Methods for Constructing Normalised Reference Scores: An Application for Assessing Child Development at 24 Months of Age.

The use of the lambda-mu-sigma (LMS) method for estimating centiles and producing reference ranges has received much interest in clinical practice, especially for assessing growth in childhood. However, this method may not be directly applicable where measures are based on a score calculated from question response categories that is bounded within finite intervals, for example, in psychometrics. In such cases, the main assumption of normality of the conditional distribution of the transformed response measurement is violated due to the presence of ceiling (and floor) effects, leading to biased fitted centiles when derived using the common LMS method. This paper describes the methodology for constructing reference intervals when the response variable is bounded and explores different distribution families for the centile estimation, using a score derived from a parent-completed assessment of cognitive and language development in 24 month-old children. Results indicated that the z-scores, and thus the extracted centiles, improved when kurtosis was also modeled and that the ceiling effect was addressed with the use of the inflated binomial distribution. Therefore, the selection of the appropriate distribution when constructing centile curves is crucial.

Differentiating the Preterm Phenotype: Distinct Profiles of Cognitive and Behavioral Development Following Late and Moderately Preterm Birth.

OBJECTIVES: To explore patterns of comorbidity in cognitive and behavioral outcomes at 2 years' corrected age among children born late or moderately preterm (LMPT) and to identify predictors of different patterns of comorbidity. STUDY DESIGN: Geographical, prospective population-based cohort study of 1139 infants born LMPT (320/7 to 366/7 weeks' gestation) and 1255 infants born at term (370/7 to 426/7 weeks' gestation). Parent questionnaires were obtained to identify impaired cognitive and language development, behavioral problems, delayed social-emotional competence, autistic features, and clinically significant eating difficulties at 24 months corrected age for 638 (57%) children born LMPT and 765 (62%) children born at term. RESULTS: Latent class analysis revealed 2 profiles of development among the term group: optimal (84%) and a profile of social, emotional, and behavioral impairments termed "nonoptimal" (16%). These 2 profiles were also identified among the LMPT group (optimal: 67%; nonoptimal: 26%). In the LMPT group, a third profile was identified (7%) that was similar to the phenotype previously identified in infants born very preterm. Nonwhite ethnicity, socioeconomic risk, and not receiving breast milk at hospital discharge were risk factors for nonoptimal outcomes in both groups. Male sex, greater gestational age, and pre-eclampsia were only associated with the preterm phenotype. CONCLUSIONS: Among children born LMPT with parent-reported cognitive or behavioral impairments, most had problems similar to the profile of difficulties observed in children born at term. A smaller proportion of children born LMPT had impairments consistent with the "very preterm phenotype" which are likely to have arisen through a preterm pathway. These results suggest that prematurity may affect development through several etiologic pathways in the late and moderately preterm population.

Infants born late/moderately preterm are at increased risk for a positive autism screen at 2 years of age.

OBJECTIVES: To assess the prevalence of positive screens using the Modified Checklist for Autism in Toddlers (M-CHAT) questionnaire and follow-up interview in late and moderately preterm (LMPT; 32-36 weeks) infants and term-born controls. STUDY DESIGN: Population-based prospective cohort study of 1130 LMPT and 1255 term-born infants. Parents completed the M-CHAT questionnaire at 2-years corrected age. Parents of infants with positive questionnaire screens were followed up with a telephone interview to clarify failed items. The M-CHAT questionnaire was re-scored, and infants were classified as true or false positives. Neurosensory, cognitive, and behavioral outcomes were assessed using parent report. RESULTS: Parents of 634 (57%) LMPT and 761 (62%) term-born infants completed the M-CHAT questionnaire. LMPT infants had significantly higher risk of a positive questionnaire screen compared with controls (14.5% vs 9.2%; relative risk [RR] 1.58; 95% CI 1.18, 2.11). After follow-up, significantly more LMPT infants than controls had a true positive screen (2.4% vs 0.5%; RR 4.52; 1.51, 13.56). This remained significant after excluding infants with neurosensory impairments (2.0% vs 0.5%; RR 3.67; 1.19, 11.3). CONCLUSIONS: LMPT infants are at significantly increased risk for positive autistic screen. An M-CHAT follow-up interview is essential as screening for autism spectrum disorders is especially confounded in preterm populations. Infants with false positive screens are at risk for cognitive and behavioral problems.

