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Zinc supplements for treating thalassaemia and sickle cell disease

  1. Kye Mon Min Swe1,*,
  2. Adinegara BL Abas1,
  3. Amit Bhardwaj2,
  4. Ankur Barua3,
  5. N S Nair4

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 28 JUN 2013

Assessed as up-to-date: 20 JUN 2013

DOI: 10.1002/14651858.CD009415.pub2


How to Cite

Swe KMM, Abas ABL, Bhardwaj A, Barua A, Nair NS. Zinc supplements for treating thalassaemia and sickle cell disease. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD009415. DOI: 10.1002/14651858.CD009415.pub2.

Author Information

  1. 1

    Melaka-Manipal Medical College (MMMC), Department of Community Medicine, Melaka, Malaysia

  2. 2

    Melaka-Manipal Medical College (MMMC), Department of Orthopaedics, Melaka, Melaka, Malaysia

  3. 3

    International Medical University (IMU), Department of Community Medicine, Kuala Lumpur, Malaysia

  4. 4

    Manipal University, Department of Statistics, Manipal, Karnataka, India

*Kye Mon Min Swe, Department of Community Medicine, Melaka-Manipal Medical College (MMMC), Jalan Batu Hampar, Bukit Baru, Melaka, 75150, Malaysia. khmoneminswe@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 28 JUN 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms
 

Description of the condition

Haemoglobinopathies, inherited disorders of haemoglobin synthesis (thalassaemia) or structure (sickle cell disorders), are responsible for significant morbidity and mortality all over the world (Tracey 2005). The WHO estimates that globally 5% of adults are carriers of a haemoglobin condition, 2.9% of thalassaemia and 2.3% of sickle cell disease (WHO 2006). Carriers are found worldwide as a result of migration of various ethnic groups to different regions of the world (Stewart 2007).

Sickle cell haemoglobinopathies are heredity disorders in which red cells contain haemoglobin S, due to a mutation in the beta-globin gene. There are different types of sickle cell disease (SCD) (e.g. sickle cell anaemia (SS), sickle cell haemoglobin C (SC), sickle cell beta thalassaemia (SBThal), etc) and these can be diagnosed with blood tests or genetic testing. In SCD, the red blood cells become rigid and distorted assuming a sickle shape. This leads to a reduction in oxygen-carrying capacity and these abnormal cells block the blood vessels resulting in tissue hypoxia and consequent pain. Symptoms such as severe anaemia, susceptibility to infections and damage to major organs are also seen. Treatment involves managing the anaemia, chronic pain, and organ damage caused by SCD.

Thalassaemia is a heterogeneous group of disorders with a genetically determined reduction in one or more types of haemoglobin polypeptide chain, resulting in a decrease in the amount of haemoglobin involving the affected chain. The most common types are alpha and beta thalassaemia. Children affected with thalassaemia show no symptoms at birth, but anaemia emerges in the first few months of life, becoming progressively severe and leading to pallor, easy fatigability, failure to thrive, a delay in maturity and fever. Treatment based on blood transfusions is helpful but not curative. Early treatment of thalassaemia has proved to be very effective in improving the quality of life of patients (Firkin 1989).

The low haemoglobin in SCD and thalassaemia patients is obviously due to haemolysis caused by the genetic mutation of haemoglobin, and hence one should not expect haemoglobin levels to increase following zinc supplementation.

Zinc is primarily an intracellular component and hence decreased plasma levels of zinc are not necessarily markers of zinc deficiency.  Red blood cells, neutrophils and platelets are very rich in zinc. Plasma zinc assays are unreliable unless the blood is processed within two hours after collection.In vitro haemolysis of blood samples from patients with SCD after two hours of collection raises the plasma zinc level thus obscuring the distinction between people who are zinc-sufficient and those who are zinc-deficient. Zinc deficiency is best diagnosed by the decreased content of intracellular zinc in red blood cells, neutrophils and platelets. Moreover, patients with SCD also have hyperzincuria which contributes to zinc deficiency (Prasad 1966; Prasad 1975). In thalassaemia, the expected low serum zinc level is due to haemolysis, loss in urine and inadequate dietary intake (Prasad 1965).

 

Description of the intervention

Zinc is one of the essential micronutrients in humans and acts as a co-factor for more than 300 enzymes. It plays a particular role in human growth and development. Zinc is present in all tissues, fluids, and secretions in the body and is critical to cellular metabolism, physical growth, immune-competence, reproductive functions, integrity of intestinal mucosa and neuro-behavioural development (Mahyar 2010). Zinc has several roles in biochemical and hormonal functions of various endocrine organs (Prasad 1985).

