Early Empirical Antibiotics and Adverse Clinical Outcomes in Infants Born Very Preterm: A Population-Based Cohort.

OBJECTIVE: The objective of this study was to evaluate the association between empirical antibiotic therapy in the first postnatal week in uninfected infants born very preterm and the risk of adverse outcomes until discharge. STUDY DESIGN: Population-based, nationwide registry study in Norway including all live-born infants with a gestational age <32 weeks surviving first postnatal week without sepsis, intestinal perforation, or necrotizing enterocolitis (NEC) between 2009 and 2018. Primary outcomes were severe NEC, death after the first postnatal week, and/or a composite outcome of severe morbidity (severe NEC, severe bronchopulmonary dysplasia [BPD], severe retinopathy of prematurity, late-onset sepsis, or cystic periventricular leukomalacia). The association between empirical antibiotics and adverse outcomes was assessed using multivariable logistic regression models, adjusting for known confounders. RESULTS: Of 5296 live-born infants born very preterm, 4932 (93%) were included. Antibiotics were started in first postnatal week in 3790 of 4932 (77%) infants and were associated with higher aOR of death (aOR 9.33; 95% CI: 1.10-79.5, P = .041), severe morbidity (aOR 1.88; 95% CI: 1.16-3.05, P = .01), and severe BPD (aOR 2.17; 95% CI: 1.18-3.98; P = .012), compared with those not exposed. Antibiotics ≥ 5 days were associated with higher odds of severe NEC (aOR 2.27; 95% CI: 1.02-5.06; P = .045). Each additional day of antibiotics was associated with 14% higher aOR of death or severe morbidity and severe BPD. CONCLUSIONS: Early and prolonged antibiotic exposure within the first postnatal week was associated with severe NEC, severe BPD, and death after the first postnatal week.

Preterm birth in the Nordic countries-Capacity, management and outcome in neonatal care.

AIM: Organisation of care, perinatal and neonatal management of very preterm infants in the Nordic regions were hypothesised to vary significantly. The aim of this observational study was to test this hypothesis. METHODS: Information on preterm infants in the 21 greater healthcare regions of Denmark, Finland, Iceland, Norway and Sweden was gathered from national registers in 2021. Preterm birth rates, case-mix, perinatal interventions, neonatal morbidity and survival to hospital discharge in very (<32 weeks) and extremely preterm infants (<28 weeks of gestational age) were compared. RESULTS: Out of 287 642 infants born alive, 16 567 (5.8%) were preterm, 2389 (0.83%) very preterm and 800 (0.28%) were extremely preterm. In very preterm infants, exposure to antenatal corticosteroids varied from 85% to 98%, live births occurring at regional centres from 48% to 100%, surfactant treatment from 28% to 69% and use of mechanical ventilation varied from 13% to 77% (p < 0.05 for all comparisons). Significant regional variations within and between countries were also seen in capacity in neonatal care, case-mix and number of admissions, whereas there were no statistically significant differences in survival or major neonatal morbidities. CONCLUSION: Management of very preterm infants exhibited significant regional variations in the Nordic countries.

Enhanced nutrient supply and intestinal microbiota development in very low birth weight infants.

BACKGROUND: Promoting a healthy intestinal microbiota may have positive effects on short- and long-term outcomes in very low birth weight (VLBW; BW < 1500 g) infants. Nutrient supply influences the intestinal microbiota. METHODS: Fifty VLBW infants were randomized to an intervention group receiving enhanced nutrient supply or a control group. Fecal samples from 45 infants collected between birth and discharge were analyzed using 16S ribosomal RNA (rRNA) amplicon sequencing. RESULTS: There was considerable individual variation in microbiota development. Microbial richness decreased towards discharge in the controls compared to the intervention group. In the intervention group, there was a greater increase in diversity among moderately/very preterm (MVP, gestational age ≥ 28 weeks) infants and a steeper decrease in relative Staphylococcus abundance in extremely preterm (EP, gestational age < 28 weeks) infants as compared to controls. Relative Bifidobacterium abundance tended to increase more in MVP controls compared to the intervention group. Abundance of pathogens was not increased in the intervention group. Higher relative Bifidobacterium abundance was associated with improved weight gain. CONCLUSION: Nutrition may affect richness, diversity, and microbiota composition. There was no increase in relative abundance of pathogens among infants receiving enhanced nutrient supply. Favorable microbiota development was associated with improved weight gain.

