Pediatr Blood Cancer REVIEW Micronutrients and Sickle Cell Disease, Effects on Growth, Infection and Vaso-Occlusive Crisis: A Systematic Review Louise H. Dekker, MSc, 1,2 * Karin Fijnvandraat, MD, PhD, 3 Bernard J. Brabin, MD, PhD, 4 and Michael Boele van Hensbroek, MD, PhD 2 INTRODUCTION Sickle cell disease (SCD) is an inherited disorder of hemoglo- bin, with the highest incidence in sub-Saharan Africa and the Caribbean [1] and is designated by the World Health Organization as a public health priority [2]. SCD is characterized by chronic hemolytic anemia and vascular occlusion. Patients with SCD may experience growth impairment [3,4], increased susceptibility to infection [5,6], acute painful episodes [vaso-occlusive crises (VOC)], and irreversible damage to vital organs [1,7,8]. Micronu- trient deficiencies have been cited as possible contributors to the frequency and severity of these complications. However, the clin- ical significance of micronutrient deficiency in SCD is not well understood [7,9]. Energy and nutrient supply may be limited in SCD due to a combination of factors including: (i) reduced intake and absorp- tion secondary to anorexia [9,10], as well as through damage to the intestinal mucosa [11,12]; (ii) a hyper dynamic circulation [7] and increased requirements from an elevated basal metabolic rate [13,14]; (iii) raised requirements secondary to increased produc- tion of red cells (e.g., folate [15], B6, and B12 [16]) and (vi), loss of nutrients through increased renal excretion [13]. Several studies have reported reduced or deficient blood concentrations of micro- nutrients in SCD, including vitamins B6, B12 [17], C [18], E [19], and D [20]), magnesium [21], omega-3 fatty acids [22], and zinc [23]. The NHS Sickle Cell & Thalassaemia Screening Programme advises zinc supplementation in children with SCD who are growth retarded [9]. Although micronutrient supplementation might influence SCD-related morbidity, a systematic evaluation of the effect of micronutrient supplementation has not been reported. It is essential to identify and summarize the available evidence and to assess its methodological quality. This will iden- tify intervention priorities and potential knowledge gaps in this high-risk group of children. We have conducted a systematic literature review to address the following question: does supple- mentation of vitamins (A, B6, B12, C, D, and E), iron, magne- sium, folic acid, omega-3 fatty acids, or zinc in patients with SCD improve their growth, reduce susceptibility to infection or reduce the frequency of VOC? METHODS Literature Search and Study Identification This systematic review was undertaken according to the Pre- ferred Reporting Items for Systematic reviews and Meta-Analyses (referred to as ‘‘PRISMA’’) Statement [24]. The trials considered for inclusion in the current review were identified through searches in MEDLINE (National Library of Medicine, Bethesda, MD), EMBASE (Elsevier, Amsterdam, the Netherlands), Lilacs (database on Latin American and Caribbean Health Sciences), the Cochrane Central Register of Controlled Trials (CENTRAL; Wiley InterScience, Hoboken, NJ) and computerized bibliograph- ic databases spanning the years 1966–2011. The searches were completed in June 2011. To minimize possible publication bias, searches were also conducted on databases that contained unpub- lished scientific trials in order to identify all available trials that were not captured in the database searches. These databases in- cluded ‘‘ClinicalTrials.gov,’’ and ‘‘ClinicalTrialResults.org.’’ In the electronic databases, a structured strategy included searches with key words including: ‘‘sickle cell anemia,’’ ‘‘sickle cell disease,’’ ‘‘folic acid,’’ ‘‘zinc,’’ ‘‘vitamin A,’’ ‘‘vitamin B6,’’ ‘‘vi- tamin B12,’’ ‘‘vitamin C,’’ ‘‘vitamin D,’’ ‘‘vitamin E,’’ ‘‘iron,’’ Patients with Sickle cell disease (SCD) exhibit signs of poor growth, increased susceptibility to infection and recurrent episodes of painful vaso-occlusive crises. Micronutrient deficiencies may increase susceptibility to these outcomes. We conducted a system- atic review to assess the strength of evidence for improved out- comes related to micronutrient interventions. Six randomized- controlled trials of moderate quality met the inclusion criteria. Zinc supplementation was associated with improved growth and decreased incidence of infection and is a promising intervention in the management of SCD patients. Omega-3 fatty acid supplemen- tation was associated with limited reduction in vaso occlusive crises. This review identifies key knowledge gaps, which are impor- tant research priorities for nutritional interventions. Pediatr Blood Cancer ß 2012 Wiley Periodicals, Inc. Key words: growth; infection; micronutrients; sickle cell disease; vaso-occlusive crisis Additional Supporting Information may be found in the online version of this article. 1 Department of Public Health, Academic Medical Center, Amster- dam, The Netherlands; 2 Global Child Health Group, Emma Child- ren’s Hospital, Academic Medical Center, Amsterdam, The Netherlands; 3 Department of Pediatrics Hematology, Emma Child- ren’s Hospital, Academic Medical Center, Amsterdam, The Netherlands; 4 Department of Child and Reproductive Health, Liver- pool School of Tropical Medicine, Liverpool, UK Conflict of interest: Nothing to declare. *Correspondence to: Louise H. Dekker, MSc, Department of Public Health, Room K2-206, Academic Medical Center, P.O. Box 22660, Amsterdam, The Netherlands. E-mail: l.h.dekker@amc.uva.nl Received 22 November 2011; Accepted 15 March 2012 ß 2012 Wiley Periodicals, Inc. DOI 10.1002/pbc.24163 Published online in Wiley Online Library (wileyonlinelibrary.com).