Chronic Neonatal Respiratory Disorders

Key Points

• Bronchopulmonary dysplasia (BPD), as determined near term corrected age in former preterm newborns < 32 weeks’ gestational age is a marker for chronic respiratory morbidity.

• Newborns that are most immature and those born from an adverse intrauterine environment, affected by maternal vascular disorders and decreased intrauterine growth, are most susceptible to early neonatal respiratory illness.

• Early neonatal respiratory illness, marked by increased exposure to supplemental oxygen and use of mechanical ventilation, is associated with BPD and later respiratory morbidity.

• Former preterm newborns have evidence of lung dysfunction near the time of initial hospital discharge.

• Lung dysfunction, immune deficits and environmental factors confer vulnerability to lower respiratory tract infection and wheezing illness in infancy and early childhood.

• Composite respiratory morbidity outcomes ascertained during infancy primarily reflect resource utilization due to respiratory disease, vary widely in prevalence based on population of interest, and reflect a broad spectrum of severity.

• Dysplastic development of both the lung and airway in former preterm newborns occurs. However, the most prominent long-term morbidity of former preterm newborns is obstructive lung disease and wheezing illness or asthma.

Introduction

Chronic lung disease of infancy following preterm birth was first described by Northway and colleagues in 1967. These investigators identified clinical, radiographic and histopathological findings of lung fibrosis and airway disease in former preterm newborns with death or ongoing pulmonary dysfunction after exposure to prolonged mechanical ventilation and hyperoxia. They termed this disorder bronchopulmonary dysplasia (BPD), reflecting dysplastic extrauterine development of the lung parenchyma and airways following preterm birth prior to or early in the alveolar stage of lung development. Subsequent investigations (1) confirmed and expanded the description of post-mortem lung histopathology, noting pulmonary vascular changes consistent with observed right ventricular hypertrophy and cor pulmonale, and (2) demonstrated fixed and reactive airway obstruction, with symptomatic lung disease, susceptibility to infection and chest wall deformity in survivors with BPD at a mean age of 18 years. Many of the newborns cared for in these reports were born at ≥30 weeks’ gestational age (GA). However, as approaches to preterm infant care evolved, rates of survival and successful separation from respiratory support improved for infants at these gestational ages and lower, prompting investigations of a clinical marker for subsequent morbidity and mortality. In a retrospective analysis of former preterm infants born at 25 to 32 weeks’ GA, Shennan et al. evaluated the ongoing use of supplemental oxygen up to 38 weeks’ post-menstrual age (PMA) as a predictor for later respiratory morbidity or death up to 2 years of age. They proposed 36 weeks’ PMA as the most appropriate time point to discriminate between those infants with and without morbidity and mortality. The use of supplemental oxygen with or without positive pressure at 36 weeks’ PMA evolved into the clinical definition of BPD, used as a benchmark and quality metric for neonatal care, and as an endpoint for clinical trials designed to improve respiratory outcomes in extremely preterm newborns.

With further advances in perinatal and neonatal care, including the use of antenatal steroids, exogenous surfactant and lung protective strategies for early respiratory support, histopathological airway disease and lung fibrosis became less prominent post-mortem findings in former preterm newborns. The changing landscape of respiratory illness in low and extremely low gestational age newborns (ELGAN) and interest in further discriminating respiratory outcomes in former preterm infants were addressed in a National Institutes of Health (NIH) sponsored expert workshop in June 2000. Attendees developed a tiered, severity-based approach to the definition of BPD, proposing categories of mild, moderate, and severe BPD based on level of respiratory support at 36 weeks’ PMA (degree of supplemental oxygen and use of positive pressure) for infants born at < 32 weeks’ GA. Investigators from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) subsequently validated this NIH consensus definition in follow-up of survivors of preterm birth at 18 to 22 months corrected age. They demonstrated increasing proportions of infants with use of respiratory medications, rehospitalization for respiratory cause, growth failure and neurodevelopmental impairment with increasing severity of BPD. Notably, the addition of an abnormal chest radiograph demonstrating parenchymal lung disease did not improve discrimination for these later morbidities.

