Jaundice in Navajo Neonates John D. Johnson, M.D.
Introduction ethnic group in the United States that has been reported to have exaggerated neonatal hyperbilirubinemia is the Navajo.’ However, the data for this contention are rather meager. This paper reviews the evidence for this claim and the evidence suggesting that accentuated production of bilirubin is at least one factor contributing to this exaggerated neonatal hyperbilirubinemia. ne
Comparison of Navajo and Caucasian Neonates The initial
study
of
jaundice
among Navajo neonates was published by Saland et al in 1974.1 This group of investigators studied 47 term Navajo infants born at the US Public Health Service hospital in Tuba City, Arizona, and determined serum bilirubin concentrations and inhibition of bilirubin glucuronyl transferase activity in maternal milk samples vs a control population in New York City. The major findings of Saland et all
Department of Pediatrics University of New Mexico School of Medicine
Albuquerque, New Mexico Address
correspondence to: John D.
Johnson, M.D., Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM 87131-5311
(505) 272-5551
716
that total serum bilirubin concentrations in Navajo neonates were significantly higher than those of controls from New York City throughout the first four days of life (e.g., mean serum bilirubin 12.5 mg/dL [213.7 pmol/L] for Navajos on day 3 vs 6 mg/dL [102.6 pmol/L] for controls) and that breast-fed Navajo newborns had higher bilirubin values than bottlefed Navajos on days 3 and 4. Further, these workers reported that inhibition of bilirubin glucuronyl transferase activity in rat liver homogenates by milk samples from Navajo mothers was significantly greater than for the control group (mean percent inhibition 29.9% for Navajo breast milk vs 3.8% for control samples), with a positive correlation between inhibitory activity of milk and peak serum concentration of bilirubin. The major conclusion of this study that exaggerated neonatal was jaundice in the Navajo is related to breast-feeding. However, it is clear from this study that formula-fed Navajo neonates also had elevated concentrations of bilirubin in serum vs the control population from New York City. Thus, factors in addition to human milk-feeding must play a role in the relative hyperbilirubinemia of Navajo neonates. Our group at the University of New Mexico explored further the mechanism of exaggerated hyperbilirubinemia in the Navajo by measuring rates of bilirubin production in Navajo neonates and in a control population of Caucasians.2 We studied 25 control (12 Hispanic, were
13 Anglo) and 16 Navajo neonates with gestational ages between 36 and 42 weeks (Table 1), all of appropriate weight for gestational age (10th to 90th percentile). None had isoimmunization or significant bruising. Pregnancies and deliveries were uncomplicated. We determined rates of bilirubin production by measuring the endogenous excretion of carbon at close to 48 monoxide hours of age by a previously described technique.’ The major source of endogenous CO excretion is the CO liberated from the conversion of biliverdin to bilirubin, so that the VECO closely approximates the rate of bilirubin production.4 We also measured the concentrations of serum bilirubin and hemoglobin and the reticulo-
(VECO)
’:~s;xe
;
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-
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~flgi~ j§~?§i~l)§ , % .~, &~
Downloaded from cpj.sagepub.com at NANYANG TECH UNIV LIBRARY on June 7, 2015
~
&dquo;
&dquo; ~
&dquo;
&dquo; ’
and reticulocytes. 5,6 When we considered only neonates studied at >_36 hours, differences in total concentration of bilirubin were accentuated (control, 6.9 ± 2.3 mg/dL [118.0 ± 39.3 pmol/L]; Navajo, 9.2 ± 2.3 mg/dL [157.3 ± 39.3 and the difference in Jlmol/L]) VECO remained highly significant (Table 3). When we analyzed the infants with gestational age >38 weeks and postnatal age >36 hours at the time of study, VECO was still higher in Navajo vs control infants. Thus, neither of the potentially confounding variables of gestational age and postnatal age explains the highly significant difference in VECO between Navajo and control newborns in this study. Within the control group, we found no differences in bilirubin concentration in serum or VECO between Hispanics and Anglo newborns ; there was no difference in the incidence of breast-vs-formula feeding in Navajo vs control newborns, but there were significant differences in VECO between Navajo and control infants, regardless of the mode of feeding. This study confirms the finding of exaggerated neonatal hyperbilirubinemia among Navajo newborns reported previously. We had been concerned that the control group used in the study of Saland et all was not appropriate. Recent retrospective77 and prospcctive8 studies have demonstrated an increased incidence of neonatal hyperbilirubinemia at high altitudes. The Navajo newborns in the study of Saland et all were born in Tuba City, Arizona, at an altitude of 1,250 m, vs controls born in New York City at sea level. However, in our study, both control and Navajo infants were born in Albuquerque, New Mexico, at an altitude of 1,500 m, and Navajo newborns still exhibited higher concentrations of bilirubin in serum at age 2 days. Our findings also illustrate the rum
TaMe2 j
COMPARISON OF CONT~,
cyte count within four hours of the VECO determinations.
reticulocyte
ever,
two groups. age is known to influence VtCO,3 we also analyzed those infants who had completed at least 38 weeks’ gestation (Table 3).
