Nigel Kennea

Natural History of Brain Lesions in Extremely Preterm Infants Studied With Serial Magnetic Resonance Imaging From Birth and Neurodevelopmental Assessment

OBJECTIVES. The aim was to survey the range of cerebral injury and abnormalities of cerebral development in infants born between 23 and 30 weeks’ gestation using serial MRI scans of the brain from birth, and to correlate those findings with neurodevelopmental outcome after 18 months corrected age. METHODS. Between January 1997 and November 2000, consecutive infants born at <30 weeks’ gestational age underwent serial MRI brain scans from birth until term-equivalent age. Infants were monitored after 18 months of age, corrected for prematurity, with the Griffiths Mental Development Scales and neurologic assessment. RESULTS. A total of 327 MRI scans were obtained from 119 surviving infants born at 23 to 30 weeks of gestation. Four infants had major destructive brain lesions, and tissue loss was seen at term for the 2 survivors. Fifty-one infants had early hemorrhage; 50% of infants with term scans after intraventricular hemorrhage had ventricular dilation. Twenty-six infants had punctate white matter lesions on early scans; these persisted for 33% of infants assessed at term. Early scans showed cerebellar hemorrhagic lesions for 8 infants and basal ganglia abnormalities for 17. At term, 53% of infants without previous hemorrhage had ventricular dilation and 80% of infants had diffuse excessive high signal intensity within the white matter on T2-weighted scans. Complete follow-up data were available for 66% of infants. Adverse outcomes were associated with major destructive lesions, diffuse excessive high signal intensity within the white matter, cerebellar hemorrhage, and ventricular dilation after intraventricular hemorrhage but not with punctate white matter lesions, hemorrhage, or ventricular dilation without intraventricular hemorrhage. CONCLUSIONS. Diffuse white matter abnormalities and post–hemorrhagic ventricular dilation are common at term and seem to correlate with reduced developmental quotients. Early lesions, except for cerebellar hemorrhage and major destructive lesions, do not show clear relationships with outcomes.

Neonatal infections in England: the NeonIN surveillance network.

Introduction Neonatal infection is an important cause of morbidity and mortality. Neonatal infection surveillance networks are necessary for defining the epidemiology of infections and monitoring changes over time. Design Prospective multicentre surveillance using a web-based database. Setting 12 English neonatal units. Participants Newborns admitted in 2006–2008, with positive blood, cerebrospinal fluid or urine culture and treated with antibiotics for at least 5 days. Outcome measure Incidence, age at infection, pathogens and antibiotic resistance profiles. Results With the inclusion of coagulase negative Staphylococci (CoNS), the incidence of all neonatal infection was 8/1000 live births and 71/1000 neonatal admissions (2007–2008). The majority of infections occurred in premature (<37 weeks) and low birthweight (<2500 g) infants (82% and 81%, respectively). The incidence of early onset sepsis (EOS; ≤48 h of age) was 0.9/1000 live births and 9/1000 neonatal admissions, and group B Streptococcus (58%) and Escherichia coli (18%) were the most common organisms. The incidence of late onset sepsis (LOS; >48 h of age) was 3/1000 live births and 29/1000 neonatal admissions (7/1000 live births and 61/1000 admissions including CoNS) and the most common organisms were CoNS (54%), Enterobacteriaceae (21%) and Staphylococcus aureus (18%, 11% of which were methicillin resistant S aureus). Fungi accounted for 9% of LOS (72% Candida albicans). The majority of pathogens causing EOS (95%) and LOS (84%) were susceptible to commonly used empiric first line antibiotic combinations of penicillin/gentamicin and flucloxacillin/gentamicin, respectively (excluding CoNS). Conclusions The authors have established NeonIN in England and defined the current epidemiology of neonatal infections. These data can be used for benchmarking among units, international comparisons and as a platform for interventional studies.

Bacteria and Inflammatory Cells in Fetal Membranes Do Not Always Cause Preterm Labor

Intrauterine infection has been frequently linked with preterm labor before 30 wk of human pregnancy. Many different species of organisms have been detected, leading to the suggestion that infection-induced preterm labor is a generic inflammatory response to organisms rather than a specific response to a limited number of pathogens. The detection of organisms by microbiological culture is a laborious and unreliable process, so the aim of this study was to harness modern molecular techniques to detect organisms in tissues from human pregnancy. A DNA probe specific for conserved regions of bacterial 16S ribosomal RNA sequence was designed and labeled with fluorescein for fluorescence in situ hybridization. Organisms were detected in the great majority (>80%) of fetal membranes after prolonged premature rupture of the fetal membranes and after preterm labor, which was consistent with previous data. Organisms were also detected in fetal membranes after preterm delivery without labor and in term deliveries (with or without labour). Inflammatory cells were found frequently in the amnion or chorion of preterm fetal membranes but not in term tissues. Our primary finding is that fluorescence in situ hybridization is an appropriate method to detect organisms in human fetal membranes. In addition, our data show that bacteria may be present in fetal membranes without necessarily causing an inflammatory response, so the mere presence of bacteria may not be sufficient to cause preterm labor.

