BACKGROUND: Kernicterus spectrum disorder (KSD) resulting from neonatal hyperbilirubinemia remains a common cause of cerebral palsy worldwide. This 12-month prospective cohort study followed neonates with hyperbilirubinemia to determine which clinical measures best predict KSD. METHODS: The study enrolled neonates ≥35 weeks gestation with total serum bilirubin (TSB) ≥ 20 mg/dl admitted to Aminu Kano Hospital, Nigeria. Clinical measures included brain MRI, TSB, modified bilirubin-induced neurologic dysfunction (BIND-M), Barry-Albright Dystonia scale (BAD), auditory brainstem response (ABR), and the modified KSD toolkit. MRI signal alteration of the globus pallidus was scored using the Hyperbilirubinemia Imaging Rating Tool (HIRT). RESULTS: Of 25 neonates enrolled, 13/25 completed 12-month follow-up and six developed KSD. Neonatal BIND-M ≥ 3 was 100% sensitive and 83% specific for KSD. Neonatal ABR was 83% specific and sensitive for KSD. Neonatal HIRT score of 2 was 67% sensitive and 75% specific for KSD; this increased to 100% specificity and sensitivity at 12 months. BAD ≥ 2 was 100% specific for KSD at 3-12 months, with 50-100% sensitivity. CONCLUSIONS: Neonatal MRIs do not reliably predict KSD. BIND-M is an excellent screening tool for KSD, while the BAD or HIRT score at 3 or 12 months can confirm KSD, allowing for early diagnosis and intervention. IMPACT: The first prospective study of children with acute bilirubin encephalopathy evaluating brain MRI findings over the first year of life. Neonatal MRI is not a reliable predictor of kernicterus spectrum disorders (KSD). Brain MRI at 3 or 12 months can confirm KSD. The modified BIND scale obtained at admission for neonatal hyperbilirubinemia is a valuable screening tool to assess risk for developing KSD. The Barry Albright Dystonia scale and brain MRI can be used to establish a diagnosis of KSD in at-risk infants as early as 3 months.

BACKGROUND: Neonatal encephalopathy (NE) remains a common cause of infant morbidity and mortality. Neuropathological corollaries of NE associated with acute hypoxia-ischemia include a central injury pattern involving the basal ganglia and thalamus, which may interfere with thermoregulatory circuits. Spontaneous hypothermia (SH) occurs in both preclinical models and clinical hypoxic-ischemic NE and may provide an early biomarker of injury severity. To determine whether SH predicts the degree of injury in a ferret model of hypoxic-ischemic NE, we investigated whether rectal temperature (RT) 1 h after insult correlated with long-term outcomes. METHODS: Postnatal day (P)17 ferrets were presensitized with Escherichia coli lipopolysaccharide before undergoing hypoxia-ischemia/hyperoxia (HIH): bilateral carotid artery ligation, hypoxia-hyperoxia-hypoxia, and right ligation reversal. One hour later, nesting RTs were measured. RESULTS: Animals exposed to HIH were separated into normothermic (NT; ≥34.4 °C) or spontaneously hypothermic (SH; <34.4 °C) groups. At P42, cortical development, ex vivo MRI, and neuropathology were quantitated. Whole-brain volume and fractional anisotropy in SH brains were significantly decreased compared to control and NT animals. SH brains also had significantly altered gyrification, greater cortical pathology, and increased corpus callosum GFAP staining relative to NT and control brains. CONCLUSION: In near-term-equivalent ferrets, nesting RT 1 h after HIH may predict long-term neuropathological outcomes. IMPACT: High-throughput methods to determine injury severity prior to treatment in animal studies of neonatal brain injury are lacking. In a gyrified animal model of neonatal inflammation-sensitized hypoxic-ischemic brain injury in the ferret, rectal temperature 1 h after hypoxia predicts animals who will have increased cortical pathology and white matter changes on MRI. These changes parallel similar responses in rodents and humans but have not previously been correlated with long-term neuropathological outcomes in gyrified animal models. Endogenous thermoregulatory responses to injury may provide a translational marker of injury severity to help stratify animals to treatment groups or predict outcome in preclinical studies.