Strictly controlled glucose infusion rates are associated with a reduced risk of hyperglycaemia in extremely low birth weight preterm infants.

AIM: We evaluated a strict strategy that aimed to avoid fluctuations in glucose infusion rates (GIRs) and assessed the independent effects of maximal daily GIRs on the hyperglycaemia risk among extremely low birth weight (ELBW) infants receiving early enhanced parenteral nutrition. METHODS: This study comprised all ELBW infants admitted to the neonatal intensive care unit of Oslo University Hospital Rikshospitalet, Norway, before (2007-2009) and after (2012-2013) implementing a strict GIR strategy. Severe hyperglycaemia was defined as two consecutive blood glucose values over 12 mmol/L. Maximum daily GIRs (mg/kg/min) were categorised into low (<5.1), intermediate (5.1-7.0) or high (>7.0). Mixed effects logistic regression modelling for repeated measurements was applied to investigate independent determinants of hyperglycaemia. RESULTS: We included 1293 treatment days for 195 infants. The maximum daily GIR decreased (6.3 versus 5.8 mg/kg/min), while mean daily glucose and energy intakes were maintained in the post-strategy period. The prevalence of severe hyperglycaemia (48% versus 23%), insulin use (39% versus 16%) and mortality (26% versus 10%) fell. Intermediate GIR (odds ratio 2.11) and high GIR (odds ratio 2.85) were significant independent predictors of severe hyperglycaemia compared to low GIR. CONCLUSION: A strict GIR strategy reduced the risk of severe hyperglycaemia and adverse outcomes.

Early surfactant and non-invasive ventilation versus intubation and surfactant: a propensity score-matched national study.

OBJECTIVE: To compare outcome after less invasive surfactant administration (LISA) and primary endotracheal intubation (non-LISA) in infants born before gestational age (GA) 28 weeks. SETTING: All neonatal intensive care units (NICUs) in Norway during 2012-2018. METHODS: Defined population-based data were prospectively entered into a national registry. We compared LISA infants with all non-LISA infants and with non-LISA infants who received surfactant following intubation. We used propensity score (PS) matching to identify non-LISA infants who were similar regarding potential confounders. MAIN OUTCOME VARIABLES: Rate and duration of mechanical ventilation (MV), survival, neurological and gastrointestinal morbidity, and need of supplemental oxygen or positive pressure respiratory support at postmenstrual age (PMA) 36 and 40 weeks. RESULTS: We restricted analyses to GA 25-27 weeks (n=843, 26% LISA) because LISA was rarely used at lower GAs. There was no significant association between NICUs regarding proportions treated with LISA and proportions receiving MV. In the PS-matched datasets, fewer LISA infants received MV (61% vs 78%, p<0.001), and they had fewer days on MV (mean difference 4.1, 95% CI 0.0 to 8.2 days) and lower mortality at PMA 40 weeks (absolute difference 6%, p=0.06) compared with all the non-LISA infants, but only a lower rate of MV (64% vs 97%, p<0.001) and fewer days on MV (mean difference 5.8, 95% CI 0.6 to 10.9 days) compared with non-LISA infants who received surfactant after intubation. CONCLUSION: LISA reduced the rate and duration of MV but had no other clear benefits.

Predictors of extubation success: a population-based study of neonates below a gestational age of 26 weeks.

OBJECTIVE: The aim of the study was to investigate first extubation attempts among extremely premature (EP) infants and to explore factors that may increase the quality of clinical judgement of extubation readiness. DESIGN AND METHOD: A population-based study was conducted to explore first extubation attempts for EP infants born before a gestational age (GA) of 26 weeks in Norway between 1 January 2013 and 31 December 2018. Eligible infants were identified via the Norwegian Neonatal Network database. The primary outcome was successful extubation, defined as no reintubation within 72 hours after extubation. RESULTS: Among 482 eligible infants, 316 first extubation attempts were identified. Overall, 173 (55%) infants were successfully extubated, whereas the first attempt failed in 143 (45%) infants. A total of 261 (83%) infants were extubated from conventional ventilation (CV), and 55 (17%) infants were extubated from high-frequency oscillatory ventilation (HFOV). In extubation from CV, pre-extubation fraction of inspired oxygen (FiO2) ≤0.35, higher Apgar score, higher GA, female sex and higher postnatal age were important predictors of successful extubation. In extubation from HFOV, a pre-extubation FiO2 level ≤0.35 was a relevant predictor of successful extubation. CONCLUSIONS: The correct timing of extubation in EP infants is important. In this national cohort, 55% of the first extubation attempts were successful. Our results suggest that additional emphasis on oxygen requirement, sex and general condition at birth may further increase extubation success when clinicians are about to extubate EP infants for the first time.