Modelling time to death or discharge in neonatal care: an application of competing risks.

BACKGROUND: Understanding length of stay for babies in neonatal care is vital for planning services and for counselling parents. While previous work has focused on the length of stay of babies who survive to discharge, when investigating resource use within neonatal care, it is important to also incorporate information on those babies who die while in care. We present an analysis using competing risks methodology which allows the simultaneous modelling of babies who die in neonatal care and those who survive to discharge. METHODS: Data were obtained on 2723 babies born at 24-28 weeks gestational age in 2006-10 and admitted to neonatal care. Death and discharge alive are two mutually exclusive events and can be treated as competing risks. A flexible parametric modelling approach was used to analyse these two competing events and obtain estimates of the absolute probabilities of death or discharge. RESULTS: The absolute probabilities of death or discharge are presented in graphical form showing the cause-specific cumulative incidence over time by gender, gestational age and birthweight. The discharge of babies alive generally occurred over a longer time period for babies of lower gestational age and smaller birthweight than for bigger babies. CONCLUSION: This study has presented a useful statistical method for modelling the length of stay where there are significant rates of in-unit mortality. In health care systems that are increasingly focusing on costs and resource planning, it is essential to consider not only length of stay of survivors but also for those patients who die before discharge.

Estimated neonatal survival of very preterm births across the care pathway: a UK cohort 2016-2020.

OBJECTIVE: Currently used estimates of survival are nearly 10 years old and relate to only those babies admitted for neonatal care. Due to ongoing improvements in neonatal care, here we update estimates of survival for singleton and multiple births at 22+0 to 31+6 weeks gestational age across the perinatal care pathway by gestational age and birth weight. DESIGN: Retrospective analysis of routinely collected data. SETTING: A national cohort from the UK and British Crown Dependencies. PATIENTS: Babies born at 22+0 to 31+6 weeks gestational age from 1 January 2016 to 31 December 2020. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Survival to 28 days. RESULTS: Estimates of neonatal survival are provided for babies: (1) alive at the onset of care during the birthing process (n=43 763); (2) babies where survival-focused care was initiated (n=42 004); and (3) babies admitted for neonatal care (n=41 158). We have produced easy-to-use survival charts for singleton and multiple births. Generally, survival increased with increasing gestational age at birth and with increasing birth weight. For all births with a birthweight over 1000 g, survival was 90% or higher at all three stages of care. CONCLUSIONS: Survival estimates are a vital tool to support and supplement clinical judgement within perinatal care. These up-to-date, national estimates of survival to 28 days are provided based on three stages of the perinatal care pathway to support ongoing clinical care. These novel results are a key resource for policy and practice including counselling parents and informing care provision.

The probability of being identified as an outlier with commonly used funnel plot control limits for the standardised mortality ratio.

