Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome.

GRIA1 encodes the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4. Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F0 models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.

Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study.

OBJECTIVE: To evaluate associations between neurologic outcomes and early measurements of basal ganglia (BG) and thalamic (Th) perfusion using color Doppler ultrasonography (CDUS) in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Prospective study of infants with mild (n = 18), moderate (n = 17), and severe HIE (n = 14) and controls (n = 17). Infants with moderate-severe HIE received therapeutic hypothermia (TH). CDUS was performed at 24-36 hours and brain magnetic resonance imaging (MRI) at a median of 10 days. Development was followed through 2.5-5 years. The primary outcome was the association between BG and Th perfusion and brain MRI injury. Secondary analyses focused on associations between perfusion measurements and admission neurologic examinations, MRI scores in infants treated with TH, and motor and sensory disability, or death. An exploratory analysis assessed the accuracy of BG and Th perfusion to predict brain MRI injury in infants treated with TH. RESULTS: Increased BG and Th perfusion on CDUS was observed in infants with severe MRI scores and those with significant motor and neurosensory disability or death through 2.5-5 years (P < .05). Infants with severe HIE showed increased BG and Th perfusion (P < .005) compared with infants with moderate HIE. No differences were identified between the between the control and mild HIE groups. Th perfusion ≥0.237 cm/second (Area under the curve of 0.824) correctly classified 80% of infants with severe MRI scores. CONCLUSIONS: Early dynamic CDUS of the BG and Th is a potential biomarker of severe brain injury in infants with HIE and may be a useful adjunct to currently used assessments.

Neurodevelopmental outcomes of preterm with necrotizing enterocolitis: a systematic review and meta-analysis.

While neonatal necrotising enterocolitis (NEC) is associated with high mortality rates in newborns, survivors can face long-term sequelae. However, the relationship between NEC and neurodevelopmental impairment (NDI) in preterm infants remains unclear. To explore the relationship between neonatal NEC and neurodevelopmental outcomes in preterm infants, we searched PubMed, EMBASE, and the Cochrane Library from their inception to February 2024 for relevant studies. Studies included were cohort or case-control studies reporting neurodevelopmental outcomes of NEC in preterm infants. Two independent investigators extracted data regarding brain damage and neurodevelopmental outcomes in these infants at a corrected age exceeding 12 months. Odds ratios (ORs) were pooled using a random effects model. We included 15 cohort studies and 18 case-control studies, encompassing 60,346 infants. Meta-analysis of unadjusted and adjusted ORs demonstrated a significant association between NEC and increased odds of NDI (OR 2.15, 95% CI 1.9-2.44; aOR 1.89, 95% CI 1.46-2.46). Regarding brain injury, pooled crude ORs indicated an association of NEC with severe intraventricular haemorrhage (IVH) (OR 1.42, 95% CI 1.06-1.92) and periventricular leucomalacia (PVL) (OR 2.55, 95% CI 1.76-3.69). When compared with conservatively treated NEC, surgical NEC potentially carries a higher risk of NDI (OR 1.78, 95% CI 1.09-2.93) and severe IVH (OR 1.57, 95% CI 1.20-2.06). However, the risk of PVL did not show a significant difference (OR 1.60, 95% CI 0.47-5.40). CONCLUSIONS:  Our meta-analysis provides evidence suggesting an association between NEC and NDI. Additionally, the severity of intestinal lesions appears to correlate with a higher risk of NDI. Further high-quality studies with comprehensive adjustments for potential confounding factors are required to definitively establish whether the association with NDI is causal. WHAT IS KNOWN: • NEC is a serious intestinal disease in the neonatal period with a high mortality rate, and surviving children may have digestive system sequelae. • Compared with non-NEC preterm infants, the reported incidences of brain injury and neurodevelopmental disorders in NEC preterm infants are not the same. WHAT IS NEW: • The risk of neonatal brain injury and neurodevelopmental disorders in preterm infants with NEC is higher than that in non-NEC infants, and the risk of NDI in surgical NEC infants is higher than that in the conservative treatment group. • NEC may increase the risk of motor, cognitive, language development delays, and attention deficits in children.

