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ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 2  |  Page : 734-739

Role of vitamin E supplementation in neonates with hyperbiirubinemia


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pediatrics, Benha Teaching Hospital, Benha, Egypt

Date of Submission17-Jan-2019
Date of Acceptance05-Mar-2019
Date of Web Publication25-Jun-2019

Correspondence Address:
Nashwa A Abd El Samie El Refaey
Zefita - Gharpyia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_27_19

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  Abstract 

Objective
The objective of this study was to evaluate the effect of vitamin E supplementation in the treatment of indirect hyperbilirubinemia in neonates receiving phototherapy.
Background
Hyperbilirubinemia is a common neonatal problem. Phototherapy is the primary treatment in neonates with indirect hyperbilirubinemia.
Patients and methods
This randomized controlled clinical trial was conducted on 150 full-term neonates with indirect hyperbilirubinemia, received phototherapy in the neonatal ICU of Menoufia University Hospital. They were randomly divided into three groups: (a) case group (n = 50) who received 25 mg/kg/day oral vitamin E with phototherapy, (b) case group (n = 50) who received 50 mg/kg/day oral vitamin E with phototherapy, and (c) control group (n = 50) who received only phototherapy. Total serum bilirubin (TSB) levels were measured every day until cessation of phototherapy.
Results
There was a highly significant difference in the duration of hospital stay of the studied groups. There was no significant difference in TSB on admission, but there was a highly significant difference in TSB at discharge of the studied groups. There was a highly significant difference in bilirubin decline of the studied groups, groups II and I and groups I and III, but no significant difference between groups II and III. There was no correlation between age and body weight in bilirubin decline in all groups. There was no significant difference in bilirubin decline with regard to sex in all groups.
Conclusion
The addition of oral vitamin E 25 mg/kg/day to phototherapy in the treatment of indirect hyperbilirubinemia is better than oral vitamin E 50 mg/kg/day or phototherapy alone.

Keywords: bilirubin, hyperbilirubinemia, neonate, phototherapy, vitamin E


How to cite this article:
El Mashad GM, El Sayed HM, Abd El Samie El Refaey NA. Role of vitamin E supplementation in neonates with hyperbiirubinemia. Menoufia Med J 2019;32:734-9

How to cite this URL:
El Mashad GM, El Sayed HM, Abd El Samie El Refaey NA. Role of vitamin E supplementation in neonates with hyperbiirubinemia. Menoufia Med J [serial online] 2019 [cited 2019 Sep 20];32:734-9. Available from: http://www.mmj.eg.net/text.asp?2019/32/2/734/260890




