Diarrhea in neonatal intensive care unit

Abstract

AIM: To investigate the frequency, etiology, and current management strategies for diarrhea in newborn.

METHODS: Retrospective, nationwide study involving 5801 subjects observed in neonatal intensive care units during 3 years. The main anamnesis and demographic characteristics, etiology and characteristics of diarrhea, nutritional and therapeutic management, clinical outcomes were evaluated.

RESULTS: Thirty-nine cases of diarrhea (36 acute, 3 chronic) were identified. The occurrence rate of diarrhea was 6.72 per 1000 hospitalized newborn. Etiology was defined in 29 of 39 newborn (74.3%): food allergy (20.5%), gastrointestinal infections (17.9%), antibiotic-associated diarrhea (12.8%), congenital defects of ion transport (5.1%), withdrawal syndrome (5.1%), Hirschsprung’s disease (2.5%), parenteral diarrhea (2.5%), cystic fibrosis (2.5%), and metabolic disorders (2.5%). Three patients died due to complications related to diarrhea (7.7%). In 19 of 39 patients (48.7%), rehydration was performed exclusively by the enteral route.

CONCLUSION: Diarrhea in neonates is a challenging clinical condition due to the possible heterogeneous etiologies and severe outcomes. Specific guidelines are advocated in order to optimize management of diarrhea in this particular setting.

Key Words: Chronic diarrhea; Congenital diarrhea; Food allergy; Oral rehydration solution; Rotavirus

INTRODUCTION

Diarrhea and neonatal age are two major factors responsible for pediatric mortality worldwide[1,2]. The neonate has increased susceptibility to complications related to diarrhea due to immaturity of the systems that regulate fluid homeostasis and immunologic response[3]. Early diagnosis and timely treatment are crucial because diarrhea in neonates may rapidly lead to life-threatening dehydration and malnutrition[4,5]. Clinical and epidemiologic studies defining severity and etiology are needed in order to improve diagnostic and therapeutic approaches for neonatal diarrhea. Starting with these considerations, the Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP), on behalf of the Italian Society of Neonatology (SIN), designed a nationwide study aimed at investigating the frequency, etiology, clinical features, nutritional management, therapeutic approach, and outcomes of diarrhea observed in hospitalized neonates.

MATERIALS AND METHODS

A multicenter, retrospective study was planned. The study design and aims were presented and discussed during two meetings of the SIGENP and the SIN. We invited the participation of the chiefs of neonatal intensive care units (NICUs) of urban children’s hospitals, university medical centers or large community hospitals, observing at least 100 newborns per year and having the following diagnostic facilities: determination of fecal electrolyte concentrations, full microbiological examination, food allergy tests, gastrointestinal endoscopy and histology, metabolic tests and genetic counselling. The neonatologists operating in the participating centers were invited to review the data of 3 consecutive years (i.e. 2000-2002). Inclusion criteria were: (1) age at hospitalization ≤ 28 d; (2) gestational age at birth ≥ 24 wk; (3) clinical chart and hospital records available for review; and (4) presence of diarrhea, defined on the basis of increased frequency and watery consistency of stools along with dehydration. This definition, which was adopted in a previous study of neonates[4], is in accordance with the traditional definition employed in pediatric gastroenterology[6] and to the more recent guidelines for the management of acute gastroenteritis of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)/European Society for Paediatric Infectious Diseases (ESPID)[7]. Data were recorded in a specific reporting form made up of 5 sections: (1) demographic characteristics: sex, gestational age, birth weight, age at hospitalization and at diarrhea onset; (2) anamnesis: intrauterine growth restriction, polyhydramnios, risk for allergy according to American Academy of Pediatrics (AAP) guidelines[8], familiarity for chronic diseases including diarrhea, surgery, diet before diarrhea onset; (3) characteristics of diarrhea: number of bowel movements, stool consistency, presence of blood and mucus in the stools, severity of dehydration, complications, development of chronic diseases, diarrhea duration and presence of other intestinal or extra-intestinal symptoms; (4) etiology of diarrhea; and (5) nutritional and therapeutic management, clinical outcomes.

To better define the study population and to establish the diarrhea occurrence rate, the number of hospital admissions and the main demographic characteristics of all subjects observed during the study period, in each participating NICU, were also evaluated. Diarrhea was classified as acute or chronic if it lasted < 14 d or > 14 d, respectively, according to the definition of the World Health Organization[9,10]. The study protocol was approved by the Ethics Committee of our institution. No competing interest was declared by the investigators involved in the study.

