Long-term Neurodevelopmental Disability Research Articles

Provision of Sedation and Treatment of Seizures During Neonatal Therapeutic Hypothermia.

Hypoxic-ischemic encephalopathy (HIE) produces a high rate of long-term neurodevelopmental disability in survivors. Therapeutic hypothermia dramatically improves the incidence of intact survival, but does not eliminate adverse outcomes. The ideal provision of sedation and treatment of seizures during therapeutic hypothermia represent therapeutic targets requiring optimization in practice. Physiologic stress from therapeutic hypothermia may obviate some of the benefits of this therapy. Morphine is commonly utilized to provide comfort, despite limited empiric evidence supporting safety and efficacy. Dexmedetomidine represents an interesting alternative, with preclinical data suggesting direct efficacy against shivering during induced hypothermia and neuroprotection in the setting of HIE. Pharmacokinetic properties must be considered when utilizing either agent, with safety dependent on conservative dosing and careful monitoring. HIE is the leading cause of neonatal seizures. Traditional therapies, including phenobarbital, fosphenytoin, and benzodiazepines, control seizures in the vast majority of neonates. Concerns about the acute and long-term effects of these agents have led to the exploration of alternative anticonvulsants, including levetiracetam. Unfortunately, levetiracetam is inferior to phenobarbital as first-line therapy for neonatal seizures. Considering both the benefits and risks of traditional anticonvulsant agents, treatment should be limited to the shortest duration indicated, with maintenance therapy reserved for neonates at high risk for recurrent seizures.

MiR-410-3p overexpression ameliorates neurological deficits in rats with hypoxic-ischemic brain damage

Neonatal hypoxic-ischemic encephalopathy (HIE) is major cause of neonatal death or long-term neurodevelopmental disabilities, which becomes a major practical problem currently in clinic. Whereas, its pathophysiology and underlying molecular mechanism is not clear. MicroRNAs are involved in the normal growth and development of neuronal cells. Herein, the objective of this research was to examine the roles of miR-410-3p in neurological deficits, neuronal injury and neuron apoptosis after hypoxic-ischemic and to explore its associated mechanisms. We established the hypoxic-ischemic brain damage (HIBD) model and oxygen glucose deprivation (OGD) model. Zea-longa score and TTC staining were used to detect the acute cerebral dysfunction after HIBD. QPCR verification exhibited notable downregulation of miR-410-3p expression at 24 h in rats after HIBD as well as that in PC12, SY5Y cells and primary cortical neurons post OGD. To further determine the function of miR-410-3p, lentivirus-mediated overexpression virus was applied in vivo and in vitro. Behavioral tests, including Morris water maze, open field test, Y maze test, neurological severity score and rotating rod test, were performed to evaluate long-term behavioral changes of rats at 1 month post HIBD. The results showed that the number of cells together with the axonal length were reduced post OGD. While the increase of cells number and the axonal length was measured after upregulating miR-410-3p. Meanwhile, miR-410-3p overexpression inhibited neuron apoptosis and enhanced neuronal survival. In addition, long-term motor and cognitive functions were remarkably recovered in HIBD rats with miR-410-3p overexpression. Together, miR-410-3p exerts a critical role in protecting neuronal growth as well as promoting motor and cognitive function recovery in neonatal rats subjected to HIBD. The current study therefore provides critical insights to develop the activator of miR-410-3p for the clinical treatment of HIBD in future clinic trial.

Incidence, Intrapartum Risk Factors, and Prognosis of Neonatal Hypoxic-Ischemic Encephalopathy Among Infants Born at 35 Weeks Gestation or More.

