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Commentary

Free Access

Should All Extremely Premature Infants Be Screened for Pulmonary Hypertension?

Young K.C. · Bancalari E.

Author affiliations

Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA

Corresponding Author

Eduardo Bancalari, MD

Division of Neonatology, Department of Pediatrics (R-131)

University of Miami Miller School of Medicine

1580 NW 10th Avenue, Miami, FL 33136 (USA)

E-Mail ebancalari@med.miami.edu

Related Articles for ""

Neonatology 2018;113:89-91

Disordered vascular development is a major contributor to the pathogenesis of bronchopulmonary dysplasia (BPD) [1]. Premature birth along with factors such as infection, maternal pre-eclampsia, hyperoxia, and poor nutrition can lead to alterations in angiogenic signaling pathways and increased BPD risk [2,3]. Postmortem analyses of lungs obtained from infants with BPD demonstrate decreased and abnormal distribution of pulmonary capillary vessels along with aberrant angiogenesis-related gene expression [4]. According to one report, at least 1 in 6 extremely low birthweight (ELBW) infants have evidence of pulmonary hypertension (PH) during their hospital course [5]. In addition, early signs of pulmonary vascular disease at 7 days of age are associated with an increased risk of BPD and PH at 36 weeks' postmenstrual age (PMA) [6].

Most recent prospective studies suggest that 4-14% of extremely preterm infants have signs of PH at 36 weeks' PMA [6,7]. This includes an incidence of up to 14% in preterm infants with no or mild BPD and 8-29% in infants with moderate or severe BPD [6,7]. In retrospective studies, the reported incidence of PH complicating moderate to severe BPD is even higher, with estimates up to 58% [8], mortality rates as high as 48% at 2 years of age [9], and survivors more likely to have prolonged hospitalization and neurodevelopmental impairment [10,11]. Epidemiological data show that intrauterine growth retardation, oligohydramnios, prolonged rupture of membranes, prolonged ventilator support, early onset sepsis, and necrotizing enterocolitis are associated with an increased risk of PH [7,12,13,14]. However, there are multiple unresolved issues. There is uncertainty about whom to screen, when to screen, whom and how to treat, and when to start treatment in infants with PH. To compound this, echocardiographic measures of PH in preterm infants are often inaccurate [15], and transient alterations in pulmonary vascular bed dynamics due to agitation, hypoxia, hypercarbia, and changes in airway pressure make accurate diagnosis a challenge.

The study by Mehler et al. [16] in this issue of Neonatology prospectively evaluated 360 ELBW preterm infants for echocardiographic signs of PH. Infants with BPD were evaluated at 36 weeks' PMA while those without BPD were studied shortly before discharge. Follow-up echocardiograms were performed at variable intervals after discharge depending on whether the infants were diagnosed with PH. One of the aims of the study was to define a reasonable echocardiographic screening program for at-risk ELBW infants. Using the presence of tricuspid regurgitant jet velocity of more than 2.8 m/s, septal flattening, or right atrial/ventricular dilatation as echocardiographic evidence of PH, the authors report that 18% of ELBW infants had signs of PH and that 41% of these cases were diagnosed after discharge. Some signs of PH were evident in 8.5% of infants with mild or no BPD and in 38% of infants with moderate or severe BPD. Thus, this study confirms the high incidence of PH in infants with moderate/severe BPD and highlights the presence and persistence of pulmonary vascular disease in some ELBW infants who are not diagnosed with BPD.

The PH rates in this study are in keeping with some published reports, but this may not accurately reflect the PH incidence in ELBW infants. Nearly 50% of the population in this study either died prior to 36 weeks' PMA or were lost to follow-up, and thus there may have been some selection bias resulting in under- or overestimation of PH incidence. Echocardiographic findings such as septal flattening and right ventricular dilatation can be subjective, and tricuspid regurgitant jet velocity is often insufficient to accurately estimate right ventricular systolic pressure [6]. Indeed, of the infants diagnosed with PH prior to discharge, only 55% had a tricuspid regurgitant jet velocity greater than 2.8 m/s. Milder cases of PH may, therefore, have been missed prior to discharge. The authors also performed echocardiograms in infants with prolonged hypoxic spells, infants with BPD at 36 weeks' PMA, and shortly prior to discharge in infants without a diagnosis of BPD. It is possible that some infants in this latter group may have had signs of PH at 36 weeks' PMA which resolved by the time of the discharge echocardiogram. The routine use of a lower oxygen saturation target limit of 85% in infants less than 37 weeks' PMA may also have increased the reported incidence of PH in this population. In addition, 35% of the infants diagnosed with PH after discharge had a concomitant respiratory infection, potentially producing a transient increase in pulmonary vascular resistance and the reported incidence of PH after discharge.