Statistical analysis

Patients were classified according to the duration of diarrhea into the acute and chronic groups. For continuous variables, the t-test for equality of means was used. For categorical variables, the χ² test and Fisher’s exact test were used. Possible correlations between the duration of diarrhea and gestational age, birth weight, sex, number of bowel movements, antibiotic use, age at diagnosis and severity of dehydration were investigated by linear regression analysis. The level of significance for all statistical tests was 2-sided P < 0.05. Statistical analysis was performed using SPSS software (Version 14.0 for Windows, SPSS Inc., Chicago, IL, USA).

RESULTS

Sixteen NICUs were invited to participate in the study and 7 accepted. The clinical charts of 5801 cases were reviewed, and 39 cases of diarrhea were reported. The occurrence rate of diarrhea was estimated at 6.72 per 1000 hospitalized newborn. The number of cases observed during the study period was: 12 in the first, 14 in the second and 13 in the third year of the study. Diarrhea was the main cause of hospital admission in 14 of 39 subjects (35.9%). Diarrhea was classified as acute in 36 patients (92.3%) and chronic in 3 neonates (7.7%). The etiology of diarrhea was identified in 29 of 39 patients (74.3%) (Table 1).

Table 1 Etiology of diarrhea in the study population.

	Acute	Chronic	Overall
Number of patients	36	3	39
Unknown etiology	10	-	10
Cow’s milk allergy	8	-	8
Infections	7	-	7
Rotavirus	4	-
Salmonella paratyphi	1	-
Shigella flexneri	1	-
Enterotoxigenic Escherichia coli	1	-
Antibiotic-associated diarrhea	5	-	5
Neonatal withdrawal syndrome	2	-	2
Congenital diarrheal disorders	-	2	2
Glucose-galactose malabsorption	-	1	1
Congenital chloride diarrhea	-	1	1
Parenteral diarrhea
Urinary tract infection	1	-	1
Hirschsprung’s disease	1	-	1
Cystic fibrosis	-	1	1
Immunodeficiency
Adenosine deaminase deficiency	1	-	1
Metabolic disorders
Urea cycle defect	1	-	1

A diagnosis of cow’s milk allergy (CMA) was reported in 8 cases. Five of these cases were considered to be at risk for allergic diseases according to the AAP definitions[8]. In patients with CMA, diarrhea was associated with eczema or vomiting in 6 and in 5 subjects, respectively. Specific IgE titers against milk proteins were positive in 6 of 8 patients (> 5.0 kU/L)[11]. In each case of CMA, the diagnosis was confirmed by observation when an antigen elimination diet with an extensively hydrolyzed casein formula (Nutramigen^®, Mead-Johnson Nutritionals, Italy) resulted in symptomatic improvement, and the re-introduction of cow’s milk after 4 wk caused symptoms to reappear. An open food challenge was performed in 5 of 8 subjects during hospitalization in consultation with a pediatric allergy specialist, and in 3 of 8 patients after discharge, in a tertiary Center of Pediatric Gastroenterology and Food Allergy.

Seven patients were classified as having intestinal infection according to the results of microbiological analysis. The microorganisms responsible for diarrhea are reported in Table 1. One patient initially classified as having gastrointestinal infection had a familial history of immunodeficiency and a clinical course characterized by growth delay, recurrent opportunistic infections, lymphopenia, associated with defective cellular and humoral immune responses. In this case, molecular analysis confirmed the clinical diagnosis of adenosine deaminase deficiency (OMIM 608958)[12].

Five babies presented with antibiotic-associated diarrhea. The microbiological analysis, including the search for Clostridium difficile, was negative in all these subjects.

According to clinical findings and the results of molecular analysis, two patients received a diagnosis of congenital diarrheal disorders (OMIM 251850): one with glucose-galactose malabsorption (OMIM 182380); and one with congenital chloride diarrhea (OMIM 214700)[13].

Neonatal withdrawal syndrome-induced diarrhea was reported in 2 subjects from mothers with a history of drug abuse (heroin and methadone) during pregnancy[14]. One case of Hirschsprung’s disease was diagnosed according to the clinical history (no passage of meconium in the first 72 h of life, bloating of the abdomen) and the results of diagnostic tests, including rectal manometry, barium enema, and rectal biopsy[15]. This patient had diarrhea as a consequence of severe enterocolitis requiring broad-spectrum antibiotic therapy. Parenteral diarrhea induced by extra-intestinal infection caused by Klebsiella pneumonia-induced urinary infection was reported in one full-term baby during the first week of life. In this patient, diarrhea started before antibiotic treatment, all microbiological evaluations on stools were negative, and diarrhea improved rapidly when the urinary infection disappeared. For one subject with a familial history of cystic fibrosis (CF), intrauterine growth retardation, and chronic diarrhea, a final diagnosis of CF was achieved by a sweat test and was confirmed by the identification of a CFTR ΔF508 mutation, at the age of 4 mo[16]. A urea defect cycle was diagnosed in one patient by the presence of diarrhea together with metabolic acidosis, hyperammoniemia and protein load intolerance[17].

