Widespread divergence between incipient Anopheles gambiae species revealed by whole genome sequences.

The Afrotropical mosquito Anopheles gambiae sensu stricto, a major vector of malaria, is currently undergoing speciation into the M and S molecular forms. These forms have diverged in larval ecology and reproductive behavior through unknown genetic mechanisms, despite considerable levels of hybridization. Previous genome-wide scans using gene-based microarrays uncovered divergence between M and S that was largely confined to gene-poor pericentromeric regions, prompting a speciation-with-ongoing-gene-flow model that implicated only about 3% of the genome near centromeres in the speciation process. Here, based on the complete M and S genome sequences, we report widespread and heterogeneous genomic divergence inconsistent with appreciable levels of interform gene flow, suggesting a more advanced speciation process and greater challenges to identify genes critical to initiating that process.

High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial.

OBJECTIVE: To compare two dosing regimens for caffeine citrate in the periextubation period for neonates born at less than 30 weeks gestation in terms of successful extubation and adverse effects. DESIGN: A multicentre, randomised, double blind, clinical trial. SETTING: Four tertiary neonatal units within Australia. PATIENTS: Infants born less than 30 weeks gestation ventilated for more than 48 hours. INTERVENTIONS: Two dosing regimens of caffeine citrate (20 v 5 mg/kg/day) for periextubation management. Treatment started 24 hours before a planned extubation or within six hours of an unplanned extubation. MAIN OUTCOME MEASURE: Failure to extubate within 48 hours of caffeine loading or reintubation and ventilation or doxapram within seven days of caffeine loading. RESULTS: A total of 234 neonates were enrolled. A significant reduction in failure to extubate was shown for the 20 mg/kg/day dosing group (15.0% v 29.8%; relative risk 0.51; 95% confidence interval (CI) 0.31 to 0.85; number needed to treat 7 (95% CI 4 to 24)). A significant difference in duration of mechanical ventilation was shown for infants of less than 28 weeks gestation receiving the high dose of caffeine (mean (SD) days 14.4 (11.1) v 22.1 (17.1); p = 0.01). No difference in adverse effects was detected in terms of mortality, major neonatal morbidity, death, or severe disability or general quotient at 12 months. CONCLUSIONS: This trial shows short term benefits for a 20 mg/kg/day dosing regimen of caffeine citrate for neonates born at less than 30 weeks gestation in the periextubation period, without evidence of harm in the first year of life.

Psychoeducational outcome at school age of preterm infants with bronchopulmonary dysplasia.

OBJECTIVE: To investigate the cognitive performance and educational attainment at school-age of children with bronchopulmonary dysplasia (BPD), compared with a preterm control group of children. METHODS: Seventy preterm infants with BPD and 61 birth weight matched controls were prospectively followed-up to school-age. The Weschler Intelligence Scale for Children - III (WISC), the Wide Range Achievement Test (WRAT) and the Developmental Test of Visual Motor Integration (VMI) were administered. The results were compared between the two groups and multiple regression analyses were performed to determine the effect of confounding variables. RESULTS: The children in the BPD group performed less well on the Full Scale IQ (mean 86.7 vs 93.5; 95% CI, 1.9-11.7), Verbal IQ (mean 87.1 vs 94.1; 95% CI, 2.0-12.0) and the Performance IQ (mean 88.6 vs 95.2; 95% CI, 2.0-11.2) of the WISC, the reading component of the WRAT (mean 93.8 vs 98.9; 95% CI, 0.3-9.8) and the VMI (mean 88.9 vs 93.3; 95%, CI 1.1-7.8). Despite controlling for social and biological variables, statistical differences persisted for Full Scale and Verbal IQ and reading. A Verbal IQ >1 SD below the mean was found in 41% of BPD children compared to 21% of controls, while on the reading component of the WRAT a greater proportion of BPD children also had scores>1 SD below the mean. CONCLUSION: Impaired psychoeducational performance was found in preterm children with BPD compared to controls, especially in the areas of language abilities and reading skills. This supports a greater need for special educational services and counseling for parents for these children.

Conductive hearing loss in preterm infants with bronchopulmonary dysplasia.