Duration of Mechanical Ventilation and Extubation Success among Extremely Premature Infants.

OBJECTIVE: The objective of this study was to examine the duration of mechanical ventilation (MV) in days until the first successful extubation and the cumulative duration of MV until discharge of infants with gestational age (GA) <26 weeks. We also aimed to explore associations between early clinical variables and the cumulative duration of MV. DESIGN AND SETTING: This population-based study analysed data reported to the Norwegian Neonatal Network on extremely premature infants admitted between January 1, 2013, and December 31, 2018. RESULTS: A total of 406 infants were included, of which 293 (72%) survived to discharge. The proportion successfully extubated on their first attempt was 34% of the infants born at GA 22-23 weeks, 50% at GA 24 weeks, and 70% at GA 25 weeks. Median postmenstrual age (PMA) at the first successful extubation was 27 weeks. The median duration of MV was 35, 24, and 12 days for infants born at GA 22-23, 24, and 25 weeks, respectively. Male sex and low 5-min Apgar score were independent early predictors for prolonged MV duration adjusted for GA in regression analyses. CONCLUSIONS: Most of the infants born at GA 25 weeks were successfully extubated on the first attempt. However, half of the infants born <26 weeks experienced unsuccessful extubations, indicating a lack of useful clinical predictors of successful extubation. The median duration of MV in survivors was 4 weeks longer for infants at GA 22-23 weeks than for infants born at GA 25 weeks, while the difference in median PMA at the first successful extubation was 2 weeks.

Unexpected death in children with severe congenital heart defects in Norway 2004-2016.

AIMS: Updated knowledge on the rates and causes of death among children with severe congenital heart defects (CHDs) is needed to further improve treatment and survival. This study investigated nationwide mortality rates in children with severe CHDs with an emphasis on unexpected mortality unrelated to cardiac intervention. METHODS AND RESULTS: Data on all pregnancies and live-born children in Norway from 2004 to 2016 were obtained from national registries, the Oslo University Hospital's Clinical Registry for CHDs and medical records. Among 2359 live-born children with severe CHDs, 234 (10%) died before 2 years of age. Of these, 109 (46%) died in palliative care, 58 (25%) died of causes related to a cardiac intervention and 67 (29%) died unexpectedly and unrelated to a cardiac intervention, either before (n=26) or following (n=41) discharge after a cardiac intervention. Comorbidity (38/67, 57%), persistent low oxygen saturation (SaO2; <95%; 41/67, 61%), staged surgery (21/41, 51%), residual cardiac defects (22/41, 54%) and infection (36/67, 54%) were frequent in children who died unexpectedly unrelated to an intervention. Two or more of these factors were present in 62 children (93%). The medical reports at hospital discharge lacked information on follow-up in many patients who died unexpectedly. CONCLUSIONS: The numbers of unexpected deaths unrelated to cardiac intervention in children <2 years of age without comorbidity were low in Norway. However, close follow-up is recommended for infants with comorbidities, persistent low oxygen saturation, staged surgery or residual cardiac defects, particularly when an infection occurs.

Reduced Antibiotic Exposure by Serial Physical Examinations in Term Neonates at Risk of Early-onset Sepsis.

