible, it is Maternal smoking 12/49 2/31
possible that differences in breast-feed¬ Bowel movements per day 3.2 ±0.2 3.7 ±0.2
ing practices between the nurseries Caput/hematoma 19/49 4/311
may have contributed to this distinction Weight gain by day 7, % 0.6±1.1 1.0±1.8
between feeding types. The nursing Sun exposure, U 3.2 ±0.1 3.8±0.1 +
staff at Children's Hospital/St Luke's
Values are given as mean ± SEM.
(1600 m) promoted frequent breast¬ tP<.05.
feeding and discouraged supplementa- ±P<.01.

Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/19/2015

 tion. Frequent supplementation was
encouraged at St Vincent's nursery
(3100 m) to prevent dehydration at the
higher altitude. Several studies have
suggested that there is a relationship
between energy or fluid intake and neo¬
natal jaundice.*12 The possibility that
the effect of altitude on bilirubin levels
was masked by greater energy or fluid
intake in breast-fed infants at 3100 m
relative to 1600 m is supported by the
greater proportion of breast-fed infants
who received supplements and the high¬
er frequency of supplementation at
3100 m vs 1600 m, but refuted by the
lower frequency of breast-feeding in
breast-fed infants at 3100 m vs 1600 m
(Table 2). Conclusions are limited by
small sample sizes and the lack of data
on fluid and energy intake in breast-fed
infants.
One difference between samples that
could not be controlled was the adminis¬
tration of supplemental 02 to all infants
at 3100 m. However, there was no cor¬
relation between bilirubin level and the
length of time the infant was receiving
supplemental 02 (r=.06; =.75). Be¬
cause barometric pressure is lower at
3100 m, the inspired Po2 with 24% 02 at
3100 m was the same as that with room
air at 1600 m.
Elevated serum bilirubin values in
cord blood samples at 3100 m vs 1600 m
suggested that the mechanisms respon¬
sible for the altitude-associated neona¬
tal hyperbilirubinemia began before
birth. We considered the possibility
that increased bilirubin values observed
at the higher altitude were a result of
decreased intrauterine Poz, leading to
increased red blood cell production and
in turn increased bilirubin formation.
Increased red blood cell production at
high altitude has been interpreted as a
compensatory response acting to in¬
crease 02 capacity and help defend arte¬
rial 02 content.13 The higher hematocrit
values at day 3 at 3100 m are in agree¬
ment with previous studies that suggest
the possibility ofincreased red blood cell
volume in the newborn at high alti¬
tude. M Although higher hematocrit val¬
ues at day 3 at 3100 m may have resulted
from insensible fluid loss, no evidence of
dehydration at the higher altitude was
found when infants at 3100 m and 1600 m
were compared for percent of weight
gain by day 7 (Table 2). The elevated
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/19/2015
Fig 3.—Mean ( ± SEM) carboxyhemoglobin values corrected for ambient air carbon monoxide
(COHbc) for newborns at sea level (n 22), 1500 m (n 17), 1600 m (n 8), and 3100 m ( 17).
= =
erythropoietin levels in the high-alti¬
tude sample are consistent with the pos¬
sibility that higher hematocrit values at
3100 m reflected increased red blood cell
production possibly secondary to fetal
or neonatal hypoxemia.1516 Such an in¬
terpretation is limited by reports that
increased cord blood erythropoietin lev¬
el may be an acute response to the stress
of labor and delivery rather than an in¬
dex of the stimulus to red blood cell
production in utero.17,18 The small num¬
ber of deliveries without labor at 1600 m
and 3100 m precluded comparison of
erythropoietin levels in the absence of
confounding effects of labor.
