You are here

Article Text

Article menu

Download PDFPDF

XML
Haematology
Original article
High body mass index in children with sickle cell disease: a retrospective single-centre audit
  1. Rachael Hall1,
  2. Kate Gardner2,
  3. David C Rees2,3,
  4. Subarna Chakravorty2,3
  1. 1 Department of Haematology, Imperial College London, London, UK
  2. 2 Department of Haematological Medicine, King’s College London, London, UK
  3. 3 Department of Paediatric Haematology, King’s College Hospital, London, UK
  1. Correspondence to Dr Subarna Chakravorty; subarna.chakravorty{at}nhs.net

Abstract

Objective To assess the prevalence of high body mass index (BMI) in children with sickle cell disease and assess correlation between BMI and disease severity.

Design Retrospective chart review followed by statistical analysis.

Setting A single tertiary paediatric clinic in inner city London.

Patients All patients with sickle cell disease, including homozygous haemoglobin (HbSS) and compound heterozygous Hb (HbSC), age 2–18 years receiving clinical care at the centre, were included in the study.

Interventions Height and weight measurements, steady-state laboratory blood tests, hospital admission rates, adjunct therapy such as hydroxycarbamide or blood transfusions and obstructive sleep apnoea (OSA) data were obtained from the hospital electronic patient records.

Main outcome measures To study the prevalence of high BMI and to identify any correlation between BMI and disease severity.

Results 385 patients were included. 64 children (17%) were overweight or obese, of which a significantly higher number of children with HbSC were obese or overweight (23 out of 91, 25%) compared with those with HbSS (36 out of 273, 13%), p≤0.001. No correlation was found between high BMI and presence of OSA, and markers of disease severity such as admission rates, fetal haemoglobin or lactate dehydrogenase levels.

Conclusions High BMI did not correlate with disease severity in this cohort of patients with sickle cell disease. Obesity was more prevalent in females and those with HbSC. Further prospective studies are needed to determine long-term effects of BMI in disease severity and outcome.

  • obesity
  • haematology
  • comm child health

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjpo-2018-000302

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    What is already known on this topic?

    • Children with sickle cell disease (SCD), especially those with the homozygous disease, were historically underweight due to increased metabolic demand and frequent ill health.

    • In the USA, increased frequency of childhood obesity within the general population is also reflected among patients with SCD.

    • Obesity in SCD is not associated with disease severity.

    What this study hopes to add?

    • One in six children with sickle cell disease (SCD) in a large single-centre UK-based cohort were overweight or obese, while only 1 in 20 children with SCD were underweight.

    • There was a trend for higher haemoglobin values in children who were overweight or obese compared with those with normal body mass index (BMI) centiles, even when corrected for age and hydroxyurea use and genotype, highlighting the need for further study in this area.

    • Overweight or obese children did not have higher rates of hospitalisation compared with those with normal BMI.

    Introduction

    Sickle cell disease (SCD) is one of the most common clinically significant genetic disorder in England, affecting up to 1 in 300 live births in urban areas.1 The most common and severe form of SCD, sickle cell anaemia, refers to homozygosity for the sickle haemoglobin (Hb), known as HbSS.2 Two major pathophysiological processes of SCD, vaso-occlusion with ischaemia-reperfusion injury and chronic haemolytic anaemia, are driven by HbS polymerisation within erythrocytes.3

    Historically, it is well documented that children with SCD were underweight, particularly those with HbSS.4 Poor growth in children with SCD is complex and multiple factors are likely to contribute, including increased energy and nutrient requirements resulting from increased haemolysis and erythropoiesis, and elevated protein turnover.5

    Obesity in the UK is increasing with recent figures suggesting that nearly one-third (31%) of boys and more than one in four girls (28%) aged between 2 and 15 years are overweight or obese.6 Although the increasing incidence is almost certainly due environmental factors, genetic factors also strongly affect susceptibility to obesity.7

