Non Breast-Milk-Fed Very Preterm Infants Are at Increased Risk of Iron Deficiency at 4-6-Months Corrected Age: A Retrospective Population-Based Cohort Study.

Iron supplementation is routinely recommended for breast-milk-fed preterm infants. However, the Canadian Pediatric Society recommends no additional iron supplementation for preterm infants fed primarily with iron-rich formula. Other pediatric societies don't provide specific guidance on supplemental iron for formula-fed preterm infants. This study investigated how feeding type influences iron status of very preterm infants at 4-6-months corrected age (CA). A retrospective cohort study was conducted using a population-based database on all very preterm infants (<31 weeks gestational age) born in Nova Scotia, Canada from 2005-2018. Information about feeding type, iron intake from formula, supplemental iron therapy and iron status at 4-6-months CA was extracted. Iron deficiency (ID) was defined as serum ferritin <20 and <12 µg/L at 4-and 6-months CA, respectively. Of 392 infants, 107 were "breast-milk-fed" (exclusively or partially) and 285 were "not breast-milk-fed" (exclusively fed with iron-rich formula) at 4-6-months CA. Total daily iron intake was higher in the non-breast-milk-fed group (2.6 mg/kg/day versus 2.0 mg/kg/day). Despite this, 36.8% of non-breast-milk-fed infants developed ID versus 20.6% of breast-milk-fed infants. ID is significantly more prevalent in non-breast-milk-fed infants than breast-milk-fed infants despite higher iron intake. This suggests the need to revisit recommendations for iron supplementation in non-breast-milk-fed preterm infants.

Parent-reported health outcomes at preschool age in preterm survivors: a population-based cohort study.

OBJECTIVE: Literature on health status (HS) and health-related quality of life of preterm survivors at preschool age is sparse. Further, little is known about the relationship between parent-reported HS outcomes and standardised neurodevelopmental outcomes measured in preterm survivors at preschool age. Our objective was to evaluate parent-reported child HS outcomes and their relationship to neurodevelopmental outcomes at 36 months of age in very preterm survivors. DESIGN: Prospective population-based cohort study. SETTING: Perinatal follow-up programme. PATIENTS: Infants <31 weeks' gestational age born from 2014 to 2016. OUTCOME MEASURES: Parents completed the Health Status Classification System for Pre-School Children questionnaire at 36 months. At the same age, neurodevelopmental assessments were completed to determine neurodevelopmental impairment (NDI). NDI was categorised as none, 'mild' or 'significant' (moderate or severe cerebral palsy, Bayley Scales of Infant and Toddler Development - Third Edition <70, blind or required hearing aid). RESULTS: Of 118 children, 87 (73.7%) parents reported their child had an HS concern (mild: 61 (51%); moderate: 16 (13.6%); and severe: 10 (8.5%)). Mild and significant NDIs were observed in 17 (14.4%) and 14 (11.9%) children, respectively. For the 14 (12%) children with significant NDI, 7 (50.0%) parents reported severe and 4 (28.6%) reported moderate concerns. Conversely, for 26 (22%) children with parent-reported moderate to severe concerns, 11 (42.3%) met the criteria for significant NDI. There was a moderate positive correlation between parental concern and NDI status (Spearman correlation=0.46, p<0.0001). CONCLUSIONS: Parental HS concerns only moderately correlated with the NDI status. Of the 12% of children with significant NDI, only half of the parents reported severe HS concerns.

Accuracy of reticulocyte hemoglobin for diagnosing iron deficiency in former very preterm infants: a population-based cohort study.

