- Email: [email protected]
Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia
Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia Hussnain Mirza, MD1, James Ziegler, MD2, Sara Ford, MD2, James Padbury, MD1, Richard Tucker, BA1, and Abbot Laptook, MD1 Objective To determine whether early pulmonary hypertension (PH) at 10-14 days of life in preterm infants is associated with bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age (PMA).
Study design This was a prospective observational cohort study of infants <28 weeks’ gestation. Exclusion criteria were any major anomaly, genetic syndrome, or death before the initial echocardiogram. Echocardiograms were performed between 10 and 14 days of life and at 36 weeks’ PMA to assess PH. BPD and its severity were determined at 36 weeks PMA by the National Institutes of Health workshop definition. Results From March 2011 to April 2013, of 146 consecutively admitted infants <28 weeks, 120 were enrolled. One infant was excluded, 17 did not consent, and 8 died before undergoing a study echocardiogram. At 10-14 days of life, 10 infants had early PH (8%). Male sex (56% vs 40%), gestational age (26+2 1+2 vs 25+6 1+4 weeks), birth weight (837 205 g vs 763 182 g), and small for gestational age (14% vs 20%) were not significantly different among infants with no PH and early PH, respectively. Infants with early PH required >0.3 fraction of inspired oxygen by day 10 of life (70% vs 27%, P < .01). Moderate/severe BPD or death was greater among infants with early PH (90%) compared with no PH (47%, relative risk 1.9, 95% CI 1.43-2.53). Conclusion In this prospective, single-center cohort, early PH was associated with moderate/severe BPD or death at 36 weeks’ PMA. (J Pediatr 2014;165:909-14).
B
ronchopulmonary dysplasia (BPD) is the most common complication of prematurity, affecting more than 10 000 infants per year in the US.1 Despite recent advances in neonatal care, the incidence of BPD has increased2; however, the “new BPD” differs from the BPD first described in 1967 by Northway et al.3 Rather than fibrosis and scarring of the lungs, the new BPD is characterized by alveolar simplification and pulmonary vascular hypoplasia or dysplasia.4,5 The risk factors for BPD include mechanical ventilation, oxygen toxicity, inflammation, and pulmonary edema caused by fluid overload or excessive left to right shunting; however, preterm infants without such risk factors can still develop BPD.6-8 There is a complex crosstalk between pulmonary alveolar and vascular development.9 A number of studies have found an association between pulmonary hypertension (PH) and respiratory distress syndrome (RDS)10 or BPD.11 Among infants with BPD, PH has been a well-recognized association or complication.12 In a retrospective study of infants with BPD, no risk factor for PH associated with BPD was identified on multivariate analysis; however, the role of early PH was not assessed.13 PH frequently is associated with severe RDS.14 Subhedar and Shaw15 reported that pulmonary artery pressure (PAP) remained elevated up to 1 year of age among infants with chronic lung disease. These observations raise the possibility that PH that occurs in association with severe RDS may not resolve in infants who develop BPD and may persist for years. The role of early PH as a risk factor for BPD and late-onset PH among extremely premature infants remains unclear. We conducted a prospective, single-center cohort study to examine the association of early PH with moderate/severe BPD and late-onset PH or death at 36 weeks’ postmenstrual age (PMA). We hypothesized that echocardiographic evidence of early PH (PH between 10 and 14 days of life) is associated with moderate or severe BPD or death at 36 weeks’ PMA. Our secondary hypothesis was that early PH is associated with late PH or death at 36 weeks’ PMA.
Methods This was a prospective, observational cohort study of preterm infants (<28 weeks’ gestation based on obstetric criteria) admitted to the neonatal intensive care unit (NICU) of Women & Infants BPD FiO2 NICU PAP PDA PH PMA
Bronchopulmonary dysplasia Fraction of inspired oxygen Neonatal intensive care unit Pulmonary artery pressure Patent ductus arteriosus Pulmonary hypertension Postmenstrual age
RDS RR sBP sPAP SpO2 TR VSD
Respiratory distress syndrome Relative risk Systolic blood pressure Systolic pulmonary artery pressure Pulse oximetry Tricuspid regurgitation Ventricular septal defect
From the 1Department of Pediatrics, Women & Infants Hospital/The Alpert Medical School of Brown University; and 2Division of Pediatric Cardiology, Hasbro Children’s Hospital/The Alpert Medical School of Brown University, Providence, RI The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.07.040
909
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Hospital of Rhode Island. With Institutional Review Board approval and parental consent, infants were enrolled before 14 days of life. We excluded infants with congenital heart disease (except patent ductus arteriosus [PDA], small ventricular septal defect [VSD], atrial septal defect, or patent foramen ovale), congenital pulmonary anomaly (cystic adenomatoid malformation, lobar emphysema, etc), congenital diaphragmatic hernia, or death before the first study echocardiogram. All infants were managed by the clinical teams in the NICU according to the local guidelines. Clinical teams targeted an oxygen saturation (SpO2) as close to 90% as possible (lower and upper alarm limits of 85% and 95%, respectively) and fraction of inspired oxygen (FiO2) was adjusted by the nurses. Study echocardiograms were performed with real-time pulse oximetry. Initial minimum and maximum SpO2, along with the respective FiO2 values, were recorded during echocardiography; however, SpO2 and FiO2 data were not collected for clinical echocardiograms. If echocardiography was performed for clinical indications, a study echocardiogram was not performed, and data were obtained from clinical studies. All study echocardiograms were performed by a pediatric echocardiography technician, a NICU fellow (trained under the supervision of a pediatric cardiologist), or either of the 2 pediatric cardiologists (J.Z., S.F.) on the study team. In addition, both pediatric cardiologists were blinded to the clinical status of each infant and either one reviewed each echocardiogram for the presence and severity of PH. Management in the NICU was otherwise according to the discretion of the clinical care teams responsible for the infant. Right ventricular pressure gradient was estimated by measuring the peak velocity of tricuspid regurgitation (TR max) if there were reproducible holosystolic envelopes. We used the modified Bernoulli equation to convert Doppler derived velocity to pressure (pressure gradient between right ventricle and right atrium = 4 [TR max2]). Systolic PAP (sPAP) was calculated by adding right atrial pressure (5 mm Hg) to estimated right ventricle pressure gradient. In the absence of measureable TR, we relied upon a PDA or VSD gradient to estimate sPAP and identify the severity of PH as described previously. The severity of PH was determined by comparing simultaneously estimated sPAP with systemic systolic blood pressure (sBP). PH was categorized as none or mild if the estimated sPAP to sBP ratio was <0.5, moderate if the pulmonary to systemic systolic ratio was $0.5 but <1, and severe or suprasystemic if sPAP $ sBP.16 In the absence of TR, PDA, or VSD, sPAP was estimated by assessing the end-systolic interventricular septal position at the papillary muscle level in short-axis view through the multiple acoustic windows. PH by septal position was categorized as follows: normal or mild if the septum was rounded at end systole, moderate if the septum was flattened, and suprasystemic if the septum was bowed into the left ventricle at end systole.11 Infants with moderate or severe PH on the initial echocardiogram (10-14 days of life) were classified as having early PH. Infants with mild or no PH on the initial echocardiogram were identified as no PH group. For the purpose of 910
Vol. 165, No. 5 this study, PH identified by echocardiogram at 36 weeks’ PMA has been described as late PH. Study echocardiogram findings, which were deemed noncritical to the clinical care of infants, were not conveyed to the family or the clinical teams. Potentially important echocardiographic findings (eg, severe PH, hemodynamically significant PDA, hypertrophic cardiomyopathy with dynamic left ventricular outflow tract obstruction, or cardiac valvular lesions) were revealed to the clinical team. Clinical management of divulged echocardiographic findings was at the discretion of providers in the NICU. BPD was diagnosed if an infant received supplemental oxygen for $28 days. BPD was classified into mild, moderate, or severe forms at 36 weeks’ PMA, as described by Jobe and Bancalari.17 Mild BPD was the absence of supplemental oxygen, moderate BPD was the need for <0.3 FiO2, and severe BPD was the use of positive pressure ventilation or need for >0.3 FiO2. The need for continuing oxygen therapy was determined by an O2/room air challenge reduction as outlined by Walsh et al.18 We calculated sample size using the incidence of moderate or severe BPD at Women & Infants Hospital in 2006 (34%) and an estimated frequency of early PH (15%). To detect a 30% increase in moderate/severe BPD secondary to early PH, 120 infants were required, using a power of 80% and an alpha of 0.05. Maternal, perinatal, and neonatal data were collected to characterize the demographic and clinical characteristics of the study cohort. Infants were dichotomized based on the presence or absence of early PH at 1014 days of life. c2 tests were used for categorical variables, and Student t tests were used to compare continuous variables for infants with and without early PH. Bivariate analysis was performed to identify associations between early PH and study outcomes of BPD or late PH at 36 weeks’ PMA. Associations between early PH and BPD or late PH were expressed as a relative risk (RR) with 95% CI.
