Observations on neonatal hyperbilirubinemia.
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Bilirubin↗
Biomedical subjects
D K Stevenson
Publications and source records attributed to D K Stevenson.
Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years of age.
To estimate the effect of neonatal hyperbilirubinemia on long-term cognitive ability in full-term newborns with a negative Coombs test, we performed a 17-year historical prospective study of 1948 subjects. Intelligence tests and medical examinations performed at the military draft board were stratified according to serum bilirubin concentration. A logistic regression analysis was used to adjust for the confounding effects of gestational age, birth weight, Apgar score, ethnic origin, socioeconomic class, paternal education, birth order, and the administration of phototherapy and exchange transfusion. No direct linear association was shown between neonatal bilirubin levels and intelligence test scores or school achievement at 17 years of age. However, the risk for low intelligence test scores (IQ score less than 85) was found to be significantly higher (P = .014) among full-term male subjects with serum bilirubin levels above 342 mumol/L (20 mg/dL) (odds ratio, 2.96; 95% confidence interval, 1.29-6.79). This association was not observed among female subjects. We conclude that severe neonatal hyperbilirubinemia, among full-term male newborns with a negative Coombs test, could be associated with lower IQ scores at 17 years of age.
Adolescent↗
Apgar scores and cognitive performance at 17 years of age.
The association between low Apgar scores (7 or less) at 1 and 5 minutes and cognitive performance in late adolescence was assessed. A 17-year follow-up of 1942 subjects was performed. The intelligence test scores at 17 years of age were matched with 1- and 5-minutes Apgar scores. A multiple linear regression analysis was used to control for the possible confounding effect of perinatal factors (birth weight, gestational age, serum bilirubin levels, birth order) and demographic characteristics (ethnic origin, paternal education, social class). The sensitivity and positive predictive value of a low 1-minute Apgar score were 8 and 8% and of a low 5-minute Apgar score 1.5 and 5%, respectively. Low Apgar scores are poorly correlated with long-term intellectual outcome.
Adolescent↗
A longitudinal study of birth weight and being overweight in late adolescence.
A total of 33,413 infants born in Jerusalem between 1964 and 1971 were followed up at 17 years of age by matching computerized database files. A logistic regression model was used to estimate the odds ratios for being overweight at 17 years of age for 500-g birth weight categories from less than 2500 g to 4500 g or greater. Information on the ethnic origin, paternal education, birth order, maternal age, and area of residence at birth was available, and these factors were used as possible confounders. The adjusted odds ratios for being overweight (greater than or equal to 90th percentile; body mass index greater than 24.6 kg/m2) and severely overweight (greater than or equal to 97th percentile; body mass index greater than 27.8 kg/m2) at 17 years of age was elevated for the three birth weight categories above the normal reference category of 3000 to 3499 g, with an estimate of 2.16 and 2.30 for male subjects with a birth weight greater than 4500 g and 2.95 and 4.39 for female subjects. The data suggest that higher birth weights correlate strongly with being overweight in late adolescence independently of other factors considered. However, the predictive power of this association is poor.
Adolescent↗
Laboratory evaluation of jaundice in newborns. Frequency, cost, and yield.
Neonates with hyperbilirubinemia commonly undergo a battery of laboratory tests. We used a computerized database and medical records to study the frequency, cost, and yield of these tests in 2443 infants born at the University of California, San Francisco, between 1980 and 1982. Four hundred forty-seven (18%) of the infants met standard criteria for "nonphysiologic" hyperbilirubinemia; the incidence varied from 9% in blacks to 31% in Asian infants. About 55% of these 447 infants received a $125 "hyperbilirubinemia workup." Hospital discharge diagnoses on all 447 hyperbilirubinemic infants were reviewed. In 214 (48%), no cause of the jaundice was identified. An additional 145 (32%) had a possible cause apparent from history, physical examination, or initial hematocrit determination. The only diagnosis made as a result of routine investigations of hyperbilirubinemia was possible ABO or Rh isoimmunization in 75 infants (17%). Nonphysiologic hyperbilirubinemia may be more common than previously reported. The recommended tests are expensive and rarely lead to diagnoses other than ABO or Rh isoimmunization. Their routine use should be reevaluated.
Cost-Benefit Analysis↗
Limiting treatment for extremely premature, low-birth-weight infants (500 to 750 g).