Background: Serum ferritin (SF) is commonly used to diagnose iron deficiency (ID) but has limitations. Reticulocyte hemoglobin (Ret-He) is being increasingly used for ID diagnosis. This study aimed to assess accuracy of Ret-He for ID diagnosis in former very preterm infants (VPI) at 4-6 months corrected age (CA). Methods: A retrospective population-based cohort study was conducted on all live VPI born between 23 and 30 weeks of gestational age (GA) in Nova Scotia from 2012 to 2018. Infants underwent SF and Ret-He testing at 4-6 months CA. ID was defined using two definitions. The first defined ID as SF < 20 mcg/L at both 4- and 6-months CA, and the second as SF < 30 mcg at at both 4- and 6-months CA. The accuracy of Ret-He for identifying ID was assessed using the area under the receiver operating characteristic curve (AUC). Results: ID was present in 39.7% (62) of 156 infants in the first definition and 59.6% (93) in the second at 4-6 months CA. The AUC of Ret-He for ID diagnosis was 0.64 (p = 0.002) in the first definition and 0.59 (p = 0.04) in the second. The optimal cut-off was 29.4pg in the first and 29.7 in the second definition. The sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) at the 29.4 pg cut-off were 50.0%, 78.7%, 60.8%, and 70.5% for definition 1 and 44.1%, 74.6%, 71.9%, and 47.5% at the 29.7pg cut-off for definition 2. Conclusion: Ret-He had low diagnostic accuracy for ID diagnosis in former VPI. Caution is advised when using Ret-He alone for ID diagnosis. Further research is needed to establish optimal approaches for identifying ID in VPI.

Generic Health-Related Quality of Life Utility Measure for Preschool Children (Health Utilities Preschool): Design, Development, and Properties.

OBJECTIVES: Health Utilities Preschool (HuPS) was developed to fill the need for a generic preference-based measure (GPM) applicable in early childhood. A GPM has all the properties for higher-order summary measures, such as quality-adjusted life-years, required to inform important policy decisions regarding health and healthcare services. METHODS: Development was in accordance with published standards for a GPM, statistical procedures, and modeling. HuPS incorporates key components of 2 existing measurement systems: Health Status Classification System for Preschool Children and Health Utilities Index Mark 3 (HUI3). The study included a series of 4 measurement surveys: definitional, adaptational, quantificational, and evaluational health-related quality of life (HRQL). HuPS measurements were evaluated for reliability, validity, interpretability, and acceptability. RESULTS: Definitional measurements identified 8 Health Status Classification System for Preschool Children attributes in common with HUI3 (vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain and discomfort), making the HUI3 scoring equation commensurate with HuPS health states. Adaptational measurements informed the content of attribute-level descriptions (n = 35). Quantificational measurements determined level scoring coefficients. HRQL scoring inter-rater reliability (intraclass correlation coefficient = 0.79) was excellent. Continuity of HRQL scoring with HUI3 was reliable (intraclass correlation coefficient = 0.80, P < .001) and valid (mean absolute difference = 0.016, P = .396). CONCLUSIONS: HuPS is an acceptable, reliable, and valid GPM. HRQL scoring is continuous with HUI3. Continuity expands the applicability of GPM (HUI3) scoring to include subjects as young as 2 years of age. Widespread applications of HuPS would inform important health policy and management decisions as HUI3 does for older subjects.

Postdischarge Iron Status in Very Preterm Infants Receiving Prophylactic Iron Supplementation after Birth.

OBJECTIVE: To determine postdischarge iron status and associated factors in very preterm infants. STUDY DESIGN: A retrospective cohort study was conducted through a provincial database on all very preterm infants born in Nova Scotia between 2005 and 2018. As a standard of care, all infants received prophylactic iron supplements starting at 2-4 weeks of chronological age and were tested for iron deficiency at 4 or 6 months corrected age. Iron deficiency was defined as serum ferritin <20 g/L at 4 months or <12 g/L at 6 months. Multivariate logistic regression analysis identified factors associated with iron deficiency. RESULTS: Among 411 infants, 132 (32.1%) had iron deficiency and 11 (2.7%) had iron deficiency anemia. The prevalence of iron deficiency decreased over time, from 37.6% in 2005-2011 to 25.8% in 2012-2018. Gestational hypertension in the mother (P = .01) and gestational age <27 weeks (P = .02) were independent risk factors for iron deficiency. In addition, the odds of iron deficiency were lower in the mixed-fed group (ie, with breast milk and formula combined) compared with the exclusive formula-fed group (P = .01). CONCLUSIONS: Iron deficiency was prevalent in 32% of the very preterm infants despite early iron prophylaxis. These results demonstrate the importance of monitoring iron stores during preterm follow-up. Information about risk factors is important to mitigate iron deficiency in very preterm infants.

Parent-reported health status of preterm survivors in a Canadian cohort.

