Journal of Clinical Neonatology

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 5  |  Issue : 3  |  Page : 162--167

Therapeutic difference in some treatment modalities of jaundice in Egyptian neonates


Mohamed Shawky El-Frargy1, Hamed M El-Sharkawy1, Gihan Fathy Attia2,  
1 Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Gharbia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Gharbia, Egypt

Correspondence Address:
Dr. Mohamed Shawky El-Frargy
Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Gharbia
Egypt

Abstract

Background: Jaundice is a significant problem in the early neonatal period due to excessive destruction of red blood cells or immature liver enzymes detoxifying bilirubin which may lead to neurotoxicity and brain damage in severe cases. Patients and Methods: A prospective clinical trial study was conducted on 120 neonates in neonatal Intensive Care Unit at Tanta University Hospital from May 2014 to August 2015. All of them suffering from neonatal jaundice. All of them received phototherapy, sixty of them (Group I) received phenobarbitone, and sixty of them (Group II) received fenofibrate. Results: There was no statistically significant difference between the two studied groups as regard total serum bilirubin (TSB) at time of admission (peak of TSB) P = 0.8, while there was a high statistical significant difference between both groups as regard TSB after 24 h P = 0.000, TSB after 48 h P = 0.000, and TSB at time of discharge (TSBD) P = 0.000, mean of TSB at time of admission is 17.9 ± 2.2 mg/dl in Group I and 18 ± 2.3 mg/dl in Group II, mean of TSB after 24 h is 16.3 ± 0.9 mg/dl in Group I and 11.5 ± 2.4 mg/dl in Group II, mean of TSB after 48 h is 12.8 ± 3 mg/dl in Group I and 6.7 ± 1.7 mg/dl in Group II, and finally mean of TSBD is 9.2 ± 0.6 mg/dl in Group I and 6.5 ± 1.4 md/dl in Group II. Conclusion: We concluded that oral fenofibrate in a dose of (10 mg/kg single dose) with phototherapy is more effective than oral phenobarbitone in a dose of (3 mg/kg/day for 3 days) with phototherapy in neonatal jaundice, so oral fenofibrate in this dose-treated neonatal jaundice more effective than oral phenobarbitone with avoidance of most of its side effects.



How to cite this article:
El-Frargy MS, El-Sharkawy HM, Attia GF. Therapeutic difference in some treatment modalities of jaundice in Egyptian neonates.J Clin Neonatol 2016;5:162-167


How to cite this URL:
El-Frargy MS, El-Sharkawy HM, Attia GF. Therapeutic difference in some treatment modalities of jaundice in Egyptian neonates. J Clin Neonatol [serial online] 2016 [cited 2022 Jul 2 ];5:162-167
Available from: https://www.jcnonweb.com/text.asp?2016/5/3/162/191248


Full Text

 INTRODUCTION



Neonatal jaundice is a yellowish discoloration of the skin, mucous membranes, and sclera caused by hyperbilirubinemia (increased level of bilirubin more than 85 ΅mol/l (5 mg/dL).[1]

Hyperbilirubinemia is a significant problem in the early neonatal period due to excessive destruction of red blood cells or immature liver enzymes detoxifying bilirubin which may lead to neurotoxicity.[1],[2]

Neonatal jaundice is a cause for anxiety in parents as well as physicians due to its complications and prolonged hospital stay with increased cost. With early discharge practice, neonatal hyperbilirubinemia has become an important cause of readmission.[2]

However, if significant jaundice is untreated, very high levels of bilirubin can damage the brain. For babies who require treatment, the treatment is usually quite effective. Sometimes, special blue lights used on infants whose levels are very high. This is called phototherapy. In the most severe cases of jaundice, an exchange transfusion is required. Treating severely jaundiced babies with intravenous immunoglobulin may also be very effective at reducing bilirubin level.[3],[4],[5],[6],[7]

Phenobarbitone is a controversy drug; researches proved that it is effective in decreasing hyperbilirubinemia; others proved that it is not helpful in reducing hyperbilirubinemia.[8]

Fibrates have been used for several years as a hypolipidemic drug. Fibrates also increase bilirubin conjugation and excretion via induction of glucuronyl transferase activity. Its potency to induce bilirubin conjugation is many times more phenobarbitone. The effect of clofibrate on uncomplicated hyperbilirubinemia was proposed in some studies. Clofibrate effect on reducing serum bilirubin level of neonates beyond the 1st week of life. Clofibrate, however, is no longer routinely used for hyperlipidemia in adults due to its adverse effects. Fenofibrate is now the most widely used fibrate in treating hyperlipidemia and has a comparatively much better safety profile than clofibrate.[9],[10],[11],[12]

 Patients and Methods



A prospective clinical trial study was conducted on 120 neonates. They admitted in Neonatal Intensive Care Unit (NICU) at Tanta University Hospital from May 2014 to August 2015. This study was approved by the Ethics Committee of Faculty of Medicine, Tanta University. Written informed consents were obtained from the parents of all subjects of the study.

