Transfontanellar shear wave elastography of the neonatal brain for quantitative evaluation of white matter damage.

Cerebral white matter damage (WMD) is the most frequent brain lesion observed in infants surviving premature birth. Qualitative B-mode cranial ultrasound (cUS) is widely used to assess brain integrity at bedside. Its limitations include lower discriminatory power to predict long-term outcomes compared to magnetic resonance imaging (MRI). Shear wave elastography (SWE), a promising ultrasound imaging modality, might improve this limitation by detecting quantitative differences in tissue stiffness. The study enrolled 90 neonates (52% female, mean gestational age = 30.1 ± 4.5 weeks), including 78 preterm and 12 term controls. Preterm neonates underwent B-mode and SWE assessments in frontal white matter (WM), parietal WM, and thalami on day of life (DOL) 3, DOL8, DOL21, 40 weeks, and MRI at term equivalent age (TEA). Term infants were assessed on DOL3 only. Our data revealed that brain stiffness increased with gestational age in preterm infants but remained lower at TEA compared to the control group. In the frontal WM, elasticity values were lower in preterm infants with WMD detected on B-mode or MRI at TEA and show a good predictive value at DOL3. Thus, brain stiffness measurement using SWE could be a useful screening method for early identification of preterm infants at high WMD risk.Registration numbers: EudraCT number ID-RCB: 2012-A01530-43, ClinicalTrial.gov number NCT02042716.

Maternal and neonatal outcomes of French prospective multicenter cohort study COVIPREG during the first two COVID-19 waves.

BACKGROUND: SARS-CoV-2 infection on pregnant women was the subject of many questions since the COVID-19 pandemic. METHODS: We aim to assess maternal and neonatal outcomes of SARS-CoV-2 infection contracted during 2nd and 3rd trimesters of pregnancy during the first two COVID-19 waves across a prospective French multicenter cohort study. Patients were included between April 2020 and January 2021 in 10 maternity hospitals in Paris area with two groups (i) pregnant women with a positive SARS-CoV-2 nasopharyngeal RT-PCR between [14WG; 37WG[(symptomatic infection), (ii) pregnant women with a negative serology (or equivocal) at delivery and without a positive SARS-CoV-2 nasopharyngeal RT-PCR at any time during pregnancy (G2 group) MAIN FINDINGS: 2410 pregnant women were included, of whom 310 had a positive SARS-CoV-2 nasopharyngeal RT-PCR and 217 between [14WG; 37WG[. Most infections occurred between 28 and 37 weeks of gestation (56 %). Most patients could be managed as outpatients, while 23 % had to be hospitalized. Among women with a positive RT-PCR, multiparous women were over-represented (OR = 2.45[1.52;3.87]); were more likely to deliver before 37 weeks of gestation (OR = 2.19[1.44;3.24]) and overall cesarean deliveries were significantly increased (OR = 1.53[1.09;2.13]). CONCLUSIONS: This study highlights the maternal, obstetrical, and neonatal burden associated with SARS-CoV-2 infections during the first two pandemic waves before availability of vaccines. TRIAL REGISTRATION: NCT04355234 (registration date: 21/04/2020).

Association between Portal Vein Thrombosis after Umbilical Vein Catheterization and Neonatal Asphyxia.

INTRODUCTION: Neonatal portal vein thrombosis (PVT) is frequently related to umbilical venous catheterization (UVC), but risk factors remain unclear. This study aims to analyze the variables associated to PVT in near- to full-term newborns with UVC, with a focus on newborns exposed to controlled therapeutic hypothermia (CTH) for hypoxic ischemic encephalopathy (HIE). METHODS: This is retrospective cohort study of infants delivered at or after 36 weeks and with a birthweight over 1,500 g. All infants were assessed for UVC location and PVT using ultrasonography performed between day 5 and day 10 after catheterization. RESULTS: Among 213 eligible patients, PVT was diagnosed in 57 (27%); among them, 54 (95%) were localized in the left portal vein branch. With all significant factors in univariate analysis considered, higher gestational age at birth (adjusted OR 1.35; 95% CI: 1.12-1.64, p = 0.002) and duration of UVC placement (adjusted OR 1.36; 95% CI: 1.11-1.67, p = 0.004) were the main risk factors of PVT. Among 87 infants who were cooled for HIE, 31 (36%) had PVT compared to 26 (21%) in infants without CTH. Using a multivariate model including variables linked to treatment procedures only, an increased PVT incidence was statistically associated with UVC duration (adjusted OR 1.33; 95% CI: 1.08; 1.63, p = 0.01) and CTH (adjusted OR 1.94; 95% CI: 1.04-3.65, p = 0.04). CONCLUSION: Left PVT was frequently observed in near- to full-term neonates with UVC. Among factors linked to treatment procedures, both duration of UVC and CTH exposure for HIE were found to be independent risk factors of PVT.

