INTRODUCTION — Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease (CLD), is an important cause of respiratory illness in preterm newborns. The pathogenesis of BPD is based on disruption of lung development in a preterm infant and injury of the immature vulnerable lung due to mechanical overdistension, oxygen toxicity, and infection. Many strategies have been attempted to prevent BPD. Success has been limited, in part, because the etiology of the disorder is multifactorial and multiple interventions are likely needed.
Potential strategies to prevent BPD are reviewed here. The pathogenesis, clinical features, management, and prognosis of this disorder are discussed separately. (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features" and "Bronchopulmonary dysplasia: Management" and "Outcome of infants with bronchopulmonary dysplasia".)
TERMINOLOGY
Prematurity — Different degrees of prematurity are defined by gestational age (GA), which is calculated from the first day of the mother's last period, or birth weight (BW), as summarized in the table (table 1).
Bronchopulmonary dysplasia — Clinically, BPD is defined by a requirement of oxygen supplementation either at 28 days postnatal age or 36 weeks postmenstrual age (PMA) [1-3]. More nuanced definitions that account for both the supplemental oxygen requirement and mode of ventilatory support are summarized in the table (table 2) and are discussed in greater detail separately. (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Definitions'.)
The definition of BPD has evolved over time because of changes in the population at risk (ie, more surviving neonates at earlier gestational ages [GAs]) and advances in neonatal care (ie, surfactant, antenatal glucocorticoid therapy, early use of noninvasive respiratory support), which have altered the clinical course of BPD. When evaluating the literature, it is important to recognize that the definition may vary across studies [4,5].
OUR APPROACH — The following is a summary of the strategies that we use to reduce the incidence of BPD in very low birth weight (VLBW) infants who are at risk for developing BPD. The combination of interventions addresses the multiple risk factors implicated in the pathogenesis of BPD (algorithm 1). (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Pathogenesis and risk factors'.)
Initial general measures — General measures are provided to all infants who are at risk for BPD (extremely preterm [EPT] infant, gestational age <28 weeks).
●Antenatal steroids – Antenatal glucocorticoids are appropriate for pregnant woman at 23 to 34 weeks of gestation at high risk for preterm delivery within the next seven days. This is discussed separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
●Fluid management – After the first week of life, fluid intake is generally restricted to 130 to 140 mL/kg per day to maintain neutral or slightly negative fluid balance. Fluid status and nutritional status is monitored frequently, and fluid intake modified to avoid dehydration and overhydration and to ensure adequate growth. (See "Management of respiratory distress syndrome in preterm infants", section on 'Fluid management'.)
●Nutrition – In our centers, nutritional goals are set to provide adequate caloric intake to promote somatic and lung growth [6]. Mother's breast milk is the preferred nutritional source, and if not available, we use donor breast milk. (See "Approach to enteral nutrition in the premature infant".)
●Caffeine – We administer caffeine to all EPT infants within the first 24 hours of life. These neonates have the highest risk for BPD. (See "Management of apnea of prematurity", section on 'Caffeine'.)
●Vitamin A – One of the authors of this topic routinely uses vitamin A (if available) in ventilator-dependent extremely low birth weight (ELBW) infants (birth weight <1000 g). (See 'Vitamin A' below.)
Respiratory support — The goal for respiratory support for infants at risk for BPD is to maintain adequate oxygenation and ventilation while minimizing respiratory intervention that may lead to lung injury. Our approach is briefly summarized here. Most of these interventions are discussed in detail separately. (See "Management of respiratory distress syndrome in preterm infants" and "Approach to mechanical ventilation in very preterm neonates".)
●In infants who require supplemental oxygen, we set target pulse oximetry saturation between 90 and 95 percent. (See 'Ventilation strategies to minimize lung injury' below and "Neonatal target oxygen levels for preterm infants".)
●In most preterm infants, we use early continuous positive airway pressure (CPAP) as initial respiratory support. (See "Management of respiratory distress syndrome in preterm infants", section on 'Nasal continuous positive airway pressure (nCPAP)'.)
