Nutritional Perspectives On Sickle Cell Disease In Africa: A Systematic Review

doi:10.21203/rs.3.rs-20049/v1

Background

Sickle Cell Disease (SCD) is an inherited blood disorder and mostly affects individuals living in sub-Saharan Africa. Whilst there is an established link between its pathophysiology and nutritional status, research in this area in Africa is limited and evidence-based nutritional guidelines lacking. This systematic review aimed to evaluate studies in sub-Saharan Africa focused on nutritional aspects of SCD, codify results, and highlight gaps in knowledge that could inform priority-setting for future research.

Methods

The study was conducted using the Preferred Reporting items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We sought to include all studies involving original research of nutritional status of individuals (children and adults) with SCD in Africa. ‘Nutritional status’ was defined as topics related to dietary intake, measurements of growth or anthropometry, and nutritional-related biomarkers. Studies of anemia alone in non-SCD individuals were excluded as well as studies that assessed individuals with sickle cell trait (i.e., carriers). The databases used were Ovid Embase, Medline, Biosis and Web of Science. Studies conducted between 1995 and 2018 were included in the analyses.

Results

The search returned 366 articles from which 66 studies were included in the final analyses. Most investigations (70%) were conducted in Nigeria. Studies were categorized into one of three main categories: descriptive studies of anthropometric characteristics (47% of studies), descriptive studies of macro- or micronutrient levels (36% of studies), and interventional studies (14% of studies). There were fairly uniform findings that demonstrate that the growth of SCD patients in sub-Saharan Africa was impaired, especially in childhood and adolescence. Studies assessing macro- and micro-nutrients generally had small sample sizes and were exploratory in nature. Only two randomized, placebo-controlled trials were identified, which measured the impact of fatty acid supplementation and lime juice on health outcomes.

Conclusions

The findings of this review are consistent with data from other regional settings that describe a significant risk of malnutrition in individuals with SCD. There appears to be a substantial unmet need for clinical research to better understand the potential utility of nutritional-related interventions for patients with SCD in sub-Saharan Africa, to promote optimal growth and improve health outcomes.

Nutrition & Dietetics

nutritional status

malnutrition

sickle cell disease

sickle cell anemia

systematic review

Sickle cell disease (SCD) is the most common inherited blood disease worldwide, with the vast majority of cases occurring in sub-Saharan Africa. Sickle Cell Anemia (HbSS) is a type of SCD. The condition derives from a point mutation of the β-globin gene found on the short chain of chromosome 11 within the hemoglobin molecule. This causes the hydrophilic amino acid glutamic acid to be substituted with the hydrophobic amino acid valine at the sixth position.^1,2 Deoxygenation and acidosis causes polymerization of sickle hemoglobin and the development of “sickle” erythrocytes with stiff, sticky membranes that promote occlusion of small blood vessels.³ Acute painful crises and organ damage resulting from tissue ischemia are some of the disease’s clinical hallmarks.⁴ Life threatening complications of SCD include acute splenic sequestration, aplastic crises, acute chest syndrome, infection, heart failure, and stroke.^5,6 In sub-Saharan Africa, it is suggested that the overall prevalence of SCD is substantially underestimated and that up to 90% of babies born with SCD die before five years of age.⁷

In high resource countries, mortality from SCD has decreased dramatically over the past five decades. This is attributed in part to the development of programmed for newborn screening.⁸, In addition to adequate nutrition, pneumococcal and influenza vaccine and penicillin prophylaxis. Early detection of disease enables clinicians and families to institute measures to proactively prevent complications and facilitate timely treatment when needed. For example, the risk of fatal infection can be reduced through vaccination and prophylactic antibiotics.⁹ Furthermore, improved symptom management and treatment with blood transfusion or hydroxyurea therapy has led to superior outcomes in the long term. Whilst still at an early stage, there are agendas in several high-income countries to better align SCD management with health policies, and to implement more efficient systems and communication channels at a population level.¹⁰ Unfortunately, the availability of effective interventions and support for relevant health policies is highly variable in sub-Saharan Africa, where it is an urgent priority to increase access to care practices with demonstrated efficacy.¹¹ In parallel, there is the need for further research to better understand features of SCD with implications for clinical management that may be context specific and of particular relevance to patients living in sub-Saharan Africa.

There is evidence that the pathophysiology of SCD has substantial nutritional implications including higher energy and nutrients requirements, nutrient deficiencies and growth abnormalities.^12–14 It is theorized that a main driver of disease complications is higher rates of metabolic expenditure in individuals with SCD resulting from increased hematopoiesis, increased cardiac output, chronic inflammation, and related processes.^15,16 Since nutritional interventions could be a mechanism for addressing increased energy expenditure, attention to nutritional care is increasingly seen to be an important aspect of supportive management for patients with SCD,^17,18 especially in resource limited settings such as sub-Saharan African and specifically, Ghana. However, studies of SCD patients in African countries are limited and evidence-based nutritional guidelines in the region are lacking.^12,13 We undertook this systematic review to evaluate the existing literature focused on nutritional aspects of SCD in sub-Saharan Africa. Specifically, we sought to determine (a) the nature of relevant studies; (b) the findings and conclusions of previous research; and (c) gaps in knowledge that could inform priority-setting for future research.

Eligibility criteria. We sought to include all studies involving original research that focused on the nutritional status of individuals with SCD in an African population. Studies involving nutritional status were defined as those that investigated topics of dietary intake, measurements of growth or anthropometry, and nutrition-related biomarkers. Studies that did not differentiate the cause of the anemia were excluded. Studies involving both children and adults were included. The focus was on studies involving individuals with various forms of SCD (e.g. HbSS and HbSC) and excluded studies that only involved individuals with sickle cell trait. Case reports and review articles were also excluded.

Informational sources and search strategy. The databases employed for this search were Ovid Embase, Medline, Biosis, and Web of Science. The date range was January 1st, 1995, through May 31st, 2018, such that the reference list covered a period of approximately 20 years. We performed a Boolean search using specific Boolean operators and the following search terms: “Sickle cell disease” or “sickle cell anemia” or “hemoglobinopathy” AND Africa or specific African countries (all African countries were individually listed) AND various nutrition-related terms (i.e., nutrition, growth, macronutrient, micronutrient, vitamin, mineral, anthropometric, height, length, weight, head circumference, mid-upper arm circumference, MUAC, dietary intake, recommended dietary allowance, RDA, nutritional status) along with associated terms (both indexed and non-indexed) for nutrition, diet and growth, and specific vitamins and minerals. We also allowed for inclusion of articles that were identified through review of the bibliographies of papers that underwent full-text review. Investigations written in any language were included provided sufficient translation into English could be assured.

Data management and selection process. Titles and abstracts were each screened by two independent reviewers. Any title or abstract that appeared to meet inclusion criteria or for which there was uncertainty prompted a full text review. Reviewing of full text articles were assigned to individual investigators. If eligibility of a full text article was unclear, it was resolved by discussing it with at least two other reviewers on the research team who were not earlier assigned the full text article using the inclusion criteria. To maximize consistency among reviewers, each reviewer initially reviewed 10 articles and the review team together discussed the initial dataset that had been extracted to ensure accuracy and completeness. The review process then proceeded according to the process described.

Data synthesis. All data for the study were extracted into standardized forms using Microsoft Excel (Microsoft, Redmond, USA) where it was organized for analyses. Depending on the nature of the articles that met inclusion criteria, we planned to extract information relating to geography, subject age group, sample size, comparison groups, biomarkers, and other relevant variables. Since a main purpose of this investigation was to broadly understand the types of nutrition-related studies that have been conducted, involving individuals with SCD in Africa, we chose not to systematically judge the quality of evidence or risks of bias within individual studies. Rather, we planned to discuss specific merits and limitations of individual studies where appropriate in the context of major themes that would emerge in the analyses. We planned for a quantitative categorization of articles (e.g., descriptive versus interventional studies) and a narrative synthesis of data in table and text format to summarize and assess the results.

PRISMA. The study was conducted and reported according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines.^19,20

Search results. Three hundred and sixty-six unique titles and abstracts were identified through the literature search. Of those, 204 studies clearly failed to meet inclusion criteria and 162 full-text articles were assessed. Sixty-six studies were deemed eligible and included in the final analyses (Figure 1).

Results overview. Each study was placed into one of three main categories according to the primary nature of the investigation: (a) descriptive study of anthropometric characteristics (31 articles; 47%); (b) descriptive study of macro- or micronutrient levels (24 articles; 36%); and (c) interventional studies (9 articles; 14%). The studies are summarized in Tables 1-3 and described in greater detail below.

Descriptive studies of anthropometric characteristics. Nearly half of all the studies identified focused on anthropometric characteristics. The studies typically assessed height, weight, and body mass index (BMI). Other measurements included head circumference, arm span, and various body composition parameters.