OBJECTIVE: To determine the risk of conductive hearing loss in preterm infants with bronchopulmonary dysplasia (BPD) and preterm controls. METHODOLOGY: The study population consisted of 78 infants with BPD of 26-33 weeks gestation and 78 controls of similar gestational age matched for broad-based birthweight categories. An auditory brainstem response (ABR) audiology was performed shortly before hospital discharge. Visual reinforcement orientation audiometry (VROA) and impedance audiometry were performed at 8-12 months corrected for prematurity. Infants with persistent audiological abnormalities were referred for evaluation to paediatric ENT surgeons. RESULTS: Infants with BPD had a significantly higher rate of ABR abnormalities (BPD: 22%, controls: 9%; P = 0.028). On VROA and impedance audiometry, the infants with BPD also had a higher rate of persistent abnormalities. Following ENT assessment, 22.1% of infants with BPD and 7.7% of controls had persistent conductive dysfunction requiring myringotomy and grommet tube insertion (P = 0.03). Most of these infants had normal ABR audiometry at hospital discharge. CONCLUSIONS: Preterm infants with BPD are at high risk of persistent conductive hearing loss late in the first year of life compared to controls. An ABR audiology conducted at the time of hospital discharge does not predict accurately later conductive hearing problems. Infants with BPD should have routine audiological evaluation toward the end of the first year of life.

A parent-completed developmental questionnaire: follow up of ex-premature infants.

OBJECTIVE: Premature infants are at increased risk of developmental disability. Early identification of problems allows intervention to ameliorate or attenuate problems. A reliable screening tool allows triage of children in this high-risk population by identifying those unlikely to need full developmental assessment. To explore the test characteristics of an established parent-completed developmental assessment questionnaire 'Ages and Stages Questionnaire' (ASQ) in follow up of an Australian population of premature infants. METHODOLOGY: One hundred and sixty-seven children born prematurely with corrected ages 12- to 48-months attending the Growth and Development Clinic at the Mater Children's Hospital in Brisbane, Queensland, Australia; 136 questionnaires 'ASQ' were returned completed (81%) and were compared to formal psychometric assessment (Griffith Mental Development Scales for 12- and 24-months, Bayley Mental Development Intelligence Scale for 18-months, McCarthy General Cognitive Intelligence Scale for 48-months). Developmental delay was considered to be present if any of the above psychometric assessments fell below 1.0 standard deviations (SD). The ASQ cut-off used was 2.0 SD (US data derived means and SD). RESULTS: Aggregate results for all age groups comparing ASQ to psychometric assessments as 'gold standards' found the ASQ to have the following test characteristics: sensitivity (90%); specificity (77%); positive predictive value (40%); negative predictive value (98%); % over-referred (20%); % under-referred (1%); % agreement (79%). Likelihood ratio for children failing the ASQ was 3.8 and for passing the ASQ was 0.13. Twenty-one children with known disabilities were included in the study and in 14 of these, the ASQ overall score agreed with the psychometric assessment (67%). CONCLUSION: The high negative predictive value of the ASQ supports its use as a screening tool for cognitive and motor delays in the follow up of ex-premature infants. This would need to be combined with other strategies as part of a comprehensive follow up program for ex-premature infants.

Gender differences in cognitive abilities at 2 years in ELBW infants. Extremely low birth weight.

Gender differences in cognitive abilities exist for children born at term. For very preterm infants uncertainty exists regarding the presence and extent of such differences and their relationship to perinatal brain injury and neurological impairment. This study examined gender differences in cognitive abilities in a cohort of 336 extremely low birth weight (ELBW) infants at 2 years corrected age. Infants were classified as at low or high perinatal risk at birth according to four perinatal risk factors. A subgroup of 33 neurologically impaired infants was identified. Outcome at 2 years was measured by the overall General Quotient (GQ) on the Griffiths scale and its five subscale scores. Female ELBW children were superior to male ELBW children by 4.1 GQ points (95% CI 1.0, 7.1). If the impaired subgroup was excluded, the difference in GQ was 3.2 points (95% CI 0.4, 5.6), and this difference was predominantly due to female infants being superior in the hearing and speech subscale (6.0 points, 95% CI 2.6, 9.5). These differences were relatively independent of perinatal risk status. Gender differences in the Griffiths GQ for ELBW infants are similar to expected differences for term infants and are unlikely to cause substantial bias in interpreting outcome studies for ELBW infants, unless these involve tests of specific cognitive abilities such as language.

