Severe Neurodevelopmental Impairment Research Articles

Longitudinal analysis of urinary I-FABP in extremely preterm infants that develop necrotizing enterocolitis.

Intestinal fatty acid binding protein (I-FABP) is an intestinal epithelial protein detectable in infants with necrotizing enterocolitis (NEC). The longitudinal behavior of I-FABP following NEC or its association with gastrointestinal or neurodevelopmental outcomes is unknown. In this secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, we compared infants with and without NEC. Urine I-FABP concentrations in matched infants (n = 70) were measured serially using ELISA and compared using paired analysis. In infants with NEC, the associations of I-FABP levels with short-term outcomes and neurodevelopmental outcomes at 22-26 months corrected age were determined using non-parametric analysis. Infants with NEC were more likely to have cholestasis, death or severe neurodevelopmental impairment, cerebral palsy, and lower Bayley-III motor scores. Baseline urinary I-FABP levels were similar between groups. When compared to controls, infants with NEC had urinary I-FABP concentrations that were higher at diagnosis (median 11 vs 2.6 ng/ml, p = 0.006) and lower post-NEC (median 1 vs 5 ng/ml, p = 0.002). Diagnosis I-FABP levels were not associated with gastrointestinal or neurodevelopmental outcomes at 22-26 months corrected age. In extremely preterm infants, urinary I-FABP was elevated at NEC diagnosis and lower post-NEC compared to matched controls. I-FABP levels were not associated with adverse gastrointestinal or neurodevelopmental outcomes. Urinary intestinal fatty acid binding protein (I-FABP) levels are increased at diagnosis of NEC and fall to below baseline after NEC in extremely preterm infants. Urine I-FABP levels at NEC diagnosis are not associated with cholestasis, intestinal stricture or obstruction, need for additional intestinal surgery after NEC, or neurodevelopmental outcomes at 22-26 months corrected age. Urine I-FABP levels may be useful in the diagnosis of NEC. Diagnostic I-FABP levels do not predict short-term gastrointestinal or neurodevelopmental outcomes after NEC.

Need for national guidance regarding proactive care of infants born at 22-23 weeks' gestation.

With recent rapid improvements in neonatal intensive care, the limit of viability has shifted downward to 22-23 weeks' gestation. The younger the gestational age of preterm infants, the higher the risk of survival despite severe neurodevelopmental impairments. For infants born at 22-23 weeks' gestation, the limit of viability, neurodevelopmental outcomes, and survival rates may be determined by the quality of proactive care. Owing to the high risk of severe neurodevelopmental impairment in 22-23 weeks' gestation, proactive care is sometimes withheld according to ethical or legal considerations, and there are significant differences in the provision of proactive care and survival rates across countries or institutions. Additionally, there are differing or even lacking guidelines regarding the care of these infants across countries and institutions. Japan and Sweden are countries with well-established national guidance and proactive care for infants born at 22-23 weeks' gestation, resulting in higher survival rates among them. In Korea, where there is an extreme shortage of neonatologists, maternal transfer before delivery at 22-23 weeks' gestation to high-activity regions with appropriate neonatal intensive care unit resources, such as adequate personnel and facilities similar to the centralized care model seen in Sweden, is crucial for improving the survival rates of infants born at 22-23 weeks' gestation. The survival of these infants largely depends on the quality of proactive care provided. This rate is not static and can be improved through proactive case management based on national guidance and the implementation of enhanced neonatal intensive care practices, including centralization of care.

Most babies born at a French hospital before 26 weeks survived with good outcomes.

The aim of this French study was to determine the neonatal morbidity, mortality and neurodevelopmental outcomes when infants born at the limit of viability reached 2 years of corrected age. We then compared the results with national and international cohorts. This study focused on 294 French infants born from 22 to 25 weeks of gestation in a single tertiary perinatal centre from January 2010 to December 2019. We used data on neonatal mortality and morbidity to calculate the survival rates of infants without moderate to severe neurodevelopmental and sensory deficits at 2 years of corrected age. These outcomes were compared with data from contemporary epidemiological studies of similar populations. Nearly two-thirds (60.5%) of the infants survived to discharge, with varying rates based on their gestational ages, and 57.3% had no severe neonatal morbidity. The vast majority (90.4%) of the 166 alive and available at 2 years of corrected age were free of moderate to severe neurodevelopmental impairment. Our survival rates exceeded a national French cohort study, but were closely aligned with international cohorts. These findings highlight the importance of incorporating local data into ethical decision-making about life-saving treatment for infants at the limit of viability.