All of them suffering from neonatal indirect hyperbilirubinemia (neonatal jaundice). All of them received phototherapy according to the American Academy of Pediatrics guidelines for management of hyperbilirubinemia in term newborn,[13] sixty of them (Group I) received phenobarbitone and sixty of them (Group II) received fenofibrate.

The studied neonates divided into two groups:

Group I

This group included sixty of full-term neonates with neonatal indirect hyperbilirubinemia. All of neonates in this group received phenobarbitone with phototherapy. Phenobarbitone was administered orally (3 mg/kg/day) divided into two doses every 12 h for 3 days.[14]

Group II

This group included sixty of full-term neonates with neonatal indirect hyperbilirubinemia. All of neonates in this group received fenofibrate with phototherapy. Fenofibrate suspension was administered orally (10 mg/kg) single dose.[15]

Inclusion criteria

Full-term neonates (with gestational age of 37-41 weeks)Total serum bilirubin (TSB) between 15 and 20 mg/dlWeight between 2500 and 3500 g.

Exclusion criteria

Preterm <37 weeksNeonate with conjugated bilirubin >2 mg/dlNeonates with congenital anomaliesNeonates with sepsis or exchange transfusionNeonates with respiratory distressNeonates with cephalhematoma or subgaleal bleeding.

All newborns included in the study were subjected to:

Onset and duration of neonatal jaundiceHistory taking: This includes: Family history of jaundice and anemiaClinical examinationGestational age according to expanded new Ballard score[16]Measurement of weight, length, and head circumferenceSkin as regards: Jaundice and pallorLaboratory investigations.

On admission of cases, 5 ml of venous blood collected on two tubes. The first one contained ethylenediaminetetraacetic acid (EDTA) as an anticoagulant in which 2 ml were collected 1 ml for complete hemogram, and the remaining 1 ml for blood group, Rh factor typing, and Coombs' test. The second tube was a plain tube, in which 3 ml were added and allowed for complete clotting in a water bath at 37°C, after clotting, centrifugation at ×1500 for 10 min was performed. Serum separated was collected for TSB and C-reactive protein (CRP) then 0.5 ml of blood collected for TSB every 24 h. One milliliter of maternal venous blood was collected on a tube contained EDTA as anticoagulant for blood group and Rh factor typing to be compared with neonatal blood type.

Complete blood count

Two milliliters of venous blood were taken from each neonate on 20-µL EDTA solution, and the differential count was done on Leishman stained peripheral blood smear. The evaluation was done using Coulter T660.[17] The obtained parameters were: Hemoglobin concentration, hematocrit, red blood cells count, platelets count, leukocytic count, and reticulocytes count.

Blood type and Rh factor for both mother and the newborn

Also detected by agglutination test:[3]

Direct antiglobulin (Coombs') test

It is antiglobulin agglutination test by using polyclonal antihuman immunoglobulin. It indicates the presence of antibodies around fetal red blood cells. It is diagnostic for ABO and/or Rh incompatibility with the presence of high reticulocytes count.[18]

Bilirubin (total and direct)

The total bilirubin concentration is determined in the presence of caffeine by the reaction with diazotized sulfanilic acid to produce an intensely colored diazo dye (560-600 nm). The intensity of the color of this dye formed is proportional to the concentration of total bilirubin. Direct bilirubin is determined in the absence of caffeine by the direct reaction with diazotized sulfanilic acid to form red colored azobilirubin, the color intensity of which measured at 546 nm is proportional to the concentration of direct bilirubin in the sample.[18] Bilirubin (total and direct) values were determined on admission and every 24 h.

C-reactive protein

CRP value was determined on admission and every 48 h.

Before discharge

Three milliliters of venous blood collected on a plain tube, allowed for complete clotting in a water bath at 37°C, after clotting, centrifugation at ×1500 for 10 min was performed. Serum separated was collected for alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine.

Treatment

Phototherapy

All enrolled neonates received double phototherapy, a blue light lamp with a wavelength 425-475 nm was used, neonates were incubated naked (except for eyes and genitalia), the distance between the infant's skin and the light source, not more than 50 cm.