Results Between March 2011 to April 2013, 146 infants of <28 weeks’ gestation were admitted to the NICU at Women & Infants Hospital of Rhode Island, and 120 were enrolled. Consent was declined for 17 infants, and 8 died before undergoing the initial study echocardiogram. Only 1 infant was excluded because of vertebral and chest wall anomalies. The initial echocardiography on 12 2 days of life indicated the presence of PH (early PH) in 10 infants (8%) and 110 had no PH. All infants with early PH had moderate PH. The diagnosis of early PH (n = 10) was based on TR in 2 infants, a PDA gradient in 5, and septal position in 3 infants. Because PH had not been diagnosed clinically, specific treatment for PH was not administered to these infants. Three infants, previously treated with inhaled nitric oxide during their first week of life because of persistent PH, were not receiving inhaled nitric oxide at the time of initial study echocardiogram; only 1 of those 3 infants with persistent PH had early PH diagnosed on day 14 of life. Maternal Mirza et al
ORIGINAL ARTICLES
November 2014 demographic and clinical characteristics (Table I) did not differ between infants with and without early PH. Compared with infants with no PH, infants with early PH were of lower gestation and lower birth weight, but the differences did not reach statistical significance (Table II). Infants with early PH differed in their need for respiratory support. Infants with early PH were more likely to receive >0.3 FiO2 and to require >7 days of invasive ventilation by 10 days of life (P < .01). A study echocardiogram was performed in 118 of 120 infants at 36 weeks’ PMA. One infant died at 33 weeks’ PMA as the result of sepsis/necrotizing enterocolitis, and the other infant was transferred to a level 2 nursery at 34 weeks’ PMA. There were 5 infants with late PH at 36 weeks’ PMA. Late PH (n = 5) was diagnosed by TR for 3 infants, PDA for 1 infant, and septal position for 1 infant. Real-time SpO2 data were collected for 97% of infants with an echocardiogram at 10-14 days of life and 82% of infants with an echocardiogram at 36 weeks (Table III; available at www.jpeds.com). There were no differences in the median and IQRs of the initial, minimum, and maximum SpO2 among infants with and without PH. There was 1 infant with severe BPD and moderate PH whose PAP increased to suprasystemic levels during a transient desaturation to approximately 50% during the echocardiogram at 36 weeks’ PMA. We did not observe any other infant with acute changes in PAP, in association with transient changes in SpO2 during echocardiograms. The overall incidence of moderate or severe BPD was 50% (n = 60) in this cohort. Infants with early PH were at significantly greater risk for moderate/severe BPD or death compared with infants with no PH (90% vs 47%, RR 1.9, 95% CI 1.43-2.53; Table IV); however, there was no association between early PH and late PH at 36 weeks’ PMA (10% vs 4%, RR 2.7, 95% CI 0.34-21.9). The clinical
Table I. Maternal demographics and clinical characteristics (n = 120) Characteristics Maternal age, y <20 20-30 >30 Diabetes Hypertension Smoking Use of NSAIDs (>7 days) during pregnancy Use of SSRIs during pregnancy Oligohydramnios Chorioamnionitis (histologic) Antenatal steroids Antenatal Mg+ Antenatal indomethacin PROM Cesarean delivery Multiple birth
No early PH PH P (n = 110) (n = 10) value 16 53 41 11 26 21 6 17 4 59 88 62 31 21 75 17
1 6 3 0 1 1 1 2 1 6 9 6 4 1 8 2
.78 .29 .32 .48 .59 .70 .33 .70 .44 .89 .47 .43 .48 .69
NSAIDs, nonsteroidal anti-inflammatory drugs; PROM, premature rupture of membranes; SSRIs, selective serotonin reuptake inhibitors.
Table II. Perinatal and neonatal characteristics (n = 120) Characteristics Mean gestational age, wk Mean birth weight Male sex SGA Race (white) Low Apgar (<5 at 5 min) Prolonged IPPV (>7 d) by day 10 FiO2 > 0.3 by 10 day Median IPPV days (IQR) PDA requiring drug treatment or ligation Sepsis (culture positive) by day 14
No PH (n = 110)
PH (n = 10)
P value
26+2 1+2 837 205 62 16 54 22 31 30 7 (2-23) 11
25+6 1+4 763 182 4 2 7 1 7 7 26 (14-34) 5
.13 .27 .33 .62 .19 .44 <.01 <.01 <.01 .60
5
0
.49
IPPV, intermittent positive pressure ventilation; SGA, small for gestational age.
outcomes of BPD and late PH are shown in the Figure. Among infants with moderate/severe BPD, the overall incidence of late PH was 8% (3% for moderate and 15% for severe BPD). In each of these infants with BPD and late PH, there had been an intercurrent neonatal complication at the time of echocardiography as shown in Table V (available at www.jpeds.com). Of note, late PH was not identified in infants with mild or no BPD at 36 weeks’ PMA.
Discussion In this prospective observational cohort study, early PH was noted in 8% of premature infants <28 weeks between 10 and 14 days of life. Early PH was associated with a greater risk for moderate/severe BPD or death. The incidence of late PH at 36 weeks’ PMA was 3% among infants with moderate BPD and as high as 15% among infants with severe BPD. There was no association between early and late PH, but the CI was broad. In a study with serial echocardiograms from the presurfactant era, preterm infants who developed chronic lung disease had greater PAP at $2 weeks of life.19 The time required to complete pulmonary transition in preterm infants is not precisely known. To allow adequate time for pulmonary transition, we screened preterm infants for PH by echocardiography at 10-14 days of life. We found early PH in 8% of infants. Assessment of PH depends upon multiple factors such as FiO2 and SpO2. Our results support that changes in SpO2 did not contribute to the observed PH. The diagnosis of PH was based upon reproducible holosystolic Doppler envelopes or end-systolic interventricular septal position, assessed in multiple acoustic windows during echocardiograms performed over the course of 45-60 minutes. We are not aware of any other prospective, populationbased study to report PH in preterm infants at this age. Bhat et al20 reported a 6% incidence of early PH between 4 and 6 weeks of life among preterm infants of a similar gestation. Our slightly greater incidence of early PH may reflect screening at 10-14 days of life when pulmonary transition
Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia
911
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Table IV. Early PH and moderate/severe BPD or death and or late PH at 36 weeks’ PMA (n = 120) Early PH (n = 10) Yes No RR (95% CI)
Moderate or severe BPD or death (n = 61)
Mild or no BPD (n = 59)
9 1 52 58 1.90 (1.43-2.53)
Late PH (n = 5) 1 4
No PH at 36 wk (n = 113)*
9 104 7.7 (0.34-21.9)
*One infant died and one infant did not had echocardiogram at 36 wk PMA (n = 118).