Since
Results The results of our studies are shown in Table 2. Navajo neonates had significantly higher concentrations of total serum bilirubin; how-
counts were no
different between the
The
gestational
VECO
was
still
significantly
greater in Navajo than in control Postnatal age affects the concentration of bilirubin in seneonates.
Downloaded from cpj.sagepub.com at NANYANG TECH UNIV LIBRARY on June 7, 2015
717
multifactorial nature of accentuated jaundice in Navajo newborns. We found greater rates of bilirubin production in Navajo than in control newborns, regardless of whether or not infants were fed human milk. Saland et all demonstrated the presence of an unidentified factor in human milk from Navajo mothers that inhibited the bilirubin conjugation system in vitro. Chen and Lee’ reported both increased heme catabolism and diminished glucuronide-conjugating capacity in Chinese newborns with hyperbilirubinemia. Other reports of exaggerated neonatal hyperbilirubinemia among American groups have been published, but only in abstract form (e.g., for Siouxl° and southwestern tribes such as the Pima and Papagoll). Native Americans are believed to be derived from Asians who migrated across the Bering land mass centuries ago. Thus, it is of interest to observe exaggerated neonatal jaundice and accentuated bilirubin production in both some Native American tribes and some Asian groupS.12
718
Conclusion
5.
In summary, Navajo neonates exhibit higher levels of serum bilirubin than do black, Anglo, and Hispanic newborns and resemble certain Asian groups in this propensity. The pathogenesis of this finding relates, at least in part, to increased bilirubin production.
6.
Gartner LM, Lee KS, Vaisman S, et al. Development of bilirubin transport and metabolism in the newborn mon-
J Pediatr 1977;90:513-531. key. . Oski FA, Naiman JL. Hematologic Problems in the Newborn. 3rd ed. Phila-
delphia,
PA:
WB
Saunders
Co;
1982:12-13. 7.
Moore LG, Newberry MA, Freeby GM, et al. Increased incidence of neona-
tal hyperbilirubinemia at 3100 m in Colorado. Am J Dis Child.
1984;138:157-161.
REFERENCES 1.
McNamara H, Cohen MI. Navajo jaundice: a variant of neonatal hyperbilirubinemia associated with J Pediatr. 1974 ;85 :271breast-feeding.
Saland
8.
Leibson C, Brown M, Thibodeau S, et al. Neonatal hyperbilirubinemia at high altitude. Am J Dis Child.
9.
Chen SH, Lee TC. Carboxyhemoglobin and glucuronide formation in Chinese newborn infants with hyperbilirubinemia. J Formos Med Assoc. 1980;79:314-322.
10.
Trygstad CW, McCracken CH. The pattern of physiologic jaundice in
J,
1989;143:983-987.
275. 2.
3.
Johnson JD, Angelus P, Aldrich M, Skipper BJ. Exaggerated jaundice in Navajo neonates. The role of bilirubin production. Am J Dis Child. 1986;140:889-890. al. Pulmonary excretion rates of carbon monoxide using a modified technique: differences between premature and fullterm infants.
4.
the Sioux. Soc Pediatr Res.
duction in
11.
Chopra DR, Meyer HBP, Daily WJR. An unusual pattern of jaundice in the Southwest American Indian neonate. Clin Res. 1971;19:219.
12.
Fischer
Biol Neonate. 1982 ;41 :289-293.
Stevenson DK, Ostrander CR, Cohen RS, Johnson JD. Relationship of heme catabolism to jaundice. Bilirubin pro-
infancy.
1966;86.
Abstract.
Cohen RS, Ostrander CR, Cowen BE, et
Perinatol Neonatol.
1981;5:35-44.
Downloaded from cpj.sagepub.com at NANYANG TECH UNIV LIBRARY on June 7, 2015
AF, Nakamura H, Uetani Y, et al. Comparison of bilirubin production in Japanese and Caucasian inJ Pediatr Gastroenterol Nutr. fants.
1988;7:27-29.
