Peak Serum Bilirubin Levels Research Articles

Risk factors for severe hyperbilirubinemia in neonates.

The incidence of severe neonatal hyperbilirubinemia is higher in Asians than in whites. A case-control study was designed to investigate the effects of eight known risk factors [breast feeding, ABO incompatibility, premature birth, infection, cephalohematoma, asphyxia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene] and a suspicious analog [organic anion transporter 2 (OATP 2) gene] on severe hyperbilirubinemia in Taiwanese neonates. The 72 study subjects and 100 hospital control subjects consisted of neonates with peak serum bilirubin levels > or =342 microM and <256.5 microM, respectively. The PCR-restriction fragment length polymorphism method was applied to detect the UGT1A1, OATP 2, and G6PD genes. The results of multivariate logistic regressions, adjusted for covariates, revealed odds ratios (ORs) of 4.64 [95% confidence interval (CI): 2.25-9.57; p < 0.001], 3.36 (95% CI: 1.54-7.35; p=0.002), and 3.02 (95% CI: 1.30-6.99; p=0.010) for neonates who were fed with breast milk, and carry the variant UGT1A1 gene at nucleotide 211 and the variant OATP 2 gene at nucleotide 388, respectively. The ORs, adjusted for covariates, for the other six risk factors were not statistically significant. The ORs in neonates who had one, two, and three significant risk factors were 8.46 (95% CI: 2.75-34.48; p < 0.001), 22.0 (95% CI: 5.50-88.0; p < 0.001), and 88.0 (95% CI: 12.50-642.50; p < 0.001), respectively. In conclusion, neonates who carry the 211 and 388 variants in the UGT1A1 and OATP 2 genes, respectively, as well as feed with breast milk are at high risk to develop severe hyperbilirubinemia.

Impact of portal venous pressure on regeneration and graft damage after living-donor liver transplantation

Several reports claim that portal hypertension after living-donor liver transplantation (LDLT) adversely affects graft function, but few have assessed the impact of portal venous pressure (PVP) on graft regeneration. We divided 32 adult LDLT recipients based on mean PVP during the 1st 3 days after LDLT into a group with a PVP > or = 20 mm of Hg (H Group; n = 17), and a group with a PVP < 20 mm of Hg (L Group; n = 15). Outcome in the H Group was poorer than in the L Group (58.8 vs. 92.9% at 1 year). Peak peripheral hepatocyte growth factor (HGF) during the 1st 2 weeks was higher in the H Group (L: 1,730 pg/mL, H: 3,696 pg/mL; P < .01), whereas peak portal vascular endothelial growth factor (VEGF) level during the 1st week was higher in the L Group (L: 433 pg/mL, H: 92 pg/mL; P < .05). Graft volume (GV) / standard liver volume (SLV) was higher in the H Group (L / H, at 2, 3, and 4 weeks, and at 3 months: 1.02 / 1.24, .916 / 1.16, .98 / 1.27, and .94 / 1.29, respectively; P < .05). Peak serum aspartate aminotransferase, bilirubin levels, and international normalized ratio after LDLT were significantly higher in the H Group, as was mean ascitic fluid volume. In conclusion, early postoperative PVP elevation to 20 mm of Hg or more was associated with rapid graft hypertrophy, higher peripheral blood HGF levels, and lower portal VEGF levels; and with a poor outcome, graft dysfunction with hyperbilirubinemia, coagulopathy, and severe ascites. Adequate liver regeneration requires an adequate increase in portal venous pressure and flow reflected by clearance of HGF and elevated VEGF levels.

Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants.