Zinc deficiency is observed in pathological conditions including haemoglobinopathies. Many studies have shown that zinc deficiency is fairly common in patients with SCD (Daeschner 1981; Phebus 1988). Patients with beta thalassaemia major suffer from zinc deficiency which could be seen as one of the causes of delayed maturity. Zinc deficiency is also found in patients with SCD and several clinical manifestations of this disorder have been subsequently related to it. The daily requirement of zinc varies with age. For adults, the recommended dietary allowance (RDA) of 15 mg daily is regarded as adequate to prevent deficiencies. For infants and children aged seven to 10 years, the RDA is 7 mg and 10 mg per day respectively (RDA 1989). A number of zinc supplements are available, with zinc sulphate being the most frequently used (Aggett 1995; Bhatangar 2004). The recommended dose of zinc supplementation for optimal effects on incidences of infection and pain crises is usually 50 mg to 75 mg elemental zinc daily. This dose of zinc could be associated with copper deficiency. If the dose of elemental zinc is greater than 50 mg/d, 1 mg of elemental copper as sulfate should be added to the regimen to prevent copper deficiency.

 

How the intervention might work

In cases of thalassaemia, zinc supplementation corrects the risk of zinc deficiency from various causes including desferrioxamine injections. Studies have shown that zinc supplementation in patients with thalassaemia increases bone mass, improves linear growth and corrects immunodeficiency and growth delay.

For SCD, studies have shown that zinc can improve the sickle cell membrane status, antagonise intracellular calcium, and affect red cell dehydration (Bennekou 2001). Studies have demonstrated a significant reduction in the number of sickle-related events in people treated with zinc sulphate and also suggested a benefit for other problems in SCD, including leg ulcers, growth, infection and androgen deficiency in male participants (Nagalla 2010). Zinc supplementation has also been found to decrease the incidence of infection and pain crises by correcting T helper 1 functions and cell-mediated immunity (Prasad 1999). In addition, improvement in the rate of linear growth has been demonstrated after zinc supplementation in pre-pubertal children with SCD (Zemel 2002).

Zinc also facilitates red cell deformability, so that in the case of haemoglobinopathies, there is a reduction in the amount of red cells destroyed by the spleen. For haemoglobinopathies, some evidence suggests that preventive zinc supplementation may reduce mortality and morbidity, particularly in sickle cell anaemia and thalassaemia (Arcasoy 1987).

 

Why it is important to do this review

It has been estimated that approximately 5% of the world's population are carriers of haemoglobinopathies (WHO 2006) and that 300,000 to 400,000 babies with severe forms of these diseases are born each year. If left untreated these result in death in the first few years of life (WHO 1989). Various studies have found beneficial effects of zinc supplementation to zinc-deficient SCD and thalassaemia patients (Arcasoy 1987; Prasad 2007; Zemel 2002).

Zinc is an easily available supplement; and intervention programs have been carried out to prevent deficiency in people with thalassaemia or sickle cell anaemia. It is important to evaluate the role of zinc supplementation in the treatment of thalassaemia and SCD to reduce deaths due to complications.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms

To assess the effect of zinc supplementation in the treatment of thalassaemia and SCD.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised control trials (RCTs) and controlled clinical trials.

 

Types of participants

People of all ages who have been diagnosed with thalassaemia or SCD.

Diagnosis of SCD, sickle cell trait and thalassaemia can be done through blood testing, using a technique called haemoglobin electrophoresis; Hb-S may be demonstrated on cellulose acetate at PH 8.6 between Hb A and Hb A2 in SCD and the amount of Hb A2 level and Hb F will increase in different types of thalassaemia (Firkin 1989).

 

Types of interventions

Oral zinc supplements regardless of dosage and type versus oral supplements without zinc (placebo).

 

Types of outcome measures

 

Primary outcomes

 
Thalassaemia

  1. Haemoglobin level
  2. Serum zinc level
  3. Anthropometry measurements

 
Sickle cell disease

  1. Haemoglobin level
  2. Serum zinc level
  3. Anthropometry measurements

 

Secondary outcomes

 
Thalassaemia

  1. Bone mineral index
  2. Frequency of blood transfusion
  3. Duration of blood transfusion

 
Sickle cell disease

  1. Number of sickle cell crises
  2. Complications due to underlying disease (e.g. infection, renal effects, red blood cell dehydration, leg ulcers)
  3. Quality of life

 

Search methods for identification of studies

 

Electronic searches

Relevant studies were identified from the Cystic Fibrosis & Genetic Disorders Review Group's Haemoglobinopathies Trials Register using the term: zinc.

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.

Date of the last search: 01 February 2013.

 

Searching other resources

References of the identified relevant trials were scrutinized for additional citations. We contacted organisations and researchers working in this field as well as manufacturers of zinc supplements to identify additional trials (including unpublished and ongoing trials).

 

Data collection and analysis

 

Selection of studies

The review authors (KM and ALA) independently assessed trial eligibility and screened all available titles and abstracts for inclusion using an eligibility form designed in accordance with the specified inclusion criteria. For those trials we were unable to ascertain the relevance of by simply screening the title and abstract, we retrieved and reviewed the full text of the articles. We resolved disagreements by discussion and by consultation with a third review author. We also displayed trials excluded from the review in the form of a table along with the reason for exclusion.