Early developmental alterations of CA1 pyramidal cells in Dravet syndrome

Dravet Syndrome (DS) is most often caused by heterozygous loss-of-function mutations in the voltage-gated sodium channel gene SCN1A (Nav1.1), resulting in severe epilepsy and neurodevelopmental impairment thought to be cause by reduced interneuron excitability. However, recent studies in mouse models suggest that interneuron dysfunction alone does not completely explain all the cellular and network impairments seen in DS. Here, we investigated the development of the intrinsic, synaptic, and network properties of CA1 pyramidal cells in a DS model prior to the appearance of overt seizures. We report that CA1 pyramidal cell development is altered by heterozygous reduction of Scn1a, and propose that this is explained by a period of reduced intrinsic excitability in early postnatal life, during which Scn1a is normally expressed in hippocampal pyramidal cells. We also use a novel ex vivo model of homeostatic plasticity to show an instability in homeostatic response during DS epileptogenesis. This study provides evidence for the early effects of Scn1a haploinsufficiency in pyramidal cells in contributing to the pathophysiology of DS.

Trends in sex differences in neurodevelopmental outcomes among extremely preterm infants

ObjectiveTo examine whether changes in survival without moderate or severe neurodevelopmental impairment (NDI) at 18–26 months’ corrected age from 1999 to 2018 differed between male and female infants.DesignThis retrospective cohort...

Fetoscopic laser photocoagulation: a medically reasonable treatment option in the management of types II and III vasa previa.

Vasa previa is a condition where unprotected fetal vessels cross the cervix within the membranes, posing a considerable risk of fetal death or severe morbidity if the membranes rupture before or during delivery. There has not been a definitive in utero treatment for this condition. Patients are typically closely monitored and hospitalized in the early third trimester and scheduled for cesarean delivery before term. This approach poses considerable physical, social, psychological, and financial challenges for pregnant patients and their families. Furthermore, fetal vessel rupture may lead to severe hypoxic-ischemic injury and consequent neurodevelopmental impairment. Finally, babies delivered early due to vasa previa may face both the short- and long-term consequences of prematurity. Recently, fetoscopic laser photocoagulation using a single-port fetoscope has emerged as a potential therapeutic option for patients with types II and III vasa previa. This innovative approach aims to reduce hospital stays, increases the chance of successful vaginal delivery, and potentially allows pregnancies to reach full term, providing lifelong benefits for the infant. Preliminary clinical studies on human subjects have demonstrated promising results concerning the feasibility, safety, and efficacy of this intervention for a subset of patients with types II and III vasa previa. After reviewing the current state of the art, we argued that offering fetoscopic laser photocoagulation in specialized centers under IRB supervision meets the ethical obligations of beneficence and non-maleficence for both pregnant and fetal patients, as well as the autonomy-based obligations for pregnant patients.

Prolonged oligohydramnios and the adverse composite outcome of death or severe neurodevelopmental impairment at 3 years of age in infants born at 22–29 gestational weeks

ObjectiveTo investigate the association between prolonged oligohydramnios and a composite outcome of death or severe neurodevelopmental impairment (NDI) at 3 years of age. MethodsThis single-center retrospective cohort study enrolled infants born at 22–29 weeks of gestational age without major congenital anomalies. The patients were classified into three groups depending on the existence and duration of oligohydramnios: no/non-prolonged oligohydramnios (no or 0–7 days of oligohydramnios), prolonged oligohydramnios (8–14 days), and very prolonged oligohydramnios (> 14 days). The primary outcome was a composite of death or severe NDI, which was defined as severe cerebral palsy, developmental delay, severe visual impairment, or deafness at age 3. ResultsOut of the 843 patients, 784 (93 %), 30 (3.6 %), and 29 (3.4 %) were classified into the no/non-prolonged, prolonged, and very prolonged oligohydramnios groups, respectively. After excluding patients lost to follow-up, the adverse composite outcome at 3 years of age was observed in 194/662 (29 %), 7/26 (27 %), and 8/23 (35 %) in the corresponding groups. The composite outcome showed no significant trend with the duration of oligohydramnios (P = 0.70). In a logistic regression model controlling the known predictors of gestational age, birth weight, small-for-gestational-age, male sex, multiple pregnancy, hypertensive disorders of pregnancy, antenatal corticosteroids, and the number of family–social risk factors, the duration of oligohydramnios was not independently associated with the composite outcome; odds ratio 1.3 (95 % confidence interval, 0.78–2.0). ConclusionProlonged oligohydramnios was not associated with the composite outcome of death or severe NDI at 3 years of age.

