Fetal hemoglobin level and its relationship with spleen size and malaria parasite density in Nigerian children with sickle cell anemia


Background: Sickle cell anemia (SCA) is a major global public health concern. Fetal hemoglobin level (HbF) is a major modulating factor of the clinical manifestation of the disease. In Nigeria, data on HbF level of children with SCA and its relationship with the spleen, a major reticuloendothelial organ, are scanty. Methods: In this cross-sectional comparative study, we determined steady-state HbF levels of children with SCA aged 1–15 years by high-performance liquid chromatography and compared with their age-, sex-, and socioeconomic class-matched HbAA controls. The spleen size was determined clinically and sonographically. Relationships between HbF level and spleen size and malaria parasite density were also determined. Results: About two-thirds of children with SCA had HbF level of <10%. However, they had significantly higher mean HbF level (9.6% ± 5.9%) compared with matched controls (0.5% ± 0.7%; P< 0.001). Higher proportion (9.8%) of children with SCA who were ≥8 years developed autosplenectomy compared to none of those <8 years (P = 0.012). There was no significant relationship between HbF levels and spleen size, although children with autosplenectomy had significantly lower mean HbF levels compared with those without autosplenectomy (3.5% ± 1.4% vs. 8.3% ± 3.5%, 95% confidence interval = 1.1–8.4, P = 0.012). HbF levels had no significant correlation with malaria parasite density, P > 0.05. Conclusion: Children with SCA had higher HbF levels compared with matched controls. Furthermore, patients with autosplenectomy had significantly lower HbF levels. Further studies exploring the roles of foetal haemoglobin on spleen functions in children with SCA are advocated, since spleen dysfunction is central to morbidity and mortality in this group of patients.

Keywords: Autosplenectomy, children, fetal hemoglobin, sickle cell anemia, spleen size

How to cite this article:
Akinlosotu MA, Adeodu OO, Adegoke SA, Oseni SB, Ayoola OO. Fetal hemoglobin level and its relationship with spleen size and malaria parasite density in Nigerian children with sickle cell anemia. Ann Trop Med Public Health 2018;11:133-9


How to cite this URL:
Akinlosotu MA, Adeodu OO, Adegoke SA, Oseni SB, Ayoola OO. Fetal hemoglobin level and its relationship with spleen size and malaria parasite density in Nigerian children with sickle cell anemia. Ann Trop Med Public Health [serial online] 2018 [cited 2020 Aug 5];11:133-9. Available from: https://www.atmph.org/text.asp?2018/11/4/133/272558



Sickle cell anemia (SCA) is the most common inherited genetic disorder worldwide.[1] It results from the homozygous inheritance of two abnormal hemoglobin S genes. The hemoglobin S gene results from a single-gene mutation in the deoxyribonucleic acid base sequencing in the region 15.4 of the short arm of human chromosome 11.[2] This leads to the replacement of the soluble AA glutamic acid by the insoluble valine in the sixth position of the β-globin chain of hemoglobin.[2] This alteration results in red blood cells sickling under hypoxic stress and the characteristic multisystemic manifestations of SCA.[3]

Nigeria has the largest burden of SCA worldwide with a prevalence of 2%–3% among the general population and also with high mortality rate ranging between 5% and 16%.[4] Despite the burden of SCA, there is yet no focused public health drive regarding this health problem in the National Health Agenda.

The spleen is a major reticuloendothelial organ with a vital role in SCA. It plays a major role in the removal of effete cells from circulation and also produces opsonins which aid the destruction of encapsulated organisms.[5] The function of the spleen is impaired in SCA because of repeated infarctions, leading to autosplenectomy and functional hyposplenism in these children usually after the age of 8 years.[5] Children with autosplenectomy are unduly prone to infections from encapsulated organisms.[5] Despite repeated infarctions, many African children older than 8 years have been found to have persistent splenomegaly compared with their African American children. Adekile et al.[6] reported a higher prevalence of splenomegaly among Nigerian children (22.3%) compared to American children (8%) with SCA.[6] Some other workers in Africa have also reported a high prevalence of persistent splenomegaly ranging between 15% and 33%.[6],[7],[8],[9],[10] This high prevalence is attributed to malaria endemicity. In contrast, however, Sadarangani et al. in an observational study in Kenya found no correlation between splenomegaly and the number of episodes of malaria or the level of parasitemia.[11]

The few available reports on the relationship between spleen size of children with SCD and fetal hemoglobin (Hbf) level give inconsistent conclusion. Stevens et al.[12] found that about a third of the children with low Hbf developed splenomegaly early, while Jamaican children with high level had persistent splenomegaly.[13] In Nigeria, there is a paucity of data on the relationship between Hbf levels and spleen size in children with SCA. As research questions, we explored into whether HbF level is a determining factor of splenic size in Nigerian children with SCA and whether the degree of malaria parasitemia influences splenic size in these patients even in steady state.


