Arild Rønnestad

Early Death, Morbidity, and Need of Treatment Among Extremely Premature Infants

Objective. To determine outcomes, in terms of perinatal and early death, need for treatment, and morbidity at the time of discharge home, among extremely preterm infants. Design. A prospective observational study of all infants with a gestational age (GA) of 22 to 27 completed weeks or a birth weight of 500 to 999 g who were born in Norway in 1999 and 2000. Results. Of 636 births, 174 infants (27%) were stillborn or died in the delivery room, 86 (14%) died in the NICU, and 376 (59%) were discharged from the hospital. The risk of being registered as stillborn or not being resuscitated increased with decreasing GA below 25 weeks. The survival rates for all births and for infants admitted to a NICU were, respectively, 0% for <23 weeks, 16% and 39% for 23 weeks, 44% and 60% for 24 weeks, 66% and 80% for 25 weeks, 72% and 84% for 26 weeks, 82% and 93% for 27 weeks, and 69% and 90% for >27 weeks. For the survivors, days of mechanical ventilation decreased from a median of 37 days to 3 days and the proportion in need of oxygen at 36 weeks’ postconceptional age decreased from 67% to 26% at 23 and 27 weeks’ GA, respectively. At 40 weeks’ postconceptional age, the respective figures were 11% and 6%. The proportion with retinopathy of prematurity (ROP) requiring treatment decreased from 33% for GA of 23 weeks to 0% for >25 weeks. Periventricular hemorrhage of more than grade 2 occurred for 6% of the survivors and significant periventricular leukomalacia occurred for 5%, with no significant association with GA. The proportion of survivors without severe neurosensory or pulmonary morbidity increased from 44% for 23 weeks’ to 86% for 27 weeks’ GA. Apart from ROP, the morbidity rate was not associated with GA. Conclusions. The survival rate was high and the morbidity rate at discharge home was low in the present study, compared with previous population-based studies. With the exception of ROP, the morbidity rates among the survivors were not higher at the lowest GAs, possibly because withholding treatment was considered more acceptable for the most immature infants. The need for intensive care increased markedly for survivors with the lowest GAs.

Late-Onset Septicemia in a Norwegian National Cohort of Extremely Premature Infants Receiving Very Early Full Human Milk Feeding

Objectives. To investigate the occurrence of and risk factors for late-onset septicemia (LOS) in a national cohort of extremely premature infants who received very early full human milk feeding. Methods. A prospective study of all infants born in Norway in 1999 and 2000 with gestational age of <28 weeks or birth weight of <1000 g was performed. Extensive clinical information, including data on feeding practices and episodes of septicemia, was collected on predefined forms. LOS was defined as growth of bacteria or fungi in blood cultures in conjunction with clinical symptoms consistent with systemic infection occurring after day 6 of life. Cox regression models, including models allowing for time-dependent covariates, were applied in the analysis of LOS. Results. Of 464 eligible infants, 462 (99.6%) were enrolled and 405 (87.7%) survived until day 7. LOS was diagnosed for 80 (19.7%). The predominant pathogens were coagulase-negative staphylococci, followed by Candida spp. Case fatality rates associated with septicemia were 10% in general and 43% for Candida spp septicemia. Necrotizing enterocolitis or bowel perforation was diagnosed for 19 infants (4%). Enteral feeding with human milk was initiated within the third day for 98% of patients, and 92% were receiving full enteral feeding (FEF) with human milk within the third week. Both high Clinical Risk Index for Babies scores and an umbilical venous catheter in situ at 7 days of age significantly predicted LOS. However, the overall most influential risk factor for LOS was the number of days without establishment of FEF with human milk, with an adjusted relative risk of 3.7 (2.0–6.9) for LOS if FEF was not established within the second week of life. Conclusions. The incidence and case fatality rate of septicemia for this cohort of extremely preterm infants were lower than values in comparable studies. The main difference, compared with other studies, was the feeding practice, and the data suggest that very early FEF with human milk significantly reduces the risk of LOS among extremely premature infants.

