Long-term Neurodevelopmental Disability Research Articles

In vivo neural regeneration via AAV-NeuroD1 gene delivery to astrocytes in neonatal hypoxic-ischemic brain injury

BackgroundNeonatal hypoxic-ischemic brain injury (HIBI) is a significant contributor to neonatal mortality and long-term neurodevelopmental disability, characterized by massive neuronal loss and reactive astrogliosis. Current therapeutic approaches for neonatal HIBI have been limited to general supportive therapy because of the lack of methods to compensate for irreversible neuronal loss. This study aimed to establish a feasible regenerative therapy for neonatal HIBI utilizing in vivo direct neuronal reprogramming technology.MethodsNeonatal HIBI was induced in ICR mice at postnatal day 7 by permanent right common carotid artery occlusion and exposure to hypoxia with 8% oxygen and 92% nitrogen for 90 min. Three days after the injury, NeuroD1 was delivered to reactive astrocytes of the injury site using the astrocyte-tropic adeno-associated viral (AAV) vector AAVShH19. AAVShH19 was engineered with the Cre-FLEX system for long-term tracking of infected cells.ResultsAAVShH19-mediated ectopic NeuroD1 expression effectively converted astrocytes into GABAergic neurons, and the converted cells exhibited electrophysiological properties and synaptic transmitters. Additionally, we found that NeuroD1-mediated in vivo direct neuronal reprogramming protected injured host neurons and altered the host environment, i.e., decreased the numbers of activated microglia, reactive astrocytes, and toxic A1-type astrocytes, and decreased the expression of pro-inflammatory factors. Furthermore, NeuroD1-treated mice exhibited significantly improved motor functions.ConclusionsThis study demonstrates that NeuroD1-mediated in vivo direct neuronal reprogramming technology through AAV gene delivery can be a novel regenerative therapy for neonatal HIBI.

Optimising Functional Recovery in a Paediatric Stroke patient secondary to Sickle Cell Disease: A Case Report

Out of many causes of Paediatric Stroke, Sickle Cell Disease is one of the crucial conditions with the risk of Stroke highest during the first decade that is between the ages of 2 & 5 years. Reported here, however, is a case of a 10-year-old male child with sudden onset left side hemiplegia with facial muscle weakness, who was a known case of Sickle Cell disease since 6 months of age. With the inability to use the upper extremities & walk independently, the patient was functionally dependent with a Fugl Meyer score of 55/126 & Berg balance scale score of 18/56. After 4 months of Physiotherapy Treatment patient was able to use the Upper extremities for functional activities and was able to walk independently with a Berg balance scale score of 46/56. With very few cases of pediatric Stroke receiving Physiotherapy care being reported in the literature, this case report establishes the role of Physiotherapy in preventing long-term neurodevelopmental disability. KEYWORDS: Functional Motor Recovery, Paediatric Stroke, Physical Rehabilitation, Sickle Cell Disease.

1620. Identification of plasma biomarkers of neurological complications in patients with congenital cytomegalovirus infection by proteome analysis

Abstract Background Congenital cytomegalovirus infection (cCMV) is the leading cause of non-hereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities. To consider antiviral treatment, it is important to differentiate between symptomatic and asymptomatic patients by early infancy. However, it is difficult to identify neurological complications in some cases. This study aimed to identify candidate plasma biomarkers for neurological complications of cCMV during the neonatal period using proteome analysis. Methods This study retrospectively enrolled five patients with asymptomatic cCMV and nine patients with symptomatic cCMV, including those with hearing loss and/or abnormal brain imaging. Plasma samples were obtained during the neonatal period. After extraction of 14 high-abundant proteins from the plasma, proteins were digested by trypsin. The peptides were analyzed by liquid chromatography–mass spectrometry using an Orbitrap Fusion mass spectrometer. Protein quantification was performed using Proteome Discoverer. Levels of differently expressed proteins were validated by enzyme-linked immunosorbent assay. Results In total, 456 proteins were identified and quantified. Levels of 65 proteins were significantly higher in patients with symptomatic cCMV than in those with asymptomatic cCMV. The top two enriched categories for these proteins according to pathway enrichment analysis were “complement and coagulation cascade” and “inflammatory response.” In contrast, levels of 30 proteins were significantly higher in patients with abnormal brain imaging. Plasma levels of fms-related receptor tyrosine kinase 4 (FLT4) were significantly higher in patients with symptomatic cCMV than in those with asymptomatic cCMV. Moreover, levels of plasma peptidylprolyl isomerase A (PPIA) were significantly higher in patients with abnormal brain imaging than in those without. Conclusion Proteome analysis showed that the proteins related to inflammatory response pathways were upregulated in patients with symptomatic cCMV. FLT4 and PPIA can be used as novel diagnostic biomarkers for neurological complications of cCMV to enable early therapeutic intervention with antiviral agents. Disclosures All Authors: No reported disclosures

Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm.

Preterm infants face a significant risk of brain injury in the perinatal period, as well as potential long-term neurodevelopmental disabilities. However, preterm children with brain injury lack specific clinical manifestations in the early days. Therefore, timely and accurate diagnosis of brain injury is of vital importance. This study was to explore the diagnostic efficiency of myelin basic protein (MBP) and 8-oxo-deoxyguanosine (8-oxo-dG) serum levels in brain injury of premature infants. A total of 75 preterm infants with gestational age between 28 and 32 weeks and birth weight higher than 1,000 g were prospectively included. MBP serum levels were significantly higher in premature infants with white matter injury (WMI). 8-oxo-dG serum levels were significantly increased in both WMI and periventricular-intraventricular hemorrhages (PIVH). MBP and 8-oxo-dG were significantly correlated. The area under the curve was 0.811 [95% confidence interval (CI) 0.667-0.955; p = 0.002] in MBP and 0.729 (95% CI 0.562-0.897; p = 0.020) in 8-oxo-dG. Therefore, the results showed that high MBP levels indicated a possibility of WMI in the premature brain during the early postnatal period, while high 8-oxo-dG levels were closely related to both WMI and PIVH, thus suggesting that MBP and 8-oxo-dG could be used as potential neuro-markers of preterm brain injury.

Functional neuropathology of neonatal hypoxia-ischemia by single-mouse longitudinal electroencephalography.

Neonatal cerebral hypoxia-ischemia (HI) results in symptomatic seizures and long-term neurodevelopmental disability. The Rice-Vannucci model of rodent neonatal HI has been used extensively to examine and translate the functional consequences of acute and chronic HI-induced encephalopathy. Yet, longitudinal electrophysiological characterization of this brain injury model has been limited by the size of the neonatal mouse's head and postnatal maternal dependency. We overcome this challenge by employing a novel method of longitudinal single-mouse electroencephalography (EEG) using chronically implanted subcranial electrodes in the term-equivalent mouse pup. We characterize the neurophysiological disturbances occurring during awake and sleep states in the acute and chronic phases following newborn brain injury. C57BL/6 mice underwent long-term bilateral subcranial EEG and electromyographic electrode placement at postnatal day 9 followed by unilateral carotid cauterization and exposure to 40 minutes of hypoxia the following day. EEG recordings were obtained prior, during, and intermittently after the HI procedure from postnatal day 10 to weaning age. Quantitative EEG and fast Fourier transform analysis were used to evaluate seizures, cortical cerebral dysfunction, and disturbances in vigilance states. We observed neonatal HI-provoked electrographic focal and bilateral seizures during or immediately following global hypoxia and most commonly contralateral to the ischemic injury. Spontaneous chronic seizures were not seen. Injured mice developed long-term asymmetric EEG background attenuation in all frequencies and most prominently during non-rapid eye movement (NREM) sleep. HI mice also showed transient impairments in vigilance state duration and transitions during the first 2 days following injury. The functional burden of mouse neonatal HI recorded by EEG resembles closely that of the injured human newborn. The use of single-mouse longitudinal EEG in this immature model can advance our understanding of the developmental and pathophysiological mechanisms of neonatal cerebral injury and help translate novel therapeutic strategies against this devastating condition.