Neonatal hypoxic-ischemic encephalopathy (HIE) is associated with neonatal mortality, acute neurological injury, and long-term neurodevelopmental disabilities; however, the association between intrapartum factors and HIE remains unclear. This population-based cohort study used linked obstetrical and newborn data derived from the Nova Scotia Atlee Perinatal Database (NSAPD, 1988-2015) and the AC Allen Perinatal Follow-Up Program Database (2006-2015) for all pregnancies with live, non-anomalous newborns ≥35 weeks gestation, not delivered by pre-labour cesarean section. Temporal trends in HIE incidence were described, and logistic regression estimated odds ratios (OR) with 95% confidence intervals (CI) for the association of intrapartum factors with HIE. The NSAPD identified 227 HIE cases in the population of 226 711 deliveries from 1988 to 2015. Women with clinical chorioamnionitis in labour (OR 8.0; 95% CI 3.9-16), emergency cesarean delivery (OR 10; 95% CI 7.6-14), shoulder dystocia (OR 3.5; 95% CI 2.1-5.7), placental abruption (OR 18; 95% CI 11-29), and cord prolapse (OR 30; 95% CI 15-61) were more likely to have newborns with HIE. Two-thirds of newborns with HIE had an abnormal intrapartum fetal heart rate tracing. The mortality rate among infants with HIE was 27% by 3 years of age. Neurodevelopmental outcomes in the surviving infants were normal in 43% and showed severe developmental delay in 40%. Overall, the rate of HIE was low in infants born at ≥35 weeks gestation. The identification of associated intrapartum factors should promote increased surveillance in these clinical situations and emphasize the importance of careful management to optimize newborn outcomes.

Neonatal Herpes Simplex Virus: The Long Road to Improved Outcomes.

Herpes simplex virus (HSV) acquired during delivery places the neonate at risk for mortality or long-term neurodevelopmental disability. Exposure generally occurs from recurrent genital herpes infection, although primary infections result in the highest risk of neonatal disease. Neonates generally present in the second or third week of life with lesions. Encephalitis with seizures indicates the presence of central nervous system involvement, and other end organs may also be impacted. Clinical suspicion for neonatal HSV infection warrants immediate initiation of appropriate antiviral therapy. In the last 50 years, antiviral therapy has progressed from agents with prohibitive toxicity or cumbersome administration to herpes virus-specific agents that dramatically improve clinical outcomes with manageable toxicity. Multicenter clinical trials have demonstrated the superiority of high-dose intravenous acyclovir for acute therapy, followed by long-term oral suppressive therapy. This work has dramatically reduced morbidity and mortality from neonatal HSV, representing the benchmark for future clinical trials in neonatal pharmacotherapy.

Clinician Identification of Birth Asphyxia Using Intrapartum Cardiotocography Among Neonates With and Without Encephalopathy in New Zealand

Despite improvements in antenatal care and increasing cesarean delivery rates, birth asphyxia leading to neonatal encephalopathy (NE) continues to contribute to neonatal death and long-term neurodevelopmental disability. Cardiotocography (CTG) has been used in labor for several decades to detect a stressed fetus so that delivery can be expedited and NE avoided. To investigate whether experienced clinicians can detect and respond to abnormal readings from CTGs during the penultimate hour before birth in infants with moderate to severe NE but no acute peripartum event. This case-control study included 10 practicing obstetricians and midwives at maternity hospitals in New Zealand. Participants, who were masked to the perinatal outcome, were asked to assess CTG tracings from 35 neonates with NE and evidence of birth hypoxia (ie, cases) and 105 neonates without NE or birth hypoxia (ie, controls), all of whom were born in 2010 to 2011. Data analysis was conducted from May to December 2017. Brief clinical details and 1 hour of CTG tracings from the penultimate hour before birth were provided for each baby. Clinicians assessed the CTG tracings and recommended a plan. Intra-assessor and interassessor agreement on CTG findings and action plans as well as sensitivity (ie, detection of NE) and specificity (ie, ruling out those without NE) for the assessment of abnormal CTG readings leading to immediate action (ie, fetal blood sample or immediate delivery) were reported. A total of 35 infants (mean [SD] gestational age, 40 [1.4] weeks; 16 [45.7%] cesarean deliveries) were designated cases, and 105 infants (mean [SD] gestational age, 39.4 [1.2] weeks; 22 [21.0%] cesarean deliveries) were designated controls. No infants had congenital anomalies. The mean (range) sensitivity for detection of abnormal CTG results and for recommending immediate action for all assessors was 75% (63%-91%) and 41% (23%-57%), respectively, with a mean (range) specificity of 67% (53%-77%) and 87% (65%-99%), respectively. A sensitivity analysis including only assessors with 80% or more interassessor agreement only differed from the main analysis by 6% or less (mean [range] sensitivity for detection, 76% [63%-91%]; sensitivity for action plan, 36% [25%-49%]; specificity for detection, 71% [53%-77%]; and specificity for action plan, 93% [88%-99%]). Experienced clinicians detected 3 of 4 infants who were subsequently diagnosed with NE. Action to expedite delivery was recommended for more than 40% of infants with NE. These results indicate that CTG does not identify all infants at risk of NE, and that there is a need for further investment in new approaches to fetal surveillance in labor.