The NIH consensus definition has raised concerns as to its usefulness at both lower and higher levels of severity. Specifically, the discrimination of infants classified as no versus mild BPD may not be clinically important. Infants classified as severe BPD may represent too broad a category to be clinically meaningful, as it includes a spectrum spanning infants receiving support by nasal cannula and those remaining on mechanical ventilation. In October 2016, an NICHD expert panel proposed a modification of the prior consensus definition of BPD, still defined at 36 weeks’ PMA, using various cut-offs for inspired oxygen concentration (FiO ₂ ) and nasal cannula flow at different levels of BPD. Notable features of this modification were a change in terminology to Grades I-III, with the highest grade, Grade III, including only infants on mechanical ventilation with FiO ₂ > 21% or infants requiring noninvasive pressure support with FiO ₂ ≥ 30% (e.g., continuous positive airway pressure [CPAP], high flow nasal cannula (HFNC) > 3 L/min); a special category IIIA would be assigned to infants that died prior to 36 weeks’ PMA due to lung disease. Alternatively, Abman and colleagues from the US-based Bronchopulmonary Dysplasia Collaborative proposed retaining the original NIH consensus categories while subdividing severe BPD into two subtypes: severe type 1 BPD would encompass infants supported by low flow nasal cannula with an FiO ₂ ≥ 30% or any administration of noninvasive positive pressure support or HFNC, and severe type 2 BPD for all infants supported with mechanical ventilation. Neither group evaluated the ability of these particular cut-offs to predict later respiratory morbidity, but this task was taken on by Jensen and colleagues from the NICHD NRN, using the outcome of death or severe respiratory morbidity ascertained at 18 to 26 months of age. Their exploration of discriminatory cut-offs for various levels of respiratory support at 36 weeks’ PMA yielded three levels of BPD, termed Grades 1 to 3, defined solely by mode of support without regard for FiO ₂ . Grade 3 includes all infants on mechanical ventilation, Grade 2 all infants on noninvasive positive pressure or nasal cannula flow > 2 LPM and Grade 1 all infants on nasal cannula flow ≤2 LPM. Similarly, Isayama and colleagues found that the dichotomous classification of use of supplemental oxygen or any mode of positive pressure respiratory support (including nasal cannula flow >1.5 LPM) was the strongest predictor of respiratory outcome at 18 to 21 months corrected age, in data from the Canadian Neonatal Network.

These proposed definitions of BPD as either a predictor or surrogate outcome for later respiratory morbidity do not address the underlying pathophysiology of chronic respiratory illness in former extremely preterm newborns. The evolution of the histopathology related to early respiratory insufficiency, with alveolar simplification accompanying less prominent fibrosis, generated the concept of a “new BPD,” that develops in vulnerable preterm newborns born during the late canalicular or early saccular stage of lung development and characterized by extrauterine arrested alveolar and microvascular development. Yet symptomatic and functional airway obstruction remains the most prominent manifestation of persistent pulmonary disease in former preterm newborns and is not explained by arrested lung growth nor the recovery from that arrest. Additional contributions to chronic respiratory illness may be pulmonary vascular disease, susceptibility to infection, environmental exposures and the influence of other socioeconomic circumstances, each of which are variably related to lung parenchyma versus airway development and dysplasia. Thus, early dysplastic, arrested lung growth and ongoing clinical airway disease suggest that these conditions may themselves be related but separate co-travelers that lay the path to chronic respiratory illness in former preterm infants.

Epidemiology of Bronchopulmonary Dysplasia and the Vulnerable Preterm Lung

The primary risk factors for BPD and its severity are related to the degree of immaturity at birth, reflected by gestational age or birth weight. Various US-based publications including contemporary data from the population-based California Perinatal Quality Care Collaborative (CPQCC), the multicenter NICHD NRN and the nationwide Vermont Oxford Network (VON) collaborative, demonstrate these important relationships, and provide estimates of the incidence and severity of BPD in extremely preterm newborns born at 22 to 29 weeks’ GA ( Table 43.1 ). Overall incidence of (1) BPD or death at 36 weeks’ PMA was 47% in CPQCC, (2) BPD among survivors at 36 weeks’ PMA was 45% in the NICHD NRN, and (3) Grade 1/2 BPD (any use of nasal cannula or noninvasive positive pressure) was 41% and Grade 3 BPD (mechanical ventilation) was 4% in survivors at 36 weeks’ PMA in VON. Given the variability in both the patient populations and the diagnostic criteria for BPD, these estimates are remarkably consistent, with outcomes reported in over 44,000 infants spanning 12 birth years. These estimates were determined by clinical prescription of respiratory support and could be affected by provider variability. However, the use of a physiologic challenge consisting of a monitored decrease in nasal cannula flow and FiO ₂ at 36 weeks’ PMA does not substantively affect the proportion of infants classified with BPD.

In addition to immaturity, elements of the fetal environment influence early respiratory morbidity of BPD. Investigators in the multicenter ELGAN Study classified over 1000 singleton pregnancies into one of six presenting conditions leading to delivery at < 28 weeks’ gestation. Their analyses produced two primary phenotypes for preterm delivery, an inflammatory phenotype, and a vascular (placental) phenotype, associated with maternal preeclampsia or fetal indications for delivery. These delivery indications were used to evaluate risk of BPD, along with birth weight z-scores, reflecting fetal growth. Low birth weight z-scores (<−2 and between −2 and −1) conferred increased odds of BPD, with the greatest effect seen in newborns with the most severe intrauterine growth restriction, even when adjusting for delivery indication. Other single center studies similarly reported that pre-eclampsia greatly increased the odds of BPD while adjusting for birth weight z-score and severe intrauterine growth restriction in combination with maternal vascular disease greatly increased the odds for BPD and BPD or death. In the EPIPAGE-2 cohort, a French prospective population-based study of outcomes of prematurity, birth weight z-score was an independent predictor of BPD (decreasing z-score increased odds of BPD) while adjusting for GA and vascular/placenta-based complications of pregnancy. Consistent with these findings, maternal vascular underperfusion identified in the placentas of extremely preterm newborns was also associated with increased odds of BPD. These findings support the concept that the adverse fetal environment affects intrauterine lung growth and development, increasing the vulnerability of the immature lung to further insults.