Neurodevelopmental outcomes in extremely preterm infants with placental pathologic evidence of fetal inflammatroy response.

Neonates born with fetal inflammatory response (FIR) are at increased risk for adverse neonatal outcomes. Our objective was to determine whether FIR and its severity is associated with neurodevelopmental impairment (NDI) at 2 years of age or death among preterm infants. A retrospective cohort study of prospectively collected data of all infants born <29 weeks gestational age (GA). FIR and its severity were diagnosed according to the Amsterdam Placental Workshop Group Consensus Statement. Neurodevelopmental outcomes among all participants were quantified according to Bayley III. Mothers of infants with FIR were significantly younger (P = 0.04) and had a greater prevalence of antenatal steroid use (P < 0.01), infection during pregnancy (P = 0.01), PPROM (P < 0.01), and clinical chorioamnionitis (P < 0.01). Infants with FIR had longer duration of hospitalization (P < 0.01), days on oxygen (P < 0.01), congenital pneumonia (P = 0.03), moderate/severe bronchopulmonary dysplasia (BPD; P < 0.01). Notably, infants with FIR were not at increased risk of NDI or death (primary outcome). Those with moderate to severe FIR (≥ stage 2 FIR) were at increased risk of developing motor & language impairment or death (P < 0.01). This is the first report demonstrating an association between the severity of FIR and subsequent NDI in preterm infants born. Fetal Inflammatory Response (FIR) is not associated Neurodevelopmental Impairement (NDI) or Death in preterm infants However, there is significant relationship between moderate to severe FIR and NDI at 2 years of age in preterm infants. This is the first study demonstrating the impact of progression and severity of FIR on NDI or Death in preterm infants. These observations provide additional insight into understanding the impact of intrauterine exposure to inflammation on the NDI or death in preterm infants.

Synthetic magnetic resonance-based relaxometry and brain volume: cutoff values for predicting neurocognitive outcomes in very preterm infants

BackgroundEarly neurorehabilitation can enhance neurocognitive outcomes in very preterm infants (<32 weeks), and conventional magnetic resonance imaging (MRI) is commonly used to assess neonatal brain injury; however, the predictive value for neurodevelopmental delay is limited. Timely predictive quantitative biomarkers are needed to improve early identification and management of infants at risk of neurodevelopmental delay.ObjectiveTo evaluate the potential of quantitative synthetic MRI measurements at term-equivalent age as predictive biomarkers of neurodevelopmental impairment and establish practical cutoff values to guide clinical decision-making.Materials and methodsThis retrospective study included 93 very preterm infants who underwent synthetic MRI at term-equivalent age between January 2017 and September 2020. Clinical outcomes were assessed using the Bayley-III scale of infant development (mean age 2.1 years). The predictive value for impaired development was analyzed using receiver operating characteristic curves for synthetic MRI-based volumetry and T1 and T2 relaxation measurements.ResultsThe T1 relaxation time in the posterior limb of the internal capsule was a potent predictor of severe (sensitivity, 92%; specificity, 80%; area under the curve (AUC), 0.91) and mild or severe (AUC, 0.75) developmental impairment. T2 relaxation time in the posterior limb of the internal capsule was a significant predictor of severe impairment (AUC, 0.76), whereas the brain parenchymal volume was a significant predictor of severe (AUC, 0.72) and mild or severe impairment (AUC, 0.71) outperforming the reported qualitative MRI scores (AUC, 0.66).ConclusionThe proposed cutoff values for T1 relaxation time in the posterior limb of the internal capsule and for total brain volume measurements, derived from synthetic MRI, show promise as predictors of both mild and severe neurodevelopmental impairment in very preterm infants.Graphical

Severe brain injury and trends of gestational‐age‐related neurodevelopmental outcomes in infants born very preterm: A population cohort study

