A Neglected and Promising Predictor of Severe Hyperbilirubinemia Due to Hemolysis: Carboxyhemoglobin.

Aims: We investigated the relationship between total serum bilirubin (TSB) and carboxyhemoglobin (COHb) in term neonates with detected and treated hemolysis within a particular time frame with the aim of augmenting the case for early diagnosis and prevention of morbidity in hemolysis. Materials and Methods: The study group comprised term newborns who were above the 95th percentile for TSB, underwent intravenous immunoglobulin (IVIG) or applied total exchange transfusion due to hemolysis. Newborns without hemolysis who were above the 95th TSB percentile and required phototherapy comprised the control group. Results: At a cutoff COHb value of 2.2%, 80.8% sensitivity, 95.5% specificity, 18.1 likelihood ratio, positive predictive value of 94.7%, and negative predictive value of 83.2% were identified. Conclusion: We found that COHb is a sensitive and specific method for detecting hemolysis, and it can be used in the early diagnosis of hemolytic diseases causing early and severe hyperbilirubinemia.

Breastfeeding during breast milk jaundice - a pathophysiological perspective.

INTRODUCTION: Exclusive breastfeeding for the initial six months of life is crucial and it is recommended . Breast milk jaundice is an innocuous condition that occurs in some healthy, breastfed infants. However, the potential dangers of jaundice in the neonate such as bilirubin induced neuronal pathology, mandates a better understanding of the pathophysiology of breast milk jaundice and the impact of breastfeeding during jaundice. In this context , advice on continued breastfeeding must consider both the benefits of breastfeeding and the possible disadvantages of the jaundice. METHODS: Reviewing literature and integrating relevant information facilitated the appraisal of this important topic. This article reviewed neonatal jaundice, the entry of bilirubin into the immature brain and how breastfeeding may impact jaundice in the neonate. RESULTS: While some substances in breast milk may be responsible for jaundice on the one hand, there is an irrefutable spectrum of advantages conferred by continued breastfeeding, on the other. As the breastfed infant benefits from fewer infections, enhanced organ and physiological barrier maturity, as well as the prospect of genetic modification of certain diseases, these useful actions could also reduce risks of early jaundice and its complications. DISCUSSION: An exciting field for further research, holistic integration of knowledge clarifies both the overall advantages of breastfeeding and wisdom of its continued counsel. In fact, breast milk jaundice may reflect a holistic expression of tissue protection and enhanced neonatal survival.

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.

A Pilot Metabolic Profiling Study of Patients With Neonatal Jaundice and Response to Phototherapy.

Phototherapy has been widely used in treating neonatal jaundice, but detailed metabonomic profiles of neonatal jaundice patients and response to phototherapy have not been characterized. Our aim was to depict the serum metabolic characteristics of neonatal jaundice patients relative to controls and changes in response to phototherapy. A (1) H nuclear magnetic resonance (NMR)-based metabonomic approach was employed to study the metabolic profiling of serum from healthy infants (n = 25) and from infants with neonatal jaundice (n = 30) pre- and postphototherapy. The acquired data were processed by multivariate principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA). The PLS-DA and OPLS-DA model identified nine metabolites capable of distinguishing patients from controls. In addition, 28 metabolites such as ß-glucose, α-glucose, valine, and pyruvate changed in response to phototherapy. This study offers useful information on metabolic disorders in neonatal jaundice patients and the effects of phototherapy on lipids, amino acid, and energy metabolism.

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.

Heliotherapy for Neonatal Hyperbilirubinemia in Southwest, Nigeria: A Baseline Pre-Intervention Study.

