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Abstract
Objectives While acquired pulmonary vein stenosis (PVS) is an often lethal anomaly with poor long-term prognosis and high mortality, little is known about the causes of this disease process. The purpose of this study was to describe the possible association between acquired PVS and necrotising enterocolitis (NEC) in premature infants.
Study design We performed a retrospective review of all premature infants (<37 weeks’ gestation) diagnosed with acquired PVS in our institution. Babies with congenital heart disease with known association with PVS were excluded. The hospital records were reviewed for prior history of NEC, as defined by Bell's staging criteria. We also reviewed serial echocardiograms performed during their hospitalisation. Outcomes assessed were worsening or resolution of the PVS and death.
Results Twenty patients met inclusion criteria and were diagnosed with acquired PVS. The median gestational age was 27 weeks. 50% (10/20) of the infants had NEC during their hospital course. The NEC group had significantly lower birth weights in comparison to the non-NEC group. There was no difference between groups with regards to the age at diagnosis of PVS. The mean gradient across the pulmonary veins was higher in the NEC group, as was mortality.
Conclusions There appears to be a high incidence of NEC in premature infants who are diagnosed with acquired PVS. Future large controlled studies are needed to further analyse this association and to evaluate the possible role of abdominal inflammation in the development of PVS in premature infants.
- Cardiology
- Neonatology
- Gastroenterology
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What is already known on this topic
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Pulmonary vein stenosis (PVS) appears to have an association with prematurity as well as presence of left to right shunts.
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Vascular endothelial growth factor (VEGF) and tyrosine kinases have been implicated in its development.
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The prognosis of acquired PVS is poor.
What this study adds
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This is the first study that suggests an association between necrotising enterocolitis and pulmonary vein stenosis.
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We speculate that since there is a common embryologic origin to splanchnic vasculature and pulmonary veins, VEGF-mediated inflammation in one system (gut) may affect cells with similar embryologic origins in the other system (pulmonary veins).
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Our suggestion: Pulmonary veins should be carefully interrogated in all echocardiograms performed on preterm neonates to evaluate or follow-up pulmonary hypertension, especially in the presence of necrotising enterocolitis.
Introduction
Pulmonary vein stenosis (PVS) is a narrowing of either the pulmonary vein itself or the junction between the vein and its entrance to the left atrium, leading to obstruction of pulmonary venous return and possibly pulmonary hypertension.1 It can present as congenital PVS, usually associated with congenital heart lesions such as repair of total anomalous pulmonary venous return, or as acquired PVS, a rare cardiac lesion. Acquired PVS is an often lethal anomaly with poor long-term prognosis and high mortality.2 ,3 Due to its rare nature, there are limited published data describing the prevalence of this lesion, although the available data indicate an association with prematurity and bronchopulmonary dysplasia (BPD), and with presence of left to right shunts like a patent ductus arteriosus (PDA) and ventricular septal defects (VSD) in preterm babies.2 Other risk factors have not been clearly defined for this lesion. Prior studies have suggested that an inflammatory process may cause intimal proliferation leading to stenosis of the pulmonary veins.4
In premature infants, necrotising enterocolitis (NEC) is an important cause of morbidity and mortality, with an estimated incidence of 6–7% in premature infants.5 The pathophysiology of NEC is unclear, and the cause is thought to be multifactorial. We report a cohort of 20 premature patients with acquired PVS, 10 of whom were noted to have NEC during their neonatal intensive care unit (NICU) course. We speculate that there may be an association between the development of PVS and NEC in preterm infants.
Methods
Study design
All study activities were approved by the Columbia University Medical Center IRB. Study subjects were identified via a search of the Paediatric Cardiology echocardiographic database for all patients with a diagnosis of PVS from 2006 to 2012. The medical records of these patients were reviewed for gestational age, birth weight, age at diagnosis of PVS, history of NEC and the time of diagnosis. Serial echocardiograms were reviewed for progression of PVS and pulmonary hypertension. Neonates diagnosed with total anomalous pulmonary venous return or hypoplastic left heart syndrome were excluded as these conditions are known to have a significant association with PVS. Infants ≥37 weeks’ gestation were also excluded.
Measures
Diagnosis of PVS was made by echocardiography. PVS was diagnosed by an abnormal flow pattern that was turbulent and continuous as opposed to the normal flow pattern with well-defined systolic and diastolic peaks and a mean pulse wave Doppler gradient ≥3 mm Hg.3 In one case, diagnosis was made by cardiac catheterisation. NEC was defined according to modified Bell's staging criteria II or III.6 ,7
Statistical analysis
All statistical analyses were performed using SPSS V.19 statistical software. Characteristics of the samples were summarised using means, SDs and percentages. Statistical analysis included both continuous and categorical variables. Continuous variables are expressed as mean±SD, and categorical variables as numbers and percentage. Student t test was used for comparison of continuous variables. χ2 or Fisher's exact test was used for categorical or dichotomous variables. A p value <0.05 was considered statistically significant.
