COVID-19 infection, admission and death and the impact of corticosteroids among people with rare autoimmune rheumatic disease during the second wave of COVID-19 in England: results from the RECORDER Project.

OBJECTIVES: To calculate the rates of COVID-19 infection and COVID-19-related death among people with rare autoimmune rheumatic diseases (RAIRD) during the second wave of the COVID-19 pandemic in England, and describe the impact of corticosteroids on outcomes. METHODS: Hospital Episode Statistics data were used to identify people alive on 1 August 2020 with ICD-10 codes for RAIRD from the whole population of England. Linked national health records were used to calculate rates and rate ratios of COVID-19 infection and death up to 30 April 2021. Primary definition of COVID-19-related death was mention of COVID-19 on the death certificate. NHS Digital and Office for National Statistics general population data were used for comparison. The association between 30-day corticosteroid usage and COVID-19-related death, COVID-19-related hospital admissions and all-cause deaths was also described. RESULTS: Of 168 330 people with RAIRD, 9961 (5.92%) had a positive COVID-19 PCR test. The age-standardized infection rate ratio between RAIRD and the general population was 0.99 (95% CI: 0.97, 1.00). 1342 (0.80%) people with RAIRD died with COVID-19 on their death certificate and the age-sex-standardized mortality rate for COVID-19-related death was 2.76 (95% CI: 2.63, 2.89) times higher than in the general population. There was a dose-dependent relationship between 30-day corticosteroid usage and COVID-19-related death. There was no increase in deaths due to other causes. CONCLUSIONS: During the second wave of COVID-19 in England, people with RAIRD had the same risk of COVID-19 infection but a 2.76-fold increased risk of COVID-19-related death compared with the general population, with corticosteroids associated with increased risk.

The incidence of Kawasaki disease using hospital admissions data for England 2006-2021.

OBJECTIVE: To describe the incidence of Kawasaki Disease (kDa) between 2006 and 2021 in England. METHODS: We identified all cases in hospital episode statistics with an ICD-10 diagnostic code M303 (for kDa) between 1 April 2006 and 31 March 2021. We validated 83 diagnoses using hospital medical records and found >97% accuracy. We calculated incidence rate ratios (IRRs) using Poisson regression and assessed the influence of age, sex, ethnicity and index of multiple deprivation (IMD). We used Office for National Statistics population estimates for England as the denominator. RESULTS: We identified a total of 5908 cases of kDa in all children under the age of 16 (mean age 3.8, s.d.=3.2, 95% CI: 3.7, 3.9). Incidence in children aged <5 years was 8.9 (95% CI: 8.6, 9.2)/100 000 person-years; in children aged 5-9, 2.4 (95% CI: 2.3, 2.6)/100 000 person-years; and in children aged 10-15, 0.6 (95% CI: 0.6, 0.7). Male : female ratio was 1.5 : 1. Incidence was higher among non-White than White ethnicities [adjusted IRR 2.1 (2.0-2.2) for Asian, 3.0 (2.8-3.3) for Black and 4.5 (4.2-4.8) for other ethnicities]. The incidence increased with socioeconomic deprivation; the adjusted IRR of the least deprived IMD quintile compared with the most deprived quintile was 0.81 (0.77-0.84). CONCLUSIONS: Incidence rates of kDa derived from hospital admission data in England were higher than in studies relying on clinician reporting. We confirm previous findings on the influence of sex and ethnicity on kDa incidence and observe that there was a higher incidence of kDa within more deprived socioeconomic groups.

Incidence, prevalence and survival in patients with Langerhans cell histiocytosis: A national registry study from England, 2013-2019.

This analysis is the largest population-based study to date to provide contemporary and comprehensive epidemiological estimates of all third edition of the International Classification of Diseases for Oncology (ICD-O-3) coded Langerhans cell histiocytosis (LCH) from England. People of all ages were identified from the National Cancer Registration Dataset using ICD-O-3 morphologies 9751-9754 for neoplasms diagnosed in 2013-2019. A total of 658 patients were identified, of whom 324 (49%) were children aged <15 years. The age-standardised incidence rate was 4.46 (95% confidence interval [CI] 3.99-4.98) per million children and 1.06 (95% CI 0.94-1.18) per million adults aged ≥15 years. Prevalence of LCH was 9.95 (95% CI 9.14-10.81) per million persons at the end of 2019. The 1-year overall survival (OS) was 99% (95% CI 97%-100%) for children and 90% (95% CI 87%-93%) for adults. Those aged ≥60 years had poorer OS than those aged <15 years (hazard ratio [HR] 22.12, 95% CI 7.10-68.94; p < 0.001). People in deprived areas had lower OS than those in the least deprived areas (HR 5.36, 95% CI 1.16-24.87; p = 0.03). There will inevitably be other environmental factors and associations yet to be identified, and the continued standardised data collection will allow further evaluation of data over time. This will be increasingly important with developments in LCH management following the large collaborative international trials such as LCH IV.

