PEDIATRICS Vol. 122 No. 3 September 2008, pp. e656-e661 (doi:10.1542/peds.2008-0075)
ARTICLE |
Pulmonary Vein Stenosis: Prematurity and Associated Conditions
Sibley Heart Center, Children's Healthcare of Atlanta, Atlanta, Georgia; Department of Pediatrics, Emory University, Atlanta, Georgia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Pulmonary vein stenosis is a rare, although often lethal, anomaly. Risk factors for the diagnosis of pulmonary vein stenosis are poorly characterized. In this study we sought to identify factors associated with pulmonary vein stenosis, paying particular attention to preterm birth.
METHODS. By review of the cardiac database we identified all of the subjects with pulmonary vein stenosis over a 10-year period at our institution. Those children with anomalous pulmonary venous connection were not included. Patient-related variables were analyzed for their association with pulmonary vein stenosis. Pulmonary vein stenosis was diagnosed by spectral Doppler interrogation of the pulmonary veins (continuous, turbulent flow with calculated mean gradient > 5 mm Hg) and confirmed by cardiac catheterization in nearly all of the cases.
RESULTS. Twenty-six patients with pulmonary vein stenosis were identified. The median age at diagnosis was 7.4 months; range: 1 day to 35 months. Congenital heart defects were present in the majority of subjects. Associated genetic syndromes were present in 8 subjects (31%). The 2-year survival rate from diagnosis was 43%. The majority of subjects (16 [61%]) were preterm. Gestational ages ranged from 24.2 to 41.0 weeks, and birth weights ranged from 460 to 4445 g. Preterm birth was strongly associated with the diagnosis of pulmonary vein stenosis, odds ratio 10.2 (95% CI 4.7–22.6), p < .001. Eleven (42%) of the 26 subjects were treated for bronchopulmonary dysplasia before being diagnosed with pulmonary vein stenosis.
CONCLUSIONS. Prematurity is associated with the diagnosis of pulmonary vein stenosis. It is interesting to note that many of these patients also have intracardiac shunt lesions, which may act in concert with preterm endothelium to produce pulmonary vein stenosis.
Key Words: pulmonary vein stenosis • cardiology • chronic lung disease • prematurity
Abbreviations: PVS—pulmonary vein stenosis • AVSD—atrioventricular septal defect • BPD—bronchopulmonary dysplasia • PDA—patent ductus arteriosus • ASD—atrial septal defect • VSD—ventricular septal defect • VEGF—vascular endothelial growth factor
Pulmonary vein stenosis (PVS) is a rare, although often lethal anomaly.1,2 Despite various palliative or reparative procedures, such as surgical venoplasty, catheterization angioplasty, or intravascular stents, and lung transplantation, outcomes remain poor.2,3 Because of the rare nature of this disorder, the population prevalence of PVS has not been reported. In addition, the limited published data have suggested that PVS may be an acquired rather than a congenital disorder.4 To date, risk factors for the development of PVS in those subjects with normal pulmonary venous connections have been poorly characterized.2,3 It is known that the presence of other congenital heart defects is associated with the development of PVS.5,6 In a review of previously published literature, there has been a suggestion that prematurity may be associated with the development of PVS.2,5 In the present study we sought to identify risk factors for the development of PVS, paying particular attention to the relationship of preterm birth.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The study was approved by the institutional review board of Children's Healthcare of Atlanta. By review of the cardiac database we identified all of the subjects with PVS from November 1, 1997, to November 1, 2007. Those children with Scimitar syndrome, anomalous pulmonary venous connection, or hypoplastic left heart syndrome with restrictive atrial septum were not included. Patient-related variables were analyzed for their association with the development of PVS. Prematurity was defined as a gestational age of <36 weeks.
In most cases, diagnosis of PVS was based on echocardiographic findings. PVS was diagnosed by spectral Doppler interrogation of the pulmonary veins (continuous, turbulent flow with calculated mean gradient > 5 mm Hg). There were isolated cases in which diagnosis was made by cardiac catheterization. For these instances, PVS was defined as obstruction, hypoplasia, or acquired atresia defined by angiography (Fig 1). When possible, direct pullback measurements of obstruction within the pulmonary veins were made with an end-hole catheter. For those who met inclusion criteria, we determined the number of veins affected, gestational age, birth weight, age at diagnosis, intervention, outcome, associated cardiac anomalies, and associated medical conditions.