The majority (23/31; 74%) of studies were conducted in Nigeria, including nine investigations from the major metropolitan area of Lagos. Other studies involved populations in Democratic Republic of Congo (DRC), Ghana, Tanzania, Egypt, and Algeria. In addition, a multi-country study involved patients in Cameroon, Ivory Coast, Gabon, Mali, and Senegal.²¹ The majority of reports focused on children and adolescents; only one study exclusively involved adults.²² Most studies evaluated approximately 50-200 patients and a similar number of age- and gender-matched healthy controls; two large studies enrolled over 1,000 SCD patients each.^21,23 Several studies used WHO growth standards for comparison rather than a non-sickle cell disease control group. Male and female subjects were generally equally represented in the study populations.

The two largest studies found significant growth defects compared to healthy controls. A multi-country study of 3,627 SCD patients (aged 10-24 years) with 943 controls in Cameroon, Ivory Coast, Gabon, Mali, and Senegal was designed to evaluate determinants of vascular complications.²¹ Anthropometric analyses showed that SCD patients were significantly shorter and had lower BMI than controls; weight was not reported. A caveat of the study was that the control group was significantly older (median age 24 vs 16 for patients) and more likely to be female (60% vs 54% for patients) than the SCD group. Another large study collected anthropometric data on 1,041 SCD patients aged 6 months to 48 years along with 717 healthy controls in Tanzania.²³ The cohort was followed for more than five years. SCD was significantly associated with stunting, underweight, and wasting, with the most pronounced effects associated with adolescent age and male gender. Adult men were seven times more likely than adult women to be underweight, and were significantly more likely to be stunted and wasted. Females demonstrated improved catch-up growth compared with males following growth deficits that were identified during adolescence.

The studies involving smaller sample sizes showed variable results, but some trends emerged. Several reports recapitulated the finding that males were more likely to show growth defects than females.^24–27 Multiple studies also noted that growth deficits became more pronounced with age. For example, a study that involved the youngest patients (aged 6-35 months, 14 of whom had HbSS genotype) showed no association of any inherited blood disorder with wasting, stunting, or underweight status.²⁸ A study of 233 children aged 2-17 years with SCD in Lagos, Nigeria found that the factor most significantly associated with both wasting and stunting was older age.²⁴ Additional studies similarly detected one or more growth deficits in adolescents but not in younger children.^29–34 In several Nigerian studies, SCD patients were found to be underweight or to have low BMI, but showed no difference in height compared to controls ^{27,32,35–38}; while other Nigerian studies showed differences in both weight and height.^{22,25,26,37,39,40} Reports from DRC, Egypt, and Ghana found that children with SCD had a higher prevalence of stunting compared to controls, but did not always show differences in wasting or BMI.^41–43SCD was also associated with delayed puberty.^43,44 Three studies from Nigeria reported the presence of overweight and obesity among patients with SCD although lower proportions, an average of less than 3% of the sample population.^24,36,45

Descriptive studies of macro- or micronutrient levels. The second most common group of studies identified involved assessment of biomarkers from serum samples for macronutrients or micronutrients`. Most studies were conducted in Nigeria (17/22, 77%); other studies took place in DRC, Tanzania, Egypt, Kenya, and Malawi. Nutritional parameters measured included proteins/amino acids, fatty acids, vitamins, and minerals. The majority of studies included less than 100 patients. Both children and adults were studied, with male and female subjects generally equally represented.

Serum protein levels were investigated in one small study (13 SCD children and 17 healthy controls) in Nigeria in which no significant differences were reported in the concentrations of total protein or albumin between SCD patients and controls.²⁷However, for the SCD population serumprealbumin levels were significantly lower, which was hypothesized to result from poor nutrition or existing disease-related inflammation. The serum concentrations of all amino acids except alanine, glutamic acid, proline were significantly reduced in SCD patients.A small study (11 participants) in Tanzania measured the nutrition status of SCD patients who died compared with those who were alive at the end of the study period. The trend observed for those who died was that they had a significantly lower BMI, plasma taurine levels and arginine bioavailability before succumbing to death.⁴⁶

Proportions of fatty acid and the state of metabolism were evaluated in four related studies of young SCD patients in Nigeria. ^25,39,47,48 These reports found perturbed pathways of fatty acid elongation and desaturation in children with SCD. Specifically, arachidonic acid, eicosapentanoic acid (EPA), and decosahexanoic acid (DHA) were significantly reduced, whereas saturated (palmitic acid) and monounsaturated (oleic acid) were significantly elevated in patients compared to controls. A fifth study in a separate population of 26 SCD patients aged 11- 43 in Enugu, Nigeria recapitulated the finding that EPA and DHA fatty acids are reduced in SCD patients, at least in some types of phospholipids.⁴⁹ The authors of these studies hypothesized that reduced polyunsaturated fatty acids in the phospholipids of the cell membrane of SCD patients can lead to their being more rigid, thereby contributing to disease symptoms. On the other hand, a study of 30 children with SCD in Egypt found that patients also had significantly lower cholesterol, triglycerides, and LDL (but not HDL) compared to healthy controls in the blood plasma.⁵⁰

Interpretation of plasma concentrations of vitamins and minerals can be problematic in patients who have ongoing inflammation and caution is advised. Furthermore, the effect of nutrient-nutrient interactions makes simple interpretation problematic. Analysis of serum vitamin levels in SCD patients generally indicated lower concentrations of vitamin A,^49,51 vitamin C,⁵¹ and vitamin E,^49–52 although one study of 14 SCD patients in Kenya found no association of HbSS genotype and low concentrations vitamin A deficiency.²⁸ Three reports of a related study population in Ilese, Nigeria investigated vitamin D status of young SCD patients.^53–55 When compared to healthy controls, mean 25-hydroxyvitamin D levels were significantly lower in SCD patients and suboptimal vitamin D levels were seen in greater than 10% of patients. However, no SCD patients with severe vitamin D deficiency (defined as <20 ng/ml) were observed. A limitation of the latter two studies was the lack of a healthy comparator group; each used vitamin D deficiency cut-off values for a healthy population in other published studies as reference.

Selected minerals were evaluated in eight small studies of SCD patients and compared to healthy controls, Serum iron concentration was reduced in patients compared to controls in all studies that measured it.^56–58 Serum or plasma zinc was also generally reduced in SCD patients,^57–61 although zinc was elevated in one population of 59 Nigerian adult SCD patients.⁵⁶ Measures of other minerals showed mixed results. Magnesium levels were either reduced,^58,59 elevated⁶⁰ or unchanged^56,58,62 in SCD patients compared to healthy controls. Similarly, copper was reduced,⁵⁹ elevated, ⁶⁰ or unchanged^56,58 in SCD patients. Other minerals were measured in too few studies to draw robust conclusions, including manganese, chromium, selenium, potassium, rubidium, cadmium, and calcium.

Interventional studies. Few clinical studies of nutritional interventions in SCD patients in African countries were identified. There were two randomized, placebo-controlled trials.^63,64 The first was a study of 128 SCD patients (aged 2-24 years) in Sudan, which investigated the impact of one year of treatment with oral omega-3 capsules containing EPA and DHA fatty acids (using age- and weight-dependent dosing) compared to placebo. The hypothesis was that omega-3 fatty acids could reduce red blood cell aggregation, adherence, and inflammation that occur during sickle cell disease-mediated vaso-occlusive crises. The treatment group had significantly fewer clinical vaso-occlusive events, as well as reduced rates of severe anemia and need for blood transfusions. The study was not powered to detect changes in other outcomes such as stroke, sequestration crisis, or vascular necrosis.⁶⁴ A second study of 125 SCD patients in Nigeria (children aged 1 year and above) tested the effect of lime juice on SCD parameters. All patients in the treatment group (n=65) as well as controls (n=60) were given folic acid, vitamin B complex, and proguanil, with the treatment group also given twice-daily oral lime juice (weight-based dosing ranging from 5-15 mL). Each child was assessed monthly for 6 months. The group receiving lime juice was reported to have significantly fewer pain episodes, febrile illnesses, and hospital admission rates. There was no change in transfusion rate, organomegaly, or jaundice. The positive effect was postulated to result from vitamin C, amino acids (especially phenylalanine), and flavonoids contained in the juice, but no direct evidence for this was provided.⁶³

Other interventional studies included vitamin D supplementation and administration of ready-to-use-supplementary food (RUSF). A small treatment arm was nested in a Nigerian study comparing levels of vitamin D and pro-inflammatory cytokines in the blood.⁵⁵ The hypothesis was that low vitamin D levels might lead to a pro-inflammatory environment that exacerbates SCD symptoms. Twelve children with SCD who were determined to have low vitamin D levels were given 3 months of oral vitamin D supplementation (2000 U). At the end of treatment, mean serum 25-hydroxyvitamin D levels were significantly increased compared to baseline, levels of several proinflammatory cytokines were significantly decreased, and the levels of anti-inflammatory cytokine IL-11 were significantly increased. RUSF food was studied in 119 children with SCD in Tanzania. Two different formulations of the supplements were compared: a commercially available (Nutriset, France) RUSF fortified with vitamins and minerals according to recommended daily allowances, and an “enhanced” version of the same RUSF that was additionally fortified with arginine and citrulline. Arginine is the substrate for endothelial nitric oxide synthase, a natural vasodilator, and has been implicated in pathophysiology of SCD complications. In the cross-over study design, children received each treatment for 4 months, with 4-month washout periods following the intervention. Ready-to-use-supplementary food led to small weight gains, an increased arginine bioavailability ratio, and improved measures of endothelial function compared to baseline; addition of arginine and citrulline to the supplement did not provide additional benefits.⁶⁵