BACKGROUND: Sudden infant death syndrome (SIDS) has been considered to be triggered by a combination of underlying immune dysregulation and infections. The thymus is a crucial lymphatic organ responsible for T cell development in infancy. We hypothesized that an altered thymic immune status may be detectable by intrathymic cytokine profiling in SIDS. METHODS: 27 cytokines in protein lysates of thymus tissue and thymus weights were assessed in 26 SIDS cases and 16 infants who died of other reasons. RESULTS: Seventeen out of 27 cytokines were increased in thymic tissue of SIDS compared to controls without infections, and the most significant discrepancy was in infants younger than 20 weeks. The thymic cytokine profiles in SIDS cases were similar to those in controls with severe infection; however, the magnitude of the cytokine concentration elevation in SIDS was less pronounced, indicating sub-clinical infections in SIDS. In contrast to SIDS, intrathymic cytokine concentrations and thymus weight were increased with age in control children. CONCLUSIONS: Elevated thymic cytokine expression and thymus weight, as well as impaired age-related alterations in SIDS, may be influenced by subclinical infection, which may play a role in initiating SIDS in infants with a compromised immune response. IMPACT STATEMENT: Increased thymic weight and cytokine concentration may suggest possible subclinical infection in SIDS. Elevated thymic weight and cytokine concentration mainly in SIDS cases aged <20 weeks. Age-related impairment in the thymic weight and cytokine expression may be impaired by subclinical infection in SIDS.

The neurovascular unit (NVU) within the brain is a multicellular unit that synergistically acts to maintain blood-brain barrier function and meet cerebral metabolic demand. Recent studies have indicated disruption to the NVU is associated with neuropathology in the perinatal brain. Infants with fetal growth restriction (FGR) are known to be at increased risk of neurodevelopmental conditions including motor, learning, and behavioural deficits. There are currently no neuroprotective treatments for these conditions. In this review, we analyse large animal studies examining the effects of FGR on the perinatal NVU. These studies show altered vascularity in the FGR brain as well as blood-brain barrier dysfunction due to underlying cellular changes, mediated by neuroinflammation. Neuroinflammation is a key mechanism associated with pathological effects in the FGR brain. Hence, targeting inflammation may be key to preserving the multicellular NVU and providing neuroprotection in FGR. A number of maternal and postnatal therapies with anti-inflammatory components have been investigated in FGR animal models examining targets for amelioration of NVU disruption. Each therapy showed promise by uniquely ameliorating the adverse effects of FGR on multiple aspects of the NVU. The successful implementation of a clinically viable neuroprotective treatment has the potential to improve outcomes for neonates affected by FGR. IMPACT: Disruption to the neurovascular unit is associated with neuropathology in fetal growth restriction. Inflammation is a key mechanism associated with neurovascular unit disruption in the growth-restricted brain. Anti-inflammatory treatments ameliorate adverse effects on the neurovascular unit and may provide neuroprotection.

BACKGROUND: Prenatal alcohol exposure (PAE) impacts the neurodevelopment of the fetus, including the infant's ability to self-regulate. Heart rate variability (HRV), that is, the beat-to-beat variability in heart rate, is a non-invasive measurement that can indicate autonomic nervous system (ANS) function/dysfunction. METHODS: The study consisted of a subset of our ENRICH-2 cohort: 80 participants (32 PAE and 48 Controls) who had completed three visits during pregnancy. The participants completed a comprehensive assessment of PAE and other substances throughout pregnancy and assessments for stress, anxiety, and depression in the third trimester. At 24 h of age, infant HRV was assessed in the hospital during the clinically indicated heel lance; 3- to 5-min HRV epochs were obtained during baseline, heel lancing, and recovery episodes. RESULTS: Parameters of HRV differed in infants with PAE compared to Controls during the recovery phase of the heel lance (respiratory sinus arrhythmia (RSA) and high-frequency (HF), p < 0.05). Increased maternal stress was also strongly associated with abnormalities in RSA, HF, and low-frequency / high-frequency (LF/HF, p's < 0.05). CONCLUSIONS: Alterations in ANS regulation associated with PAE and maternal stress may reflect abnormal development of the hypothalamic-pituitary-adrenal axis and have long term implications for infant responsiveness and self-regulation. IMPACT: Previous studies have focused on effects of moderate to heavy prenatal alcohol exposure (PAE) on autonomic dysregulation, but little is known about the effects of lower levels of PAE on infant self-regulation and heart rate variability (HRV). Prenatal stress is another risk factor for autonomic dysregulation. Mild PAE impacts infant self-regulation, which can be assessed using HRV. However, the effect of prenatal stress is stronger than that of mild PAE or other mental health variables on autonomic dysregulation.

