Recently, the role of the microbiome for health and disease has received significant attention. The microbiome development in the first weeks of life is highly dynamic and provides a window of opportunity, particularly for susceptible infants such as extremely preterm babies. The "healthy" microbiome implies a symbiotic life of the host with "friendly" microbes, which provides metabolic homeostasis and protection from invasive infection and sustained inflammation. It seems obvious that newborn infants are sensitive to microbiome-disturbing factors which can cause dysbiosis – an imbalance with reduced microbial diversity and deficient metabolic capacity to control potential pathogens ("foes"). Presumably, gut dysbiosis may contribute to adverse short-term outcome (e.g., sepsis and necrotizing enterocolitis) but may also be associated with long-term health problems such as asthma, growth failure, or neurodevelopmental deficits. In this review, we present the latest insights into our understanding on the physiological development of the microbiome and its interaction with the host. We will discuss the role of the microbiome in neonatal disease states and the potential of modifications advantageous to the susceptible newborn.
Being born small for gestational age (SGA), defined as a birth weight and/or length below –2 SDS, has several consequences. Short-term consequences include a higher mortality, hypothermia, and hypoglycemia. In the long term, being born SGA is associated with persistent short stature, metabolic and cardiovascular alterations, lower cognition, more behavioral problems, and social and psychological problems. Children born SGA with persistent short stature benefit from growth hormone (GH) treatment which increases longitudinal growth and adult height, and has positive effects on metabolic and cardiovascular health. Additional treatment with GnRHa for 2 years in early puberty can improve adult height even further in children born SGA with an expected adult height <–2.5 SDS at the start of puberty. GH treatment is well tolerated, and serious side effects are uncommon. The safety profile of GH treatment alone or combined with GnRHa is good.
This section gives a brief overview of exposure assessment and current outcome definitions in neonatology. Although the comparison of exposure and outcome data is a cornerstone of modern neonatology, patient-focused outcome definitions which were defined by the United States Food and Drug Administration as "how a patient feels, functions or survives" are scarce in neonatal outcome assessment. In contrast to this remarkable lack of sufficient outcome assessment tools for neonates, a vast amount of exposure data was collected in recent years.
Intrauterine life, perinatal events, and the development of the subsequent neonatal period represent crucial phases in newborns' life, influencing the health of their mothers, too. In recent years, research made several steps forwards in the comprehension of such a vulnerable period and the factors affecting these pathophysiological events, especially through the application of innovative omics technologies. Among these, metabolomics revealed a very promising role in the early diagnosis of various fetal, perinatal, and neonatal conditions through the detection of specific biomarkers in several maternal or neonatal fluids. Thus, conditions affecting both intrauterine and postnatal life can be investigated by metabolomic tools. In recent years, research enriched our knowledge and encouraged several clinical applications; in particular, metabolomics seems promising in various fields, such as the prevention of numerous pathologies and monitoring of their progression. Finally, drug-related toxicity and the response to a performed tailored approach could be, in the next future, precociously evaluated through metabolomics.
The specialty of neonatology has undergone comprehensive changes with improved diagnostic tools and therapeutic measures, thereby improving the health care for vulnerable fetuses and newborns. Neonatologists are now involved in prenatal, perinatal, and postnatal care. Developments in fetal imaging have broadened the time period in which multidisciplinary counseling concerning prenatal and postnatal strategies can be performed. Lethal congenital defects have changed into treatable defects with improved neonatal outcomes, which lead to new ethical dilemmas for health care professionals and parents. These include considerations regarding termination of pregnancy, performing fetal in utero interventions, and withdrawal of postnatal care. Clinical trials have provided new insights regarding strategies in the delivery room, thereby adapting the practice in the "golden hour" of neonatal life. In newborns requiring support during the fetal-neonatal transition, optimal timing of cord clamping, steps securing the airways, and initial ventilation strategies should be based on individual characteristics. Moreover, many neonatal intensive care guidelines have changed to evidence-based recommendations as a result of numerous innovative trials conducted in the past decades. This chapter will discuss the most recent developments and improvements for neonatal conditions outside the scope of prematurity, illustrating the role of the neonatologist in each time period and highlighting aims for future clinical research projects.
The current paradigm of best clinical practice for stabilizing preterm infants with respiratory distress is to support the baby with non-invasive (NIV) respiratory support to prevent death or bronchopulmonary dysplasia. Today, there are various methods of NIV respiratory support available. Whilst the evidence base is reasonably strong for certain methods, others have yet to be proven to be effective. The underlying pathophysiology of lung disease, the gestation period, and aspects of local neonatal facilities need to be considered when choosing the best possible form of NIV respiratory support. This review presents the currently best available evidence on techniques providing NIV respiratory support for preterm infants, acknowledging the infants' changing needs for respiratory support due to disease progression from acute respiratory distress to more long-standing respiratory insufficiency caused by delayed lung maturation. Methods reviewed included are nasal continuous positive airways pressure, nasal high-flow cannula therapy, nasal NIV intermittent positive airway pressure ventilation, and nasal high-frequency oscillation ventilation. The various modes are discussed, and a staged respiratory support strategy, stratified by disease stage, is proposed.