Incidence and survival of haemophagocytic lymphohistiocytosis: A population-based cohort study from England.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a rare hyper-inflammatory condition with poor outcomes. OBJECTIVES: Few population-based estimates of the incidence and survival in adults exist. We aimed to provide these data for England. METHODS: We used population-based linked data from primary care, secondary care, cancer registries and mortality databases in England to identify people diagnosed with HLH between 1 January 2000 and 31 December 2016. We calculated annual incidence rates by age and sex, modelled change in incidence over time with Poisson regression, calculated overall 1-year survival using Kaplan-Meier methods and estimated adjusted hazard ratios (HRs) of death using a Cox proportional hazards model. RESULTS: We identified 214 patients with HLH. The reported age and sex-adjusted incidence increased twofold over the period, from around one to around two per million. Incidence was highest in those below 1 year (14.6 per million) and ≥75 years (2.2 per million), and lowest in those aged 15-44 years (0.8 per million). One-year survival varied by age and sex from 77% (95% confidence interval [CI] 63%-86%) in those <15 years to 30% (95% CI 14%-49%) in those ≥75. In patients with haematological cancer, the adjusted HR for death was 2.60 (95% CI 1.45-4.66) compared to patients with no malignant or rheumatological disease. CONCLUSION: The incidence of HLH diagnosis in England has increased between 2000 and 2016 and occurs in all ages with varying underlying diseases. One-year survival varies substantially, being particularly poor in those aged over 75 years and those with haematological malignancy.

COVID-19 infection, admission and death among people with rare autoimmune rheumatic disease in England: results from the RECORDER project.

OBJECTIVES: To calculate the rates of COVID-19 infection and COVID-19-related death among people with rare autoimmune rheumatic diseases (RAIRD) during the first wave of the COVID-19 pandemic in England compared with the general population. METHODS: We used Hospital Episode Statistics to identify all people alive on 1 March 2020 with ICD-10 codes for RAIRD from the whole population of England. We used linked national health records (demographic, death certificate, admissions and PCR testing data) to calculate rates of COVID-19 infection and death up to 31 July 2020. Our primary definition of COVID-19-related death was mention of COVID-19 on the death certificate. General population data from Public Health England and the Office for National Statistics were used for comparison. We also describe COVID-19-related hospital admissions and all-cause deaths. RESULTS: We identified a cohort of 168 680 people with RAIRD, of whom 1874 (1.11%) had a positive COVID-19 PCR test. The age-standardized infection rate was 1.54 (95% CI: 1.50, 1.59) times higher than in the general population. A total of 713 (0.42%) people with RAIRD died with COVID-19 on their death certificate and the age-sex-standardized mortality rate for COVID-19-related death was 2.41 (2.30-2.53) times higher than in the general population. There was no evidence of an increase in deaths from other causes in the RAIRD population. CONCLUSIONS: During the first wave of COVID-19 in England, people with RAIRD had a 54% increased risk of COVID-19 infection and more than twice the risk of COVID-19-related death compared with the general population. These increases were seen despite shielding policies.

A validation study of the identification of haemophagocytic lymphohistiocytosis in England using population-based health data.

We assessed the validity of coded healthcare data to identify cases of haemophagocytic lymphohistiocytosis (HLH). Hospital Episode Statistics (HES) identified 127 cases within five hospital Trusts 2013-2018 using ICD-10 codes D76.1, D76.2 and D76.3. Hospital records were reviewed to validate diagnoses. Out of 74 patients, 73 were coded D76.1 or D76.2 (positive predictive value 89·0% [95% Confidence Interval {CI} 80·2-94·9%]) with confirmed/probable HLH. For cases considered not HLH, 44/53 were coded D76.3 (negative predictive value 97·8% [95% CI 88·2-99·9%]). D76.1 or D76.2 had 68% sensitivity in detecting HLH compared to an established active case-finding HLH register in Sheffield. Office for National Statistics (ONS) mortality data (2003-2018) identified 698 patients coded D76.1, D76.2 and D76.3 on death certificates. Five hundred and forty-one were coded D76.1 or D76.2 of whom 524 (96·9%) had HLH in the free-text cause of death. Of 157 coded D76.3, 66 (42·0%) had HLH in free text. D76.1 and D76.2 codes reliably identify HLH cases, and provide a lower bound on incidence. Non-concordance between D76.3 and HLH excludes D76.3 as an ascertainment source from HES. Our results suggest electronic healthcare data in England can enable population-wide registration and analysis of HLH for future research.

Risk of death among people with rare autoimmune diseases compared with the general population in England during the 2020 COVID-19 pandemic.

