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Perinatal/Neonatal Case Presentation

Development of necrotizing enterocolitis in premature infants receiving thickened feeds using SimplyThick®

Abstract

SimplyThick®(ST) has been safely used as a thickener to treat adults who have dysphagia, but the safety of this product has not been studied in premature infants. Xanthan gum is the ingredient in ST that results in thickening and also is an effective laxative. We recently began using ST to treat premature infants with dysphagia and/or gastroesophageal reflux. We describe three cases of premature infants who developed necrotizing enterocolitis (NEC) after they were fed ST. Unlike classic NEC, all three cases presented with late-onset colonic NEC.

Introduction

SimplyThick® (ST) is a xanthan gum-based thickener used in the management of dysphagia. Its thickening mechanism might be related to the water-holding capacity of xanthan gum, a high molecular weight non-starch polysaccharide that acts as a soluble food fiber.1 Xanthan gum has been reported to have no adverse effects in adult animals2 and man,3 but no studies have been published describing the use of either ST or xanthan gum in infants.

Dysphagia is a common problem among infants who require neonatal intensive care, such as those born prematurely. Based on our experience, ST is a more effective thicker of human milk than rice cereal. Here we report three premature infants who developed necrotizing enterocolitis (NEC), a life-threatening condition characterized by intestinal inflammation and necrosis, after feeding with human milk or formula thickened with ST.

Case

Case 1

Baby B was born at weeks gestational age (GA) with a birth weight of 725 g. He had a relatively uncomplicated course in his birth hospital. His clinically diagnosed gastroesophageal reflux was treated by thickening feeds with ST on day of life (DOL) 58 at postmenstrual age (PMA) of 37 weeks. He was discharged on DOL 73 on feeding ad lib with a 22-calorie formula thickened with ST. A week after discharge, he was admitted to a regional emergency department for feeding difficulties and irritability. Physical examination revealed abdominal distension and tenderness, bloody stools, oxygen desaturation and hypothermia. An abdominal radiograph showed possible pneumatosis in the transverse and sigmoid colon (Figure 1a). He was transferred to neonatal intensive care unit for management of NEC.

Figure 1
figure1

Abdominal X-rays of the three premature infants taken when they were sick after receiving thickened feeds using ST (SimplyThick®). (a) case 1, (b) case 2 and (c) case 3. The radiology reports are shown in the Table 1.

Case 2

Baby C was born at weeks GA with a birth weight of 750 g. On DOL 5, he was transferred from his birth hospital for small intestine perforation, which required surgical resection of his distal ileum and cecum, and creation of an ileostomy. On DOL 100, he underwent re-anastomosis of the bowel. After recovery from surgery, feeding of human milk was restarted on DOL 106. On DOL 108 at PMA of weeks, ST then Hydra-Aid®, another xanthan gum product, was added to the feedings in order to improve sucking and swallowing coordination. On DOL 117, he developed bloody stools and abdominal tenderness. An abdominal film showed pneumatosis in the rectum, sigmoid and descending colon (Figure 1b). Treatment for NEC was initiated.

Case 3

Baby I was born at weeks GA with a birth weight of 950 g. On DOL 7, she was transferred from her birth hospital for evaluating multiple congenital anomalies. She was discharged on DOL 53 on feeding ad lib with a 22-calorie formula. On DOL 57 at PMA of weeks, she was readmitted for chocking episodes during feedings followed by apnea and cyanosis. A pharyngeal function study was completed, and thickening feeds with ST was initiated to treat dysphagia. On DOL 60, she developed apnea, poor feeding, temperature instability, abdominal distension and markedly elevated C reactive protein. An abdominal film was suspicious for pneumatosis in the left colon (Figure 1c). She was then treated for NEC.

These three cases are summarized in Table 1.

Table 1 Summary of development of NEC after thickening feeds with ST in the three premature infants

Discussion

NEC affects 7% of premature infants with a birth weight <1500 g, and is associated with significant morbidity and mortality.4 The onset of NEC is unpredictable with nonspecific clinical presentation, but it often occurs after initiation of enteral feeding during the first month of life and usually involves the ileum.5 In contrast, these three infants described here presented after the second postnatal month following ingesting feeds thickened with ST, and the predominant area of involvement was thought to be the colon. Although prematurity, enteral feeding and bacteria colonization are predisposing factors for NEC, the etiology and pathogenesis are incompletely understood and most likely multifactorial. Human milk feeding is associated with a lower risk of NEC.

The thickening function of ST depends on xanthan gum, a polysaccharide produced by the plant pathogen Xanthomonas campestris. It is one of the most extensively studied microbial polysaccharide for use as a thickener and laxative.6 It increased stool output and frequency, and flatulence in man,7 and caused 400% increase in intraluminal water and 150% increase in sugars in distal small intestine in rats,8 which probably can not be tolerated by premature infants and may cause injury to their immature gut. As the consequence of accumulation of luminal sugars, fecal bacteria fermentation of xanthan gum increases the production of H2 and short-chain fatty acids (SCFA) in the colon of man7 and rats.9 SCFA-induced colonic mucosal injury in neonatal rat was found inversely with maturation,10 and excess luminal SCFA may have a role in the pathogenesis of NEC.11 In addition, xanthan gum causes an increase in fecal bile acid excretion.3 Accumulation of cytotoxic bile acids in the ileal lumen is a critical component for development of NEC in a neonatal rat model.12

Premature infants have highly immunoreactive intestinal mucosa, which probably predisposes them to intestinal injury. An excessive inflammation in response to intestinal stimuli is a component of the pathogenesis of NEC.13 Feeding premature infants with xanthan gum-based ST not only stimulates the immature gut by increase in water, sugars, SCFA and bile acids in the distal small intestine and colon, but also may directly active gut lymphocytes and macrophages to trigger an excessive inflammatory cascade. In mice, xanthan gum activates lymphocyte and macrophage almost as much as lipopolysaccharide and this effect is more prominent with neonatal than adult cells.14 In vitro, xanthan gum, as a Toll-like receptor-4 ligand, induced tumor necrosis factor-α and interleukin-12 production in macrophages of mice.15 This pathway might also be involved in the pathogenesis of NEC.13 Thus, we speculate that late-onset NEC in premature infants fed with ST was most likely caused by the stimulation to immature gut by xanthan gum. After receiving reports of intestinal complications in premature infants fed with ST, the FDA issued a recommendation that this product should not be used in premature infants. However, because of its special biological properties, ST might be useful in research into the pathogenesis of NEC.

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Acknowledgements

We thank Dr Michael O’Shea for his critical reading of this manuscript.

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Correspondence to Q Yang.

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Woods, C., Oliver, T., Lewis, K. et al. Development of necrotizing enterocolitis in premature infants receiving thickened feeds using SimplyThick®. J Perinatol 32, 150–152 (2012). https://doi.org/10.1038/jp.2011.105

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Keywords

  • necrotizing enterocolitis
  • dysphagia
  • premature infant
  • SimplyThick®
  • thickened feeds
  • xanthan gum

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