Adequate pulmonary function is crucial for preterm infants. In addition to being structurally immature, the preterm lung is susceptible to injury resulting from different prenatal conditions and postnatal insults. Lung injury may result in impaired postnatal lung development, contributing to chronic lung disease, and many preterm infants who survive go on to develop this pathology. This is probably caused by persistent inflammation in the lungs, and thus chronic lung disease is a major problem for infants in neonatal intensive care units and is associated with higher mortality rates and worse long-term outcomes in survivors.

Chronic lung disease after preterm birth, also known as bronchopulmonary dysplasia (BPD), a major morbidity of the very preterm infant, is remarkably resistant to therapeutic interventions, and negatively affects neurodevelopmental outcomes. There is a complex interaction between lung injury, lung inflammation, lung repair, and altered lung development. Also, there are interactions between fetal, perinatal, and postnatal factors modulating lung injury.

Preterm birth is greatly associated with respiratory distress syndrome (RDS), caused by structural and functional immaturity of the newborn lung. In addition to simple structural immaturity, the preterm lung is susceptible to injury resulting from different prenatal conditions such as intrauterine growth restriction or oligohydramnios, genetic disposition, transition at birth, and postnatal procedures and insults such as mechanical ventilation–induced trauma from volume and pressure changes, extension of tissue and oxygen toxicity, sepsis, hypoxia, and others. These early alterations may interfere with lung development and therefore exert lasting effects on pulmonary plasticity and integrity, finally resulting in structural and functional impairment. Although growing experimental evidence can elucidate the link between lung injury, lung inflammation, lung repair, and altered lung development, the interactions between injurious insults and inflammatory stimuli on different levels are complex and remain to be fully understood [1]. Furthermore, recent findings support the hypothesis that chronic lung injury originating in this early period of life or even antenatally may indeed have long-term adverse respiratory effects, and studies report an association between chorioamnionitis and both recurrent wheezing and physician-diagnosed asthma [2]. In addition, young adult survivors of moderate and severe BPD may be left with residual functional and characteristic structural pulmonary abnormalities, most notably emphysema. The premise is that extremely preterm infants may have immature adrenal gland function, predisposing them to a relative adrenal insufficiency and inadequate anti-inflammatory capability during the first several weeks of life.

Since persistent inflammation of the lungs is the most likely cause, corticosteroid drugs have been used to either prevent or treat chronic lung disease because of their strong anti-inflammatory effects particularly in babies who cannot be weaned from assisted ventilation. The beneficial effects were a shorter time on the ventilator and less chronic lung disease, but the adverse effects included high blood pressure, bleeding from the stomach or bowel, perforation of the bowel, an excess of glucose in the bloodstream, and an increased risk of cerebral palsy at follow-up. There were significant benefits for the following outcomes: lower rates of failure to extubate and decreased risks of chronic lung disease at both 28 days’ and 36 weeks’ postnatal age; death or chronic lung disease at 28 days’ and 36 weeks’ postmenstrual postnatal age; patent ductus arteriosus; and retinopathy of prematurity, including severe forms of this condition. There were no significant differences in the rates of neonatal or subsequent mortality, infection, severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, or pulmonary hemorrhage. Gastrointestinal bleeding and intestinal perforation were significant adverse effects, and the risks of hyperglycemia, hypertension, hypertrophic cardiomyopathy, and growth failure were also increased.

Long-term follow-up studies [3] report an increased risk of abnormal neurological findings and cerebral palsy. However, the methodological quality of the studies determining long-term outcomes is limited in some cases; the surviving children were assessed predominantly before school age, and no study was sufficiently powered to detect important adverse long-term neurosensory outcomes. There is a compelling need for the long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all the randomized trials of early postnatal corticosteroid treatment. Dexamethasone was used in most studies, and only few used hydrocortisone. In subgroup analyses by type of corticosteroid, most of the beneficial and harmful effects were attributable to dexamethasone; hydrocortisone had little effect on any outcomes except for an increase in intestinal perforation and a borderline reduction in patent ductus arteriosus. Hydrocortisone appears to have less neurological impact than dexamethasone, even with adjustment for dose equivalency [4].

There are certain biological differences between these agents that may be of neurological relevance. Hydrocortisone differs from dexamethasone as it has both mineralocorticoid and glucocorticoid actions. In animal models, dexamethasone, which binds only to glucocorticoid receptors, induced neuronal degeneration within the hippocampus. In humans, alterations in hippocampal volume and synaptic plasticity and associative memory were reported with dexamethasone in preterm infants [5]. High-dose postnatal dexamethasone treatment for BPD was associated with decreased brain volumes on magnetic resonance imaging at 18 years of age, specifically total brain tissue, cortical white matter, thalamus, and basal ganglia nuclei. Surprisingly, some studies found no significant differences in the hippocampus or cerebellum, which are brain areas with very high concentrations of glucocorticoid receptors. Even in the absence of significant postnatal medical sequelae, preterm birth has a profound effect on neuroanatomical structures in childhood and adolescence [6–8]. Some authors have reported that individuals born extremely preterm have smaller brain volumes than term-born controls at 18 years of age, including the hippocampus and cerebellum as well as other brain regions; other authors have reported similar findings following preterm birth, including extremely preterm infants without “serious neurologic or medical conditions” at 7–10 years of age. They found that these children had smaller total brain volumes, white and gray matter volumes, and smaller basal ganglia and thalami than term-born controls [6–8]. These studies highlight the difficulty of distinguishing the effects of prematurity and its complications from the effects of a specific therapeutic intervention.