Economic costs associated with moderate and late preterm birth: a prospective population-based study.

OBJECTIVE: We sought to determine the economic costs associated with moderate and late preterm birth. DESIGN: An economic study was nested within a prospective cohort study. SAMPLE: Infants born between 32(+0) and 36(+6)  weeks of gestation in the East Midlands of England. A sample of infants born at ≥37 weeks of gestation acted as controls. METHODS: Data on resource use, estimated from a National Health Service (NHS) and personal social services perspective, and separately from a societal perspective, were collected between birth and 24 months corrected age (or death), and valued in pounds sterling, at 2010-11 prices. Descriptive statistics and multivariable analyses were used to estimate the relationship between gestational age at birth and economic costs. MAIN OUTCOME MEASURES: Cumulative resource use and economic costs over the first two years of life. RESULTS: Of all eligible births, 1146 (83%) preterm and 1258 (79%) term infants were recruited. Mean (standard error) total societal costs from birth to 24 months were £12 037 (£1114) and £5823 (£1232) for children born moderately preterm (32(+0) -33(+6)  weeks of gestation) and late preterm (34(+0) -36(+6)  weeks of gestation), respectively, compared with £2056 (£132) for children born at term. The mean societal cost difference between moderate and late preterm and term infants was £4657 (bootstrap 95% confidence interval, 95% CI £2513-6803; P < 0.001). Multivariable regressions revealed that, after controlling for clinical and sociodemographic characteristics, moderate and late preterm birth increased societal costs by £7583 (£874) and £1963 (£337), respectively, compared with birth at full term. CONCLUSIONS: Moderate and late preterm birth is associated with significantly increased economic costs over the first 2 years of life. Our economic estimates can be used to inform budgetary and service planning by clinical decision-makers, and economic evaluations of interventions aimed at preventing moderate and late preterm birth or alleviating its adverse consequences. TWEETABLE ABSTRACT: Moderate and late preterm birth is associated with increased economic costs over the first 2 years of life.

Experiences with maternal and perinatal death reviews in the UK--the MBRRACE-UK programme.

Established in 1952, the programme of surveillance and Confidential Enquiries into Maternal Deaths in the UK is the longest running such programme worldwide. Although more recently instituted, surveillance and confidential enquiries into perinatal deaths are also now well established nationally. Recent changes to funding and commissioning of the Enquiries have enabled both a reinvigoration of the processes and improvements to the methodology with an increased frequency of future reporting. Close engagement with stakeholders and a regulator requirement for doctors to participate have both supported the impetus for involvement of all professionals leading to greater potential for improved quality of care for women and babies.

Assessment of liquid captopril formulations used in children.

OBJECTIVE: Unlicensed liquid captopril formulations are commonly used to treat children with heart disease. This study assessed the bioequivalence of two liquid preparations against a licensed tablet form. DESIGN: An open label, single dose, three-treatment, three-period, crossover trial. SETTING: Outpatient. PATIENTS: Healthy adult volunteers (n=18). INTERVENTIONS: Each subject was randomly assigned to one of six dosing sequences, and dosed with 25 mg captopril on each of three dosing visits separated by a washout of at least 14 days. Blood samples for pharmacokinetic analysis were taken at regular intervals (0 min to 10 h) post-dose. MAIN OUTCOME MEASURES: Bioequivalence of the formulations would be concluded if the 90% CI for the estimated ratio of the means of C(max) (maximum plasma concentrations) and area under curve(AUC) (extent of absorption) lay entirely within the range 0.8 to 1.25 RESULTS: Both liquid formulations failed the bioequivalence assessment with respect to C(max) and AUC. The 90% CI of the mean ratios of liquid/licensed tablet for both C(max) and AUC, fell outside the 0.8 to 1.25 limits. There was also considerable within-subject variability in C(max) (97.5%) and AUC (78.5%). CONCLUSIONS: Unlicensed captopril formulations are not bioequivalent to the licensed tablet form, or to each other, and so cannot be assumed to behave similarly in therapeutic use. Thus formulation substitution must be done with care and may require a period of increased monitoring of the patient. There is also significant within-subject variability in performance which has clinical implications with respect to titrating to an optimum therapeutic dose.

