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Serum Unbound Bilirubin Versus Transcutaneous Bilirubin in Jaundiced Preterm NeonatesAkram E. Elsadek(a), Eman G. Behiry(b) (a) department of Pediatrics , Faculty of Medicine – Benha University, (b) department of Clinical and Chemical Pathology, Faculty of Medicine – Benha University, Egypt.Corresponding Author Name: Akram Elshafey ElsadekPhone Number:01022080859 Email:AbstractTotal serum bilirubin (TSB) represents the total amount of circulating bilirubin. In transcutaneous bilirubinometry (TCB), the bilirubinometer is pressed against the skin causing pallor, and bilirubin levels are measured. The aim was to describe the relationship between serum UB(unbound bilirubin) and TcB in late preterm jaundiced neonates. This prospective case controlled study was conducted on 100 patients. Group (I) : Included 50 hyperbilirubinemic preterm neonates. Group (II) :Included 50 healthy preterm neonates as control group. All neonates were subjected to complete history taking, clinical examination and laboratory investigations TCB, UB,TSB and albumin. Jaundiced preterm neonates were significantly associated with high TSB, TSB/albumin when compared to healthy preterm neonates. Jaundiced preterm neonates showed significantly higher UB /TSB when compared to healthy preterm neonates. Best cut off value of UB was 0.24 ug/dL, at which Sensitivity was 94%, specificity was 68%. TCB Best cut off value was 2.5 mg/dL, at which Sensitivity was 66%, specificity was 98%. No significant differences were found between AUC of UB and TCB . A high correlation between TCB and TSB measurements. ROC curve of UB and TCB was conducted for discrimination between jaundiced and healthy preterm neonates. UB showed good AUC. Key words: Jaundice- Preterm– Serum Unbound Bilirubin- Transcutaneous Bilirubin.Introduction:Neonatal jaundice is associated with increased unconjugated bilirubin concentrations caused by the breakdown of red blood cells. Bilirubin can damage neurologic tissue and lead to bilirubin-induced neurologic dysfunction (14). Hyperbilirubinemia is a common finding in neonates. 60% of term neonates and 80% of preterm neonates suffer from jaundice during the first week of life (16). For the better treatment of neonatal jaundice, measuring bilirubin levels is vital; which is usually done by visual, cutaneous, and serum evaluations. Although visual assessment is simple, it has two major shortcomings; it is dependent on the physicians experience with no accurate and reliable criteria, and possible estimations in this method are based on the cephalocaudal trend of jaundice. Moreover, the color of skin and clothes as well as the lighting affect visual estimation (22). TSB measurement is also not an ideal method of measurement because it could have complications such as infection, anemia, pain, and stress because of frequent blood sampling. Moreover, this method is stressful, time consuming and expensive (. In cases at a high risk of kernicterus such as day-one icter, hepatosplenomegaly, etc, TSB measurements are necessary (16).TSB poorly correlates with bilirubin neurotoxicity. This lack of correlation might be due to the presence of co-morbidities and/or risk factors, but also TSB measurement being a poor marker in itself. In fact, TSB merely represents the total amount of circulating bilirubin, which consists of different species. The UB /TSB ratio, which represents the combination of magnitude (represented by TSB) and distribution (represented by UB ) of the accumulated bilirubin load, has been proved to correlate better with automated auditory brain stem response than either UB or TSB alone and is suggested to be the best bilirubin-induced neurotoxicity disease (BIND) predictor.