 

Data extraction and management

Two review authors (KM and AB) independently collected the data (trial characteristics and results), for thalassaemia and SCD separately, compared the results and corrected errors. We resolved disagreements through discussion, and by consultation with the third review author. We planned to report outcomes at up to one month, over one month to three months, over three months to six months and over six months to one year and more than one year. They were to also consider additional follow-up data recorded at other time periods. However, in the current version of the review we were only able to include three-month, six-month and one-year data as provided in the included trials.

 

Assessment of risk of bias in included studies

Two authors (KM, ALA) independently assessed the risk of bias of the included trials by using the criteria outlined in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). We assessed sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential sources of bias. We also judged each domain as having either a ‘low risk’, ‘high risk, or ‘unclear risk’ of bias.

 

Measures of treatment effect

For dichotomous data, we presented results as odds ratios (OR) with 95% confidence intervals (CIs). For continuous data, where outcomes were measured in the same way between trials, we used the mean difference (MD) with 95% CIs. Where publications presented the MD and standard error (SE), we calculated the standard deviation (SD). One cross-over trial was included in the review and reported data for one of the review's primary outcomes (serum zinc level). These data were presented for each individual and we calculated the MD and the SE for each treatment arm and entered these data into the meta-analysis using the generic inverse variance method.

For future updates, when appropriate, we plan to use the standardized mean difference (SMD) to combine trials that measured the same outcome, but used different methods (Higgins 2011). For count data we calculated the MD.

 

Unit of analysis issues

In this review we have treated the participant as the unit of analysis. This is important as the meta-analytic techniques used assume independence between measurements, and more than one treated event (e.g. 'crisis') per participant would not be statistically independent. A result of ignoring this unit of analysis issue could be overly optimistic CIs. Where the data are reported as events, rather than as participants, we have reported these data within an additional table.

 

Dealing with missing data

In order to allow an intention-to-treat analysis, we searched for full reports from the investigators where trials have been published in abstract form only, presented at meetings or reported to the co-authors. Where information was missing or unclear, we contacted the investigators for further details.

 

Assessment of heterogeneity

We used the Chi2 test for heterogeneity (significance level P < 0.1) and quantify the degree of heterogeneity by means of the I2 statistic. We used the following guidelines for the interpretation of the I2 values (Higgins 2011):

0% to 40%: might not be important;

30% to 60%: may represent moderate heterogeneity;

50% to 90%: may represent substantial heterogeneity;

75% to 100%: considerable heterogeneity.

Where the I2 value was at 50% or more, we regarded as significant heterogeneity.

 

Assessment of reporting biases

We did comprehensive searches in an attempt to minimise publication and reporting biases and the likelihood of these biases will be considered. Within studies, selective outcome reporting was considered as part of risk of bias assessment. We compared the ’Methods’ section of the full published paper to the ’Results’ section to ensure that all outcomes which were measured, were reported. We planned to assess publication bias by using a funnel plot. However, there were insufficient trials with similar outcome measures to undertake these analyses.

 

Data synthesis

Where trials were clinically and methodologically comparable, we carried out meta-analysis using the Review Manager software (RevMan 2011). Given there was no significant heterogeneity and trials were sufficiently similar, the authors used a fixed-effect meta-analysis model for combining data. For future updates, if we find significant heterogeneity, we plan to use a random-effects model.

 

Subgroup analysis and investigation of heterogeneity

Providing there were sufficient trials, and if we found significant heterogeneity, we planned to carry out the subgroup analyses listed below, however, there were insufficient trials with similar outcome measures to undertake these analyses. We plan to undertake these subgroup analyses in future versions of the review if there are a sufficient number of trials included for either disease (10 or more).

  1. Different durations of zinc supplementation (less than three months, three months to one year, one year to five years)
  2. Different doses of zinc used (low dose versus high dose)
  3. Haemoglobin level of participants (baseline haemoglobin level less than 10 mg/dl and more than 10 mg/dl)
  4. Different types of complication (infection, sickle cell crisis, leg ulcers, linear growth)

 

Sensitivity analysis

We planned to carry out a sensitivity analysis to explore the effect of the risk of bias of the trials (assessed by concealment of allocation), by excluding trials with a high risk of bias for this domain. However, there were insufficient trials with similar outcome measures to do this analysis in this version of the review.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms
 

Description of studies

 

Results of the search

We identified 17 records of which 11 records were identified through database searching and another six were identified through other sources such as MEDLINE and PubMed. From this list, we removed three records that were considered as duplicates, leaving us a total of 14 trials. We proceeded to obtain the full text of all 14 trials. Following the assessment of these full text articles, we considered nine trials (published in eight papers) for inclusion in this review and excluded six trials. We listed one trial (zinc and bone health in thalassaemia by the Children's Hospital and Research Centre Oakland (NCT00459732)) as ongoing (Figure 1).