When considering chronic neonatal respiratory disorders, it is important to recognize the interface of early respiratory support and supplemental oxygen due to respiratory insufficiency, with the markers and effectors of lung dysfunction and dysplasia a precursor to chronic lung disease. Laughon et al. demonstrated that the pattern of supplemental FiO ₂ over the first 14 days of life is highly associated with later risk of BPD in newborns 23 to 27 weeks’ GA enrolled in the ELGAN Study. Regardless of the mode of respiratory support, newborns with consistently low FiO ₂ (≤25%) in the first 14 days had an incidence of BPD of only 17%, whereas those with higher early and escalating FiO ₂ had a BPD incidence of 67%, and newborns with an initial decrease and then escalation of FiO ₂ had an intermediate BPD incidence of 51%. In refinement of this risk and vulnerability, these investigators also showed that within each of these patterns, those newborns with birth weight z-score < −1 had an elevated risk of BPD. In a secondary analysis of data from the Trial of Late Surfactant (TOLSURF) that enrolled preterm infants who remained mechanically ventilated at 7 to 14 days of life, cumulative supplemental oxygen exposure over the first 14 days of life accurately predicted later outcomes of BPD or death and BPD in survivors. In multivariate modeling, cumulative mean airway pressure over the same 14-day time period was also an independent predictor of these adverse respiratory outcomes. Using data from the NICHD NRN for newborns 23 to 30 weeks’ gestation, Laughon et al. found that gestational age, birth weight, mode of respiratory support and FiO ₂ were all selected as important predictors of BPD or death over the first 28 days of life, but the importance of these variables shifted over time. At days 1 and 3, gestational age and birth weight were the most influential factors, but at days 7 to 28, mode of respiratory support was the most important factor, and FiO ₂ was the second most important factor at days 21 and 28. Taken together, these studies highlight the risks associated with the need for early or prolonged respiratory support, and the chronic consequences of that support.

Randomized trials designed to evaluate limitation of exposure to invasive mechanical ventilation and oxygen supplementation in extremely preterm infants have shown modest effects on the occurrence of BPD (primary noninvasive respiratory support vs. mechanical ventilation and surfactant). Moreover, these approaches may have unintended consequences (lower vs. higher oxygen saturation targets) and may not decrease later respiratory morbidity in at-risk populations. Two meta-analyses published in 2016 describe the effects of the primary strategy of providing noninvasive positive pressure (CPAP) versus intubation and mechanical ventilation. These analyses had different approaches and their results differed somewhat. The meta-analysis from the Cochrane Library, using data from three trials, demonstrated decreased risk ratios for BPD (0.89; 95% CI 0.79, 0.99) and BPD or death (0.89; 95% CI 0.81, 0.97) with the strategy of applying and continuing CPAP soon after birth. This strategy was accompanied by significant reductions in the use of mechanical ventilation and surfactant administration. The other study applied network meta-analyses to 2 of the 3 studies included in the Cochrane analysis, producing network odds ratios that had similar effect sizes as the reported risk ratios, but confidence intervals for BPD and BPD or death that crossed the null boundary. The implementation of noninvasive strategies has been widespread and short-term benefits may increase with use of noninvasive surfactant administration, for newborns meeting specific criteria . However, broad clinical implementation of a strategy to limit invasive mechanical ventilation has been also been associated with an increase in overall duration of respiratory support and worse lung function parameters at school age.

The international Neonatal Oxygenation Prospective Meta-analysis (NeOProM) collaborative aligned study protocols and shared data to allow for an individual patient data meta-analysis of 5 double-blind randomized, controlled clinical trials. These studies compared oxygen saturation targets of 85% to 89% versus 91% to 95% for extremely preterm newborns receiving supplemental oxygen. Although the primary outcome of the collaborative was the effect of oxygen saturation targets on neurodevelopmental disability, the group analyzed secondary outcomes and sub-group effects. Importantly, mortality was increased in the lower oxygen saturation group up to 18 to 24 months corrected age, including at 36 weeks’ PMA (risk difference 2.5%; 95% CI 0.5, 4.5%). Severe necrotizing enterocolitis (NEC) was also increased with lower oxygen saturation targets (risk difference 2.3%; 95% CI 0.8, 3.8). Among survivors, BPD, defined as oxygen supplementation at 36 weeks’ PMA, was decreased by 5.6% (95% CI −8.5, −2.7%), relative risk (RR) 0.81 (95% CI 0.74, 0.90), an effect that was even greater in SGA infants (adjusted RR 0.54 (CI 0.37, 0.77). These results provide more direct insight into the effects of oxygen supplementation on the development of chronic respiratory disease in these vulnerable populations. However, the increase in mortality and NEC when targeting oxygen saturations < 90% suggests that more targeted strategies will be needed to improve respiratory outcomes.