Improving head growth in very preterm infants--a randomised controlled trial I: neonatal outcomes.

BACKGROUND: Infants born very preterm are at an increased risk of poor growth in the post-natal period. Poor brain growth in this critical period may result from inadequate nutrition, and has long-term effects on neurodevelopmental outcome. AIMS: To examine the feasibility of providing macronutrients at amounts above current recommendations (hyperalimentation) to improve nutrition and head growth in preterm infants. METHODS: 142 infants <29 weeks' gestation were randomised to hyperalimented or standard parenteral and enteral nutrition. Growth was monitored from birth to 36 weeks' postmenstrual age (PMA). The primary outcome measure was occipitofrontal circumference (OFC) at 36 weeks' PMA. RESULTS: 55 infants in the intervention group and 59 infants in the control group survived to 36 weeks' PMA. 11 (16%) infants in the intervention group and 13 (18%) infants in the control group were small for gestational age (SGA). There was no statistically significant difference between the two groups in the primary outcome measure or other growth variables. Babies in the intervention group received significantly more energy and protein, but 80% were still in a cumulative protein/energy deficit at the end of 4 weeks. 20 (24%, p = 0.008) of those in deficit at 4 weeks had an OFC of more than 2 SD below the mean at 36 weeks' PMA, as opposed to none of those not in deficit. CONCLUSION: Cumulative energy/protein deficit is predictive of poor head growth, but the delivery of adequate intakes remains a challenge in the preterm.

Preterm mortality and morbidity over 25 years.

Changing preterm population variables have masked improvements in neonatal survival over time. Increased use of antenatal steroids, caesarean section, and surfactant may have reduced the likelihood of mortality and periventricular haemorrhage by a third and doubled that of chronic lung disease, persistent duct, and septicaemia.

Are there critical periods for brain growth in children born preterm?

BACKGROUND: Children born very preterm who attend mainstream schools have a high prevalence of minor motor, behavioural, and learning disorders. These appear to be associated with reduced postnatal growth, particularly of the head. It is unclear when this poor growth occurs and whether growth restriction during different periods has different effects on later function. OBJECTIVE: To identify periods during early development, in children born preterm, when impaired head growth may influence minor motor and cognitive function. POPULATION: A geographically defined cohort of 194 infants born in Merseyside during 1980-81 and weighing less than 1500 g. METHODS: Measurements of head circumference (occipitofrontal circumference (OFC)) were available at birth, hospital discharge, 4 years, and 15 years of age. Assessments of intelligence (intelligence quotient (IQ)) and minor motor impairment (test of motor impairment (TOMI)) were made at 8 years of age. Clinical, social, and demographic variables were obtained from the clinical record and maternal interviews. RESULTS: IQ correlated significantly with OFC at 4 and 15 years of age after correction for growth restriction at birth (intrauterine growth restriction (IUGR)) and social class. TOMI scores correlated significantly with OFC at all four times, but especially with OFC at discharge and with change in OFC between birth and discharge. They were not affected by correction for social class or IUGR. CONCLUSION: Although both IQ and minor motor impairments correlate strongly with each other at school age in very low birthweight children, the factors determining them and their timing of operation are different. Interventions designed to improve IQ in this population would need to reduce IUGR and improve later childhood growth. Those aimed to improve motor ability need to be targeted more at brain protection during the neonatal period.

Prevalence of severe fatigue in primary care.

A postal survey of 1024 UK GP practices showed the prevalence of medically unexplained severe fatigue over three months in 5-19 year olds to be 62/100,000. Cases were predominantly adolescent girls and were more likely to come from practices in less deprived areas, which could reflect consulting behaviours.

Perinatal and postnatal factors in very preterm infants and subsequent cognitive and motor abilities.

