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Year : 2018  |  Volume : 23  |  Issue : 3  |  Page : 131-139

A clinical study on congenital diaphragmatic hernia in neonates: Our institutional experience

1 Department of Paediatric Surgery, IGICH, Bengaluru, Karnataka, India
2 Department of Biochemistry, IGICH, Bengaluru, Karnataka, India

Date of Web Publication4-Jul-2018

Correspondence Address:
Dr. Jayalaxmi Shripati Aihole
Department of Paediatric Surgery, IGICH, Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiaps.JIAPS_179_17

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Background: Congenital diaphragmatic hernia (CDH) is a complex developmental defect having a multifactorial etiology; i majority of cases (~80%), the cause is not known. Survival rates for patients with CDH have increased over the past decade with early prenatal detection and better postnatal management including surgery. Clinical profile and the outcome of 83 CDH neonates were studied and analyzed over a period of 12 years in our institute.
Aims and Objectives: The clinical study was to analyze the clinical profile and outcome of CDH among the neonates in a tertiary care referral neonatal and pediatric center in Karnataka, India.
Materials and Methods: This was a retrospective and prospective observational study conducted from January 2005 to March 2017, over a period of 12 years in a tertiary care referral neonatal and pediatric center in southern India. Clinical characteristics and risk factors of 83 neonates admitted and diagnosed with CDH were compared between survivors and nonsurvivors both preoperatively and postoperatively. Neonates with clinical and intraoperative diagnosis of diaphragmatic eventration were not included in this study. Multivariate logistic regression analysis was performed to determine independent predictors for mortality.
Results: A total of 83 neonates admitted and diagnosed with CDH were included in this study; 73 of them underwent surgical repair. The total survival rate in neonates with CDH was 70/83 (84.33%) and the overall operative mortality was 3/73 (4.1%). There was a significant difference between CDH neonates who survived 70/83 (84.33%) and those who died 13/83 (15.67%), in the age on admission, 5 min Apgar score, onset of respiratory distress, preoperative ventilation, the presence of persistent pulmonary hypertension of the newborn (PPHN), high-frequency oscillatory ventilation (HFOV), and length of hospital stay with P < 0.05. Using multivariate logistic regression analysis, the following factors independently predicted mortality: onset of respiratory distress in hours (odds ratio: 0.5, 95% confidence interval: 0.37–0.82) and preoperative ventilation (odds ratio: 0.02; 95% confidence interval: 0.0028–0.1558). When we compared CDH neonates who survived after surgery (n = 70) with those who expired (n = 3) postoperatively, there was a significant difference in the gestational age in weeks, side of CDH, PPHN, HFOV and length of hospital stay with P < 0.05.
Conclusion: CDHs are common on the left side with fairly good prognosis. Though, the right-sided CDH are rare; they do carry a good prognosis, as it was seen in our experience.

Keywords: Congenital diaphragmatic hernia, neonatal outcome, pulmonary hypertension

How to cite this article:
Aihole JS, Gowdra A, Javaregowda D, Jadhav V, Babu M N, Sahadev R. A clinical study on congenital diaphragmatic hernia in neonates: Our institutional experience. J Indian Assoc Pediatr Surg 2018;23:131-9

How to cite this URL:
Aihole JS, Gowdra A, Javaregowda D, Jadhav V, Babu M N, Sahadev R. A clinical study on congenital diaphragmatic hernia in neonates: Our institutional experience. J Indian Assoc Pediatr Surg [serial online] 2018 [cited 2023 Jun 9];23:131-9. Available from: https://www.jiaps.com/text.asp?2018/23/3/131/235895

   Introduction Top

Congenital diaphragmatic hernia (CDH) is one of the most important surgical causes of respiratory distress in neonates. Its incidence is 1 in 2500–4000 live births. CDH was first described by Vincent Bochdalek from Chek in 1848, but first successful repair of CDH in a neonate was conducted by Gross in 1946.[1] The standard of care was immediate neonatal surgery followed by postoperative stabilization till the 1980s. Later on, it has been proved that neonatal CDH is a physiological emergency rather than a surgical emergency.

