Robert M. Kliegman

Necrotizing Enterocolitis: Treatment Based on Staging Criteria

Neonatal necrotizing enterocolitis is the most important cause of acquired gastrointestinal morbidity or mortality among low birthweight infants. Prematurity alone is probably the only identifiable risk factor. Although the etiology is unknown NEC has many similarities to an infectious disease. Proper staging helps improve reporting and the management of NEC.

Beneficial effects of early hypocaloric enteral feeding on neonatal gastrointesting function: Preliminary report of a randomized trial

In a prospective randomized trial, we studied the effects of early hypocaloric enteral feedings (PO) begun at 48 hours of age in 19 infants compared with 20 infants who received no enteral feedings (NPO) for at least the first 9 days of life. Both groups initially received the majority of their calories by parenteral alimentation. The groups were similar with respect to birth weight, gestational age, sex, Apgar score, and major neonatal diagnoses. The early enteral feeds proved to be significantly beneficial without an increased incidence of complications. The PO group reached full enteral feedings faster than the NPO group (31.2 vs 47.3 days). The PO group had a greater decline in serum bilirubin concentration over the first 2 weeks of life and spent less time under phototherapy (6.8 vs 9.5 days). Less cholestasis was observed among the PO infants (6.7% vs 33%), and peak direct bilirubin levels were also lower (0.7 vs 2.5 mg/dL). Osteopenia of prematurity, manifested by significantly lower alkaline phosphatase activity, was also decreased in the PO group, perhaps because of greater calcium intake during the first month among PO infants (1.3 vs 0.8 g). Compared with complete bowel rest, early onset of hypocaloric enteral feedings has beneficial effects on indirect hyperbilirubinemia, cholestatic jaundice, and metabolic bone disease of very low birth weight infants.

Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates

To determine the pharmacokinetics of amphotericin B and 5-fluorocytosine in neonates, we measured serum concentrations at first dose and after 5 days of therapy by high-performance liquid chromatography in 13 neonates (mean birth weight 1.2 +/- 0.8 kg). The dose of amphotericin B was serially increased from 0.1 to 0.5 mg/kg/day in 10 infants but was decreased from 0.8 to 1.0 to 0.5 mg/kg/day in three infants. Amphotericin B concentrations were not detectable in infants receiving 0.1 mg/kg/day. Amphotericin B cerebrospinal fluid concentrations were 40% to 90% of serum values obtained simultaneously. Serum concentrations after oral administration of 5-fluorocytosine (dose 25 to 100 mg/kg/day) were detectable in all infants. We found extreme interindividual variability for the half-life, volume of distribution, and clearance for both drugs. Four infants had minimal elimination for both drugs between doses, a finding that correlates with rises in serum creatinine (greater than 0.4 mg/dl, 40 mumol/L) and blood urea nitrogen (greater than 10 mg/dl, 3.6 mmol/L). We recommend that the dose of amphotericin B given on the first day of treatment be greater than the usual testing dose of 0.1 mg/kg/day. We also recommend an initial 24-hour dosing interval for amphotericin B and 5-fluorocytosine. Serum drug concentrations may need to be monitored in high-risk, low birth weight infants.

Necrotizing enterocolitis : research agenda for a disease of unknown etiology and pathogenesis

