[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Figure 1.
CDH Study Group Staging System
CDH Study Group Staging System

A left diaphragmatic defect is shown as viewed from the peritoneal cavity looking toward the thorax. A, Smallest defect with the large majority of the hemidiaphragm present and a completely intramuscular defect that does not extend to the chest wall. B, Most (50%-75%) of the hemidiaphragm is present; this defect involves less than 50% of the chest wall. C, Approximately 25% of the hemidiaphragm is present; this defect involves more than 50% of the chest wall. D, With the largest defect, minimal or no diaphragm is present; this defect involves the vast majority of the chest wall and is also known as agenesis.

Figure 2.
Flowchart of Study Cohort
Flowchart of Study Cohort

iNO indicates inhaled nitric oxide; pHTN, pulmonary hypertension.

Figure 3.
Association Between Inhaled Nitric Oxide (iNO) Use, Center, and Mortality P = .01 for Trend
Association Between Inhaled Nitric Oxide (iNO) Use, Center, and Mortality P = .01 for Trend

Overall, there was a positive association between the trend of iNO use and mortality by center.

Figure 4.
Trend in Inhaled Nitric Oxide (iNO) and Extracorporeal Membrane Oxygenation (ECMO) Use Among Patients With Congenital Diaphragmatic Hernia
Trend in Inhaled Nitric Oxide (iNO) and Extracorporeal Membrane Oxygenation (ECMO) Use Among Patients With Congenital Diaphragmatic Hernia

There was an increasing trend of iNO use (R2 = 0.605; Cochran-Armitage test for trend, P = .01) but a relatively unchanged frequency of ECMO use (R2 = 0.067; Cochran-Armitage test for trend, P = .52) during the study period.

Table.  
Patient Characteristics of Those With and Without pHTN Who Received iNO
Patient Characteristics of Those With and Without pHTN Who Received iNO
1.
Kinsella  JP, Ivy  DD, Abman  SH.  Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension.  Semin Perinatol. 2005;29(2):123-128.PubMedGoogle ScholarCrossref
2.
Logan  JW, Rice  HE, Goldberg  RN, Cotten  CM.  Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies.  J Perinatol. 2007;27(9):535-549.PubMedGoogle ScholarCrossref
3.
Mohseni-Bod  H, Bohn  D.  Pulmonary hypertension in congenital diaphragmatic hernia.  Semin Pediatr Surg. 2007;16(2):126-133.PubMedGoogle ScholarCrossref
4.
Roberts  JD  Jr, Fineman  JR, Morin  FC  III,  et al; Inhaled Nitric Oxide Study Group.  Inhaled nitric oxide and persistent pulmonary hypertension of the newborn.  N Engl J Med. 1997;336(9):605-610.PubMedGoogle ScholarCrossref
5.
Ichinose  F, Roberts  JD  Jr, Zapol  WM.  Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential.  Circulation. 2004;109(25):3106-3111.PubMedGoogle ScholarCrossref
6.
Campbell  BT, Herbst  KW, Briden  KE, Neff  S, Ruscher  KA, Hagadorn  JI.  Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia.  Pediatrics. 2014;134(2):e420-e426.PubMedGoogle ScholarCrossref
7.
Neonatal Inhaled Nitric Oxide Study Group (NINOS).  Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia.  Pediatrics. 1997;99(6):838-845.PubMedGoogle ScholarCrossref
8.
Clark  RH, Kueser  TJ, Walker  MW,  et al; Clinical Inhaled Nitric Oxide Research Group.  Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn.  N Engl J Med. 2000;342(7):469-474.PubMedGoogle ScholarCrossref
9.
Finer  NN, Barrington  KJ.  Nitric oxide for respiratory failure in infants born at or near term.  Cochrane Database Syst Rev. 2001;(4):CD000399.PubMedGoogle Scholar
10.
Raval  MV, Wang  X, Reynolds  M, Fischer  AC.  Costs of congenital diaphragmatic hernia repair in the United States-extracorporeal membrane oxygenation foots the bill.  J Pediatr Surg. 2011;46(4):617-624.PubMedGoogle ScholarCrossref
11.
Porter  ME.  What is value in health care?  N Engl J Med. 2010;363(26):2477-2481.PubMedGoogle ScholarCrossref
12.
Carey  WA, Ellsworth  MA, Harris  MN.  Inhaled nitric oxide use in the neonatal intensive care unit: rising costs and the need for a new research paradigm.  JAMA Pediatr. 2016;170(7):639-640.PubMedGoogle ScholarCrossref
13.
Lally  KP, Lasky  RE, Lally  PA,  et al; Congenital Diaphragmatic Hernia Study Group.  Standardized reporting for congenital diaphragmatic hernia—an international consensus.  J Pediatr Surg. 2013;48(12):2408-2415.PubMedGoogle ScholarCrossref
14.
Nam  JM.  A simple approximation for calculating sample sizes for detecting linear trend in proportions.  Biometrics. 1987;43(3):701-705.PubMedGoogle ScholarCrossref
15.
Rubin  DB.  Estimating causal effects from large data sets using propensity scores.  Ann Intern Med. 1997;127(8 Pt 2):757-763.PubMedGoogle ScholarCrossref
16.
Becker  SO, Ichino  A.  Estimation of average treatment effects based on propensity scores.  Stata J. 2002;2:358-377.Google Scholar
17.
Austin  PC.  An introduction to propensity score methods for reducing the effects of confounding in observational studies.  Multivariate Behav Res. 2011;46(3):399-424.PubMedGoogle ScholarCrossref
18.
Haukoos  JS, Lewis  RJ.  The propensity score.  JAMA. 2015;314(15):1637-1638.PubMedGoogle ScholarCrossref
19.
Rosenbaum  PR, Rubin  DB.  The central role of the propensity score in observational studies for causal effects.  Biometrika. 1983;70(1):41-55.Google ScholarCrossref
20.
Pawlik  TD, Porta  NFM, Steinhorn  RH, Ogata  E, deRegnier  RA.  Medical and financial impact of a neonatal extracorporeal membrane oxygenation referral center in the nitric oxide era.  Pediatrics. 2009;123(1):e17-e24.PubMedGoogle ScholarCrossref
21.
Puligandla  PS, Grabowski  J, Austin  M,  et al.  Management of congenital diaphragmatic hernia: a systematic review from the APSA Outcomes and Evidence Based Practice Committee.  J Pediatr Surg. 2015;50(11):1958-1970.PubMedGoogle ScholarCrossref
Original Investigation
December 2016