AbstractAimTo investigate the impact of severe neonatal brain injury (SNBI) on gestational age‐related trends in neurodevelopmental impairment (NDI) outcome in infants born very preterm.MethodA population‐based cohort study recruited 1091 infants born at a gestational age of less than 31 weeks between 2011 and 2020. The trends in neonatal morbidities, mortality, and 24‐month NDI severity (no/mild, moderate, severe) by epoch (2011–2015, 2016–2020) and gestational age (22–25 weeks, 26–28 weeks, 29–30 weeks) were determined in infants with and without SNBI inclusion.ResultsThere was increased antenatal steroid use and higher maternal education and socioeconomic status over time. The rates of neonatal morbidities and mortality had no temporal changes. Among 825 infants with follow‐up, those in the 22 to 25 weeks gestational age group had declining trends in cerebral palsy and severe cognitive impairment, with decreased rates of severe NDI from 19% to 8% across epochs, particularly in those without SNBI (from 16% to 2%). Relative to its occurrence in epoch 2011 to 2015, risk of severe NDI was significantly reduced in epoch 2016 to 2020 (adjusted relative risk 0.39, 95% confidence interval 0.16–0.96) for infants born at 22 to 25 weeks gestational age, and the risk dropped even lower in these infants without SNBI (0.12, 0.02–0.84).InterpretationInfants born at 22 to 25 weeks gestational age had decreased rates of severe NDI in the decade between 2011 and 2020, particularly those without SNBI. The improvement might be attributed to better perinatal/neonatal and after‐discharge care.

Report of a New Pediatric Patient with the SLC1A4 Variant and a Brief Review of the Literature

AbstractSpastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) is an autosomal recessive disorder characterized by the onset of those features and severely impaired global development in early infancy, and caused by biallelic deleterious SLC1A4 variants. SLC1A4 encodes for the neutral amino acid transporter, ASCT1, which is necessary for L-serine and D-serine cellular transport to neurons. The objective of this study was to contribute to the genotype–phenotype correlation of SLC1A4 variants. We evaluated a Turkish patient presenting with SPATCCM without seizures and reviewed all previously reported cases of the SLC1A4 mutation. Whole exome sequencing revealed a missense biallelic p.R457W variant in SLC1A4 in a child of Palestinian origin. We suggest that the SLC1A4 should be considered in the diagnosis of unexplained severe early-onset neurodevelopmental impairment, progressive microcephaly, and spastic tetraparesis with or without epilepsy, regardless of ethnicity and encourage the analysis of SLC1A4 variants via molecular genetic testing. The presence or absence of epilepsy should not distract from the diagnosis.

Association of maternal pre-pregnancy or first trimester body mass index with neurodevelopmental impairment or death in extremely low gestational age neonates.

To compare the rates of death or survival with severe neurodevelopmental impairment (sNDI) at 2 years among extremely preterm infants in relation to pre-pregnancy or first-trimester maternal body mass index (BMI). This retrospective cohort study included extremely preterm infants (gestational age 220/7-266/7 weeks). The study was conducted at National Institute of Child Health and Human Development Neonatal Research Network sites. The primary outcome was death or sNDI at 2 years. Data on the primary outcome were available for 1208 children. Death or sNDI was not different among the three groups: 54.9% in normal, 56.1% in overweight, and 53.4% in obese group (p = 0.39). There was no significant difference in mortality, sNDI, moderate/severe cerebral palsy, Bayley Scales of Infant Development (BSID)-III cognitive composite score <70, BSID-III language composite score <70 in adjusted models. Neurodevelopmental outcome was not significantly associated with maternal pre-pregnancy BMI among extreme preterm infants.

