•Both low and moderate doses of hydroxyurea are efficacious for secondary stroke prevention in low-resource settings.•The median time between the initial stroke and death was less than a year, 0.8 ...years (interquartile range, 0.2-0.9).
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We tested the hypothesis that fixed oral moderate-dose hydroxyurea (20 mg/kg per day) for initial treatment of secondary stroke prevention results in an 80% relative risk reduction of stroke or death when compared with fixed oral low-dose hydroxyurea (10 mg/kg per day) in a phase 3 double-blind, parallel-group, randomized controlled trial in children with sickle cell anemia (SCA) living in Nigeria. A total of 101 participants were randomly allocated to low-dose (n = 49) and moderate-dose (n = 52) hydroxyurea treatment groups. The median participant follow-up was 1.6 years (interquartile range, 1.0-2.3), with a planned minimum follow-up of 3.0 years. A total of 6 recurrent strokes and 2 deaths vs 5 recurrent strokes and 3 deaths occurred in the low- and moderate-dose groups, respectively. The incidence rate ratio (IRR) of the primary outcome measure of stroke or death in the low- and moderate-dose hydroxyurea treatment groups was 0.98 (95% confidence interval CI, 0.32-3.00; P = .97). The trial was stopped early owing to no clinical difference in the incidence rates of the primary outcome measure. The incidence rates of recurrent strokes were 7.1 and 6.0 per 100 person-years in the low- and moderate-dose groups, respectively, (IRR, 1.18; 95% CI, 0.30-4.88; P = .74). As a measure of adherence to the oral hydroxyurea therapy, the median percent of returned pills was 3.0% and 2.6% in the low- and moderate-dose groups, respectively. No participant had hydroxyurea therapy stopped for myelosuppression. For children with SCA in low-income settings without access to regular blood transfusion therapy, initial low-dose hydroxyurea is a minimum known efficacious dose for secondary stroke prevention.
The risk of recurrent stroke in untreated sickle cell anemia (SCA) is high, necessitating chronic transfusion therapy where resources allow. To identify feasible alternative therapy for children with SCA in resource-limited areas, Abdullahi and colleagues undertook a randomized, double-blind trial of 2 fixed-dose regimens of hydroxyurea. In this Plenary Paper, the authors provide evidence that both low- and moderate-dose hydroxyurea regimens are effective for secondary stroke prevention when chronic transfusion therapy is not possible.
An association between assisted reproductive technique (ART) and specific imprinting mutations, such as Beckwith-Wiedemann syndrome (BWS), has recently been documented. Based on experiments in farm ...animals that demonstrated an association between alterations in culture media during ART and large offspring syndrome, we hypothesized that the culture media could be implicated as a common factor among the children with BWS conceived after ART.
Retrospective case series.
Registry from Academic Medical Center.
Nineteen children born after ART were identified within the registry.
Demographics of patients, type of ART, culture media, IVF parameters.
Twelve of the 19 medical records from the reproductive endocrine centers were successfully obtained. Ten of 12 mothers of children with BWS had IVF, but no single, consistent culture media was used in this group. Half of the patients underwent IVF with intracytoplasmic sperm injection (ICSI; n = 5), whereas the other half had routine IVF. One child was conceived through clomiphene citrate (CC) stimulation and artificial insemination, whereas another patient conceived through gonadotropin stimulation with intrauterine insemination (IUI). The gonadotropin dosage and quantity of embryos transferred also varied significantly. The only consistent finding was that all 12 women received some type of ovarian stimulation medication.
Large epidemiologic studies are needed to further study the association between BWS and ART.
Conflicting evidence has suggested that low mean nocturnal hemoglobin oxygen saturation (SpO2) predicts future hospital days for acute severe pain in children with sickle cell anemia (SCA). In an ...unselected multicenter prospective cohort study, we tested the hypothesis that either low mean nocturnal SpO2 or high obstructive apnea‐hypopnea index (OAHI; the number of obstructive apneas and hypopneas with ≥ 3% desaturation or arousal per hour of sleep) or high oxygen desaturation index (ODI; number of ≥ 3% desaturation from baseline saturation per hour of sleep) is associated with increased incidence rates of pain. A total of 140 children with SCA with a median age of 10.8 years (interquartile range 7.2) were followed for a median of 4.9 years (interquartile range 1.8). Overnight polysomnography evaluations at baseline health exam were measured and adjudicated centrally. Multivariable models created in two steps were included. First, all plausible covariates were included in a screening model. Subsequently, covariates meeting level of statistical significance of P < .20 were included in the final model. Contrary to our hypothesis, higher (but not lower) mean nocturnal SpO2 was associated with higher rates of pain episodes (Incidence rate ratio (IRR) 1.10, 95% CI 1.03‐1.18, P = .004). Higher log OAHI did not pass screening criteria. Higher log ODI was not significantly associated with higher rates of pain episodes (IRR 0.93, 95% CI 0.82‐1.06, P = .28). Neither low nocturnal SpO2, higher OAHI, nor higher ODI were associated with clinically relevant increased incidence rates of acute severe pain episodes.
