Journal Information
Vol. 96. Issue 5.
Pages 527-532 (September - October 2020)
Vol. 96. Issue 5.
Pages 527-532 (September - October 2020)
Open Access
Congenital diaphragmatic hernia: 25 years of shared knowledge; what about survival?
Hérnia diafragmática congênita: 25 anos de conhecimento compartilhado; e a sobrevivência?
Satyan Lakshminrusimha, Payam Vali
Corresponding author

Corresponding author.
University of California, Department of Pediatrics, Davis, United States
This item has received

Under a Creative Commons license
Article information
Full Text
Download PDF
Figures (3)
Show moreShow less
Full Text

Congenital diaphragmatic hernia (CDH) remains one of the most dreaded congenital anomalies in the neonatal intensive care units (NICUs). Herniation of the abdominal organs through a malformed and defective diaphragm during fetal development can lead to near-lethal pulmonary hypoplasia and cardiac deformation. Severe persistent pulmonary hypertension of the newborn (PPHN), hypoxic respiratory failure, and cardiac dysfunction often complicate the medical course of newborns with CDH. Recognizing the interdependence of the pulmonary and cardiovascular systems, especially in the context of abnormal physiology, is of paramount importance when providing medical management to these patients.

The incidence of CDH is estimated at approximately one case per 3,000 live births. A reliable estimation, however, is complicated by termination of pregnancy, inaccurate data collection, and unreported cases of newborns who die of the disease without a known prenatal diagnosis (referred to as “hidden mortality”).1 The condition is uncommon enough so that the majority of regional NICUs manage less than a dozen cases of CDH annually, which also explains the ongoing challenges in conducting prospective randomized studies. In 1995, the CDH Study Group (CDHSG) registry was established with the purpose to unite tertiary referral centers across four continents to compile data on live born infants with CDH, and to assess therapies and outcomes.2 Short of randomized controlled trials, registries such as the CDHSG and observational studies such as the study by Carmo et al.3 in this issue of Jornal de Pediatria provide an important source of knowledge.

There were 129 newborns with a prenatal diagnosis of CDH delivered at a large NICU in Rio de Janeiro, Brazil during the years 2005–2015. The reported newborn characteristics (i.e., gestational age at birth, sex, side of the CDH, liver herniation, associated incidence of congenital anomalies, etc.) are similar to other published reports on CDH. The overall mortality of 61%, however, is significantly higher compared to the estimated mortality of approximately 20–30% reported from large registries that include centers where extracorporeal membrane oxygenation (ECMO) is available.2–6 This large discrepancy in mortality can partly be explained by the lack of ECMO. Given that 30.3% of CDH patients reported to the registry between 2007 and 2013 were placed on ECMO4 and nearly 51% of CDH undergoing ECMO do not survive,7 only half of the deaths reported by Carmo et al.3 can probably explained by lack of ECMO. Gaining a better understanding on why mortality would be so much higher in a large tertiary NICU with other resources is crucial to identify areas of inadequacy that can be addressed to improve outcomes. As is the nature with observational studies, the present work suffers from limitations that make interpretation of the prognostic indicators incomplete. No information is provided regarding fetal lung volume assessment, echocardiographic assessment of cardiac function, or defect size, factors that have all shown to strongly correlate with survival (Fig. 1).

Figure 1.

Factors associated with poor prognosis in congenital diaphragmatic hernia (CDH).

Antenatal factors such as low fetal lung volume, associated anomalies (especially cardiac), polyhydramnios, abnormal karyotype, and liver in the chest can be associated with lower survival. Postnatal factors associated with severe pulmonary hypertension (low PaO2), lung hypoplasia (high PaCO2), large defect requiring patch repair, ventricular dysfunction, and need for vasoactive agents and/or ECMO are associated with higher mortality.

Copyright Satyan Lakshminrusimha.


