Investigating the impact of severe maternal SARS-CoV-2 infection on infant DNA methylation and neurodevelopment.

Maternal infections during pregnancy can increase the risk to offspring of developing a neurodevelopmental disorder. Given the global prevalence and severity of infection with Severe Acute Respiratory Syndrome related Coronavirus 2 (SARS-CoV-2), the objective of this study was to determine if in utero exposure to severe maternal SARS-CoV-2 infection alters infant neurodevelopmental outcomes at 12 months and to identify potential biological markers of adverse infant outcomes. Mother-infant dyads exposed to severe SARS-CoV-2 infection (requiring hospitalization) during pregnancy and age and sociodemographic matched control dyads were recruited from Monash Medical Centre, Australia in 2021/22 and prospectively assessed over 12 months. Maternal serum cytokine levels and Edinburgh Postnatal Depression Scale (EPDS) scores were assessed at birth. DNA methylation was assessed from infant buccal swabs at birth (Illumina EPIC BeadChip). Infant neurodevelopmental outcomes at 12 months were assessed using the Ages and Stages Questionnaire (ASQ-3). Mothers exposed to severe SARS-CoV-2 exhibited elevated serum IL-6 and IL-17A and higher EPDS scores than controls at birth. Infants exposed to severe SARS-CoV-2 in utero demonstrated over 3000 significant differentially methylated sites within their genomes compared to non-exposed (adjusted p-value < 0.05), including genes highly relevant to ASD and synaptic pathways. At 12 months, severe SARS-CoV-2 exposed infants scored lower on the ASQ-3 than non-exposed infants, and communication and problem-solving scores negatively correlated with maternal IL-6 levels at birth. DNA methylation changes therefore unveil potential mechanisms linking infection exposure to delayed neurodevelopment and maternal serum IL-6 levels may be a potential biomarker of child developmental delay. Mothers exposed to severe SARS-CoV-2 infections show elevated pro-inflammatory cytokines. Infants exposed in utero to severe SARS-CoV-2 infection show altered DNA methylation at birth and delayed development at 12 months of age. Created in Biorender.com.

The Knowledge Translation of Early Cerebral Palsy (KiTE CP) Study: Implementing Screening Among a High-Risk Prospective Cohort of Australian Infants.

OBJECTIVE: To describe the implementation of the international guidelines for the early diagnosis of cerebral palsy (CP) and engagement in the screening process in an Australian cohort of infants with neonatal risk factors for CP. STUDY DESIGN: Prospective cohort study of infants with neonatal risk factors recruited at <6 months corrected age from 11 sites in the states of Victoria, New South Wales, and Queensland, Australia. First, we implemented a multimodal knowledge translation strategy including barrier identification, technology integration, and special interest groups. Screening was implemented as follows: infants with clinical indications for neuroimaging underwent magnetic resonance imaging and/or cranial ultrasound. The Prechtl General Movements Assessment (GMA) was recorded clinically or using an app (Baby Moves). Infants with absent or abnormal fidgety movements on GMA videos were offered further assessment using the Hammersmith Infant Neurological Examination (HINE). Infants with atypical findings on 2/3 assessments met criteria for high risk of CP. RESULTS: Of the 597 infants (56% male) recruited, 95% (n = 565) received neuroimaging, 90% (n = 537) had scorable GMA videos (2% unscorable/8% no video), and 25% (n = 149) HINE. Overall, 19% of the cohort (n = 114/597) met criteria for high risk of CP, 57% (340/597) had at least 2 normal assessments (of neuroimaging, GMA or HINE), and 24% (n = 143/597) had insufficient assessments. CONCLUSIONS: Early CP screening was implemented across participating sites using a multimodal knowledge translation strategy. Although the COVID-19 pandemic affected recruitment rates, there was high engagement in the screening process. Reasons for engagement in early screening from parents and clinicians warrant further contextualization and investigation.