The most direct evidence for in¬
creased bilirubin production at high alti¬
tude was provided by increased car¬
boxyhemoglobin levels in the samples at
3100 m. Carbon monoxide is produced
as a by-product of heme catabolism in
equimolar amounts with bilirubin,19 and
measurement of carboxyhemoglobin
has been shown to provide reliable esti¬
mates of endogenously produced carbon
monoxide and bilirubin production.8,20,21
Supportive evidence for greater biliru¬
bin production at higher altitude was
provided by values for mean percent of
saturation carboxyhemoglobin correct¬
ed for ambient air, on newborns at sea
level (0.58% ±0.04%; =
22) and at
1500 m (0.66% ±0.02%; =
17) (Fig 3).
Samples were analyzed for carboxy¬
hemoglobin in the same laboratory as
those obtained at 1600 m and 3100 m.
The association between endogenous
carbon monoxide production and car-
= =
boxyhemoglobin is dependent on cer¬
tain assumptions. These include lack of
variance in inspired air carbon monox¬
ide content, diffusing capacity, alveolar
ventilation, and oxygen tension.21 Vari¬
ation in inspired carbon monoxide was
controlled for by correcting for ambient
carbon monoxide. Variation in diffusing
capacity (perfusion mismatching or
physiologic shunting) would not be ex¬
pected to have influenced study results
to the extent that subjects in both sam¬
ples were healthy term newborns. With
regard to alveolar ventilation, previous
studies have suggested levels of endog¬
enous carbon monoxide production, and
therefore bilirubin production, are un¬
derestimated by measured carboxyhe¬
moglobin values on infants with in¬
creased alveolar ventilation.8 We did
not measure ventilation in the present
study, but alveolar ventilation is typi¬
cally increased at high altitude.22 To the
extent that infants at 3100 m exhibited
increased alveolar ventilation relative
to infants at 1600 m, measured values of
carboxyhemoglobin would have under¬
estimated the true values of bilirubin
production, in which case differences
between altitudes would have been
even greater than reported. Carboxy¬
hemoglobin levels are also affected by
02 tension; higher values at 3100 m
might be predicted simply as a result of
the reduced competition for hemoglobin
binding at the higher altitude.21 Howev¬
er, if estimates of arterial 02 tension at
3100 m (CL., M.B., unpublished data,
1986) arecompared with sea level val-
 ues,28,24 the expected increase in car¬
boxyhemoglobin levels at 3100 m would
only be 0.13%. Thus, reduced competi¬
tion for hemoglobin binding cannot ac¬
count for the almost twofold increase in
carboxyhemoglobin levels observed in
infants at 3100 m compared with that in
infants at sea level (Fig 3).
The second major source of elevated
bilirubin levels in newborns is de¬
creased capacity for clearance. De¬
creased capacity can result from im¬
paired hepatic function as well as from
incomplete degradation and increased
enterohepatic circulation of bilirubin.
The effects of hypoxemia on hepatic
function, including impaired bilirubin
conjugation, have been demonstrated in
adults, animal models, and tissue cul¬
ture."*
Few tests are available for measuring
hepatic function or enterohepatic circu¬
lation that can be performed on healthy
newborns. To the extent that time and
occurrence of first bowel movement
provide an index of enterohepatic circu¬
lation, similar findings for these mea-
1. Moore LG, Newberry MA, Freeby GM, Crnic
LS. Increased incidence of neonatal hyperbilirubin-
emia at 3100 m in Colorado. AJDC. 1984;138:157\x=req-\
161.
2. Ballard J, Kazmaier K, Driver M. A simplified
assessment of gestational age. Pediatr Res.
1977;11:374.
3. O'Brien D, Ibbott F, Rodgerson D, eds. Lab
Manual of Pediatric Microbiochemical Tech-
niques. New York, NY: Harper & Row Publishers
Inc; 1968:187.
4. Naulty C, Cheskin H, Blumenfeld T. Biliru-
bin. In: Hicks JM, Boecks RL, eds. Pediatric Clini-
cal Chemistry. Philadelphia, Pa: WB Saunders Co;
1984:17-31.
5. Williams R, Pitts L, Weinerth J, Dimmette
RM. Clinical laboratory investigation ofthe Ameri-
can optical bilirubinometer. J Pediatr. 1971;79:671\x=req-\
674.