  Introduction Top


Jaundice is the most common condition that requires medical attention and hospital admission in newborns. The yellow coloration of the skin and sclera in newborns with jaundice is the result of the accumulation of unconjugated bilirubin. In most infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. However, in some infants, serum bilirubin levels may rise excessively, which can be a cause for concern, because unconjugated bilirubin is neurotoxic and can cause death in newborns and lifelong neurologic sequelae in infants who survive (kernicterus). For these reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation[1]. Postnatal hyperbilirubinemia is universal and manifests as newborn jaundice in over 80% of all newborns. Usually, bilirubin levels increase soon after birth and generally follow their hour-specific percentile track, remain within their risk zones, and decline by the end of the first week. However, in some, the rate of rise for bilirubin levels either continues or accelerates. Thus, unmonitored and untreated severe hyperbilirubinemia may progress to excessive levels that are likely to be associated with evident bilirubin neurotoxicity[2]. The injury usually manifests as irreversible posticteric sequelae; the hallmark sign, usually at autopsy, is the icteric (yellow) staining of the basal ganglia, specifically the globus pallidus; ABE includes progressive changes in an infant's mental (behavioral) status, muscle tone, and cry with varying degrees of drowsiness, poor feeding, hypotonia, and alternating tone followed by increasing hypertonia, especially of the extensor muscles, retrocollis and opisthotonus, intermittent and then more severe and constant[3]. Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia and is used as a prophylactic in most infants of 35 weeks of gestation to prevent further elevation of total serum bilirubin (TSB). The most effective irradiance is delivered by a light source (such as special blue fluorescent lamps or LED systems) that will deliver irradiance predominately in the 430–490 nm band[4]. If, in spite of phototherapy, the TSB continues to rise, the irradiance can be increased either by bringing the phototherapy lamp closer to the baby or by increasing the body surface area of the infant exposed to phototherapy. Because there is significant variation in the irradiance measurements provided by commercial radiometers, it is difficult to recommend a specific irradiance level. Nevertheless, when possible, clinicians should use the radiometer recommended by the manufacturer of the phototherapy system and provide sufficient irradiance to prevent an increase in the TSB[5]. Medications are not usually administered in infants with physiologic neonatal jaundice. However, in certain instances, phenobarbital, an inducer of hepatic bilirubin metabolism, has been used to enhance bilirubin metabolism, as it reduces mean serum bilirubin values during the first week of life[6]. Vitamin E comprises a group of eight biologically active tocopherols, among which d-alpha-tocopherol has the highest antioxidant activity per mg of tocopherol (1.49 IU/mg). Vitamin E is one of several antioxidants that preterm infants can use as scavenger free radicals, thereby potentially limiting processes that can lead to chronic lung disease and retinopathy of prematurity[7]. The primary function of vitamin E is protective, nutritional antioxidant function, which is very important in our present-day society with widespread pollution, processed food diets, and chemical exposure. It is protective because it helps reduce oxidation of lipid membranes and unsaturated fatty acids, and it prevents the breakdown of other nutrients by oxygen[8]. Vitamin E protects polyunsaturated fatty acids in membranes and other cellular structures from attack by free radicals and protects red blood cells against hemolysis. Protection against oxygen radical damage seems to be important for the development and maintenance of nerve and muscle function[9]. Our study aimed to find out the effect of vitamin E supplementation in the treatment of indirect hyperbilirubinemia in neonates receiving phototherapy with the hope to reduce the duration of phototherapy and hospitalization. Because of the lack of similar studies in Egypt, we conducted this study in the NICU of Menoufia University.


  Patients and Methods Top


The present study was carried out on 150 children with the diagnosis of indirect hyperbilirubinemia. The patients were randomly selected from those attending the NICU of Menoufia University hospital in the period spanning from October 2017 to March 2018 after taking a written consent from their parents. The local ethics committee of the Menoufia University approved the study protocol.

Sample size calculation

Neonates included babies who were full-term and healthy at birth, aged 1–10 days, and with a gestational age of more than 37 weeks. Neonates of diabetic mothers, with pathological jaundice and sepsis, were excluded. The neonates included in the study were divided into three groups: group I comprising patients who were treated with phototherapy and oral vitamin E 25 mg/kg/day, group II comprising patients who were treated with phototherapy and oral vitamin E 50 mg/kg/day, and group III comprising patients who were treated with phototherapy only.

The randomization sequence was created using NCSS PASS 11 (11.0.8 portable) statistical software with a 1:1 allocation using random block sizes of 50 patients per block.

Randomization or random allocation process was carried out using block randomization method, in which 100 patients were randomized into two blocks.

Allocation concealment mechanism

The allocation sequence was concealed from the researcher enrolling and assessing participants in sequentially numbered, opaque, sealed, and stapled envelopes. Corresponding envelopes were opened only after the enrolled participants completed all baseline assessments and it was time to allocate the intervention.

All patients were subjected to the following protocol:

History: prenatal history, natal history, postnatal history, and family history.

Clinical examination: complete general and local examination.

Laboratory investigation: complete blood count (by kits from Prokan PE Company, Egypt, 11 Hussein Gad St, Heliopolis, Egypt, Cairo), serum total bilirubin, direct and indirect levels by spectrophotometry using blood samples (kits from Biomed Company, New Cairo, Cairo, Egypt), blood film and reticulocyte count, blood grouping and Rh for infant and mother, C-reactive protein and random blood sugar.

Follow-up: patients were followed-up by clinical examination and total bilirubin level measured every 24 h by blood sampling.

The three groups were compared with regard to total bilirubin levels at different time points, rate of bilirubin decline and the duration of hospital stay.

Statistical analysis

Data were collected, tabulated, and statistically analyzed using an IBM personal computer with statistical package for the social sciences, version 23 (IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.) where the following statistics were applied.

Descriptive statistics

Data presented using range, mean and standard deviation for quantitative variables and frequency and percentage for qualitative ones.

Decline of TSB was calculated as follows:



Comparison of qualitative variables was carried out through χ2 test, while comparison of quantitative variables was carried out through Mann–Whitney and Kruskal–Wallis tests (due to lack of normality).