Neonatal intensive care outcomes and resource utilisation of infants born <26 weeks in the former Trent region: 2001-2003 compared with 1991-1993.

OBJECTIVES: To provide survival data and rates of severe disability at 2 years of corrected age in infants born prior to 26 weeks' gestation in 2001-2003 and to compare these outcomes with an earlier cohort from 1991 to 1993. DESIGN: Population-based prospective cohort study. SETTING: Former Trent region of UK covering a population of approximately five million and around 55 000 births per annum. PARTICIPANTS: The authors identified a 3-year cohort of infants born before 26 weeks' gestation between 1 January 2001 and 31 December 2003 from The Neonatal Survey (TNS). Questionnaires based on the Oxford minimum dataset were completed. MAIN OUTCOME MEASURES: Survival, service use and disability levels were compared between the 2001- 2003 cohort and the cohort from 1991 to 1993. RESULTS: In 2001-2003, 0%, 18% and 35% of live born babies were alive at 2 years without any evidence of severe disability at 23, 24 and 25 weeks' gestation, respectively. Overall, of those children admitted to neonatal care, the proportion with no evidence of severe disability at 2 years corrected age improved from 14.5% in 1991-1993 to 26.5% in 2001-2003. There was an increase in the proportion of children with at least one severe disability, out of total admissions to neonatal unit (8% vs 17%) and of those assessed at 2 years (35% vs 39%). CONCLUSIONS: This study has shown an improvement in survival to discharge in babies admitted for neonatal care. However, this improved survival has been associated with an increase in the proportion of children with at least one severe disability at a corrected age of 2 years.

Estimates of length of neonatal stay for very premature babies in the UK.

OBJECTIVE: To describe simple estimates of likely duration of stay for very premature babies born in the UK and discharged home. DESIGN: Statistical modelling of data from thirty neonatal units in a geographically defined region of the UK. PARTICIPANTS: All babies born at 23 to 32 completed weeks of gestation in 2005, 2006 and 2007 who were discharged home with the expectation that they would survive. MAIN OUTCOME MEASURE: Total duration of stay in the neonatal service. RESULTS: 5528 babies were initially identified. 558 (10.1%) who died or who did not follow a normal care pathway were excluded. In a further 27, data were either missing or inadequate, leaving a study population of 4702 babies. As expected, gestation and birthweight exhibited strong influence on length of stay. Of the other variables tested, initial reason for admission (need for early respiratory support) showed the most consistent association. These factors were combined to produce predictive tables. The predictive performance of the tables was found to fit the data well for various groups, with the exception of multiple births who tended to have longer stays. However, when tested against individual units, much greater variation was seen independent of unit size and case mix. CONCLUSION: The prediction tables should permit parents to make sensible estimates about the duration of their baby's stay in the neonatal service; however, there appear to be important differences between units. The variation noted in length of stay between otherwise similar units merits further investigation.

Predicting neonatal mortality among very preterm infants: a comparison of three versions of the CRIB score.

OBJECTIVE: To validate Clinical Risk Index for Babies (CRIB) and CRIB II mortality prediction scores in a UK population of infants born at

Nursing workload in UK tertiary neonatal units.

