Cochrane Database of Systematic Reviews
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Mishra S, Cheema A, Agarwal R, Deorari A, Paul V
Mishra S, Cheema A, Agarwal R, Deorari A, Paul V. Oral zinc for the prevention of hyperbilirubinaemia in neonates. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD008432. DOI: 10.1002/14651858.CD008432.pub2.
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Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 1 Incidence of hyperbilirubinaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 2 Proportion of neonates receiving phototherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 3 Incidence of vomiting. Analysis 1.4. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 4 Incidence of diarrhoea. Analysis 1.5. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 5 Incidence of rash. . . Analysis 1.6. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 6 Mean total serum bilirubin, mg/dL, at 72±12 hours of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 7 Duration of phototherapy (hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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[Intervention Review]
Oral zinc for the prevention of hyperbilirubinaemia in neonates Satish Mishra1 , Aminderjit Cheema1 , Ramesh Agarwal2 , Ashok Deorari2 , Vinod Paul2 1 Neonatology,
Lifeline Advanced Neonatal Centre, Jalandhar, India. 2 Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India Contact address: Ramesh Agarwal, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. [email protected].
Editorial group: Cochrane Neonatal Group. Publication status and date: New, published in Issue 7, 2015. Review content assessed as up-to-date: 30 November 2014. Citation: Mishra S, Cheema A, Agarwal R, Deorari A, Paul V. Oral zinc for the prevention of hyperbilirubinaemia in neonates. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD008432. DOI: 10.1002/14651858.CD008432.pub2. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT Background Between 6% and 15% of neonates develop hyperbilirubinaemia requiring treatment. Successful management of neonatal hyperbilirubinaemia relies on prevention and early treatment, with phototherapy being the mainstay of treatment. Oral zinc has been reported to decrease the serum total bilirubin (STB), presumably by decreasing the enterohepatic circulation. Objectives To determine the effect of oral zinc supplementation compared to placebo or no treatment on the incidence of hyperbilirubinaemia in neonates during the first week of life and to assess the safety of oral zinc in enrolled neonates. Search methods We searched CENTRAL (The Cochrane Library 2014, Issue 1), MEDLINE (1966 to November 30, 2014), and EMBASE (1990 to November 30, 2014). Selection criteria Randomised controlled trials were eligible for inclusion if they enrolled neonates (term and preterm) to whom oral zinc, in a dose of 10 to 20 mg/day, was initiated within the first 96 hours of life, for any duration until day seven, compared with no treatment or placebo. Data collection and analysis We used the standard methods of The Cochrane Collaboration and its Neonatal Review Group for data collection and analysis. Main results Only one study met the criteria of inclusion in the review. This study compared oral zinc with placebo. Oral zinc was administered in a dose of 5 mL twice daily from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or with a spoon. Incidence of hyperbilirubinaemia, defined as serum total bilirubin (STB) ≥ 15 mg/ dL, was similar between groups (N = 286; risk ratio (RR) 0.94, 95% confidence interval (CI) 0.58 to 1.52). Mean STB levels, mg/dL, at 72 ± 12 hours were comparable in both the groups (N = 286; mean difference (MD) -0.20; 95% CI -1.03 to 0.63). Although the duration of phototherapy in the zinc group was significantly shorter compared to the placebo group (N = 286; MD -12.80, 95% CI Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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16.93 to -8.67), the incidence of need for phototherapy was comparable across both the groups (N = 286; RR 1.20; 95% CI 0.66 to 2.18). Incidences of side effects like vomiting (N = 286; RR 0.65, 95% CI 0.19 to 2.25), diarrhoea (N = 286; RR 2.92, 95% CI 0.31 to 27.71), and rash (N = 286; RR 2.92, 95% CI 0.12 to 71.03) were found to be rare and statistically comparable between groups. Authors’ conclusions The limited evidence available has not shown that oral zinc supplementation given to infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.
PLAIN LANGUAGE SUMMARY Oral zinc for the prevention of hyperbilirubinaemia in neonates Review question In newborn infants less than one week old, does oral zinc salt supplementation compared to placebo or no treatment decrease the incidence of hyperbilirubinaemia (jaundice)? Background Jaundice, or yellowish discolouration of the skin, can occur due to an increased amount of bilirubin pigment in the blood. It is a commonly observed and usually harmless condition in newborn infants during the first week after birth. However, in some babies, the amount of bilirubin pigment can increase to dangerous levels and necessitate treatment. Bilirubin is metabolised in the liver and is excreted via the intestine in faeces. Increased reabsorption of bilirubin from the intestine is one of the major factors inducing hyperbilirubinaemia in newborn infants. Oral zinc salt, a relatively harmless medicine, can reduce the bilirubin level in newborn infants by decreasing its reabsorption from the intestine. Study characteristics Researchers from Cochrane searched for all available literature up to 30 November 2014. One randomised controlled trial met our inclusion criteria. Results In this review, the efficacy of oral zinc salt was compared with placebo. One study enrolling 294 infants was identified. This study evaluated oral zinc salt, given in a dose of 5 mg twice daily to infants between 25 and 168 hours old. The administration of oral zinc salt did not affect the incidence of jaundice (hyperbilirubinaemia) in these infants.
BACKGROUND
Description of the condition More than 60% of neonates develop jaundice during the first week of life. Mostly, in these neonates, the level of serum bilirubin lies within the physiologic range. Between 6% and 15% of neonates develop hyperbilirubinaemia (serum total bilirubin (STB) levels that have a high likelihood of requiring intervention to prevent bilirubin toxicity) (Maisels 1988; Narang 1997). The most devastating complication of neonatal hyperbilirubinaemia is bilirubin-
induced encephalopathy and its chronic sequelae (Shapiro 2003). The fundamental principle for the management of neonatal hyperbilirubinaemia is prevention and early treatment. Phototherapy is commonly used and is a very effective therapy for neonatal hyperbilirubinaemia. Phototherapy causes photoisomerization of bilirubin into a water-soluble form that can be excreted by the kidneys. Phototherapy effectively decreases the STB in jaundiced newborn infants and decreases the need for exchange blood transfusion (Maisels 1992). Metalloporphyrins are a relatively new but potentially effective mode of management of neonatal hyperbilirubinaemia. Metalloporphyrins are heme analogues that in-
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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hibit heme oxygenase, the rate-limiting enzyme in the catabolism of heme to bilirubin. By preventing the formation of bilirubin, they have the potential to reduce the level of unconjugated bilirubin in neonates. However, more research is required on their safety and to compare them with other well-established treatments (Suresh 2003).
Description of the intervention Oral zinc has been reported to decrease the STB levels in animal models (Méndez-Sánchez 2001; Vitek 2005); and in adults with Gilbert syndrome (Méndez-Sánchez 2002). However, currently little is known about the role of oral zinc salt in jaundiced neonates. In a randomised intervention trial, potential adverse effects of oral zinc salt like diarrhoea, vomiting, and rash were reported to be rare, and similar among both oral zinc and placebo groups (Rana 2011).
1. To determine the effect of oral zinc salt supplementation compared to placebo or no treatment on the incidence of hyperbilirubinaemia in neonates during the first week of life. 2. To assess the safety of oral zinc in enrolled neonates.
METHODS
Criteria for considering studies for this review
Types of studies All randomised controlled trials in which oral zinc supplementation was compared with no treatment or placebo were included in this review.
How the intervention might work Studies have suggested that enterohepatic circulation (EHC) might play a significant role in the metabolism of bilirubin (Bloomer 1976). EHC may be exaggerated in the neonatal period, in part because the newborn intestinal tract is not yet colonised with bacteria that convert unconjugated bilirubin (UCB) to urobilinogens and because intestinal beta glucuronidase activity is high (Madan 2005). Various strategies have been used to bind the bilirubin in the intestinal lumen to substances that resist absorption in order to counteract the process of enhanced EHC. Products such as oral agar have been used but with inconsistent results (Odell 1983). Oral zinc salts, which flocculate at physiological pH, reduce the STB, presumably by precipitating UCB from unsaturated micellar solution of bile salts and consequently inhibit the EHC of bilirubin (Méndez-Sánchez 2001; Vitek 2005).
Types of participants All healthy term and preterm neonates were included. We excluded neonates with Rhesus isoimmunisation, major gross congenital anomaly, sepsis (receiving intravenous antibiotics), postnatal age more than four days at initiation of the intervention, and neonates who required treatment for jaundice within 24 hours of birth or required intensive care for more than 24 hours within the first seven days of life.
