Efficacy of Prophylactic Phototherapy for Prevention of Hyperbilirubinemia in Very Low Birth Weight Newborns

: Background: Jaundice is a common clinical condition in newbom occurring in approximately 60% of term and 80% of preterm infants. Unconjugated hyperbilirubinemia is universally coflrmon in all preterm infants especially in newboms with very low bir*r weight. Low birth weight and premature infants are at major risk for exaggerated hyperbilirubinemia that can lead to bilirubin encephalopathy. Significant heterogeneity in the approach to the treatment ofjaundiced neonates exists throughout the world. Phototherapy is the most common treatrnent for neonatal hyperbilirubinemia and could be most effective in preventing the sequelae of hyperbilirubinemia if initiated prophylactically. This randomized clinical trial has been proposed with the objective ofassessing the efficacy ofprophylactic phototherapy in preventing significant rise of unconjugated hyperbilirubinemia in premature neonates weighing less than 1500 gram and therefore to decrease the need for exchange transfusion and finally to reduce hospital stay due to hyperbilirubinemia. Methods: This randomized contolled clinical trial enrolled sixty newborns with birth weight less than 1500 gram. They were divided into two groups: 1) Prophylactic group, in whom phototherapy was started within 24 hours of birth and continued for 7 days and 2) Control group in whom therapeutic phototherapy was started considering serum bilirubin level and other clinical conditions as per institutional guidelines. Mean value of total serum bilirubin (TSB), duration of phototherapy, the need for exchange transfusion and duration of hospital stay in both groups were analyzed. Results: The maximum mean TSB level in prophylactic gtoup was observed on 7th day and in control group it was observed on 3rd day of life. The total serum bilirubin levels were significantly lower in the 3rd and 5th days of life in the prophylactic group in comparison to contol group (P value 0.001). Total serum bilirubin level exceeded therapeutic range in 6 (21%) and 14 (50 %) newborns of the prophylactic group and control groups respectively (P value 0.026).No documented side effects of prophylactic phototherapy was observed. Conclusion: The use of prophylactic phototherapy for infants weighing less than 1500 gm is effective and safe when compared to ttre control group, considering satisfactory maintenance of low total serum bilirubin levels during first 7 days of life.


Introduction:
Jaundice is a common clinical condition in newborn occurring in approximately 60% of term infants and S0% of pretern infants.Unconjugated hyperbilirubinemia is universally common in all preterm infants especially in newborns with very low birth weight.Studies showed that the large amount of short-lived red blood cells and the increase in enterohepatic circulation of bilirubin and the deficient hepatic conjugation'of bilirubin are the most Address for Correspondence: M A Mannan Professor, Department of Neonatology Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka.
to the treatment ofjaundiced neonate was documented in an international survey conducted by Hensen3.Until 20024, the American Academy of Pediatrics considered that there was a paucity of properly designed studies and observational data on low birth weight newborns without hemolytic disease, which hinders the development of a specific treatment routine.But in relation to unconjugated hyperbilirubinemia in preterm newborns, in several studies published in the 1990ss'6 , causal relationship between Hyperbilirubinemia (total serum billirubin <15 mg/dl) and neurological, hearing, visual, speech and developmental disorders is not evident.
Nevertheless, in 2001, Sugam a et al.7 questioned the rare occuffences of bilirubin encephalopathy in preterm newborns after they detected kernicterus in two patients at 3l and 34 weeks of gestational age respectively, with bilirubin levels between 13.1 and 14.1 mgldl; none of the patients had symptoms that could suggest the disease in the neonatal period.with this background, because of the high frequency, serious sequelae, and hazardous as well as risky and costly management especially where exchange transfusion is indic ated, neonatal jaundice is a good candi- date for preventive treatment.Phototherapy as well as phenobarbitone has been evaluated as prophylactic agents for neonataljaundice.Both the modalities are effective in decreasing the peak TSB 8'e.Several clinical trials have been done worldwide using phenobarbitone to newborns as prophylaxis of non-hemolytic hyperbilirubin.*iu10-13.
But requirement of high prophylactic dose (10-I2mglkg) and its side effect recornmends further research on this regard.
Neonatal phototherqy, a noninvasive, safe and easily available therapy, has been exclusively used for the treatment of neonatal jaundice worldwide for more than half a century'+" Its effic acy in decreasing plasma bilirubin concentration is well documented, and phototh erapy leads to greatly reduced exchange transfusion rates for neonates with hyperbilirubinemia.
Prophylactic phototherapy signifies initiation of photo- therapy between 1 2 and 24 hours of life, regardless of the bilirubin level.Few trials on prophylactic phototherapy have been conducted worldwide.Hansen, in 19963, ts2 attempted to compare the several types of treatment for neonatal jaundice in several countries.Of 218 question- naires, 108 were filled out and refurned, of which 53(49%) showed the use of prophylactic phototherapy.Leite & Facchinils inBrazil assessed early and late initia- tion of phototherapy.The authors concluded that early treatment is safer that late treatment.
Therefore prevention of kernicterus in preteffin infants is still afi unsolved problem.There is no level, there probably never was a level, nor there will be a level of bilirubin to exclude the disease'6, so this field constitutes an important field for preventive care.So far we know, no trial has been reported on prophylactic phototherapy anywhere in our country.With this background this study has been designed in a tertiary care hospital to assess the efficacy of prophylactic phototherapy in preventing significant rise of unconjugated bilirubinemia in prema- ture neonate weighing less than 1500 grams and therefore to decrease the need for exchange transfusion and finally to reduce hospital stay due to hyperbilirubinemia.