BACKGROUND: Neonatal intensive care requires adequate numbers of trained neonatal nurses to provide safe, effective care, but existing research into the relationship between nurse numbers and the care needs of babies is over 10 years old. Since then, the preterm population and treatment practices have changed considerably. AIMS: To validate the dependency categories of the British Association of Perinatal Medicine (BAPM, 2001) and to revalidate the Northern Region categories (NR, 1993) in relation to contemporary nursing workload. SETTING: Three tertiary neonatal intensive care services in England. METHODS: Nursing activity around each baby was captured every 10 min by direct observations by trained observers. Time spent on each nursing activity was related to the baby's dependency category and the nurse's grade. RESULTS: Both scales detected differences between categories. Discrimination between individual categories was improved when nasal continuous positive airway pressure (nCPAP) was distinguished from ventilation and combined with BAPM2/NRA. On this revised four-point scale, babies in BAPM1/NRA occupied nursing time for a median of 56 min per hour (IQR 48-70), those on nCPAP or in BAPM2/NRB for 36 min, (27-42), those in BAPM3/NRC for 20-22 min (15-33) and those in BAPM4/NRD for 31-32 min (24-36). The NR scale was easier to apply and had greater interobserver agreement (98.5%) than the BAPM scale (93%). All categories attracted more time compared to 1993. CONCLUSIONS: Both scales predict average nursing workload. A revised categorisation which separates nCPAP from ventilation is more robust and practical. Nursing time attracted in all categories has increased since 1993.

Antenatal umbilical Doppler abnormalities: an independent risk factor for early onset neonatal necrotizing enterocolitis in premature infants.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) emergency seen in neonatal units. Many factors have been considered as potentially important aetiologically, including gut ischaemia, sepsis and feeding. However, evidence remains equivocal. OBJECTIVE: This study investigated whether preterm babies born to mothers with abnormal antenatal umbilical Dopplers (absent or reversed end diastolic flow--AREDF), that is exposed to antenatal gut ischaemia, are at an identical risk of developing NEC early in life, compared to babies born to mothers with normal Dopplers. METHODS: All preterm (

Geographically based investigation of the influence of very-preterm births on routine mortality statistics from the UK and Australia.

BACKGROUND: Comparisons of national perinatal and neonatal mortality often neglect the underlying causes. OBJECTIVE: To assess effects of very-preterm births in the UK and Australia. SETTING: Two geographically defined populations: the former Trent Health Region of the UK and New South Wales (NSW)/the Australian Capital Territory (ACT), Australia. METHOD: All births 22(+0) to 31(+6) weeks in 2000, 2001 and 2002 were identified by established surveys of perinatal care. Rates of birth and death were compared. RESULTS: The population of NSW/ACT was 35% higher and there were 66% more births than in Trent (273 495 vs 164 824). The proportion of liveborn infants between 22 and 31 weeks gestation was about 25% higher in Trent (NSW/ACT 2945, rate per 1000 live births 10.82 (95% CI 10.43 to 11.22); Trent 2208, rate per 1000 live births 13.47 (95% CI 12.92 to 14.05)). The proportion of these infants admitted to a neonatal unit was also higher in Trent (91.2% vs 94.4%; OR 1.63 (95% CI 1.30 to 2.05)). Unadjusted mortality in infants admitted to a neonatal unit was similar: NSW/ACT 332/2686 (12.4%); Trent 284/2085 (13.6%); unadjusted OR 1.12 (95% CI 0.94 to 1.33; p = 0.21). CONCLUSIONS: The higher rates of very premature birth and more ready admission to neonatal intensive care for infants in the UK may help to explain why perinatal and neonatal mortality are higher there than in Australia. Efforts to understand why the rate of premature birth in the UK is so high should be a national priority.

Referral pattern of neonates with severe respiratory failure for extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) remains the mainstay of management in neonates with severe but potentially reversible respiratory failure. In the UK, ECMO is available only as a supraregional service at four centres. OBJECTIVE: To explore regional variations in ECMO referrals and neonatal deaths due to severe respiratory failure in England, Wales and Northern Ireland. METHODS: In this retrospective study, data regarding ECMO referrals due to neonatal respiratory failure from January to December 2002 were obtained from the four UK ECMO centres and then subdivided according to the Government Office Regions. Anonymised data regarding neonatal deaths was obtained from Confidential Enquiry into Maternal and Child Health. Neonatal deaths were classified into four groups (group 1: deaths potentially avoidable by ECMO; group 2: deaths where it was unclear whether ECMO would have been of benefit; group 3: neonates not eligible for ECMO; and group 4: data inadequate to classify deaths). RESULTS: There was significant regional variation in the rates of both ECMO referral (0.10 to 0.46 per 1000 live births; (p<0.001)) and neonatal deaths (groups 1 and 2) (0.09 to 0.32 per 1000 live births; (p<0.001)). Regions with high referral rates for ECMO tended towards having higher group 1 plus group 2 neonatal death rates (correlation coefficient = 0.75). CONCLUSION: It is possible that there are significant regional variations in the uptake of ECMO and in neonatal mortality due to severe respiratory failure. A confidential prospective study may further clarify these observations and identify the factors that might lead to these variations.