Intrapartum Characteristics and Prognosis Associated With Neonatal Hypoxic-Ischemic Encephalopathy [15F

INTRODUCTION: Neonatal hypoxic-ischemic encephalopathy (HIE) is associated with neonatal mortality, acute neurological injury and long-term neurodevelopmental disabilities; the role of intrapartum factors remains unclear. METHODS: This population-based cohort study employed linked obstetrical and newborn data derived from the Nova Scotia Atlee Perinatal Database (NSAPD, 1988-2015) and the Perinatal Follow-Up Program Database (2006-2015) for all pregnancies with live, non-anomalous newborns ≥35 weeks, born without pre-labor caesarean section. HIE was defined using standard definitions. Temporal trends in HIE incidence are described; Fisher's exact test and logistic regression were used to test the associations of intrapartum factors with HIE. RESULTS: The NSAPD identified 227 HIE cases out of a population of 226,711 pregnancies from 1988 to 2015, with a decrease in incidence from 0.14% to 0.1% through those years (P=0.01). Women with clinical chorioamnionitis in labor (OR 8.0, 95% CI 4.7-17), emergency operative delivery (OR 9.9, 95% CI 7.3-13), shoulder dystocia (OR 3.4, 95% CI 2.1-5.4), placental abruption (OR 19, 95% CI 12-29), and cord prolapse (OR 32, 95% CI 17-61) were more likely to have newborns with HIE. Two-thirds of newborns with HIE had an abnormal intrapartum FHR tracing. There was an infant mortality rate of 28% by age 3; neurodevelopmental outcomes in the surviving infants with HIE were normal in 33% and showed severe developmental delay in 37%. CONCLUSION: Overall, the rate of HIE was low in late-preterm and term infants. The identification of associated intrapartum factors should promote increased surveillance and careful management to optimize newborn outcomes.

Effect of the HDAC Inhibitor, Sodium Butyrate, on Neurogenesis in a Rat Model of Neonatal Hypoxia\u2013Ischemia: Potential Mechanism of Action

Neonatal hypoxic–ischemic (HI) brain injury likely represents the major cause of long-term neurodevelopmental disabilities in surviving babies. Despite significant investigations, there is not yet any known reliable treatment to reduce brain damage in suffering infants. Our recent studies in an animal model of HI revealed the therapeutic potential of a histone deacetylase inhibitor (HDACi). The neuroprotective action was connected with the stimulation of neurogenesis in the dentate gyrus subgranular zone. In the current study, we investigated whether HDACi—sodium butyrate (SB)—would also lead to neurogenesis in the subventricular zone (SVZ). By using a neonatal rat model of hypoxia–ischemia, we found that SB treatment stimulated neurogenesis in the damaged ipsilateral side, based on increased DCX labeling, and restored the number of neuronal cells in the SVZ ipsilateral to lesioning. The neurogenic effect was associated with inhibition of inflammation, expressed by a transition of microglia to the anti-inflammatory phenotype (M2). In addition, the administration of SB increased the activation of the TrkB receptor and the phosphorylation of the transcription factor—CREB—in the ipsilateral hemisphere. In contrast, SB administration reduced the level of HI-induced p75NTR. Together, these results suggest that BDNF–TrkB signaling plays an important role in SB-induced neurogenesis after HI. These findings provide the basis for clinical approaches targeted at protecting the newborn brain damage, which may prove beneficial for treating neonatal hypoxia–ischemia.