    Two reports in the USA found that 19%–22% of children with SCD were overweight or obese.8 9 Nutritional status and growth may have improved in SCD due to the increased use of SCD-directed therapies and lifestyle factors.9 Children in the Stroke Prevention Trial in Sickle Cell Anaemia who regularly received transfusions over 24 months demonstrated a significant improvement in z-scores for height, weight and body mass index (BMI).10 Hydroxycarbamide (HC), which was, until recently, the only drug licensed for the use in SCD, lowers resting energy expenditure, improving energy balance and growth.11 Preventing obesity in children with SCD is vital as obesity is associated with obstructive sleep apnoea (OSA), which increases the risk of nocturnal hypoxia and vaso-occlusive episodes (VOEs).12

    There is limited data assessing the prevalence of high BMI in children with SCD in the UK and the relationship between BMI and disease severity. One study in the USA demonstrated that there was a 36% increase in odds of being overweight or obese for each 1.0 g/dl increase in baseline Hb levels.9 Another study failed to demonstrate an association between the extremes of BMI of patients and hospitalisation for VOE.8 The purpose of this study is to assess the prevalence of high BMI in an urban population of children with SCD in the UK and evaluate whether there is a correlation between BMI and disease severity.

    Methods

    Data collection

    A retrospective chart review was performed on patients aged 2–18 years with SCD who were registered to the National Haemoglobinopathy Register13 and attended a paediatric haematology outpatient clinic in a single tertiary hospital in inner city London, between April 2015 and April 2017. Patients transferred to other centres were excluded.

    Clinical and laboratory data

    All children are weighed and measured when they attend clinic by trained clinical staff using standard, calibrated equipment. BMI and BMI percentile documented from the most recent clinic visit were recorded. Age-specific and gender-specific definitions of BMI percentiles were used, based on the British 1990 growth reference charts, as recommended in England by the National Obesity Observatory.14 15 Overweight or high BMI was defined as ≥85th percentile for age and gender (obese was defined as ≥95th percentile for age and gender), while underweight or low BMI was defined as ≤5th BMI percentile. Patients were assigned to one of three groups based on their age-dependent percentile: underweight, normal weight, overweight/obese as per well-established clinical classifications.16 Data were categorised in order to study the influence of obesity on disease severity.

    Through retrospective chart review, markers of disease severity were recorded, including acute sickle cell-related accident and emergency (A&E) attendances and hospital admissions during the 24-month period. Elective admissions were excluded. Patients were assigned to none, 1 or >1 A&E attendances and none, 1 or >1 hospital admissions. Other indices of disease severity were recorded, including Hb, reticulocyte count, lactate dehydrogenase (LDH) levels and fetal Hb (HbF) level from the most recent blood test. Hb was a mean of the last three steady-state results. The use of SCD-directed treatments during this period was recorded.

    Statistical analysis

    Association between BMI group and independent variables was examined by χ2 test for categorical variables and independent samples t-test for continuous variables. Given the small number of low BMI subjects in this study (n=20), only normal and high BMI groups were compared for differences with respect to laboratory data. Given the difference in disease severity by genotype, HbSS and heterozygous Hb (HbSC) clinical and laboratory data were assessed separately.17 Linear multiple regression analysis was undertaken to predict the relationship of BMI centiles with independent variables such as laboratory markers of disease severity and use of HC. P values less than 0.05 were considered significant. All analyses were performed using the IBM SPSS Statistics, V.24 (IBM).

    Ethical considerations

    This study involved retrospective chart reviews and no identifiable patient data have been reported. Hence, this was classified as a clinical audit.

    Results

    Patient population

    Three hundred and eighty-five children and adolescents with SCD between ages 2 and 18 years were included in the study. Seventy-one per cent children (n=273) had HbSS and 24% children (n=91) had HbSC disease (table 1). Fifty-three per cent (n=204) were male. Twenty-eight per cent patients (n=108) were receiving HC therapy and 7% (n=27) chronic transfusions. Fifty-five patients (14%) had a clinical diagnosis of OSA.