Emerging Concepts in Congenital Cytomegalovirus.

Over a century of research has focused on improving our understanding of congenital cytomegalovirus (cCMV), yet it remains the most common congenital infection in the United States, affecting 3 to 6 per 1000 live born infants each year. Pregnancies affected by cCMV are at a heightened risk of spontaneous abortion and intrauterine fetal demise. Neonates born with cCMV are also at substantial risk for long-term neurodevelopmental sequelae and disability, including sensorineural hearing loss, even those born without clinically apparent disease. Considerable progress has been made in recent years in study of the epidemiology and transmission of cCMV, developing better diagnostic strategies, implementing newborn screening programs, improving therapeutics, and launching vaccine trials. In this article, we review recent developments in the understanding of the virology and immunobiology of cytomegalovirus. We further discuss how this knowledge informs our understanding of the pathophysiology of cCMV and directs strategies aimed at improving outcomes and quality of life for congenitally infected children. We also provide an update on the epidemiology of cCMV in the United States, evolving scientific understanding of maternal-fetal transmission, enhanced screening approaches, and recognition of neonatal and long-term sequelae. Finally, we review the current landscape of pediatric cCMV research and provide recommendations for novel and high-priority areas for future investigation.

Neurological Surveillance in Moderate-Late Preterm Infants-Results from a Dutch-Canadian Survey.

Preterm birth remains an important cause of abnormal neurodevelopment. While the majority of preterm infants are born moderate-late preterm (MLPT; 32–36 weeks), international and national recommendations on neurological surveillance in this population are lacking. We conducted an observational quantitative survey among Dutch and Canadian neonatal level I–III centres (June 2020–August 2021) to gain insight into local clinical practices on neurological surveillance in MLPT infants. All centres caring for MLPT infants designated one paediatrician/neonatologist to complete the survey. A total of 85 out of 174 (49%) qualifying neonatal centres completed the survey (60 level I–II and 25 level III centres). Admission of MLPT infants was based on infant-related criteria in 78/85 (92%) centres. Cranial ultrasonography to screen the infant’s brain for abnormalities was routinely performed in 16/85 (19%) centres, while only on indication in 39/85 (46%). In 57/85 (67%) centres, neurological examination was performed at least once during admission. Of 85 centres, 51 (60%) followed the infants’ development post-discharge, with follow-up duration ranging from 1–52 months of age. The survey showed a wide variety in neurological surveillance in MLPT infants among Dutch and Canadian neonatal centres. Given the risk for short-term morbidity and long-term neurodevelopmental disabilities, future studies are required to investigate best practices for in-hospital care and follow-up of MLPT infants.

Implementing use of sucrose analgesia (non-pharmacological management of neonatal pain) in a standalone private facility level 3 neonatal care unit using point of care quality improvement methodology

BackgroundNeonatal pain not only has negative impact on the acute physiological parameters of the neonate but also has got the potential to cause long-term neurodevelopmental disabilities. However, neonatal pain especially...

Fetal Zone Steroids Show Discrete Effects on Hyperoxia-Induced Attenuation of Migration in Cultured Oligodendrocyte Progenitor Cells.