BACKGROUND: Suspected early-onset sepsis (EOS) results in antibiotic treatment of a substantial number of neonates who are uninfected. We evaluated if an approach using serial physical examinations (SPEs) can reduce antibiotic exposure for suspected EOS in term neonates during the first 3 days of life, without affecting safety. METHODS: Within a quality-improvement framework, SPEs for 24-48 hours for neonates with suspected EOS was implemented in the neonatal intensive care unit, Stavanger, Norway. The proportion of neonates ≥37 weeks gestation exposed to antibiotics, antibiotic therapy-days and the safety outcome time from birth to start antibiotics were compared between a baseline period (April 2014-February 2016), when a risk factor based approach was used, and a post-SPE-implementation period (January 2017-November 2018). RESULTS: We included all term live born neonates (n = 17,242) in the 2 periods. There was a 57% relative reduction in neonates exposed to antibiotics; 2.9% in the baseline and 1.3% in the post-implementation period, P < 0.001. There was a 60% relative reduction in mean antibiotic therapy-days/1000 patient-days; from 320 to 129, P < 0.001, and a 50% relative reduction in time to initiate antibiotics in suspected EOS-cases, from median (interquartile range) 14 (5-28) to 7 (3-17) hours, P = 0.003. The incidence of culture-positive EOS remained unchanged. There were no infection-attributable deaths. CONCLUSIONS: Implementing SPE to guide empiric antibiotic therapy in term neonates with suspected EOS more than halved the burden of antibiotic exposure, without delay of antibiotic treatment of infected neonates or increased sepsis-related mortality.

Severe congenital heart defects: incidence, causes and time trends of preoperative mortality in Norway.

BACKGROUND AND AIMS: Severe congenital heart defects (CHDs) still represent one of the main causes of infant death. The risk factors associated with cardiac surgery and postoperative mortality are well known. We aimed to describe the rates, causes and time trends of mortality before surgery-including termination of pregnancies and palliative care-in fetuses and children below 2 years of age with severe CHDs. METHODS AND RESULTS: Data concerning all 789 345 pregnancies in Norway from 2004 to 2016 were retrieved from the Medical Birth Registry of Norway, the Oslo University Hospital's Clinical Registry for Congenital Heart Defects, the Norwegian Cause of Death Registry, the National Registry, Statistics Norway, autopsy reports and medical records. When including termination of pregnancy and stillbirths, the number of fetuses and children with severe CHDs that did not reach the age of 2 years was 31%. Mortality among the 2359 live-born infants with severe CHDs was 10%, of whom 58% died before surgery. Of the preoperative deaths, 81% died in a palliative care setting, and comorbidity and univentricular CHDs were common among these infants. Together, palliative care and termination of pregnancy accounted for 86% of deaths in cases of severe CHDs, and this proportion increased during the study period (annual percent changes 1.3, 95% CI 0.4 to 2.1, p<0.001), mainly due to an increased termination rate. CONCLUSIONS: Termination of pregnancy accounted for the majority of the deaths in fetuses and children with severe CHDs. Among live-born children, most preoperative deaths occurred in a palliative care setting and were strongly related to comorbidities and/or univentricular hearts.

Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency.

Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With written parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in IL2RG, RAG2, and RMRP were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the IL2RG-SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky RAG2-SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with RMRP-SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in DCLRE1C, JAK3, NBN, and IL2RG were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal cytomegalovirus (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID.

Intestinal microbiota development and gestational age in preterm neonates.

The intestinal microbiota is an important contributor to the health of preterm infants, and may be destabilized by a number of environmental factors and treatment modalities. How to promote the development of a healthy microbiota in preterm infants is largely unknown. We collected fecal samples from 45 breastfed preterm very low birth weight (birth weight < 1500 g) infants from birth until 60 days postnatal age to characterize the intestinal microbiota development during the first weeks of life in preterm infants. Fecal microbiota composition was determined by 16S rRNA amplicon sequencing. The main driver of microbiota development was gestational age; antibiotic use had strong but temporary effects and birth mode had little influence. Microbiota development proceeded in four phases indicated by the dominance of Staphylococcus, Enterococcus, Enterobacter, and finally Bifidobacterium. The Enterococcus phase was only observed among the extremely premature infants and appeared to delay the microbiota succession. The results indicate that hospitalized preterm infants receiving breast milk may develop a normal microbiota resembling that of term infants.

Neonatal Morbidity and 1-Year Survival of Extremely Preterm Infants.