Despite impressive recent advances in neonatology, outcomes for extremely premature, very-low-birth-weight infants (500 to 750 g) remain uneven. In a situation of inherent uncertainty, treating patients vigorously could do violence to the moral principles of nonmaleficence and (distributive) justice. Equally, failing to treat patients vigorously because of concerns about nonmaleficence and (distributive) justice could violate the principle of patient-centered beneficence. Compounding this dilemma is the legacy of the "Baby Doe Regulations." International perspectives on this particular quandary are provided. We assert that at Stanford (Calif) University the "individualized prognostic strategy" rather than the "wait until certainty" approach prevails. Four concluding questions are posed: Why is prevention not encouraged more than after-the-fact heroic intervention? Is it possible to develop a more rational view of stopping aggressive therapy once having started? Can we ignore the finitude of our medical resources? Is there a need to redefine the nature of autonomy?
Beneficence↗
Metalloporphyrin-enhanced photodegradation of bilirubin in vitro.
Solutions of bilirubin containing human serum albumin were exposed in vitro in the presence of 10 mumols/L of tin and zinc metalloporphyrins at 37 degrees C for 30 minutes to light sources used clinically for phototherapy of neonates. Bilirubin in the model solutions was photodegraded to approximately 60% of dark control in cool white light (17 microW/cm2 per nanometer). The presence of zinc protoporphyrin and zinc mesoporphyrin further reduced the bilirubin concentration slightly, but the tin analogues caused a significant enhancement of degradation to 35% and 25% of dark control, respectively. The results provide evidence that the zinc and tin metalloporphyrins are photosensitizers capable of enhancing the native photodegradation of bilirubin in biologic matrices, but that the tin compounds are more potent. The metalloporphyrin time course, dose-response curve, oxygen effects, and efficacy of phototherapy light sources were also studied.
Bilirubin↗
Metalloporphyrin phototoxicity.
The phototoxicities of six metalloporphyrin dimethylesters (i.e. cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), tin (Sn) and zinc (Zn) were investigated. Hemolysis of human erythrocytes and inactivation of two enzymes (acetylcholinesterase and beta-galactosidase) were used to assess the phototoxic efficacy of these metal chelates. Tin protoporphyrin (SnPP), the only porphyrin found to hemolyze erythrocytes at a concentration of 40 microM (radiation dose, 230 kJ m-2), was much less efficient than either free protoporphyrin IX or hematoporphyrin. SnPP completely inactivated beta-galactosidase at concentrations above 15 microM (radiation dose, 75 kJ m-2) and drastically interfered with acetylcholinesterase activity at a concentration of 150 microM (radiation dose, 75 kJ m-2). CoPP, CuPP, MnPP, NiPP and ZnPP were ineffective photohemolytic agents at 40 microM (radiation dose, 230 kJ m-2), but inactivated acetylcholinesterase and beta-galactosidase activity to varying degrees. These results suggest that (i) metal ions reduce the phototoxicity of protoporphyrin IX, (ii) different metal ions reduce the phototoxic activity of protoporphyrin IX to different degrees and (iii) the biological activities of the various metal complexes vary in different assay systems.
Cholinesterase Inhibitors↗
A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome.
Nifedipine, a dihydropyridone calcium entry blocker, has been used with increasing frequency in the treatment of preterm labor. We studied 66 patients in this prospective, randomized trial to evaluate the efficacy and maternal, fetal, and neonatal outcome associated with tocolysis with nifedipine or ritodrine. Delivery was delayed for 48 hours, 7 days, and until the thirty-sixth week of gestation in 84%, 70%, and 41%, respectively, of patients in the nifedipine group, compared with 72%, 63%, and 52% of patients in the ritodrine group (difference not significant). Maternal side effects were more common and more serious in the group of patients who received ritodrine compared with those who received nifedipine (18 of 38 versus 5 of 38, p less than 0.01); however, fetal and neonatal outcome appeared to be similar when the groups were compared. On the basis of this study, it appears that tocolysis with either nifedipine or ritodrine is equally efficacious; however, maternal side effects are less common with nifedipine treatment. We conclude that nifedipine may have a role in the treatment of preterm labor but suggest further careful evaluation of this agent before it is considered for routine clinical use.
Female↗
Zinc protoporphyrin administration for suppression of increased bilirubin production by iatrogenic hemolysis in rhesus neonates.
