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). Data on BPD is often based upon the following classification of preterm infants categorized by BW or GA (table 1).

Bronchopulmonary dysplasia — It has been challenging to maintain a consistent definition of BPD and its severity because of changes in the population at risk (ie, greater number of patients at earlier GAs) and advances in neonatal management (ie, surfactant and antenatal glucocorticoid therapy and less aggressive mechanical ventilation) have altered the pathology and clinical course of BPD and led to revisions in its definition and categorization of severity (table 2). (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Definitions'.)

However, when evaluating the literature, it is important to have an appreciation of the definitions used and their limitations, especially if comparing data across different studies and to ensure that results are applicable to the clinical setting at hand [1,2]. Most of the evidence cited in this topic have used one of the following definitions:

●Oxygen requirement either at 28 postnatal days or 36 weeks postmenstrual age (PMA) [3-5].

●2001 National Institute of Child Health and Human Development (NICHD) definition, which added criteria that included GA, severity of disease, and timing of assessment based on GA [6].

●Further changes were suggested at a 2016 NICHD workshop that renamed categories for BPD severity and added newer modes of noninvasive ventilation (eg, nasal cannula flow) not included in the previous definition, radiologic evidence of disease as a criterion, and a new category (IIIA) of early lethal BPD [7].

●A 2019 subsequent revision resulted in a simplified method to define severity of BPD, which is dependent only on the mode of respiratory support and not the degree of oxygen supplementation (table 2).

The discussion that reviews the ongoing challenge of establishing a consensus definition is reviewed separately. (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Definitions'.)

INTERVENTIONS

Overview — The following interventions are generally used in combination to improve outcome and/or reduce the risk of BPD in at-risk preterm infants, especially extremely preterm infants (EPT; gestational age [GA] <28 weeks) (algorithm 1):

●Antenatal glucocorticoid therapy

●Protective ventilatory strategies that minimize barotrauma or volutrauma in infants who require respiratory support for neonatal respiratory distress, especially very preterm infants (GA <32 weeks) (table 3)

●Mother's breast milk

●Caffeine

●Fluid restriction

●If available, vitamin A supplementation

However, if one is determining the effectiveness of these preventive measures based on the number of patients needed to be treated to prevent one case of BPD, the baseline risk for BPD must be considered [8]. Preterm infants who continue to receive mechanical ventilation at one week after birth are at high risk for developing BPD, especially severe BPD. As a result, management of these patients may include more aggressive preventive measures including:

●Postnatal glucocorticoid therapy

●Diuretic therapy

Measures that are not recommended include:

●Ineffective or unproven interventions including inhaled nitric oxide (iNO), superoxide dismutase, docosahexaenoic acid, pentoxifylline, and administration of late surfactant.

●Routine use of postnatal glucocorticoid therapy in at-risk preterm infants because of concerns that its known adverse effects outweigh potential benefit. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids".)

The management approach utilizing these measures is discussed below. (See 'Our approach' below.)

Glucocorticoids

Antenatal glucocorticoids — Antenatal glucocorticoid therapy is recommended to any pregnant woman from 23 to 34 weeks of gestation who is at risk for preterm delivery within the next seven days. Antenatal glucocorticoids decrease the neonatal risk of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and mortality. In particular, trials have consistently confirmed a significant reduction in the frequency of RDS among neonates who received antenatal glucocorticoid therapy resulting in less need for mechanical ventilation and oxygen supplementation, which are risk factors for BPD. However, antenatal glucocorticoid therapy has not decreased the incidence of BPD because the increased survival rate associated with its use results in survival of more infants at risk for BPD. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

Postnatal glucocorticoids — We do not routinely administer systemic postnatal glucocorticoids despite their ability to reduce the rate of BPD at 36 weeks postmenstrual age (PMA). This is based on data that suggest the potential benefits of systemic glucocorticoids, particularly dexamethasone, are outweighed by their known short-term and long-term adverse effects, including cerebral palsy, and are consistent with guidelines from the American Academy of Pediatrics (AAP) and the Canadian Paediatric Society (CPS). (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids", section on 'Systemic corticosteroids'.)

