Long-term surgical outcomes in congenital diaphragmatic hernia: observations from a single institution

Background/Purpose

Surgical complications are common in survivors of congenital diaphragmatic hernia (CDH), but little is known about long-term incidence patterns and associated predictors.

Methods

A cohort of 99 CDH survivors was prospectively followed at a single-institution multidisciplinary clinic. Data were gathered regarding the adverse surgical outcomes of hernia recurrence, chest and spinal deformity, and operative small bowel obstruction (SBO), and then were retrospectively analyzed in relation to perinatal and perioperative markers of disease severity to determine significant predictors. Statistical methods used included univariate and multivariate regression analysis, hazard modeling, and Kaplan-Meier analysis.

Results

At a median cohort age of 4.7 (range, 0.2-10.6) years, 46% of patients with patch repairs and 10% of those with primary repairs had a hernia recurrence at a median time of 0.9 (range, 0.1-7.3) years after repair. Chest deformity was detected in 47%. Small bowel obstruction and scoliosis occurred in 13%. Recurrence and chest deformity were significantly more common with patch repair, liver herniation, age at neonatal extubation greater than 16 days, oxygen requirement at discharge, and prematurity. The strongest predictor of SBO was patch repair. Multivariate analysis showed that patch repair was independently predictive of recurrence and early chest deformity (odds ratios of 5.0 and 4.8, confidence intervals of 1-24 and 1-21, P < .05). Use of an absorbable patch was associated with the highest risk of surgical complications.

Conclusions

For long-term survivors of CDH, specific perinatal and operative variables, particularly patch repair, are associated with subsequent adverse surgical outcomes.     

Perinatal profile of ventricular overload markers in congenital diaphragmatic hernia

Background

In congenital diaphragmatic hernia (CDH), pulmonary hypertension increases right ventricle (RV) afterload, which could impair heart function and contribute to poor outcome for most affected infants. Nevertheless, the real significance of vascular pulmonary alterations in perinatal hemodynamics is largely unknown. It is defined that ventricular pressure overload induces increased myocardium gene expression of B-type natriuretic peptide (BNP) and components of the renin-angiotensinogen and endothelin (ET)-1 systems. Our aim was to evaluate perinatal myocardium expression of these genes associated with ventricular pressure overload in a nitrofen-induced CDH rat model.

Methods

In the nitrofen-induced CDH rat model, fetuses from dated pregnant Sprague-Dawley rats at 15.5, 17.5, 19.5 and 21.5 days postcoitum as well as newborn pups were assigned to 3 experimental groups: control, nitrofen (exposed to nitrofen, without CDH), and CDH (exposed to nitrofen, with CDH). Myocardial samples collected from the RV and left ventricle (LV) were processed for quantification of messenger RNA (mRNA) of BNP, angiotensinogen, and ET-1.

Results

The perinatal expression of BNP, angiotensinogen, and ET-1 mRNA in the RV and LV of the control group revealed daily changes. During gestation, the expression of BNP and angiotensinogen mRNA underwent significant oscillation compared with control in both nitrofen-exposed fetuses, although we cannot identify significant differences between the nitrofen and CDH groups. After birth, we found a significant increasing expression of all studied genes only in the RV of CDH pups.

Conclusions

Perinatal myocardial quantification of BNP, angiotensinogen, and ET-1 mRNA levels suggests that both nitrofen-exposed and control pups revealed prenatal variations of expression of the studied genes. Moreover, CDH is associated with significant molecular alterations only in the RV after birth.     

Prenatal pulmonary hypertension index: novel prenatal predictor of severe postnatal pulmonary artery hypertension in antenatally diagnosed congenital diaphragmatic hernia

Purpose

This study aim to assess the potential of prenatal predictors of postnatal severe pulmonary artery hypertension (PAH) in isolated left congenital diaphragmatic hernia (CDH) and to define a new prenatal pulmonary hypertension index (PPHI).