(1).In recent decades, noninvasive bilirubin measurements have been presented for reducing patients’ stress, laboratory expenses, and the need for blood sampling. One of these noninvasive methods is TCB. In TCB, the bilirubinometer is pressed against the skin causing pallor, and bilirubin levels are measured in different ways using light waves (22) The aim of this work to describe the relationship between UB and TcB in late preterm jaundiced neonates. Analyze the relation between UB and the UB/TSB ratio with GA (gestational age), BW (birth weight) and gender.Subjects and MethodsThis prospective case controlled study was conducted on patients attending Neonatal Intensive Care Units (NICUs) of the Pediatric Department, Benha University Hospital and Benha children hospital. All laboratory works were done in Clinical Pathology Department, Benha University Hospital.2.1Subjects: This study was conducted on 100 patients.Group (I) : Included 50 neonates with unconjugated hyperbilirubinemia, Patients aged from 1 day to 1 month with Gestational age <37 weeks, treated in the neonatal intensive care unit.Group (II) :Included 50 healthy pre term neonates as control group. 2.2Exclusion criteria: Age more than 1 month, Gestational age>37 weeks or Major congenital malformations, clinical syndromes, or chromosomal abnormalities.2.3Ethical considerations: Informed consents was obtained from all cases and control's parents. This study was approved by the local ethical committee of Benha University.2.4Methods: All neonates incorporated in this study were subjected to the following:Complete history taking and clinical examination. The following laboratory investigations were done:UBUB/TSB ratio.Albumin.TSB/albumin (B/A ratio) . TcB by transcutanous bilirubinometer using Jaundice Meter JM-103 device (manufactured by Draeger Medical Systems, Inc., Lubeck, Germany). TcB were checked within the first 6 hours of life and then every 24 hour until discharge.All the measurements were performed with a single Jaundice Meter JM-103 device in accordance with the manufactures' recommendations. The device is housed in the form of a handheld assembly which has a fiber-optic probe that is placed strategically which allows for a convenient application to the forehead or sternum of the infant. Once the appropriate skin application is established, the light source is triggered and the measured values appear on display. TSB measurement was ordered when TcB crosses the 75th percentile of transcutaneous bilirubin normogram (20). TcB measurement and blood sampling were performed within 1 hour from each other.Sampling: One ml of venous blood was collected on glass plain tube. Sample was centrifuged to separate serum immediately, during sample taking; the blood was allowed to be dropped slowly on the wall of the tube (to avoid hemolysis). Assessment of levels of albumin, TSB,UB are competed automatically using biosystem A-15 (Spain).by enzyme linked immuno sorbent assay(ELISA) by kits purchased by sun red(china)with catalogue number 201-12-6286 2.5 Statistical analysis The collected data was revised, coded, tabulated and introduced to a PC using Statistical package for Social Science (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Data were presented and suitable analysis was done according to the type of data obtained for each parameter. Mean, Standard deviation (± SD) for parametric numerical data, while Median and range for non-parametric numerical data. Shapiro test was done to test the normality of data distribution. Significant data was considered to be nonparametric. Student T Test was used to assess the statistical significance of the difference between two study group means. For the comparison of the three groups’ means, one way analysis of variance (ANOVA) was used. Chi-Square test was used to examine the relationship between two qualitative variables. Fisher’s exact test: was used to examine the relationship between two qualitative variables when the expected count is less than 5 in more than 20% of cells. Correlation analysis: To assess the strength of association between two quantitative variables. The ROC Curve provides a useful way to evaluate the optimum cut off point which maximized the AUC value.The area under the ROC curve (AUC) results were considered excellent for AUC values between 0.9-1, good for AUC values between 0.8-0.9, fair for AUC values between 0.7-0.8, poor for AUC values between 0.6-0.7 and failed for AUC values between 0.5-0.6. Logistic regression analysis was used for prediction of risk factors, P<0.05 