    View this table:
    Table 1

    Demographics of the study population

    In the whole cohort, 17% children (n=64) were overweight or obese. Of these, 33 children (9% of the whole cohort) were classified as overweight; with BMI on or between the 85th and 95th centile for age and gender, and 31 children (8% of the whole cohort), were classified as obese; with BMI greater than 95th centile for age and gender. Twenty children (5%) had a low BMI (≤5th centile for age and gender) and 301 children (78%) had a normal BMI (table 2). Significantly more females had a high BMI (26%, n=47) than males (8%, n=17) (p≤0.001). Patients in the low BMI group were significantly more likely to be older than those in the normal BMI group. Significantly more patients with HbSC disease were overweight or obese (23 out of 91, 25%) than patients with HbSS (36 out of 273,13%) (p=0.006). There was no significant difference between BMI group and ethnic origin, chronic transfusions and OSA.

    View this table:
    Table 2

    Baseline characteristics by BMI group

    BMI and HC therapy

    Twenty-eight per cent patients with HbSS received HC therapy (n=104), see table 3. There was no significant difference between BMI group and HC treatment (p=0.47).

    View this table:
    Table 3

    Hydroxycarbamide therapy by BMI group in patients with HbSS genotype

    BMI, clinical and laboratory data

    No significant difference in the number of A&E attendances or hospital admissions between the three BMI groups in patients with HbSS or HbSC disease (table 4).

    View this table:
    Table 4

    A&E attendances and hospital admissions by BMI group for a 2-year period from April 2015

    View this table:

    The median Hb was significantly higher in the high BMI group (9.5 g/dl) compared with the normal BMI group (8.6 g/dl) for patients with HbSS (p≤0.001) (table 5). Further analysis indicated that the association may persist even when corrected for age at visit, HbF percentage, use of HC and genotype (HbSS vs HbSC) (p=0.048), data not shown. Although the median absolute reticulocyte count and the median HbF percentage were significantly lower in the high BMI group compared with the normal BMI group, this correlation did not achieve significance when corrected for HC use. Additionally, there was no significant difference between BMI group and LDH level or for all laboratory markers of disease severity between low and normal BMI groups.

    View this table:
    Table 5

    Laboratory data by BMI group for patients with HbSS and HbSC

    View this table:

    There was no significant difference for patients with HbSC disease between normal and high BMI groups and laboratory markers of disease severity.

    Discussion

    Seventeen per cent of children with SCD, including 25% of those with HbSC disease, in this single-centre cohort were overweight or obese. There was no association between BMI group and clinical disease severity, determined by the number of A&E attendances and hospital admissions.

    The proportion of overweight or obese children with SCD noted in this London cohort is similar to that in two centres in the USA, where 19%–22% children were reported to be overweight or obese. However, it is noteworthy that fewer children with SCD are overweight or obese compared with all children across London, where 35%–40% children fall in these weight categories.8 9 18 This is understandable as multiple factors increase the demand for energy and nutrients in SCD.5 19 Females were more likely to be overweight or obese than males, similar to one other study,20 but not another.9 A high BMI was more often associated with the HbSC genotype, consistent with other reports.8 9 It is also consistent with data demonstrating that growth in children with HbSC disease is not significantly different from that in normal children.21

    It is of note that in our cohort, SCD is predominantly prevalent among individuals of African or Afro-Caribbean heritage. BMI centile charts used in this study were based on children of white ethnicity only,22 as this is the recommended BMI reference source in England.14 Although it is likely that ethnic variation in BMI is prevalent in the UK, this may not be of relevance to the SCD population, as the vast majority of patients with SCD in the UK belong to ethnicities similar to that noted in our cohort.23

    It is known that HC can decrease the resting energy expenditure by 8%, by decreasing the severity of anaemia and increasing red cell survival, making more energy available for normal growth.11 24 25 A randomised study looking at the effect of growth in patients with HbSS receiving HC in the BABYHUG trial did not show any difference in growth parameters at study entry and exit.26 However, that study involved infants only, and the duration of the study may not have been long enough to demonstrate the effect of HC on growth. The duration of SCD-directed treatment was not collected in this study and some patients may only be taking HC for a short period.