Methods

A retrospective chart review of CDH patients between May 2005 and October 2008 was conducted. Ten patients with systemic/suprasystemic and 9 patients with subsystemic pulmonary hypertension at 3 weeks of age were identified. Diameters of the right pulmonary artery, left pulmonary artery (LPA_d), aorta, and the length of vermis of the cerebellum were obtained from prenatal magnetic resonance imaging to calculate the PPHI [=(LPA_d/length of vermis of the cerebellum) × 10] and the modified McGoon index (MGI) [=(diameter of the right pulmonary artery + LPA_d)/diameter of aorta]. Prenatal pulmonary hypertension index and MGI were compared with lung-to-head ratio, percent predicted lung volume, and total lung volume for pulmonary hypertension and survival.

Results

The PPHI and MGI had a significant, negative correlation with pulmonary hypertension (r = −0.61, P = .005, and r = −0.72, P < .005, respectively). The PPHI and MGI are significantly lower in the systemic/suprasystemic PAH group compared with the subsystemic PAH group (1.11 ± 0.32 versus 1.63 ± 0.28, P = .004, and 0.71 ± 0.15 versus 1.05 ± 0.11, P < .001, respectively). There were no significant differences between the groups comparing the lung-to-head ratio, percent predicted lung volume, and total lung volume.

Conclusion

Both PPHI and MGI accurately predict the severity of postnatal PAH in isolated left CDH.     

Redefining outcomes in right congenital diaphragmatic hernia

Purpose

Available data comparing the management and outcome of right-sided (R-CDH) vs left-sided congenital diaphragmatic hernia (L-CDH) are inconsistent. Large-volume CDH studies are limited by small numbers of R-CDH or are confounded by compilations from multiple institutions with multiple treatment strategies. Consequently, they are underpowered to draw conclusions. To define the behavior and outcomes of R-CDH better, we report the largest single-institution series of R-CDH and ask if factors traditionally linked to poor prognosis in L-CDH were applicable to R-CDH.

Methods

We reviewed a single institution's experience with 267 consecutive evaluable neonates with unilateral CDH repaired from 1990 to 2006, with specific focus on R-CDH. χ² tests were performed for disease-related categorical variables. Two-tailed unpaired t tests were used for continuous variables. Factors associated with morbidity and survival were determined by univariate regression. Statistical significance was set at P < .05.

Results

Forty right-sided (15%) and 227 (85%) left-sided cases of CDH were identified. Prenatal diagnosis was made in 20 right-sided vs 170 left-sided defects (50% vs 75%, P < .01). Survival was 22 of 40 in R-CDH compared with 175 of 227 in L-CDH (55% vs 77%, P < .01). Extracorporeal membrane oxygenation was required in 16 right-sided and 33 left-sided cases (40% vs 15%, P < .001). A diaphragmatic patch was used in 22 of 29 right-sided compared with 82 of 199 left-sided repairs (76% vs 41%, P < .01); rates of abdominal wall prosthesis were also higher in right-sided hernias (38% vs 19%, P < .05). No differences were detected in right-sided vs left-sided recurrences (14% vs 8%, P = .38), mean time from birth to operation (5.3 vs 4.8 days, P = .80), or presence of cardiac anomalies (15% vs 12%, P = .63). Morbidity persisting beyond 6 months of age was present in 16 of 22 R-CDH survivors compared with 76 of 175 L-CDH survivors (73% vs 43%, P > .05). Among R-CDHs, prenatal diagnosis was the only factor to predict survival by univariate regression (P < .01). Use of a prosthesis in the diaphragm (P < .05) for R-CDH repair correlated with morbidity.

Conclusion

Although previous reports suggest that associated anomalies, need for extracorporeal membrane oxygenation, and time to repair can influence L-CDH survival, these data do not support extrapolation to R-CDH survival. Right-sided CDH carries a disproportionately high morbidity and mortality. Prenatal diagnosis was the only factor predictive of R-CDH survival. Morbidity may correlate with use of prosthetic material for R-CDH repair. Right-sided CDH is a unique disease that may require a modified antenatal consultation.     

Gastric antrum hypertrophy causing outlet obstruction in an infant with congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is associated with multiple congenital anomalies affecting several organ systems, including the gastrointestinal system. Pyloric stenosis and bands are known and previously reported etiologies of gastric outlet obstruction in infants with CDH. We report the first case of gastric antrum hypertrophy causing gastric outlet obstruction in an infant with CDH.     

