Clinical profile and outcome of neonates with congenital diaphragmatic hernia: A 16-year experience from a developing country

Abstract

Recent advances in the perinatal interventions for neonates with congenital diaphragmatic hernia have remarkably improved the outcome in developed countries, but high mortality for such cases continues to be a challenge in resource-poor settings. This study examines clinical profiles and short-term outcome of neonates with congenital diaphragmatic hernia, using a retrospective analysis of medical records of neonates operated for congenital diaphragmatic hernia at a tertiary care center in North India from January 2001 to December 2016. Forty-two neonates were operated during the study period with male:female ratio = 1.6:1. Postoperative survival rate was 69% (29/42). Average birth weight in the survivors was 2528±267 g as compared with 2132±309 g in the non-survivors. The average gestational age in the two groups was 37.2±0.8 weeks and 34.8±1.8 weeks respectively. Twenty-one patients presented in the initial 48 h of life, out of them 52% (11/21) survived. Congenital heart diseases were associated with seven and malrotation of the gut in five neonates. The most significant factors resulting in the unfavorable outcome were preterm gestation, low birth weight, hypothermia and shock at presentation, the onset of symptoms <48 h of life, liver-up, need of postoperative inotropes and mechanical ventilation. In addition to establishing advanced therapeutic modalities, good antenatal screening, better awareness in peripheral health workers about the malformation leading to timely referral, well-equipped inter-hospital and intra-hospital transport facilities and development of level III neonatal intensive care units can improve survival in neonates with congenital diaphragmatic hernia in developing countries.

Introduction

Congenital diaphragmatic hernia (CDH) is a fatal malformation where abdominal viscera are herniated in the thoracic cavity through a developmental defect in the diaphragm. The reported incidence of CDH is one in 2000–5000 live births. ¹ Neonates with CDH usually present with severe respiratory distress and circulatory insufficiency immediately after birth. The underlying pulmonary hypoplasia and persistent pulmonary hypertension are the cornerstones of CDH pathophysiology. ² Nowadays, delayed surgical interventions are preferred after initial stabilizing measures, resulting in the postoperative survival rate of 60–80% in high volume centers.^3–5 However, many of these interventions and facilities are not yet in place in resource-poor countries where postoperative outcome still remains dismal. The aim of this study is to highlight the factors which are associated with poor outcome in a developing country.

Material and methods

We conducted a retrospective record-based analysis of neonates with CDH who were admitted to the Department of Pediatric Surgery at our institute situated in northern India. The study period spanned from 2001 to 2016. Our hospital is a government tertiary care hospital providing health services to the entire population of the region, and most of the population is of rural background having poor access to advanced diagnostic or therapeutic modalities. At the time of the study, high frequency oscillatory ventilation (HFOV), extracorporeal membrane oxygenation (ECMO) and inhaled nitrous oxide facilities were not available at our center.

Data collected was analyzed for the status of prenatal screening, gestational age, gender, age on arrival at our center, clinical presentation, anatomic site of the diaphragmatic defect, associated congenital malformations and outcome at the end of the first hospital stay.

Statistical analysis

Chi-square test was used to analyze the categorical data and odds ratio (OR), along with 95% confidence interval (CI), was calculated, taking death as an event. p < 0.05 was considered statistically significant.

Results

Demographic details

A total of 42 neonates were operated during the study period with a male:female ratio of 1.6:1. Only 26% (11/42) patients were diagnosed prenatally with ultrasound (USG) screening. Thirty-three neonates were born by vaginal delivery. Nineteen (45%) neonates in the study were preterm and none of them required surfactant therapy. Sixty-four percent of neonates (27/42) were delivered at peripheral health facilities where pediatricians were not available.

Clinical presentations

Twenty-one neonates presented within the initial 48 h of life, 15 patients between the third and the seventh day of life and six patients between the eighth and the 28th day of life. Respiratory distress was the most common presenting feature in all 42 neonates. Feeding difficulties (9/42) and delayed passage of meconium (5/42) were other presenting features. At the periphery, intravenous fluids and antibiotics were prescribed in 38% (16/42) neonates, suspecting neonatal sepsis. Due to misdiagnosis, 30% (13/42) neonates were fed before being referred. Fourteen patients (33%) were in the state of shock (tachycardia (heart rate >160 beats/min), weak peripheral pulses and capillary refill time >3 s) and 11 patients (26%) were hypothermic at arrival in the emergency room (ER). Eight neonates were referred to multiple hospitals before they were diagnosed correctly as CDH.

Anatomic details

Left posterolateral (Bochdalek) hernia was the commonest type, in 91% (38/42), and right-sided lesion was observed in four neonates. Pre-operatively, both small and large intestine were herniated in 100% followed by spleen in 55% (23/42), liver and stomach in 26% (11/42) neonates. Associated congenital malformations were seen in 33% (14/42) patients, congenital heart diseases (CHDs) being commonest, seen in seven, followed by malrotation of the gut in five neonates (Table 1). Omphalocele minor and limb defect were present in one patient each.