Neonatal magnesium sulphate for neuroprotection: A systematic review and meta-analysis.

AIM: To review the evidence of the effects of neonatal magnesium sulphate for neuroprotection in perinatal asphyxia and hypoxic-ischaemic encephalopathy (HIE). METHOD: This was a systematic review of randomized controlled trials (RCTs) (with meta-analysis) and non-RCTs assessing magnesium sulphate for treating perinatal asphyxia and HIE at 35 weeks or more gestation (primary outcomes: neonatal death and death or long-term major neurodevelopmental disability). RESULTS: Twenty-five RCTs (2099 infants) and four non-RCTs (871 infants) were included, 23 in low- and middle-income countries (LMICs). In RCTs, reductions in neonatal death with magnesium sulphate versus placebo or no treatment (risk ratio [RR] = 0.68; 95% confidence interval [CI] = 0.53-0.86; 13 RCTs), and magnesium sulphate with melatonin versus melatonin alone (RR = 0.74; 95% CI = 0.58-0.95; one RCT) were observed. No difference in neonatal death was seen for magnesium sulphate with therapeutic hypothermia versus therapeutic hypothermia alone (RR = 0.66, 95% CI = 0.34-1.26; three RCTs), or magnesium sulphate versus phenobarbital (RR = 3.00; 95% CI = 0.86-10.46; one RCT). No reduction in death or long-term neurodevelopmental disability (RR = 0.52; 95% CI = 0.14-1.89; one RCT) but reductions in several short-term adverse outcomes were observed with magnesium sulphate. Evidence was low- to very-low certainty because of risk of bias and imprecision. INTERPRETATION: Given the uncertainty of the current evidence, further robust neonatal magnesium sulphate research is justified. This may include high-quality studies to determine stand-alone effects in LMICs and effects with and after therapeutic hypothermia in high-income countries.

Neonatal well-being and timing of brain injury in persons with cerebral palsy born at term or late preterm.

AIM: To describe the distribution of neuroimaging patterns in a term/late preterm population-based cohort with cerebral palsy (CP), ascertain associations between neuroimaging patterns and neonatal well-being, estimate the proportion with antenatal or perinatal timing of neuropathology, and apply this information to the understanding of common mechanisms of brain injury and causal pathways. METHOD: The cohort for this observational study comprised 1348 persons born between 1999 and 2017 in Victoria, Australia. Using algorithms designed for the study, neonatal well-being and timing of brain injury were tabulated for the whole cohort and across neuroimaging patterns and birth epochs. RESULTS: Clinical and demographic profiles, neonatal well-being, and timing of brain injury differed across neuroimaging patterns. An estimated 57% of the cohort had a complicated neonatal period. Timing of brain injury was antenatal in 57% and perinatal in 41%. A decrease in the relative proportions of perinatal timing of brain injury was observed over a period when the rates of CP in live births at term decreased. INTERPRETATION: This study begins to bridge the knowledge gap about causation in CP, moving towards better description of the main mechanisms of brain injury and their contribution within CP cohorts, and facilitating the ability to monitor changes over time and the success of preventive measures. WHAT THIS PAPER ADDS: In a population-based, term/late preterm cohort with cerebral palsy, 57% had a complicated neonatal period. In the same cohort, 57% had presumed antenatal timing of brain injury. The relative proportion with perinatal injury decreased over time.

Major structural congenital anomalies and causal pathways in people with cerebral palsy.

