In this report we described the hospital course of five premature infants (32 0/7 and 33 5/7 weeks GA) that presented with isolated bloody stools at our institution. These five case reports depict a very common occurrence in many level 2-3 NICUs and much discussion typically surrounds decision making [2,3]. Questions such as laboratory and imaging needs, indications to withhold enteral feedings and for how long, the need to start antibiotics or not and for how long to continue them are among the most common. This lead us to inquire what other practitioners would do when faced with this common scenario. As we had initially speculated, there seems to be significant variability in the management approach of the moderate/late premature infant that presents with isolated bloody stools.
In spite of the perceived increased incidence of isolated bloody stools in premature babies, few clinical reports are available [1,3]. One of the most detailed reports is by Maayan-Metzger et al., who described the characteristics and medical management of 103 preterm infants with isolated bloody stools and normal abdominal X-rays during a 12 year retrospective study in the same institution in Israel . The authors analyzed 2 time periods before and after the introduction of a more liberal approach (shortened NPO and antibiotic use) in the treatment of isolated bloody stools. They found that the rate of isolated bloody stools, the use of antibiotics and feeding cessation decreased in the second period in premature infants. Importantly, the authors attributed the decreased rate of bloody stools to the significant increase in breast milk feedings in the second period. With the more liberal approach, there was no increase in complications following the episode of bloody stools.
The most common differential diagnoses once NEC is ruled out (negative KUB for pneumatosis intestinalis, no evidence of ileus) includes the presence of anal and rectal fissures, ecchymotic colitis, viral Gastroenteritis (GE) and/or milk feeding (protein) intolerance [5-8]. A thorough exam is warranted in all patients presenting with blood in the stools and if a diagnosis of anal fissure is made and abdominal films are normal, then a conservative approach with symptomatic treatment is recommended. Symptoms are typically self-resolving but may reoccur. It is important to point out that deeper rectal fissures can be easily missed and therefore the real incidence of GI fissures remains uncertain . The opposite scenario (anal fissures “masking” NEC) should also be considered .
Viral GE secondary to organisms such as Rotavirus, Adenovirus and Enterovirus can in some instances present with isolated bloody stools, relatively normal KUBs and benign laboratory and physical findings [7,8,10].
Milk protein intolerance is a more complicated diagnosis to make, especially in premature infants. The incidence of protein allergy early in life is low, 2-3 % in developed countries, and has also been reported in premature infants but is rare [11,12]. Allergic enterocolitis can present as recurrent NEC . Family history of milk protein allergy can be helpful in establishing a diagnosis. Patients may present with isolated bloody stools but no other symptoms of intolerance such as abdominal distention, vomiting and/or diarrhea. Furthermore, both premature and term infants do not typically present with cutaneous or respiratory symptoms observed in older infants. Blood laboratory findings associated with this disorder may include elevated IgE, microcytic anemia and the presence of eosinophilia. However these findings are very nonspecific and can be absent [14,15]. In the future, advanced diagnostic testing using microarray technology and epitope analysis may improve the diagnostic accuracy of milk protein allergy by determination of specific IgE against specific allergen components of cow's milk protein . The basic treatment (and most times the best diagnostic tool) of milk protein intolerance is avoidance of milk protein containing products. In neonates a milk substitute such as hydrolyzed formulas are recommended. In case of intolerance to extensively hydrolyzed formulas, a formula based on amino acids can be suggested.
As in many case scenarios in babies with isolated bloody stools, none of these differential diagnoses applied to the 5 cases presented from our institution. In the 5 patients, duration of blood in the stool was <24 hours, time of NPO ranged from 2 to up to 7 days, all viral studies were negative, abdominal x-rays were non-specific and only one of the infant’s had recurrence of bloody stool at 28 days. In all cases, an attempt was made to reinitiate feedings using breast milk or formula. All patients tolerated this approach and therefore milk protein allergy was excluded by clinical response. In the absence of a strong family history, it would seem safe and fair to challenge these infants without using dietary restrictions; however should symptoms reoccur substitution with a hydrolyzed formula should be considered. A small randomized study by Arvola et al., found that in patients with isolated bloody stools elimination of cow’s milk protein in 19 of 39 infants did not reduce the length of bloody stools .
A possible, but less understood, entity termed “ecchymotic colitis” can present in the same manner. These neonates typically are asymptomatic except for the presence of blood in the stool. The etiology remains unknown but endoscopic and Histopathological studies showed patches of hemorrhagic and inflammatory lesions in the rectum, sigmoid and/or colon amid normal mucosa [5,16-18]. In a report by Cordero et al., 19/46 (41%) of the patients with isolated blood in the stool were deemed to have isolated rectal bleeding with ecchymotic colitis . Unfortunately, performing an invasive procedure such as endoscopy with biopsy to establish this diagnosis is not an option since this is a self-limited condition with a very benign course. Therefore, hemorrhagic colitis also remains a diagnosis of suspicion in our reported cases. Lastly, despite universal use of vitamin K for prophylaxis of vitamin K deficiency bleeding (formerly known as “hemorrhagic disease of the newborn”) in both term and preterm infants, coagulation disturbances should be part of the differential diagnosis in patients that present with isolated bloody stools, in particular if there is history of no vitamin K prophylaxis .
Survey findings included a wide variability in treatment of the well-appearing, moderate premature infant on full enteral feedings who present with a first episode of bloody stools. The majority of respondents would obtain a CBC and a KUB, half of the respondents would make the baby NPO for any duration of time and start empiric antibiotics, and only a third would start TPN. Return to full enteral feedings would be achieved quite rapidly and, in most cases, using the original type of nutrition. The majority of practitioners would order empiric antibiotics, for an average of 48-72 hours of treatment as long as cultures remained negative. Interestingly, a significant proportion of surveyed practitioners would not start antibiotics based on diagnostic criteria as presented in the survey. Follow up to this survey could include the type of antibiotics used to manage presumed sepsis/NEC, but would likely reveal the same variability in treatment.
A limitation of this review includes the lack of long-term follow up after the infants’ discharge from the hospital. It is unknown at this time if these patients had further feeding problems or recurrent blood in the stool. Further evaluation of the type of human milk fortifier would also be beneficial to delineate if powder vs liquid fortifiers and the type of protein would be better tolerated at increasing nutrient and caloric densities for this population. During the current case evaluations a powder fortifier was used. Liquid fortifier has since been introduced without an observed increase in feeding intolerance or bloody stools to date.
In conclusion, most surveyed practitioners in Utah evaluate a healthy, moderate to late well appearing premature infant receiving full enteral feedings who presents with a first episode of bloody stools with limited tests. Only half of the surveyed practitioners would make the baby NPO and only a third would start TPN. Moreover, empiric antibiotics are ordered only by half of the participants. Return to full enteral feedings is achieved more rapidly and in most instances using the original type of nutrition. We speculate that there is a trend among practitioners to treat isolated bloody stools in this population as a benign condition, with cautious 48-72 hour evaluation period and a rapid return to baseline enteral feedings. Based on the practice variability encountered in this report, this work could become the basis of a quality improvement project with a goal to standardize the approach and management of isolated bloody stools in the moderate/late premature infant.