●In preterm infants who require intubation soon after birth, we provide early surfactant therapy. (See "Management of respiratory distress syndrome in preterm infants", section on 'Surfactant therapy'.)
●In preterm infants with respiratory failure, we use a mechanical ventilation strategy that aims to minimize ventilator-induced lung injury (VILI). The approach is summarized in the table (table 3) and is discussed in detail separately. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Clinical approach'.)
●In infants with severe persistent respiratory failure despite optimal settings on conventional ventilation, a trial of high-frequency ventilation (HFV) is used to minimize VILI. This is discussed separately. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Transition to HFV'.)
The role that mechanical ventilation and oxygen toxicity play in the pathogenesis of BPD is discussed separately. (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Pathogenesis and risk factors'.)
Postnatal corticosteroids — We do not routinely administer postnatal systemic or inhaled corticosteroids to prevent BPD. Systemic steroids are reserved for EPT infants who remain ventilator-dependent and/or require oxygen supplementation >50 percent at a postnatal age of two to four weeks. This is discussed in detail separately. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids".)
INTERVENTIONS
Overview
●Measures that are routinely used – The following interventions are generally used in combination to improve outcomes (including a reduction in the risk of BPD) in at-risk preterm infants, especially extremely preterm infants (EPT; gestational age [GA] <28 weeks) (algorithm 1):
•Antenatal corticosteroid therapy (see "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery").
•Protective ventilatory strategies that minimize barotrauma or volutrauma in infants who require respiratory support for neonatal respiratory distress (RDS) (table 3) (see "Management of respiratory distress syndrome in preterm infants", section on 'Early positive pressure' and "Approach to mechanical ventilation in very preterm neonates").
•Mother's breast milk (see "Approach to enteral nutrition in the premature infant" and "Infant benefits of breastfeeding").
•Caffeine (see "Management of apnea of prematurity", section on 'Caffeine').
•Fluid restriction (see "Fluid and electrolyte therapy in newborns" and "Management of respiratory distress syndrome in preterm infants", section on 'Fluid management').
●Measures that are used selectively – Preterm infants who remain ventilator-dependent at one week after birth are at high risk for developing BPD. Such neonates may benefit from additional preventive measures, including:
•Selective us of postnatal corticosteroid therapy in high-risk EPT infants (see "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids").
•Some centers use vitamin A supplementation (if available) in EPT infants who mechanical ventilation support (see 'Vitamin A' below).
•Selective use of a trial of diuretic therapy (see "Bronchopulmonary dysplasia: Management", section on 'Diuretics' and "Management of respiratory distress syndrome in preterm infants", section on 'Fluid management').
●Measures that are not used – These include:
•Routine use of postnatal glucocorticoid therapy in all at-risk preterm infants. This is because of concerns of adverse effects, particularly adverse neurodevelopmental outcome, with early corticosteroid therapy, as discussed separately. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids", section on 'Adverse effects'.)
•Routine use of inhaled nitric oxide (iNO), since this does not appear to be effective. (See "Management of respiratory distress syndrome in preterm infants", section on 'Inhaled nitric oxide'.)
•Late surfactant administration, since this does not appear to be effective. (See "Management of respiratory distress syndrome in preterm infants", section on 'Timing'.)
Corticosteroids
Antenatal corticosteroids — Antenatal corticosteroid therapy is an effective intervention for prevention of respiratory distress syndrome (RDS) resulting in less need for mechanical ventilation and oxygen supplementation (risk factors for BPD). Antenatal corticosteroids are appropriate for pregnant women from 23 to 34 weeks of gestation who are at risk for preterm delivery within the next seven days. This is discussed separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
Postnatal corticosteroids — We do not routinely administer postnatal systemic or inhaled corticosteroids to prevent BPD. Systemic corticosteroids are reserved for EPT infants who remain ventilator-dependent and/or require oxygen supplementation >50 percent at a postnatal age of two to four weeks. This is discussed in detail separately. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids".)
