Pediatric Research

29/04/2023

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14/03/2023

Prenatal and perinatal factors associated with neonatal neurobehavioral profiles in the ECHO Program
https://www.nature.com/articles/s41390-023-02540-2

• Prior research on predictors of neonatal neurobehavior have included single-cohort studies, which limits generalizability of findings.
• In a multi-cohort study of preterm and term-born infants, we found six distinct neonatal neurobehavioral profiles, with two profiles being identified as dysregulated.
• Hypo- and hyper-aroused neurobehavioral profiles had distinct perinatal antecedents.
• Understanding perinatal factors associated with dysregulated neurobehavior could help promote positive developmental outcomes.

14/03/2023

Hypothermia increases cold-inducible protein expression and improves cerebellar-dependent learning after hypoxia ischemia in the neonatal rat
https://www.nature.com/articles/s41390-023-02535-z

• Hypoxic ischemic produced tissue loss and a learning deficit in the cerebellum.
• Hypothermia reversed both the tissue loss and learning deficit.
• Hypothermia increased cold-responsive protein expression in the cerebellum and hippocampus.
• Our results confirm cerebellar volume loss contralateral to the carotid artery ligation and injured cerebral hemisphere, suggesting crossed-cerebellar diaschisis in this model.
• Understanding the endogenous response to hypothermia might improve adjuvant interventions and expand the clinical utility of this intervention.

Hypoxic ischemic encephalopathy remains a significant cause of developmental disability.1,2 The standard of care for term infants is hypothermia, which has multifactorial effects.3–5 Therapeutic hypothermia upregulates the cold-inducible protein RNA binding motif 3 (RBM3) that is highly expressed ...

14/03/2023

Hypothermia increases cold-inducible protein expression and improves cerebellar-dependent learning after hypoxia ischemia in the neonatal rat
https://www.nature.com/articles/s41390-023-02535-z

• Hypoxic ischemic produced tissue loss and a learning deficit in the cerebellum.
• Hypothermia reversed both the tissue loss and learning deficit.
• Hypothermia increased cold-responsive protein expression in the cerebellum and hippocampus.
• Our results confirm cerebellar volume loss contralateral to the carotid artery ligation and injured cerebral hemisphere, suggesting crossed-cerebellar diaschisis in this model.
• Understanding the endogenous response to hypothermia might improve adjuvant interventions and expand the clinical utility of this intervention.

14/03/2023

Neonatal prophylactic antibiotics after preterm birth affect plasma proteome and immune development in pigs
https://www.nature.com/articles/s41390-023-02492-7

1. Neonatal prophylactic antibiotics alter the plasma proteome and suppress systemic immune development in preterm pigs
2. The effects of prophylactic antibiotics last beyond the days of treatment.
3. Neonatal antibiotics treatment for compromised human newborns may predispose to longer-term risks of impaired immunity and infections.

Most preterm infants receive antibiotics to prevent serious infections shortly after birth. However, prolonged antibiotic treatment predisposes to gut dysbiosis and late-onset sepsis. Using preterm pigs as model, we hypothesized that neonatal prophylactic antibiotics impair systemic immune developme...

14/03/2023

Short-term multidisciplinary family-centered workshop for preschool children with global developmental delays
https://www.nature.com/articles/s41390-023-02507-3

• The effectiveness of short-term family-centered workshops on children with global developmental delays remains uncertain.
• Short-term family-centered workshops improved the children’s emotions, physical functional performance, and occupational performance in daily life.
• The short-term family-centered workshop is practical and effective for children with global developmental delays.
• Further long-term, large-scale, prospective, randomized trials are warranted to confirm these results.