Previously we demonstrated that 90% of infarcts in children with sickle cell anemia occur in the border zone regions of cerebral blood flow (CBF). We tested the hypothesis that adults with sickle ...cell disease (SCD) have silent cerebral infarcts (SCIs) in the border zone regions, with a secondary hypothesis that older age and traditional stroke risk factors would be associated with infarct occurrence in regions outside the border zones.
Adults with SCD 18-50 years of age were enrolled in a cross-sectional study at 2 centers and completed a 3T brain MRI. Participants with a history of overt stroke were excluded. Infarct masks were manually delineated on T2-fluid-attenuated inversion-recovery MRI and registered to the Montreal Neurological Institute 152 brain atlas to generate an infarct heatmap. Border zone regions between anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA) were quantified using the Digital 3D Brain MRI Arterial Territories Atlas, and logistic regression was applied to identify relationships between infarct distribution, demographics, and stroke risk factors.
Of 113 participants with SCD (median age 26.1 years, interquartile range IQR 21.6-31.4 years, 51% male), 56 (49.6%) had SCIs. Participants had a median of 5.5 infarcts (IQR 3.2-13.8). Analysis of infarct distribution showed that 350 of 644 infarcts (54.3%) were in 4 border zones of CBF and 294 (45.6%) were in non-border zone territories. More than 90% of infarcts were in 3 regions: the non-border zone ACA and MCA territories and the ACA-MCA border zone. Logistic regression showed that older participants have an increased chance of infarcts in the MCA territory (odds ratio OR 1.08; 95% CI 1.03-1.13;
= 0.001) and a decreased chance of infarcts in the ACA-MCA border zone (OR 0.94; 95% CI 0.90-0.97;
< 0.001). The presence of at least 1 stroke risk factor did not predict SCI location in any model.
When compared with children with SCD, in adults with SCD, older age is associated with expanded zones of tissue infarction that stretch beyond the traditional border zones of CBF, with more than 45% of infarcts in non-border zone regions.
Pregnancy in women with sickle cell disease (SCD) is a life-threatening condition. In both high- and low-income countries, there is an 11-fold increased risk of maternal death and a 4-fold increased ...risk of perinatal death. We highlight the epidemiology of SCD-specific and obstetric complications commonly seen during pregnancy in SCD and propose definitions for acute pain and acute chest syndrome (ACS) episodes during pregnancy. We conducted a systematic review of the recent obstetric and hematology literature using full research articles published within the last 5 years that reported outcomes in pregnant women with SCD. The prevalence of acute pain episodes during pregnancy ranged between 4% and 75%. The prevalence of ACS episodes during pregnancy ranged between 4% and 13%. The estimated prevalence of pulmonary thromboembolism in women with SCD during pregnancy is approximately 0.5 to 1%. ACS is the most common cause of death and is often preceded by acute pain episodes. The most crucial time to develop these complications in pregnancy is during the third trimester and postpartum period. In a pooled analysis from studies in low- and middle-income settings, maternal death in women with SCD is approximately 2393 and 4300 deaths per 100 000 live births with and without multidisciplinary care, respectively. In comparison, in the US and northern Europe, the general maternal mortality rate is approximately 23.8 and 8 deaths per 100 000 live births, respectively. A multidisciplinary SCD obstetrics care approach reduces maternal and perinatal morbidity and mortality in low- and middle-income countries.
The objective of this study was to investigate the association between cognitive functioning, coping, and depressive symptoms in children and adolescents with sickle cell disease (SCD).
Forty-four ...children (M age = 9.30, SD = 3.08; 56.8% male) with SCD completed cognitive assessments measuring working memory (Wechsler Intelligence Scale for Children-Fourth Edition) and verbal comprehension (Wechsler Abbreviated Scale of Intelligence-Second Edition). Participants' primary caregivers completed questionnaires assessing their child's coping and depressive symptoms.
