Mortality and neurodevelopmental outcomes at 2 years' corrected age of very preterm infants with necrotising enterocolitis or spontaneous intestinal perforation: The EPIPAGE-2 cohort study.

PURPOSE: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG). METHODS: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire. RESULTS: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0-9.1) but not NEC as compared with controls. CONCLUSION: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA.

Staphylococcus capitis isolated from bloodstream infections: a nationwide 3-month survey in 38 neonatal intensive care units.

To increase the knowledge about S. capitis in the neonatal setting, we conducted a nationwide 3-month survey in 38 neonatal intensive care units (NICUs) covering 56.6% of French NICU beds. We demonstrated 14.2% of S. capitis BSI (S.capBSI) among nosocomial BSIs. S.capBSI incidence rate was 0.59 per 1000 patient-days. A total of 55.0% of the S.capBSIs were late onset catheter-related BSIs. The S. capitis strains infected preterm babies (median gestational age 26 weeks, median birth weight 855 g). They were resistant to methicillin and aminoglycosides and belonged to the NRCS-A clone. Evolution was favorable in all but one case, following vancomycin treatment.

Impact of fetal growth restriction on neurodevelopmental outcome at 2 years for extremely preterm infants: a single institution study.

AIM: We evaluated the impact of fetal growth restriction on neurodevelopmental outcomes at 2 years corrected age for infants born before 27 weeks gestational age. METHOD: Data on infants born before 27 weeks gestational age between 1999 and 2008 (n=463), admitted to a tertiary neonatal unit in Paris, were used to compare neurological outcomes at 2 years for infants with birthweight lower than the 10th centile and birthweight of at least the 10th centile, using intrauterine reference curves. Outcomes were cerebral palsy (CP) and the Brunet-Lézine assessment of cognitive development, which provides age-corrected overall and domain-specific (global and fine motor skills, language and social interaction) developmental quotients. Models were adjusted for perinatal and social factors. RESULTS: Seventy-two percent of infants were discharged alive. Eighty-three percent (n=268) were evaluated at 2 years. Six percent had CP. Fetal growth restriction was not associated with the risk of CP. After adjustment, children with a birthweight lower than the 10th centile had a global developmental quotient 4.7 points lower than those with birthweight of at least the 10th centile (p<0.001); differences were greatest for fine motor and social skills (-4.7, p=0.053 and -7.3, p<0.001 respectively). INTERPRETATION: In extremely preterm children, fetal growth restriction was associated with poorer neurodevelopmental outcomes at 2 years, but not with CP.

Unbound bilirubin does not increase during ibuprofen treatment of patent ductus arteriosus in preterm infants.

OBJECTIVE: To determine whether ibuprofen displaces bilirubin from albumin in preterm infants. STUDY DESIGN: A total of 34 preterm neonates (<32 weeks gestation) treated by ibuprofen (10-5-5 mg/kg) were included in this prospective open-label study. Total bilirubin (TB), unbound bilirubin (UB), and ibuprofen concentrations were measured before, 1 hour, and 6 hours after the first dose; before and 1 hour after the second dose; and 72 hours after the beginning of treatment. The infants were screened by auditory brainstem responses and by neurologic examination at term. RESULTS: At baseline, TB, UB, apparent binding affinity of albumin (Ka), and albumin concentrations were 6.0±1.6 mg/dL, 1.9±2.2 µg/dL, 14.1±5.8 L·µmol(-1), and 28.7±2.3 g/L, respectively. Ibuprofen treatment had no effect on TB, UB, or Ka values. No correlation between UB or Ka and ibuprofen concentrations was found. No neurologic symptoms or significant modifications of auditory brainstem responses were observed at term. CONCLUSION: Ibuprofen (10-5-5 mg/kg) did not displace bilirubin in preterm infants with a baseline TB concentration <8.8 mg/dL.

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth.