is significant (S). (18).Results: Table (1) Comparison of age and gender between studied groups.Healthy pretermN=50Jaundiced preterm N=50pAge (hours)mean±SD35.8±11.232.9±10.80.431?Birth weight (kg)mean±SD2.6±0.62.5±0.60.318?Gestational age (week)mean±SD36.3±1.635.3±1.10.001?MalesN, %336629580.410?FemalesN, %17342142SD, standard deviation; ?, t student test; ?, chi square.This table shows that, there is no significant differences were found in age, gender and birth weight between both groups. Jaundiced preterm neonates were significantly associated with younger GA. Table (1)Table(2) Comparison of baseline laboratory findings and bilirubin measures among studied groups.Healthy pretermN=50Jaundiced pretermN=50pMean±SDMean±SDHemoglobin (g/dL)14.11.715.12.30.116Hematocrit (%)43.15.445.57.50.070Platelet (X109/L)221.764.8226.965.40.737TLC (X109L)9.53.111.53.20.032Urea (mg/dL)22.56.731.810.1<0.001Creatinine (mg/dL)0.50.10.50.10.219AST (U/L)24.3832.29.8<0.001ALT (U/L)18.25.223.97.1<0.001Albumin (g/dL)3.50.23.30.40.109Ca (mg/dL)9.40.59.40.60.629Na141.66.1140.65.40.399K4.40.54.50.40.221TSB (mg/dL)1.70.36.42.1<0.001tTSB/Albumin0.480.081.90.03<0.001t ?, t student testJaundiced preterm neonates were significantly associated with higher TLC, urea, AST and ALT when compared to healthy preterm neonates. Jaundiced preterm neonates were significantly associated with higher TSB, TSB/albumin when compared to healthy preterm neonates. Table (2)Figure (1) TCB at 6 and 24 hours peak among studied jaundiced preterm cases.Table (3) Comparison of UB, UB/TSB between studied groups. Healthy pretermN=50Jaundiced pretermN=50pMean±SDMean±SDUB (ug/dL)0.220.060.410.560.022tUB/TSB0.10.030.050.01<0.001t?, t student testMean TCB at 6 hours was 2.4± 0.7 mg/dl, at 24 hours was 5.1± 1.1mg/dL. Mean age at TCB peak was 32± 10.2hours. Figure (1). Jaundiced preterm neonates showed significantly higher unbound bilirubin (mean =0.41 ±0.56 ug/dL) when compared to healthy preterm neonates (mean =0.22 ±0.06 ug/dL), (p=0.022). Jaundiced preterm neonates showed significantly higher UB/TSB when compared to healthy preterm neonates Table (3)Figure(2) Correlation unbound bilirubin with TSB in jaundiced preterm group.UB showed significant positive correlation with TSB (r=0.864, p<0.001). (fig: 2)Table(4)AUC and performance characteristics of UB and TCB for discrimination between jaundiced and healthy preterm neonates.UBTCBAUC0.8320.79395% CI0.749-0.9150.701-0.885P<0.001<0.001Cut off value (?g/dL)0.242.5Sensitivity (%)9466Specificity (%)6898PPV (%)74.697.1NPV (%)91.974.2p0.538ROC, receiver operating curve; AUC, area under ROC curve; PPV, positive predictive value; NPV, negative predictive value. Figure (3) ROC curve of UB and TCB for discrimination between jaundiced and healthy preterm neonates.ROC curve of unbound bilirubin and TCB was conducted for discrimination between jaundiced and healthy preterm neonates. UB showed good AUC (AUC=0.832, p<0.001). Best cut off value of UB was 0.24 ug/dL, at which Sensitivity was 94%, specificity was 68%. TCB showed fair AUC (AUC=0.793, p<0.001). Best cut off value was 2.5 mg/dL, at which Sensitivity was 66%, specificity was 98%. No significant differences were found between AUCs of UB and TCB. Table (4) Fig. (3).Table (5) Regression analysis for prediction of hyperbilirubinemia within preterm neonates. age0.4270.9910.9691.013Sex0.4101.2380.7452.056Gestational age 0.0010.7400.6160.889RH incompatibility0.0213.7331.22511.376IDM0.1762.4140.6738.660TCB<0.0012.1331.09715.065UB0.0052.2541.89910.702OR, odds ratio; CI, confidence interval; logistic regression test was used.Regression analysis was conducted for prediction of hyperbilirubinemia within preterm neonates, using age, gender, GA, risk factors, TCB and UB as covariates. Younger GA, higher TCB, UB, presence of RH incompatibility were considered as predictors of hyperbilirubinemia within preterm neonates. Table (5)DiscussionThis study showed that, there were no statistically significant difference between cases with hyper bilirubinemia and without hyper bilirubinemia as regarding (sex, birth weight and age).This agreed with (9) who found that, There were no