14/03/2023

Early prediction of severe retinopathy of prematurity requiring laser treatment using physiological data
https://www.nature.com/articles/s41390-023-02504-6

• Routinely monitored physiological data from the first postnatal month are predictive of later development of ROP requiring laser treatment, although model performance was not significantly better than baseline characteristics (gestational age, birth weight, s*x, multiple birth, prenatal glucocorticosteroids, route of delivery, and Apgar scores) alone.
• A balanced accuracy of 0.81 (0.72–0.87), a sensitivity of 0.73 (0.64–0.81), and a specificity of 0.88 (0.80–0.93) was achieved with a model including the SpO2/FiO2 ratio and baseline characteristics.
• Physiological data have potential to play a significant role for future ROP prediction and provide opportunities for early interventions to protect infants from abnormal retinal development.

14/03/2023

Premature infants born

14/03/2023

Preschooler screen time and temperamental anger/frustration during the COVID-19 pandemic
https://www.nature.com/articles/s41390-023-02485-6

• Key message: this study observes prospective bidirectional associations between preschoolers screen time and temperamental displays of anger or frustration during the COVID-19 pandemic.
• What does it add: we provide evidence that preschool screen time at age 3.5 prospectively contributes to the tendency to react in anger/frustration at age 4.5. In contrast, greater proneness to anger/frustration did not predict later exposure to screen time.
• What is the impact: health practitioners should enquire about media use habits during well-child visits to foster children’s healthy development during the preschool years.

In the context of increased media use and family distress during the pandemic, we examine whether preschooler screen time at age 3.5 contributes to later expressions of anger/frustration at 4.5, while also considering the inverse association. Data are from a cohort of 315 Canadian preschool-aged chi...

14/03/2023

Association of maternal s***f use and smoking with Sudden Infant Death Syndrome: a national register study
https://www.nature.com/articles/s41390-022-02463-4

• Maternal s***f use and smoking in early pregnancy were associated with increased risks of post neonatal mortality, SIDS, and SUID.
• Cessation of smoking and s***f use before the first antenatal visit was associated with reduced risks of SIDS and SUID.
• The common substance in cigarette smoke and s***f is ni****ne. Our findings suggest that ni****ne contributes to an elevated risk of SIDS and SUID.
• The implication of our findings is that all forms of ni****ne should be avoided in pregnancy.

The aim was to study whether non-combustible ni****ne (Swedish s***f) use in pregnancy is associated with elevated risk of post neonatal mortality, Sudden Infant Death Syndrome (SIDS), and Sudden Unexpected Infant Death (SUID) and to study how cessation before the antenatal booking influenced these....

14/03/2023

Intravenous immunoglobulin resistance in Kawasaki disease patients: prediction using clinical data
https://www.nature.com/articles/s41390-023-02519-z

• We demonstrated that laboratory, echocardiographic, and clinical findings cannot predict intravenous immunoglobin (IVIG) resistance to a clinically meaningful extent using machine learning in a homogenous Asian or ethnically diverse population of patients with Kawasaki disease (KD).
• Visualizing these features using uniform manifold approximation and projection (UMAP) is an important step to evaluate predictive utility in a qualitative manner.
• Further attempts to predict IVIG resistance in KD patients will need to incorporate novel biomarkers or other specialized features such as genetic differences or transcriptomics to be clinically useful.

About 10–20% of Kawasaki disease (KD) patients are resistant to the initial infusion of intravenous immunoglobin (IVIG). The aim of this study was to assess whether IVIG resistance in KD patients could be predicted using standard clinical and laboratory features. Data were from two cohorts: a Kore...

14/03/2023

Intravenous immunoglobulin resistance in Kawasaki disease patients: prediction using clinical data
https://www.nature.com/articles/s41390-023-02519-z

• We demonstrated that laboratory, echocardiographic, and clinical findings cannot predict intravenous immunoglobin (IVIG) resistance to a clinically meaningful extent using machine learning in a homogenous Asian or ethnically diverse population of patients with Kawasaki disease (KD).
• Visualizing these features using uniform manifold approximation and projection (UMAP) is an important step to evaluate predictive utility in a qualitative manner.
• Further attempts to predict IVIG resistance in KD patients will need to incorporate novel biomarkers or other specialized features such as genetic differences or transcriptomics to be clinically useful.