INTRODUCTION: Necrotizing enterocolitis (NEC) is a significant neonatal public health problem that affects low-birth weight infants in neonatal intensive care units throughout the country. As the survival rate of low-birth weight infants continues to increase and as the number of low-birth weight births remains unchanged, we can anticipate that NEC will continue to be a cause of significant morbidity and mortality in the future.Despite many reports about NEC that describe demographic risk factors and short-term or long-term outcome, there is a paucity of basic science information about neonatal gastrointestinal physiology and pathophysiology in human preterm and even full-term infants. It has become increasingly evident that we need a much better understanding about the developmental aspects of gastrointestinal function in health and disease before we can achieve further advances in our understanding of and thus rational therapy for and prevention of NEC.The purpose of the National Institute of Child Health and Human Development conference “Necrotizing Enterocolitis: Basic Science Approaches to Gut Maturation and Pathogenesis” was to bring together basic science investigators, clinical epidemiologists, and clinical scientists to identify important areas of research that need to be applied to the problem of NEC. The concept of applying the “bench to bedside” type of collaborative research was emphasized and encouraged because many clinical neonatologists may have little scientific interaction with basic scientists. In addition, many basic scientists may be unaware of NEC and the implications for targeted research related to this disease. Finally, there have been major advances in our ability to study diseases of unknown etiology, as witnessed by recent discoveries of the microbiologic agents that cause AIDS, non A-non B hepatitis, roseola, and Whipple disease, and various agents that cause infectious diarrhea.Invited participants represented a broad spectrum of basic science and clinical disciplines and included investigators with expertise in adult gastroenterology, animal physiology, cell biology, molecular virology, host defense, inflammatory mediators, vascular physiology, surgery, pathology, and neonatology. The goals of the participants were to address the gaps in our knowledge about NEC, to reconcile basic science observations about gastrointestinal disease with those in the clinical disease, and to recommend promising areas of investigation worthy of further study. This report summarizes the current concepts of neonatal gastrointestinal physiology and pathophysiology that were presented by experts in the areas relevant to NEC. The report then presents recommendations for future areas of collaborative research initiatives to fill the gaps in our knowledge about NEC. This research agenda is also the basis of a request for applications from the National Institute of Child Health and Human Development to address the next stage of investigations. The names of the participants are included in the acknowledgement.

Effects of cocaine/polydrug exposure and maternal psychological distress on infant birth outcomes

To assess teratogenic effects of cocaine exposure and maternal psychological distress on birth outcomes, we conducted a longitudinal prospective study of 415 infants (218 cocaine-exposed--CE, 197 nonexposed--NE). Drug exposure was determined through a combination of maternal self-report, urine, and meconium screens. Maternal psychological distress postpartum was evaluated through a standardized, normative, self-report assessment. An extensive set of confounding variables was controlled, including severity of exposure to alcohol, tobacco, marijuana and other drugs, maternal age, race, parity, number of prenatal care visits, educational, marital, and socioeconomic status, and verbal and nonverbal intelligence. CE infants were smaller on all birth parameters and more likely to be preterm, small for gestational age, and microcephalic than NE infants. Forty-one percent of cocaine users had clinically significant psychological symptoms, compared to 20% of a high-risk comparison group of noncocaine users. Consistent with a teratologic model, cocaine exposure independently predicted offspring birthweight, length, and head circumference. Maternal psychological distress self-reported postnatally also independently predicted head circumference. Tobacco, alcohol, and marijuana exposures were also significant independent predictors of some fetal growth parameters. In addition, maternal distress symptoms, which may be reflective of maternal mental health disorders or responses to stress, added significantly to the risk for poorer fetal growth.

Epidemiologic study of necrotizing enterocolitis among low-birth-weight infants. Absence of identifiable risk factors.

Necrotizing enterocolitis has been associated with a variety of perinatal problems which have been purported to be risk factors predisposing the neonate to NEC. The present investigation compares the perinatal histories of 48 low-birth-weight infants (less than 1,500 gm) with NEC to those of 553 high-risk infants of equivalent birth weight who did not have NEC but who were present in the nursery during a four-year observation period. The two populations were equivalent with regard to maternal factors such as socioeconomic status, education, race, and age. Both the antenatal and intrapartum risk scores were similar, as were the position of presentation and mode of delivery. The incidence of pre-eclampsia, prolonged rupture of the membranes, and placenta previa was also equivalent. Birth weight and gestational age were identical, as well as intrauterine growth retardation and low Apgar scores. The placement of umbilical artery catheters or the performance of exchange transfusions were not more frequent among patients with NEC. Infants who developed NEC demonstrated significantly different incidences of only three variables. Mothers of these infants were usually married, and their infants had less respiratory distress syndrome; the only adverse factor present more frequently was abruptio placenta. These data raise further questions concerning the significance of previously reported risk factors of NEC.