However, we do reserve administration of low-dose corticosteroids for preterm infants at high risk for BPD (GA <28 weeks) who remain ventilator-dependent at three to four weeks of age and/or have an oxygen requirement of >50 percent [9,10]. Typically, these patients have failed at least one attempt at extubation. Rarely, steroid therapy is used in an infant at two weeks of age who requires extremely high levels of respiratory support to prevent further lung damage from volutrauma from mechanical ventilation and high concentration of supplemental oxygen. The use of postnatal corticosteroids to prevent BPD is discussed in greater detail separately. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids", section on 'Systemic corticosteroids' and 'Ventilation strategies to minimize lung injury' below.)

There is no confirmed evidence that inhaled glucocorticoid prevents BPD in at-risk preterm infants, and there is a concern for increased mortality associated with inhaled therapy. As a result, we do not administer inhaled glucocorticoids to at-risk preterm infants to prevent BPD, which is consistent with the recommendation of the AAP and the CPS. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids", section on 'Inhaled corticosteroid'.)

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). However, similar to antenatal glucocorticoid therapy, surfactant has not reduced the incidence of BPD because of the increased survival rate of very low birth weight (VLBW) infants who are at risk for BPD. The use of early surfactant to prevent and treat RDS is discussed separately. (See "Prevention and treatment of respiratory distress syndrome in preterm infants", section on 'Surfactant therapy'.)

Fluid management

Fluid balance — Although data are limited, fluid management after the first week of life in our practice is typically restricted to 130 to 140 mL/kg per day to maintain neutral or slightly negative fluid balance. 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", section on 'Monitoring tools'.)

Data supporting moderate fluid restriction were provided by the following:

●In a retrospective report of preterm infants (birth weight [BW] between 401 and 1000 g) from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network study, infants who either died or developed BPD had a higher fluid intake and a lower weight loss during the first 10 days of life compared with those who survived without BPD [11]. A retrospective single center Canadian study of EPT infants also reported that a higher cumulative fluid balance at day 10 of life was associated with a higher risk of BPD and death [12].

●In a systematic review of the literature of five trials, fluid restriction decreased the risk of a hemodynamically significant patent ductus arteriosus (PDA), and there was a trend to a reduced risk of BPD in the analysis of 526 preterm in four trials that reported BPD as an outcome, but this was not statistically significant (relative risk [RR] 0.85, 95% CI 0.63-1.14) [13]. However, this analysis of all five trials also reported that fluid restriction was associated with a significant postnatal weight loss, which may increase the risk of dehydration.

Diuretic therapy — There is no good evidence to support the use of diuretic therapy in maintaining a neutral or negative fluid balance to prevent BPD. In our practice, diuretic therapy is tried in chronically ventilator-dependent infants with moderate to severe lung function impairment after a trial of fluid restriction (130 to 140 mL/kg) has failed to significantly improve their pulmonary status. The diuretic is continued if improvement is seen by the ability to lower ventilatory support.

Typically, a trial of enteral furosemide is given for three to five days at 2 mg/kg per day. If there is no response in improved respiratory status, diuretics are discontinued. If the patient improves, furosemide may be continued, or the diuretic is changed to a thiazide. If diuretic therapy is continued, ongoing and frequent monitoring of serum electrolyte status is required. Not infrequently, supplemental electrolytes, particularly potassium chloride, may need to be provided to maintain normal serum electrolytes. (See "Fluid and electrolyte therapy in newborns", section on 'Hypokalemia'.)

The use of furosemide is supported by weak observational data in a cohort of 37,693 preterm infants (GA <29 weeks) that included 19,235 infants exposed to furosemide that reported that a longer duration of furosemide exposure administered between day 7 and 36 weeks after birth was associated with a decreased risk of BPD and the combined outcome of BPD and death [14].

Ventilation strategies to minimize lung injury — Mechanical ventilation 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, strategies have been developed to reduce or avoid the trauma of mechanical ventilation, in the hopes of decreasing BPD in preterm infants with respiratory insufficiency (or distress), while maintaining target hemoglobin oxygen saturation (SpO₂) between 90 and 95 percent (table 3). (See "Approach to mechanical ventilation in very preterm neonates" and "Approach to mechanical ventilation in very preterm neonates", section on 'Clinical approach'.)

These include:

●Avoidance of MV through preferential use of noninvasive respiratory support (eg, nasal continuous positive airway pressure [nCPAP]) when possible.

●Use of minimal volume-targeted ventilation (VTV).

●Use of high-frequency oscillatory or jet ventilation (HFOV or HFJV) as a rescue therapy.