Factors contributing to high morbidity and mortality include associated pulmonary hypoplasia, primary pulmonary hypertension and the presence of other lethal anomalies. True estimate of mortality of this malformation remains underestimated worldwide due to hidden mortality related to the lack of timely intervention in these babies as first described by Harrison et al.[2]

These neonates should be managed in a tertiary care referral center with a team of skilled neonatologists and pediatric surgeons having well equipped Neonatal Intensive Care Unit (NICU) with skilled medical staff.

We carried out this study to evaluate the clinical profile and analyzed the various factors affecting the outcome in neonatal CDH in our institute over a period of 12 years.

   Materials and Methods Top

This was a combination of retrospective and prospective observational cohort study conducted from January 2005 to February 2017 over a period of 12 years at a tertiary care neonatal referral center in Karnataka, India. The data were collected from NICU medical records, pediatric surgical registry, and the questionnaire putforth to the parents or caregivers. Neonates from day 0 to day 30 referred with a clinical suspicion of CDH were included in this study. The diagnosis of CDH was made from chest roentgenography and ultrasonography [Figure 1]a and [Figure 1]b. Contrast-enhanced computerized tomography (CECT) was done in doubtful cases. Neonates with diaphragmatic eventration and infants aged more than 30 days were excluded from this study. Repair of CDH under general anesthesia was adopted as treatment modality after initial medical stabilization [Figure 1]c and [Figure 1]d. Assisted ventilation was provided for neonates requiring ventilation both preoperatively and postoperatively. Surgery was performed when the neonate's general condition improved, and blood gases were stabilized for at least 24 h. [Figure 4] showing the course and outcome of all CDH neonates enrolled in the study is presented in [Figure 2]. The onset of respiratory distress was defined as the time of respiratory distress starting after delivery. Cardiac malformations were diagnosed using two-dimensional (2D) echocardiography. Persistent pulmonary hypertension of the newborn (PPHN) was defined as preductal and postductal oxygen saturation difference >10% and confirmed by 2D echocardiography. The size of the diaphragmatic defect was determined by the surgeon at the time of repair. Stabilization was defined by the following criteria (a) normal hemodynamic variables: mean blood pressure >40 mmHg (b) disappearance of preductal or postductal saturation difference and the signs of PPHN on 2D echo (c) switch to controlled mode of ventilation well tolerated with moderate values of peak inspiratory pressure (15–20 cm H2O) and adequate oxygenation achieved with FiO2 ≤0.4. Oxygenation Index (OI) was calculated by the following formula: (MAP × FiO2 × 100)/post ductal O2, where mean airway pressure (MAP) is MAP. FiO2 is fractional inspired oxygen and PaO2 partial pressure of oxygen in arterial blood. Duration of mechanical ventilation was defined as the days of ventilation before surgery. The Institutional Ethics Committee has approved this study.
Figure 1: (a) Chest X-ray of left congenital diaphragmatic hernia (b) Chest X-ray of right congenital diaphragmatic hernia (c) intraoperative picture of left congenital diaphragmatic hernia, showing stomach as content (d) intraoperative picture of right congenital diaphragmatic hernia

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Figure 4: The overall outcome of congenital diaphragmatic hernia neonates. Survival rate - 84.33% (73/83), Operative mortality - 4.1% (3/73)

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Figure 2: Bar chart showing significant risk factors among congenital diaphragmatic hernia neonates

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Statistical analysis

The following factors were statistically analyzed such as gestational age in weeks, birth weight in grams, age on admission in hours, gender, onset of respiratory distress in hours, laterality, Apgar score at 1 and 5 min, the presence of cardiac malformations, PPHN, requirement of preoperative ventilation, high frequency oscillatory ventilation (HFOV) and length of hospital stay among survivors and nonsurvivors. Continuous variables were reported using mean ± standard deviation, median, and interquartile range. Categorical variables were reported using frequencies and percentages. Student's t-test and Chi-square test were used to find the association between variables [Table 1] and [Table 2].
Table 1: Comparison between survivors and non survivors of CDH neonates.

