Open Access Original Article

The Therapeutic Effect of Zinc Sulfate on Neonatal Hyper-

bilirubinemia
Somayyeh Hashemian1, Ashraf Mohammadzadeh2*, Ahmadshah Farhat2, Mohammad
Ramezani3, Seyed Javad Seyedi4
1. Department of Pediatric Endocrinology and Metabolism .Imam Reza Hospital , Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad,
Iran
2. ween the 3rd and 7th days of life was also more significant among the zinc sulfate group Medical Sciences, Mashhad, Iran
3. Pharmaceutical and Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
4. Neonatal Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

ABSTRACT
Background: Approximately 60% of term neonates and 80% of preterm ones suffer from hyperbilirubinemia in their
first week of life. This study sought to characterize the therapeutic effect of oral zinc sulfate on neonatal
hyperbilirubinemia.
Methods: In this randomized, double-blind, placebo-controlled clinical trial, 70 term neonates with total serum
bilirubin (TSB) level 20 mg/dl were enrolled. Thirty-four cases were treated with phototherapy and zinc (10 mg/day,
single dose) as case, while the remainder received phototherapy plus placebo. TSB level was measured at the onset of
the intervention, as well as 12, 24 and 48 h after the intervention and compared with each other.
Results: The mean TSB levels were significantly lower in the zinc group after 12, 24 and 48 h (P=0.038, 0.005, 0.001,
respectively). The mean durations of phototherapy in the case and control groups were 2.030.174 and 2.330.478
days, respectively, being significantly less in the case group (P=0.002).
Conclusion: This study revealed that oral zinc sulfate at a single dose of 10 mg/day diminished TSB level and duration
of phototherapy.

Keywords: Hyperbilirubinemia, Neonate, Treatment, Zinc sulfate

Introduction
In the recent years, a substantial body of sequel (1, 5). Such complications underscore the
research has been carried out to predict neonates importance of finding further treatments for this
who are most likely to develop hyperbilirubinemia. disease. As of yet, phototherapy and exchange
Reliable prediction can reduce hospital stay for transfusion were the treatment of choice in such
low-risk neonates and identify high-risk neonates cases; however, both of these approaches have
facilitating their closer follow-up (1). several disadvantages (4).
In general, 60% of term newborns and 80% of Exchange transfusion poses the risk of graft
preterm ones present with hyperbilirubinemia in versus host disease and a higher mortality rate
their first week of life (2, 3). The incidence of severe (2). Phototherapy induces parental anxiety due to
neonatal hyperbilirubinemia is the highest in hospitalization and cost of care. Furthermore, it
Asians (2), accounting for one-thirds of neonatal hinders mother-infant bonding. Drug therapy, on
admissions in Iran (3). Jaundice in such cases is the other hand, is more practical, acceptable and
mainly physiologic and diagnosed by ruling out cost-effective.
other causes of jaundice such as hemolysis, In several studies, the associations between
infection, or metabolic diseases, whereas 5-10% microneutrients and jaundice have been proposed.
require intervention (3, 4). The fundamental aim of Some of them, such as zinc sulfate, bind to bilirubin
detecting and treating severe neonatal jaundice is in the small intestine, reduce its absorption and
to prevent bilirubin encephalopathy and its chronic therefore prevent enterohepatic circulation, but
* Corresponding author: Ashraf Mohammadzadeh, Neonatal Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad
University of Medical Sciences, Mashhad, Iran. Tel: (+98)5118521121; Fax: (+98) 5118525316; Email: mohamadzadeha@mums.ac.ir

Please cite this paper as:

Hashemian S, Mohammadzadeh A, Farhat A, Ramezani M, Seyedi SJ. The Therapeutic Effect of Zinc Sulfate on Neonatal
Hyperbilirubinemia. 2017 Jun: 8(2). DOI: 10.22038/ijn.2016.7777
 Hashemian S et al Effect of Zinc Sulfate on Hyperbilirubinemia