Evaluation of Variability in Inhaled Nitric Oxide Use and Pulmonary Hypertension in Patients With Congenital Diaphragmatic Hernia

Author Affiliations
  • 1Department of Pediatric Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston
  • 2Department of Pediatric Surgery, Children’s Memorial Hermann Hospital, Houston, Texas
  • 3Department of Neonatology, Bambino Gesù Children’s Hospital, IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Rome, Italy
  • 4Department of Cardiothoracic and Vascular Surgery, McGovern Medical School, University of Texas Health Science Center, Houston
 

Copyright 2016 American Medical Association. All Rights Reserved.

JAMA Pediatr. 2016;170(12):1188-1194. doi:10.1001/jamapediatrics.2016.2023
Key Points

Question  What is the variability of inhaled nitric oxide use and its association with pulmonary hypertension and mortality among patients with congenital diaphragmatic hernia?

Findings  In this population-based study of 70 centers in 13 countries including 3367 patients with congenital diaphragmatic hernia, review of prospectively collected data from the Congenital Diaphragmatic Hernia Study Group registry demonstrated that inhaled nitric oxide use is widespread, highly variable, and frequently unrelated to pulmonary hypertension. Furthermore, the use of inhaled nitric oxide in this patient population may be associated with increased mortality.

Meaning  Inhaled nitric oxide is a costly and commonly used therapy among patients with congenital diaphragmatic hernia, yet its efficacy for improving survival is questionable.

Abstract

Importance  Inhaled nitric oxide (iNO) is an expensive, commonly used therapy among patients with congenital diaphragmatic hernia (CDH); however, data to support its ongoing use in this patient population are lacking.

Objective  To describe the spectrum of iNO use among patients with CDH and its association with pulmonary hypertension (pHTN) and mortality.

Design, Setting, and Participants  A review was conducted of prospectively collected patient data in the Congenital Diaphragmatic Hernia Study Group registry between January 1, 2007, and December 31, 2014, from 70 participating centers in 13 countries. A total of 3367 newborn infants diagnosed with CDH and entered into the registry were reviewed. On the basis of echocardiogram data, pHTN was defined as right ventricular systolic pressure greater than or equal to two-thirds of the systemic systolic pressure. Propensity score and regression analyses were performed.

Intervention  Use of iNO.

Main Outcomes and Measures  Variability in iNO use and its association with pHTN and mortality. These outcomes were formulated prior to data evaluation.

Results  Sixty-eight (97.1%) centers used iNO. Of 3367 patients with CDH (1366 [40.6%] females; median estimated gestational age, 38 weeks; range, 23-42 weeks), a total of 2047 (60.8%) received iNO; the mean percentage of those receiving iNO per center was 62.3% (range, 0%-100%). Median iNO dose and duration were 20 (range, 0.1-80) ppm and 8 (range, 0-100) days. Of the 2174 infants with pHTN, 1613 infants (74.2%) received iNO. Of the 943 infants without pHTN, 343 infants (36.4%) were treated with iNO. Based on propensity score analysis incorporating 10 clinically relevant variables, iNO use was significantly associated with increased mortality (average treatment effect on the treated: 0.15; 95% CI, 0.10-0.20).

