Search

AIM We aimed to assess the receipt of recommended care for young children with sickle cell disease (SCD) in a central SCD clinic in Kampala Uganda, focusing on standard vaccination and antibacterial and antimalarial prophylaxis. METHODS A cross-sectional assessment of immunisation status and timeliness and prescribed antibacterial and antimalarial prophylaxis was performed in a sample with SCD aged ≤71 months in Mulago Hospital SCD Clinic. Government-issued immunisation cards and clinic-issued visit records for prescribed prophylaxis were reviewed. RESULTS Vaccinations were documented by immunisation cards in 104 patients, mean age 31.7 months (range 3-70 months). Only 48 (46.2%) received all doses of each of the four recommended vaccine types, including pneumococcal 10-valent conjugate vaccine (pneumococcal conjugate vaccine (PCV)-10), which became available in 2014. Vaccination completion was associated with younger age and, for polio, maternal employment. PCV-10 series was completed in 54.8% of the sample and in 18.2% of those aged 48-71 months. Of children completing all vaccination types, an average 68.8% were immunised on time, defined as

Purpose Based on standard screening techniques, sickle retinopathy reportedly occurs in 10% of adolescents with sickle cell disease (SCD). We performed a prospective, observational clinical study to determine if ultra-widefield fluorescein angiography (UWFA), spectral-domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCT-A) detect more-frequent retinopathy in adolescents with SCD. Design Cross-sectional study. Methods Setting : Institutional. Subjects : Sixteen adolescents with SCD, aged 10–19 years (mean age 14.9 years), and 5 age-equivalent controls (mean age 17.4 years). Observation Procedures : Examinations including acuity, standard slit-lamp biomicroscopy, UWFA, SD-OCT, and OCT-A were performed. Main Outcome Measures : Sickle retinopathy defined by biomicroscopic changes, Goldberg stages I-V, Penman scale, flow void on OCT-A, or macular thinning on SD-OCT. Results While 22 of 32 SCD eyes (68.8%) had retinopathy on biomicroscopy, by UWFA 4 of 24 (16.7%) SCD eyes had peripheral arterial occlusion (Goldberg I), and 20 of 24 eyes (83.3%) had peripheral arteriovenous anastomoses (Goldberg II) in addition. No patients had Goldberg stages III-V. By SD-OCT and OCT-A, thinning of the macula and flow voids in both the superficial and deep retinal capillary plexus were found in 6 of 30 (20%) eyes. Conclusions All 24 eyes with adequate UWFA studies demonstrated sickle retinopathy. SD-OCT and OCT-A, which have not been previously reported in the adolescent population, detected abnormal macular thinning and flow abnormalities undetected by biomicroscopy. These findings suggest that pediatric sickle retinopathy may be more prevalent than previously suspected. If these findings are confirmed with larger cross-sectional and prospective analyses, these approaches may enhance early screening for sickle retinopathy.

Sickle retinopathy reflects disease-related vascular injury of the eye, which can potentially result in visual loss from vitreous hemorrhage or retinal detachment. Here we review sickle retinopathy among children with sickle cell disease, describe the epidemiology, pediatric risk factors, pathophysiology, ocular findings, and treatment. Newer, more sensitive ophthalmological imaging modalities are available for retinal imaging, including ultra-widefield fluorescein angiography, spectral-domain optical coherence tomography, and optical coherence tomography angiography. Optical coherence tomography angiography provides a noninvasive view of retinal vascular layers that could previously not be imaged and can be quantified for comparative or prospective analyses. Ultra-widefield fluorescein angiography provides a more comprehensive view of the peripheral retina than traditional imaging techniques. Screening for retinopathy by standard fundoscopic imaging modalities detects a prevalence of approximately 10%. In contrast, these more sensitive methods allow for more sensitive examination that includes the retina perimeter where sickle retinopathy is often first detectable. Use of these new imaging modalities may detect a higher prevalence of early sickle pathology among children than has previously been reported. Earlier detection may help in better understanding the pathogenesis of sickle retinopathy and guide future screening and treatment paradigms.

Progressive neurovasculopathy in children with sickle cell disease (SCD) results in decreased cognitive function and quality of life (QoL). Hematopoietic cell transplantation (HCT) is believed to halt progression of neurovasculopathy. Quantitative analysis of T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) for white matter hyperintensity (WMH) burden provides a meaningful estimate of small vessel cerebrovascular disease. We asked if quantitative analysis of WMH could complement standardized clinical assessment of MRI/magnetic resonance angiography (MRA) for assessing SCD central nervous system vasculopathy before and after HCT. Retrospective longitudinal clinical examination of scheduled annual MRI/MRA and quantitative analysis of WMH were performed before and 1 to 7 years after HCT at scheduled annual intervals, along with QoL measurements, in children who had engrafted after HCT. Of 18 patients alive and persistently engrafted (median age, 9.1 years), pretransplantation MRI demonstrated that 9 and 5 had sickle-related stroke and/or small infarcts, respectively. Patients were divided into WMH severity tertiles based on pretransplantation WMH volumes. MRI and WMH were assessed 1 to 7 years after HCT. MRI/MRA and WMH volume were stable or slightly better in 17 of 18 patients. By parent- and self-report, post-HCT QoL improved for children in the lowest WMH tertile significantly more than in the other groups. Based on this single-institution retrospective sample, we report that WMH appears to quantitatively support MRI-based findings that HCT stabilizes long-term small and large vessel cerebrovascular changes and is associated with the degree of improved QoL. While confirmation in larger prospective studies and evaluation by neurocognitive testing are needed, these findings suggest that WMH is a useful biomarker of neurovasculopathy after transplantation for SCD.

BackgroundChildren with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Detailed evaluations in sub-Saharan Africa are limited.MethodsWe aimed to establish the frequency and types of pediatric brain injury in a cross-sectional study at a large SCA clinic in Kampala, Uganda in a randomly selected sample of 265 patients with HbSS ages 1–12 years. Brain injury was defined as one or more abnormality on standardized testing: neurocognitive impairment using an age-appropriate test battery, prior stroke by examination or transcranial Doppler (TCD) velocities associated with stroke risk in children with SCA (cerebral arterial time averaged mean maximum velocity ≥ 170 cm/second).ResultsMean age was 5.5 ± 2.9 years; 52.3% were male. Mean hemoglobin was 7.3 ± 1.01 g/dl; 76.4% had hemoglobin p p = 0.04). In adjusted models, neurocognitive dysfunction was strongly related to prior stroke (OR 6.88, 95%CI 1.95–24.3,p = .003) and to abnormal TCD (OR 4.37, 95%CI 1.30,p = 0.02). In a subset of 81 subjects who were enriched for other abnormal results, magnetic resonance imaging and angiography (MRI/MRA) detected infarcts and/or arterial stenosis in 52%. Thirteen subjects (25%) with abnormal imaging had no other abnormalities detected.ConclusionsThe high frequency of neurocognitive impairment or other abnormal results describes a large burden of pediatric SCA brain disease in Uganda. Evaluation by any single modality would have underestimated the impact of SCA. Testing the impact of hydroxyurea or other available disease-modifying interventions for reducing or preventing SCA brain effects is warranted.

The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype-phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.Genet Med 19 1, 121-126.

Community health workers (CHW) are increasingly recognized as a strategy to improve health outcomes for the underserved with chronic diseases but has not been formally explored in adolescents with sickle cell disease (SCD). SCD primarily affects African American, Hispanic and other traditionally underserved populations. Hydroxyurea (HU), an oral, once-daily medication, is the only approved therapeutic drug for sickle cell disease and markedly reduces symptoms, morbidity and mortality and improves quality of life largely by increasing hemoglobin F blood levels. This paper presents the rationale, study design and protocol for an open label randomized controlled trial to improve parent-youth partnerships in self-management and medication adherence to HU in adolescents with SCD.A CHW intervention augmented by text messaging was designed for adolescents with SCD ages 10-18years and their parents to improve daily HU adherence. Thirty adolescent parent dyads will be randomized with 2:1 intervention group allocation. Intervention dyads will establish a relationship with a culturally aligned CHW to identify barriers to HU use, identify cues to build a habit, and develop a dyad partnership to improve daily HU adherence and achieve their individualized "personal best" hemoglobin F target. Intervention feasibility, acceptability and efficacy will be assessed via a 2-site trial. Outcomes of interest are HU adherence, dyad self-management communication, quality of life, and resource use.Despite known benefits, poor HU adherence is common. If feasible and acceptable, the proposed intervention may improve health of underserved adolescents with SCD by enhancing long-term HU adherence.NCT02029742.

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA.