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm

Infants born extremely preterm receive transfusions at higher platelet count thresholds than older children and adults due to concerns for intracranial hemorrhage. A recent randomized trial comparing 2 platelet transfusion thresholds showed the higher threshold was associated with increased risk of long-term adverse neurodevelopmental outcomes. To evaluate the association of platelet transfusion exposure with death and severe neurodevelopmental impairment (NDI) at 2 years' corrected age in a cohort of infants born extremely preterm. An observational cohort study and secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, a randomized, placebo-controlled clinical trial of erythropoietin neuroprotection in neonates born extremely preterm, was conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 819 infants born extremely preterm at 24 to 27 completed weeks of gestation who had a documented outcome (death or neurodevelopmental assessment). Analysis was performed in April 2023. Any platelet transfusion during neonatal intensive care unit hospitalization. The primary composite outcome was death or severe NDI evaluated at 2 years' corrected age using the Bayley Scales of Infant Development-Third Edition (BSID-III) and the Gross Motor Function Classification System and was defined as the presence of severe cerebral palsy or a BSID-III composite motor or cognitive score 2 SDs below the mean. Confounding by indication for platelet transfusion was addressed with covariate adjustment and propensity score methods. Of the 819 infants included in the analysis (429 [52.4%] male; mean [SD] gestational age, 25.5 [1.1] weeks), 245 (30.0%) received at least 1 platelet transfusion during their initial hospitalization. The primary outcome occurred in 46.5% (114 of 245) of infants exposed to a platelet transfusion and 13.9% (80 of 574) of nonexposed infants with a corresponding odds ratio of 2.43 (95% CI, 1.24-4.76), adjusted for propensity score, gestational age at birth, and trial treatment group. The individual components of death and severe NDI were directionally consistent with the overall composite outcome. The findings of this study suggest that platelet transfusion in infants born extremely preterm may be associated with an increased risk of death or severe NDI at 2 years' corrected age, although the possibility of residual confounding by indication cannot be excluded.

Application of desirability of outcome ranking to the milking in non-vigorous infants trial

ObjectivesNeonatal trials have traditionally used binary composite short-term (such as death or bronchopulmonary dysplasia) or longer-term (such as death or severe neurodevelopmental impairment) outcomes. We applied the Desirability Of Outcome Ranking (DOOR) method to rank the overall patient outcome by best (no morbidities) to worst (death). Study designUsing a completed large multicenter trial (Milking In Non-Vigorous Infants [MINVI]) of umbilical cord milking (UCM) vs. early cord clamping (ECC), we applied the DOOR methodology to neonatal outcomes. Six outcomes were chosen and ranked: no interventions or NICU admission (most desirable); received initial cardiorespiratory support at birth; neonatal intensive care unit (NICU) admission for predefined criteria; mild hypoxic-ischemic encephalopathy (HIE); moderate to severe HIE; and death (least desirable). Results1524 non-vigorous newborns born between 35 and 42 weeks' gestation had data for analysis. The DOOR distribution was different between the UCM and ECC arms, with a significantly greater probability (55.8 % [95 % CI 53.1–58.5 %; p < 0.0001]) of a randomly selected neonate having a more desirable outcome if they were in the UCM arm. DOOR probabilities of averting individual adverse outcomes such as NICU admission for predefined criteria (52.8 %; 95%CI 50.5–55.1 %) and cardiorespiratory support (54.0 %; 95%CI 51.6–56.4 %) were significantly higher among those in the UCM group. ConclusionDOOR provides an overall assessment of the benefits and harms with greater insight than typical binary composite measures to clinicians and parents when evaluating an intervention. Future neonatal trials should consider the a priori use of the DOOR methodology to evaluate trial outcomes.

Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial

To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2mg/kg/dose enterally every 12hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. ClinicalTrials.govNCT02812433.

Association between intermittent hypoxemia and neurodevelopmental outcomes in extremely premature infants: A single-center experience

ObjectiveTo describe the association between intermittent hypoxemic events (IHEs) and severe neurodevelopmental impairment (SNDI) or death in extremely premature infants. Study designRetrospective study of extremely premature infants 230/7–276/7 weeks gestational age (GA) and birthweight (BW) ≤1250 g (g) admitted to a level IV neonatal intensive care unit (NICU) from 2013 to 2017. IHEs, defined as events with SpO2 ≤ 80 % lasting 10 s to 5 min, were algorithmically identified using data extracted from bedside monitors at 2 s intervals (0.5 Hz). The primary outcome was SNDI at 18–24 months corrected age (CA), defined as a Bayley-III motor, language or cognitive composite score ≤69, or death before discharge while the secondary outcome was SNDI alone. We used mixed-effects regression models to evaluate the relationship between mean daily IHE rate per postnatal week of life for the first 12 weeks and the outcomes, and logistic regression models to assess the association between outcomes and summary measures of hypoxic burden for the entire NICU hospitalization. ResultsThe mortality rate was 7 % (18/249) during NICU hospitalization. Of 249 infants born during this time period, IHE and neurodevelopmental outcome data were fully available for 65 infants (mean GA 26 ± 1.4 weeks, mean birth weight (BW) 738 ± 199 g). The outcome of SNDI alone occurred in 34 % (22/65) with a majority demonstrating motor or language delay on the Bayley-III. Although mean daily IHE rate/week was not associated with SNDI or death, total IHE duration was associated with increased odds of SNDI (OR (95 % CI) 1.03 (1.01, 1.05), p = 0.008) in models adjusted for GA. ConclusionsIn a cohort of extremely premature infants 23–27 weeks GA, each hour of total IHE duration (SpO2 ≤ 80 %) was associated with a 2.7 % (0.7 %, 4.8 %) increase in the odds of SNDI at 18–24 months CA.

NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron.

Pathogenic gene variants encoding nuclear pore complex (NPC) proteins were previously implicated in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). The NUP85 gene, encoding nucleoporin, is related to a very rare form of SRNS with limited genotype-phenotype information. We identified an Italian boy affected with an SRNS associated with severe neurodevelopmental impairment characterized by microcephaly, axial hypotonia, lack of achievement of motor milestones, and refractory seizures with an associated hypsarrhythmic pattern on electroencephalography. Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum and a simplified gyration of the cerebral cortex. Since the age of 3 years, the boy was followed up at our Pediatric Nephrology Department for an SRNS, with a focal segmental glomerulosclerosis at renal biopsy. The boy died 32 months after SRNS onset, and a Whole-Exome Sequencing analysis revealed a novel compound heterozygous variant in NUP85 (NM_024844.5): 611T>A (p.Val204Glu), c.1904T>G (p.Leu635Arg), inherited from the father and mother, respectively. We delineated the clinical phenotypes of NUP85-related disorders, reviewed the affected individuals so far reported in the literature, and overall expanded both the phenotypic and the molecular spectrum associated with this ultra-rare genetic condition. Our study suggests a potential occurrence of severe neurological phenotypes as part of the NUP85-related clinical spectrum and highlights an important involvement of nucleoporin in brain developmental processes and neurological function.

Neurodevelopmental Outcomes in Infants Screened for Retinopathy of Prematurity

Preterm infants screened for retinopathy of prematurity (ROP) are at risk for heterogenous neurodevelopment outcomes that are difficult to predict. To characterize the potential association between socioeconomic and clinical risk factors and neurodevelopmental outcomes in a diverse, multicenter cohort of premature neonates screened for ROP. This was a retrospective cohort study using electronic medical records and US Census Bureau income data. This study was performed at academic (University of California, Los Angeles [UCLA] Mattel Children's Hospital and UCLA Santa Monica Hospital), community (Cedars-Sinai Medical Center), and LA county (Harbor-UCLA Medical Center) neonatal intensive care units. Participants included infants who met American Academy of Pediatrics guidelines for ROP screening and had records from at least 1 Bayley Scales of Infant and Toddler Development (BSID) neurodevelopment assessment between 0 and 36 months of adjusted age. Data analyses were conducted from January 1, 2011, to September 1, 2022. Demographic and clinical information, proxy household income, and health insurance type were collected as risk factors. Neurodevelopmental outcomes in the cognitive, language, and motor domains measured via BSID were the primary outcomes. A total of 706 infants (mean [SD] age, 28.6 [2.4] weeks; 375 male [53.1%]) met inclusion criteria. In a multivariable model, which included adjustments for birth weight, sex, insurance type, intraventricular hemorrhage (IVH), and age at assessment, public health insurance was associated with a 4-fold increased risk of moderate to severe neurodevelopmental impairment (NDI) in cognitive and language domains (cognitive, odds ratio [OR], 3.65; 95% CI, 2.28-5.86; P = 8.1 × 10-8; language, OR, 3.96; 95% CI, 2.61-6.02; P = 1.0 × 10-10) and a 3-fold increased risk in the motor domain (motor, OR, 2.60; 95% CI, 1.59-4.24; P = 1.4 × 10-4). In this adjusted model, clinical factors that were associated with an increased risk of moderate to severe NDI included lower birth weight, diagnosis of IVH, male sex, and older age at time of Bayley assessment. In unadjusted analyses, infants who received either laser or anti-VEGF treatment, compared with infants without treatment-requiring ROP, had lower BSID scores in multiple domains at 0 to 12 months, 12 to 24 months, and 24 to 36 months (DATA). In the multivariable model, treatment type was no longer associated with worse neurodevelopmental outcomes in any domain. Study results suggest an association between public insurance type and NDI in a diverse population screened for ROP, indicating the complexities of neurodevelopment. This study also supports the early neurodevelopmental safety of anti-VEGF treatment, as anti-VEGF therapy was not found to be independently associated with worse NDI in any domain.