Nutrition in early infancy and especially in the perinatal period of extremely premature born infants has attracted increased attention in clinical research in the last 15 years due to its great impact not only on early infant development and health but also on health in later life and on the development of adult diseases. Human milk is an extraordinary invention by nature to supply infants with macro- and micronutrients with optimal bioavailability combined with hormones, enzymes, and growth factors, anti-infective factors, stem cells, RNA with the power of programming, prebiotic molecules, a bundle of specific microbiota with probiotic properties, and many other components. It is obvious that breast milk is considered the gold standard for infant nutrition in both term-born and preterm infants. Following the decrease in mortality rates in preterm infants in the neonatal period, the biggest challenge for neonatologists was to promote optimal neurocognitive development without long-term sequelae. Recent research paid particular attention to the nonnutritional bioactive factors of human milk and their impact on infant health. Another important aspect of research is to define optimal postnatal growth, and how this is achieved with optimized macronutrient supply while avoiding an unfavorable body composition and adverse metabolic programming, which predisposes to later metabolic diseases.
Neonatal care has changed significantly over the past decades. Despite increased survival rates in extremely preterm infants, there was no significant improvement with regard to morbidity. Regenerative approaches seem to have a great potential in preventing several diseases associated with impaired fetal organ development. Mesenchymal stromal cells (MSC) play an important role in regulating fetal organ development. Pregnancy-associated diseases or exposure of the fetus to an extrauterine environment leads to severe deterioration in endogenous MSC, which subsequently interferes with fetal organ development. Data from cell and animal experiments suggest that this deterioration is – at least in part – compensated by administration of exogenous MSC. Whereas results of these studies seem to be promising, some of the more recent large trials in human adults failed to prove a benefit. Nevertheless, this therapy still has great potential – not only for neonatal medicine. To use that potential, lessons have to be learned from previous experience. The biggest challenge currently, however, is to translate bench data to bedside as quickly but also as safely as possible.
Invasive mechanical ventilation has been the mainstay of respiratory care in premature infants. Recently, noninvasive support has been used increasingly, and sophisticated techniques have been developed to support infants while avoiding invasive mechanical ventilation. However, a number of clinical situations still exist where invasive ventilation is indispensable. A large body of evidence demonstrates that low tidal volumes are the most important goal in avoiding lung injury during invasive mechanical ventilation. Finding an adequate end-expiratory pressure to avoid atelectasis and overdistention is equally important, although finding the optimal settings for individual patients remains challenging. Furthermore, ventilation can be optimized using the optimal blood gas targets. A number of techniques were developed to return more aspects of breathing control back to the patient in order to reduce lung injury and increase patient comfort. However, the benefits of many modalities remain unproven. This also applies to high-frequency ventilation, which has many theoretical advantages, but improved clinical outcomes have not been unequivocally demonstrated. Limited data suggest long-term benefits, which may not even be demonstrable in the perinatal period. Recent developments focus on incorporating more artificial intelligence into mechanical ventilators enabling them to make automatic adjustments of settings in response to the patient’s changing condition.
Thanks to powerful heat therapy devices, maintaining the right temperature in (preterm) neonates does not seem to be a major problem anymore. Nevertheless, admission hypothermia continues to be an issue, even in high-income countries. Beyond their limited capacities to control heat losses and increase heat production, the thermal lability of preterm neonates is due to the delayed postnatal increase in basal metabolic rate that prevents them from building up a reasonable gradient between body and ambient temperature. Radiant heaters replace heat losses by heat supply. However, in contrast to natural solar heat, their long-waved infrared radiation is mostly absorbed by the outer layers of human skin and may thus lead to superficial overheating. Humidified incubators reduce heat losses to a degree that allows the babies to keep warm without thermoregulatory efforts regardless of their low metabolic rates. However, incubator care is usually directed to maintain a body temperature of 37°C although thermoneutrality is defined by the metabolic rate rather than by the body temperature, and the intrauterine "breeding temperature" would be 0.5–1.0°C higher. Altogether, the availability of powerful heat therapy devices does not mean that the promise of "thermoneutral care" has been unreservedly fulfilled from a physiological point of view.
Many adults born very preterm are healthy and well. However, very preterm birth may be regarded as a "chronic condition" with a higher risk of long-term morbidities that warrant attention or follow-up in adult life, and the degree of maturity at birth should be routinely assessed by health care professionals. Morbidities seen more frequently in very preterm born adults include somatic (lung function, cardiorespiratory fitness, and hypertension), cognitive, behavioral, and motor problems. Apart from these "classic outcome parameters," compared to term-born adults, those born very preterm are less likely to acquire a higher educational qualification, they receive more often social benefits, and they have more often periods of unemployment. They show less risk-taking behavior, are less likely to partner, and less likely to have children of their own. In contrast, little is known about resilience or protective factors that may reduce adverse outcomes.