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To determine whether prematurity was significantly associated with the development of PVS, the National Center for Health Statistics estimate of prematurity in our state was used as a referent.7 In Georgia in 2005, 13.5% of newborns were premature. Fisher's exact test was used to calculate the risk ratios. To calculate an estimated incidence of PVS, we determined the number of infants with PVS born in Georgia identified over the 10-year study period. The number of children at risk was calculated to be the number of births in Georgia over that same 10-year period (n = 1 444 218). On the basis of previous internal analysis, we that found that 82% of all congenital heart surgeries performed in children residing Georgia (excluding patent ductus arteriosus ligation) were performed at our institution (Georgia Hospital Association, written communication, 2008). Therefore, we assumed that the population at risk was 1 184 259. A Kaplan-Meier curve was constructed to report survival data. To determine which patient- or procedure-related risk factors were associated with survival, a Cox proportional hazards model was constructed. Statistical analysis was performed with Stata 6.0 (Stata Corp, College Station, TX). Significance was determined at a P value of <.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Twenty-six patients were diagnosed as having PVS. The median age at diagnosis was 7.4 months (range: 1 day of life to 35 months). On the basis of Georgia vital records, we calculated a minimal annual incidence of 1.7 per 100 000 children <2 years old.
The primary method of diagnosis was by echocardiography. Eighteen (69%) of 26 were diagnosed initially with echocardiography. There were 8 (31%) of 26 subjects who were diagnosed as having PVS at the time of cardiac catheterization. Of these 8, 3 subjects were found to have elevated right heart pressure by echocardiography and were referred to our institution for a catheterization to evaluate pulmonary vascular resistance. An echocardiogram performed at our institution just before cardiac catheterization demonstrated PVS. For 3 additional subjects, none of the echocardiograms performed before catheterization made mention of PVS. A subsequent review of previous echocardiograms for these 3 subjects by 1 author (Dr Mahle) suggested PVS on the basis of aliasing of the color Doppler signal. One subject had normal pulmonary vein Doppler on an echocardiogram performed at 3 days of life, but subsequent studies did not profile pulmonary veins well. For 1 subject, previous echocardiographic studies were not available for review. All but 1 subject in this series underwent cardiac catheterization to evaluate the pulmonary veins. That 1 subject had both transthoracic and transesophageal imaging to confirm stenosis of the pulmonary veins before proceeding to surgical repair of atrioventricular septal defect (AVSD) and left upper PVS.
Nearly all of the subjects in the study had 
1 echocardiogram performed earlier in childhood that did not identify PVS. Seventeen (65%) of the 26 subjects had 3 previous echocardiograms that did not identify PVS on color flow mapping of the pulmonary veins before the confirmation of PVS by echocardiography and/or catheterization.
The median gestational age for this cohort was 32.0 weeks, with a range of 24.2 to 41.0 weeks. Birth history revealed 16 (61%) of 26 to be born premature, with 5 subjects being small for gestational age. Preterm birth was strongly associated with the development of PVS (odds ratio: 10.2; 95% confidence interval: 4.7–22.6; P < .001). The median birth weight was 1925 g, with a range of 460 to 4445 g. Associated medical conditions in this cohort were significant for 11 (42%) of the 26 diagnosed as having bronchopulmonary dysplasia (BPD). On the basis of published national data, the presence of BPD was significantly associated with PVS in univariate analysis (P < .01).8 Associated genetic syndromes were present in 8 (30%) children: the most common genetic syndrome was trisomy 21 (n = 5).
Associated cardiac defects were present in the majority (23 of 26 [88%]) of the subjects. These defects included the following: patent ductus arteriosus (PDA) in 12 (46%), atrial septal defect (ASD) in 10 (38%), ventricular septal defect (VSD) in 8 (31%), and AVSD in 4 (15%). Fourteen (54%) of the 26 subjects underwent surgical interventions to treat intracardiac shunt lesions before the diagnosis of PVS. Nine (75%) of the 12 subjects with a PDA, 3 (30%) of the 10 with an ASD, and 3 (38%) of the 8 with a VSD were identified with having PVS after surgical corrections of the associated shunt lesions. For a complete overview of the clinical characteristics in this cohort, see Table 1.
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The median number of stenotic pulmonary veins was 2 (range: 1–4). The mean systolic pulmonary pressure and mean pulmonary artery pressure determined at catheterization were 60 mm Hg (±29 mm Hg) and 42 mm Hg (±22 mm Hg), respectively. The left lower pulmonary vein was most likely to be stenosed (17 of 26 [65%]), followed by the left upper pulmonary vein (13 of 26 [50%]) and the right upper pulmonary vein (12 of 26 [46%]). The mean systolic gradient for each stenotic vein is as follows: left lower pulmonary vein, 10 ± 5.1 mm Hg; left upper pulmonary vein, 11.6 ± 6.7 mm Hg; right lower pulmonary vein, 10.4 ± 6.3 mm Hg; and the right upper pulmonary vein, 11 ± 6.3 mm Hg. These numbers do not reflect all of the veins affected, because some were hypoplastic or atretic with no flow entering the left atrium.