BACKGROUND: Intrauterine exposure to hypertensive disorders of pregnancy, including gestational hypertension (GH) and preeclampsia (PE), may influence infant growth and have long-term health implications. This study aimed to compare growth outcomes of infants exposed to a normotensive pregnancy (NTP), GH, or PE from birth to 2 years. METHODS: Infants were children of women enroled in the prospective Postpartum Physiology, Psychology and Paediatric (P4) cohort study who had NTP, GH or PE. Birth, 6-month (age-corrected) and 2-year (age-corrected) weight z-scores, change in weight z-scores, rapid weight gain (≥0.67 increase in weight z-score) and conditional weight gain z-scores were calculated to assess infant growth (NTP = 240, GH = 19, PE = 66). RESULTS: Infants exposed to PE compared to NTP or GH had significantly lower birth weight and length z-scores, but there were no differences in growth outcomes at 6 months or 2 years. GH and PE-exposed infants had significantly greater weight z-score gain [95% CI] (PE = 0.93 [0.66-1.18], GH = 1.03 [0.37-1.68], NTP = 0.45 [0.31-0.58], p < 0.01) and rapid weight gain (GH = 63%, PE = 59%, NTP = 42%, p = 0.02) from birth to 2 years, which remained significant for PE-exposed infants after confounder adjustment. CONCLUSION: In this cohort, GH and PE were associated with accelerated infant weight gain that may increase future cardiometabolic disease risk. IMPACT: Preeclampsia exposed infants were smaller at birth, compared with normotensive pregnancy and gestational hypertension exposed infants, but caught up in growth by 2 years of age. Both preeclampsia and gestational hypertension exposed infants had significantly accelerated weight gain from birth to 2 years, which remained significant for preeclampsia exposed infants after adjustment for confounders including small for gestational age. Monitoring of growth patterns in infants born following exposure to a hypertensive disorder of pregnancy may be indicated to prevent accelerated weight gain trajectories and obesity.

BACKGROUND: We aimed to examine predictive measures for medium and giant coronary artery aneurysms (CAA) in Kawasaki disease (KD) patients. METHODS: Patients who were diagnosed with KD from 2015 to 2021 were retrospectively reviewed. The clinical and laboratory data were compared between medium-giant group and non-medium-giant group. RESULTS: A total of 1331 KD patients were investigated, of whom 63 patients (4.7%) developed medium-giant CAA including 27 patients (2%) with giant CAA. Sex, age, fever duration, intravenous immunoglobulin (IVIG) resistance, platelet count, and albumin level independently predicted medium or giant CAA by multivariate logistic regression analysis. Male, age, duration of fever, IVIG resistance, platelet count, hemoglobin, and erythrocyte sedimentation rate were independent predictors for giant CAA. The two new scoring systems using these factors in identifying patients with medium-giant CAA and giant CAA had respectively sensitivities of 86.89% and 92.59%, and specificities of 81.65% and 87.93%. Validation in 2021 dataset (193 KD patients) showed comparable sensitivity and specificity to development dataset. CONCLUSIONS: Male, age, fever duration, IVIG resistance, platelet count, albumin, hemoglobin, and erythrocyte sedimentation rate might be significant predictors of medium and giant CAA. The sensitivity and specificity in our risk prediction model were higher than in previous research. IMPACT: This is the first study to search for risk factors and establish a prediction model for the development of medium-giant CAA in the Chinese population using z-scores and absolute inner diameter values based on large sample sizes. The sensitivity and specificity in our model were higher than in previous studies. Our research could help clinicians better predict medium-giant CAA and choose more appropriate treatment.