Sleep-disordered breathing is common among term and near term infants in the NICU.

Among older infants and children, sleep-disordered breathing (SDB) has negative neurocognitive consequences. We evaluated the frequency and potential impact of SDB among newborns who require intensive care. Term and near-term newborns at risk for seizures underwent 12-h attended polysomnography in the neonatal intensive care unit (NICU). Bayley Scales of Infant Development, third edition (Bayley-III) were administered at 18-22 months. The 48 newborns (EGA 39.3 ± 1.6) had a median pediatric apnea-hypopnea index (AHI) of 10.1 (3.3-18.5) and most events were central (vs obstructive). Maternal and prenatal factors were not associated with AHI. Moreover, neonatal PSG results were not associated with Bayley-III scores (P > 0.05). SDB is common among term and near-term newborns at risk for seizures. Follow-up at ages when more nuanced testing can be performed may be necessary to establish whether neonatal SDB is associated with long-term neurodevelopmental disability.

935: Can cerebroplacental ratios predict perinatal and delivery outcomes for viable fetuses?

To evaluate the relationship between fetal ultrasound assessments and perinatal and delivery outcomes in singleton term pregnancies. A retrospective cohort study of singleton deliveries ≥ 24 weeks’ gestation was conducted at a community hospital between January 2016 and January 2018. The fetal cerebroplacental ratio (CPR) is the ratio of the fetal middle cerebral artery (MCA) pulsatility index (PI) to umbilical artery (UA) PI. CPR is gaining momentum to be a proxy for suboptimal fetal growth as it quantifies suboptimal placental function and subsequent fetal circulatory adaptations. We hypothesize the use of CPR as a generalized marker and potential screening tool as it looks as placental resistance and fetal physiologic response to reach growth potential for Small for Gestational Age (SGA) fetuses and Appropriate for Gestational Age (AGA) fetuses. The UA PI, MCA PI, and CPR were compared to maternal BMI, fetal weight at birth, delivery outcomes, and APGAR scores. Logistic regression analysis was performed to identify, and adjust for, potential confounders using SAS version 9.4 with a p < 0.05 considered as significant. The study cohort included 1732 singleton pregnancies. CPR had a linear association with fetal weight and gestational age (p < 0.0001). The average CPR ratio of spontaneous vaginal deliveries was higher than of caesarean-sections (C-sections) (p= 0.0193). The average UA PI of spontaneous vaginal deliveries was lower than of C-sections (p= 0.0150). The CPR had a weak positive and UA PI ratio had a weak negative correlation with APGAR score at 1 and 5 minutes. CPR and UA PI had no significant association with maternal BMI (p= 0.2330). Our study shows that lower fetal CPR is associated with higher C-section rates in both SGA and AGA fetuses. Since low CPR is directly correlated with an elevated UA PI Doppler, this surveillance may be independently associated with delivery outcomes. These fetal ultrasound assessments may be valuable in predicting delivery outcomes of pregnancies at risk of operative deliveries, potential placental hypoxemia and cerebral redistribution affecting long-term neurodevelopmental disability.

Review article: Neonatal Sepsis in Thailand

Neonatal sepsis is a burden around the world and causes high mortality and morbidity as well. Long-term neurodevelopmental disability may occur in survivors. General physicians, pediatricians, and neonatologists need be attentive to the proper diagnosis, starting, de-escalating or stopping empirical antimicrobials therapy in neonatal sepsis. Furthermore, multidrug resistant organisms have emerged among adults, children, and neonates in developing countries. Local epidemiology studies and antimicrobial stewardship programs are important for application of the best and specific treatments. Knowledge, definitions, and clinical practice of neonatal sepsis are updated in this review.