Methods:
It was a prospective randomrzed controlled trral conducted during a period of six months from July 2012 to Decemb er 2012 in the Neonatal Intensive Care Unit (NICll) of Bangabandhu Sheik Mujib Medical University (BSMMU).The study population were premature newborn infants weighing < 1500 gram .The objective of the study was to assess the efficacy of prophylactic phototherapy in preventing significant rise of unconjugated hyperbilirubinemia in premature neonates weighing less than 1500 grams and therefore to decrease the need for therapeutic phototherapy as well as exchange transfusion and finally to reduce hospital stay due to hyperbilirubine- mia.Inc1usioncriteriawerepretermnewborninfants< 1500 gram who were admitted within24 hours of birth in NICU during the study period.Exclusion criteria were neonates with severe RDS, perinatal asphyxia, severe sepsis, hemolytic disease of newborn, infants with major congenital abnormalities and babies born to mother receiving phenobarbitone in the antenatal period.The study was approved by the Institutional review board.
Informed written consents were obtained from the EfficacY of ProphYlactic Phototherapv for Prevention of Hvpeibilirubinemia iil Verv Low Birth Weiqht Newboms MAMM et al parents Enrolled infants were randomly assigned into prophylactic and control group.Phototherapy was started within 24 hours of birth in the prophylactic group and continued up to 7 days.Therapeutic phototherapy was started in control group considering serum bilirubin level and other clinical conditions as per existing institutional guidelines.Photo- therapy was administered continuously by standard phototherapy units (ARDO,Amelux) using standard procedures in both the groups.A11 phototherapy units contained four special blue lamps (Philips, maximum power 36 watt) and were adjusted to be 20cm above the infants.Lamps were changed regularly after 1000 hours of utilization.Serum bilirubin was measured at the start of phototherapy and then every aLternate day for 7 days.First sample was taken to measure baseline serum bilirubin along with sample for blood group and complete blood count on day 1.Second sample was taken with routine biochemical tests on day 3.Other tests were done when clinically indicated.Serum bilirubin level (total and direct) was measured by Bilirubinometer and determina- tion of direct bilirubin was made by the colorimetric method of Lathe and Ruthven.The criteria to omit phototherapy and to initiate exchange transfusion were same for both the groups.A11 other therapeutic interventions were unintemrpted.Primary outcome variables were maximum bilirubin level and days required for serum bilirubin to come down to a safe level (2 mg/dl below the photo- therapy range) in both groups.Secondary outcome variables were duration of hospital stay and need for exchange transfusion in both the groups.
Data were collected by standard questionnaire and check list.The obtaine d datawere transferred to coding sheets in a computer database.A11 analyses were performed using SPSS software 19 version for windows.Descriptive statis- tics was presented as proportions for categorical variables and mean * SD for continuous variables.Numeric variables were comp ared between the two groups using the independent Student's t test.The Chi-square test was used to compare categorical "variables between the two groups.A P-value of less than 0.05 was considered statis- tically signific ant.

Results:
A total of 60 very low birth weight (vLBw) newborn infants of < 1500 gtam were included and randomly assigned to prophylactic or control group.TWo babies from each group died due to severe RDS and sepsis.Data were analyzed for 28 babies from prophylactic group and 28 babies from control group.
There were no significant differences between both the groups regarding the mean gestational d}a, birth weight, occipitofrontal circumference(OFC), length, gender distribution, and mode of delivery (  Discussions: In this study, the mean serum bilirubin was significantly lower in prophylactic group compared with that in control group on 3'd and 5th day of life.Total serum bilirubin level exceeded therapeutic range in 6 (21 %) and 14 (50 %) Table-I).Mean serum bilirubin level was significantly lower in the prophylactic group on 3rd and 5th days of life in comp ari- son to control group (P value 0.001).Also maximum mean total serum bilirubin was low(5.25 *1.27)in prophylactic group and it reached at day 7 while it was (8.7 * 3.9) in control group which was observed earlier on day 3 (Table-II).serumbilirubin of prophylactic and control groups newborns of the prophylactic group and control group respectively (P value 0.026).Another controlled randomrzed clinical trial by Leite &Facchinils assessed early and late initiation of photo- therapy in newborns weighing less than 2000 gram without hemolytic disease.The authors measured the concentration of transcutaneous bilirubin on a datly basis and concluded that early treatment, implemented at 12 hours of life, is safer that late treatment because it main- Totalthe findings of the study done by Tripathi et al.
18min et a1.18conducted a similar type of study in Iran with the aim to compare two phototherapy methods (prophylactic vs therapeutic) for the management of III showing total serum bilirubin level exceeded therapeutic range in 6 (2I %) and 14 (50 %) newborns of the prophylactic group and control groups respectively (P value 0.026).No difference was found in respect to duration of hospital stay in both the groups.rsB exceeded therap::,?:;#r,and hospitat stay in Prophylactic phototherapy was started earlier and was continuing for longer duration in prophylactic group in comparison to control group (P value 0.001).One neonate in the control group required exchange transfusion due to sepsis.There was no major side effects of phototherapy was observed and all were discharged in good health.
mean TCB was 7 .7I*1.84mgld| which happened on the third day.In the treatment group, it was 8.74*1.12mg/dl on the fourth duy of life.The TCB values in prophylactic Table