BACKGROUND: Many children born very preterm have cognitive and minor motor problems later, even if attending mainstream schools. OBJECTIVE: To examine associations between this suboptimal performance and perinatal and postnatal clinical factors. PARTICIPANTS AND METHODS: A geographically determined cohort of 280 infants born at less than 32 weeks gestation in 1991-92 in Liverpool, free of major disability and attending mainstream school at 7 years of age. A perinatal and postnatal data set were obtained from the clinical records retrospectively. Measurements of height, weight, and head circumference at 7 years were made, together with assessments of intelligence (Wechsler intelligence scale for children, IQ) and motor impairment (Movement assessment battery for children, MABC). RESULTS: Multiple regression analysis showed IQ at 7 years to be independently significantly related to gestation, persistence of the arterial duct (PDA), and head circumference at 7 years. MABC was only significantly related to gestation. PDA was related to periventricular haemorrhage (OR 2.7, 95% confidence interval (CI) 1.3 to 5.8) and parenchymal lesions including ventriculomegaly (OR 4.1, 95% CI 1.5 to 11.4). CONCLUSION: Cognitive ability in children born preterm is significantly related to gestation, but may also be related to the effects of PDA on early brain development, through either periventricular haemorrhage/ventriculomegaly or other disturbance of early brain growth.

Antibiotic regimens for suspected early neonatal sepsis.

BACKGROUND: Early acquired infection may cause severe illness or death in the neonatal period. Prompt treatment with antibiotics has shown to reduce mortality. It is not clear which antibiotic regimen is suitable for treatment of presumed early neonatal sepsis. OBJECTIVES: To compare effectiveness and adverse effects of antibiotic regimens for treatment of presumed early neonatal sepsis. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2003), MEDLINE (1966 to August 2003), EMBASE (1980 to September 2003) and ZETOC (1993 to August 2003) databases were searched for possible studies. Pharmaceutical companies were contacted for any unpublished data. SELECTION CRITERIA: Randomised and quasi-randomised controlled studies comparing antibiotic regimens for the treatment of early neonatal sepsis (both monotherapies and combination therapies). DATA COLLECTION AND ANALYSIS: Both reviewers screened abstracts and full reports against the inclusion criteria, appraised the quality of and extracted data from papers. For dichotomous outcomes, treatment effect was expressed as relative risk with 95% confidence interval. Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Two small studies had compared monotherapy with combination therapy. There was no significant difference in mortality, treatment failure or bacteriological resistance. REVIEWERS' CONCLUSIONS: There is no evidence from randomised trials to suggest that any antibiotic regimen may be better than any other in the treatment of presumed early neonatal sepsis. More studies are needed to resolve this issue.

Ophthalmic impairment at 7 years of age in children born very preterm.

AIMS: To determine the prevalence of ophthalmic impairments in very preterm compared with term infants, the relation between impairments and cerebral ultrasound appearances and retinopathy, and the correlation with visual perception and motor and cognitive measures. SUBJECTS: 279 children at 7 years of age born before 32 weeks gestation within Liverpool during 1991-92 and attending mainstream schools, and 210 term controls. METHODS: Visual acuity was assessed by Snellen chart, and strabismus by the cover test. Stereopsis was determined using the TNO random dot test, and contrast sensitivity using the Cambridge low contrast gratings. Visual and motor abilities were assessed using the Developmental test of motor integration (VMI) and the Movement ABC. Intelligence was measured with the Wechsler intelligence scale for children UK. Perinatal cranial ultrasound and retinopathy data were extracted from clinical records. RESULTS: Children born preterm were significantly more likely to wear glasses, to have poor visual acuity, reduced stereopsis, and strabismus than term controls, but they showed no significant decrease in contrast sensitivity. Ophthalmic impairments were significantly related to poorer scores on the VMI, Movement ABC, and Wechsler IQ tests, but were not significantly related to neonatal cranial ultrasound appearances. Stage 3 retinopathy was related to poorer subsequent acuity. CONCLUSIONS: Children born very preterm and without major neurodevelopmental sequelae have an increased prevalence of ophthalmic impairments at primary school age which are associated with visual perceptional, motor, and cognitive defects. The cause may be a generalised abnormality of cortical development rather than perinatally acquired focal lesions of the brain.

Health, lifestyle, and quality of life for young adults born very preterm.

BACKGROUND: Children born very preterm and able to attend mainstream schools have been shown to have a high prevalence of behavioural, minor motor, and learning difficulties. It is not clear whether these problems persist into adulthood, impacting on lifestyle and quality of life. METHODS: A previously studied cohort of very low birth weight infants born between 1980 and 1983, together with term classmate controls, were assessed at age 19-22 years using a postal questionnaire. The questionnaire included the SF-36 to assess quality of life, a social activities scale, a lifestyle questionnaire, the Hospital Anxiety and Depression Scale, and questions on current height, weight, health, family structure, and education and occupation. RESULTS: Of the 138 preterm and 163 term controls in the cohort, 79 preterm and 71 term returned questionnaires. Quality of life was assessed as similar on six of eight domains of the SF-36. Social activities were also similar. Preterms drank less alcohol, used fewer illicit drugs, but smoked as often. Rates for sexual intercourse were similar, although preterms had more children. Preterms were shorter than controls and were less satisfied with their appearance. They were more likely to use a regular prescription medicine. Fewer were or had been in higher education, and some remained unemployed. CONCLUSION: The problems experienced by very preterm infants at school appear to influence lifestyle and health, but not perceived quality of life in early adulthood.