BACKGROUND: Emphasis is increasingly being placed on the monitoring of clinical outcomes for health care providers. Funnel plots have become an increasingly popular graphical methodology used to identify potential outliers. It is assumed that a provider only displaying expected random variation (i.e. 'in-control') will fall outside a control limit with a known probability. In reality, the discrete count nature of these data, and the differing methods, can lead to true probabilities quite different from the nominal value. This paper investigates the true probability of an 'in control' provider falling outside control limits for the Standardised Mortality Ratio (SMR). METHODS: The true probabilities of an 'in control' provider falling outside control limits for the SMR were calculated and compared for three commonly used limits: Wald confidence interval; 'exact' confidence interval; probability-based prediction interval. RESULTS: The probability of falling above the upper limit, or below the lower limit, often varied greatly from the nominal value. This was particularly apparent when there were a small number of expected events: for expected events ≤ 50 the median probability of an 'in-control' provider falling above the upper 95% limit was 0.0301 (Wald), 0.0121 ('exact'), 0.0201 (prediction). CONCLUSIONS: It is important to understand the properties and probability of being identified as an outlier by each of these different methods to aid the correct identification of poorly performing health care providers. The limits obtained using probability-based prediction limits have the most intuitive interpretation and their properties can be defined a priori. Funnel plot control limits for the SMR should not be based on confidence intervals.

Etiology of overactive bladder: a diet and lifestyle model for diabetes and obesity in older women.

OBJECTIVE: To evaluate a coherent, evidence-based hypothesis that specific modifiable lifestyle factors implicated in the development of diabetes and associated obesity are related to the onset of OAB. METHODS: A hypothetical causative model for OAB involving modifiable lifestyle factors implicated in the development of diabetes and obesity was constructed, based on a systematic literature review. Secondary analysis of data was undertaken in a prospective cohort of women aged 40 and over, living in Leicestershire, UK. Subjects included 3,411 women free from OAB at baseline and 277 incident cases of OAB. Reported diet, lifestyle, morbid, and social factors were measured at baseline and incident cases at 1-year follow-up. Graphical chain modeling was used to estimate the associations between variables and identify likely pathways involved. RESULTS: All hypothesized lifestyle factors (physical activity, high glycemic index, and high energy intake) plus diabetes and obesity were retained within the graph as potential contributors. However, low physical activity was the only direct risk factor linked prospectively to the onset of OAB (RR 2.47; 95% CI 1.82, 3.36), in addition to older age. CONCLUSIONS: Poor lifestyle factors causally linked to diabetes and obesity may contribute to the onset of OAB; low physical activity appears to be an important modifiable causal factor for OAB operating directly as well as indirectly via pathways involving obesity or diabetes. Further research is needed to demonstrate a causal link between lifestyle and OAB.

Understanding ethnic inequalities in stillbirth rates: a UK population-based cohort study.

OBJECTIVES: To investigate inequalities in stillbirth rates by ethnicity to facilitate development of initiatives to target those at highest risk. DESIGN: Population-based perinatal mortality surveillance linked to national birth and death registration (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK). SETTING: UK. PARTICIPANTS: 4 391 569 singleton births at ≥24+0 weeks gestation between 2014 and 2019. MAIN OUTCOME MEASURES: Stillbirth rate difference per 1000 total births by ethnicity. RESULTS: Adjusted absolute differences in stillbirth rates were higher for babies of black African (3.83, 95% CI 3.35 to 4.32), black Caribbean (3.60, 95% CI 2.65 to 4.55) and Pakistani (2.99, 95% CI 2.58 to 3.40) ethnicities compared with white ethnicities. Higher proportions of babies of Bangladeshi (42%), black African (39%), other black (39%) and black Caribbean (37%) ethnicities were from most deprived areas, which were associated with an additional risk of 1.50 stillbirths per 1000 births (95% CI 1.32 to 1.67). Exploring primary cause of death, higher stillbirth rates due to congenital anomalies were observed in babies of Pakistani, Bangladeshi and black African ethnicities (range 0.63-1.05 per 1000 births) and more placental causes in black ethnicities (range 1.97 to 2.24 per 1000 births). For the whole population, over 40% of stillbirths were of unknown cause; however, this was particularly high for babies of other Asian (60%), Bangladeshi (58%) and Indian (52%) ethnicities. CONCLUSIONS: Stillbirth rates declined in the UK, but substantial excess risk of stillbirth persists among babies of black and Asian ethnicities. The combined disadvantage for black, Pakistani and Bangladeshi ethnicities who are more likely to live in most deprived areas is associated with considerably higher rates. Key causes of death were congenital anomalies and placental causes. Improved strategies for investigation of stillbirth causes are needed to reduce unexplained deaths so that interventions can be targeted to reduce stillbirths.