Improved Cognitive Development Among Preterm Infants Attributable to Early Supplementation of Human Milk With Docosahexaenoic Acid and Arachidonic Acid

OBJECTIVE. The objective of our study was to evaluate the effect of supplementation with docosahexaenoic acid and arachidonic acid for human milk-fed preterm infants. The primary end point was cognitive development at 6 months of age. METHODS. The study was a randomized, double-blind, placebo-controlled study among 141 infants with birth weights of <1500 g. The intervention with 32 mg of docosahexaenoic acid and 31 mg of arachidonic acid per 100 mL of human milk started 1 week after birth and lasted until discharge from the hospital (on average, 9 weeks). Cognitive development was evaluated at 6 months of age by using the Ages and Stages Questionnaire and event-related potentials, a measure of brain correlates related to recognition memory. RESULTS. There was no difference in adverse events or growth between the 2 groups. At the 6-month follow-up evaluation, the intervention group performed better on the problem-solving subscore, compared with the control group (53.4 vs 49.5 points). There was also a nonsignificant higher total score (221 vs 215 points). The event-related potential data revealed that infants in the intervention group had significantly lower responses after the standard image, compared with the control group (8.6 vs 13.2). There was no difference in responses to novel images. CONCLUSIONS. Supplementation with docosahexaenoic acid and arachidonic acid for very preterm infants fed human milk in the early neonatal period was associated with better recognition memory and higher problem-solving scores at 6 months.

Coagulase-negative staphylococcal sepsis in neonates. Association between antibiotic resistance, biofilm formation and the host inflammatory response.

Background: Coagulase-negative staphylococci (CoNS) are the most prevalent pathogens causing late onset sepsis in neonates. They are often multiresistant to antibiotics, and the ability to form biofilm is considered their main virulence determinant. Methods: During a 12-year period, we identified 150 neonates having 164 suspected septic episodes with growth of CoNS in blood culture. We examined the relationship between antibiotic resistance, phenotypic biofilm production and genetic determinants for biofilm formation in different CoNS species and their correlation with neonatal inflammatory response. Results: Eighty-five episodes were classified as true sepsis, and 79 episodes of CoNS growth in blood culture were considered contaminations. Sixty-one percent of Staphylococcus epidermidis isolates produced biofilm compared with 26% of CoNS non-epidermidis (P < 0.001). We observed no difference in phenotypic biofilm production or genetic determinants for biofilm formation between invasive isolates and contaminants. C-reactive protein levels as a marker of inflammatory response were higher in CoNS sepsis caused by methicillin and aminoglycoside resistant versus susceptible isolates (P = 0.031). In contrast, there was a significant association between a lower C-reactive protein response and biofilm-positive isolates (P = 0.018). Antibiotic resistance was significantly correlated with biofilm production in S. epidermidis, but not in other CoNS species. Conclusions: CoNS sepsis with biofilm-forming strains was associated with a decreased host inflammatory response, potentially limiting the immune system to counteract the infection. The impact of antibiotic resistance and virulence determinants on clinical outcome of neonatal CoNS sepsis warrants additional clinical studies.

Prediction of Neurodevelopmental and Sensory Outcome at 5 Years in Norwegian Children Born Extremely Preterm