Perioperative course of pulmonary hypertension in infants with congenital diaphragmatic hernia: impact on outcome following successful repair

Background

Pulmonary hypertension (PH) associated with congenital diaphragmatic hernia (CDH) remains a significant cause of morbidity and mortality. For improved outcomes, preoperative stabilization is commonly practiced to control the PH in infants with CDH. Some CDH infants who have been considered stabilized and ready for surgery have nevertheless developed significant PH after surgical repair. In fact, the markers and consequences of the preoperative stabilization are still unclear. Therefore, we examine the perioperative course of PH to evaluate the impact of preoperative PH severity on mortality and morbidity of infants who underwent surgical repair of CDH.

Methods

The medical charts of all newborns (n = 49) with CDH who were treated at our institution between January 2000 and December 2009 were reviewed. General management and perioperative data were evaluated for all infants. The ratio of estimated pulmonary artery pressure to systemic pressure (P/S ratio or PSR), based on echocardiographic data, was used to assess the PH severity during the perioperative period.

Results

The overall survival rate in our group of infants with CDH was 71.4%. Of the 49 infants with CDH, 9 (18.4%) died during the preoperative phase. Forty infants underwent CDH repair at a median age of 3.5 days (range, 1-46 days). Five of these infants (12.5%) subsequently deteriorated and died after surgery. Using receiver operating characteristic curve analysis, a PSR cutoff value before surgery of 0.9 predicted mortality in CDH infants with a sensitivity of 100% and specificity of 84% and with an area under the curve of 0.93 (P = .002). Accordingly, 2 groups of infants with distinct outcomes were identified, as follows: a low-PSR cohort (PSR ≤0.9) with a survival rate of 100% and a high-PSR cohort (PSR >0.9) with a survival rate of 50% (P = .001). The rate of pneumothorax and the frequency of use of several inotropic agents after surgery were significantly higher in the high-PSR group (P = .001 and .007, respectively). Compared with low-PSR infants, infants with high PSR were operated on later (P = .03) and were postoperatively ventilated longer (P = .01). During the entire perioperative period, significant differences in the PH severity were noted between the 2 PSR groups. During the first week of life, infants in the high-PSR group had significantly higher PSRs than those in the low-PSR group (P = .001); and similar tendencies continued to be significant between the 2 groups after CDH repair (P = .04).

Conclusions

During the perioperative period, PH severity monitoring via the serial assessment of PSR is beneficial. Better outcomes were observed with a preoperative PSR less than or equal to 0.9, and this association needs to be confirmed by prospective study.     

“Acquired” congenital diaphragmatic hernia

“Acquired” congenital diaphragmatic hernia (ACDH), has been defined as delayed or late appearance of a congenital diaphragmatic hernia after a documented time period of postnatal life with no evidence of herniation. Three new cases are presented. This diagnosis has been characterized on the basis of a review of these cases and 14 additional patients from the literature. A classification based upon timing of herniation and state of pulmonary development is presented.     

Risk-stratification enables accurate single-center outcomes assessment in congenital diaphragmatic hernia (CDH)

BackgroundManagement of CDH is highly variable from center to center, as are patient outcomes. The purpose of this study was to examine risk-stratified survival and extracorporeal membrane oxygenation (ECMO) rates at a single center, and to determine whether adverse outcomes are related to patient characteristics or management.MethodsA retrospective single-center review of CDH patients was performed, and outcomes compared to those reported by the CDH Study Group (CDHSG) registry. Patient demographics, disparities, and clinical characteristics were examined to identify unique features of the cohort. A model derived using the registry that estimates probability of ECMO use or death in CDH newborns was used to risk-stratify patients and assess mortality rates. Observed over expected (O/E) ECMO use rates were calculated to measure whether “excess” or “appropriate” ECMO use was occurring.ResultsThere were 81 CDH patients treated between 2004–2017, and 5034 in the CDHSG registry. Mortality in ECMO-treated patients was higher than the registry. Socioeconomic variables were not significantly associated with outcomes. The strongest predictors of mortality were ECMO use and early blood gas variables. The risk model accurately predicted ECMO use with a c-statistic of 0.79. Compared with the registry, the disparity in mortality rates was greatest for moderate-risk patients. O/E ECMO use was highest in low and moderate-risk patients.ConclusionsECMO use is a more consistent predictor of mortality than CDH severity at a single center, and there is relative overuse of ECMO in lower-risk patients. Risk stratification allows for more accurate institutional assessment of mortality and ECMO use, and other centers could consider such an adjusted analysis to identify opportunities for outcomes improvement.Level of EvidenceIII.     