Surfactant — Exogenous surfactant therapy given within the first 30 to 60 minutes of life is effective in the prevention and treatment of RDS resulting in less need for mechanical ventilation and oxygen supplementation (risk factors for BPD). The use of early surfactant to prevent and treat RDS is discussed separately. (See "Management of respiratory distress syndrome in preterm infants", section on 'Surfactant therapy'.)
Fluid management — The goal of fluid management is to maintain neutral or slightly negative fluid balance. Our usual practice is to restrict total fluid intake to 130 to 140 mL/kg per day after the first week of life. However, the fluid status of the patient must be monitored frequently to avoid dehydration or overhydration as fluid needs widely vary in preterm infants due to differences in insensible fluid loss. Caloric intake and growth should be closely monitored. (See "Fluid and electrolyte therapy in newborns".)
The available evidence does not support the routine use of diuretic therapy in maintaining a neutral or negative fluid balance to prevent BPD. However, it may be reasonable to selectively use diuretic therapy as a trial in chronically ventilator-dependent infants with moderate to severe pulmonary impairment despite adequate fluid restriction. This is discussed in greater detail separately. (See "Management of respiratory distress syndrome in preterm infants", section on 'Fluid management'.)
Use of diuretics in the management of infants with established BPD is discussed separately. (See "Bronchopulmonary dysplasia: Management", section on 'Diuretics'.)
Ventilation strategies to minimize lung injury — Mechanical ventilation (MV) has been a lifesaving intervention in the care of preterm infants at risk for RDS due to premature lung development. However, mechanical ventilation causes tissue injury and inflammation due to volutrauma that contributes to BPD. As a result, MV strategies aim to minimize lung injury while achieving adequate oxygenation and ventilation. These strategies include:
●Avoidance of MV through preferential use of noninvasive respiratory support (eg, nasal continuous positive airway pressure [nCPAP]) when possible. (See "Management of respiratory distress syndrome in preterm infants", section on 'Early positive pressure'.)
●Use of volume-targeted ventilation (VTV) using low tidal volumes (4 to 6 mL/kg). (See "Approach to mechanical ventilation in very preterm neonates", section on 'Clinical approach'.)
●Use of high-frequency oscillatory or jet ventilation (HFOV or HFJV) as a rescue therapy. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Transition to HFV'.)
The approach is summarized in the table (table 3), and discussed in greater detail separately. (See "Approach to mechanical ventilation in very preterm neonates".)
Caffeine — For most ELBW infants (BW <1000 g), we suggest prophylactic caffeine starting on the first day of life. The available clinical trial data suggest this intervention is safe and effective for reducing BPD and perhaps other long-term outcomes. This is discussed separately. (See "Management of apnea of prematurity", section on 'Caffeine'.)
Vitamin A — EPT infants may have vitamin A deficiency, which may promote the development of BPD [7]. However, data are conflicting as to whether vitamin A supplementation reduces the incidence of BPD. If there is a benefit, it appears to be modest.
Since the incidence of BPD varies among neonatal intensive care units (NICUs), the decision to use vitamin A supplementation may depend upon the local incidence of BPD and the availability and cost of the drug [8]. For example, one of the authors of this topic routinely uses vitamin A supplementation at their center as a preventive measure in EPT infants who require mechanical ventilation (if the drug is available); whereas the other author does not routinely use it at their center. At most centers where vitamin A is used, its use is limited to EPT infants who require mechanical ventilation.
When vitamin A is given, it is administered within 24 hours after birth as an intramuscular (IM) injection of 5000 international units. This dose is then provided three times per week for four weeks.
Enteral water-soluble vitamin A is not used for this purpose because, although it may increases plasma retinol levels in EPT infants, it does not appear to reduce the severity of BPD [9,10].