14/03/2023

Current pain management practices for preterm infants with necrotizing enterocolitis: a European survey
https://www.nature.com/articles/s41390-023-02508-2

• This study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units.
• Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries.
• A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU.
• The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC.

14/03/2023

Current pain management practices for preterm infants with necrotizing enterocolitis: a European survey
https://www.nature.com/articles/s41390-023-02508-2

• This study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units.
• Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries.
• A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU.
• The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC.

Necrotizing enterocolitis (NEC) is a highly painful intestinal complication in preterm infants that requires adequate pain management to prevent short- and long-term effects of neonatal pain. There is a lack of international guidelines for pain management in NEC patients. Therefore, this study aims....

14/03/2023

How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?
https://www.nature.com/articles/s41390-023-02510-8

• Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia.
• Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment.
• Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI.
• Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol....

14/03/2023

Patent ductus arteriosus and the risk of bronchopulmonary dysplasia-associated pulmonary hypertension
https://www.nature.com/articles/s41390-023-02522-4

• In our study, preterm infants (

The aim of the study was to determine whether prolonged exposure to a moderate/large patent ductus arteriosus left-to-right shunt (PDA) increases the risk of late (beyond 36 weeks) pulmonary hypertension (BPD-PH) and pulmonary vascular disease (BPD-PVD) during the neonatal hospitalization in preterm...

09/02/2023

Establishing a Global Regulatory Floor for Children’s Decisions about Participation in Clinical Research
https://www.nature.com/articles/s41390-023-02483-8

Enrolling children in clinical trials requires the permission of a parent/guardian ± the assent of the minor.
Differing global regulatory requirements for enrolling children complicate the conduct of multicenter and multinational trials.
The authors identify points of ambiguity and/or contradiction in the International Council for Harmonization guidelines and offer recommendations for a common ethical platform for conducting global pediatric research.

Enrolling children in clinical trials typically requires parental or guardian permission and, when appropriate, child assent. Aligning requirements across jurisdictions would facilitate multisite pediatric trials. Guidance from the International Council for Harmonisation of Technical Requirements fo...

09/02/2023

Prevalence and risk factors of disseminated intravascular coagulation in childhood acute lymphoblastic leukemia
https://www.nature.com/articles/s41390-023-02475-8

There are only two studies, both published before 2000, evaluating risk factors of DIC in pediatric ALL patients without reporting outcomes.
DIC was associated with lower remission and survival rates in pediatric ALL patients. We identified the risk factors of DIC at presentation as antibiotics prior to admission, hyperleukocytosis, thrombocytopenia and high NCI risk. The risk factors of DIC during induction chemotherapy were antibiotics prior to admission, high peripheral blasts and aspartate transaminitis.
Pediatric ALL patients who have the aforementioned risk factors should be closely monitored for DIC secondary to infection, and early treatment with appropriate antimicrobial agents is recommended.

Few studies have examined disseminated intravascular coagulation (DIC) in childhood acute lymphoblastic leukemia (ALL). Our aims were to evaluate the prevalence, risk factors and outcomes of DIC at ALL presentation and during induction chemotherapy. The medical records of ALL patients aged

09/02/2023

Risk factors for cerebral palsy and movement difficulties in 5-year-old children born extremely preterm
https://www.nature.com/articles/s41390-022-02437-6

Young maternal age, male s*x and bronchopulmonary dysplasia similarly increased risks of both cerebral palsy and non-cerebral palsy movement difficulties.
Cerebral palsy was strongly related to clinical risk factors including severe brain lesions and other neonatal morbidities, while non-cerebral palsy movement difficulties were more associated with sociodemographic risk factors.
These results on the similarities and differences in risk profiles of children with cerebral palsy and non-cerebral palsy movement difficulties raise questions for etiological research and provide a basis for improving the identification of children who may benefit from follow-up and early intervention.