 FigureFigure 1. Study flow diagram

 

Included studies

We identified nine trials that met our inclusion criteria. Two of these trials were in patients with thalassaemia (Acrasoy 1987; Rashidi 2011) (n = 152) and the remaining seven trials were in patients with sickle cell anaemia (n = 307) (Bao 2008; Gupta 1995; Prasad 1981 (1); Prasad 1981 (2); Prasad 1999; Serjeant 1970; Zemel 2002). The 1981 Prasad paper reported on two separate trials (Prasad 1981 (1); Prasad 1981 (2)).

 

Thalassaemia

Two trials were on individuals with thalassaemia (Acrasoy 1987; Rashidi 2011).

One trial was a RCT conducted at a Turkish hospital (Acrasoy 1987), while another was double-blind RCT conducted in the Golestan province in northern Iran (Rashidi 2011). In the Acrasoy study, zinc acetate in the form of 22.5 mg elemental zinc in gelatin capsules was used, while in the Rashidi trial, 220 mg zinc sulphate containing 50 mg zinc daily for three months was used (Acrasoy 1987; Rashidi 2011). In the Acrasoy trial the duration of zinc therapy ranged from one to seven years in both groups and linear growth of all patients was assessed in to comparison with the growth curves of Turkish children (Acrasoy 1987). In the Rashidi trial, zinc supplementation was given over a three-month period (Rashidi 2011). Regarding age, in Acrasoy trial, the age range was from 1 to 18 years (Acrasoy 1987) and in Rashidi trial, the participants were over 18 years of age (Rashidi 2011).The outcomes in the Acrasoy trial centred mainly on growth (height velocity) (Acrasoy 1987), while the outcomes for the Rashidi trial were serum zinc levels, serum vitamin E levels and enzymes, such as super oxide dismutase activity and total antioxidant capacity activity (Rashidi 2011).

 

Sickle cell disease

Seven trials were on individuals with sickle cell anaemia (Bao 2008; Gupta 1995; Prasad 1981 (1); Prasad 1981 (2); Prasad 1999; Serjeant 1970; Zemel 2002). One trial was conducted in India (Gupta 1995), one in Jamaica (Serjeant 1970) and the remaining five in the USA (in regions of Detroit and Philadelphia). There were six parallel trials and one cross-over trial (Prasad 1981 (1)).

Regarding the type of zinc used, in five trials the intervention groups received zinc acetate (Bao 2008; Prasad 1981 (1); Prasad 1981 (2); Prasad 1999; Zemel 2002) and in remaining two trials zinc sulphate was used (Gupta 1995; Serjeant 1970).

The duration of zinc supplementation varied (as well as the evaluation periods), the interval being three months for one trial (Bao 2008), six months for another (Serjeant 1970) and one year for the remaining four trials (Prasad 1981 (1); Prasad 1981 (2); Prasad 1999; Zemel 2002).

The age range also varied across different trials; four of these recruited only adults: Bao 2008 (18 to 47 years); Prasad 1981 (1) and Prasad 1981 (2) (16 to 28 years); and Prasad 1999 (19 to 49 years). For a further trial the participants were over five years of age (Gupta 1995) and in the Zemel trial participants were aged 4 to 11 years (Zemel 2002). Serjeant did not report an age range (Serjeant 1970).

Regarding the outcomes across trials, three trials had similar outcomes (Bao 2008; Gupta 1995; Prasad 1999). Gupta measured sickle cell crises as the primary outcome (Gupta 1995), Prasad measured the total number of sickle cell crises and the total number of infections (Prasad 1999) and Bao hypothesized that zinc supplementation would promote the immune system and measured the number of sickle cell crises and the number of infections (Bao 2008). Two trials by Prasad assessed the effect of serum testosterone level in zinc supplementation and measured serum zinc level in SCD patients as one of the outcomes (Prasad 1981 (1); Prasad 1981 (2)). The major outcome of the trial was the improvement of leg ulcers in patients with SCD (Serjeant 1970); and Zemel measured for growth and body composition, especially height, in prepubertal children after supplementation with zinc (Zemel 2002).

 

Excluded studies

There were a total of four trials excluded (Mehdizadeh 2008Prasad 1975Prasad 1983a; Tschumi 1981). Three trials were not RCTs (Mehdizadeh 2008; Prasad 1975; Prasad 1983a) and the fourth trial did not include individuals with SCD or thalassaemia (Tschumi 1981).

 

Risk of bias in included studies

Please refer to the figures for an overall assessment of the risk of bias (Figure 2; Figure 3).