with inconsistent results (1, 6). nurses were explained to repeat the dose after 5-
Zinc is one of the essential elements in 10 min if the child vomited the drug.
neonatal growth, protein synthesis and regulation Total and direct serum bilirubin levels were
of inhibitory and stimulatory synapses of the measured at the outset of the intervention, as well
brain. It has been shown to lower bilirubin level as 12, 24 and 48 h after receiving the intervention
by inhibition of the normal enterohepatic cycling and in cases of extended hospitalization after 72 h.
of unconjugated bilirubin (7-9). Therefore, the A written informed consent was signed by the
anticipated role of zinc supplementation in parents of each infant prior to the study. The
neonatal jaundice seems to be an attractive issue. parents were assured that they could withdraw
This randomized clinical trial was conducted their neonates from the study at any time.
on term neonates to characterize the therapeutic The study protocol was approved by the
effect of oral zinc sulfate on neonatal jaundice. Ethics Committee of the Deputy of Research of
Mashhad University of Medical Sciences
Methods (IRCT201306031162N19).
This randomized, double-blind, placebo-
controlled clinical trial was performed during Statistical analysis
July-December 2013. Seventy term neonates who The minimum sample size was calculated based
were admitted to neonatal intensive care unit of on Babaei et al. study (12). Data were analyzed
Imam Reza Hospital of Mashhad, Iran, were using SPSS, version 11.5. Quantitative variables are
selected for the study. The inclusion criteria presented as meanstandard deviation. The normal
comprised of gestational age 38 weeks, birth distribution of variables was proved by
weight 2500 gr and total serum bilirubin level Kolmogorov-Smirnov test. We used independent
20 mg/dl. All cases with hemolysis, glucose-6- samples t-test and Mann-Whitney U test for
phosphate dehydrogenase deficiency disease, comparison of the variables with and without
sepsis, severe respiratory disease requiring normal distribution, respectively. Pearson
mechanical ventilation, congenital anomalies and correlation coefficient and Chi-squared test were
a total serum bilirubin (TSB) of exchange level on used for comparison of qualitative variables.
admission were excluded. Among the 70 enrolled P-value less than 0.05 was considered statistically
neonates, four cases were excluded due to significant.
mechanical removal of bilirubin after exchange
blood transfusion (1 case and 3 controls). Serum Results
bilirubin level was measured using Unistar In the present study, 66 term newborns
Bilirubinometer (Reichert-Jung, Germany). Direct completed the study (n=33 for each group). There
bilirubin was determined by the colorimetric were no significant differences between the two
method proposed by Lathe and Ruthven. groups regarding age, sex, date of jaundice onset,
Phototherapy initiation, duration and termi- mothers parity, route of delivery, birth weight
nation point were decided based on the American and weight at inclusion (Table 1).
Academy of Pediatrics guidelines (AAP 2004) Moreover, laboratory indices including
(10). Each phototherapy unit had four special blue reticulocyte count, hematocrit, as well as total and
lamps (Philips Co, Germany) and was adjusted to direct bilirubin were measured, showing no
25 cm above the infants cots. remarkable differences between the two groups
All the neonates received phototherapy during (Table 1).
the study period. In the study group, besides In the current study, at the first visit which was
phototherapy, 10 mg/day zinc sulfate was 12 h after receiving the medication, a significant
prescribed by the treating physician at a single difference was observed between the zinc and
dose in the form of syrup (based on Maamouri et placebo groups regarding total serum bilirubin
al. study) (11). level (P=0.038). This difference was also present
The control group received placebo with a 24 and 48 h after initiating the medication
similar color, taste, volume and package to the (P=0.005 and 0.001, respectively). Direct serum
zinc sulfate syrup for the same duration and at the bilirubin showed no significant differences
same dosage. The zinc and placebo syrups were between the two groups over time.
distributed by a single physician who was blinded Figure 1 depicts the changes in total serum
to the group allocations and the study protocol. bilirubin level (mg/dl) over time compared to
The pediatrician who visited the neonates was baseline in the two groups.
also blind to the type of intervention. The on-duty Changes in total and direct serum bilirubin

14 Iranian Journal of Neonatology 2017; 8(2)

Effect of Zinc Sulfate on Hyperbilirubinemia Hashemian S et al

Table 1. Demographic characteristics of the case and control groups

Zn Placebo P-value
Sex (%Female) 41.2 47.2 0.611
Age (day) 6.62.57 5.81.89 0.138
Date of jaundice onset (day) 3.31.35 3.00.95 0.300
Parity (Number) 1.40.65 1.60.75 0.326
Delivery route (%NVD) 75.0 52.0 0.095
Birth weight (gr) 3080.7564.60 3155.2458.17 0.592
Weight at inclusion (gr) 3159.6489.37 3173.0437.74 0.915
Hematocrit (%) 46.55.90 45.95.40 0.641
Reticulocyte count (%) 1.31.45 1.01.01 0.487
Total serum bilirubin (mg/dl) 22.52.31 21.51.61 0.052
Direct serum bilirubin (mg/dl) 0.620.218 0.670.224 0.718