The relationship between diaphragmatic defect size and survival was first reported following the analysis of 3,062 cases of CDH from data gathered by the CDHSG registry spanning nine years from 1995 to 2004, and the size of the defect has been found to have the most important impact on survival.8 Thereafter, a classification system including defect size (graded “A” for small to “D” as agenesis of the diaphragm – Fig. 1)9 and presence or absence of associated major cardiac anomalies has been included in the data analysis. Later reports have shown that babies with a size “A” defect and no major cardiac anomalies have a survival of 99%, compared to 39% survival in patients who have a size “D” defect with a major congenital heart defect.10 The most recent analysis from the CDHSG registry – including 7,617 cases since the inception of the registry in 1995 until 2013 – has reported a marginal increase in overall survival from 67.6% in 1995–2000 to 71.6% in 2007–2013.4 However, patients who required a patch repair saw a greater increase in survival, from 68.1% to 76.9%.4 In spite of a possible higher incidence of larger defects over the past couple of decades, as indicated by the greater need for patch repair, the improved survival in these patients shows a promising trend. It should be kept in mind, however, that most centers in this registry have access to ECMO, which may increase the chances of survival.11

Prenatal diagnosis of CDH, better imaging modalities (magnetic resonance imaging [MRI] vs. ultrasound), and the use of fetal echocardiography can provide information that may help determine success of survival and need for ECMO. Data from the Canadian Pediatric Surgery Network including 140 infants with antenatally diagnosed CDH (75 inborn and 65 outborn) reported that the likelihood of mortality was significantly higher for outborn deliveries (odds ratio 2.8) when adjusting for severity of illness.6 In the aforementioned study, mortality between inborn and outborn infants did not reach statistical significance at 17/75 (20%) compared to 21/65 (38%), respectively (p = 0.25). However, inborn patients had a significantly higher illness severity score. In a more recent analysis from data of the Diaphragmatic Hernia Research and Exploration, Advancing Molecular Science (DHREAMS) study including 220 cases of CDH, patients that were transferred (i.e., outborn) to one of the seven referring centers had higher survival, at 85% (68/80) compared to 71.4% (100/140) for inborn patients.5 No definitive conclusions can be drawn in respect to these studies regarding survival rate and location of delivery, but the data support that outborn newborns with a diagnosis of CDH who survive transfer to a referral center may have less severe disease.

If a prenatal diagnosis of CDH is confirmed, careful fetal evaluation by ultrasound, MRI, and fetal echocardiography can identify several prognostic predictors of newborn outcomes, which include herniation of the liver into the thoracic cavity, assessment of lung volume (e.g., lung-to-head ratio [LHR], percent predicted lung volume [PPLV], and total lung volume [TLV]), evidence of left ventricular (LV) hypoplasia, and any associated congenital anomalies.12 In a recent meta-analysis, confirmation of liver herniation (407 fetuses) compared to no visualization of the liver in the thoracic cavity (303 fetuses) was associated with significantly lower survival (45.4% vs. 73.9%, respectively).13 Furthermore, need for ECMO has been found to be significantly higher in cases of CDH with liver herniation.14 MRI has shown to have superior predictive value compared to ultrasound in assessing lung volume.15 PPLV < 15% and TLV < 20 mL have been shown to be strong predictors of poor outcome and higher ECMO use,16 as would be expected, since lower lung volumes imply severe hypoplasia. Estimation of fetal lung volume can, therefore, improve survival of the most severely affected infants if maternal transfer prior to delivery to a center with ECMO capability can be arranged.

Observations made on post-mortem anatomy studies over three decades ago in infants who died of CDH revealed hypoplastic left hearts and decreased cardiac mass.17 In addition, fetal echocardiography studies in fetuses with CDH showing evidence of LV hypoplasia before 24 weeks gestation have reported 100% mortality after birth.18 Recently, early assessment of cardiac function by echocardiography in infants with CDH has shown that decreased cardiac function is a better predictor for the need for ECMO than severity of pulmonary hypertension.19

The timing and preferred mode of delivery in CDH pregnancies continues to be controversial. Stevens et al. initially suggested that early term delivery may confer an advantage in CDH.20 However, Hutcheon et al. showed that infant mortality significantly decreased with advancing gestation, from 36% at 37 weeks of gestation to 20% at 40 weeks of gestation.21 In addition, a study by Odibo et al. of 107 CDH cases found that gestational age at delivery was inversely correlated to the need for ECMO.22 In contrast, Safavi et al. found no difference in mortality when dividing gestational age at delivery categorically as under 37 weeks, 37–38 weeks, and beyond 39 weeks.23 There was no difference in mortality between vaginal and cesarean delivery. In the absence of strong evidence, it seems reasonable to schedule delivery at 39 weeks or beyond and in a setting with access to tertiary NICU services.

Delayed cord clamping is being investigated in a pilot trial for infants born with CDH (NCT03314233). Studies in lambs suggest that physiological/delayed cord clamping reduces pulmonary vascular resistance (PVR) and significantly increases pulmonary blood flow in CDH.24 A strategy combining ventilation using lower levels of inspired oxygen with lower ventilator pressures25,26 and with an intact cord might be an effective approach during the delivery room resuscitation of CDH (Fig. 2).