BACKGROUND: A novel filtered-sunlight phototherapy (FSPT) device has been demonstrated to be safe and efficacious for treating infants with neonatal jaundice in resource-constrained tropical settings. We set out to provide baseline data for evaluating the clinical impact of this device in a referral pediatric hospital. METHODS: We reviewed the medical records of infants admitted for neonatal hyperbilirubinemia in an inner-city Children's Hospital in Lagos, between January 2012 and December 2014 to determine the pattern, treatment and outcomes during the pre-intervention period. Factors associated with adverse outcomes were identified through multivariable logistic regression. RESULTS: Of the 5,229 neonatal admissions over the period, a total of 1,153 (22.1%) were admitted for neonatal hyperbilirubinemia. Complete records for 1,118 infants were available for analysis. The incidence of acute bilirubin encephalopathy (ABE) and exchange transfusion (ET) were 17.0% (95% CI: 14.9%-19.3%) and 31.5% (95% CI: 28.8%-34.3%) respectively. A total of 61 (5.5%, 95% CI: 4.3%-6.9%) of the jaundiced infants died. Weight on admission, peak total serum bilirubin (TSB), sepsis and exposure to hemolytic products were predictive of ABE, while age on admission, peak TSB, ABO incompatibility and ABE were predictive of ET. Rhesus incompatibility, asphyxia, exposure to hemolytic substances and ABE were associated with elevated mortality risk, while ET was a protective factor. Lack of routine irradiance monitoring and steady energy supply were frequent challenges for conventional blue-light phototherapy. CONCLUSIONS: Severe hyperbilirubinemia is associated with high rates of ABE and ET in this setting, and remains a significant contributor to neonatal admissions and mortality. To be impactful, FSPT, complemented with improved diagnostic facilities, should effectively curtail jaundice-related adverse outcomes in this and comparable settings.

Effects of baby massage on neonatal jaundice in healthy Iranian infants: A pilot study.

OBJECTIVE: To evaluate the effects of baby massage on transcutaneous bilirubin levels and stool frequency of healthy term newborns. METHODS: This Pilot study was conducted on 50 healthy newborns in Valiasr Hospital of IKHC. The infants were randomly allocated to two treatment (massage) and control group. The massage group received massage therapy (according to Touch Therapy) for four days from the first day postnatal while the control group received routine care. Main variable studied were transcutaneous bilirubin level (TCB) and stool frequency which were compared in two groups. RESULTS: There were 50 newborns in the study 25 in each group (50%). There was a significant difference in the TCB levels between two groups (p=0.000) with those in the massage group having lower bilirubin levels. As for the stool frequency there was a significant difference in two groups on the first day showing more defecation in the control group (p=0.042) which on the consequent days was not significant and the frequencies were almost similar. CONCLUSION: Massage group had a lower transcutaneous billirubin levels compared to the control group, thus, these pilot results indicate that massaging the newborns can be accompanied by a lower bilirubin level in the healthy term newborn.

William A Silverman lecture.

This is the text of the William A Silverman lecture given by Dr David K Stevenson at the Pediatric Academic Societies Annual Meeting in Washington, DC, May 4-7, 2013.

Phototherapy rash in newborn infants: does it differ between conventional and light emitting diode phototherapy?

Data comparing the cutaneous side effects of light emitting diode (LED) phototherapy (LP) and conventional phototherapy (CP) devices in jaundiced newborn infants are very limited. We investigated the incidence and extent of skin eruptions caused by different phototherapy devices in preterm infants who are more prone to neonatal jaundice. This prospective, randomized controlled trial was conducted in the neonatal intensive care unit (NICU) of Hacettepe University Ihsan Dogramaci Childrens' Hospital in Ankara, Turkey. Preterm infants without skin lesions before and requiring phototherapy in the first week of life were included in the study. The infants were randomly assigned to receive CP or LP and were monitored closely for skin eruptions during phototherapy. Fifty-eight infants were included in the study: 25 (43.1%) received CP while 33 (56.9%) received LP. The duration of phototherapy was similar in the two groups (30.4 ± 9.6 hours and 31.8 ± 15.6 hours, respectively). Baseline and control bilirubin levels were similar for the two groups (p = 0.101 and p = 0.105, respectively). The frequency of skin eruptions was 36% in the CP group and 33% in the LP group (p = 0.83). The skin eruptions were macules in 13 (22.4%), papules in 5 (8.6%), and maculopapular rashes in 2 (3.4%) infants.There were no differences in the incidence and extent of skin eruptions in preterm infants who received CP or LP.

The role of CK7, Ki-67, CD34 and vimentin in the differentiation between biliary atresia and idiopathic neonatal hepatitis in Egyptian cholestatic neonates.

The differentiation between biliary atresia (BA) and idiopathic neonatal hepatitis (INH) is challenging with many histological overlaps especially in the first weeks of life. This study aimed to investigate the role of immunohistochemical staining of CK7, Ki67, CD34, and vimentin in addition to other clinicopathological features in the differentiation between BA and INH. Cases included 30 infants with BA and 30 infants with INH. The diagnosis was based on clinical, laboratory, and liver biopsy examination. Female gender and elevated serum gamma glutamyle transferase were in favor of BA. Portal tract changes, such as bile ductular proliferation documented by CK7, Ki67 immunostaining and angiogenesis documented by CD34 immunostaining, favored the diagnosis of BA. Copper associated protein was positive in 70% of BA cases, but not detected in INH cases. Parenchymatous changes, such as giant cell transformation and positive iron deposition and Kupffer cell proliferation documented by vimentin immunostaining, favored the diagnosis of INH.CK7, Ki67, CD34, and vimentin are helpful adjuvant immunostaining in the differentiation between BA and INH.