OBJECTIVE: To determine 1-year survival and major neonatal morbidities (intracranial hemorrhage grade >2, cystic periventricular leukomalacia, retinopathy of prematurity grade >2, necrotizing enterocolitis, severe bronchopulmonary dysplasia) among extremely preterm infants in Norway in 2013-2014, and to compare the results to the first Norwegian Extreme Prematurity Study 1999-2000 and similar contemporary European population-based studies. METHODS: Population-based study of all infants born at 22 through 26 weeks' gestation in Norway in 2013-2014. Prospectively collected data were obtained by linking data in the Norwegian Neonatal Network to the Medical Birth Registry of Norway. RESULTS: Of 420 infants (incidence 3.5 per 1000 births), 145 were stillborn (34.5%), 275 were live-born (82.3% of the 334 fetuses alive at admission for obstetrical care), and 251 (91.3% of live-born infants) were admitted to a neonatal unit. The survival among live-born infants was 18% at 22 weeks, 29% at 23 weeks, 56% at 24 weeks, 84% at 25 weeks and 90% at 26 weeks (for each week increment in gestational age: odds ratio 3.3; 95% confidence interval, 2.4-4.4). Among infants surviving to 1 year of age, major neonatal morbidity was diagnosed in 55%. Decreasing gestational age was moderately associated with rates of major morbidity (odds ratio 1.6; 95% confidence interval, 1.2-2.2). CONCLUSIONS: Compared to the previous 1999-2000 cohort, the rate of stillbirth before admission to an obstetrical unit increased, whereas the survival rate among live born infants was similar in our 2013-2014 cohort. Neonatal morbidity rates remain high among extremely preterm infants.

Enhanced nutrient supply to very low birth weight infants is associated with higher blood amino acid concentrations and improved growth.

BACKGROUND & AIMS: Customized nutrient supply is vital to ensure optimal growth among very low birth weight infants (birth weight < 1500 g). The supply of amino acids is especially important due to their impact on protein synthesis and growth. The objectives of this study were to evaluate the impact of enhanced nutrition on growth, blood concentrations of amino acids, and explore possible associations between amino acid concentrations and common neonatal morbidities. We hypothesized higher amino acids levels and growth velocity among infants on enhanced nutrient supply. METHODS: This randomized controlled trial was performed in three university neonatal intensive care units in Oslo, Norway. Fifty very low birth weight infants were randomized to a control or intervention group. Within 24 h after birth, infants in the intervention group received enhanced supply of energy, amino acids, lipids, long-chain polyunsaturated fatty acids and vitamin A, whereas the control group received a standard nutrient supply. The intervention continued until 52 weeks postmenstrual age or until a body weight of 5.5 kg was reached. Amino acid analyses were performed at birth, day 3, 5 weeks of age and 5 months corrected age. Detailed information about nutrient intake, morbidities, blood amino acid concentrations and growth velocity were collected from 44 infants (6 infants excluded). High-performance liquid chromatography was used for amino acid analysis. RESULTS: The intervention group (n = 23) received higher supply of proteins, with higher blood concentrations of amino acids measured at 5 weeks of age, and improved growth velocity (mean 17.4 vs 14.3 g/kg/day, p < 0.001) at 36 weeks postmenstrual age, compared to the control group (n = 21). The correlation between concentrations of branched chain amino acids (leucine, isoleucine and valine) and growth was stronger and more positive among infants: a) in the control group (correlation coefficient ≥ 0.68, p ≤ 0.004); b) born with birth weight appropriate for gestational age (correlation coefficient ≥ 0.53, p ≤ 0.009) and c) not diagnosed with septicemia (correlation coefficient ≥ 0.63, p ≤ 0.005). CONCLUSION: Enhanced nutrient supply to very low birth weight infants led to higher blood amino acid concentrations and improved growth. The correlations between amino acid concentrations and growth velocity were weaker in the intervention group as compared to the control group. This could reflect an upper threshold for protein synthesis and growth with our intervention, whereas a potential for further growth with increasing amino acid supply was possible for the control group. CLINICAL TRIAL REGISTRATION NO: NCT01103219.

Early-onset Sepsis and Antibiotic Exposure in Term Infants: A Nationwide Population-based Study in Norway.