To assess the association between peak total serum bilirubin (PSB) levels during the first 2 weeks of life and neurodevelopmental outcomes of extremely low birth weight (ELBW) infants at 18 to 22 months' postmenstrual age. A retrospective analysis was conducted of a cohort of ELBW infants (401-1000 g) who survived to 14 days of age in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1, 1994, and December 31, 1997. Demographic and clinical risk factors and PSB levels during the first 14 days were analyzed with reference to death or adverse neurodevelopmental outcomes at 18 to 22 months' postmenstrual age. The neurodevelopmental variables considered were Psychomotor Developmental Index (PDI) <70, Mental Developmental Index (MDI) <70, moderate or severe cerebral palsy (CP), hearing impairment (needs hearing aids), and a composite category designated as neurodevelopmental impairment (NDI). The NDI is defined as infants with any 1 or more of the following: PDI <70, MDI <70, moderate to severe CP, bilateral blindness, or bilateral hearing impairment requiring amplification. The subjects of this cohort analysis are infants who were admitted to the Network centers during calendar years 1994-1997 and survived beyond 14 days and had PSB recorded during the 14-day period. From this cohort, 3246 infants survived at discharge, 79 died after discharge, and 592 were lost to follow-up. Thus, 2575 of 3167 infants were seen in the follow-up clinics with a compliance rate of 81%. Logistic regression analysis showed that various demographic and clinical variables are associated with poor neurodevelopmental outcomes. After adjustment for these risk factor, significant association were found between PSB (mg/dL) and death or NDI (odds ratio: 1.068; 95% confidence interval [CI]: 1.03-1.11); PDI <70 (R = 1.057; 95% CI: 1.00-1.12), and hearing impairment requiring hearing aids (odds ratio: 1138; 95% CI: 1.00-1.30). There was no significant association between PSB (mg/dL) and CP, MDI <70, and NDI. PSB concentrations during the first 2 weeks of life are directly correlated with death or NDI, hearing impairment, and PDI <70 in ELBW infants. The statistical association based on retrospective analysis of observational data and relatively small effect size should be interpreted with caution. Furthermore, because of the possibility of compounding effects of variables on outcome, the potential benefits of moderate hyperbilirubinemia and the potential adverse effects of phototherapy, a randomized, controlled trial of aggressive and conservative phototherapy is needed to address this controversial issue.

Does elevated peak bilirubin protect from retinopathy of prematurity in very low birthweight infants.

Bilirubin is a potent in vitro antioxidant. Despite repeated study, its in vivo significance has yet to be defined. Bilirubin is universally elevated in very low birthweight (VLBW) infants. Retinopathy of prematurity (ROP) is a disease thought to be associated with exposure to oxygen free radicals in VLBW infants. The objective of this study was to determine whether there was an association between peak bilirubin levels and ROP. The risk for ROP, stages III and IV was measured as a function of increasing peak bilirubin levels in VLBW infants admitted to the neonatal ICU. A similar analysis was performed on a subgroup of VLBW infants with prolonged (> or =28 days) oxygen requirement. The relation between peak bilirubin level and the duration of oxygen requirement was tested by logistic regression analysis. All analyses were conducted after controlling for birthweight and presence of intraventricular hemorrhage (IVH). There was an increased risk for ROP, stages III and IV (OR 1.187; 95% CI 1.013 to 1.390; p=0.034) with elevated peak serum bilirubin levels in the entire population. Duration of oxygen requirement was not related to peak bilirubin (p>0.1). In the subgroup of infants with prolonged oxygen requirement (> or =28 days), there was no association between peak serum bilirubin levels and ROP III and IV (p>0.1); however, there was an association with further increased duration of oxygen requirement (p=0.034). Elevated peak bilirubin does not protect from and may be a risk for ROP in VLBW infants.

Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation

Liver toxicity caused by high-dose myeloablative therapy leads to significant morbidity after hematopoietic cell transplantation. We examined the hypothesis that liver toxicity after cyclophosphamide and total body irradiation is related to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver toxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of liver toxicity, nonrelapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23 (16%) developed moderate or severe sinusoidal obstruction syndrome. The median peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). Metabolism of cyclophosphamide was highly variable, particularly for the metabolite o-carboxyethyl-phosphoramide mustard, whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk for nonrelapse mortality than did patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Increased exposure to toxic metabolites of cyclophosphamide leads to increased liver toxicity and nonrelapse mortality and lower overall survival after hematopoietic cell transplantation.