AIM: To determine the proportion of persons with cerebral palsy (CP) with major congenital anomalies, factors associated with the presence of anomalies, body systems involved, potential contribution to CP aetiology, and causal pathway subgroups implicated. METHOD: This population-based, observational study involved a cohort of 2238 persons born in one Australian state between 1999 and 2017. Major congenital anomalies were classified as affecting cerebral, cardiac, or other body systems, with further categorization as single or multisystem. We determined the potential for anomalies to contribute to the development of CP across causal pathway subgroups that were broadly categorized as developmental or involving destructive brain insults. RESULTS: Of persons with CP, 23% had major congenital anomalies and 17% of the cohort had anomalies that potentially contributed to the development of CP. Consistent with higher odds of parental consanguinity, maternal grand multiparity, and dysmorphic features in the group with anomalies, 82% of pathogenic anomalies, present in 14% of the cohort, were cerebral and involved developmental causal pathways. Only 3% (predominantly severe cardiac anomalies) were related to destructive brain insults. INTERPRETATION: The study provides context for the impact on rates of CP of preventive measures or other changes in incidence or management of congenital anomalies.

Intellectual Functioning of Children With Isolated PRS, PRS-Plus, and Syndromic PRS.

OBJECTIVE: Describe the intelligence quotient (IQ) of children with Pierre Robin sequence (PRS). DESIGN: Prospective cohort study. SETTING: Neurodevelopmental follow-up clinic within a hospital. PATIENTS: Children with PRS (n = 45) who had been in the Neonatal Intensive Care Unit (NICU) were classified by a geneticist into 3 subgroups of isolated PRS (n = 20), PRS-plus additional medical features (n = 8), and syndromic PRS (n = 17) based on medical record review and genetic testing. MAIN OUTCOME MEASURE: Children with PRS completed IQ testing at 5 or 8 years of age with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III) or Fourth Edition (WPPSI-IV) or the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) or Fifth Edition (WISC-V). RESULTS: IQ scores were more than 1 to 2 standard deviations below the mean for 36% of the overall sample, which was significantly greater compared to test norms (binomial test P = .001). There was a significant association between PRS subtype and IQ (Fisher's exact P = .026). While only 20% of children with isolated PRS were within 1 standard deviation below average and 35% of children with syndromic PRS were below 1 to 2 standard deviations, 75% of PRS-plus children scored lower than 1 to 2 standard deviations below the mean. CONCLUSION: PRS subgroups can help identify children at risk for cognitive delay. The majority of children with PRS-plus had low intellectual functioning, in contrast to the third of children with syndromic PRS who had low IQ and the majority of children with isolated PRS who had average or higher IQ.

Early neurodevelopmental outcomes of extreme preterm infants exposed to paracetamol: a retrospective cohort study.

BACKGROUND: Paracetamol is commonly used for analgesia and patent ductus arteriosus (PDA) treatment in preterm infants. We aimed to evaluate early neurodevelopmental outcomes of extreme preterm infants exposed to paracetamol during their neonatal admission. METHODS: This retrospective cohort study included surviving infants born at <29 weeks gestation, or with a birth weight of <1000 grams. Neurodevelopmental outcomes studied were early cerebral palsy (CP) or high risk of CP diagnosis, Hammersmith Infant Neurological Examination (HINE) score and Prechtl General Movement Assessment (GMA) at 3-4 months corrected age. RESULTS: Two hundred and forty-two infants were included, of which 123 were exposed to paracetamol. After adjusting for birth weight, sex and chronic lung disease, there were no significant associations between paracetamol exposure and early CP or high risk of CP diagnosis (aOR 1.46, 95% CI 0.61, 3.5), abnormal or absent GMA (aOR 0.82, 95% CI 0.37, 1.79) or HINE score (adjusted ß -0.19, 95% CI -2.39, 2.01). Subgroup analysis stratifying paracetamol exposure into <180 mg/kg or ≥180 mg/kg cumulative dose found that neither had significant effects on outcomes. CONCLUSIONS: In this cohort of extreme preterm infants, no significant association was found between exposure to paracetamol during the neonatal admission and adverse early neurodevelopment. IMPACT: Paracetamol is commonly used in the neonatal period for analgesia and patent ductus arteriosus treatment in preterm infants, although prenatal paracetamol use has been associated with adverse neurodevelopmental outcomes. Exposure to paracetamol during the neonatal admission was not associated with adverse early neurodevelopment at 3-4 months corrected age in this cohort of extreme preterm infants. The findings from this observational study is consistent with the small body of literature supporting the lack of association between neonatal paracetamol exposure and adverse neurodevelopmental outcomes in preterm infants.