Cerebral oxygenation disturbances contribute to the pathogenesis of brain lesions in preterm infants with white matter damage. These children are at risk of developing long-term neurodevelopmental disabilities. Preterm birth is associated with sudden hormonal changes along with an untimely increase in oxygen tissue tension. There is a persistent high postnatal production of fetal zone steroids (FZS), which serve in the fetoplacental unit as precursors for placental estrogen synthesis during pregnancy. The role of FZS in events associated with oxygenation differences and their impact on the developing white matter is not well understood. Therefore, we investigated the effect of hyperoxia (80% O2) and subsequent administration of FZS on the protein composition and migration capabilities of immature oligodendrocytes using the OLN93 (rat-derived OPC) cell line as an experimental model. We tested the effect of the FZS, dehydroepiandrosterone (DHEA), 16α-OH-DHEA, and adiol (5-androstene-3β, 17β-diol). After 24-hour exposure to hyperoxia, we monitored the changes in the proteome profile following treatment and observed significant alterations in pathways regulating cytoskeletal remodelling, cell migration, and cell survival. Additionally, hyperoxia leads to impaired migration of the OLN93 cells in culture. Administration of the FZS showed positive effects on the migration process under normoxic conditions in general. However, under hyperoxic conditions, the trend was less prominent. The observed effects could be related to changes in levels of cofilin/LIMK pathway-associated proteins. Adiol had a negative effect when administered together with estradiol, and the proteomic data reveal the activation of ephrin receptor signalling that might be responsible for the attenuation of migration. The results suggest that FZS can differentially regulate pathways involved in the migration of OLN93 cells. A deeper insight into the precise role of endogenous FZS would be an essential prerequisite for developing new treatment strategies including supplementation of estradiol and other steroids in preterm infants.

Health Care Resource Utilization and Economic Burden Associated With Congenital Cytomegalovirus Infection: A Longitudinal Analysis of Data From Clinical Practice at a Large Health Care Provider in Israel

PurposeCongenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities; however, data on the economic burden of cCMVi during early childhood are scarce. The primary objective of the study was to describe longitudinal patterns of health care resource utilization (HCRU) and direct medical costs among infants with cCMVi compared to infants unexposed to cCMVi. MethodsA retrospective cohort study was performed using data on infants born between 2013 and 2017, as captured in the database of Maccabi Healthcare Services, a 2.5 million–member health care organization in Israel. cCMVi cases were identified by physician diagnosis and/or dispensed valganciclovir within 90 days after birth. Infants born to mothers CMV-seronegative throughout pregnancy were selected for comparison (unexposed controls). Infants were retrospectively followed up through December 31, 2018, or 4 years of age (Y4). HCRU included physician visits, hospital admissions, audiology tests/procedures, imaging, and valganciclovir treatment. Direct medical costs, in US dollars per person per year (USD PPPY) were calculated from the health-system perspective. To compare costs of cCMVi cases and controls, direct medical costs were estimated using a generalized linear model with a log link function and γ distribution after adjustment for patient characteristics. FindingsA total of 351 cCMVi cases and 11,733 control infants with continuous follow-up during their first year of life (Y1) were included in the study. In Y1, cases were more likely to have a hospital admission (8.5% cases vs 4.5% control; P < 0.001) and higher numbers of pediatrician visits (median, 18 vs 15), audiology visits and tests, and cranial ultrasounds (all, P < 0.05). Longitudinally, incremental costs associated with cases were highest in Y1 (1686.7 USD PPPY; cost ratio = 2.6; P < 0.001) and remained elevated through Y4. ImplicationscCMVi was associated with substantial increases in HCRU and economic burden during early childhood, and particularly during the first year of life.

A Simplified Paradigm of Late Gestation Transient Prenatal Hypoxia to Investigate Functional and Structural Outcomes from a Developmental Hypoxic Insult.

Late-gestation transient intrauterine hypoxia is a common cause of birth injury. It can lead to long-term neurodevelopmental disabilities even in the absence of gross anatomic injury. Currently, postnatal models of hypoxia-ischemia are most commonly used to study the effect of oxygen deprivation in the fetal brain. These models, however, are unable to take into account placental factors that influence the response to hypoxia, exhibit levels of cell death not seen in many human patients, and are unable to model preterm hypoxia. To address this gap in research, we have developed a protocol to induce transient hypoxia in fetal mice. A pregnant dam at gestational day 17.5 is placed into a hypoxia chamber. Over 30 min, the inspired oxygen is titrated from 21% (ambient air) to 5%. The dam remains in the chamber for up to 8 h, after which fetal brains can be collected or pups delivered for postnatal studies. This protocol recapitulates phenotypes seen in human patients exposed to transient in utero hypoxia and is readily reproducible by researchers. Graphical abstract.