6. Garcia JF, Sherwood J, Goldwasser E. Radio-
immunoassay of erythropoietin. Blood Cells.
1979;5:405-419.
7. Vreman HJ, Kwong LK, Stevenson DK. Car-
bon monoxide in blood: an improved microliter
blood-sample collection system, with rapid analysis
by gas chromatography. Clin Chem. 1984;30:1382\x=req-\
1386.
8. Ostrander CR, Cohen RS, Hopper AO,
Cowan BE, Stevens GB, Stevenson DK. Paired
determinations of blood carboxyhemoglobin con-
centration and carbon monoxide excretion rate in
term and preterm infants. J Lab Clin Med.
1982;100:745-755.
9. Linn S, Schoenbaum SC, Monson RR, Rosner
B, Stubblefield PG, Ryan KJ. Epidemiology of neo-
natal hyperbilirubinemia. Pediatrics. 1985;75:770\x=req-\
774.
10. Maisels MJ, Gifford K, Antle CE, Leib GR.
Jaundice in the healthy newborn infant: a new ap-
proach to an old problem. Pediatrics. 1988;81:505\x=req-\
511.
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/19/2015
sures at 1600 m and 3100 m did not
support increased enterohepatic circu¬
lation at high altitude. Although de¬
creased conjugating capacity may be re¬
sponsible for the lower levels of
conjugated bilirubin among infants at
3100 m compared with 1600 m (Table 1),
no conclusions can be drawn because
total assay variability at this level of
measurement is high (SD, 3 µ /L;
8.6% coefficient of variation).
Decreased capacity for clearance has
been implicated as the mechanism re¬
sponsible for the higher peak values and
sustained elevation of bilirubin levels
typically exhibited by breast-fed vs for¬
mula-fed infants.30'82 A study by Meyers
et al38 suggested that the higher biliru¬
bin levels observed for breast-fed vs for¬
mula-fed infants were not attributable
to increased bilirubin production. Al¬
though the higher carboxyhemoglobin,
erythropoietin, and hematocrit values
found for infants at 3100 m relative to
1600 m are consistent with increased
bilirubin production at the higher alti¬
tude, we cannot exclude the possibility
References
11. Felsher BF, Carpio NM. Caloric intake and
unconjugated hyperbilirubinemia. Gastroenterol-
ogy. 1975;69:42-47.
12. De Carvalho M, Klaus M, Merkatz R. Fre-
quency of breast feeding and serum bilirubin con-
centration. AJDC. 1982;136:737-738.
13. Albrecht E, Albrecht H. Metabolism and he-
matology at high altitude and the effect of drugs on
acclimation. Fed Proc. 1960;28:118-123.
14. Ballew C, Haas JD. Hematologic evidence of
fetal hypoxia among newborn infants at high alti-
tude in Bolivia. Am J Obstet Gynecol. 1986;155:166\x=req-\
169.
15. Finne PH. Erythropoietin levels in cord
blood as an indicator of intrauterine hypoxia. Acta
Paediatr Scand. 1966;55:478-489.
16. Halvorsen S. Plasma erythropoietin levels in
cord blood and in blood during the first week of life.
Acta Paediatr. 1963;52:425-435.
17. Stevenson DK, Bucalo R, Cohen R, Vreman
HJ, Ferguson JE, Schwartz HC. Increased immu-
noreactive erythropoietin in cord plasma and neo-
natal production in normal term infants after labor.
Obstet Gynecol. 1986;67:69-73.
18. Widness JA, Clemons GK, Garcia JF, Oh W,
Schwartz R.Increased immunoreactive erythro-
poietin in cord serum after labor. Am J Obstet
Gynecol. 1984;148:194-197.
19. Landaw SA, Callahan EW, Schmed R. Ca-
tabolism ofheme in vivo: comparison ofthe simulta-
neous production of bilirubin and carbon monoxide.
J Clin Invest. 1970;49:914-925.