    No correlation between BMI group and clinical markers of disease severity was found. The results are similar to a single centre, retrospective chart review of children with SCD from the USA where no association was found between extremes of BMI and frequency of hospitalisations for VOE.8 The study only used the first admission during the study period in data analysis and did not look at the total number of admissions. This may not represent the true severity of SCD.

    Hb levels demonstrated an association with high BMI in patients with HbSS compared with those with normal BMI even when corrected for HC use, genotype and HbF levels. This is an interesting finding and requires further study. One study found that for each 1.0 g/dL increase in baseline Hb, there was a 36% in increase in odds of being overweight or obese.9 It could be hypothesised that less severe anaemia decreases the need for a hyperdynamic circulation, which reduces energy and nutrient demand, and could also be a marker of a less severe phenotype in general.19

    No significant difference was found between BMI group and laboratory markers in patients with HbSC disease. Some haematological features of HbSC disease are more like those of a normal individual as there is less haemolysis, a milder anaemia and fewer reticulocytes.17

    This study has some limitations. As it is retrospective, it is not possible to establish causation. Only data concerning attendances and admissions to our hospital were obtainable and it does not cover all potential A&E attendances or admissions. The patient sample is only representative of an urban population of children with SCD in the UK and will not be generalisable to all children with SCD. Duration of UK residency was not recorded, which could underestimate the prevalence of high BMI as children from low-income and middle-income countries are frequently underweight.4

    Several studies have suggested that waist circumference and waist to height ratio are better determinants of obesity in children than BMI, but body fat measured by dual-energy X-ray absorptiometry (DEXA) is shown to be strongly correlated with BMI and weight to height ratio, suggesting that either can be used when DEXA is not available.21 27 Despite the advantages of using BMI percentiles for age and gender, there are limitations of BMI. BMI is an imperfect tool to determine weight status because it does not distinguish between excess fat or lean muscle mass.28 BMI may not be appropriate for young children because they grow at different rates and so weight to height ratio does not accurately represent whether they are overweight.29

    Longitudinal cohort studies monitoring BMI of children over time and markers of severity in SCD would produce greater evidence of the impact of a high BMI on disease severity. Preventing obesity is vital in SCD as OSA increases the risk of night time hypoxia and VOE.12 Obesity is also associated with hypertension, which increases the risk of stroke and death in SCD.30 Given that a significant proportion of children with SCD are overweight or obese and patients with SCD commonly have multiple nutrient deficiencies, creating the optimum nutrition and exercise regimen for children and adolescents with SCD is vital to assist them in maintaining a healthy BMI.31

    Conclusion

    The historical observation that children with SCD were underweight is no longer true, at least in high-income countries. Nearly one-sixth of children with SCD in this cohort were overweight or obese, with a high BMI more often associated with females and HbSC genotype. In this study, no association was found between BMI levels and several disease severity markers, including hospital admission rates. Further longitudinal prospective study looking at growth and BMI in children with SCD and its effect on disease severity and the effect of the use of sickle-directed therapies on BMI is needed.

