This study tracking outcomes of extremely preterm births in a large geographically defined population showed improved survival in 2006 compared with 1995 and several markers of improved clinical practice. Despite this, the pattern of major short term morbidities and the associations between early clinical items and adverse outcomes were similar.
EPICure 2 represents the first opportunity to report the changes over time for perinatal and neonatal outcomes of a whole country’s extremely preterm births. Planning support for survivors of preterm birth requires an understanding of their needs through childhood and adolescence into adult life. The survivors from the first EPICure study, who were born in 1995, form the largest reported population based cohort of extremely preterm survivors; their follow-up has documented a range of problems associated with preterm birth with lifelong implications.5
EPICure 2 provides not only more recent information but also the opportunity to study any changes in the pattern of morbidity in survivors so that we can better understand whether the longer term outcomes of the 1995 EPICure cohort are valid for babies born more recently.
We decided to limit the study to England for practical reasons in anticipation of around 3500 births and 1650 admissions; in 1995 there had been no differences in major morbidities between England and the other UK countries and Ireland. We included births at a gestational age of 26 weeks in 2006 because of lack of population based data for those babies and because such babies are routinely offered intensive care, thus providing a useful comparator group. We found no stepwise differences in outcome between 25 and 26 weeks, rather a continuum of morbidity-free survival across the gestation range.
The rates of preterm birth in the UK, while lower than in the US, seem to be higher than in other European countries.3
The significant increase in admissions before 26 weeks’ gestation between the two cohorts needs to be better understood. In the East Midlands Region of the UK, there was no increase in extremely preterm admissions over the same time period,11
suggesting that there might be geographical variation. The change in the ethnicity profile between the two cohorts is difficult to interpret and takes no account of new waves of immigration over this period, which covers the incorporation of Eastern European countries in to the European Union with associated economic migration into the UK; details of the country of birth of the mother were not collected.
Overall survival in 2006 has increased since 1995, although not significantly for births before 24 weeks’ gestation. This change results from improved survival to the end of the first week, with little difference thereafter. There is evidence of increased adherence to evidence based practice in 2006, which could account for improved condition of babies shortly after birth and explain improved outcomes in the first week. The prevalence of major morbidities in survivors, however, seems not to have improved either when evaluated alone or after adjustment for status within 24 hours of birth.
The apparent absence of improved survival in 2006 after the first week is clinically important. Increased survival in the first week could result in a population entering the second week at higher risk of complications because of the survival of babies who would previously have died. This is supported by increased reporting of sepsis confirmed by blood culture and necrotising enterocolitis as the primary cause of death in those surviving the first week. Set against this, the lack of improvement in somatic or head growth over the admission to neonatal intensive care and the high rates of nosocomial infection reported in 2006 emphasise the urgency of developing safe and effective strategies to improve early growth and prevent late infective complications if further improvement in outcome is to be achieved. In this context three aspects of care after admission are noteworthy.
Firstly, from around 2003 the historical dispersed pattern of provision of neonatal intensive care in England was reorganised into networks with designated tertiary neonatal intensive care units and improved access to dedicated postnatal transfer services.24
Despite encouragement of antenatal maternal transfer, 42% of live births at less than 26 weeks’ gestation in 2006 took place outside the tertiary centres, and the proportion of babies transferred within 24 hours of birth for intensive care had increased significantly since 1995 (table 3). Perhaps because of better trained and equipped transport teams, however, babies transferred in 2006 did not show the adverse outcomes associated with transfer seen in 1995 (table 5).
Secondly, in 2006 the use of postnatal steroid in survivors declined from 71% to 21% and median length of treatment declined from 21 to 12 days. In the 1995 cohort this was associated in a dose dependent manner with severe motor impairment at 30 months.25
Furthermore, it is likely that the median starting dose (0.2 mg/kg/day) is lower and the overall exposure to steroid greatly reduced.
Thirdly, the use of any maternal breast milk in survivors, associated in 1995 with improved psychomotor developmental index at 30 months,22
increased in 2006 for those born before 26 weeks from 86% to 96%. In 2006, 43% of all surviving babies were receiving breast milk at discharge.
The emerging picture would seem to favour improved outcomes and yet the pattern of major neonatal morbidities (fig 2) is strikingly similar to that in 1995. The observed increase in treated retinopathy of prematurity might represent a change of practice, with improved access to retinal screening and ophthalmologists recommending treatment at earlier stages of disease. Likewise the observed increase in the number of babies being discharged while still receiving supplementary oxygen, which is associated with earlier discharge from hospital, is likely to represent improved access to community nursing support. Neither explanation can be confirmed. Some of the variation in the strength of associations apparent in the analyses is probably because of the increased size of the 2006 cohort. A small change in reporting in 2006 to distinguish antepartum haemorrhage from placental abruption could explain the differential effect in the two cohorts, and different clinical indications for treatment of retinopathy could account for the altered association with CRIB I score. The most striking outcome of these analyses, however, is the consistency between the two cohorts and the lack of evidence, after adjustment for the condition of the baby shortly after birth, of improved survival or changed proportion of survivors with either bronchopulmonary dysplasia or severe abnormality on cerebral ultrasonography.
Clinical condition around the time of preterm birth is increasingly understood to be a critical determinant of later outcome.26
The consistency of the predictive models for short term outcomes across the two EPICure cohorts suggests that early predictors of outcomes in the 1995 cohort25
will remain predictive of longer term outcomes in the 2006 cohort.