Dendritic growth is pivotal in the neurogenesis of cortical neurons. The sodium pump, or Na,K-ATPase, is an evolutionarily conserved protein that, in addition to its central role in establishing the electrochemical gradient, has recently been reported to function as a receptor and signaling mediator. Although a large body of evidence points toward a dual function for the Na,K-ATPase, few biological implications of this signaling pathway have been described. Here we report that Na,K-ATPase signal transduction triggers dendritic growth as well as a transcriptional program dependent on cAMP response element binding protein (CREB) and cAMP response element (CRE)-mediated gene expression, primarily regulated via Ca(2+)/calmodulin-dependent protein (CaM) kinases. The signaling cascade mediating dendritic arbor growth also involves intracellular Ca(2+) oscillations and sustained phosphorylation of mitogen-activated protein (MAP) kinases. Thus, our results suggest a novel role for the Na,K-ATPase as a modulator of dendritic growth in developing neurons.

Predictors of early-onset neonatal sepsis in premature newborns: Case-control study.

INTRODUCTION: Early-onset neonatal sepsis (EOS) is difficult to diagnose clinically because the semiology of premature newborns is poor during the first days of life. This study aimed to identify predictive factors of EOS in neonates less than 37 weeks' gestational age in neonatal care at Louis Mourier Hospital, France. METHOD: This was a case-control study of all newborns less than 37 weeks of gestational age diagnosed and managed for EOS from January 1 to December 31, 2019. The main parameters studied were demographic characteristics, risk factors, laboratory, and bacteriological characteristics. At the benchmarking level, the statistical tests used were the McNemar test for qualitative variables and the paired Student's t-test for quantitative variables. RESULTS: A total of 50 mother-child pairs were included in this study (25 cases and 25 matched controls). The results showed a statistically significant relationship between the birth of a child with EOS and between a premature rupture of membranes of > 18 h (68% of cases vs. 36% of controls; p = 0.042); a positive culture of the placenta (p = 0.0002); C-reactive protein levels of > 6 mg/L (88% of cases vs. 20% of controls; p = 0.001); a procalcitonin level of > 0.6 ng/mL (72% of cases vs. 16% of controls; p = 0.001). Gram-negative bacteria including Escherichia coli (44.5%) and Haemophilus influenzae (14.8%) were the most common pathogens found. CONCLUSION: The search for risk factors must be systematic and the clinic must remain at the center of the diagnostic approach.

Contribution of vaginal culture to predict early onset neonatal infection in preterm prelabor rupture of membranes.

BACKGROUND: Preterm prelabor rupture of membranes (PPROM) is a major cause of morbidity and mortality for both the mother and the newborn. The vaginal germ profile in PPROM is poorly known, particularly regarding the risk of early-onset neonatal infection (EONI). OBJECTIVE: To determine microbiological risk factors for EONI in case of PPROM before 34 weeks of gestation (WG). STUDY DESIGN: A retrospective single-center cohort of patients with PPROM before 34 W G from 2008 to 2016. Vaginal swabs were obtained at admission and at delivery as per usual care and were analyzed by Gram stain and culture for vaginal dysbiosisi.e lactobacilli depletion and/or presence of potential pathogens. RESULTS: Among 268 cases of PPROM, 39 neonates had EONI 14.55 %; (95 %CI 0.11 - 0.19) Overall, vaginal samples culture was positive in 16.67 % (95 %CI 11.95 %-22.32 %) at the time of rupture and 24.76 % (95 %CI 19.02 %-31.23 %) at delivery, with no significant differences between EONI and no-EONI groups (p = 0.797 and 0.486, respectively), including for Group B Streptococci (GBS) and Escherichia coli. EONI was significantly associated with dysbiosis at the time of rupture (23.94 % versus 10.35 % in the absence of dysbiosis, p = 0.009) and at delivery (19.70 % versus 3.90 % if no dysbiosis, p < 0.001). Clinical intra-uterine infection was present in 78.5 % (n = 31) of the EONI group versus 37.2 % (n = 85) in the non-EONI group (p < 0.001) and chorioamnionitis and/or funisitis were found in 97.3 % and 91.9 %, respectively in the EONI group, versus 56.11 % and 53.96 %, respectively, in the non-EONI group (p < 0.001). CONCLUSION: Dysbiosis following rupture and at delivery, but not the presence of pathogens in the VS culture, was associated with the risk of EONI in case of PPROM.