EPICE cohort: two-year neurodevelopmental outcomes after very preterm birth.

OBJECTIVE: To determine whether the variation in neurodevelopmental disability rates between populations persists after adjustment for demographic, maternal and infant characteristics for an international very preterm (VPT) birth cohort using a standardised approach to neurodevelopmental assessment at 2 years of age. DESIGN: Prospective standardised cohort study. SETTING: 15 regions in 10 European countries. PATIENTS: VPT births: 22+0-31+6 weeks of gestation. DATA COLLECTION: Standardised data collection tools relating to pregnancy, birth and neonatal care and developmental outcomes at 2 years corrected age using a validated parent completed questionnaire. MAIN OUTCOME MEASURES: Crude and standardised prevalence ratios calculated to compare rates of moderate to severe neurodevelopmental impairment between regions grouped by country using fixed effects models. RESULTS: Parent reported rates of moderate or severe neurodevelopmental impairment for the cohort were: 17.3% (ranging 10.2%-26.1% between regions grouped by country) with crude standardised prevalence ratios ranging from 0.60 to 1.53. Adjustment for population, maternal and infant factors resulted in a small reduction in the overall variation (ranging from 0.65 to 1.30). CONCLUSION: There is wide variation in the rates of moderate to severe neurodevelopmental impairment for VPT cohorts across Europe, much of which persists following adjustment for known population, maternal and infant factors. Further work is needed to investigate whether other factors including quality of care and evidence-based practice have an effect on neurodevelopmental outcomes for these children.

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

BACKGROUND: Studies have shown that interventions which reduce total and low-density lipoprotein cholesterol levels also reduce coronary heart disease (CHD) and stroke events in those with a history of CHD. However, it is uncertain whether treatment to alter cholesterol levels can prevent recurrence of either stroke or subsequent cardiovascular events and whether differences in outcomes exist between classes of lipid-lowering therapy. This is an update of a Cochrane review first published in 2002. OBJECTIVES: To investigate the effect of altering serum lipids pharmacologically for preventing subsequent cardiovascular disease and stroke recurrence in patients with a history of stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched December 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2008), MEDLINE (1966 to December 2008) and EMBASE (1980 to December 2008). We contacted pharmaceutical companies known to produce a lipid-lowering agent for information on relevant publications or unpublished work. SELECTION CRITERIA: Unconfounded randomised trials of participants aged 18 years and over with a history of stroke or transient ischaemic attack (TIA). DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality and extracted data. MAIN RESULTS: We included eight studies involving approximately 10,000 participants. The active interventions were pravastatin, atorvastatin, simvastatin, clofibrate, and conjugated oestrogen. Fixed-effect analysis showed no overall effect on stroke recurrence but statin therapy alone had a marginal benefit in reducing subsequent cerebrovascular events in those with a previous history of stroke or TIA (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.77 to 1.00). There was no evidence that such intervention reduced all-cause mortality or sudden death (OR 1.00, 95% CI 0.83 to 1.20). Three statin trials showed a reduction in subsequent serious vascular events (OR 0.74, 95% CI 0.67 to 0.82). AUTHORS' CONCLUSIONS: There is evidence that statin therapy in patients with a history of ischaemic stroke or TIA significantly reduces subsequent major coronary events but only marginally reduces the risk of stroke recurrence. There is no clear evidence of beneficial effect from statins in those with previous haemorrhagic stroke and it is unclear whether statins should be started immediately post stroke or later. In view of this and the evidence of the benefit of statin therapy in those with a history of CHD, patients with ischaemic stroke or TIA, with or without a history of established CHD, should receive statins.

