Necrotizing enterocolitis in the preterm: newborns medical and nutritional Management in a Single-Center Study

In our case series, enteral nutrition started on average after 6.7 ± 9.6 days of life. This delay in starting nutrition could be related to prematurity. Considering the type of milk administered before NEC, 5 groups of newborns were identified: 2 newborns were fed with breast milk and hydrolyzed formula, 5 with breast milk and preterm formula, 2 with preterm formula and 8 with breast milk only; 1 newborn developed NEC before the initiation of enteral feeding. In the 17 newborns who developed NEC after the beginning of enteral feeding, it was stopped for food intolerance after 15.5 ± 13 days of life. Infants of this case series performed enteral nutrition for 11,3 ± 11,6 days before the NEC onset. Considering the interval between disease onset and enteral reintroduction, an average fasting period of 24 ± 18.9 days was performed. Figure 3 describes the days distribution for the enteral fasting after NEC onset.

The time to reach a full enteral feeding was evaluated by measuring the interval between the day of enteral reintroduction and the day of parenteral stop. 8 infants were excluded (7 for an early exitus and 1 for lack of clinical data).

Table 2 sums up types of milk administered during the enteral feeding reintroduction phase.

In our series, due to the prematurity, many infants started parenteral nutrition before NEC onset. It should be noted that in the event of death, the day of exitus was considered the day of parenteral suspension. On average, infants in our population practiced parenteral nutrition for 50 ± 28 days. Regarding the composition of the parenteral formula administered,12 newborns received olive oil lipid emulsions, 5 received soy-bean lipid emulsions and 1 received parenteral with lipid-free formula.

4 patients did not have surgery (22.2%) and 14 had surgery (77.8%). Surgery was performed on average after 32.5 ± 27.1 days of life. Among operated infants, 5 had an intestinal resection with ileostomy placement (27.8%), 4 had only ileostomy packaging (22.2%), 1 had a colostomy, 2 had neither resection nor ileostomy. 2 patients were treated exclusively with an abdominal drainage. Within the group of operated infants, the reintroduction of enteral nutrition occurred on average after 17.7 ± 17.9 days from surgery.

Iron, D and K vitamins supplementation is essential in preterm newborns [8] Our population, in addition to the inherent risk of prematurity, was more exposed to a vitamin malabsorption and to trace elements lack. In addition to this, newborns who practice parenteral nutrition for long periods may develop carnitine deficiency [8]. We evaluated vitamin supplementation in our population: 2 newborns received carnitine, 4 oral iron, 1 injected trace elements and 9 received oral multivitamins.

We evaluated the administration of antacids and ursodeoxycholic acid (UDCA) in our population, trying to identify an indirect parameter that would give us an overview on main gastroenterological sequences of NEC (ex. gastric hypersecretion and liver disease). Many neonates with NEC, especially those who had jejunostomies, showed an increased gastric secretion that may require antacids [5]. In our population 6 infants received antiacids. Furthermore, infants with NEC, due to a prolonged parenteral nutrition, show higher risk of developing liver disease and cholestasis. These conditions need for nutritional modifications and UDCA supplementation. In our population 4 infants received UDCA.

Many clinical and radiological signs were evaluated from the onset of NEC. Principal signs of food intolerance which brought to the interruption of enteral feeding were abdominal distension (83.2%), stagnation (33.3%) and intestinal bleeding (27.7%) (Table 3). Most frequent systemic signs were the increase of inflammation indices (55.5%) and thrombocytopenia (27.8%) (Table 4). Radiological findings observed were pneumoperitoneum (38.9%), hydro-aerial levels (38.9%) and failure to gasify the rectum (33.3%) (Table 5). Portal pneumatosis and aerobilia were less frequent radiological signs.

Medical NEC therapy consists of the administration of broad-spectrum antibiotics, the fasting and the initiation of parenteral nutrition. The duration of fasting depends on clinical, laboratory and instrumental evaluation [18]. According to recent evidence, early reintroduction of enteral feeding is associated with fewer complications, shorter duration of antibiotic therapy, faster progression to nutritional goals by age, and shorter hospitalization [19, 20]. A recent review [5] suggests that in patients on stage 1 and 2, fasting must last between 7 and 14 days. Conversely, a meta-analysis reports that there are no significant differences in terms of complications if the enteral is introduced before the fifth day [19]. A prolonged enteral fasting could have multiple negative consequences:

Clinicians should minimize fasting, reintroducing enteral nutrition as soon as there is a clinical improvement witnessed by the stability of vital signs, the abdominal physical examination, and the normalization of platelet count and radiologic signs The identification of biomarkers (NIRS, I-FABP, intestinal alkaline phosphatase) [21, 22], capable of reflecting the severity of NEC and intestinal recovery, could help to personalize the moment of resumption of enteral feeding, minimizing the consequences of a prolonged fasting. In addition to the correct timing for the resumption of enteral nutrition, the type of formula to be used is an important factor. The superiority of breast milk seems undisputed, but when it is not available, it is not known whether the adapted formula or the hydrolysate is preferable. In our series, 10 newborns resumed enteral nutrition with breast milk (5 exclusively, 3 associated with hydrolyzed formula, 2 associated with adapted formula), 4 resumed enteral nutrition with hydrolyzed milk, the remaining 4 did not resume enteral nutrition because they died earlier. After enteral nutrition reintroduction, it is necessary to assist the newborn until full enteral feeding is reached: this interval in our population lasted after 17.2 ± 8.2 days on average.