Conclusions and Relevance  Inhaled nitric oxide use is common but highly variable among centers, and 36% of patients without pHTN received iNO therapy. Based on data from 70 centers, iNO use in patients with CDH may be associated with increased mortality. Future efforts should be directed toward data-driven standardization of iNO use to ensure cost-effective practices.

Introduction

Congenital diaphragmatic hernia (CDH) is an uncommon but complex syndrome associated with significant costs, morbidity, and mortality. Outcomes in neonates with CDH are primarily driven by the degree of pulmonary hypoplasia and pulmonary hypertension (pHTN), which often lead to respiratory failure.1 Multiple costly and complex treatment strategies, including permissive hypercapnia, high-frequency oscillatory ventilation, extracorporeal membrane oxygenation (ECMO), and inhaled nitric oxide (iNO) administration, are commonly used.2,3

The use of iNO has been demonstrated4 to improve oxygenation in neonates with persistent pHTN. After inhalation, iNO diffuses rapidly across the alveolar-capillary membrane and into the pulmonary vasculature where it causes local vasodilation and decreased ventilation perfusion mismatching.5 Despite iNO’s biological plausibility of efficacy and its common use among neonates with CDH,6 several high-quality studies7-9 have failed to demonstrate its role in improving survival or reducing ECMO use in this population when used as a rescue strategy. Treatment with iNO is very costly, with average daily charges greater than $5000.6 Not surprisingly, CDH is one of the top 5 most expensive conditions treated in the United States, with estimated annual health care costs likely exceeding $250 million.10 With the growing impetus to provide value-based care, health care systems and clinicians need to reexamine the ongoing use of expensive and unproven treatment strategies.11,12 The goals of the present study were to describe the spectrum of iNO use, identify its association with pHTN, and evaluate the effect of iNO on mortality among patients with CDH.

Methods
Data Source and Design

This study was a review of the Congenital Diaphragmatic Hernia Study Group (CDHSG) registry from January 1, 2007 (the beginning of data capture), to December 31, 2014. The CDHSG registry is a voluntary registry of live-born infants with CDH from more than 60 international institutions including more than 9000 total patients. Before the present study, institutional review board approval with waiver of informed consent was obtained from the University of Texas Health Science Center, Houston. Informed consent was not required since all data in the CDHSG registry are deidentified.

Relevant Outcomes

The primary outcome was variation in iNO use and its association with pHTN. The secondary outcome was mortality.

Covariates

Patient and clinical data, including estimated gestational age at birth, side of defect, CDHSG defect size staging system (categories A-D as shown in Figure 1),13 and echocardiogram findings, were reviewed. Patients were classified as having pHTN if their initial echocardiogram demonstrated a right ventricular systolic pressure that was two-thirds or more of the systemic systolic pressure; criteria were established a priori.3 Treatment and outcome data, including ECMO use, iNO use, and mortality, were also recorded. Only data from patients with posterolateral CDH defects were analyzed.

Statistical Analysis

Data were analyzed based on their distribution. Normally distributed categorical and continuous data were described using frequencies and means and analyzed with χ2 or 2-tailed, unpaired t tests, respectively. Nonparametric data were described using medians, and Mann-Whitney tests were performed. The Cochran-Armitage test14 for trend was used to evaluate the trends in iNO and ECMO use during the study period.

A propensity score analysis was also performed to evaluate the effect of iNO on mortality. Propensity score matching has been found15 to reduce bias introduced in large observational studies by imbalanced covariates between the treated and untreated groups. A propensity score designates the likelihood of receiving an intervention, and a score was assigned to each patient based on objective and clinically important factors, including sex, estimated gestational age, prenatal diagnosis, Apgar score at 5 minutes, inborn (born at the same hospital where the intervention occurred) or outborn (born at a different hospital than where the intervention occurred) status, side of defect, size of defect, pHTN status, and the presence of cardiac or chromosomal anomalies. Using the stratification method, we divided propensity scores into 10 different strata. The mean propensity scores between the treated and untreated patients in each stratum were assessed and balanced. Patients with incomplete data (missing echocardiogram and/or baseline characteristic data) were excluded from this analysis. The average of the treatment on the treated was estimated, which represents the absolute risk difference associated with the treatment.16,17 Bootstrapping of SEs was performed to compute 95% CIs. To further validate the findings of the propensity-stratified analysis and to adjust for potential clustering among centers, a propensity score–adjusted logistic regression analysis, using center as a random-effect parameter, was performed to evaluate the association between iNO use and mortality. All data were analyzed using Stata/IC, version 13.1 (StataCorp LP).

Results
Study Population

A total of 3367 patients from 70 centers were identified from 2007 to 2014 (8 years). The median number of patients per center was 49 (range, 1-116). There were 1366 females (40.6%), the median estimated gestational age was 38 (range, 23-42) weeks, and 2264 cases of CDH (67%) were diagnosed prenatally. A total of 1536 infants (46%) were inborn, 753 (22%) were premature, and 2830 (84%) had left-sided hernias. Among 2808 patients undergoing CDH repair, the distribution of diaphragmatic defect size was as follows: A, 387 (14%); B, 1138 (41%); C, 896 (32%); and D, 387 (14%). Major cardiac anomalies were documented for 269 patients (8%), and 197 patients (6%) had chromosomal anomalies.