    References

    1. 1.↵
      NHS Screening Programmes. Data collection and performance analysis report- newborn blood spot screening 2015/16: Public Health England.
    2. 2.↵
      2. Piel FB ,
      3. Steinberg MH ,
      4. Rees DC
      . Sickle cell disease. N Engl J Med Overseas Ed 2017;376:1561–73.doi:10.1056/NEJMra1510865
      OpenUrl
    3. 3.↵
      2. Rees DC ,
      3. Williams TN ,
      4. Gladwin MT
      . Sickle-cell disease. The Lancet 2010;376:2018–31.doi:10.1016/S0140-6736(10)61029-X
      OpenUrl
    4. 4.↵
      2. Thomas PW ,
      3. Singhal A ,
      4. Hemmings-Kelly M , et al
      . Height and weight reference curves for homozygous sickle cell disease. Arch Dis Child 2000;82:204–8.doi:10.1136/adc.82.3.204
      OpenUrlAbstract/FREE Full Text
    5. 5.↵
      2. Barden EM ,
      3. Zemel BS ,
      4. Kawchak DA , et al
      . Total and resting energy expenditure in children with sickle cell disease. J Pediatr 2000;136:73–9.doi:10.1016/S0022-3476(00)90053-2
      OpenUrlCrossRefPubMedWeb of Science
    6. 6.↵
      Health and Social Care Information Centre. Statistics on obesity, physical activity and diet. England 2013.
    7. 7.↵
      2. El-Sayed Moustafa JS ,
      3. Froguel P
      . From obesity genetics to the future of personalized obesity therapy. Nat Rev Endocrinol 2013;9:402–13.doi:10.1038/nrendo.2013.57
      OpenUrlCrossRefPubMed
    8. 8.↵
      2. Zivot A ,
      3. Apollonsky N ,
      4. Gracely E , et al
      . Body Mass Index and the Association With Vaso-occlusive Crises in Pediatric Sickle Cell Disease. J Pediatr Hematol Oncol 2017;39:314–7.doi:10.1097/MPH.0000000000000787
      OpenUrl
    9. 9.↵
      2. Chawla A ,
      3. Sprinz PG ,
      4. Welch J , et al
      . Weight status of children with sickle cell disease. Pediatrics 2013;131:e1168–e1173.doi:10.1542/peds.2012-2225
      OpenUrlAbstract/FREE Full Text
    10. 10.↵
      2. Wang WC ,
      3. Morales KH ,
      4. Scher CD , et al
      . Effect of long-term transfusion on growth in children with sickle cell anemia: results of the STOP trial. J Pediatr 2005;147:244–7.doi:10.1016/j.jpeds.2005.02.030
      OpenUrlCrossRefPubMedWeb of Science
    11. 11.↵
      2. Fung EB ,
      3. Barden EM ,
      4. Kawchak DA , et al
      . Effect of hydroxyurea therapy on resting energy expenditure in children with sickle cell disease. J Pediatr Hematol Oncol 2001;23:604–8.doi:10.1097/00043426-200112000-00010
      OpenUrlCrossRefPubMed
    12. 12.↵
      2. Hargrave DR ,
      3. Wade A ,
      4. Evans JP , et al
      . Nocturnal oxygen saturation and painful sickle cell crises in children. Blood 2003;101:846–8.doi:10.1182/blood-2002-05-1392
      OpenUrlAbstract/FREE Full Text
    13. 13.↵
      National Haemoglobinopathy Register. NHR Information Service Patient Number by Centre and Diagnosis: National Haemoglobinpathy Register, 2016. http://www.nhr.nhs.uk/wp-content/uploads/2016/05/NumberPatientsByCentre.pdf
    14. 14.↵
      National Obesity Observatory. A simple guide to classifying body mass index in children: Public Health Observatories in England, 2011.
    15. 15.↵
      2. Dinsdale HRC ,
      3. Ells L
      . A simple guide to classifying Body Mass index in children. National Obesity Observatory: Oxford, 2011.
    16. 16.↵
      2. Cole TJ
      . Growth monitoring with the British 1990 growth reference. Arch Dis Child 1997;76:47–9.doi:10.1136/adc.76.1.47
      OpenUrlAbstract/FREE Full Text
    17. 17.↵
      2. Nagel RL ,
      3. Fabry ME ,
      4. Steinberg MH
      . The paradox of hemoglobin SC disease. Blood Rev 2003;17:167–78.doi:10.1016/S0268-960X(03)00003-1
      OpenUrlCrossRefPubMedWeb of Science
    18. 18.↵
      2. Townsend NBP ,
      3. Wickramasinghe K ,