Long term outcome of twin-twin transfusion syndrome.

AIMS: To compare the perinatal mortality and morbidity of infants with twin-twin transfusion syndrome (TTTS) with those of gestation matched twin controls and to assess the neurodevelopmental outcome of surviving twins with TTTS. METHODS: A cohort of 17 consecutive pregnancies with TTTS was enrolled over three years together with gestation matched twin pregnancies unaffected by TTTS. Serial amnioreduction for the TTTS pregnancies was performed as appropriate. Perinatal death and neonatal morbidities were recorded for both the TTTS cohort and controls. The TTTS survivors had neurodevelopmental follow up to at least 2 years of age. RESULTS: In 12 of the pregnancies, serial amniocenteses were performed, but, in five, the infants were born before intervention. The mean gestational age at delivery was 29.1 weeks (range 23-36). There were five intrauterine deaths in the TTTS cohort and six neonatal deaths (survival 68%). In the control group, there was one intrauterine death and five neonatal deaths (survival 82%). Infants in the TTTS group had a greater requirement for inotropes (p = 0.04) and a higher incidence of renal failure (p = 0.005). Periventricular leucomalacia and cerebral atrophy were seen in 17% of the TTTS group, but none of the controls (p = 0.03). The 23 surviving TTTS infants were all followed up, with 22% having significant neurological morbidity: cerebral palsy and global developmental delay. CONCLUSIONS: Twins with TTTS have high perinatal mortality and neonatal morbidity, and long term neurodevelopmental morbidity in survivors is high. Further investigation into the pathogenesis and management of TTTS is required.

The genome sequence of Drosophila melanogaster.

The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes approximately 13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.

Head circumference in ELBW babies is associated with learning difficulties and cognition but not ADHD in the school-aged child.

This study examines whether a small head circumference (HC) and low head-circumference growth velocity (HGV) during the first year of life predict consequences at school age in learning, cognition, and concentration. A total of 124 extremely-low-birthweight (ELBW) infants (birthweight 500 to 999 g) born between 1977 and 1986 were eligible for follow-up at the corrected ages of 4, 8, and 12 months and 2, 4, and 6 years. Infants were categorized as having a small HC (< 3% or 3 to 10%) on the basis of the 1990 British growth data which allowed standardized z-scores to be calculated for HC, independent of gestation and corrected age. HGV measurements were calculated using differences in the HC z-scores. In 1995, parents of 87 children agreed to participate in a study of learning and attention at school age. Attention-deficit-hyperactivity disorder (ADHD) was assessed using the Du Paul Rating Scale. Academic performances were based on a teacher questionnaire dealing with aspects of reading, writing, mathematics, and spelling. A child was considered to have a learning difficulty if academic problems were present in at least one of these four areas. Intellectual ability was assessed using the McCarthy Scale at 6 years. HC < 3% and 3 to 10% at 8 months' corrected age was strongly associated with school-aged learning problems (P=0.004), with a moderate specificity (70%), positive predictive value (PPV) (67%), and sensitivity (67%). HGV < or = 10% from birth to 4 months was also associated with learning problems at school age (P=0.01) with a higher specificity (98%) and PPV (88%) but lower sensitivity (20%). A logistic regression analysis was performed with the risk for learning difficulties at 8 months as the dependent variable. Sex, gestation, birthweight, multiple births, and a history of intraventricular hemorrhage did not substantially alter the unadjusted odds ratio (4.7; 95% CI 1.9 to 13.6). Maternal age and education did not confound the relation. No association was found between HC or HGV and ADHD. HC < 3% at 4 months (P<0.02), 8 months (P=0.02), and 12 months (P=0.04), and HGV between birth and 4 months (P<0.01) were significantly associated with low cognitive ability at 6 years.

The influence of growth on development outcome in extremely low birthweight infants at 2 years of age.

