Emergent Prophylactic, Reparative and Restorative Brain Interventions for Infants Born Preterm With Cerebral Palsy

Worldwide, an estimated 15 million babies are born preterm (<37 weeks' gestation) every year. Despite significant improvements in survival rates, preterm infants often face a lifetime of neurodevelopmental disability including cognitive, behavioral, and motor impairments. Indeed, prematurity remains the largest risk factor for the development of cerebral palsy. The developing brain of the preterm infant is particularly fragile; preterm babies exhibit varying severities of cerebral palsy arising from reductions in both cerebral white and gray matter volumes, as well as altered brain microstructure and connectivity. Current intensive care therapies aim to optimize cardiovascular and respiratory function to protect the brain from injury by preserving oxygenation and blood flow. If a brain injury does occur, definitive diagnosis of cerebral palsy in the first few hours and weeks of life is difficult, especially when the lesions are subtle and not apparent on cranial ultrasound. However, early diagnosis of mildly affected infants is critical, because these are the patients most likely to respond to emergent treatments inducing neuroplasticity via high-intensity motor training programs and regenerative therapies involving stem cells. A current controversy is whether to test universal treatment in all infants at risk of brain injury, accepting that some patients never required treatment, because the perceived potential benefits outweigh the risk of harm. Versus, waiting for a diagnosis before commencing targeted treatment for infants with a brain injury, and potentially missing the therapeutic window. In this review, we discuss the emerging prophylactic, reparative, and restorative brain interventions for infants born preterm, who are at high risk of developing cerebral palsy. We examine the current evidence, considering the timing of the intervention with relation to the proposed mechanism/s of action. Finally, we consider the development of novel markers of preterm brain injury, which will undoubtedly lead to improved diagnostic and prognostic capability, and more accurate instruments to assess the efficacy of emerging interventions for this most vulnerable group of infants

The cause-specific morbidity and mortality, and referral patterns of all neonates admitted to a tertiary referral hospital in the northern provinces of Vietnam over a one year period.

OBJECTIVE: To describe the cause-specific morbidity and mortality, and referral patterns of all neonates admitted to a tertiary referral hospital in the northern provinces of Vietnam. DESIGN: A prospective hospital based observational study. SETTING: The Neonatal Department, National Hospital of Pediatrics, Hanoi, Vietnam. PATIENTS: All admissions to the Neonatal Department over a 12 month period. MAIN OUTCOME MEASURES: Cause-specific morbidity and mortality; deaths. RESULTS: There were 5064 admissions with the commonest discharge diagnoses being infection (32%) and prematurity (29%). The case fatality ratio (CFR) was 13.9% (n = 703). Infection (38%), cardio/respiratory disorders (27%), congenital abnormalities (20%) and neurological conditions (10%) were the main causes of death. Of all the deaths, 38% had an admission weight ≥2500g. Higher CFR were associated with lower admission weights. Very few deaths (3%) occurred in the first 24 hours of life. Most referrals and deaths came from Hanoi and neighbouring provincial hospitals, with few from the most distant provinces. Two distant referral provinces had the highest CFR. CONCLUSIONS: The CFR was high and few deaths occurred in neonates <24 hours old. The high rates of infection call for an improvement in infection control practices and peripartum antibiotic use at provincial and tertiary level. Understanding provincial hospital capacity and referral pathways is crucial to improving the outcomes at tertiary centres. A quality of care audit tool would enable more targeted interventions and monitoring of health outcomes

Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial

Objective: To investigate the effects of hypothermia treatment on magnetic resonance imaging (MRI) patterns of brain injury in newborns with hypoxic-ischemic encephalopathy compared with normothermia, including the prognostic utility of MRI for death and/or disability at a postnatal age of 2 years

Tracking regional brain growth up to age 13 in children born term and very preterm

Serial regional brain growth from the newborn period to adolescence has not been described. Here, we measured regional brain growth in 216 very preterm (VP) and 45 full-term (FT) children. Brain MRI was performed at term-equivalent age, 7 and 13 years in 82 regions. Brain volumes increased between term-equivalent and 7 years, with faster growth in the FT than VP group. Perinatal brain abnormality was associated with less increase in brain volume between term-equivalent and 7 years in the VP group. Between 7 and 13 years, volumes were relatively stable, with some subcortical and cortical regions increasing while others reduced. Notably, VP infants continued to lag, with overall brain size generally less than that of FT peers at 13 years. Parieto-frontal growth, mainly between 7 and 13 years in FT children, was associated with higher intelligence at 13 years. This study improves understanding of typical and atypical regional brain growth