Pulmonary Hypertension

Initial echocardiograms were performed for 3143 patients (93%). The median day of life at the time of the initial echocardiogram was 0 (0-8), and results from 3117 (99.2%) of these echocardiograms were recorded and available for analysis. A total of 2174 patients (69.7%) met the criteria for pHTN (Figure 2). Additional echocardiograms were performed for 2166 of the overall 3367 patients (64.3%) on median day of life 24 (range, 1-256). Of 2107 patients with 2 echocardiograms and evaluable data, 432 (20.5%) never had pHTN, 60 (2.8%) developed pHTN between the time of the first and second echocardiograms, 614 (29.1%) had persistent pHTN, and 1001 (47.5%) had resolution of pHTN by the second echocardiogram. Of 674 patients with pHTN demonstrated on the second echocardiogram, 24 (3.6%) had iNO initiated on or after the day of the second echocardiogram. Among the 60 infants who transitioned from not having pHTN on the first echocardiogram to having pHTN on the second echocardiogram, only 1 (1.7%) had iNO initiated on (and none after) the day of the second echocardiogram.

Variability in iNO Use

Sixty-eight centers (97.1%) used iNO during the study period. The mean percentage of patients treated with iNO by center was 62.3% (range, 0%-100%) (Figure 3). In addition, the mean percentage of patients receiving iNO treatment was found to be trending upward during the study period from as low as 58% in 2009 to 66% in 2013 (P = .01 for trend) (Figure 4).

A total of 2047 patients (60.8%) were treated with iNO. The median iNO dose was 20 (range, 0.1-80) ppm, treatment duration was 8 (range, 0-100) days, and day of life at iNO initiation was 1 (range, 0-189) day. Seventy patients (3.4%) received 2 iNO treatments, and 7 patients (0.3%) received more than 2 iNO treatments.

Of the 2174 patients with pHTN identified on the initial echocardiogram, 1613 patients (74.2%) were treated with iNO. Their median iNO dose, treatment duration, and day of life at initiation were 20 (range, 10-60) ppm, 9 (range, 0-100) days, and 0 (range, 0-174) days, respectively. A total of 943 patients (43.4%) had no pHTN, and 343 patients (36.4%) were treated with iNO. Overall, in the 943 patients without pHTN, median iNO dose, treatment duration, and day of life at initiation were 20 (range, 0.1-80) ppm, 6 (range, 0-91) days, and 0 (range, 0-189) days, respectively. Compared with the patients without pHTN who received iNO therapy, those with pHTN who received iNO were diagnosed prenatally more often, had lower Apgar scores at 5 minutes, and had larger CDH defect sizes overall (Table).

Nearly one-third of patients (989 [29.4%]) received ECMO during the study period. Patients diagnosed with pHTN were more likely to receive ECMO than were patients without pHTN (825 of 2174, 37.9%; vs 141 of 943; 15%; P < .001). Only 74 patients (7.5%) underwent ECMO without receiving iNO therapy, whereas 915 patients (92.5%) received both ECMO and iNO. Of these 915 patients, 843 individuals (92.1%) received iNO prior to or on the same day as ECMO. Of the 2378 patients who did not undergo ECMO during the study period, 1132 patients (47.6%) still received iNO. The frequency of ECMO use during the study period remained relatively unchanged (range, 27%-34%) (Figure 4).

Mortality

We found a positive association between the trend of iNO use and mortality per center (r2 = 0.605) (Figure 3). To better evaluate the association between iNO use and mortality, 2515 patients (1487 [59.1%] receiving iNO; 1028 [40.9%] not receiving iNO) were stratified into 10 propensity score strata. Eight hundred fifty-two patients (25.3%) were excluded from the original cohort (n = 3367) owing to incomplete data for an appropriate propensity analysis. The mean propensity score for this cohort of patients was 0.59 (range, 0.03-0.99), and the mean propensity scores for each treatment group were balanced within each strata. The average effect of the treatment on the treated of iNO on mortality was 0.15 (95% CI, 0.10-0.20), indicating that treatment with iNO was associated with a 15% higher absolute mortality rate when taking into account the multiple patient and operative characteristics listed previously.

The effect of the center on the association between iNO and mortality was further evaluated using a multilevel mixed-effects logistic regression model including the propensity score and using center as the random-effects variable. This model demonstrated that the effect of iNO on mortality remained unchanged.

