Summary After decades of rising preterm birth rates in the USA and other countries, recent prematurity rates seem to be on the decline. Despite this optimistic trend, preterm birth rates remain higher in the USA, where nearly one in every eight infants is born early, compared to other developed countries. The prevention of preterm birth is considered a public health priority because of the potential to reduce infant and childhood morbidity and mortality related to this condition. Unfortunately, progress has been modest. One of the greatest challenges in studying this outcome is that preterm birth is a complex condition resulting from multiple etiologic pathways. Recently, experts have developed innovative frameworks for classifying and studying preterm birth based on phenotype. These proposed classification systems have only recently been adopted, but a different perspective on a longstanding problem has the potential to lead to new discoveries.
Summary Considerable research has investigated the consequences of being born very preterm (VP; <32 weeks of gestation), especially in relation to cognitive functioning. While numerous cognitive and neuropsychological outcome studies have been published, it is important to consider methodological issues when reviewing this research, as the generalizability of the studies varies greatly. This article describes the nature of cognitive difficulties confronting VP children, both in terms of the frequency and severity of deficits. The breadth of cognitive difficulties reported in this population implies a generalized cognitive impairment; however, the presence of selective or primary cognitive deficits is discussed. It is concluded that whereas mortality and neonatal morbidity rates have decreased significantly in VP infants in recent decades, these children continue to be at significant risk for cognitive impairments and need to be closely monitored throughout childhood.
Summary Recent polymerase chain reaction (PCR)-based studies estimate the prevalence of microbial invasion of the amniotic cavity (MIAC) to be ≥30–50% higher than that detected by cultivation-based methods. Some species that have been long implicated in causing MIAC remain among the common invaders (e.g. Ureaplasma spp., Mycoplasma spp., Fusobacterium spp. Streptococcus spp., Bacteroides spp. and Prevotella spp.). Yet we now know from studies based on PCR of the 16S ribosomal DNA that cultivation-resistant anaerobes belonging to the family Fusobacteriaceae (particularly Sneathia sanguinegens , and Leptotrichia spp.) are also commonly found in amniotic fluid. Other diverse microbes detected by PCR of amniotic fluid include as-yet uncultivated and uncharacterized species. The presence of some microbial taxa is associated with specific host factors (e.g. Candida spp. and an indwelling intrauterine device). It appears that MIAC is polymicrobial in 24–67% of cases, but the potential role of pathogen synergy is poorly understood. A causal relationship between diverse microbes, as detected by PCR, and preterm birth is supported by types of association (e.g. space, time and dose) proposed as alternatives to Koch's postulates for inferring causality from molecular findings. The microbial census of the amniotic cavity remains unfinished. A more complete understanding may inform future research directions leading to improved strategies for preventing, diagnosing and treating MIAC.
Summary The common marmoset ( Callithrix jacchus ), a small New World primate, has been attracting much attention in the research field of biomedical science and neuroscience, based on its (i) cross-reactivity with human cytokines or hormones, (ii) comparative ease in handling due to its small size, (iii) high reproductive efficiency, (iv) establishment of basic research tools, and (v) advantages of its unique behavioral and cognitive characters. Various neurological disease models have been developed in the common marmoset, including Parkinson's disease, Huntington's disease, Alzheimer's disease, stroke, multiple sclerosis and spinal cord injury. We recently developed transgenic common marmoset with germline transmission, which is expected to provide a new animal model for the study of human diseases. In this review, we summarize the recent progress of biomedical research and neuroscience using common marmoset as an excellent model system.
Summary The global burden of preterm birth (PTB) includes the morbidity and mortality of babies born before 37 completed weeks of gestation. Prematurity has been the leading worldwide cause of neonatal mortality for at least a decade, but has now also become the leading cause of childhood mortality through age five years. Globally, each year, 15 million babies are born preterm, which is estimated to be about 11% of all deliveries. Preterm birth appears to be increasing in most countries. This review will address the epidemiology, rates, and etiology of PTB around the globe as well as survival by gestational age and interventions and preventative measures known to improve outcomes in high-burden countries.