A prospective, longitudinal, case-control study to evaluate the neurodevelopment of children from birth to adolescence exposed to COVID-19 in utero.

BACKGROUND: The Coronavirus disease (COVID-19) pandemic has created unprecedented acute global health challenges. However, it also presents a set of unquantified and poorly understood risks in the medium to long term, specifically, risks to children whose mothers were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Infections during pregnancy can increase the risk of atypical neurodevelopment in the offspring, but the long-term neurodevelopmental impact of in utero COVID-19 exposure is unknown. Prospective, longitudinal studies are needed to evaluate children exposed in utero to SARS-CoV2 to define this risk. METHODS: We have designed a prospective, case-controlled study to investigate the long-term impacts of SARS-CoV2 exposure on children exposed in utero. Women infected with SARS-CoV-2 during pregnancy will be recruited from Monash Health, the Royal Women's Hospital and Western Health (Melbourne, Australia) and Londrina Municipal Maternity Hospital Lucilla Ballalai and PUCPR Medical Clinical (Londrina, Brazil). A control group in a 2:1 ratio (2 non-exposed: 1 exposed mother infant dyad) comprising women who gave birth in the same month of delivery, are of similar age but did not contract SARS-CoV-2 during their pregnancy will also be recruited. We aim to recruit 170 exposed and 340 non-exposed mother-infant dyads. Clinical and socio-demographic data will be collected directly from the mother and medical records. Biospecimens and clinical and epidemiological data will be collected from the mothers and offspring at multiple time points from birth through to 15 years of age using standardised sample collection, and neurological and behavioural measures. DISCUSSION: The mapped neurodevelopmental trajectories and comparisons between SARS-CoV-2 exposed and control children will indicate the potential for an increase in atypical neurodevelopment. This has significant implications for strategic planning in the mental health and paediatrics sectors and long-term monitoring of children globally.

The impact of assisted reproductive technology and ovulation induction on breech presentation: A whole of population-based cohort study.

AIMS: Multiple studies have suggested a likely association between breech presentation and assisted reproductive technology (ART) for conception. The aims were to determine whether conception via in vitro fertilisation (IVF) and ovulation induction (OI) is associated with fetal malpresentation at birth and to ascertain what mediating factors most significantly contribute to fetal malpresentation. METHODS: This whole-population-based cohort study included 355 990 singleton pregnancies born in Queensland, Australia, between July 2012 and July 2018. Multinomial logistic regression models estimated the adjusted odds of breech, transverse/shoulder and face/brow malpresentations in pregnancies conceived via spontaneous conception, OI (OI group) and IVF with or without intracytoplasmic sperm injection (ART group). RESULTS: After adjustment for potential confounding factors, breech presentation occurred approximately 20% more often in singleton pregnancies conceived via both ART (adjusted odds ratio: 1.20, 95% confidence interval: 1.10-1.30, P < 0.001) and OI (1.21, 95% confidence interval: 1.04-1.39, P < 0.05). No significant associations were observed between the three modes of conception and transverse/shoulder or face/brow presentations. Low birthweight was found to be the most significant mediating factor for breech presentation in pregnancies conceived via ART and OI. CONCLUSIONS: Similar levels of increased odds of breech presentation are present in pregnancies conceived via OI and ART, suggesting a shared underlying mechanism for the aetiology of breech presentation. For women who are considering or have conceived via these methods, counselling with respect to this increased risk is recommended.

The Role of the Interleukin-1 Family in Complications of Prematurity.