Risk factors for PDA ligation and neurodevelopmental outcomes at corrected 18-24 months in very low birth weight infants.

BACKGROUND: Patent ductus arteriosus (PDA) is commonly encountered morbidity which often occurs as up to 60% of extremely preterm infants born at < 29 weeks gestational age (GA). PURPOSE: This study aims to assess the clinical risk factors associated with PDA ligation among very low birth weight infants (VLBWI) and evaluate the neurodevelopmental outcomes of those who underwent PDA ligation. METHODS: A total of 540 VLBWI were initially diagnosed with PDA in our 50-bed level IV NICU at Seoul St. Mary's Hospital, The Catholic University of Korea, between January 2015 and June 2023. Among these 540 VLBWI with PDA, only 221 had consistent hemodynamically significant (hs) PDA which required intervention including fluid restriction, medical treatment, or surgical ligation. In this study, only those 221 VLBWI with hsPDA who underwent neurodevelopmental assessment at corrected 18-24 months of age were included in this study analysis. RESULTS: Out of 221 VLBWI diagnosed with hemodynamically significant (hs) PDA, 133 (60.2%) underwent PDA ligation, while the remaining 88 (39.8%) had their hs PDAs closed either medically or with fluid restriction. The mean gestational age and birth weight were significantly lower in PDA ligation group compared to no PDA ligation group (27.02 ± 2.17 vs. 27.98 ± 2.36, 907.31 ± 258.36 vs. 1006.07 ± 283.65, p = 0.001, 0.008). Resuscitation including intubation at delivery and intraventricular hemorrhage (IVH) (grade ≥ 3) were significantly higher in PDA ligation group. The clinical outcomes in the PDA ligation group revealed significantly worse oucomes compared to the no PDA ligation group. Both resuscitation, including intubation at delivery, and IVH (grade ≥ 3), consistently exhibited an increased risk for PDA ligation in a multivariable logistic regression analysis. Concerning neurodevelopmental outcomes, infants who underwent PDA ligation demonstrated significantly lower cognitive scores. However, only IVH (grade ≥ 3) and PVL were consistently associated with an increased risk of abnormal neurodevelopment at the corrected age of 18-24 months. CONCLUSION: In our study, despite the consistent association between cognitive developmental delays in VLBWI who underwent PDA ligation, we observed that sicker and more vulnerable VLBWIs, specifically those experincing severe IVH, consistently exhibited an increased risk for both PDA ligation and abnormal neurodevelopment at the corrected age of 18-24 months.

Two-year neurodevelopmental outcome in extremely preterm-born children: The Austrian Preterm Outcome Study Group.

AIM: The current study determined the neurodevelopmental outcome of extremely preterm infants at 2 years of age. METHODS: All live-born infants 23-27 weeks of gestation born between 2011 and 2020 in Austria were included in a prospective registry. Neurodevelopmental outcome at 2 years of corrected age was assessed using Bayley Scales of Infant Development for both motor and cognitive scores, along with a neurological examination and an assessment of neurosensory function. RESULTS: 2378 out of 2905 (81.9%) live-born infants survived to 2 years of corrected age. Follow-up data were available for 1488 children (62.6%). Overall, 43.0% had no, 35.0% mild and 22.0% moderate-to-severe impairment. The percentage of children with moderate-to-severe neurodevelopmental impairment decreased with increasing gestational age and was 31.4%, 30.5%, 23.3%, 19.0% and 16.5% at 23, 24, 25, 26 and 27 weeks gestational age (p < 0.001). Results did not change over the 10-year period. In multivariate analysis, neonatal complications as well as male sex were significantly associated with an increased risk of neurodevelopmental impairment. CONCLUSION: In this cohort study, a 22.0% rate of moderate-to-severe neurodevelopmental impairment was observed among children born extremely preterm. This national data is important for both counselling parents and guiding the allocation of health resources.

Neurodevelopmental impairment following surgical necrotizing enterocolitis with gestational age ≥ 28 weeks: who is at risk?

