Accuracy of transcutaneous bilirubinometry in the preterm infants: a comprehensive meta-analysis.

BACKGROUND: Transcutaneous bilirubin (TcB) measurement is widely used in term babies. But its effectiveness till debated in preterm infants. So, our objective was to pool data to see the accuracy of transcutaneous bilirubinometry in preterm infants. METHOD: MEDLINE, Embase, Cochrane Library database were searched from 2000 to July 2017. The included studies had compared TcB with total serum bilirubin (TSB) in preterm infants before phototherapy and data were presented as correlation coefficients. Data were extracted by two reviewers and checked for accuracy by the third reviewer. The risk bias assessments were done by an assessment quality assessment of diagnostic accuracy studies tool. Pooled correlation coefficient assed after Fisher's z transformation and then converted to r. RESULTS: We included 28 studies; all those studies reported results as correlation coefficients. In combination of both sternal and forehead site measurement, our pooled estimates of r = 0.82 (95% CI: 0.78-0.85) in random effect and r = 0.803 (95% CI: 0.78-0.81) in fixed effect model. For separate sites of measurement of TcB pooled r for forehead and sternum were comparable, r = 0.82 (95% CI: 0.78-0.85), and pooled correlation coefficient for the two devices JM103 and Bilicheck the estimated pooled r were also comparable (Pooled r = 0.83). CONCLUSION: Our study found that TcB measurement is well related with TSB values and can represent a reliable method for evaluating preterm infants with possible hyperbilirubinemia. Our findings support the use of investigated devices at both forehead and sternum sites in preterm infants.

Phototherapy for neonatal hyperbilirubinemia.

Approximately 60 years ago in England, phototherapy for neonatal hyperbilirubinemia was used in clinical practice. It was introduced in Japan approximately 50 years ago. At that time, the mechanism underlying the serum bilirubin concentration decrease by phototherapy was still unknown. The mechanism was identified by chemists, biochemists, and pediatricians. Clarification started with the report that unconjugated bilirubin was excreted into bile after photoirradiation in Gunn rats. After confirmation of the molecular structure of bilirubin on X-ray analysis, the mechanism for bile excretion of unconjugated bilirubin was verified based on geometric configurational photoisomers in the Gunn rat. Finally, the reaction and excretion of structural bilirubin photoisomers was proved to be the main mechanism for the decrease in serum bilirubin during phototherapy for neonatal hyperbilirubinemia, which differs from the mechanism in the Gunn rat. The most effective and safest light source and the optimal method to evaluate phototherapy, however, remain unknown. Moreover, as for bronze baby syndrome, which is a well-known adverse reaction to phototherapy, the etiology is unclear. Hence, we review phototherapy for hyperbilirubinemia including a fundamental understanding of the bilirubin photochemical reactions, and discuss the subclinical carcinogenic risk of phototherapy and the increased mortality rate of extremely low-birthweight infants due to aggressive phototherapy, which is becoming an increasing problem.

Modulation of bilirubin neurotoxicity by the Abcb1 transporter in the Ugt1-/- lethal mouse model of neonatal hyperbilirubinemia.

Moderate neonatal jaundice is the most common clinical condition during newborn life. However, a combination of factors may result in acute hyperbilirubinemia, placing infants at risk of developing bilirubin encephalopathy and death by kernicterus. While most risk factors are known, the mechanisms acting to reduce susceptibility to bilirubin neurotoxicity remain unclear. The presence of modifier genes modulating the risk of developing bilirubin-induced brain damage is increasingly being recognised. The Abcb1 and Abcc1 members of the ABC family of transporters have been suggested to have an active role in exporting unconjugated bilirubin from the central nervous system into plasma. However, their role in reducing the risk of developing neurological damage and death during neonatal development is still unknown.To this end, we mated Abcb1a/b-/- and Abcc1-/- strains with Ugt1-/- mice, which develop severe neonatal hyperbilirubinemia. While about 60% of Ugt1-/- mice survived after temporary phototherapy, all Abcb1a/b-/-/Ugt1-/- mice died before postnatal day 21, showing higher cerebellar levels of unconjugated bilirubin. Interestingly, Abcc1 role appeared to be less important.In the cerebellum of Ugt1-/- mice, hyperbilirubinemia induced the expression of Car and Pxr nuclear receptors, known regulators of genes involved in the genotoxic response.We demonstrated a critical role of Abcb1 in protecting the cerebellum from bilirubin toxicity during neonatal development, the most clinically relevant phase for human babies, providing further understanding of the mechanisms regulating bilirubin neurotoxicity in vivo. Pharmacological treatments aimed to increase Abcb1 and Abcc1 expression, could represent a therapeutic option to reduce the risk of bilirubin neurotoxicity.