Evidence supporting IM vitamin A supplementation includes the following:
●In a meta-analysis of five trials (884 neonates), IM vitamin A supplementation compared with control modestly reduced rates of BPD; however, the finding did not achieve statistical significance (68 versus 74 percent; relative risk [RR] 0.93, 95% CI 0.86-1.01) [11].
●A subsequent multicenter retrospective study from the Pediatrix Medical Group of neonates from 2010 to 2012 reported that the shortage of vitamin A in the United States that began in 2010 did not affect the incidence of mortality or BPD in the participating NICUs [12]. During the study period, vitamin A supplementation in patients decreased from a level of 27 percent to 2 percent as the supply of vitamin decreased. A multivariable analysis demonstrated that vitamin A supplementation was not an independent risk factor for death or BPD.
●Vitamin A may be beneficial in a subset of preterm infants, as suggested by a post-hoc subgroup analysis of data from the largest placebo-controlled trial [13]. In this report, the benefit of vitamin A therapy was greater for infants at a lower risk for BPD than those at a higher risk. However, as noted by the authors, data used for this study was from 1996 to 1997 and other aspects of clinical care have changed, which may have impacted these results.
Breast milk — Mother's own milk is the preferred form of nutrition for preterm infants as it offers several advantages over formula, including prevention of BPD. (See "Human milk feeding and fortification of human milk for premature infants", section on 'Benefits of mother's milk'.)
A meta-analysis of 17 cohort studies and 5 RCTs (8661 neonates) demonstrated that human milk compared with formula is associated with a lower incidence of BPD, although the certainty of this finding is low [14]. In addition, an observational study found breast milk from the mother reduced the risk of BPD and reported a dose-response relationship with an increased reduction in BPD as the volume of consumed breast milk increased [15]. However, the results of this study are limited by the potential of confounding factors.
Other interventions — Interventions that are ineffective in preventing BPD include inhaled nitric oxide alone or in combination with surfactant, supplementation with docosahexaenoic acid, and sustained inflation in the delivery room for infants requiring respiratory support.
●Inhaled nitric oxide (iNO) – The available data do not support the use of iNO (either alone or in combination with surfactant) as an intervention to prevent BPD. We agree with the guidance of the expert panel convened by the National Institute of Health and a 2014 American Academy of Pediatrics clinical report that recommend against the use of iNO in the routine management of preterm infants below 34 weeks gestation who require respiratory support [16,17].
Data on the use of iNO in the management of preterm neonates with RDS are discussed separately. (See "Management of respiratory distress syndrome in preterm infants", section on 'Inhaled nitric oxide'.)
However, iNO is a well-established treatment for term or late preterm infants with persistent pulmonary hypertension, as discussed separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome".)
●Late surfactant therapy – Late deficiency of postnatal surfactant production or surfactant dysfunction has been proposed as a contributor for the pathogenesis of BPD because it may be associated with episodes of respiratory deterioration in ventilator-dependent preterm infants. However, late administration of surfactant does not appear to reduce the risk of BPD, as discussed separately. (See "Management of respiratory distress syndrome in preterm infants", section on 'Timing'.)
●Combination of steroid and surfactant – Data on the use of combination surfactant plus budesonide are limited. This therapy cannot be recommended until there are more definitive data establishing its safety and efficacy. The data supporting this intervention are discussed separately. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids", section on 'Intratracheal corticosteroids'.)
●Long-chain fatty acids – Docosahexaenoic acid (DHA) and other omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) are integral components of the brain and retinal phospholipid membrane. Preterm infants miss some of the fetal accretion of DHA, which normally occurs during the third trimester of pregnancy. Based upon the available evidence, direct or indirect LCPUFA supplementation does not appear to prevent BPD. However, LCPUFA supplementation appears to have other beneficial effects in preterm infants, particularly on neurocognitive and visual development. Recommendations regarding maternal and infant LCPUFA supplementation are provided separately. (See "Long-chain polyunsaturated fatty acids (LCPUFA) for preterm and term infants".)