OBJECTIVES: Health status (HS)/ health-related quality of life measures, completed by self or proxy, are important outcome indicators. Most HS literature on children born preterm includes adolescents and adults with limited data at preschool age. This study aimed to describe parent-reported HS in a large national cohort of extreme preterm children at preschool age and to identify clinical and sociodemographic variables associated with HS. METHODS: Infants born before 29 weeks' gestation between 2009 and 2011 were enrolled in a prospective longitudinal national cohort study through the Canadian Neonatal Network (CNN) and the Canadian Neonatal Follow-Up Network (CNFUN). HS, at 36 months' corrected age (CA), was measured with the Health Status Classification System for Pre-School Children tool completed by parents. Information about HS predictors was extracted from the CNN and CNFUN databases. RESULTS: Of 811 children included, there were 79, 309 and 423 participants in 23-24, 25-26 and 27-28 weeks' gestational age groups, respectively. At 36 months' CA, 78% had a parent-reported health concern, mild in >50% and severe in 7%. Most affected HS attributes were speech (52.1%) and self-care (41.4%). Independent predictors of HS included substance use during pregnancy, infant male sex, Score for Neonatal Acute Physiology-II, bronchopulmonary dysplasia, severe retinopathy of prematurity, caregiver employment and single caregiver. CONCLUSION: Most parents expressed no or mild health concerns for their children at 36 months' CA. Factors associated with health concerns included initial severity of illness, complications of prematurity and social factors.

A population-based study of cystic white matter injury on ultrasound in very preterm infants born over two decades in Nova Scotia, Canada.

OBJECTIVE: To identify the temporal trends, risk factors and outcomes of cystic white matter injury (WMI) detected by ultrasound in a population-based cohort of very preterm infants (VPI) with a minimal risk of selection bias. STUDY DESIGN: All live-born VPIs between 22 and < 31 weeks gestational age born in Nova Scotia, Canada from 1993 to 2013. RESULTS: Cystic WMI was identified in 87 (7%) out of 1184 eligible infants. The gestational age and mortality adjusted prevalence of cystic WMI decreased over time (p = 0.04). In multivariable analysis, chorioamnionitis, antenatal steroids, admission hypothermia, ventilator support, inotropes, and non-Coagulase-negative Staphylococcal and fungal infections were independently associated with cystic WMI. Cerebral palsy was the most common disability in the survivors, however, half of the survivors had none or mild disability. CONCLUSIONS: This cohort study demonstrated a decreasing trend in the incidence of cystic WMI and reported population-based neurological outcomes with cystic WMI, which is important for health-care planning and parental counseling.

Health-related quality of life and its determinants in paediatric arterial ischaemic stroke survivors.

OBJECTIVE: Health-related quality of life (HRQL) instruments are patient or proxy-reported outcome measures that provide a comprehensive and subjective assessment of patient's well-being and hence vital for health outcomes evaluation. A clear and thorough understanding of HRQL and its determinants is especially important to appropriately guide health-improving interventions. In this study, HRQL of paediatric arterial ischaemic stroke survivors was assessed using guidelines recommended for interpretation and reporting of the patient-reported outcome data. Determinants of HRQL were also explored. METHODS: Children diagnosed with arterial ischaemic stroke between 2003 and 2012 were assessed at least 1 year poststroke using the parent-proxy report versions of the Pediatric Quality of Life Inventory 4.0 and Pediatric Stroke Recurrence and Recovery Questionnaire. HRQL data were compared with population norms and used as outcome in multiple linear regression analysis. RESULTS: 59 children were evaluated. Mean age at diagnosis of stroke was 2.2 years. Mean age at assessment and time elapsed since stroke was 7 years and 5 years, respectively. A total of 41% children had normal global outcome, whereas 51% had moderate to severe deficits. A lower overall HRQL was observed in both self and proxy reports. Parents reported the maximum impairment in emotional domain, whereas children indicated physical functioning to be the most affected. Neurological outcome, site of stroke and socioeconomic status were independently associated with overall HRQL. CONCLUSIONS: Lower HRQL was demonstrated in children who survived arterial ischaemic stroke. Socioeconomic status of families was an important determinant of HRQL, over and above clinical parameters.

