Introduction

Necrotising Enterocolitis (NEC) is a serious, life-threatening condition which almost exclusively affects premature or low birth weight babies. In NEC, the lining of the gut (gastrointestinal tract) becomes inflamed, which can lead to bacterial invasion, this leads to damage and death of the wall of the intestine. 

If left untreated, a hole in the gut wall can occur, causing bacteria to enter the abdomen, which can result in life-threatening infection and death. NEC is the leading cause of morbidity and death in preterm infants, where the mortality rate is as high as 50%.¹

Pathogenesis of NEC

Necrotising Enterocolitis is a disorder characterised by inflammation and death of the gut wall, which, if untreated, can progress to a more severe, systemic (body-wide) infection, organ failure and death.

The development of NEC is a result of multiple factors. It is the result of a complex interaction of an immature lining of the gut wall, disruption of the balance of good and bad bacteria within the gut, the feeding type a preterm baby receives, and an uncontrolled immune response. 

When the gut wall is immature, it has undeveloped immune cells and a poor blood supply, which can compromise its ability to function as a barrier. Therefore, when the wall is exposed to bacteria within the gut, it can lead to severe infection and inflammation.¹

Risk factors

There are several factors which increase the risk of the development of NEC. 

These risk factors include: ²

• Premature birth
• Feeding practices
• Bacteria in the gut
• Birth defects: particularly heart or gut anomalies
• Infections
• Mechanical breathing support delivery

Premature birth

Premature birth is the main risk factor for NEC development, with approximately 7% of premature babies born at a weight of less than 1500 grams being affected by NEC.

The gut is composed of a complex interaction of many cell types which normally work together to absorb nutrients, recognise harmful bacteria, and protect and maintain the gut wall barrier, acting as the first major barrier of the gut immune system.³

When a baby is born, the ecosystem within the gut is fragile, as it is exposed to the external environment for the first time and must distinguish between self and non-self antigens. This process is more challenging in premature babies, where normal intestinal development is suddenly interrupted. In premature babies there is a lower number of specialised cells lining the gut in comparison to babies born at term.By having less mature cells, their gut is more sensitive to the detection of bacteria and has an inappropriate response.. This may lead to an increase in bacteria in the gut, causing infection, inflammation, and injury to the gut wall. Therefore, the more premature a baby is, the higher the risk of them developing NEC.⁴

These babies can commonly be critically unwell, and require a prolonged stay in the neonatal intensive care unit and antibiotic use and increased nutritional demands. Together, these can result in bacterial imbalances, inflammation and contribute to the disruption of the gut barrier.⁵

Feeding newborns receives 

Feeding practices can have a very important impact on the vulnerable gut of preterm babies. Factors such as type of feeding, whether or not fortification is used, duration of feeding, and rate of advancement can all impact the development of NEC in preterm babies.

Premature babies are usually fed with feeding tubes, which are widely recognised as a significant risk factor for NEC development, where 99% of babies who develop NEC are fed through a tube.

Breast milk is protective against NEC, and is an established optimal source of nutrition and support for a babies immune system. Babies fed with breast milk have a significant decrease in the incidence of NEC compared to formula-fed infants, however, this does not completely eliminate the risk of disease development. 

The protective effects of breast milk are likely due to the key nutrients and protective immune components within breast milk – these include antibodies, and protective gut bacteria delivered from mother to the baby, which helps the babies gut develop a healthy bacterial composition.^6,7

Bacteria in the gut

The type of bacteria which exist in the gut is called the gut microbiome. Usually, babies’ intestines are filled with helpful bacteria, however, sometimes harmful bacteria can grow instead.

In NEC, particularly harmful bacteria communities rapidly grow within the premature babies gut, which can interact with the immature immune system of a premature baby and cause injury to the gut wall. Risk factors such as antibiotic use and formula feeding can all affect bacterial communities within the gut, contributing to NEC development.⁸

How NEC Develops Inside the Body

Given the risk factors, NEC develops most commonly in babies born prematurely within their second to third week of life after they are administered formula feeding. Although the exact mechanism of NEC is not fully understood, the development of the disorder in high-risk premature babies is influenced by multiple factors, and initiates with the uncontrolled infection of bacteria within the gut.¹

Bacterial infection

Bacterial colonies develop in the premature babies gut, often after the administration of formula feed and antibiotic use.

Immune activation

The premature cells that line the gut of a preterm baby are increasingly more reactive to the microbes which invade, compared to a full-term baby, and have an exaggerated, uncontrolled immune response to the bacteria.

Disruption of the gut barrier and resulting gut damage

An exaggerated, uncontrolled immune response results in damage to the gut wall barrier. The immature immune cells have an impaired ability to heal properly and which is further affected by reduced blood flow to the gut. As a result, damage to the cells which line the gut wall continues to occur.^8,9,10

The development of NEC usually presents with symptoms such as distension of the abdomen, vomiting, blood in their stools and intolerance to food.¹¹

Progression of disease

Progression of the disorder can range from initial localised damage in the gut wall to more severe gut wall death, leading to a hole in the intestines, which can result in body-wide infection, sepsis and death.

Localised damage

The initial increased, uncontrolled response of immune cells to bacteria within the gut causes damage to the gut wall.t. If this immune response is not controlled, it will result in injury, which causes cell death. As it progresses, this can lead to more severe localised damage, such as development of a hole in the gut wall.^12,13

Body-wide systemic involvement

When a hole in the gut wall occurs, this is a life-threatening complication, where mortality rates can be as high as 76%. Spillage of contents of the gut into the abdomen can result in body-wide spreading of infection, causing multi-organ damage, sepsis and shock.¹¹

Complications

A majority of cases are treated medically, however, 20-40% of babies will require urgent surgical care. Complications increase in those requiring surgical intervention, where the death rate is as high as 50%. Babies who survive often have long-term complications such as short-bowel syndrome, cholestasis, prolonged hospital stays, growth impairment and poor neurodevelopment, which can result in conditions such as cerebral palsy.⁹

Summary

NEC is a serious, life-threatening emergency and the most common emergency affecting the gut of preterm babies. Certain risk factors such as preterm birth, formula feeding and use of antibiotics increase the chance of the development of NEC. This is due to the immature cells of the gut being unable to initiate an appropriate immune response to bacteria within it. This leads to a localised inflammation, which can eventually cause a hole in the gut, and spread of infection to other organs, with severe consequences such as sepsis, shock and multi-organ failure.

NEC has a high morbidity and mortality rate, with about 30% of babies who develop it requiring surgical intervention, and up to 50% of babies dying as a result. Of those who survive, babies can have significant long-term consequences, such as short-gut syndrome, impact on normal growth, cerebral palsy and learning disabilities. 

As a result, urgent preventative and treatment strategies, such as optimising feeding practices and early identification of risk factors, are critical to prevent the development of this disease and improve neonatal outcomes.