Hemolysis in Preterm Neonates.

Hemolysis can be an important cause of hyperbilirubinemia in premature and term neonates. It can result from genetic abnormalities intrinsic to or factors exogenous to normal to red blood cells (RBCs). Hemolysis can lead to a relatively rapid increase in total serum/plasma bilirubin, hyperbilirubinemia that is somewhat slow to fall with phototherapy, or hyperbilirubinemia that is likely to rebound after phototherapy. Laboratory methods for diagnosing hemolysis are more difficult to apply, or less conclusive, in preterm infants. Transfusion of donor RBCs can present a bilirubin load that must be metabolized. Genetic causes can be identified by next-generation sequencing panels.

Biology of Bilirubin Photoisomers.

Phototherapy is the main treatment for neonatal hyperbilirubinemia. In acute treatment of extreme hyperbilirubinemia, intensive phototherapy may have a role in 'detoxifying' the bilirubin molecule to more polar photoisomers, which should be less prone to crossing the blood-brain barrier, providing a 'brain-sparing' effect. This article reviews the biology of bilirubin isomers. Although there is evidence supporting the lower toxicity of bilirubin photoisomers, there are studies showing the opposite. There are methodologic weaknesses in most studies and better-designed experiments are needed. In an infant acutely threatened by bilirubin-induced brain damage, intensified phototherapy should be used expediently and aggressively.

Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus.

Hyperbilirubinemia occurs frequently in newborns, and in severe cases can progress to kernicterus and permanent developmental disorders. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human enzymopathies, is a major risk factor for hyperbilirubinemia and greatly increases the risk of kernicterus even in the developed world. Therefore, a novel treatment for kernicterus is needed, especially for G6PD-deficient newborns. Oxidative stress is a hallmark of bilirubin toxicity in the brain. We propose that the activation of G6PD via a small molecule chaperone is a potential strategy to increase endogenous defense against bilirubin-induced oxidative stress and prevent kernicterus.

Bronze baby syndrome.

An in-depth review of jaundice in the newborn was covered in this column in the September/October 2007 issue. This article will include a brief review of bilirubin formation and discuss what is currently known about bronze baby syndrome (BBS). This column will include a short review of bilirubin formation and conclude with an unusual case study of a patient who developed BBS in the absence of direct hyperbilirubinemia.

The effect of phototherapy on fecal calprotectin levels.

OBJECTIVE: Fetal calprotectin levels increase in the early stages of necrotizing enterocolitis. Although the effects of several factors on fetal calprotectin have been studied, the effect of phototherapy is not known. In this study, we analyzed the effect of phototherapy on fetal calprotectin levels. METHODS: Ninety breast-fed newborns (46 male, 44 female) who were hospitalized for indirect hyperbilirubinemia and treated with phototherapy were included to the study. Forty-two of them were term and 44 of them were preterm. Newborns treated with phototherapy (n = 53) constituted the phototherapy group (29 preterm, 24 term) and 37 newborns who did not receive phototherapy (19 preterm, 18 term) constituted the control group. Fecal samples were collected 24 hours after phototherapy had been started. Fecal samples (100 mg) were weighed with sensitive scales and preserved at -80°C after buffering with a special solution. All samples were studied at the same time with a fecal calprotectin kit by using enzyme-linked immunosorbent assay. RESULTS: There were no statistically significant difference between fecal calprotectin levels of term and preterm babies who received phototherapy and babies who did not receive phototherapy. CONCLUSION: There was no effect of 24-hour phototherapy on fecal calprotectin levels in preterm and term newborns.

Interleukin 1beta level in human colostrum in relation to neonatal hyperbilirubinemia.

Breast-fed infants have higher bilirubin level than formula-fed infants which is of undetermined etiology. The cholestatic effect of cytokines (e.g. IL-1beta, IL-6) is believed to result from the repression of genes that normally mediated the hepatic uptake, metabolism, and biliary excretion of bile salts and bilirubin. The present study aimed to assess the level of interleukin 1beta (IL1beta) in early milk of nursing mothers and its relation to neonatal jaundice. Sixty full term neonates and their mothers were included. They were classified into two groups; group I included Forty neonates patients with physiological jaundice and group 11 included twenty age and sex matched controls neonates without jaundice. Milk samples were collected from mothers for estimation of serum IL-1beta level by ELISA, and blood samples were collected from the neonates for measuring total serum bilirubin (TSB) level. A significant difference (P < 0.01) in the level (pg/dl) of IL-1beta was found in early milk between group I (10.25 +/- 4.23) and group II (3.75 +/- 2.07). The total serum bilirubin level was higher in group I than group II (10.91 +/- 3.25 mg/dl versus 3.88 +/- 0.78 mg/dl) (P < 0.01). A significant positive correlation was found between of IL-1beta in breast milk and total serum bilirubin levels (r = 0.494, P < 0.001). It is concluded that Elevated levels of IL-1beta in the colostrum provide additional data to understand one of path physiologic mechanisms of breast milk jaundice.

