NECROTIZING ENTEROCOLITIS

Necrotizing enterocolitis (NEC) is the most common gastrointestinal medical and/or surgical emergency occurring in neonates. With mortality rates approaching 50% in infants who weigh less than 1500 g, NEC represents a significant clinical problem. Although, it is more common in premature infants, it can also be observed in term babies. Despite intensive study over the past 30 years, its etiology remains elusive.

Pathophysiology of necrotizing enterocolitis : NEC affects the gastrointestinal tract and, in severe cases, can have profound systemic impact. Initial symptoms may be subtle and can include the following:
• Feeding intolerance
• Delayed gastric emptying
• Abdominal distention and/or tenderness
• Ileus/decreased bowel sounds
• Abdominal wall erythema (advanced stages)
• Hematochezia

Systemic signs of necrotizing enterocolitis can include the following:
• Apnea
• Lethargy
• Decreased peripheral perfusion
• Shock (in advanced stages)
• Cardiovascular collapse
• Bleeding diathesis (consumption coagulopathy)

Nonspecific laboratory abnormalities can include the following:
• Hyponatremia
• Metabolic acidosis
• Thrombocytopenia
• Leukopenia and leukocytosis with left shift
• Neutropenia
• Prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), decreasing fibrinogen, rising fibrin split products (in cases of consumption coagulopathy)

Although the exact etiology is still unknown, research suggests that it is multifactorial; ischemia and/or reperfusion injury may play a role. Cases that cluster in epidemics suggest an infectious etiology; however, a single causative organism has not been identified. Organisms isolated from stool cultures from affected babies are also isolated from healthy babies. Therefore, no single organism has been identified as the culprit responsible for triggering the disease. Some experimental work suggests that translocation of intestinal flora across an incompetent mucosa may play a role in spreading disease and systemic involvement. Such a mechanism would account for the apparent protection breastfed infants have against fulminant NEC.

Animal model research studies have shed light on the pathogenesis of this disease. Regardless of the triggering mechanisms, the resultant outcome is significant inflammation of the intestinal tissues and the release of inflammatory mediators (eg, leukotrienes, tumor necrosis factor, platelet-activating factor), which lead to variable degrees of intestinal damage.

Frequency of necrotizing enterocolitis:
In the US: Frequency varies from nursery to nursery without correlation with season or geographic location. Outbreaks of NEC seem to follow an epidemic pattern within nurseries, suggesting an infectious etiology even though a specific causative organism is unknown. Population studies conducted in the United States over the past 25 years indicate a relatively stable incidence, ranging from 0.3-2.4 cases per 1000 live births. Because more premature babies are surviving, expecting an increase in the overall incidence of NEC is reasonable.
Internationally: Population-based studies from other countries suggest an attack rate similar to the United States.

Mortality/Morbidity of necrotizing enterocolitis:
• The mortality rate ranges from 10-44% in infants weighing less than 1500 g, compared to 0-20% mortality rate for babies weighing more than 2500 g. Extremely premature infants (1000 g) are particularly vulnerable, with reported mortality rates of 40-100%. One study compared mortality rates for term versus preterm infants and reported rates of 4.7% for term infants and 11.9% for premature babies.

• Survivors can have significant short-term and long-term morbidities. Patients with medical NEC (see Bell stage II under Medical Care) must remain on nothing by mouth (NPO) for protracted periods, compromising the nutrition that is essential for a premature infant. Many of these babies have difficult IV access; the need for prolonged parenteral nutrition requires placing central venous catheters, which have attendant risks and complications of their own. Prolonged hyperalimentation and the absence of enteral nutrition can cause cholestasis and direct hyperbilirubinemia.

• Patients with significant disease can develop strictures, which require surgical intervention and further compromise successful enteral feeding. Patients who are severely affected require intestinal resection. In rare cases, the entire intestine can be involved, precluding surgical intervention. Depending on the location and extent of the bowel removed, long-term morbidities can include the need for colostomy, repeated surgical procedures, prolonged parenteral nutrition, poor nutrition, malabsorption syndromes, failure to thrive, and multiple hospitalizations.

