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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Br J Haematol. 2020 May 16;190(6):939–944. doi: 10.1111/bjh.16746

Low educational status of head of household as a proxy for poverty, is associated with severe anemia amongst children with sickle cell disease living in a low-resource setting: evidence from the spring trial

Halima Bello-Manga 1, Aisha A Galadanci 2, Shehu Abdullahi 3, Shehi Ali 4, Binta Jibir 5, Safiya Gambo 6, Lawal Haliru 7, Lori C Jordan 8, Muktar H Aliyu 9, Mark Rodeghier 10, Adetola A Kassim 11, Michael R DeBaun 12, Najibah A Galadanci 13
PMCID: PMC7669582  NIHMSID: NIHMS1633099  PMID: 32415792

Abstract

Severe anemia, defined as hemoglobin level <6.0 g/dL, is an independent risk factor for death in individuals with sickle cell disease living in resource-limited settings. We conducted a cross-sectional study of 941 children with sickle cell anemia; defined as phenotype HbSS or HbSβ0 thalassemia, aged 5 to 12 years screened for enrollment into a large primary stroke prevention trial in Nigeria (SPRING; NCT02560935). The main aim of the study was to determine the prevalence and risk factors for severe anemia. We found severe anemia to be present in 3.9% (37 of 941) of the SPRING study participants. Severe anemia was significantly associated with a lower educational status of head of household (P=0.003) and a greater number of children per room in the household (P=0.004). Body mass index was not associated with severe anemia. The etiology of severe anemia in children living with sickle cell anemia in Nigeria is likely to be multifactorial with an interplay between an individual’s disease severity and other socio-economic factors related to poverty.

Keywords: sub-Saharan Africa, sickle cell disease, severe anemia

INTRODUCTION

The cardinal manifestation of sickle cell disease (SCD) is chronic hemolytic anemia due to an abnormal hemoglobin S (HbS). Severe anemia, defined as hemoglobin (Hb) <6 g/dL is associated with significant morbidity and mortality in individuals with SCD. HbS polymerizes when deoxygenated, resulting in structural changes to the red blood cell membrane, leading to recurrent hemolysis.(Novelli and Gladwin, 2016) The chronic anemia that ensues can be exacerbated by both SCD and non-SCD-related factors, including infections and nutritional deficiencies, which can result in severe anemia and associated morbidity and premature death.(Meier et al., 2014, Makani et al., 2011) ((Van-Dunem et al., 2007)

Severe anemia in SCD is associated with strokes,(Ohene-Frempong et al., 1998, DeBaun and Kirkham, 2016) severe cognitive deficits (King et al., 2008), growth impairment,(Wolf et al., 2015) renal insufficiency,(Gladwin, 2016) and left ventricular diastolic dysfunction.(Gladwin and Sachdev, 2012) Severe anemia is also an independent risk factor for death among children with SCD in resource-limited settings,(Makani et al., 2011) where > 90% of the children with SCD are born.(Piel et al., 2013)

The risk factors associated with severe anemia in children with the most severe form of SCD, sickle cell anemia (SCA), living in low-resource settings have not been fully elucidated. In a cross-sectional study, we tested the hypothesis that head of household education status, as a proxy for household income, was a primary risk factor for severe anemia (Hb < 6.0 g/dL) in older children with SCA in a low-income setting.

METHODS

Study Design and Population

The study was approved by the Institutional review board (IRB) of Vanderbilt University Medical Center in Nashville, Tennessee, U.S.A, and the respective ethics committees of the 3 sites participating in the National Institute of Health (NIH)-funded multicenter phase III randomized controlled trial Primary Prevention of Stroke in Children with SCD in Sub-Saharan Africa, “SPRING trial”, NCT02560935. The sites included Aminu Kano Teaching Hospital and Murtala Mohammad Specialist Hospital in Kano, Nigeria and Barau Dikko Teaching Hospital in Kaduna, Nigeria and cumulatively provide medical care for over 20,000 children with SCD. We conducted a cross-sectional analysis of a cohort of 941 children with SCA who attend the 3 SPRING sites for their routine medical care. Children with severe anemia (Hb<6g/dl and excluded for the SPRING trial), at baseline, were included in this cross-sectional study to determine the prevalence and risk factors for severe anemia (Hb <6 g/dL). The inclusion criteria for the study are confirmed diagnosis of SCA (HbSS or Sβ0); ages 5 to 12 years; informed parental consent (assent when applicable); non-missing screening Hb, and not on hydroxyurea at the time of screening.