Figure 2.

Delivery room management in congenital diaphragmatic hernia (CDH).

Oxidative stress plays an important role in the pathogenesis of pulmonary hypertension and injury to hypoplastic lungs in CDH. Delayed cord clamping, limiting barotrauma (with low ventilator pressures), and restricting FiO2 to target preductal SpO2 in the mid-80 s to low 90 s are important strategies to limit oxidative stress in CDH.

DCC, delayed cord clamping; PEEP, positive end-expiratory pressure.

Copyright Satyan Lakshminrusimha.


CDH is a complex and unforgiving syndrome, whereby an incomplete understanding of the pathophysiology underlying the hypoxic respiratory failure – as well as the associated PPHN and cardiac dysfunction – can risk an abrupt deterioration of the patient if medical management is not optimized. The hypoplastic lungs are particularly sensitive to ventilator-induced lung injury. Gentle ventilation using low tidal volumes (3–4 mL/kg), low mean airway pressures, and low positive end-expiratory pressure (thereby accepting permissive hypercapnia with CO2 values between 50–65 mm Hg) have shown to improve outcomes and should be considered before high-frequency ventilation.27 Ensuring adequate preductal oxyhemoglobin saturation (SpO2) targets (85–95%) and preventing extremes of hypoxemia (SpO2 < 80%; shown to increase pulmonary vascular resistance) or hyperoxia (SpO2 >95%; known to produce excess reactive oxygen species and cause biotrauma) will optimize oxygenation (Fig. 3).28

Figure 3.

Postnatal management of congenital diaphragmatic hernia (CDH) in the neonatal intensive care unit (NICU).

Tolerating preductal oxygenation saturations in 85–95% range, preference of conventional ventilation with a low PEEP, and permissive hypercapnia using strategies of gentle ventilation are important elements of NICU management of CDH.

HFJV, high frequency jet ventilation; CMV, conventional mechanical ventilation; HFOV, high frequency oscillatory ventilation; PEEP, positive end-expiratory pressure; PIP, positive inspiratory pressure.

Copyright Satyan Lakshminrusimha.


Despite clinicians’ best efforts to adopt lung protective strategies and readily available access to selective pulmonary vasodilators (e.g., inhaled nitric oxide [iNO]), the overall number of infants who are placed on ECMO has not changed over the past decade. CDH remains the most common indication to start ECMO, and only approximately half of patients survive to discharge.7 The reason there has been no decrease in the number of CDH ECMO cases and no improvement in survival following ECMO in this population could be because contemporary CDH patients rescued onto ECMO are more critically ill as a result of better medical management compared to their predecessors a few years ago.

Emerging evidence suggests that cardiac dysfunction (especially decreased LV function) may be at the root of impending irreversible cardiopulmonary failure, more so than the severity of PPHN.19,29,30 Poor LV function would be expected to lead to increased left atrial pressure with resultant pulmonary venous congestion and increased pulmonary venous pressure. Decreasing pulmonary arterial pressure in the setting of poor LV function can lead to pulmonary edema and further exacerbate respiratory status. Supporting cardiac function, therefore, may be as critical as managing PPHN in infants with CDH. The role of milrinone (a pulmonary vasodilator also known to have cardiac inotropic and lusitropic effects) is currently being evaluated in a randomized trial in participating centers of the neonatal research network.31 A concomitant European multicenter randomized controlled trial is investigating intravenous sildenafil and iNO incorporating cardiac function assessment (CoDiNOS trial – EudraCT number 2017-000421-13).

Creating algorithms that address the cardiac pathophysiology associated with CDH is likely to lead to substantial improvements in the care of these patients. The aforementioned clinical trials investigating the role of cardiotropic and pulmonary vasodilator drugs may help resolve this hypothesis and improve survival. An evidence-based and systematic approach to CDH management in the delivery room (Fig. 2) and NICU (Fig. 3) has the potential to reduce mortality.


The work has been supported by NIH grants HD096299 (PV) and HD072929 (SL).

Conflicts of interest

The authors declare no conflicts of interest.