Prematurity ranks among the most frequent causes of mortality and morbidity in the newborn period and infancy. Of note, the rate of preterm birth has increased in recent years worldwide, and a significant number of preterm babies die in the early newborn period (<7 days) and in the first 12 h after birth. To overcome this situation, a series of changes in newborn resuscitation protocols have been introduced in the last decade. Regionalization of perinatal care or specialized transport to the referral centers as well as antenatal administration of steroids and magnesium sulfate has become a common practice. Stabilization after birth following the "soft-landing" approach includes delaying cord clamping, keeping the baby's temperature, cutaneous stimulation, noninvasive ventilation, and continuous monitoring of heart rate and oxygen saturation. In addition, individualized inspired oxygen fraction adjustment according to SpO2 readings pursues avoiding the negative consequences of hyper- or hypoxia. Finally, novel interventions such as sustained lung inflation or initiating ventilation before cord clamping to improve cardiorespiratory physiological adaptation after birth are being explored. These interventions are performed during the first golden minutes of the very preterm infant after birth and are meant to optimize postnatal adaptation and improve the chances of an intact survival.
In 2017, approximately 2.5 million neonates died, and most of them died within the first week of life. Preterm births continue to be the leading cause of neonatal mortality. Whilst evidence-based interventions for success are well documented in the literature, the majority of neonatal deaths are concentrated in Southern Asia and sub-Saharan Africa, areas where provision of these interventions is low. A key area of unmet needs is towards reducing the number of stillbirths occurring globally. In this post-Millennium Development Goals era, the focus is now towards reducing disparities in quality and coverage of care, and empowering women and their societies, in order to achieve the new targets set by the Sustainable Development Goals for neonatal mortality.
To have access to your parents is an indisputable right for all newborn children, irrespective of the child being born preterm or in need of neonatal care for other reasons. Therefore, the development of care strategies that allow parents from the very beginning to not only be present, but also to actively participate in the care and to be an integrated part of their own baby’s life is essential. The neonatal intensive care environment is often a challenge in itself, and the intrinsic difficulties facing a preterm or sick infant are numerous. The concept of family-centered care has evolved over time and now includes a wider framework described as infant- and family-centered developmental care (IFCDC). IFCDC is founded on the Declaration of Children’s Rights as well as concepts of neurobehavior and neurodevelopment, parent-infant interaction and early relationship, breastfeeding promotion, and environmental and hospital systems adaption. In this chapter, the evidence for parental involvement and early bonding is reviewed, the core pillars and principles of IFCDC are described, and barriers versus facilitators for implementation in the neonatal setting are outlined.
Surfactant replacement in preterm infants with respiratory distress syndrome (RDS) has been a major therapeutic breakthrough and the most intensively studied intervention in neonatal medicine. Surfactant whether given prophylactically in the delivery room or in babies with established RDS reduces the severity of RDS, the incidence of air leaks and pneumothorax and, most importantly, neonatal death. Many randomized controlled trials have explored different strategies to optimize the effect of surfactant administration and have further improved neonatal outcome. Whenever indicated, surfactant should be administered as early as possible in the course of the RDS.
Cortical development malformations (CDM) and specifically disorders of neuronal migration are a group of congenital malformations of the central nervous system (CNS) that are linked to some of the neurodevelopment disorders frequently described in children, such as mental retardation, autism, schizophrenia and epilepsy, among others. CDM are classified into three groups: Group I for alterations in proliferation and/or glial and neuronal apoptosis; Group II for neuronal migration disorders; and group III for secondary malformations due to postmigrational alterations of development. Neocortical neurons migration occurs preferentially from the fifth week of gestation until the twenty-second gestational week. Neuronal migration disorders are classified into four groups: II. A lissencephaly, II. B periventricular heterotopia, II. C subcortical heterotopia and II. D sublobar dysplasia and cobblestone malformations.
Developing countries disproportionally suffer from mortality and morbidity especially for children. Research leading to scientific progress in understanding causes of death has resulted in reduction in child morbidity and mortality in developed nations. However due to resource limitations, human and otherwise, in developing countries the progress towards achieving development goals, has been minimal. The collaborations and partnerships between developed and developing nations provides multiple opportunities for research and thereby learning, leading to reduction in child mortality. The scientists in both developed and developing nations need to understand the challenges that may occur while conducting research. In this paper we provide a framework for the researchers in both developing and developed nations to try to understand and develop research agenda and ideas that could not only address child health problems in developing countries but could also result in the progress of science benefitting the world at large.
The prevalence of child maltreatment in different countries and within different groups of children and families has been difficult both to estimate and to compare. Reasons for the wide variation in i
The present chapter aims to assist young scientists in preparing the different steps necessary to conduct a study. The description of different study designs and data sources as well as the presentation of different ways of data analysis represent key points of this chapter. Furthermore, we give an overview of available statistical software and provide information on data protection and standardization.