Quantification of brain-wide vascular resistivity via ultrafast Doppler in human neonates helps early detection of white matter injury.

Preterm birth is associated with cerebrovascular development disruption and can induce white matter injuries (WMI). Transfontanellar ultrasound Doppler is the most widely used clinical imaging technique to monitor neonatal cerebral vascularisation and haemodynamics based on vascular indexes such as the resistivity index (RI); however, it has poor predictive value for brain damage. Indeed, these RI measurements are currently limited to large vessels, leading to a very limited probing of the brain's vascularisation, which may hinder prognosis. Here we show that ultrafast Doppler imaging (UfD) enables simultaneous quantification, in the whole field of view, of the local RI and vessel diameter, even in small vessels. Combining both pieces of information, we defined two new comprehensive resistivity parameters of the vascular trees. First, we showed that our technique is more sensitive in the early characterisation of the RI modifications between term and preterm neonates and for the first time we could show that the RI depends both on the vessel diameter and vascular territory. We then showed that our parameters can be used for early prediction of WMI. Our results demonstrate the potential of UfD to provide new biomarkers and pave the way for continuous monitoring of neonatal brain resistivity.

High Amino Acid Intake in Early Life Is Associated With Systolic but Not Diastolic Arterial Hypertension at 5 Years of Age in Children Born Very Preterm.

BACKGROUND: The life course of individuals born very premature is a topic of increasing concern. The association between high early amino acid intake and later high blood pressure (HBP) in preterm neonates is debated. METHODS AND RESULTS: In a national, prospective, population-based birth cohort, EPIPAGE-2 (Etude Epidémiologique sur Petits Ages Gestationnels), we assessed blood pressure at 5 years. Eligible infants were those born between 24 and 29 weeks of gestation. Infants were distributed in 2 groups of 717 infants matched on propensity score on whether or not they were exposed to high amino acid intake (>3.5 g/kg per day at day 7); 455 control term infants were also enrolled. A value ≥95th percentile of reference values for age and height defined systolic or diastolic HBP. Blood pressure at 5 years of age was assessed for 389 and 385 children in the exposed and nonexposed groups, respectively. Rates (in percent) of systolic and diastolic HBP were 18.0% (95% CI, 14.5%-22.2%), 13.3% (95% CI, 10.3%-17.0%), 8.5% (95% CI, 6.5%-11.1%), and 9.0% (95% CI, 6.6%-12.3%), 10.2% (95% CI, 7.5%-13.6%), and 5.4% (95% CI, 3.8%-7.6%) in exposed, nonexposed, and term-born groups, respectively. Exposure to high early amino acid intake and maximal serum creatinine (by 50 µmol/L) between day 3 and day 7 were 2 independent risk factors for systolic HBP (adjusted odds ratio [aOR], 1.60 [95% CI, 1.05-2.43] and aOR, 1.59 [95% CI, 1.12-2.26], respectively) but not for diastolic HBP (aOR, 0.84 [95% CI, 0.50-1.39] and aOR, 1.09 [95% CI, 0.71-1.67], respectively). After adjustment for 5-year weight Z score, the aOR between high early amino acid intake and systolic HBP was 1.50 [95% CI, 0.98-2.30]. CONCLUSIONS: These results suggest that mechanisms of childhood systolic HBP involve neonatal renal challenge by high amino acid intake or dysfunction.

Use of Machine Learning for Dosage Individualization of Vancomycin in Neonates.

