A variety of brain injuries originating from fetal, perinatal, and neonatal periods
may cause mortality, and many of the survivors of those injuries suffer from life-long
morbidity. It is our task as researchers to prevent and reduce such brain injuries
in infants. This is why we Topic Editors chose the theme “Preventing developmental
brain injury—from animal models to clinical trials.”
Among those developing brain injuries, neonatal encephalopathy in full-term infants
has been the most crucial issue for decades (1). Neonatal encephalopathy refers to
newborns with symptoms of acute cerebral dysfunction such as depressed consciousness,
abnormal muscle tone, respiratory distress, feeding difficulties, and seizures (2,
3). Hypoxic-ischemic injury is the most common (up to 85% of cases), and ischemic/hemorrhagic
stroke is the second most common, etiology and pathophysiology of neonatal encephalopathy
(3). Approximately 3% of babies born in the world die by 4 weeks of age, and asphyxia,
i.e., neonatal encephalopathy accounts for 23% of neonatal mortality (4); hence, the
mortality rate due to neonatal encephalopathy is estimated to be 70/1,000 livebirths.
Almost all (99%) neonatal mortality occurs in resource-limited countries (4). The
incidence of neonatal encephalopathy in term newborns has been declining in resource-rich
countries, and is currently 1/1,000 livebirths or less (5, 6). Nevertheless, nearly
half of infants with neonatal encephalopathy in resource-rich countries die or develop
permanent neurological disabilities, such as cerebral palsy, intellectual disability,
and epilepsy (7). Therefore, the burden of neonatal encephalopathy remains high for
patients, caregivers, and society.
Currently, the most common brain injuries caused during fetal, perinatal, and neonatal
periods are those associated with prematurity, i.e., fetal growth restriction, preterm
birth, and low birth weight (8). Approximately 15 million newborns were estimated
to be born preterm (<37 weeks of gestation) in 2010, which accounted for 11% of all
livebirths worldwide, ranging from 5% in some European countries to 18% in some African
countries (9). The preterm birth rate has been increasing over the past two decades
(9). Similarly, the rate of low birth weight (birth weight is <2,500 g) has been increasing:
7–9% of all live births in resource-rich countries (10, 11) and 11–12% in resource-limited
countries (12). Intrauterine hypoperfusion and inflammation are the two leading causes
of brain injuries associated with prematurity (13–16). Although most infants do not
present obvious neurological symptoms during the neonatal period, they may develop
cerebral palsy and neurodevelopmental disorders such as attention-deficit/hyperactive
disorders and autistic spectrum disorders during childhood (17, 18). Survivors of
very low birth weight (<1,500 g) may present cerebral palsy in 5–10% of the individuals
and cognitive/behavioral/attentional deficits in ~50% of these individuals (19, 20).
The main focus of outcome studies in neonatal care has been the extremely low-birth-weight
(<1,000 g) infants and extremely preterm infants [born before 28 weeks of gestation
(9)]. Recent studies, however, have shown that even infants born with mild prematurity
(birth weight is 1,500– <2,500 g; gestational age is 32– <37 weeks) have significantly
higher risks of developing numerous neurological, psychological, and general health
problems later in life (21). This phenomenon is now widely known as DOHaD (developmental
origin of health and diseases) (22). While many preclinical studies have been conducted
in neonatal encephalopathy, a limited number of preclinical studies have been conducted
regarding brain injuries associated with prematurity.
Neonatal encephalopathy and brain injury associated with prematurity seem to be contrasting
problems, as the former is a medical emergency during the neonatal period, while the
latter is a gradually emerging problem in childhood. While it is important to shed
light on rare brain injuries, neonatal encephalopathy in term infants and brain injuries
associated with prematurity are the most prominent issues that researchers and funding
sources need to address considering their impact on patients and society.
This Research Topic collects 29 articles: 20 animal studies (including 1 in vitro
study), 3 clinical studies, 1 combined study with clinical and animal studies, and
5 reviews. Of the 21 animal studies, the majority used rodents, and 3 studies used
large animals, i.e., piglets or lambs. Hypoxic-ischemic injury was the most frequently
used model (11 articles) in this Research Topic collection. Other models included
intrauterine ischemia/inflammation (3 articles) and irradiation (2 articles). As the
theme of this Research Topic was “preventing developing brain injury,” many of the
animal studies explored the effects of novel therapies. Five studies examined the
effects of cell-based therapies, 2 studies examined erythropoietin, and others examined
melatonin, inhaled carbon dioxide therapy, and protective ventilation strategies.
Some studies examined the effects of certain genomic modifications as possible targets
of novel therapies. Clinical studies investigated EEG and blood pressure, IL-10 gene
polymorphism, and cerebral lactate in infants with brain damage. Despite the Topic
Editors' expectations, there was no manuscript submission of an interventional clinical
trial, which may suggest a scarcity of clinical trials and difficulty in conducting
clinical trials of novel therapies in sick infants. The review articles summarized
the effects of therapies, such as oxytocin, magnesium, and nitric oxide synthase inhibition.
With respect to the demographics of this Research Topic collection, the corresponding
author's laboratories are located in a variety of countries: Japan (6 articles), the
United States (5 articles), France (4 articles), the United Kingdom (3 articles),
Sweden (3 articles), the Netherlands (2 articles), Switzerland (1 article), Germany
(1 article), China (1 article), South Korea (1 article), Canada (1 article), and Australia
(1 article). Thirteen articles represent international collaborative studies.
The Topic Editors are pleased to have a wide variety of 29 articles from many countries
around the world. None of the articles in this collection, however, are from the resource-limited
world. It is important to encourage research in this area in resource-limited countries
where developmental brain injuries are expected to be most prevalent. We hope that
research on neonatal brain injuries will become even more active and will contribute
to better preventions and treatments for these injuries in the near future.
Author Contributions
MT wrote the draft. SS and OB critically reviewed the manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.