Use of prostaglandin E1 to treat pulmonary hypertension in congenital diaphragmatic hernia

Background/Purpose

Prostaglandin E1 (PGE) has been used to maintain ductus arteriosus patency and unload the suprasystemic right ventricle (RV) in neonates with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension (PH). Here we evaluate the PH response in neonates with CDH and severe PH treated with PGE.

Congenital diaphragmatic hernia: a simplified postnatal predictor of outcome

Background/Purpose

The incidence of congenital diaphragmatic hernia (CDH) approximates 1 in 3000 births, with mortality rates up to 50%. The ability to accurately and easily predict the outcomes of these infants could be a valuable management tool. The purpose of this study was to develop and validate a simplified clinical method for predicting survival outcomes in infants born with CDH.

Methods

The Wilford Hall/Santa Rosa clinical prediction formula (WHSR_PF = highest Pao₂ − highest Pco₂) was generated from arterial blood gas values obtained during the initial 24 hours of life, but before surgical repair or extracorporeal membrane oxygenation, in a local group of infants with CDH identified by prospective and retrospective review. The WHSR_PF was validated using a comparative group from the Congenital Diaphragmatic Hernia Study Group (CHDSG). Bivariate, multivariable, and area under the receiver operating curve (AUC) analysis was performed using SigmaStat and SPSS statistical programs (SPSS, Chicago, Ill).

Results

As initially developed from the local data, the WHSR_PF had a positive predictive value (PPV) of 82%, a negative predictive value of 88% and AUC of 0.87. When validated against the CDHSG data, the positive predictive value was 83%, negative predictive value was 66%, and AUC 0.79. Area under the receiver operating curve analysis by the previously published CDHSG predictive equation was 0.76.

Conclusion

This novel formula is an easy to apply clinical tool with similar or better predictive abilities compared to previous methods of predicting survival in infants born with CDH. Currently, no method appears to have sufficient clinical accuracy for predicting the outcome of an individual infant with CDH. Further studies are indicated.     

Potential survival benefit with repair of congenital diaphragmatic hernia (CDH) after extracorporeal membrane oxygenation (ECMO) in select patients: Study by ELSO CDH Interest Group

PurposeStudying the timing of repair in CDH is prone to confounding factors, including variability in disease severity and management. We hypothesized that delaying repair until post-ECMO would confer a survival benefit.MethodsNeonates who underwent CDH repair were identified within the ELSO Registry. Patients were then divided into on-ECMO versus post-ECMO repair. Patients were 1:1 matched for severity based on pre-ECMO covariates using the propensity score (PS) for the timing of repair. Outcomes examined included mortality and severe neurologic injury (SNI).ResultsAfter matching, 2,224 infants were included. On-ECMO repair was associated with greater than 3-fold higher odds of mortality (OR 3.41, 95% CI: 2.84–4.09, p < 0.01). The odds of SNI was also higher for on-ECMO repair (OR 1.49, 95% CI: 1.13–1.96, p < 0.01). A sensitivity analysis was performed by including the length of ECMO as an additional matching variable. On-ECMO repair was still associated with higher odds of mortality (OR 2.38, 95% CI: 1.96–2.89, p < 0.01). Results for SNI were similar but were no longer statistically significant (OR 1.33, 95% CI: 0.99–1.79, p = 0.06).ConclusionsOf the infants who can be liberated from ECMO and undergo CDH repair, there is a potential survival benefit for delaying CDH repair until after decannulation.Type of StudyTreatment StudyLevel of EvidenceIII     