PURPOSE: Surgical necrotizing enterocolitis (NEC) is a severe medical condition that, even after surgery, a portion of the survival infants may still have neurological sequelae. The objective of this study was to identify the risk factors associated with the development of permanent neurodevelopmental impairment (NDI) in neonates with surgical NEC. METHODS: Between January 2016 and June 2022, a retrospective data collection was conducted on 98 individuals who experienced surgical NEC with gestational age ≥ 28 weeks. Among these patients, 27 patients were diagnosed with NDI, while the remaining 71 patients did not have NDI. Based on this division, the patients were categorized into the NDI group and the Non-NDI group. Demographics, comorbidities, and admission lab results were analyzed using univariate and logistic regression analyses. RESULTS: Of the 98 neonates following surgical NEC, 27(27.6%) developed permanent neurodevelopmental impairment (NDI). Predictors of NDI were identified through the final multivariable logistic regression analysis, which revealed that gestational age ≤ 32 weeks (p = 0.032; odds ratio [OR], 5.673), assisted mechanical ventilation after NEC onset (p = 0.047; OR, 5.299), postoperative acute kidney injury (p = 0.040; OR, 5.106), CRP day 3 after NEC onset (p = 0.049; OR, 1.037), time from presentation to surgery (p = 0.003; OR, 1.047) were significant risk factors. CONCLUSIONS: Our study identified gestational age ≤ 32 weeks, assisted mechanical ventilation after NEC onset, postoperative acute kidney injury, CRP day 3 after NEC onset, and time from presentation to surgery as significant risk factors for NDI in neonates with surgical NEC. These factors would be helpful to refine treatment modalities for better disease outcomes. We also determined the cut-off values of CRP day 3 after NEC onset and time from presentation to surgery, allowing for the individualized evaluation of NDI risk and the implementation of earlier targeted laparotomy.

Changes in In-Hospital Survival and Long-Term Neurodevelopmental Outcomes of Extremely Preterm Infants: A Retrospective Study of a Japanese Tertiary Center.

OBJECTIVES: The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation. STUDY DESIGN: This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models. RESULTS: Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively. CONCLUSION: Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.

Children Newly Diagnosed with Fetal and Neonatal Alloimmune Thrombocytopenia: Neurodevelopmental Outcome at School Age.

OBJECTIVE: To evaluate the neurodevelopmental outcome at school age in children newly diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT). STUDY DESIGN: This observational cohort study included children diagnosed with FNAIT between 2002 and 2014. Children were invited for cognitive and neurological testing. Behavioral questionnaires and school performance results were obtained. A composite outcome of neurodevelopmental impairment (NDI) was used, defined, and subdivided into mild-to-moderate and severe NDI. Primary outcome was severe NDI, defined as IQ <70, cerebral palsy with Gross Motor Functioning Classification System level ≥ III, or severe visual/hearing impairment. Mild-to-moderate NDI was defined as IQ 70-85, minor neurological dysfunction or cerebral palsy with Gross Motor Functioning Classification System level ≤ II, or mild visual/hearing impairment. RESULTS: In total, 44 children were included at a median age of 12 years (range: 6-17 years). Neuroimaging at diagnosis was available in 82% (36/44) of children. High-grade intracranial hemorrhage (ICH) was detected in 14% (5/36). Severe NDI was detected in 7% (3/44); two children had high-grade ICH, and one had low-grade ICH and perinatal asphyxia. Mild-to-moderate NDI was detected in 25% (11/44); one child had high-grade ICH, and eight children were without ICH, yet for two children, neuroimaging was not performed. Adverse outcome (perinatal death or NDI) was 39% (19/49). Four children (9%) attended special needs education, three of whom had severe NDI and one had mild-to-moderate NDI. Total behavioral problems within the clinical range were reported in 12%, which is comparable with 10% in the general Dutch population. CONCLUSION: Children who are newly diagnosed with FNAIT are at increased risk for long-term neurodevelopmental problems, even those without ICH. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (Identifier: NCT04529382).

The Impact of Intraventricular Hemorrhage and Periventricular Leukomalacia on Mortality and Neurodevelopmental Outcome in Very Preterm and Very Low Birthweight Infants: A Prospective Population-based Cohort Study.