BACKGROUND: Human scalp hair is a validated bio-substrate for monitoring various exposures in childhood including contextual stressors, environmental toxins, prescription or non-prescription drugs. Linear hair growth rates (HGR) are required to accurately interpret hair biomarker concentrations. METHODS: We measured HGR in a prospective cohort of preschool children (N = 266) aged 9-72 months and assessed demographic factors, anthropometrics, and hair protein content (HPC). We examined HGR differences by age, sex, race, height, hair pigment, and season, and used univariable and multivariable linear regression models to identify HGR-related factors. RESULTS: Infants below 1 year (288 ± 61 μm/day) had slower HGR than children aged 2-5 years (p = 0.0073). Dark-haired children (352 ± 52 μm/day) had higher HGR than light-haired children (325 ± 50 μm/day; p = 0.0019). Asian subjects had the highest HGR overall (p = 0.016). Younger children had higher HPC (p = 0.0014) and their HPC-adjusted HGRs were slower than older children (p = 0.0073). Age, height, hair pigmentation, and HPC were related to HGR in multivariable regression models. CONCLUSIONS: We identified age, height, hair pigment, and hair protein concentration as significant determinants of linear HGRs. These findings help explain the known hair biomarker differences between children and adults and aid accurate interpretation of hair biomarker results in preschool children. IMPACT: Discovery of hair biomarkers in the past few decades has transformed scientific disciplines like toxicology, pharmacology, epidemiology, forensics, healthcare, and developmental psychology. Identifying determinants of hair growth in children is essential for accurate interpretation of hair biomarker results in pediatric clinical studies. Childhood hair growth rates define the time-periods of biomarker incorporation into growing hair, essential for interpreting the biomarkers associated with environmental exposures and the mind-brain-body connectome. Our study describes age-, sex-, and height-based distributions of linear hair growth rates and provides determinants of linear hair growth rates in a large population of children. Age, height, hair pigmentation, and hair protein content are determinants of hair growth rates and should be accounted for in child hair biomarkers studies. Our findings on hair protein content and linear hair growth rates may provide physiological explanations for differences in hair growth rates and biomarkers in preschool children as compared to adults.

BACKGROUND: The normative blood pressure values in preterm infants still not well defined during postnatal transition. We aimed to create normative blood pressure (BP) reference values in preterm infants <29 weeks gestational age recorded hourly during the postnatal transition. METHODS: We included only data from hemodynamically stable newborns. Only BP values measured by umbilical arterial catheter (UAC) were included. The regression model showed that only gestational age and postnatal age in hours determine the BP. RESULTS: We included 206 out of 547 admitted preterm infants. The BP increases with increasing gestational ages and overtime during the postnatal transition. We constructed 5 BP centile values for each gestational group. BP histograms show that the BP most of the time fluctuated between the 5th and 75th centile values, particularity during day one of life. CONCLUSIONS: The BP trend values gradually increase in stable preterm infants during the postnatal transition, and preterm infants who do not follow this trend might require hemodynamics assessment. IMPACT: The normative blood pressure is increasing gradually during the first 3 days after birth and is different with gestational ages. This is first normative blood pressure centile values in stable preterm infant and based on invasive blood pressure monitoring. The data enable more accurate monitoring of hemodynamics in preterm infants during postnatal transition.

Preterm infants often experience breathing instability and a hampered lung function. Therefore, these infants receive cardiorespiratory monitoring and respiratory support. However, the current respiratory monitoring technique may be unreliable for especially obstructive apnea detection and classification and it does not provide insight in breathing effort. The latter makes the selection of the adequate mode and level of respiratory support difficult. Electromyography of the diaphragm (dEMG) has the potential of monitoring heart rate (HR) and respiratory rate (RR), and it provides additional information on breathing effort. This review summarizes the available evidence on the clinical potential of dEMG to provide cardiorespiratory monitoring, to synchronize patient-ventilator interaction, and to optimize the mode and level of respiratory support in the individual newborn infant. We also try to identify gaps in knowledge and future developments needed to ensure widespread implementation in clinical practice. IMPACT: Preterm infants require cardiorespiratory monitoring and respiratory support due to breathing instability and a hampered lung function. The current respiratory monitoring technique may provide unreliable measurements and does not provide insight in breathing effort, which makes the selection of the optimal respiratory support settings difficult. Measuring diaphragm activity could improve cardiorespiratory monitoring by providing insight in breathing effort and could potentially have an important role in individualizing respiratory support in newborn infants.