Phenobarbitone

Neonates of Group I received oral phenobarbitone with phototherapy. Phenobarbitone administered orally (3 mg/kg/day) divided into two doses every 12 h for 3 days. Cases also monitored for side effects of oral phenobarbitone such as excessive sleepiness, dehydration, or neurological dysfunction.[14]

Fenofibrate

Neonates of Group II received oral fenofibrate with phototherapy. Fenofibrate suspension administered orally single dose (10 mg/kg).[15] Because of fenofibrate present in tablet and capsule forms, we dissolved the content of the capsule in water to get fenofibrate suspension (e.g., 300 mg tablet dissolved in 10 ml distilled water to get concentrated 30 mg of fenofibrate in 1 ml).

Follow-up

Following up bilirubin measurement within a week after discharge was done, and two cases of Group I (receiving phenobarbitone with phototherapy) reentered our NICU after discharge by 5 and 7 days by neonatal jaundice, the cause of the neonatal jaundice in both cases was neonatal septicemia, both cases reentered our NICU and investigations of neonatal septicemia were done, both cases received antibiotics according to the culture and phototherapy.

The aim of this work is to compare between the efficacy of oral phenobarbitone and oral fenofibrate in the treatment of indirect neonatal hyperbilirubinemia.

Statistical analysis was performed by using SPSS for Windows, version 20. Data were expressed as a range and mean ± standard deviation. Differences between groups in continuous variables were tested for significance with independent t-test while Chi-square test used to compare categorical variables. For all statistical tests done, P < 0.05 was considered significant.

 RESULTS



The studied neonates divided into two groups:

Group I

This group included sixty of full-term neonates with neonatal indirect hyperbilirubinemia. All of the neonates in this group received phenobarbitone with phototherapy. Phenobarbitone was administered orally (3 mg/kg/day) divided into two doses every 12 h for 3 days.[14]

Group II

This group included sixty of full-term neonates with neonatal indirect hyperbilirubinemia. All of the neonates in this group received fenofibrate with phototherapy. Fenofibrate suspension was administered orally (10 mg/kg) single dose.[15]

[Table 1] shows that there was no statistically significant difference between Group I and Group II as regards age and sex because P > 0.05, P = 0.8 in sex, and P = 0.9 in age; also it shows that Group I included sixty full-term neonates with indirect neonatal hyperbilirubinemia 34 males about 56.7% and 26 females about 43.3%, Group II included sixty full term neonates with indirect neonatal hyperbilirubinemia 32 males about 53.3% and 28 females about 46.7%.{Table 1}

[Table 2] shows the mode of delivery of the studied neonates in which neonates delivered by normal vaginal delivery were 18 neonates in Group I (30%) and 28 neonates in Group II (46.7%). Moreover, neonates delivered by caesarean section in Group I were 42 neonates (70%) and in Group II were 32 neonates (53.3%).{Table 2}

[Table 3] shows that there was no statistically significant difference between both groups as regard diagnosis, P = 1. Cases of neonatal jaundice due to exaggerated physiological jaundice were 24 neonates about 40% in Group I and 24 neonates about 40% in Group II, Cases of jaundice due to ABO incompatibility were 24 neonates about 40% in Group I and 24 neonates about 40% in Group II, finally cases of jaundice due to RH incompatibility were 12 neonates about 20% in Group I and 12 neonates about 20%in Group II.{Table 3}

[Table 4] shows that there was no statistically significant difference between the two studied groups as regard TSB at time of admission (TSB1) P = 0.8 while there was a high statistical significant difference between both groups as regard TSB after 24 h (TSB2) where P = 0.000, TSB after 48 h (TSB3) where P = 0.000, and TSB at time of discharge (TSBD) where P = 0.000, mean of TSB at time of admission is 17.9 ± 2.2 mg/dl in Group I and 18 ± 2.3 mg/dl in Group II, mean of TSB after 24 h is 16.3 ± 0.9 mg/dl in Group I and 11.5 ± 2.4 mg/dl in Group II, mean of TSB after 48 h is 12.8 ± 3 mg/dl in Group I and 6.7 ± 1.7 mg/dl in Group II, finally mean of TSBD is 9.2 ± 0.6 mg/dl in Group I and 6.5 ± 1.4 md/dl in Group II.{Table 4}

[Table 5] shows that there was no statistical significant difference between both groups as regard ALT and AST P = 0.8 and 0.5, respectively, while there was a statistical significant difference between both groups as regard the level of serum urea and creatinine P = 0.01 and 0.005, respectively.{Table 5}