Spearman's correlation coefficients were calculated to assess the association between different quantitative variables.

P value of less than 0.05 was considered statistically significant.


  Results Top


Considering the sex distributions in group I, there were 21 male babies and 29 female babies. In group II, there were 27 male babies and 23 female babies and, in group III, there were 23 male babies and 27 female babies, with no significant difference being found between the three groups.

The mean age of the studied neonates was 4.12 ± 0.98 (3–7 days) in group I, 3.86 ± 0.97 (3–6) in group II, and 3.84 ± 1.04 (2–6 days) in group III, and no significant difference was found between the three groups.

The mean body weight of the studied neonates was 3 ± 0.41 in group I, 2.99 ± 0.44 in group II, and 2.89 ± 0.49 in group III, and no significant difference was found between the two groups [Table 1].
Table 1: Comparison of the demographic data of the studied groups

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The mean of TSB at the time of admission, first, second, third days of therapy and at discharge were as follows: in group I, it was 15.84 ± 1.47, 13.06 ± 1.89, 10.96 ± 1.66, 8.91 ± 1.17, and 6.62 ± 0.6, respectively. In group II, it was 16.36 ± 1.47, 14.27 ± 1.5, 12.08 ± 1.57, 9.87 ± 1.41, and 6.41 ± 0.61, respectively. In group III, it was 16.07 ± 1.64, 14.08 ± 1.7, 12.08 ± 1.58, 10.04 ± 1.49, and 6.08 ± 0.71, respectively. These results show that there was a highly significant difference between the three groups. TSB was highly significantly decreased in patients receiving vitamin E 25 mg/kg compared with other groups [Table 2].
Table 2: Comparison of total serum bilirubin level of the studied groups

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The mean duration of hospital stay of the studied neonates was 4.76 ± 1 (3–6 days) in group I, 5.54 ± 0.79 (3–7 days) in group II, and 5.22 ± 0.82 (3–6 days) in group III. A highly significant difference was found between the three groups and a highly significant decrease in the duration of hospital stay in group I than in group II. However, no significant difference was found between groups I and III and groups II and III [Table 3].
Table 3: Comparison of duration of hospital stay and bilirubin decline percent of the studied groups

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The mean of bilirubin decline percent was 43.82 ± 4.82 in group I, 39.82 ± 5.22 in group II, and 37.61 ± 5.74 in group III. A highly significant difference was found between three groups and a highly significant increase in bilirubin decline percent in group I than in groups II and III [Table 3].

The mean of bilirubin decline percent with regard to sex was 43.35 ± 4.47 in male babies and 44.16 ± 5.11 in female babies in group I, 39.44 ± 4.32 in male babies and 40.27 ± 6.19 in female babies in group II, and 37.47 ± 5.36 in male babies and 37.73 ± 6.15 in female babies in group III. No significant difference was found between the three groups [Table 4].
Table 4: Comparison of bilirubin decline with regard to sex within each group separately

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Lastly, there was no correlation between age and sex according to bilirubin decline percent within each group [Table 5].
Table 5: Correlation of bilirubin decline with age and weight within each group separately

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  Discussion Top


Neonatal hyperbilirubinemia is a common problem and in most cases a benign problem in neonates. It is defined as a TSB above 5 mg/dl or a TSB more than 95th percentile. It affects half of the full-term and almost all of the preterm infants, according to the study carried out by Mitra and Rennie[1]. Although most jaundiced infants are otherwise perfectly healthy, they make us anxious because bilirubin is potentially toxic to the central nervous system Maisels et al.[2].

Typically, phototherapy is used for reducing bilirubin in neonates; however, it has disadvantages, such as being expensive and preventing the relationship between the mother and the baby because of the need for an incubator and closure of the infant's eyes Therefore, using adjuvant therapies, which reduce the duration of phototherapy and hyperbilirubinemia, can be highly effective Morris et al.[5]. In contrast, very few studies with regard to the role of vitamin E in neonatal jaundice exist, and the results are unclear. Hence, through this work, we aimed to find out the effect of vitamin E supplementation in the treatment of indirect hyperbilirubinemia in neonates receiving phototherapy with the hope to reduce the duration of phototherapy and hospitalization. Because of the lack of similar studies in Egypt, we conducted this study in the NICU of Menoufia University.