Ethnic variations in the incidence and outcome of severe retinopathy of prematurity.

BACKGROUND: The aim of this study was to assess the incidence and outcome of severe retinopathy of prematurity (ROP) among different ethnic groups in a geographically defined population in the U.K. Severe ROP was defined as any stage 3 or worse disease. METHODS: This was a retrospective study of children born over a 6-year period with a birth weight of 1250 g or less. Threshold ROP was treated with diode laser. RESULTS: Severe disease developed in 37 out of 355 neonates (10.4%) who underwent ROP screening. The difference in the incidence of severe ROP between infants of Caucasian and South Asian ethnic origin was not statistically significant: 10.2% vs. 10.8% (odds ratio = 1.06; 95% confidence interval: 0.44 to 2.57). This conclusion held after single-variable adjustment for birth weight, gestational age, and score on the Clinical Risk Index for Babies. The incidence of threshold ROP was 3% among infants of both Caucasian and South Asian ethnic origin. There was no significant difference in terms of visual outcome between the Caucasian and South Asian infants. INTERPRETATION: This study showed no statistical evidence for a difference in the incidence or outcome of severe ROP among infants of South Asian ethnic origin compared with those of Caucasian origin. Although the small numbers in our study mean that a clinically important difference cannot be excluded, it is very unlikely that the 5-fold higher incidence in Asian babies described in the literature is correct for the population from which our subjects were drawn.

Respiratory outcome in late childhood after neonatal continuous negative pressure ventilation.

BACKGROUND: The outcome in late childhood for children entered into a randomised trial of continuous negative extrathoracic pressure (CNEP) versus standard respiratory management for the treatment of neonatal respiratory distress was studied. In the original trial, there were advantages in the duration of oxygen and the prevalence of chronic lung disease for those assigned to receive CNEP. AIM: To determine whether the above differences had persisted into childhood. METHODS: Outpatient evaluation of children by a paediatrician using Spirometry (Vitalograph Spirometer 2120, Ennis, Ireland) and MicroRint (Micro Medical, Rochester, Kent, UK) techniques independently of the original trial. Parents completed questionnaires about their child's respiratory history and social-demographic information. RESULTS: 133 (65%) survivors were evaluated at 9.6-14.9 years of age. The group examined were representative of the original cohort and no significant baseline differences were observed between children evaluated who had been allocated to CNEP or standard treatments. We compared Rint (before and after bronchodilator) and forced expiratory flow, volume and vital capacity between the two study groups; none were significant. Children in the standard group had received paediatric intensive care more often (p = 0.19) and were more likely to be receiving inhaled drugs for asthma (p = 0.19; all not significant). CONCLUSIONS: No important differences were found at follow-up in late childhood in respiratory outcomes for children treated with neonatal CNEP or standard treatment. Caution should be exercised, as the original trial was not powered to show these differences, but there seems to be no long-term detriment in respiratory outcomes for children treated with CNEP in the neonatal period.

Socioeconomic inequalities in very preterm birth rates.