Discussion

During the study period, the use of iNO was highly variable among centers, and more than one-third of the patients without pHTN still received iNO. Although iNO was being used with increasing frequency, the data from this multicenter study suggest that iNO use was not beneficial and may be associated with poorer outcomes. Although this finding is not altogether surprising, since patients with the most severe CDH are the most likely to receive this therapy and previous work6,7 has shown similar results, our analyses attempted to account for this selection bias in a robust way. Taken together, these findings emphasize the need for randomized trials to determine the efficacy of iNO in patients with CDH as well as the need for standardization of iNO treatment to optimize patient outcomes while ensuring cost-effective practices.

To our knowledge, this is one of the first studies to describe the variability in use of iNO among patients with CDH at a multinational level6 and the only one that has evaluated its use in the context of pHTN. Among the 70 centers in this study, 68 centers (97.1%) used iNO to treat patients with CDH, and the percentage of patients treated with iNO among these centers ranged from 28% to 100%. These findings are similar to those reported by Campbell and colleagues,6 who documented that, among the centers in the Pediatric Health Information System database from 2003 to 2011, iNO use by center ranged from 34% to 92%. In addition, a similar upward trend of iNO use among Pediatric Health Information System patients (1.4% per year) was noted in the CDHSG population (0.4% per year). When evaluated using pHTN data, the mean rate of iNO use increased in patients with pHTN (74.2%) but was not insignificant in patients without pHTN (36.4%). Dosing and duration of therapy were also variable, even among the pHTN and non-pHTN groups. The wide variation in iNO use among centers and the fact that more than one-third of patients without pHTN still received iNO demonstrate that current indications for its use are poorly defined and/or implemented.

To date, there is a paucity of data supporting the use of iNO in patients with CDH. One of the original trials4 examining the use of iNO found that it improved oxygenation in infants with persistent pHTN. However, the trial excluded several groups of patients, including those with CDH or those undergoing treatment strategies such as high-frequency oscillatory ventilation or ECMO, thereby limiting the generalizability of its results. The 1997 trial by the Neonatal Inhaled Nitric Oxide Study group7 is probably the most well-known study examining the use of iNO in patients with CDH. Due to lack of efficacy, the data safety monitoring committee stopped the trial prematurely since iNO failed to reduce the risk of death and led to higher ECMO use. A subsequent trial by Clark and colleagues8 found similar results in the post hoc analysis, concluding that iNO use among infants with CDH does not lead to reduced ECMO use. Several observational studies1,3,6 and a Cochrane review9 have also come to similar conclusions. The results of the present study are in line with these more recent data. In addition, by using a multicenter approach, including patient details such as echocardiogram-defined pHTN and defect size, and using both propensity stratification and regression analyses, our data strengthen the conclusion that iNO use in patients with CDH is likely ineffective and may even be harmful.

Although a randomized clinical trial would be the highest standard for evaluating iNO’s true efficacy in patients with CDH, the costs and efforts required to conduct such a study for this infrequent condition may be prohibitive. In this setting, propensity score analysis is particularly valuable because it can provide an approximation of the likely treatment effect with the least amount of bias.18 Essentially, a propensity score is the probability that a patient would receive the treatment of interest, and the score is derived from patient characteristics as well as characteristics of the treating physician and clinical environment.19 Using a large database, including as many important patient variables as possible, increasing the number of propensity score stratum, and achieving balance among the strata were all methods we used to strengthen our propensity score model.18 We reported the average effect of the treatment on the treated, as opposed to the average treatment effect, because average treatment effect is an estimation of the average effect of moving an entire population from untreated to treated, an effect that is most appropriately identified using randomized trial methodology.17 Although these sophisticated methods reduce the likelihood of bias and confounding when analyzing nonrandomized observational data, the time has come to consider an alternative research paradigm.12

Despite the lack of evidence to support its use, iNO continues to be administered regularly for patients with CDH, leading to increased health care costs without clear improvement in care.6,10,20 With more than 10% of hospital charges attributed to iNO therapy, which are greater than the costs of all other medication charges combined for patients with CDH,6 the implications of instituting evidence-based protocols for iNO use are clear. A recent systematic review21 from the American Pediatric Surgical Association’s Outcomes and Evidence-Based Practice Committee found that, based on level 2 evidence, iNO cannot be recommended to routinely treat pHTN in patients with CDH.

There are several limitations in this study. As a registry study, outcomes must be interpreted with caution because the data represent a wide spectrum of disease treated at a heterogeneous group of international institutions with potentially varied treatment strategies. Along these lines, initial and follow-up echocardiograms were not performed for all patients or at standardized times. That said, greater than 95% of the initial echocardiograms were performed within the first 48 hours of life. Nevertheless, echocardiograms are operator dependent, so results may be biased based on institutional proficiency or experience. Although one of the goals of this study was to evaluate the variability in iNO timing, dosing, and duration, the variability in treatment strategies also limited our ability to assess iNO therapy and its association with mortality. However, we performed a robust analysis using propensity score stratification matching, which helps to minimize the amount of bias from observational data. Finally, the registry does not capture cost data; thus, a cost analysis could not be conducted.