Several longitudinal studies evaluated multi-faceted interventions that included nutritional supplementation, but did not test the effects of nutrition directly. A large study in Nigeria enrolled 1,223 patients (6 months-62 years of age) over a period of 8 years and involved multiple interventions including health education, nutritional supplementation (folic acid, vitamins B and C), vaccines, malarial prophylaxis, and improved access to analgesics, antibiotics, and antimalarials. Over the study period, there was a marked decline in mortality, hospitalization rates, and blood transfusions.⁶⁶ A longitudinal study in Benin enrolled 236 children (aged 8 months-12 years) with SCD. Severe SCD-related adverse outcomes, such as vaso-occlusive crises, hospitalization, and transfusions during the study period of up to 6.5 years were compared to parents’ reports of outcomes prior to the study period. The interventions included health and nutrition education, folic acid supplementation, vaccines, malarial prophylaxis, and pneumococcal prophylaxis with oral penicillin. Disease severity appeared to be lower during the study period than prior to the intervention, although the study was limited since the period before the intervention had not been observed by the investigators.⁶⁷Another study in Benin evaluated prenatal care for 108 pregnant women with HbSS and HbSC genotypes; the intervention included the provision of education about SCD and nutrition, malaria prevention, early detection of bacterial infections, and restricted use of blood transfusion. The nutritional education was described by the authors as “drawing attention to affordable local products that have a high nutritional value.”⁶⁷The maternal mortality rate decreased (compared to a small historical data set) to a rate comparable with the overall maternal mortality rate for the maternity unit where the study was conducted (1.8% for SCD mothers vs 1.2% overall). However, the fetal loss rate of 11.9% for SCD mothers remained higher than the average for the hospital maternity unit (6.3%).⁶⁸

To our knowledge this is the first review of nutrition-related studies involving individuals living with SCD in sub-Saharan Africa. We identified investigations in the past two decades that provide evidence of significant risk of growth faltering in SCD patients during childhood and adolescence. Studies also correlated poor nutritional status with other disease complications, suggesting nutritional status to be a possible independent factor in disease severity. This indicates the importance of monitoring nutritional status of patients in this setting as part of routine clinical management of the disease. There were many exploratory studies of various nutrient levels, although it was difficult to draw definitive conclusions from this group of studies since they largely involved small patient populations and some results were inconsistent when compared across studies. Few interventional studies with robust methodologies were identified that were designed to measure the impact of an isolated nutritional intervention. Studies involving supplementation with fatty acids or lime juice reported clinical benefits and ideally these findings need to be confirmed in follow-up investigations. Nutrient supplementation with arginine has proved to be beneficial in reducing vaso-occlusive crisis among those with SCD. Supplementation with Ready-to-Use-Supplementary-Food (RUSF) led to modest weight gain and improvement in measures of arginine regulation that would need to be further studied to determine potential associations with other clinical benefits.

The findings of this study are consistent with nutrition-related investigations involving SCD patients in other parts of the world. More than 50 years ago, poor growth was first reported in patients with SCD, and that observation has since been repeated in multiple studies involving SCD populations in Jamaica, Brazil, India, and North America.^{12,14,69−75} Many of these studies specifically note that the growth faltering occurred in patients that were receiving recommended daily protein and calorie intakes. The pathophysiology of growth problems in SCD patients has come into sharper focus in recent decades. A leading view is that the increased rate of red cell turnover, the primary feature of SCD patients underlies a hypermetabolic state. The biochemical and physiological factors that contribute include increased protein turnover, increased myocardial activity, and production of proinflammatory cytokines.^76–80 The supposition is that the energy and nutrient requirements normally recommended are not adequate in patients with SCD given their increased energy expenditures and other unusual metabolic demands. These demands compete directly with those required for healthy body growth.

Evidence derived from interventional studies is important to support recommendations for specific nutrition-related practices in the care of patients with sickle cell disease. We identified studies from Africa that demonstrated positive results on health outcomes following fatty acid supplementation and supplementary feeding. These types of interventions have also been studied in populations outside of Africa.^71,81 However, it seems that interventional studies have not yet provided sufficient evidence to establish universally accepted nutritional care practices for patients with SCD since guidelines from several internationally recognized organizations still do not provide special guidance for nutritional care.^82,83 Given that the risk of poor growth in SCD patients is increasingly delineated, and there is a growing body of literature that describes a rational pathophysiology for nutritional disturbances in SCD patients, there appears to be a substantial gap in research in this area to inform much needed evidence-based recommendations. Perhaps one of the most important indirect observations of this review was that individuals with SCD that benefited from better health care in general, of which high quality nutrition was an integral component, appeared to suffer fewer adverse outcomes. This reinforces the idea that holistic approaches to managing SCD patients should be adopted whenever possible.

Limitations of this systematic review include the fact that nearly half of studies identified were largely anthropometry-based descriptive studies. Few studies involving nutritional interventions in sub-Saharan Africa were identified, only several had robust methodologies, and none have been validated in repeated studies. In addition, the studies involving analyses of vitamin and mineral levels in SCD patients in sub-Saharan Africa overall involved small numbers of patients and generally were unable to link findings with meaningful clinical correlations in ways that might influence nutritional care practices. Another limitation is that most investigations (45/64; 70%) identified took place in the single country of Nigeria; however, it is relevant that Nigeria is home to the largest population of SCD patients globally.

Despite the fact that most SCD patients in the world live in Africa, and the pathophysiology of malnutrition (nutritional disturbances) in SCD patients is increasingly well described, up until now there has only been limited attention given to the nutritional aspects of the clinical care of individuals with SCD living in sub-Saharan Africa. A systematic review of the literature revealed studies that consistently highlighted the risk of growth faltering and malnutrition in African SCD patients during childhood and adolescence, without clearly defined interventions of benefit. This indicates an urgent need for robust programming to effectively address the problem of nutrition in SCD patients in sub-Saharan Africa. The high rate of nutritional deficiencies among individuals with SCD contributes to the widely recognized malnutrition burden in sub-Saharan Africa. Ways forward may include routine monitoring of nutritional status in this population, assembly of research to inform evidence-based nutritional guidance, and targeted interventions in the routine clinical management of patients with SCD. Relevant future research is needed to advance understanding of macro- and micronutrient deficiencies that could have clinically significant physiologic effects, and also to evaluate the impact of various nutritional interventions. Since it is possible that improvements in nutritional status may reduce disease severity and improve health outcomes, research in this area should be a priority to better understand how supportive nutrition care should best be delivered in the management of individuals with SCD in sub-Saharan Africa. Additional future studies can also explore the contribution of sickle cell disease-related-malnutrition to the malnutrition and anemia burden in sub-Saharan Africa so that its management can be more tailored.

SCD - Sickle Cell Disease

EPA - Eicosapentanoic Acid

DHA - Decosahexanoic Acid

PRISMA- Preferred Reporting items for Systematic Reviews and Meta-Analysis

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this published article

Competing Interests

Rajiv Shah works for Novartis Global Health and Corporate Responsibility. Jonathan Spector is an employee at Novartis Institutes for BioMedical Research.

Funding

No financial support was required to conduct this study and there was no sponsor of the study. Non-financial sources of support were the provision of information specialist services by Novartis Institutes for BioMedical Research to assist with the mechanics of the database searches and acquisition of full text articles.

Author’s contributions

EBN was responsible for coordinating the entire project and is the guarantor of the review. EBN, CJ, JS, and MSA developed the project. EBN, CJ, RS, AKD and JS reviewed the abstracts and articles included in this study and carried out the data collection. EBN, CJ, JS, and MSA participated in the analyses. EBN and CJ wrote the first version of the manuscript. AJ, AKD, EM, AO, RS, JS, SAA, ABB, HIH and MSA reviewed and edited the manuscript during its production. All authors read and approved the final manuscript.

Acknowledgements

We thank Mary Isgro, Emily Mannix and Sherri Schwaninger for database searches and collection of articles.