Preterm birth is a major contributor to neonatal morbidity and mortality. Complications of prematurity such as bronchopulmonary dysplasia (BPD, affecting the lung), pulmonary hypertension associated with BPD (BPD-PH, heart), white matter injury (WMI, brain), retinopathy of prematurity (ROP, eyes), necrotizing enterocolitis (NEC, gut) and sepsis are among the major causes of long-term morbidity in infants born prematurely. Though the origins are multifactorial, inflammation and in particular the imbalance of pro- and anti-inflammatory mediators is now recognized as a key driver of the pathophysiology underlying these illnesses. Here, we review the involvement of the interleukin (IL)-1 family in perinatal inflammation and its clinical implications, with a focus on the potential of these cytokines as therapeutic targets for the development of safe and effective treatments for early life inflammatory diseases.

Impact of current Australian paid parental leave on families of preterm and sick infants.

AIM: Parents of preterm or sick infants are at increased risk of mental health problems. The financial stress associated with an infant's prolonged hospital stay can have an additional negative effect on families' wellbeing and child development. This study explores parent use of Australian paid parental leave (PPL) and the financial impact of having an infant requiring neonatal care. METHODS: Retrospective, cross-sectional, online survey study conducted from November 2020 to February 2021. Participants were parents of babies born from 1 January 2013, admitted to a neonatal intensive care unit or special care nursery in Australia. The survey explored use of Australian Government and private sector PPL, and financial stress. Parent-reported anxiety and depression were measured using the EuroQol Group 5D-5L Anxiety and Stress Subscale. RESULTS: Two hundred and thirty-one parents responded of which 93% had a preterm infant. Seventy-three percent of infants were hospitalised for more than 1 month, and 34% were readmitted to hospital within the first year following discharge home. Eighty-three percent of parents reported moderate, severe or extreme levels of anxiety or depression. Seventy-six percent reported that having a child in hospital had a moderate-very large financial impact on their family. Parents identified main costs to be travel, food, inability to work and direct medical costs. CONCLUSIONS: Having an infant born preterm or sick has significant emotional and financial implications for families. The current Australian Government PPL scheme does not adequately support parents of preterm or sick infants, and a change is urgently needed to improve outcomes for this vulnerable population.

Missing out on precious time: Extending paid parental leave for parents of babies admitted to neonatal intensive or special care units for prolonged periods.

In Australia, approximately 18% of newborn babies are admitted to a neonatal intensive or special care nursery. While most babies admitted to a neonatal intensive or special care nursery are discharged home within a few weeks, around 6% of babies spend more than 2 weeks in hospital. For the parents of these babies, much of their leave entitlements (Australian Government Paid Parental Leave Scheme is up to18 weeks for the primary care giver and up to 2 weeks for partners) are used before their baby comes home from hospital. The time babies and parents spend together in the early developmental period, during the hospitalisation and when the baby is discharged home, is crucial for optimal child development and bonding. Yet care givers who have a baby admitted to neonatal intensive or special care for extended periods are not currently entitled to any extra parental leave payments in Australia. We recommend the Australian Paid Parental Leave Act is changed to allow primary carers access to 1 week of extra parental leave pay for every week in hospital (for babies admitted to hospital for more than 2 weeks), up to a maximum of 14 weeks. For fathers and partners of these babies, we recommend an additional 2 weeks of extra Dad and Partner Pay. The net cost, taking into account likely productivity benefits, would be less than 1.5% of the current cost of the scheme and would improve health and socio-economic outcomes for the baby, family and society.

Fatigue Following Pediatric Arterial Ischemic Stroke: Prevalence and Associated Factors.