BACKGROUND: Sepsis is a leading cause of neonatal morbidity and mortality. Clinical suspicion may lead to overuse of antibiotics. The objective of this study was to assess the epidemiology of early-onset sepsis (EOS) and antibiotic exposure during the first week of life in Norwegian term infants. METHODS: This is a nationwide population-based study from the Norwegian Neonatal Network. During the 3-year study period (2009-2011), 20 of Norway's 21 neonatal units prospectively collected data. Among 168,877 live-born (LB) term infants born during the study period, 10,175 (6.0%) infants were hospitalized in the first week of life and included in the study. RESULTS: There were 91 cases of culture-confirmed EOS (0.54 per 1000 LB) and 1447 cases classified as culture-negative EOS (8.57 per 1000 LB). The majority of culture-confirmed EOS cases were caused by Gram-positives (83/91; 91%), most commonly group B streptococci (0.31 per 1000 LB). Intravenous antibiotics were administered to 3964 infants; 39% of all admissions and 2.3% of all LB term infants. Empiric therapy consisted of an aminoglycoside and either benzylpenicillin or ampicillin in 95% of the cases. The median (interquartile range) treatment duration was 8 (7-10) days for culture-confirmed EOS and 6 (5-7) days for culture-negative EOS. There was 1 EOS-attributable death (group B streptococcal EOS) during the study period. CONCLUSIONS: In this registry-based study, the incidence of culture-confirmed EOS was in line with previous international reports and the mortality was very low. A large proportion of infants without infection were treated with antibiotics. Measures should be taken to spare neonates unnecessary antibiotic treatment.

Enhanced nutrition improves growth and increases blood adiponectin concentrations in very low birth weight infants.

BACKGROUND: Adequate nutrient supply is essential for optimal postnatal growth in very low birth weight (VLBW, birth weight<1,500 g) infants. Early growth may influence the risk of metabolic syndrome later in life. OBJECTIVE: To evaluate growth and blood metabolic markers (adiponectin, leptin, and insulin-like growth factor-1 (IGF-1)) in VLBW infants participating in a randomized nutritional intervention study. DESIGN: Fifty VLBW infants were randomized to an enhanced nutrient supply or a standard nutrient supply. Thirty-seven infants were evaluated with growth measurements until 2 years corrected age (CA). Metabolic markers were measured at birth and 5 months CA. RESULTS: Weight gain and head growth were different in the two groups from birth to 2 years CA (weight gain: pinteraction=0.006; head growth: pinteraction=0.002). The intervention group improved their growth z-scores after birth, whereas the control group had a pronounced decline, followed by an increase and caught up with the intervention group after discharge. At 5 months CA, adiponectin concentrations were higher in the intervention group and correlated with weight gain before term (r=0.35) and nutrient supply (0.35≤r≤0.45). Leptin concentrations correlated with weight gain after term and IGF-1 concentrations with length growth before and after term and head growth after term (0.36≤r≤0.53). CONCLUSION: Enhanced nutrient supply improved early postnatal growth and may have prevented rapid catch-up growth later in infancy. Adiponectin concentration at 5 months CA was higher in the intervention group and correlated positively with early weight gain and nutrient supply. Early nutrition and growth may affect metabolic markers in infancy.Clinical Trial Registration (ClinicalTrials.gov) no.: NCT01103219.

Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants.