OBJECTIVE: To determine if weight < 3rd and < 10th centile at 2 years in extremely low birthweight (ELBW) infants is associated with problems of development and motor skills, and whether this association is explained by perinatal risk status. METHODOLOGY: One hundred and ninety-eight of 226 (88%) surviving ELBW infants born between January 1987 and December 1992 were assessed at 2 years corrected age. Children were classified as being at low perinatal risk (n = 128) or high perinatal risk (n = 70) for adverse developmental outcome based on perinatal risk factors. Weight at 2 years was classified as < 3rd, 3rd-9th or > or = 10th centile for age and gender. Development was assessed using the Griffiths Mental Developmental Scales and motor skills using the Neurosensory Motor Developmental Assessment (NSMDA). RESULTS: For the total study group weight centile was strongly related to General Quotient (GQ) and motor abilities. For children < 3rd percentile (n = 48) mean (GQ) was 90.4 (SD, 15.9), for children between the 3rd-9th percentile (n = 49) 91.5 (SD, 17.9), and for children > or = 10th percentile (n = 99) mean GQ was 99.8 (SD, 8.6). The association with mean GQ and NSMDA category occurred for the high-risk subgroup and became non-significant in the low-risk subgroup if neurologically abnormal children were excluded. Other perinatal risk factors, exposure to breast milk, level of maternal education, marital status and history of feeding problems or infections over the 2 years did not confound this association. CONCLUSION: Low weight percentile at 2 years was related to adverse developmental outcome in ELBW infants at high perinatal risk or with neurological impairment, though minimal association was present for neurologically normal infants at low perinatal risk.

Solid-phase sequence scanning for drug resistance detection in tuberculosis.

DNA chip arrays hold considerable promise for diagnostic sequencing of polymerase chain reaction (PCR) products. To date, however, arrays have been relatively expensive, complex to use and difficult to interpret, preventing their adaptation to the clinical lab. A moderate density array method has been developed that enables efficient, easy-to-interpret and robust solid-phase PCR product sequencing. Here, the results of Mycobacterium tuberculosis rifampin resistance mutation detection by primer-extension-based sequence scanning of the rpo B gene of M. tuberculosis are presented. Rifampin resistant clinical isolates were identified in as little as 1 h post PCR amplification with visual results detection.

Immobilization of oligonucleotides onto a glass support via disulfide bonds: A method for preparation of DNA microarrays.

The covalent attachment of disulfide-modified oligonucleotides to a mercaptosilane-modified glass surface is described. This method provides an efficient and specific covalent attachment chemistry for immobilization of DNA probes onto a solid support. Glass slides were derivatized with 3-mercaptopropyl silane for attachment of 5-prime disulfide-modified oligonucleotides via disulfide bonds. An attachment density of approximately 3 x 10(5) oligonucleotides/microm2 was observed. Oligonucleotides attached by this method provided a highly efficient substrate for nucleic acid hybridization and primer extension assays. In addition, we have demonstrated patterning of multiple DNA probes on a glass surface utilizing this attachment chemistry, which allows for array densities of at least 20,000 spots/cm2.

Mortality and neurodevelopmental outcome for infants receiving adrenaline in neonatal resuscitation.

OBJECTIVE: To document the outcome, in terms of mortality and morbidity, for all infants requiring adrenaline as part of initial neonatal resuscitation, and to identify the differences between term and preterm infants. METHODS: All infants in a five-year period who received adrenaline during delivery room resuscitation were retrospectively identified. Data from the perinatal period were ascertained by chart review. Details of survivors at 1 year or later were reviewed. RESULTS: Seventy-eight infants were identified representing 0.2% of all deliveries. Over half of all infants survived, with the proportion increasing with advancing gestational age from 30% below 29 weeks to 67% at term. Seventy-three per cent of survivors were normal at follow-up to at least 1 year, with more preterm infants being normal than term infants (79% vs. 64%). Over half of survivors below 29 weeks' gestation were normal, but overall 78% of this group either died or showed evidence of neurodevelopmental disability. Asystolic infants did not differ from the bradycardic infants in terms of survival or rates of disability. Adrenaline may be contraindicated in asystolic very preterm infants. CONCLUSIONS: Adrenaline retains a role in term and mature preterm infants where there is an acute cause for depression at delivery. In very preterm infants its use is associated with a high rate of death and disability. Failure to stabilise with adequate ventilatory support should be seen as a poor prognostic sign in this group.