may not be complete in some infants. Small for gestational age, oligohydramnios, chorioamnionitis, maternal obesity, diabetes, asthma, and intake of selective serotonin reuptake inhibitors or nonsteroidal anti-inflammatory drugs during pregnancy have all been reported as risk factors for PH in neonates.21-24 We did not identify any maternal or neonatal risk factor for PH possibly because of the small size of our early PH group (n = 10). Infants with early PH were noted to have a prolonged need for mechanical ventilation and greater supplemental oxygen. On the basis of our data, we cannot determine whether early PH was causing severe respiratory disease or vice versa. No standard grading systems for assessing the severity of neonatal PH has been established. Mourani et al25 defined PH as mild or moderate if sPAP:sBP is <0.67 and severe if the ratio is $0.67. In a recent study, moderate PH was diagnosed if estimated PAP is >50% but <75% of systemic sBP, and severe PH if >75%.26 In the absence of quantifiable Doppler velocity of TR, PDA, or VSD jets, we adapted the grading of PAP using interventricular septal position per King et al.16 We acknowledge that assessment of interventric-
Figure. Incidence of late PH and BPD as determined at 36 weeks’ PMA. Percent incidence is plotted on the y-axis, and the severity of BPD is marked on the x-axis. No BPD (n = 35), mild BPD (n = 24), moderate BPD (n = 34 and only one has late PH), and severe BPD (n = 26 and 4 has late PH) are shown. One infant with moderate BPD did not have an echocardiogram at 36 weeks’ PMA. Overall incidence of late PH among infants with moderate or severe BPD is 8%. 912
Vol. 165, No. 5 ular septal position is imprecise and has limited sensitivity for diagnosing mild PH. We were thus unable to screen these infants to identify mild PH. Infants with early PH were at greater risk to develop moderate/severe BPD or death compared with those infants with no PH. Previous studies had shown persistently increased PAP among infants at risk for developing chronic lung disease.19 In a recent cohort, the incidence of BPD was greater among infants with PH at 4-6 weeks.20 In models of lung injury, PH even for as little as 4 minutes can cause injury to the pulmonary endothelium and alveolar epithelium, but long-term effects have not been assessed.27 Our incidence of BPD associated late PH (8%) was lower than previous reports, which range as high as 43%11,13; however, these reports may be subject to selection bias because of their retrospective study design and enrollment of infants with severe respiratory disease who were referred for evaluation of PH. In contrast, we screened all preterm infants (with or without BPD) for the presence of PH at 36 weeks’ PMA. It is possible that some infants with BPD developed PH after 36 weeks’ PMA. The reported median age for the diagnosis of BPD and PH is 4.5 months (IQR 2.4-7.8 months).26 A role for chronic or intermittent hypoxia in the development of PH has been suggested among infants with BPD after discharge from a NICU.28 Another possible difference could be the proportion of classic and “new BPD” in our cohort. Infants in historic cohorts are more likely to have classic BPD, which is a severe form of the disease and maybe more likely to be associated with PH.29 Only 2 prospective studies have reported the incidence of BPD associated PH. Bhat et al20 reported that up to 10% of extremely low birth weight infants have PH at hospital discharge; however, all infants with BPD were not screened for PH at 36 weeks’ PMA or later. Kim et al30 prospectively screened 98 infants with moderate or severe BPD and reported a 25% incidence of BPD associated PH. In their study, 7% of infants with moderate BPD and 52% with severe BPD had PH. We cannot reconcile the latter report with our results. Evans and Archer10 reported that up to one-third of premature infants recovering from RDS had echocardiographic evidence of persistently elevated PAP even if breathing room air at hospital discharge. In contrast to these historic cohorts, we found that early PH resolves even if BPD develops. We did not find any association between early and late PH at 36 weeks’ PMA; however, the CI was broad (95% CI 0.3421.9), and this study was not powered for this secondary outcome. Our study has some limitations. Because the natural history of pulmonary transition in extremely premature infants is not known, it was not possible to determine the optimal time to screen for PH. With our methodology, we cannot distinguish mild PH (sPAP <50% of systemic sBP) from the absence of PH. For the purpose of this study, we did not discriminate infants based upon the underlying etiology for PH, ie, increased pulmonary vascular resistance or increased pulmonary blood flow. PAP can change in response to changes in lung inflation, mean airway pressure, hypoxia, Mirza et al
ORIGINAL ARTICLES
November 2014 and inadequate mechanical ventilation. We did not perform chest radiographs or arterial blood gases concurrent with echocardiographic assessment of PH. Therefore, we cannot comment on the adequacy of lung expansion or optimized ventilation. Echocardiography is not the gold standard for assessing PAP. Mourani et al25 have raised questions about the quantitative assessment of PH by echocardiography compared with cardiac catheterization. Nonetheless, other expert opinions have endorsed echocardiography as a reliable tool for the diagnosis of PH in infants with BPD.31,32 Despite limitations, echocardiography remains the most feasible and widely used choice for PH screening in extremely preterm infants. Our study has strengths that include its prospective design and a predetermined sample size to test our primary hypothesis. Because we are the regional referral center for neonatal care in southern New England, this is a representative, population-based cohort. In this study, extremely premature infants were universally screened for early (10-14 days of life) and late PH (36 weeks’ PMA) to report early and late PH incidences. We monitored SpO2 and FiO2 at the time of echocardiographic assessment for PH. To decrease interobserver variability, 1 of only 2 pediatric cardiologists on our research team reviewed all study echocardiograms without knowledge of the clinical status of the patient. Some experts have recommended universal screening for PH in extremely premature infants with severe respiratory disease or infants with moderate or severe BPD20,26; however, the optimal timing for this screening has not been determined.33 Furthermore, whether early recognition and intervention to treat PH in extremely premature infants can decrease the incidence of adverse outcomes, including BPD, is unknown. Further research is needed to determine the optimal time for PH screening and to assess potential benefits of treating early PH in extremely premature infants. n We are thankful to the Division of Pediatric Cardiology at Hasbro Children’s Hospital for their continued support and guidance, NICU service teams, and families who have enrolled their infants in this study. Submitted for publication Dec 26, 2013; last revision received Jul 3, 2014; accepted Jul 23, 2014. Reprint requests: Abbot Laptook, MD, Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI 02905. E-mail: alaptook@ wihri.org
References 1. Stenmark KR, Abman SH. Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol 2005;67:623-61. 2. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443-56. 3. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 1967;276:357-68. 4. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73-81.