Postbiotics, as emerging products, were added to infant formula, but their safety and efficacy are unclear. To clarify this issue, we wrote this meta-analysis. We searched PubMed, Embase, Web of Science and ProQuest from its establishment to February 2023. The review was registered on PROSPERO database (CRD42022352405). The effects of infant formula with and without postbiotics were compared, and the incidence of serious adverse events (SAEs), digestive symptoms, concentration of stool secretory immunoglobulin A (SIgA), and growth and development indexes were analyzed. Nine randomized controlled trials with 2065 participants were included. The addition of postbiotics to infant formula was found to increase the concentration of stool SIgA (P < 0.05) with very low certainty of evidence, without significantly impacting the incidence of SAEs, infantile colic, flatulence, diarrhea, vomiting, abdominal pain and gastrointestinal disorders, the daily weight gain, the total gain in body length and the daily head circumference gain (all P > 0.05). Adding postbiotics to the formula is safe for infants, which would not increase the incidence of SAEs, infantile colic, flatulence, diarrhea, vomiting, abdominal pain, and gastrointestinal disorders, and could increase the concentration of stool SIgA. IMPACT: Our study provides evidence that the addition of postbiotics to infant formula is safe but not effective. This is the first systematic review and meta-analysis of postbiotics. This study provides strong evidence for the safety of postbiotics and lays a foundation for related clinical trials.

BACKGROUND: Pathogenic GATA6 variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenic GATA6 variation in humans remains to be fully understood. METHODS: Exome sequencing was performed in a family where four members had CHD. In vitro functional analysis of the GATA6 variant was performed using immunofluorescence, western blot, and dual-luciferase reporter assay. RESULTS: A novel, heterozygous missense variant in GATA6 (c.1403 G > A; p.Cys468Tyr) segregated with affected members in a family with CHD, including three with persistent truncus arteriosus. In addition, one member had childhood onset diabetes mellitus (DM), and another had necrotizing enterocolitis (NEC) with intestinal perforation. The p.Cys468Tyr variant was located in the c-terminal zinc finger domain encoded by exon 4. The mutant protein demonstrated an abnormal nuclear localization pattern with protein aggregation and decreased transcriptional activity. CONCLUSIONS: We report a novel, familial GATA6 likely pathogenic variant associated with CHD, DM, and NEC with intestinal perforation. These findings expand the phenotypic spectrum of pathologic GATA6 variation to include intestinal abnormalities. IMPACT: Exome sequencing identified a novel heterozygous GATA6 variant (p.Cys468Tyr) that segregated in a family with CHD including persistent truncus arteriosus, atrial septal defects and bicuspid aortic valve. Additionally, affected members displayed extracardiac findings including childhood-onset diabetes mellitus, and uniquely, necrotizing enterocolitis with intestinal perforation in the first four days of life. In vitro functional assays demonstrated that GATA6 p.Cys468Tyr variant leads to cellular localization defects and decreased transactivation activity. This work supports the importance of GATA6 as a causative gene for CHD and expands the phenotypic spectrum of pathogenic GATA6 variation, highlighting neonatal intestinal perforation as a novel extracardiac phenotype.

BACKGROUND: To characterize neurodevelopmental abnormalities in children up to 36 months of age with congenital Zika virus exposure. METHODS: From the U.S. Zika Pregnancy and Infant Registry, a national surveillance system to monitor pregnancies with laboratory evidence of Zika virus infection, pregnancy outcomes and presence of Zika associated birth defects (ZBD) were reported among infants with available information. Neurologic sequelae and developmental delay were reported among children with ≥1 follow-up exam after 14 days of age or with ≥1 visit with development reported, respectively. RESULTS: Among 2248 infants, 10.1% were born preterm, and 10.5% were small-for-gestational age. Overall, 122 (5.4%) had any ZBD; 91.8% of infants had brain abnormalities or microcephaly, 23.0% had eye abnormalities, and 14.8% had both. Of 1881 children ≥1 follow-up exam reported, neurologic sequelae were more common among children with ZBD (44.6%) vs. without ZBD (1.5%). Of children with ≥1 visit with development reported, 46.8% (51/109) of children with ZBD and 7.4% (129/1739) of children without ZBD had confirmed or possible developmental delay. CONCLUSION: Understanding the prevalence of developmental delays and healthcare needs of children with congenital Zika virus exposure can inform health systems and planning to ensure services are available for affected families. IMPACT: We characterize pregnancy and infant outcomes and describe neurodevelopmental abnormalities up to 36 months of age by presence of Zika associated birth defects (ZBD). Neurologic sequelae and developmental delays were common among children with ZBD. Children with ZBD had increased frequency of neurologic sequelae and developmental delay compared to children without ZBD. Longitudinal follow-up of infants with Zika virus exposure in utero is important to characterize neurodevelopmental delay not apparent in early infancy, but logistically challenging in surveillance models.