Standardisation of the Parent Report of Children's Abilities-Revised (PARCA-R): a norm-referenced assessment of cognitive and language development at age 2 years.

BACKGROUND: The Parent Report of Children's Abilities-Revised (PARCA-R) can be used to identify preterm born children at risk for developmental delay at age 24 months. However, standardised scores for assessing all children in the general population and quantifying development relative to the norm are unavailable, thus limiting the use of the questionnaire. We aimed to develop scores that are standardised by age and sex for the PARCA-R to assess children's cognitive and language development at age 24-27 months. METHODS: Anonymised data from PARCA-R questionnaires that were completed by parents of 2-year-old children in three previous studies were obtained to form a standardisation sample that was representative of the UK general population. Anonymised data were obtained from three further studies to assess the external validity and clinical validity of the standardised scores. We used the lambda-mu-sigma (lambda for skewness, mu for median, sigma for the coefficient of variation) method to develop scores that are standardised by age and sex for three scales (non-verbal cognitive development, language development, and total parent report composite [PRC]) for children in four 1-month age bands, spanning age 23·5-27·5 months. FINDINGS: We included 6402 children (mean age 25 months and 1 day [range 23 months and 16 days to 27 months and 15 days]) in the standardisation sample and 709 (mean age 24 months and 19 days [23 months and 16 days to 27 months and 15 days]) to test the external validity and 1456 (mean age 24 months and 8·5 days [23 months and 16 days to 27 months and 15 days]) to test the clinical validity of the standardised scores. For all PARCA-R scales, mean standardised scores approximated 100 (SD 15) in both sexes and all age groups. These scores were independent of socioeconomic status. Standardised scores were close to 100 (15) in the external validation sample, showing the validity of the scores. Standardised scores for the total PRC scale for children born very preterm (<32 weeks' gestation) were 0·47 SD lower on average than the normative mean, and for children with neonatal sepsis were 0·73 SD lower on average than the normative mean. These scores were equivalent to a standardised score of 93 (95% CI 91-94) for children born very preterm and 89 (88-91) for children with neonatal sepsis, thus showing clinical validity. INTERPRETATION: The PARCA-R provides a norm-referenced, standardised assessment of cognitive and language development at 24-27 months of age. The questionnaire is available non-commercially in English with translations available in 14 other languages, thus providing clinicians and researchers with a cost-effective tool for assessing development and identifying children with delay. FUNDING: Action Medical Research (Ref: GN2580).

Estimating neonatal length of stay for babies born very preterm.

OBJECTIVE: To predict length of stay in neonatal care for all admissions of very preterm singleton babies. SETTING: All neonatal units in England. PATIENTS: Singleton babies born at 24-31 weeks gestational age from 2011 to 2014. Data were extracted from the National Neonatal Research Database. METHODS: Competing risks methods were used to investigate the competing outcomes of death in neonatal care or discharge from the neonatal unit. The occurrence of one event prevents the other from occurring. This approach can be used to estimate the percentage of babies alive, or who have been discharged, over time. RESULTS: A total of 20 571 very preterm babies were included. In the competing risks model, gestational age was adjusted for as a time-varying covariate, allowing the difference between weeks of gestational age to vary over time. The predicted percentage of death or discharge from the neonatal unit were estimated and presented graphically by week of gestational age. From these percentages, estimates of length of stay are provided as the number of days following birth and corrected gestational age at discharge. CONCLUSIONS: These results can be used in the counselling of parents about length of stay and the risk of mortality.

Assessing the deprivation gap in stillbirths and neonatal deaths by cause of death: a national population-based study.