A cross-sectional comparative study was carried out in the pediatric sickle cell disease clinic of the hospital. A total of 182 children comprising 91 children with SCA between the ages of 1 and 15 years and 91 apparently healthy hemoglobin AA children matched for age, sex, and socioeconomic status were recruited. The children with SCA were in steady state at the time of recruitment (no crisis, infection, or fever for at least 4 weeks and no blood transfusion in the preceding 3 months). Children with other hematological disorders such as glucose-6-phosphate dehydrogenase deficiency and those with chronic liver, kidney, and heart diseases were excluded. Furthermore, SCA children on hydroxyurea and children without parental consent/assent were not included. The study was approved by the hospital ethics/research committee, and consent was obtained from each parent/caregiver and assent from the children as appropriate. The hemoglobin genotype of controls was determined using cellulose acetate paper electrophoresis at pH 8.6. A data pro forma was used to obtain the sociodemographic characteristics such as age, sex, and socioeconomic class of participants as described by Oyedeji based on rank assessment of parental occupation and the level of education.[14]

Abdominal examination to determine the splenic size was done using an inelastic tape rule. Splenic size ≥10 cm was regarded as massive splenomegaly, whereas persistent gross splenomegaly was taken as steady-state splenic size of 10 cm or more in those 8 years or olders.[15]

Hbf level was determined using BIO-RAD D10 high-performance liquid chromatography (HPLC) machine at the Haematology Laboratory of the National Sickle Cell Foundation, Lagos, Nigeria. The process took about 3 min for each sample to be analyzed by the machine. Hbf levels were stratified into undetectable, low level (0.1 to <10%), and high level (10% or more).[16]

Malaria parasite detection

Thick blood film was prepared on a glass slide for malaria parasite quantification. This was allowed to dry in the air and was stained with Giemsa stain and again allowed to dry. The parasites were then counted by the parasitologist. Quantification of the parasite density on the thick film was determined according to the number of parasite counted against 200 white blood cells (WBC), assuming a total WBC count of 8000/microliter (μL) of blood.[17]

Parasite density counts were classified into mild (1–999/μL), moderate (1000–9999/μL), and severe (>10,000/μL). Malaria hyperparasitemia was taken as parasite count >250,000/μL.[18]

Abdominal ultrasound scanning

Abdominal ultrasound scans (USS) for the patients were done by one of the authors (AOO), a consultant radiologist, using a D6 Mindray ultrasonography machine with Doppler facility and a low-frequency probe 3.5–5.0 MHz. The subject to be scanned was placed in supine position and the abdomen exposed from the nipple area to the pubic symphysis. The spleen was located in the left hypochondriac region as a uniform parenchymal echotexture superoanterior to the left kidney. The longitudinal length (the distance between the dome of the diaphragm and the lower tip of the spleen) was measured to determine the size. The normal range of spleen size in children aged between 1 and 15 years was taken to be 5–13 cm.[19] Autosplenectomy was defined as absence of spleen or presence of fibrotic calcified nodule that was too small to be ultrasonographically measured.[7]

Statistical analysis

Statistical analysis was done using Statistical Package for Social Sciences Statistics for Windows Version 17.0, (SPSS Incorporation, Chicago, USA) with both parametric and nonparametric tests as appropriate. Independent sample t-test and analysis of variance (ANOVA) were used to compare continuous data such as splenic size, malaria parasite density, Hbf, and other hematological parameters among groups with SCA and matched HbAA controls. Possible associations between categorical variables such as sociodemographic parameters of SCA and controls were tested by Chi-square test or Fisher’s exact test and the statistical significance level for the alpha error was taken as P ≤ 0.05.


A total of 101 (55.5%) of the 182 children, comprising 53 with SCA and 48 with HbAA, were male. There was no statistical difference in the gender distribution between the SCA subjects and the controls (χ2 = 0.556; P = 0.456). Furthermore, there was no significant difference in the mean age of the SCA subjects (7.6 ± 3.5 years) and controls (7.3 ± 3.3 years), P = 0.731.