Results
A total of 20 patients who met inclusion criteria were diagnosed with acquired PVS. Clinical characteristics for all patients are given in table 1. Initial diagnosis was made by echocardiography in 19 patients. The remaining patients were diagnosed by cardiac catheterisation. Of these patients, 17 had normal echocardiograms documented prior to the diagnosis of PVS. The remaining patients were transferred from other institutions and reportedly had normal echocardiograms at the original institution. The three patients who were transferred were all transferred due to increasing oxygen requirements and the concern for pulmonary hypertension. None of the patients were transferred due to a concern for PVS. The median gestational age for the study group was 27 weeks, with a range of 23–36 weeks.
Clinical characteristics of patients with acquired PVS
Ten patients (50%) were diagnosed with NEC during their NICU course, all prior to diagnosis of PVS. The mean gestational age was significantly different between the two groups (non-NEC 29 weeks (±4.1 weeks), NEC 26 weeks (±1.8 weeks); p=0.02, 95% CI 0.5 to 6.8). There was also a statistically significant difference in the mean birth weight between the two groups (non-NEC 1303±661 g, NEC 593 g±195 g; p=0.01, 95% CI 186 to 1232). Birth weight was not available for two patients (a 26-week gestation infant and a 29-week gestation infant, both transferred from outside institutions) in the non-NEC group. The mean age at diagnosis of NEC was 4.5 weeks (±2 weeks), with the mean age at diagnosis of PVS in that group being 20 weeks. There was no difference between the groups with regards to the mean age at diagnosis of PVS (non-NEC 21 weeks (±10.1 weeks), NEC 20 weeks (±8.7 weeks); p=0.9). The mean gradient across the pulmonary veins was higher in the NEC group (non-NEC 7.7 mm Hg (±2.5 mm Hg), NEC 11 mm Hg (±7.0 mm Hg); p=0.09, 95% CI −8.8 to 0.8).
In the NEC group, seven of the patients were treated with antibiotics alone. One of these patients had recurrence of NEC, which was also treated medically. The three remaining patients required surgical intervention for NEC, with varying degrees of bowel resection.
Associated cardiac lesions were present in 9 of the 10 patients in the non-NEC group (90%) and 7 of the 10 patients in the NEC group (70%), p=1. The lesions included atrial septal defect (ASD), PDA, VSD, atrioventricular canal, truncus arteriosus and interrupted aortic arch. In both groups, the median number of stenotic veins was 2, ranging from 1 to 3 veins in the non-NEC group and 1 to 4 in the NEC group.
All the patients had some form of pulmonary hypertension, although the severity was found to correlate with the severity of the PVS. Those patients with higher gradients across the pulmonary veins had more severe pulmonary hypertension.
The outcomes for the two groups of patients are given in figure 1. Five patients in the entire cohort underwent surgical repair of the PVS. Two were in the NEC group, one of whom showed improvement and one who died from progression of the disease. Three were in the non-NEC group, with two showing improvement and one who was lost to follow-up. In the NEC group as a whole, one patient showed improvement in their PVS after surgical repair, four had improvement in gradient or were unchanged over a mean follow-up of 6.5 months, three died from progression of the PVS and one died from septic shock. In the non-NEC group, two patients improved after surgical repair, two patients improved spontaneously with a mean follow-up of 26 months, two were unchanged over a mean period of 32 months and two died from progression of their disease. The remaining patients died from septic shock. Survival data are given in figure 2. Improvement was determined by serial echocardiograms that showed decreasing gradients across the pulmonary veins.
Outcomes of patients with acquired pulmonary vein stenosis with and without necrotising enterocolitis.
Kaplan–Meier survival plot after diagnosis of pulmonary vein stenosis stratified according to diagnosis of necrotising enterocolitis. Survival is shown on the y-axis. Follow-up time in months is shown on the x-axis.
Discussion
This is the first study to report acquired PVS exclusively in premature infants, suggesting a co-occurrence with NEC. In our neonatal unit, 50% of preterm infants diagnosed with acquired PVS from 2006 to 2012 also had a diagnosis of NEC. Since NEC and other problems like intraventricular haemorrhage and retinopathy of prematurity (ROP) occur in babies of similar gestational ages and neonatal stressors, a large case–control study including all these factors will be required to prove a significant association between these events.
There are several limitations to this series. Due to the retrospective format, it was not possible to get values for inflammatory mediators like C-reactive protein or vascular endothelial growth factor (VEGF) levels at the time PVS was first noted. This would have given additional proof to an inflammatory aetiology. All patients with NEC were treated with antibiotics as per protocol; however, sepsis or treatment with antibiotics in the non-NEC group was not recorded as the exact timing of onset of the PVS was not definitive. Since serial echocardiograms are not performed routinely on all patients in the NICU, it is certainly possible that their PVS developed earlier than when it was actually diagnosed. Our diagnosis was generally only made once the patients developed symptoms of pulmonary hypertension or chronic oxygen requirements that could not be weaned. Additionally, the cohort of patients who developed NEC had other factors putting them at increased risk, including earlier gestational ages and lower birth weights, suggesting possible fetal growth restriction.