Pauling, L. & Itano, H. Sickle cell anemia a molecular disease. Science110, 543–8 (1949).
Ingram, V. M. Abnormal human haemoglobins. I. The comparison of normal human and sickle-cell haemoglobins by fingerprinting. Biochimica et Biophysica Acta28, 539–45 (1958).
Bunn, H. & Forget, B. Hemoglobin: Molecular, genetic and clinical aspects. (WB Saunders, 1986).
Ware, R. E., de Montalembert, M., Tshilolo, L. & Abboud, M. R. Sickle cell disease. The Lancet390, 311–323 (2017).
Mbanya, N. Sickle cell disease in subsaharan Africa. Vox Sanguinis109, 63–64 (2015).
Otoikhian, C. S. O. & Okoror, L. E. Sickle cell disease african killer: Biologists alternative. International Journal of Pharma Medicine and Biological Sciences1, 232–245 (2012).
Grosse, S. D. et al. Sickle cell disease in Africa: A neglected cause of early childhood mortality. American Journal of Preventive Medicine41, (2011).
Consensus conference. Newborn screening for sickle cell disease and other hemoglobinopathies. JAMA258, 1205–9 (1987).
Lanzkron, S., Carroll, C. P. & Haywood, C. Mortality Rates and Age at Death from Sickle Cell Disease: U.S., 1979–2005. Public Health Reports128, 110–116 (2013).
Hulihan, M., Hassell, K. L., Raphael, J. L., Smith-Whitley, K. & Thorpe, P. CDC Grand Rounds: Improving the Lives of Persons with Sickle Cell Disease. Morbidity and Mortality Weekly Report (MMWR)66, 1269–1271 (2017).
McGann, P. T. Time to Invest in Sickle Cell Anemia as a Global Health Priority. Pediatrics137, e20160348–e20160348 (2016).
Al-Saqladi, A.-W. M., Cipolotti, R., Fijnvandraat, K. & Brabin, B. Growth and nutritional status of children with homozygous sickle cell disease. Annals of Tropical Paediatrics28, 165–189 (2008).
Bello-Manga, H., DeBaun, M. R. & Kassim, A. A. Epidemiology and treatment of relative anemia in children with sickle cell disease in sub-Saharan Africa. Expert Review of Hematology 1031–1042 (2016). doi:10.1080/17474086.2016.1240612
Platt, O. S., Rosenstock, W. & Espeland, M. A. Influence of Sickle Hemoglobinopathies on Growth and Development. New England Journal of Medicine311, 7–12 (1984).
Akohoue, S. A. et al. Energy expenditure, inflammation, and oxidative stress in steady-state adolescents with sickle cell anemia. Pediatric Research61, 233–8 (2007).
Hyacinth, H. I., Gee, B. E. & Hibbert, J. M. The Role of Nutrition in Sickle Cell Disease. Nutrition and Metabolic Insights3, 57–67 (2010).
Canadian Haemoglobinopathy Association. Consensus Statement on the Care of Patients with Sickle Cell Disease in Canada. Ottawa; 2014.
National Health Service. Sickle Cell Disease in Childhood: Standards and Guidelines for Clinical Care. (2010).
Liberati, A. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clinical research ed.)339, b2700 (2009).
Shamseer, L. et al. Preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: Elaboration and explanation. BMJ349, (2015).
Ranque, B. et al. Arterial stiffness impairment in sickle cell disease associated with chronic vascular complications. Circulation134, 923–933 (2016).
Aderibigbe, A., Omotoso, A. B., Awobusuyi, J. O. & Akande, T. M. Arterial blood pressure in adult Nigerian sickle cell anaemia patients. West African Journal of Medicine18, 114–118 (1999).
Cox, S. E. et al. Nutritional status, hospitalization and mortality among patients with sickle cell anemia in Tanzania. Haematologica96, 948–953 (2011).
Esezobor, C. I., Akintan, P., Akinsulie, A., Temiye, E. & Adeyemo, T. Wasting and stunting are still prevalent in children with sickle cell anaemia in Lagos, Nigeria. Italian Journal of Pediatrics42, 45 (2016).
Glew, R. H., Casados, J., Huang, Y. S., Chuang, L. T. & VanderJagt, D. J. Correlation of the fatty acid composition and fluid property of the cholesteryl esters in the serum of Nigerian children with sickle cell disease and healthy controls. Prostaglandins Leukotrienes and Essential Fatty Acids68, 61–68 (2003).
VanderJagt, D. J., Bonnett, C., Okolo, S. N. & Glew, R. H. Assessment of the bone status of Nigerian children and adolescents with sickle cell disease using calcaneal ultrasound and serum markers of bone metabolism. Calcified Tissue International71, 133–140 (2002).
VanderJagt, D. J., Kanellis, G. J., Isichei, C., Pastuszyn, A. & Glew, R. H. Serum and urinary amino acid levels in sickle cell disease. Journal of Tropical Pediatrics43, 220–225 (1997).
Tsang, B. L., Sullivan, K. M., Ruth, L. J., Williams, T. N. & Suchdev, P. S. Nutritional status of young children with inherited blood disorders in Western Kenya. American Journal of Tropical Medicine and Hygiene90, 955–962 (2014).
Oredugba, F. & Savage, K. Anthropometric finding in Nigerian children with sickle cell disease. Pediatric Dentistry24, 321–325 (2002).
Senbanjo, I. O., Oshikoya, K. A., Salisu, M. & Diaku-Akinwumi, I. N. Head circumference of children with sickle cell disease in Lagos, Nigeria. The Pan African Medical Journal25, (2016).
Akodu, S. O., Diaku-Akinwumi, I. N., Kehinde, O. A. & Njokanma, O. F. Evaluation of Arm Span and Sitting Height as Proxy for Height in Children with Sickle Cell Anemia in Lagos, Nigeria. Journal of the American College of Nutrition33, 437–441 (2014).
VanderJagt, D. J., Okolo, S. N., Rabasa, A. I. & Glew, R. H. Bioelectrical impedance analysis of the body composition of Nigerian children with sickle cell disease. Journal of Tropical Pediatrics46, 67–72 (2000).
Iwalokun, B. A., Iwalokun, S. O., Hodonu, S. O., Aina, A. O. & Agomo, P. U. Serum levels of leptin in Nigerian patients with sickle cell anaemia. BMC Blood Disorders11, (2011).
Eke, C. B., Chukwu, B. F., Ikefuna, A. N., Ezenwosu, O. U. & Emodi, I. J. Bioelectric impedance analysis of body composition of children and adolescents with sickle cell anemia in enugu, Nigeria. Pediatric Hematology and Oncology32, 258–268 (2015).
Animasahun, B. A., Temiye, E. O., Ogunkunle, O. O., Izuora, A. N. & Njokanma, O. F. The influence of socioeconomic status on the hemoglobin level and anthropometry of sickle cell anemia patients in steady state at the Lago; University Teaching Hospital. Nigerian Journal of Clinical Practice14, 422–427 (2011).
Bismarck Eke, C., Onyeka Edelu, B., Nnaemeka Ikefuna, A., Josephine Emodi, I. & Chidozie Ibe, B. Obesity in Preschool-Aged Children with Sickle Cell Anemia: Emerging Nutritional Challenge in a Resource Limited Setting. Pediatric Hematology and Oncology32, 390–398 (2015).
Odetunde, O. I., Chinawa, J. M., Achigbu, K. I. & Achigbu, E. O. Body Mass Index and other anthropometric variables in children with sickle cell anaemia. Pakistan Journal of Medical Sciences32, 341–346 (2016).
Onukwuli, V. O., Ikefuna, A. N., Nwokocha, A. R., Emodi, I. J. & Eke, C. B. Relationship between zinc levels and anthropometric indices among school-aged female children with sickle cell anemia in enugu, Nigeria. Nigerian Journal of Clinical Practice20, 1461–1467 (2017).
Vandegt, D. J., Huang, Y. S., Chuang, L. T., Bonnett, C. & Glew, R. H. Phase angle and n-3 polyunsaturated fatty acids in sickle cell disease. Archives of Disease in Childhood87, 252–254 (2002).
Sokunbi, O. J., Ekure, E. N., Temiye, E. O., Anyanwu, R. & Okoromah, C. A. N. Pulmonary hypertension among 5 to 18 year old children with sickle cell anaemia in Nigeria. PLoS ONE12, (2017).
Lukusa Kazadi, A., Ngiyulu, R. M., Gini-Ehungu, J. L., Mbuyi-Muamba, J. M. & Aloni, M. N. Factors Associated with Growth Retardation in Children Suffering from Sickle Cell Anemia: First Report from Central Africa. Anemia1, (2017).
Osei-Yeboah, C., Rodrigues, O. & Enweronu-Laryea, C. Nutritional status of children with sickle cell disease at Korle Bu Teaching Hospital, Accra, Ghana. West African Journal of Medicine30, 262–267 (2011).
Soliman, A. T., ElZalabany, M., Amer, M. & Ansari, B. M. Growth and pubertal development in transfusion-dependent children and adolescents with thalassaemia major and sickle cell disease: A comparative study. Journal of Tropical Pediatrics45, 23–30 (1999).
Aina, O. F., Fadaka, K., Temiye, E. & Renner, J. K. Sexual Maturation and Psychiatric Morbidity among Persons with Sickle Cell Anaemia in a Nigerian Teaching Hospital. The International Journal of Psychiatry in Medicine40, 31–43 (2010).
Akodu, S. O., Diaku-Akinwumi, I. N. & Njokanma, O. F. Obesity-does it occur in Nigerian children with sickle cell anemia. Pediatric Hematology and Oncology29, 358–364 (2012).