Types of interventions Oral zinc salt, in a dose of 10 to 20 mg/day, initiated within the first 96 hours after birth for any duration until day seven, compared to no treatment or placebo.
Why it is important to do this review In animal models, oral zinc has been used for hyperbilirubinaemia with inconsistent results (Méndez-Sánchez 2001; Vitek 2005). Based on available data from animal and adult human studies, it seems plausible that oral zinc salt may reduce the incidence of hyperbilirubinaemia and the need for phototherapy and exchange transfusion in jaundiced neonates. However, there are very few published reports evaluating the effectiveness of oral zinc salt in neonatal hyperbilirubinaemia. The aim of this review is to systematically assess and compile the available evidence from randomised trials on this issue.
OBJECTIVES
Types of outcome measures
Primary outcomes
Incidence of hyperbilirubinaemia any time within the first seven days postpartum. (Hyperbilirubinemia was defined as: • for term and near-term neonates (neonates ≥ 35 weeks’ gestation): STB level that would qualify for phototherapy requirement as described in American Academy of Pediatrics 2004’s guidelines or absolute STB level ≥ 15 mg/dL; • for preterm neonates (< 35 weeks’ gestation): STB level > 1% of body weight.)
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Secondary outcomes
Assessment of risk of bias in included studies
1. Mean STB level (mg/dL) at 72 ± 12 hours of age 2. Proportion of neonates receiving or received phototherapy 3. Duration of phototherapy (hours) 4. Incidence of vomiting 5. Incidence of diarrhoea 6. Incidence of rash 7. Duration of hospital stay (days) 8. Incidence of exchange transfusion (number of babies requiring exchange transfusions regardless of the number of transfusions in a particular baby) 9. Mortality (defined as all-cause death during the intervention or within a week of stopping the intervention)
We used the standard methods of the Cochrane Neonatal Review Group for assessing the methodological quality of the studies. All the review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion among all the authors.
Search methods for identification of studies
Electronic searches We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2014, Issue 1), MEDLINE (1966 to November 30, 2014), and EMBASE (1990 to November 30, 2014) using MeSH term infant-newborn AND text terms zinc AND hyperbilirubinaemia OR phototherapy OR jaundice. Additional search of clinical trial registries (ClinicalTrials.gov, controlled-trials.com) were done. Language restriction was not placed during electronic searches.
Searching other resources • Reference lists from the above, and from review articles. • Personal communication with primary authors from the above to retrieve unpublished data related to published articles.
Data collection and analysis We used the standard methods of the Cochrane Neonatal Review Group for data collection and analysis.
Selection of studies All the authors independently examined the title and abstract of each retrieved study to assess eligibility and identified the studies to be included.
Data extraction and management Two authors (SM and AC) independently extracted data using a data extraction form. Differences were resolved after discussion among all the review authors.
We assessed the methodological quality of the studies using the following criteria. Sequence generation (selection bias)
For the included study, we assessed the method of sequence generation as: • low risk: when sequences were generated using true randomisation process; • high risk: when any non-random process was used for sequence generation; • unclear risk: when methodology of sequence was unclear. Allocation concealment (selection bias)
For the included study, we assessed the method of allocation concealment as: • low risk: when adequate methods were used for allocation concealment (e.g. consecutively numbered, sealed, opaque envelopes); • high risk: when allocation concealment was inadequately done; • unclear risk: when methodology of allocation concealment was unclear. Blinding (performance bias and detection bias)
For the included study, we categorised the methods used to blind study participants and personnel from the knowledge of which intervention a participant received. We assessed the process of blinding separately for different outcomes and categorised the methods as: • low risk, high risk or unclear risk for participants; • low risk, high risk or unclear risk for personnel; • low risk, high risk or unclear risk for outcome assessors. Incomplete outcome data (attrition bias)
For the included study, we examined the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We categorised the method as:
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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• low risk: < 20% missing data; • high risk: > 20% missing data; • unclear risk.
Assessment of reporting biases A comprehensive search of eligible studies including from prospective clinical trial registries and conference proceedings was done to decrease publication bias and skewing of the conclusion.
Selective reporting (reporting bias)
For the included study, we investigated the possibility of selective outcome reporting. We categorised the method as: • low risk: when all the study’s pre-specified outcomes and expected outcomes of interest were reported; • high risk: when not all the pre-specified outcomes were reported or one or more primary outcomes were not prespecified; • unclear risk: when information provided was unclear.
Other source of bias
For the included study, we have described our concerns about other possible sources of bias. Based on potential sources of bias we described the included study as: • low risk; • high risk; • unclear risk.
Data synthesis Data were synthesised using fixed-effect model. Subgroup analysis and investigation of heterogeneity We planned to examine outcomes separately in the following subgroups, however no data were available for the comparison: 1. term and near-term versus preterm neonate; 2. all neonates versus neonates at risk of hyperbilirubinaemia; 3. low dose (≤ 10 mg/day) versus high dose (11 to 20 mg/ day) of oral zinc; 4. short (< 72 hours) versus long (≥ 72 hours) duration of treatment. Sensitivity analysis We planned sensitivity analyses for situations where this might affect the interpretation of significant results. However, we could find only one eligible study and there were no significant missing data. Therefore, we did not need it.
Measures of treatment effect For categorical data the risk ratio (RR), risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (CI) were calculated. Continuous data were analysed using mean difference (MD).
RESULTS
Description of studies Unit of analysis issues Unit of analysis was the individual patient. We compared neonates receiving oral zinc supplementation with neonates receiving no treatment or placebo in overall analysis.
Dealing with missing data We contacted the original investigators with requests for any missing data.
Results of the search A total of 17 studies were retrieved from detailed literature search. Of these, only one study reported the efficacy of zinc on hyperbilirubinaemia and met inclusion criteria for the review (Rana 2011). The study was conducted at a tertiary care hospital in New Delhi, India, and included at-risk neonates (STB levels ≥ 6mg/ dL at 24 ± 6 hours postpartum) born at ≥ 35 weeks gestation. Included studies
Assessment of heterogeneity We planned the estimation of the degree of statistical heterogeneity using the I² statistic (< 25% none, 25% to 49% low, 50% to 74% moderate, and > 75% high heterogeneity) if we had found two or more studies for inclusion in this meta analysis. However, with detailed search we could find only one study, so did not need this analysis.
The study conducted by Rana 2011 is a double-blind, placebocontrolled, randomised trial conducted at a tertiary care neonatal centre in New Delhi, India. All neonates born at ≥ 35 weeks’ gestational age were potentially eligible for enrolment in the study. Neonates with Rhesus incompatibilities, major gross congenital anomalies, sepsis (requiring intravenous antibiotics), those who required exchange blood transfusion or phototherapy within 24
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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hours of birth, or those requiring intensive care for more than 24 hours were all excluded. All potentially eligible neonates were screened for STB at 24 ± 6 hours after birth. A total of 294 neonates with STB value ≥ 6 mg/dL at 24 ± 6 hours postpartum were enrolled in the study. Of these, 148 neonates received the oral zinc gluconate in a dose of 5 mL twice daily on days 2 to 7 postpartum and 146 neonates received the identical placebo syrup in a similar manner. Both zinc salt and placebo were provided in identical 60 mL bottles. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or a spoon. Eight infants were lost to follow up on day seven, so 145 children
in the zinc group and 141 in the placebo group were analysed for the primary outcome.
Excluded studies None
Risk of bias in included studies Risk of bias in the included study was found to be low (Figure 1).
Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.
Allocation The random sequence generation method is well described in the study. Random sequence were generated using permuted blocks of fixed size, six each, by a statistical package. The randomisation and numbered packing of intervention drug (oral zinc or placebo) was prepared off site by staff not involved in the study. The random sequences were kept in safe custody at two places by staff not involved in the study. Risk of bias was low.
Incomplete outcome data The study reported complete outcome data.
Selective reporting The study is assessed to be free of risk of selective reporting bias.
Blinding
Other potential sources of bias
The blinding process is well described. Oral zinc and placebo were identical in colour, taste, and appearance and packaged in bottles indistinguishable from each other. The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed. Risk of bias was low.