In our practice, for preterm infants who are at risk for neonatal RDS who have a sustained strong respiratory effort and a requirement of oxygen supplementation below a fraction of inspired oxygen (FiO₂) 0.40, CPAP is the initial modality used for respiratory support, thereby avoiding intubation and mechanical ventilation and reducing the risk of BPD [15]. For infants receiving CPAP who fail to maintain target hemoglobin oxygen saturation (SpO₂) levels between 90 and 95 percent in FiO₂ .>0.4 to 0.5, are unable to maintain a partial pressure of carbon dioxide (PaCO₂) <65, or have significant work of breathing, mechanical ventilation is provided.

In this setting, volume-targeted synchronized intermittent ventilation (SIMV) with low tidal volumes (4 to 6 mL/kg) and permissive hypercapnia is used (table 3). Positive end-expiratory pressure (PEEP) of 5 to 6 cm H₂O is provided, which generally minimizes atelectasis and counters the development of pulmonary edema. Ventilatory settings are adjusted to maintain PaCO₂ at targeted values between 50 and 55 mmHg during the acute respiratory illness (first 10 to 14 days of life) and PaCO₂ up to 60 mmHg with pH ≥7.25 in infants greater than two weeks who remain ventilator dependent. A trial of high-frequency ventilation (HFV) is provided to infants with persistent, severe respiratory failure unresponsive to conventional volume-targeted mechanical ventilation as a rescue intervention to minimize volutrauma. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Clinical approach' and "Neonatal target oxygen levels for preterm infants" and "Prevention and treatment of respiratory distress syndrome in preterm infants", section on 'Noninvasive positive airway pressure'.)

The preferred use of VTV compared with pressure-limited ventilation (PLV) to minimize lung injury from mechanical injury is based on the following:

●A systematic review of the literature of 1065 infants less than 44 weeks postmenstrual age (PMA) reported VTV compared with PLV did not reduce death rate (RR 0.75, 95% CI 0.53-1.07) but was associated with a lower rate of the primary combined outcome of death and BPD compared with PLV (RR 0.73, 95% CI 0.59-0.89) [16].

●A second systematic review reported VTV compared with PLV was associated with a lower rate of BPD (RR 0.61, 95% CI 0.46-0.82) and duration of ventilation (mean difference [MD] -2 days, 95% CI -3.14 to -0.86) but not death (RR 0.73, 95% CI 0.51-1.05) [17].

Because it is difficult to measure delivered tidal volume in preterm infants, neonatal randomized trials comparing low versus high tidal volume ventilation have not been performed. Permissive hypercapnia (defined as PaCO₂ between 50 and 55 mmHg) is used as a clinical surrogate for low tidal volume ventilation in studies of preterm infants [18-20]. However, the optimal PaCO₂ target has not been established. Limited data suggest that target PaCO₂ that exceeds 60 mmHg does not provide any additional benefit beyond our preferred range of 50 and 55 mmHg as noted by the following:

●In a multicenter trial of 362 extremely low birth weight (ELBW) preterm infants (BW <1000 g), there was no difference in the combined primary outcome of death or BPD between preterm infants assigned to a high target PaCO₂ (target ranging from 60 to 75 mmHg) compared with the standard control group (45 to 60 mmHg) [21]. In a follow-up report, there was no difference in neurodevelopmental outcome between the two groups [22].

●Secondary analysis of data from the SUPPORT study reported higher PaCO₂ levels were associated with increased risk of mortality, BPD, and neurodevelopmental impairment [23]. In this cohort, the average PaCO₂ level was 48 mmHg and the authors concluded that clinical practice had evolved to maintain permissive hypercapnia in the 45 to 55 mmHg range.

Caffeine — We administer prophylactic caffeine in doses used to treat apnea of prematurity within the first day of life to ELBW infants (BW <1000 g) as there is good evidence that this intervention reduces BPD and may improve long-term outcome. A loading dose of 20 mg/kg of caffeine citrate (equivalent to 10 mg/kg caffeine base) is given intravenously, or enterally, followed by a daily maintenance dose of 5 to 10 mg/kg per dose (equivalent to 2.5 to 5 mg/kg caffeine base) started 24 hours after the loading dose, which can also be administered either intravenously or orally. (See "Management of apnea of prematurity", section on 'Efficacy'.)