Background: Children with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Inflammation is a risk factor for acute stroke. In a cross-sectional study of Ugandan children, we asked whether inflammatory markers correlated with findings on neurological and neurocognitive testing and magnetic resonance imaging (MRI). Methods: Stored plasma samples were obtained at a well study visit from 81 children, a subset within a larger sample of study participants with HbSS ages 1-12 years recruited at the Mulago Hospital sickle cell clinic in Kampala. Participants underwent 4 standardized assessments: neurocognitive testing using the Mullen Scales of Early Learning (for ages 1-4 years) or Kaufman Assessment Battery for Children, 2nd edition (for ages 5-12) (abnormal at z-score of -2 or lower), examination for prior stroke (PedsNIHSS) and transcranial Doppler ultrasound (TCD) using criteria for pediatric SCA, plus a non-contrast MRI/MRA on a 1.5 Telsa scanner, analyzed for T1- and T2- weighted images and T2 FLAIR. MR scans were interpreted by clinical and research methods, the latter per SWiTCH protocol (Helton, Blood 2014). Adjudication of differing reads was performed by a blinded third neuroradiologist. Participants undergoing MRI intentionally included 29 without any abnormal findings on the three other evaluations. Plasma samples were examined for key cytokines and markers of vascular activation by a 20-plex Luminex immunoassay. Immune markers included IL1b, IL1RA, IL2, IL4, IL10, IL18, IL22, IFNg, TNFa, TNFb, sFasL, CXCL1, CXCL8 (IL8), PDGFBB, VEGFA, serpin E1 (Plasminogen Activator Inhibitor (PAI)-1), sICAM1, VCAM1, TGFa, plus assay of hsCRP. Raw immune data were transformed using Box-Cox transformations and standardized; markers with persistently skewed (non-Gaussian) distributions after transformation were dichotomized for analysis. Continuous immune variables were analyzed by repeated measures ANOVA (unadjusted) and ANCOVA (adjusted for baseline covariates of age, sex, hemoglobin and 25-hydroxy-vitamin D3/D2. Dichotomized biomarkers were analyzed using generalized linear mixed-effects models. For these exploratory biomarker discovery-focused analyses, all significance tests were performed 2-tailed without adjustment for multiple comparisons, with a=0.1 for main effects. Results: Mean age was 6.48 ± 2.75 years, 50.6% male. Mean hemoglobin was 7.26±0.90 g/dl; 16.7% were malnourished using standard international measures established for age and sex. Infarcts on MRI were detected in 42 (52%), including 13 (25%) with no other test abnormalities. Of the 20 inflammatory markers tested, the levels of 13 markers were associated with one or more abnormality. One or more infarcts on MRI as the sole abnormality ("silent" stroke) were associated with levels IL1b, IL2 and TGFb (Table 1). Neurocognitive dysfunction alone was associated only with levels of IL22. Abnormal TCD (primarily "conditional" values) or prior stroke was associated with levels of VEGFA, IL4 and TNFb. In contrast, abnormal TCD or stroke by examination plus neurocognitive dysfunction was associated with nine cytokines levels: CXCL8, CXCL1, IFNg, TNFa, sFasL, IL18, IL22, sICAM1 and VEGFA. In all cases, cytokine levels were negatively associated with each of the abnormal neurological, neurocognitive or imaging results. Adjusting for age, sex, hemoglobin and malnutrition had only modest effects on statistically significant results. No associations were found between the test results and any of the other eight inflammatory markers, including hsCRP. Conclusions: In this exploratory biomarker analysis in a sample with highly prevalent abnormal test results, the presence of those abnormalities correlated with levels of a majority of the inflammatory markers assayed. The clinically well status at sampling and the finding of lower markers levels associated with existing abnormalities suggest that these children were not currently inflamed. As a cross-sectional analysis, cerebral vasculopathy underlying those abnormalities had previously occurred. Lower levels of inflammation may reflect a survivor status of children affected by a chronic illness with high local mortality. Our findings need to be confirmed in a prospective study children, and may be most interesting at acute events and for subjects receiving disease-modifying therapy. Disclosures No relevant conflicts of interest to declare.

Background: Vitamin D, in addition to its role in calcium and bone homeostasis, is a multifunctional regulator of inflammation and of innate and adaptive immune responses. Deficiencies are prevalent in sickle cell disease. We conducted a randomized double- blind active-controlled clinical trial comparing high- (100,000 IU/month) and low-dose (12,000 IU/month) oral vitamin D3 in 62 children with sickle cell disease to reduce respiratory complications including infection, asthma exacerbation and acute chest syndrome (ViDAS trial: Vitamin D for sickle cell respiratory complications; NCT01443728). A secondary aim was to examine the effects of vitamin D on immune function and inflammation. Methods: Using stored serum samples collected from subjects at steady state, we examined hsCRP (single-plex assay) and key cytokines and markers of vascular activation (20-plex immunoassay) at baseline and year-1 in a subset of 36 subjects with HbSS (high-dose: n=17; low-dose: n=19), mean age 7.8 years, 53% females and 67% on hydroxyurea. Immune markers included IL1β, IL1RA, IL2, IL4, IL10, IL18, IL22, IFNγ, TNFα, TNFβ, sFasL, CXCL1, CXCL8 (IL8), PDGFBB, VEGFA, serpin E1 (PAI1), sICAM1, VCAM1, TGFα and TGFβ. Raw immune data were transformed using Box-Cox transformations and standardized; markers with persistently skewed (non-Gaussian) distributions after transformation were dichotomized for analysis. Continuous immune variables were analyzed by repeated measures ANOVA (unadjusted) and ANCOVA (adjusted for baseline covariates of age, sex and baseline total 25-hydroxyvitamin D3 and D2). Dichotomized biomarkers were analyzed using generalized linear mixed-effects models. Secondary analyses stratified on hydroxyurea status were also pursued. For these exploratory biomarker discovery-focused analyses, all significance tests were performed 2-tailed without adjustment for multiple comparisons, with α=0.1 for main effects and 0.2 for interactions. Results: Independent of vitamin D3 dose, serum concentrations of immune markers declined from baseline to the 1-year timepoint for the pro-inflammatory markers IL2, CXCL8 (IL8), IFNγ, TGFα, CXCL1 and PDGFBB and the counter-regulatory molecule, IL10. Among all subjects, interactions of dose group*time were found for IL2, sICAM1 and hsCRP; subjects on hydroxyurea additionally demonstrated dose group*time interactions for serpin E1 (PAI1), IFNγ and TNFα. Subjects on hydroxyurea in the high-dose group also demonstrated decreases over 1-year follow-up in serum IL2, serpin E1, IFNγ, TNFα, sICAM1 and hsCRP whereas serum levels of these immune markers increased among subjects in the low-dose group taking hydroxyurea. This crossover pattern in direction of the dose group*time interaction effect was also observed for the larger study population for sICAM1 and hsCRP. Table 1 shows the markers that tested significantly for main effects and/or interactions. Effects for the rest of the markers were not statistically significant. Conclusions: Our data support the immunomodulatory properties of vitamin D, with variable responses to high and low doses. Effects involved several salient immune and vascular markers for sickle cell disease, including IL2, serpin E1, IFNγ, TNFα, sICAM1 and hsCRP, and appeared to be more pronounced among subjects on high-dose vitamin D3 who were also taking hydroxyurea. Table 1 Disclosures Brittenham: Nestec, Inc.: Consultancy; Novartis International: Consultancy; Tesseract Health, Inc.: Consultancy; Vifor Fresenius Medical Care: Consultancy; Ambys Medicines: Consultancy; Dispersol Technologies: Consultancy; Rockwell Medical, Inc.: Consultancy.

Background: Children with sickle cell anemia (SCA) are highly susceptible to stroke, impaired neurocognitive function and other manifestations of pediatric cerebral vasculopathy. Detailed multifaceted evaluations of children with SCA in sub-Saharan Africa are limited, including neurocognitive testing. Methods: We aimed to establish the prevalence and types of neurocognitive dysfunction in a cross-sectional study in a randomly selected sample of patients with HbSS ages 1-12 years at a large SCD clinic in Kampala, Uganda. Neurocognitive function was assessed by Mullen Scales of Early Learning (ages 1-4) and Kaufman Assessment Battery for Children, 2nd edition (ages 5-12) using linguistically validated local translations (John CC, Pediatrics 2008; Bangirana P., Clin Infect Dis. 2014). The Behavioral Rating Inventory for Executive Function was used to assess executive function. Children also underwent standardized stroke examination (PedsNIHSS) and transcranial Doppler ultrasound (TCD) for measuring stroke risk by arterial velocities in pediatric SCD. Results: Experienced testers performed neurocognitive assessment in 242 participants: 100 (41%) ages of 1-4 years and 142 ages 5-12 years (58.7%). Mean age was 5.44 ±2.9 years; 51.6% were male. Mean hemoglobin was 7.3 ±1.02 g/dl; 76.5% had hemoglobin Conclusion: In children with SCA, executive function was the most common impairment. Overall, only 11% of the SCA children had impaired neurocognitive function. The major predictors of impairment were age, prior stroke and elevated TCD arterial velocity. These abnormalities were highly prevalent in the sample, and identifies significant disease-associated morbidity. Disease-modifying therapy should be assessed for improved neuropsychological function in these children. Disclosures No relevant conflicts of interest to declare.