Data Collection and Definitions

Data on demographics, socioeconomic status (including parental education and employment status), baseline clinical and laboratory values, including hemoglobin, white blood count (WBC), mean corpuscular volume (MCV), blood pressure (mmHg), oxygen saturation, complete physical examination, and anthropometric measures; [height (cm) and weight (kg)] were collected by a trained research assistant, nurse or a physician. Height and weight were used to calculate body mass index (BMI, kg/m2). Study data were collected using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at Vanderbilt University Medical Center.(Harris et al., 2009) All data were de-identified and participants were assigned study identification numbers.

Severe anemia was defined as a Hb level of <6.0 g/dL. (Brown et al., 1994) Sickle cell anemia (SCA) was referred to as hemoglobin phenotype HbSS and HbSβ0 thalassemia; Sickle cell anemia (SCA) was referred to as hemoglobin phenotype HbSS and HbSβ0 thalassemia; though genotyping was not done, any patient with HbSβ0 thalassemia was captured as HbSS, because physicians cannot reliably distinguish the two SCD phenotypes based on laboratory data. (Day et al., 2019)

Statistical Analysis

The demographics and anthropometric characteristics of all children were summarized as mean and standard deviations for continuous variables; while frequencies and percentages were used for dichotomous variables. Comparisons were made using the chi-square and student’s t-test were used for categorical and continuous variables, respectively. A penalized logistic regression was used to identify demographic and household characteristics associated with severe anemia. A two-sided P-value of 0.05 was considered statistically significant. Data analysis was conducted using SPSS version 25 (Armonk, NY: IBM Corp.).

RESULTS

Demographics

Between July 2016 and June 2018, a total of 956 children with SCA between 5 to 12 years of age were screened for the SPRING trial. A total of 98.4% (941/956) participants had a baseline complete blood count (CBC) and were included in the final analysis for this study. The median age of study participants was 8.0 years (IQR 6.2 – 10.2), and approximately half were female (51.9%). The mean Body Mass Index of participants was 13.6kg/m2 (1.7). Evaluation of the educational status of the head of the household was available for 96.4% (908) of eligible participants. Level of education attained in respondents (parents/caregivers) included elementary or no formal education 27.3% (248), high school 34.0% (309), Ordinary National Diploma (OND) 17.6% (160), and university and graduate-level education 21.0% (191). A total of 88.3% (828/938) of the heads of households were employed, while the median number of persons per household was 9.0 (IQR 6.0 – 13.0) and the median number of persons per room was 2.5 (IQR 1.7 – 3.3).

Severe anemia (Hemoglobin < 6.0g/dL) was associated with clinical and laboratory parameters.

Severe anemia (Hb <6.0g/dL) was present in 3.9% (37/941) of children screened. There was no significant association of median (IQR) oxygen saturation between participants with Hb<6g/dL and those with Hb≥6g/dL was 97.0% (90.0–98.0) and 95.0% (91.0–98.0), respectively, (p=0.294). Among participants with severe anemia, 8.1% (3) and 54.1% (20) had MCV of <80 fl and >90 fl, compared to 26.5% (239) and 22.3% (201), for participants with Hb ≥6.0 g/dL (p = 0.012 and p<0.001), respectively. Participants with severe anemia had a higher BMI than participants with Hb ≥6/dL (14.1 and 13.5; P=0.045)

Lower educational status of head of household and a higher number of persons living per room are predictors of severe anemia (Hemoglobin <6.0g/dL) in children with SCA living in a low-resource setting

The educational status of the head of the household, a proxy measure for poverty, was significantly associated with severe anemia (P=0.003). Higher educational level (University or Graduate level degree) was associated with a lower percentage of children with Hb level <6.0 g/dL, Table 1. There was no association between employment status and the presence of severe anemia among participants (P=0.113). As a secondary measure of poverty, the number of persons per room in the household was significantly associated with severe anemia (P=0.018), with more persons per room for participants with severe anemia compared to participants without severe anemia (median 3.0 and 2.5, respectively). The number of children per room in the household was also higher for those with severe anemia, with a median of 1.8 and 1.4, respectively (P=0.011).

Table 1.

Baseline demographic characteristics of children with sickle cell anemia with and without severe anemia screened for the SPRING trial.

