Short-term Outcome of Low Birth Weight Preterm Infants with Necrotizing Enterocolitis: A Prospective Cohort Study

Aim: The purpose of this study was to analyze the nature of the disease, the surgical procedures, complications, and survival of preterm infants with necrotizing enterocolitis (NEC) from two tertiary care referral neonatal intensive units in central India. Materials and Methods: A prospective study of a cohort of 110 preterm neonates with gestational age <36 weeks and weight <1600 g infants diagnosed to have NEC were followed for 90 days. All the neonates were born between January 2015 and December 2017 and treated at two neonatal intensive care units. Infants with sepsis, congenital gastrointestinal anomalies, major cardiac problems, and intraventricular hemorrhage were excluded. Results: Mean gestational age in this cohort was 32.40 ± 3.87 weeks, and the mean age of NEC onset was 13.04 ± 3.54 postnatal days. There were 39 neonates with Stage 1, 45 with Stage 2, and 26 with stage 3 NEC. Pneumoperitoneum, positive paracentesis and progressive clinical deterioration were the indications for laparotomy. The most common complications were sepsis 97/110 (88.18%). Post-operative complications occurred in 22 (84.61%) infants, wound infection in 19 (73.07%), intestinal stricture in 9 (34.61%), wound dehiscence in 7 (26.92%), stoma stenosis in 3 (11.53%), ileostomy prolapse in 2 (7.69%), and burst abdomen in 1 (3.84 %). The overall 90-day survival rate was 87.27% (96/110), and the post-operative survival rate was 46.15% (12/26). The age of gestation, weight, and extent of the disease were the main risk factor for mortality. Conclusion: The short-term outcomes for Stage 3 NEC were associated with high morbidity and mortality. The outlook for infants with Stage 1 and 2 NEC was favorable.


INTRODUCTION
Necrotizing enterocolitis (NEC) is still the most common cause of gastrointestinal-associated morbidity and mortality in neonatal intensive care unit (NICU) [1].Prematurity and low birth weight are the most consistently agreed risk factors [2].The disease prevalence is approximately 9-14% of infants born below 1500g [3].It typically occurs in the second to 3 rd week of life in premature, formula-fed infants and is associated with high morbidity and mortality (20-45%) [4].The pathogenesis is multifactorial and has often been linked to enteral feedings, bowel ischemia, and infectious sources [5].The process is thought to be headed by an ischemic or toxic event that causes damage to the immature gastrointestinal mucosa and loss of mucosal integrity [6].The initiation of enteral feedings allows the proliferation of bacteria, and damaged mucosa is invaded by gas-produc-ing bacteria leading to sepsis, necrosis or perforation of the bowel [7].
The clinical manifestation of NEC reflects a heterogeneous disease process with some infants manifesting localized intestinal injury, while others presenting with diffuse involvement and fulminant necrosis of the intestines.The recent consensus is that the immature intestine of premature infants exists in a hyperactive state due to abnormal bacterial colonization, which triggers an inflammatory response and impairment of intestinal perfusion [8].The study evaluated the short-term outcome of preterm infants with NEC at different stages of diseases.
Absolute indication for laparotomy was pneumoperitoneum (n = 13), and relative indications included progressive clinical deterioration (n = 7) and positive paracentesis (n = 6).Table 2 shows the attributes of surgical patients.Perforation was found during the operation in 19 (73.07%) neonates, detected preoperatively in 13 neonates.Multifocal disease was found in 19 (73.07%), 4 (15.3%) had localized, and 3 (11.5%)was pan-intestinal.There were 16 neonates with only small bowel involvement, a combination of small and large bowel involvement in 8, and only large bowel involvement in 2. The ileum was the most commonly affected location (n = 24, 92.30%).As for the surgical approaches, enterostomy creation with necrotic bowel resection was the initial procedure in 19 patients.In 4 neonates, enterostomy without resection of gut was performed (2 jejunostomies and 2 transverse colostomies).Three children underwent laparotomy and simple drainage for pan-intestinal involvement with near total intestinal compromise (Table 3).
The most common post-operative complications were sepsis (n = 20, 76.92%).Other surgical complications are shown in Table 4.The median length of survival of the 14 deaths after surgery was 9 days (range 3-17).Three children died within 3 days of surgery.The cause of death was mainly attributed to pan intestinal NEC in these neonates.The remaining death resulted from sepsis, severe short bowel effects, respiratory distress syndrome, and multiple organ failures (Table 4).and post-operative survival rate was 46.15%.There was no death occurred after stoma closure.Figure 2 showing the flowchart of 110 NNEC patients of this study.