Sixty-eight (37.4%) of the population were from the lower social class (Classes IV and V), whereas the middle and upper classes constituted 33.5% and 29.1%, respectively. Similar pattern of socioeconomic class distribution was observed among subjects and controls as shown in [Table 1].

Table 1: Sociodemographic characteristics of subjects and controls

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Splenic size determination

Clinically determined splenic size

The splenic size of the SCA subjects by palpation method ranged from 0 to 16 cm with a mean of 1.5 ± 3.5 cm whereas that of the HbAA subjects ranged from 0 to 4 cm. The mean spleen size of the SCA was significantly higher than 0.1 ± 0.6 cm for the HbAA controls, t = 3.895, P < 0.001. Six (6.6%) SCA children had massive splenomegaly and 3 (3.3%) had persistent splenomegaly. In 71 (78.0%) children with SCA, spleen was not palpable, 8 (8.8%) had splenic size of 1–5 cm, 9 (9.9%) had size of 6–10 cm, and 3 (3.3%) had spleen size >10 cm. Overall, 12 (13.2%) children with SCA, as against none of the controls, had splenic size >5 cm (χ2 = 22.520; P < 0.001).

Ultrasound-determined spleen size

Ultrasound scanning was done in 88 (96.7%) of 91 SCA subjects to determine their longitudinal splenic size. The remaining three subjects did not show up for ultrasound scanning. The mean splenic size measured using ultrasound was 7.3 ± 3.2 cm, with a range from 0 to 18.5 cm. Majority (60; 68.2%) had spleen size of 6–10 cm. Age was a determinant of autosplenectomy. Autosplenectomy was found in 4 (9.8%) of the 41 SCA subjects who were at least 8 years old compared to none of the 47 who were younger than 8 years (χ2 = 6.329; P = 0.012) [Table 2].

Table 2: Splenic size distribution in the subjects’ age groups as measured by ultrasound

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Comparison of splenic size by ultrasound among subjects and controls

[Table 3] shows that there was no statistically significant difference between the mean ultrasound-determined splenic size of SCA subjects and controls (7.3 ± 3.2 cm vs. 7.5 ± 1.3 cm; t = −0.484; P = 0.629). However, the spleen could not be visualized on abdominal ultrasound scanning in 4 (4.6%) children with SCA unlike none (0%) in the control group (χ2 = 29.720 by Fisher’s exact; P < 0.001).

Table 3: Comparison of splenic sizes among subjects and controls

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Fetal hemoglobin levels in the subjects and controls

[Table 4] shows that the mean HbF level of children with SCA was higher (9.6% ± 5.9%) than that of the controls (0.5% ± 0.7%, t = 14.624; P < 0.001). Although, none of the subjects with SCA had HbF level of 0%, 46 (50.5%) of the controls had (χ2 = 167.482, P < 0.001). The remaining 45 controls had HbF values 2.8% or lower. Majority of the SCA subjects (60; 65.9%) had low HbF levels, whereas 31 (34.1) had high HbF level.

Table 4: Comparison of the fetal hemoglobin levels of subjects and controls

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Relationship between fetal hemoglobin and spleen size in children with sickle cell anemia

There was no significant correlation between hemoglobin F level and ultrasound-determined spleen size (r = 0.008; P = 0.940). However, the mean HbF level of the four children with autosplenectomy (3.5% ± 0.1.4%) was significantly lower than the mean HbF level (8.3% ± 3.5%) of the 37 children ≥8 years without autosplenectomy (t = −2.65, 95% confidence interval = 1.1–8.4; P = 0.012).

Furthermore, there was no correlation between hemoglobin F levels and splenic size by palpation method (r = 0.000; P = 0.997) among the subjects. Using ANOVA, the mean HbF levels of groups with no splenomegaly (9.5% ± 6.0%) and splenomegaly of 1–5 cm (12.0 ± 4.90), 6–10 cm (9.3 ± 6.8), and massive >10 cm (6.1 ± 1.5) were similar (F = 0.780; P = 0.508). The mean HbF levels of the 20 children with splenomegaly (9.9% ± 5.7%) and 71 children without splenomegaly (9.5% ± 6.0%) were also comparable (t = −0.246; P = 0.806). Likewise, the presence of splenomegaly was not significantly associated with elevated Hbf levels (χ2 = 0.402; P = 0.526).

Malaria parasitemia among the subjects and controls

Among the 91 SCA subjects, malaria parasite counts range from 0 to 3740/μl (mean 383.0 ± 649.9/μl, median of 160.0 μl). Seventy-five (82.4%) of these subjects had demonstrable parasitemia.