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

All of the trials reported the use of randomisation techniques, however, only two provided further details of these and we therefore assessed these as having a low risk of bias in this domain (Gupta 1995; Rashidi 2011). We have assessed the remaining four trials as having an unclear risk of bias for this domain (Acrasoy 1987; Bao 2008; Prasad 1999; Zemel 2002).

None of the included trials described the method of allocation concealment and we have therefore assessed all as having an unclear risk of bias.

 

Blinding

Six of the nine trials included in the analysis reported the use of a double-blinding procedure during the trial (blinding of some or all relevant individuals involved in the trial) (Bao 2008; Gupta 1995; Prasad 1981 (1); Prasad 1981 (2); Serjeant 1970; Rashidi 2011) (we have classified five trials as having a low risk of bias for the blinding of participants, personnel and outcome assessors, and one trial as having a low risk of bias for participants and personnel and an unclear risk for outcome assessors). The remaining three trials did not provide details of the blinding procedure and were therefore categorised as having an unclear risk of bias (Acrasoy 1987; Prasad 1999; Zemel 2002).

 

Incomplete outcome data

Six of nine trials included in the analysis had complete outcome data (Acrasoy 1987; Bao 2008; Prasad 1981 (1); Prasad 1981 (2); Prasad 1999; Rashidi 2011). The remaining three trials presented incomplete outcome data (Gupta 1995; Serjeant 1970; Zemel 2002). We regarded two of these trials as adequately accounting for the incomplete data (Serjeant 1970; Zemel 2002) but the third trial did not account for the 10% of recruited participants who were lost to follow up. (Gupta 1995). Therefore, we classified five trials as having a low risk of bias for this domain (Acrasoy 1987; Bao 2008; Prasad 1981 (1); Prasad 1981 (2); Prasad 1999; Rashidi 2011; Serjeant 1970; Zemel 2002) and one as having an unclear risk of bias (Gupta 1995).

 

Selective reporting

None of the trials included in the analysis showed any evidence of selective reporting, although this was difficult to assess because the outcomes of interest in this review were not the primary outcomes of any of the trials.

 

Other potential sources of bias

None of the included trials reported any other potential sources of bias. There was no clear evidence of any other bias in any of the trials included in the analysis.

 

Effects of interventions

 

Thalassaemia

We identified two trials (n = 152) for inclusion (Acrasoy 1987; Rashidi 2011). Zinc acetate was supplemented in the first trial (n = 32) (Acrasoy 1987) and zinc sulphate in the second (n = 120) (Rashidi 2011).

 

Primary outcomes  

 
1. Haemoglobin level

This outcome was not assessed in either of the included trials (Acrasoy 1987; Rashidi 2011).

 
2. Serum zinc level

One trial reported on this outcome (Rashidi 2011). There was no significant difference noted in serum zinc level between the group receiving zinc sulphate supplementation and control group, MD 47.70 (95% CI -12.59 to 107.99) (Rashidi 2011) ( Analysis 1.1).

 
3. Anthropometry measurement

One trial reported on body mass index (Rashidi 2011). In the analysis of body mass index there was no significant difference observed between the group receiving zinc sulphate supplementation and the control group, MD 0.70 (95% CI -0.55 to 1.95) (60 participants included) (Rashidi 2011) ( Analysis 1.2). Regarding height velocity, Acrasoy reported that this was significantly increased in patients who acquired zinc acetate supplementation for one year duration, MD 3.37 (95% CI 2.36 to 4.38) (Acrasoy 1987) ( Analysis 1.3).

 

Secondary outcomes  

 
1. Bone mineral index

This outcome was not assessed in either of the included trials (Acrasoy 1987; Rashidi 2011).

 
2. Frequency of blood transfusion

This outcome was not assessed in either of the included trials (Acrasoy 1987; Rashidi 2011).

 
3. Duration of blood transfusion

This outcome was not assessed in either of the included trials (Acrasoy 1987; Rashidi 2011).

 

Sickle cell disease

We identified seven trials (n = 307) for inclusion (Bao 2008; Gupta 1995; Prasad 1981 (1), Prasad 1981 (2) Prasad 1999; Serjeant 1970; Zemel 2002). Zinc acetate was supplemented in five trials (n = 128) (Bao 2008; Prasad 1981 (1); Prasad 1981 (2); Prasad 1999; Zemel 2002) and zinc sulphate in two trials (n = 179) (Gupta 1995; Serjeant 1970).

 

Primary outcomes  

 
1. Haemoglobin level

Two trials included analysis of haemoglobin level (Bao 2008; Prasad 1999). In one trial, the duration of zinc acetate supplementation was three months and there was no significant difference noted between the group receiving zinc acetate supplementation and control group in haemoglobin level, MD 0.06 (95% CI -0.84 to 0.96) (Bao 2008) ( Analysis 2.1). In the Prasad trial there was no significant difference noted between the group receiving zinc acetate supplementation and control group in haemoglobin level, MD - 0.07 (95% CI -1.40 to 1.26) (Prasad 1999) ( Analysis 2.1).

