The Heterogeneity of Long‐Term Cardiopulmonary Outcomes in Children Born Preterm May Benefit from Pulmonary Hypertension‐Specialty Outpatient Follow‐Up

ABSTRACT

Preterm birth survivors reaching adulthood are a growing population, with bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, common among this cohort. Infants with BPD are at increased risk for pulmonary vascular disease (PVD) including the development of pulmonary hypertension (PH). We present three preterm patients with a history of BPD‐associated PH (BPD‐PH) with monitoring throughout their childhood and young adulthood, highlighting the variation in management and late outcomes of each patient. Resolution of PH is reported on transthoracic echocardiogram (TTE) in all patients early in their life. Long‐term follow‐up was discontinued for one patient, while long‐term monitoring in the other two individuals showed evidence of cardiopulmonary complications requiring PH‐specialty management. The burden of cardiopulmonary disease associated with prematurity exists beyond early childhood and further research on the long‐term management of this population is necessary to mitigate complications.

1. Case Descriptions

1.1. Patient 1

A 5‐year‐old male former 770‐g infant born at 28 weeks gestational age (GA) with history of Grade 1 BPD [1], resolved PH, gastroesophageal reflux disease, eczema, and moderate persistent asthma. In the NICU, he was diagnosed with PH via transthoracic echocardiography (TTE) showing moderately increased right ventricular pressure (RVP). He did not require PH‐targeted therapy but did discharge home with supplemental oxygen and PH‐specialty follow‐up. During his first year of life, TTE showed resolution of PH features, and he discontinued oxygen therapy. Approximately 2 years later, intermittent screening TTEs remained normal. As his clinical course remained uncomplicated thereafter, at age 3 he was transitioned to as needed follow‐up.

2. Patient 2

A 20‐year‐old male former 1040‐g infant born at 25 weeks GA with a history of Grade 2 BPD [1], PH, and attention deficit/hyperactivity disorder (ADHD) who was transitioned off the PH‐specific therapy, sildenafil, by age 5 years. Throughout childhood his ADHD was managed on methylphenidate with close monitoring by the PH specialist due to the theoretical risk of stimulant exposure for patients with a history of PH. Disease monitoring with TTEs showed intermittent elevation in RVP starting at age 7 years. Cardiac catheterization (cath) at both ages 11 and 17 confirmed mild precapillary PH (mean pulmonary artery pressure [mPAP] 24 and 24 mmHg, pulmonary vascular resistance indexed (PVRi) 5 and 4 Wood units·m², mean pulmonary capillary wedge pressure (PCWP) 9 and 10 mmHg, respectively), but he remained clinically well without PH‐specific therapy. Serial TTEs every 6 months since, have findings varying intermittently from normal to consistent with mild PH features.

3. Patient 3

A 10‐year‐old female former 520‐g infant born at 26 weeks GA with a history of Grade 2 BPD [1], PH, and isolated left lower pulmonary vein stenosis (PVS) identified on TTE at age 16 months. She required no PH‐targeted therapy, while oxygen therapy was discontinued by age 2 years. Cath at 2‐years‐old showed normal pulmonary pressures but was notable for left PVS at a common confluence of both left upper and lower pulmonary veins (LUPV and LLPV) prompting balloon angioplasty. Six months later, cath showed mild PH (PVRi 3 Wood units·m² (using mPAP 29 mmHg, mean LA pressure 6 mmHg; L pulmonary vein pressure 13 mmHg), left mPCWP 13, mLAP 6 mmHg); she underwent repeat balloon angioplasty of the LUPV and LLPV. Subsequent monitoring with TTEs every 3–6 months showed no evidence of PH features. At 6‐years‐old, surveillance CT angiography revealed narrowing of the left side pulmonary veins at the entrance to the left atrium; surgical intervention was deferred in the absence of symptoms and PH. At age 9, a perfusion scan demonstrated significant flow disparity, with 28% flow to the left lung. Subsequent successful and uncomplicated cardiac surgery for membrane resection relieved the stenosis.