Among the controls, the mean malaria parasite count was 441.8 ± 1401.0/μl (median of 120.0/μl) and ranged from 0 to 12,800/μl. There was no statistically significant difference in the density of malaria parasitemia between subjects and controls (P = 0.652, Mann–Whitney U-test applied).

Furthermore, there was no significant correlation between the splenic size either by palpation or USS and malaria parasitemia (r = 0.018 and P = 0.867 and r = −0.055 and P = 0.469, respectively). The mean density of malaria parasitemia was also similar between groups with splenomegaly (392.0 ± 549.2/μl) and those without splenomegaly (352.0 ± 678.9/μl) (P = 0.923 [Mann-Whitney U-test Applied]).


Interest in issues relating to Hbf in SCD has been on the increase in the last six decades during which its huge protective effects on the timing and severity of the disease symptomatology and the development of multiorgan dysfunction became subjects of scientific research.[20] However, in most part of Sub-Saharan Africa including Nigeria, where the burden of the disease is highest, studies on Hbf in children with sickle cell disease are scanty.

Hbf has been known to be a major modulatory factor of sickle cell disease severity.[20] In the present study, children with SCA had significantly higher Hbf levels compared to controls. This may be due to the adaptive genetic modulators present in SCA children that induce higher HbF production compared to the normal HbAA individuals.[21] Furthermore, in SCA, there is a delay in the genetically controlled postnatal switch of HbF to HbA which consequently leads to a surge in the levels of HbF. Although the exact mechanism for this delayed switch is unknown, it might be related to accelerated expansion of early erythroid progenitors which still possess the ability to express γ-globin. The increased expansion of progenitor cells is linked directly to increased hemolysis and associated increased erythropoeisis that occur in SCD.[20] This finding of higher levels of HbF in SCA than HbAA control is similar to reports of some researchers from developing nations.[8],[22],[23]

On the other hand, about two-third of the children with SCA (65.9%) were found to have low Hbf levels. This may possibly predispose them to more severe disease and complications in the near future. This is consistent with the findings by Mpalampa et al.[16] among children with SCA in Uganda where 63% were reported to have Hbf level <10%. Furthermore, females in the present study had significantly higher HbF levels compared to males. This is similar to the finding by Mouele[9] among Congolese adults with SCA. Olaniyi et al. in Ibadan, Nigeria, however, found no difference in the HbF levels in both adult males and females with SCA.[24] The exact reason for the higher levels of hemoglobin F among girls remains unclear, perhaps the X-linked codominant gene controlling the production of HbF may lead to double dose of the gene in the case for females unlike males, resulting in higher elaboration of the gene products and higher HbF levels in females than males.[25]

The mean HbF level of the children with SCA in this study was higher than what had been reported previously in most Nigerian studies. Isah[26] in Sokoto found mean HbF levels of 2.99% ± 5.16% as against 9.6% ± 5.9% in the present study. Furthermore, the mean HbF level in this study was higher than 7.2% ± 5.0% reported by Tshilolo in Congo.[23] This may be due to the difference in the methods used for Hbf estimation. The Betke method of alkali denaturation was used by Isah, whereas HPLC which is a more sensitive method was used in the present study. In addition, age difference might also account for the differences in the hemoglobin F level obtained in the studies of adult sickle cell patients by Omoti in Benin (2.17% ± 1.81%), Durosinmi in Ife (4.26% ± 4.33%), and Olaniyi in Ibadan (5.16% ± 4.04%).[7],[22],[24]

A study among children with SCA in Uganda reported a mean HbF level of 9.0% ± 5.58% despite using alkali denaturation test.[16] A higher value (12.2% ± 7.1%) was also reported in India by Rao et al.[27] The reason for the differences may be due to the effect of various factors that influence Hbf production in SCA individuals. One of these factors is beta gene globin haplotype. The Senegal, Saudi, and Indian haplotypes are generally associated with higher levels of Hbf and milder disease course, whereas the Benin and Cameroon haplotypes are intermediate and of varying clinical manifestation. However, the Bantu haplotype is associated with severe disease and low Hbf production.[28] Other factors that affect Hbf level include hydroxyurea use. Hydroxyurea is a hypomethylating agent that is now being used all over the world in the management of children with sickle cell disease. Unfortunately, most children in Nigeria and other resource-poor countries in Sub-Saharan Africa with the largest burden of the disease are not benefitting due nonavailability and/or unaffordability of the drug.[29] Locally available fruits such as Terminalia catappa (tropical almond) have been identified as anin vitro HbF-inducing agent.[30] In Nigeria, where this fruit is readily available and cheap, a multicenter, clinical trial of this agent is recommended. Meanwhile, efforts must be put in place to ensure availability and affordability of hydroxyurea to patients in Nigeria.