Supportive data for prophylactic caffeine include:

●In a multicenter trial that randomly assigned caffeine or placebo to 2006 preterm infants (BW between 500 and 1250 g) during the first 10 days of life (Caffeine for Apnea of Prematurity [CAP] trial), infants who received caffeine compared with controls had a lower incidence of BPD, defined as oxygen treatment at 36 weeks PMA (36 versus 47 percent, adjusted odds ratio [aOR] 0.63; 95% CI 0.52-0.76) [24]. In this cohort, the median age for initiation of study drug was three days. In a post-hoc analysis, reduction of duration of respiratory support was greater in infants started on caffeine on or before three days than between 4 and 10 days of age [25]. The difference in the incidence of BPD was attributed in part to a shorter period (approximately one week) of positive pressure support in the caffeine-treated patients compared with the controls.

Although evaluation of survivors at 18 to 21 months corrected age demonstrated caffeine compared with placebo was associated with a lower incidence of the primary combined outcome of death or neurodevelopmental disability (40.2 versus 46.2 percent, aOR 0.77; 95% CI 0.64-0.93) [26], the difference between the two groups in death or survival with severe disability at follow-up at five years corrected age was not statistically significant (21.1 versus 24.8 percent, aOR 0.82; 95% CI, 0.65-1.03) [27]. However, a subsequent secondary analysis suggested that improved motor outcomes were sustained in the caffeine group [28]. Follow-up of patients at 11 years of age found that children assigned caffeine had better respiratory function than controls [29].

●In a large cohort study using data from the Pediatrix Medical Group, the use of early caffeine therapy before three days of life was associated with a lower incidence of BPD compared with later use (on or after three days of life) (23 versus 31 percent, OR 1.23, 99% CI 1.05-1.43) [30].

Vitamin A — EPT infants may have vitamin A deficiency, which may promote the development of BPD [31]. However, data are conflicting as to whether vitamin A supplementation reduces the incidence of BPD. At most, it appears that vitamin A intramuscular supplementation given in optimal circumstances would only result in a modest reduction of BPD. Since the incidence of BPD varies among neonatal intensive care units (NICUs), the decision to use vitamin A supplementation may depend upon balancing several factors, including the local incidence of BPD, the value of, at most, a modest decrease in BPD, the need for repeated intramuscular injections (painful), and the availability and cost of medication [32]. If vitamin A is available, practitioners may consider its administration to EPT infants who require ventilatory support. In one author's center, vitamin A is administered to in EPT infants who require ventilatory support within 24 hours after birth as an intramuscular injection of 5000 international units three times per week for four weeks. Although enteral water-soluble vitamin A increases plasma retinol levels in EPT infants, it does not appear to reduce the severity of BPD [33].

Evidence for vitamin A supplementation includes the following:

●A meta-analysis with 1165 infants reported a small benefit of systemic supplementation compared with controls in the combined outcome of death and BPD (74 versus 80 percent; relative risk [RR] 1.08, 95% CI 1.01-1.14) [34]. In the largest of the included trials, there was no difference in neurodevelopmental outcome at 18 to 22 months (corrected for prematurity) for survivors who received supplemental vitamin A versus controls [31].

●A subsequent trial in 196 VLBW infants trials also reported a modest benefit in reducing death and BPD with large doses of oral vitamin A [35].

●However, 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 [36]. 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.

The difference in the results of these studies may be due to the other improvements in the clinical management of ELBW infants (eg, antenatal corticosteroid and the increased use of caffeine and noninvasive respiratory support) during the study periods that diminished or eliminated the benefit of vitamin A. Another potential factor is that vitamin A may be beneficial in a subset of preterm infants, as suggested by a post-hoc reanalysis of data from the largest clinical trial [37]. In this report, the effect of vitamin A therapy versus placebo was greater for infants at a lower risk for BPD than those at a higher risk based on risk modeling estimates. 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 systematic review concluded that human milk compared with formula was associated with a lower incidence of BPD, although the quality of the evidence is low [38]. 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 [39]. However, the results of this study are limited by the potential of confounding factors.

Ineffective and potentially harmful 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 — It is well-established that iNO provides benefit in the treatment of term or late preterm infants with persistent pulmonary hypertension. However, available data do not show that iNO prevents BPD. We do not recommend the routine administration of iNO to preterm infants with RDS. This approach is consistent with the conclusions of an expert panel convened by the National Institute of Health and a 2014 American Academy of Pediatrics clinical report that do not support the use of iNO in the treatment of preterm infants below 34 weeks gestation who require respiratory support [40,41]. (See "Persistent pulmonary hypertension of the newborn".)