A number of medical and surgical interventions were undertaken in this patient population. Transcatheter interventions included balloon dilation of affected pulmonary veins in 6 of the subjects. These procedures were considered acutely successful in 5 (83%) of 6 cases. Acute success was defined as a patent pulmonary vein with a mean gradient <4 mm Hg on direct pullback. Surgical intervention was undertaken in 12 of the subjects, with 1 subject undergoing surgical intervention after a previous attempt at transcatheter intervention. The surgical techniques included sutureless pulmonary vein repair and limited pulmonary venoplasty. The surgical interventions were considered acutely successful (mean pulmonary vein Doppler gradient of <5 mm Hg as measured by transesophageal echocardiography at the conclusion of the case) in 10 of 12 cases.
There were 5 cases in which oral pharmacotherapy was used to manage pulmonary hypertension. Bosentan was administered to 2 subjects, and sildenafil was given to 5 subjects. No subjects in this series underwent lung transplantation. In total, 5 subjects were treated medically for pulmonary hypertension, with 60% having a 2-year survival rate.
Despite improvement in pulmonary vein gradients after interventions, the overall survival rate was poor. Thirteen subjects (50%) died at a median interval of 5.5 months (range: 3 days to 17.0 months) from the time of diagnosis. Because the overall follow-up period for the entire cohort was relatively short, the 2-year survival rate from the time of diagnosis was 43% (Fig 2A). Among the subjects who underwent transcatheter interventions, the 2-year survival rate was 25%. In addition, the 2-year survival rate was 66% for those receiving surgical intervention for PVS. Neither premature birth nor earlier age at diagnosis was independently associated with poorer survival (Fig 2B). PVS was more likely to be identified in the more recent era of our analysis (2002–2007) than in the earlier era (1997–2001; odds ratio: 5.3 [95% confidence interval: 1.8–15.3]; P = .001).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study demonstrates that PVS is primarily an acquired disorder that occurs in
1.7 per 100 000 children under the age of 2 years. Preterm birth is associated with the development of PVS. Prematurity is associated with congenital heart defects. There is approximately a twofold risk of preterm birth among children with congenital heart disease.9 Similarly, other types of congenital defects, such as diaphragmatic hernia and neural tube defects are associated with preterm birth.10,11 It has been hypothesized that the presence of the congenital defect may lead to preterm delivery. However, the mechanism underlying the association between prematurity and PVS is likely different. In the preterm population described in our study, nearly all of the subjects had echocardiographic studies soon after birth that did not demonstrate abnormalities of the pulmonary veins. This would support the notion that stenosis of the pulmonary veins is an acquired lesion. Why prematurity might be associated with PVS is a matter of speculation. It has been shown that the development of retinopathy of prematurity is characterized by pathologic vessel growth, which is mediated by vascular endothelial growth factor (VEGF).12 Similarly, BPD is an inflammatory process, mediated in part by VEGF, which results in abnormal development and remodeling of pulmonary arterial and venous beds.13,14 It is possible that some of the same factors mediate the development of PVS in the preterm infant. A histologic study of acquired PVS by Riedlinger et al15 suggested that intimal lesions are the result of myofibroblast-like proliferation. This process seemed to be mediated in part by expression of receptor tyrosine kinases, such as VEGF.
Several previous publications have not demonstrated a significant association between prematurity and the identification of PVS. Some of the published series did not report gestational age.4,16 In the largest study published to date, 8 (26%) of 31 of children with PVS were said to have prematurity. However, because these data were derived from a multi-institutional registry, it is unclear whether gestational age was known for all of the subjects included in the series. In a smaller series by Chakrabarti et al,5 4 (57%) of 7 subjects with PVS were preterm: all were born at <30 weeks’ gestation. Our series similarly demonstrated that the majority of subjects with PVS were preterm. We do not believe that this is because of a referral bias, because our hospital system provides cardiac care for 82% of the children in our state, and all but 1 of the subjects in this series were born in the state. It is interesting to note that, although we reviewed records from a 10-year period, >80% of the cases of PVS in preterm infants were identified in the most recent 5-year period. This may represent a sampling bias or increased vigilance among cardiologists for PVS in this population. Alternatively, it is possible changes in the management strategy for preterm infants may be impacting the development of PVS. For example, many clinicians have adopted conservative oxygen saturation parameters (ie, 88%–92%).8
As has been reported by a number of investigators, PVS often occurs in the setting of other congenital heart lesions. The most common congenital heart lesions were PDA, ASD, VSD, and AVSD. Obstructive heart lesions, such as aortic stenosis or coarctation, were uncommon. These data would suggest that lesions that result in a large left-to-right shunt and, hence, increased flow through the pulmonary veins might predispose to PVS. This might be exaggerated by the vascular abnormalities of the preterm infant. Whether earlier intervention to abolish the shunt should prevent or delay the development of PVS is unknown. PVS was not identified until a median age of 7.4 months, and nearly all of the forms of heart surgery can be performed in the first weeks of life if indicated. Therefore, there may be an opportunity to intervene early in life and modify the course of PVS. Although mortality and morbidity related to congenital heart surgery continues to decrease, it should be recognized that infants with congenital heart disease who are born prematurely are at increase risk for perioperative complications and mortality.17 The risk of intervention in premature infants to reduce the potential risk of developing PVS must be balanced against the higher operative mortality in low birth weight or early gestation patients. Definitive recommendations for the role of earlier intervention to eliminate intracardiac shunts in the preterm population cannot be made on the basis of the data of this or other series. Lastly, it should be recognized that, whereas both prematurity and intracardiac shunt lesions have an association with PVS on the basis of data from the Metropolitan Atlanta Congenital Defects Program, we would estimate that <1 in 100 preterm infants with a intracardiac shunt lesion is likely to develop stenosis of the pulmonary veins.