IMPORTANCE: Efforts to optimize early parenteral nutrition (PN) in extremely low-birth-weight (ELBW) infants to promote growth and development may increase hyperglycemia risk. Recent studies have identified an association between early hyperglycemia and adverse outcomes in ELBW infants. OBJECTIVES: To examine the prevalence of early hyperglycemia and clinical outcomes among ELBW infants before (2002-2005) and after (2006-2011) the implementation of an early enhanced PN protocol and to assess the independent effects of early enhanced PN and early hyperglycemia on mortality. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study in a level III neonatal intensive care unit. Prospectively collected clinical data in the neonatal intensive care unit's medical database, nutritional information, and blood glucose levels were merged for analysis. All ELBW infants born between January 1, 2002, and December 31, 2011, without lethal malformations and still alive at 12 hours of life were eligible for inclusion in the study. MAIN OUTCOMES AND MEASURES: Mortality was the main outcome measure. Severe hyperglycemia was defined as 2 consecutive blood glucose levels exceeding 216 mg/dL at least 3 hours apart. A multivariable logistic regression model was applied to determine the independent effects of early enhanced PN and hyperglycemia on mortality. RESULTS: In total, 343 infants were included in the study, 129 in a historical comparison group before the enhanced PN protocol and 214 in the early enhanced PN group. Baseline characteristics were similar between the study groups. After the introduction of early enhanced PN, the prevalence of severe hyperglycemia during the first week of life was higher in the early enhanced PN group (11.6% [15 of 129] vs 41.6% [89 of 214], P < .001), as was the mortality (10.9% [14 of 129] vs 24.3% [52 of 214], P = .003). When adjusting for background characteristics, treatment, and nutritional data, early severe hyperglycemia remained a strong independent risk factor for death (odds ratio, 4.68; 95% CI, 1.82-12.03), together with gestational age (odds ratio, 0.62; 95% CI, 0.49-0.79). CONCLUSIONS AND RELEVANCE: The implementation of an enhanced PN protocol was correlated with an increased prevalence of severe hyperglycemia and higher mortality. In the multivariable analysis, an enhanced PN regimen per se was not predictive of mortality, whereas early severe hyperglycemia remained strongly predictive of death. To avoid detrimental effects on outcomes in ELBW infants, the optimal composition of early PN to avoid postnatal growth failure must be carefully balanced against hyperglycemia risk.

Enhanced nutrient supply to very low birth weight infants is associated with improved white matter maturation and head growth.

BACKGROUND: Extrauterine growth restriction is common among very low birth weight infants (VLBW, BW <1,500 g). Optimal postnatal nutrient supply is essential to limit growth restriction and ensure adequate growth and neurodevelopment. OBJECTIVES: We compared an enhanced postnatal nutrient supply to a standard supply and evaluated the effects on growth velocity, head circumference growth and cerebral maturation - the latter by magnetic resonance diffusion tensor imaging (DTI). We hypothesized increased growth velocity, head circumference growth and decreased mean diffusivity (MD) in cerebral white matter (WM) areas, suggesting improved cerebral maturation among infants on the enhanced nutrient supply. METHODS: In this randomized controlled trial, infants on the enhanced nutrient supply received increased amounts of energy, protein, fat, essential fatty acids and vitamin A until discharge. DTI was performed close to term equivalent age. Outcomes were growth velocity, head circumference growth and WM mean diffusivity. RESULTS: Among the 50 included infants, 14 in the intervention group and 11 controls underwent a successful DTI. Infants on the enhanced diet achieved improved growth velocity (16.5 vs. 13.8 g/kg/day, p = 0.01) and increased head circumference (Δz score: 0.24 vs. -0.12, p = 0.15). A significantly lower MD was seen in a large WM area such as the superior longitudinal fasciculi (1.19 × 10(-3) vs. 1.24 × 10(-3) mm(2)/s, p = 0.04, adjusted for age when scanned). CONCLUSIONS: Enhanced nutrient supply to VLBW infants is associated with improved growth velocity, increased head circumference growth and decreased regional WM mean diffusivity, suggesting improved maturation of cerebral connective tracts.

Improved Visual Perception in Very Low Birth Weight Infants on Enhanced Nutrient Supply.

BACKGROUND: Optimal nutrient supply to very low birth weight (VLBW: BW <1,500 g) infants is important for growth and neurodevelopment. Growth restriction is common among these infants and may be associated with neurocognitive impairments. OBJECTIVES: To compare an enhanced nutrient supply to a routine supply given to VLBW infants and to evaluate the effects on visual perception of global form and motion measured by visual event-related potentials (VERP). METHODS: A total of 50 VLBW infants were randomized to an intervention group that received an increased supply of energy, protein, fat, essential fatty acids, and vitamin A or a control group that received standard nutritional care. At 5 months' corrected age the infants were examined using VERP to investigate the responses to global form and motion. VERP were analysed at the first (f1) and third (f3) harmonics of the stimulus frequency. RESULTS: Data from 31 subjects were eligible for analysis. The motion VERP responses for the f1 and f3 components were stronger in the area near the posterior midline region in the intervention group compared to the controls in the group analyses (p = 0.02 and p = 0.001, respectively). CONCLUSION: The results showed a more consistent response to global motion among infants receiving enhanced nutrition. The intervention may have improved visual perception of global motion.