Recent advances in the pharmacotherapy for hyperbilirubinaemia in the neonate

Jaundice is a common cause for diagnostic works-up and therapeutic intervention in neonates. This is motivated by the risk for severe neurological sequelae (kernicterus). The mainstays of treatment for the past decades have been exchange transfusion and phototherapy. Exchange transfusion is now becoming rare due to immune prophylaxis in Rhesus-negative women, and treatment of sensitised infants with intravenous immunoglobulin. Several different pharmacological approaches have been studied as far as the treatment of neonatal jaundice. Of these, the focus of attention in recent years has been on the haem oxygenase inhibitors (metal meso- and protoporphyrins). These are effective inhibitors of bilirubin production and have been shown to significantly reduce peak serum bilirubin levels in several clinical trials, both when used prophylactically and therapeutically. However, questions remain regarding long-term safety, as well as the advisability of whole-scale inhibition of bilirubin production. Nevertheless, in selected infants with a high risk of severe jaundice, the use of haem oxygenase inhibitors may be acceptable. Pharmacotherapy in jaundiced infants is fraught with risks, as many drugs may increase the entry of bilirubin into the brain and presumably, the risk for neurotoxicity. Both the displacement of bilirubin from its albumin binding and interference with the function of phosphoglycoprotein in the blood–brain barrier are documented mechanisms in this respect.

Spectrum of outcome in infants with extreme neonatal jaundice

The increasing number of case reports on neurologic sequelae related to hyperbilirubinaemia may represent a re-emergence of kernicterus in the industrialized world. However, not much has been written about infants who survived extreme levels of serum bilirubin without neurologic damage. We present three cases of extreme neonatal hyperbilirubinaemia, all with peak serum bilirubin levels >600 micromol/L. Two of the infants developed neurologic sequelae, but the third infant did not. In contrast to the two with sequelae, the infant without sequelae was female, had a positive Coombs' test, less clinical signs compatible with bilirubin encephalopathy, and a shorter exposure to serum bilirubin values >400 micromol/L. The basic mechanism of bilirubin neurotoxicity remains unknown, and it is not clear why some infants do not develop neurologic injury at serum bilirubin levels at which others do. We speculate that a comparison between patients with sequelae and those without may yield important information.

Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization.

To investigate biological and health services predictors of extreme neonatal hyperbilirubinemia in a health maintenance organization. Nested case-control study. Eleven Northern California Kaiser Permanente hospitals. The cohort consisted of 51,387 newborns born at 36 weeks or later weighing 2000 g or more. Cases were newborns with peak total serum bilirubin levels greater than or equal to 428 micromol/L (> or =25 mg/dL) (n = 73). Controls were a random sample of newborns from the cohort with peak bilirubin levels less than 428 micromol/L (<25 mg/dL) (n = 423). Review of medical records and telephone interviews. Early jaundice was most strongly associated with case status (odds ratio [OR] = 7.3). After excluding subjects with early jaundice, the strongest predictors of hyperbilirubinemia were family history of jaundice in a newborn (OR = 6.0), exclusive breastfeeding (OR = 5.7), bruising (OR = 4.0), Asian race (OR = 3.5), cephalhematoma (OR = 3.3), maternal age of 25 years or older (OR = 3.1), and lower gestational age (OR = 0.6/week). These variables identified 61% of newborns as very low risk (about 1/4200). However, the risk in the remaining 39% was still low (1/370). More cases (79%) than controls (59%) had newborn length-of-stay and follow-up consistent with the American Academy of Pediatrics guidelines, but phototherapy use within 8 hours of the time that the guidelines recommend was uncommon in both cases (26%) and controls (33%). There were no apparent cases of kernicterus. Prevention of extreme hyperbilirubinemia may require closer follow-up than is currently recommended by the American Academy of Pediatrics and more use of phototherapy than was observed in this study. To prevent extreme hyperbilirubinemia (> or =428 micromol/L [> or =25 mg/dL]) in 1 newborn, many newborns would need to receive these interventions.

An analysis of the mechanism of postoperative hyperbilirubinemia following resection of thoracic esophageal cancer in terms of hepatic venous oxygen saturation and excessive systemic reactions

Hepatic venous oxygen saturation (ShvO2), parameters of systemic circulation and cytokine (Interleukin 6) (IL-6)) level were measured in 21 patients with thoracic esophageal cancer in order to analyze the mechanism of occurrence of postoperative hyperbilirubinemia (PHB). ShvO2 fell during operation, especially during intrathoracic procedures, and a significant correlation was noted between the total time during which ShvO2 was below 60% and the postoperative peak serum bilirubin level (peak-Bil) (r = 0.595, p = 0.0037). Patients with PHB (group H) had worse systemic circulation and a lower oxygen supply postoperatively than patients without PHB (group N). Body weight and water balance recovered earlier in group N. Postoperatively, numbers of peripheral lymphocytes and platelets changed lower in group H, while CRP and IL-6 changed higher in group H. Furthermore, a significant correlation was noted between the IL-6 level just after operation and peak-Bil (r = 0.669, p = 0.0006). These results suggests PHB results from intraoperative liver hypoxia and poor postoperative systemic circulation. Individual severeness of reactions to the operative stress, excessive or adequate, plays a role in the occurrence of PHB as well.