OBJECTIVE: To examine the prevalence of neurodevelopmental disability and the predictive value of pre-, peri-, and postnatal data on neurologic, sensory, cognitive, and motor function in children born extremely preterm. METHODS: This was a prospective observational study of all infants born in Norway between 1999 and 2000 with gestational ages between 22 and 27 weeks or birth weights between 500 and 999 g. Cognitive function was assessed with the Wechsler Preschool and Primary Scale of Intelligence–Revised, motor function with the Movement Assessment Battery for Children, and severity of cerebral palsy with the Gross Motor Function Classification for Cerebral Palsy. Disabilities were described as mild, moderate, or severe. RESULTS: Of 371 eligible children, 306 (82%) were examined at a mean (SD) age of 5 years and 10 (4) months. For gestational age less than 28 weeks (n = 239), 26 (11%) children had cerebral palsy alone (n = 21) or in combination with blindness (n = 3) or deafness (n = 2); 1 was blind and 1 was deaf. Of the remaining children, the mean full-scale IQ was 94 ± 15, and significant predictors were (values given as the difference in IQ points [95% confidence intervals]) high maternal education (9.6 [5.7–13.4]), preeclampsia (−7.7 [−12.7 to −2.7]), and retinopathy of prematurity higher than grade 2 (−17.5 [−27.1 to −8.0]). Movement Assessment Battery for Children scores were positively associated with gestational age and prenatal steroids and negatively associated with being small for gestational age, male gender, and having retinopathy of prematurity. Moderate to severe neurodevelopmental disability was more common for gestational ages 25 weeks or less (28 of 87 children) than for 26 to 27 weeks (12 of 152 children; P < .001) and 28 weeks or more (7 of 67 children; P = .001). CONCLUSIONS: The outcome was poorer for children with gestational ages of 25 weeks or less compared with those with gestational ages between 26 and 27 weeks. For those without cerebral palsy, blindness, or deafness, however, gestational age had a limited association with cognitive and motor function.

Septicemia in the first week of life in a Norwegian national cohort of extremely premature infants.

Objectives. To investigate the incidence, causes, predictors, and outcomes of septicemia in the first week of life in a national cohort of extremely premature infants. Methods. A prospective study of survival of all infants with gestational age of <28 weeks or birth weight of <1000 g who were born in Norway in 1999–2000 was performed. Data on the maternal prenatal history, delivery, and neonatal course, including detailed information on episodes of microbiologically verified septicemia, were collected on predefined forms. Septicemia was reported in 2 groups, ie, episodes diagnosed on the day of delivery (ie, very early-onset septicemia [VEOS]) and episodes diagnosed from day 2 to day 7 of life (ie, early-onset septicemia [EOS]). Logistic regression models were used for the selection of variables for predictor analysis in each group. Results. Of 462 included infants, VEOS occurred for 15 (32.5 per 1000 population) and EOS for 15 (35.5 per 1000 population). The most prevalent bacteria were Escherichia coli in VEOS (n = 9) and staphylococci (coagulase-negative staphylococci and Staphylococcus aureus) (n = 15) in EOS. Case fatality rates were 40% and 13%, respectively. Independent predictive factors for VEOS were clinical chorioamnionitis (odds ratio [OR]: 10.5; 95% confidence interval [CI]: 3.3-33.4) and high maternal age (OR: 1.2; 95% CI: 1.0–1.3), whereas not receiving systemic antibiotic therapy within 2 days of age (OR: 13.6; 95% CI: 3.7–50.2) and receiving nasal continuous positive airway pressure (n-CPAP) support at 24 hours of age (OR: 9.8; 95% CI: 2.5–38.4) independently predicted septicemia after the first day of life. Conclusions. Whereas vertically transmitted septicemia was dominated by Gram-negative bacteria, with predictors being exclusively of maternal origin, EOS was dominated by typically nosocomial flora, with n-CPAP treatment at 24 hours of age being a powerful predictor. Early n-CPAP treatment, as opposed to mechanical ventilation, as a powerful predictor of septicemia in the early neonatal period, even with adjustment for early systemic antibiotic treatment, is a new observation among extremely premature infants that warrants additional study.

Growth and nutrient intake among very-low-birth-weight infants fed fortified human milk during hospitalisation.