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Table 2: Comparison of congenital diaphragmatic hernia patients with survivors and nonsurvivors after surgery

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CDH outcome was studied using multivariate logistic regression analysis of the above-mentioned factors. The odds ratio associated with a given factor was an estimate of the risk for mortality of CDH when the factor was present relative to that when the factor was absent; 95% confidence intervals were used as a measure of the statistical precision of each odds ratio. A P < 0.05 was considered as statistically significant. Data were collected on structured proforma using MS Excel Version 2010. All the statistical analysis was performed using SPSS software version 18.0. (IBM, New York: Routledge)

   Results Top

A total of 83 neonates with CDH were enrolled in this study. 73/83 (88%) underwent various surgical procedures. 10/83 (12%) did not undergo any surgical procedures [Figure 2], [Figure 3], [Figure 4]. Of those who underwent surgery, 70/83 (84.33%) survived and 3/83 (3.6%) neonates expired postoperatively. Those who did not undergo any surgical procedures, 10/83 (12%) expired [Figure 2] and [Table 1], [Table 2].
Figure 3: Various surgical procedures done and outcome of 83 congenital diaphragmatic hernia neonates

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In our study, 65/83 (78%) were males and18/83 (22%) were females with a male to female ratio of 4:1. Left-sided CDH predominated with 75/83 (90%) and right-sided CDH were 8/83 (10%). When comparison was made between survivors and nonsurvivors of right-sided and left-sided CDH in neonates, we found both carried fairly good prognosis with a P > 0.05 which was not significant statistically. In our study, we did not encounter any neonate with bilateral CDH, Morgagni hernia or Larrey's hernia. Mean gestational age at birth of the survivors was 36.75 ± 1.46 weeks (median age 37.2 weeks; range; 33. 3–39.2 weeks). Mean birth weight of survivors was 2537 ± 474 g (median weight 2495 g; range 1600–3800 g). The mean hours of life that neonates were admitted was 142 ± 143 h (median 65 h, range 24–765 h) among survivors. Mean Apgar score at 1 min for survivors was 7.4 ± 1.03 (median 5.5, range 5–8). Mean Apgar score at 5 min was 7.5 ± 0.90 (median 7, range 5–8). Mean onset of respiratory distress in hours was 5.27 ± 1.94 (median 3.5, range 1–12). 45/70 (64%) had nonlethal cardiac malformations. In this study, none of the neonates had any lethal or cyanotic congenital heart diseases. PPHN was observed in 16/70 (23%) of surviors. 15/70 (21.4%) of survivors required preoperative ventilation. 5/70 (7%) of the survivors required HFOV. Mean length of hospital stay was 22.64 ± 4.9 days (median 27.5 days, range 13–32 days) among the survivors [Table 1]. When comparison was made among the survivors (n = 70) and nonsurvivors (n = 13), length of hospital stay was significantly longer for survivors with CDH with a P < 0.001 which was highly significant statistically [Table 1] and [Table 2].

In our series, we operated on six right-sided CDH cases. Of these, five underwent open surgical repair, and in a single case, thoracoscopy was attempted. All are doing well. 67 babies with left-sided CDH underwent various surgical procedures. Of these 63 underwent the open procedure, one required laparoscopic approach, and in another one, the laparoscopic procedure was attempted. Two neonates underwent thoracoscopic repair. Three of them expired postoperatively, one following open surgical repair and another two following open mesh repair [Figure 3] and [Figure 4].

There were a total of 13/83 (16%) deaths in our study. 8/75 (10.6%) neonates with left-sided CDH died preoperatively and 3/75 (4%) died postoperatively. Whereas 2/8 (25%) neonates with right-sided CDH expired preoperatively. In our study, none of the neonates with right-sided CDH died postoperatively. Overall operative mortality was (3/73) 4.1%.

Univariate analysis comparing survivors and nonsurvivors with CDH revealed that mortality was not associated with the following factors such as gestational age (weeks), birth weight (grams), gender, Apgar score at 1 min, the presence of cardiac malformation and laterality [Table 2] with P > 0.05 which was not statistically significant.

However, mortality was associated with the following factors; age on admission (h), 5 min Apgar score, the onset of respiratory distress, the presence of PPHN, length of hospital stay, the requirement for preoperative ventilation and HFOV with P < 0.05 which was statistically significant.

Following multivariate forward stepwise logistic regression analysis, only the onset of respiratory distress and preoperative ventilation were found to be significant [Table 3] in our study.
Table 3: Multivariate forward stepwise logistic regression analyses of risk factors for mortality in neonatal congenital diaphragmatic hernia

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10/83 (12%) CDH neonates did not undergo surgery and consequently died. We compared clinical characteristics of CDH neonates who survived after surgery (n = 70) and those who died postoperatively (n = 3), we found a significant difference in the gestational age in weeks, laterality, PPHN, the requirement for HFOV and length of hospital stay as shown in [Table 2].