Specialization and integration of functional thalamocortical connectivity in the human infant

Significance We investigated the way in which the human thalamus and cortex are functionally connected at the time of normal birth. We found the functional parcellation of the thalamus to be a good facsimile of that found in adult studies. However, although primary cortical regions were almost entirely connected to specific thalamic regions, heteromodal cortex was more widely connected to multiple thalamic regions, giving the potential for an integrative role for these circuits. Development seemed to have been modulated by the experience of premature extrauterine life, with an increase in connectivity to primary sensory cortex, but reduced connectivity between areas of the thalamus and heteromodal cortex known to support higher cognitive functions. Connections between the thalamus and cortex develop rapidly before birth, and aberrant cerebral maturation during this period may underlie a number of neurodevelopmental disorders. To define functional thalamocortical connectivity at the normal time of birth, we used functional MRI (fMRI) to measure blood oxygen level-dependent (BOLD) signals in 66 infants, 47 of whom were at high risk of neurocognitive impairment because of birth before 33 wk of gestation and 19 of whom were term infants. We segmented the thalamus based on correlation with functionally defined cortical components using independent component analysis (ICA) and seed-based correlations. After parcellating the cortex using ICA and segmenting the thalamus based on dominant connections with cortical parcellations, we observed a near-facsimile of the adult functional parcellation. Additional analysis revealed that BOLD signal in heteromodal association cortex typically had more widespread and overlapping thalamic representations than primary sensory cortex. Notably, more extreme prematurity was associated with increased functional connectivity between thalamus and lateral primary sensory cortex but reduced connectivity between thalamus and cortex in the prefrontal, insular and anterior cingulate regions. This work suggests that, in early infancy, functional integration through thalamocortical connections depends on significant functional overlap in the topographic organization of the thalamus and that the experience of premature extrauterine life modulates network development, altering the maturation of networks thought to support salience, executive, integrative, and cognitive functions.

Managing and preventing outbreaks of Gram-negative infections in UK neonatal units

De novo guidance on the management of Gram-negative bacteria outbreaks in UK neonatal units was developed in 2012 by a Department of Health, England Antimicrobial Resistance and Healthcare Associated Infection working group. The recommendations included activation of an organisational response and establishing a control team when an outbreak is suspected; screening for the specific organism only during an outbreak; undertaking multidisciplinary reviews of cleaning routines, hand hygiene and Gram-negative bacteria transmission risks; considering deep-cleaning; cohorting colonised and infected babies preferably but not necessarily in isolation cubicles; and considering reducing beds or closing a unit to new admissions as a way of improving spacing and staff:patient ratios until the outbreak is under control. The group advised establishing mechanisms to communicate effectively across the network; informing parents of the outbreak as early as possible, and providing prewritten ‘infection outbreak’ information sheets. For prevention of outbreaks, the group advised meeting national staffing and cot-spacing requirements; following a Water Action Plan; using infection reduction care bundles and benchmarking; and introducing breast milk early and limiting antibiotic use.

NICE neonatal early onset sepsis guidance: greater consistency, but more investigations, and greater length of stay

Background In August 2012, new national guidance (National Institute of Health and Care Excellence (NICE) CG149) for management of early onset sepsis (EOS) was introduced in the UK. The guidance outlined a consistent approach for septic screens in newborn infants based on risk factors, and suggested biochemical and clinical parameters to guide management. In particular, it advised a second C-reactive protein level (CRP) 18–24 h into treatment to help determine length of antibiotic course, need for lumbar puncture (LP), and suggested review of blood culture at 36 h. Objective We evaluated impact of this guidance in our neonatal unit. Methods We compared two time periods, before and following the guidance. We evaluated length of stay, second CRP 18–24 h into treatment, percentage of babies having LP and duration of antibiotics. Results Before NICE guidance, 38.1% of screened babies stayed <72 h. This reduced to 18.4% following guidance. Before guidance, 20.9% babies stayed >5 days, which increased to 27.7% following NICE recommendations. Repeat CRP measurements increased from 45% to 97%. In 58% of these babies, repeat CRPs influenced management and hospital stay. An increase in LPs performed from 14% to 23% was noted. There were no positive blood cultures or LP results. Conclusions We envisaged shorter hospital stays with new NICE standards, particularly, with the aim of 36 h blood culture reporting. However, repeat CRP led to further investigations, increased LPs and longer durations of treatment and stay. This, in turn, impacted on workload and cost, and influenced parental experience in the first few days of life.

Neonatal invasive fungal infection in England 2004-2010.