Background and Purpose: The aims of this study were to assess the prevalence of multidimensional fatigue symptoms 5 years after pediatric arterial ischemic stroke and identify factors associated with fatigue. Methods: Thirty-one children (19 males) with pediatric arterial ischemic stroke, participating in a larger prospective, longitudinal study, were recruited to this study at 5 years poststroke. Parent- and self-rated PedsQL Multidimensional Fatigue Scale scores were compared with published normative data. Associations between parent-rated PedsQL Multidimensional Fatigue Scale, demographics, stroke characteristics, and concurrent outcomes were examined. Results: Parent-rated total, general and cognitive fatigue were significantly poorer than population norms, with more than half of all parents reporting fatigue symptoms in their children. One-third of children also reported experiencing fatigue symptoms, but their ratings did not differ significantly from normative expectations, as such, all further analyses were on parent ratings of fatigue. Older age at stroke and larger lesion size predicted greater general fatigue; older age, female sex, and higher social risk predicted more sleep/rest fatigue. No significant predictors of cognitive fatigue were identified and only older age at stroke predicted total fatigue. Greater fatigue was associated with poorer adaptive functioning, motor skills, participation, quality of life, and behavior problems but not attention. Conclusions: Fatigue is a common problem following pediatric arterial ischemic stroke and is associated with the functional difficulties often seen in this population. This study highlights the importance of long-term monitoring following pediatric arterial ischemic stroke and the need for effective interventions to treat fatigue in children.

Social Cognitive Dysfunction Following Pediatric Arterial Ischemic Stroke: Evidence From a Prospective Cohort Study.

Background and Purpose: Childhood and adolescence coincide with rapid maturation of distributed brain networks supporting social cognition; however, little is known about the impact of early ischemic brain insult on the acquisition of these skills. This study aimed to examine the influence of arterial ischemic stroke (AIS) on facial emotion recognition and theory of mind (ToM) abilities of children and adolescents initially recruited to a single-center, prospective longitudinal study of recovery following AIS. Methods: The study involved 67 participants, including 30 children with AIS (mean time since stroke=5 years) and 37 age-matched typically developing controls who were assessed on measures of cognitive ToM, facial emotion recognition, and affective ToM. Acute clinical magnetic resonance imaging, including diffusion-weighted imaging sequences, were used to evaluate prospective structure-function relationships between acute lesion characteristics (size, location, and arterial territories affected) and long-term social cognitive abilities. Results: Relative to age-matched typically developing controls, children with AIS showed significantly worse performance on measures of basic facial emotion processing, cognitive ToM, and affective ToM. In univariate models, poorer ToM was associated with larger infarcts, combined cortical-subcortical pathology, and involvement of multiple arterial territories. In multivariate analyses, larger lesions and multiterritory infants were predictive of ToM processing but not facial emotion recognition. Poorer cognitive ToM predicted less frequent prosocial behavior and increased peer problems. Conclusions: Social cognitive skills appear vulnerable to disruption from early ischemic brain insult. In the first study to examine social cognition in a prospective cohort of children with AIS, our findings suggest that acute magnetic resonance imaging-based lesion characteristics may have predictive value for long-term social cognitive outcomes and may assist to identify children at elevated risk for social cognitive dysfunction.

Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia.

Therapeutic hypothermia (TH) is standard care in high-resource birth settings for infants with neonatal encephalopathy. TH is partially effective and adjuvant therapies are needed. Here, we examined whether the antioxidant melatonin (MLT) provides additive benefit with TH, compared to TH alone or MLT alone, to improve recovery from acute encephalopathy in newborn lambs. Immediately before cesarean section delivery, we induced asphyxia in fetal sheep via umbilical cord occlusion until mean arterial blood pressure fell from 55 ± 3 mm Hg in sham controls to 18-20 mm Hg (10.1 ± 1.5 minutes). Lambs were delivered and randomized to control, control + MLT (60 mg iv, from 30 minutes to 24 hours), asphyxia, asphyxia + TH (whole-body cooling to 35.1 ± 0.8°C vs. 38.3 ± 0.17°C in sham controls, from 4-28 hours), asphyxia + MLT, and asphyxia + TH + MLT. At 72 hours, magnetic resonance spectroscopy (MRS) was undertaken, and then brains were collected for neuropathology assessment. Asphyxia induced abnormal brain metabolism on MRS with increased Lactate:NAA (P = .003) and reduced NAA:Choline (P = .005), induced apoptotic and necrotic cell death across gray and white matter brain regions (P < .05), and increased neuroinflammation and oxidative stress (P < .05). TH and MLT were independently associated with region-specific reductions in oxidative stress, inflammation, and cell death, compared to asphyxia alone. There was an interaction between TH and MLT such that the NAA:Choline ratio was not significantly different after asphyxia + TH + MLT compared to sham controls but had a greater overall reduction in neuropathology than either treatment alone. This study demonstrates that, in newborn lambs, combined TH + MLT for neonatal encephalopathy provides significantly greater neuroprotection than either alone. These results will guide the development of further trials for neonatal encephalopathy.