We studied the effect of intravenous zinc protoporphyrin (ZnPP) administration on total body carbon monoxide excretion (VeCO), (an index of heme degradation), blood carboxyhemoglobin level, plasma bilirubin level, and tissue homogenate heme oxygenase activity 24 hours after delivery of rhesus neonates treated at 12 hours of age with heat-damaged erythrocytes (32 mumol heme/kg birth weight). All neonates were delivered by cesarean section and received ampicillin and gentamicin to suppress intestinal flora. The control group (n = 4) was treated with saline solution and ZnPP solvent; the erythrocyte-treated control group (n = 4) received erythrocytes and ZnPP solvent; and two experimental groups received erythrocytes and one dose of 10 (n = 3) or 40 (n = 4) mumol ZnPP/kg body weight, respectively. At 24 hours, administration of erythrocytes alone doubled the VeCO (p less than 0.05), carboxyhemoglobin level, (p less than 0.05), and plasma total bilirubin level (p less than 0.05). Treatment with ZnPP, 40 mumol/kg body weight, caused a significant decrease in VeCO (p less than 0.05), carboxyhemoglobin (p less than 0.05), bilirubin (p less than 0.05), and spleen heme oxygenase (p less than 0.05). Treatment of the erythrocyte-loaded animals with ZnPP, 10 mumol/kg body weight, also significantly (p less than 0.05) lowered VeCO and spleen heme oxygenase activity but did not cause a significant lowering of blood carboxyhemoglobin or plasma bilirubin concentration. We conclude that ZnPP is an effective, dose-dependent in vivo inhibitor of heme oxygenase in the newborn rhesus with latrogenic hemolysis, and that it suppresses both bilirubin production and subsequent accumulation.
Animals↗
Epidemiology of neonatal jaundice in the Jerusalem population.
Of 10,122 singleton babies born from January 1, 1984 to March 31, 1988, we compared 1,154 term infants with high serum bilirubin levels (greater than 12.9 mg/dl) to 1,154 infants with low serum bilirubin levels (less than or equal to 12.9 mg/dl) randomly selected from the remaining 8,968 subjects. We found that a high bilirubin level was significantly associated with male sex; maternal diabetes (chronic and gestational); pregnancy-induced hypertension; previous sibling with neonatal jaundice; delivery by cesarean section, vacuum, or forceps; epidural anesthesia; mother with blood type O; first delivery; cephalohematoma; short gestation; lower birth weight; and lower birth order (p less than 0.01); and older maternal age, low percentile for birth weight, and the percentage of weight loss during hospitalization (p less than 0.05). Variables with significantly different frequencies in control and study groups were used in a multivariate analysis, thus further refining the data by the use of logistic regression. Teenage mothers (less than or equal to 19 years old) had the lowest risk, whereas older mothers (greater than 35 years old) had the highest risk of all age groups for having an infant with neonatal jaundice. First delivery and previous sibling with neonatal jaundice were also risk factors. Male sex, short gestation, and delivery by vacuum extraction were other notable risk factors. Our results suggest that, even among industrialized Western societies, risk factors may interact differently to produce higher neonatal serum bilirubin levels. The importance of a risk factor may also be dependent upon its relative prevalence in a parturient population.
Female↗
Regulation of intestinal ontogeny by intraluminal nutrients.
Major events in gastrointestinal ontogeny occur in the infant rat in association with weaning, resulting in striking alterations in small intestinal structure and function. Although the dietary changes attendant to weaning are not essential for the initiation of these events, dietary nutrients have been shown to participate in the maturation of some intestinal parameters. In order to define more precisely the role of intraluminal nutrients in the regulation of small intestinal ontogeny, a longitudinal study was conducted using a unique animal model in which intraluminal nutrients were excluded from the intact maturing intestine in vivo throughout the entire weaning period without major compromise in nutritional status. The absence of intraluminal nutrients over the weaning period resulted in diminished lengthening and accretion of mucosal mass, suggesting a slower rate of intestinal growth. Lower mucosal DNA, protein, and mitotic indices in intestines of animals receiving no intraluminal nutrients suggested that the lack of intraluminal nutrients resulted in the blunting of the striking increases in cellular proliferation normally exhibited by the developing intestinal mucosa at this time. Maturation of intestinal lactase-phlorizin hydrolase and maltase-glucoamylase was not affected by the absence of intraluminal nutrients. Although the appearance of sucrase-isomaltase was not altered by the absence of intraluminal nutrients, activity levels rose to only 50% of control levels. These data suggest that during this period of rapid intestinal maturation, intestinal growth is more dependent upon intraluminal nutrients than are the characteristic enzymic alterations normally expressed during this period.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The use of antibiotics in neonates weighing less than 1200 grams.
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Absorption↗
Carbon monoxide production by nonbacterial sources after heme feeding of neonatal rats.
We determined the relative potential for nonbacterial CO production after oral heme feeding of 12-hour-old rats. The intestinal flora was eliminated by treatment with kanamycin, ampicillin, and neomycin. CO excretion (VeCO) was measured after oral administration of heme (0.64 mumol/animal). Antibiotic treatment alone did not significantly affect the VeCO of rats gavaged with saline. Heme administration increased (p less than 0.05) the VeCO during t = 1-11 h with a peak at 3 h. Antibiotic treatment reduced this VeCO (p less than 0.05) during t = 2-8 h, but its level (peak at t = 2-3 h) was still significantly (p less than 0.05) above its nonheme control. The results confirm that bacterial degradation of heme is an important source of CO in suckling rats not pretreated with broad-spectrum antibiotics. However, oral heme feeding of gut-sterilized animals yielded transiently significantly increased VeCO. HO-mediated degradation of enteral heme is a likely nonbacterial source of CO and possibly bilirubin in the neonate.