   Discussion Top

The present study was a combination of retrospective and prospective observational cohort study of CDH in neonates, to measure risk factors for mortality and outcomes of CDH. Over the past 30 years, CDH has been recognized as a syndrome, which includes pulmonary hypoplasia, lung immaturity, left heart hypoplasia, and PPHN of the newborn.[1],[2],[3]

It is well known that some live-born infants with CDH die before referral to a tertiary center. Consequently, the population of infants reaching a tertiary care center commonly represents only 40%–50% of the total number of cases of CDH. This disparity reflects the “hidden mortality” of CDH as first described by Harrison et al. (intrauterine demise, stillbirth, and death on transfer).[1],[2],[3]

Mean gestational age in the present study among survivors was 36.75 ± 1.46 weeks and among nonsurvivors was 36.69 ± 1.03 weeks without much difference.

The age on admission, the onset of respiratory distress and the prevalence of PPHN were high-risk factors related to the severity of clinical characteristics in CDH neonates. The median age on admission was 142 h in survivors and 20 h in nonsurvivors. This result suggests that, the earlier the onset and severe the respiratory distress, higher the mortality. The low 1 and 5 min Apgar scores have been said to be major independent predictors of total mortality rate. Our result also suggests that the nonsurvivor group had lower Apgar scores compared to survivor group. Lower Apgar score is associated with severe asphyxia. Early prenatal diagnosis and elective intubation following birth and resuscitation (avoiding barotraumas to the hypoplastic lungs) should be led by a highly skilled neonatology team. Bag and mask ventilation is contraindicated as this increases the mediastinal shift, respiratory distress, and risk of gastric perforation. The respiratory distress in CDH is due to a combination of two factors: Uncorrectable pulmonary hypoplasia and potentially reversible pulmonary hypertension.[4]

A female predominance for a Bochdalek hernia observed by some authors has been well documented; however, others have observed a male predominance.[5] In our study also male preponderance was seen.

The prenatal detection rate for CDH varies enormously in published studies, from 10% to 79%. Most are detected after 24 weeks of gestation.[3],[5] Earlier detection is associated with increased mortality but not reported in all the studies.[4],[5] However, prenatal detection of CDH is rare in developing countries due to inadequate facilities.[5] In our cohort 17/83 (20%) of the cases were diagnosed prenatally; most were detected at 35 weeks, only before delivery. Polyhydramnios has been reported up to 80% of CDH cases.[6] 3D estimation of the fetal lung volume, calculation of the right lung area to thoracic area ratio, and calculation of the lung to thoracic circumference ratio has been the most widely used as prognostic indicators.[4],[7]

CDH is usually diagnosed immediately after birth with respiratory distress, scaphoid abdomen, bowel sounds in the chest, and mediastinal shift on chest X-ray.[4],[5],[6],[7],[8]

The other modalities of diagnosing the CDH are postnatal ultrasonography; CECT and barium meal follow through in doubtful cases.

Cardiac malformations are most common anomalies associated with CDH, but their etiology is still unclear. In this study, none of the neonates had cyanotic congenital heart disease/lethal or any associated syndromes. Among the nonlethal cardiac malformations, atrial septal defect, ventricular septal defect, and patent foramen ovale predominated. Among the gastrointestinal anomalies, Ladd's procedure was performed in 3/63 (5%) cases.

Pulmonary hypertension was graded into mild, moderate, and severe based on pressure gradient through ductus arteriosus. We found that degree of lung hypoplasia and PPHN correlated well with survival as well as morbidity. Lung hypoplasia is the major determinant of survival, and the degree of pulmonary hypoplasia correlates with the severity of PPHN.[9]

In our study, 16/70 (23%) neonates with PPHN survived and among nonsurvivors 10/13 (77%) had PPHN with a P < 0.001 which was highly statistically significant [Table 1] and [Table 2].