Early prediction of neonatal hyperbilirubinemia

The study aim was to predict, using serum bilirubin level measured 18 to 24 hours (SB, 18-24) after birth, the occurrence of peak serum bilirubin level > 15 mg/dL (hyperbilirubinemia) or the requirement of phototherapy, any time from the second to fifth postnatal day. The study was conducted on a prospective cohort of 274 neonates born in north India. The main outcome measures were (a) hyperbilirubinemia and (b) phototherapy. Serum bilirubin level was estimated at 18-24 hours of age and then daily from second to fifth postnatal day. Exclusion criteria were Rh incompatibility, asphyxia and life threatening congenital malformations; and neonates of women with gestational diabetes or history intake of drugs affecting the fetal liver. Hyperbilirubinemia was found in 12.8%; and 19.3% neonates received phototherapy. Dichotomous SB 18-24, using a cut-off of > 3.99 mg/dL, as the "prediction test" had the following sensitivity and specificity for predicting (a) hyperbilirubinemia: 67% and 67%, respectively, and (b) the treatment with phototherapy: 64% and 68%, respectively. We concluded that by using SB 18-24 as the "prediction test", approximately two-thirds of neonates were test negative and had about one in ten chances of re-admission for treatment of hyperbilirubinemia, if discharged. After further validation, our results will be of benefit to neonates delivered in developing countries.

The Le(a) antigen and neonatal hyperbilirubinemia in Taiwan.

Neonatal jaundice is known to be more severe in Taiwanese infants than in Caucasian infants. Although ABO fetomaternal incompatibility and glucose-6-phosphate dehydrogenase deficiency have been shown to play a role in the etiology of neonatal jaundice in some Taiwanese infants, the etiology in the majority of cases is unknown. In this study we found that in Taiwanese newborn infants, the red cell Le(a) antigen appeared later in infants who were jaundiced (peak serum bilirubin levels of > 12 mg/dl during the first week of life) than in infants who were not. However, the Leb antigen, and hence the transferase encoded by the Se and Se(w) genes, did not appear to be similarly involved in the etiology of physiological jaundice. Thus it would appear that the Le gene-specified transferase is less active or has a delayed function, in jaundiced infants. The relationship between the Le gene-specified transferase and bilirubin has yet to be established.

Early Meconium Evacuation: Effect on Neonatal Hyperbilirubinemia

Delayed passage of meconium may increase enterohepatic circulation of bilirubin, which appears to be an important contributor to neonatal jaundice. To evaluate the effect of early meconium evacuation on neonatal hyperbilirubinemia, between January 1993 and December 1993, 265 healthy neonates were studied and randomly divided into two groups. Group 1 consisted of 130 neonates who received glycerin enema (1 mL of glycerin mixed with 1 mL of warmed normal saline) within 30 minutes after birth and the same procedure was repeated at 12 hours of age. Group 2 consisted of 135 neonates receiving no glycerin enema throughout their hospital stay. Determination of total serum bilirubin using capillary samples was performed daily for 7 days. Our data showed that 12 neonates (15.4%) in group 1 and 18 neonates (13.3%) in group 2 had serum bilirubin level 15 mg/dL or higher and received phototherapy. We conclude that early evacuation of meconium by using glycerin enema within 30 minutes after birth and 12 hours after birth in order to reduce enterohepatic circulation of bilirubin has no effect on lowering peak serum bilirubin levels or on serum bilirubin concentrations in the first 7 days of life.