Conclusions

Use of iNO was highly variable among a large cohort of national and international institutions that treat patients with CDH. Current data are lacking to support the widespread use of iNO in this patient population because more recent data have found that its use may be associated with worse outcomes. Finally, as a very costly therapy, future efforts should be directed toward data-driven standardization of iNO use to ensure cost-effective practices.

Back to top
Article Information

Corresponding Author: Matthew T. Harting, MD, MS, Department of Pediatric Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, MSB 5.220, Houston, TX 77030 (matthew.t.harting@uth.tmc.edu).

Accepted for Publication: June 7, 2016.

Published Online: October 10, 2016. doi:10.1001/jamapediatrics.2016.2023

Author Contributions: Dr Harting had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Putnam, Tsao, Miller, K. P. Lally, Harting.

Acquisition, analysis, or intepretation of data: All authors.

Drafting of the manuscript: Putnam, Harting.

Critical revision of the manuscript for important intellectual content: Tsao, Morini, P. A. Lally, Miller, K. P. Lally, Harting.

Statistical analysis: Putnam, Tsao, Miller, Harting.

Obtaining funding: K. P. Lally, Harting.

Administrative, technical, or material support: P. A. Lally, K. P. Lally, Harting.

Study supervision: Tsao, K. P. Lally, Harting.

Conflict of Interest Disclosures: None reported.

