Necrotising enterocolitis in preterm infants: frequency, risk factors, laboratory diagnosis and microbiological etiology

Abstract

Nekrotisoiva enterokoliitti on keskosilla esiintyvä suolistosairaus, joka pahimmillaan voi vaurioittaa suolta niin, että suoli puhkeaa. Tällöin leikkaushoito on välttämätön. Tämä vaikein tautimuoto on yksi tärkeistä kuolinsyistä pienillä keskosilla. Keskosten tehohoitokäytännöissä on tapahtunut kehittymistä ja yhä pienempiä ja epäkypsempiä keskosia jää henkiin ja näille ennenaikaisille vastasyntyneille kehittyy nekrotisoiva enterokoliitti. Nekrotisoivan enterokoliitin esiintyvyys näyttää muuttuvan ja uutta tietoa taudin riskitekijöistä, laboratoriodiagnostiikasta ja etiologiasta kaivataan keskosten hoidon parantamiseksi.

Väitöskirjatutkimuksessa seurataan nekrotisoivan enterokoliitin esiintymistä tiettynä ajanjaksona (vuosina 1998-1999) Tampereen yliopistollisessa sairaalassa hoidetuilla, alle 33 raskausviikon iässä syntyneillä keskosilla, selvitetään epidemiologisesti nekrotisoivan enterokoliitin syntyyn vaikuttavia tekijöitä, siihen liittyviä laboratoriolöydöksiä sekä suoliston mikrobiflooran muutoksien yhteyttä nekrotisoivann enterokoliittiin.

Tampereen yliopistollisessa sairaalassa syntyi vuosina 1998-1999 140 lasta alle 33 raskausviikolla. Nekrotisoiva enterokoliitti on yleinen alle 33 raskausviikolla syntyneillä keskosilla: lähes viidesosalla (18.6%) esiintyi tämän taudin oireita ja 8.6% kehitti pitkälle edenneen, vaikean tautimuodon. Nekrotisoivaan enterokoliittiin oli yhteydessä äidillä esiintyvä infektio raskauden lopussa, sikiön kasvuhäiriö ja pitkä hengityskonehoito. Varhainen rintamaitoruokinta oli yhteydessä vähenevään nekrotisoivan enterokoliitin riskiin, kun taas rintamaidon vahvistaminen proteiinilisällä oli yhteydessä lisääntyneeseen nekrotisoivan enterokoliitin riskiin. Morfiinilääkitys oli yhteydessä lisääntyneeseen nekrotisoivan enterokoliitin riskiin.

Laboratoriotutkimuksissa todettiin nekrotisoivaa enterokoliittia hyvin ennustaviksi löydöksiksi matalat verihiutalearvot, happo-emäs-tasapainon muuttuminen happamaan suuntaan ja korkea verensokeri.

Suoliston bakteerifloora tutkittiin bakteeriseinämien rasvahappoprofiilia kaasukromatografisesti analysoiden ja taudin alkaessa suolistofloorassa tapahtui muutos, joka voi viitata suolen bakteerien liikakasvuun ja muutos voi olla taustalla keskosen nekrotisoivan enterokoliitin syntyprosessissa.

Necrotising enterocolitis (NEC) is a neonatal disease characterised by gastrointestinal symptoms and various systemic manifestations, and by typical radiological findings and histological lesions from necrotic inflammation of the intestinal wall. It is most common among preterm infants in neonatal intensive care units (NICU). The present aims were to investigate the frequency of and risk factors associated with NEC in preterm infants, to identify laboratory parameters predictive of NEC, to study the effects of mode of delivery and of NEC on the intestinal microflora and to evaluate the rate of nosocomial rotavirus and adenovirus infections in hospitalised neonates and to detect rotaviruses and adenoviruses in infants with NEC symptoms.

Frequency and risk factors in NEC were assessed prospectively among 140 infants born before 33 weeks gestation in Tampere University Hospital during the years 1998-1999. Twenty-six (18.6%) infants developed NEC stage I-III and 12 (8.6%) severe NEC (stage II-III). Maternal chorionamnionitis was associated with NEC. Intrauterine growth retardation (IUGR) and duration of assisted ventilation seemed to be associated with severe NEC. Early initiation of feeding with breast milk seemed to be associated with reduced risk and exposure to breast milk fortifier to be associated with increased risk of NEC. Increased duration of morphine administration seemed to be the strongest predictor of NEC and severe NEC. Further studies are needed to establish whether morphine is a causative factor in NEC. The laboratory findings predictive of NEC were recorded in a prospective follow-up of 140 infants born before 33 weeks gestation. Twenty-six infants developed NEC (grades I-III) and for each infant two birth weight, gestational age and postnatal age-matched controls were selected. Blood counts, glucose and electrolyte levels, C-reactive protein and acid-base balance were recorded three, two and one day prior to and at the onset of NEC, and at corresponding ages from the controls. Metabolic acidosis occurred, platelet levels decreased and blood glucose levels increased on successive days in the infants with grade NEC II-III. At the onset of NEC, the infants had lower platelet and higher blood glucose levels compared to controls. More than half of those with intestinal perforation had leucocyte levels above 30 x 109/l and pH less than 7.25, and their mean blood glucose levels increased >1.5 mmol/L in 24 hours. Such findings should alert the physician to look for signs of NEC in a preterm infant.

Symptoms suggestive of NEC in 140 infants born before 33 weeks gestation were followed up prospectively and stool samples for gas-liquid chromatography (GLC) and microbial culture were collected twice weekly. For each infant with NEC (n=21), two control infants matched for birth weight and gestational age were selected. In GLC analysis, the fecal bacterial microflora of infants born via cesarean section differed from the gut microflora of those born via the vaginal route, and the intestinal microflora showed alterations at the onset of NEC. Correspondingly, fecal colonisation with Enterococcus species and Candida albicans was more frequent at the onset of symptoms in NEC infants than in the asymptomatic matched controls. In infants with positive blood and/or intestinal biopsy cultures, concomitant stool samples revealed the same microbial pathogens. Pathogens detected in the stools at NEC onset might have a causative role in the development of the disease. The rate of nosocomial rotavirus and adenovirus infections and the association between rotaviruses and adenoviruses detected in stools evincing symptoms of NEC were studied in 308 infants treated longer than one week in the neonatal unit during a period of 15 months from the beginning of February 1998, covering two rotavirus epidemics in the surrounding community. Altogether 1020 stool samples from the infants were collected weekly. Fecal samples were also obtained from infants with NEC at the onset of symptoms. All stool samples were tested for rotavirus and adenovirus by means of enzyme-linked immunosorbent assay (ELISA). The positive samples were further analysed by polymerase chain reaction (PCR). ELISA revealed five adeno-positive infants, who tested negative by PCR. Out of 16 NEC infants, one was adenovirus- and another rotavirus-positive when tested by PCR. Routine rotavirus and adenovirus screening in hospitalised neonates seems to be unnecessary. Viral diagnostic examinations should be considered in infants with NEC.