Accuracy of neonatal transcutaneous bilirubin measurement in the outpatient setting.

OBJECTIVE. To evaluate the effectiveness of transcutaneous bilirubin (TcB) measurement in predicting risk for neonatal hyperbilirubinemia in outpatients. DESIGN. Subjects were infants ≤8 days old seen in an outpatient clinic. Infants discharged with high-risk (HR) or high-intermediate risk (HIR) total serum bilirubin (TSB) values and jaundiced infants were recruited. TSB and TcB (BiliChek) levels were plotted on an hour-specific nomogram to determine risk for hyperbilirubinemia. RESULTS. A total of 79 infants provided 87 sets of TcB and TsB values. Mean bias and standard deviation between TcB and TsB was 1.5 ± 2.1 mg/dL for outpatients, compared with 2.7 ± 1.3 mg/dL for inpatients. The sensitivity and specificity of HR or HIR TcB for predicting an HR or HIR TSB were 87% and 58%, respectively. Of 9 infants readmitted for phototherapy, 1 had a low-risk TcB and high-risk TSB. CONCLUSIONS. TcB screening in the outpatient environment may not be safe and efficient.

The role of phototherapy in the crash-cart approach to extreme neonatal jaundice.

Extreme neonatal jaundice occurs infrequently but carries a high risk of permanent sequelae (kernicterus) when it does. Rapid therapeutic intervention has the potential to reduce this risk in some infants. Several case reports of infants with acute intermediate to advanced bilirubin encephalopathy shows that reversal may be possible. Phototherapy can be instituted at the flip of a switch, whereas other therapeutic measures necessarily involve delays. Therefore, high-intensity phototherapy must be regarded as an emergency measure in infants presenting with extreme jaundice and even more so in the presence of neurological symptoms. The principal and well-described effect of phototherapy involves conversion of bilirubin IXα (z, z) to more polar isomers, which are excreted in bile and urine. When care is taken to maximize the spectral power of phototherapy lights, and whenever possible with measures added to reduce the enterohepatic circulation of bilirubin, very rapid reductions in total serum bilirubin levels are possible. A hypothesis has been advanced that conversion of bilirubin to more polar photoisomers, which can reach relative concentrations of 20%-25% of total serum bilirubin within 1-2 hours, might have a direct neuroprotective effect. This theory posits that because polar molecules generally require a transporter to cross the blood-brain barrier, bilirubin photoisomers should be less prone to enter the brain. Although this theory has some support in in vitro toxicity studies, the evidence is controversial. Until further experimental support can be gained, photoconversion of bilirubin does not constitute a viable argument against instituting further measures against bilirubin neurotoxicity, such as intravenous immune globulin (when indicated) and exchange transfusion. Conversely, neither is the state of evidence an argument against immediate and effective phototherapy in the medical emergency of extreme neonatal jaundice.

Effect of oncostatin M on uridine diphosphate-5'-glucuronosyltransferase 1A1 through cross talk with constitutive androstane receptor.

Hyperbilirubinemia remains a common condition in neonates. The constitutive androstane receptor (CAR) is an orphan nuclear receptor that has been shown to participate in the activation of the uridine diphosphate-5'-glucuronosyltransferase 1A1 (UGT1A1) gene, which plays an important role in bilirubin clearance. Oncostatin M (OSM), a member of the IL-6 family, is involved in the maturation of fetal hepatocytes. We have demonstrated that low OSM levels are a potential indicator of neonatal jaundice and the need for phototherapy. In this study we examined the effects of OSM on CAR-mediated signaling to investigate its potential role in neonatal jaundice via the CAR-UGT1A1 pathway. We observed that OSM positively augmented the CAR and UGT1A1 expressions and CAR-mediated signaling in vivo and in vitro, through cross talk between the nuclear CAR receptor and the plasma membrane OSM receptor, via the MAPK cascade. These data suggest that OSM might play a role in bilirubin metabolism via the CAR-UGT1A1 pathway.