Table 1.

Details of associated congenital anomalies in neonates with congenital diaphragmatic hernia.

Associated anomalies	Total patients
Cardiovascular system
Atrial septal defect	4
Ventricular septal defect	2
Patent ductous arteriosus	1
Gastrointestinal system
Malrotation of gut	5
Omphalocele minor	1
Skeletal (limb deformity)	1
Total	14

Management

All patients were optimized initially with temperature stabilization, intravenous fluids and assisted ventilation as and when required. Nasogastric aspiration was done to decompress the bowel. Chest radiograph had confirmed the diagnosis in 92% (39/42) and three patients required barium meal follow through. Computed tomography (CT) and magnetic resonance imaging (MRI) was done in 18 and eight patients respectively, where the clinical examination was suggestive of other congenital malformations. The MRI scan helped in demonstrating massive liver herniation in three patients, spleen in seven and intra-thoracic kidneys in one patient. We had used CT scan before surgery in neonates where chest radiograph findings were non-conclusive or not favoring clinical examination in the late-presenting babies. Complete blood counts, blood culture, C-reactive protein, renal functions with serum electrolytes, and blood sugar levels were monitored.

After optimization, all neonates were managed with surgical intervention through the trans-abdominal approach and none of them required chest tube drainage in the postoperative period. Mean age at surgery in the index study was 4.1 days. In neonates with CHDs (i.e. ventricular septal defect, atrial septal defect, patent ductous arteriosus), conservative management with continuous monitoring done. Associated malrotation of the gut was reduced by Ladd’s procedure and primary surgical repair was performed in omphalocele minor. Postoperatively, the neonates were monitored in the neonatal intensive care unit (NICU) and managed with intravenous fluid and antibiotics, and assisted ventilation was provided if needed. After stabilization, oral feeds were started when bowel sounds returned and the baby had passed feces. The average duration of hospital stay was 14.5±4.2 days.

Mortality

With 13 deaths, postoperative survival was 69% in our study (Table 2). Out of 13 deaths, eight neonates were with gestation. Among 11 patients who were prenatally diagnosed, seven survived (OR 2.694, 95% CI 0.676–10.739, p 0.144). In 14 neonates with shock at arrival, six survived (OR 6.13, 95% CI 1.46–25.72, p 0.009). In 11 neonates who were hypothermic at arrival, four survived (OR 7.292, 95% CI 1.599–33.259, p 0.006). Three patients with associated CHDs expired. Among the eight neonates with multiple referrals, only two survived to discharge. Only 52% (11/21) neonates who presented in the initial 48 h of life survived as compared with 90% (19/21) among late-presenting cases (OR 10.45, 95% CI 1.928–56.637, p 0.003). Among 11 neonates with liver herniation, five patients expired (three had massive liver herniation and in two only a small part of the left lobe was herniated). In the postoperative period, 19 neonates needed mechanical ventilation, out of which six survived to discharge (OR 3.16, 95% CI 1.634–6.138, p 0.001). Inotropes were needed in 20 patients postoperatively and, eight survived (OR 4.25, 95% CI 1.804–10.013, p 0.001). Associated gastrointestinal malformations had not affected survival in the present series (OR 0.639, 95% CI 0.500–0.817, p 0.91). Postoperatively, sepsis was seen in five neonates, who were managed successfully with intravenous antibiotics (OR 0.649, 95% CI 0.512–0.822, p 0.144). However, the mean hospital stay was significantly prolonged in neonates with sepsis, to 17.5±3.5 days.

Table 2.

Comparison of clinical profile between survivors and non-survivors.

Characteristics	Survivors	Non-survivors	p-value
Gestation (weeks)	37.2±0.8	34.8±1.8	<0.001
Birth weight (g)	2528±267	2132±309	0.008
Prenatally diagnosed (n = 11)	6	5	0.144
Multiple referral (n = 8)	3	5	0.040
History of feeding (n = 13)	5	8	0.030
Hypothermia on arrival in ER (n = 11)	4	7	0.006
Shock on arrival in ER (n = 14)	6	8	0.009
Symptomatic in <48 h of life (n = 21)	10	11	0.030
Liver-up (n = 11)	6	5	0.020
Postoperative ventilation (n = 19)	6	13	0.001
Postoperative inotropes (n = 20)	8	12	0.001
Postoperative sepsis (n = 5)	5	0	0.111

ER: emergency room.

Discussion

CDH was successfully repaired first by Gross in 1946. ⁶ Since that time, many advances in pharmacological and respiratory interventions and intensive care management of CDH have taken place. ⁷ The ‘CDH-EURO’ consortium group had formulated standardized guidelines for the management of CDH infants in 2010 and 2015.^8,9 Nowadays, with a better understanding of the CDH pathophysiology, the concept of emergency surgery has changed to that of delaying repair after an initial period of stabilization. ¹⁰ With this approach, certain high-volume centers have reported survival rates of 90% or more.^11,12 However, these advancements are still to take place in developing countries, where survival remains much lower when compared with the western world. In the index study, the survival rate was 69%.