A number of randomized masked controlled clinical trials have been conducted to evaluate the safety and efficacy of iNO to prevent BPD and reduce mortality in preterm infants with respiratory distress syndrome (RDS) [42-49]. Although there are important differences in study design (eg, dose, duration, early versus late administration of iNO, and severity of illness), iNO has not been shown to be more effective than placebo in any subgroup, with the possible exception of Black American infants [48,50-53]. In a meta-analysis of four trials (n = 1924) examining routine use of iNO in preterm infants requiring respiratory support, rates of BPD were similar in the iNO and control groups (40 versus 42 percent; RR 0.95, 95% CI 0.85-1.05) [52]. Another patient-level meta-analysis of three trials that enrolled preterm infants (GA <34 weeks) receiving respiratory support and that included a minimum of 10 Black American patients reported a significant subgroup effect according to race [53]. In this analysis, iNO reduced rates of BPD among Black infants (42 versus 57 percent; RR 0.88, 95% CI 0.8-0.98), but the effect in White infants was nonsignificant (61 versus 63 percent; RR 0.98, 95% CI 0.85-1.12). There was no apparent subgroup effect on the outcome of mortality. However, given the large number of subgroup analyses performed, it is possible that the difference in the effect according to race may represent a spurious finding.

Combination of surfactant and inhaled nitric oxide — It appears that the combination of late surfactant and iNO is no more effective than iNO alone in reducing mortality and BPD for preterm infants (GA ≤28 weeks) who are mechanically ventilated. As a result, we do not routinely use the combination of iNO and surfactant in preterm infants to prevent BPD.

In a multicenter trial (Trial of Late Surfactant [TOLSURF]) from 2010 to 2013 of 511 EPT infants (GA ≤28 weeks) between 7 to 14 days of age who were mechanically ventilated, the group who received both iNO and surfactant and the control group who were only treated with iNO had similar survival without BPD at 36 weeks PMA (31 versus 32 percent, RR 0.98; 95% CI 0.75-1.28) or at 40 weeks PMA (59 versus 54 percent, RR 1.08; 95% CI 0.92-1.27) [54]. A follow-up report found no benefit for the combination therapy for the primary outcome of pulmonary morbidity based on care providers' recall on the use of medications, hospitalization, and home respiratory support at one year corrected age [55].

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. Evidence suggests that direct or indirect DHA supplementation does not prevent BPD. However, LCPUFA supplementation may have beneficial effects on neurocognitive and visual development for preterm infants. Recommendations regarding maternal and infant dietary intake and supplementation are provided separately. (See "Long-chain polyunsaturated fatty acids (LCPUFA) for preterm and term infants", section on 'Rationale for LCPUFA supplementation'.)

The data regarding LCPUFAs and prevention of BPD include the following:

●Direct administration – A 2019 meta-analysis that reported omega-3 long-chain polyunsaturated fatty acids (N-3 LCPUFAs) including DHA did not reduce the risk of BPD [56]. In one of the included studies, the largest multicenter study of preterm infants (GA <29 weeks) deemed to be of high quality evidence, DHA supplementation (60 mg/kg per day) increased the risk of BPD compared with placebo (49.1 versus 43.9 percent; adjusted RR 1.13, 95% CI 1.02-1.25) [57]. DHA was also associated with a higher risk of the composite secondary outcome of mortality or BPD (52.3 versus 46.4 percent; adjusted RR 1.11, 95% CI 1.00-1.23).

●Maternal supplementation – A multicenter trial of preterm infants (GA<29 weeks) who were receiving maternal breastmilk reported no benefit in preventing BPD from maternal supplementation of DHA compared with placebo [58]. This trial was stopped early due to concern of harm based on the findings from the previously discussed trial of DHA supplementation in infants [57] and an interim review of results in this trial. Based on the data from the 523 infants who completed this trial, there was trend to a lower survival without BPD rate (primary outcome) in the maternal supplemented DHA versus placebo groups (55 versus 62 percent, RR 0.8-1.04). Comparing the DHA and placebo groups for the two major secondary outcomes, mortality was 6 versus 10 percent (RR 0.61, 0.33-1.13), and the risk of BPD for survivors was 42 versus 31 percent (RR 1.36, 1.07-1.73). There was no difference in the other prespecified secondary outcomes except a lower risk of severe intraventricular hemorrhage was associated with maternal supplementation of DHA (8 versus 16 percent, RR 0.48, 0% CI 0.29-0.80). These results suggest that maternal supplementation of DHA is not beneficial; however, early termination of the trial limits the interpretation of the data.