5. Bland RD. Neonatal chronic lung disease in the post-surfactant era. Biol Neonate 2005;88:181-91. 6. Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr 1995;126:605-10. 7. Charafeddine L, D’Angio CT, Phelps DL. Atypical chronic lung disease patterns in neonates. Pediatrics 1999;103:759-65. 8. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res 1999; 46:641-3. 9. Morrisey EE, Cardoso WV, Lane RH, Rabinovitch M, Abman SH, Ai X, et al. Molecular determinants of lung development. Ann Am Thorac Soc 2013;10:S12-6. 10. Evans NJ, Archer LN. Doppler assessment of pulmonary artery pressure and extrapulmonary shunting in the acute phase of hyaline membrane disease. Arch Dis Child 1991;66:6-11. 11. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007;120:1260-9. 12. Collaco JM, Romer LH, Stuart BD, Coulson JD, Everett AD, Lawson EE, et al. Frontiers in pulmonary hypertension in infants and children with bronchopulmonary dysplasia. Pediatr Pulmonol 2012;47:1042-53. 13. An HS, Bae EJ, Kim GB, Kwon BS, Beak JS, Kim EK, et al. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J 2010;40:131-6. 14. Gill AB, Weindling AM. Raised pulmonary artery pressure in very low birthweight infants requiring supplemental oxygen at 36 weeks after conception. Arch Dis Child Fetal Neonatal Ed 1995;72:F20-2. 15. Subhedar NV, Shaw NJ. Changes in pulmonary arterial pressure in preterm infants with chronic lung disease. Arch Dis Child 2000;82:F243-7. 16. King M, Braun H, Goldblatt A, Liberthson R, Weyman A. Interventricular septal configuration as a predictor of right ventricular systolic hypertension in children: a cross-sectional echocardiographic study. Circulation 1983;68:68-75. 17. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 18. Walsh M, Engle W, Laptook A, Kazzi SN, Buchter S, Rasmussen M, et al. Oxygen delivery through nasal cannulae to preterm infants: can practice be improved? Pediatrics 2005;116:857-61. 19. Gill AB, Weindling AM. Pulmonary artery pressure changes in the very low birthweight infant developing chronic lung disease. Arch Dis Child 1993;68:303-7. 20. Bhat R, Salas AA, Foster C, Carlo WA, Ambalavanan N. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 2012;129:e682-9. 21. Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354: 579-87. 22. Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics 2007;120:e272-82. 23. Williams MC, Wyble LE, O’Brien WF, Nelson RM, Schwenke JR, Casanova C. Persistent pulmonary hypertension of the neonate and asymmetric growth restriction. Obstet Gynecol 1998;91:336-41. 24. Woldesenbet M, Perlman JM. Histologic chorioamnionitis: an occult marker of severe pulmonary hypertension in the term newborn. J Perinatol 2005;25:189-92. 25. 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;121:317-25. 26. del Cerro MJ, Sabate Rotes A, Carton A, Deiros L, Bret M, Cordeiro M, et al. Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes. Pediatr Pulmonol 2014;49:49-59. 27. West JB, Tsukimoto K, Mathieu-Costello O, Prediletto R. Stress failure in pulmonary capillaries. J Appl Physiol 1991;70:1731-42.
Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia
913
THE JOURNAL OF PEDIATRICS
www.jpeds.com
28. Berkelhamer SK, Mestan KK, Steinhorn RH. Pulmonary hypertension in bronchopulmonary dysplasia. Semin Perinatol 2013;37:124-31. 29. Bancalari E, Claure N. Definitions and diagnostic criteria for bronchopulmonary dysplasia. Semin Perinatol 2006;30:164-70. 30. 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;101:40-6.
Vol. 165, No. 5 31. Abman SH. Monitoring cardiovascular function in infants with chronic lung disease of prematurity. Arch Dis Child 2002;87:F15-8. 32. Farquhar M, Fitzgerald DA. Pulmonary hypertension in chronic neonatal lung disease. Paediatr Respir Rev 2010;11:149-53. 33. Ambalavanan N, Mourani P. Pulmonary hypertension in bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol 2014; 100:240-6.
50 Years Ago in THE JOURNAL OF PEDIATRICS The Syndrome of Pancreatic Insufficiency and Bone Marrow Dysfunction Shwachman H, Diamond LK, Oski FA, Khaw K-T. J Pediatr 1964;65:645-63
I
n 1964, Shwachman et al described 5 children with diarrhea, failure to thrive, pancreatic exocrine enzyme insufficiency, neutropenia with bone marrow hypoplasia, elevated fetal hemoglobin, and growth retardation. A sixth child, a sibling of 2 of the children described, had growth failure with decreased pancreatic enzyme activity but normal bone marrow cellularity and no diarrhea. Concern for cystic fibrosis was dispelled on the basis of no pulmonary disease and a negative sweat test. It was postulated this was a new syndrome, possibly genetically predetermined because of the occurrence in siblings. Today we know this as Shwachman-Diamond syndrome (SDS), inheritance is autosomal recessive and about 90% of cases have an identifiable mutation in the Shwachman-Bodian-Diamond syndrome (SBDS) gene located on chromosome 7q11. The gene is involved in ribosome assembly, but its role in the clinical manifestations of SDS remains unknown. Estimated incidence of SDS is about 1 in 75 000 with a slight male predominance (1.6:1) but no racial or ethnic predilection. Patients typically present in infancy or early childhood with a variable combination of diarrhea/steatorrhea, growth failure, and recurrent infections. Pancreatic exocrine dysfunction results from fatty replacement of pancreatic acini, and imaging demonstrates a small shrunken pancreas or lipomatosis. Pancreatic function often improves with age and about one-half of affected children no longer require pancreatic supplements by age 4 years. Over 90% have neutropenia, which is intermittent in most but constant in about one-third of cases. This is related to bone marrow hypoplasia, which affects other cell lines in some patients. Growth failure is characteristic and does not improve with pancreatic supplements or resolution of pancreatic insufficiency. In addition to the features described by Shwachman, we now recognize a variety of additional manifestations including skeletal abnormalities such as metaphyseal dysostosis, developmental delay, learning disorders, and an increased risk for infections, myelodysplastic syndrome, and acute myeloid leukemia. Diagnosis is based on the characteristic clinical manifestations and confirmed by identifying a mutation in the SBDS gene. However, a negative genetic test does not exclude the diagnosis as 10% do not have a known mutation. When an SBDS mutation is identified, this can be used to screen other family members. Treatment is largely directed at specific clinical manifestations. In those with bone marrow failure, hematopoietic stem cell transplantation is an option although currently there are limited data on outcomes in these cases. Ivor D. Hill, MB, ChB, MD Division of Pediatric Gastroenterology Nationwide Children’s Hospital Columbus, Ohio http://dx.doi.org/10.1016/j.jpeds.2014.04.042
914
Mirza et al
ORIGINAL ARTICLES
November 2014
Table III. Real-time SpO2 monitoring during echocardiography P value
Echocardiogram Initial Initial SpO2 Minimum SpO2 Maximum SpO2 36 weeks’ PMA Initial SpO2 Minimum SpO2 Maximum SpO2
Table V. Clinical characteristics of infants with late PH at 36 wk PMA (n = 5)
Early PH (n = 10)* 92 (90-93) 80 (76-90) 94 (94-95) Late PH (n = 5)z 90 (90-91) 82 (61-88) 95 (93-95)
All data are median (IQR). *Data available for 9 infants. †Data available for 107 infants. zData available for 3 infants. xData available for 94 infants.
†
No PH (n = 110) 92 (90-92) 88 (81-90) 96 (94-96) No PH (n = 113)x 92 (90-92) 90 (84-91) 96 (94-97)
.35 .13 .10 .27 .14 .08
Infants with late PH Clinical features
1
2
3
4
5
Gestation (at birth) SGA Early PH BPD FiO2 > 0.3* Invasive ventilation* Upper airway problems† Pneumonia Sepsis PDA (at 36 wk) Miscellaneous
26+5 No No Severe No No No No No Yes No
24 No No Severe Yes Yes No Yes Yes No No
24+1 No No Severe Yes Yes Yes No No No No
25+3 No No Moderate No No No No No No ASD
27 Yes Yes Severe Yes No No No No No No
ASD, atrial septal defect; SGA, small for gestational age. *At the time of echocardiography (36 wk PMA). †Severe subglottic stenosis detected 1 week before echocardiography at 36 wk PMA.
Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia
914.e1
Study design This was a prospective observational cohort study of infants <28 weeks’ gestation. Exclusion criteria were any major anomaly, genetic syndrome, or death before the initial echocardiogram. Echocardiograms were performed between 10 and 14 days of life and at 36 weeks’ PMA to assess PH. BPD and its severity were determined at 36 weeks PMA by the National Institutes of Health workshop definition. Results From March 2011 to April 2013, of 146 consecutively admitted infants <28 weeks, 120 were enrolled. One infant was excluded, 17 did not consent, and 8 died before undergoing a study echocardiogram. At 10-14 days of life, 10 infants had early PH (8%). Male sex (56% vs 40%), gestational age (26+2 1+2 vs 25+6 1+4 weeks), birth weight (837 205 g vs 763 182 g), and small for gestational age (14% vs 20%) were not significantly different among infants with no PH and early PH, respectively. Infants with early PH required >0.3 fraction of inspired oxygen by day 10 of life (70% vs 27%, P < .01). Moderate/severe BPD or death was greater among infants with early PH (90%) compared with no PH (47%, relative risk 1.9, 95% CI 1.43-2.53). Conclusion In this prospective, single-center cohort, early PH was associated with moderate/severe BPD or death at 36 weeks’ PMA. (J Pediatr 2014;165:909-14).
B
ronchopulmonary dysplasia (BPD) is the most common complication of prematurity, affecting more than 10 000 infants per year in the US.1 Despite recent advances in neonatal care, the incidence of BPD has increased2; however, the “new BPD” differs from the BPD first described in 1967 by Northway et al.3 Rather than fibrosis and scarring of the lungs, the new BPD is characterized by alveolar simplification and pulmonary vascular hypoplasia or dysplasia.4,5 The risk factors for BPD include mechanical ventilation, oxygen toxicity, inflammation, and pulmonary edema caused by fluid overload or excessive left to right shunting; however, preterm infants without such risk factors can still develop BPD.6-8 There is a complex crosstalk between pulmonary alveolar and vascular development.9 A number of studies have found an association between pulmonary hypertension (PH) and respiratory distress syndrome (RDS)10 or BPD.11 Among infants with BPD, PH has been a well-recognized association or complication.12 In a retrospective study of infants with BPD, no risk factor for PH associated with BPD was identified on multivariate analysis; however, the role of early PH was not assessed.13 PH frequently is associated with severe RDS.14 Subhedar and Shaw15 reported that pulmonary artery pressure (PAP) remained elevated up to 1 year of age among infants with chronic lung disease. These observations raise the possibility that PH that occurs in association with severe RDS may not resolve in infants who develop BPD and may persist for years. The role of early PH as a risk factor for BPD and late-onset PH among extremely premature infants remains unclear. We conducted a prospective, single-center cohort study to examine the association of early PH with moderate/severe BPD and late-onset PH or death at 36 weeks’ postmenstrual age (PMA). We hypothesized that echocardiographic evidence of early PH (PH between 10 and 14 days of life) is associated with moderate or severe BPD or death at 36 weeks’ PMA. Our secondary hypothesis was that early PH is associated with late PH or death at 36 weeks’ PMA.
Methods This was a prospective, observational cohort study of preterm infants (<28 weeks’ gestation based on obstetric criteria) admitted to the neonatal intensive care unit (NICU) of Women & Infants BPD FiO2 NICU PAP PDA PH PMA
Bronchopulmonary dysplasia Fraction of inspired oxygen Neonatal intensive care unit Pulmonary artery pressure Patent ductus arteriosus Pulmonary hypertension Postmenstrual age
RDS RR sBP sPAP SpO2 TR VSD
Respiratory distress syndrome Relative risk Systolic blood pressure Systolic pulmonary artery pressure Pulse oximetry Tricuspid regurgitation Ventricular septal defect
From the 1Department of Pediatrics, Women & Infants Hospital/The Alpert Medical School of Brown University; and 2Division of Pediatric Cardiology, Hasbro Children’s Hospital/The Alpert Medical School of Brown University, Providence, RI The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.07.040
909
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Hospital of Rhode Island. With Institutional Review Board approval and parental consent, infants were enrolled before 14 days of life. We excluded infants with congenital heart disease (except patent ductus arteriosus [PDA], small ventricular septal defect [VSD], atrial septal defect, or patent foramen ovale), congenital pulmonary anomaly (cystic adenomatoid malformation, lobar emphysema, etc), congenital diaphragmatic hernia, or death before the first study echocardiogram. All infants were managed by the clinical teams in the NICU according to the local guidelines. Clinical teams targeted an oxygen saturation (SpO2) as close to 90% as possible (lower and upper alarm limits of 85% and 95%, respectively) and fraction of inspired oxygen (FiO2) was adjusted by the nurses. Study echocardiograms were performed with real-time pulse oximetry. Initial minimum and maximum SpO2, along with the respective FiO2 values, were recorded during echocardiography; however, SpO2 and FiO2 data were not collected for clinical echocardiograms. If echocardiography was performed for clinical indications, a study echocardiogram was not performed, and data were obtained from clinical studies. All study echocardiograms were performed by a pediatric echocardiography technician, a NICU fellow (trained under the supervision of a pediatric cardiologist), or either of the 2 pediatric cardiologists (J.Z., S.F.) on the study team. In addition, both pediatric cardiologists were blinded to the clinical status of each infant and either one reviewed each echocardiogram for the presence and severity of PH. Management in the NICU was otherwise according to the discretion of the clinical care teams responsible for the infant. Right ventricular pressure gradient was estimated by measuring the peak velocity of tricuspid regurgitation (TR max) if there were reproducible holosystolic envelopes. We used the modified Bernoulli equation to convert Doppler derived velocity to pressure (pressure gradient between right ventricle and right atrium = 4 [TR max2]). Systolic PAP (sPAP) was calculated by adding right atrial pressure (5 mm Hg) to estimated right ventricle pressure gradient. In the absence of measureable TR, we relied upon a PDA or VSD gradient to estimate sPAP and identify the severity of PH as described previously. The severity of PH was determined by comparing simultaneously estimated sPAP with systemic systolic blood pressure (sBP). PH was categorized as none or mild if the estimated sPAP to sBP ratio was <0.5, moderate if the pulmonary to systemic systolic ratio was $0.5 but <1, and severe or suprasystemic if sPAP $ sBP.16 In the absence of TR, PDA, or VSD, sPAP was estimated by assessing the end-systolic interventricular septal position at the papillary muscle level in short-axis view through the multiple acoustic windows. PH by septal position was categorized as follows: normal or mild if the septum was rounded at end systole, moderate if the septum was flattened, and suprasystemic if the septum was bowed into the left ventricle at end systole.11 Infants with moderate or severe PH on the initial echocardiogram (10-14 days of life) were classified as having early PH. Infants with mild or no PH on the initial echocardiogram were identified as no PH group. For the purpose of 910
Vol. 165, No. 5 this study, PH identified by echocardiogram at 36 weeks’ PMA has been described as late PH. Study echocardiogram findings, which were deemed noncritical to the clinical care of infants, were not conveyed to the family or the clinical teams. Potentially important echocardiographic findings (eg, severe PH, hemodynamically significant PDA, hypertrophic cardiomyopathy with dynamic left ventricular outflow tract obstruction, or cardiac valvular lesions) were revealed to the clinical team. Clinical management of divulged echocardiographic findings was at the discretion of providers in the NICU. BPD was diagnosed if an infant received supplemental oxygen for $28 days. BPD was classified into mild, moderate, or severe forms at 36 weeks’ PMA, as described by Jobe and Bancalari.17 Mild BPD was the absence of supplemental oxygen, moderate BPD was the need for <0.3 FiO2, and severe BPD was the use of positive pressure ventilation or need for >0.3 FiO2. The need for continuing oxygen therapy was determined by an O2/room air challenge reduction as outlined by Walsh et al.18 We calculated sample size using the incidence of moderate or severe BPD at Women & Infants Hospital in 2006 (34%) and an estimated frequency of early PH (15%). To detect a 30% increase in moderate/severe BPD secondary to early PH, 120 infants were required, using a power of 80% and an alpha of 0.05. Maternal, perinatal, and neonatal data were collected to characterize the demographic and clinical characteristics of the study cohort. Infants were dichotomized based on the presence or absence of early PH at 1014 days of life. c2 tests were used for categorical variables, and Student t tests were used to compare continuous variables for infants with and without early PH. Bivariate analysis was performed to identify associations between early PH and study outcomes of BPD or late PH at 36 weeks’ PMA. Associations between early PH and BPD or late PH were expressed as a relative risk (RR) with 95% CI.