Lo shock settico nei primi tre mesi di vita

Shock is a generalized tissue hypoperfusion that leads to severe cellular distress and complicates some cases of paediatric and neonatal sepsis. Although a reduction in associated sepsis mortality has been observed in the last decades, it remains one of the most important causes of death or long-term neurodevelopmental disabilities in children. Prompt recognition of this condition is therefore essential to improve survival and long-term outcome. The paediatrician and the neonatologist must therefore be able to promptly recognize the signs and symptoms of sepsis and septic shock to set up an adequate treatment according to the most recent international guidelines. This article provides epidemiological data from Italian and international studies, describes the pathophysiology and clinical manifestations of sepsis and septic shock, as well as the therapeutic indications according to very recent recommendations.

Changes in long-term survival and neurodevelopmental disability in infants born extremely preterm in the post-surfactant era

Extremely preterm birth before 28 weeks’ gestation accounts for less than 1% of births in high-income countries but is associated with high rates of perinatal and infant mortality, and of neurodevelopmental disability in surviving children. Survival rates have increased over time, both overall, and within each week of gestational age since the introduction of exogenous surfactant into clinical care in the early 1990s. However, rates of major neurodevelopmental disability in survivors, whether they be in early childhood or at school-age, have not clearly improved in parallel with the increases in survival. An important strategy to improve survival free of major neurodevelopmental disability is to birth extremely preterm infants in a tertiary perinatal center, where specialist obstetric care for the mother and ongoing intensive care for the infant can both be provided without the potential morbidities associated with postnatal transfer.

Neonatal hypoxic-ischemic encephalopathy diagnosis and treatment: a National Survey in China

BackgroundNeonatal hypoxic-ischemic encephalopathy (HIE) affects as many as 100,000 infants each year in China. Therapeutic hypothermia reduces HIE related mortality and long-term neurodevelopmental disabilities. National guidelines for HIE management were published a decade ago. This study aimed to investigate the current status of HIE diagnosis and treatment in China.MethodThis prospective cross-sectional national survey used a questionnaire evaluating practices related to HIE management. Descriptive statistics and Chi-square or Fisher’s exact test were used, and a p-value of < 0.05 was considered significant.ResultsThe 273 hospitals that completed the survey were located in 31 of the 34 provincial districts in China. Eighty-eight percent of the hospitals were Level III hospitals, and 74% treated 10 or more HIE cases annually. Awareness rates of the national guidelines for HIE diagnosis, HIE treatment, and therapeutic hypothermia protocol were 85, 63, and 78%, respectively. Neurological manifestations and blood gas were used as HIE diagnostic criteria by 96% (263/273) and 68% (186/273) of the hospitals, respectively. Therapeutic hypothermia was used in 54% (147/273) of hospitals. The percentage of general hospitals that implemented therapeutic hypothermia (43%, 71/165) was significantly lower than that in maternity and infant hospitals (67%, 49/73) (χ2 = 11.752, p = 0.001) and children’s hospitals (77%, 27/35) (χ2 = 13.446, p < 0.001). Reasons for not providing therapeutic hypothermia included reduction of HIE cases in recent years (39%), high cost of cooling devices and treatment (31%), lack of training (26%), and safety concerns (4%). Among the hospitals that provided therapeutic hypothermia, 27% (39/147) were in full compliance with the recommended protocol. Eighty-one percent (222/273) of the hospitals treated HIE infants with putative neuroprotective agents alone or in combination with cooling. Ninety-one percent of the hospitals had long-term neurodevelopmental follow-up programs for infants with HIE.ConclusionsThere is significant heterogeneity in HIE diagnosis and treatment in China. Therapeutic hypothermia has not become a standard of care for neonatal HIE nationwide. Unproven agents are widely used for HIE treatment. Nationwide standardization of HIE management and dissemination of therapeutic hypothermia represent the opportunities to reduce mortality and improve long-term neurodevelopmental outcomes of children affected by HIE.

Is intravenous fish oil associated with the neurodevelopment of extremely low birth weight preterm infants on parenteral nutrition?

