Preterm Infants With Bronchopulmonary Dysplasia and Pulmonary Hypertension

We present the case of a male infant born preterm with a postnatal course complicated by grade 3 bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) who was followed in our multidisciplinary neonatal intensive care unit (NICU) follow-up clinic.The infant was born at 251/7 weeks’ gestation to a 28-year-old gravida 1 para 0 woman via vaginal delivery secondary to preterm labor and concern for chorioamnionitis. Pregnancy was complicated by subchorionic bleeding noted on 20-week ultrasonogram. The pregnant woman had received an incomplete course of betamethasone prior to delivery. Delivery was significant for meconium-stained amniotic fluid. The infant was initially vigorous with good tone but quickly developed poor respiratory effort and hypoxemia requiring intubation in the delivery room. The infant’s Apgar scores were 7 and 8 at 1 and 5 minutes of age, respectively. The infant’s birth weight was 760 g, which was appropriate for gestational age. He was admitted to a level III NICU for further management.Upon admission, he received a dose of surfactant and was extubated to continuous positive airway pressure the following day. In the first week of age, he received a course of ibuprofen to facilitate patent ductus arteriosus (PDA) closure that was diagnosed on echocardiography. He was reintubated and placed on conventional ventilation at 6 days of age following multiple apnea and bradycardia events. Three days later, he was found to have a total parenteral nutrition–related pericardial effusion with cardiac tamponade that resolved after pericardiocentesis and removal of the peripherally inserted central line. At 12 days of age, he had worsening respiratory failure, and he was treated with 14 days of antibiotics for culture-positive Escherichia coli bacteremia and pneumonia. At 31 days of age, systemic dexamethasone via the Dexamethasone: A Randomized Trial protocol1 was initiated to facilitate weaning of respiratory support, but it was discontinued early due to worsening respiratory failure requiring escalation to high-frequency oscillatory ventilation. Infectious workup at this time was notable for sputum culture positive for E. coli and Stenotrophomonas, and after completion of antibiotic therapy, he transitioned to conventional ventilation. An additional course of systemic dexamethasone was initiated at 54 days of age. He weaned on respiratory support throughout his course but ultimately was unable to be extubated. During this time, diuretics were initiated. At 356/7 weeks’ postmenstrual age (PMA), he had a failed extubation attempt. At 36 weeks’ PMA, he was on invasive mechanical ventilation and met Jensen criteria for grade 3 BPD. He remained on the conventional ventilator until arrival at our facility.He transferred to our facility at 39 weeks’ PMA for potential PDA device closure and further management of chronic lung disease. Plain chest radiograph was obtained on admission (Figure 1). The PDA was found to have spontaneously closed. He was initiated on an additional course of systemic dexamethasone on DOL 99 and extubated from conventional ventilation to continuous positive airway pressure. At 44 weeks’ PMA, a follow-up echocardiogram was performed due to his continued tachypnea and need for respiratory support. He was found to have a new diagnosis of right ventricular hypertension based on interventricular septum position during systole and tricuspid regurgitation pressure gradient of 41 mm Hg (normal <32 mm Hg) (Figure 2). Over the course of 3 months, he slowly weaned to 0.25 L per minute (LPM) supplemental oxygen via nasal cannula (NC). Given his overall clinical appearance and ability to wean on oxygen support, he was not initiated on pulmonary vasodilator therapy, and echocardiograms remained stable. At time of discharge, he was on 0.25 LPM supplemental oxygen via NC and being treated with budesonide and chlorothiazide.His overall NICU course was also significant for feeding intolerance requiring continuous postpyloric feedings. He was slowly transitioned to nasogastric (NG) feeds, and by the time of discharge, he was tolerating a combination of oral feeding and NG gavage feedings. The family received education on NG insertion prior to discharge. Multiple head ultrasonograms were negative for intraventricular hemorrhage, and his retinas matured appropriately without intervention. He passed his hearing screen bilaterally prior to discharge.At the time of discharge, the infant was 6 months old in chronologic age, or 51 weeks’ PMA. Prior to discharge, the team discussed with the family that he required close outpatient monitoring and management of numerous health concerns. It was anticipated that he would slowly be able to wean off all oxygen support and diuretics. Cardiology would continue to follow his PH closely. His family was counseled that he may require a gastrostomy tube in the outpatient setting if his oral feeding did not progress. Scheduled discharge follow-up included a multidisciplinary BPD clinic, cardiology, occupational therapy for developmental and oral feeding support, and a referral to early intervention.The child is now 5 years old, and he was followed in the BPD multidisciplinary clinic until the age of 3 years. The clinic team included neonatology, pulmonology, occupational therapy, physical therapy, and speech therapy. He also was followed separately by cardiology for PH management.Due to his severe BPD, the decision to wean his respiratory support as an outpatient was made in collaboration between BPD and cardiology clinic