OBJECTIVE: To investigate socioeconomic inequalities in cause-specific stillbirth and neonatal mortality to identify key areas of focus for future intervention strategies to achieve government ambitions to reduce mortality rates. DESIGN: Retrospective cohort study. SETTING: England, Wales, Scotland and the UK Crown Dependencies. PARTICIPANTS: All singleton births between 1 January 2014 and 31 December 2015 at ≥24 weeks' gestation. MAIN OUTCOME MEASURE: Cause-specific stillbirth or neonatal death (0-27 days after birth) per 10 000 births by deprivation quintile. RESULTS: Data on 5694 stillbirths (38.1 per 10 000 total births) and 2368 neonatal deaths (15.9 per 10 000 live births) were obtained from Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK). Women from the most deprived areas were 1.68 (95% CI 1.56 to 1.81) times more likely to experience a stillbirth and 1.67 (95% CI 1.48 to 1.87) times more likely to experience a neonatal death than those from the least deprived areas, equating to an excess of 690 stillbirths and 231 neonatal deaths per year associated with deprivation. Small for gestational age (SGA) unexplained antepartum stillbirth was the greatest contributor to excess stillbirths accounting for 33% of the deprivation gap in stillbirths. Congenital anomalies accounted for the majority (59%) of the deprivation gap in neonatal deaths, followed by preterm birth not SGA (24-27 weeks, 27%). CONCLUSIONS: Cause-specific mortality rates at a national level allow identification of key areas of focus for future intervention strategies to reduce mortality. Despite a reduction in the deprivation gap for stillbirths and neonatal deaths, public health interventions should primarily focus on socioeconomic determinants of SGA stillbirth and congenital anomalies.

Wide variation in severe neonatal morbidity among very preterm infants in European regions.

OBJECTIVE: To investigate the variation in severe neonatal morbidity among very preterm (VPT) infants across European regions and whether morbidity rates are higher in regions with low compared with high mortality rates. DESIGN: Area-based cohort study of all births before 32 weeks of gestational age. SETTING: 16 regions in 11 European countries in 2011/2012. PATIENTS: Survivors to discharge from neonatal care (n=6422). MAIN OUTCOME MEASURES: Severe neonatal morbidity was defined as intraventricular haemorrhage grades III and IV, cystic periventricular leukomalacia, surgical necrotizing enterocolitis and retinopathy of prematurity grades ≥3. A secondary outcome included severe bronchopulmonary dysplasia (BPD), data available in 14 regions. Common definitions for neonatal morbidities were established before data abstraction from medical records. Regional severe neonatal morbidity rates were correlated with regional in-hospital mortality rates for live births after adjustment on maternal and neonatal characteristics. RESULTS: 10.6% of survivors had a severe neonatal morbidity without severe BPD (regional range 6.4%-23.5%) and 13.8% including severe BPD (regional range 10.0%-23.5%). Adjusted inhospital mortality was 13.7% (regional range 8.4%-18.8%). Differences between regions remained significant after consideration of maternal and neonatal characteristics (P<0.001) and severe neonatal morbidity rates were not correlated with mortality rates (P=0.50). CONCLUSION: Severe neonatal morbidity rates for VPT survivors varied widely across European regions and were independent of mortality rates.

Outcome after neonatal continuous negative-pressure ventilation: follow-up assessment.

BACKGROUND: A previous randomised trial of continuous negative extrathoracic pressure (CNEP) versus standard treatment for newborn infants with respiratory distress syndrome raised public concerns about mortality and neonatal morbidity. We studied the outcome in late childhood of children entered into the trial to establish whether there were long-term sequelae attributable to either mode of ventilation. METHODS: Outpatient assessment of neurological outcome, cognitive function, and disability was done by a paediatrician and a psychologist using standardised tests. 133 of 205 survivors from the original trial were assessed at 9-15 years of age. Of the original pairs randomly assigned to each ventilation mode, the results from 65 complete pairs were available. The primary outcome was death or severe disability. FINDINGS: Primary outcome was equally distributed between groups (odds ratio for the CNEP group 1.0; 95% CI 0.41-2.41). In unpaired analysis there was no significant difference between treatment modalities (1.05; 0.54-2.06). Full IQ did not differ significantly between the groups, but mean performance IQ was 6.8 points higher in the CNEP group than in the conventional-treatment group (95% CI 1.5-12.1). Results of neuropsychological testing were consistent with this finding, with scores on language production and visuospatial skills being significantly higher in the CNEP group. INTERPRETATION: We saw no evidence of poorer long-term outcome after neonatal CNEP whether analysis was by original pairing or by unpaired comparisons, despite small differences in adverse neonatal outcomes. The experience of our study indicates that future studies of neonatal interventions with the potential to influence later morbidity should be designed with longer-term outcomes in mind.