The zinc and placebo bottles were made available free of cost by manufacturer. As per additional information provided by authors “Zinc and placebo bottles were provided by Shalakas Pharmaceuticals Pvt.Ltd. However, they had no role in the design, conduct, analysis and reporting of the study.”
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Effects of interventions
DISCUSSION
Oral zinc salt supplementation compared to placebo (comparison 1)
Summary of main results
Incidence of hyperbilirubinaemia during first week of age (outcome 1.1)
The incidence of hyperbilirubinaemia was reported in 286 neonates. There was no significant difference in the incidence of hyperbilirubinaemia among both the groups, 17.9% in oral zinc group vs 19.1% in placebo group (RR 0.94, 95% CI 0.58 to 1.52; RD -0.01, 95% CI -0.10 to 0.08).
Proportion of neonates receiving or received phototherapy (outcome 1.2)
Requirement of phototherapy within first seven days of age was reported in 286 neonates. There was no significant difference between the zinc and the placebo groups in the incidence of need for phototherapy (RR 1.20, 95% CI 0.66 to 2.18; RD -0.05, 95% CI -0.13 to 0.04).
Side effects (Incidence of vomiting, diarrhoea, and rash) (outcome 1.3 to 1.5)
Incidences of side effects were reported for 286 neonates. Events of vomiting (RR 0.65, 95% CI 0.19 to 2.25; RD 0.65, 95% CI 0.19 to 2.25), diarrhoea (RR 2.92, 95% CI 0.31 to 27.71; RD 0.01, 95% CI -0.01 to 0.04), and rash (RR 2.92, 95% CI 0.12 to 71.03; RD 0.01, 95% CI -0.01 to 0.03) were found to be rare and statistically similar between groups.
Mean STB level at 72±12 hours of age (outcome 1.6)
Mean STB levels, mg/dL, at 72 ± 12 hours were reported for 286 neonates. The mean STB levels at 72 ± 12 hours of age between the two groups were similar (MD -0.20, 95% CI -1.03 to 0.63).
After a detailed literature search, we could find only one study fulfilling the criteria of inclusion in this systematic review (Rana 2011). It compared oral zinc and placebo for prevention of hyperbilirubinaemia in neonates. Data suggested that oral zinc salt as compared to placebo did not decrease the incidence of hyperbilirubinaemia, or mean serum bilirubin at 72 ± 12 hours postpartum. Though duration of phototherapy was lower in the oral zinc group, the incidence of need for phototherapy was comparable across both the groups. Side effects of oral zinc were rare and comparable between groups.
Overall completeness and applicability of evidence Prevention of enterohepatic circulation of bilirubin via enhancement of bilirubin sequestration or degradation in intestinal lumen is an exciting approach for prevention of neonatal hyperbilirubinaemia. Among compounds having this potential, zinc salts were demonstrated to be promising both in vitro and in vivo. Rana 2011, the study included in this review, compared oral zinc and placebo for prevention of hyperbilirubinaemia in at-risk neonates. Authors used oral zinc gluconate in a dose of 5 mL twice daily from day 2 to 7 following birth. Data revealed that administration of oral zinc salt did not reduce the incidence of subsequent hyperbilirubinaemia among at-risk neonates during the first week of life. Though the zinc administration was not associated with any reduction in proportion of neonates requiring phototherapy, duration of phototherapy was lower in the group supplemented with oral zinc compared to the placebo group. The mean serum total bilirubin at 72 ± 12 hours postpartum was also comparable in the oral zinc and placebo groups. The side effects (diarrhoea, vomiting, and rash) were rare and comparable between groups.
Quality of the evidence Duration of phototherapy (outcome 1.7)
This outcome was reported in total of 286 neonates. The duration of phototherapy, in hours, in the zinc group was significantly shorter compared to placebo group (MD -12.80, 95% CI -16.93 to -8.67).
The study included in the review is a well-conducted, doubleblind, placebo-controlled, randomised trial which enrolled an adequate number of infants (Figure 1). The estimate of effect on primary outcome, the incidence of hyperbilirubinaemia during the first week of life, and reported secondary outcomes is reasonably precise.
Other clinical outcomes: duration of hospital stay (days), incidence of exchange transfusion, mortality
Potential biases in the review process
These outcomes were not reported in the trial included in this review (Rana 2011).
Four authors of the review are also authors of the study included in this review.
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Agreements and disagreements with other studies or reviews To the best of our knowledge there is no other published review comparing the efficacy of oral zinc and placebo for prevention of hyperbilirubinaemia in neonates.
any meaningful improvement in hyperbilirubinaemia with oral zinc supplementation, there is a strong rationale to use oral zinc supplementation as an agent to prevent enterohepatic circulation of bilirubin via enhancement of bilirubin sequestration or degradation in the intestinal lumen. The estimates of effect from this single study are broad enough to consider further adequately powered trials to address this issue.
AUTHORS’ CONCLUSIONS Implications for practice The limited evidence available has not shown that oral zinc supplementation in infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.
Implications for research Although Rana 2011, the only available study, does not suggest
ACKNOWLEDGEMENTS The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
REFERENCES
References to studies included in this review Rana 2011 {published data only} Rana N, Mishra S, Bhatnagar S, Paul V, Deorari AK, Agarwal R. Efficacy of zinc in reducing hyperbilirubinemia among at-risk neonates: a randomized, double-blind placebo-controlled trial. Indian Journal Pediatrics 2011;78 (9):1073–8. [PUBMED: 21455724]
Additional references American Academy of Pediatrics 2004 American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114(1):297-316. Bloomer 1976 Bloomer JR, Zaccaria J. Effect of graded bilirubin load on bilirubin transport by perfused rat liver. American Journal of Physiology 1976;230(3):736–42. [PUBMED: 1266978]
Maisels 1988 Maisels MJ, Gifford K, Antle CE, Leib GR. Jaundice in the healthy newborn infant: a new approach to an old problem. Pediatrics 1988;81(4):505–11. [PUBMED: 3353184] Maisels 1992 Maisels MJ. Neonatal jaundice. In: Sinclair JC, Bracken MB editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:507–19. Méndez-Sánchez 2001 Méndez-Sánchez N, Roldán-Valadez E, Flores MA, Cárdenas-Vázquez R, Uribe M. Zinc salts precipitate unconjugated bilirubin in vitro and inhibit enterohepatic cycling of bilirubin in hamsters. European Journal of Clinical Investigation 2001;31(9):773–80. [PUBMED: 11589719] Méndez-Sánchez 2002 Méndez-Sánchez N, Martínez M, González V, RoldánValadez E, Flores MA, Uribe M. Zinc sulphate inhibits the enterohepatic cycling of unconjugated bilirubin in subjects with Gilbert’s syndrome. Annals of Hepatology 2002;1(1): 40–3. [PUBMED: 15114295]
Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Narang 1997 Narang A, Gathwala G, Kumar P. Neonatal jaundice: an analysis of 551 cases. Indian Pediatrics 1997;34(5):429–32. [PUBMED: 9332119]
Madan 2005 Madan A, McMahon JR, Stevenson DK. Neonatal hyperbilirubinemia. In: Taeusch HW, Ballard RA, Gleason CA editor(s). Textbook of Neonatology. 8th Edition. Philadelphia: Elsevier Saunders, 2005:1226–56.
Odell 1983 Odell GB, Gutcher GR, Whitington PF, Yang G. Enteral administration of agar as an effective adjunct to phototherapy of neonatal hyperbilirubinemia. Pediatric Research 1983;17(10):810–4. [PUBMED: 6415606]
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Shapiro 2003 Shapiro SM. Bilirubin toxicity in the developing nervous system. Pediatric Neurology 2003;29(5):410–21. [PUBMED: 14684236] Suresh 2003 Suresh GK, Martin CL, Soll RF. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD004207] Vitek 2005 Vitek L, Muchova L, Zelenka J, Zadinova M, Malina J. The effect of zinc salts on serum bilirubin levels in hyperbilirubinemic rats. Journal of Pediatric Gastroenterology and Nutrition 2005;40(2):135–40. [PUBMED: 15699685] ∗ Indicates the major publication for the study
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID] Rana 2011 Methods
Randomised, double blind, placebo-controlled trial.