Background: Children with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Detailed evaluations of children with SCA in sub-Saharan Africa are limited, especially magnetic resonance imaging and angiography (MRI/MRA). In a sample of Ugandan children receiving care at the Mulago Hospital sickle cell clinic in Kampala and were not on disease-modifying therapy, we examined the range of MR imaging findings, and how those findings correlated with standardized demographic, clinical, neurological and neurocognitive assessments. Methods: From within a larger sample of 265 participants with HbSS ages 1-12 years not taking disease-modifying therapy and enrolled in the BRAIN SAFE study, a sub-sample of 81 underwent non-contrast MRI/MRA on a 1.5 Telsa scanner. Participants also underwent 3 standardized assessments: neurocognitive testing by experienced testers using the Mullen Scales of Early Learning (for ages 1-4 years) or Kaufman Assessment Battery for Children, 2nd edition (for ages 5-12) (abnormal z-score of -2 or lower), stroke examination (PedsNIHSS) and transcranial Doppler ultrasound (TCD) using criteria for pediatric SCA. Participants undergoing MRI/MRA intentionally included 29 without any abnormal findings. MRI scans included T1- and T2- weighted images, T2 FLAIR and MRA three-dimensional time-of-flight technique. MR scans were interpreted by clinical and research methods, the latter per SWiTCH protocol (Helton, Blood 2014). Adjudication of differing reads was performed by a blinded third neuroradiologist. Results: A total of 81 children with SCA were examined by MRI/MRA. Mean age was 6.48 ± 2.75 years; 50.6% were male. Mean hemoglobin was 7.26±0.90 g/dl; 75% had hemoglobin Conclusion: High prevalence of pediatric cerebral vasculopathy was found on MR scanning. Despite clinical evidence suggesting abnormal neuropsychological testing or a prior stroke, not all of the children who had clinical evidence of neurological disorders had MRI evidence of a stroke. Additionally, a number with no evidence of stroke had infarct(s) on MRI, so-called "silent stroke." The strongest predictors of an abnormal MRI reading included having a detectable stroke or an abnormal TCD. MR imaging is a critical aspect of evaluating cerebral vasculopathy in this patient population, and will be an important measure when prospectively assessing impact in a treatment trial. Disclosures No relevant conflicts of interest to declare.

Hydroxyurea (HU) is the sole approved pharmacological therapy for sickle cell disease (SCD). Higher levels of fetal hemoglobin (HbF) diminish deoxygenated sickle globin polymerization in vitro and clinically reduce the incidence of disease morbidities. Clinical and laboratory effects of HU largely result from induction of HbF expression, though to a highly variable extent. Baseline and HU-induced HbF expression are both inherited complex traits. In children with SCD, baseline HbF remains the best predictor of drug-induced levels, but this accounts for only a portion of the induction. A limited number of validated genetic loci are strongly associated with higher baseline HbF levels in SCD. For induced HbF levels, genetic approaches using candidate single-nucleotide polymorphisms (SNPs) have identified some of these same loci as being also associated with induction. However, SNP associations with induced HbF are only partially independent of baseline levels. Additional approaches to understanding the impact of HU on HbF and its other therapeutic effects on SCD include pharmacokinetic, gene expression-based, and epigenetic analyses in patients and through studies in existing murine models for SCD. Understanding the genetic and other factors underlying the variability in therapeutic effects of HU for pediatric SCD is critical for prospectively predicting good responders and for designing other effective therapies.

Severe congenital neutropenia type IV (SCN IV) is a syndrome of severe neutropenia, cardiac and urogenital defects, prominent superficial veins, facial dysmorphism, failure to thrive (FTT), and intermittent thrombocytopenia, caused by a glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene mutation. SCN IV has been linked to glycogen storage disease type 1b as both disorders involve disruption of the glucose-6-phosphatase/glucose-6-phosphate transporter complex, leading to arrested neutrophil maturation. Emerging evidence suggests that neutrophil function plays an important role in intestinal integrity, evidenced by inflammatory bowel disease in certain neutropenic patients. Here, we report 3 unrelated Hispanic males from the Dominican Republic with classic features of SCN IV found to share an identical inherited canonical splice-site mutation of the G6PC3 gene (c.218+1GA). All 3 patients presented with severe FTT and gastrointestinal manifestations. Two of the patients had significant improvement in growth and resolution of gastrointestional symptoms with initiation of granulocyte colony-stimulating factor. We hypothesize that the gene variant described represents a founder mutation in the Dominican Republic, the first to be described in this geographical region. We discuss the potential associations between neutropenia and gastrointestinal disease with FTT and the role of granulocyte colony-stimulating factor in improving neutrophil count and intestinal integrity and growth.

Background Hydroxyurea (HU) is highly effective treatment for Sickle Cell Disease (SCD). While pediatric use of HU is accepted clinical practice, barriers to use may impede its potential benefit.

Objective To conduct a systematic review to assist the United States Secretary of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) to determine whether Hemoglobin H screening should be included among the core recommended conditions for newborn screening. Study design We identified 21 articles in MEDLINE from 1989 to March 2010 that provided evidence regarding screening, treatment, and outcomes associated with Hemoglobin H disease. Results In California, newborn screening has identified 9 cases per 100 000 of deletional hemoglobin H disease and 0.6 cases per 100 000 of nondeletional hemoglobin H disease. Five cases of hemoglobin Bart's hydrops fetalis syndrome were also identified in over ten years of screening for Hemoglobin H disease. Although Hemoglobin H disease is associated with a wide range of morbidity, no studies were found that evaluated the benefits of early identification and treatment. Conclusions The SACHDNC found the data insufficient to recommend that states adopt newborn screening for Hemoglobin H disease.

Sickle Cell Anemia (SCA) is a leading cause of childhood stroke in sub-Saharan Africa and sickle cell brain vasculopathy manifests either as overt stroke or clinically "silent infarcts". This study aimed to describe brain abnormalities seen on magnetic resonance imaging in Ugandan SCA children. Our hypothesis was that multi-model abnormalities would be associated with cerebrovasculopathy found on MRI/MRA. Methods As part of a larger study to determine the burden and spectrum of neurological and cognitive impairments in SCA children in Uganda, we selected 81 children ages 1-12 years with HbSS, a sample enriched for possible brain pathology from Mulago hospital SCA clinic out of a random sample of 265 stable children. None was receiving hydroxyurea. All had detailed clinical history, and physical, neurological and cognitive testing, trans-cranial Doppler (TCD) cerebral blood flow velocity determination and non-contrasted brain MRI/MRA using a 1.5 Tesla scanner. Cognitive testing was performed using age-specific tools validated for Ugandan children. Results Of the 81 participants imaged, 61 had one or more of history of stroke, an abnormal neurological exam, cognitive impairment or abnormal TCD, while 20 had normal test results. MR abnormalities were seen in 35/61 (63.9%) participants with probable brain pathology and in 4/20 (20.0%) without any probable brain pathology. They included different structural abnormalities seen in all brain regions ranging from only T2 weighted hyper-intensities, white matter lacuna infarction to bilateral ischemic and multi-focal cerebral infarcts with associated compensatory hydrocephalus. MRA abnormalities ranged from cerebral microangiopathy to multiple stenosis and occlusions of major arteries, including moya-moya in 4 subjects. Severe vessel obstructions were also seen in multiple young children Conclusions Brain injury in Uganda children with SCA begins early in childhood and becomes a common finding during later childhood. Early screening for stroke and intervention therapy is warranted to prevent sickle brain vasculopathy initiated early after diagnosis. The risk factors for such early brain injury should be investigated. Disclosures No relevant conflicts of interest to declare.