Signal processing system to extract serum bilirubin concentration from diffuse reflectance spectrum of human skin.

Neonatal jaundice is a medical condition which occurs in newborns as a result of an imbalance between the production and elimination of bilirubin. Excess bilirubin in the blood stream diffuses into the surrounding tissue leading to a yellowing of the skin. The extra-vascular bilirubin act as interfering signal that limits the estimation of serum bilirubin from reflectance spectrum of human skin. This is particularly an issue for neonates who are being subjected to phototherapy (a common treatment for neonatal jaundice). Unfortunately, analytical models developed to study the light transport in human skin do not consider the effects of extra-vascular bilirubin (and other absorbing chromophores). A biomedical signal processing method that estimates serum bilirubin in presence of confounding signals such as melanin and extra-vascular bilirubin concentrations is presented. The new system model and nonlinear solver have been successful in estimating the serum bilirubin concentration on simulated spectral databases within an average error of 15%.

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.

Cytokines in human colostrum and neonatal jaundice.

Breast-fed infants have higher bilirubin levels than formula-fed infants, possibly because of variations in the composition of the breast milk. The aim of this study was to investigate whether there is a relationship between cytokine levels in the colostrum of nursing mothers and neonatal jaundice (NJ). Breast milk samples were collected from breast-feeding mothers of healthy full-term neonates, 32 with NJ and 29 without jaundice. The concentrations of IL-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha were measured by chemiluminescence enzyme immunometric assays. Mothers of infants with NJ had a higher concentration of IL-1beta in colostrum, compared with those feeding neonates without NJ, and similar trends were seen for IL-6, IL-8, IL-10, and for TNF-alpha. The concentrations of IL-1beta significantly correlated with IL-6, IL-8, IL-10, and TNF-alpha concentrations, but not with serum bilirubin levels of infants with NJ. In conclusion, the concentrations of IL-1beta were increased in colostrum from breast-feeding mothers whose infants had NJ. The correlation between the concentrations of cytokines involved in the function of hepatic uptake and excretory systems and in the enterohepatic circulation of bilirubin provides additional data to the delineation of the cascade of pathophysiological events that can lead to NJ.

[Predictive value of umbilical cord blood bilirubin level for subsequent neonatal jaundice].

OBJECTIVE: To investigate the predictive value of umbilical cord serum (UCS) bilirubin for subsequent jaundice in healthy term newborns. METHODS: Five hundred and twenty-three healthy term newborns (275 boys, 248 girls) were selected. The cord blood total serum bilirubin concentration and the serum albumin concentration were determined. All the infants were assessed for jaundice daily by measurement of transcutaneous bilirubin (TCB). When the infant's TCB was >or= 18 within the first 24 h after birth, >or= 21 at 48 h, >or= 25 at or after 72 h, the venous total serum bilirubin (TSB) was determined and treatment against jaundice was applied as needed. The infants were aligned into four groups according to their UCS bilirubin levels, starting from < 30 micromol/L(group 1); >or= 30 micromol/L(group 2); >or= 36 micromol/L(group 3); >or= 42 micromol/L(group 4). The frequency of hyperbilirubinemia and phototherapy (PT) were compared among the four groups. An analysis of UCS bilirubin as a predictor of later development of jaundice was performed. The characteristics of the infants who became jaundiced (jaundiced group) were compared with the normal infants (non-jaundiced group). RESULTS: A clear correlation between UCS bilirubin level and the development of hyperbilirubinemia was found in all populations of the four groups. Only eight of the 194 infants in group 1 showed a TCB index >or= 25. TSB values > 205 micromol/L but < 257 micromol/L were observed in 2 newborns. None of the infants in this group showed TSB > 257 micromol/L or needed PT. Thirty-two infants in group 2 showed TCB >or= 25, 12 infants had TSB > 205 micromol/L but < 257 micromol/L, 2 infants had TSB > 205 micromol/L and received PT. In group 3, one infant developed hyperbilirubinemia at 48 h after birth and received PT. Thirty-nine infants showed TCB >or= 25, 16 infants TSB > 205 micromol/L but < 257 micromol/L, 2 infants had TSB > 205 micromol/L and also received PT. In group 4, 4 infants showed a range of TSB from 200 to 215 micromol/L at 48 h and received PT. Twenty-two infants showed TCB >or= 25, 17 of them showed TSB > 205 micromol/L but < 257 micromol/L, and 5 of them had TSB > 205 micromol/L and received PT. The frequency of TSB > 205 micromol/L increased from 1.03% in group 1, 5.77% in group 2, 19.75% in group 3 and to 42.5% in group 4. None of the 194 newborns in group 1 needed phototherapy, whereas 0.96%, 3.70% and 22.5% of the newborns in groups 2 - 4, needed PT. The frequency of patients with hyperbilirubinemia or phototherapy increased with increasing UCS bilirubin levels. For the prediction of TCB >or= 25 using a UCS bilirubin cut-off level, such as >or= 35 micromol/L, we found a positive predictive value of 45.68% and sensitivity of 68.27%. It is significant to predict neonatal jaundice by UCS bilirubin levels (P < 0.001). In the jaundiced group (TCB >or= 25) UCS bilirubin levels were significantly higher than those in the non-jaundiced group (t = 10.96, P < 0.001). No significant differences were found in the cord blood serum albumin concentration (t = 2.38, P > 0.05), the gestational age (t = -0.90, P > 0.05), and birthweight (t = 0.10, P > 0.05) between the jaundiced and non-jaundiced groups. CONCLUSIONS: UCS bilirubin level is useful in predicting the subsequent jaundice in healthy term infants. The use of UCS bilirubin values may help detect infants at low or high risk for hyperbilirubinemia and minimize an unnecessary prolongation of hospitalization.