with phototherapy can significantly reduce TSB

level. Moreover, we found a significant difference
in the mean TSB levels after 12, 24 and 48 h of
treatment between the zinc and placebo groups,
suggesting that zinc sulfate may play a certain role
in reducing neonatal hyperbilirubinemia.
Drug therapy is associated with high compliance
and low cost of care. Clofibrate, phenobarbtal, bile
salts, dipenycilamine, and zinc compounds were
found to act through different mechanisms such as
production inhibition, stimulation of hepatic
clearance and enzymatic inhibition (3, 13-16).
Figure 1. Changes in mean total serum bilirubin level over However, none of them has been proposed as a
time in the study and control groups common therapeutic method so far.
Zinc salts were demonstrated to be promising
in Table 2. both in-vitro and in-vivo (1). In other words, the
Moreover, one of the case and 11 of the control action of zinc in hyperbilirubinemia depends on
group subjects required treatment continuation its ability to reach the distal intestine where it is
up to 72 h. The other infants were all discharged once again absorbed into the blood, and therefore,
after 48 h of treatment. reduces the enterohepatic circulation.
The mean durations of phototherapy in the The first human study on this issue was carried
case and control groups were 2.030.174 and out by Mendez-Sanchez et al. on 20 adult patients
2.330.478 days, respectively, showing a of Gilbert syndrome. They reported that zinc sulfate
significantly shorter duration in the zinc sulfate significantly decreased serum unconjugated
group based on Mann-Whitney test (P=0.002). bilirubin level (9).
During the treatment period, no drug-related In another study, Rana et al. (1) investigated
side effects were observed in either group. the impact of oral zinc salt on the incidence of
hyperbilirubinemia and need for phototherapy in
Discussion term and late-preterm at-risk neonates between 25
This study revealed that zinc sulfate and 168 h of age. They concluded that twice-daily
supplementation at a dose of 10 mg/day along

Table 2. Changes in total and direct serum bilirubin levels after the intervention
Zn (n=33) Control (n=33)
Plasma bilirubin level (mg/dl) Mean (SD) Mean (SD) P-value
range range
22.5 (2.31) 21.5 (1.61)
Total serum bilirubin, baseline 0.052
20-26 20-26.5
17.3 (1.62) 18.2 (1.33)
Total serum bilirubin, after 12h 0.038
14.2-21.9 15.6-22.0
13.8 (1.98) 15.2 (1.72)
Total serum bilirubin, after 24h 0.005
7.1-17.4 12.3-18.0
10.3 (2.09) 11.9 (1.74)
Total serum bilirubin, after 48h 0.001
6.0-13.0 7.7-15.5
11.4 (1.17)
Total serum bilirubin, after 72h 8.6 0.045
9.8-12.6

15 Iranian Journal of Neonatology 2017; 8(2)

 Hashemian S et al Effect of Zinc Sulfate on Hyperbilirubinemia

administration of oral zinc at a dose of 10 mg does Recommended Dietary Allowance recommend-

not reduce the incidence of hyperbilirubinemia in dations and the available literature, yet a different
such cases during the first week of life (1). dosage may have resulted differently. In addition,
Mosayebi et al. evaluated the serum zinc level starting the treatment sooner might have
alterations before and after phototherapy in influenced our findings and limited the impact of
hyperbilirubinemic newborns. They concluded other variables existing between birth and
that phototherapy increases serum zinc level by admission. Furthermore, we did not check the zinc
reducing bilirubin level, such that additional serum level before and after the intervention.
supplementation of this element can potentially
lead to zinc toxicity (17). Conclusion
Mafinejad et al. (2012) studied the prophylactic Administering oral zinc sulfate at a single dose
effects of zinc sulfate in neonatal hyperbilirubinemia. of 10 mg/day reduced the mean TSB level and
They showed that administration of zinc sulfate duration of phototherapy. Zinc, as a micronutrient,
neither affected hyperbilirubinemia nor delayed may be recommended as a safe and effective
jaundice manifestation. They observed that the medication in neonatal non-hemolytic jaundice
duration of phototherapy and hospitalization were besides phototherapy. Further studies with larger
less in zinc group. Weight gain between the 3rd and sample sizes, different dosages and formulations
7th days of life was also more significant among the of zinc, and more precise laboratory studies are
zinc sulfate group (11). recommended to confirm our findings.
In Vitek et al. study, the oral administration of
zinc salts efficiently decreased serum bilirubin Acknowledgments
level in hyperbilirubinemic rats, most probably The authors wish to thank Deputy of Research
due to the inhibition of enterohepatic circulation of Mashhad University of Medical Sciences for
of bilirubin. They suggested that this approach funding this project. We would also like to extend
might be useful for the treatment of severe our gratitude to Miss Mozhdeh Mahmoodi for data
unconjugated hyperbilirubinemia (8). capture and Miss Najmeh Saberi for her assistance
Nevertheless, Patton et al. studied the effect of with typing the article.
oral zinc on 60 neonates with hyperbilirubinemia.
The neonates received 5 mg oral zinc twice daily Conflicts of interests
for five days. They reported that bilirubin level None
measurement on day 5 of treatment showed no
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