Purpose: To summarize the evidence regarding screening, diagnosis, and treatment of early-infantile Krabbe disease in consideration of its addition to the core panel for newborn screening as has been done in New York state. Methods: Systematic review of articles indexed in MEDLINE and Embase published between January 1988 and July 2009. Thirteen articles describing studies related to screening, diagnosis, or treatment were included in this review. Results: Case series studies suggest that allogeneic hematopoietic stem-cell transplantation soon after the development of signs or symptoms of early-infantile Krabbe disease decreases early-childhood mortality and may improve neurodevelopment. However, limited data suggest there may be loss of motor function among some children who undergo transplantation. No long-term follow-up data are available from these case series. Of the ∼550,000 newborns reported to have been screened in New York, 25 tested positive. None of these were clinically recognized to have Krabbe disease prior these results. Four were considered to be high risk for early-onset Krabbe disease. Two were subsequently diagnosed and underwent stem-cell transplantation, of whom one died from complications. No data are available regarding the impact on families of a positive newborn screen. Conclusions: Although early treatment with hematopoietic stem-cell transplant seems to alter early-childhood mortality and some of the morbidity associated with early-infantile Krabbe disease, significant gaps in knowledge exist regarding the accuracy of screening, the strategy for establishing diagnosis, the affect of a positive screen on families, the benefits and harms of treatment, and long-term prognosis.

CONTEXT: Severe combined immunodeficiency (SCID) is a group of disorders that leads to early childhood death as a result of severe infections. Recent research has addressed potential newborn screening for SCID. OBJECTIVE: To conduct a systematic review of the evidence for newborn screening for SCID, including test characteristics, treatment efficacy, and cost-effectiveness. METHODS: We searched Medline and the OVID In-Process & Other Non-Indexed Citations databases. We excluded articles if they were reviews, editorials or other opinion pieces, or case series of fewer than 4 patients or if they contained only adult subjects or nonhuman data. The remaining articles were systematically evaluated, and data were abstracted by 2 independent reviewers using standardized tools. For topics that lacked published evidence, we interviewed experts in the field. RESULTS: The initial search resulted in 719 articles. Twenty-six met inclusion criteria. The results of several small studies suggested that screening for SCID is possible. Interviews revealed that 2 states have begun pilot screening programs. Evidence from large case series indicates that children receiving early stem-cell transplant for SCID have improved outcomes compared with children who were treated later. There is some inconclusive evidence regarding the need for donor-recipient matching and use of pretransplant chemotherapy. Few data on the cost-effectiveness of a SCID-screening program. CONCLUSIONS: Evidence indicates the benefits of early treatment of SCID and the possibility of population-based newborn screening. Better information on optimal treatment and the costs of treatment and screening would benefit policy makers deciding among competing health care priorities.

Introduction This study examined hydroxyurea usage in young children with sickle cell anemia within New York State (NYS). The cohort was 273 children with sickle cell anemia born in NYS in 2006–2009 and enrolled essentially continuously in Medicaid for the first 4 years of life. Methods Medicaid data were used to examine hydroxyurea usage in this group by age at first prescription fill, persistence, region, treatment institution, and year. Log-binomial regression models were used to estimate the likelihood of receiving hydroxyurea treatment. Data from birth through 2014 for all members of the study group were assembled and analyzed in 2015. Results About 25% of the cohort had at least one filled hydroxyurea prescription by their fifth birthday, and nearly 40% by the end of the study period. The mean proportion of days covered for the first year of therapy was 56.3%. Adherence was also assessed by calculating medication possession ratios for individual treatment periods. Slightly more than one third of treated children showed 80% coverage by these measures. There was a consistent, but not statistically significant, trend toward younger age at first fill. Significant regional and treatment center differences in initiation of hydroxyurea use, but not in persistence after initiation, were noted among NYS centers. Conclusions Subsequent to clinical studies demonstrating safety, current NYS-wide use of hydroxyurea in young children with sickle cell anemia appears to be widespread and increasing. However, practice differences between treatment centers and inadequate adherence may limit the full disease-modifying effects of hydroxyurea.

OBJECTIVE: A multicenter, randomized placebo-controlled trial among women with singleton pregnancies and a history of spontaneous preterm birth found that weekly injections of 17 alpha-hydroxyprogesterone caproate (17P), initiated between 16 and 20 weeks of gestation, reduced preterm birth by 33%. The current study estimated both preterm birth recurrence and the potential reduction in the national preterm birth rate. METHODS: Using 2002 national birth certificate data, augmented by vital statistics from 2 states, we estimated the number of singleton births delivered to women eligible for 17P through both a history of spontaneous preterm birth and prenatal care onset within the first 4 months of pregnancy. The number and rate of recurrent spontaneous preterm births were estimated. To predict effect, the reported 33% reduction in spontaneous preterm birth attributed to 17P therapy was applied to these estimates. RESULTS: In 2002, approximately 30,000 recurrent preterm births occurred to women eligible for 17P, having had a recurrent preterm birth rate of 22.5%. If 17P therapy were delivered to these women, nearly 10,000 spontaneous preterm births would have been prevented, thereby reducing the overall United States preterm birth rate by approximately 2%, from 12.1% to 11.8% (P < .001), with higher reductions in targeted groups of eligible pregnant women. CONCLUSION: Use of 17P could reduce preterm birth among eligible women, but would likely have a modest effect on the national preterm birth rate. Additional research is urgently needed to identify other populations who might benefit from 17P, evaluate new methods for early detection of women at risk, and develop additional prevention strategies. (Obstet Gynecol 2005;105:267‐72. © 2005 by The American College of Obstetricians and Gynecologists.) LEVEL OF EVIDENCE: III

The authors describe a case of acute lymphoblastic leukemia with two subsequent isolated central nervous system (CNS) relapses, each accompanied by cerebrospinal fluid (CSF) eosinophilia and basophilia. Despite marked peripheral blood and bone marrow eosinophilia at initial diagnosis, the patient had no blood or bone marrow eosinophilia, basophilia, or leukemic blasts at the time of either CNS relapse. The literature is reviewed and a possible cytokine-based mechanism is proposed for the unusual finding of simultaneous CSF eosinophilia, basophilia, and leukemic blasts.

Objectives. The prevalence of stroke among children with sickle cell disease (SCD) in sub-Saharan Africa was systematically reviewed. Methods. Comprehensive searches of PubMed, Embase, and Web of Science were performed for articles published between 1980 and 2016 (English or French) reporting stroke prevalence. Using preselected inclusion criteria, titles and abstracts were screened and full-text articles were reviewed. Results. Ten full-text articles met selection criteria. Cross-sectional clinic-based data reported 2.9% to 16.9% stroke prevalence among children with SCD. Using available sickle gene frequencies by country, estimated pediatric mortality, and fixed- and random-effects model, the number of affected individuals is projected as 29 800 (95% confidence interval = 25 571-34 027) and 59 732 (37 004-82 460), respectively. Conclusion. Systematic review enabled the estimation of the number of children with SCD stroke in sub-Saharan Africa. High disease mortality, inaccurate diagnosis, and regional variability of risk hamper more precise estimates. Adopting standardized stroke assessments may provide more accurate determination of numbers affected to inform preventive interventions.