Participants
A total of 294 at-risk neonates, neonates with STB levels ≥ 6 mg/dL at 24 ± 6 hours postpartum, (148 intervention, 146 placebo)
Interventions
Zinc gluconate (10 mg/day) or placebo was provided in identical syrup form and administered in twice- daily doses from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or a spoon
Outcomes
Primary outcome: Incidence of hyperbilirubinaemia (STB ≥15 mg/dl) anytime between 25 and 168 hours of age Secondary outcome: • Mean STB level at 72±12 hours of age; • Proportion of infants requiring phototherapy; • Duration of phototherapy.
Notes
The enrolled neonates were administered the intervention drug in a dose of 5 mL twice daily on day 2 to 7 of age. Intervention drug was either zinc gluconate, 5 mg/5 mL or identical placebo syrup provided in 60 mL bottles
Risk of bias Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk bias)
“Random sequence were generated using permuted blocks of fixed size, 6 each, by a statistical package.”
Allocation concealment (selection bias)
Low risk
“The randomisation and numbered packing of intervention drug (zinc or placebo) was prepared off site by a staff not involved in the study. The random sequences were kept in safe custody at two places by staff not involved in the study.”
Blinding of participants and personnel Low risk (performance bias) All outcomes
“Zinc and placebo were identical in colour, taste, and appearance and packaged in similar looking bottles. The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed.”
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Rana 2011
(Continued)
Blinding of outcome assessment (detection Low risk bias) All outcomes
“The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed.”
Incomplete outcome data (attrition bias) All outcomes
Low risk
In view of lack of data on day seven of age for eight neonates, who were lost to follow up, 145 children in the zinc group and 141 in the placebo group were analysed for the primary outcome
Selective reporting (reporting bias)
Low risk
Authors have reported all the clinically relevant outcomes. Risk of bias due to selective reporting is unlikely. Study protocol is available from ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT00692224)
Other bias
Low risk
Zinc and placebo bottles were provided by a pharmaceuticals company. However, authors have stated that they did not have any role in the design, conduct, analysis and reporting of the study
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DATA AND ANALYSES
Comparison 1. Oral zinc salt supplementation compared to placebo
Outcome or subgroup title
No. of studies
No. of participants
1 1
286 286
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
0.94 [0.58, 1.52] 0.76 [0.45, 1.27]
1 1 1 1
286 286 286 286
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
0.65 [0.19, 2.25] 2.92 [0.31, 27.71] 2.92 [0.12, 71.03] -0.20 [-1.03, 0.63]
1
286
Mean Difference (IV, Fixed, 95% CI)
-12.8 [-16.93, -8.67]
1 Incidence of hyperbilirubinaemia 2 Proportion of neonates receiving phototherapy 3 Incidence of vomiting 4 Incidence of diarrhoea 5 Incidence of rash 6 Mean total serum bilirubin, mg/dL, at 72±12 hours of age 7 Duration of phototherapy (hours)
Statistical method
Effect size
Analysis 1.1. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 1 Incidence of hyperbilirubinaemia. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 1 Incidence of hyperbilirubinaemia
Study or subgroup
Rana 2011
Total (95% CI)
Oral zinc
Placebo
n/N
n/N
Risk Ratio
Weight
26/145
27/141
100.0 %
0.94 [ 0.58, 1.52 ]
145
141
100.0 %
0.94 [ 0.58, 1.52 ]
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 26 (Oral zinc), 27 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.26 (P = 0.79) Test for subgroup differences: Not applicable
0.01
0.1
ZincFavours experimental
1
10
100
PlaceboFavours control
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Analysis 1.2. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 2 Proportion of neonates receiving phototherapy. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 2 Proportion of neonates receiving phototherapy
Study or subgroup
Rana 2011
Oral zinc
Placebo
n/N
n/N
21/145
27/141
100.0 %
0.76 [ 0.45, 1.27 ]
145
141
100.0 %
0.76 [ 0.45, 1.27 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 21 (Oral zinc), 27 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.05 (P = 0.29) Test for subgroup differences: Not applicable
0.01
0.1
1
ZincFavours experimental
10
100
PlaceboFavours control
Analysis 1.3. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 3 Incidence of vomiting. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 3 Incidence of vomiting
Study or subgroup
Rana 2011
Total (95% CI)
Oral zinc
Placebo
n/N
n/N
Risk Ratio
Weight
4/145
6/141
100.0 %
0.65 [ 0.19, 2.25 ]
145
141
100.0 %
0.65 [ 0.19, 2.25 ]
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 4 (Oral zinc), 6 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.68 (P = 0.49) Test for subgroup differences: Not applicable
0.01
0.1
ZincFavours experimental
1
10
100
PlaceboFavours control
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Analysis 1.4. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 4 Incidence of diarrhoea. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 4 Incidence of diarrhoea
Study or subgroup
Rana 2011
Total (95% CI)
Oral zinc
Placebo
n/N
n/N
Risk Ratio
Weight
3/145
1/141
100.0 %
2.92 [ 0.31, 27.71 ]
145
141
100.0 %
2.92 [ 0.31, 27.71 ]
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 3 (Oral zinc), 1 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.93 (P = 0.35) Test for subgroup differences: Not applicable
0.01
0.1
1
ZincFavours experimental
10
100
PlaceboFavours control
Analysis 1.5. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 5 Incidence of rash. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 5 Incidence of rash
Study or subgroup
Rana 2011
Total (95% CI)
Oral zinc
Placebo
n/N
n/N
Risk Ratio
Weight
1/145
0/141
100.0 %
2.92 [ 0.12, 71.03 ]
145
141
100.0 %
2.92 [ 0.12, 71.03 ]
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 1 (Oral zinc), 0 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.66 (P = 0.51) Test for subgroup differences: Not applicable
0.01
0.1
ZincFavours experimental
1
10
100
PlaceboFavours control
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Analysis 1.6. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 6 Mean total serum bilirubin, mg/dL, at 72±12 hours of age . Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 6 Mean total serum bilirubin, mg/dL, at 72 12 hours of age
Study or subgroup
Oral zinc
Rana 2011
Total (95% CI)
Mean Difference
Placebo
N
Mean(SD)
N
Mean(SD)
145
11.3 (3.3)
141
11.5 (3.8)
145
Weight
Mean Difference
100.0 %
-0.20 [ -1.03, 0.63 ]
100.0 %
-0.20 [ -1.03, 0.63 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
141
Heterogeneity: not applicable Test for overall effect: Z = 0.47 (P = 0.64) Test for subgroup differences: Not applicable
-100
-50
0
ZincFavours experimental
50
100
PlaceboFavours control
Analysis 1.7. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 7 Duration of phototherapy (hours). Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 7 Duration of phototherapy (hours)
Study or subgroup
Oral zinc
Rana 2011
Total (95% CI)
Mean Difference
Placebo
N
Mean(SD)
N
Mean(SD)
145
22.8 (19.4)
141
35.6 (16.1)
145
Weight
IV,Fixed,95% CI
Mean Difference IV,Fixed,95% CI
141
100.0 %
-12.80 [ -16.93, -8.67 ]
100.0 %
-12.80 [ -16.93, -8.67 ]
Heterogeneity: not applicable Test for overall effect: Z = 6.08 (P < 0.00001) Test for subgroup differences: Not applicable
-100
-50
0
ZincFavours experimental
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100
PlaceboFavours control
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CONTRIBUTIONS OF AUTHORS Satish Mishra: search, data extraction, data entry, data analysis, writing and editing of the review. Aminderjit Cheema: search, data extraction, data entry, data analysis, writing and editing of the review. Ramesh Agarwal: reviewed manuscript. Ashok Deorari: reviewed manuscript. Vinod Paul: reviewed manuscript.
DECLARATIONS OF INTEREST No conflict of interest.
SOURCES OF SUPPORT Internal sources • No source of support, India.
External sources • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA. Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C
DIFFERENCES BETWEEN PROTOCOL AND REVIEW None noted.