With routine use of USG screening, diagnosing CDH in the prenatal period has become the norm in developed countries. ¹³ The prenatal detection rate for CDH varies widely in various parts of the world, ranging from 10% to 79%.^14,15 In the present study, 26% (11/42) of neonates were diagnosed prenatally; all of them after 28 weeks of gestation. As already reported, diagnosing CDH on prenatal screening does not always guarantee a good outcome.^16,17 In a recent review with 3746 patients, Burgos et al. documented better survival rates in postnatally diagnosed as compared with prenatally diagnosed CDH (83% versus 65% respectively). ¹⁸ This might be due to the bigger size of diaphragmatic defect allowing massive visceral herniation along with marked pulmonary hypoplasia and presence of life-threatening congenital malformations, which made them easily detectable on screening. We had not found any significant association between survival rate and availability of prenatal diagnosis (p 0.144). However, it may be advantageous to identify CDH prenatally, especially in developing countries, so that the baby can be referred in-utero to a well-equipped center for better postnatal management. In the index study, all prenatally diagnosed cases were institutional deliveries which were provided with well-planned perinatal management, resulting in better survival. Another advantage of prenatal screening is the identification of associated anomalies (e.g. lethal chromosomal anomalies) which are incompatible with life, so that termination of the pregnancy can be considered.

We had observed a poor survival rate among neonates who were either hypothermic or in state of shock at presentation. As in developing countries, most of the advanced surgical facilities are located in metropolitan cities, forcing the referral of these neonates from the peripheral hospitals. In the present study, almost two-thirds of neonates were delivered at peripheral health centers where pediatricians were not available. Owing to lack of infrastructure and awareness of the anomaly, many of the cases were either missed or identified very late after birth; some of the patients were even fed. The transport services are sub-optimal; the babies are exposed to hypoxia and hypothermia during long distance traveling. The temperature, metabolic and hemodynamic instabilities that routinely occur due to sub-optimal transport facilities can be compromising in these high risk newborns. In remote areas, simple interventions like avoiding bag-mask ventilation, insertion of a nasogastric/orogastric tube for bowel decompression, establishment of intravenous access and provision of oxygenation/endotracheal intubation are not available routinely. Eight neonates were referred to multiple hospitals due to worsening of respiratory distress before being correctly diagnosed; out of these only two survived to discharge. Hence, the opportunity to utilize the concept of ‘initial stabilization’ is completely missed and the patient’s condition is further jeopardized. As reported by Nasr and Langer ¹⁹ and Fallahi et al., ²⁰ the location of the delivery place and hemodynamic status at arrival in the ER significantly influence the survival of neonates with CDH and out-born babies are associated with higher mortality. Therefore, to achieve a better outcome, neonates with CDH should be delivered at centers with well-equipped NICUs and surgical facilities.

CDH can occur as an isolated lesion, or as part of a complex genetic disease. In the literature, CDH is said to be associated with developmental malformations in 40–60% of live-born neonates.^21,22 These additional developmental abnormalities with CDH are independent factors for the mortality rate of up to 90%.^1,23 In the index study, associated congenital anomalies were seen in 33% of neonates, but none of them was life-threatening. These associated anomalies can be diagnosed with prenatal USG screening and fetal MRI-scans. Moreover, a multidisciplinary team and advanced operation theaters are required for managing these patients. As chromosomal basis is also suggested, genetic counseling may be helpful to these parents before planning for their next pregnancy. However, these advanced facilities are available only at a few centers in resource-limited setups, which are accessible to only a limited number of pregnancies.

Lastly, non-availability of well-equipped NICUs, in terms of both staff and equipment, worsens the scenario further. With the evolution of prenatal therapeutic interventions like the fetal endotracheal occlusion trial (FETO), gentle ventilation techniques like HFOV, inhaled nitrous oxide and ECMO, CDH management has entered a new era. ⁸ Most of these techniques remain a distant dream for developing countries due to huge expenditure and lack of trained staff. However, the present situation can be improved with: (1) providing better health facilities at peripheries, such as prenatal screening for diagnosing as well as risk stratification; (2) increasing awareness among health workers so that malformation can be diagnosed early and timely referral can be possible; (3) adequately supervised neonatal transport services so that the initial ‘golden time’ can be used to stabilize the patient; (4) establishing well-equipped NICUs.

This study has limitations due to its retrospective nature and small sample size. The limited number of patients did not permit us to employ more advanced statistical analysis to determine the factors contributing to the poor survival rate.

Conclusion

CDH is a lethal birth defect that poses a management challenge for pediatric surgeons, neonatologists and anesthetists. It is associated with high mortality rates, especially in the developing countries. The outcome may be improved with better prenatal screening, increasing awareness in peripheral health workers of the anomalies, well-supervised neonatal transport services and development of well-equipped NICUs.