providers. Three weeks after discharge, he was weaned from 0.25 LPM NC to 0.125 LPM NC. Approximately 1 month later, he weaned off supplemental oxygen during the day and remained on 0.125 LPM at night.Echocardiography 4 months after discharge showed continued mild right ventricular hypertension; therefore, cardiology recommended he not be weaned further and remain on his nocturnal supplemental oxygen. A nocturnal home oximetry study was then performed in room air at 7 months’ corrected age, which showed no oxyhemoglobin desaturation below 90% and an oxyhemoglobin desaturation event index of 2.4 (Figure 3). The reference values for this index are not officially established in former preterm infants and are under investigation in infants aged less than 1 year, but evidence shows it would typically be less than 5 to 10 at this age in healthy infants. A repeat echocardiogram at 8 months’ corrected age showed resolution of right ventricular hypertension, and he was subsequently weaned off supplemental oxygen support. Chlorothiazide was discontinued at 5 months’ corrected age, and budesonide was discontinued at 8 months’ corrected age. He did not require albuterol after discharge. An echocardiogram was completed off supplemental oxygen, which continued to show no evidence of right ventricular hypertension. He never required pulmonary vasodilators, and he had no respiratory-related readmissions.From a feeding perspective, he progressed to full oral feedings and his NG tube was removed within 1 week of discharge. He continued to advance in his oral motor skills appropriately and did not require feeding therapy. He demonstrated adequate growth postdischarge, and at his last NICU follow-up clinic appointment, his weight was in the 85th percentile, and length was in the 88th percentile. Due to NICU stay greater than 5 days, audiology follow-up was obtained. On a routine otoacoustic emissions test at 14 months’ corrected age, there was concern for abnormal cochlear function of his right ear, but an auditory brainstem response evaluation was performed and was normal bilaterally.At 43 weeks’ PMA, he had poor repertoire writhing movements on a general movements assessment, but at 51 weeks’ PMA, he had an assessment that demonstrated normal age-specific fidgety movements. He was followed by outpatient occupational therapy twice a month from the time of discharge until approximately 9 months’ corrected age and by early intervention physical therapy from 5 to 12 months’ corrected age. He was discharged from both disciplines due to appropriate developmental progression. Per family report, there were no concerns about developmental delay at follow-up visits. At 22 months’ corrected age, concern was raised for expressive language delay at a routine developmental follow-up appointment with neonatology. He underwent Bayley-III Developmental Assessment at 25 months’ corrected age. This revealed he was delayed in all 3 categories: cognitive (composite score 60, 0.4 percentile), language (composite score 68, 2nd percentile), and motor (composite score 79, 8th percentile). He was referred to outpatient speech therapy and received therapy biweekly until he started preschool, at which time his services were transitioned to school-based therapy. He is currently in kindergarten and continues to have evidence of global developmental delay. He is receiving speech therapy and occupational therapy and has an individualized education plan. He enjoys school and is continuing to make developmental progress.Overall, he has been in great health since discharge from the NICU. He had 1 emergency department visit at 12 months’ corrected age for right acute otitis media and left lower lobe pneumonia, which resolved with amoxicillin. He had snoring, chronic nasal congestion, and recurrent right otitis media and so ultimately underwent bilateral adenoidectomy and right myringotomy at 15 months’ corrected age with resolution of symptoms. He continues to follow up with pulmonology annually and currently does not require any medications. He had 1 final echocardiogram at 2 years of age that continued to show no evidence of PH; therefore, he was discharged from the cardiology clinic.BPD is the most common pulmonary morbidity related to prematurity.2 BPD arises from abnormal postnatal development of the lung and is defined by alveolar simplification, fibrosis, inflammation, and abnormal vascular development. Infants with BPD are at increased risk of poorer pulmonary outcomes compared with premature infants without a diagnosis of BPD, including increased emergency department visits, hospital readmissions, health care utilization, and requirement of respiratory support after initial hospital discharge.3,4 Rates of discharge to home on supplemental oxygen vary from 28% to 50% of premature infants with BPD.5,6 For patients with BPD who are discharged on supplemental oxygen, reported duration of home oxygen needs is as short as 2 to 3 months to more than 12 months of age.7–9 Those discharged on supplemental oxygen have even further increases in rate of respiratory rehospitalization, total number of hospitalizations, asthma or BPD medication use, and home nursing care in the first 2 years of age.10 Infants born <1250 g with severe BPD requiring supplemental oxygen at the time of discharge are more likely to require respiratory medications than both survivors with less severe BPD and survivors without BPD at 3-year follow-up.11Infants with BPD are also at increased risk of sleep-disordered breathing, including obstructive sleep apnea, central sleep apnea, hypoventilation, and nonapneic