AIMS: To investigate the extent of socioeconomic inequalities in the incidence of very preterm birth over the past decade. METHODS: Ecological study of all 549 618 births in the former Trent health region, UK, from 1 January 1994 to 31 December 2003. All singleton births of 22(+0) to 32(+6) weeks gestation (7 185 births) were identified from population surveys of neonatal services and stillbirths. Poisson regression was used to calculate incidence of very preterm birth (22-32 weeks) and extremely preterm birth (22-28 weeks) by year of birth and decile of deprivation (child poverty section of the Index of Multiple Deprivation). RESULTS: Incidence of very preterm singleton birth rose from 11.9 per 1000 births in 1994 to 13.7 per 1000 births in 2003. Those from the most deprived decile were at nearly twice the risk of very preterm birth compared with those from the least deprived decile, with 16.4 per 1000 births in the most deprived decile compared with 8.5 per 1000 births in the least deprived decile (incidence rate ratio 1.94; 95% CI (1.73 to 2.17)). This deprivation gap remained unchanged throughout the 10-year period. The magnitude of socio-economic inequalities was the same for extremely preterm births (22-28 weeks incidence rate ratio 1.94; 95% CI (1.62 to 2.32)). CONCLUSIONS: This large, unique dataset of very preterm births shows wide socio-economic inequalities that persist over time. These findings are likely to have consequences on the burden of long-term morbidity. Our research can assist future healthcare planning, the monitoring of socio-economic inequalities and the targeting of interventions in order to reduce this persistent deprivation gap.

Neonatal disease severity scoring systems.

Illness severity scores have become widely used in neonatal intensive care. Primarily this has been to adjust the mortality observed in a particular hospital or population for the morbidity of their infants, and hence allow standardised comparisons to be performed. However, although risk correction has become relatively commonplace in relation to audit and research involving groups of infants, the use of such scores in giving prognostic information to parents, about their baby, has been much more limited. The strengths and weaknesses of the existing methods of disease severity correction in the newborn are presented in this review.

The potential impact on costs and staffing of introducing clinical networks and British Association of Perinatal Medicine standards to the delivery of neonatal care.

OBJECTIVE: To produce models to estimate the impact of introducing clinical networks and the 2001 BAPM standards to the delivery of neonatal care. DESIGN: Prospective observational study using a geographically defined population and data collected by questionnaire on staffing levels and cot availability. SETTING: Trent Health Region UK. SUBJECTS: All infants born to Trent resident mothers at or before 32 weeks gestation between 1 January 1998 and 31 December 1999. Staffing numbers and cot availability for neonatal care in 2001. METHODS: A modelling exercise was carried out using information for all neonatal admissions for Trent resident infants. Three models were investigated: (a). the current care provision; (b). a network where three lead centres provided the intensive care for the region and the remaining units provided either high dependency or special care alone; (c). a network where six lead centres provided the intensive care for the region and the remaining units provided either high dependency or special care alone. Overall costings, staffing levels, and cot requirements were calculated for each model. Data on staffing levels and cot availability were used to calculate current care provision costings. RESULTS: The current cost of running the service is approximately pound 33.35 million, although a proportion of nursing posts are currently unfilled. Estimates for the introduction of a three centre model meeting BAPM 2001 standards range from pound 37.31 to pound 43.40 million. Equivalent figures for the six centre model were: pound 36.32 to pound 42.62 million. Approximately 370 and 230 babies a year would be involved in transfer in the three and six centre models respectively. This is in contrast with 374 and 368 urgent transfers that actually took place in 1998 and 1999 respectively. CONCLUSION: The costs associated with the introduction of managed clinical networks and meeting BAPM standards of care are not excessive, especially when considered against the likely implementation timetable of perhaps 7-10 years. Attracting and retaining sufficient staff will pose the major challenge.

Experimental infection with BCG as a model of tuberculosis in the brushtail possum (Trichosurus vulpecula).