4. Discussion

BPD‐PH in infants associates with significant morbidity and mortality [2, 3], with growing evidence that former preterm children are at increased risk for persistence of or development of PH later in life [4, 5]. These three patients, summarized in Figure 1, demonstrate the complexity of disease monitoring during childhood and young adulthood even after the perceived resolution PH for those with BPD. While specific recommendations for BPD‐PH care are published, detailed information to guide monitoring and screening for PH, and care for those formerly preterm children subsequently diagnosed with PH, are lacking [6, 7, 8]. Patient 1 had Grade 1 BPD and had a relatively mild disease course with early reported resolution of PH, while Patient 3's disease course, with Grade 2 BPD, was more severe with PVS, a known complication for children with BPD and BPD‐PH [9]. A review on the long‐term outcomes and severity of disease in children with BPD‐PH reported approximately 24% of patients who died during the study had a concurrent diagnosis of PVS, and of those patients, 60% had a known diagnosis of Grade 3 BPD [7]. Similarly, 6 (24%) of the 25 patients who died in a recent 320 subject study of pulmonary hemodynamics and long‐term outcomes among BPD‐PH patients in the Pediatric Pulmonary Hypertension Network (PPHNet) research cohort had PVS [4]. Lifelong monitoring for Patient 2, also with Grade 2 BPD, demonstrated the complex decision‐making providers may need to make overtime as additional challenges, in this case ADHD, arise. In this case, the question was raised if a stimulant, such as methylphenidate, increased the risk of PH. However, this case series does not represent the most severe form of BPD, Grade 3, each case highlights how individuals with Grade 1 or 2 BPD may present with management challenges later in life related to their complex hemodynamic profile and the interplay of comorbid conditions [10].

Figure 1.

Longitudinal clinical course and surveillance timelines of three patients with bronchopulmonary dysplasia‐associated pulmonary hypertension (BPD‐PH). Horizontal plotted lines compare the side‐by‐side lifetime management of each case from birth through current tracking age. Patient 1 is the dark blue line, Patient 2 is the dark green line, and Patient 3 is the dark purple line. Circles denote NICU diagnoses; light green squares indicate initial PH resolution and discontinuation of therapy; gray hexagon denotes discharged from PH clinic; red triangles signify intervention (e.g., angioplasty, cardiac catheterization); orange diamonds signify TTE with abnormal findings (PH features, PVS), blue rectangles indicate serial TTE monitoring without PH features, and arrows signify active ongoing longitudinal follow‐up. Angio, balloon angioplasty; BPD, bronchopulmonary dysplasia; BW, birth weight; Cath, cardiac catheterization; GA, gestational age; PH, pulmonary hypertension; PVS, pulmonary vein stenosis; TTE, transthoracic echocardiogram.

Despite high care support needs during infancy, each patient presented had minimal or no cardiopulmonary symptoms reported on routine clinic visits later in childhood. The cases highlight the challenges clinicians face regarding determining a long‐term follow‐up plan in former preterm children as many of these patients may be asymptomatic later in life. Further, there is growing evidence that former preterm young adults have elevated pulmonary pressures and right ventricular dysfunction, especially with exercise testing; but it is unknown what the true prevalence of PVD burden is in asymptomatic young adults [5]. Accordingly, long‐term follow‐up should be individualized based on the degree of BPD and PH early in life rather than the present symptoms. Guidance provided by a PH‐specialty team on individualized plans may be an appropriate strategy to inform long‐term follow‐up.

These three cases illustrate the heterogeneity of long‐term cardiopulmonary outcomes in children born preterm and the importance of optimizing outpatient monitoring and management of PH in this high‐risk population. There is a lack of detailed recommendations for risk stratification of former preterm children to determine for whom routine TTE and other forms of screening for PVD should be conducted later in life. Care for patients with BPD‐PH necessitates lasting comprehensive management and PH‐specialty outpatient follow‐up. Further studies are needed to understand the factors that may increase the risk of PVD in former preterm children as well as to improve our approach to screening and management to mitigate long‐term cardiopulmonary complications.

Author Contributions

Dr. Meaghan Rousset drafted the initial manuscript, participated in the concept and design, analysis and interpretation of data, and reviewing and revising of the manuscript. Dr. Eric Austin obtained consent from the patient's family, conceptualized the case report, participated in interpretation of data, and critically reviewed and revised the manuscript for important intellectual content. Dr. Rachel Sullivan, Samantha Eagle, and Anna Brown each participated in interpretation of data and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Ethics Statement

Verbal informed consent from each patient (or guardian) was obtained for anonymized patient information to be published in this article.

Conflicts of Interest

The authors Dr. Meaghan Rousset, Dr. Rachel Sullivan, Ms. Samantha Eagle, Ms. Rebecca Brown, and Dr. Eric Austin declare that there is no conflict of interest.

Guarantor

Eric D. Austin is the guarantor of this work and accepts full responsibility for the work, had full access to the data, and controlled the decision to publish.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.