Sickle Cell Anemia (SCA) is highly prevalent in sub-Saharan Africa (SSA). In Uganda, approximately 20,000 children are born with SCA annually (Ndeezi G, 2016). Sickle brain vasculopathy causes both overt strokes and clinically "silent infarcts," affecting neurological and cognitive function (DeBaun MR, 2012). Incidence of strokes has markedly decreased through standardized preventative measures. Study objectives are to determine the age-related spectrum and burden of brain injury associated with SCA in Ugandan children, determine predisposing risk factors and build capacity to support interventions for stroke prevention. Here we present preliminary results. Methods: BRAIN SAFE is a cross-sectional study of a random sample of 250 children with SCA, ages 1-12 years, who receive care at the Mulago Hospital SCD clinic in Kampala.Potential participants were randomly selected from the clinic roster. Study exclusion criteria: hemoglobinopathy other than HbSS or HbS B0 thalassemia, age >12, acute illness, Hb Stroke history and examination: were performed using the pediatric NIH Stroke Scale. Psychometric testing: Age-appropriate KABC-II, TOVA, BRIEF and Mullen testing were performed by skilled testers using validated versions in English or the predominant local language. Transcranial doppler ultrasounds (TCDs) were performed (with good inter-operator reliability) by two study staff, both health professionals. They had been trained by a U.S.-based "STOP" trial TCD research nurse and a co-investigator who had TCD training in the U.S. The latter also performed standardized readings (Adams RJ, 1998). Quality assurance for TCD readings was provided by an independent stroke neurologist. Brain Magnetic imaging (MRI/MRA): Using a single 1.5T scanner, a subset of subjects enriched for a history of stroke, abnormal neurological exam and/or cognitive testing. Two radiologists performed clinical reads. An independent neuroradiologist assessed sickle vasculopathy, per "SWiTCH" protocol (Helton KJ, 2014), blinded to clinical and radiological data. Primary and secondary stroke prevention : Subjects with persistently non-normal TCDs on repeat testing or vasculopathy on MRI/MRAswill be offered hydroxyurea . Results: Of the 248 participants screened in the 1st funding year, 233 were enrolled (mean age 5.62 years (range 1-12). Study exclusions due to age >12, acute illness, severe anemia, recent transfusion or participation in another study. History and neurological exam : Overall, 7 of 233 had history consistent with a stroke, and an abnormal neurological exam, 5 had a history consistent with stroke but a normal neurological exam, 6 had abnormal neurological findings but no history of stroke (total abnormal 18/233, 7.7%). Psychometrics : To date, cognitive test data results have been performed on 80 children; 30 (37.5%) were impaired with varying severity. (Full reports to follow.) TCDs : A total of 224 non-imaging TCDs have been performed. Using standard criteria, 190 were normal, 4 abnormal (1.8%), and 30 conditional (13.4%). Repeat TCDs have been performed on 13 of those with non-normal reads and so far, 2 were abnormal, 6 conditional, 4 normal,1 had difficult windows. MRI/MRAs: A subset of 29 subjects were selected with more clinical and/or historical stroke pathology (N= 25, 86%) and have undergone MR imaging to date (see Table). Mean age was 7.1 years (range 3-12); male: 55%. Of 26 with clinical radiological reads, 16 / 26 (61.5%) were abnormal. To date, scans from 12 subjects have had SCD vascular reads: 2 had no vasculopathy; 10 were abnormal: 6 with infarcts and arterial stenoses, 3 with infarcts only, 1 with bilateral stenoses only. Conclusions: BRAIN SAFE, a Kampala-based cross-sectional study, has already enrolled and completed a large proportion of study procedures. Considerable brain pathology has been identified in all aspects tested, with high prevalence of abnormal history or physical findings, abnormal psychometrics, abnormal cerebral blood flow and/or brain MR imaging. Completion of enrollment and testing for the target sample will provide baseline data for longitudinal assessment and intervention. Building research capacity for faculty and trainees is ongoing. Acknowledgments: 1R21HD089791 (PIs: Idro, Green) and Latanya Bowman, RN, Augusta University Sickle Cell Center. Disclosures No relevant conflicts of interest to declare.

Background: Chronic disease regimens for youth require self-management skills for a daily medication habit. Incomplete adherence to hydroxyurea (HU) is a treatment barrier for sickle cell disease (SCD) (Walsh KE, Pediatrics 2014). HU induction of fetal hemoglobin (HbF) is dose-dependent but not a standardized target (Ware RE, Hematology Am Soc Hematol Educ Program, 2015). In a previous 2-site retrospective analysis of youth with SCD, large deviation from historical personal best (PBest) HbF, a clinic-based form of maximum dose (Green NS, PBC, 2016), was common and correlated with increased acute hospital use. Here we hypothesized that: 1) A HU habit can develop through education and support of youth-parent dyads from a structured intervention of community health workers (CHW), augmented by text messaging; 2) Improved used will increase HbF; 3) The intervention is feasible and acceptable. Methods: We conducted a 2-site R21-funded randomized controlled feasibility trial (RCT), "Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment: HABIT" (Smaldone A, Contemp Clin Trials, 2016)." Youth- parent dyads (youth ages 10-18) were recruited for the 6-month intervention. Eligibility required a ≥15% drop from PBest HbF on stable HU dose over the preceding year. Intervention dyads received a 6-month structured intervention of education and support by CHWs with home visits and text messaging, versus educational materials. Primary outcomes were HbF, % deviation from PBest HbF and HU pharmacy refills. Results: Using 2:1 randomization, 28 parent-youth dyads participated (18 intervention, 10 control): mean age 14.3±2.6 years, 42.9% female. At baseline, no differences were seen in HbF (10.5% vs. 13.4%, p=0.25), but deviation from PBest HbF was higher in the control group (-42.6%) than the intervention (18.1%, p=0.009). Using a growth model for % deviation from PBest HbF, the intervention group demonstrated a modest absolute improvement in deviation from PBest (2.2% per month higher in the intervention group), peaking at month 4 (p=0.31), and modest gain in mean HbF (3 versus 1.8). Four subjects exceeded their PBest. Compared to the year before intervention, pharmacy refills improved for the intervention group: 64.6% year prior, 80.7% (months 0 to 3), 85.9% (months >3 to 6), while the control group was unchanged (79.2% year prior, 83.6% months 0 to 3, 79.4% months >3 to 6). Intervention feasibility and acceptability by dyads were excellent. Conclusions: The 6-month pilot RCT "HABIT" may improve HU adherence measured by improved HbF, deviation from PBest and pharmacy refill, was feasible and acceptable, and suggests utility as an intervention. Based on these findings, a multi-center HABIT RCT of 1-year duration powered to test efficacy is planned. Funded by 5R21NR013745 (PIs Green, Smaldone) Figure Figure. Disclosures No relevant conflicts of interest to declare.

Introduction: Sickle cell retinopathy (SCR) reflects disease-related vascular injury. Previous studies of pediatric SCR using standard imaging approaches reported retinopathy in Results: Eight children (mean age 16.3 years; 5 HbSS, 2 HbSC,1 HbS-Beta thalassemia0) were evaluated. Three were on hydroxyurea therapy, 1 on chronic transfusion, 1 on both and 3 on no therapy. No patient had vision disturbance at the time of examination. Biomicroscopic examination revealed sunburst lesions in the mid-peripheral retina in 3 patients and subtle vascular changes in the far periphery of all patients. In contrast, UWFA detected extensive capillary non- perfusion of the peripheral retina with abnormal vascular loops (Goldberg Stage I) in all 8 patients; 3 patients had peripheral arteriovenous anastomoses (Goldberg Stage II) that were undetectable by biomicroscopy. No patient had Goldberg Stages III-V. SD-OCT demonstrated thinning of the temporal macula in 2 patients, and OCT-A of both patients revealed flow voids in both the superficial and deep retinal capillary plexus in the area of thinned retina. Both the SD- OCT and OCT-A abnormalities were undetectable with standard biomicroscopy. Conclusions: All 8 children with SCD in this case series demonstrated evidence of SCR using the combination of standard biomicroscopy, UWFA, SD-OCT, and OCT-A imaging. Findings from these sensitive imaging modalities suggest that pediatric SCR is more prevalent than previously suspected. Additional patients and age-equivalent controls will be included in this report to validate the specificity of findings to SCD. Larger cross-sectional and prospective analyses using sensitive retina imaging are needed to confirm our findings and identify their significance for detecting pathology. If confirmed, these approaches may enhance early screening for patients at risk of vision-threatening consequences of SCR. Supported by the Irving Institute CTSA at CUMC and by 2T35HL007616 (DP). Retinal findings in pediatric sickle cell disease patients SD-OCT: Spectral-domain optical coherence tomography; OCT-A: Optical coherence tomography angiography; UWFA: Ultra-widefield fluorescein angiography. Retinal findings in pediatric sickle cell disease patients. / SD-OCT: Spectral-domain optical coherence tomography; OCT-A: Optical coherence tomography angiography; UWFA: Ultra-widefield fluorescein angiography. Disclosures No relevant conflicts of interest to declare.

Has the recent availability of newborn hemoglobinopathy screening results within patient electronic medical records (EMR) of birth hospitals facilitated follow-up by primary care pediatric providers?An online survey of all 137 primary care pediatric providers at a New York City academic medical center was conducted in 2008-2009 to assess practices for hemoglobin-apathy trait follow-up. Physicians were resurveyed 1 year later, following educational outreach and a letter of instruction underscoring the availability of screening results in the EMR. All 62 primary care pediatricians were surveyed at a nearby city hospital for comparison.Overall response rate for the initial survey at the teaching hospital was 58% for pediatricians (N = 57) and family physicians (N = 23), and 50% for pediatricians at the city hospital (N = 31). Despite high prevalence of hemoglobinopathies in the population served and screening results in EMRs, only 46.2% of providers surveyed at the academic center reported routinely checking results of their infant patients: 38.6% of pediatricians and 66.7% of family practitioners. Some respondents were unaware that results are available in the EMR. The proportion of providers checking screening results was not significantly affected by educational intervention (N = 40). Provision of recommended follow-up for a positive trait result was modestly improved, especially in referring families for genetic counseling (25% to 50%, p.01). In contrast, most pediatricians (83%) at the city hospital routinely check and perform follow-up.Despite access to results in the EMR and targeted educational outreach, follow-up of hemoglobinopathy screening by primary care varies widely across clinical sites.