Cox, S. E. et al. Global arginine bioavailability in Tanzanian sickle cell anaemia patients at steady-state: a nested case control study of deaths versus survivors. British Journal of Haematology155, 522–524 (2011).
Enomoto, T. M., Isichei, C., Vanderjagt, D. J., Fry, D. E. & Glew, R. H. Decreased polyunsaturated fatty acids in sickle cell anaemia. Journal of Tropical Pediatrics44, 28–34 (1998).
Glew, R. H., Casados, J. K., Huang, Y. S., Chuang, L. T. & VanderJagt, D. J. The fatty acid composition of the serum phospholipids of children with sickle cell disease in Nigeria. Prostaglandins Leukotrienes and Essential Fatty Acids67, 217–222 (2002).
Ren, H. et al. Patients with sickle cell disease have reduced blood antioxidant protection. International Journal for Vitamin and Nutrition Research78, 139–147 (2008).
Hamdy, M., Mosallam, D., Rabie, W. & ... Vitamin E and selenium in Egyptian thalassemia and sickle cell disease patients: Are they deficient? Haematologica99, 741 (2014).
Jiya, N. M., Matazu, I. K., Bilbis, L. S. & Shehu, R. A. Serum levels of antioxidant vitamins in foetal haemoglobin (HbF) persistent sickle cell anaemia children in Sokoto, Nigeria. Annals of African Medicine4, 168–171 (2005).
Shukla, P. et al. Sickle cell disease and vitamin E deficiency in children in developing countries. Transactions of the Royal Society of Tropical Medicine and Hygiene94, 109 (2000).
Adegoke, S. A., Oyelami, O. A., Adekile, A. & Figueiredo, M. S. Influence of serum 25-hydroxyvitamin D on the rate of pain episodes in Nigerian children with sickle cell anaemia. Paediatrics and International Child Health37, 217–221 (2017).
Adegoke, S. A., Smith, O. S., Adekile, A. D. & Figueiredo, M. S. Relationship between serum 25-hydroxyvitamin D and inflammatory cytokines in paediatric sickle cell disease. Cytokine96, 87–93 (2017).
Adegoke, S. A., Figueiredo, M. S., Adekile, A. D. & Braga, J. A. P. Comparative study of the growth and nutritional status of Brazilian and Nigerian school-aged children with sickle cell disease. International Health9, 327–334 (2017).
Olaniyi, J. A. & Arinola, O. G. Nitric oxide and trace metals in relation to haemoglobin F concentration in Nigerian sickle cell disease patients. Turkish Journal of Medical Sciences40, 109–113 (2010).
Ojo, J. O., Oluwole, A. F., Osoniyi, R. O., Durosinmi, M. A. & Aboderin, A. O. Determination of trace elements status of Nigerians with sickle cell anaemia using INAA and PIXE. Afr J Med Med Sci35, 461–467 (2006).
Arinola, O. G., Olaniyi, J. A. & Akiibinu, M. O. Evaluation of antioxidant levels and trace element status in Nigerian sickle cell disease patients with Plasmodium parasitaemia. Pakistan Journal of Nutrition7, 766–769 (2008).
Ajayi, G. Zinc, magnesium, and copper concentrations in serum, erythrocytes, and urine in sickle cell homozygotes and heterozygote Nigerian women. Trace Elements and Electrocytes14, 69–71 (1997).
Akenami, F. O., Aken’Ova, Y. A. & Osifo, B. O. Serum zinc, copper and magnesium in sickle cell disease at Ibadan, south western Nigeria. African Journal of Medicine and Medical Sciences28, 137–139 (1999).
Sungu, J. K. et al. Trace elements in children suffering from sickle cell anemia: A case–control study. Journal of Clinical Laboratory Analysis32, (2018).
Oladipo, O. O., Temiye, E. O., Ezeaka, V. C. & Obomanu, P. Serum magnesium, phosphate and calcium in Nigerian children with sickle cell disease. West African Journal of Medicine24, 120–123 (2005).
Adegoke, S. A., Shehu, U. A., Mohammed, L. O., Sanusi, Y. & Oyelami, O. A. Influence of Lime Juice on the Severity of Sickle Cell Anemia. The Journal of Alternative and Complementary Medicine19, 588–592 (2013).
Daak, A. A. et al. Effect of omega-3 (n-3) fatty acid supplementation in patients with sickle cell anemia: Randomized, double-blind, placebo-controlled trial. American Journal of Clinical Nutrition97, 37–44 (2013).
Cox, S. E. et al. Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial. The Lancet Haematology5, E147–E160 (2018).
Akinyanju, O. O., Otaigbe, A. I. & Ibidapo, M. O. O. Outcome of holistic care in Nigerian patients with sickle cell anaemia. Clinical and Laboratory Haematology27, 195–199 (2005).
Rahimy, M. C. et al. Effect of a comprehensive clinical care program on disease course in severely ill children with sickle cell anemia in a sub-Saharan African setting. Blood102, 834–838 (2003).
Rahimy, M. & Gangbo, A. Effect of active prenatal management on pregnancy outcome in sickle cell disease in an African setting. Blood96, 1685–1689 (2000).
Scott, R., Ferguson, A., Jenkins, M. & Clark, H. Studies in sickle-cell anemia. VIII. Further observations on the clinical manifestations of sickle-cell anemia in children. A.M.A. American Journal of Diseases of Children90, 682–91 (1955).
Whitten, C. Growth Status of Children with Sickle-Cell Anemia. Archives of Pediatrics & Adolescent Medicine102, 355 (1961).
Heyman, M. B. et al. Growth retardation in sickle-cell disease treated by nutritional support. Lancet1, 903–6 (1985).
Ashcroft, M. T., Serjeant, G. R. & Desai, P. Heights, weights, and skeletal age of jamaican adolescents with sickle cell Anaemia. Archives of Disease in Childhood (1972). doi:10.1136/adc.47.254.519
Nikhar, H., Shinde, G. & Meshram, S. An anthropometric and hematological comparison of sickle cell disease children from rural and urban areas. Indian Journal of Human Genetics18, 40 (2012).
Mitchell, M. J. et al. Growth status in children and adolescents with sickle cell disease. Pediatric Hematology and Oncology (2009). doi:10.1080/08880010902896882
Silva, C. M. & Viana, M. B. Growth deficits in children with sickle cell disease. Archives of Medical Research (2002). doi:10.1016/S0188-4409(01)00360-5
Badaloo, A., Jackson, A. A. & Jahoor, F. Whole body protein turnover and resting metabolite rate in homozygous sickle cell disease. Clinical Science77, 93–7 (1989).
Barden, E. M. et al. Total and resting energy expenditure in children with sickle cell disease. Journal of Pediatrics36, 73–9 (2000).
Hibbert, J. M. et al. Erythropoiesis and myocardial energy requirements contribute to the hypermetabolism of childhood sickle cell anemia. Journal of Pediatric Gastroenterology and Nutrition43, 680–7 (2006).
Hibbert, J. M. et al. Proinflammatory Cytokines and the Hypermetabolism of Children with Sickle Cell Disease. Experimental Biology and Medicine230, 68–74 (2005).
Umeakunne, K. & Hibbert, J. M. Nutrition in sickle cell disease: recent insights. Nutrition and Dietary Supplements11, 9–17 (2019).
Tomer, A. et al. Reduction of pain episodes and prothrombotic activity in sickle cell disease by dietary n-3 fatty acids. Thrombosis and Haemostasis85, 966–74 (2001).
Yawn, B. P. et al. Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members. Journal of the American Medical Association312, 1033–1048 (2014).
National Institutes of Health. Evidence-based management of sickle cell disease. Expert Panel Report, 2014.
Vanderjagt, D. J. et al. Pulmonary function correlates with body composition in Nigerian children and young adults with sickle cell disease. Journal of Tropical Pediatrics54, 87–93 (2008).
Tebbani, F. et al. Descriptive approach for sickle cell disease in Eastern of Algeria. International Journal of Pharmaceutical Sciences Review and Research25, 97–101 (2014).
Akingbola, T. S. et al. Comparison of patients from Nigeria and the USA highlights modifiable risk factors for sickle cell anemia complications. Hemoglobin38, 236–243 (2014).
Oluwole, O. B., Noll, R. B., Winger, D. G., Akinyanju, O. & Novelli, E. M. Cognitive functioning in children from Nigeria with sickle cell anemia. Pediatric Blood and Cancer63, 1990–1997 (2016).
Mikobi, T. M. et al. Clinical phenotypes and the biological parameters of Congolese patients suffering from sickle cell anemia: A first report from Central Africa. Journal of Clinical Laboratory Analysis1, (2017).
Afolabi, I. S. et al. Solenostemon monostachyus, Ipomoea involucrata and Carica papaya seed oil versus Glutathione, or Vernonia amygdalina: Methanolic extracts of novel plants for the management of sickle cell anemia disease. BMC Complementary and Alternative Medicine12, 262 (2012).
Imaga, N. A., Chukwu, C. E., Blankson, A. & Gbenle, G. O. Biochemical assessment of Ciklavit®, a nutraceutical used in sickle cell anaemia management. Journal of Herbal Medicine3, 137–148 (2013).