INDEX TERMS Medical Subject Headings (MeSH) Administration, Oral; Hyperbilirubinemia, Neonatal [epidemiology; ∗ prevention & control]; Incidence; Phototherapy; Randomized Controlled Trials as Topic; Zinc [∗ administration & dosage]
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MeSH check words Humans; Infant, Newborn
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Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Mishra S, Cheema A, Agarwal R, Deorari A, Paul V
Mishra S, Cheema A, Agarwal R, Deorari A, Paul V. Oral zinc for the prevention of hyperbilirubinaemia in neonates. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD008432. DOI: 10.1002/14651858.CD008432.pub2.
www.cochranelibrary.com
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 1 Incidence of hyperbilirubinaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 2 Proportion of neonates receiving phototherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 3 Incidence of vomiting. Analysis 1.4. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 4 Incidence of diarrhoea. Analysis 1.5. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 5 Incidence of rash. . . Analysis 1.6. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 6 Mean total serum bilirubin, mg/dL, at 72±12 hours of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 7 Duration of phototherapy (hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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[Intervention Review]
Oral zinc for the prevention of hyperbilirubinaemia in neonates Satish Mishra1 , Aminderjit Cheema1 , Ramesh Agarwal2 , Ashok Deorari2 , Vinod Paul2 1 Neonatology,
Lifeline Advanced Neonatal Centre, Jalandhar, India. 2 Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India Contact address: Ramesh Agarwal, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. [email protected].
Editorial group: Cochrane Neonatal Group. Publication status and date: New, published in Issue 7, 2015. Review content assessed as up-to-date: 30 November 2014. Citation: Mishra S, Cheema A, Agarwal R, Deorari A, Paul V. Oral zinc for the prevention of hyperbilirubinaemia in neonates. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD008432. DOI: 10.1002/14651858.CD008432.pub2. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT Background Between 6% and 15% of neonates develop hyperbilirubinaemia requiring treatment. Successful management of neonatal hyperbilirubinaemia relies on prevention and early treatment, with phototherapy being the mainstay of treatment. Oral zinc has been reported to decrease the serum total bilirubin (STB), presumably by decreasing the enterohepatic circulation. Objectives To determine the effect of oral zinc supplementation compared to placebo or no treatment on the incidence of hyperbilirubinaemia in neonates during the first week of life and to assess the safety of oral zinc in enrolled neonates. Search methods We searched CENTRAL (The Cochrane Library 2014, Issue 1), MEDLINE (1966 to November 30, 2014), and EMBASE (1990 to November 30, 2014). Selection criteria Randomised controlled trials were eligible for inclusion if they enrolled neonates (term and preterm) to whom oral zinc, in a dose of 10 to 20 mg/day, was initiated within the first 96 hours of life, for any duration until day seven, compared with no treatment or placebo. Data collection and analysis We used the standard methods of The Cochrane Collaboration and its Neonatal Review Group for data collection and analysis. Main results Only one study met the criteria of inclusion in the review. This study compared oral zinc with placebo. Oral zinc was administered in a dose of 5 mL twice daily from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or with a spoon. Incidence of hyperbilirubinaemia, defined as serum total bilirubin (STB) ≥ 15 mg/ dL, was similar between groups (N = 286; risk ratio (RR) 0.94, 95% confidence interval (CI) 0.58 to 1.52). Mean STB levels, mg/dL, at 72 ± 12 hours were comparable in both the groups (N = 286; mean difference (MD) -0.20; 95% CI -1.03 to 0.63). Although the duration of phototherapy in the zinc group was significantly shorter compared to the placebo group (N = 286; MD -12.80, 95% CI Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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16.93 to -8.67), the incidence of need for phototherapy was comparable across both the groups (N = 286; RR 1.20; 95% CI 0.66 to 2.18). Incidences of side effects like vomiting (N = 286; RR 0.65, 95% CI 0.19 to 2.25), diarrhoea (N = 286; RR 2.92, 95% CI 0.31 to 27.71), and rash (N = 286; RR 2.92, 95% CI 0.12 to 71.03) were found to be rare and statistically comparable between groups. Authors’ conclusions The limited evidence available has not shown that oral zinc supplementation given to infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.
PLAIN LANGUAGE SUMMARY Oral zinc for the prevention of hyperbilirubinaemia in neonates Review question In newborn infants less than one week old, does oral zinc salt supplementation compared to placebo or no treatment decrease the incidence of hyperbilirubinaemia (jaundice)? Background Jaundice, or yellowish discolouration of the skin, can occur due to an increased amount of bilirubin pigment in the blood. It is a commonly observed and usually harmless condition in newborn infants during the first week after birth. However, in some babies, the amount of bilirubin pigment can increase to dangerous levels and necessitate treatment. Bilirubin is metabolised in the liver and is excreted via the intestine in faeces. Increased reabsorption of bilirubin from the intestine is one of the major factors inducing hyperbilirubinaemia in newborn infants. Oral zinc salt, a relatively harmless medicine, can reduce the bilirubin level in newborn infants by decreasing its reabsorption from the intestine. Study characteristics Researchers from Cochrane searched for all available literature up to 30 November 2014. One randomised controlled trial met our inclusion criteria. Results In this review, the efficacy of oral zinc salt was compared with placebo. One study enrolling 294 infants was identified. This study evaluated oral zinc salt, given in a dose of 5 mg twice daily to infants between 25 and 168 hours old. The administration of oral zinc salt did not affect the incidence of jaundice (hyperbilirubinaemia) in these infants.
BACKGROUND
Description of the condition More than 60% of neonates develop jaundice during the first week of life. Mostly, in these neonates, the level of serum bilirubin lies within the physiologic range. Between 6% and 15% of neonates develop hyperbilirubinaemia (serum total bilirubin (STB) levels that have a high likelihood of requiring intervention to prevent bilirubin toxicity) (Maisels 1988; Narang 1997). The most devastating complication of neonatal hyperbilirubinaemia is bilirubin-
induced encephalopathy and its chronic sequelae (Shapiro 2003). The fundamental principle for the management of neonatal hyperbilirubinaemia is prevention and early treatment. Phototherapy is commonly used and is a very effective therapy for neonatal hyperbilirubinaemia. Phototherapy causes photoisomerization of bilirubin into a water-soluble form that can be excreted by the kidneys. Phototherapy effectively decreases the STB in jaundiced newborn infants and decreases the need for exchange blood transfusion (Maisels 1992). Metalloporphyrins are a relatively new but potentially effective mode of management of neonatal hyperbilirubinaemia. Metalloporphyrins are heme analogues that in-
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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hibit heme oxygenase, the rate-limiting enzyme in the catabolism of heme to bilirubin. By preventing the formation of bilirubin, they have the potential to reduce the level of unconjugated bilirubin in neonates. However, more research is required on their safety and to compare them with other well-established treatments (Suresh 2003).
Description of the intervention Oral zinc has been reported to decrease the STB levels in animal models (Méndez-Sánchez 2001; Vitek 2005); and in adults with Gilbert syndrome (Méndez-Sánchez 2002). However, currently little is known about the role of oral zinc salt in jaundiced neonates. In a randomised intervention trial, potential adverse effects of oral zinc salt like diarrhoea, vomiting, and rash were reported to be rare, and similar among both oral zinc and placebo groups (Rana 2011).
1. To determine the effect of oral zinc salt supplementation compared to placebo or no treatment on the incidence of hyperbilirubinaemia in neonates during the first week of life. 2. To assess the safety of oral zinc in enrolled neonates.
METHODS
Criteria for considering studies for this review
Types of studies All randomised controlled trials in which oral zinc supplementation was compared with no treatment or placebo were included in this review.
How the intervention might work Studies have suggested that enterohepatic circulation (EHC) might play a significant role in the metabolism of bilirubin (Bloomer 1976). EHC may be exaggerated in the neonatal period, in part because the newborn intestinal tract is not yet colonised with bacteria that convert unconjugated bilirubin (UCB) to urobilinogens and because intestinal beta glucuronidase activity is high (Madan 2005). Various strategies have been used to bind the bilirubin in the intestinal lumen to substances that resist absorption in order to counteract the process of enhanced EHC. Products such as oral agar have been used but with inconsistent results (Odell 1983). Oral zinc salts, which flocculate at physiological pH, reduce the STB, presumably by precipitating UCB from unsaturated micellar solution of bile salts and consequently inhibit the EHC of bilirubin (Méndez-Sánchez 2001; Vitek 2005).
Types of participants All healthy term and preterm neonates were included. We excluded neonates with Rhesus isoimmunisation, major gross congenital anomaly, sepsis (receiving intravenous antibiotics), postnatal age more than four days at initiation of the intervention, and neonates who required treatment for jaundice within 24 hours of birth or required intensive care for more than 24 hours within the first seven days of life.