Results Between March 2011 to April 2013, 146 infants of <28 weeks’ gestation were admitted to the NICU at Women & Infants Hospital of Rhode Island, and 120 were enrolled. Consent was declined for 17 infants, and 8 died before undergoing the initial study echocardiogram. Only 1 infant was excluded because of vertebral and chest wall anomalies. The initial echocardiography on 12 2 days of life indicated the presence of PH (early PH) in 10 infants (8%) and 110 had no PH. All infants with early PH had moderate PH. The diagnosis of early PH (n = 10) was based on TR in 2 infants, a PDA gradient in 5, and septal position in 3 infants. Because PH had not been diagnosed clinically, specific treatment for PH was not administered to these infants. Three infants, previously treated with inhaled nitric oxide during their first week of life because of persistent PH, were not receiving inhaled nitric oxide at the time of initial study echocardiogram; only 1 of those 3 infants with persistent PH had early PH diagnosed on day 14 of life. Maternal Mirza et al
ORIGINAL ARTICLES
November 2014 demographic and clinical characteristics (Table I) did not differ between infants with and without early PH. Compared with infants with no PH, infants with early PH were of lower gestation and lower birth weight, but the differences did not reach statistical significance (Table II). Infants with early PH differed in their need for respiratory support. Infants with early PH were more likely to receive >0.3 FiO2 and to require >7 days of invasive ventilation by 10 days of life (P < .01). A study echocardiogram was performed in 118 of 120 infants at 36 weeks’ PMA. One infant died at 33 weeks’ PMA as the result of sepsis/necrotizing enterocolitis, and the other infant was transferred to a level 2 nursery at 34 weeks’ PMA. There were 5 infants with late PH at 36 weeks’ PMA. Late PH (n = 5) was diagnosed by TR for 3 infants, PDA for 1 infant, and septal position for 1 infant. Real-time SpO2 data were collected for 97% of infants with an echocardiogram at 10-14 days of life and 82% of infants with an echocardiogram at 36 weeks (Table III; available at www.jpeds.com). There were no differences in the median and IQRs of the initial, minimum, and maximum SpO2 among infants with and without PH. There was 1 infant with severe BPD and moderate PH whose PAP increased to suprasystemic levels during a transient desaturation to approximately 50% during the echocardiogram at 36 weeks’ PMA. We did not observe any other infant with acute changes in PAP, in association with transient changes in SpO2 during echocardiograms. The overall incidence of moderate or severe BPD was 50% (n = 60) in this cohort. Infants with early PH were at significantly greater risk for moderate/severe BPD or death compared with infants with no PH (90% vs 47%, RR 1.9, 95% CI 1.43-2.53; Table IV); however, there was no association between early PH and late PH at 36 weeks’ PMA (10% vs 4%, RR 2.7, 95% CI 0.34-21.9). The clinical
Table I. Maternal demographics and clinical characteristics (n = 120) Characteristics Maternal age, y <20 20-30 >30 Diabetes Hypertension Smoking Use of NSAIDs (>7 days) during pregnancy Use of SSRIs during pregnancy Oligohydramnios Chorioamnionitis (histologic) Antenatal steroids Antenatal Mg+ Antenatal indomethacin PROM Cesarean delivery Multiple birth
No early PH PH P (n = 110) (n = 10) value 16 53 41 11 26 21 6 17 4 59 88 62 31 21 75 17
1 6 3 0 1 1 1 2 1 6 9 6 4 1 8 2
.78 .29 .32 .48 .59 .70 .33 .70 .44 .89 .47 .43 .48 .69
NSAIDs, nonsteroidal anti-inflammatory drugs; PROM, premature rupture of membranes; SSRIs, selective serotonin reuptake inhibitors.
Table II. Perinatal and neonatal characteristics (n = 120) Characteristics Mean gestational age, wk Mean birth weight Male sex SGA Race (white) Low Apgar (<5 at 5 min) Prolonged IPPV (>7 d) by day 10 FiO2 > 0.3 by 10 day Median IPPV days (IQR) PDA requiring drug treatment or ligation Sepsis (culture positive) by day 14
No PH (n = 110)
PH (n = 10)
P value
26+2 1+2 837 205 62 16 54 22 31 30 7 (2-23) 11
25+6 1+4 763 182 4 2 7 1 7 7 26 (14-34) 5
.13 .27 .33 .62 .19 .44 <.01 <.01 <.01 .60
5
0
.49
IPPV, intermittent positive pressure ventilation; SGA, small for gestational age.
outcomes of BPD and late PH are shown in the Figure. Among infants with moderate/severe BPD, the overall incidence of late PH was 8% (3% for moderate and 15% for severe BPD). In each of these infants with BPD and late PH, there had been an intercurrent neonatal complication at the time of echocardiography as shown in Table V (available at www.jpeds.com). Of note, late PH was not identified in infants with mild or no BPD at 36 weeks’ PMA.
Discussion In this prospective observational cohort study, early PH was noted in 8% of premature infants <28 weeks between 10 and 14 days of life. Early PH was associated with a greater risk for moderate/severe BPD or death. The incidence of late PH at 36 weeks’ PMA was 3% among infants with moderate BPD and as high as 15% among infants with severe BPD. There was no association between early and late PH, but the CI was broad. In a study with serial echocardiograms from the presurfactant era, preterm infants who developed chronic lung disease had greater PAP at $2 weeks of life.19 The time required to complete pulmonary transition in preterm infants is not precisely known. To allow adequate time for pulmonary transition, we screened preterm infants for PH by echocardiography at 10-14 days of life. We found early PH in 8% of infants. Assessment of PH depends upon multiple factors such as FiO2 and SpO2. Our results support that changes in SpO2 did not contribute to the observed PH. The diagnosis of PH was based upon reproducible holosystolic Doppler envelopes or end-systolic interventricular septal position, assessed in multiple acoustic windows during echocardiograms performed over the course of 45-60 minutes. We are not aware of any other prospective, populationbased study to report PH in preterm infants at this age. Bhat et al20 reported a 6% incidence of early PH between 4 and 6 weeks of life among preterm infants of a similar gestation. Our slightly greater incidence of early PH may reflect screening at 10-14 days of life when pulmonary transition
Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia
911
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Table IV. Early PH and moderate/severe BPD or death and or late PH at 36 weeks’ PMA (n = 120) Early PH (n = 10) Yes No RR (95% CI)
Moderate or severe BPD or death (n = 61)
Mild or no BPD (n = 59)
9 1 52 58 1.90 (1.43-2.53)
Late PH (n = 5) 1 4
No PH at 36 wk (n = 113)*
9 104 7.7 (0.34-21.9)
*One infant died and one infant did not had echocardiogram at 36 wk PMA (n = 118).
