Transcranial doppler velocity in iron‐deficient Nigerian children with sickle cell anemia
Authors: Shehu Umar Abdullahi, Surayya Sunusi, Hauwa Aminu, Rashida Umar, Mohammed Sani Abba, Binta W. Jibir, Saifuddeen Sani, Safiya Gambo, Halima Bello‐Manga, Najibah A. Galadanci, Brittany Covert Greene, Adetola A. Kassim, Lori C. Jordan, Muktar H. Aliyu, Mark Rodeghier, Michael R. DeBaun, Emmanuel J. Volanakis
Journal: American Journal of Hematology (2024)

Oral iron supplementation in iron deficient children with sickle cell anemia and normal transcranial Doppler ultrasound (TCD) velocities does not reduce arterial flow in the middle cerebral artery. As a follow-up to our previous reports describing the feasibility of primary stroke prevention with initial dosing of hydroxyurea,1 we elected to determine whether iron deficiency may be a modifiable risk factor associated with an elevated transcranial Doppler (TCD) velocity. Iron deficiency is the most common cause of anemia in children in low-income countries.2, 3 In a prospective study in northern Nigeria, including children with sickle cell anemia (SCA) between 5 and 12 years old and TCD velocity <200 cm/s, we tested the hypothesis that for those children with iron deficiency, iron supplementation will significantly decrease blood velocity through the middle cerebral artery. The World Health Organization estimates that 275 000 babies are born with sickle cell disease (SCD) every year, of whom approximately 79% are in Africa. Adapting clinical management guidelines, which were developed largely in high-resource countries, for use in Africa requires sensitive consideration of local resources and potential epidemiologic exposures. We recently conducted a trial of hydroxyurea for primary stroke prevention in Northern Nigeria.4 Iron deficiency anemia (IDA) affects an estimated 34% of Nigerian children without SCA.5 In North American children with SCA, lower hemoglobin concentrations are associated with higher blood flow velocity through the cerebral arteries, as measured by TCD ultrasound. These considerations raised the possibility that IDA may contribute to higher TCD velocities among Nigerian children with SCA, which could influence both the prognostic value of the measurements and the effectiveness of therapeutic interventions guided by them. We conducted a prospective sub-study to test the hypothesis that for children with evidence of depleted body iron stores and TCD velocities through the middle cerebral artery less than 200 cm/s, iron supplementation would decrease TCD velocity. The study was conducted at the pediatric sickle cell anemia clinic of Aminu Kano Teaching Hospital (AKTH) in Kano, Nigeria. It was reviewed and approved by the Ethics Committee of AKTH and the Institutional Review Board of Vanderbilt University. Between November 1, 2017 and March 30, 2019, we screened 117 children with SCA for iron deficiency and abnormal TCD velocity. Participants were eligible if they had a confirmed diagnosis of hemoglobin SS or Sβ0, were age 5 to 12 years, had TCD velocity <200 cm/s, and gave parental consent and participant assent. Children were excluded if they were on hydroxyurea or had received a red blood cell (RBC) transfusion in the preceding 3 months. Baseline demographic data included age, sex, weight, height, parental socioeconomic status, and diet history. Complete blood count, serum ferritin, and TCD velocity were measured at baseline and again after 3 months. TCD ultrasounds were performed using a non-imaging technique with a Sonartrek Portable TCD System sonography machine by a physician certified and trained in TCD for SCA. The TCD value used for the study was the time-averaged mean maximum velocity obtained from the middle cerebral arteries. Children with a serum ferritin <30 μg/L were prescribed ferrous sulfate 3 mg/kg/day elemental iron in a single daily dose, with a maximum dose of 60 mg elemental iron. Parents were encouraged to administer the iron between meals and with juice to maximize enteric absorption. Children with ferritin ≥30 μg/L received no treatment. Of the 117 children with SCA who were screened, 93 met all inclusion criteria and were enrolled. Of these, 24 (25.8%) were found to have serum ferritin <30 μg/L and were treated with iron supplementation, and 69 (74.2%) had ferritin ≥30 μg/L and were observed. This prevalence of iron deficiency is similar to that previously reported for Nigerian children without SCA.5 As an indicator of iron deficiency, ferritin has the advantage of being widely available and commonly used in clinical practice. RBC indices are not reliable in the