OBJECTIVE: To survey the incidence of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) by gestational age and to report the impact on mortality and neurodevelopmental outcome in very preterm/very low birthweight infants. STUDY DESIGN: This was a population-based cohort study of 1927 very preterm/very low birthweight infants born in 2014-2016 and admitted to Flemish neonatal intensive care units. Infants underwent standard follow-up assessment until 2 years corrected age with the Bayley Scales of Infant and Toddler Development and neurological assessments. RESULTS: No brain lesion was present in 31% of infants born at <26 weeks of gestation and 75.8% in infants born at 29-32 weeks of gestation. The prevalence of low-grade IVH/PVL (grades I and II) was 16.8% and 12.7%, respectively. Low-grade IVH/PVL was not related significantly to an increased likelihood of mortality, motor delay, or cognitive delay, except for PVL grade II, which was associated with a 4-fold increase in developing cerebral palsy (OR, 4.1; 95% CI, 1.2-14.6). High-grade lesions (III-IV) were present in 22.0% of the infants born at <26 weeks of gestational and 3.1% at 29-32 weeks of gestation, and the odds of death were ≥14.0 (IVH: OR, 14.0; 95% CI, 9.0-21.9; PVL: OR, 14.1; 95% CI, 6.6-29.9). PVL grades III-IV showed an increased odds of 17.2 for motor delay and 12.3 for cerebral palsy, but were not found to be associated significantly with cognitive delay (OR, 2.9; 95% CI, 0.5-17.5; P = .24). CONCLUSIONS: Both the prevalence and severity of IVH/PVL decreased significantly with advancing gestational age. More than 75% of all infants with low grades of IVH/PVL showed normal motor and cognitive outcome at 2 years corrected age. High-grade PVL/IVH has become less common and is associated with adverse outcomes.

Survival and Long-Term Outcomes of Children Who Survived after End-of-Life Decisions in a Neonatal Intensive Care Unit.

OBJECTIVE: To investigate long-term outcomes of infants who survive despite life-and-death discussions with families and a decision to withdraw or withhold life-sustaining interventions (WWLST) in one neonatal intensive care unit. STUDY DESIGN: Medical records for neonatal intensive care unit admissions from 2012 to 2017 were reviewed for presence of WWLST discussions or decisions, as well as the 2-year outcome of all children who survived. WWLST discussions were prospectively recorded in a specific book; follow-up to age 2 years was determined by retrospective chart review. RESULTS: WWLST discussions occurred for 266 of 5251 infants (5%): 151 (57%) were born at term and 115 (43%) were born preterm. Among these discussions, 164 led to a WWLST decision (62%) and 130 were followed by the infant's death (79%). Of the 34 children (21%) surviving to discharge after WWLST decisions, 10 (29%) died before 2 years of age and 11 (32%) required frequent medical follow-up. Major functional limitations were common among survivors, but 8 were classified as functionally normal or with mild-to-moderate functional limitations. CONCLUSIONS: When a WWLST decision was made in our cohort, 21% of the infants survived to discharge. By 2 years of age, the majority of these infants had died or had major functional limitations. This highlights the uncertainty of WWLST decisions during neonatal intensive care and the importance of ensuring that parents are informed of all possibilities. Additional studies including longer-term follow-up and ascertaining the family's views will be important.

Guilt and Regret Experienced by Parents of Children Born Extremely Preterm.

OBJECTIVES: To explore decisional regret of parents of babies born extremely preterm and analyze neonatal, pediatric, and parental factors associated with regret. STUDY DESIGN: Parents of infants born <29 weeks of gestational age, aged between 18 months and 7 years, attending neonatal follow-up were enrolled. Hospital records were reviewed to examine morbidities and conversations with parents about levels of care. Parents were asked the following question: "Knowing what you know now, is there anything you would have done differently?" Mixed methods were used to analyze responses. RESULTS: In total, 248 parents (98% participation) answered, and 54% reported they did not have regret. Of those who reported regret (n = 113), 3 themes were most frequently invoked: 35% experienced guilt, thinking they were responsible for the preterm birth; 28% experienced regret about self-care decisions; and 20% regretted decisions related to their parental role, generally wishing they knew sooner how to get involved. None reported regret about life-and-death decisions made at birth or in the neonatal intensive care unit. Impairment at follow-up, gestational age, and decisions about levels/reorientation of care were not associated with regret. More mothers reported feeling guilt about the preterm birth (compared with fathers); parents of children with severe lesions on ultrasonography of the head were less likely to report regret. CONCLUSIONS: Approximately one-half of the parents of infants born extremely preterm had regrets regarding their neonatal intensive care unit stay. Causes of regret and guilt should be addressed and minimized.

Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial.

BACKGROUND: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels. OBJECTIVE: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born ≤ 750 g or < 27 weeks' gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered. METHODS: Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks' gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34-36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22-26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis. DISCUSSION: Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing. TRIAL REGISTRATION: Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol version: Version 3.2 (10/5/2022).

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OBJECTIVES: To investigate the difference in intestinal microbiota between preterm infants with neurodevelopmental impairment (NDI) and those without NDI. METHODS: In this prospective cohort study, the preterm infants who were admitted to the neonatal intensive care unit of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region from September 1, 2019 to September 30, 2021 were enrolled as subjects. According to the assessment results of Gesell Developmental Scale at the corrected gestational age of 1.5-2 years, they were divided into two groups: normal (n=115) and NDI (n=100). Fecal samples were collected one day before discharge, one day before introducing solid food, and at the corrected gestational age of 1 year. High-throughput sequencing was used to compare the composition of intestinal microbiota between groups. RESULTS: Compared with the normal group, the NDI group had a significantly higher Shannon diversity index at the corrected gestational age of 1 year (P<0.05). The principal coordinate analysis showed a significant difference in the composition of intestinal microbiota between the two groups one day before introducing solid food and at the corrected gestational age of 1 year (P<0.05). Compared with the normal group, the NDI group had a significantly higher abundance of Bifidobacterium in the intestine at all three time points, a significantly higher abundance of Enterococcus one day before introducing solid food and at the corrected gestational age of 1 year, and a significantly lower abundance of Akkermansia one day before introducing solid food (P<0.05). CONCLUSIONS: There are significant differences in the composition of intestinal microbiota between preterm infants with NDI and those without NDI. This study enriches the data on the characteristics of intestinal microbiota in preterm infants with NDI and provides reference for the microbiota therapy and intervention for NDI in preterm infants.

South Indian Children's Neurodevelopmental Outcomes After Group B Streptococcus Invasive Disease: A Matched-Cohort Study.

BACKGROUND: This study is part of a multicountry matched-cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI) of children exposed to invasive group B Streptococcus (iGBS). The specific objective of this paper is to compare NDI across domains of iGBS survivors with a matched non iGBS group in our population. METHODS: Survivors of iGBS in a South Indian hospital were identified and recruited between January 2020 and April 2021. Cases were compared with age- and gender-matched non iGBS children. Participants were assessed using Bayley Scales of Infant and Toddler Development-3rd edition (BSID-III), Wechsler Preschool and Primary Scale of Intelligence-4th edition (WPPSI-IV), Wechsler Intelligence Scale for Children-5th edition (WISC-V), Child Behavior Checklist (CBCL), and Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition (BOT-2), depending on age. RESULTS: Our cohort comprised 35 GBS-exposed and 65 matched non iGBS children, aged 1-14 years. The iGBS-exposed group had 17 (48.6%) children with impairment in ≥1 domain compared to 25 (38%) in the non iGBS group (unadjusted OR, 1.51; 95% CI, .65-3.46), 9 (26%) children with "multi-domain impairment" compared to 10 (15.4%) in the non iGBS group (unadjusted OR, 1.90; 95% CI, .69-5.24), and 1 (2.9%) child with moderate to severe impairment compared to 3 (4.6%) in the non iGBS group (unadjusted OR, .60; 95% CI, .06-6.07). In the iGBS group, more children had motor impairments compared with the non iGBS group (unadjusted OR, 10.7; 95% CI, 1.19-95.69; P = .034). CONCLUSIONS: Children with iGBS seem at higher risk of developing motor impairments compared with a non iGBS group.

Prematurity Modifies the Risk of Long-term Neurodevelopmental Impairments After Invasive Group B Streptococcus Infections During Infancy in Denmark and the Netherlands.