The Gupta trial (zinc sulphate) reported haemoglobin concentration as a percentage; however, only the mean value was reported, there was no report of the SD (Gupta 1995). There was also not enough data to consider imputation of the SD.

 
2. Serum zinc level

Four trials reported analysis of serum zinc level (Bao 2008; Prasad 1981 (1); Prasad 1981 (2); Prasad 1999). In one trial with a three-month intervention (zinc acetate), there were significant increases in serum zinc level, MD 14.90 (95% CI 6.94 to 22.86) (Bao 2008); and in two further trials the group receiving zinc acetate supplementation for one year had significantly higher serum zinc levels as compared to the control group, MD 20.25 (95% CI 11.73 to 28.77) (Prasad 1981 (2); Prasad 1999 ) ( Analysis 2.2). In the remaining trial (a cross-over trial) the results show a significant difference in favour of zinc acetate supplementation, MD -35.00 (95%CI -53.95 to -16.05) (Prasad 1981 (1)) ( Analysis 2.3).

The Gupta trial (zinc sulphate) did actually report serum zinc level in microgram per decilitre (Gupta 1995). However, only the mean value with no SD was reported. There was also not enough data to consider imputation of the SD.

 
3. Anthropometry measurement

One trial reported on this outcome (Zemel 2002). There was no significant difference observed with regards to body mass index between the group receiving zinc acetate supplementation and control group, MD 0.00 (95% CI -1.13 to 1.13) (Zemel 2002) ( Analysis 2.4). As for weight, there was no significant difference observed between zinc acetate supplementation and control group, MD -1.50 (95% CI -5.07 to 2.07) (Zemel 2002) ( Analysis 2.5).

 

Secondary outcomes  

 
1. Number of sickle cells crises

Two trials reported on number of sickle cell crises (Gupta 1995; Prasad 1999).

The Gupta trial on zinc sulphate supplementation reported a reduction in the number of crises at three months, for those receiving zinc sulphate supplementation (n = 65) as compared to the control group (n = 65) (Gupta 1995). Given the 'crisis' was the unit of analysis for this outcome we are not able to enter these data into RevMan and they are instead are provided in an additional table ( Table 1).

Only two trials reported on the mean number of sickle cell crises at one year, the group receiving zinc supplementation was noted to have significantly fewer crises as compared to control group, MD -2.83 (95% CI -3.51 to -2.15) (n = 130) (P < 0.00001) for zinc sulphate, but no significant difference was noted in zinc acetate group, MD 1.54 (95% CI -2.01 to 5.09) (n = 22) (Gupta 1995; Prasad 1999) ( Analysis 2.6).

 
2. Complications due to underlying disease (e.g. infection, renal effects, red blood cell dehydration, leg ulcers)
 
Infection

Three trials reported on this outcome (Bao 2008; Prasad 1999; Serjeant 1970).

For the number of clinical infections at three months, the group receiving zinc acetate supplementation was found to have fewer infections as compared to the control group, OR 0.05 (95% CI 0.01 to 0.43) (Bao 2008) ( Analysis 2.7).

Similarly, at one year, with regards to the number of clinical infections, the group receiving zinc acetate supplementation was found to have fewer infections as compared to the control group, MD -7.64 (95% CI -10.89 to -4.39) (Prasad 1999) ( Analysis 2.8).

One trial reported on the improvement of leg ulcers (Serjeant 1970). The group receiving zinc sulphate supplementation was found to have more healing leg ulcers as compared to the control group, OR 4.06 (95% CI 0.63 to 26.13) ( Analysis 2.9).

 
3. Quality of life

This outcome was not assessed in any of the included trials.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms
 

Summary of main results

We identified nine trials for inclusion and all nine contributed some outcome data. Four out of seven trials, on sickle cell anaemia, showed an increase in the level of zinc amongst the intervention group as compared to the control group (Bao 2008; Prasad 1981 (1); Prasad 1981 (2); Prasad 1999). However, caution is required when interpreting this finding as the raised plasma zinc level may be associated with intravascular haemolysis in blood samples of patients that were not processed immediately (Prasad 1983b). Regarding anthropometry, there was no significant change in either body mass index or weight after one year of zinc supplementation. However, height velocity was noted to be significantly increased in patients who received zinc supplementation for one year duration.

The mean number of sickle cell crises were significantly decreased in the zinc sulphate (but not the zinc acetate) supplementation group in comparison with the control group in SCD patients after one year of zinc supplementation.

The total number of clinical infections were significantly decreased in the zinc supplementation group in comparison with the control group in SCD patients after three months and one year of zinc supplementation.

A significant improvement in the healing of ulcers was found by Serjeant in the zinc supplementation group in comparison with the control group in people with SCD (Serjeant 1970).