Verbal comprehension was significantly positively associated with secondary control coping (cognitive reappraisal, acceptance, distraction), and both working memory and secondary control coping were negatively associated with depressive symptoms. In partial support of the primary study hypothesis, verbal comprehension had an indirect association with depressive symptoms through secondary control coping, whereas working memory had a direct association with depressive symptoms.
The results provide new evidence for the associations between cognitive function and coping, and the association of both of these processes with depressive symptoms in children with SCD. Findings provide potential implications for clinical practice, including interventions to improve children's cognitive functioning to attenuate depressive symptoms.
Abstract Background Readmission to the hospital within 30 days is a measure of quality care; however, only few modifiable risk factors for 30-day readmission in adults with sickle cell disease are ...known. Methods We performed a retrospective review of the medical records of adults with sickle cell disease at a tertiary care center, to identify potentially modifiable risk factors for 30-day readmission due to vasoocclusive pain episodes. A total of 88 patients ≥18 years of age were followed for 3.5 years between 2010 and 2013, for 158 first admissions for vasoocclusive pain episodes. Of these, those subsequently readmitted (cases) or not readmitted (controls) within 30 days of their index admissions were identified. Seven risk factors were included in a multivariable model to predict readmission: age, sex, hemoglobin phenotype, median oxygen saturation level, listing of primary care provider, type of health insurance, and number of hospitalized vasoocclusive pain episodes in the prior year. Results Mean age at admission was 31.7 (18-59) years; median time to readmission was 11 days (interquartile range 20 days). Absence of a primary care provider listed in the electronic medical record (odds ratio 0.38; 95% confidence interval, 0.16-0.91; P = .030) and the number of vasoocclusive pain episodes requiring hospitalization in the prior year were significant risk factors for 30-day readmission (odds ratio 1.30; 95% confidence interval, 1.16-1.44; P <.001). Conclusion Improved discharge planning and ensuring access to a primary care provider may decrease the 30-day readmission rate in adults with sickle cell disease.
Individuals with sickle cell anemia experience cognitive deficits, even in the absence of cerebral infarcts or strokes. This study tested the hypothesis that elevated cerebral blood flow and oxygen ...extraction fraction are associated with lower executive function in individuals with sickle cell anemia.
Three-Tesla brain magnetic resonance imaging was performed, including anatomic, gray matter cerebral blood flow, and global oxygen extraction fraction imaging. Executive function was measured using the working memory index from an age-appropriate Wechsler battery and tasks from the National Institutes of Health Toolbox Cognition Battery. Bivariate and multivariate models were examined (significance:
<0.05).
Fifty-four participants (age range=6-31 years) with sickle cell anemia were enrolled. Hematocrit was positively related to fluid cognition, cerebral blood flow was inversely related to working memory and inhibitory control, and oxygen extraction fraction was inversely related to processing speed. Associations remained significant in multivariate analyses controlling for age, income, and infarcts.
Elevated cerebral blood flow and oxygen extraction fraction, markers of hemodynamic impairment, are associated with deficits in executive function in individuals with sickle cell anemia.
To ascertain the prevalence of and risk factors for obstructive sleep apnea syndrome (OSAS) in children with sickle cell anemia (SCA).
Cross-sectional baseline data were analyzed from the Sleep and ...Asthma Cohort Study, a multicenter prospective study designed to evaluate the contribution of sleep and breathing abnormalities to SCA-related morbidity in children ages 4 to 18 years, unselected for OSAS symptoms or asthma. Multivariable logistic regression assessed the relationships between OSAS status on the basis of overnight in-laboratory polysomnography and putative risk factors obtained from questionnaires and direct measurements.
Participants included 243 children with a median age of 10 years; 50% were boys, 99% were of African heritage, and 95% were homozygous for β(S) hemoglobin. OSAS, defined by obstructive apnea hypopnea indices, was present in 100 (41%) or 25 (10%) children at cutpoints of ≥1 or ≥5, respectively. In univariate analyses, OSAS was associated with higher levels of habitual snoring, lower waking pulse oxygen saturation (Spo2), reduced lung function, less caretaker education, and non-preterm birth. Lower sleep-related Spo2 metrics were also associated with higher obstructive apnea hypopnea indices. In multivariable analyses, habitual snoring and lower waking Spo2 remained risk factors for OSAS in children with SCA.
The prevalence of OSAS in children with SCA is higher than in the general pediatric population. Habitual snoring and lower waking Spo2 values, data easily obtained in routine care, were the strongest OSAS risk factors. Because OSAS is a treatable condition with adverse health outcomes, greater efforts are needed to screen, diagnose, and treat OSAS in this high-risk, vulnerable population.
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