Premedication practices for neonatal tracheal intubation: Results from the EPIPPAIN 2 prospective cohort study and comparison with EPIPPAIN 1.

To describe the frequency and nature of premedication practices for neonatal tracheal intubation (TI) in 2011; to identify independent risk factors for the absence of premedication; to compare data with those from 2005 and to confront observed practices with current recommendations. Data concerning TI performed in neonates during the first 14 days of their admission to participating neonatal/pediatric intensive care units were prospectively collected at the bedside. This study was part of the Epidemiology of Procedural Pain in Neonates study (EPIPPAIN 2) conducted in 16 tertiary care units in the region of Paris, France, in 2011. Multivariate analysis was used to identify factors associated with premedication use and multilevel analysis to identify center effect. Results were compared with those of the EPIPPAIN 1 study, conducted in 2005 with a similar design, and to a current guidance for the clinician for this procedure. One hundred and twenty-one intubations carried out in 121 patients were analyzed. The specific premedication rate was 47% and drugs used included mainly propofol (26%), sufentanil (24%), and ketamine (12%). Three factors were associated with the use of a specific premedication: nonemergent TI (Odds ratio (OR) [95% CI]: 5.3 [1.49-20.80]), existence of a specific written protocol in the ward (OR [95% CI]:4.80 [2.12-11.57]), and the absence of a nonspecific concurrent analgesia infusion before TI (OR [95% CI]: 3.41 [1.46-8.45]). No center effect was observed. The specific premedication rate was lower than the 56% rate observed in 2005. The drugs used were more homogenous and consistent with the current recommendations than in 2005, especially in centers with a specific written protocol. Premedication use prior to neonatal TI was low, even for nonemergent procedures. Scientific consensus, implementation of international or national recommendations, and local written protocols are urgently needed to improve premedication practices for neonatal intubation.

Population pharmacokinetic analysis of Ibuprofen enantiomers in preterm newborn infants.

The aim of this pharmacokinetic analysis was to develop and validate a population pharmacokinetic model for R- and S-ibuprofen from samples obtained after 3 successive administrations of ibuprofen (10-5-5 mg/kg) at 24-hour intervals to preterm newborn infants aged from <6 hours to 8 days of life. A model including unilateral bioconversion of R-ibuprofen into S-ibuprofen was developed using the software NONMEM. R- and S-ibuprofen plasma concentrations were adequately fitted by this model. Estimated clearance and volume of distribution were 3.5 mL/h/kg and 173 mL/kg, respectively, with a calculated half-life (t((1/2))) of 34.3 hours for S-ibuprofen. Estimated clearance at birth and volume of distribution were 25.5 mL/h/kg and 306 mL/kg with a t((1/2)) at birth of 8.3 hours for R-ibuprofen. R-ibuprofen elimination increased during the first week of life, whereas S-ibuprofen pharmacokinetics were weakly modified. Therefore, because the activity of the 2 enantiomers differs, it is important that subsequent studies consider R- and S-enantiomers separately. Mean simulated ibuprofen concentrations at various dose regimens were in agreement with observed concentrations. The present analysis allows a more accurate estimation of the ibuprofen pharmacokinetics as parameters could be estimated separately for each enantiomer and the effect of postnatal age on the elimination of R-ibuprofen was elicited.

Usefulness of multiplex PCR methods and respiratory viruses' distribution in children below 15 years old according to age, seasons and clinical units in France: A 3 years retrospective study.