Sustained inflation in the delivery room — During neonatal resuscitation in the delivery room, the use of sustained inflation, defined as a positive pressure breath held at full inflation pressure for 10 to 20 seconds, has been postulated to reduce the risk of BPD compared with standard intermittent positive pressure ventilation (ventilatory rate of 40 to 60 breaths per minute) [59-61]. However, published data do not show a benefit of sustained inflation at delivery in reducing the risk of BPD or death [62-66]. In a systematic review of 1406 preterm infants who required resuscitation, there was a nonsignificant trend towards death before hospital discharge associated with sustained inflation compared with standard intermittent positive pressure ventilation (11.5 versus 3.6 percent, adjusted risk difference 3.6 percent, 95% CI -0.7 to 7.9 percent) [64]. Of note, the largest trial was stopped early after enrolling 426 infants because of early death within 48 hours of age associated with sustained versus standard ventilation (7.4 versus 1.4 percent, adjusted risk difference [aRD] 5.6%, 95% CI 2.1-9.1%) [63]. Thus, in the delivery room, we continue to use standard intermittent positive pressure for preterm infants who require resuscitation with a ventilatory rate of 40 to 60 times per minute without sustained inflation. (See "Neonatal resuscitation in the delivery room", section on 'Positive pressure ventilation'.)

Unproven interventions — Interventions that are unproven in preventing BPD due to insufficient data include:

●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 [67,68]. Superoxide dismutase is not available and remains an investigational drug. We do not routinely administer superoxide dismutase in preterm infants to prevent BPD.

●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 [69]. As a result, we do not routinely administer pentoxifylline in preterm infants at risk for BPD.

●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, it appears that late administration of surfactant does not reduce the risk of BPD [70,71]. As a result, we do not routinely administer late surfactant to prevent BPD.

●Combination of steroid and surfactant — In two small trials of VLBW (BW <1500 g), infants with RDS requiring mechanical ventilation and FiO₂ >50 percent were randomized to budesonide mixed in surfactant (as the delivery vehicle) versus surfactant alone [72-74]. In both studies, the budesonide in surfactant group had a decrease in the incidence of BPD or death. There was no significant difference in neurodevelopmental outcomes between the groups. However, larger multicenter trials are needed to study this combination therapy and determine the efficacy and risks for this intervention prior to its use in routine care.

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 glucocorticoids are given to any pregnant woman at 23 to 34 weeks of gestation at high risk for preterm delivery within the next seven days. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

●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 'Fluid management' above.)

●In our centers, nutritional goals are set to provide adequate caloric intake to promote somatic and lung growth [75]. Mother's breast milk is the preferred nutritional source, and if not available, we use donor breast milk. (See "Growth management in preterm infants", section on 'Growth in the NICU'.)

●We administer caffeine to all EPT infants within the first 24 hours of life as they have the highest risk for BPD. (See 'Caffeine' above and "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Epidemiology'.)

Respiratory support — The goal for respiratory support for infants at risk for BPD is to maintain adequate oxygenation while minimizing respiratory intervention that may lead to lung injury. (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Oxygen toxicity' and "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features", section on 'Mechanical ventilation'.)

●In infants who require supplemental oxygen, we set target pulse oximetry saturation between 90 and 95 percent. (See 'Ventilation strategies to minimize lung injury' above.)

●In active preterm infants without respiratory failure who require oxygen supplementation, we use early continuous positive airway pressure (CPAP) as initial respiratory support. In our centers, we do not routinely use noninvasive mechanical ventilation as it does not appear to offer significant additional benefit over the use of early CPAP. (See "Prevention and treatment of respiratory distress syndrome in preterm infants".)

●In preterm infants who require intubation soon after birth, we provide early surfactant therapy. (See "Prevention and treatment of respiratory distress syndrome in preterm infants", section on 'Surfactant therapy'.)