Deprivation and infection among spontaneous very preterm births.

OBJECTIVE: To explore the relationship between infection and socioeconomic deprivation among mothers of spontaneous very preterm infants to contribute to the understanding of the deprivation gap in the incidence of very preterm birth. METHODS: We used comprehensive data from a large retrospective study of very preterm birth in a U. K. health region (representing approximately 1 in 12 U.K. births) between 1994 and 2005. We report the relationship between fetal or maternal infection before birth and deprivation quintile of all singleton live births at 22 0/7 to 32 6/7 weeks of gestation associated with spontaneous onset of labor. RESULTS: Overall, 24% of the 4,987 spontaneous very preterm singleton births had recorded evidence of maternal or fetal infection. Rates of infection increased significantly with increasing deprivation. Spontaneous very preterm births to mothers from the most deprived quintile were at 43% increased odds of being associated with infection compared with those from the least deprived quintile (odds ratio 1.43, 95% confidence interval 1.13-1.80) after adjusting for gestation, year of birth, and mother's age. CONCLUSION: Spontaneous very preterm births to mothers from more deprived areas are more likely to be associated with infection before birth. LEVEL OF EVIDENCE: II.

Mortality patterns among very preterm babies: a comparative analysis of two European regions in France and England.

OBJECTIVE: To explore the differences in outcome of very preterm pregnancies between two geographically defined populations in Europe with similar socioeconomic characteristics and healthcare provision but different organisational arrangements for perinatal care. DESIGN: Prospective cohort study. SETTING: Nord Pas-de-Calais (NPC), France, and Trent, UK. PARTICIPANTS: All pregnancy outcomes 22(+0) to 32(+6) weeks' gestational age for resident mothers. OUTCOME MEASURES: Mortality patterns (antepartum death, intrapartum death, labour ward death and neonatal unit death) among very preterm babies were analysed by region. Multinomial logistic regression was used to model regional differences for a variety of pregnancy outcomes and to adjust for regional differences in the organisation of perinatal care. RESULTS: Delivery of very preterm infants was significantly higher in Trent compared with NPC (1.9% v 1.5% of all births, respectively (p<0.001)). Stillbirth rate was significantly higher in NPC than in Trent (23.0%, 95% CI 20.0% to 26.5% v 14.4%, 95% CI 12.3% to 16.6%, respectively (p<0.001)) and survival to discharge was higher in Trent than in NPC (74.6%, 95% CI 71.9% to 77.1% v 66.7%, 95% CI 63.3% to 69.9%, respectively (p<0.001)). Probability of intrapartum and labour ward death in NPC was more than five times higher than Trent (relative risk 5.3, 95% CI 2.2 to 13.1 (p<0.001)). CONCLUSION: The high rate of very preterm deliveries and the larger proportion of these infants recorded as live born in Trent appear to be the cause of the excess neonatal mortality seen in the routine statistics. Information about very preterm babies (not usually included in routine statistics) is vital to avoid inappropriate interpretation of international perinatal and infant data. This study highlights the importance of including deaths before transfer to neonatal care and emphasises the need to include the outcome of all pregnancies in a population in any comparative analysis.

Causes and temporal changes in nationally collected stillbirth audit data in high-resource settings.