BACKGROUND: Preterm birth and neonatal infections are both associated with mortality and long-term neurodevelopmental impairments (NDIs). We examined whether the effect of invasive group B Streptococcus disease (iGBS) on mortality and long-term NDI differs for preterm and term infants, and whether co-occurrence of iGBS and prematurity leads to worse outcome. METHODS: Nationwide cohort studies of children with a history of iGBS were conducted using Danish and Dutch medical databases. Comparison cohorts of children without iGBS were matched on birth year/month, sex, and gestational age. Effects of iGBS on all-cause mortality and NDI were analyzed using Cox proportional hazards and logistic regression. Effect modification by prematurity was evaluated on additive and multiplicative scales. RESULTS: We identified 487 preterm and 1642 term children with a history of iGBS and 21 172 matched comparators. Dutch preterm children exposed to iGBS had the highest mortality rate by 3 months of age (671/1000 [95% CI, 412-929/1000] person-years). Approximately 30% of this mortality rate could be due to the common effect of iGBS and prematurity. Preterm children with iGBS had the highest NDI risk (8.8% in Denmark, 9.0% in the Netherlands). Of this NDI risk 36% (Denmark) and 60% (the Netherlands) might be due to the combined effect of iGBS and prematurity. CONCLUSIONS: Prematurity is associated with iGBS development. Our study shows that it also negatively impacts outcomes of children who survive iGBS. Preterm infants would benefit from additional approaches to prevent maternal GBS colonization, as this decreases risk of both preterm birth and iGBS.

Every Country, Every Family: Time to Act for Group B Streptococcal Disease Worldwide.

The global burden of Group B Streptococcus (GBS) was estimated for 2015 prompting inclusion of GBS as a priority in the Global Meningitis Roadmap. New estimates for the year 2020 and a WHO report analysing the full value of GBS maternal vaccines has been launched to advance evidence based decision making for multiple stakeholders. In this first of a 10-article supplement, we discuss the following (1) gaps in evidence and action, (2) new evidence in this supplement, and (3) what actions can be taken now and key research gaps ahead. We call for investment in the research pipeline, notably description, development, and delivery, in order to accelerate progress and address the large burden of GBS for every family in every country.

How lung injury and therapeutic oxygen could alter white matter development.

Developmental brain injury describes a spectrum of neurological pathologies resulting from either antenatal or perinatal injury. This includes both cognitive and motor defects that affect patients for their entire lives. Developmental brain injury can be caused by a spectrum of conditions including stroke, perinatal hypoxia-ischemia, and intracranial hemorrhage. Additional risk factors have been identified including very low birth weight, mechanical ventilation, and oxygen (O2 ) supplementation. In fact, infants with bronchopulmonary dysplasia, an inflammatory disease associated with disrupted lung development, have been shown to have decreased cerebral white matter and decreased intracranial volumes. Thus, there appears to be a developmental link between the lung, O2 , and the brain that leads to proper myelination. Here, we will discuss what is currently known about the link between O2 and myelination and how scientists are exploring mechanisms through which supplemental O2 and/or lung injury can affect brain development. Consideration of a link between the diseased lung and developing brain will allow clinicians to fine tune their approaches in managing preterm lung disease in order to optimize brain health.

High-Risk Neighborhoods and Neurodevelopmental Outcomes in Infants Born Preterm.