Introduction ethnic group in the United States that has been reported to have exaggerated neonatal hyperbilirubinemia is the Navajo.’ However, the data for this contention are rather meager. This paper reviews the evidence for this claim and the evidence suggesting that accentuated production of bilirubin is at least one factor contributing to this exaggerated neonatal hyperbilirubinemia. ne
Comparison of Navajo and Caucasian Neonates The initial
study
of
jaundice
among Navajo neonates was published by Saland et al in 1974.1 This group of investigators studied 47 term Navajo infants born at the US Public Health Service hospital in Tuba City, Arizona, and determined serum bilirubin concentrations and inhibition of bilirubin glucuronyl transferase activity in maternal milk samples vs a control population in New York City. The major findings of Saland et all
Department of Pediatrics University of New Mexico School of Medicine
Albuquerque, New Mexico Address
correspondence to: John D.
Johnson, M.D., Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM 87131-5311
(505) 272-5551
716
that total serum bilirubin concentrations in Navajo neonates were significantly higher than those of controls from New York City throughout the first four days of life (e.g., mean serum bilirubin 12.5 mg/dL [213.7 pmol/L] for Navajos on day 3 vs 6 mg/dL [102.6 pmol/L] for controls) and that breast-fed Navajo newborns had higher bilirubin values than bottlefed Navajos on days 3 and 4. Further, these workers reported that inhibition of bilirubin glucuronyl transferase activity in rat liver homogenates by milk samples from Navajo mothers was significantly greater than for the control group (mean percent inhibition 29.9% for Navajo breast milk vs 3.8% for control samples), with a positive correlation between inhibitory activity of milk and peak serum concentration of bilirubin. The major conclusion of this study that exaggerated neonatal was jaundice in the Navajo is related to breast-feeding. However, it is clear from this study that formula-fed Navajo neonates also had elevated concentrations of bilirubin in serum vs the control population from New York City. Thus, factors in addition to human milk-feeding must play a role in the relative hyperbilirubinemia of Navajo neonates. Our group at the University of New Mexico explored further the mechanism of exaggerated hyperbilirubinemia in the Navajo by measuring rates of bilirubin production in Navajo neonates and in a control population of Caucasians.2 We studied 25 control (12 Hispanic, were
13 Anglo) and 16 Navajo neonates with gestational ages between 36 and 42 weeks (Table 1), all of appropriate weight for gestational age (10th to 90th percentile). None had isoimmunization or significant bruising. Pregnancies and deliveries were uncomplicated. We determined rates of bilirubin production by measuring the endogenous excretion of carbon at close to 48 monoxide hours of age by a previously described technique.’ The major source of endogenous CO excretion is the CO liberated from the conversion of biliverdin to bilirubin, so that the VECO closely approximates the rate of bilirubin production.4 We also measured the concentrations of serum bilirubin and hemoglobin and the reticulo-
(VECO)
’:~s;xe
;
0
-
,xh~jgg§fgj$~f$ &dquo; ~&dquo;~ ~ ~ ~ ’ ~ ~’~ ~
~flgi~ j§~?§i~l)§ , % .~, &~
Downloaded from cpj.sagepub.com at NANYANG TECH UNIV LIBRARY on June 7, 2015
~
&dquo;
&dquo; ~
&dquo;
&dquo; ’
and reticulocytes. 5,6 When we considered only neonates studied at >_36 hours, differences in total concentration of bilirubin were accentuated (control, 6.9 ± 2.3 mg/dL [118.0 ± 39.3 pmol/L]; Navajo, 9.2 ± 2.3 mg/dL [157.3 ± 39.3 and the difference in Jlmol/L]) VECO remained highly significant (Table 3). When we analyzed the infants with gestational age >38 weeks and postnatal age >36 hours at the time of study, VECO was still higher in Navajo vs control infants. Thus, neither of the potentially confounding variables of gestational age and postnatal age explains the highly significant difference in VECO between Navajo and control newborns in this study. Within the control group, we found no differences in bilirubin concentration in serum or VECO between Hispanics and Anglo newborns ; there was no difference in the incidence of breast-vs-formula feeding in Navajo vs control newborns, but there were significant differences in VECO between Navajo and control infants, regardless of the mode of feeding. This study confirms the finding of exaggerated neonatal hyperbilirubinemia among Navajo newborns reported previously. We had been concerned that the control group used in the study of Saland et all was not appropriate. Recent retrospective77 and prospcctive8 studies have demonstrated an increased incidence of neonatal hyperbilirubinemia at high altitudes. The Navajo newborns in the study of Saland et all were born in Tuba City, Arizona, at an altitude of 1,250 m, vs controls born in New York City at sea level. However, in our study, both control and Navajo infants were born in Albuquerque, New Mexico, at an altitude of 1,500 m, and Navajo newborns still exhibited higher concentrations of bilirubin in serum at age 2 days. Our findings also illustrate the rum
TaMe2 j
COMPARISON OF CONT~,
cyte count within four hours of the VECO determinations.
reticulocyte
ever,
two groups. age is known to influence VtCO,3 we also analyzed those infants who had completed at least 38 weeks’ gestation (Table 3).