M.R. Harrison, N.S. Adzick, J.M. Estes, L.J. Howell.
A prospective study of the outcome for fetuses with diaphragmatic hernia.
JAMA, 271 (1994), pp. 382-384
M.T. Harting, K.P. Lally.
The congenital diaphragmatic hernia study group registry update.
Semin Fetal Neonatal Med, 19 (2014), pp. 370-375
R.I. Carmo, F.M. Filho, A. Bueno, M. Fonseca, S.C. Junior.
Prognostic factors of death in children during the first year of life due to congenital diaphragmatic hernia: analysis of a hospital cohort from 2005 to 2015.
F. Morini, K.P. Lally, P.A. Lally, R.M. Crisafulli, I. Capolupo, P. Bagolan.
Treatment strategies for congenital diaphragmatic hernia: change sometimes comes bearing gifts.
Front Pediatr, 5 (2017), pp. 195
J. Wynn, U. Krishnan, G. Aspelund, Y. Zhang, J. Duong, C.J. Stolar, et al.
Outcomes of congenital diaphragmatic hernia in the modern era of management.
A. Nasr, J.C. Langer, C.P.S. Network.
Influence of location of delivery on outcome in neonates with congenital diaphragmatic hernia.
J Pediatr Surg, 46 (2011), pp. 814-816
M.L. Paden, S.A. Conrad, P.T. Rycus, R.R. Thiagarajan, E.L.S.O. Registry.
Extracorporeal life support organization registry report 2012.
ASAIO Journal, 59 (2013), pp. 202-210
K.P. Lally, P.A. Lally, R.E. Lasky, D. Tibboel, T. Jaksic, J.M. Wilson, et al.
Defect size determines survival in infants with congenital diaphragmatic hernia.
Pediatrics, 120 (2007), pp. e651-7
K.P. Lally, R.E. Lasky, P.A. Lally, P. Bagolan, C.F. Davis, B.P. Frenckner, et al.
Standardized reporting for congenital diaphragmatic hernia – an international consensus.
J Pediatr Surg, 48 (2013), pp. 2408-2415
F. Morini, L. Valfrè, I. Capolupo, K.P. Lally, P.A. Lally, P. Bagolan, et al.
Congenital diaphragmatic hernia: defect size correlates with developmental defect.
J Pediatr Surg, 48 (2013), pp. 1177-1182
D.W. Kays.
ECMO in CDH: is there a role?.
Semin Pediatr Surg, 26 (2017), pp. 166-170
D. Chatterjee, R.J. Ing, J. Gien.
Update on congenital diaphragmatic hernia.
Anesth Analg, (2019),
D. Mullassery, M.E. Ba’ath, E.C. Jesudason, P.D. Losty.
Value of liver herniation in prediction of outcome in fetal congenital diaphragmatic hernia: a systematic review and meta-analysis.
Ultrasound Obstet Gynecol, 35 (2010), pp. 609-614
H.L. Hedrick, E. Danzer, A.M. Merchant, M.W. Bebbington, H. Zhao, A.W. Flake, et al.
Liver position and lung-to-head ratio for prediction of extracorporeal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia.
Am J Obstet Gynecol, 197 (2007), pp. e1-4
M. Bebbington, T. Victoria, E. Danzer, J. Moldenhauer, N. Khalek, M. Johnson, et al.
Comparison of ultrasound and magnetic resonance imaging parameters in predicting survival in isolated left-sided congenital diaphragmatic hernia.
Ultrasound Obstet Gynecol, 43 (2014), pp. 670-674
T.C. Lee, F.Y. Lim, S.G. Keswani, J.S. Frischer, B. Haberman, P.S. Kingma, et al.
Late gestation fetal magnetic resonance imaging-derived total lung volume predicts postnatal survival and need for extracorporeal membrane oxygenation support in isolated congenital diaphragmatic hernia.
J Pediatr Surg, 46 (2011), pp. 1165-1171
J.R. Siebert, J.E. Haas, J.B. Beckwith.
Left ventricular hypoplasia in congenital diaphragmatic hernia.
J Pediatr Surg, 19 (1984), pp. 567-571
D.C. Crawford, V.M. Wright, D.P. Drake, L.D. Allan.
Fetal diaphragmatic hernia: the value of fetal echocardiography in the prediction of postnatal outcome.
Br J Obstet Gynaecol, 96 (1989), pp. 705-710
G. Altit, S. Bhombal, K. Van Meurs, T.A. Tacy.
Ventricular performance is associated with need for extracorporeal membrane oxygenation in newborns with congenital diaphragmatic hernia.
J Pediatr, 191 (2017), pp. 28-34
T.P. Stevens, E. van Wijngaarden, K.G. Ackerman, P.A. Lally, K.P. Lally.
Timing of delivery and survival rates for infants with prenatal diagnoses of congenital diaphragmatic hernia.
Pediatrics, 123 (2009), pp. 494-502
J. Hutcheon, B. Butler, S. Lisonkova, G. Marquette, C. Mayer, A. Skoll, et al.
Timing of delivery for pregnancies with congenital diaphragmatic hernia.
A.O. Odibo, T. Najaf, A. Vachharajani, B. Warner, A. Mathur, B.W. Warner.
Predictors of the need for extracorporeal membrane oxygenation and survival in congenital diaphragmatic hernia: a center’s 10-year experience.
Prenat Diagn, 30 (2010), pp. 518-521
A. Safavi, Y. Lin, E.D. Skarsgard, Canadian Pediatric Surgery Network.
Perinatal management of congenital diaphragmatic hernia: when and how should babies be delivered? Results from the Canadian Pediatric Surgery Network.
J Pediatr Surg, 45 (2010), pp. 2334-2339
A.J. Kashyap, R.J. Hodges, M. Thio, K.A. Rodgers, B.J. Amberg, E.V. McGillick, et al.
Physiologically based cord clamping improves cardiopulmonary haemodynamics in lambs with a diaphragmatic hernia.
Arch Dis Child Fetal Neonatal Ed, (2019),
J.S. Riley, R.M. Antiel, N.E. Rintoul, A.M. Ades, L.N. Waqar, N. Lin, et al.
Reduced oxygen concentration for the resuscitation of infants with congenital diaphragmatic hernia.
J Perinatol., 38 (2018), pp. 834-843
S. Lakshminrusimha, D.D. Swartz, S.F. Gugino, C.X. Ma, K.A. Wynn, R.M. Ryan, et al.
Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension.
Pediatr Res., 66 (2009), pp. 539-544
K.G. Snoek, I. Capolupo, J. van Rosmalen, Le J. Hout, S. Vijfhuize, A. Greenough, et al.
Conventional mechanical ventilation versus high-frequency oscillatory ventilation for congenital diaphragmatic hernia: a randomized clinical trial (The VICI-trial).
Ann Surg, 263 (2016), pp. 867-874
P. Vali, S. Lakshminrusimha.
The fetus can teach us: oxygen and the pulmonary vasculature.
Children (Basel), 4 (2017),
N. Patel, A.C. Massolo, A. Paria, E.J. Stenhouse, L. Hunter, E. Finlay, et al.
Early postnatal ventricular dysfunction is associated with disease severity in patients with congenital diaphragmatic hernia.
J Pediatr, 203 (2018),
J.P. Kinsella, R.H. Steinhorn, M.P. Mullen, R.K. Hopper, R.L. Keller, D.D. Ivy, et al.
The left ventricle in congenital diaphragmatic hernia: implications for the management of pulmonary hypertension.
J Pediatr., 197 (2018), pp. 17-22
S. Lakshminrusimha, M. Keszler, H. Kirpalani, K. Van Meurs, P. Chess, N. Ambalavanan, et al.
Milrinone in congenital diaphragmatic hernia - a randomized pilot trial: study protocol, review of literature and survey of current practices.
Matern Health Neonatol Perinatol., 3 (2017), pp. 27