The degree of fetal hemoglobin (HbF) expression is a major determinant of phenotypic severity of sickle cell disease (SCD). Genetic regulation of HbF production is complex and can vary among ethnic groups. The pediatric sickle cell population at our institution is approximately half Hispanic, nearly all from the Dominican Republic. Hydroxyurea (HU) is the only Food and Drug Administration (FDA)-approved drug to ameliorate symptoms of SCD. We retrospectively compared baseline and HU-induced percent HbF (%HbF) in African American (AA) and Hispanic (H) patients aged 4 to 21 years with homozygous Sickle hemoglobin or HbSβ(0)Thalassemia. No significant differences were detected in average baseline %HbF between AA (N=48) and H (N=58) patients (P=0.63). In the subset of children taking HU who reached maximum tolerated dose (MTD), no differences were found between the ethnic groups in laboratory response to drug, measured by %HbF at MTD (P=0.28), the increase in %HbF (P=0.31) or mean red cell volume (MCV) (P=0.93), or the MTD of HU (P=0.95). Regulation of HbF at baseline and in response to HU are comparable between Hispanics and African Americans at our center. If generalizable, our results support combining these 2 groups in future clinical and translational analyses focused on HbF and response to HU in this ethnically mixed patient population.

OBJECTIVE. The objective of this study was to estimate national hospital costs for infant admissions that are associated with preterm birth/low birth weight.METHODS. Infant (35 million hospital discharges nationwide. Hospital costs, based on weighted cost-to-charge ratios, and lengths of stay were calculated for preterm/low birth weight infants, uncomplicated newborns, and all other infant hospitalizations and assessed by degree of prematurity, major complications, and expected payer.RESULTS. In 2001, 8% (384200) of all 4.6 million infant stays nationwide included a diagnosis of preterm birth/low birth weight. Costs for these preterm/low birth weight admissions totaled $5.8 billion, representing 47% of the costs for all infant hospitalizations and 27% for all pediatric stays. Preterm/low birth weight infant stays averaged $15100, with a mean length of stay of 12.9 days versus $600 and 1.9 days for uncomplicated newborns. Costs were highest for extremely preterm infants (CONCLUSIONS. Costs per infant hospitalization were highest for extremely preterm infants, although the larger number of moderately preterm/low birth weight infants contributed more to the overall costs. Preterm/low birth weight infants in the United States account for half of infant hospitalization costs and one quarter of pediatric costs, suggesting that major infant and pediatric cost savings could be realized by preventing preterm birth.

We thank Ross for suggesting a potential improvement in newborn screening (NBS) for cystic fibrosis (CF) by adding a second-tier enzyme-linked immunosorbent assay for pancreatic-associated protein for those samples screening positive by immunoreactive trypsinogen (IRT).1 The addition of pancreatic-associated protein may improve the specificity of screening, perhaps bypassing some of the difficulties that we note with secondary DNA-based CF screening as it is currently practiced.2 However, the limitations of DNA-based screening by assay of only a minority of the known mutations in the CF gene can be better addressed by increasing the number of mutations analyzed. Accurate genotyping will be useful in confirming disease detection and could provide genotype-phenotype predictions of disease course and related clinical utility,3 such as for clinically less severe variants of galactosemia (i.e., the Duarte mutation) or CF (e.g., the R117H mutation). Even as protein assays progress, NBS will increasingly use DNA as a tool for the identification and treatment of children affected by CF and other disorders. Therefore, programs will be best served by improving both protein- and DNA-based screening strategies, making them more accurate, predictive, and inclusive for the diverse population of neonates. Incorporating new technologies to improve NBS and decrease health disparities remains an essential element of providing optimal public health service. Some disorders may require primary DNA-based screening. For example, a screening assay has recently been reported for severe combined immune deficiency (SCID).4,5 While we had raised questions about NBS for SCID because treatment requires bone marrow cell transplantation,2 recent evidence suggests that transplant with banked cord blood or partially matched donor hematopoietic stem cells for treatment—and cure—of SCID can be made widely available6,7 and may be cost effective.8 Such evidence reminds us that NBS should remain open to new opportunities for screening and treatment. Finally, we emphatically echo Ross’s call that NBS should help to redress, not exacerbate, health care disparities. The screening component of NBS is as close to a universal health service as exists in the United States. We must also assure that all children identified by NBS receive the care they need. The hodgepodge of eligibility criteria and funding streams that characterize health care in the United States makes this a difficult challenge, the solution to which will be found in policy, not technology.

Introduction: Sickle cell disease (SCD) CNS vasculopathy (SCNSV) is a frequent indication for hematopoietic stem cell transplantation (HSCT). Untreated, SCNSV can be progressive and impair quality of life (QoL) and cognitive functioning. By clinical MRI/MRA assessment, HSCT is thought to halt progression of SCNSV. Quantitative analysis of T2-weighted FLAIR MRI for white matter hyperintensity (WMH) can provide a meaningful estimate of small vessel cerebrovascular burden. Adding WMH assessment, we asked whether HSCT for SCD halted long-term progression of SCNSV, including small vessel involvement, despite transplant-associated CNS risks. QoL assessment can track school functioning and physical, emotional and social functioning. Methods: This retrospective single site study compared MRI analyses pre-transplant to 1-7-years post-HSCT. Subject eligibility required availability of clinical MRI scans from within 2 months pre-HSCT and at 1-year intervals for at least one year post-HSCT. Interim scans performed for acute clinical indications were not included in the analysis. MRI scans were evaluated independent to the initial clinical read by one neuroradiologist, and via in-house developed software to quantitate WMH burden. QoL was completed by parent- and child-report pre-HSCT and annually thereafter using the Peds QL 4.0TM with scores 0-100; higher numbers reflected higher QoL. Results: 25 patients who received HSCT for SCD between 2003-2014 were evaluated. Median age at HSCT was 9.9 years (1.4-21.9); male:female 18:7; HbSS (17), HbSC (3), HbS-Bthalassemia (5). Donors were related (14) or unrelated (11). Stem cell sources were: related bone marrow (BM) (10), unrelated BM (5), related cord blood (CB) (3), unrelated CB (6), or related peripheral blood stem cells (1). Eight patients had CNS pathology as the indication for HSCT. Transplant complications were: PRES (2), stroke (1), graft failure (2), death (1). Duration of follow-up was: 1 yr (9), 2 yrs (10), >2 yrs (6). Only a minority of patients had normal pre-HSCT MRI (5) and normal MRA (11; 6 had 1-2 stenoses Conclusions: Most children in this retrospective cohort had MRI abnormalities pre-HSCT, and all but 1 were stable or improved post-HSCT, despite PRES and other potential CNS complications. Pre-HSCT WMH appeared to be unchanged for most of these patients, while stroke-induced WMH appears to decrease over time, suggesting stable small vessel SCNSV following transplantation. Overall, by MRI/MRA and by preliminary WMH, HSCT appears to have stabilized large and small vessel SCNSV in all but 1 of 25 children. While only a modest number of patients were assessed, WMH was reproducible at multiple annual time points. Long-term parent and self-reported QoL indicated improvement from HSCT. Chronically transfused SCD patients could not be compared due to lack of annualized assessment. Future transplant protocols will include enhanced MRI-based tracking, in conjunction with QoL and neuropsychological assessments. These data could be useful for decision-making about SCD transplantation. Disclosures No relevant conflicts of interest to declare.

Throughout much of Western history, the uterus was considered an independent organism, a voracious animal within the female body that required “feeding”. That conceptualization rendered women mere bearers of children, despite very high risks of maternal and infant mortality. While complication rates have plummeted, having children is no longer viewed as satisfaction for the ravenous animal within. Yet as Debora Spar aptly describes in The baby business: how money, science and politics drive the commerce of conception, this hunger for children drives the booming business of reproductive technology. Approximately 15% of all couples in the United States admit to some degree of infertility. Thankfully, infertility is no longer considered a taboo-ridden measure of female or male inadequacy.

Preterm birth (PTB) is a common, serious, and costly health problem affecting nearly 1 in 8 births in the United States. Burdens from PTB are especially severe for the very preterm infant (

Based on animal studies, epidemiologic studies and intervention trials, maternal folic acid is known to be protective for neural tube defects (NTD), primarily spina bifida and anencephalus. To reduce the risk of NTD, the U.S. Food and Drug Administration mandated that all enriched cereal grain products be fortified with folic acid as of January 1998. Recent data demonstrate that this public health action is associated with increased folate blood levels among U.S. women of childbearing age and that the national rate of spina bifida has decreased by 20%. Rates of anencephaly appear not to have declined. Epidemiologic data on use of folate and folate antagonists have also implicated folic acid in prevention of other birth defects such as facial clefts and cardiac and limb defects. Dietary folic acid is likely to be inadequate for maximal protection against NTD. Because about half of pregnancies in the U.S. are unplanned, according to the March of Dimes, birth defect prevention includes a recommended daily dose of 400 micro g synthetic folic acid for women of childbearing age. Uniform compliance is estimated to decrease the incidence of NTD by up to 70%. This could reduce the overall incidence from 2 to 0.6 per 1000 pregnancies and prevent disease in approximately 2000 babies per year in the U.S. Four thousand micrograms of folic acid per day is recommended for women with previous pregnancies affected by NTD.