Statistical analysis of the results showed that both groups that received vitamin E supplementation and the control group were age, sex, and body weight matched, with no significant differences between them. This implies good selection of the cases. The results of this study showed also that there was a highly significant difference according to the duration of hospital stay of the studied groups. There was a highly significant shorter duration of hospital stay in group I than in group II. However, there was no significant difference in the duration of hospital stay between groups I and III and between groups II and III. The results of this study showed also that there was no significant difference in TSB on admission in the studied groups. This implies good selection of cases. However, there was a highly significant difference in TSB at discharge of the studied groups. There was highly significant higher TSB at discharge in group I than in group III, but there was no significant difference between groups II and I and between groups II and III. There was a highly significant difference in bilirubin decline percent of the studied groups. There was a highly significant higher bilirubin decline percent in group I than in groups II and III, but there was no significant difference between groups II and III. In addition, our results showed that there was no significant difference in bilirubin decline percent with regard to sex in all groups. In addition, there was no correlation between age and body weight, with regard to bilirubin decline percent in all groups.

There was no previous study similar to our results, but Gross et al.[10] studied 10 infants who received vitamin E that was administered intramuscularly in a total dose of 125 mg/kg during days 3–7 of life; 10 infants served as controls. The mean percent carboxyhemoglobin level fell significantly from day 3 to day 8 in the treated group (1.08–0.78%), whereas the mean value remained unchanged at 0.96% in the control group. The administration of vitamin E seems to reduce but not eliminate the accelerated red cell destruction that characterizes the preterm infant.

Gross[11] studied 20 infants with a birth weight between 1000 and 1500 g and 20 infants with birth weights between 1501 and 2000 g. Half the infants in each birth weight group received vitamin E that was administered intramuscularly in a total dose of 50 mg/kg during days 1–3 of life; the remaining infants served as controls. Infants with birth weights less than or equal to 1500 g who received vitamin E demonstrated a significant decrease in serum bilirubin on day 3 of life as well as a significant decrease in peak serum bilirubin during the first week of life. The duration of phototherapy was also significantly less in the vitamin E-supplemented group. These differences were less pronounced in infants with birth weights more than 1500 g.

Hadjigeorgiou et al.[12] studied the serum vitamin E levels of 11 full-term and 10 premature infants who were jaundiced and subjected to phototherapy; the levels were measured and compared with nine premature and 10 full-term jaundiced control infants. No differences were observed before or after phototherapy or 1 week after stopping it. The same negative results were noted in the two groups of infants with regard to the values of microhematocrit, hemoglobin, and reticulocytes.

Westergren and Betty[13] showed that in both placebo-supplemented and vitamin E-supplemented groups, vitamin E levels were significantly higher on days 3 and 7 compared with day 1. Bilirubin production was not significantly different on day 3 compared with day 1 in either group, but it was significantly lower in both groups by day 7 compared with day 1. There were no significant differences in hemoglobin and serum bilirubin levels between the two groups at any point in time. Vitamin E supplementation significantly raises vitamin E levels; placebo-supplemented premature infants also achieved vitamin E sufficiency and a decrease in bilirubin production by day 7 of age.

Kaplan et al.[14] found that there were negative significant correlations between vitamin E and bilirubin among the jaundiced neonates. Increased hemolysis and marked hyperbilirubinemia observed in neonatal jaundice may be due to vitamin E deficiency.

Fischer et al.[15] carried out a randomized double-blind study of the efficacy of oral vitamin E supplementation as a prophylactic treatment for hyperbilirubinemia that was undertaken in preterm infants weighing less than 1500 g. Serum total bilirubin levels were determined in each patient on the first and third days of the study. We found no differences between the vitamin E-treated and placebo-treated groups with respect to serum bilirubin levels on day 1 or 3. In addition, we still observed no differences in serum bilirubin levels on day 1 or 3. The results of our study suggest that supplemental oral vitamin E therapy has no major effect on bilirubin production during the first 3 days of life in premature infants weighing less than 1500 g at birth.

Stevenson et al.[16] reported that the vitamin E-treated group of infants had a mean birth weight of 1272 ± 379 g, with a mean gestational age of 29 ± 2.7 weeks and a male: female ratio of 12: 7. The placebo group had a mean birth weight of 1214 ± 318 g, with a mean gestational age of 29 ± 2.0 weeks and an M:F ratio of 11%. The serum bilirubin levels on days 2, 3, and 4 in the vitamin E-treated and placebo-treated groups were not different.