Types of interventions Oral zinc salt, in a dose of 10 to 20 mg/day, initiated within the first 96 hours after birth for any duration until day seven, compared to no treatment or placebo.
Why it is important to do this review In animal models, oral zinc has been used for hyperbilirubinaemia with inconsistent results (Méndez-Sánchez 2001; Vitek 2005). Based on available data from animal and adult human studies, it seems plausible that oral zinc salt may reduce the incidence of hyperbilirubinaemia and the need for phototherapy and exchange transfusion in jaundiced neonates. However, there are very few published reports evaluating the effectiveness of oral zinc salt in neonatal hyperbilirubinaemia. The aim of this review is to systematically assess and compile the available evidence from randomised trials on this issue.
OBJECTIVES
Types of outcome measures
Primary outcomes
Incidence of hyperbilirubinaemia any time within the first seven days postpartum. (Hyperbilirubinemia was defined as: • for term and near-term neonates (neonates ≥ 35 weeks’ gestation): STB level that would qualify for phototherapy requirement as described in American Academy of Pediatrics 2004’s guidelines or absolute STB level ≥ 15 mg/dL; • for preterm neonates (< 35 weeks’ gestation): STB level > 1% of body weight.)
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Secondary outcomes
Assessment of risk of bias in included studies
1. Mean STB level (mg/dL) at 72 ± 12 hours of age 2. Proportion of neonates receiving or received phototherapy 3. Duration of phototherapy (hours) 4. Incidence of vomiting 5. Incidence of diarrhoea 6. Incidence of rash 7. Duration of hospital stay (days) 8. Incidence of exchange transfusion (number of babies requiring exchange transfusions regardless of the number of transfusions in a particular baby) 9. Mortality (defined as all-cause death during the intervention or within a week of stopping the intervention)
We used the standard methods of the Cochrane Neonatal Review Group for assessing the methodological quality of the studies. All the review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion among all the authors.
Search methods for identification of studies
Electronic searches We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2014, Issue 1), MEDLINE (1966 to November 30, 2014), and EMBASE (1990 to November 30, 2014) using MeSH term infant-newborn AND text terms zinc AND hyperbilirubinaemia OR phototherapy OR jaundice. Additional search of clinical trial registries (ClinicalTrials.gov, controlled-trials.com) were done. Language restriction was not placed during electronic searches.
Searching other resources • Reference lists from the above, and from review articles. • Personal communication with primary authors from the above to retrieve unpublished data related to published articles.
Data collection and analysis We used the standard methods of the Cochrane Neonatal Review Group for data collection and analysis.
Selection of studies All the authors independently examined the title and abstract of each retrieved study to assess eligibility and identified the studies to be included.
Data extraction and management Two authors (SM and AC) independently extracted data using a data extraction form. Differences were resolved after discussion among all the review authors.
We assessed the methodological quality of the studies using the following criteria. Sequence generation (selection bias)
For the included study, we assessed the method of sequence generation as: • low risk: when sequences were generated using true randomisation process; • high risk: when any non-random process was used for sequence generation; • unclear risk: when methodology of sequence was unclear. Allocation concealment (selection bias)
For the included study, we assessed the method of allocation concealment as: • low risk: when adequate methods were used for allocation concealment (e.g. consecutively numbered, sealed, opaque envelopes); • high risk: when allocation concealment was inadequately done; • unclear risk: when methodology of allocation concealment was unclear. Blinding (performance bias and detection bias)
For the included study, we categorised the methods used to blind study participants and personnel from the knowledge of which intervention a participant received. We assessed the process of blinding separately for different outcomes and categorised the methods as: • low risk, high risk or unclear risk for participants; • low risk, high risk or unclear risk for personnel; • low risk, high risk or unclear risk for outcome assessors. Incomplete outcome data (attrition bias)
For the included study, we examined the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We categorised the method as:
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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• low risk: < 20% missing data; • high risk: > 20% missing data; • unclear risk.
Assessment of reporting biases A comprehensive search of eligible studies including from prospective clinical trial registries and conference proceedings was done to decrease publication bias and skewing of the conclusion.
Selective reporting (reporting bias)
For the included study, we investigated the possibility of selective outcome reporting. We categorised the method as: • low risk: when all the study’s pre-specified outcomes and expected outcomes of interest were reported; • high risk: when not all the pre-specified outcomes were reported or one or more primary outcomes were not prespecified; • unclear risk: when information provided was unclear.
Other source of bias
For the included study, we have described our concerns about other possible sources of bias. Based on potential sources of bias we described the included study as: • low risk; • high risk; • unclear risk.
Data synthesis Data were synthesised using fixed-effect model. Subgroup analysis and investigation of heterogeneity We planned to examine outcomes separately in the following subgroups, however no data were available for the comparison: 1. term and near-term versus preterm neonate; 2. all neonates versus neonates at risk of hyperbilirubinaemia; 3. low dose (≤ 10 mg/day) versus high dose (11 to 20 mg/ day) of oral zinc; 4. short (< 72 hours) versus long (≥ 72 hours) duration of treatment. Sensitivity analysis We planned sensitivity analyses for situations where this might affect the interpretation of significant results. However, we could find only one eligible study and there were no significant missing data. Therefore, we did not need it.
Measures of treatment effect For categorical data the risk ratio (RR), risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (CI) were calculated. Continuous data were analysed using mean difference (MD).
RESULTS
Description of studies Unit of analysis issues Unit of analysis was the individual patient. We compared neonates receiving oral zinc supplementation with neonates receiving no treatment or placebo in overall analysis.
Dealing with missing data We contacted the original investigators with requests for any missing data.
Results of the search A total of 17 studies were retrieved from detailed literature search. Of these, only one study reported the efficacy of zinc on hyperbilirubinaemia and met inclusion criteria for the review (Rana 2011). The study was conducted at a tertiary care hospital in New Delhi, India, and included at-risk neonates (STB levels ≥ 6mg/ dL at 24 ± 6 hours postpartum) born at ≥ 35 weeks gestation. Included studies
Assessment of heterogeneity We planned the estimation of the degree of statistical heterogeneity using the I² statistic (< 25% none, 25% to 49% low, 50% to 74% moderate, and > 75% high heterogeneity) if we had found two or more studies for inclusion in this meta analysis. However, with detailed search we could find only one study, so did not need this analysis.
The study conducted by Rana 2011 is a double-blind, placebocontrolled, randomised trial conducted at a tertiary care neonatal centre in New Delhi, India. All neonates born at ≥ 35 weeks’ gestational age were potentially eligible for enrolment in the study. Neonates with Rhesus incompatibilities, major gross congenital anomalies, sepsis (requiring intravenous antibiotics), those who required exchange blood transfusion or phototherapy within 24
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hours of birth, or those requiring intensive care for more than 24 hours were all excluded. All potentially eligible neonates were screened for STB at 24 ± 6 hours after birth. A total of 294 neonates with STB value ≥ 6 mg/dL at 24 ± 6 hours postpartum were enrolled in the study. Of these, 148 neonates received the oral zinc gluconate in a dose of 5 mL twice daily on days 2 to 7 postpartum and 146 neonates received the identical placebo syrup in a similar manner. Both zinc salt and placebo were provided in identical 60 mL bottles. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or a spoon. Eight infants were lost to follow up on day seven, so 145 children
in the zinc group and 141 in the placebo group were analysed for the primary outcome.
Excluded studies None
Risk of bias in included studies Risk of bias in the included study was found to be low (Figure 1).
Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.
Allocation The random sequence generation method is well described in the study. Random sequence were generated using permuted blocks of fixed size, six each, by a statistical package. The randomisation and numbered packing of intervention drug (oral zinc or placebo) was prepared off site by staff not involved in the study. The random sequences were kept in safe custody at two places by staff not involved in the study. Risk of bias was low.
Incomplete outcome data The study reported complete outcome data.
Selective reporting The study is assessed to be free of risk of selective reporting bias.
Blinding
Other potential sources of bias
The blinding process is well described. Oral zinc and placebo were identical in colour, taste, and appearance and packaged in bottles indistinguishable from each other. The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed. Risk of bias was low.
The zinc and placebo bottles were made available free of cost by manufacturer. As per additional information provided by authors “Zinc and placebo bottles were provided by Shalakas Pharmaceuticals Pvt.Ltd. However, they had no role in the design, conduct, analysis and reporting of the study.”