Growth impairment in the very preterm and cognitive and motor performance at 7 years.

BACKGROUND: Infants born of low birth weight often have poor subsequent growth (especially if they were born very preterm), which has been shown to relate to later motor and cognitive development. AIMS: To assess a cohort of preterm infants at the age of 7 years for growth, motor, and cognitive measures, and investigate the effects of growth impairment on school performance. METHODS: A cohort of 280 children born before 32 completed weeks of gestation were tested, together with 210 term controls. RESULTS: Preterm children were significantly lighter and shorter than term controls and had smaller heads and lower body mass index (BMI). Median centiles for weight, height, head circumference, and BMI were 25, 25, 9, and 50 for boys and 50, 25, 9, and 50 for girls compared with 50, 50, 50, and 75 for controls. They performed significantly less well on all tests with a mean score of 91 (9.2) on the Developmental Test of Visual-Motor Integration, 89 (14.5) on the Wechsler-III IQ test, and 30.7% scoring at or below the 5th centile on the Movement Assessment Battery for Children. In boys, short stature and small heads were the best predictors of poor performance; in girls, a small head alone was a predictor for poor motor and cognitive performance. CONCLUSION: Poor postnatal growth in preterm infants, especially of the head, is associated with increased levels of motor and cognitive impairment at 7 years of age. This growth restriction appears to occur largely in the postnatal rather than antenatal period and may be amenable to intervention and subsequent improvement in outcome.

Motor, cognitive, and behavioural disorders in children born very preterm.

Children born preterm have been shown to exhibit poor motor function and behaviour that is associated with school failure in the presence of average intelligence. A geographically determined cohort of two-hundred and eighty preterm children (151 males, 129 females) born before 32 weeks' gestation and attending mainstream schools were examined at 7 to 8 years of age together with 210 (112 males, 98 females) age- and sex-matched control participants were tested for motor, cognitive, and behavioural problems. Tests applied were the Movement Assessment Battery for Children (MABC), Clinical Observations of Motor and Postural Skills (COMPS), Developmental Test of Visual-Motor Integration (VMI), Wechsler Intelligence Scale for Children, and Connors' Teacher Rating Scale for attention-deficit-hyperactivity disorder (ADHD). Control children scored significantly better than the preterm group on all motor, cognitive, and behavioural measures. The lowest birthweight and most preterm individuals tended to score the lowest. Motor impairment was diagnosed in 86 (30.7%) of the preterm group and 14 (6.7%) of the control children using the MABC; 97 (42.7%) and 18 (10.2%) using the COMPS; and 68 (24.3%) and 17 (8.1%) respectively using the VMI. Each test of motor function identified different children with disability, although 23 preterm children were identified as having motor disability by all three tests. Preterm children were more likely to have signs of inattention and impulsivity and have a diagnosis of ADHD. Minor motor disabilities persist in survivors of preterm birth despite improvements in care and are not confined to the smallest or most preterm infants. They may exist independently of cognitive and behavioural deficits, although they often co-exist. The condition is heterogeneous and may require more than one test to identify all children with potential learning problems.

Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn.

OBJECTIVES: To assess the effectiveness of high dose intravenous immunoglobulin (HDIVIG) in reducing the need for exchange transfusion in neonates with proven haemolytic disease due to Rh and/or ABO incompatibility. To assess the effectiveness of HDIVIG in reducing the duration of phototherapy and hospital stay. DESIGN: Systematic review of randomised and quasi-randomised controlled trials comparing HDIVIG and phototherapy with phototherapy alone in neonates with Rh and/or ABO incompatibility. RESULTS: Significantly fewer infants required exchange transfusion in the HDIVIG group (relative risk (RR) 0.28 (95% confidence interval (CI) 0.17 to 0.47); number needed to treat 2.7 (95% CI 2.0 to 3.8)). Also hospital stay and duration of phototherapy were significantly reduced. CONCLUSION: HDIVIG is an effective treatment.

