The Impact of Hydroxyurea Therapy on the Prevalence of Retinopathy in a Pediatric Sickle Cell Cohort

Approximately 15–17% of children with HbSS and 11% of those with HbSβ⁰thalassemia (HbSβ⁰thal) develop sickle retinopathy (SR) by 18 years of age. Sickle retinopathy is a spectrum of vascular lesions that insidiously evolve as a result of ischemia from vaso-occlusion of capillary and precapillary arterioles in the peripheral retina. These lesions are usually clinically silent but can progress to spontaneous vitreous hemorrhage or retinal detachment and lead to blindness. Therefore, periodic screening retinal exams are recommended for children and adults with sickle cell disease (SCD). Prior reports from Jamaica identified low fetal hemoglobin (HbF) concentration as a potential risk factor for retinopathy in HbSS patients. Hydroxyurea (HU), an increasingly utilized treatment in children with HbSS/HbSB⁰thal, increases %HbF levels. However, there are no reports describing the effects of HU therapy on the prevalence of retinopathy in children with SCD. In our institution, all children with SCD are referred to ophthalmology for a screening dilated fundoscopic exam (DFE) beginning at 10 years of age and then every 2 years.

Define the prevalence of retinopathy in children with HbSS/HbSβ⁰thal and analyze the effects of treatment with HU and %HbF levels on the prevalence of retinopathy.

After IRB approval, a retrospective chart review was performed on children with HbSS/HbSβ⁰thal who received a DFE without fluorescein angiography at St Jude Children's Research Hospital between 2003 and 2010. Children who received chronic transfusion therapy or hematopoietic stem cell transplantation were excluded from analysis. Records of DFEs were reviewed for a diagnosis of non-proliferative or proliferative SR. Laboratory data were collected at multiple time points from patients' electronic medical records, including: prior to initiation of HU, following two years of therapy with HU, and immediately prior to diagnosis of retinopathy. Time of observation was defined as birth to diagnosis of SR or to date of last DFE. Summary statistics are reported and the HU and non-HU groups are compared with the Wilcoxon-Mann-Whitney Exact test.

Of 182 children referred to ophthalmology, 142 (78%; 126 HbSS, 16 HbSβ⁰thal) received an initial DFE at a median age of 13.1 ± 3.3 years (range: 1.6–18.7 years). The median number of DFEs per patient was 1.7 ± 1.4 (range: 1–12) during the time of observation. Sickle retinopathy was diagnosed in 9.9% (14/142) of children, at an average age of 15 ± 2.5 years. Of the children who received a DFE, 63% (90/142) had initiated HU therapy at an average age of 9.8 ±4.8 years. The average age at initial DFE was not different in patients receiving HU (13.1 ± 3.2 years) and those who did not (13 ± 3.5 years). The total number of DFEs performed in both groups was also similar (1 ± 1.2 in HU-treated group vs. 1 ± 1.6 in untreated group). Retinopathy was diagnosed in 7.8% (7/90) of children who received HU and 13.5% (7/52) of children who did not (p=0.27). The median age at diagnosis of SR was similar for patients treated with HU (15.4 ± 2.5 years, range: 11.3–18.2 years) compared to untreated children (14.6 ± 2.6 years, range: 10.8–17.3 years; p=0.6). Among patients receiving HU, those who developed retinopathy started treatment at a later age, however the difference was not statistically significant (12.2 ± 5 years vs. 9.3 ± 4.5 years; p=0.23). Among the HU treated group, %HbF following 2 years of HU therapy was similar in those who developed SR (16.1 ± 7.7%) and those who did not (20.0 ± 6.8%; p=0.24).

Although the average age at diagnosis with retinopathy in these children with HbSS/HbSβ⁰thal was similar to previously reported untreated pediatric cohorts, the overall prevalence of retinopathy was lower. Treatment with HU did not affect the development of retinopathy nor did %HbF levels in those treated with HU. More studies are necessary to analyze the effects of HU treatment on development of SR. In the meantime, continued adherence to screening guidelines for ophthalmology evaluations are necessary for children with HbSS and HbSβ⁰thal being treated with hydroxyurea.

Off Label Use: Use of hydroxyurea in children with sickle cell anemia.