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Effects of interventions
DISCUSSION
Oral zinc salt supplementation compared to placebo (comparison 1)
Summary of main results
Incidence of hyperbilirubinaemia during first week of age (outcome 1.1)
The incidence of hyperbilirubinaemia was reported in 286 neonates. There was no significant difference in the incidence of hyperbilirubinaemia among both the groups, 17.9% in oral zinc group vs 19.1% in placebo group (RR 0.94, 95% CI 0.58 to 1.52; RD -0.01, 95% CI -0.10 to 0.08).
Proportion of neonates receiving or received phototherapy (outcome 1.2)
Requirement of phototherapy within first seven days of age was reported in 286 neonates. There was no significant difference between the zinc and the placebo groups in the incidence of need for phototherapy (RR 1.20, 95% CI 0.66 to 2.18; RD -0.05, 95% CI -0.13 to 0.04).
Side effects (Incidence of vomiting, diarrhoea, and rash) (outcome 1.3 to 1.5)
Incidences of side effects were reported for 286 neonates. Events of vomiting (RR 0.65, 95% CI 0.19 to 2.25; RD 0.65, 95% CI 0.19 to 2.25), diarrhoea (RR 2.92, 95% CI 0.31 to 27.71; RD 0.01, 95% CI -0.01 to 0.04), and rash (RR 2.92, 95% CI 0.12 to 71.03; RD 0.01, 95% CI -0.01 to 0.03) were found to be rare and statistically similar between groups.
Mean STB level at 72±12 hours of age (outcome 1.6)
Mean STB levels, mg/dL, at 72 ± 12 hours were reported for 286 neonates. The mean STB levels at 72 ± 12 hours of age between the two groups were similar (MD -0.20, 95% CI -1.03 to 0.63).
After a detailed literature search, we could find only one study fulfilling the criteria of inclusion in this systematic review (Rana 2011). It compared oral zinc and placebo for prevention of hyperbilirubinaemia in neonates. Data suggested that oral zinc salt as compared to placebo did not decrease the incidence of hyperbilirubinaemia, or mean serum bilirubin at 72 ± 12 hours postpartum. Though duration of phototherapy was lower in the oral zinc group, the incidence of need for phototherapy was comparable across both the groups. Side effects of oral zinc were rare and comparable between groups.
Overall completeness and applicability of evidence Prevention of enterohepatic circulation of bilirubin via enhancement of bilirubin sequestration or degradation in intestinal lumen is an exciting approach for prevention of neonatal hyperbilirubinaemia. Among compounds having this potential, zinc salts were demonstrated to be promising both in vitro and in vivo. Rana 2011, the study included in this review, compared oral zinc and placebo for prevention of hyperbilirubinaemia in at-risk neonates. Authors used oral zinc gluconate in a dose of 5 mL twice daily from day 2 to 7 following birth. Data revealed that administration of oral zinc salt did not reduce the incidence of subsequent hyperbilirubinaemia among at-risk neonates during the first week of life. Though the zinc administration was not associated with any reduction in proportion of neonates requiring phototherapy, duration of phototherapy was lower in the group supplemented with oral zinc compared to the placebo group. The mean serum total bilirubin at 72 ± 12 hours postpartum was also comparable in the oral zinc and placebo groups. The side effects (diarrhoea, vomiting, and rash) were rare and comparable between groups.
Quality of the evidence Duration of phototherapy (outcome 1.7)
This outcome was reported in total of 286 neonates. The duration of phototherapy, in hours, in the zinc group was significantly shorter compared to placebo group (MD -12.80, 95% CI -16.93 to -8.67).
The study included in the review is a well-conducted, doubleblind, placebo-controlled, randomised trial which enrolled an adequate number of infants (Figure 1). The estimate of effect on primary outcome, the incidence of hyperbilirubinaemia during the first week of life, and reported secondary outcomes is reasonably precise.
Other clinical outcomes: duration of hospital stay (days), incidence of exchange transfusion, mortality
Potential biases in the review process
These outcomes were not reported in the trial included in this review (Rana 2011).
Four authors of the review are also authors of the study included in this review.
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Agreements and disagreements with other studies or reviews To the best of our knowledge there is no other published review comparing the efficacy of oral zinc and placebo for prevention of hyperbilirubinaemia in neonates.
any meaningful improvement in hyperbilirubinaemia with oral zinc supplementation, there is a strong rationale to use oral zinc supplementation as an agent to prevent enterohepatic circulation of bilirubin via enhancement of bilirubin sequestration or degradation in the intestinal lumen. The estimates of effect from this single study are broad enough to consider further adequately powered trials to address this issue.
AUTHORS’ CONCLUSIONS Implications for practice The limited evidence available has not shown that oral zinc supplementation in infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.
Implications for research Although Rana 2011, the only available study, does not suggest
ACKNOWLEDGEMENTS The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
REFERENCES
References to studies included in this review Rana 2011 {published data only} Rana N, Mishra S, Bhatnagar S, Paul V, Deorari AK, Agarwal R. Efficacy of zinc in reducing hyperbilirubinemia among at-risk neonates: a randomized, double-blind placebo-controlled trial. Indian Journal Pediatrics 2011;78 (9):1073–8. [PUBMED: 21455724]
Additional references American Academy of Pediatrics 2004 American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114(1):297-316. Bloomer 1976 Bloomer JR, Zaccaria J. Effect of graded bilirubin load on bilirubin transport by perfused rat liver. American Journal of Physiology 1976;230(3):736–42. [PUBMED: 1266978]
Maisels 1988 Maisels MJ, Gifford K, Antle CE, Leib GR. Jaundice in the healthy newborn infant: a new approach to an old problem. Pediatrics 1988;81(4):505–11. [PUBMED: 3353184] Maisels 1992 Maisels MJ. Neonatal jaundice. In: Sinclair JC, Bracken MB editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:507–19. Méndez-Sánchez 2001 Méndez-Sánchez N, Roldán-Valadez E, Flores MA, Cárdenas-Vázquez R, Uribe M. Zinc salts precipitate unconjugated bilirubin in vitro and inhibit enterohepatic cycling of bilirubin in hamsters. European Journal of Clinical Investigation 2001;31(9):773–80. [PUBMED: 11589719] Méndez-Sánchez 2002 Méndez-Sánchez N, Martínez M, González V, RoldánValadez E, Flores MA, Uribe M. Zinc sulphate inhibits the enterohepatic cycling of unconjugated bilirubin in subjects with Gilbert’s syndrome. Annals of Hepatology 2002;1(1): 40–3. [PUBMED: 15114295]
Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Narang 1997 Narang A, Gathwala G, Kumar P. Neonatal jaundice: an analysis of 551 cases. Indian Pediatrics 1997;34(5):429–32. [PUBMED: 9332119]
Madan 2005 Madan A, McMahon JR, Stevenson DK. Neonatal hyperbilirubinemia. In: Taeusch HW, Ballard RA, Gleason CA editor(s). Textbook of Neonatology. 8th Edition. Philadelphia: Elsevier Saunders, 2005:1226–56.
Odell 1983 Odell GB, Gutcher GR, Whitington PF, Yang G. Enteral administration of agar as an effective adjunct to phototherapy of neonatal hyperbilirubinemia. Pediatric Research 1983;17(10):810–4. [PUBMED: 6415606]
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Shapiro 2003 Shapiro SM. Bilirubin toxicity in the developing nervous system. Pediatric Neurology 2003;29(5):410–21. [PUBMED: 14684236] Suresh 2003 Suresh GK, Martin CL, Soll RF. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD004207] Vitek 2005 Vitek L, Muchova L, Zelenka J, Zadinova M, Malina J. The effect of zinc salts on serum bilirubin levels in hyperbilirubinemic rats. Journal of Pediatric Gastroenterology and Nutrition 2005;40(2):135–40. [PUBMED: 15699685] ∗ Indicates the major publication for the study
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID] Rana 2011 Methods
Randomised, double blind, placebo-controlled trial.
Participants
A total of 294 at-risk neonates, neonates with STB levels ≥ 6 mg/dL at 24 ± 6 hours postpartum, (148 intervention, 146 placebo)
Interventions
Zinc gluconate (10 mg/day) or placebo was provided in identical syrup form and administered in twice- daily doses from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or a spoon
Outcomes
Primary outcome: Incidence of hyperbilirubinaemia (STB ≥15 mg/dl) anytime between 25 and 168 hours of age Secondary outcome: • Mean STB level at 72±12 hours of age; • Proportion of infants requiring phototherapy; • Duration of phototherapy.