Persistent reduction in sialylation of cerebral glycoproteins following postnatal inflammatory exposure

BackgroundThe extension of sepsis encompassing the preterm newborn’s brain is often overlooked due to technical challenges in this highly vulnerable population, yet it leads to substantial long-term neurodevelopmental disabilities. In this study, we demonstrate how neonatal neuroinflammation following postnatal E. coli lipopolysaccharide (LPS) exposure in rat pups results in persistent reduction in sialylation of cerebral glycoproteins.MethodsMale Sprague-Dawley rat pups at postnatal day 3 (P3) were injected in the corpus callosum with saline or LPS. Twenty-four hours (P4) or 21 days (P24) following injection, brains were extracted and analyzed for neuraminidase activity and expression as well as for sialylation of cerebral glycoproteins and glycolipids.ResultsAt both P4 and P24, we detected a significant increase of the acidic neuraminidase activity in LPS-exposed rats. It correlated with significantly increased neuraminidase 1 (Neu1) mRNA in LPS-treated brains at P4 and with neuraminidases 1 and 4 at P24 suggesting that these enzymes were responsible for the rise of neuraminidase activity. At both P4 and P24, sialylation of N-glycans on brain glycoproteins decreased according to both mass-spectrometry analysis and lectin blotting, but the ganglioside composition remained intact. Finally, at P24, analysis of brain tissues by immunohistochemistry showed that neurons in the upper layers (II–III) of somatosensory cortex had a reduced surface content of polysialic acid.ConclusionsTogether, our data demonstrate that neonatal LPS exposure results in specific and sustained induction of Neu1 and Neu4, causing long-lasting negative changes in sialylation of glycoproteins on brain cells. Considering the important roles played by sialoglycoproteins in CNS function, we speculate that observed re-programming of the brain sialome constitutes an important part of pathophysiological consequences in perinatal infectious exposure.

Xenon as an adjuvant to therapeutic hypothermia in near-term and term newborns with hypoxic-ischaemic encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) is a serious birth complication affecting term and late preterm newborns. Although therapeutic hypothermia (cooling) has been shown to be an effective therapy for neonatal HIE, many cooled infants have poor long-term neurodevelopmental outcomes. In animal models of neonatal encephalopathy, inhaled xenon combined with cooling has been shown to offer better neuroprotection than cooling alone. To determine the effects of xenon as an adjuvant to therapeutic hypothermia on mortality and neurodevelopmental morbidity, and to ascertain clinically important side effects of xenon plus therapeutic hypothermia in newborn infants with HIE. To assess early predictors of adverse outcomes and potential side effects of xenon. We used the standard strategy of the Cochrane Neonatal Review Group to search the Cochrane Library (2017, Issue 8), MEDLINE (from 1966), Embase (from 1966), and PubMed (from 1966) for randomised controlled and quasi-randomised trials. We also searched conference proceedings and the reference lists of cited articles. We conducted our most recent search in August 2017. We included all trials allocating term or late preterm encephalopathic newborns to cooling plus xenon or cooling alone, irrespective of timing (starting age and duration) and concentrations used for xenon administration. Two review authors independently assessed results of searches against predetermined criteria for inclusion, assessed risk of bias, and extracted data. We performed meta-analyses using risk ratios (RRs), risk differences (RDs), and number needed to treat for an additional beneficial outcome (NNTB) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) for continuous data. A single randomised controlled trial enrolling 92 participants was eligible for this review. Researchers have not reported long-term neurodevelopmental outcomes, including the primary outcome of this review - death or long-term major neurodevelopmental disability in infancy (18 months to three years of age). Cooling plus xenon was not associated with reduced mortality at latest follow-up, based upon low quality evidence. Investigators noted no substantial differences between groups for other secondary outcomes of this review, such as biomarkers of brain damage assessed with magnetic resonance imaging and occurrence of seizures during primary hospitalisation. Available data do not show an increased adverse event rate in the cooling plus xenon group compared with the cooling alone group. Current evidence from one small randomised controlled pilot trial is inadequate to show whether cooling plus xenon is safe or effective in near-term and term newborns with HIE. Further trials reporting long-term neurodevelopmental outcomes are needed.