Table 1. Studies of anthropometric characteristics of individuals living with sickle cell disease in Africa

Authors and year of publication	Location	Ages	No. of subjects	Control group	Weight	Height	Body mass index	Other assessments
VanderJagt et al., 1997²⁷	Jos, Nigeria	10 months-14 years (mean 7 years for males; mean 6 years for females)	13	17 age- and gender-matched controls	Significantly lower weight in males with SCD	No significant differences in height reported	No statistical difference in BMI as both weight and height were lower for SCD patients	· Significantly lower head circumference in males with SCD versus controls · No differences in MUAC or triceps skin fold · No differences reported for females
Soliman et al., 1999⁴³	Alexandria, Egypt	Mean 7 years	110	200 healthy age-matched children, 30 children with constitutional growth delay, 25 children with growth hormone deficiency	N/A	· Height and growth velocity significantly lower in SCD patients than healthy controls · Bone age delay in SCD patients by 2.4 years	· BMI not significantly different between SCD patients and healthy controls	· Lower MUAC and triceps skin fold thickness in SCD patients versus healthy controls · Significant age delays in puberty in SCD patients
Aderibigbe et al., 1999²²	Ilorin, Nigeria	18-54 years (mean 22 years)	64	60 adults aged 18-57	Significantly lower weight in individuals with SCD	Significantly shorter height in individuals with SCD	N/A
VanderJagt et al., 2000³²	Jos, Nigeria	3-20 years	48	51 healthy controls	Significantly lower weight in males with SCD aged 10-18 years; no differences for females	No differences	Significantly lower BMI for males with SCD aged 10-18; no differences for females	· Significantly lower fat free mass in males with SCD aged 10-18 · Significantly higher body fat and % body fat in individuals with SCD aged >10 years
Vandegt et al., 2002³⁹	Jos, Nigeria	Mean 13 years for males and females	72	68 age- and gender-matched controls	Significantly lower weight in females and males with SCD	Significantly lower height in females and males with SCD	Significantly lower BMI in females and males with SCD
VanderJagt et al., 2002²⁶	Jos, Nigeria	8-22 years (mean 14 years for males; mean 13 years for females)	80	41 male and 38 female age-matched controls; 51 male and 71 female additional controls for ultrasound component	Significantly lower weight in females and males with SCD	Significantly lower height in females and males with SCD	Significantly lower BMI in males and females with SCD	· Significantly lower bone density in individuals with SCD by ultrasound measurement · Some differences in serum markers of bone resorption and formation · No differences in triceps skin fold · Significantly lower MUAC, FFM, and % FFM in males and females with SCD; males with SCD also had significantly lower body fat
Oredugba et al., 2002²⁹	Lagos, Nigeria	1-18 years (mean 10 years)	117	122 children and adolescents aged 1-18 years from well-baby clinics and surgical outpatient unit	Significantly lower weight in individuals with SCD aged 18 years	No differences	N/A	· Significantly lower MUAC in individuals with SCD · No differences in mean head circumference
Glew et al., 2003²⁵	Jos, Nigeria	10-18 years (mean 14 years for males; mean 13 years for females)	77	75 age- and gender-matched controls	Significantly lower weight in individuals with SCD	Significantly lower height in individuals with SCD	Significantly lower BMI in males with SCD; no differences for females
VanderJagt et al., 2007⁸⁴	Jos, Nigeria	7-35 years (mean 15 years for males; mean 17 years for females)	102	104 healthy age and gender matched controls	Significantly lower weight in individuals with SCD	· Significantly lower mean sitting height in individuals with SCD · Significantly lower standing height in males with SCD (not significantly different for females)	Significantly lower BMI in females with SCD; no differences for males	· Significantly lower FFM in individuals with SCD; no differences in FFM% and fat % · Significantly lower phase angle (measure of overall nutritional status) in individuals with SCD · Significantly lower MUAC and triceps skin fold in females with SCD (not for males)
Aina et al., 2010⁴⁴	Lagos, Nigeria	10-19 years (mean 14 years)	136	136 age- and gender-matched controls	N/A	N/A	N/A	Delayed puberty in males and female with SCD
Cox et al., 2011²³	Dar es Salaam, Tanzania	6 months-48 years (mean 10 years)	1041	717 HbAA siblings, clinic walk-ins, and referrals	SCD status was significantly associated with underweight; adult males were more likely to be underweight than females	SCD was significantly associated with stunting; adult males were more likely to be stunted than females	SCD was significantly associated with wasting; adult males were more likely to have wasting than females
Osei-Yeboah, 2011⁴²	Ghana	1-12 years (mean 7 years)	357; genotypes included SS, SC, SD, S Beta thal	70 HbAA siblings	· Significantly lower weight-for-age in individuals with SCD · Prevalence of malnutrition higher in individuals with SCD (61%) versus controls (29%) · No significant differences in rates of wasting (weight-for-height)	Prevalence of stunting higher in individuals with SCD (35%) versus controls (3%)	N/A
Iwalokun et al., 2011³³	Lagos, Nigeria	5-35 years	55 (31 steady-state and 24 unstable/ crisis)	22 “non-SCD” individuals aged 5-30	Significantly lower weight for males >16 years; not different in other age groups	N/A	Significantly lower BMI in females with SCD (all age groups) and males with SCD (>16 years)	· Significantly lower fat mass in males with SCD (>16 years); not significantly different for other age groups · Significantly lower leptin levels in males with SCD (≤16 years) and all female age groups
Animasahun et al., 2011³⁵	Lagos, Nigeria	1-10 years (mean 6 years)	100	100 individuals with genotype HbAA matched by age, socio-economic class, and gender	Significantly lower mean weight and weight-for-height in individuals with SCD	Mean height showed no difference between SCD patients and controls	No difference in mean BMI
Akodu et al., 2012⁴⁵	Lagos, Nigeria	2-15 years (mean 8 years)	80	80 individuals with genotype HbAA	No statistical difference reported	N/A	Significantly lower BMI in individuals with SCD
Tebbani et al., 2014⁸⁵	Annaba city, Algeria	6-12 years	30	WHO standard references	Lower weight in individuals with SCD compared with WHO standards	Height was below WHO standard references for SCD patients	N/A
Akingbola et al., 2014⁸⁶	Ibadan, Oyo, Nigeria and Chicago, USA	11-30 years	214	209 individuals with SCD aged 11-30 years living in USA (compares characteristics of individuals with SCD in Nigeria to those in US)	Significantly lower weight in individuals with SCD in Nigeria vs US in patients ≥18 years old	Significantly lower height in individuals with SCD in Nigeria vs US in patients ≥18 years old	Significantly lower BMI in individuals with SCD in Nigeria vs US in patients ≥18 years old
Akodu et al., 2014³¹	Lagos, Nigeria	8 months-15 years (mean 6 years)	100	100 HbAA age- and sex-matched controls	N/A	Significantly lower sitting height in individuals with SCD aged >10 years; height not significantly different	N/A	Significantly shorter arm span in individuals with SCD aged >10 years
Tsang et al., 2014²⁸	Nyanza Province, Western Kenya	6-35 months	14	288 children from random sample of 882; Underweight, stunting and wasting were defined using WHO 2006 standards	No significant association of HbSS with underweight	No significant association of HbSS with stunting	No significant association of HbSS with wasting
Eke et al., 2015³⁴	Enugu, Nigeria	6-18 years (mean 11 years)	132	132 age- and gender-matched HbAA children and adolescents from nearby schools	Significantly lower weight in females with SCD aged 10-18 years; no differences in males	No differences	Significantly lower BMI in females with SCD aged 10-18 years; no differences in males	· No differences in body fat % or visceral fat % · Significantly lower skeletal muscle % in males with SCD aged 6-9 years
Eke et al., 2015³⁶	Enugu, Nigeria	1-5 years (mean 3 years)	58	58 age- and gender-matched HbAA individuals	· Significantly lower weight-for-age in individuals with SCD · Significantly lower rate of obesity in individuals with SCD (3.4% vs 22.4%)	No difference in height-for-age	Significantly lower BMI in individuals with SCD	· Significantly lower weight-for-height in individuals with SCD
Ranque et al., 2016²¹	Cameroon, Ivory Coast, Gabon, Mali, Senegal	10-24 years (median 16 years)	3,627	943 controls aged 14-33 years; controls were significantly older (median age 24 years versus 16 years for SCDpatients) and more likely to be female (60% vs 54%)	N/A	Significantly lower height in individuals with SCD	Significantly lower BMI in individuals with SCD
Odetunde et al., 2016³⁷	Enugu State, Nigeria	6-20 years (mean 12 years)	40	40 age-, gender-, socioeconomic status-matched HbAA individuals from area schools	Significantly lower weight in individuals with SCD	No differences in height	48% with SCD were underweight (BMI < 5^thpercentile); 13% of controls were underweight
Esezobor et al., 2016²⁴	Lagos, Nigeria	2-17 years (mean 9 years)	233	Compared with WHO 2007 standards	23% of individuals with SCD had wasting (low weight-for-height) or severe wasting	12% of SCD patients were stunted or severely stunted; 75.5% were normal height	2% of individuals with SCD were overweight or obese
Senbanjo et al. 2016³⁰	Lagos, Nigeria	Children up to age 15 years (mean 7 years)	118 (114 HbSS and 4 HbSC genotype)	118 age-, gender-, and socioeconomic class-matched; stunting/malnutrition based on WHO 1995 standards	Significantly higher rate of “thinning” in individuals with SCD aged 11-15 years	Significantly higher rate of stunting in individuals with SCD aged 11-15 years	N/A	No overall difference in mean head circumference
Oluwole et al., 2016⁸⁷	Lagos, Nigeria	6-16 years (mean 9 years)	56	44 individuals without SCD	Significantly lower weight-for-age in individuals with SCD	Significantly lower height in individuals with SCD	Significantly lower BMI in individuals with SCD
Adegoke et al., 2017⁵⁵	Ilesa, Nigeria	4-11 years	95	109 Brazilian children with SCD aged 4-11 years; 36 were hydroxyurea (HU)-naive to match Nigerian patients (study compares SCD populations in Nigeria and Brazil)	30% of SCD patients in Nigeria had low weight-for-height; 4.3% were overweight or obese	13% of SCD patients in Nigeria were of short stature; 8.4 % were tall for age; significantly lower mean height-for-age among Nigerian patients compared with Brazilian HU-naive patients	Significantly lower BMI in Nigerian individuals with SCD	Significantly lower triceps skin fold, upper arm area, upper arm muscle area, and fat % among Nigerian patients compared with the Brazilian HU-naive patients
Mikobi et al., 2017⁸⁸	Kinshasa, DRC	Mean 25 years	140	Study compared groups of SCD patients stratified by disease severity	N/A	N/A	Significantly lower BMI in patients with greater disease severity
Kazadi et al., 2017⁴¹	Kinshasa, DRC	Under 12 years	159	296 age-, gender-, and neighborhood-matched individuals with HbAA; comparisons focused on children under age 12 years; underweight, stunting and wasting were defined using WHO 2006 standards	Significantly lower weight in individuals with SCD(39.6% of individuals with SCD versus 12.2% of controls)	Significantly more stunting in individuals with SCD(34.6% in individuals with SCD versus 9,8% of controls)	N/A	Factors significantly associated (P<0.01) with poor growth included frequency of crises, age <1 yr. at first transfusion, and hand-foot syndrome
Sokunbi et al., 2017⁴⁰	Nigeria	5-18 years (mean 9 years)	175	175 age-matched HbAA individuals	No statistical difference reported	Significantly lower height in individuals with SCD	No statistical difference reported
Onukwuli et al., 2018³⁸	Enugu, Nigeria	6-18 years (females only)	81 (females only)	81 age- and socioeconomic class-matched HbAA individuals recruited from outpatient clinic	Significantly lower mean weight in individuals with SCD	No differences in mean height	Significantly lower BMI in individuals with SCD