Summary Preterm birth affects 12.5% of all births in the USA. Infants of Black mothers are disproportionately affected, with 1.5 times the risk of preterm birth and 3.4 times the risk of preterm-related mortality. The preterm birth rate has increased by 33% in the last 25 years, almost entirely due to the rise in late preterm births (34–36 weeks’ gestation). Recently attention has been given to uncovering the often subtle morbidity and mortality risks associated with moderate (32–33 weeks’ gestation) and late preterm delivery, including respiratory, infectious, and neurocognitive complications and infant mortality. This section summarizes the epidemiology of moderate and late preterm birth, case definitions, risk factors, recent trends, and the emerging body of knowledge of morbidity and mortality associated with moderate and late preterm birth.
Summary The human gastrointestinal tract harbors a diverse and complex community of microbes, termed gut microbiota, that normally assemble during the first postnatal years of life. This evolution-driven process has been shown to contribute to the developmental programming of epithelial barrier function, gut homeostasis, and angiogenesis, as well as the development and function of the immune system. Research over the last few years has revealed that the actions of the gut microbiota have much wider effects on host physiology and development than originally believed, including the modulation of brain development and behavior. This article briefly reviews recent findings on the impact of the gut microbiota on brain development, and how disturbances in the assembly and maturation of the gut microbiota may impact development of motor, social, and cognitive functions. The potential link between microbiota and metabolic requirements of the developing brain is also considered.
Summary Preterm labor is defined as labor that begins before 37 completed weeks of pregnancy. More than 12% of infants born in the USA are preterm. At least 40% of preterm births are associated with intrauterine infection. Toll-like receptors (TLRs) are members of a family of cell-surface proteins responsible for recognition of a diverse spectrum of bacterial, viral and fungal pathogens. TLRs initiate the host innate (i.e. non-adaptive) immune response, inducing a proinflammatory cascade involving cytokines, chemokines, prostaglandins, and other effector molecules that result in the characteristic phenomena of labor, such as uterine contractions and rupture of fetal membranes. These cascades may also be activated by mechanisms that are not primarily infectious but are accompanied by inflammatory responses. Now that the molecular mechanisms linking infection and labor have been, to a large extent, elucidated, the challenge is to identify points of overlap with non-infectious causes of labor and to find intervention strategies that can minimize the negative impact of preterm delivery.
Summary The increasing appreciation of the role of the cerebellum in motor and non-motor functions is crucial to understanding the outcomes of acquired cerebellar injury and developmental lesions in high-risk fetal and neonatal populations, children with cerebellar damage (e.g. posterior fossa tumors), and neurodevelopmental disorders (e.g. autism). We review available data regarding the relationship between the topography of cerebellar injury or abnormality and functional outcomes. We report emerging structure–function relationships with specific symptoms: cerebellar regions that interconnect with sensorimotor cortices are associated with motor impairments when damaged; disruption to posterolateral cerebellar regions that form circuits with association cortices impact long-term cognitive outcomes; and midline posterior vermal damage is associated with behavioral dysregulation and an autism-like phenotype. We also explore the impact of age and the potential role for critical periods on cerebellar structure and child function. These findings suggest that the cerebellum plays a critical role in motor, cognitive, and social–behavioral development, possibly via modulatory effects on the developing cerebral cortex.
Summary Beyond its nutritional aspects, human milk contains several bioactive compounds, such as microbes, oligosaccharides, and other substances, which are involved in host–microbe interactions and have a key role in infant health. New techniques have increased our understanding of milk microbiota composition, but few data on the activity of bioactive compounds and their biological role in infants are available. Whereas the human milk microbiome may be influenced by specific factors – including genetics, maternal health and nutrition, mode of delivery, breastfeeding, lactation stage, and geographic location – the impact of these factors on the infant microbiome is not yet known. This article gives an overview of milk microbiota composition and activity, including factors influencing microbial composition and their potential biological relevance on infants' future health.