hypoxemia,12 and may require polysomnography as an outpatient prior to being weaned off supplemental oxygen. It has been reported that infants with BPD who require home supplemental oxygen have more abnormalities on polysomnography, particularly increased central events, compared with infants with BPD who are discharged in room air.13 The risk of airway obstruction and/or obstructive sleep apnea due to prematurity may even persist until adulthood.14 The presence of sleep-disordered breathing may increase the duration of time that an infant is required to remain on supplemental oxygen after discharge. The patient described in this case required an adenoidectomy after discharge due to adenoid hypertrophy with associated snoring, but there have not been published reports documenting increased rates of tonsillectomies or adenoidectomies in former preterm infants, and predischarge magnetic resonance imaging performed in preterm and full-term newborns did not demonstrate differences in adenoidal or tonsillar volumes at near-term and term PMAs.15Beyond infancy, children with BPD have higher rates of wheezing and asthma compared with preterm survivors without BPD and are more likely to use bronchodilators up to the age of 2 years, with more persistent wheezing between 2 and 5 years.3,4 Rates of rehospitalization, wheezing/asthma, and medication use in former premature infants decrease stepwise in the first 5 years of age and beyond,3,16 but symptoms may continue and remain higher in children with BPD than those without. Children with BPD are 4.5 times more likely to have wheezing and chronic cough than matched preterm controls without BPD at 9.5 years of age.17 Compared with 0 control patients, a quarter of these children are also receiving asthma medications at this age. On the contrary, an additional study found that prematurity alone is associated with increased risk of hospitalization and respiratory complaints between ages 5 and 11 years, but having a diagnosis of BPD was not significantly associated with risk.16 Not only do these children potentially remain symptomatic, but those with BPD have persisting structural abnormalities in their lungs on computed tomography (CT). Abnormalities on CT were detected in 81% of school-aged children, with most abnormalities in the children who had the most severe BPD, which may imply continued long-term pulmonary symptoms.18Children with BPD have consistently been shown to have lung function impairment throughout childhood and adolescence that is primarily characterized by obstructive respiratory disease, although some children have a mixed obstructive and restrictive pattern.19–21 Furthermore, former preterm infants with and without BPD have impaired diffusion capacity and reduced exercise tolerance even into adulthood.22,23 Perhaps more concerning, former preterm infants with BPD have early-onset decline in lung function by the teenage years24; the combination of decreased lung function and early-onset decline in lung function sets these vulnerable children up for the development of early-onset chronic obstructive pulmonary disease.25 Despite the significant ongoing respiratory challenges for these patients throughout their life span, there are no specific therapies for impaired lung function in BPD, although 1 clinical trial showed improvement in expiratory flow rate with a combination of inhaled steroids and long-acting beta agonists.26Several long-term studies have demonstrated that infants with BPD have abnormal pulmonary function into adulthood as well as increased risk of pulmonary vascular diseases.27 Duration of mechanical ventilation in the neonatal period is the strongest predictor of mean pulmonary artery pressure in adults. Adults who were born premature are also at increased risk of developing hypertension, glucose intolerance, and congestive heart failure.28,29 Due to these findings, it is imperative that patients with a diagnosis of BPD have lifelong follow-up with a pulmonologist.Along with adverse pulmonary outcomes, infants with BPD may have comorbid cardiovascular disease. In a study reported from the Children’s Hospital Neonatal Consortium, 22% of patients with severe BPD had concomitant PH.30 The diagnosis of PH is typically made via transthoracic echocardiography during the neonatal intensive care hospitalization, and screening should occur in any infant with established BPD at 36 weeks’ PMA as well as prior to discharge. The etiology of BPD-related PH is likely multifactorial, but it is hypothesized to be related to hypoxia/hyperoxia-induced vascular remodeling, persistent hypercapnia, vascular growth arrest, and pulmonary overcirculation related to intra- or extracardiac shunts that promote pulmonary vasoconstriction.31 In addition, in the BPD lung, intermittent hypoxemia adversely affects alveolar development and vascular remodeling and growth.32 Infants with BPD born at younger gestational ages and lower birth weights are at highest risk of PH.33 Risk of PH increases significantly with the severity of BPD from 6%, 12%, and 39% for those with mild, moderate, and severe BPD, respectively.34 Infants with BPD-related PH can be managed medically with supplemental oxygen and/or pulmonary vasodilators. The American Thoracic Society clinical practice guideline for home oxygen therapy for affected children strongly recommends home oxygen therapy be prescribed in children with PH. This is due to the potential benefit of lessening the undesirable consequences of chronic hypoxemia because it directly interrupts the vicious cycle of which in the PH can also be managed with pulmonary