The Le^a Antigen and Neonatal Hyperbilirubinemia in Taiwan

Neonatal jaundice is known to be more severe in Taiwanese infants than in Caucasian infants. Although ABO fetomatemal incompatibility and glucose-6-phosphate dehydrogenase deficiency have been shown to play a role in the etiology of neonatal jaundice in some Taiwanese infants, the etiology in the majority of cases is unknown. In this study we found that in Taiwanese newborn infants, the red cell Le^a antigen appeared later in infants who were jaundiced (peak serum bilirubin levels of > 12 mg/dl during the first week of life) than in infants who were not. However, the Le^b antigen, and hence the transferases encoded by the Se and Se^4 genes, did not appear to be similarly involved in the etiology of physiological jaundice. Thus it would appear that the Le gene-specified transferase is less active or has a delayed function, in jaundiced infants. The relationship between the Le gene-specified transferase and bilirubin has yet to be established.

Risk Factors Associated with Hearing Loss in Term Neonates with Hyperbilirubinaemia

A study of 128 jaundiced term neonates showed that 28 (22 per cent) had hearing loss based on brain stem-evoked response. There was no significant difference in the percentage of neonates with hearing loss between those with peak serum bilirubin levels of less than 340 mumol/l (16 per cent) and those with hyperbilirubinaemia > 339 mumol/l (33 per cent) (P = 0.11). Logistic regression analysis showed that severe jaundice which required exchange transfusion and earlier age of onset of hyperbilirubinaemia were statistically significant risk factors associated with hearing loss (P = 0.038 and P = 0.012, respectively).

Risk of Sepsis in Newborns With Severe Hyperbilirubinemia

Because bacterial infection is a potential cause of hyperbilirubinemia, some authors suggest that newborns with significant unexplained indirect hyperbilirubinemia should be evaluated for sepsis. We reviewed the charts of 306 newborns admitted to a pediatric ward within 21 days of birth with a diagnosis of indirect hyperbilirubinemia (peak serum bilirubin level 316 +/- 48, range 217 to 498 mumol/L) (18.5 +/- 2.8, 12.7 to 29.1 mg/dL). Ninety percent were fully or partially breast-fed. Sepsis was identified in 0 of 306 newborns (upper 95% confidence limit for the risk of sepsis = 1%). The overwhelming majority of newborns who require readmission to hospital for indirect hyperbilirubinemia are healthy, breast-fed newborns and do not need to be investigated for sepsis. If indirect hyperbilirubinemia is ever the only manifestation of bacteremia or incipient sepsis, it must be a rare event.

Nonoperative therapy of a complicated biliary stricture

Three recent reports have described external placement of biliary drains for common bile duct (CBD) strictures in children. We report combining endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC), and transductal stenting for the precise diagnosis and management of a complicated CBD stricture. A $$5{\raise0.5ex\hbox{$\scriptstyle 1$}\kern-0.1em/\kern-0.15em\lower0.25ex\hbox{$\scriptstyle 2$}}$$ -year-old boy diagnosed with hepatic rhabdomyosarcoma was treated with induction chemotherapy and extended left hepatic resection. Postoperative neutrophil dysfunction contributed to multiple septic complications requiring three operative procedures for drainage. During these septic episodes cholangitis occurred with a peak serum bilirubin level of 30 mg/dl that finally stabilized at 20 mg/dl. The patient could not be cleared of biliary sepsis. PTC was performed with simultaneous ERCP. A well-defined, discrete CBD stricture was delineated and an external biliary drain was placed. Three weeks later, after the sepsis had cleared and the bilirubin level had markedly decreased, a transhepatic intraductal stent was placed exiting in the duodenum. This was later internalized and remained in place. The patient died 6 months later from a massive pelvic recurrence of his tumor. He suffered no further biliary complications and maintained normal bilirubin levels until his death. We conclude that modalities well-documented in adults for non-operative management of biliary strictures (PTC, ERCP, stents) can be used successfully in the pediatric population in selected cases.

Association between glucose-6-phosphate dehydrogenase deficiency and neonatal jaundice: interaction with multiple risk factors.

This nonconcurrent cohort study was carried out to evaluate the association of neonatal jaundice with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and its interactions with other risk factors. The G-6-PD enzyme activity of 12,379 neonates was screened by a semi-quantitative fluorometric assay and double-checked by a quantitative method to identify a G-6-PD deficient cohort of 333 neonates. Matched with these on birth date, sex and delivery hospital were a G-6-PD normal cohort of 653 neonates. Neonatal jaundice was defined by a peak serum bilirubin (PSB) level of > or = 15 mg/dl. A significant association between G-6-PD deficiency and neonatal jaundice was observed in male but not female neonates. There was an inverse dose-response relation between G-6-PD activity and neonatal jaundice among male neonates. Both hypoxia/asphyxia and maternal hepatitis B surface antigen (HBsAg) carrier status were associated with an increased risk of neonatal jaundice among G-6-PD deficient but not G-6-PD normal male neonates. Based on multiple regression analyses, an additively synergistic effect on PSB level and severe jaundice (PSB > or = 20 mg/dl) was observed for G-6-PD deficiency and maternal HBsAg carrier status.