In the context of other population based studies, direct international comparisons are complicated by a lack of standardised data collection. In a review including population based reports of live births before 26 weeks’ gestation between 1995 and 2000,2
survival for the 1995 EPICure cohort seemed to be the lowest, with the highest being from the northern part of Sweden. This was attributed to a positive approach on the part of both obstetricians and neonatologists with centralisation of specialist services and high rates of caesarean section and provision of neonatal intensive care.29
Subsequently the EXPRESS study reported outcomes for 1011 births between 22 and 26 weeks’ gestation from the whole of Sweden for 2004-07, with high survival at 12 months of age (70% of live births overall, 53% born at 23 weeks, and 85% born at 26 weeks).30
We derived a definition of survival without major morbidity for the EPICure 2006 cohort (table 2) that is close to that used in the EXPRESS study. Three of the babies who survived to discharge, all of whom had major morbidity, died before their first birthday. Despite such big differences in survival between the two studies, the proportions of survivors without major morbidity at one year in the EPICure 2 (41%, 95% confidence interval 38% to 44%) and EXPRESS cohorts (45%, 41% to 50%) are similar.
Strengths of this study
The main strengths of this study are the size of the cohort, representing a complete national cohort and recruited with high ascertainment, and the quality of the data. All the babies were born over a short time span, and our findings are relevant to current practice. We received high cooperation from clinical staff and are confident that ascertainment is virtually 100%. As in the first study, all outlying and ambiguous data were checked with contributors and further checked and corrected if necessary at analysis. All data were double entered to check validity, in contrast with the first study in which only 10% of data were double entered.
We constrained our definitions of variables to match those of the original study, and it was therefore possible to track changes over time in clinical outcomes for this important vulnerable population. Additionally, in 2006 enhanced data were collected for all births, including stillbirths, so that outcomes could reliably be expressed with relevant denominators including total and live births and that further analyses could be undertaken to understand determinants of condition at birth.
Limitations of the study
In 2006 it was not possible to collect these data electronically because of patchy access to suitable computer facilities in maternity and neonatal units, and yet all data items would be expected to be available in the clinical record. The data collection imposed a huge volume of additional work for clinical staff and the checking of missing and ambiguous data is time consuming and causes delay in closing of databases and analysis. Since 2006, standardised electronic data have been collected in English neonatal units, and this is now almost universal with developing systems for the centralisation of data for audit and research purposes.31
In future, electronic data captured for routine clinical purposes should be of sufficient quality to provide the basis for such studies, making them easier, less expensive, and with results more readily available.
Gestational age is the most important predictor of survival for the preterm baby and is favoured over birth weight as the principal criterion for defining preterm cohorts. Nonetheless, the determination of gestation remains imprecise. Best practice for the estimate of gestation has changed over time; consequently a different algorithm was used for each cohort. This produced only minor differences in survival and major morbidities, so for this reason and for ease of comparison with other contemporary cohorts, we have presented outcomes for the 2006 cohort with the contemporary algorithm.
Recent changes in neonatal practice
It is important to consider whether changes since 2006 might have affected our findings. We are not aware of any reliable data supporting further centralisation of delivery of babies born before 27 weeks’ gestation in England or further improvement in the condition of babies at birth. Interest continues in minimising overexpansion of the lungs at birth and exposure to unnecessarily high concentrations of oxygen.32
Randomised trials have confirmed that the early application of nasal continuous positive airway pressure (CPAP) to babies who establish breathing spontaneously33
and, more recently, the use of nebulised surfactant replacement35
can reduce the number of babies who require endotracheal intubation. The role of probiotics to prevent sepsis, necrotising enterocolitis, and death remains controversial.36
Few babies born between 22 and 26 weeks’ gestation are included in the published trials of any of these interventions, and longer term outcomes have not been reported. Other factors that might in time feed through to better outcomes include collaborative quality improvement initiatives,37
which through the introduction of standardised “care bundles,” have been shown to be effective in reducing catheter related sepsis in newborn infants.38
Given the lack of change in the pattern of morbidity in surviving extremely preterm babies between 1995 and 2006, a period when evidence based practice was increasing, it seems unlikely that it has changed since 2006.
Our findings support the validity of using longer term outcome data from the 1995 EPICure cohort when considering the prognosis for contemporary babies. Though the pattern of major short term morbidities and the associations of early clinical items with adverse outcomes were similar, there has been a 44% increase in the numbers of extremely immature babies being admitted to our neonatal intensive care units. Increased admissions, increased survival, and unchanged rates of major adverse outcomes suggest that the while the total number of children surviving extremely preterm birth free from impairments will rise, so will the number with long term health problems. This represents an important increase in workload for health, educational, and social services.
What is already known on this topic
- Mortality and morbidity are high after extremely preterm birth
- Children who survive preterm birth experience a range of problems requiring additional help from health, educational, and social services and with lifelong implications
What this study adds
- Between 1995 and 2006, the number of admissions to neonatal intensive care units of babies born between 22 and 25 weeks’ gestation increased by 44%
- Survival of babies born between 22 and 25 weeks’ gestation has increased, but the proportion of survivors with major neonatal morbidity is unchanged
- These changes suggest that the total number of children in the community with lifelong health problems attributable to extremely preterm birth will rise