Congenital diaphragmatic hernia: searching for answers

BACKGROUND: Pulmonary hypoplasia and hypertension are the primary causes of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). At present, the origin of CDH and the causes of pulmonary hypoplasia and hypertension are unknown. DATA SOURCES: This article reviews the available published data regarding the origin of CDH and the pathogenesis of the associated pulmonary hypertension and hypoplasia. These investigations have employed human tissues as well as two types of CDH animal models. CONCLUSIONS: Investigations performed to date have not yet provided definitive answers regarding the pathogenesis of CDH. However, they have yielded many new and exciting discoveries and several opportunities for intervention. Ongoing research should open new possibilities to improve the outcome for these unfortunate babies with CDH.     

Prenatally versus postnatally diagnosed congenital diaphragmatic hernia – Side,stage, and outcome

Aim

To compare outcomes between prenatally and postnatally diagnosed CDH in a large multicenter database of prospectively collected data and evaluate factors associated with poorer outcome for prenatally diagnosed CDH.

Outcomes of multigestational pregnancies affected by congenital diaphragmatic hernia

Background/purpose

The prognosis for multiple vs singleton pregnancies affected by congenital diaphragmatic hernia (CDH) is not known. To improve the counseling of families with multiple gestation pregnancies complicated by CDH, we examined outcomes of a consecutive series of CDH cases occurring in multiple gestation pregnancy referrals.

Methods

Clinical characteristics and morbidity and mortality data were gathered for a consecutive series of infants with CDH from 16 multiple gestation pregnancies. Outcomes were compared to a cohort of 91 patients with CDH from singleton pregnancies. Multivariate regression was also used in an attempt to determine whether multiple gestation pregnancy was independently predictive of subsequent long-term adverse outcomes.

Results

Four pregnancies were lost to follow-up, and 1 underwent selective reduction. Overall mortality for live-born multiple gestation fetuses affected by CDH was 30% and was 8% for unaffected siblings. No pregnancy was concordant. Clinical features were not different between the case series and control infants, except median gestational age at delivery, which was significantly lower for the multigestational infants (34 [range, 32-36] vs 38 [range, 28-41] weeks) (P = .02). Long-term morbidity was comparable between cases and controls.

Conclusions

In terms of mortality, outcomes of multigestational pregnancies affected by CDH are no worse than for CDH pregnancies in general. Long-term risk may depend more on CDH severity rather than the presence of multiple fetuses.     

Risk factors for recurrence after thoracoscopic repair of congenital diaphragmatic hernia (CDH)

Purpose

To identify technical modifications concerning factors that may lower the risk of recurrence following thoracoscopic repair of congenital diaphragmatic hernia (CDH).

Long-term neurodevelopmental outcomes of congenital diaphragmatic hernia survivors not treated with extracorporeal membrane oxygenation

Background/Purpose

Although there has been a marked improvement in the survival of children with congenital diaphragmatic hernia (CDH) in the past 2 decades, there are few reports of long-term neurodevelopmental outcome in this population. The present study examined neurodevelopmental outcomes in 10- to 16-year-old CDH survivors not treated with extracorporeal membrane oxygenation (ECMO).

Methods

Parents of 27 CDH survivors completed questionnaires assessing medical problems, daily living skills, educational outcomes, behavioral problems, and executive functioning. Fifteen CDH survivors and matched full-term controls completed standardized intelligence, academic achievement, phonological processing, and working memory tests.

Results

Non-ECMO-treated CDH survivors demonstrated high rates of clinically significant difficulties on standardized academic achievement measures, and 14 of the 27 survivors had a formal diagnosis of specific learning disability, attention deficit hyperactivity disorder, or developmental disability. Specific problems with executive function, cognitive and attentional weaknesses, and social difficulties were more common in CDH patients than controls. Perioperative hypocapnia was linked to executive dysfunction, behavioral problems, lowered intelligence, and poor achievement in mathematics.

Conclusions

Non-ECMO-treated CDH survivors are at substantial risk for neurodevelopmental problems in late childhood and adolescence.     