Breast feeding practices and severe hyperbilirubinaemia

This study establishes the association between early onset severe hyperbilirubinaemia (serum bilirubin (SBR) level greater than or equal to 272 mumol/L) with no assigned cause and breast feeding. The rates of breast feeding at hospital discharge increased from 46.4 to 75.4% in non-insured (public) women and 58.6 to 89.2% in insured (private) women between 1975 and 1987, and were accompanied by an increase in severe hyperbilirubinaemia from 1.6 to 3.1% in public and 0.9 to 3.6% in private babies. The case control study involved 125 term breast feeding infants born between 1 July 1985 and 1 July 1986 with severe hyperbilirubinaemia (SBR level 272 mumol/L) with no assigned cause who were compared with 125 matched controls who had peak SBR levels less than or equal to 272 mumol/L. Severe hyperbilirubinaemia was associated with primiparous and non-Caucasian mothers, non-smoking and oxytocin usage. Univariate analysis of feeding practice variables revealed that less frequent breast feeds, greater weight loss and less frequent stools over the first 3 days related to severe hyperbilirubinaemia (P less than 0.05). Multivariate analysis of the eight significant univariate factors revealed that maternal non-smoking, less frequent breast feeding, less frequent stooling and excessive infant weight loss were the best predictors of severe hyperbilirubinaemia. With the wide promotion of breast feeding, the contribution of individual feeding practices to severe hyperbilirubinaemia demands ongoing analysis and review.

Isoniazid-rifampin-induced hepatitis in hepatitis B carriers

From January 1984–December 1987, 1783 patients received combination therapy of isoniazid, rifampin, and ethambutol for the control of tuberculosis. Forty-two developed symptomatic hepatitis during the period of treatment. Fifteen were hepatitis B virus carriers, and the remaining 27 were noncarriers. The peak serum transaminase and bilirubin levels were higher in carriers. Seven carriers died of fulminant or subacute hepatic failure, and only 1 noncarrier died. Eleven carriers had detectable serum hepatitis B virus deoxyribonucleic acid during the acute stage of hepatitis. The roles of isoniazid-rifampin combination therapy and hepatitis B virus in the adverse outcomes of carriers were discussed.

Decreased Neonatal Serum Bilirubin With Plain Agar: A Meta-Analysis

Neonatal jaundice is one of the most common problems leading to prolonged hospitalization of the newborn. Therefore, an effective low-risk, low-cost therapy reducing hospitalization is highly desirable. Plain dried agar, an extract of seaweed, is low cost and low risk; it can bind bilirubin in the gut, decreasing its enterohepatic circulation, thereby decreasing serum levels. Because of conflicting conclusions in the studies of agar's effectiveness in the prevention and treatment of neonatal jaundice, a meta-analysis of their methodologies was done. Criteria for assessing prospective controlled therapeutic trials of agar were established in six areas: hypothesis and clinical outcome, patient selection, treatment group allocation, therapeutic maneuver, use of cotherapies, and data analysis. Nine prospective clinical trials of agar therapy were evaluated using these six criteria. The seven studies with negative conclusions regarding agar's efficacy failed to meet the criteria in several categories: patient selection, therapeutic maneuver, use of cotherapies, or data analysis. All of the studies, including the positive studies, were at risk for biased treatment allocation. Although the pooled data analysis suggests that prophylactic agar treatment is associated with reduced peak serum bilirubin levels, this observation must be interpreted cautiously in light of heterogenous patient populations and the methodologic problems described. Based on this meta-analysis, agar therapy for neonatal jaundice can neither be recommended nor rejected. The methodologic analysis gives clear guidance for future research concerning the effectiveness of agar in treating neonatal jaundice and provides a model for meta-analysis of other prospective trials in pediatrics.