DISCUSSION
Low birth weight and low gestational age are the most significant prognostic factor.Among the other important risk factors for developing NEC, the following are considered important: Low Apgar score [10], the need for surfactant application for respiratory distress syndrome [11], assisted ventilation, patent ductus arteriosus, late-onset bloodstream infections, enteral feeding, maternal hypertensive disease of pregnancy, placental abruption, absent or reversed end diastolic flow velocity, use of umbilical catheters, and hypotension requiring inotropic treatment [12].In this study out of 14 deaths, five neonates were very preterm (28-31 weeks) and 9 were extremely preterm (27 weeks).In addition, nearly 80% had birth weights under 1kg who died.
Clinical and radiographic findings are often nonspecific in the initial period.The early and correct diagnosis of NEC is of utmost importance.According to the literature, bowel dilatation is present in 75-90% of cases in initial NEC, and focal or separated dilatation reflects more-advanced disease [13].In our study, generalized intestinal dilatation was observed in 55.45% of neonates in Stage 1 and 2. In advanced NEC, the most common sign was pneumoperitoneum (11.81%).Persistent loop sign is the hallmark of impending perforation which was present in 30.76% of patients undergoing surgery.The presence of portal venous gas is associated with severe disease and higher mortality rates with the specificity and positive predictive value of 100% for intestinal necrosis [14].However, pneumoperitoneum is considered an absolute indication for surgical treatment and is presented in only 50-75% of all patients with bowel perforation secondary to NEC [14].In our study, pneumoperitoneum was found in 13 (50%) out of 26 neonates who underwent surgery.
Fixed abdominal masses and erythema of the abdominal wall which is strongly predictive of NEC are reported to present in 10% of patients [15], but in our series, we have found in 34.61% of the patients in Stage 3 (Figure 1c).
In patients with Stage 1 and Stage 2 NEC, the applied feeding program relied on parentral feeding, while oral feeding was prohibited, until patient started to thrive and tested for enteral feeding tolerance by 1-week increments of the amount of oral intake.Support for respiratory and cardiovascular failure was made.Frequent clinical examination and serial, abdominal radiography is required to identify the deterioration or progression of diseases.In Stage 1 of our study group feeding was resumed within 9-11 days and in Stage 2 feeding was resumed after 13-19 days.Recent studies reported that abdominal sonography could be used to evaluate bowel perfusion, viability, peristalsis, and fluid collections [16].In this study, USG was used in 77 patients but could not predict the evolution of the disease.
Approximately 20-40% of cases with NEC require surgical intervention [17].In our group of patients, n = 26 (23.63%) were surgically treated.The principal indication for operative intervention in NEC was perforated or necrotic intestine.Although the free intraperitoneal air was an absolute indication for surgical intervention, in this study, it was only seen in 50% (13/26).Paracentesis was utilized as an adjunctive in 31 patients but was positive in 6 patients.Other indications were erythema in the abdominal wall, gas in the portal vein, and clinical deterioration despite maximum medical therapy.
During operation, every effort needed was done to preserve maximum intestinal length.Resection of necrotic bowel with enterostomy was performed in n = 19 (73.07%) of localized and multifocal cases.Literature has mentioned higher post-operative complication rates after NEC surgery, at times in excess of 50% [18].The post-operative complication rate and stoma-related morbidity were high 73.07% in our series (Figure 1d).Wound dehiscence and wound infection remain troublesome complications, especially in wounds with stomas, where protecting the wound from stoma effluent requires diligent stoma care.The outcome of pan-intestinal NEC (NEC totalis) remained poor with a mortality rate of 100%.Sepsis was the most frequent complication seen in 39.09%.Prematurity, central line access and prolonged parenteral nutrition contribute to increased incidence of septic complication [19].Intestinal strictures develop in 9-32% of patients who underwent the operation [20].Stricture occurred after both medical and surgical treatment for NEC and in both functional and defunctionalized bowel.In this study, we found stricture in n = 9 (75%) of living child who had an initial operation and n = 8 (17.77%) of a patient with Stage 2 NNEC.A contrast study is advisable to rule out strictures or complete obstruction before restoration of intestinal continuity.Intestinal strictures result from collagen deposition; fibrosis and wound contraction over a variable period following an episode of acute inflammation.It is the reparative process following an acute decrease in flow through the ral blood vessels [21].Short bowel syndrome remains a major problem and has been reported as a surgical sequel in about a quarter of NEC patients [22].NEC remains the most common cause of short bowel syndrome in neonates, with associated high mortality ranging from 6 to 47% and high morbidity [23].In this series, only 2/26 patients (7.69%) had short bowel syndrome, and both could not be saved.Concerning short-term outcome; 96 patients (87.27%) passed hospital course, tolerated oral feeding and started to thrive (84 responded to medical therapy, and 12 after surgical intervention).Significantly higher success rate and lower morbidity and mortality rates were among patients who had a medical intervention as  [25,26].
Limitations of our study include an inherent risk of selection bias.As some diseases, such as focal intestinal perforation, Hirschsprung enterocolitis, and milk protein allergy, share similar clinical features with NEC, misclassification bias is possible, although the pathological reports, operative notes, and radiographic images were assessed in these neonates for arriving the inclusion criteria.The strength was prospective nature of the study and close monitoring with no loss of patients to follow-up.