Conclusion and recommendations

  1. Vitamin E supplementation has an important role in the treatment of hyperbilirubinemia in neonates
  2. Early administration of vitamin E in neonates resulted in a significant decrease of serum bilirubin as well as improvement of red cell hemolysis. Moreover, vitamin E shortens the duration of phototherapy needed for treatment of hyperbilirubinemia.


We recommend the administration of vitamin E for all neonates from day 1 of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Mitra S, Rennie J. Neonatal jaundice: aetiology, diagnosis and treatment. Br J Hosp Med 2017; 78:699–704.  Back to cited text no. 1
    
2.
Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Hyperbilirubinemia in the newborn infant≥35 weeks' gestation: an update with clarifications. Pediatrics 2009; 124:1193–1198.  Back to cited text no. 2
    
3.
Burke BL, Robbins JM, Mac Bird T, Hobbs CA, Nesmith C, Tilford JM. Trends in hospitalizations for neonatal jaundice and kernicterus in the United States, 1988–2005. Pediatrics 2009; 123:524–532.  Back to cited text no. 3
    
4.
Bhutani VK, Committee on Fetus and Newborn. Technical report: phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011; 128:e1046–e1052.  Back to cited text no. 4
    
5.
Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O'Shea TM, et al. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med 2008; 359:1885–1896.  Back to cited text no. 5
    
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El-Frargy M, El-Sharkawy H, Attia G. Therapeutic difference in some treatment modalities of jaundice in Egyptian neonates. J Clin Neonatol 2016; 5:162–162.  Back to cited text no. 6
    
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Skouroliakou M, Konstantinou D, Koutri K, Kakavelaki C, Stathopoulou M, Antoniadi M, et al. A double blind randomized clinical trial of the effect of ω-3 fatty acids on the oxidative stress of preterm neonates fed through parenteral nutrition. Eur J Clin Nutr 2010; 64:940.  Back to cited text no. 7
    
8.
Abdulrazzaq NA, Saifullah PH, Mohammed SK. Oxidative stress and antioxidant defense in patients with jaundice. Kerbala J Med 2014; 7:2000–2008.  Back to cited text no. 8
    
9.
González-Pérez Ó, Moy-López NA, Guzmán-Muñiz J. Alpha-tocopherol and alpha-lipoic acid. An antioxidant synergy with potential for preventive medicine. Rev Invest Clin 2008; 60:58–67.  Back to cited text no. 9
    
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Gross SJ, Landaw SA, Oski FA. Vitamin E and neonatal hemolysis. Pediatrics 1978; 61:549–549.  Back to cited text no. 10
    
11.
Gross SJ. Vitamin E and neonatal bilirubinemia. Pediatrics 1979; 64:321–323.  Back to cited text no. 11
    
12.
Hadjigeorgiou E, Tzortzatou F, Malamitsi-Puchner A, Papadatos J, Papadakis D, Nicolopoulos D. Vitamin E serum levels in newborn infants undergoing phototherapy. Neonatology 1980; 38:210–213.  Back to cited text no. 12
    
13.
Westergren T, Betty K. Dosage and formulation issues: oral vitamin E therapy in children. Eur J Clin Pharmacol 2010; 66:109–118.  Back to cited text no. 13
    
14.
Kaplan M, Hammerman C, Vreman HJ, Wong RJ, Stevenson, DK. Hemolysis and hyperbilirubinemia in antiglobulin positive, direct ABO blood group heterospecific neonates. J Pediatr 2010; 157:772–777.  Back to cited text no. 14
    
15.
Fischer AF, Inguillo D, Martin DM, Ochikubo CG, Vreman HJ, Stevenson DK, et al. Carboxyhemoglobin concentration as an index of bilirubin production in neonates with birth weights less than 1,500 grams: a randomized double-blind comparison of supplemental oral vitamin E and placebo. J Pediatr Gastroenterol Nutr 1987; 6:748–751.  Back to cited text no. 15
    
16.
Stevenson DK, Vreman HJ, Lenert LA, Leonard MB, Gale R. Continuous parenteral infusion of vitamin E pharmacokinetics and bilirubin production in premature neonates a. Ann New York Acad Sci 1989; 570:352–357.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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