Sildenafil was attempted in moderate-to-severe degrees of PPHN with a good outcome.[8],[9]

Wung et al. introduced the novel concept of gentle ventilation strategies (permissive hypercapnea), characterized using the preservation of spontaneous ventilation, permissive levels of hypercapnea (PaCO2 60–65 mmHg or 9 kPa) and avoidance of high inspiratory airway pressures (ideally not exceeding 25 cm H2O) to reduce iatrogenic lung injury from barotrauma, which is being followed in our institute.[10],[11] HFOV has also been utilized in the perinatal management of CDH both as a “rescue therapy” before extracorporeal membrane oxygenation (ECMO) and as a primary ventilatory modality in an attempt to reduce pulmonary barotraumas. In our institute, so far we do not have the ECMO facility.

In our institute, HFOV has been introduced since 5 years. Hence, most of the neonates were managed by conventional ventilation. In this study, 15/70 (21%) of the survivors received conventional ventilation. Among nonsurvivors 11/13 (85%) received conventional mode of ventilation with a P < 0.0001 value of which was highly significant statistically.

In our study, 5/70 (7%) survivors received HFOV and among nonsurvivors, 3/13 (23%) received HFOV with a P < 0.005 value of which was highly statistically significant. When used as an initial mode of therapy, HFOV may be a more effective mode of ventilatory support than conventional ventilation.[12] None of our neonates required HFOV postoperatively.

Among nonsurvivors, 3/10 (30%) with severe pulmonary hypertension required HFOV. None of the survivors with PPHN required HFOV.

The operation for CDH is no longer an emergency procedure. It is increasingly being recognized that stabilization of labile physiology is paramount and delayed repair is now frequently employed in most of the surgical centers. Preoperative stabilization aims to optimize respiratory function and allow full clinical and cardiac assessment.

An operative correction was generally performed through an upper transverse or subcostal abdominal incision. Minimally invasive approaches such as thoracoscopy and laparoscopy have been described.[4],[12]In utero surgical correction of CDH has been described without very encouraging results because of procedure-related maternal and fetal mortality.[4],[12]

In our series, we operated on six right-sided CDH cases. Of these, five underwent open surgical repair, and in a single case, thoracoscopy was attempted. All are doing well. A total of 67 babies with left-sided CDH underwent various surgical procedures. Of these 63 underwent the open procedure, one required laparoscopic approach, in another one, laparoscopic procedure was attempted. Two neonates underwent thoracoscopic repair.[12] Three of them expired postoperatively, one following open surgical repair and another two following open mesh repair [Figure 4].

The size of the diaphragmatic defect has been described by previous studies to be a risk factor for poor outcome of CDH. It has been shown to correlate well with mortality as well as morbidity in live born infants with CDH. Defect size is likely to be a marker for the degree of pulmonary hypoplasia. The study results did not confirm that defect size is an independent predictor for mortality.[13]

In our study, we used polypropylene mesh in two left-sided CDH cases, which had >5 cm defect size needing the open procedure. However, unfortunately, they did not recover. None of the right-sided CDH cases required mesh repair.[14]

The presence of a hernial sac significantly improves the prognosis in CDH neonates which is formed of parietal peritoneum and lung pleura and has been reported in approximately 20% of cases in the literature. In our study, we found intraoperatively, the presence of sac in 10/70 (14.3%) neonates; all of them survived.[15]

With regard to the contents of organs in the chest cavity, the presence of the spleen in the chest cavity was associated with higher survival which correlated well with our study.[3],[15] 1/63 (1.6%) with left-sided CDH had splenic laceration while delivering it out, which was successfully sutured and child is doing well at 2 years follow-up.

The position of the stomach has been proposed as a prognostic indicator by a number of investigators.[6],[15] Survival rates of infants with CDH with the stomach properly located below the diaphragm at the time of diagnosis have been reported to be as high as 100% but are only 30% when the stomach had herniated into the chest. Other studies have shown no predictive value of such positioning.[7],[8],[15] We had 10/63 (16%) neonates having stomach up; all of them survived. The presence of stomach was not correlated with higher mortality in our cohort as compared to others.[3],[15]

The presence of liver herniation into the chest (liver up) is considered to be a poor prognostic indicator.[8],[9],[10],[15] Some studies have reported higher mortality among the right-sided CDH [12],[13],[14],[15],[16],[17] whereas others did not find a statistical difference in mortality rate when compared to left-sided defects.[15],[18]

In our study, we found 20/63 (31.7%) cases of the left lobe of liver inside the left thoracic cavity. One patient died postoperatively 1/20 (5%) due to uncontrolled subcapsular hematoma while delivering it down.