BACKGROUND: To date, only influenza and RSV testing are recommended for respiratory viruses' detection in paediatric units. In this study, we described, according to seasons, ages and clinical units, the results obtained in children (<15 years old) by multiplex-PCR (mPCR) tests allowing a quick and wide range detection of all respiratory viruses. These results were also compared with RSV specific detection. METHODS: All nasopharyngeal mPCR and RSV tests requested by clinicians in our French teaching hospitals group between 2011 and 2014 were retrospectively included. All repeated samples for the same children in the same month were discarded. RESULTS: Of the 381 mPCR tests (344 children) performed, 51.4% were positive. Positivity and viral co-infection rates were higher in the 6-36 months old strata (81% and 25%, p<0.0001 and p = 0.04, respectively). Viral distribution showed strong variations across ages. During specific influenza epidemic periods, only 1/39 (2.5%) mPCR tests were positive for influenza and 19/39 (48.7%) for other viruses. During specific RSV epidemic periods, only 8/46 (17.4%) mPCR tests were positive for RSV and 14/46 (30.4%) for other viruses. 477/1529 (31.2%) of RSV immunochromatography-tests were positive. Among the negatives immunochromatography-test also explored by mPCR, 28/62 (31%) were positive for other respiratory viruses. CONCLUSION: This study provides a wide description of respiratory viruses' distribution among children in hospital settings using mPCR over 3 years. It emphasizes the number of undiagnosed respiratory viruses according to the current diagnosis practice in France and gives a better picture of respiratory viruses identified in hospital settings by mPCR all over the year in France.

Study of the Factors Leading to Fetal and Neonatal Dysthyroidism in Children of Patients With Graves Disease.

CONTEXT: Neonatal hyperthyroidism was first described in 1912 and in 1964 was shown to be linked to transplacental passage of maternal antibodies. Few multicenter studies have described the perinatal factors leading to fetal and neonatal dysthyroidism. OBJECTIVE: To show how fetal dysthyroidism (FD) and neonatal dysthyroidism (ND) can be predicted from perinatal variables, in particular, the levels of anti-thyrotropin receptor antibodies (TRAbs) circulating in the mother and child. DESIGN AND PATIENTS: This was a retrospective multicenter study of data from the medical records of all patients monitored for pregnancy from 2007 to 2014. SETTING: Among 280,000 births, the medical records of 2288 women with thyroid dysfunction were selected and screened, and 417 women with Graves disease and positive for TRAbs during pregnancy were included. RESULTS: Using the maternal TRAb levels, the cutoff value of 2.5 IU/L best predicted for FD, with a sensitivity of 100% and specificity of 64%. Using the newborn TRAb levels, the cutoff value of 6.8 IU/L best predicted for ND, with a sensitivity of 100% and a specificity of 94%. In our study, 65% of women with a history of Graves disease did not receive antithyroid drugs during pregnancy but still had infants at risk of ND. CONCLUSIONS: In pregnant women with TRAb levels ≥2.5 IU/L, fetal ultrasound monitoring is essential until delivery. All newborns with TRAb levels ≥6.8 IU/L should be examined by a pediatrician with special attention for thyroid dysfunction and treated, if necessary.

Epidemiology and neonatal pain management of heelsticks in intensive care units: EPIPPAIN 2, a prospective observational study.

BACKGROUND: Heelstick is the most frequently performed skin-breaking procedure in the neonatal intensive care units (NICUs). There are no large multicenter studies describing the frequency and analgesic approaches used for heelsticks performed in NICUs. OBJECTIVES: To describe the frequency of heelsticks and their analgesic management in newborns in the NICU. To determine the factors associated with the lack of specific preprocedural analgesia for this procedure. DESIGN: EPIPPAIN 2 (Epidemiology of Procedural PAin In Neonates) is a descriptive prospective epidemiologic study. SETTING: All 16 NICUs in the Paris region in France. PARTICIPANTS: All newborns in the NICU with a maximum corrected age of 44 weeks +6 days of gestation on admission who had at least one heelstick during the study period were eligible for the study. The study included 562 newborns. METHODS: Data on all heelsticks and their corresponding analgesic therapies were prospectively collected. The inclusion period lasted six weeks, from June 2, 2011 to July 12, 2011. Newborns were followed from their admission to the 14th day of their NICU stay or discharge, whichever occurred first. RESULTS: The mean (SD) gestational age was 33.3 (4.4) weeks and duration of participation was 7.5 (4.4) days. The mean (SD; range) of heelsticks per neonate was 16.0 (14.4; 1-86) during the study period. Of the 8995 heelsticks studied, 2379 (26.4%) were performed with continuous analgesia, 5236 (58.2%) with specific preprocedural analgesia. Overall, 6764 (75.2%) heelsticks were performed with analgesia (continuous and/or specific). In a multivariate model, the increased lack of preprocedural analgesia was associated with female sex, term birth, high illness severity, tracheal or noninvasive ventilation, parental absence and use of continuous sedation/analgesia. CONCLUSIONS: Heelstick was very frequently performed in NICUs. Although, most heelsticks were performed with analgesia, this was not systematic. The high frequency of this procedure and the known adverse effects of repetitive pain in neonates should encourage the search of safe and effective strategies to reduce their number.