●In preterm infants with respiratory failure, synchronized intermittent ventilation is initiated using low tidal volumes (4 to 6 mL/kg) with permissive hypercapnia in either a volume control or volume guarantee (for infants with spontaneous breathing) mode (volume-targeted ventilation) (table 3). Ventilatory settings are adjusted to maintain partial pressure of carbon dioxide (PaCO₂) at targeted values between 50 and 55 mmHg during the acute respiratory illness (first 10 to 14 days of life) and PaCO₂ up to 60 mmHg with pH ≥7.25 in infants who remain ventilator dependent after two weeks of life. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Clinical approach'.)

●In infants with persistent, severe respiratory failure despite the use of maximal settings for conventional ventilation, a trial of high-frequency ventilation (HFV) is used to minimize volutrauma. In general, we consider a trial of several days of HFV if mean airway pressure on conventional ventilation exceeds 10 to 12 cm H₂0 to maintain acceptable gas exchange or if peak inspiratory pressures exceed 25 to 28 cm H₂0 to achieve target tidal volumes of 4 to 6 mL/kg. (See "Approach to mechanical ventilation in very preterm neonates", section on 'Transition to HFV'.)

●If available in one author's center, vitamin A is administered to ventilator-dependent extremely low birth weight (ELBW) infants (birth weight <1000 g) within the first day of life as an intramuscular injection of 5000 international units three times per week for four weeks. (See 'Vitamin A' above.)

Persistent mechanical ventilation — 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 three to four weeks [10]. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids".)

Interventions not used — Interventions that we do not use to prevent BPD based on available evidence include:

●Inhaled nitric oxide either alone or in combination with surfactant (see 'Inhaled nitric oxide' above)

●Docosahexaenoic acid to prevent BPD in preterm infants (see 'Long-chain fatty acids' above)

●Unproven interventions including superoxide dismutase, late surfactant alone or in combination with budesonide, and pentoxifylline. (See 'Unproven interventions' above.)

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 5^th to 6^th 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 10^th to 12^th 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. (See 'Breast milk' above and 'Fluid management' above and "Approach to enteral nutrition in the premature infant", section on 'Nutritional goals' and "Parenteral nutrition in premature infants", section on 'Parenteral nutritional requirements'.)

•Appropriate oxygen target levels – In preterm infants who require supplemental oxygen, target hemoglobin 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 "Prevention and treatment of respiratory distress syndrome in preterm infants", section on 'Clinical approach' and "Approach to mechanical ventilation in very preterm neonates".)

•Intermittent positive pressure ventilation – For preterm infants requiring resuscitation in the delivery room, we recommend standard intermittent positive pressure ventilation (ventilatory rate of 40 to 60 breaths per minute) rather than sustained inflation ventilation (Grade 1B). (See 'Sustained inflation in the delivery room' above.)

•Caffeine therapy – We recommend prophylactic caffeine therapy for all EPT infants (Grade 1B). We suggest starting caffeine within the first few days of life rather than later administration (Grade 2C). At our institutions, caffeine is typically administered on the first day of life. (See 'Caffeine' above and "Management of apnea of prematurity", section on 'Other therapies'.)

•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 – Although postnatal corticosteroids are effective in preventing BPD, any potential benefit of routine postnatal systemic glucocorticoid therapy is likely outweighed by its known adverse effects, and thus their routine use is precluded. Postnatal corticosteroids and its role in preventing BPD are discussed separately. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids".)

●Ineffective interventions – Interventions that are not effective for prevention of BPD in EPT infants include:

•Inhaled nitric oxide (iNO) – We suggest not routinely using prophylactic iNO (Grade 2C). (See 'Inhaled nitric oxide' above.)

•Docosahexaenoic acid (DHA) – Available evidence suggests that DHA does not prevent BPD. However, long-chain polyunsaturated fatty acids may have beneficial effects on neurocognitive and visual development. (See 'Long-chain fatty acids' above and "Long-chain polyunsaturated fatty acids (LCPUFA) for preterm and term infants", section on 'Rationale for LCPUFA supplementation'.)

●Unproven interventions – Interventions that are unproven in preventing BPD due to insufficient data include superoxide dismutase, pentoxifylline, and late surfactant alone or in combination with budesonide. (See 'Unproven interventions' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge James Adams, Jr., MD, who contributed to an earlier version of this topic review.