Group Information: The Congenital Diaphragmatic Hernia Study Group consists of the following centers and contributors: Centers: Alberta Children’s Hospital, Calgary, Alberta, Canada; Arkansas Children’s Hospital, Little Rock; Astrid Lindgren Children’s Hospital, Stockholm, Sweden; Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; BC Children’s & Women's Health Centre, Vancouver, British Columbia, Canada; Carolinas Medical Center, Levine Children’s Hospital, Charlotte, North Carolina; Children’s Hospital & Research Center Oakland, Oakland, California; Children’s Hospital at Skanes University Hospital, Lund, Sweden; Children’s Hospital Boston, Boston, Massachusetts; Children's Hospital of Akron, Akron, Ohio; Children's Hospital of Illinois, Peoria; Children's Hospital of Los Angeles, Los Angeles, California; Children’s Hospital of Oklahoma, Oklahoma City; Children’s Hospital of Wisconsin, Milwaukee; Children’s Hospital Omaha, Omaha, Nebraska; Children’s Hospital, University Bonn, Bonn, Germany; Children's Hospitals and Clinics, Minneapolis, Minnesota; Children's Memorial Hermann Hospital, Houston, Texas; Children’s Hospital of Alabama, Birmingham; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Cleveland Clinic Foundation–Children’s Hospital, Cleveland, Ohio; Connecticut Children’s Medical Center, Hartford; Dell Children’s Medical Center of Central Texas, Austin; Duke University Medical Center, Durham, North Carolina; Emory University, Atlanta, Georgia; Georgia Health Sciences University, Augusta; Golisano Children’s Hospital at Strong, Rochester, New York; Hospital Clinico Universidad Católica de Chile, Santiago, Región Metropolitana, Chile; IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; Juan P. Garrahan Children’s Hospital, Buenos Aires, Argentina; Kosair Children’s Hospital, Louisville, Kentucky; Le Bonheur Children’s Medical Center, Memphis, Tennessee; Legacy Emanuel Children’s Hospital, Portland, Oregon; Loma Linda University Children’s Hospital, Loma Linda, California; Lucile Salter Packard Children’s Hospital, Palo Alto, California; Mattel Children’s Hospital at UCLA, Los Angeles, California; Miami Valley Hospital, Dayton, Ohio; National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan; NICU Health Sciences Centre, Winnipeg, Manitoba, Canada; Ospedale Pediatrico Bambino Gesù, Rome, Italy; Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Palmetto Health Richland, Columbia, South Carolina; Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland; Primary Children’s Hospital, Salt Lake City, Utah; Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia; Research Institute at Nationwide Children’s Hospital, Columbus, Ohio; Royal Children's Hospital, Parkville, Victoria, Australia; Royal Hospital for Sick Children, Glasgow, Scotland; San Diego Children's Hospital, San Diego, California; Shands Children’s Hospital/University of Florida, Gainesville; Sophia Children’s Hospital, Rotterdam, the Netherlands; St Francis Children’s Hospital, Tulsa, Oklahoma; St Joseph’s Hospital and Medical Center, Phoenix, Arizona; St Louis Children's Hospital, St. Louis, Missouri; Stollery Children’s Hospital, Edmonton, Alberta, Canada; Sydney Children’s Hospital, Randwick, New South Wales, Australia; The Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania; The Hospital for Sick Children, Toronto, Ontario, Canada; UNC School of Medicine, Chapel Hill; University of Malaya Medical Centre, Kuala Lumpur, Malaysia; University of Michigan, C. S. Mott Children’s Hospital, Ann Arbor; University of Nebraska Medical Center, Omaha; University of Padua, Padua, Italy; University of Texas Medical Branch at Galveston, Galveston; University of Virginia Medical School, Charlottesville; Vanderbilt Children’s Hospital, Nashville, Tennessee; Vladivostok State Medical University, Vladivostok, Russia; Winnie Palmer Hospital for Women & Babies, Orlando, Florida; and Yale-New Haven Children's Hospital, New Haven, Connecticut. Contributors: Mary Brindle, MD; Melvin Dassinger III, MD; Allen Harrison, MD, BSN; Bjorn Frenckner, MD; Cristina Bellan, MD; Stefania Pedretti, MD; Erik Skarsgard, MD; Golde Dudell, MD; David Durand, MD; Kristina Bergentz, MD; Jana Brodszki, MD; Kristjan Dereksson, MD; Lars Lindberg, MD; Povilas Sladkevicius, MD; Lil Valentin, MD; Gunnar Westbacke, MD; Hans Winberg, MD; Terry Buchmiller, MD; Tom Jaksic, MD; Jay Wilson, MD; David Andrews, MD; Harriet Feick, MD; Kamlesh Macwan, MD; James Stein, MD; Robert Letton, MD; Cameron Mantor, MD; Susan Day, MD; Ganesh Konduri, MD; Shahab Abdessalam, MD; Robert Cusick, MD; Brian Jones, MD; Stephen Raynor, MD; Florian Kipfmueller, MD; Aaron Swenson, MD; Matthew Harting, MD; Kevin Lally, MD; Pam Lally, MD; Tiffany Ostovar-Kermani, MD, MPH; KuoJen Tsao, MD; Scott Anderson, MD; Mike Chen, MD; Reed Dimmitt, MD; Robert Russell, MD; Beth Haberman, MD; Foong Lim, MD; James Hagadorn, MD; Jeffrey Horowitz, MD; Obinna Adibe, MD; Augusto Sola, MD; Mark Wulkan, MD; Jatinder Bhatia, MD; Charles Howell, MD; Timothy Stevens, MD; Matias Luco, MD; Lorenna Canazza, MD; Mariarosa Colnaghi, MD; Antonio Di Ceasare, MD; Valerio Gentilino, MD; Ernesto Leva, MD; Maurizio Torricelli, MD; Mara Vanzati, MD; Diana Farina, MD; Gisela Salas, MD; Cynthia Downard, MD; Dan Stewart, MD; Tim Jancelewicz, MD; Max Langham, MD; Martha Nelson, MD; Joanne Baerg, MD; Don Moores, MD; Ed Tagge, MD; Krisa Van Meurs, MD; James Dunn, MD; Stephen Shew, MD; Jeffrey Christian, MD; Tamisha Samiec, MD; Shoichiro Amari, MD; Keiji Goishi, MD; Michael Narvey, MD; Pietro Bagolan, MD; Irma Capolupo, MD; Francesco Morini, MD; Laura Valfrè, MD; Hiroomi Okuyama, MD; Stanton Adkins, MD; Juan Camps, MD; David Marsh, MD; Stephen Watson, MD; Iwona Maroszyńska, MD, PhD; Marta Niedźwiecka, MD; Katarzyna Piestrzeniewicz, MD; Douglas Barnhart, MD; Shaji Menon, MD; Rebecka Meyers, MD; Michael Rollins, MD; Bradley Yoder, MD; Horst Scharbatke, MD; Arno van Heijst, MD; Artem Burov, MD; Dimitry Degtyarev, MD; Larry Moss, MD; Leif Nelin, MD; Rod Hunt, MD; Ricardo Palma Dias, MD; Michael Stewart, MD; Russell Taylor, MD; Carl Davis, MD; Denise Suttner, MD; Ulrike Kraemer, MD; Dick Tibboel, MD; Danielle Veenma, MD; Rachel Davis-Jackson, MD; Mark Molitor, MD; Tasnim Najaf, MD; Adam Vogel, MD; Brad Warner, MD; Santiago Ensenat, MD; Ernest Phillipos, MD; Bruce Currie, MD; Guy Henry, MD; Andrew Numa, MD; Beverly Brozanski, MD; Burhan Mahmood, MD; Doug Potoka, MD; Priscilla Chiu, MD; Peter Cox, MD; Sean Mclean, MD; Lucy Lum Chai See, MD; Chin Seng Gan, MD; Anis Siham Zainal Abidin, MD; Ronald Hirschl, MD; Ann Mehringer, MD; Ann Anderson, MD; Piergiorgio Gamba, MD; Paola Lago, MD; Alberto Sgro, MD; Rafael Fonseca, MD; Ravi Radhakrishnan, MD; David Kaufman, MD; Eugene McGahren, MD; Martin Blakely, MD; Dai Chung, MD; John Pietsch, MD; William Walsh, MD; Anna Shapkina, MD, PhD; Gregor Alexander, MD; Jose Perez, MD; and Orly Levit, MD.