Neonates with NEC should start early parenteral nutrition with an adequate dose of amino acids (3.5–4 g/kg/day), in order to maintain a positive nitrogen balance, an improvement of weight growth and allowing the repair of damaged tissues [1, 23‐25]. Parenteral nutrition can be discontinued when enteral nutrition is sufficient to meet the nutritional needs. Prolonged parenteral nutrition is associated with higher risk of infections and metabolic problems, such as dyslipidemia and liver disease. The duration of parenteral nutrition in our series is particularly long if compared to other studies in the literature, but this data could be due to the prematurity and severity of NEC in our newborns. In our series, parenteral nutrition was started on average on the second day of life and practiced for an interval of 50 ± 28 days. In our case series, 12 newborns received olive oil lipid emulsions; 5 received soybean lipid emulsions; finally, 1 newborn practiced parenteral nutrition without lipids.

Main metabolic complications of the parenteral nutrition are liver disease and intestinal failure (IFALD) [26]. These complications incidence could be modified by reducing the duration of parenteral nutrition, preferring cyclic infusions and using suitable lipid mixtures. Several factors should be taken into consideration when choosing the lipid emulsion to use for parenteral: the content of essential fatty acids, the ratio of omega-6 and omega-3 and the amount of α-tocopherol and phytosterols. Soy-bean lipid emulsions have an omega-6: omega-3 ratio of 7:1, while the ideal ratio should be 4: 1 [27, 28]. In addition, they have a high content of phytosterols which cause liver inflammation and cholestasis [29, 30]. Fish oil lipid emulsions are mainly composed of omega-3 and contain low amounts of omega-6 [31]. Therefore, fish oil emulsions are approved as IFALD therapy, but not for ordinary pediatric parenteral nutrition due to the risk of deficiency of essential omega-6 fatty acids.

Recently, new lipid mixtures called Smoflipid have been developed. They are composed by soybean oil (30%), coconut oil (30%), olive oil (25%) and fish oil (15%).

In children with cholestatic jaundice, there is an improvement in liver function after switching from soy-bean lipid emulsions to Smoflipid [32]. Smoflipid has a positive impact on liver enzymes thanks to the low content of phytosterols and to the high content of vitamin E. Its use determines a reduction in the lipid peroxidation and an optimization of the ratio between PUFA omega-3: omega-6 which creates a minor pro-inflammatory insult [33].

In cases of NEC complicated by intestinal perforation, surgery is required. In our sample, 14 newborns underwent surgery. Among the 14 operated infants, 5 underwent intestinal resection with enterostomy packaging, 5 had enterostomy packaging only, 2 underwent a laparotomy without resection or enterostomy, and finally 2 were treated exclusively with the placement of an abdominal drainage. After extensive bowel resections intestinal failure can develop [34]. This condition can be overcome thanks to an intestinal adaptation that allows the achievement of enteral autonomy [35]. The length of the residual intestine and the type of nutrition influence intestinal adaptation. Post-operative nutrition strategies that aim to enhance intestinal adaptation are a cornerstone of treatment.

In our series, patients who received surgery resumed enteral nutrition 17.7 ± 17.9 days after the intervention. Figure 4 describe the distribution of different intervals of enteral refeeding in patients who underwent surgery. 7 newborns were refed with breast milk (4 exclusively, 3 together with the hydrolyzed formula), while 4 took the enteral exclusively with the hydrolyzed formula. Breast milk offers numerous benefits on the intestinal adaptation, thanks to the high content of growth factors [36]. Breast milk contains oligosaccharides such as 2-fucosyllactose (2-FL) which positively regulate the intestinal microbiome by stimulating the proliferation of enterocytes [37].

In patients of our series with NEC at stage III (n = 14), parenteral was practiced for 53.4 ± 29 days: 11/14 received olive oil lipid emulsions, 2/14 soybean lipid emulsions, finally 1/14 received lipid-free emulsions. Surgical NEC typically requires prolonged use of parenteral nutrition (> 21 days) [5]. Patients with fewer residual bowels require more days of parenteral nutrition [38‐42]. Parenteral support after 28 days of surgery is associated with an increase in mortality at 1 year [43]. In clinical practice, intestinal failure can be indirectly measured by the length of parenteral nutrition required for normal or recovery growth [44].

Ostomies result in losses of mineral salts and micronutrients, especially zinc. Intestinal resections alter the absorption of certain nutrients, depending on the intestinal tract resected. In case of jejunostomy, the absorption of iron and zinc can be impaired. In ileal resections and fasting, the absorption of vitamin B12 and the resorption of biliary salts is altered. In addition, infants who practice prolonged exclusive parenteral may develop carnitine deficiency. Prolonged parenteral can cause cholestasis that reduces the resorption of fat-soluble vitamins.