Recurrent diaphragmatic hernia and small bowel obstruction are the dominant surgical challenges following initial repair.[3],[15],[18] Overall recurrence rates are approximately 15% in the first 2 years of life. Risk factors for recurrence include large defect size and the need for a patch.[12],[15],[18]

Recurrent hernias may occur in up to 50% of infants undergoing mesh repairs and in 10% of primary repairs.[14],[18] They tend to occur in the first 4 years of life.[4],[12],[18] In our series, we encountered a single case of recurrent left-sided CDH presenting as para-esophageal hernia at 9 months of age, which was successfully repaired and is doing well on 4 years follow-up. We encountered 2 cases of adhesive small bowel obstructions postoperatively at 2 months and 8 months, respectively, which were managed by adhesiolysis successfully.[4],[11],[12],[18]

Usui et al., reported 14% incidence of pneumothorax [17] among 510 neonates with CDH.[16],[17],[18] In our study, none of our neonates had preoperative pneumothorax; a total of 3/67 (4.5%) neonates had pneumothorax postoperatively, all of them survived.

In our study, we compared CDH neonates, who survived with nonsurvivors and found that survivors were associated with a longer NICU hospital stay.[13],[16],[18] Among the other associated conditions were an infection, acidosis, and neonatal jaundice which added to the morbidity. This result suggests that CDH neonates have a high morbidity and mortality rate in early life. This may reflect the fact that survivors had less severe pulmonary hypoplasia and the absence of lethal associated anomalies and that the combined degree of pulmonary hypoplasia and PPHN determine survival rate.[7],[16],[18]

64/67 (95.5%) of neonates with left CDH survived postoperatively. 6/6 (100%) of patients survived postoperatively among right-sided CDH with P < 0.05 which was statistically significant. Some studies have shown that right-sided CDH are associated with higher mortality.[12],[13],[14],[15],[16],[17],[19] In this study, 11/75 (15%) of neonates with left-sided CDH had mortality. 2/8 (25%) of right-sided CDH had mortality with P < 0.05 which was statistically significant. Exceptionally in our study, right-sided CDH carried a better prognosis.

Grover et al. reported 50% mortality for preterm neonates with CDH (<34 weeks or birth weight <2000 g), compared to 27% mortality for neonates >34 weeks.[20],[21],[22],[23],[24],[25],[26] In this study, we had three cases of neonates with <34 weeks gestational age; all of them survived. Only 1/12 (8.3%) neonates with birth weight of 1900 g (neonates <2000 g group) died at 37 weeks of gestational age preoperatively. In our series, lowest weight of a neonate was 1600 g which survived following surgery.[20],[21],[22],[23],[24],[25],[26]

According to various recent studies, the overall survival rate of CDH neonates in NICU ranges from 21% to 83%.[27],[28] Chandrasekaran et al., have reported on their 12 years' experience, survival of 78%.[26],[27],[28] Similarly, Panda et al. in their study reported survival of 61% for postoperative CDH neonates (n = 70).[15],[29] Jain et al. in their study reported survival of 87.5% for CDH, but many infants presented after 1 week of life in their study.[26],[27],[28],[29],[30] Other studies from developing countries have shown the survival of 50%–65% for antenatal and postnatally detected CDH neonates. Recent studies from developed countries have shown improved survival for isolated CDH to 85%–90%, which involves the implementation of protocols such as aggressive methods of pulmonary hypertension management, huge monetary support, and availability of ECMO.[19],[29],[30]

In our study, conducted over a period of 12 years, without ECMO, showed the survival of 70/83 (84.3%) and the overall operative mortality was 3/73 (4.1%).

The limitations of this study were that antenatal ultrasonographic findings (lung-head ratio, liver up and stomach up) and OI values were not available in the medical case records.

   Conclusion Top

CDHs are common on the left side with fairly good prognosis. Although, the right-sided CDH are rare; they do carry a good prognosis, as it was seen in our experience. The overall survival rate among neonates with CDH in our institutional experience was good.


The authors would like to thank the Director, pediatric surgical colleagues, pediatric anesthetists, Radiologists, OT staffs of IGICH, Bengaluru, Karnataka, India.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

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  [Table 1], [Table 2], [Table 3]

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