Effect of treatment of clinical seizures vs electrographic seizures in full-term and near-term neonates : a randomized clinical trial

Importance: Seizures in the neonatal period are associated with increased mortality and morbidity. Bedside amplitude-integrated electroencephalography (aEEG) has facilitated the detection of electrographic seizures; however, whether these seizures should be treated remains uncertain. Objective: To determine if the active management of electrographic and clinical seizures in encephalopathic term or near-term neonates improves survival free of severe disability at 2 years of age compared with only treating clinically detected seizures. Design, Setting, and Participants: This randomized clinical trial was conducted in tertiary newborn intensive care units recruited from 2012 to 2016 and followed up until 2 years of age. Participants included neonates with encephalopathy at 35 weeks’ gestation or more and younger than 48 hours old. Data analysis was completed in April 2021. Interventions: Randomization was to an electrographic seizure group (ESG) in which seizures detected on aEEG were treated in addition to clinical seizures or a clinical seizure group (CSG) in which only seizures detected clinically were treated. Main Outcomes and Measures: Primary outcome was death or severe disability at 2 years, defined as scores in any developmental domain more than 2 SD below the Australian mean assessed with Bayley Scales of Neonate and Toddler Development, 3rd ed (BSID-III), or the presence of cerebral palsy, blindness, or deafness. Secondary outcomes included magnetic resonance imaging brain injury score at 5 to 14 days, time to full suck feeds, and individual domain scores on BSID-III at 2 years. Results: Of 212 randomized neonates, the mean (SD) gestational age was 39.2 (1.7) weeks and 122 (58%) were male; 152 (72%) had moderate to severe hypoxic-ischemic encephalopathy (HIE) and 147 (84%) had electrographic seizures. A total of 86 neonates were included in the ESG group and 86 were included in the CSG group. Ten of 86 (9%) neonates in the ESG and 4 of 86 (4%) in the CSG died before the 2-year assessment. The odds of the primary outcome were not significantly different in the ESG group compared with the CSG group (ESG, 38 of 86 [44%] vs CSG, 27 of 86 [31%]; odds ratio [OR], 1.83; 95% CI, 0.96 to 3.49; P = .14). There was also no significant difference in those with HIE (OR, 1.77; 95% CI, 0.84 to 3.73; P = .26). There was evidence that cognitive outcomes were worse in the ESG (mean [SD] scores, ESG: 97.4 [17.7] vs CSG: 103.8 [17.3]; mean difference, −6.5 [95% CI, −1.2 to −11.8]; P = .01). There was little evidence of a difference in secondary outcomes, including time to suck feeds, seizure burden, or brain injury score. Conclusions and Relevance: Treating electrographic and clinical seizures with currently used anticonvulsants did not significantly reduce the rate of death or disability at 2 years in a heterogeneous group of neonates with seizures

Willingness to Pay to Reduce Mortality Risks: Evidence from a Three-Country Contingent Valuation Study

Valuing a change in the risk of death is a key input into the calculation of the benefits of environmental policies that save lives. Typically such risks are monetized using the Value of a Statistical Life (VSL). Because the majority of the lives saved by environmental policies are those of older persons, there has been much recent debate about whether the VSL should be lower for the elderly to reflect their fewer remaining life years. We conducted a contingent valuation survey in the UK, Italy and France designed to answer this question. The survey was administered in these three countries following a standardized protocol. Persons of age 40 and older were asked questions about their willingness to pay for a specified risk reduction. We use their responses to these questions to estimate the willingness to pay (WTP) for such a risk reduction and VSL. Our results suggest that the VSL ranges between €1.052 and €2.258 million. The VSL is not significantly lower for older persons, but is higher for persons who have been admitted to the hospital or emergency room for cardiovascular and respiratory problems. These results suggest that there is no evidence supporting that VSL should be adjusted to reflect the age of the beneficiaries of environmental policy. They are also partly inconsistent with the QALY-based practice of imputing lower values for persons with a compromised health status. We also find that income is positively and significantly associated with WTP. The income elasticities of the WTP increase gradually with income levels and are typically between 0.15 and 0.5 for current income levels in EU countries. We use the responses to the WTP questions to estimate the value of an extension in remaining life expectancy. We find that the value of a month's extension in life expectancy increases with age and with serious cardiovascular and respiratory illnesses experienced by the respondent. The value of a loss of one year's life expectancy is between €55,000 and €142,000