Introduction: Hydroxyurea (HU) induction of fetal hemoglobin (HbF) is a major therapeutic effect for sickle cell disease (SCD) HbSS or HbSB0thalassemia. Non-adherence to a HU daily regimen is a barrier to its full effect. As no uniform level of HbF induction exists, we hypothesized that a child’s historical “personal best” (PB) HbF level at maximum clinical dose can be used as a marker for HU adherence. The NIH-funded “HABIT” study is a two-site randomized trial to improve patient-centered HU adherence in adolescents age 10-18 years. Eligibility is determined by fall-off from PB HbF over the previous year. Adherence measures include tracking HbF, pharmacy refill data and self-report. Methods: In a cross-sectional analysis of the entire 2-site clinic-based sample of 95 youth with SCD on HU, ages 10-18 years, and from the subset enrolled in HABIT to date, we assessed demographics, HU use and HbF at pre-treatment, PB and a recent time point. Here, HU non-adherence was defined as ≥20% deviation from PB HbF. Data were analyzed using descriptive statistics and Pearson correlation; groups were stratified by site and participation in HABIT, and were compared using chi-square and student’s t-tests. Results: Only ethnicity and mean HU dosing significantly differed by site (more Latinos/other and lower HU dosing at Columbia vs. Einstein). Only 39 (41%) youth remained within 20% of their PB HbF, with no significant differences in deviation from PB HbF by: site, gender; ethnicity; age (< or ≥14 years); higher induced PB (HbF of ≥20%); or time to PB (≤ or >1 year). For the 39 adherent to HU, mean deviation from PB HbF was 7.3±8.4% (median 7.2); for the 56 non-adherent, mean deviation was 40.5±16.4% (median 36.8; p Conclusion: Our definition of HU non-adherence as ≥20% deviation from Personal Best HbF identified two non-overlapping patient groups ages 10-18 years, with the majority found to be non-adherent. These findings also suggest that HU initiation at younger ages may increase risk of under-adherence during adolescence. PB HbF appears to be a useful marker for HU adherence, and may aid in clinical and patient-centered assessment and intervention. These results underscore the need to assess HU adherence in adolescent patients and for intervention trials such as HABIT. Abstract 1383. Table: Characteristics of the 2-site sample on hydroxyurea and subjects enrolled in the HABIT study Total(N =95) Columbia (N=39) Einstein (N=56) P value HABIT (N=13) P1 value N % N % N % N % Female gender 43 45.3 18 46.2 25 44.6 0.88 5 38.5 0.60 Ethnicity Hispanic/other2 African Amer 25 59 26.3 62.1 22 17 56.4 43.6 14 42 25.0 75.0 0.002 9 4 69.2 30.8 0.03 Age group 10-13 years 14-18 years 44 51 46.3 53.7 21 18 53.9 46.1 23 33 41.1 58.9 0.22 3 10 23.1 76.9 0.07 Mean SD Mean SD Mean SD Mean SD Current age (years) 14.3 2.6 14.1 2.7 14.4 2.5 0.63 15.7 2.3 0.03 Age at HU initiation (years) 9.2 3.7 8.8 4.3 9.5 3.7 0.44 9.1 4.8 0.91 Age at Personal Best (years) 11.9 3.3 11.2 3.7 12.3 3.0 0.14 13.2 3.7 0.12 HU duration (years) 4.6 3.2 4.9 3.5 4.3 2.9 0.36 6.0 4.2 0.10 Pre-HU HbF HU 7.7 4.8 7.2 4.6 8.1 4.9 0.41 6.6 2.0 0.42 Time to Personal Best (years) 2.5 2.3 2.5 2.7 2.4 2.1 0.96 4.0 3.3 0.09 Personal Best HbF 18.7 6.6 18.5 6.6 18.7 6.7 0.87 18.0 5.8 0.72 HU dose at Personal Best (mg/kg/day) 24.1 3.8 22.6 4.1 25.1 3.3 0.002 25.0 3.8 0.32 Recent HbF 13.6 6.3 13.2 6.4 13.8 6.3 0.62 12.1 5.9 0.36 HbF increase from pre-HU to PB 10.8 6.0 11.6 4.7 10.2 6.8 0.29 11.0 7.2 0.92 Recent HU dose (mg/kg/day) 23.9 4.0 21.9 4.5 25.4 2.7 20% deviation) 56 58.9 24 61.5 32 57.1 10 76.9 1Comparing HABIT subjects to the remaining 82 patients in the sample. 2Designation of “other” includes multi-racial HABIT: Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment Funding: 5R21NR013745 (PIs NSG and AMS) Disclosures Off Label Use: Hydroxyurea is not FDA approved for use in children..

SUMMARYImmunoglobulin gene somatic mutation leads to antibody affinity maturation through the introduction of multiple point mutations in the antigen binding site. No genes have as yet been identified that participate in this process. Bloom's syndrome (BS) is a chromosomal breakage disorder with a mutator phenotype. Most affected individuals exhibit an immunodeficiency of undetermined aetiology. The gene for this disorder, BLM, has recently been identified as a DNA helicase. If this gene were to play a role in immunoglobulin mutation, then people with BS may lack normally mutated antibodies. Since germ-line, non-mutated immunoglobulin genes generally produce low affinity antibodies, impaired helicase activity might be manifested as the immunodeficiency found in BS. Therefore, we asked whether BLM is specifically involved in immunoglobulin hypermutation. Sequences of immunoglobulin variable (V) regions were analysed from small unsorted blood samples obtained from BS individuals and compared with germ-line sequences. BS V regions displayed the normal distribution of mutations, indicating that the defect in BS is not related to the mechanism of somatic mutation. These data strongly argue against BLM being involved in this process. The genetic approach to identifying the genes involved in immunoglobulin mutation will require further studies of DNA repair- and immunodeficient individuals.

To the Editor .— Newborn screening (NBS) for cystic fibrosis (CF) in the United States has been implemented by some states for up to a decade. However, complex technical and ethical issues still surround NBS for CF, including considerations regarding clinical benefits of early diagnosis, availability of follow-up, therapies to treat CF, and optimum screening protocols.1–3 Amid ongoing discussion, we conducted a survey of state programs to understand how they perform CF screening. The National Newborn Screening & …