BACKGROUND AND OBJECTIVE: High variability in vancomycin exposure in neonates requires advanced individualized dosing regimens. Achieving steady-state trough concentration (C0) and steady-state area-under-curve (AUC0-24) targets is important to optimize treatment. The objective was to evaluate whether machine learning (ML) can be used to predict these treatment targets to calculate optimal individual dosing regimens under intermittent administration conditions. METHODS: C0 were retrieved from a large neonatal vancomycin dataset. Individual estimates of AUC0-24 were obtained from Bayesian post hoc estimation. Various ML algorithms were used for model building to C0 and AUC0-24. An external dataset was used for predictive performance evaluation. RESULTS: Before starting treatment, C0 can be predicted a priori using the Catboost-based C0-ML model combined with dosing regimen and nine covariates. External validation results showed a 42.5% improvement in prediction accuracy by using the ML model compared with the population pharmacokinetic model. The virtual trial showed that using the ML optimized dose; 80.3% of the virtual neonates achieved the pharmacodynamic target (C0 in the range of 10-20 mg/L), much higher than the international standard dose (37.7-61.5%). Once therapeutic drug monitoring (TDM) measurements (C0) in patients have been obtained, AUC0-24 can be further predicted using the Catboost-based AUC-ML model combined with C0 and nine covariates. External validation results showed that the AUC-ML model can achieve an prediction accuracy of 80.3%. CONCLUSION: C0-based and AUC0-24-based ML models were developed accurately and precisely. These can be used for individual dose recommendations of vancomycin in neonates before treatment and dose revision after the first TDM result is obtained, respectively.

Determinants of morbidity and mortality related to health care-associated primary bloodstream infections in neonatal intensive care units: a prospective cohort study from the SEPREVEN trial.

Background: Health care-associated primary bloodstream infections (BSIs), defined as not secondary to an infection at another body site, including central line-associated BSI, are a leading cause of morbidity and mortality in patients in neonatal intensive care units (NICUs). Our objective was to identify factors associated with severe morbidity and mortality after these infections in neonates in NICUs. Methods: This ancillary study of the SEPREVEN trial included neonates hospitalized ≥2 days in one of 12 French NICUs and with ≥ 1 BSI during the 20-month study period. BSIs (all primary and health care-associated) were diagnosed in infants with symptoms suggestive of infection and classified prospectively as possible (one coagulase-negative staphylococci (CoNS)-growing blood culture) or proven (two same CoNS, or ≥1 recognized pathogen-growing blood culture). BSI consequences were collected prospectively as moderate morbidity (antibiotic treatment alone) or severe morbidity/mortality (life-saving procedure, permanent damage, prolonged hospitalization, and/or death). Results: Of 557 BSIs identified in 494 patients, CoNS accounted for 378/557 (67.8%) and recognized bacterial or fungal pathogens for 179/557 (32.1%). Severe morbidity/mortality was reported in 148/557 (26.6%) BSIs. Independent factors associated with severe morbidity/mortality were corrected gestational age <28 weeks (CGA) at infection (P < .01), fetal growth restriction (FGR) (P = .04), and proven pathogen-related BSI vs. CoNS-related BSI (P < .01). There were no differences in severe morbidity and mortality between proven and possible CoNS BSIs. In possible BSI, S. epidermidis was associated with a lower risk of severe morbidity than other CoNS (P < .01), notably S. capitis and S. haemolyticus. Conclusions: In BSIs in the NICU, severe morbidity/mortality was associated with low CGA at infection, FGR, and proven pathogen-related BSIs. When only one blood culture was positive, severe morbidity/mortality were less frequent if it grew with S. epidermidis compared to other CoNS. Further studies to help distinguish real CoNS BSIs from contaminations are needed. Study registration: ClinicalTrials.gov (NCT02598609).

Stimulating the motor development of very premature infants: effects of early crawling training on a mini-skateboard.