Dynamic tracheal occlusion improves lung morphometrics and function in the fetal lamb model of congenital diaphragmatic hernia

Background

Congenital diaphragmatic hernia (CDH) is associated with significant neonatal morbidity and mortality. Although prenatal complete tracheal occlusion (cTO) causes hypoplastic CDH lungs to enlarge, improved lung function has not been demonstrated. Furthermore, cTO interferes with the dynamic pressure change and fluid flow associated with fetal breathing.

Purpose

The purpose of the study was to assess a novel dynamic tracheal occlusion (dTO) device that preserves pressure changes and fluid flow.

Methods

In this pilot study, CDH was created in fetal lambs at 65 days of gestational age (GA). At 110 days GA, a cTO device (n = 3) or a dTO device (n = 4) was placed in the fetal trachea. At 135 days GA, lambs were delivered and resuscitated. Unoperated lamb co-twins (n = 5), sham thoracotomy lambs (n = 2), and untreated CDH lambs (n = 3) served as controls.

Results

Tracheal opening pressure, lung volume, lung fluid total protein, and phospholipid were significantly higher in the cTO group than in the dTO and unoperated control groups. Maximal oxygenation and lung compliance were significantly lower in the cTO group when compared with the unoperated control and dTO groups.

Conclusion

Preliminary results suggest that in the fetal lamb CDH model, dTO restores normal lung morphometrics and function, whereas cTO leads to enlarged but less functional lungs.     

Current consequences of prenatal diagnosis of congenital diaphragmatic hernia

Background

Today, the diagnosis of congenital diaphragmatic hernia (CDH) can readily be made in the prenatal period during screening ultrasound examination. Patients ought to be referred to rule out associated anomalies, and in isolated cases, prognosis is poor when the liver is intrathoracic and the lung-to-head ratio (LHR) is less than 1. In these patients, prenatal intervention aiming to reverse pulmonary hypoplasia can be considered.

Methods

We present our current algorithm for counselling patients presenting with CDH. Patients with a poor prognosis are offered percutaneous fetal endoluminal tracheal occlusion (FETO) with a balloon, inserted at 26 to 28 weeks. We report on the evolution of technique and results in a consecutive homogeneous case series and compare outcome in cases with similar severity managed in the postnatal period.

Results

Within a period of 28 months, FETO was performed between 26 and 28 weeks in 24 fetuses with severe left-sided CDH. Under general (n = 5), epidural (n = 17) or local (n = 2) anesthesia, the balloon was successfully positioned at first surgery (23/24) with a mean operation time of 20 minutes (range, 3-60 minutes). There were no serious maternal complications or direct fetal adverse effects. In the first 2 weeks after FETO, LHR increased from 0.7 to 1.7. Premature prelabour rupture of the membrane (PPROM) occurred in 16.7% and 33.3% at 28 and 32 weeks or earlier, respectively. Gestational age at delivery was 33.5 weeks. Patency of airways was restored either in the prenatal (n = 12) or perinatal period (n = 12). Early (7 days) and late (28 days) survival, and survival at discharge were 75% (18/24), 58.3% (14/24) and 50% (12/24), respectively. Half of nonsurvivors (n = 6) died of pulmonary hypoplasia and hypertension, in combination with PPROM and preterm delivery (n = 4) and balloon dislodgement (n = 2), which coincided with a short tracheal occlusion (TO) period (12 days). In the other 6, TO period was comparable to that in the 12 survivors (47 vs 42 days, respectively). In that group of 6 babies, only 2 died of pulmonary problems. Late neonatal survival (28 days) was higher with prenatal vs perinatal balloon retrieval 83.3% vs 33.3% (P = .013). In a multicentre study validating the criteria, survival till discharge in 37 comparable cases was 9% (3/32) and 13% (5/37) of parents opted for termination.

Conclusion

Fetuses with isolated left-sided CDH, liver herniation, and LHR of less than 1 have a poor prognosis. Percutaneous FETO is minimally invasive and may improve the outcome in these highly selected cases. Airways can be restored before birth, allowing vaginal delivery and return to the referring tertiary unit and may improve survival rate. The procedure carries a risk for PPROM, although that may decrease with experience.