The spleen is a key reticuloendothelial organ which plays a major role in the morbidities seen in children with sickle cell disease. Malaria endemicity has been widely reported as the sole reason for persistent splenomegaly among patients with sickle cell disease in Nigeria and many other countries in Sub-Saharan Africa.[7],[8],[9],[10],[11] In this study, significantly more children with SCA compared to the controls had splenomegaly by both the palpation method and with the use of abdominal ultrasound scanning. This may be due to increased splenic reticuloendothelial function of removing effete cells from circulation and possible sequestration of blood in the spleen in sickle cell children compared with the controls. This finding is consistent with some previous reports on spleen size among children and adults with SCA in Nigeria. Abdullahi et al.[31] in a case–control study carried out in Kano, Nigeria, to determine spleen size in SCA children found a higher prevalence of splenomegaly of 35% among the cases. Similar finding was documented by Olatunji and Olatunji[32] in Ilorin, Nigeria.

It is also interesting to note that for every ten SCA children who were at least 8 years in our SCD clinic, only one of them would have autosplenectomy. The prevalence of autosplenectomy in SCD varies greatly depending on the age of the patients included in the study as well as the region of the study. In Zaria, North West, Nigeria, Babadoko et al.[33] reported a prevalence of 55.4% among adults with SCA. On the other hand, Olatunji and Olatunji[32] at the University of Ilorin Teaching Hospital did not confirm anatomical autosplenectomy in their study of 98 patients with SCA. The high prevalence of autosplenectomy in the Zaria study may most likely be due to inclusion of adults, because they would have had longer time in life for the processes which engender autosplenectomy. In Saudi Arabia, autosplenectomy prevalence of 6.6% was reported among 363 patients with SCD.[34] This is expected considering the presence of a less severe Arabian-Indian haplotype in their area of study. Autosplenectomy has also been reported to be high among Turkish[35] patients, where autosplenectomy was found in most adult patients with SCD.

In the present study, the patients with autosplenectomy had lower mean HbF levels. As previously observed, autosplenectomy, apart from being commonly seen in older homozygous SCA patients, is frequently encountered in areas associated with severe SCD phenotype and low levels of Hbf.[32] It has also been suggested that it is less frequently seen in areas of malaria endemicity where persistent splenomegaly syndrome is more prevalent.[33]

No significant relationship was found between the spleen size and malaria parasitemia, consistent with reports by Sadarangani et al.[11] from Kenya, East Africa. In Ile-Ife, Nigeria, Adekile et al. documented a significant positive correlation between splenic size and malaria-specific immunoglobulin (Ig) G and IgM antibodies in children with SCA.[7] They hypothesized that persistent splenomegaly in African children with SCA follows recurrent malaria infection. Studies in adults, however, found no positive correlation between malaria parasitemia and splenic size.[7],[8],[9],[10] Further large-scale studies are needed to either support or refute our claim on noncorrelation between these two variables.

This study did not find any relationship between splenic size and Hbf levels in the subjects studied. There are inconsistencies in the conclusion of different studies on this subject. While our data are similar to the findings by Durosinmi et al.[7] among adult SCA population with splenomegaly in Ile-Ife, Nigeria, Serjeant[13] found that persistent splenomegaly in Jamaican children with SCD was associated with high levels of Hbf. The exact reason for persistent splenomegaly in SCA is still a subject of conjecture that warrants further studies in the light of the possibility of multiple and interrelated factors that may be confounders. Perhaps the extramedullary erythropoiesis, congestion, and occasional sequestration may be contributory.


That children with SCA had a higher HbF levels than matched controls, although about two-third of these patients had levels <10%. It appears that no significant relationship exists between spleen size and malaria parasite density in children with SCA. In addition, Hbf level was not significantly related to the presence or absence of splenomegaly in these children, although those with autosplenectomy had lower mean HbF than those without autosplenectomy. It is, therefore, recommended that early determination of Hbf and possibly induction will be necessary in the care of children with SCA to reduce morbidity.

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Conflicts of interest

There are no conflicts of interest.



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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ATMPH.ATMPH_393_17


[Table 1], [Table 2], [Table 3], [Table 4]

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