Increased incidence of necrotizing enterocolitis in premature infants born to HIV-positive mothers.

OBJECTIVE: To examine if being born to an HIV-positive mother may increase the risk of necrotizing enterocolitis in premature infants. DESIGN: Case-control study. SETTING: Neonatal unit of a level 3 perinatal centre. METHODS: : Over a period of 8.5 years, all cases of necrotizing enterocolitis occurring in premature infants admitted to the neonatal unit were identified. For each case, two controls were retrospectively chosen that matched for postmenstrual age at birth, intrauterine growth and year of birth. Perinatal characteristics were studied in all infants. MAIN RESULTS: There were 79 cases of necrotizing enterocolitis, which were compared with 158 controls. Using multivariate analysis, multiple pregnancy [odds ratio (OR), 2.29; 95% confidence interval (CI), 1.23-4.25; P = 0.009], abnormal umbilical artery velocity (OR, 2.21; 95% CI, 1.08-4.54; P = 0.030), abnormal fetal heart rate (OR, 2.14; 95% CI, 1.05-4.36; P = 0.036) and HIV-positive mother (OR, 6.63; 95% CI, 1.26-34.8; P = 0.025) were significantly more frequent in fetuses who subsequently developed necrotizing enterocolitis. CONCLUSIONS: This preliminary report suggests an association, not previously reported, between maternal HIV-positive status and an increased risk of necrotizing enterocolitis in premature infants. Despite the limitations of this study, we suggest that premature newborn infants of HIV-positive mothers should be monitored very carefully for a possible increased risk of necrotizing enterocolitis.

Effect of ibuprofen on bilirubin-albumin binding during the treatment of patent ductus arteriosus in preterm infant.

Ibuprofen carries the theoretical risk of increasing bilirubin encephalopathy by displacing bilirubin from albumin binding sites. Indeed, ibuprofen displaces bilirubin from albumin binding site at high concentrations in vitro. The first results in vivo seem to demonstrate no displacement of bilirubin in preterm infants treated by the current recommended doses of 10-5-5 mg/kg/day and when total bilirubin levels are below 10 mg/dL. However, this study does not provide information about possible risks of ibuprofen (IBU) use, when the bilirubin levels are higher than 10 mg/dL or if higher IBU doses are used.

Transient inhibition of astrocytogenesis in developing mouse brain following postnatal caffeine exposure.

Caffeine is frequently administered in human preterm newborns. Although some data suggest a potential risk for the developing brain, its impact has not been fully evaluated. We used a murine model of postnatal caffeine treatment in which mouse pups received intraperitoneal injections of caffeine from postnatal days 3 to 10. Caffeine exposure resulted in a transient reduction of glial fibrillary acidic protein and S100beta protein expression in various brain areas during the first 2 postnatal weeks (19.8% and 23.2% reduction in the hippocampus at P15, respectively). This effect was dose-dependent and at least partly involved a reduction of glial proliferation, as a caffeine-induced decrease of 5-bromodeoxyuridine incorporation was observed in the dentate gyrus and subventricular zone (25.8% and 26.6%, respectively) and no increase of programmed cell death (cleaved caspase-3 immunostaining) was observed at postnatal day 7. This effect could be reproduced with an antagonist of A(2a) adenosine receptor (A(2a)R) and was blocked by co-injection of an agonist. These results suggest that postnatal caffeine treatment might induce an alteration of astrocytogenesis via A(2a)R blockade during brain development. Although no obvious neuritic abnormalities (microtubule-associated protein 2 and synaptophysin immunostaining) were observed, postnatal caffeine treatment could have long-term consequences on brain function.