Preterm infants are at increased risk of long-term neurodevelopmental disabilities (NDD). Long chain n-3 fatty acids play a key role during the development of the central nervous system and some studies in preterm infants showed benefits of docosahexaenoic acid and arachidonic acid supplementation for visual and cognitive development. In recent years fish oil has been added to the fat blend of intravenous (IV) lipid emulsions (LE) but to date scanty data are available on neurodevelopmental outcome of preterm infants that received fish oil containing LE. We studied the effect of fish oil containing IV LE vs standard IV LE on neurodevelopment in a large cohort of preterm infants who received routine parenteral nutrition (PN) from birth. We retrospectively reviewed the neurodevelopmental outcome of 477 preterm infants (birth weight (BW): 400-1249g and gestational age (GA) at birth: 24+0 - 35+6 weeks (W)) admitted to our NICU between Oct-2008 and June-2017, who received routine PN with different LE, with and without fish oil (IV-FO vs CNTR). We compared neurodevelopment at 2 years corrected age by the Bayley III development scale and the incidence of NDD. Demographics, birth data and the incidence of the main clinical short-term outcomes of prematurity were similar in the two groups (IV-FO: n=178, GA 197±14 days, BW 931±182g; CNTR: n=192, GA 198±15 days, BW 944±194g). No differences were found in maternal demographics nor in parental education between the two groups. Cognitive score was not significantly different between IV-FO and CNTR (92±15 vs 93±13, p=0.5). No differences were found in motor and language scores, and in the incidence of NDD in the two groups. Contrary to our hypothesis, the use of fish oil containing LE in a large cohort of preterm infants on routine PN did not result in better neurodevelopment. Large randomized controlled trials powered for neurodevelopment are needed to clarify the impact of the widely used fish oil containing LE on neurodevelopment of preterm infants.

Serial plasma biomarkers of brain injury in infants with neonatal encephalopathy treated with therapeutic hypothermia.

Background:Neonatal encephalopathy (NE) is a major cause of long-term neurodevelopmental disability in neonates. We evaluated the ability of serially measured biomarkers of brain injury to predict adverse neurological outcomes in this population.Methods:Circulating brain injury biomarkers including BDNF, IL-6, IL-8, IL-10, VEGF, Tau, GFAP, and NRGN were measured at 0, 12, 24, 48, 72, and 96 hours of cooling from 103 infants with NE undergoing TH. The biomarkers’ individual and combinative ability to predict death or severe brain injury and adverse neurodevelopmental outcomes beyond 1 year of age was assessed.Results:Early measurements of inflammatory cytokines IL-6, 8, and 10 within 24 HOL (AUC=0.826) and late measurements of Tau from 72–96 HOL (AUC=0.883, OR 4.37) were accurate in predicting severe brain injury seen on MRI. Late measurements of Tau were predictive of adverse neurodevelopmental outcomes (AUC=0.81, OR 2.59).Conclusions:Tau was consistently a predictive marker for brain injury in neonates with NE. However, in the first 24 HOL, IL-6, 8, and 10 in combination were most predictive of death or severe brain injury. The results of this study support the use of a serial biomarker panel to assess brain injury over the time course of disease in NE.

Predicting long-term neurodevelopmental outcomes in very preterm neonates by umbilical cord gas parameters