[Table 6] shows that there was a statistical significant difference between both studied groups as regard duration of stay at the hospital (duration of exposure to phototherapy) P = 0.03. Mean of duration of stay at the hospital is 5 ± 1.8 days in Group I and 4 ± 1.8 days in Group II.{Table 6}

 DISCUSSION



Hyperbilirubinemia is a significant problem in neonate due to excessive destruction of red blood cells or immature liver enzymes detoxifying bilirubin.[19]

In the current study, phenobarbitone was given with a dose of 3 mg/kg/day divided every 12 h in agreement with some studies.[20] We used phenobarbitone in oral route to avoid the side effects of the parental route as: Too rapid administration may cause severe respiratory depression, apnea, laryngospasm, hypertension, or vasodilation with fall of blood pressure. Moreover, parental solution of barbiturate is highly alkaline. Therefore, extreme care should be taken to avoid perivascular or extravasation or intra-arterial injection. Extravascular injection may cause local tissue damage with subsequent necrosis.[21]

Kumar et al.[22] used 10 mg/kg loading dose of phenobarbitone on day 1 followed by maintenance 5 mg/kg/day from day 2 to day 5, while Arya et al.[23] used phenobarbitone by a low dose (5 mg/kg) without loading dose as the present study.

Phenobarbitone was given orally in the current study. This was in agreement with Arya et al. study, and disagreement with other studies as Kumar et al. phenobarbitone was given intravenously.

The duration of phenobarbitone therapy in the present study was similar to Arya et al. study 3 days only, but in Kumar et al. study phenobarbitone was given for 5 days.

In contrary to Arya et al. 2004 study using phenobarbitone in dose 5 mg/kg orally only 5.4% of phenobarbitone group required phototherapy. In Kumar et al. study using 5 mg/kg only 64% required phototherapy, but all cases of Group I in the current study received phototherapy. Hence, by using phenobarbitone in dose 3 mg/kg orally, 100% of cases required phototherapy (phenobarbitone group). None of the cases that received phenobarbitone and phototherapy (Group I) required an exchange. In contrary exchange, transfusion was required in 14% of cases that received phenobarbitone in Kumar et al. study.

Deep sleepiness is a side effect of phenobarbitone that appears in the present study. About 12% of cases that received phenobarbitone were suffering from excessive sleepiness, this was in agreement with Arya et al. 2004 study about 13.5% of cases that received phenobarbitone was suffering from deep sleepiness, the sedative effect of phenobarbitone, apnea, and cyanotic spells have also been reported and was more commonly seen in low birth weight infants, but these side effects were not observed in the present study.[24]

Fibrates also increase bilirubin conjugation and excretion via induction of glucuronyl transferase activity. Its potency to induce bilirubin conjugation is many times more than phenobarbitone. The effect of clofibrate on uncomplicated hyperbilirubinemia was proposed in some studies.[11],[25]

Clofibrate, however, is no longer routinely used for hyperlipidemia in adult due to its adverse effects. Fenofibrate is now the most widely fibrate in treating hyperlipidemia and has a comparatively mush better safety profile than clofibrate.[10],[12]

In this study, Group II received phototherapy plus a single oral dose of fenofibrate in a dose of 10 mg/kg in agreement with some studies.[15] Both groups received phototherapy under standard conditions with four special blue 420-480 nm lamp, adjusted to about 50 cm above the neonate, we found that babies in fenofibrate group showed lower values in successive TSB levels and lower duration of stay in comparison to phenobarbitone group.

Fenofibrate decreases the time needed for phototherapy and lessens the duration of hospital stay. Thus, fenofibrate appears to be an effective and probably safe drug for uncomplicated neonatal hyperbilirubinemia with no side effect.[26]

 CONCLUSION



We concluded that oral fenofibrate in a dose of (10 mg/kg single dose) with phototherapy is more effective than oral phenobarbitone in a dose of (3 mg/kg/day for 3 days) with phototherapy in full term at risk (exaggerated physiological, ABO or RH incompatibility) neonates decrease the peak of TSB and duration of stay at hospital. Hence, oral fenofibrate in this dose treated neonatal indirect hyperbilirubinemia more effective than oral phenobarbitone with avoidance of most of its side effects.

Recommendation

Early and proper management of neonatal indirect hyperbilirubinemia can minimize its complication, especially neurotoxic complication. Using oral fenofibrate in a dose of (10 mg/kg single dose) with phototherapy in full term at risk (exaggerated physiological, ABO, or RH incompatibility) neonates decrease the peak of TSB, duration of exposure to phototherapy and duration of stay in the hospital.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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