Inflammation has been implicated in the mechanisms responsible for preterm and term parturition, as well as fetal injury. Out of all of the suspected causes of preterm labour and delivery, infection and/or inflammation is the only pathological process for which both a firm causal link with preterm birth has been established and a molecular pathophysiology defined. Inflammation has also been implicated in the mechanism of spontaneous parturition at term. Most cases of histopathological inflammation and histological chorioamnionitis, both in preterm and term labour, are sub-clinical in nature. The isolation of bacteria in the amniotic fluid, known as microbial invasion of the amniotic cavity, is a pathological finding; the frequency of which is dependent upon the clinical presentation and gestational age. There is a window of time during which it may be possible to detect a ‘molecular signature of inflammation’ by analysis of the transcriptome before histological evidence is observed. This article reviews the role of inflammation in preterm and term parturition. It is possible that modulation of inflammation using anti-inflammatory cytokines, corticoids, antioxidants and/or other factors may complement antibiotic therapy and limit fetal injury.
Summary A large number of children (6 to 11% of all births) are born at a gestational age between 32 and 36 weeks. Little is known of long term outcomes for these moderate and late preterm children. In this review, results of 28 studies on school outcome, cognitive functioning, behaviour problems, and psychiatric disorders are presented. Overall, more school problems, less advanced cognitive functioning, more behaviour problems, and higher prevalence of psychiatric disorders were found in moderate and late preterm born infants, children, and adults compared with full term peers. Suggestions for future research are discussed.
Summary The study of the interplay of the generation of reactive oxygen and nitrogen species with their related antioxidant enzymes at the maternal–placental–fetal interfaces during normal and abnormal pregnancy is in its ‘infancy’. Our understanding of the role of antioxidant systems during fetal and neonatal development is constantly changing with research better defining the biological roles of these highly reactive species and the maintenance of optimal oxidant/antioxidant balance. The antioxidant enzyme system is upregulated during the last 15% of gestation, a timeframe when non-enzymatic antioxidants are also crossing the placenta in increasing concentrations. These developmental changes provide for the transition from the relative hypoxia of intrauterine development to the oxygen-rich extrauterine environment. Preterm birth is associated with an increased oxidant burden which places these infants at much higher risk of injury. This is especially true since studies have failed to reveal significant induction of antioxidants in response to the increased generation of these reactive species. Improved understanding of these relationships will be necessary for the development of rational treatments aimed at improving pregnancy outcomes and reducing the burden of oxidative stress to premature newborns.
Summary Hypothermia is a potential neuroprotective intervention to treat neonatal post-asphyxial (hypoxic–ischemic) encephalopathy (HIE). In this meta-analysis of 13 clinical trials published to date, therapeutic hypothermia was associated with a highly reproducible reduction in the risk of the combined outcome of mortality or moderate-to-severe neurodevelopmental disability in childhood. This improvement was internally consistent, as shown by significant reductions in the individual risk for death, moderate-to-severe neurodevelopmental disability, severe cerebral palsy, cognitive delay, and psychomotor delay. Patients in the hypothermia group had higher incidences of arrhythmia and thrombocytopenia; however, these were not clinically important. This analysis supports the use of hypothermia in reducing the risk of the mortality or moderate-to-severe neurodevelopmental disability in infants with moderate HIE.
Summary Oxygen has a central role in the evolution of complex life on Earth mainly because of the biochemical symmetry of oxygenic photosynthesis and aerobic respiration that can maintain homeostasis within our planet biosphere. Oxygen can also produce toxic molecules, reactive oxygen species (ROS). ROS is a collective term that includes both oxygen radicals and certain oxidizing agents that are easily converted into radicals. They can be produced from both endogenous and exogenous substances. ROS play a dual role in biological systems, since they can be either harmful or beneficial to living systems. They can be considered a double-edged sword because on the one hand oxygen-dependent reactions and aerobic respiration have significant advantages but, on the other, overproduction of ROS has the potential to cause damage.