Association of EEG Background and Neurodevelopmental Outcome in Neonates With Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin or placebo for neonates with HIE treated with therapeutic hypothermia. Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at 5 1-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire continuous video EEG monitoring recording was calculated using the arithmetic mean of the 5 EEG background ratings (normal = 0; discontinuous = 1; severely abnormal = 2) as follows: "predominantly normal" (mean = 0), "normal/discontinuous" (0 < mean<1), "predominantly discontinuous" (mean = 1), "discontinuous/severely abnormal" (1 < mean<2), or "predominantly severely abnormal" (mean = 2). Primary outcome was death or neurodevelopmental impairment (NDI) defined as cerebral palsy, Gross Motor Function Classification Score ≥1, or cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition at age 2 years. Neurodevelopment was also categorized into a 5-level ordinal measure: no, mild, moderate, severe NDI, or death for secondary analysis. We used generalized linear regression models with robust standard errors to assess the relative risk of death or NDI by EEG background in both unadjusted and adjusted analyses controlling for the effects of treatment group, sex, HIE severity, and study recruitment site. Among 142 neonates, the predominant background EEG pattern was predominantly normal in 35 (25%), normal/discontinuous in 68 (48%), predominantly discontinuous in 11 (7.7%), discontinuous/severely abnormal in 16 (11%), and predominantly severely abnormal in 12 (8.5%). Increasing severity of background across monitoring epochs was associated with increasingly worse clinical outcomes. Children with severe EEG background abnormality at any time point (n = 36, 25%) were significantly more likely to die or have severe NDI at 2 years (adjusted relative risk: 7.95, 95% CI 3.49-18.12). EEG background is strongly associated with NDI at age 2 years. These results can be used to assist health care providers to plan follow-up care and counsel families for decision-making related to goals of care.

Risk factors for catheter-related bloodstream infections associated with home parental nutrition in children with intestinal failure: A prospective cohort study

Catheter-related bloodstream infection (CRBSI) is the most common, potentially life-threatening complication of long-term parenteral nutrition (PN). We prospectively assessed the incidence and risk factors for CRBSI in children receiving long-term home PN (HPN) for intestinal failure (IF) in a single IF rehabilitation center. Data regarding episodes and potential risk factors for CRBSI in children on HPN were prospectively recorded. Forty-one of 75 children were diagnosed with CRBSI. The overall CRBSI rate was 1.61 per 1000 catheter days. The indications for HPN were gastrointestinal motility disorders in 35%, short bowel syndrome (SBS) in 28% graft versus host disease (GvHD) post bone marrow transplant in 17%, congenital enteropathy in 15%, and severe neurodevelopmental impairment in 5%. Gastrointestinal motility disorders had significantly higher CRBSI rate compared to other groups (p<0.0005; 2.74 in motility group vs 1.54 in GvHD group vs 0.52 in congenital enteropathies vs 0.36 in SBS group vs 0.67 in severe neurodevelopmental delay). Multivariate analysis revealed that enterocutaneous distal stoma (ileostomy or colostomy) (HR 3.35 [95% CI, 1.63-6.86]; p<0.001), age <2 years (HR 0.28 [95% CI, 0.15-0.53]; p<0.0001), male sex (HR 2.28 [95% CI, 1.51-3.43]; p<0.0001), non-use of taurolidine citrate lock (HR 2.70 [95% CI, 1.72-4.11]; p<0.0001) and gastrointestinal motility disorder (HR 3.02 [95% CI, 1.81-4.91]; p<0.001) were independent risk factors for developing CRBSI. Extra care in managing PN connections and disconnections should be taken in children with an underlying gastrointestinal motility disorder, distal enterocutaneous stoma, male sex and those aged <2 years since they are at a significantly higher risk of CRBSI. Early introduction of taurolidine lock should be considered.