BACKGROUND: This study is a preliminary clinical investigation with the objective to evaluate the facial thermal response of premature and term neonates to a non-painful stressor (hunger) using infrared thermography (IRT). The development of objective and reliable parameters to monitor pain and stress is of relevance for optimal neonatal outcome and achieving a better management of patient comfort. METHODS: We enrolled 12 neonates ranging from 27 to 39 weeks gestation (median: 34) and aged 3-79 days (median: 13). Recordings were performed before and after feeding, with and without hunger. Six regions of interest were chosen for evaluation (nose tip, periorbital and corrugator region, forehead, perioral and chin region). RESULTS: There was an increase in the facial temperature in infants immediately prior to their next feed relative to infants who were not hungry, with the nasal tip being the facial evaluation site with the greatest temperature change. CONCLUSIONS: The IRT appears to be a feasible and suitable method to detect changes in the neonatal patient. The thermal variations observed seem to reflect an arousal mediated by the parasympathetic nervous system, which has been described in existing infant stress research. IMPACT: This is the first study to examine the use of infrared thermography (IRT) in monitoring the facial thermal response to a mild stressor (hunger) in premature and term neonates. Hunger as a mild, non-pain-associated stressor showed a significant effect on the facial temperature. The thermal signature of the regions of interest chosen showed hunger-related thermal variations. Results suggest the feasibility and suitability of IRT as an objective diagnostic tool to approach stress and changes in the condition of the neonatal patient.

BACKGROUND: The relationship between infant colic and breast milk beta-endorphin (BE) and relaxin-2 (RLX-2) has not been studied before. METHODS: Thirty colic infants and their mothers constituted the study group, and the same sex, similar age and healthy infants and their mothers formed the control group. Maternal predisposing factors were analysed with questionnaires. RESULTS: The frequency of headache and myalgia in the mothers was significantly higher in the study group compared to the control group. Sleep quality of mothers in the study group was worse than in the control group (p = 0.028). While breast milk RLX-2 level in the study group was not different from the control group, breast milk BE level in the study group was significantly higher than the control group (p = 0.039). A positive correlation was found between breast milk BE levels and crying times, and between sleep quality scores and crying times. Headache, myalgia, sleep quality and breast milk BE levels were found to have a significant effect on infant colic. CONCLUSIONS: Breast milk RLX-2 has no role on infant colic. Breast milk BE may act as a biological mediator in transmitting of maternal predisposing factors such as poor sleep quality, headache and myalgia from mother to infant. IMPACT: The relationship between infant colic and breast milk beta-endorphin (BE) and elaxin-2 (RLX-2) has not been studied before. Maternal sleep quality, headache, and myalgia are predisposing factors associated with infant colic. Breast milk RLX-2 has no effect on infant colic. Breast milk BE may play a role as a biological mediator in transmitting the effects of predisposing factors from mother to infant. Breast milk BE may be a mediator in biological communication between mother and infant.