The main anamnestic and demographic characteristics of the neonates with diarrhea are shown in Table 2. Symptoms associated with diarrhea are reported in Table 3. The neonates affected by diarrhea of unknown origin showed a birth weight significantly lower (1920 g, IQR 1418 g) than subjects with an established etiologic diagnosis (2870 g, IQR 705 g) (P < 0.040). The mean number of bowel movements per day was 7.4 (95% CI: 7.0-7.8) without differences between acute and chronic diarrhea. The mean number of daily bowel movements was not influenced by etiology. The mean duration of diarrhea was similar for full term (9.08 d, 95% CI: 4.7-13.4) and preterm neonates (4.7 d, 95% CI: 3.9-5.6, P = 0.953). Linear regression analysis using a stepwise method demonstrated that diarrhea duration had a negative relationship with age at symptom onset (B -0.80; Beta -0.48; P = 0.005). In contrast, birth weight, sex, gestational age, antibiotic use, severity of dehydration, rehydration or re-feeding strategies, and consumption of breast milk did not correlate with duration of diarrhea.

Table 2 Main demographic and anamnestic data of the study population n (%).

	Acute	Chronic
Number of patients	36	3
Demographic data
Male	15 (41.7)	1 (33.3)
Birth weight (g)	2504 ± 778	2560 ± 664
Gestational age (wk)	36.4 ± 3.8	37.7 ± 1.5
Age at diarrhea onset (d)	8.3 ± 6.6	5.7 ± 4.4
Age at hospitalizationa (d)	6.2 ± 8.5	19.7 ± 10.1
Anamnestic data
Intrauterine growth restriction	6 (16.7)	1 (33.3)
Polyhydramniosa	1 (2.8)	2 (66.7)
Premature birth	12 (33.3)	1 (33.3)
Familial for chronic diarrheaa	1 (2.8)	2 (66.7)
Newborns at high risk of developing allergy	12 (33.3)	-
Exclusively fed breast milk	3 (8.33)	-

^aP < 0.05. Data are expressed as mean ± SD when not specified.

Table 3 Main associated symptoms in the study population n (%).

	Acute	Chronic
Number of patients	36	3
Gastrointestinal
Vomiting	18 (50.0)	1 (33.3)
Mucus in the stools	13 (36.1)	1 (33.3)
Blood in the stools	9 (25.0)	-
Abdominal distension	24 (66.7)	2 (66.7)
Systemic
Fever	4 (11.1)	-
Hypovolemiaa	1 (2.8)	1 (33.3)
Eczema	7 (19.4)	-
Seizuresa	3 (8.3)	1 (33.3)

^aP < 0.05.

Data on dehydration and rehydration strategies are reported in Table 4. As a re-feeding strategy in patients with acute diarrhea, an extensive casein hydrolyzed formula (Nutramigen^®, Mead-Johnson Nutritionals, Italy) was administered to all subjects with a suspected diagnosis of CMA, and in only 6 of 31 of the remaining subjects (19.3%). Nine of 39 subjects with diarrhea were fed breast milk, 3 received breast milk exclusively at diarrhea onset. After diarrhea onset, breast milk was continued in 3 subjects, temporally withdrawn (24 h) in 2, and definitively suspended in 4 of 9 newborn.

Table 4 Severity of dehydration, modalities of rehydration and clinical outcomes n (%).

	Acute	Chronic
Number of patients	36	3
Degree of dehydration
Severe dehydrationa	5 (13.9)	2 (66.7)
Rehydration modalities
Exclusively oral rehydration	18 (50.0)	1 (33.3)
Exclusively parenteral rehydration	2 (5.6)	1 (33.3)
Oral plus parenteral rehydration	16 (44.4)	1 (33.3)
Clinical outcomes
Duration of diarrheaa (d)	5.7 ± 2.5	44.3 ± 6.7
Electrolyte abnormalities	8 (22.2)	2 (66.7)
Deaths	2 (5.5)	1 (33.3)

^aP < 0.05. Data are expressed as mean ± SD when not specified.

The clinical outcomes of diarrhea are reported in Table 4. Three deaths were reported among the 39 subjects (7.7%). Patients affected by adenosine deaminase deficiency, CF, and Hirschsprung’s disease died due to complications related to fatal systemic infections at 1, 12 and 7 mo of life, respectively.