Additional Contributions: We acknowledge the ongoing contributions of highly committed Congenital Diaphragmatic Hernia Study Group member centers that voluntarily participated in the study of congenital diaphragmatic hernia.

References
1.
Kinsella  JP, Ivy  DD, Abman  SH.  Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension.  Semin Perinatol. 2005;29(2):123-128.PubMedGoogle ScholarCrossref
2.
Logan  JW, Rice  HE, Goldberg  RN, Cotten  CM.  Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies.  J Perinatol. 2007;27(9):535-549.PubMedGoogle ScholarCrossref
3.
Mohseni-Bod  H, Bohn  D.  Pulmonary hypertension in congenital diaphragmatic hernia.  Semin Pediatr Surg. 2007;16(2):126-133.PubMedGoogle ScholarCrossref
4.
Roberts  JD  Jr, Fineman  JR, Morin  FC  III,  et al; Inhaled Nitric Oxide Study Group.  Inhaled nitric oxide and persistent pulmonary hypertension of the newborn.  N Engl J Med. 1997;336(9):605-610.PubMedGoogle ScholarCrossref
5.
Ichinose  F, Roberts  JD  Jr, Zapol  WM.  Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential.  Circulation. 2004;109(25):3106-3111.PubMedGoogle ScholarCrossref
6.
Campbell  BT, Herbst  KW, Briden  KE, Neff  S, Ruscher  KA, Hagadorn  JI.  Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia.  Pediatrics. 2014;134(2):e420-e426.PubMedGoogle ScholarCrossref
7.
Neonatal Inhaled Nitric Oxide Study Group (NINOS).  Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia.  Pediatrics. 1997;99(6):838-845.PubMedGoogle ScholarCrossref
8.
Clark  RH, Kueser  TJ, Walker  MW,  et al; Clinical Inhaled Nitric Oxide Research Group.  Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn.  N Engl J Med. 2000;342(7):469-474.PubMedGoogle ScholarCrossref
9.
Finer  NN, Barrington  KJ.  Nitric oxide for respiratory failure in infants born at or near term.  Cochrane Database Syst Rev. 2001;(4):CD000399.PubMedGoogle Scholar
10.
Raval  MV, Wang  X, Reynolds  M, Fischer  AC.  Costs of congenital diaphragmatic hernia repair in the United States-extracorporeal membrane oxygenation foots the bill.  J Pediatr Surg. 2011;46(4):617-624.PubMedGoogle ScholarCrossref
11.
Porter  ME.  What is value in health care?  N Engl J Med. 2010;363(26):2477-2481.PubMedGoogle ScholarCrossref
12.
Carey  WA, Ellsworth  MA, Harris  MN.  Inhaled nitric oxide use in the neonatal intensive care unit: rising costs and the need for a new research paradigm.  JAMA Pediatr. 2016;170(7):639-640.PubMedGoogle ScholarCrossref
13.
Lally  KP, Lasky  RE, Lally  PA,  et al; Congenital Diaphragmatic Hernia Study Group.  Standardized reporting for congenital diaphragmatic hernia—an international consensus.  J Pediatr Surg. 2013;48(12):2408-2415.PubMedGoogle ScholarCrossref
14.
Nam  JM.  A simple approximation for calculating sample sizes for detecting linear trend in proportions.  Biometrics. 1987;43(3):701-705.PubMedGoogle ScholarCrossref
15.
Rubin  DB.  Estimating causal effects from large data sets using propensity scores.  Ann Intern Med. 1997;127(8 Pt 2):757-763.PubMedGoogle ScholarCrossref
16.
Becker  SO, Ichino  A.  Estimation of average treatment effects based on propensity scores.  Stata J. 2002;2:358-377.Google Scholar
17.
Austin  PC.  An introduction to propensity score methods for reducing the effects of confounding in observational studies.  Multivariate Behav Res. 2011;46(3):399-424.PubMedGoogle ScholarCrossref
18.
Haukoos  JS, Lewis  RJ.  The propensity score.  JAMA. 2015;314(15):1637-1638.PubMedGoogle ScholarCrossref
19.
Rosenbaum  PR, Rubin  DB.  The central role of the propensity score in observational studies for causal effects.  Biometrika. 1983;70(1):41-55.Google ScholarCrossref
20.
Pawlik  TD, Porta  NFM, Steinhorn  RH, Ogata  E, deRegnier  RA.  Medical and financial impact of a neonatal extracorporeal membrane oxygenation referral center in the nitric oxide era.  Pediatrics. 2009;123(1):e17-e24.PubMedGoogle ScholarCrossref
21.
Puligandla  PS, Grabowski  J, Austin  M,  et al.  Management of congenital diaphragmatic hernia: a systematic review from the APSA Outcomes and Evidence Based Practice Committee.  J Pediatr Surg. 2015;50(11):1958-1970.PubMedGoogle ScholarCrossref
×