Variable Total participants N=941 Participants with Hb<6 g/dL N=37 Participants with Hb≥6 g/dL N=904 P value*
Age (years), median (interquartile range), 8.0 (6.2 – 10.2) 7.6 (6.3 – 10.6) 8.0 (6.2 – 10.2)) 0.833#
Gender (female), n (%) 488 (51.9) 16 (43.2) 472 (52.2) 0.285
BMI (kg/m2) mean (sd), (n=935) 13.6 (1.7) 14.1 (2.5) 13.5 (1.6) 0.045
O2 saturation, median (interquartile range), (n=940) 95.0 (91.0 – 98.0) 97.0 (90.0 – 98.0) 95.0 (91.0 – 98.0) 0.294#
MCV (<80 fl), n (%), (n=939) 242 (25.8) 3 (8.1) 239 (26.5) 0.012
MCV (>90 fl) n (%), (n=939) 221 (23.5) 20 (54.1) 201 (22.3) <0.001
Education of head of household n (%), (n=908) 0.003
 None or primary only 248 (27.3) 14 (40.0) 234 (26.8)
  Secondary 309 (34.0) 18 (51.4) 291 (33.3)
  (OND) Ordinary National Diploma 160 (17.6) 2 (5.7) 158 (18.1)
  University degree or higher 191 (21.0) 1 (2.9) 190 (21.8)
Employment of head of household (yes), n (%), (n=938) 828 (88.3) 36 (97.3) 792 (87.9) 0.113‡
Number of persons per room, median (IQR), (n=922) 2.5 (1.7 – 3.3) 3.0 (2.0 – 4.0) 2.5 (1.7 – 3.3) 0.018#
Number of children per room, median (IQR), (n=928) 1.4 (1.0 – 2.0) 1.8 (1.2 – 2.7) 1.4 (1.0 – 2.0) 0.011#
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BMI = body mass index, kilogram/meters2

IQR = Interquartile range

*

Chi-square test for categorical variables and t-test for continuous variables unless otherwise noted.

#

Mann-Whitney U test

‡

Fisher’s exact test

Head of household education level and number of children per room predict severe anemia

A penalized logistic regression was constructed with sex, age at screening, the highest level of education for the head of household, and mean number of children per room to identify demographic and household-level characteristics associated with severe anemia (Table 2). Penalized logistic regression was used because of the skewed distribution of hemoglobin status (3.9% with severe anemia). The overall effect of the educational level was significant (p=0.009). Compared to heads of households with a university or graduate degree, those with primary or no formal education or secondary education had a greater chance of having a child with severe anemia (odds ratio=6.38, p=0.033; odds ratio=6.72, p=0.027, respectively). A higher number of children per room was associated with severe anemia (odds ratio=1.34, p=0.050), Table 2. Neither age nor sex was associated with severe anemia (p=0.933 and p=0.396, respectively).

Table 2.

Penalized logistic regression model predicting hemoglobin < 6.0 g/dL with demographic and household-level characteristics (n=897).

Variable Odds Ratio 95% Confidence Interval P-Value
Sex (male) 1.34 0.68 – 2.65 0.396
Age at screening 0.99 0.86 – 1.15 0.933
Number of children per room 1.34 1.00 – 1.81 0.050
Highest level of education of the head of household* 0.009
 None or primary education 6.38 1.16 – 35.06 0.033
 Secondary 6.72 1.25 – 36.26 0.027
 Ordinary National Diploma (OND) 1.88 0.24 – 14.41 0.544
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*

Reference category is University degree or higher

DISCUSSION

Given the magnitude of SCA in sub-Saharan Africa, understanding the epidemiology and risk factors associated with severe anemia is necessary to maximize the health of this vulnerable population. We demonstrate a prevalence (3.9%, 37/941) of severe anemia in children with SCA ages between 5 to 12 years old living in northern Nigeria, a low resource setting. Severe anemia was associated with risk factors of poverty (Yusuf et al., 2019), including the lower educational status of the head of household, and a greater number of persons, particularly children, living per room in the household. The risk factors identified reflect the low socioeconomic status and educational gaps prevalent in northern Nigeria, and other regions in sub-Saharan Africa, where more than a third of the global burden of SCD is found.(Getaneh et al., 2017)

The level of parental education has previously been identified as a critical factor predictive of health-related outcomes in children.(Choi et al., 2011) Our study demonstrated a decline in the prevalence of severe anemia with increasing parental education. We found only one child with severe anemia from a household where the head had a university or graduate-level education. This finding is similar to reports by Simbauranga and colleagues, where they showed a low educational level of the caretaker was significantly associated with severe anemia [OR=2.4; 95% CI=1.1–5.3; p=0.031] among children less than 5 years of age in Tanzania.(Simbauranga et al., 2015) Similarly, Mesfin in eastern Ethiopia reported a higher risk of severe anemia in children with low paternal education [adjusted prevalence ratio (APR)=1.109; 95% CI=1.04–1.18]. (Mesfin et al., 2015). Despite the high employment rate of heads of households in our study, in northern Nigeria, a predominantly low resource region in Africa, approximately 70% of the population live on less than one dollar a day (<$1/day)(Adegboye, 2016) which is less than ~$50/month.