Two trials assessed patients with thalassaemia. In one trial, neither the serum zinc level value nor body mass index showed a difference between zinc supplemented group and control group. However, in the second trial, height velocity was significantly increased in patients who received zinc supplements for between one and seven years.

 

Overall completeness and applicability of evidence

Although the total number of trials is small, the overall conclusion is that zinc supplementation gave mixed evidence on beneficial effects in both sickle cell anaemia and beta thalassaemia patients. Currently, there are limited treatment options for patients with SCD to prevent both infection and painful crises, the two most difficult complications of this disease; zinc seems to be the only therapeutic option available at present.

 

Quality of the evidence

The trial evidence included is generally of good quality, with a low risk of bias. Four of the eight trials reported detailed explanations on blinding procedures. Three of the eight included trials were found to have some degree of loss to follow up (Gupta 1995; Serjeant 1970; Zemel 2002). However, given we regarded an overall attrition rate of greater than 20% to indicate a high risk of bias (Thomas 2006), on this basis these three trials (for this domain) were considered to be of low risk of bias. The majority of the trials were carefully conducted hospital-based trials, with active mechanisms in place to promote adherence to the intervention, and active-case finding. However, although all of the trials reported the use of randomised methods, the majority did not elaborate on the method used nor on the allocation concealment methods employed.

 

Potential biases in the review process

Although zinc supplementation in SCD patients was observed to improve serum zinc level and reduce complications such as number of sickle cell crises and clinical infections, there were some limitations noted in the trials. For instance, there were variations with regards to the the duration of zinc supplementations received. To reduce bias, we used the results of zinc supplementation at three months, six months and one year. The age of the participants was also not homogenous, but due to the limited number of included trials our planned subgroup analysis was not possible. In addition, there were two types of zinc used as supplements (zinc sulphate and zinc acetate), which were not combined; furthermore, these were of different doses. Another limitation of the trials was the lack of reported data, which highlights the need for better reporting of trials.

 

Agreements and disagreements with other studies or reviews

We are unaware of similar reviews covering this topic.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms

 

Implications for practice

There is evidence that, in SCD, zinc sulphate is associated with an increased serum zinc level after supplementation of zinc for one year and also with a reduction in pain crises and other complications such as infections. This was despite the treatment not being associated with an improvement in any of the haematological outcomes. Zinc is the only possible therapeutic modality available at present, the use of which is supported by this review.

In thalassaemia, there has been no evidence to indicate that zinc supplementation will lead to an increased serum zinc level, but there has been an improvement in some anthropometry measurements.

 
Implications for research

Initial results do seem to favour zinc supplementation in patients with SCD; however further trials need to be conducted to improve the validity of the review. For instance, multicentre RCTs of zinc supplementation should be conducted in both patients with SCD and thalassaemia. To investigate whether the findings previously reported were consistent and sustained, these future trials should involve more participants and should have a longer duration of zinc supplementation than those reported in this review.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms

We would like to thank Professor Datuk Dr. Abdul Razzak, the Chief Executive of Melaka-Manipal Medical College and Professor Dr. Jaspal Singh Sahota, Dean of Melaka-Manipal Medical College (MMMC) Malaysia for providing administrative support and helping us with their constant encouragement, meticulous supervision and constructive comments on this protocol.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms
Download statistical data

 
Comparison 1. Zinc versus placebo (thalassaemia)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Serum zinc level1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 At 3 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Body mass index1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 At 3 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Height velocity1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    3.1 At
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Zinc versus placebo (sickle cell disease)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Haemoglobin2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 At 3 months
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 At 1 year
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Serum zinc level3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 At 3 months
136Mean Difference (IV, Fixed, 95% CI)14.90 [6.94, 22.86]

    2.2 At 1 year
235Mean Difference (IV, Fixed, 95% CI)20.25 [11.73, 28.77]

 3 Serum zinc level1Mean Difference (Fixed, 95% CI)Totals not selected

    3.1 At 1 year
1Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Body mass index1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 At 1 year
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Weight1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 At 1 year
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Sickle cell crisis2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 Zinc sulphate (at 1 year)
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 Zinc acetate (at 1 year)
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Total number of infection1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    7.1 At 3 months
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Total number of infection1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    8.1 At 1 year
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Improvement in leg ulcer1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    9.1 At 6 months
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms


Preliminary database searchDr Kye Mon, Dr Adinegara

Develop and run the search strategiesDr Kye Mon and the Group's Trials Search Co-ordinator performed these

BackgroundDr Kye Mon, Dr Adinegara, Dr Amit, Dr Ankur Barua

ObjectivesDr Kye Mon, Dr Adinegara

MethodologyDr Kye Mon,Dr Adinegara, Dr Amit, Dr NS Nair



 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Contributions of authors
  11. Declarations of interest
  12. Index terms