setting of hemoglobinopathy, and alternative measures of iron deficiency such as soluble transferrin receptor, RBC protoporphyrin, or reticulocyte hemoglobin equivalent, are not locally performed. Iron staining of bone marrow aspirate requires an unacceptably invasive procedure. For a continuous variable like ferritin concentration, selecting an appropriate cutoff to define a dichotomous condition such as iron deficiency entails a balance between sensitivity and specificity. The World Health Organization (WHO) recommends 15 μg/L as a cutoff when using ferritin as the sole marker of iron deficiency in a healthy population.6 However, ferritin is elevated in the setting of inflammation. People with SCA have systemic inflammation at baseline due to chronic hemolysis and endothelial activation and experience exacerbations with episodic ischemia–reperfusion injuries. With these considerations in mind, and in accordance with WHO guidelines, we selected a conservative cutoff of 30 μg/L.6 While this might result in the inclusion of some iron-replete children in the treatment cohort, it ensures that all iron-deficient participants received treatment. The median age of participants in the treatment and comparison groups was 8.2 and 8.9 years, respectively (p = .677). The two cohorts had similar age, sex, and anthropometric distributions, and the heads of households in both groups had similar educational attainment and employment status, with no statistical differences. The two groups had no detectable difference in the dietary intake of red meat, vegetables, grains, or citrus fruits. At baseline, the mean (standard deviation) TCD velocities were 129.1 (23.1) cm/s in the treatment group and 127.2 (23.5) cm/s in the comparison group (p = .730). No children in the treatment group were found to have a conditional TCD velocity (≥170 but <200 cm/s). After 3 months of oral iron replacement therapy, the velocities were 125.3 (23.3) cm/s in the treatment group and 121.5 cm/s (22.2) cm/s in the comparison group (p = .487). The 3.8 cm/s drop in TCD velocity after treatment was not significant (p = .301). The median (interquartile range [IQR]) baseline serum ferritin was significantly lower in the treatment group compared with the comparison group, (11.3 [6.2–16.4] μg/L vs. 226.1 [118.2–341/5] μg/L, respectively; p < .001). However, the baseline hemoglobin levels were not different between the two groups, 7.9 and 7.5 g/dL, respectively; p = .258. After 3 months of oral iron replacement therapy, the median serum ferritin in the treatment group was 205.8 (63.2–399.1) μg/L, a significant increase from baseline (p < .001). Also, the mean serum ferritin level in the therapy group at 3 months was not different from the comparison group's baseline ferritin levels (p = .343). The hemoglobin levels at 3 months were not different between the treatment and comparison groups (7.9 and 7.4, respectively, p = .137). Only one participant in the treatment group did not achieve serum ferritin ≥30 μg/L. This child was evaluated further, as is the standard of care outside the study. Surprisingly, no significant differences were observed in hemoglobin and mean corpuscular volume between the treatment and comparison groups at baseline and following 3 months of iron therapy. Iron replacement therapy for children with iron deficiency anemia and no hemoglobinopathy is expected to produce at least a 1 g/dL increase in hemoglobin concentration. The discordance between the clinically relevant low ferritin but no significant difference between the baseline hemoglobin levels and the absence of an increase in the hemoglobin levels after treatment indicates the patients did not have iron-limited erythropoiesis. The failure of iron replacement to affect hemoglobin may account for the absence of change in TCD velocities. We could not determine whether iron-limited erythropoiesis (iron deficiency anemia associated with a decrease in hemoglobin from baseline) could increase TCD velocities in children with SCA. In summary, iron deficiency which does not result in iron-limited erythropoiesis is not a risk factor for elevated TCD velocities in children with SCA. Iron replacement therapy should be offered to restore iron stores with no expectations that iron therapy will decrease TCD velocities. The authors wish to acknowledge the funding support from the Thrasher Foundation. The authors declare no conflicts of interest. Fully anonymized data may be shared upon request from any qualified investigator with approved study and data transfer agreement between Vanderbilt University Medical Center and the Institution.