It is interesting to note that a number of the subjects in our series were also diagnosed with BPD. As outlined above, many of the factors that predispose to the development of BPD may also contribute to the intimal proliferation seen in PVS. Alternatively, it is possible that PVS may produce venous congestion, interstitial edema, and elevated pulmonary artery pressures that may be indistinguishable from BPD. The present study does suggest that the diagnosis of PVS needs to be considered in preterm infants who have clinical findings consistent with BPD. Somewhat surprisingly, in a significant number of subjects, the diagnosis of PVS was first made at cardiac catheterization. There are several explanations for this finding. After an initial complete echocardiogram, subsequent studies were limited and, hence, may not have adequately examined pulmonary venous flow. In addition, one of the known challenges in this patient population is that chronic lung disease often limits the acoustic windows needed for echocardiographic diagnosis. In such cases, diagnostic cardiac catheterization or other imaging modalities, such as MRI, should be considered.
The outcome for young children diagnosed with PVS is quite poor. The 2-year actuarial survival rate after diagnosis was 43%. These data are in agreement with other published series.18,19 None of the subjects in this series underwent lung transplantation. Importantly, the survival rate for those subjects who were preterm was not significantly less than those born at term. There also did not seem to be a difference in the number of pulmonary veins that were stenosed between these 2 populations.
Surgical and transcatheter techniques to treat PVS seemed to lower gradients in affected veins, although they seemed to have little impact on overall survival. Debate exists as to which treatment strategy is superior for the management of PVS. The sutureless repair of PVS has been proposed as the ideal approach, because the technique avoids anastomosis, which might result in postoperative obstruction.19 Transcatheter stenting or balloon dilatation would seem to be an attractive option. However, to date the outcomes for this approach have been disappointing.6,20 Stenting is often complicated by rapid intimal proliferation and recurrent obstruction. Moreover, PVS is often a progressive disease, and localized therapies may not modify the course.
Limitations of the present study include possible incomplete ascertainment of cases of PVS. Given the finding that a number of PVS cases were "missed" by echocardiography, there may have been other patients with pulmonary hypertension who had stenosis of the pulmonary veins that was not recognized. Importantly, many large congenital centers do no routinely performed pulse width Doppler interrogation of all of the pulmonary veins. As such, careful assessment of color Doppler patterns is crucial to identifying PVS. The data from the present study would suggest that identification of PVS using color Doppler can be challenging. Our institution now routinely undertakes cardiac catheterization in young children with pulmonary hypertension (even when the etiology is thought to be explained by BPD) to assess responsiveness to vasodilators and to exclude PVS. In addition, there may be a referral bias in the patient population. We believe that such a bias is unlikely given that our medical center provides the majority of cardiac care for our region.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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PVS is a rare disorder, occurring in
2 per 100 000 children. PVS occurs more frequently in the preterm population than among those born at term. Cardiac shunt lesions often occur in association with PVS. Whether early intervention to abolish intracardiac shunts can change the course of PVS remains a matter of speculation.
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FOOTNOTES |
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Accepted May 6, 2008.
Address correspondence to William T. Mahle, MD, Children's Healthcare of Atlanta, Emory University School of Medicine, 1405 Clifton Rd, NE, Atlanta, GA 30322-1062. E-mail: wmahle{at}emory.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject PVS is a rare and often lethal condition. The limited published data have suggested that PVS may be an acquired rather than a congenital disorder.
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| What This Study Adds PVS is primarily an acquired disorder, and preterm birth is strongly associated with its development. Nearly all of the subjects had echocardiographic studies soon after birth that did not demonstrate abnormalities, supporting the notion that PVS is an acquired lesion.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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