Katherine J. Lee

Intussusception following rotavirus vaccine administration: Post-marketing surveillance in the National Immunization Program in Australia

INTRODUCTION In Australia, post-marketing surveillance for intussusception following vaccination commenced with funding of RotaTeq(®) and Rotarix(®) vaccines under the National Immunization Program (NIP) in July 2007. METHODS Two active surveillance mechanisms (hospital-based case ascertainment and monthly reports from paediatricians) identified intussusception cases between 1st July 2007 and 31st December 2008 in four states. Linkage to vaccination records identified cases occurring within 1-7 and 1-21 days of rotavirus vaccination. Expected cases within the post-vaccination windows were calculated by applying rates of intussusception from national hospitalisation data over 6 years (mid-2000 to mid-2006), by age and state, to numbers vaccinated (by dose) according to the Australian Childhood Immunization Register. RESULTS Combining exposure windows associated with all doses of rotavirus vaccine from 1 to 9 months of age, there was no evidence of an increased risk of intussusception following vaccination for either vaccine. However, in infants 1 to <3 months of age, there was suggestive evidence of excess intussusception cases 1-7 and 1-21 days following dose 1 (1-7 days: RotaTeq(®) relative risk (RR)=5.3, 95% confidence interval [CI] 1.1,15.4; Rotarix(®) RR 3.5, 95% CI 0.7,10.1; 1-21 days: RotaTeq(®) RR 3.5, 95% CI 1.3, 7.6; Rotarix(®)RR 1.5, 95% CI 0.4, 3.9). There was no evidence that clinical outcome of intussusception occurring within 21 days of rotavirus vaccination differed from that in cases occurring later post-vaccination. CONCLUSION Although we found no overall increase in intussusception following receipt of rotavirus vaccine, there was some evidence of an elevated risk following the first dose of both vaccines. Larger population-based studies using linked databases are required to provide more definitive evidence.

Arterial ischemic stroke risk factors: The international pediatric stroke study

To describe presumptive risk factors (RFs) for childhood arterial ischemic stroke (AIS) and explore their relationship with presentation, age, geography, and infarct characteristics.

Early Sensitivity Training for Parents of Preterm Infants: Impact on the Developing Brain

After birth, preterm infants face a stressful environment, which may negatively impact early brain development and subsequent neurobehavioral outcomes. This randomized controlled trial involving 45 women with infants <30-wk gestation, assessed the effectiveness of training parents in reducing stressful experiences. Intervention consisted of 10 sessions in the Neonatal Intensive Care Unit (NICU). Postintervention, at term-equivalent (40-wk postmenstrual age), magnetic resonance imaging (MRI) was performed to evaluate brain structure and development. Quantitative volumetric techniques were used to estimate overall and regional brain volumes for different tissue types including CSF, CGM, DNGM, UWM, and MWM. DTI was used to evaluate the integrity and maturation of white matter by ADC and FA. Maturation and connectivity of white matter, characterized by diffusion MR measures of ADC and FA, were significantly enhanced in the intervention group, who displayed greater restriction in ADC and increase in FA. There were no significant effects on either brain volumes or on short-term medical outcomes. Thus, sensitivity training for parents in the NICU is associated with improved cerebral white matter micro-structural development in preterm infants.

Prevalence of motor-skill impairment in preterm children who do not develop cerebral palsy: A systematic review

Aim  Motor skill impairment is a common negative outcome in children born preterm who do not develop cerebral palsy (CP). This study aimed to conduct a systematic review of current data to provide an accurate estimate of the prevalence of non‐CP motor impairment in preterm children at school age.

Intussusception Risk and Disease Prevention Associated With Rotavirus Vaccines in Australia's National Immunization Program