DISCUSSION

This is the first systematic study describing diarrhea in patients hospitalized in the NICU in an industrialized country and outside outbreak conditions. The results of our investigation showed that, in this particular setting, diarrhea is a relatively uncommon but insidious condition underlying a broad spectrum of illnesses. The list of diseases and mechanisms responsible for diarrhea in neonates is large and the number of possible etiologies is higher when compared to older pediatric patients[7,13,18,19]. In recent years, new diseases have been described (i.e. enteric anendocrinosis), and more accurate knowledge about neonatal enteropathies has been obtained[5,20]. The pathophysiology of these conditions is extremely variable and requires a complex diagnostic work up in order to rapidly adopt adequate therapy. We believe that all these steps should be performed as a result of tight collaboration between the neonatologist, pediatric gastroenterologist, immunologist, geneticist, and nutritionist. The most common etiology identified in our patients was food allergy (FA). Recently, the International Study of Asthma and Allergies in Childhood reported an increase in allergic disease prevalence occurring in the younger pediatric age group[21]. 20.5% of neonates in our population had FA-related diarrhea, and none were adherent to the recommendations of the AAP for primary prevention of FA[8]. These data highlight the importance of a high index of suspicion for FA in neonates presenting with diarrhea, and the application of preventive strategies[8,22,23]. The most frequent infective etiology was Rotavirus, which represents the leading cause of infectious diarrhea in childhood[24]. All patients acquired Rotavirus infection during hospitalization. Considering that Rotavirus is implicated in up to 50% of nosocomial pediatric diarrheal episodes, our data further support the importance of accurate surveillance against the spread of infection in the NICU[24].

In this study we reported the lack of a univocal rehydration and re-feeding strategy for hospitalized newborn with diarrhea, indicating the necessity for further prospective studies to optimize therapeutic approaches. The vast majority of newborn patients with diarrhea were rehydrated by the enteral route and received enteral feeding within 4-6 h, without complications. Despite the fact that it is difficult to assess the efficacy of rehydration and re-feeding strategies in patients with such different disorders, our results suggest that the therapeutic strategies for diarrhea which are commonly adopted in older subjects, could also be successfully used in newborn hospitalized in the NICU. This is of particular importance because the available guidelines for diarrhea management are mainly focused on older pediatric patients[7,25,26].

To conclude, despite the limits derived from the retrospective design, our study showed that neonatal diarrheal diseases are challenging clinical conditions due to their heterogeneous etiologies and possible severe outcomes. We believe that this study will help neonatologists to prevent diarrhea from becoming a severe clinical condition, and to recognize and correctly manage rare chronic cases who need the assistance of a specialized team dedicated to their long-term treatment. Specific guidelines for the management of diarrheal disorders in neonates are advocated.

COMMENTS

Background

Diarrhea represents a major condition responsible for pediatric mortality worldwide. The onset of neonatal diarrhea may rapidly lead to life threatening dehydration and malnutrition. Thus, early diagnosis and timely treatment are both crucial in the management of diarrhea in neonates. Clinical and epidemiologic studies defining severity and etiology are needed in order to improve diagnostic and therapeutic approaches for the management of neonatal diarrhea.

Research frontiers

This study showed that neonatal diarrheal diseases are challenging clinical conditions due to their heterogeneous etiology and possible severe outcomes. The list of diseases and mechanisms responsible for diarrhea in neonates is large and the number of possible etiologies is higher compared with older pediatric patients. Specific guidelines for the management of diarrheal disorders in neonates are advocated.

Innovations and breakthroughs

This is the first systematic study describing diarrhea in patients hospitalized in the neonatal intensive care unit in an industrialized country and outside outbreak conditions. The results of the authors' investigation showed that, in this particular setting, diarrhea is a relatively uncommon but insidious condition underlying a broad spectrum of illnesses.

Applications

This research opens the way for new investigations in the area of diarrheal diseases with neonatal onset. The authors believe that these studies will help neonatologists to prevent diarrhea from becoming a severe clinical condition, and to recognize and correctly manage rare chronic cases who need the assistance of a specialized team dedicated to their long-term treatment.

Terminology

A neonatal intensive care unit, usually abbreviated to NICU, is a unit of a hospital specializing in the care of ill or premature newborn infants.

Peer review

This well-written informative and innovative manuscript convincingly shows that neonatal diarrheal diseases are challenging clinical conditions because of the heterogeneous etiology and possible severe outcomes. This study will help neonatologists to prevent diarrhea from becoming a severe clinical condition.