Aim: To examine the effects of an early home-based 8-week crawling intervention performed by trained therapists on the motor and general development of very premature infants during the first year of life. Methods: At term-equivalent age, immediately following discharge from the Neonatal Intensive Care Unit (NICU), we randomly allocated 44 premature infants born before 32 weeks' gestation without major brain damage to one of three conditions in our intervention study: crawling on a mini-skateboard, the Crawliskate (Crawli), prone positioning control (Mattress), or standard care (Control). The Crawli and Mattress groups received 5 min daily at-home training administered by trained therapists for 8 consecutive weeks upon discharge from the NICU. The outcomes of greatest interest included gross motor development (Bayley-III) at 2, 6, 9, and 12 months (primary outcome) corrected age (CA), mature crawling at 9 months CA and general development at 9 and 12 months CA [Ages and Stages Questionnaires-3 (ASQ-3)]. The study was registered at www.clinicaltrials.gov; registration number: NCT05278286. Results: A 3 (Condition) × 4 (Age) repeated measures ANOVA revealed that Crawli group infants had significantly higher Bayley-III gross motor development scores than Mattress and Control group infants. Crawli group infants also scored significantly higher on groups of Bayley-III items related to specific motor skills than infants in the other groups, including crawling at 9 months CA. We found significant differences in favor of the Crawli group in separate one-way ANOVAs at each of the ages we examined. A 3 (Condition) × 2 (Age) repeated measures ANOVA revealed that the Crawli group scored significantly higher than the Control group for the ASQ-3 total score and communication score and significantly higher for the fine motor score than the Control and Mattress groups. We found additional significant differences in favor of the Crawli group for other dimensions of the ASQ-3 in separate one-way ANOVAs at 9 and 12 months CA. Interpretation: Early crawling training on a Crawliskate provides an effective way to promote motor and general development in very premature infants. The findings also provide clear evidence for a link between newborn crawling and more mature crawling later in development.

Probing the Impact of Prematurity on Segmentation Abilities in the Context of Bilingualism.

Infants born prematurely are at a high risk of developing linguistic deficits. In the current study, we compare how full-term and healthy preterm infants without neuro-sensorial impairments segment words from fluent speech, an ability crucial for lexical acquisition. While early word segmentation abilities have been found in monolingual infants, we test here whether it is also the case for French-dominant bilingual infants with varying non-dominant languages. These bilingual infants were tested on their ability to segment monosyllabic French words from French sentences at 6 months of (postnatal) age, an age at which both full-term and preterm monolinguals are able to segment these words. Our results establish the existence of segmentation skills in these infants, with no significant difference in performance between the two maturation groups. Correlation analyses failed to find effects of gestational age in the preterm group, as well as effects of the language dominance within the bilingual groups. These findings indicate that monosyllabic word segmentation, which has been found to emerge by 4 months in monolingual French-learning infants, is a robust ability acquired at an early age even in the context of bilingualism and prematurity. Future studies should further probe segmentation abilities in more extreme conditions, such as in bilinguals tested in their non-dominant language, in preterm infants with medical issues, or testing the segmentation of more complex word structures.

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.

Renal vein thrombosis in neonates: a case series of diagnosis, treatment and childhood kidney function follow-up.

BACKGROUND: Neonatal renal vein thrombosis (NRVT) is a rare condition with little data available. METHODS: We retrospectively analyzed newborns diagnosed with NRVT admitted to 3 pediatric nephrology units in Paris from 2005 to 2020. RESULTS: Twenty-seven patients were analyzed (male = 59%). The median age at diagnosis was 2.5 days (1 - 4.5). Diagnosis was suspected based on at least one of the three cardinal signs of renal vein thrombosis in 93%: flank mass (67%), hematuria (67%) and thrombocytopenia (70%). In all patients, diagnosis was confirmed by ultrasound. All patients had at least one known perinatal risk factor. A prothrombotic risk factor was found in 13 patients (48%). NRVT was unilateral in 70%, involving the left renal vein in 58%. Among 25 treated patients, 19 (76%) received low molecular weight heparin (LMWH) as initial therapy, 2 (8%) received unfractionated heparin and 4 (16%) received fibrinolysis. Median duration of treatment was 8 weeks (4 - 12). Bleeding occurred significantly more often with fibrinolysis than with LMWH/supportive therapy (3 of 4: 75% vs 0 of 4: 0%, p = 0.05). Clot resolution in patients treated with fibrinolysis did not differ significantly from those treated with LMWH/supportive therapy. After a median follow-up of 5.7 years (3 years - 9.9 years), pathological kidney features were observed in 73% of the patients (19 of 26), kidney atrophy in 18 (69%), hypertension in 2 (8%), chronic kidney disease (CKD) in 1 (4%) and proteinuria in 2 (8%). CONCLUSIONS: NRVT remains a challenging condition, which still requires further study because of its associated morbidity. A higher resolution version of the Graphical abstract is available as Supplementary information.