Congenital methemoglobinaemia due to Hb F-M-Fort Ripley in a preterm newborn.

Methemoglobinaemia is a rare cause of cyanosis in newborns. Congenital methemoglobinaemias due to M haemoglobin or deficiency of cytochrome b5 reductase are even rarer. We present a case of congenital methemoglobinaemia presenting at birth in a preterm infant. A baby boy born at 29 weeks and 3 days of gestation had persistent central cyanosis immediately after delivery, not attributable to a respiratory or cardiac pathology. Laboratory methemoglobin levels were not diagnostic. Cytochrome b5 reductase levels were normal and a newborn screen was unable to pick up any abnormal variants of fetal haemoglobin. Genetic testing showed a γ globin gene mutation resulting in the M haemoglobin, called Hb F-M-Fort Ripley. The baby had no apparent cyanosis at a corrected gestational age of 42 weeks. Although rare, congenital methaemoglobin aemia should be considered in the differential in a preterm with central cyanosis and investigated with genetic testing for γ globin chain mutations if other laboratory tests are non-conclusive.

Validation of the "Quality of Life in School" instrument in Canadian elementary school students.

Background. School is an integral component of the life of a child, and thus quality of school life is an important part of the overall quality of life experienced by a child. There are a few instruments available to measure the quality of school life but they are often not available in English, or they are not appropriate for use alongside other instruments in a survey of young children. The Quality of Life in School (QoLS) instrument is a short, self-report measure to assess elementary school students' perception of their quality of school life in four domains. The instrument was developed in Israel and has been validated among Hebrew-speaking children. The aim of the current study was to evaluate the psychometric properties of the QoLS measure in Canadian elementary school children. Methods. A total of 629 children attending grades 4-6 were recruited in a population-based cross-sectional study. The QoLS measure was administered to participating children by trained research assistants. In addition, their socio-demographic details and academic data were also obtained. The psychometric testing included exploratory factor analysis and reliability estimation using internal consistency (Cronbach's Alpha). Construct validity was investigated using the known groups comparisons for discriminative validity and via convergent validity. Results. A four-factor structure was generated explaining 39% of the total variance in the model. The results showed good internal consistency and acceptable floor and ceiling effects. Cronbach's Alpha ranged from 0.75 to 0.93. Known groups comparisons showed that the QoLS measure discriminated well between subgroups on the basis of gender, grade, and academic achievement, thus providing evidence of construct validity. The convergent validity was also appropriate with all the four domains demonstrating moderate to strong correlations to each other and to the total QoLS score. Conclusions. QoLS appears to be a valid and reliable measure for quality of school life assessment in young Canadian children.

Age at stroke onset influences the clinical outcome and health-related quality of life in pediatric ischemic stroke survivors.

AIM: Stroke in children occurs across different phases of brain development. Age at onset may affect outcome and health-related quality of life (HRQL). We evaluated the influence of age at stroke onset on the long-term neurological outcomes and HRQL of pediatric stroke survivors. METHOD: Children with ischemic stroke were recruited into three groups according to their age at onset of stroke (presumed perinatal, neonatal, and childhood). Neurological outcomes were assessed using the Pediatric Stroke Recovery and Recurrence Questionnaire. HRQL was evaluated using proxy report versions (2-18y) of the Pediatric Quality of Life Inventory (PedsQL 4.0). A χ(2) /Fisher's exact test and multivariable logistic regression analysis was performed for the neurological outcomes. HRQL scores from the different age groups were compared using linear regression. RESULTS: Ninety participants (presumed perinatal stroke, n=31; neonatal stroke, n=36; childhood stroke, n=23) were enrolled. Median age at the onset of stroke was 0.5 days and 3.7 years in neonatal and childhood participants respectively. Of the three groups, participants with presumed perinatal stroke demonstrated the worst global (p<0.002) and motor (p<0.001) outcomes and the lowest level of independence in daily activities (p<0.001). Parents reported the best global outcome and overall HRQL (p=0.007) after neonatal stroke. INTERPRETATION: The age at stroke onset has important implications regarding long-term clinical outcomes and HRQL for survivors. Individuals with presumed perinatal stroke should be considered at high-risk for poor outcomes.