Notwithstanding these limitations, this study highlights several important points. Recognition of the risk of PH crises in ELBW infants with respiratory infection after discharge is important. The authors screened infants with hypoxic spells for PH, but there is no clear data exploring whether the frequency/severity of intermittent hypoxic spells in preterm infants predisposes to or predicts PH. They also report that all ELBW infants with PH who were treated with sildenafil had resolution of PH after a median period of 13 months. Whether this was the result of the therapy or a spontaneous resolution of the disease is not clear and must be addressed in a multicenter, randomized, controlled study.

The issue of when and whom to screen remains unresolved. The present study confirms known risk factors such as prolonged rupture of membranes and intrauterine growth restriction, but whether all ELBW infants with known PH risk factors should be screened is not clear. Although Mourani et al. [6] reported that early signs of PH at 7 days are associated with PH at 36 weeks' PMA, other data by Mirza et al. [7] found no association between signs of PH at 10-14 days and later PH. While methodological differences and population characteristics may account for this disparity, it underscores the need to identify better predictive biomarkers of PH in ELBW infants. The authors stress the fact that a number of infants without a diagnosis of BPD also developed PH. The diagnostic criteria for BPD are arbitrary, and the fact that babies do not fulfill these criteria does not mean that they have normal lungs or cardiovascular function. Most studies that have evaluated pulmonary function in extremely preterm infants without BPD show persistent abnormalities in airway function. It is, therefore, not surprising that they may also have abnormal vascular development and a higher risk for PH. It is clear from this report and others that screening only infants with a diagnosis of BPD is inadequate, and better algorithms should be developed to identify ELBW infants who should be screened and followed up after discharge.


References

  1. Thébaud B, Abman SH: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2007;175:978-985.
  2. Manuck TA, Levy PT, Gyamfi-Bannerman C, Jobe AH, Blaisdell CJ: Prenatal and perinatal determinants of lung health and disease in early life: a National Heart, Lung, and Blood Institute workshop report. JAMA Pediatr 2016;170:e154577.
  3. Stenmark KR, Abman SH: Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol 2005;67:623-661.
  4. Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, Maniscalco WM: Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;164:1971-1980.
  5. Bhat R, Salas AA, Foster C, Carlo WA, Ambalavanan N: Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 2012;129:e682-e689.
  6. Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, Poindexter BB, Ingram DA, Abman SH: Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med 2015;191:87-95.
  7. Mirza H, Ziegler J, Ford S, Padbury J, Tucker R, Laptook A: Pulmonary hypertension in preterm infants: prevalence and association with bronchopulmonary dysplasia. J Pediatr 2014;165:909-914 e901.
  8. An HS, Bae EJ, Kim GB, Kwon BS, Beak JS, Kim EK, Kim HS, Choi J-H, Noh CI, Yun YS: Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J 2010;40:131-136.
  9. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, Mullen MP: Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007;120:1260-1269.
  10. Nakanishi H, Uchiyama A, Kusuda S: Impact of pulmonary hypertension on neurodevelopmental outcome in preterm infants with bronchopulmonary dysplasia: a cohort study. J Perinatol 2016;36:890-896.
  11. Stuart BD, Sekar P, Coulson JD, Choi SEJ, McGrath-Morrow SA, Collaco JM: Health-care utilization and respiratory morbidities in preterm infants with pulmonary hypertension. J Perinatol 2013;33:543-547.
  12. Weismann CG, Asnes JD, Bazzy-Asaad A, Tolomeo C, Ehrenkranz RA, Bizzarro MJ: Pulmonary hypertension in preterm infants: results of a prospective screening program. J Perinatol 2017;37:572-577.
  13. Kumar VH, Hutchison AA, Lakshminrusimha S, Morin FC III, Wynn RJ, Ryan RM: Characteristics of pulmonary hypertension in preterm neonates. J Perinatol 2007;27:214-219.
  14. Kim DH, Kim HS, Choi CW, Kim EK, Kim BI, Choi JH: Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia. Neonatology 2012;101:40-46.
  15. Mourani PM, Sontag MK, Younoszai A, Ivy DD, Abman SH: Clinical utility of echocardiography for the diagnosis and management of pulmonary vascular disease in young children with chronic lung disease. Pediatrics 2008;121:317-325.
  16. Mehler K, Udink Ten Cate FE, Keller T, Bangen U, Kribs A, Oberthuer A: An echocardiographic screening program helps to identify pulmonary hypertension in extremely low birthweight infants with and without bronchopulmonary dysplasia: a single-center experience. Neonatology 2018;113:81-88.