BACKGROUND Estimates of the risk of intussusception (IS) associated with currently licensed rotavirus vaccines (RV1 [Rotarix; GSK] and RV5 [RotaTeq; Merck]) diverge. Contemporaneous introduction of both vaccines in Australia enabled a population-based assessment of risk. METHODS Confirmed cases of IS in infants aged 1 to <12 months were identified from national hospitalization databases, supplemented by active hospital-based surveillance, from July 2007 through June 2010. Vaccination histories were verified by the Australian Childhood Immunisation Register, which was also used to identify age-matched controls. Self-controlled case series and case-control methods were used to assess the risk of IS associated with both vaccines in prespecified periods after vaccination. The estimated burden of vaccine-attributable IS was compared with estimated reductions in gastroenteritis hospitalizations. RESULTS Based on 306 confirmed cases of IS, the relative incidence of IS in the 1-7-day period after the first vaccine dose, was 6.8 (95% confidence interval, 2.4-19.0; P < .001) for RV1, and 9.9 (95% confidence interval, 3.7-26.4; P < .001) for RV5. There was a smaller increased risk 1-7 days after the second dose of each vaccine. The case-control analysis gave similar results. We estimate an excess of 14 IS cases and >6500 fewer gastroenteritis hospitalizations in young children annually in Australia after vaccine introduction. CONCLUSIONS We found a similarly increased risk of IS after both vaccines, but the balance of benefits and risks at population level was highly favorable, a finding likely to extend to other settings despite varying incidence of IS and potentially higher morbidity and mortality from both gastroenteritis and IS.

Psychiatric outcomes at age seven for very preterm children: rates and predictors

BACKGROUND   Uncertainty remains about the rate of specific psychiatric disorders and associated predictive factors for very preterm (VPT) children. The aims of this study were to document rates of psychiatric disorders in VPT children aged 7 years compared with term born children, and to examine potential predictive factors for psychiatric diagnoses in VPT children. METHODS   Participants were 177 VPT and 65 term born children. Perinatal medical data were collected, which included brain abnormalities detected using magnetic resonance imaging. The Infant-Toddler Social-Emotional Assessment (ITSEA) and Strengths and Difficulties Questionnaire (SDQ) were administered at 2 and 5 years respectively. At 7 years of age, the Developmental and Well-being Assessment (DAWBA) was used to indicate psychiatric diagnoses. RESULTS   Compared with term born children, VPT children had three times the odds of meeting criteria for any psychiatric diagnosis at age 7 years (odds ratio 3.03; 95% confidence interval 1.23, 7.47, p = .02). The most common diagnoses were anxiety disorders (11% VPT, 8% term), attention-deficit/hyperactivity disorder (10% VPT, 3% term) and autism spectrum disorder (4.5% VPT, 0% term). For VPT children, those with severe global brain abnormalities (p = .02), those who displayed social-emotional problems at age 5 (p = .000) and those with higher social risk at age 7 (p = .001) were more likely to meet criteria for a psychiatric illness at age 7. CONCLUSIONS Compared with term born children, VPT children have higher rates of psychiatric diagnoses at early school age, predicted by neonatal brain abnormalities, prior social-emotional problems and social factors.

Clustering by health professional in individually randomised trials.

Patient outcomes in many randomised trials depend crucially on the health professional delivering the intervention, but the resulting clustering is rarely considered in the analysis Almost all trials that randomise individuals assume that the observed outcomes of participants are independent. The validity of this assumption is doubtful, however, in some situations. One example is when more than one health professional (such as surgeons, nurses, general practitioners, or therapists) delivers a non-pharmaceutical intervention to participants. Because health professionals may vary in their effectiveness, observations on participants treated by the same professional may be somewhat similar or clustered. Clustering of outcomes may also appear less obviously (such as in clustering by centre in a multicentre trial) or in a more dominant form (as in cluster randomised trials). In each of these situations the assumption of independence is violated, which means that standard statistical methods are invalid and may give misleading conclusions. The presence of clustering in a trial inflates standard errors and reduces the effective sample size, thus reducing the power of the trial. We examine the prevalence and importance of potential clustering in individually randomised trials and present an example of the effect it can have on the overall results and conclusions of a trial. In a trial comparing a new one stop clinic with a dedicated breast clinic for breast cancer screening,1 patients were randomised to a clinic, where they attended an appointment with one of several consultants. The main outcome was patient anxiety, which is likely to be influenced by the consultant treating the patient, yielding potential clustering by consultant. In this trial the clustering is imposed by the design of the trial because of the interventions being compared and is nested within treatment groups since each consultant participates in one treatment arm only (fig 1). Fig 1 Structure …

Neonatal white matter abnormality predicts childhood motor impairment in very preterm children

Aim  Children born very preterm are at risk for impaired motor performance ranging from cerebral palsy (CP) to milder abnormalities, such as developmental coordination disorder. White matter abnormalities (WMA) at term have been associated with CP in very preterm children; however, little is known about the impact of WMA on the range of motor impairments. The aim of this study was to assess whether WMA were predictive of all levels of motor impairments in very preterm children.