      4. Williams J , et al
      . Children and Young People Statistics- British Heart Foundation, 2013.
    19. 19.↵
      2. Al-Saqladi AW ,
      3. Cipolotti R ,
      4. Fijnvandraat K , et al
      . Growth and nutritional status of children with homozygous sickle cell disease. Ann Trop Paediatr 2008;28:165–89.doi:10.1179/146532808X335624
      OpenUrlCrossRefPubMedWeb of Science
    20. 20.↵
      2. Mitchell MJ ,
      3. Carpenter GJ ,
      4. Crosby LE , et al
      . Growth status in children and adolescents with sickle cell disease. Pediatr Hematol Oncol 2009;26:202–15.doi:10.1080/08880010902896882
      OpenUrlCrossRefPubMed
    21. 21.↵
      2. Martin-Calvo N ,
      3. Moreno-Galarraga L ,
      4. Martinez-Gonzalez MA
      . Association between body mass index, waist-to-height ratio and adiposity in children: A systematic review and meta-analysis. Nutrients 2016;8:512.doi:10.3390/nu8080512
      OpenUrl
    22. 22.↵
      2. Freeman JV ,
      3. Cole TJ ,
      4. Chinn S , et al
      . Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995;73:17–24.doi:10.1136/adc.73.1.17
      OpenUrlAbstract/FREE Full Text
    23. 23.↵
      2. Register NH
      . National Haemoglobinopathy Registry Annual Report 2016/17. UK 2017.
    24. 24.↵
      2. Paule I ,
      3. Sassi H ,
      4. Habibi A , et al
      . Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen. Orphanet J Rare Dis 2011;6:30.doi:10.1186/1750-1172-6-30
      OpenUrlCrossRefPubMed
    25. 25.↵
      2. Ballas SK ,
      3. Marcolina MJ ,
      4. Dover GJ , et al
      . Erythropoietic activity in patients with sickle cell anaemia before and after treatment with hydroxyurea. Br J Haematol 1999;105:491–6.doi:10.1111/j.1365-2141.1999.01339.x
      OpenUrlCrossRefPubMedWeb of Science
    26. 26.↵
      2. Rana S ,
      3. Houston PE ,
      4. Wang WC , et al
      . Hydroxyurea and growth in young children with sickle cell disease. Pediatrics 2014;134:465–72.doi:10.1542/peds.2014-0917
      OpenUrlAbstract/FREE Full Text
    27. 27.↵
      2. Savva SC ,
      3. Tornaritis M ,
      4. Savva ME , et al
      . Waist circumference and waist-to-height ratio are better predictors of cardiovascular disease risk factors in children than body mass index. Int J Obes Relat Metab Disord 2000;24:1453–8.doi:10.1038/sj.ijo.0801401
      OpenUrlCrossRefPubMedWeb of Science
    28. 28.↵
      2. Must A ,
      3. Anderson SE
      . Body mass index in children and adolescents: considerations for population-based applications. Int J Obes 2006;30:590–4.doi:10.1038/sj.ijo.0803300
      OpenUrlCrossRefPubMedWeb of Science
    29. 29.↵
      2. Olsen IE ,
      3. Lawson ML ,
      4. Ferguson AN , et al
      . BMI curves for preterm infants. Pediatrics 2015;135:e572–e581.doi:10.1542/peds.2014-2777
      OpenUrlAbstract/FREE Full Text
    30. 30.↵
      2. Pegelow CH ,
      3. Colangelo L ,
      4. Steinberg M , et al
      . Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med 1997;102:171–7.doi:10.1016/S0002-9343(96)00407-X
      OpenUrlCrossRefPubMedWeb of Science
    31. 31.↵
      2. Martyres DJ ,
      3. Vijenthira A ,
      4. Barrowman N , et al
      . Nutrient insufficiencies/deficiencies in children with sickle cell disease and its association with increased disease severity. Pediatr Blood Cancer 2016;63:1060–4.doi:10.1002/pbc.25940
      OpenUrl

    Footnotes

    • Contributors SC designed the study. RH conducted the data collection and analysis. KG and DCR assisted in data analysis. All authors wrote and reviewed the manuscript.

    • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval No formal ethical approval was sought for this study.

    • Provenance and peer review Not commissioned; externally peer reviewed.