AIMS: To study the development and progression of lesions produced following experimental inoculations of possums with Bacille Calmette-Guérin (BCG) Pasteur Strain 1173P2 and to compare these with lesions that occurred following natural Mycobacterium bovis infection. METHODS: Possums were inoculated with 5 x 106 colony forming units (cfu) of BCG via the intra-dermal (I/D) route into the dorsum of the neck (n=38) or the left brachium (n=7),orally (n=10), via the endobronchial (E/B) route (n=12), or intravenously (I/V) (n=10, half of which received 5 x 106 cfu and half of which received 5 x 107 cfu of BCG). The possums were humanely killed between 1-4 weeks post inoculation (p.i.), and the nature and distribution of lesions examined grossly and histopathologically. RESULTS: The distribution of lesions following I/D inoculation via either route was similar to that of the natural disease, but there were few lesions in the lung. Endobronchial inoculation resulted in pulmonary disease but produced few lesions outside the respiratory tract. Lesions produced by I/V inoculation were similar in distribution to those seen in terminally ill tuberculous possums. No lesions were produced following oral inoculation. Regression of lesions commenced after 3 weeks p.i. CONCLUSIONS: Although the phenomenon of lesion resolution restricts the use of BCG to the study of early lesion development, it avoids the overwhelming disease induced using M. bovis and thus allows the early phases of the development and progression of tuberculosis in this species to be observed. Intradermal inoculation produced evidence that infection through the skin is associated with lesions in superficial lymph nodes, whereas pulmonary disease was associated with E/B inoculation. The results are consistent with the hypothesis that both percutaneous and respiratory routes are important in natural infection of possums with M. bovis.

Interventions in the management of serum lipids for preventing stroke recurrence.

BACKGROUND: A close association between serum lipid levels and the incidence of coronary heart disease (CHD) has been well proven in middle aged and older persons, up to the age of 70-75 years. Individual studies have shown interventions to reduce total and low density lipoprotein (LDL) cholesterol levels, especially with 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitors (statins), to be of benefit in reducing CHD and stroke events in those with a history of coronary heart disease. However, the relation of serum cholesterol and cholesterol sub-fractions with cerebrovascular disease is less clear. It is unclear whether lipid levels in the post-stroke period are a predictor of recurrence and whether treatment to alter levels can prevent recurrence of either stroke or cardiovascular events. OBJECTIVES: To investigate the effect of altering serum lipids in the prevention of cardiovascular disease and stroke recurrence in subjects with a history of stroke. SEARCH STRATEGY: The Cochrane Group Trials Register was searched up to 8 May 2001 along with MEDLINE (from 1966), EMBASE (from 1980) and the Cochrane Controlled Trials Register. All pharmaceutical firms known to produce a lipid lowering agent were also contacted and asked to provide information on publications or unpublished work relevant to this review. SELECTION CRITERIA: This review included unconfounded randomised trials of subjects aged 18 years and over with a history of stroke or Transient Ischaemic Attack (TIA). DATA COLLECTION AND ANALYSIS: The data were extracted independently by the three reviewers. MetaView 4.1 was used for all statistical analyses. MAIN RESULTS: Five studies involving 1700 patients were included in the review. The active intervention in two of the studies was Clofibrate, Pravastatin in another two and Conjugated Oestrogen in the fifth. Fixed effects analysis showed no evidence of a difference in stroke recurrence between the treatment and placebo groups for those with a previous history of stroke or TIA (odds ratio 0.96, 95% confidence interval 0.71 to 1.30). In addition there was also no evidence, based on two studies, that intervention reduced the odds of all cause mortality (odds ratio 0.87, 95% confidence interval 0.55 to 1.39) nor, from one study, that there was any effect on subsequent vascular events (odds ratio 1.27, 95% confidence interval 0.84 to 1.89). REVIEWER'S CONCLUSIONS: These trials do not provide evidence for a benefit, or harm, from interventions to alter serum lipid levels in patients with a history solely of cerebrovascular disease. Their use, therefore, cannot yet be recommended routinely in this patient group, but ischaemic stroke patients with a history of myocardial infarction should receive statin therapy along the lines of the previous recommendations for those patients with a history of myocardial ischaemia. There are currently three ongoing trials which will recruit approximately 30,000 patients, including those with a history of stroke, and the results of these trials may have a significant effect on these conclusions.

Measuring later health status of high risk infants: randomised comparison of two simple methods of data collection.

OBJECTIVE: To test two methods of providing low cost information on the later health status of survivors of neonatal intensive care. DESIGN: Cluster randomised comparison. SETTING: Nine hospitals distributed across two UK health regions. Each hospital was randomised to use one of two methods of follow up. PARTICIPANTS: All infants born