CONCLUSION
A high risk of developing NEC is closely associated with very low birth weight neonate.Bowel perforation in premature neonates with NEC is associated with lesser gestational age, lower birth weight, apnea, mechanical ventilation, and sepsis.There is no clear evidence-based consensus on the requirement of surgery, with the exception in the evidence of bowel perforation.Short-term outcomes for preterm neonates with surgical NEC in this study were accompanied by high mortality and complications rate.The outlook for neonates with Stage 1 and 2 NEC was favorable.Further studies are required to recognize the risk factors, preventive measures, and optimal timing of surgical intervention.

Figure 1 :
Figure 1: (a) X-ray showing pneumoperitoneum.(b) X-ray showing pneumatosis intestinalis.(c) Clinical photograph showing fixed abdominal mass and erythema.(d) Clinical photograph showing ileostomy prolapse d c 7ournal of Neonatal Surgery Vol.7, 2018 Short-term Outcome of Low Birth Weight Preterm Infants with Necrotizing Enterocolitis: A Prospective Cohort Study tral India.110 preterms, gestational age <36 weeks, and weight <1600 g neonates with NEC were prospectively analyzed from January 2015 to December 2017.The study protocol was approved by the Institutional Review Board.Written informed consent was obtained from the patient's parents once the diagnosis of NEC is made.NEC stage was determined according to the modified Bell (Walsh and Kliegman) staging criteria [9].

Table 1 :
Maternal and neonatal characteristics in neonates with NEC

Table 2 :
Demographics of 26 neonates undergoing operation

Table 3 :
Laparotomy findings and procedures applied for 26 surgical neonates

Table 4 :
[24]-operative complications and causes of deaths Flow chart showing the treatment and outcome of the 110 NNEC patients compared to patients requiring surgical intervention.Murthy et al.[24]reported grave short-term outcomes after surgery for NEC, particularly for neonates born <28 weeks' gestation.The surgical outcome of NEC depends on the underlying variant pathogenesis in the population involved.It is possible that NEC exhibits different features, with a differing predictive result in different neonate populations