Postnatal growth failure in preterm infants is due to interactions between genetic and environmental factors, which are not fully understood. We assessed dietary supply of nutrients in very-low-birth-weight (VLBW, < 1500 g) infants fed fortified human milk, and examined the association between nutrient intake, medical factors and growth during hospitalisation lasting on average 70 d. We studied 127 VLBW infants during the early neonatal period. Data were obtained from medical records on nutrient intake, growth and growth-related factors. Extra-uterine growth restriction was defined as body weight < 10th percentile of the predicted value at discharge. Using logistic regression, we evaluated nutrient intake and other relevant factors associated with extra-uterine growth restriction in the subgroup of VLBW infants with adequate weight for gestational age at birth. The proportion of growth restriction was 33 % at birth and increased to 58 % at discharge from hospital. Recommended values for energy intake (>500 kJ/kg per d) and intra-uterine growth rate (15 g/kg per d) were not met, neither in the period from birth to 28 weeks post-conceptional age (PCA), nor from 37 weeks PCA to discharge. Factors negatively associated with growth restriction were energy intake (Ptrend = 0.002), non-Caucasian ethnicity (P = 0.04) and weight/predicted birth weight at birth (Ptrend = 0.004). Extra-uterine growth restriction is common in VLBW infants fed primarily fortified human milk. Currently recommended energy and nutrient intake for growing preterm infants was not achieved. Reduced energy supply and non-Caucasian ethnicity were risk factors for growth restriction at discharge from hospital.

Neonatal mortality and morbidity in extremely preterm small for gestational age infants: a population based study

Aim: To assess if growth restricted (small for gestational age, SGA) extremely preterm infants have excess neonatal mortality and morbidity. Methods: This was a cohort study of all infants born alive at 22–27 weeks’ post menstrual age in Norway during 1999–2000. Outcomes were compared between those who were SGA, defined as a birth weight less than the fifth percentile for post menstrual age, and those who had weights at or above the fifth percentile. Results: Of 365 infants with a post menstrual age of <28 weeks, 31 (8%) were SGA. Among infants with a post menstrual age of <28 weeks, only chronic lung disease was associated with SGA status (OR 2.7, 95% CI 1.0 to 7.2). SGA infants with a post menstrual age of 26–27 weeks had excess neonatal mortality (OR 3.8, 95% CI 1.3 to 11), chronic lung disease and a significantly higher mean number of days (age) before tolerating full enteral nutrition. SGA infants with a post menstrual age of 22–25 weeks had an excess risk of necrotising enterocolitis. Conclusion: Extremely preterm SGA infants had excess neonatal mortality and morbidity in terms of necrotising enterocolitis and chronic lung disease.

First year growth among very low birth weight infants.

Aim:  The aim of this study was to describe first‐year growth among very low birth weight infants and the effect of growth restriction at hospital discharge on first year growth.

Blood Culture Isolates during 6 years in a Tertiary Neonatal Intensive Care Unit

Blood culture results obtained in a single tertiary neonatal intensive care unit are reviewed. In 4416 admissions occurring over 6 y we identified 206 positive cultures (4.7/100 admissions) growing 234 bacterial and fungal isolates in 182 infants. Very early and early onset positive cultures comprised 17% and 22% each. Gram-positive bacteria dominated in very early (61%), early (91%) and late onset (78%) cultures with coagulase-negative staphylococci (CONS) as the most frequent isolate in all groups (22%, 46% and 55%, respectively). The 3 most frequent isolates following CONS were in very early onset cultures Escherichia coli (19%), anaerobic bacteria (17%) and group B streptococci (GBS) (14%), in early onset cultures Staphylococcus aureus (28%), Enterococci (7%), E. coli (6%) and Viridans streptococci (6%) and in late onset cultures S. aureus (15%), Candida species (8%) and E. coli (5%). Infants < or = 999 g birthweight, representing 6% of the admissions, contracted 37% of the positive blood cultures and nearly half (44%) of the CONS isolates. In these patients, a significant increase (p < 0.001) in the number of positive cultures/100 admissions and in the proportion of positive cultures in conjunction with an intravascular catheter were seen (p < 0.001). An intravascular catheter was more often present when CONS were isolated as compared to other organisms (p < 0.05). 23 positive cultures (11.2%), most frequently E. coli, were associated with a fatal outcome. Our microbiological pattern is dominated by a gram-positive flora, which is in agreement with recent European and North American reports, but differs from earlier Scandinavian studies in the proportion of CONS and GBS reported.