Author Contacts

Eduardo Bancalari, MD

Division of Neonatology, Department of Pediatrics (R-131)

University of Miami Miller School of Medicine

1580 NW 10th Avenue, Miami, FL 33136 (USA)

E-Mail ebancalari@med.miami.edu


Article / Publication Details

Received: September 15, 2017
Accepted: September 15, 2017
Published online: November 29, 2017
Issue release date: December 2017

Number of Print Pages: 3
Number of Figures: 0
Number of Tables: 0

ISSN: 1661-7800 (Print)
eISSN: 1661-7819 (Online)

For additional information: https://www.karger.com/NEO


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References

  1. Thébaud B, Abman SH: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2007;175:978-985.
  2. Manuck TA, Levy PT, Gyamfi-Bannerman C, Jobe AH, Blaisdell CJ: Prenatal and perinatal determinants of lung health and disease in early life: a National Heart, Lung, and Blood Institute workshop report. JAMA Pediatr 2016;170:e154577.
  3. Stenmark KR, Abman SH: Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol 2005;67:623-661.
  4. Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, Maniscalco WM: Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;164:1971-1980.
  5. Bhat R, Salas AA, Foster C, Carlo WA, Ambalavanan N: Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 2012;129:e682-e689.
  6. Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, Poindexter BB, Ingram DA, Abman SH: Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med 2015;191:87-95.
  7. Mirza H, Ziegler J, Ford S, Padbury J, Tucker R, Laptook A: Pulmonary hypertension in preterm infants: prevalence and association with bronchopulmonary dysplasia. J Pediatr 2014;165:909-914 e901.
  8. An HS, Bae EJ, Kim GB, Kwon BS, Beak JS, Kim EK, Kim HS, Choi J-H, Noh CI, Yun YS: Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J 2010;40:131-136.
  9. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, Mullen MP: Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007;120:1260-1269.
  10. Nakanishi H, Uchiyama A, Kusuda S: Impact of pulmonary hypertension on neurodevelopmental outcome in preterm infants with bronchopulmonary dysplasia: a cohort study. J Perinatol 2016;36:890-896.
  11. Stuart BD, Sekar P, Coulson JD, Choi SEJ, McGrath-Morrow SA, Collaco JM: Health-care utilization and respiratory morbidities in preterm infants with pulmonary hypertension. J Perinatol 2013;33:543-547.
  12. Weismann CG, Asnes JD, Bazzy-Asaad A, Tolomeo C, Ehrenkranz RA, Bizzarro MJ: Pulmonary hypertension in preterm infants: results of a prospective screening program. J Perinatol 2017;37:572-577.
  13. Kumar VH, Hutchison AA, Lakshminrusimha S, Morin FC III, Wynn RJ, Ryan RM: Characteristics of pulmonary hypertension in preterm neonates. J Perinatol 2007;27:214-219.
  14. Kim DH, Kim HS, Choi CW, Kim EK, Kim BI, Choi JH: Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia. Neonatology 2012;101:40-46.
  15. Mourani PM, Sontag MK, Younoszai A, Ivy DD, Abman SH: Clinical utility of echocardiography for the diagnosis and management of pulmonary vascular disease in young children with chronic lung disease. Pediatrics 2008;121:317-325.
  16. Mehler K, Udink Ten Cate FE, Keller T, Bangen U, Kribs A, Oberthuer A: An echocardiographic screening program helps to identify pulmonary hypertension in extremely low birthweight infants with and without bronchopulmonary dysplasia: a single-center experience. Neonatology 2018;113:81-88.
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