Approximately 8.1% (3/37) of the participants with severe anemia in our cohort had low MCV (<80fl). Low MCV or microcytosis in individuals with SCA can be associated with the presence of thalassemia trait. Among individuals of African descent, the prevalence of α and β thalassemia traits is reported at 30% (McGann et al., 2018) and <10%, (Kotila et al., 2009, Vincent et al., 2016) respectively. Based on population genetics in northern Nigeria, most individuals (>95%) with SCD had HbSS (Aliyu et al., 2008), with a small percentage with HbSβthal.(Omoti, 2005) Additionally, low MCV or microcytosis is one of the indicators of iron deficiency anemia, which accounts for more than half (~53%) of the causes of anemia globally, with the highest-burden among children between ages 5–14 years in resource-limited countries.(Tolentino and Friedman, 2007, Osungbade and Oladunjoye, 2012). The incidence of iron deficiency anemia amongst individuals with SCA in resource-limited settings is estimated to be around 10–11% (Kassim et al., 2012, Tshilolo et al., 2016), particularly in the non-transfused cohort. The cross-sectional nature of this analysis did not allow a detailed analysis of the hemoglobin phenotype or determination of iron studies in our cohort. Given the association between low MCV with both co-inheritance of alpha/beta-thalassemia and acquired iron deficiency anemia in children with sickle cell disease in a low resource setting, further studies in larger patient cohorts are needed to elucidate the relative contribution of thalassemia traits and iron deficiency to the microcytosis and severe anemia seen in SCD.

A priori, we postulated that a low BMI will be associated with severe anemia; however, we found evidence to the contrary. Participants with Hb<6g/dL had a higher BMI compared to those with Hb>6g/dL, (14.1kg/m2 and 13.5kg/m2; P=0.045); which is slightly lower than the BMI of healthy children without SCD in the region (15.7kg/m2 ± 2.4), where ~ 80% fall within the normal growth category.(Eze et al., 2017). Our unanticipated finding suggests that BMI has no impact on the severity of anemia. Similarly, our group recently reported that there was no significant association between severe malnutrition (using BMI) and low hemoglobin.(Ghafuri et al., 2020)

As expected with crossectional study design, our study has limitations; due to its cross-sectional design, we were unable to ascertain the causes of severe anemia and the clinical impact of severe anemia on overall health, disease-severity, and mortality. We also assumed that all heads of households in our study were male, as this is the norm in northern Nigeria. The study may have underestimated the true prevalence of severe anemia in this population, being a cross-sectional study; however, the dataset included a large sample size, which improves the precision of our results. The strengths of our study included the large sample size, multiple recruitment sites and prospective data collection as part of a clinical trial.

Severe anemia is common in children with SCA greater than five years of age living in northern Nigeria. Low educational status of head of household, a proxy for poverty, had the strongest correlation with the presence of severe anemia. Most likely the etiology of severe anemia in our cohort is multifactorial and likely a result of a complex interplay between individual disease severity, nutritional, environmental and other socio-economic factors. Large prospective studies across geographically and socioeconomically diverse settings will help to establish strategies that will decrease associated morbidity and mortality in similar settings.

Acknowledgment:

We are grateful to the research coordinators at all three sites; Mr. Bilya Sani, Mr. Awwal Gambo, Mr. Fahd Mahmoud and Mr. Abdulrasheed Sani for their tireless efforts to ensure that the SPRING trial is well coordinated. We appreciate the research nurses; Mrs. Khadija Alkali Bulama, Miss Gloria Yimi Bahago and Mrs. Murjanatu Abdullahi for facilitating the recruitment process and ensuring the successful conduct of this study. We thank the members of the DeBaun laboratory at Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease for their support of this work. Finally, we are very grateful to the patients and their families for their participation and dedication to the conduct of this trial.

Source of funding: The SPRING trial is supported by the National Institutes of Health/ Grant #1R01NS094041. The sponsor did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Footnotes

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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