Quantitative magnetic resonance imaging of the brain in survivors of very low birth weight.

BACKGROUND: Children who survive very low birth weight (VLBW) without major disability have a high prevalence of learning difficulty, attention deficit, and dyspraxia. AIMS: To determine whether learning difficulty in children with VLBW is associated with structural brain abnormalities. METHODS: A total of 87 children (aged 15-16 years) with a history of VLBW (<1500 g) and eight age matched full term controls have been studied with detailed magnetic resonance brain scans. Volume measurements of the caudate nuclei and hippocampal formations were made. RESULTS: Scans in 42.5% of the children showed evidence of perinatal brain injury. There was no significant difference in IQ, dyspraxia, or attention deficit between children with qualitatively normal and abnormal scans. However, quantitative volumetric analysis showed that children with a low IQ had smaller volume measurements for the right caudate nucleus and left hippocampus, and a smaller hippocampal ratio (left volume:right volume) than those with normal IQ. CONCLUSION: Data suggest that learning disorder, attention deficit, and dyspraxia in children who survive VLBW do not correlate with conventional markers of perinatal brain injury, and may be related to global brain growth and the development of key structures, such as the caudate nuclei and hippocampal formations.

Dependency level of babies on the neonatal unit: a comparison of two different classification systems.

BACKGROUND: Monitoring activity on the neonatal unit is important for planning service provision and as part of monitoring quality of care. The dependency level of the patients cared for must be taken into account as well as the number of patients. Two different systems for determining dependency level are in common use. AIM: To develop a system that would allow the accurate determination of dependency level for babies in our care using both the British Association for Perinatal Medicine and Neonatal Nurses Association definitions and the Northern Neonatal Network definitions and to perform a comparison between these two systems. METHOD: Forty details relating to current clinical status and treatment being given were recorded daily for every patient on two neonatal units over a 17 month period. These details were recorded in a computer database, and dependency levels were calculated for each patient day using both systems. RESULTS: A total of 21 905 patient days were recorded for 1555 patients. There was good agreement between the two systems on what constituted the highest level of dependency, but overall comparability was poor, with the two systems assigning comparable dependency levels to only 76% of patient days. CONCLUSIONS: There is limited comparability in dependency levels between these two widely used systems. There is a need for a standardisation of definitions to allow meaningful comparisons to be made between units.

Neurodevelopmental outcome in meningococcal disease: a case-control study.

AIMS: To determine long term neurodevelopmental outcome following the spectrum of meningococcal infection. METHODS: Between 1988 and 1990, 152 cases of meningococcal disease were recruited; 139 survived. Between 1998 and 1999, 115 survivors (83%) were evaluated, together with 115 sex and age matched controls. Standard measures of neurological function, coordination, cognition, behaviour, and hearing were used to assess neurodevelopmental status. RESULTS: One case has spastic quadriplegia. Gross neurological examination was normal in all other cases and all controls. Five cases and no controls have significant hearing loss. Cases performed at a lower level than controls on measures of coordination, cognition, and behaviour. Four cases and no controls had major impairments. The adjusted odds ratios for moderate and minor impairments were 3.6 (95% CI 1.3 to 10.3) and 1.6 (95% CI 0.8 to 3.4) respectively. CONCLUSION: The majority of survivors from this cohort do not have gross neurological deficits. However, when objective measures of motor function, cognitive ability, and behaviour were applied significant detriments were found in meningococcal survivors.

Improved survival and neurodevelopmental outcome after prolonged ventilation in preterm neonates who have received antenatal steroids and surfactant.

AIMS: To assess survival and neurodevelopmental outcome following prolonged ventilation beyond 27 or 49 days of postnatal life in neonates treated with antenatal steroids and surfactant. METHODS: The medical records of 84 babies born in 1994-1996 requiring ventilation after 27 postnatal days at Liverpool Women's Hospital were reviewed to determine the duration of mechanical ventilation, survival, and neurodevelopmental outcome at 3 years of age. RESULTS: Fifty six babies were mechanically ventilated after 27 postnatal days but for less than 50 days; 48 (86%) survived to 3 years. Twenty six (54%) of the survivors had normal neurodevelopment at 3 years and seven (15%) had only mild disability. Twenty eight babies were ventilated after 49 postnatal days; 14 survived to 3 years. Five of these survivors were neurodevelopmentally normal at 3 years and two had mild disability. CONCLUSIONS: Survival decreases with more prolonged ventilation. When antenatal steroids and postnatal surfactant are used, there appears to be improved survival and neurodevelopmental outcome in preterm babies who require prolonged ventilation.