None known.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Contributions of authors
  12. Declarations of interest
  13. Characteristics of studies
  14. References to studies included in this review
  15. References to studies excluded from this review
  16. References to ongoing studies
  17. Additional references
Acrasoy 1987 {published data only}
Bao 2008 {published data only}
  • Bao B, Prasad A, Beck FWJ, Swerdlow PTI. Beneficial effect of zinc supplementation on oxidative stress, cytokines and NF-KB DNA binding in sickle cell disease patients [abstract]. Blood 2006;108(11):Abstract number: 1203.
Gupta 1995 {published data only}
  • Gupta VL, Chaubey BS. Efficacy of zinc therapy in prevention of crisis in sickle cell anemia: a double blind, randomized controlled clinical trial. Journal of the Association of Physicians of India 1995;43(7):467-9.
Prasad 1981 (1) {published data only}
Prasad 1981 (2) {published data only}
  • Prasad AS, Abbasi AA, Rabbani P, Dumouchelle E. Effect of zinc supplementation on serum testosterone level in adult male sickle cell anemia subjects. American Journal of Hematology 1981; Vol. 10, issue 2:119-27. [MEDLINE: 81204397]
Prasad 1999 {published data only}
Rashidi 2011 {published data only}
  • Rashidi M,  Aboomardani M,  Rafraf M,  Arefhosseini SR,  Keshtkar A,  Joshaghani H. Effects of vitamin E and zinc supplementation on antioxidants in beta thalassemia major patients. Iranian Journal of Pediatrics 2011;21(1):8-14.
Serjeant 1970 {published data only}
  • Serjeant GR, GRE, GMC. Oral zinc sulphate in sickle-cell ulcers. Lancet 1970; Vol. 2, issue 7679:891-2. [MEDLINE: 71010522]
Zemel 2002 {published data only}
  • Fung E, Kawchak D, Zemel B, Ohene-Frempong K, Stallings V. Plasma zinc is not a sensitive indicator of zinc status in children with sickle cell disease [abstract]. Proceedings of the National Sickle Cell Disease Program Annual Meeting; 2001 April 2001:Abstract no: 82.
  • Zemel BS, Kawchak DA, Fung EB, Ohene-Frempong K, Stallings VA. Effect of zinc supplementation on growth and body composition in children with sickle cell disease. American Journal of Clinical Nutrition 2002;75(2):300-7.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Contributions of authors
  12. Declarations of interest
  13. Characteristics of studies
  14. References to studies included in this review
  15. References to studies excluded from this review
  16. References to ongoing studies
  17. Additional references
Mehdizadeh 2008 {published data only}
Prasad 1975 {published data only}
Prasad 1983a {published data only}
Tschumi 1981 {published data only}
  • Tschumi P, Floersheim GL. Tolerance of large doses of oral zinc sulfate [Zur Vertraglichkeit von hochdosiertem peroralem Zinksulfat.]. Schweizerische Medizinische Wochenschrift 1981; Vol. 111, issue 42:1573-7. [MEDLINE: 82084437]

Additional references

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  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Contributions of authors
  12. Declarations of interest
  13. Characteristics of studies
  14. References to studies included in this review
  15. References to studies excluded from this review
  16. References to ongoing studies
  17. Additional references
Aggett 1995
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Bennekou 2001
  • Bennekou P, de Franceschi L, Pedersen O, Lian L, Asakura T, Evans G, et al. Treatment with NS3623, a novel Cl-conductance blocker,ameliorates erythrocyte dehydration in transgenic SAD mice: a possible new therapeutic approach for sickle cell disease. Blood 2001;97(5):1451-7.
Bhatangar 2004
  • Bhatangar S, Natchu UC. Zinc in child health and disease. Indian Journal of Paediatrics 2004;71(11):991-5.
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Mahyar 2010
  • Mahyar A. Zinc and copper status in children with beta-thalassemia major. Iranian Journal of Pediatrics 2010;20(3):297-302.
Nagalla 2010
Phebus 1988
Prasad 1965
Prasad 1966
  • Prasad AS. Metabolism of zinc and its deficiency in human subjects. Zinc Metabolism. Springfield: Charles C. Thomas, 1966:250-303.
Prasad 1983b
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Prasad 2007
  • Prasad AS . The Role of Zinc in Human Health. Academy of Turkish Sciences, 2007.
RDA 1989
  • Subcommittee on the Tenth Edition of the RDAs of the Food and Nutrition Board. Recommended Dietary Allowances. 10th Edition. Washington DC: National Academy Press, 1989.
RevMan 2011
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  • Johnston TA. Haemoglobinopathies in pregnancy. The Obstetrician & Gynaecologist 2005;7(3):149-57.
WHO 1989
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  • WHO Secretariat. Thalassaemia and other haemoglobinopathies. http://apps.who.int/gb/ebwha/pdf_files/EB118/B118_5-en.pdf (accessed 11 February 2011).