Hyperbilirubinemia in the newborn.

After completing this article, readers should be able to: 1. List the risk factors for severe hyperbilirubinemia. 2. Distinguish between physiologic jaundice and pathologic jaundice of the newborn. 3. Recognize the clinical manifestations of acute bilirubin encephalopathy and the permanent clinical sequelae of kernicterus.4. Describe the evaluation of hyperbilirubinemia from birth through 3 months of age. 5. Manage neonatal hyperbilirubinemia, including referral to the neonatal intensive care unit for exchange transfusion.

Effect of induction of meconium evacuation using per rectal laxatives on neonatal hyperbilirubinemia in term infants: a systematic review of randomized controlled trials.

OBJECTIVE: To study the efficacy of early meconium evacuation using per rectal laxatives on the level of serum bilirubin and the need for phototherapy in healthy term infants. MATERIALS AND METHODS: Systematic review of randomized controlled trials comparing per rectal laxatives versus no intervention was conducted using English language articles identified from the Cochrane Central Register of Controlled Trials, Medline, Ovid, and CINAHL databases and bibliographies of selected articles. Eligible studies were assessed for the risk of bias in conduct and reporting. RESULTS: A total of three trials (n = 469) mostly with "unclear risk" were eligible for inclusion. Two trials used glycerin suppository whereas one used glycerin enema for meconium evacuation. Meta-analysis was not possible due to clinical heterogeneity in the choice of laxatives and frequency of intervention. In all the three studies, serum bilirubin levels at 48 h and the need for phototherapy was not significantly different between the two groups. Passage of first meconium and the transitional stools occurred significantly early in the intervention group compared to controls. CONCLUSION: Early evacuation of meconium using per rectal laxatives does not offer any significant clinical advantage for neonatal jaundice.

Evaluation of phototherapy devices used for neonatal hyperbilirubinemia.

OBJECTIVE: To compare phototherapy devices based on their physical and photo-biological characteristics viz spectral properties, maximum and mean irradiance, treatable percentage of body surface area, decay of irradiance over time and in vitro photoisomerisation of bilirubin. DESIGN: In vitro experimental study. SETTING: Ocular pharmacy laboratory at a tertiary care hospital. METHODLOGY: All the characteristics were measured at a fixed distance of 35 cm from one compact fluorescent lamp (CFL) and three light emitting diode (LED) phototherapy devices in a dark room with an irradiance of <0.1uW/cm2/nm. Estimation of products of in vitro photoisomerisation was done using liquid chromatography - tandem mass spectroscopy (LC-MS/MS). RESULTS: The emission spectral data were comparable between the phototherapy devices. The devices, however, differed in their maximum irradiance with the spot and indigenous LED units having the highest and lowest values, respectively (56.5 and 16.8uW/cm2/nm). The mean irradiance measured in 5x5cm grids falling within the silhouette of a term baby of the spot and improvised LED devices were low (26.8uW/cm2/nm and 11.5uW/cm2/nm, respectively) possibly due to unevenness in the irradiance of light falling within the silhouette. There was a significant difference in the amount of bilirubin left after exposure to light over a 2hour time period (% reduction of bilirubin) among the four devices (P=0.001); at 120 minutes after exposure, the amount of bilirubin left was lowest for the CFL (16%) and spot LED (17%) devices and highest for the indigenous LED unit (41%). CONCLUSIONS: The four phototherapy devices differed markedly in their physical and photobiological characteristics. Since the efficacy of a device is dependent not only on the maximum irradiance but also on the mean irradiance, rate of decay of irradiance, and treatable surface area of the foot print of light, each phototherapy device should have these parameters verified and confirmed before being launched for widespread use.

Controversies in bilirubin biochemistry and their clinical relevance.