BACKGROUND: Research in singletons identified fetal growth restriction (FGR) as a risk factor for retinopathy of prematurity (ROP), but is generally subject to confounding by genetic, obstetric, and maternal factors. We investigated the effect of FGR on ROP in growth-discordant identical twins, thereby controlling for confounding factors. METHODS: All data of monochorionic (MC) twin pairs with a birth weight discordance ≥20% born in our center between 2010 and 2021 were retrospectively reviewed for the presence of ROP. Potential risk factors for ROP were analyzed. Outcomes were compared between the smaller and larger twin. RESULTS: We included 88 MC twin pairs with growth discordance. In 34% (30/88), both neonates were at risk of ROP. Prevalence of ROP was higher among the smaller twin compared to the larger twin, 30% (9/30) versus 13% (4/30), respectively (OR 2.8, 95% CI: 1.2-6.6). The smaller twin had a longer duration of mechanical ventilation (8 (1-20) versus 2 (1-4) days) and received their first red blood cell transfusion at an earlier postmenstrual age (29.6 (28.1-31.6) versus 30.4 (29.7-32.6) weeks). CONCLUSIONS: In this identical twin model, FGR is associated with almost tripled odds of ROP development, suggesting that both unfavorable antenatal growth conditions and adverse neonatal outcomes affect postnatal retinal vascular proliferation. IMPACT: Fetal growth restriction in growth-discordant identical twins is associated with almost tripled odds of developing retinopathy of prematurity in the smaller twin. Since these twins do not only differ in birth weight but also duration of mechanical ventilation and timing of the first red blood cell transfusion, both unfavorable antenatal growth conditions and adverse neonatal outcomes can affect postnatal retinal vascular proliferation. More attention for preventing retinopathy of prematurity is needed in those with fetal growth restriction who received prolonged duration of mechanical ventilation, oxygen supplementation, or a first red blood cell transfusion <32 weeks postmenstrual age.

BACKGROUND: A current area of research interest is the association between ADHD and weight status. This paper aimed to describe the anthropometric status of school children with ADHD, considering age and clinical presentation (inattentive, hyperactive-impulsive, or combined), compared with control children. METHODS: Participants came from the "Epidemiological Research Project on Neurodevelopmental Disorders" and consisted of 198 preschoolers (41 with ADHD) and 389 elementary school children (163 with ADHD). ADHD was diagnosed using DSM-5 criteria. Anthropometric measurements were taken at various anatomical points, and height, weight, and body composition were also measured. RESULTS: In preschoolers, an association was found between hyperactive-impulsive ADHD and greater height and lower waist-to-height ratio. In elementary school children, regardless of the medication, combined ADHD was associated with smaller head, hip, arm, and thigh circumferences and lower weight, height, and BMI. A total of 19.7% of them were underweight. In contrast, children with inattentive and hyperactive/impulsive presentations presented the highest percentage of overweight/obesity (56%). CONCLUSION: The anthropometric status of the school children with ADHD showed differences in terms of age and presentation. Preschoolers with hyperactive-impulsive ADHD are taller, and elementary school children with combined ADHD are shorter and smaller than their age-matched control peers. IMPACT: The anthropometric status of the school children with ADHD showed differences in terms of age and presentation. Preschoolers with hyperactive-impulsive ADHD are taller than their control peers. Elementary school children with combined ADHD, regardless of the pharmacological treatment, are shorter and smaller than their control peers. Medication may anthropometrically affect the height of children with inattentive presentation. Anthropometric and dietary monitoring should be recommended to parents of children with ADHD, with and without medication.

BACKGROUND: Patterns of blood pressure (BP) change from early adolescence to young adulthood have not been well-described. The objective of this study was to examine the predictive value of pediatric BP classification on BP change and identify subpopulations with large BP increases during adolescence and early adulthood. METHODS: Baseline data were obtained from medical checkups of Japanese adolescents aged 12-13 years in 2009 or 2010 and subsequent BP values were followed for a 9-year period. Mixed-effects models were used to estimate the effects of baseline factors on subsequent BP changes. RESULTS: Hypertensive and elevated BP group consistently had higher BP values than normal BP group throughout the observation period. Multivariate mixed-effects model analyses revealed group-by-time interactions between systolic BP change and BP category in males and uric acid category in females, and between diastolic BP change and white blood cell count in males and obesity and high-density lipoprotein cholesterol in females; however, these factors had limited effects on the rate of BP increase, indicating that they are not suitable as clinical predictors of BP increase. CONCLUSIONS: Pediatric BP category predicted BP values, but there was no factor that identified subpopulations with large BP increases in adolescence and early adulthood. IMPACT: Blood pressure category in the American Academy of Pediatrics clinical practice guideline at age 12-13 years predicted subsequent blood pressure values during adolescence and early adulthood. No baseline factor that identified a subpopulation with large increase in blood pressure during adolescence and early adulthood in clinical practice was found. Our study contributes to the existing literature by demonstrating the usefulness of the American Academy of Pediatrics clinical practice guideline for blood pressure classification in a Japanese population.