Prognostic Utility of Magnetic Resonance Imaging in Neonatal Hypoxic-Ischemic Encephalopathy: Substudy of a Randomized Trial

OBJECTIVE To investigate the effects of hypothermia treatment on magnetic resonance imaging (MRI) patterns of brain injury in newborns with hypoxic-ischemic encephalopathy compared with normothermia, including the prognostic utility of MRI for death and/or disability at a postnatal age of 2 years. DESIGN Substudy of a randomized controlled trial. SETTING Participating centers in the Infant Cooling Evaluation trial. PARTICIPANTS Trial participants (gestational age ≥35 weeks with moderate to severe hypoxic-ischemic encephalopathy, randomized to whole-body hypothermia or normothermia) with available MRIs. MAIN EXPOSURE We performed qualitative evaluation of T1- and T2-weighted and diffusion MRIs. The posterior limb of the internal capsule was classified as normal or abnormal, whereas the basal ganglia and thalami, white matter, and cortical gray matter were classified as normal or mildly abnormal or moderately/severely abnormal. MAIN OUTCOME MEASURES Death or major disability at 2 years. RESULTS We evaluated 127 MRIs (66 patients treated with hypothermia and 61 with normothermia; mean age at scan, 6 postnatal days). The odds of having moderate/severe white matter or cortical gray matter abnormalities on T1- and T2-weighted MRI were reduced by hypothermia (white matter odds ratio, 0.28 [95% CI, 0.09-0.82]; gray matter odds ratio, 0.41 [0.17-1.00]). Abnormal MRI findings predicted adverse outcomes, with T1- and T2-weighted and diffusion MRI abnormalities in the posterior limb of the internal capsule and basal ganglia and thalami demonstrating the greatest predictive value. There was little evidence that prognostic value of the MRI was modified by therapeutic hypothermia (all interactions, P > .05). CONCLUSIONS Brain injury on T1- and T2-weighted MRI is reduced in hypothermia-treated newborns. Abnormal MRI findings are prognostic of long-term outcome in moderate to severe hypoxic-ischemic encephalopathy regardless of treatment with hypothermia.

Differences in factors associated with initial growth CD4 and viral load responses to ART in HIV-infected children in Kampala Uganda and the United Kingdom/Ireland.

Background:Few studies have directly compared response to antiretroviral therapy (ART) between children living in well-resourced and resource-limited settings. In resource-limited settings non-HIV contributors could reduce the beneficial effects of ART. We compare predictors of short-term immunological, virological, and growth response to ART in HIV-infected children in the United Kingdom/Ireland and Kampala. Methods:We analyzed prospective cohort data from 54 UK/Irish hospitals (the Collaborative HIV Paediatric Study) and Mulago Hospital, Kampala, Uganda. Six- and 12-month responses are described among children initiating combination ART (≥3 drugs, ≥2 classes). Six months post-ART, predictors of viral load (VL) suppression <400 copies/mL, CD4% increases >10%, and height- and weight-for-age z-score increases ≥+0.5 were investigated using logistic regression. Results:In all, 582 UK/Irish children (76% black African) were younger than 876 Kampala children at ART initiation (median 5.0 vs 7.6 years), with higher CD4% (14%, 8%), lower VL (172,491 and 346,809 copies/mL), and less stunting (−0.8, −2.8) and wasting (−0.6, −2.8). Post-ART, median 12-month changes in the United Kingdom/Ireland and Kampala in CD4% (+12%, +13%) and weight (+0.4, +0.5) were similar, but growth was less in Kampala (+0.20, +0.06, P < 0.001). Younger children in both cohorts had better immunological, weight, and growth responses (all P < 0.001). However, lower pre-ART CD4% predicted better immunological response in the United Kingdom/Ireland but poorer response in Kampala (heterogeneity P = 0.004). Although 70% children in both cohorts had suppressed <400 copies/mL at 6 months, adolescents starting ART in the United Kingdom/Ireland had somewhat poorer VL responses than those in Kampala (P = 0.15). Conclusions:Overall immunological and virologic ART responses were similar in children in both cohorts. Poorer CD4 recovery in more immunosuppressed Kampala children and blunted growth responses likely reflect higher background malnutrition and infection rates in Uganda, suggesting the need for earlier HIV diagnosis, nutritional support, cotrimoxazole prophylaxis, and ART.