Motor impairment is common after extremely preterm (EPT,

09/02/2023

Association of low physical activity with higher respiratory tract infections frequency among pre-school children
https://www.nature.com/articles/s41390-022-02436-7

In pre-school children, higher physical activity (PA) is associated with fewer days of upper respiratory tract infection symptoms (URTIS).
Children with a higher average daily step count have fewer days with URTIS over a long-term observation period.
A change in the average number of steps per day by 1000 changed the number of days with symptoms of URTI by 4 days.
The severity of URTIS was inversely related to the degree of PA.
Children who participate in sports 3 or more hours per week have fewer URTIS than those who do not engage in sports regularly.

There is no consensus on the benefits of physical activity (PA) regarding upper respiratory tract infections (URTIs) among children. This study aimed to determine an association between the PA level and URTIs in preschoolers. In 4–7-year-old participants, URTI symptoms were monitored using the Pol...

09/02/2023

Linking specific biological signatures to different childhood adversities: findings from the HERO project
https://www.nature.com/articles/s41390-022-02415-y

Different forms of early-life adversity have varied stress signatures, and investigations of early-life adversities with inflammation and HPA markers are lacking.
Children with higher socioeconomic disadvantage had higher TNF-α, IL-1β, and DHEA.
Higher family dysfunction was associated with higher hair cortisol and cortisone levels, and the association between family dysfunction and cortisol was moderated by socioeconomic disadvantage.
Biological response systems (immune and endocrine) were differentially associated with distinct forms of early-life adversities.

Although investigations have begun to differentiate biological and neurobiological responses to a variety of adversities, studies considering both endocrine and immune function in the same datasets are limited. Associations between proximal (family functioning, caregiver depression, and anxiety) and...

09/02/2023

Global burden of out-of-hospital cardiac arrest in children: a systematic review, meta-analysis, and meta-regression
https://www.nature.com/articles/s41390-022-02462-5

This systematic review addresses a significant health problem in a global context from 1995 to 2022.
The meta-regression revealed that the incidence of OHCA and mortality of children decline over the years in high-income countries despite regional dispraises among individual studies.
Body of evidence on the incidence of OHCA and mortality is lacking in low- and middle-income countries.

The incidence of out-of-hospital cardiac arrest (OHCA) and its mortality among children decreased globally over the years. However, the incidence, mortality, and its determinants are heterogeneous globally. The current study was designed to investigate the incidence of OHCA, mortality, and its deter...

09/02/2023

Longitudinal perturbations of plasma nuclear magnetic resonance profiles in neonatal encephalopathy
https://www.nature.com/articles/s41390-023-02464-x

The use of nuclear magnetic resonance (NMR) spectroscopy enables the simultaneous quantitation of 249 compounds in a small volume (i.e., 100 μL) of plasma.
Longitudinal perturbations of plasma NMR profiles were linked to magnetic resonance imaging (MRI) outcomes of infants with neonatal encephalopathy (NE).
Lactate, beta-hydroxybutyrate, pyruvate, and three triglyceride biomarkers showed the ability to discern between different degrees of brain injury according to MRI scores.
Lactate is a minimally invasive candidate biomarker for early staging of MRI brain injury in NE infants that might be readily implemented in clinical guidelines for NE outcome prediction.

Neonatal encephalopathy (NE) is a major cause of mortality and severe neurological disability in the neonatal period and beyond. We hypothesized that the degree of brain injury is reflected in the molecular composition of peripheral blood samples. A sub-cohort of 28 newborns included in the HYPOTOP....

09/02/2023

Child and family factors associated with positive outcomes among youth born extremely preterm
https://www.nature.com/articles/s41390-022-02424-x

The absence of child behavioral and communication disorders, and adverse family events, were associated with more positive health, higher global health, and better cognitive function among youth born extremely preterm.
Interventions to address behavioral disorders in early childhood, and to reduce the impact of adverse life events on the family, might promote improved health and developmental outcomes for adolescents born extremely preterm.

To analyze the relationship of child behavioral and communication disorders, and adverse family events, to later-in-life child health and cognitive function among youth born extremely preterm. The study participants were 694 children enrolled in the Extremely Low Gestational Age Newborn Study.....