●Sustained inflation in the delivery room – Sustained lung inflation during neonatal resuscitation in the delivery room may be harmful and should be avoided, as discussed separately.
●Superoxide dismutase – Preterm infants may have inadequate antioxidant defense because of nutrient deficiencies or immature enzyme development. Although observational studies had suggested postnatal administration of antioxidants (eg, superoxide dismutase) may protect against oxidant injury, randomized trials found no differences between infants who were randomly assigned superoxide dismutase and those who received placebo in the incidence of BPD at 36 weeks PMA and in growth or neurodevelopmental status at one year corrected age [18,19]. Superoxide dismutase is not available and remains an investigational drug.
●Pentoxifylline – Pentoxifylline is a synthetic methylxanthine and phosphodiesterase inhibitor that suppresses inflammation. However, data are inadequate to support the routine use of pentoxifylline as a preventive measure for BPD [20].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bronchopulmonary dysplasia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Bronchopulmonary dysplasia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Effective interventions – Interventions that are effective for reducing the risk of bronchopulmonary dysplasia (BPD) in extremely preterm (EPT) infants (gestational age [GA] <28 weeks) who are at risk for BPD include (algorithm 1):
•Antenatal corticosteroid therapy – Antenatal corticosteroid therapy for pregnant women below 34 weeks gestation who are at high risk for preterm delivery, which is discussed in detail separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
•Nutrition and fluid management – In all preterm infants, nutritional goals are set to provide adequate caloric intake to promote somatic and lung growth, and fluid intake is adjusted to maintain neutral or slightly negative water balance. Mother's breast milk is the preferred nutritional source, and if not available, donor breast milk is used. These issues are discussed separately. (See "Approach to enteral nutrition in the premature infant" and "Parenteral nutrition in premature infants" and "Fluid and electrolyte therapy in newborns" and "Human milk feeding and fortification of human milk for premature infants" and "Management of respiratory distress syndrome in preterm infants", section on 'Fluid management'.)
•Oxygen targets – In preterm infants who require supplemental oxygen, target oxygen saturation (SpO2) levels are set for values between 90 and 95 percent, as discussed separately. (See "Neonatal target oxygen levels for preterm infants", section on 'Oxygen target levels'.)
•Ventilation strategies that minimize lung injury – Use of ventilation strategies that minimize lung injury, including preferential use of noninvasive modalities (table 3), is discussed in detail separately. (See "Management of respiratory distress syndrome in preterm infants", section on 'Clinical approach' and "Approach to mechanical ventilation in very preterm neonates".)
•Caffeine therapy – Early caffeine therapy is routinely given to all EPT infants, as discussed separately. (See "Management of apnea of prematurity", section on 'Caffeine'.)
•Vitamin A supplementation – The use of vitamin A supplementation is center-dependent. If vitamin A is available, practitioners may consider its administration to EPT infants who require ventilatory support; however, the relative benefit of vitamin A supplementation in this setting appears to be small. (See 'Vitamin A' above.)
•Postnatal corticosteroids – We do not routinely administer postnatal systemic or inhaled corticosteroids to prevent BPD. Systemic corticosteroids are reserved for EPT infants who remain ventilator-dependent and/or require oxygen supplementation >50 percent at a postnatal age of two to four weeks. This is discussed in detail separately. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids".)
●Ineffective interventions – Interventions that do not appear to be effective for prevention of BPD in EPT infants include (see 'Other interventions' above):
•Inhaled nitric oxide (iNO) (see "Management of respiratory distress syndrome in preterm infants", section on 'Inhaled nitric oxide')
•Late surfactant therapy (see "Management of respiratory distress syndrome in preterm infants", section on 'Timing')
•Sustained lung inflation during neonatal resuscitation (see "Neonatal resuscitation in the delivery room", section on 'Sustained inflation')
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge James Adams, Jr., MD, who contributed to an earlier version of this topic review.