The predictive value of acidemia at birth on long-term neurodevelopmental outcomes remains poorly understood, especially in preterm neonates. This study aimed to assess the relationship between the umbilical artery acid-base status and major neurodevelopmental disability at an age of between 5 and 8 years among children born very prematurely. We performed a secondary analysis of the data from a follow-up study of a prospective cohort of 457 children aged between 23 weeks and 31 weeks and 6 days from 1996 to 2001. Arterial cord gas parameters that were <10th percentile in the original cohort of 457 neonates (ie, pH of <7.1, base deficit of <-8.6 mEq/L, and a partial pressure of CO2 of >77 mm Hg) were considered abnormal. Sensitivity analyses considered alternative definitions for abnormal cord gases including a pH of <7.0 or base deficit of <-12 mEq/L. The primary outcome was a composite of major neurodevelopmental disability, including an intelligence quotient score of <70, cerebral palsy, blindness, deafness, abnormal balance, impaired cognition, dystonia, and seizure disorder. A logistic regression analysis was used to adjust for race and caregiver intelligence quotient score and, in an additional analysis, for gestational age. A total of 259 of 261 maternal-infant dyads were evaluated at a mean child age of 6.8 years, with complete umbilical cord gas data for 228 of those. Infants with an abnormal pH and a base deficit (defined above) were over 4-fold more likely to have the composite disability and an intelligence quotient score of <70. These increased odds persisted after adjusting for age and caregiver intelligence quotient score, but when considering gestational age as well, none of the umbilical cord gas parameters significantly predicted the presence of the composite disability or an intelligence quotient score of <70. However, when using the stricter umbilical cord gas criteria (ie, pH of <7.0 and a base deficit of <-12 mEq/L), a base deficit of <-12 mEq/L was independently associated with both neurodevelopmental disability and an intelligence quotient score of <70. When defined more strictly, abnormal umbilical cord gases, specifically a base deficit of <-12 mEq/L, are associated with an increased risk for major long-term neurodevelopmental disability and an intelligence quotient score of <70 in children born very prematurely.

Community-based, population-focused preterm birth prevention programs - a review.

Preterm birth (PTB) is the leading cause of perinatal morbidity and mortality worldwide. Being born too early contributes to approximately 70% of neonatal mortality and approximately half of long-term neurodevelopmental disabilities. Various PTB prevention programs have been described going back more than 30years, and some have described possible success in decreasing the rate of PTB. In addition, there are also PTB prenatal care clinics in many parts of the world, each with the singular goal of reducing the PTB rate in their region. Interventions can be directed at all women for primary prevention and reducing the risk of PTB or used to mitigate risk in women identified to be at increased risk. A Medline and ClinicalTrials.gov ( www.clinicaltrials.gov ) search was performed (1982-2018), using preterm birth prevention program as the primary medical subject heading, reporting randomized clinical trials, quasi-experimental trials, and analytic studies (including retrospective and prospective cohort studies). We also searched Google for preterm birth prevention programs and prenatal care clinics published on-line. Some prevention programs have reported success in lowering rates of PTB, principally using historical controls although the majority were not followed by improved outcomes. Increasing knowledge and the use of social media to enhance education should now enable greater effectiveness of new programs. Development of regional and national PTB prevention programs should now be considered.

Impact of breast milk-acquired cytomegalovirus infection in premature infants: Pathogenesis, prevention, and clinical consequences?

Maternal-fetal transmission of cytomegalovirus (CMV) represents the most common infectious cause of long-term neurodevelopmental disability in children. Congenital CMV (cCMV) infection is associated with microcephaly, seizure disorders, cognitive disability, developmental delay, and sensorineural hearing loss (SNHL). Of these disabilities, SNHL is the most common, affecting approximately 10% of infants with cCMV. Although the sequelae of cCMV are well recognized, it is much less clear what long-term morbidities may occur in neonates that acquire post-natal CMV infection. Post-natal CMV (pCMV) infection is most commonly transmitted by breast-feeding, and in full-term infants is of little consequence. However, in preterm, very-low birthweight (VLBW) infants (<1500 g), pCMV can result in a severe sepsis-like syndrome, with wide-ranging end-organ disease manifestations. Although such short-term complications are well recognized among clinicians caring for premature infants, the long-term risks with respect to adverse neurodevelopmental outcomes remain controversial. In this review, we provide an overview of the clinical manifestations of breast milk-acquired pCMV infection. In particular, we summarize studies that have examined-sometimes with conflicting conclusions-the risks of long-term adverse neurodevelopmental outcome in VLBW infants that acquire pCMV from breast milk. We highlight proposed preventive strategies and antiviral interventions, and offer recommendations for high-priority areas for future basic science and clinical research.

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.