Administration, Oral↗
In vitro generation of carbon monoxide from organic molecules and synthetic metalloporphyrins mediated by light.
Tin protoporphyrin (SnPP) and analogs are being studied as possible agents for the prevention of neonatal hyperbilirubinemia through inhibition of heme oxygenase. Because SnPP is a photosensitizer, we studied its role in the photogeneration of carbon monoxide (CO) from organic compounds in vitro. Generation of CO occurred in the presence of 5 microM SnPP and cool white light (19 muW/cm2/nm or 29 W/m2) from SnPP alone, human serum albumin, glucose, histidine, ethanolamine, medium-chain triglycerides, the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH), and human plasma. More detailed studies with human serum albumin and NADPH established that the photogeneration of CO is nearly linear with time and irradiance. It is curvilinear with respect to the SnPP concentration at the concentrations tested, and it is dependent on the presence of O2 in the reactor headspace. Cool white light generated less CO from human serum albumin and NADPH than equidistantly placed blue and green phototherapy light sources. Comparison of SnPP with other metalloporphyrin heme oxygenase inhibitors indicates that tin mesoporphyrin is most and zinc protoporphyrin least photoreactive.
Carbon Monoxide↗
Developmental biology of heme oxygenase.
The regulation of heme oxygenase activity in the developing neonate is essential to the control of bilirubin production as well as intracellular heme and hemoprotein metabolism. The coordinated activity of the microsomal enzymes, heme oxygenase and NADPH-cytochrome c (P450) reductase, and the cytosolic enzyme biliverdin reductase is responsible for the degradation of heme. The complete reaction sequence requires oxygen and NADPH, and produces bilirubin and carbon monoxide in equimolar amounts. Although heme oxygenase expresses a rather broad range of substrate affinities, the oxidative degradation of heme is exclusively alpha-specific. Heme oxygenase is found in several tissues, with significant activity levels in the liver, spleen, and erythropoeitic tissue. Heme oxygenase activity is inducible by heme and other metalloporphyrins, hormones, starvation, stress, toxins, and xenobiotics. Heme oxygenase induction is generally considered to be the result of an increased protein synthesis and gene transcription. This hypothesis is supported by recent studies of the heme oxygenase gene that identified inducer element binding sites responsive to metal administration, heat shock, and nutrient availability. In the developing fetus and neonate, hepatic heme oxygenase activity and mRNA levels are elevated above that of the adult. This suggests that the elevated heme catabolism observed in neonates may be associated with an increased transcription of the heme oxygenase gene. The apparent induction of hepatic heme oxygenase during the neonatal period is probably the result of tissue-specific and time-dependent transcriptional regulating factors including potentially hormones and heme. Several metalloporphyrins, such as the tin and zinc porphyrin complexes, inhibit heme oxygenase activity and thus have therapeutic potential for the treatment of neonatal jaundice. Recent studies suggest that the meso- and bis-glycol derivatives of these metalloporphyrins may be more potent inhibitors of heme oxygenase activity in vitro and in vivo than the protoporphyrin structures. As structural analogues of heme, however, these compounds may also have other less desirable effects on the regulation of heme and hemoprotein metabolism, particularly in the developing neonate.
Chemical Phenomena↗
A randomized, controlled application of the Wallaby phototherapy system compared with standard phototherapy.
The feasibility and efficacy of a fiberoptic blanket (Wallaby Phototherapy System) for the treatment of physiologic jaundice was compared with conventional phototherapy. Forty-two full-term infants with nonhemolytic jaundice were included in the study. Infants in the study group were treated with the fiberoptic blanket and the infants in the control group were placed under a standard phototherapy unit. Both the fiberoptic blanket and the standard phototherapy unit delivered an average irradiance of 7.0 +/- 0.5 muw/cm2/nm. Incremental changes in serial plasma bilirubin levels compared with the initial bilirubin concentration did not differ between the study and control groups. For infants whose initial plasma bilirubin concentration exceeded 200 mumol/L, a statistically significant difference was found in both study and control groups between the average bilirubin level at initiation of phototherapy and the average bilirubin level at termination of treatment. We conclude that phototherapy delivered by the fiberoptic blanket is safe and has efficacy comparable to that of conventional phototherapy, providing a convenient alternative phototherapy application strategy that obviates the need for eye patches and facilitates maternal handling of the infant during therapy.
Bedding and Linens↗
Predictors of and new therapy for jaundice.
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Exchange Transfusion, Whole Blood↗