Depression during pregnancy and preterm delivery: a prospective cohort study among women attending antenatal clinic at Pumwani Maternity Hospital

BackgroundPreterm birth occurs among 9.6% of births worldwide and is the leading cause of long-term neurodevelopmental disabilities among children and also responsible for 28% of neonatal deaths. No single etiological factor is responsible for preterm birth, but various risk factors have been identified. Prior studies have reported that compromised maternal mental health occurring during pregnancy may lead to various adverse obstetric outcomes.ObjectiveTo determine whether antenatal depression is significantly associated with preterm delivery in a low resource hospital sample from the suburbs of Nairobi.Methods292 women attending the antenatal clinic at Pumwani Maternity Hospital in Nairobi meeting the study criteria were recruited. The Edinburgh Postnatal Depression Scale was administered to screen for depression. A clinical cutoff score of 10 and above was regarded as possible depression. Thereafter, a clinical interview together with the Patient Health Questionnaire-9 was administered to evaluate the participants on DSM-V criteria for major depressive disorder. Only 255 of the women were successfully followed-up to delivery with an attrition rate of 12.7%. Records of gestation at delivery and birth weight were collected at second contact.Data analysisPreterm birth was associated with various demographic, psychosocial and medical variables. Relative risks were estimated via log binomial regression analysis to determine whether depression was a risk factor for preterm birth.ResultsOf the 255 participants, 98(38.4%) found to have depressive symptoms and 27(10.7%) delivered preterm. The risk of delivering preterm was 3.8 times higher among those with depressive symptoms.ConclusionThere is a positive association between antenatal depression and preterm delivery. This highlights the importance of screening for mental health disorders in the antenatal period as a means to reduce adverse obstetric outcomes.

Fetal adrenal gland biometry and cervical elastography as predictors of preterm birth: A comparative study.

Preterm birth is a major health problem in developing and developed countries leading to rising health care costs and long-term neurodevelopmental disability. The study aims to evaluate the role of new quantitative markers, like the elastography of cervix (shear wave speed estimation), fetal adrenal zone enlargement, and corrected fetal adrenal gland volume; in preterm birth prediction and analyze their relative importance. Thus, these markers may be beneficial in early preterm birth detection and prevent the related morbidities. Thirty pregnant females (from 28 to 37 weeks of gestational age), showing clinical signs and delivery outcome of preterm birth were included in the study with an equal number of not-in-labor antenatal females at ≥37 weeks as controls. These patients were categorized as preterm and term groups. Both the groups were subjected to trans-abdominal ultrasonography where cervical length, cervical shear wave speed (dynamic elastography) and fetal adrenal gland parameters were measured. Shear wave speed estimation of the antenatal cervix showed the highest sensitivity and specificity (96.7% and 87% respectively) in the prediction of preterm birth and also showed a strong correlation with fetal adrenal gland enlargement. Fetal adrenal zone enlargement was also shown to be a reliable marker of preterm birth, however, with reduced sensitivity and specificity than shear wave speed. The elastographic advancement and fetal adrenal biometry derived quantitative markers can be used as an objective and standard criterion for accurate prediction of preterm birth.

Failure to establish spontaneous breathing at birth: A 5-year longitudinal study of newborns admitted for birth asphyxia in Enugu, Southeast Nigeria