Cranial magnetic resonance imaging and school performance in very low birth weight infants in adolescence.

AIM: To determine whether neurological deficits are associated with structural anomalies of the brain in very low birthweight (VLBW) infants with subsequent learning disorders but without cerebral palsy, or whether other factors, such as poor early growth, are responsible. METHODS: Eighty seven VLBW infants and eight term controls who had been examined at school between the ages of 12 and 13 years, had cranial magnetic resonance imaging (MRI) scans at 15-17 years of age. RESULTS: Thirty seven (42.5%) of the VLBW children had abnormalities reported on their scans (two porencephaly, 28 periventricular leucomalacia, 24 ventricular dilatation, and 15 thinning of the corpus callosum). No significant differences in intelligence quotient, motor clumsiness, or frequency of attention deficit / hyperactivity disorder were observed between those children with MRI lesions and those with normal scans. Quantitative measurements showed the VLBW infants had smaller brains, and a relatively smaller corpus callosum compared with controls. No association between brain measurements and school performance was observed among the VLBW infants. CONCLUSIONS: The difficulties experienced by VLBW children at school are unlikely to be the result of perinatal brain injury, but they might to be attributable to the effects of poor postnatal growth.

Trends in incidence of cranial ultrasound lesions and cerebral palsy in very low birthweight infants 1982-93.

AIM: To evaluate the effects of changing perinatal practice on outcome in terms of cranial ultrasound appearances and subsequent cerebral palsy rates in survivors. METHODS: A tertiary neonatal centre based prospective cohort study was undertaken of very low birthweight infants, in three 4 year periods: 1982-5, 1986-9, 1990-3. Rates of survival, parenchymal cerebral haemorrhage (PH), and leucomalacia on cerebral ultrasound scans, and cerebral palsy (CP) at the age of 3 years were compared. Antenatal steroid prophylaxis and postnatal surfactant use were also compared. RESULTS: VLBW infants (1722) were admitted over the 12 years, of whom 1268 (73.6%) were discharged home. Neonatal survival increased significantly over the three periods (69.2%, 72.9%, 79.7%; p < 0.0001). PH declined from 14.9% to 10.5% (p = 0.032) after 1990 as did CP rate (10.9% to 7.3%; p = 0.046). The use of antenatal steroids and postnatal surfactant greatly increased during this period. Steroid use was significantly associated with increased survival (OR 3.34, 2.31-4.79), decreased PH (OR 0.44, 0.28-0.71), and decreased risk of CP in survivors (OR 0.47, 0.27-0.81) after standardising for gestation, birthweight, sex, place and mode of delivery. Similar effects for surfactant did not remain significant after steroid use had been accounted for. CONCLUSION: Improved survival in VLBW infants since 1990 has been accompanied by a fall in PH and subsequent CP rates in survivors. This change is most likely to be due to the greater use of antenatal steroid prophylaxis.

Cognitive and educational outcome of very-low-birthweight children in early adolescence.

A cohort of 138 very-low-birthweight (VLBW) 12-year-old children and matched control children were assessed on objective cognitive and educational measures. School performance was rated by teachers and by the children themselves. VLBW children were shown to have lower IQ scores, and poorer scores on all objective educational measures compared with control children. Controlling for IQ differences, mathematics and reading-comprehension scores remained significantly lower for VLBW children. Teachers rated VLBW children lower in all curriculum areas. Significantly more VLBW children were found to be 'failing' in one or more subject and an increased proportion compared with the control children had received remedial education. The VLBW group showed no evidence of 'catch up' between 6 and 12 years of age. Multiple regression analyses were used to identify predictors of cognitive and educational outcome. The duration of mechanical ventilation in the neonatal period was inversely related to outcome. Full-Scale IQ at 6 years, motor-skills score at 6 years, and head circumference at 12 years all predicted outcome at 12 years, as did maternal education, family income and size. Individually, many VLBW children perform satisfactorily, but as a group VLBW children appear to be at a long-term disadvantage to peers in the areas of cognitive and educational performance.