OBJECTIVE: To study the association between neighborhood risk and moderate to severe neurodevelopmental impairment (NDI) at 22-26 months corrected age in children born at <34 weeks of gestation. We hypothesized that infants born preterm living in high-risk neighborhoods would have a greater risk of NDI and cognitive, motor, and language delays. STUDY DESIGN: We studied a retrospective cohort of 1291 infants born preterm between 2005 and 2016, excluding infants with congenital anomalies. NDI was defined as any one of the following: a Bayley Scales of Infant and Toddler Development-III Cognitive or Motor composite score <85, bilateral blindness, bilateral hearing impairment, or moderate-severe cerebral palsy. Maternal addresses were geocoded to identify census block groups and create high-risk versus low-risk neighborhood groups. Bivariate and regression analyses were run to assess the impact of neighborhood risk on outcomes. RESULTS: Infants from high-risk (n = 538; 42%) and low-risk (n = 753; 58%) neighborhoods were compared. In bivariate analyses, the risk of NDI and cognitive, motor, and language delays was greater in high-risk neighborhoods. In adjusted regression models, the risks of NDI (OR, 1.43; 95% CI, 1.04-1.98), cognitive delay (OR, 1.62; 95% CI, 1.15-2.28), and language delay (OR, 1.58; 95% CI, 1.15-2.16) were greater in high-risk neighborhoods. Breast milk at discharge was more common in low-risk neighborhoods and was protective of NDI in regression analysis. CONCLUSIONS: High neighborhood risk provides an independent contribution to preterm adverse NDI, cognitive, and language outcomes. In addition, breast milk at discharge was protective. Knowledge of neighborhood risk may inform the targeted implementation of programs for socially disadvantaged infants.

Neurodevelopmental Trajectories of Preterm Born Survivors of Twin-Twin Transfusion Syndrome: From Birth to 5 Years of Age.

OBJECTIVE: To investigate the neurodevelopmental outcome at age 2 and 5 years in survivors of twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery and born premature and/or small for gestational age. STUDY DESIGN: At 2 and 5 years of age, standardized neurologic, motor, and cognitive assessments were performed by a neonatologist, a pediatric physical therapist, and a psychologist. Behavior was assessed using a validated questionnaire completed by parents. RESULTS: Neurodevelopmental assessment at both time points was available for 73 survivors of TTTS. Mild to moderate neurodevelopmental impairment (NDI) was detected in 34% of survivors (25 of 73) at 5 years, compared with 25% (18 of 73) at 2 years (P = .178). Severe NDI was observed in 12% (9 of 73) at 5 years and in 3% (2 of 73) at 2 years (P = .035). Mean cognitive score was lower at the 5-year follow-up (90.7 ± 12.3 vs 95.6 ± 13.1 at 2 years; P = .001), and more children were diagnosed with mild cognitive impairment at 5 years (29% vs 11% at 2 years; P = .007). When comparing individual outcomes at both time points, 35% (25 of 71) moved from a normal outcome or mild to moderate impairment at 2 years toward more severe impairment at 5 years. CONCLUSIONS: A high rate of mild to moderate cognitive impairment and severe NDI at age 5 years was not identified at age 2 years. Our data highlight the importance of longitudinal follow-up of survivors of TTTS beyond age 2 years and emphasize the precautions that should be taken when diagnosing an absence of impairment before school age.

Multivariable Predictive Models of Death or Neurodevelopmental Impairment Among Extremely Low Birth Weight Infants Using Heart Rate Characteristics.

OBJECTIVE: We hypothesized that a cumulative heart rate characteristics (HRC) index in real-time throughout the neonatal intensive care unit (NICU) hospitalization, alone or combined with birth demographics and clinical characteristics, can predict a composite outcome of death or neurodevelopmental impairment (NDI). STUDY DESIGN: We performed a retrospective analysis using data from extremely low birth weight infants who were monitored for HRC during neonatal intensive care. Surviving infants were assessed for NDI at 18-22 months of age. Multivariable predictive modeling of subsequent death or NDI using logistic regression, cross-validation with repeats, and step-wise feature elimination was performed each postnatal day through day 60. RESULTS: Among the 598 study participants, infants with the composite outcome of death or moderate-to-severe NDI had higher mean HRC scores during their stay in the NICU (3.1 ± 1.8 vs 1.3 ± 0.8; P < .001). Predictive models for subsequent death or NDI were consistently higher when the cumulative mean HRC score was included as a predictor variable. A parsimonious model including birth weight, sex, ventilatory status, and cumulative mean HRC score had a cross-validated receiver-operator characteristic curve as high as 0.84 on days 4, 5, 6, and 8 and as low as 0.78 on days 50-52 and 56-58 to predict subsequent death or NDI. CONCLUSIONS: In extremely low birth weight infants, higher mean HRC scores throughout their stay in the NICU were associated with a higher risk of the composite outcome of death or NDI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00307333.