Since
Results The results of our studies are shown in Table 2. Navajo neonates had significantly higher concentrations of total serum bilirubin; how-
counts were no
different between the
The
gestational
VECO
was
still
significantly
greater in Navajo than in control Postnatal age affects the concentration of bilirubin in seneonates.
Downloaded from cpj.sagepub.com at NANYANG TECH UNIV LIBRARY on June 7, 2015
717
multifactorial nature of accentuated jaundice in Navajo newborns. We found greater rates of bilirubin production in Navajo than in control newborns, regardless of whether or not infants were fed human milk. Saland et all demonstrated the presence of an unidentified factor in human milk from Navajo mothers that inhibited the bilirubin conjugation system in vitro. Chen and Lee’ reported both increased heme catabolism and diminished glucuronide-conjugating capacity in Chinese newborns with hyperbilirubinemia. Other reports of exaggerated neonatal hyperbilirubinemia among American groups have been published, but only in abstract form (e.g., for Siouxl° and southwestern tribes such as the Pima and Papagoll). Native Americans are believed to be derived from Asians who migrated across the Bering land mass centuries ago. Thus, it is of interest to observe exaggerated neonatal jaundice and accentuated bilirubin production in both some Native American tribes and some Asian groupS.12
718
Conclusion
5.
In summary, Navajo neonates exhibit higher levels of serum bilirubin than do black, Anglo, and Hispanic newborns and resemble certain Asian groups in this propensity. The pathogenesis of this finding relates, at least in part, to increased bilirubin production.
6.
Gartner LM, Lee KS, Vaisman S, et al. Development of bilirubin transport and metabolism in the newborn mon-
J Pediatr 1977;90:513-531. key. . Oski FA, Naiman JL. Hematologic Problems in the Newborn. 3rd ed. Phila-
delphia,
PA:
WB
Saunders
Co;
1982:12-13. 7.
Moore LG, Newberry MA, Freeby GM, et al. Increased incidence of neona-
tal hyperbilirubinemia at 3100 m in Colorado. Am J Dis Child.
1984;138:157-161.
REFERENCES 1.
McNamara H, Cohen MI. Navajo jaundice: a variant of neonatal hyperbilirubinemia associated with J Pediatr. 1974 ;85 :271breast-feeding.
Saland
8.
Leibson C, Brown M, Thibodeau S, et al. Neonatal hyperbilirubinemia at high altitude. Am J Dis Child.
9.
Chen SH, Lee TC. Carboxyhemoglobin and glucuronide formation in Chinese newborn infants with hyperbilirubinemia. J Formos Med Assoc. 1980;79:314-322.
10.
Trygstad CW, McCracken CH. The pattern of physiologic jaundice in
J,
1989;143:983-987.
275. 2.
3.
Johnson JD, Angelus P, Aldrich M, Skipper BJ. Exaggerated jaundice in Navajo neonates. The role of bilirubin production. Am J Dis Child. 1986;140:889-890. al. Pulmonary excretion rates of carbon monoxide using a modified technique: differences between premature and fullterm infants.
4.
the Sioux. Soc Pediatr Res.
duction in
11.
Chopra DR, Meyer HBP, Daily WJR. An unusual pattern of jaundice in the Southwest American Indian neonate. Clin Res. 1971;19:219.
12.
Fischer
Biol Neonate. 1982 ;41 :289-293.
Stevenson DK, Ostrander CR, Cohen RS, Johnson JD. Relationship of heme catabolism to jaundice. Bilirubin pro-
infancy.
1966;86.
Abstract.
Cohen RS, Ostrander CR, Cowen BE, et
Perinatol Neonatol.
1981;5:35-44.
Downloaded from cpj.sagepub.com at NANYANG TECH UNIV LIBRARY on June 7, 2015
AF, Nakamura H, Uetani Y, et al. Comparison of bilirubin production in Japanese and Caucasian inJ Pediatr Gastroenterol Nutr. fants.
1988;7:27-29.