Early urine output monitoring in very preterm infants to predict in-hospital neonatal outcomes: a bicentric retrospective cohort study.

OBJECTIVE: To evaluate whether urine output (UO), rarely assessed in the literature, is associated with relevant neonatal outcomes in very preterm infants, and which UO threshold may be the most clinically relevant. DESIGN: Retrospective cohort study. SETTING: Two Level IV neonatal intensive care units. PATIENTS: Very preterm infants born between 240/7 and 296/7 weeks of gestation documented with eight UO measurements per day between postnatal day 1 and day 7. MAIN OUTCOME MEASURES: Composite outcome defined as death before discharge, or moderate to severe bronchopulmonary dysplasia, or severe brain lesions. The association between this outcome and UO was studied using several UO thresholds. RESULTS: Among 532 infants studied, UO <1.0 mL/kg/hour for at least 24 consecutive hours was measured in 55/532 (10%) infants and the primary outcome was recorded in 25 patients. The association between a UO threshold <1.0 mL/kg/hour and the primary outcome was found marginally significant (crude OR 1.80, 95% CI 1.02 to 3.16, p=0.04). The primary outcome was recorded in 112/242 (46%) patients with a UO <2.0 mL/kg/hour and only 64/290 (22%) patients with a UO ≥2.0 mL/kg/hour (p<0.001). This UO threshold was found significantly associated with the primary outcome (crude OR 3.1, 95% CI 2.1 to 4.7, p<0.001), an association confirmed using a multivariate logistic regression model including baseline covariates (adjusted OR 3.7, 95% CI 2.2 to 6.4, p<0.001). CONCLUSION: A UO <2 mL/kg/hour over 24 hours between postnatal day 1 and day 7 strongly predicts neonatal mortality or severe morbidities in very preterm infants.

Neurocognitive outcomes at age 5 years after prophylactic hydrocortisone in infants born extremely preterm.

AIM: To assess the 5-year neurocognitive outcomes of children born extremely preterm exposed to prophylactic hydrocortisone to improve survival without bronchopulmonary dysplasia. METHOD: This was a prespecified secondary analysis of the PREMILOC clinical trial (trial registration: EudraCT no. 2007-002041-20, NCT00623740). The primary outcome was full-scale IQ based on the Wechsler Preschool and Primary Scale of Intelligence. RESULTS: Among 109 surviving children recruited at the Robert Debré Children's Hospital, Paris, outcome data were available for 42 out of 56 infants (75%) in the group treated with hydrocortisone and 41 out of 53 (77%) in the placebo group. Mean scores were not significantly different between the two groups on full-scale IQ (hydrocortisone: 91.9 [SD = 13.9], placebo: 86.3 [SD = 15.4]; mean difference = 5.7, 95% confidence interval [CI] = -1.0 to 12.3, p = 0.10); however, working memory and retention ability were significantly better in the group treated with hydrocortisone. In a multivariate logistic regression including potential confounding variables, hydrocortisone treatment was significantly associated with a greater chance to survive at 5 years of age with a full-scale IQ equal to or greater than 90 compared to placebo (adjusted odds ratio = 4.26, 95% CI = 1.47-12.36, p = 0.008). INTERPRETATION: This exploratory analysis provides reassuring data regarding the long-term neurodevelopmental safety of prophylactic hydrocortisone in infants born extremely preterm.

Early laparoscopic-assisted surgery is associated with decreased post-operative inflammation and intestinal strictures in infants with necrotizing enterocolitis.