Rates of invasive fungal infection are highest among neonates, especially those of low birthweight. This study aimed to describe the current epidemiology of invasive neonatal fungal infections in a UK neonatal infection surveillance network. From 2004 to 2010 prospective multicentre surveillance was conducted by 14 neonatal units using a web-based database. Clinicians then completed a standardized pro forma for each positive fungal blood and/or cerebrospinal fluid culture. The overall incidence was 2.4/1000 neonatal unit admissions and was highest among babies <1000 g (extreme low birthweight, 18.8/1000). Only five infants (6%) were >1500 g. The majority of infections were caused by Candida albicans (59; 69%) and Candida parapsilosis (17; 20%); 33% of infants had received antifungal prophylaxis. Known risk factors (use of central venous catheter, parenteral nutrition, previous antibiotic use) were common among cases. The attributable case fatality rate was 21% (18/84). Extreme low birthweight infants remain at highest risk of invasive fungal infection and prophylaxis should be particularly considered for this group. The number needing to receive prophylaxis to prevent one case varies significantly among units, hence unit-specific decisions are required. Further research is still needed into the optimal empiric and therapeutic strategies.

Characteristics of Invasive Staphylococcus aureus in United Kingdom Neonatal Units.

Background: In industrialized countries, Staphylococcus aureus (SA) is a leading cause of late-onset neonatal sepsis. Methods: Culture-proven episodes were identified prospectively from neonatal units participating in the neonatal infection surveillance network. Demographic, risk factor, and outcome data were collected. Results: Between 2004 and 2009, there were 117 episodes of SA infections (including 8 methicillin-resistant SA) in 116 infants from 13 units. The median gestational age and birth-weight were 27 weeks (90% ≤37 weeks, 85% ≤32 weeks) and 850 g (90% ≤2500 g), respectively. The overall incidence was 0.6 per 1000 live births and 23/1000 in infants <1500 g. Most episodes (94%) occurred more than 48 hours after birth (late onset). There were 7 early-onset episodes (<48 hours) (median gestational age, 38.5 weeks), all due to methicillin-susceptible SA. At the time of culture, 67 of 95 (71%) infants were receiving respiratory support and 47 of 94 (50%) had a central line in situ. The majority of infants had nonspecific clinical features although evidence of focal infection (skin, soft tissue, bone, joint, or pneumonia) was ultimately seen in 41 of 91 (45%). There were 18 deaths, 4 (all late onset) directly due to methicillin-susceptible SA sepsis (4.4%). Conclusions: SA is the second most common pathogen causing late-onset neonatal infections in this neonatal network. Infants who weigh <1500 g in intensive care settings are the most vulnerable group. Clinical signs are not sufficiently distinctive to allow targeted therapy, suggesting that an antistaphylococcal agent should be part of empiric therapy for late-onset sepsis in premature infants.

Neonatal sepsis – many blood samples, few positive cultures: implications for improving antibiotic prescribing

The National Institute for Health and Clinical Excellence is finalising the clinical practice guideline on antibiotics use for early-onset neonatal infection.1 The draft guideline compliments the national Antibiotic Stewardship Programme– Start Smart – then Focus2 by promoting stopping antibiotics at 36 h in infants without signs of infection and negative blood culture results, and switching from the recommended empiric broad-spectrum antibiotic treatment to a narrower-spectrum antibiotic regimen in consultation with microbiologists in those patients with infection. Prudent antibiotic prescribing …

Effect of MRI on preterm infants and their families: a randomised trial with nested diagnostic and economic evaluation.

Background We tested the hypothesis that routine MRI would improve the care and well-being of preterm infants and their families. Design Parallel-group randomised trial (1.1 allocation; intention-to-treat) with nested diagnostic and cost evaluations (EudraCT 2009-011602-42). Setting Participants from 14 London hospitals, imaged at a single centre. Patients 511 infants born before 33 weeks gestation underwent both MRI and ultrasound around term. 255 were randomly allocated (siblings together) to receive only MRI results and 255 only ultrasound from a paediatrician unaware of unallocated results; one withdrew before allocation. Main outcome measures Maternal anxiety, measured by the State-Trait Anxiety inventory (STAI) assessed in 206/214 mothers receiving MRI and 217/220 receiving ultrasound. Secondary outcomes included: prediction of neurodevelopment, health-related costs and quality of life. Results After MRI, STAI fell from 36.81 (95% CI 35.18 to 38.44) to 32.77 (95% CI 31.54 to 34.01), 31.87 (95% CI 30.63 to 33.12) and 31.82 (95% CI 30.65 to 33.00) at 14 days, 12 and 20 months, respectively. STAI fell less after ultrasound: from 37.59 (95% CI 36.00 to 39.18) to 33.97 (95% CI 32.78 to 35.17), 33.43 (95% CI 32.22 to 34.63) and 33.63 (95% CI 32.49 to 34.77), p=0.02. There were no differences in health-related quality of life. MRI predicted moderate or severe functional motor impairment at 20 months slightly better than ultrasound (area under the receiver operator characteristic curve (CI) 0.74; 0.66 to 0.83 vs 0.64; 0.56 to 0.72, p=0.01) but cost £315 (CI £295–£336) more per infant. Conclusions MRI increased costs and provided only modest benefits. Trial registration ClinicalTrials.gov NCT01049594 https://clinicaltrials.gov/ct2/show/NCT01049594. EudraCT: EudraCT: 2009-011602-42 (https://www.clinicaltrialsregister.eu/).