Despite a century of research, several clinically relevant areas of bilirubin biochemistry remain controversial, poorly understood, or unrecognized. These include: (i) The structure and molecularity of bilirubin under physiological environments such as membranes, brain tissue and when bound to proteins. Related to this is the large number of structurally different bilirubin species that may occur in blood under pathological conditions and their potential effects on measurements of bilirubin and free bilirubin. (ii) The mechanism of phototherapy, the neurotoxicity of the photoisomers produced and their influence on measurements of bilirubin and free bilirubin. (iii) The role of membrane transporters in the passage of unconjugated bilirubin across the placenta, intestine, vascular epithelium, blood-brain barrier, and into the liver. (iv) Biochemical mechanisms of bilirubin toxicity, pharmacologic prevention of kernicterus, the contribution of bilirubin to antioxidant defenses, and the practical value of free bilirubin measurements for identifying infants at most risk of kernicterus.

Comparison between transcutaneous bilirubinometry and total serum bilirubin measurements in preterm infants <35 weeks gestation.

BACKGROUND: Neonatal hyperbilirubinaemia is a common treatable cause of brain injury. The treatment for this condition is phototherapy. The decision whether to use phototherapy is currently dependent upon serum bilirubin assay results. However, repeated blood sampling is not only traumatic but may also be a cause of anaemia in neonates. We evaluated a transcutaneous bilirubin assay method to determine whether it was suitable for routine use in preterm infants. METHODS: One hundred and eighty-three transcutaneous bilirubin measurements were taken contemporaneously with blood samples for laboratory measurement of serum bilirubin. The study was carried out with informed parental consent and approval by the local research ethics committee. RESULTS: The transcutaneous bilirubin method (BiliChek) exhibited a consistent positive bias compared with the laboratory bilirubin assay. Consequently, for a given detection rate, the transcutaneous method had a higher screen positive rate, i.e. more neonates would be given phototherapy if transcutaneous bilirubin results were used to decide. There was a margin of safety in the transcutaneous bilirubin assay calibration. CONCLUSION: The BiliChek transcutaneous bilirubin assay is a safe alternative to laboratory bilirubin assay in deciding whether to give preterm neonates phototherapy.

Pharmacological therapies for unconjugated hyperbilirubinemia.

Severe unconjugated hyperbilirubinemia, seen mainly in neonates, may cause kernicterus and death. Conventional treatment for severe unconjugated hyperbilirubinemia consists of phototherapy and exchange transfusion. Phototherapy, however, has several known disadvantages while exchange transfusion is associated with a significant morbidity, and even mortality. These harmful effects indicate the need to develop alternative pharmacological treatment strategies for unconjugated hyperbilirubinemia. Generally, these strategies aim to decrease the plasma concentration of unconjugated bilirubin (UCB) by inhibiting production, stimulating hepatic clearance, or interrupting the enterohepatic circulation of the pigment. To be considered for routine clinical use, an alternative treatment strategy should be less invasive and at least as effective and safe as phototherapy. Several pharmacological therapies such as metalloporhyrins, clofibrate, bile salts, laxatives and bilirubin oxidase may meet these criteria in the future, but none of them has yet been evaluated sufficiently to allow routine application. This review aims to discuss the state of the art and future perspectives in pharmacological treatment of neonatal jaundice.

Hyperbilirubinemia.

Hyperbilirubinemia is the most common condition requiring evaluation and treatment in newborns. The clinical manifestation of hyperbilirubinemia-jaundice-occurs in 60% of normal newborns and nearly all preterm infants. Compared with conditions that require advanced pharmacologic and technologic treatment strategies, hyperbilirubinemia seems to be overshadowed and may lose the attention it deserves as a condition that has potentially devastating effects. Nurses must be vigilant when caring for babies with "just jaundice" by monitoring bilirubin levels, identifying infants at risk for developing severe hyperbilirubinemia, and implementing prescribed treatment effectively when indicated.

Effect of hyperbilirubinemia on intestinal permeability in healthy term newborns.

UNLABELLED: We investigated the effect of serum bilirubin (SB) on intestinal permeability (IP) of healthy, term, birth weight appropriate for gestational age neonates before phototherapy. IP was measured by the dual probe (lactulose/mannitol) sugar absorption test (SAT) performed on the third day of life in 12 healthy jaundiced newborns (total bilirubin 249 +/- 39.75 micromol/L) and compared to that of 12 non-jaundiced newborns (total bilirubin 83.79 + 37.62 micromol/L) matched for sex, gestational age, birth weight and Apgar score. Jaundiced newborns have a significantly higher La/Ma ratio than non-jaundiced (0.31 +/- 0.28 vs. 0.053 +/- 0.043; p < 0.0004). A significant correlation was found between serum bilirubin level and La/Ma ratio (r = 0.56 p < 0.006). CONCLUSION: Our study demonstrates a direct effect of UCB on gut epithelial barrier of at-term newborns in whom UCB appears to be responsible for an alteration of IP that theoretically may lead to a passage of macromolecules through the intestinal epithelium increasing the risk of sensitization.