Survival and neonatal and neurodevelopmental outcome of 24-29 week gestation infants according to primary cause of preterm delivery.

A total of 189 infants of 24-29 weeks' gestation were born in a regional perinatal centre during a 2-year period. They were divided into groups according to the primary cause of preterm delivery: antepartum haemorrhage (n = 37, 20%), preeclampsia (n = 27), 14%), preterm premature rupture of membranes (n = 64, 34%), preterm labour (n = 27, 14%), chorioamnionitis (n = 16, 8%), other complications (n = 18, 10%). The perinatal mortality rate (PMR) was 286/1,000 of whom 44% were stillbirths. The 'other complication' group had the highest PMR due to a large number of intrauterine deaths, with no differences in neonatal mortality between the groups. Preeclampsia was associated with an increased risk of necrotizing enterocolitis and chorioamnionitis was associated with an increased risk of periventricular haemorrhage. Follow-up to at least 2 years was performed in 122 (97%) of survivors. Cerebral palsy occurred in 7%, while 18% had neurodevelopmental disability. No relationship was found between primary cause of preterm delivery and outcome. This information should be of value in counselling parents when preterm delivery is imminent.

Enamel hypoplasia and dental caries in very-low birthweight children: a case-controlled, longitudinal study.

This longitudinal study investigated the sequelae of enamel defects in a group of 25 white, very-low birthweight (VLBW), preterm children (mean birthweight 969 +/- 218 g, mean gestational age 27 +/- 1.9 weeks). Twenty-five race-, age-, and sex-matched, full-term normal birthweight (NBW) control children born at the same hospital, were selected randomly from hospital records. The children were examined at approximate ages of 30, 44, and 52 months. At all examinations, VLBW children had significantly higher prevalence of enamel hypoplasia than did the NBW children. At the last recall examination, 96% of VLBW group, and 45% of the NBW group had at least one tooth with enamel defect, with a mean of 7.6 +/- 4.9 affected teeth per VLBW child, and only 1.0 +/- 1.3 affected teeth per control child (P < 0.001). A significant association of enamel defects with dental caries was observed only in the VLBW group on the second and third examinations (P < 0.001). The defect identified to be most significantly associated with dental caries was a variant showing both enamel hypoplasia and opacity. In spite of a high prevalence of enamel defects, the overall prevalence of dental caries in the VLBW children was not significantly different from that of NBW controls at all three examinations (P < 0.1). Other caries risk factors such as levels of Streptococcus mutans infection, fluoride supplementation, plaque scores, toothbrushing frequency, and daily sugar exposures were examined but none was found to be related significantly to development of dental caries.

Nested genetic bit analysis (N-GBA) for mutation detection in the p53 tumor suppressor gene.

There is a growing and significant demand for reliable, simple and sensitive methods for repeated scanning of a given gene or gene fragment for detection and characterization of mutations. Solid-phase sequencing by single base primer extension of nested GBATM primers on miniaturized DNA arrays can be used to effectively scan targeted sequences for missense, insertion and deletion mutations. This paper describes the use of N-GBA arrays designed to scan the sequence of a 33 base region of exon 8 of the p53 gene (codons 272-282) encompassing a hot spot for mutations associated with the development of cancer. Synthetic DNA templates containing various missense, insertion and deletion mutations, as well as DNA prepared from pancreatic and biliary tumor cells, were genotyped using the exon 8 arrays.

School performance of ELBW children: a controlled study.

This paper examines the prevalence of learning difficulty in reading, spelling, mathematics and writing and the prevalence of attention deficit disorder (ADD) in extremely low-birthweight (ELBW) children at school compared to their peers. Parents of 87 eligible ELBW children completed an educational questionnaire and questionnaire for ADD. Teachers of the ELBW children completed a detailed educational and ADD questionnaire for the study child and two control children in the same class, matched for age and nearest in birth date to the study child. Parents reported that 4% of the ELBW children born between 1977 and 1986 were in a special education unit, 46% received remedial help and 21% repeated a grade. Teacher assessment of six aspects of reading and spelling and five aspects of mathematics and writing skills indicated that the ELBW children experienced marked problems in all areas compared to control children and were approximately 3 times more likely to be delayed by more than a year in all areas. Prevalence of ADD was not increased in the ELBW children compared to the control group, though males in both groups had a higher prevalence of symptoms. Early intervention and special education resources must be available for ELBW children attending school.