Perinatal care with a view to preventing cerebral palsy.

Birth prevalence of cerebral palsy (CP) is declining in high-income countries, to as low as 1.4 per 1000 live births in the most recent international reports. This represents a 35% reduction in birth prevalence over a 15-year period. This reduction is underpinned by a heightened focus of attention towards all aspects of CP, including: increased awareness, better data collection, development of national networks and registries, an explosion of research in basic science, perinatal care, neonatal neurology, public health, early detection, and targeted early intervention. Quick uptake of evidence into practice has ensued and overall improvements in clinical care occurred concurrently. It is anticipated that with continued partnerships with families, ongoing research driving further clinical improvement and vice versa, birth prevalence and severity of CP will further decline and the focus will shift to prevention in low- and middle-income countries. WHAT THIS PAPER ADDS: Research in the field of perinatal care and cerebral palsy (CP) prevention has increased significantly. In high-income countries, increased awareness of CP and scientific advances have improved clinical care. Population-based registers have limitations but remain the best mechanism to quantify birth prevalence of CP and accurately track trends. There have been recent reductions in the birth prevalence of CP.

Selective approach to preoperative echocardiography in esophageal atresia.

PURPOSE: Preoperative echocardiography is used routinely in neonates with esophageal atresia to identify patients in whom congenital cardiac disease will impact upon anesthetic and surgical decision-making. We aimed to determine the suitability of selective preoperative echocardiography. METHODS: We performed a single-center retrospective review of neonates with esophageal atresia over 6 years (2010-2015) at our tertiary pediatric institution. Data included preoperative clinical examination, chest x-ray, and echocardiography. Endpoints were cardiovascular, respiratory, radiological, and echocardiography findings. Selective strategies were assessed using sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: We identified 115 neonates with esophageal atresia. All underwent preoperative echocardiography. Cardiac defects were identified in 49/115 (43%) (major 9/115, moderate 4/115). Sensitivity, specificity, positive predictive value, and negative predictive value of abnormal clinical and radiologic assessment for major and moderate cardiac defects were 92%, 25%, 13%, 96%; for clinical examination alone were 92%, 25%, 14%, 96%; for absence of murmur, cyanosis, and abnormal respiratory examination were 92%, 28%, 13%, 97%. Selective strategies reduce echocardiograms performed by 22%. CONCLUSION: Selective strategies allow for identification of neonates with esophageal atresia who may have deferral of echocardiogram unill after surgery. Selection may improve timeliness of care and resource utilization, without compromising patient safety.

Thirteen-Year Outcomes in Very Preterm Children Associated with Diffuse Excessive High Signal Intensity on Neonatal Magnetic Resonance Imaging.