Table 2. Studies of micronutrient levels in individuals living with sickle cell disease in Africa

Authors and year of publication	Location	Ages	No. of subjects	Control group	Nutrient type	Findings
VanderJagt et al., 1997²⁷	Jos, Nigeria	10 months – 14 years (mean 7 years for males; mean 6 years for females)	13	17 age- and gender-matched controls	Proteins/amino acids	· No significant differences in concentrations of total protein, albumin, serum creatinine, or albumin/globulin ratios · Significantly reduced serum prealbumin levels in individuals with SCD · Significantly reduced serum concentrations of all essential amino acids and most non-essential amino acids (exceptions: alanine, glutamic acid, proline) in individuals with SCD
Cox et al., 2011⁴⁶	Dar-es-Salaam, Tanzania	Mean 17-18 years	11 patients who had succumbed	12 age- and gender-matched controls (all patients had SCD; comparison was between those alive and those who had succumbed)	Proteins/amino acids	· Significantly lower BMI, a trend for lower taurine levels, and significantly lower l arginine bioavailability in individuals with SCD who later succumbed · No differences in hemolytic markers (unconjugated bilirubin, lactate dehydrogenase, aspartate transaminase, alkaline phosphate), with the exception that conjugated bilirubin at enrollment was significantly higher in patients who later succumbed compared to those who did not
Enomoto et al., 1998⁴⁷	Jos, Nigeria	Females mean 6.3 years; males mean 6.8 years	13	14 age-matched controls	Fatty acids	· No difference in proportions of linoleic and α-linolenic fatty acids · Significantly increased levels of palmitic acid and oleic acid in individuals with SCD · Significantly reduced levels of arachidonic acid, eicosapentanoic acid, and decosahexanolc acid
Glew et al., 2002⁴⁸	Jos, Nigeria	5-17 years (mean 13 years)	77	73 age- and gender-matched controls	Fatty acids	· No differences in levels of linoleic acid · Significantly reduced α-linolenic acid and arachidonic acid in females with SCD; no difference in males · Significantly reduced eicosapentanoic acid and docosahexaenoic acid in individuals with SCD · Significantly increased proportions of palmitic acid (16:0) and oleic acid (18:1n-9) in serum phospholipids in individuals with SCD
VanderJagt et al., 2002³⁹	Jos, Nigeria	Females mean 13.2 years; males mean 13.4 years	72	68 age- and gender-matched controls	Fatty acids	· No differences in linoleic and α-linolenic acid · Significantly reduced long chain polyunsaturated fatty acids and arachidonic acid in individuals with SCD · Significantly higher palmitic acid and oleic acid in individuals with SCD
Glew et al., 2003²⁵	Jos, Nigeria	9-20 years (mean 14 years for males; mean 13 years for females)	77	75 age- and gender-matched healthy controls	Fatty acids	· Significantly reduced linoleic acid, arachidonic acid, α-linolenic acid, eicosapentanoic acid, and docosahexaenoic acid in serum cholesterol esters in individuals with SCD · Significantly increased palmitic acid and oleic acid in serum cholesterol esters in individuals with SCD
Ren et al., 2008⁴⁹	Enugu, Nigeria	11–43 years	26	30 HbAA individuals aged 22–53 years	Fatty acids	· Significantly reduced eicosapentanoic acid and docosahexaenoic acid in red blood cell choline phosphoglycerides in individuals with SCD · Significantly reduced eicosapentanoic acid in ethanolamine phosphoglycerides of individuals with SCD
Hamdy et al., 2015⁵⁰	Cairo, Egypt	6-18 years (mean 12 years)	30	30 age- and gender-matched controls	Fatty acids	· Significantly reduced cholesterol, triglycerides, and LDL in individuals with SCD · No differences in HDL
Shukla et al., 1999⁵²	Malawi	2-19 years (mean 9 years)	28	No control group; comparisons with normal range (˂ 8.0 µmol/L)	Vitamins	· Reduced vitamin E levels in 12 children (63%) · Reduced vitamin E/cholesterol ratio in 10 children (36%), indicating vitamin E deficiency
Jiya et al., 2005⁵¹	Sokoto, Nigeria	9 months – 12 years (mean 6 years)	27 with HbSS and 11 with HbSS and persistent fetal hemoglobin	32 age- and gender-matched controls	Vitamins	· Significantly lower vitamin A (retinol), vitamin C (ascorbic acid) and vitamin E (α-tocopherol) in individuals with SCD
Ren et al., 2008⁴⁹	Enugu, Nigeria	11–43 years	26	30 HbAA individuals aged 22–53 years	Vitamins	· Significantly reduced plasma retinol, α-tocopherol, and β-carotene concentrations, and reduced activity of red cell copper/zinc-superoxide dismutase, in individuals with SCD
Tsang et al., 2014²⁸	Nyanza Province, Western Kenya	6-35 months	14	288 individuals from a random sample of 882	Vitamins	· No significant association with vitamin A deficiency
Hamdy et al., 2015⁵⁰	Cairo, Egypt	6-18 years (mean 12 years)	30	30 age- and gender-matched controls	Vitamins	Significantly reduced levels of selenium and vitamin E in individuals with SCD
Adegoke et al., 2017⁵⁴	Ile-Ife, Nigeria	Mean age 7 years	95	75 age- and gender-matched HbAA individuals	Vitamins	Significantly reduced mean serum 25-hydroxy vitamin D in individuals with SCD
Adegoke et al., 2017⁵⁵	Ilesa, Nigeria	4-11 years (mean 7 years)	95	109 Brazilian children with SCD aged 4-11 years (study compares SCD populations in Nigeria and Brazil)	Vitamins	· Suboptimal vitamin D levels in 12.6% of Nigerian individuals with SCD; none had severe vitamin D deficiency
Adegoke et al., 2017⁵³	Nigeria	1-15 years (mean 8 years)	123	Study examined effect of vitamin D levels on pain (no control group)	Vitamins	· Deficient or insufficient serum 25-hydroxyvitamin D (vitamin D) in 11% of individuals with SCD; none had severe vitamin D deficiency
Ajayi et al., 1997⁵⁹	Lagos, Nigeria	Mean 21 years	30 (females only; 10 HbSS, 10 HbAS, 10 HbAC)	10 HbAA individuals	Minerals	· Significantly reduced zinc levels in individuals with SCD compared to heterozygotes and HbAA controls · Significantly reduced mean serum and erythrocyte copper in individuals with SCD compared to heterozygotes and HbAA controls · Significantly reduced serum, erythrocyte, and urine magnesium in individuals with SCD compared to heterozygotes and HbAA controls
Akenami et al., 1999⁶⁰	Ibadan, Nigeria	16-42 years	35 (23 HbSS, 12 HbSC)	25 age- and gender-matched HbAA individuals	Minerals	· Significantly reduced serum zinc in individuals with HbSS and HbSC · Significantly increased serum copper and magnesium in individuals with HbSS; no difference in individuals with HbSC
Oladipo et al., 2005⁶²	Lagos, Nigeria	7-170 months	86	45 age- and gender-matched HbAA individuals	Minerals	· Significantly increased serum phosphorus in individuals with SCD · Significantly reduced serum calcium in individuals with SCD · No differences in serum magnesium and albumin
Ojo et al., 2006⁵⁷	Ile-Ife, Nigeria	10-60 years	84 (divided by multiple methods of analysis and sample sites)	141 (divided by multiple methods of analysis and sample sites)	Minerals	· Elevated erythrocyte sodium in individuals with SCD · Significantly reduced potassium, zinc, iron, and riboflavin in whole blood and/or erythrocytes in individuals with SCD
Arinola et al., 2008⁵⁸	Ibadan, Nigeria	Not stated	20 individuals with HbSS without malaria; 24 individuals with HbSS with malaria	18 HbAA individuals with malaria; 32 HbAA individuals without malaria	Minerals	· Significantly reduced iron, zinc, and magnesium in individuals with SCD compared to controls · Significantly increased urea in non-malaria infected individuals with SCD compared with non-malaria infected controls · Significantly reduced levels of total antioxidants in non-malaria infected individuals with SCD compared with non-malaria infected controls · No differences in magnesium, copper, chromium, cadmium, and selenium in non-malaria infected individuals with and without SCD · No differences in levels of serum albumin
Olaniyi et al., 2010⁵⁶	Ibadan, Nigeria	26-55 years	59	35 age- and gender-matched controls	Minerals	· Significantly increased mean plasma levels of zinc and nitric oxide in individuals with SCD · Significantly reduced levels of serum iron, chromium, and selenium in individuals with SCD · No differences in levels of magnesium, manganese, and copper
Onukwuli et al., 2017³⁸	Enugu, Nigeria	6-18 years	81 (females only)	81 age- and socioeconomic class-matched HbAA individuals from outpatient clinic	Minerals	Significantly reduced levels of serum zinc in individuals with SCD
Sungu et al., 2018⁶¹	Kasumbalesa, DRC	2-15 years (mean 10 years)	76	76 age-, gender-, and residence area-matched controls	Minerals	Significantly reduced levels of zinc and magnesium in individuals with SCD