BACKGROUND: Extremely premature infants are at risk for circulatory collapse or respiratory failure that are often treated with hydrocortisone (HC); however, there is no information on the metabolic consequences of this therapy. METHODS: Longitudinal urine samples from infants <28 weeks gestation in the Trial of Late Surfactant were analyzed by untargeted UHPLC:MS/MS. Fourteen infants who received a tapering course of HC beginning at 3 mg/kg/day for ≥9 days were compared to 14 matched control infants. A secondary cross-sectional analysis by logistic regression used urines from 314 infants. RESULTS: Of 1145 urinary metabolites detected, abundance of 219, representing all the major biochemical pathways, changed at p < 0.05 in the HC-treated group with 90% decreasing; 3 cortisol derivatives increased ~2-fold with HC therapy. Only 11% of regulated metabolites remained responsive at the lowest HC dose. Regulated metabolites included two steroids and thiamin that are associated with lung inflammation in infants. HC responsiveness was confirmed in 57% of metabolites by cross-sectional analysis. CONCLUSIONS: HC treatment of premature infants influenced in a dose-dependent manner abundance of 19% of identified urinary metabolites of diverse biochemical systems, primarily reducing concentrations. These findings indicate that exposure to HC reversibly impacts the nutritional status of premature infants. IMPACT: Hydrocortisone treatment of premature infants with respiratory failure or circulatory collapse alters levels of a subset of urinary metabolites representing all major biochemical pathways. This is the first description of the scope, magnitude, timing and reversibility of metabolomic changes in infants in response to hydrocortisone, and it confirms corticosteroid regulation of three biochemicals that are associated with lung inflammatory status. The findings indicate a dose-dependency of hydrocortisone for metabolomic and anti-inflammatory effects, that prolonged therapy may lower the supply of many nutrients, and that monitoring concentrations of cortisol and inflammation markers may be a useful clinical approach during corticosteroid therapy.

BACKGROUND: Acute kidney injury (AKI) is common in sick neonates and associated with poor pulmonary outcomes, however, the mechanisms responsible remain unknown. We present two novel neonatal rodent models of AKI to investigate the pulmonary effects of AKI. METHODS: In rat pups, AKI was induced surgically via bilateral ischemia-reperfusion injury (bIRI) or pharmacologically using aristolochic acid (AA). AKI was confirmed with plasma blood urea nitrogen and creatinine measurements and kidney injury molecule-1 staining on renal immunohistochemistry. Lung morphometrics were quantified with radial alveolar count and mean linear intercept, and angiogenesis investigated by pulmonary vessel density (PVD) and vascular endothelial growth factor (VEGF) protein expression. For the surgical model, bIRI, sham, and non-surgical pups were compared. For the pharmacologic model, AA pups were compared to vehicle controls. RESULTS: AKI occurred in bIRI and AA pups, and they demonstrated decreased alveolarization, PVD, and VEGF protein expression compared controls. Sham pups did not experience AKI, however, demonstrated decreased alveolarization, PVD, and VEGF protein expression compared to controls. CONCLUSION: Pharmacologic AKI and surgery in neonatal rat pups, with or without AKI, decreased alveolarization and angiogenesis, producing a bronchopulmonary dysplasia phenotype. These models provide a framework for elucidating the relationship between AKI and adverse pulmonary outcomes. IMPACT: There are no published neonatal rodent models investigating the pulmonary effects after neonatal acute kidney injury, despite known clinical associations. We present two novel neonatal rodent models of acute kidney injury to study the impact of acute kidney injury on the developing lung. We demonstrate the pulmonary effects of both ischemia-reperfusion injury and nephrotoxin-induced AKI on the developing lung, with decreased alveolarization and angiogenesis, mimicking the lung phenotype of bronchopulmonary dysplasia. Neonatal rodent models of acute kidney injury provide opportunities to study mechanisms of kidney-lung crosstalk and novel therapeutics in the context of acute kidney injury in a premature infant.