INTRODUCTION: In 2015, a protocol including early laparoscopy-assisted surgery in the treatment of necrotizing enterocolitis (NEC) was implemented at our institution. Carbon dioxide insufflation during laparoscopy may have an anti-inflammatory effect. We aimed to compare post-operative outcome after early laparoscopy-assisted surgery and classical laparotomy for NEC. MATERIAL AND METHODS: Charts of premature infants undergoing surgery for NEC (2012-2021) were reviewed. Cases operated by early laparoscopy-assisted surgery (2015-2021) were compared to infants operated for NEC between 2012 and 2015 (laparotomy-NEC). Outcomes were post-operative CRP, need for reintervention, mortality, and the occurrence of post-NEC intestinal strictures. CRP was measured on the day of surgery (POD-0), 2 days (POD-2), and 7 days after surgery (POD-7). Data were compared using contingency tables for categorical variables and Student t-test or Mann-Whitney test for continuous variables. RESULTS: Infants with NEC operated by early laparoscopy (n = 48) and laparotomy (n = 29) were similar in terms of perforation (60% vs 58%, p = 0.99) and POD-0 CRP (139 vs 124 mg/L, p = 0.94). Delay between first signs of NEC and surgery was shorter in the laparoscopy group (3 vs 6 days, p = 0.004). Early laparoscopy was associated with a lower CRP on POD-2 (108 vs 170, p = 0.005) and POD-7 (37 vs 68, p = 0.002), as well as a lower rate of post-operative intestinal stricture (34% vs 61%, p = 0.04). CONCLUSIONS: In addition to being safe and feasible in premature infants, early laparoscopic-assisted surgery was associated with decreased NEC-related post-operative inflammation and strictures. A prospective, randomized study is needed in order to evaluate short and long-term effects of laparoscopy in infants with NEC. LEVEL OF EVIDENCE: Level III.

Early-onset neonatal sepsis in the Paris area: a population-based surveillance study from 2019 to 2021.

BACKGROUND: Early-onset neonatal sepsis (EOS) is a rare condition but an important cause of severe morbidity and mortality in neonates. METHODS: This is a prospective observational study in neonates born at ≥34 weeks of gestation (WG). The primary endpoint was EOS, defined by isolation of pathogenic species from blood culture and/or cerebrospinal fluid culture within 72 hours after birth. Data on EOS were collected exhaustively from all maternity wards in Paris area (April 2019-March 2021). RESULTS: 108 EOS were recorded (annual incidence, 0.32 per 1000 live births; 95% CI 0.26 to 0.38). In term infants, the most frequent pathogens were group B Streptococcus (GBS) (n=47) and Escherichia coli (n=20); in late preterm infants, the most frequent pathogens were E. coli (n=15) and GBS (n=7). Fifteen meningitis cases were diagnosed. Five E. coli strains (14%) were resistant to both amoxicillin and gentamicin, which is an empiric treatment for EOS. Of the 54 infants with GBS infections, 35 were born from mothers with negative GBS prepartum screening test and 8 from mothers with no screening. Two deaths were reported, both in term infants (Proteus mirabilis and E. coli). CONCLUSION: In neonates ≥34 WG born in the Paris area, GBS was twice as frequent as E. coli in term infants. EOS was six times more frequent in late preterm than in term infants and was due to E. coli in 60% of cases. Prevention of GBS EOS and empiric antibiotic treatment of EOS could be improved.

Urine Output Monitoring for the Diagnosis of Early-Onset Acute Kidney Injury in Very Preterm Infants.

BACKGROUND AND OBJECTIVES: The current threshold used for oliguria in the definition of neonatal AKI has been empirically defined as 1 ml/kg per hour. Urine output criteria are generally poorly documented, resulting in uncertainty in the most accurate threshold to identify AKI in very preterm infants with known tubular immaturity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a bicentric study including 473 very preterm infants (240/7-296/7 weeks of gestation) born between January 2014 and December 2018 with urine output measurements every 3 hours during the first 7 days of life and two serum creatinine measurements during the first 10 days of life. AKI was defined using the neonatal Kidney Disease Improving Global Outcomes (KDIGO) definition. We tested whether higher urine output thresholds (1.5 or 2 ml/kg per hour) in modified AKI definitions may better discriminate neonatal mortality compared with the current definition. RESULTS: Early-onset AKI was developed by 101 of 473 (21%) very preterm infants. AKI was diagnosed on the basis of urine output criteria alone (no rise in creatinine) for 27 of 101 (27%) participants. Early-onset AKI was associated with higher risk of death before discharge (adjusted odds ratio, 3.9; 95% confidence interval, 1.9 to 7.8), and the AKI neonatal KDIGO score showed good discriminative performance for neonatal mortality, with an area under the receiver operating characteristic (ROC) curve of 0.68 (95% confidence interval, 0.61 to 0.75). Modified AKI definitions that included higher urine output thresholds showed significantly improved discriminative performance, with areas under the ROC curve of 0.73 (95% confidence interval, 0.66 to 0.80) for the 1.5-ml/kg per hour threshold and 0.75 (95% confidence interval, 0.68 to 0.81) for the 2-ml/kg per hour threshold. CONCLUSIONS: Early-onset AKI was diagnosed on the basis of urine output exclusively for a quarter of the cases. Furthermore, modified AKI definitions that included higher urine output improved the discriminative performance for predicting mortality.