09/02/2023

Variations in care of neonates during therapeutic hypothermia: call for care practice bundle implementation
https://www.nature.com/articles/s41390-022-02453-6

This survey describes the current HIE care practices and variation among tertiary centres in Canada.
Variations exist in the care of neonates with NE treated with TH in NICUs across Canada.
This paper Identifies areas of variation that are not discussed in detail in the national guidelines and will help to set up quality improvement initiatives.
Elucidating the variation in care practices calls for the creation and implementation of a national, consensus-based care bundle, with the objective to improve the outcomes of these critically ill neonates.

Therapeutic hypothermia (TH) is the gold-standard treatment for moderate and severe neonatal encephalopathy (NE). Care during TH has implications for long-term outcomes. Outcome variability exists among neonatal intensive care units (NICUs) in Canada, but care variations are not understood well. Thi...

09/02/2023

Bronchopulmonary dysplasia prediction models: a systematic review and meta-analysis with validation
https://www.nature.com/articles/s41390-022-02451-8

This review aims to provide a comprehensive assessment of all BPD prediction models developed to address the uncertainty of which model is sufficiently valid and generalisable for use in clinical practice and research.
Published BPD prediction models are mostly outdated, single centre and lack external validation.
Laughon’s 2011 model is the most promising but more robust models, using contemporary data with external validation are needed to support better treatments.

Prediction models could identify infants at the greatest risk of bronchopulmonary dysplasia (BPD) and allow targeted preventative strategies. We performed a systematic review and meta-analysis with external validation of identified models. Studies using predictors available before day 14 of life to....

09/02/2023

Maternal protein intake in early pregnancy and child development at age 3 years
https://www.nature.com/articles/s41390-022-02435-8

Animal studies have shown that maternal protein restriction during pregnancy and lactation causes abnormal brain development among offspring.
Birth cohort studies to date have not assessed the effects of maternal low protein exposure during pregnancy on child development.
Severely low protein intake during early pregnancy was associated with a higher risk of child developmental delay at age 3 years.
Since nutritional imbalance in early pregnancy affects not only fetal growth but also postnatal neurodevelopment, nutritional management before pregnancy is considered important.

The current study aimed to assess the association between low maternal protein intake during pregnancy and child developmental delay at age 3 years. This research used data obtained from the Japan Environment and Children’s Study. In total, we analyzed 77,237 mother–child pairs. Dietary intake w...

09/02/2023

Right to left ventricular volume ratio is associated with mortality in congenital diaphragmatic hernia
https://www.nature.com/articles/s41390-022-02430-z

Mortality with congenital diaphragmatic hernia (CDH) is high, and evaluating left and right ventricular structures and functions may be helpful in assessing the prognosis.
Three-dimensional (3D) echocardiography indicated that the left ventricular end-diastolic volume/right ventricular end-diastolic volume ratio within 24 h after birth was associated with mortality in CDH infants.
The usefulness of this ratio should be validated in prospective multicenter studies involving larger numbers of patients.

Congenital diaphragmatic hernia (CDH) is associated with high neonatal mortality. We performed this study to test the hypothesis that left ventricular (LV) and right ventricular (RV) volumes assessed by three-dimensional echocardiography may be associated with mortality in CDH. This study was a sing...

09/02/2023

Ultrasonographic evaluation of the early brain growth pattern in very low birth weight infants
https://www.nature.com/articles/s41390-022-02425-w

We describe the brain growth pattern in very low birth weight infants during their first postnatal weeks.
Brain growth may be affected in the presence of certain perinatal factors and comorbidities, conditioning a deviation of the normal growth pattern.
The serial ultrasound follow-up of these at-risk patients allows identifying these brain growth patterns early, which offers a window of opportunity for implementing earlier interventions.

Preterm infants develop smaller brain volumes compared to term newborns. Our aim is to study early brain growth related to perinatal factors in very low birth weight infants (VLBWI). Manual segmentation of total brain volume (TBV) was performed in weekly 3D-ultrasonographies in our cohort of VLBWI.....