Background: Birth asphyxia is a leading cause of death in neonates and long-term neurodevelopmental disability in children. Identification of risk factors and implementing adequate obstetric care could help prevent its occurrence, thus averting the psychosocial and economic burden of the disease on family and society. Materials and Methods: This 5-year longitudinal study enrolled newborns admitted for birth asphyxia in the Neonatal Intensive Care Unit (NICU) of the Enugu State University Teaching Hospital and followed them up until discharge or death. Multi-level regression analysis was used to determine the factors that predicted the outcome in the admitted newborn. Results: Two thousand four hundred and fifty newborns were admitted into the NICU during the study period, and 180 were managed for birth asphyxia which resulted to an in-hospital incidence rate of 73.5 per 1000 admitted newborns (95% confidence interval 63.1—84.2). The mean age at presentation was 1.51 ± 1.59 days and mean birth weight at admission was 3.05 ± 0.67 kg. There was no significant difference in the mean age at presentation (T = 0.412, P = 0.681) and weight at admission (T = 1.295, P = 0.197) between neonates who survived and those who did not. Significant predictive association was seen between management outcome and maternal and neonate socio-demographic parameters such as gestational age at birth (P = 0.020), maternal occupation (P = 0.041), place of birth (P = 0.020), and asphyxiation score at presentation (P = 0.024). Prolonged labor (45.6%), obstructed labor (10.4%), and prematurity (8.0%) were the most common causes of asphyxiation encountered in surveyed neonates. No cause was obvious in 12% of cases. Conclusion: The incidence of birth asphyxia is unacceptably high in our setting. Practical and hands-on measures to control modifiable risk factors and prevention of causes identified in this study need to be sustained to reduce neonatal mortality and morbidity associated with birth asphyxia in resource-limited settings like ours.

Counselling and management for anticipated extremely preterm birth.

Counselling couples facing the birth of an extremely preterm infant is a complex and delicate task, entailing both challenges and opportunities. This revised position statement proposes using a prognosis-based approach that takes the best estimate of gestational age into account, along with additional factors, including estimated fetal weight, receipt of antenatal corticosteroids, singleton versus multiple pregnancy, fetal status and anomalies on ultrasound and place of birth. This statement updates data on survival in Canada, long-term neurodevelopmental disability at school age and quality of life, with focus on strategies to communicate effectively with parents. It also proposes a framework for determining the prognosis-based management option(s) to present to parents when initiating the decision-making process. This statement replaces the 2012 position statement.

Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants.

Vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm infants have low vitamin A status at birth and this has been associated with an increased risk of developing chronic lung disease. To evaluate supplementation with vitamin A on the incidence of death or neonatal chronic lung disease and long-term neurodevelopmental disability in very low birth weight (VLBW) infants compared with a control (placebo or no supplementation), and to consider the effect of the supplementation route, dose, and timing. For the original review and subsequent updates, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, Science Citation Index, and the Oxford Database of Perinatal Trials. The reference lists of relevant trials, paediatric and nutrition journals, and conference abstracts and proceedings were handsearched up to 2010.For the 2016 update, we used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1 May 2016), EMBASE (1 May 2016), and CINAHL (1 May 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised controlled trials comparing vitamin A supplementation with a control (placebo or no supplementation) or other dosage regimens in VLBW infants (birth weight ≤ 1500 grams or less than 32 weeks' gestation). Two review authors screened the search results, extracted data, and assessed the trials for risk of bias. Results were reported as risk ratios (RR), risk differences (RD), and number needed to treat to benefit (NNTB), all with 95% confidence intervals (CI). Trialists were contacted for additional data. Eleven trials met the inclusion criteria. Ten trials (1460 infants) compared vitamin A supplementation with a control and one (120 infants) compared different regimens of vitamin A supplementation. Compared to the control group, vitamin A appeared to have a small benefit in reducing the risk of death or oxygen requirement at one month of age (typical RR 0.93, 95% CI 0.88 to 0.99; typical RD -0.05, 95% CI -0.10 to -0.01; NNTB 20, 95% CI 10 to 100; 6 studies, 1165 infants) and the risk of chronic lung disease (oxygen requirement) at 36 weeks' postmenstrual age (typical RR 0.87, 95% CI 0.77 to 0.99; typical RD -0.07, 95% CI -0.13 to -0.01; NNTB 11, 95% CI 6 to 100; 5 studies, 986 infants) (moderate-quality evidence). There was a marginal reduction of the combined outcome of death or chronic lung disease (typical RR 0.92, 95% CI 0.84 to 1.01; typical RD -0.05, 95% CI -0.11 to 0.01; 4 studies, 1089 infants). Neurodevelopmental assessment of 88% of the surviving infants in the largest trial showed no difference between the groups at 18 to 22 months of age, corrected for prematurity (low-quality evidence). There is no evidence to support different vitamin A dosing regimens. No adverse effects of vitamin A supplementation were reported, but it was noted that intramuscular injections of vitamin A were painful. Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in the outcome balanced against the lack of other proven benefits and the acceptability of the treatment. Information on long-term neurodevelopmental status suggests no evidence of either benefit or harm from the intervention.

Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993 to 2012

(JAMA. 2015;314(10):1039–1051) Extremely preterm infants contribute disproportionately to the burden of neonatal morbidity, mortality, and long-term neurodevelopmental disability. This study of extremely preterm infants born at Human Development Neonatal Research Network (NRN) centers is the first comprehensive review to evaluate how care practices, major morbidities, and mortality have evolved over a 20-year period.

Functional properties of resting state networks in healthy full-term newborns.

Objective, early, and non-invasive assessment of brain function in high-risk newborns is critical to initiate timely interventions and to minimize long-term neurodevelopmental disabilities. A prerequisite to identifying deviations from normal, however, is the availability of baseline measures of brain function derived from healthy, full-term newborns. Recent advances in functional MRI combined with graph theoretic techniques may provide important, currently unavailable, quantitative markers of normal neurodevelopment. In the current study, we describe important properties of resting state networks in 60 healthy, full-term, unsedated newborns. The neonate brain exhibited an efficient and economical small world topology: densely connected nearby regions, sparse, but well integrated, distant connections, a small world index greater than 1, and global/local efficiency greater than network cost. These networks showed a heavy-tailed degree distribution, suggesting the presence of regions that are more richly connected to others (‘hubs’). These hubs, identified using degree and betweenness centrality measures, show a more mature hub organization than previously reported. Targeted attacks on hubs show that neonate networks are more resilient than simulated scale-free networks. Networks fragmented faster and global efficiency decreased faster when betweenness, as opposed to degree, hubs were attacked suggesting a more influential role of betweenness hub in the neonate network.

Warming up to the need for MRI after hypothermia

A number of clinical trials around the globe, including the Total Body Hypothermia for Neonatal Encephalopathy (TOBY), CoolCap, Infant Cooling Evaluation (ICE), and National Institute of Childhood Health and Human Development (NICHD) Neonatal Research Network (NRN) studies, have demonstrated that therapeutic hypothermia reduces the incidence of neonatal death and long-term neurodevelopmental disability among infants born with acute, moderate-to-severe neonatal encephalopathy, characterized by acidosis and low Apgar scores. Hypothermia has become a standard, though not panacea, for these at-risk newborns. As the implementation of hypothermia within 6 hours of birth has become widespread for perinatal asphyxia, what other practices should become standard? In this issue of The Journal, the NICHD NRN investigators report on the importance of neonatal brain magnetic resonance imaging (MRI) following rewarming to predict future outcome. MRIs were obtained in their trial at approximately 44 weeks postmenstrual age. A normal brain MRI had a sensitivity of 61% and positive predictive value (PPV) of 92% for normal outcome and intelligence quotient (IQ) ≥ 70 at age 6 to 7 years. However, MRI involvement of either basal ganglia, thalamus, anterior or posterior limb of the internal capsule, or an area of infarction, plus any additional cerebral lesions (or cerebral hemispheric devastation) had an 81% sensitivity and 70% PPV for death or IQ <70 at aged 6 to 7 years. These MRI patterns can be highly helpful to counsel the families of affected newborns. MRI following therapeutic hypothermia should now be a standard procedure. Article page 987▶ Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic EncephalopathyThe Journal of PediatricsVol. 167Issue 5PreviewTo examine the ability of magnetic resonance imaging (MRI) patterns of neonatal brain injury defined by the National Institute of Child Health and Human Development Neonatal Research Network to predict death or IQ at 6-7 years of age following hypothermia for neonatal encephalopathy. Full-Text PDF