Pre-eclampsia is a common and potentially dangerous disorder of human pregnancy. The maternal syndrome of hypertension, proteinuria and oedema is part of a severe systemic inflammatory response that includes leukocyte and endothelial cell activation. Although the origins of pre-eclampsia remain unclear, a major cause is the failure to develop an adequate blood supply to the placenta, leading to placental oxidative stress. This results in the excess release of placental factors, such as syncytiotrophoblast debris or soluble fms-like tyrosine kinase-1 (sFlt-1), the soluble receptor for vascular endothelial growth factor (VEGF), into the maternal circulation, where they trigger an inflammatory response and endothelial dysfunction. Alternatively, pre-eclampsia can develop in the presence of a normal placenta in women that are susceptible to systemic inflammation, such as with chronic cardiovascular disease or diabetes. While clinical management of pre-eclampsia does not currently include anti-inflammatory agents, current research is focusing on ways to reduce inflammation and oxidative stress.
Summary Congenital diaphragmatic hernia (CDH) may be isolated or associated with other structural anomalies, the latter with poor prognosis. The defect allows viscera to herniate through the defect into the chest, competing for space with the developing lungs. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension that is lethal in up to 30% of patients. When isolated, survival chances can be predicted by antenatal measurement of lung size and liver herniation. Chromosomal microarrays and exome sequencing contribute to understanding genetic factors underlying isolated CDH. Prenatal intervention aims at stimulating lung development, clinically achieved by percutaneous fetal endoscopic tracheal occlusion (FETO) under local anesthesia. The Tracheal Occlusion To Accelerate Lung growth trial ( www.totaltrial.eu ) is an international randomized trial investigating the role of fetal therapy for severe and moderate pulmonary hypoplasia. Despite an apparent increase in survival following FETO, the search for lesser invasive and more potent prenatal interventions must continue.
Understanding early human brain development is of great clinical importance, as many neurological and neurobehavioral disorders have their origin in early structural and functional cerebral organization and maturation. Diffusion tensor imaging (DTI), a recent magnetic resonance (MR) modality which assesses water diffusion in biological tissues at a microstructural level, has revealed a powerful technique to explore the structural basis of normal brain development. In fact, the tissue organization can be probed non-invasively, and the age-related changes of diffusion parameters (mean diffusivity, anisotropy) reveal crucial maturational processes, such as white matter myelination. Nevertheless, the developing human brain presents several challenges for DTI applications compared with the adult brain. DTI may further be used to detect brain injury well before conventional MRI, as water diffusion changes are an early indicator of cellular injury. This is particularly critical in infants in the context of administration of neuroprotective therapies. Changes in diffusion characteristics further provide early evidence of both focal and diffuse white matter injury in association with periventricular leukomalacia in the preterm infant. Finally, with the development of 3D fiber tractography, the maturation of white matter connectivity can be followed throughout infant development into adulthood with the potential to study correlations between abnormalities on DTI and ultimate neurologic/cognitive outcome.
Summary Parents and the family environment have a pronounced influence on child development. For children at increased risk such as those born very preterm (VPT) or with very low birth weight (VLBW), parent and family functioning can influence the child’s level of risk or resilience. This review describes parent and family outcomes after VPT/VLBW birth, specifically parental mental health, parenting stress and the impact of the child on the family. Factors associated with these outcomes are examined, as well as the specific outcomes for fathers. Overall the influence of VPT/VLBW birth on parents and the family appears to be more pronounced in early childhood, with less influence seen by the time of adolescence. Emerging evidence suggests that fathers experience high rates of psychological distress in the first months after VPT birth. Whereas characteristics of the VPT/VLBW child are strongly associated with parent and family outcomes, parent and social factors are also important influences.
Summary There is growing interest in the long-term mental health sequelae of extremely preterm birth. In this paper we review literature relating to mental health outcomes across the lifespan. Studies conducted in the preschool years, school age and adolescence, and adulthood show continuity in outcomes and point to an increased risk for inattention, socio-communicative problems and emotional difficulties in individuals born extremely preterm. Both behavioural and neuroimaging studies also provide evidence of a neurodevelopmental origin for mental health disorders in this population. Here we summarise contemporary evidence and highlight key methodological considerations for carrying out and interpreting studies in this field.