An association between prematurity and acquired PVS has been previously reported in literature.2 ,8 Seale et al,8 in a collaborative study, reported that 41/58 patients with PVS were born at <37 weeks’ gestation. Drossner et al2 enrolled 26 infants with acquired PVS, and they reported that 16 (61%) of the 26 infants were premature and concluded that PVS occurs more frequently in premature infants. However, in contrast to our study, these authors included both full term and premature infants in their study groups.
Prematurity is also known to be the most common risk factor for NEC, with the risk being inversely related to birth weight and gestational age. While the exact pathophysiology of NEC is not well known, it is hypothesised that due to intestinal tract immaturity there is an inappropriate response to any intestinal injury. Recent evidence suggests that it may result from an exaggerated inflammatory response mounted by intestinal epithelial cells and mediated by VEGF, which has also been suggested as an associated factor in acquired PVS.2 ,4 ,5 ,9 We did note that infants who had NEC tended to have worse PVS with a higher gradient across the veins, possibly due to a heightened inflammatory response.
Banyasz et al10 found that a carrier state for a mutant allele of VEGF, an important protein involved in angiogenesis, is an independent risk factor for NEC. A study published by Riedlinger et al4 focused on the histology of acquired PVS. Their findings suggested that intimal lesions are the result of a myofibroblast-like proliferation, with this process being mediated in part by expression of receptor tyrosine kinases, such as VEGF.
This might suggest a common inflammatory origin to both NEC and acquired PVS and would be a basis for future testing and management options. VEGF is also hypothesised to mediate the pathologic vessel growth seen in two additional diseases of the premature infant, ROP and BPD.11 ,12 In BPD, VEGF has been implicated in abnormal development and remodelling of the pulmonary arterial and venous beds.12 The same process may in fact be present in the development of PVS in premature infants.
Hall et al13 have suggested that the pulmonary veins originate from the splanchno-pleural mesoderm with vasculogenesis induced by VEGF. We speculate that since there is a common embryologic origin to splanchnic vasculature and pulmonary veins, VEGF-mediated inflammation in one system may affect cells with similar embryologic origins in the other system. Importantly, our series included 10 babies who had NEC preceding the identification of PVS. We speculate that the inflammatory process that causes NEC may also contribute to the endothelial proliferation described in PVS.
We found that while NEC was usually diagnosed early on in postnatal life, PVS was often diagnosed about 4–5 months postnatally. It is possible that some inflammation at the pulmonary veins may have started a period of time before the patients had an echocardiogram performed and a diagnosis of PVS made. However, it can also be that the inflammatory process that causes PVS takes longer to develop and therefore presents later in postnatal life.
In addition, acquired PVS has been reported in the setting of other congenital heart lesions,2 most commonly PDA, ASD, VSD and atrioventricular septal defect, which was similar to our case series. In our series, 17/20 (85%) of patients had associated cardiac defects, primarily lesions with left-to-right shunting, including ASD, PDA and VSD. Based on earlier studies, it was theorised that increased left-to-right shunting leads to increased flow through the pulmonary veins and might predispose to PVS, with the process possibly being exaggerated by other comorbidities in a premature infant.2 In addition, a large PDA (or a run-off lesion like truncus with regurgitation) could also have led to an increased risk of NEC due to hemodynamic steal, and at the same time, increased blood flow to the lungs and pulmonary veins, putting them at risk for development of PVS.
Conclusions
Acquired PVS is an often lethal anomaly with a poor long-term prognosis. Prematurity is a known risk factor for its development. In this series, we noted a high incidence of NEC in patients with acquired PVS. We suggest that in preterm babies who develop clinical or echocardiographic evidence of pulmonary hypertension, especially those with NEC, there should be a high index of suspicion for development of PVS. Echocardiographers should be trained to look for pulmonary vein acceleration and gradients whenever follow-up echocardiograms are performed for evaluation of pulmonary hypertension. A case–control study to further examine this association is currently underway, taking into account multiple other factors including BPD and retinopathy in premature infants. This additional study would help determine whether closer echocardiographic follow-up is necessary in premature infants who develop NEC.
Acknowledgments
The authors acknowledge the expertise of our stellar echocardiographers in imaging the pulmonary veins and measuring gradients as a routine in these extremely sick young patients.
References
Footnotes
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Correction notice The first author's middle initial was incorrect in the previous version of this paper. The first author's name is Howard J Heching.
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Contributors Data collection and chart review was performed by all the authors, and all the echocardiograms were reviewed by UK. The first draft of this manuscript was written by HH and assisted by MT. The study and manuscript preparation was envisioned and supervised by UK. CF-K provided valuable input and suggestions from the neonatology aspect.
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Competing interests None.
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Ethics approval Institutional Review Board of Columbia University: IRB-AAAI1839.
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Provenance and peer review Not commissioned; externally peer reviewed.