OBJECTIVE: To investigate the association between white matter diffuse excessive high signal intensity (DEHSI) on neonatal magnetic resonance imaging in very preterm infants and neurobehavioral outcomes at the age of 13 years. STUDY DESIGN: Magnetic resonance images of very preterm children (<30 weeks gestational age or <1250 g birth weight) were evaluated at term-equivalent age with DEHSI classified into 5 grades. Additionally, visibility of the posterior periventricular crossroads was assessed. General intelligence, memory, attention, executive function, motor abilities, and behavior were examined in 125 children at age 13 years and related to DEHSI grades using linear regression. RESULTS: DEHSI was detected in 93% of infants; 21% grade 1, 22% grade 2, 32% grade 3, and 18% grade 4. Neurobehavioral outcomes were similar for all DEHSI groups. There was weak evidence that higher DEHSI grades related to higher verbal IQ and attention and that lower DEHSI grades related to better planning ability. Adjustment for gestational age, birth weight standard score, and sex further weakened these effects. Only 12 children had invisible posterior crossroads and showed slightly poorer outcomes at 13 years of age. CONCLUSIONS: There was little evidence that neonatal DEHSI serves as a sensitive biomarker for later impairment. Further investigation on the importance of invisible posterior periventricular crossroads in larger samples is needed.

Associations of Neonatal Noncardiac Surgery with Brain Structure and Neurodevelopment: A Prospective Case-Control Study.

OBJECTIVE: To examine the associations of neonatal noncardiac surgery with newborn brain structure and neurodevelopment at 2 years of age. STUDY DESIGN: Infants requiring neonatal noncardiac surgery for congenital diaphragmatic hernia, esophageal atresia, or anterior abdominal wall defect were compared with infants who did not require surgery, matched for sex, gestation at birth, and postmenstrual age at magnetic resonance imaging. Cerebral magnetic resonance imaging was performed at a mean (SD) postmenstrual age of 41.6 (1.7) weeks. Images were assessed qualitatively for brain maturation and injury and quantitatively for measures of brain size, cerebrospinal fluid spaces, and global abnormality. Neurodevelopment was then assessed at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd edition. RESULTS: Infants requiring surgery (n = 39) were 5.9 times (95% CI, 1.9-19.5; P < .01) more likely to have delayed gyral maturation and 9.8 times (95% CI, 1.2-446; P = .01) more likely to have white matter signal abnormalities compared with controls (n = 39). Cases were more likely to have higher global abnormality scores, smaller biparietal diameters, and larger ventricular sizes than controls. Infants who had surgery had lower mean composite scores in the language (mean difference, -12.5; 95% CI, -22.4 to -2.7) and motor domains (mean difference, -13.4; 95% CI, -21.1 to -5.6) compared with controls. CONCLUSIONS: Infants requiring neonatal noncardiac surgery have smaller brains with more abnormalities compared with matched controls and have associated neurodevelopmental impairment at 2 years of age. Prospective studies with preoperative and postoperative imaging would assist in determining the timing of brain injury.

Behavioural and cognitive outcomes following an early stress-reduction intervention for very preterm and extremely preterm infants.

BACKGROUND: The landmark findings of the Mother-Infant Transaction Program (MITP) showing improved neurodevelopment of preterm infants following parent-sensitivity training delivered in the neonatal intensive care unit have not been consistently replicated. This study evaluated an MITP-type intervention in terms of neurobehavioural development to preschool age. METHODS: A randomised controlled trial involved 123 very preterm and extremely preterm infants allocated to either a parent-sensitivity intervention (PremieStart, n = 60) or to standard care (n = 63). When children were 2 and 4.5 years corrected age, parents completed the Child Behavior Checklist (CBCL). General development was assessed at 2 years with the Bayley Scales of Infant Development (Bayley-III). At 4.5 years, cognitive functioning was assessed with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and executive functioning with the NEPSY-II. RESULTS: There were no significant between-group differences in behaviour problems at 2 or 4.5 years, general development at 2 years, or cognitive and executive functioning at 4.5 years. CONCLUSION: Advances in the quality of neonatal intensive care may mean that MITP-type interventions now have limited additional impact on preterm infants' long-term neurobehavioural outcomes. The gestational age of infants and the exact timing of intervention may also affect its efficacy.