may not be complete in some infants. Small for gestational age, oligohydramnios, chorioamnionitis, maternal obesity, diabetes, asthma, and intake of selective serotonin reuptake inhibitors or nonsteroidal anti-inflammatory drugs during pregnancy have all been reported as risk factors for PH in neonates.21-24 We did not identify any maternal or neonatal risk factor for PH possibly because of the small size of our early PH group (n = 10). Infants with early PH were noted to have a prolonged need for mechanical ventilation and greater supplemental oxygen. On the basis of our data, we cannot determine whether early PH was causing severe respiratory disease or vice versa. No standard grading systems for assessing the severity of neonatal PH has been established. Mourani et al25 defined PH as mild or moderate if sPAP:sBP is <0.67 and severe if the ratio is $0.67. In a recent study, moderate PH was diagnosed if estimated PAP is >50% but <75% of systemic sBP, and severe PH if >75%.26 In the absence of quantifiable Doppler velocity of TR, PDA, or VSD jets, we adapted the grading of PAP using interventricular septal position per King et al.16 We acknowledge that assessment of interventric-
Figure. Incidence of late PH and BPD as determined at 36 weeks’ PMA. Percent incidence is plotted on the y-axis, and the severity of BPD is marked on the x-axis. No BPD (n = 35), mild BPD (n = 24), moderate BPD (n = 34 and only one has late PH), and severe BPD (n = 26 and 4 has late PH) are shown. One infant with moderate BPD did not have an echocardiogram at 36 weeks’ PMA. Overall incidence of late PH among infants with moderate or severe BPD is 8%. 912
Vol. 165, No. 5 ular septal position is imprecise and has limited sensitivity for diagnosing mild PH. We were thus unable to screen these infants to identify mild PH. Infants with early PH were at greater risk to develop moderate/severe BPD or death compared with those infants with no PH. Previous studies had shown persistently increased PAP among infants at risk for developing chronic lung disease.19 In a recent cohort, the incidence of BPD was greater among infants with PH at 4-6 weeks.20 In models of lung injury, PH even for as little as 4 minutes can cause injury to the pulmonary endothelium and alveolar epithelium, but long-term effects have not been assessed.27 Our incidence of BPD associated late PH (8%) was lower than previous reports, which range as high as 43%11,13; however, these reports may be subject to selection bias because of their retrospective study design and enrollment of infants with severe respiratory disease who were referred for evaluation of PH. In contrast, we screened all preterm infants (with or without BPD) for the presence of PH at 36 weeks’ PMA. It is possible that some infants with BPD developed PH after 36 weeks’ PMA. The reported median age for the diagnosis of BPD and PH is 4.5 months (IQR 2.4-7.8 months).26 A role for chronic or intermittent hypoxia in the development of PH has been suggested among infants with BPD after discharge from a NICU.28 Another possible difference could be the proportion of classic and “new BPD” in our cohort. Infants in historic cohorts are more likely to have classic BPD, which is a severe form of the disease and maybe more likely to be associated with PH.29 Only 2 prospective studies have reported the incidence of BPD associated PH. Bhat et al20 reported that up to 10% of extremely low birth weight infants have PH at hospital discharge; however, all infants with BPD were not screened for PH at 36 weeks’ PMA or later. Kim et al30 prospectively screened 98 infants with moderate or severe BPD and reported a 25% incidence of BPD associated PH. In their study, 7% of infants with moderate BPD and 52% with severe BPD had PH. We cannot reconcile the latter report with our results. Evans and Archer10 reported that up to one-third of premature infants recovering from RDS had echocardiographic evidence of persistently elevated PAP even if breathing room air at hospital discharge. In contrast to these historic cohorts, we found that early PH resolves even if BPD develops. We did not find any association between early and late PH at 36 weeks’ PMA; however, the CI was broad (95% CI 0.3421.9), and this study was not powered for this secondary outcome. Our study has some limitations. Because the natural history of pulmonary transition in extremely premature infants is not known, it was not possible to determine the optimal time to screen for PH. With our methodology, we cannot distinguish mild PH (sPAP <50% of systemic sBP) from the absence of PH. For the purpose of this study, we did not discriminate infants based upon the underlying etiology for PH, ie, increased pulmonary vascular resistance or increased pulmonary blood flow. PAP can change in response to changes in lung inflation, mean airway pressure, hypoxia, Mirza et al
ORIGINAL ARTICLES
November 2014 and inadequate mechanical ventilation. We did not perform chest radiographs or arterial blood gases concurrent with echocardiographic assessment of PH. Therefore, we cannot comment on the adequacy of lung expansion or optimized ventilation. Echocardiography is not the gold standard for assessing PAP. Mourani et al25 have raised questions about the quantitative assessment of PH by echocardiography compared with cardiac catheterization. Nonetheless, other expert opinions have endorsed echocardiography as a reliable tool for the diagnosis of PH in infants with BPD.31,32 Despite limitations, echocardiography remains the most feasible and widely used choice for PH screening in extremely preterm infants. Our study has strengths that include its prospective design and a predetermined sample size to test our primary hypothesis. Because we are the regional referral center for neonatal care in southern New England, this is a representative, population-based cohort. In this study, extremely premature infants were universally screened for early (10-14 days of life) and late PH (36 weeks’ PMA) to report early and late PH incidences. We monitored SpO2 and FiO2 at the time of echocardiographic assessment for PH. To decrease interobserver variability, 1 of only 2 pediatric cardiologists on our research team reviewed all study echocardiograms without knowledge of the clinical status of the patient. Some experts have recommended universal screening for PH in extremely premature infants with severe respiratory disease or infants with moderate or severe BPD20,26; however, the optimal timing for this screening has not been determined.33 Furthermore, whether early recognition and intervention to treat PH in extremely premature infants can decrease the incidence of adverse outcomes, including BPD, is unknown. Further research is needed to determine the optimal time for PH screening and to assess potential benefits of treating early PH in extremely premature infants. n We are thankful to the Division of Pediatric Cardiology at Hasbro Children’s Hospital for their continued support and guidance, NICU service teams, and families who have enrolled their infants in this study. Submitted for publication Dec 26, 2013; last revision received Jul 3, 2014; accepted Jul 23, 2014. Reprint requests: Abbot Laptook, MD, Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI 02905. E-mail: alaptook@ wihri.org
References 1. Stenmark KR, Abman SH. Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol 2005;67:623-61. 2. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443-56. 3. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 1967;276:357-68. 4. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73-81.