Necrotizing enterocolitis in neonates fed human milk

The incidence of necrotizing enterocolitis encountered in neonates fed only refrigerated human milk was comparable to that in infants fed milk and isotonic formula or isotonic formula alone. The infants fed human milk were significantly (P less than 0.05) smaller, less mature, had lower Apgar scores, and were fed later than the formula-fed infants. The mean age of onset and time between first feeding and onset of NEC was similar among the three groups. These data indicate that refrigerated human milk was not effective in lowering the incidence of NEC. Possible explanations for the occurrence of NEC in neonates fed human milk include: (1) the introduction of a pathogen via contaminated milk; (2) inadequate maternal antigenic stimulation by the neonatal gastrointestinal flora; and (3) adverse affects of storage on cell number and function.

Neonatal Necrotizing Enterocolitis: Implications for an Infectious Disease

There is a broad spectrum of presentations and severity of necrotizing enterocolitis. Because it may have several different causes, ncerotizing enterocolitis may be a syndrome rather than a specific disease. The triad of formula feeding, intestinal ischemia, and bacterial growth may be part of the pathogenesis of necrotizing enterocolitis. Bacteria are of central importance for the production of pneumatosis, a prerequisite of which is formula feeding. Bacteria may also contribute to the intestinal injury seen after ischemia. However, the disease in the low risk patient seen during an epidemic associated with a single organism is probably caused by a primary gastrointestinal infection. On the other hand, in the stressed newborn infant with mucosal injury the presence of the appropriate bacteria may be all that is needed to initiate the chain of events leading to necrotizing enterocolitis. Figure 2 illustrates the importance of bacteria in all the causes proposed to be involved in the pathogenesis of necrotizing enterocolitis. Whether bacteria are primary or secondary agents, necrotizing enterocolitis should always be approached therapeutically as an infectious disease.

Increased incidence of intraventricular hemorrhage and developmental delay in cocaine-exposed, very low birth weight infants

This study sought to determine whether very low birth weight (VLBW) infants (< 1500 gm) with fetal cocaine exposure differed from non-cocaine-exposed VLBW infants in incidence of neonatal medical complications and in later developmental outcome. Forty-one cocaine-exposed, VLBW infants, followed in a longitudinal study, were compared with 41 non-cocaine-exposed, VLBW infants of comparable race, social class, age, and incidence of bronchopulmonary dysplasia. Cocaine-exposed infants were identified on the basis of combined findings of maternal and/or infant urine immunoassay and on the basis of maternal self-report. At birth, groups did not differ on medical risk factors except that cocaine-exposed infants had a higher incidence of mild (grades I to II) intraventricular hemorrhage. Cocaine-using women were also more likely to use other drugs, especially alcohol, marijuana, and tobacco. At follow-up, at mean corrected ages of 16.5 +/- 8 months for 30 cocaine-exposed infants and 18.5 +/- 7 months for 37 non-cocaine-exposed infants, standardized assessments of cognitive (Mental Development Index) and motor (Psychomotor Development Index) development were administered. Cocaine-exposed infants had lower mean cognitive (83 +/- 27 vs 91 +/- 19), and motor (85 +/- 25 vs 96 +/- 18) scores; the incidence of developmental delay was significantly higher even after control for the effects of intraventricular hemorrhage and chronologic age. Cocaine-exposed VLBW infants were also more likely to be living with relatives or in foster homes. We conclude that these VLBW, cocaine-exposed infants were at increased risk of intraventricular hemorrhage, were more likely to be placed outside maternal care, and had higher incidences of cognitive and motor delays at follow-up.

Candida endophthalmitis in the premature infant

An attempt was made to determine the incidence and natural history of Candida endophthalmitis in the premature infant with systemic candidiasis. Each of eight premature infants were examined by indirect ophthalmoscopy within one week of their diagnosis. At this stage, four infants had multiple fluffy white lesions on both the retina and the vitreous, together with a diffuse vitreous haze. Three of the infants had interlesional and lesional-retinal vitreous strands. Three infants treated with amphotericin B and 5-fluorocytosine showed gradual disappearance of the lesions. The fourth infant died early in the course of antifungal therapy, when the eye lesions were progressing. Candida sepsis was particularly prevalent in the very low-birth-weight infant with a prolonged hospital course and treated with multiple broad-spectrum antibiotics. The course of the eye lesions indicates a good prognosis for Candida endophthalmitis, although further follow-up is necessary.