Prevalence and aetiology of neurological impairment in extremely low birthweight infants.

OBJECTIVE: To determine the prevalence and perinatal predictors of cerebral palsy, intellectual impairment, visual impairment and deafness in a cohort of extremely low birthweight (ELBW) infants at two years of age. METHODOLOGY: The study population comprised 199 of the 224 (89%) ELBW infants managed at the Mater's Mothers Hospital, Brisbane, between July 1977 and February 1990 and who survived to two years. The prevalence of cerebral palsy, intellectual impairment, blindness and deafness was measured by clinical,psychometric and audiological assessment and the association with 24 risk factors examined. RESULTS: Cerebral palsy occurred in 20 children (10%). Risk of cerebral palsy was associated with ventricular dilatation, intraventricular haemorrhage, necrotizing enterocolitis and multiple birth, though only ventricular dilatation (OR 4.41; 95% CI 1.32-14.8) remained significant in the adjusted analysis. Intellectual impairment occurred in 20 children (10%) and was independently associated with ventricular dilatation (OR 15.0; 95% CI 2.2-102.8), ventilation F(i)(2) > 80% (OR 3.4; 95% CI 1.01-11.5), vaginal delivery (OR 3.5; 95% Cl 1.09-11.4) and male sex (OR 6.1; 95% Cl 1.67-22.3). No perinatal predictor was statistically associated with risk of deafness. Retinopathy of prematurity (OR 36.9; 95% Cl 2.8-495.5) was associated with risk of later visual impairment. CONCLUSIONS: Intellectual impairment was associated with a broad range of perinatal variables. Cerebral palsy was associated with fewer variables, all of which were also associated with intellectual impairment. Neurologic injury was associated with male sex and multiple birth, which are not biological insults themselves, but may be markers of susceptibility to injury.

Changing patterns of survival and outcome at 4 years of children who weighted 500-999 g at birth.

OBJECTIVE: To evaluate the impact of changing perinatal practices on survival rates and 4 year neurodevelopmental outcome for infants of birthweight 500-999 g. METHODOLOGY: The study was a tertiary hospital-based prospective cohort study that compared survival, impairment and handicap rates between two eras, July 1977 to December 1982 (era 1) and January 1983 to June 1988 (era 2). All 348 live, inborn infants and 49 outborn infants of birthweight 500-999 g were prospectively enrolled in a study of survival and outcome. Rates of survival, neurodevelopmental impairment and functional handicap at 4 years were compared between eras. Perinatal risk factors for handicap were also compared between eras. RESULTS: Four year survival rates for inborn infants 500-999 g improved from 32.6% in era 1 to 49.2% in era 2 (OR 2.1, 95% CI 1.26-3.48) but for outborn infants the improvement between 31.8% and 53.6% was not significant. There were significant improvements in survival for inborn infants in birthweights 800-899 g and 900-999 g between study periods. The rates of functional handicap between the first and second eras (mild 10 vs 7%; severe or multiply severe 14 vs 16%) were not significantly different. Although the rate of cerebral palsy increased from 0 to 12% (P < 0.01) other rates of impairment such as blindness 0 vs 3%, deafness 2 vs 2% and developmental delay 12 vs 11% did not change. The chance of a survivor being free of handicap remained unchanged at 78% and 76% for the two eras, respectively. Although the absolute number of intact survivors more than doubled (41 vs 83) so too did the number of severe or multiply severe handicapped survivors (7 vs 17). Multivariate logistic regression analysis for the entire study cohort revealed male gender, multiple birth, prolonged mechanical ventilation and cerebral ventricular dilatation but not birthweight or gestational age to be independently associated with severe or multiply severe handicap. CONCLUSIONS: The advances in neonatal intensive care for extremely low birthweight infants between July 1977 and December 1982 and January 1983-June 1988 resulted in an increased number of non-disabled survivors but had no impact on incidence of severe disability. The application of prediction of mortality or severe handicap to clinical practice has the potential to reduce the proportion and absolute number of severely handicapped survivors.