In vivo spectroscopy of jaundiced newborn skin reveals more than a bilirubin index.

AIM: The aims of this study were to improve the algorithms for calculating a transcutaneous bilirubin index (TcB), to follow the bilirubin concentrations during phototherapy and to evaluate possible changes in skin optical parameters such as pigmentation and erythema during phototherapy. METHOD: Reflectance measurements were performed on 51 jaundiced newborns, of which 10 were subjected to phototherapy. The measurements were collected with a diode array spectrophotometer with an integrating sphere accessory, and a TcB was calculated from the measured spectra using algorithms based on diffusion theory. The newborns' birthweights were > or = 2000 g and their gestational age was > or = 35.5 wk. They had no substantial illnesses, and no newborns were submitted to the study until their second day. Heel prick blood samples were analysed for total serum bilirubin (Sbr) by the diazo reaction method. Phototherapy equipment was either an overhead lamp or lightbed. RESULTS: Measurements from the forehead gave the best correlation between TcB and Sbr (r = 0.81, p < 0.05). However, during phototherapy no significant correlation between TcB and Sbr was observed. A correlation (r = 0.45, p < 0.05) was found between phototherapy and melanin index obtained from the patients' back. CONCLUSIONS: Reflectance spectroscopy is useful in assessing bilirubin concentrations before phototherapy, and can also reveal changes in skin parameters such as pigmentation occurring as a result of phototherapy.

Noninvasive transcutaneous bilirubin as a screening test to identify the need for serum bilirubin assessment.

Hyperbilirubinemia is a common problem in the newborn infant. It can progress to develop kernicterus unless intervention is initiated. Severity and decision for management are usually based on serum bilirubin (TsB) which needs blood sampling. Transcutaneous bilirubin measurement is a noninvasive technique and the result correlates closely with TsB. A new transcutaneous bilirubinometer, Minolta AirShields Jaundice Meter, JM103, has been introduced The objectives of this study were: 1) To evaluate the accuracy of transcutaneous bilirubin (TcB) measured by JM 103, when compared to TsB, used clinically in a hospital setting (Leica Unistat Bilirubinometer) and 2) To develop a cut-off point of TcB level which indicated the need for serum bilirubin assessment. Three hundred and eighty eight term and near-term newborn infants with 460 paired TcB-TsB specimens were studied from August to November 2003. Birth weight was 3117.57 +/- 424.82 grams. TsB ranged from 4 to 19.6 mg/dL (x 10.5, SD 2.46). The correlation coefficient between TcB and TsB was significant (r 0.8, p < 0.001). TcB showed a tendency to underestimate TsB, with mean difference of 0.7 mg/dL, SD 1.6 mg/dL, and 95% confidence interval 0.85 and 0.55 mg/dL. TcB values of 8, 9, 10, 12 mg/dL were chosen as cut-off points that indicated the need for blood sampling for TsB (corresponded to hour-specific levels of 10, 12, 13 and 15 mg/dL, respectively when phototherapy should be initiated). In conclusion, noninvasive TcB assessment demonstrates significant accuracy, compared to TsB. It can be used as a screening test to identify the need for blood sampling for serum bilirubin level.