Abstract 4276 Introduction: Hematopoietic stem cell transplantation (HSCT) from an HLA matched donor is the only curative therapy for sickle cell disease (SCD), with sibling donor survival rates approaching 95%. Referral from the primary hematologist for transplant evaluation is a key step in the process. Study aims were to assess pediatric SCD providers for: 1) Current perspectives and referral patterns; 2) Whether perspectives differ for those practicing at a transplant center. Methods: All pediatric hematology providers at the designated newborn screening hemoglobinopathy centers within the seven state New York-Mid-Atlantic Consortium (NYMAC) were anonymously surveyed. Descriptive statistics and chi squared test or Fisher's exact test were used for analysis. Results: Of 197 pediatric SCD providers contacted through the NYMAC listserv, 104 (53%) responded, predominantly hematologists. Half (53%) of responders practice at sites performing HSCT for pediatric SCD. Overall, transplant centers had larger SCD patient populations (p Provider referral pattern: Most providers (89%) had referred at least one child with SCD for transplant evaluation within the past two years. A higher proportion of practitioners at a transplant center had referred at least 3 patients for transplant evaluation, 84% vs. 53% (p=0.001). Patient demographics for transplant eligibility: Overall, 77% would limit HSCT to children with HbSS or HbS-β° thalassemia. Nearly half (44%) were less likely to refer a child for evaluation with SCD than with β-thalassemia major (no significant difference (NS) by practice setting). Those practicing at transplant centers were more certain of 6–16 years as an optimal transplant age (100% vs. 84%; p=0.004). Indications: Single disease indications for transplant referral were stroke, acute chest syndrome or family request. Less commonly cited were abnormal TCD (31%) or clinically silent stroke (34%). Commonly listed treatment indications were a new stroke despite chronic transfusion (82%) or poor response to hydroxyurea (71%), not iron overload (22%) (NS by practice setting). Donor: Most would offer HSCT to a child with multiple SCD complications with (95%) or without (66%) a sibling match; 37% would refer a child with limited disease despite a sibling donor (NS by practice setting). Acceptable outcomes: The majority (78%) agreed that HSCT can improve health. Risk of mortality, lack of sibling match, and infertility were most commonly cited as barriers to referral. Most identified acceptable overall survival rates as 90–100% (divided between ≥90% or 95–100%). Providers at transplant centers were more likely to accept event-free survival rates of 75–90% (87% vs. 63%; p=0.002), rather than 95–100%. Limitations: While only one U.S. region was surveyed, NYMAC collectively diagnoses approximately 25% of all newborns with SCD (genes-r-us.uthscsa.edu). Actual referral patterns could not be verified. No adjustments were made for size of each practice site, nor were providers queried about perceived influence of payer mix or other patient demographics. Conclusions: Most pediatric SCD providers accept HSCT as a treatment option, especially for children with severe disease complications or inadequate response to other therapies. Practitioners at transplant centers reported making more referrals for evaluation, having a stronger preferred age and accepting a broader range of event-free survival. Overall, only one third of providers deem eligible those patients with a sub-clinical stroke or stroke risk, or those with a sibling donor if without major disease complications. Most providers prefer transplant for children with a limited sickle hemoglobinopathy type, and almost half favor transplantation for β-thalassemia major. These findings suggest varying enthusiasm for HSCT for pediatric SCD beyond donor availability or current survival outcomes. The SCD provider is a critical conduit for ushering families towards transplantation and weighing difficult risk-benefit ratios. Informed decisions and referral may benefit from provider education, especially for those not practicing at transplant centers, as well as professional guidelines about current indications and research comparing outcomes of SCD versus HSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 4841 Background: Pulmonary hypertension (PHT) is a significant complication of sickle cell disease. Studies in children report a 16–30% prevalence of elevated pulmonary artery pressures, as estimated by measurement of tricuspid regurgitant jet velocity (TRV) on echocardiography. The pathogenesis of elevated pulmonary artery pressures is multifactorial, with hemolysis induced endothelial dysfunction playing a major role. More recent studies highlight the role of inflammation in the pathogenesis. Hydroxyurea is a well established treatment for sickle cell disease. It acts primarily by induction of fetal hemoglobin, thereby reducing hemolysis, with possible additional effects on vascular and endothelial function. The aim of this study was to determine if early detection and treatment with hydroxyurea will decrease elevated pulmonary artery pressures in children with sickle cell disease. Methods: The study was conducted at 3 centers. Children with Hb SS and Hb Sb0 thalassemia between the ages of 5–21 years, with a screening echocardiogram showing a TRV ≥ 2.5 m/sec were identified. An echocardiogram was repeated to confirm elevated TRV. Subjects with persistent elevation of TRV ≥ 2.5 m/sec on repeat echocardiogram, were consented and started on hydroxyurea at 20 mg/kg/d with escalation to a maximum tolerated dose or a total daily dose of 30 mg/kg/d. Laboratory data and echocardiograms were repeated at 6 and 12 months to measure effect of hydroxyurea on TRV. Additionally blood and urine samples were also collected pre treatment, at 6 and 12 months post treatment for biomarker analysis, which will be performed later. Baseline and 6 month laboratory and echocardiogram data were compared using paired t test. Results: Twelve patients were enrolled. Mean age was 12.25 years (range 6–19 years) with a M:F ratio of 2:1. Average follow up is 11 months. Patients tolerated hydroxyurea well, and in 90% of patients the dose was escalated to 30 mg/kg/d. 1 patient achieved MTD at 20 mg/kg/d. Two patients went off study at 4 and 5 months respectively. As shown in Table 1, six months after starting hydroxyurea there was a significant increase in mean oxygen saturation, hemoglobin, mean corpuscular volume and fetal hemoglobin. There was a significant decrease in mean reticulocyte count, LDH and white blood cell count. There was no significant change in TRV six months after treatment with hydroxyurea. Conclusion: Hydroxyurea significantly decreased measures of hemolysis in children with sickle cell disease. Six months after treatment with hydroxyurea, there was no significant change in estimated pulmonary artery pressures measured on echocardiography. The study is ongoing to see if hydroxyurea affects pulmonary artery pressures with a longer duration of treatment. Disclosures: No relevant conflicts of interest to declare.

To the Editor: In their article on a hemoglobin variant associated with neonatal cyanosis and anemia, Crowley et al. (May 12 issue)1 describe their use of testing of arterial blood gases, a review of family medical history, and other tailored testing for well-appearing newborns with cyanosis. Universal screening in the nursery for cyanotic congenital heart disease with the use of pulse oximetry was recently recommended by a federal advisory committee.2 Although the condition described by Crowley et al. is rare, routine neonatal screening for low oxygen saturation will inevitably uncover more patients with hemoglobinopathies with low oxygen affinity.3 We describe . . .

Patients with homozygous beta-thalassemia are at increased risk of serious infections. Yersinia enterocolitica is an organism with a predilection for these and other iron-overloaded patients. Three young adult patients with beta-thalassemia who were chronically transfused and developed yersiniosis are reported. Iron overload and desferrioxamine use are predisposing factors, as supported by clinical, animal, and in vitro data. Iron excess both immunologically compromises the host and greatly enhances yersinial growth. Desferrioxamine may make host iron even more bioavailable to Yersinia. Recognition of this association and unusual manifestations in these patients such as an appendicitis-like syndrome may direct clinicians to earlier antiyersinial therapy and temporary cessation of chelation.

Objective To assess the risks of moderate prematurity for cerebral palsy (CP), developmental delay/mental retardation (DD/MR), and seizure disorders in early childhood. Study design Retrospective cohort study using hospitalization and outpatient databases from the Northern California Kaiser Permanente Medical Care Program. Data covered 141 321 children ≥30 weeks born between Jan 1, 2000, and June 30, 2004, with follow-up through Jun 30, 2005. Presence of CP, DD/MR, and seizures was based on International Classification of Diseases , Ninth Revision codes identified in the encounter data. Separate Cox proportional hazard models were used for each of the outcomes, with crude and adjusted hazard ratios calculated for each gestational age group. Results Decreasing gestational age was associated with increased incidence of CP and DD/MR, even for those born at 34 to 36 weeks gestation. Children born late preterm were >3 times as likely (hazard ratio, 3.39; 95% CI, 2.54-4.52) as children born at term to be diagnosed with CP. A modest association with DD/MR was found for children born at 34 to 36 weeks (hazard ratio, 1.25; 95% CI, 1.01-1.54), but not for children in whom seizures were diagnosed. Conclusions Prematurity is associated with long-term neurodevelopmental consequences, with risks increasing as gestation decreases, even in infants born at 34 to 36 weeks.

Whether to use a medication during pregnancy can be a concern for both women and health care providers. It has been estimated that up to 10% of congenital anomalies may be caused by environmental exposures–that is, exposures to medications, alcohol, or other exogenous factors that have adverse effects on the developing embryo or fetus [1]. Avoiding all potentially adverse exposures can prevent these adverse effects. However, it is not always possible to avoid taking medications during pregnancy. Women who are pregnant continue to experience short-term and long-term health conditions that must be managed. Discontinuing treatment of a serious condition when a woman becomes pregnant can have profound, long-term implications both for her health and that of her baby. In a retrospective study from eight health maintenance organizations, researchers estimated that approximately 59% of pregnant women were prescribed a medication other than a vitamin or mineral supplement at some time during pregnancy [2]. Use of over-the-counter medications during pregnancy may be even higher, and many women take a dietary or herbal supplement other than multivitamins or folic acid while pregnant [3, 4]. Preconception care provides the opportunity to optimize a woman’s use of medications in preparation for pregnancy. Such care includes identifying patterns of medication use before pregnancy occurs; adjusting those patterns to avoid the use of nonessential medications; minimizing exposure to medications known to be harmful to the embryo or fetus; and adjusting the dose, route of administration, and timing of essential treatments to optimize maternal health at each stage of pregnancy while safeguarding the embryo, fetus, and infant. In this paper, we summarize the basic principles of teratology and the current state of knowledge about the effects of medication use during pregnancy; outline basic components of preconception care that can help minimize the risk of birth defects; and provide examples of approaches to planning for the safe and effective use of medications during pregnancy through preconception care.

A 4-year-old boy with transient erythroblastopenia of childhood (TEC) presented with papilledema and transient hemiparesis. Upon spontaneous hematologic recovery, the papilledema resolved. It is concluded that TEC, like other forms of anemia, may present with papilledema and even focal neurologic deficit, from which spontaneous recovery may be anticipated.