Race: Some studies indicate higher frequency in black babies than in white babies, but other studies show no difference based on race.

Sex: Most studies indicate that male and female babies are affected equally. However, the higher incidence of neonatal sepsis and meningitis reported for male infants suggests otherwise.

Age:
• NEC clearly predominates in premature infants, with incidence inversely related to birth weight and gestational age. Although specific numbers range from 4% to more than 40%, infants weighing less than 1000 g at birth have the highest attack rates. This rate drops dramatically to 3.8 per 1000 live births for infants weighing 1501-2500 g at birth. Similarly, rates decrease profoundly for infants born after 35-36 weeks' postconceptional age.
• Average age at onset in premature infants seems to be related to postconceptional age, with babies born earlier developing NEC at a later chronologic age. One study reported the average age of onset as 20.2 days for babies born less than 30 weeks' estimated gestational age (EGA), 13.8 days for babies born at 31-33 weeks' EGA, and 5.4 days for babies born after 34 weeks' gestation.
• Term infants develop NEC much earlier, with the average age of onset occurring within the first week of life or sometimes occurring within the first 1-2 days of life.

History of necrotizing enterocolitis:
• NEC is more common in preterm infants.
• Epidemiologic studies demonstrate that antecedent history is usually the same for term as well as preterm babies. However, demographics, risk factors, typical patient characteristics, and clinical course differ significantly.
• Term baby
o Typically the term baby is much younger than the afflicted preterm baby, with published series reporting median age of onset from 1-3 days of life
o The affected term neonate is usually systemically ill with other conditions, such as birth asphyxia, respiratory distress, congenital heart disease, metabolic abnormalities, or has a history of abnormal fetal growth pattern.
o Maternal risk factors that reduce fetal gut flow, such as placental insufficiency from chronic disease or maternal cocaine abuse, can increase the baby's risk.
• Premature baby
o Premature babies are at risk for several weeks, with the age of onset inversely related to gestational age at birth.
o Patients are typically advancing on enteral feedings or may have achieved full-volume feeds when symptoms develop.
o Presenting symptoms may include subtle signs of feeding intolerance that progress over several days, subtle systemic signs that may be reported enigmatically by the nursing staff as "acting different," and fulminant systemic collapse.
o Symptoms of feeding intolerance can include abdominal distention/tenderness, delayed gastric emptying as evidenced by gastric residuals, and vomiting (occasionally).
o Systemic symptoms can progress insidiously to include increased apnea and bradycardia, lethargy, and temperature instability representing the primary manifestation(s).
o Patients with fulminant NEC present with profound apnea, rapid cardiovascular and hemodynamic collapse, and shock.
o The baby's feeding history can help increase the index of suspicion for early NEC. Babies who are breastfed have a lower incidence of NEC than formula-fed babies.
o Rapid advancement of formula feeding has been associated with an increased risk of NEC.

Physical:
• The pertinent physical findings in patients who develop NEC can be primarily gastrointestinal, primarily systemic, indolent, fulminant, or any combination of these. A high index of clinical suspicion is essential to minimize potentially significant morbidity or mortality.

• Gastrointestinal signs can include any or all of the following:
o Increased abdominal girth
o Visible intestinal loops
o Obvious abdominal distention and decreased bowel sounds
o Change in stool pattern
o Hematochezia
o A palpable abdominal mass
o Erythema of the abdominal wall

• Systemic signs can include any of the following:
o Respiratory failure
o Decreased peripheral perfusion
o Circulatory collapse
o With insidious onset, the severity of derangement may be mild, whereas patients with fulminant disease can present with severe clinical abnormalities.

• Several characteristic laboratory findings occur.

• If abdominal signs are present, surgical consultation may be advisable. Disease progression ranges from indolent to fulminant, and early involvement of surgical colleagues can be helpful, especially if appropriate surgical care requires transfer to another facility.