Table 3. Studies of nutritional interventions involving individuals living with sickle cell disease in Africa

Authors and year of publication	Location	Ages	No. of subjects	Intervention	Design	Outcome	Comments
Rahimy et al., 2000⁶⁸	Cotonou, Benin	Mean age 28 years	108 pregnant women (42 HbSS, 66 HbSC)	Evaluated effect of special prenatal management in women with SCD; management was based on providing information and education about SCD and improving nutritional status, malaria prevention, early detection of bacterial infections, and restricted use of blood transfusion	Open prospective design with comparison to a non-SCD group and historical SCD cohort in the same hospital	· The maternal mortality rate of 1.8% was comparable with the overall maternal mortality rate for this maternity unit (1.2%) · 86% of pregnancies ended in live births · Fetal loss rate of 12% in this study was higher than for the hospital maternity unit as a whole (6.3%)	Effect of nutritional intervention alone was not measured
Rahimy et al., 2003⁶⁷	Cotonou, Republic of Benin	8 months -12 years (median 35 months)	236	Multi-faceted intervention over several years comprised of health education including nutrition education, nutritional supplementation (e.g., folic acid), vaccines, malarial prophylaxis, and pneumococcal prophylaxis with oral penicillin	Non-comparison, longitudinal cohort	· Disease severity appeared to be lower during the study period than prior to the intervention · The intervention appeared to have beneficial effect on growth and weight in some subjects	Effect of nutritional intervention alone not measured
Akinyanju et al., 2005⁶⁶	Lagos State, Nigeria	1-65 years (mean 18 years)	7,000	Multi-faceted intervention over a period of years comprised of health education, nutritional supplementation (e.g., folic acid, vitamins B and C), vaccines, malarial prophylaxis, and improved access to analgesics, antibiotics, and antimalarials	Non-comparison, longitudinal cohort	· Over the study period, improvements were reported in mortality rate, hospital admissions, and blood transfusions	Effect of nutritional intervention alone not measured
Afolabi et al., 2012⁸⁹	Lagos State and Ogun State, Nigeria	15-48 years	Not reported	Seed oils from Solenostemon monostachyus, Ipomoea involucrateand Carica papayaplants	In vitro comparisons using blood from SCD patients; comparison groups were controls, cells treated with glutathione, and cells treated with a known anti-sickling plant extract	· All plant extracts studied led to reduction in sickled red blood cells, reduction in Fe⁺²/Fe⁺³ ratios, and reduction in lactate dehydrogenase activity when compared with controls · Individual extracts also showed varying improvements in hemoglobin concentration, sickle cell polymerization inhibition, and catalase activity	Some gender dependent differences were noted; specific bioactive compounds within each plant extract were not isolated
Imaga et al., 2013⁹⁰	Lagos State, Nigeria	15-28 years	4 (2 treated, 2 controls)	Oral ingestion for two weeks of a commercial product made from Cajanus Cajan plant extract	Non-blinded in vitrocomparison study	· Treatment group reported to have anti-sickling effect, but no statistical analyses performed · Treatment group reported to have increased fetal hemoglobin, but no statistical analyses performed · No effect reported on packed cell volume, hemoglobin, or mean corpuscular hemoglobin	Statistical analyses lacking for main outcomes
Daak et al., 2013⁶⁴	Khartou, Sudan	2-24 years	128 (67 treated, 61 controls)	Oral ingestion for 1 year of Omega-3 capsules containing EPA and DHA fatty acids; dose was weight-dependent	Double-blinded, placebo-controlled, randomized study	· Treatment group had improved primary outcome: significantly fewer clinical vaso-occlusive events · Treatment group also had reduced severe anemia, reduced blood transfusions, reduced white blood cell counts, and reduced school absences due to disease · No change in rates of stroke, sequestration crisis, or vascular necrosis	The study was not powered to detect changes in rates of stroke, sequestration crisis, or vascular necrosis
Adegoke et al., 2013⁶³	Ekiti State, Nigeria	1 year to “adolescent” (upper range not specified)	125 (65 treated, 60 controls)	Oral ingestion for 6 months of freshly squeezed lime juice; dose was weight- dependent (range: 10-30 ml daily)	Open label, randomized study	· Treated group had significantly fewer pain episodes, febrile illness, and admission rate · Treated group had significantly increased mean hematocrit · No change in transfusion rate, organomegaly, or jaundice	Effect hypothesized to result from vitamin C, amino acids (especially phenylalanine) and flavonoids
Adegoke et al., 2017⁵⁴	Ile-Ife, Nigeria	Mean age 7 years	170 (95 treated, 75 controls)	Oral ingestion for 3 months of vitamin D supplementation in children with SCD that had low 25-hydroxyvitamin D (25-OHD) levels	Age- and gender-matched controlled study	· Children with SCD and low 25-OHD levels had enhanced levels of pro-inflammatory cytokines · Treatment with vitamin D in children with SCD that had low 25-OHD levels led to an improved pro-inflammatory cytokine profile	Effect hypothesized to result from anti-inflammatory influence of supplemental vitamin D
Cox et al., 2018⁶⁵	Dar-es-Salaam, Tanzania	8-12 years (mean 10 years)	119	Oral ingestion of ready-to-use supplementary food (RUSF) with and without arginine and citrulline	Double-blind, random order crossover trial	· RUSF increased the global arginine bioavailability ratio and improved measures of endothelial function, and led to improvements in growth · RUSF fortified with arginine and citrulline did not additionally increase the plasma global arginine bioavailability ratio or improve endothelial function	Arginine is the sole substrate of endothelial nitric oxide synthase and has been implicated in pathophysiology of SCD complications

PRISMAChecklistSCDNutritionStudy.doc

Nutritional Perspectives On Sickle Cell Disease In Africa: A Systematic Review

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Methods

Results

Discussion

Conclusion

Abbreviations

DECLARATIONS

References

Tables

Supplementary Files

Status:

Journal Publication

Version 1