Few high-income countries have an active national programme of stillbirth audit. From the three national programmes identified (UK, New Zealand, and the Netherlands) steady declines in annual stillbirth rates have been observed over the audit period between 1993 and 2014. Unexplained stillbirth remains the largest group in the classification of stillbirths, with a decline in intrapartum-related stillbirths, which could represent improvements in intrapartum care. All three national audits of stillbirths suggest that up to half of all reviewed stillbirths have elements of care that failed to follow standards and guidance. Variation in the classification of stillbirth, cause of death and frequency of risk factor groups limit our ability to draw meaningful conclusions as to the true scale of the burden and the changing epidemiology of stillbirths in high-income countries. International standardization of these would facilitate direct comparisons between countries. The observed declines in stillbirth rates over the period of perinatal audit, a possible consequence of recommendations for improved antenatal care, should serve to incentivise other countries to implement similar audit programmes.

Variability in the management and outcomes of extremely preterm births across five European countries: a population-based cohort study.

OBJECTIVE: To explore international variations in the management and survival of extremely low gestational age and birthweight births. DESIGN: Area-based prospective cohort of births SETTING: 12 regions across Belgium, France, Italy, Portugal and the UK PARTICIPANTS: 1449 live births and fetal deaths between 22+0 and 25+6 weeks gestation born in 2011-2012. MAIN OUTCOME MEASURES: Percentage of births; recorded live born; provided antenatal steroids or respiratory support; surviving to discharge (with/without severe morbidities). RESULTS: The percentage of births recorded as live born was consistently low at 22 weeks and consistently high at 25 weeks but varied internationally at 23 weeks for those weighing 500 g and over (range 33%-70%) and at 24 weeks for those under 500 g (range 5%-71%). Antenatal steroids and provision of respiratory support at 22-24 weeks gestation varied between countries, but were consistently high for babies born at 25 weeks. Survival to discharge was universally poor at 22 weeks gestation (0%) and at any gestation with birth weight <500 g, irrespective of treatment provision. In contrast, births at 23 and 24 weeks weighing 500 g and over showed significant international variation in survival (23 weeks: range: 0%-25%; 24 weeks range: 21%-50%), reflecting levels of treatment provision. CONCLUSIONS: Wide international variation exists in the management and survival of extremely preterm births at 22-24 weeks gestation. Universally poor outcomes for babies at 22 weeks and for those weighing under 500 g suggest little impact of intervention and support the inclusion of birth weight along with gestational age in ethical decision-making guidelines.

Variability in Very Preterm Stillbirth and In-Hospital Mortality Across Europe.

BACKGROUND AND OBJECTIVE: Stillbirth and in-hospital mortality rates associated with very preterm births (VPT) vary widely across Europe. International comparisons are complicated by a lack of standardized data collection and differences in definitions, registration, and reporting. This study aims to determine what proportion of the variation in stillbirth and in-hospital VPT mortality rates persists after adjusting for population demographics, case-mix, and timing of death. METHODS: Standardized data collection for a geographically defined prospective cohort of VPTs (22+0-31+6 weeks gestation) across 16 regions in Europe. Crude and adjusted stillbirth and in-hospital mortality rates for VPT infants were calculated by time of death by using multinomial logistic regression models. RESULTS: The stillbirth and in-hospital mortality rate for VPTs was 27.7% (range, 19.9%-35.9% by region). Adjusting for maternal and pregnancy characteristics had little impact on the variation. The addition of infant characteristics reduced the variation of mortality rates by approximately one-fifth (4.8% to 3.9%). The SD for deaths <12 hours after birth was reduced by one-quarter, but did not change after risk adjustment for deaths ≥12 hours after birth. CONCLUSIONS: In terms of the regional variation in overall VPT mortality, over four-fifths of the variation could not be accounted for by maternal, pregnancy, and infant characteristics. Investigation of the timing of death showed that these characteristics only accounted for a small proportion of the variation in VPT deaths. These findings suggest that there may be an inequity in the quality of care provision and treatment of VPT infants across Europe.