vasodilators. to of patients with severe BPD require a pulmonary vasodilator at and therapy with is the most with PH are at even higher risk of Infants with BPD-related PH are at risk of increased with a reported rate of up to within 2 years of PH A of preterm infants with BPD-related PH reports a long-term follow-up rate of with an overall 5 times increased risk of compared with those with BPD and no the infants who with BPD-related after discharge from their initial BPD with PH is also associated with additional respiratory and feeding support at discharge. BPD with PH is associated with higher rates of supplemental oxygen use, and tube feedings initial hospital discharge compared with BPD without PH.30 PH is also associated with increased of in the first of as well as higher oxygen at discharge and supplemental oxygen It is for all to be of these to of and to adequate follow-up with PH after for infants with BPD-related PH who 6 months, the PH typically PH resolution rates are and at and corrected age, An additional study the in 44 survivors with BPD-related PH found that at 3 corrected age, had resolution of their the that had were on both oxygen and pulmonary vasodilators, and the were on oxygen or pulmonary This included patients discharged on mechanical therefore, the outcomes may a more severe A had a duration of vasodilators, with of patients weaning off by less than a of The patient described in this case followed the with of supplemental oxygen needs related to his PH but resolution of his PH by 2 years of is to that there has been evidence cardiovascular abnormalities in early adulthood in former preterm infants with BPD. preterm infants have higher mean pulmonary with criteria for or PH in the of are also noted increases in pulmonary vascular and at and during exercise in former preterm and are less able to cardiac index for younger and infants are to discharge and into early monitoring long-term cardiovascular outcomes be of the including of our of all of being born infants with BPD are at risk for poorer feeding outcomes and are at increased risk of feeding and a delay in oral feeding for age. Infants with BPD have breathing during oral feeding compared with term therefore, there is a higher risk of Compared with preterm infants without a diagnosis of BPD, infants with BPD have higher rates of after weeks’ PMA and have less of and breathing during do not follow with oral infants with BPD with or typically have a by 2 to 4 months’ corrected there are concerns feeding and ability to it is imperative for the patient to have follow-up with feeding therapy. The patient described in this case required discharge with an NG tube but progressed quickly and met feeding by about 3 months’ corrected rates of and including lower cognitive and language are in infants with BPD, even after for risk including intraventricular or This may be related to severity and associated with or associated with postnatal therapies as systemic In infants that are less than weeks’ gestational age at the risk of is higher for and higher for at 2 years of age in infants who were at 36 weeks’ PMA compared with those without Infants born g with a diagnosis of BPD are 2 times more likely to have any diagnosis of or cognitive delay at age are also reports of of cognitive from early childhood to school age in this This lower scores on the Developmental of the at the age of 3 and in general motor and at 8 years of age with higher of education services compared with both term and preterm Not only do children with BPD have lower but the of children who are significantly delayed are increased in the with in this of the children with BPD, those who had a of had lower motor and higher in In to motor and cognitive language development is reported to be delayed in children with BPD, including increased risk of significant language delay below the at age to 22 lower and total scores at 3 years of and lower scores in both expressive and language at 8 years of compared with without BPD as well as term have also been reports of in motor in patients who required a duration of supplemental oxygen in and former are overall increased in BPD, there have been multiple studies that have demonstrated outcomes between infants with BPD discharged on supplemental oxygen or breathing room including and with more severe respiratory outcomes, premature infants with a diagnosis of PH have significantly lower cognitive language and motor scores of the Bayley-III at to months’ corrected age compared with preterm In of infants with PH met criteria for cognitive In addition, weight scores and head scores were significantly lower in those with In a of infants with BPD, the cognitive score was significantly and weight score after discharge was poorer in the BPD PH compared with BPD without The patient described in this case had significant and motor at 2 corrected age, as would have been due to his clinical preterm infants with BPD are at increased risk of respiratory and outcomes, and PH is a risk of outcomes in this The evidence the of of these to support and to close and developmental follow-up with multidisciplinary follow-up to ultimately the of preterm infants with BPD and PH. patients require follow-up with pulmonology, neonatology, feeding cardiology, and developmental with multiple therapy disciplines and benefit from lifelong follow-up with It is imperative that are of these in to appropriately support and throughout their neonatal intensive care hospitalization and of the management of lung the long-term and of the of in full-term infants with risk as heart disease, and chronic lung