5. Bland RD. Neonatal chronic lung disease in the post-surfactant era. Biol Neonate 2005;88:181-91. 6. Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr 1995;126:605-10. 7. Charafeddine L, D’Angio CT, Phelps DL. Atypical chronic lung disease patterns in neonates. Pediatrics 1999;103:759-65. 8. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res 1999; 46:641-3. 9. Morrisey EE, Cardoso WV, Lane RH, Rabinovitch M, Abman SH, Ai X, et al. Molecular determinants of lung development. Ann Am Thorac Soc 2013;10:S12-6. 10. Evans NJ, Archer LN. Doppler assessment of pulmonary artery pressure and extrapulmonary shunting in the acute phase of hyaline membrane disease. Arch Dis Child 1991;66:6-11. 11. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 2007;120:1260-9. 12. Collaco JM, Romer LH, Stuart BD, Coulson JD, Everett AD, Lawson EE, et al. Frontiers in pulmonary hypertension in infants and children with bronchopulmonary dysplasia. Pediatr Pulmonol 2012;47:1042-53. 13. An HS, Bae EJ, Kim GB, Kwon BS, Beak JS, Kim EK, et al. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ J 2010;40:131-6. 14. Gill AB, Weindling AM. Raised pulmonary artery pressure in very low birthweight infants requiring supplemental oxygen at 36 weeks after conception. Arch Dis Child Fetal Neonatal Ed 1995;72:F20-2. 15. Subhedar NV, Shaw NJ. Changes in pulmonary arterial pressure in preterm infants with chronic lung disease. Arch Dis Child 2000;82:F243-7. 16. King M, Braun H, Goldblatt A, Liberthson R, Weyman A. Interventricular septal configuration as a predictor of right ventricular systolic hypertension in children: a cross-sectional echocardiographic study. Circulation 1983;68:68-75. 17. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 18. Walsh M, Engle W, Laptook A, Kazzi SN, Buchter S, Rasmussen M, et al. Oxygen delivery through nasal cannulae to preterm infants: can practice be improved? Pediatrics 2005;116:857-61. 19. Gill AB, Weindling AM. Pulmonary artery pressure changes in the very low birthweight infant developing chronic lung disease. Arch Dis Child 1993;68:303-7. 20. Bhat R, Salas AA, Foster C, Carlo WA, Ambalavanan N. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 2012;129:e682-9. 21. Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354: 579-87. 22. Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics 2007;120:e272-82. 23. Williams MC, Wyble LE, O’Brien WF, Nelson RM, Schwenke JR, Casanova C. Persistent pulmonary hypertension of the neonate and asymmetric growth restriction. Obstet Gynecol 1998;91:336-41. 24. Woldesenbet M, Perlman JM. Histologic chorioamnionitis: an occult marker of severe pulmonary hypertension in the term newborn. J Perinatol 2005;25:189-92. 25. 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;121:317-25. 26. del Cerro MJ, Sabate Rotes A, Carton A, Deiros L, Bret M, Cordeiro M, et al. Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes. Pediatr Pulmonol 2014;49:49-59. 27. West JB, Tsukimoto K, Mathieu-Costello O, Prediletto R. Stress failure in pulmonary capillaries. J Appl Physiol 1991;70:1731-42.
Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia
913
THE JOURNAL OF PEDIATRICS
www.jpeds.com
28. Berkelhamer SK, Mestan KK, Steinhorn RH. Pulmonary hypertension in bronchopulmonary dysplasia. Semin Perinatol 2013;37:124-31. 29. Bancalari E, Claure N. Definitions and diagnostic criteria for bronchopulmonary dysplasia. Semin Perinatol 2006;30:164-70. 30. 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;101:40-6.
Vol. 165, No. 5 31. Abman SH. Monitoring cardiovascular function in infants with chronic lung disease of prematurity. Arch Dis Child 2002;87:F15-8. 32. Farquhar M, Fitzgerald DA. Pulmonary hypertension in chronic neonatal lung disease. Paediatr Respir Rev 2010;11:149-53. 33. Ambalavanan N, Mourani P. Pulmonary hypertension in bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol 2014; 100:240-6.
50 Years Ago in THE JOURNAL OF PEDIATRICS The Syndrome of Pancreatic Insufficiency and Bone Marrow Dysfunction Shwachman H, Diamond LK, Oski FA, Khaw K-T. J Pediatr 1964;65:645-63
I
n 1964, Shwachman et al described 5 children with diarrhea, failure to thrive, pancreatic exocrine enzyme insufficiency, neutropenia with bone marrow hypoplasia, elevated fetal hemoglobin, and growth retardation. A sixth child, a sibling of 2 of the children described, had growth failure with decreased pancreatic enzyme activity but normal bone marrow cellularity and no diarrhea. Concern for cystic fibrosis was dispelled on the basis of no pulmonary disease and a negative sweat test. It was postulated this was a new syndrome, possibly genetically predetermined because of the occurrence in siblings. Today we know this as Shwachman-Diamond syndrome (SDS), inheritance is autosomal recessive and about 90% of cases have an identifiable mutation in the Shwachman-Bodian-Diamond syndrome (SBDS) gene located on chromosome 7q11. The gene is involved in ribosome assembly, but its role in the clinical manifestations of SDS remains unknown. Estimated incidence of SDS is about 1 in 75 000 with a slight male predominance (1.6:1) but no racial or ethnic predilection. Patients typically present in infancy or early childhood with a variable combination of diarrhea/steatorrhea, growth failure, and recurrent infections. Pancreatic exocrine dysfunction results from fatty replacement of pancreatic acini, and imaging demonstrates a small shrunken pancreas or lipomatosis. Pancreatic function often improves with age and about one-half of affected children no longer require pancreatic supplements by age 4 years. Over 90% have neutropenia, which is intermittent in most but constant in about one-third of cases. This is related to bone marrow hypoplasia, which affects other cell lines in some patients. Growth failure is characteristic and does not improve with pancreatic supplements or resolution of pancreatic insufficiency. In addition to the features described by Shwachman, we now recognize a variety of additional manifestations including skeletal abnormalities such as metaphyseal dysostosis, developmental delay, learning disorders, and an increased risk for infections, myelodysplastic syndrome, and acute myeloid leukemia. Diagnosis is based on the characteristic clinical manifestations and confirmed by identifying a mutation in the SBDS gene. However, a negative genetic test does not exclude the diagnosis as 10% do not have a known mutation. When an SBDS mutation is identified, this can be used to screen other family members. Treatment is largely directed at specific clinical manifestations. In those with bone marrow failure, hematopoietic stem cell transplantation is an option although currently there are limited data on outcomes in these cases. Ivor D. Hill, MB, ChB, MD Division of Pediatric Gastroenterology Nationwide Children’s Hospital Columbus, Ohio http://dx.doi.org/10.1016/j.jpeds.2014.04.042
914
Mirza et al
ORIGINAL ARTICLES
November 2014
Table III. Real-time SpO2 monitoring during echocardiography P value
Echocardiogram Initial Initial SpO2 Minimum SpO2 Maximum SpO2 36 weeks’ PMA Initial SpO2 Minimum SpO2 Maximum SpO2
Table V. Clinical characteristics of infants with late PH at 36 wk PMA (n = 5)
Early PH (n = 10)* 92 (90-93) 80 (76-90) 94 (94-95) Late PH (n = 5)z 90 (90-91) 82 (61-88) 95 (93-95)
All data are median (IQR). *Data available for 9 infants. †Data available for 107 infants. zData available for 3 infants. xData available for 94 infants.
†
No PH (n = 110) 92 (90-92) 88 (81-90) 96 (94-96) No PH (n = 113)x 92 (90-92) 90 (84-91) 96 (94-97)
.35 .13 .10 .27 .14 .08
Infants with late PH Clinical features
1
2
3
4
5
Gestation (at birth) SGA Early PH BPD FiO2 > 0.3* Invasive ventilation* Upper airway problems† Pneumonia Sepsis PDA (at 36 wk) Miscellaneous
26+5 No No Severe No No No No No Yes No
24 No No Severe Yes Yes No Yes Yes No No
24+1 No No Severe Yes Yes Yes No No No No
25+3 No No Moderate No No No No No No ASD
27 Yes Yes Severe Yes No No No No No No
ASD, atrial septal defect; SGA, small for gestational age. *At the time of echocardiography (36 wk PMA). †Severe subglottic stenosis detected 1 week before echocardiography at 36 wk PMA.
Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia
914.e1