differences between both groups in age, birth weight and sex.This study showed that, Jaundiced preterm neonates was significantly associated with younger GA. Our result consist with (30) who concluded that the risk of hyperbilirubinemia significantly increases with decreasing gestational age in their study about preterm neonates.This disagrees with (3) who found that, there was no difference between non-jaundiced group and jaundiced newborns as regard to gestational age.This study showed that, Jaundiced preterm neonates were significantly associated with physiologic jaundice and RH incompatibility.This agrees with (8) who concluded that the main causes of Jaundice in newborns include incomplete follow-up in acrylic babies due to ABO incompatibility, physician insensitivity, lack of routine examination of neonatal babies born to mothers with type O (Rh+) and parental insensitivity Jaundiced preterm neonates were significantly associated with TLC, while jaundiced preterm neonates were not significantly associated with Hb, Hct, PLT.But, (22) reported that in their study, risk factors identified in different investigations for the development of jaundice in neonates among blood count variables, the mean of WBC, Hb, Hct and PLT and were found to be markedly associated with hyperbilirubinemia in their present study.This study showed that, TCB at 6 and 24 hours were 2.4 and 5.1 mg/dl respectively. There was increase in TCB from 6 to 24 hours.This agrees with (31) who found that, There was statistical significant increase in serum total bilirubin at the fifth day than the third day, there was statistical significant decrease in total serum bilirubin at the seventh day than the fifth day.ROC curve of unbound bilirubin and TCB was conducted for discrimination between jaundiced and healthy preterm neonates. UB showed good AUC (AUC=0.832, p<0.001). Best cut off value was 0.24 ug/dL, at which Sensitivity was 94%, specificity was 68%, PPV was 74.6%, NPV was 91.9%. TCB showed fair AUC (AUC=0.793, p<0.001). Best cut off value was 2.5 mg/dL, at which Sensitivity was 66%, specificity was 98%, PPV was 97.1%, NPV was 74.2%. This agree with (22) who conducted that the sensitivity and specificity of different TCB measurements. The sensitivity and specificity of TCB was 95.1% and 67.7%, respectively. The positive and negative predictive values of TCB were 93.9 and 69.2. This study showed that, significant positive correlation between TSB and TcB.This agree with (13) who concluded that, higher correlations between TSB and TCB measurements were observed for bilirubin levels lower than 14 mg/dl. The researchers concluded that for levels over 14 mg/dl, serum measurements should be done (. Our results are relatively comparable with another recent study in Italy that showed a significant increase in the specificity of bilicheck 61-96 hours after birth compared with 0-60 hours (P=0.074). However, the mentioned study did not assess the sensitivity of bilicheck as well as its specificity after 96 hours from birth (26).Some researcher do not recommend the bilirubinometer as a suitable screening tool (6(. This could be attributed to the method of patient selection and higher bilirubin levels in patients.With respect to the effect of gestational age on the correlation between TCB and TSB, (10) reported a correlation coefficient of 0.79 and confirmed a lower correlation coefficient in term neonates as compared with premature ones. This study showed that, significant positive correlation between TSB and TcB.and this agree with (22) who found the mean ± SD serum and cutaneous bilirubin levels were 18.75±5.38 and 17.85±4.46 mg/dl, respectively. A high correlation (0.89) was observed between TSB and TCB.Consistently, in another study on 490 neonates over 2.5 kg a high correlation (r=0.91) was observed between TCB and TSB (5 (. But (12) did not find a clear relationship between the results of the two measurements. Conclusion: ROC curve of unbound bilirubin and TCB was conducted for discrimination between jaundiced and healthy preterm neonates. UB showed good AUC. TCB showed fair AUC. 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