Neuropathology findings in KCNQ2 neonatal epileptic encephalopathy.

PURPOSE: KCNQ2-epileptic encephalopathy (EE) is a neonatal epilepsy syndrome characterized by a typical clinical presentation and EEG recording, but without any brain or cortical abnormal development on MRI. Most of the patients have a severe developmental impairment. The epileptogenic mechanisms are thought to be the result of the changes of the M-current density causing a change of brain excitability. Although recent studies allow us to better understand the physiopathology of KCNQ2-EE, the neuropathology of this ion channel dysfunction has only been previously described in a single case report. METHODS: We report the neuropathology study of a case of KCNQ2-EE with a typical electro-phenotype due to a de novo heterozygous single nucleotide pathogenic variant in the exon 5 of the KCNQ2 gene (NM_172107.2:c.802C>T; p.Leu268Phe). RESULTS: At the macroscopic level, the brain had a normal structure with a normal neocortical gyral pattern. At the histological level, the cortex had a usual six-layer lamination in all lobes but blurred gray-white matter boundaries due to excessive heterotopic neurons in deep white matter were observed. This diffuse mild malformation of cortical development is suggestive of a neuronal migration disorder. CONCLUSION: In recent years, our understanding of the role of ion channel dysfunctions in early brain development has expanded from the occurrence of EE to brain malformation. Through this rare neuropathological report, we emphasize the role of KCNQ2 channels in the process of cortical development. As for other genetic neonatal onset epilepsies, more reports are needed to further delineate the range of neuropathological abnormalities for KCNQ2-EE.

Immaturity of Oculomotor Capabilities During a Reading Task in Children Born Prematurely: An Eye Tracker Study.

To our knowledge, there are no studies recording the reading eye movements of children born prematurely. We examined the oculomotor patterns during reading of 23 children born prematurely (M age = 7.8, SD = 0.2 years) to compare them with those from two groups of children born at full-term who were matched for chronological age or reading age, respectively. We found the oculomotor reading pattern in children who were preterm to be similar to that of children who were full-term and matched for reading age; this shared pattern was characterized by longer duration of fixations, frequent prosaccades of smaller amplitude and several backward saccades. In contrast, when these two groups were compared to full-term children matched for chronological age, the latter group showed significantly shorter duration of fixations, less frequent saccades and larger amplitude prosaccades. Thus, the oculomotor pattern we observed in 7-year-old children who were either preterm or reading-delayed, relative to their age-matched peers, reflected delayed development of brain areas involved in reading-related eye movements.

An educational programme in neonatal intensive care units (SEPREVEN): a stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: Patients in neonatal intensive care units (NICUs) are at high risk of adverse events. The effects of medical and paramedical education programmes to reduce these have not yet been assessed. METHODS: In this multicentre, stepped-wedge, cluster-randomised controlled trial done in France, we randomly assigned 12 NICUs to three clusters of four units. Eligible neonates were inpatients in a participating unit for at least 2 days, with a postmenstrual age of 42 weeks or less on admission. Each cluster followed a 4-month multifaceted programme including education about root-cause analysis and care bundles. The primary outcome was the rate of adverse events per 1000 patient-days, measured with a retrospective trigger-tool based chart review masked to allocation of randomly selected files. Analyses used mixed-effects Poisson modelling that adjusted for time. This trial is registered with ClinicalTrials.gov, NCT02598609. FINDINGS: Between Nov 23, 2015, and Nov 2, 2017, event rates were analysed for 3454 patients of these 12 NICUs for 65 830 patient-days. The event rate per 1000 patient-days reduced significantly from the control to the intervention period (33·9 vs 22·6; incidence rate ratio 0·67; 95% CI 0·50-0·88; p=0·0048). INTERPRETATION: A multiprofessional safety-promoting programme in NICUs reduced the rate of adverse events and severe and preventable adverse events in highly vulnerable patients. This programme could significantly improve care offered to critically ill neonates. FUNDING: Solidarity and Health Ministry, France.