20. Maisels MJ, Pathak A, Nelson NM, Nathan
DK, Smith CA. Endogenous production of carbon
monoxide in normal and erythroblastotic newborn
infants. J Clin Invest. 1971;50:1-8.
21. Coburn RF, Forster RE, Kane PB. Consid-
erations of the physiological variables that deter-
mine the blood carboxyhemoglobin concentration
in man. J Clin Invest. 1965;44:1899-1910.
22. Heath D, Williams DR, eds. Man at High
that decreased capacity for clearance
may have contributed to the sustained
elevation of bilirubin levels among for¬
mula-fed infants at 3100 m vs 1600 m
(Fig 2).
The question ofwhether bilirubin val¬
ues above 205 µ /L observed at high
altitude are benign or toxic remains to
be investigated. Such studies are im¬
portant for determining when laborato¬
ry investigation and therapeutic inter¬
vention are appropriate at high altitude
as well as for understanding the com¬
plex phenomenon of neonatal hyper¬
bilirubinemia.
We wish to thank the physicians, nursing staff,
and laboratory personnel of St Vincent Hospital
and Children's Hospital/St Luke's for their involve¬
ment. We also thank Robert McCalmon, PhD, of
Immunologie Associates, Denver, Colo, Leroy
Heidt of the National Center for Atmospheric Re¬
search, Boulder, Colo, and Steven Arnold of the
Colorado Department of Health, Denver, for tech¬
nical assistance. We appreciate the helpful com¬
ments of the reviewers, Peter O'Brien, PhD, and
James Naessens of the Mayo Clinic, Rochester,
Minn. We also thank Steve Hofmeister and Rosann
McCullough for their help in preparing the manu¬
script. We express thanks to the newborns and
their parents who generously participated in this
study.
Altitude: The Pathophysiology of Acclimatization
and Adaptation. New York, NY: Churchill Living-
stone Inc; 1981:39.
23. Dong SH, Liu HM, Song GW, Rong ZP, Wu
YP. Arterialized capillary blood gases and acid\x=req-\
base studies in normal individuals from 29 days to
24 years of age. AJDC. 1985;139:1019-1022.
24. Mok JY, McLaughlin FJ, Pintar M, Hak H,
Amaro-Galvez R, Levison H. Transcutaneous mon-
itoring of oxygenation: what is normal? J Pediatr.
1986;108:365-371.
25. Bristow J, Rudolph AM, Itskovitz J, et al.
Hepatic oxygen and glucose metabolism in the fetal
lamb. J Clin Invest. 1983;71:1047-1061.
26. Aw TY, Jones DP. Control of glucuronida-
tion during hypoxia: limitation by UDP-glucose
pyrophosphorylase. Biochem J. 1984;219:707-712.
27. Kaplan LD, Jones DP, Aw TY, Rudman D,
Honig E. Oxygen dependence of acetominophen
metabolism. Am Rev Respir Dis. 1983;
127(suppl):292A.
28. Newberry MA, Moore LG, Crnic LS. Biliru-
bin metabolism in the rat at high altitude. Aviat
Space Environ Med. 1984;55:377-380.
29. Peltonen T, Hirvonen L. Experimental stud-
ies on fetal and neonatal circulation. Acta Paediatr
Scand. 1965;161:5-55.
30. Kivlahan C, James EJ. The natural history of
neonatal jaundice. Pediatrics. 1984;74:364-370.
31. Gourley GR, Arend BA. \g=b\-glucuronidase
and hyperbilirubinemia in breast-fed and formula-
fed babies. Lancet. 1986;1:644-646.
32. Maisels MJ, Gifford K. Normal serum biliru-
bin levels in the newborn and the effect of breast
feeding. Pediatrics. 1986;78:837-843.
33. Meyers CH, Kwong LK, Vreman HJ, Ste-
venson DK. The role of bilirubin production in
breast fed infants with elevated serum bilirubin
concentrations at two weeks of life. Clin Pediatr.
1984;23:480-486.