Prevalence and Correlates of Growth Failure in African Patients with Sickle Cell Disease: A Multinational Study
Authors: Alexandre Laure , Diallo Dapa , Tolo Aissata , Diop Saliou , Sanogo Ibrahima , Diagne Ibrahima , Wamba Guillaume , Boidy Kouakou , Deme Ly Indou , Dembele Abdoul Karim , Belinga Suzanne , Dubert Marie , Jouven Xavier , Ranque Brigitte 
Published: April 2021

Abstract

Introduction
Growth failure has been a well-known complication of sickle cell disease (SCD) since the 70s. More recent studies show that the proportion of underweight children with SCD has decreased significantly, thanks to modern treatments (in particular hydroxyurea and iterative transfusions), with a tendency towards overweight and even obesity. However, most studies have been carried out in high-income countries, while 80% of the affected children are born in sub-Saharan Africa, where the environment and the medical care are entirely different. We carried out a case-control study nested in a multinational African cohort to study the growth of sickle cell children and the possible factors influencing growth failure.
Methods
We performed a case-control transversal study nested in the CADRE cohort that includes SCD patients from five African countries: Cameroon, Gabon, Côte d'Ivoire, Mali and Senegal. All children aged 5 to 21 years-old from this cohort were included in our study. Healthy controls were recruited among the patients' siblings or the children of health workers from each center. The main parameters studied were: medical history, height, weight, blood pressure; hemoglobin phenotype (SS, Sβ0, SC or Sβ +); complete blood count; hemolysis markers (LDH and bilirubin); microalbuminuria; echocardiographic parameters. The primary endpoint was growth failure, defined as a weight, height or BMI below the 5th percentile of the WHO growth charts. We described the frequency of growth failure according to hemoglobin phenotype, age and sex. Then we assessed by multivariate logistic regression in two SCD phenotypic groups (SS or Sβ0 and SC or Sβ +) the association between growth failure and the biological characteristics or the history of SCD-related complications.
Results
2296 patients (1799 SS, 114 Sβ0, 287 SC, 96 Sβ+ patients and 287 controls were enrolled in Cameroon (n=735), Ivory Coast (n=380), Gabon (n=298), Mali (n=589) and Senegal (n=581). Overall, 48% of the patients were male and their median [interquartile range] age was 12 [8-16] years-old. Growth failure was diagnosed in 51% of SS, 58% of Sβ0, 44% of SC, 38% of Sβ+patients and 32% of controls, with deeper underweight than linear growth retardation. Beyond the age of 18, the mean BMI of SCD patients was again similar to that of controls in girls, but remained lower in boys, whereas the mean height was similar to that of controls regardless of sex (Figures a to d). Growth failure was more frequent in boys than in girls and maximal between 13 and 16 years-old (Figures e and f). In univariate analysis, the prevalence of growth retardation was associated with the country (highest in Senegal, lowest in Cameroon), age, male sex, hemoglobin phenotype, levels of anemia and hemolysis (p &lt;.0001 for all comparisons). After adjusting for age and the country, the prevalence of growth failure was significantly higher in SS-Sβ0 patients compared to controls (OR = 2.55 [1.83-3.56]) but not different between SC-Sβ+ patients and controls (1.35 [0.91-2.01]). In multivariate analysis, growth failure in SCD patients was positively associated with male sex (OR=1.89, 95%IC=1.56-2.28), [12-15] years age class (OR=2.31, 95%IC=1.75-3.07), SS or Sβ0 phenotypes (OR=2.06 and 2.27, 95%IC=1.26-3.36 and 1.22-4.21, respectively), icterus, leukocytes count, and microalbuminuria (OR = 1.4 [1.1-1.8]). It was negatively associated with parents' secondary or upper education, mean blood pressure and hemoglobin level (OR = 1.96 [1.55-2.47] for the first quartile of hemoglobin level vs others). No association was found between growth failure and the history of clinical SCD-related complications (osteonecrosis, leg ulcers, stroke, priapism, pulmonary hypertension defined by echocardiography and retinopathy).
Conclusion
In sub-Saharan Africa, growth failure occurs in more than half of the SCD children and concerns weight more than height. Its prevalence is particularly high in SS or Sβ0 patients and during adolescence, due to pubertal delay. Growth failure in SCD children is associated with male sex, anemia and high hemolysis markers independently of the hemoglobin phenotype, but is not independently associated with the occurrence of acute or chronic vascular complications of sickle cell disease, apart from microalbuminuria. However, the long-term consequences of growth failure in sickle cell disease should be evaluated in a longitudinal study.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.