Please cite this article as: Lakshminrusimha S, Vali P. Congenital diaphragmatic hernia: 25 years of shared knowledge; what about survival? J Pediatr (Rio J). 2018.

See article by Carmo et al. in pages x-y.

Jornal de Pediatria (English Edition)
Article options
en pt
Taxa de publicaçao Publication fee
Os artigos submetidos a partir de 1º de setembro de 2018, que forem aceitos para publicação no Jornal de Pediatria, estarão sujeitos a uma taxa para que tenham sua publicação garantida. O artigo aceito somente será publicado após a comprovação do pagamento da taxa de publicação. Ao submeterem o manuscrito a este jornal, os autores concordam com esses termos. A submissão dos manuscritos continua gratuita. Para mais informações, contate Articles submitted as of September 1, 2018, which are accepted for publication in the Jornal de Pediatria, will be subject to a fee to have their publication guaranteed. The accepted article will only be published after proof of the publication fee payment. By submitting the manuscript to this journal, the authors agree to these terms. Manuscript submission remains free of charge. For more information, contact
Cookies policy Política de cookies
To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here. Utilizamos cookies próprios e de terceiros para melhorar nossos serviços e mostrar publicidade relacionada às suas preferências, analisando seus hábitos de navegação. Se continuar a navegar, consideramos que aceita o seu uso. Você pode alterar a configuração ou obter mais informações aqui.