Notes
The enrolled neonates were administered the intervention drug in a dose of 5 mL twice daily on day 2 to 7 of age. Intervention drug was either zinc gluconate, 5 mg/5 mL or identical placebo syrup provided in 60 mL bottles
Risk of bias Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk bias)
“Random sequence were generated using permuted blocks of fixed size, 6 each, by a statistical package.”
Allocation concealment (selection bias)
Low risk
“The randomisation and numbered packing of intervention drug (zinc or placebo) was prepared off site by a staff not involved in the study. The random sequences were kept in safe custody at two places by staff not involved in the study.”
Blinding of participants and personnel Low risk (performance bias) All outcomes
“Zinc and placebo were identical in colour, taste, and appearance and packaged in similar looking bottles. The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed.”
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Rana 2011
(Continued)
Blinding of outcome assessment (detection Low risk bias) All outcomes
“The code was kept blinded from the participants, investigators, and the statistician until the analysis was completed.”
Incomplete outcome data (attrition bias) All outcomes
Low risk
In view of lack of data on day seven of age for eight neonates, who were lost to follow up, 145 children in the zinc group and 141 in the placebo group were analysed for the primary outcome
Selective reporting (reporting bias)
Low risk
Authors have reported all the clinically relevant outcomes. Risk of bias due to selective reporting is unlikely. Study protocol is available from ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT00692224)
Other bias
Low risk
Zinc and placebo bottles were provided by a pharmaceuticals company. However, authors have stated that they did not have any role in the design, conduct, analysis and reporting of the study
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DATA AND ANALYSES
Comparison 1. Oral zinc salt supplementation compared to placebo
Outcome or subgroup title
No. of studies
No. of participants
1 1
286 286
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
0.94 [0.58, 1.52] 0.76 [0.45, 1.27]
1 1 1 1
286 286 286 286
Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)
0.65 [0.19, 2.25] 2.92 [0.31, 27.71] 2.92 [0.12, 71.03] -0.20 [-1.03, 0.63]
1
286
Mean Difference (IV, Fixed, 95% CI)
-12.8 [-16.93, -8.67]
1 Incidence of hyperbilirubinaemia 2 Proportion of neonates receiving phototherapy 3 Incidence of vomiting 4 Incidence of diarrhoea 5 Incidence of rash 6 Mean total serum bilirubin, mg/dL, at 72±12 hours of age 7 Duration of phototherapy (hours)
Statistical method
Effect size
Analysis 1.1. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 1 Incidence of hyperbilirubinaemia. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 1 Incidence of hyperbilirubinaemia
Study or subgroup
Rana 2011
Total (95% CI)
Oral zinc
Placebo
n/N
n/N
Risk Ratio
Weight
26/145
27/141
100.0 %
0.94 [ 0.58, 1.52 ]
145
141
100.0 %
0.94 [ 0.58, 1.52 ]
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 26 (Oral zinc), 27 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.26 (P = 0.79) Test for subgroup differences: Not applicable
0.01
0.1
ZincFavours experimental
1
10
100
PlaceboFavours control
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Analysis 1.2. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 2 Proportion of neonates receiving phototherapy. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 2 Proportion of neonates receiving phototherapy
Study or subgroup
Rana 2011
Oral zinc
Placebo
n/N
n/N
21/145
27/141
100.0 %
0.76 [ 0.45, 1.27 ]
145
141
100.0 %
0.76 [ 0.45, 1.27 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 21 (Oral zinc), 27 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.05 (P = 0.29) Test for subgroup differences: Not applicable
0.01
0.1
1
ZincFavours experimental
10
100
PlaceboFavours control
Analysis 1.3. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 3 Incidence of vomiting. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 3 Incidence of vomiting
Study or subgroup
Rana 2011
Total (95% CI)
Oral zinc
Placebo
n/N
n/N
Risk Ratio
Weight
4/145
6/141
100.0 %
0.65 [ 0.19, 2.25 ]
145
141
100.0 %
0.65 [ 0.19, 2.25 ]
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 4 (Oral zinc), 6 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.68 (P = 0.49) Test for subgroup differences: Not applicable
0.01
0.1
ZincFavours experimental
1
10
100
PlaceboFavours control
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Analysis 1.4. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 4 Incidence of diarrhoea. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 4 Incidence of diarrhoea
Study or subgroup
Rana 2011
Total (95% CI)
Oral zinc
Placebo
n/N
n/N
Risk Ratio
Weight
3/145
1/141
100.0 %
2.92 [ 0.31, 27.71 ]
145
141
100.0 %
2.92 [ 0.31, 27.71 ]
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 3 (Oral zinc), 1 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.93 (P = 0.35) Test for subgroup differences: Not applicable
0.01
0.1
1
ZincFavours experimental
10
100
PlaceboFavours control
Analysis 1.5. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 5 Incidence of rash. Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 5 Incidence of rash
Study or subgroup
Rana 2011
Total (95% CI)
Oral zinc
Placebo
n/N
n/N
Risk Ratio
Weight
1/145
0/141
100.0 %
2.92 [ 0.12, 71.03 ]
145
141
100.0 %
2.92 [ 0.12, 71.03 ]
M-H,Fixed,95% CI
Risk Ratio M-H,Fixed,95% CI
Total events: 1 (Oral zinc), 0 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.66 (P = 0.51) Test for subgroup differences: Not applicable
0.01
0.1
ZincFavours experimental
1
10
100
PlaceboFavours control
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Analysis 1.6. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 6 Mean total serum bilirubin, mg/dL, at 72±12 hours of age . Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 6 Mean total serum bilirubin, mg/dL, at 72 12 hours of age
Study or subgroup
Oral zinc
Rana 2011
Total (95% CI)
Mean Difference
Placebo
N
Mean(SD)
N
Mean(SD)
145
11.3 (3.3)
141
11.5 (3.8)
145
Weight
Mean Difference
100.0 %
-0.20 [ -1.03, 0.63 ]
100.0 %
-0.20 [ -1.03, 0.63 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
141
Heterogeneity: not applicable Test for overall effect: Z = 0.47 (P = 0.64) Test for subgroup differences: Not applicable
-100
-50
0
ZincFavours experimental
50
100
PlaceboFavours control
Analysis 1.7. Comparison 1 Oral zinc salt supplementation compared to placebo, Outcome 7 Duration of phototherapy (hours). Review:
Oral zinc for the prevention of hyperbilirubinaemia in neonates
Comparison: 1 Oral zinc salt supplementation compared to placebo Outcome: 7 Duration of phototherapy (hours)
Study or subgroup
Oral zinc
Rana 2011
Total (95% CI)
Mean Difference
Placebo
N
Mean(SD)
N
Mean(SD)
145
22.8 (19.4)
141
35.6 (16.1)
145
Weight
IV,Fixed,95% CI
Mean Difference IV,Fixed,95% CI
141
100.0 %
-12.80 [ -16.93, -8.67 ]
100.0 %
-12.80 [ -16.93, -8.67 ]
Heterogeneity: not applicable Test for overall effect: Z = 6.08 (P < 0.00001) Test for subgroup differences: Not applicable
-100
-50
0
ZincFavours experimental
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100
PlaceboFavours control
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CONTRIBUTIONS OF AUTHORS Satish Mishra: search, data extraction, data entry, data analysis, writing and editing of the review. Aminderjit Cheema: search, data extraction, data entry, data analysis, writing and editing of the review. Ramesh Agarwal: reviewed manuscript. Ashok Deorari: reviewed manuscript. Vinod Paul: reviewed manuscript.
DECLARATIONS OF INTEREST No conflict of interest.
SOURCES OF SUPPORT Internal sources • No source of support, India.
External sources • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA. Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C
DIFFERENCES BETWEEN PROTOCOL AND REVIEW None noted.
INDEX TERMS Medical Subject Headings (MeSH) Administration, Oral; Hyperbilirubinemia, Neonatal [epidemiology; ∗ prevention & control]; Incidence; Phototherapy; Randomized Controlled Trials as Topic; Zinc [∗ administration & dosage]
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MeSH check words Humans; Infant, Newborn
Oral zinc for the prevention of hyperbilirubinaemia in neonates (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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