OBJECTIVES: To quantify the risk of death among people with rare autoimmune rheumatic diseases (RAIRD) during the UK 2020 COVID-19 pandemic compared with the general population, and compared with their pre-COVID risk. METHODS: We conducted a cohort study in Hospital Episode Statistics for England from 2003 onwards, and linked data from the NHS Personal Demographics Service. We used ONS published data for general population mortality rates. RESULTS: We included 168 691 people with a recorded diagnosis of RAIRD alive on 1 March 2020. Their median age was 61.7 (IQR 41.5-75.4) years, and 118 379 (70.2%) were female. Our case ascertainment methods had a positive predictive value of 85%. A total of 1815 (1.1%) participants died during March and April 2020. The age-standardized mortality rate (ASMR) among people with RAIRD (3669.3; 95% CI: 3500.4, 3838.1 per 100 000 person-years) was 1.44 (95% CI: 1.42, 1.45) times higher than the average ASMR during the same months of the previous 5 years, whereas in the general population of England it was 1.38 times higher. Age-specific mortality rates in people with RAIRD compared with the pre-COVID rates were higher from the age of 35 upwards, whereas in the general population the increased risk began from age 55 upwards. Women had a greater increase in mortality rates during COVID-19 compared with men. CONCLUSION: The risk of all-cause death is more prominently raised during COVID-19 among people with RAIRD than among the general population. We urgently need to quantify how much risk is due to COVID-19 infection and how much is due to disruption to health-care services.

Viral infections: contributions to late fetal death, stillbirth, and infant death.

OBJECTIVE: To determine the role of viral infections in causing fetal and infant death. STUDY DESIGN: We assessed a well-validated population database of fetal (≥20 weeks gestation) and infant death for infective deaths and deaths from viruses over a 21-year period (1988-2008). We analyzed by specific viral cause, timing (late fetal loss [20-23 weeks], stillbirth [≥24 weeks], neonatal death [0-27 days], and post-neonatal infant death [28-364 days]) and across time. RESULTS: Of the 989 total infective deaths, 108 were attributable to viral causes (6.5% of late fetal losses, 14.5% of stillbirths, 6.5% of neonatal deaths, and 19.4% of postneonatal infant deaths). Global loss (combined fetal and infant losses per 100,000 registerable births) was 139.6 (95% CI, 130.9-148.3) for any infective cause and 15.2 (95% CI, 12.3-18.1) for viral infections. More than one-third (37%) of viral-attributed deaths were before live birth, from parvovirus (63%) or cytomegalovirus (33%). Parvovirus accounted for 26% (28 of 108) of all viral deaths. Cytomegalovirus was associated with a global loss rate of 3.1 (95% CI, 1.8-4.4) and an infant mortality rate of 1.3 (95% CI, 0.4-2.1) per 100,000 live births; 91% of cases were congenital infections. Herpes simplex virus caused death only after live births (infant mortality rate, 1.4; 95% CI, 0.5-2.3). No changes in rates were seen over time. CONCLUSION: We have identified a substantial contribution of viral infections to global fetal and infant losses. More than one-third of these losses occurred before live births. Considering our methodology, our estimates represent the minimum contribution of viral illness. Strategies to reduce this burden are needed.

The changing profile of infant mortality from bacterial, viral and fungal infection over two decades.

AIM: Infection is an important cause of neonatal and infant mortality. We evaluated changes in infant deaths from infections from 1988 to 2008 in the North of England. METHODS: We interrogated a population-based survey and reviewed infant deaths from infection. Proportional contribution to deaths, pathogens identified and risk factors were analysed. RESULTS: Thirteen percentage of 4366 infant deaths from a population of 704 536 livebirths were infectious. The absolute numbers of infant deaths from infection fell over time but the proportion of deaths from infection increased (12.1%, 13.6% and 14.9%). Significantly preterm infants were increasingly represented in successive epochs (14%, 24% and 38%). Infant mortality rate (IMR) from meningococcus and Group B Streptococcus (GBS) fell in the latest epoch, but there was a corresponding increase from Escherichia coli and candida. DISCUSSION: This large study shows that infections have become proportionately more important causes of death especially in very preterm infants. Recent significant reductions in death from meningococcus and GBS are likely to represent successful achievements of vaccination and antibiotic prophylactic policies. Increases in IMR from E. coli may relate to GBS prophylaxis and increases in candida to the increase from preterm populations. Further efforts to understand these changing patterns and develop additional prevention and treatment strategies and vaccines remain an urgent priority.

1-year survival in haemophagocytic lymphohistiocytosis: a nationwide cohort study from England 2003-2018.

Haemophagocytic lymphohistiocytosis (HLH) is a lethal syndrome of excessive immune activation. We undertook a nationwide study in England of all cases of HLH diagnosed between 2003 and 2018, using linked electronic health data from hospital admissions and death certification. We modelled interactions between demographics and comorbidities and estimated one-year survival by calendar year, age group, gender and comorbidity (haematological malignancy, auto-immune, other malignancy) using Cox regression. There were 1628 people with HLH identified. Overall, crude one-year survival was 50% (95% Confidence interval 48-53%) which varied substantially with age (0-4: 61%; 5-14: 76%; 15-54: 61%; > 55: 24% p < 0.01), sex (males, 46%, worse than females, 55% p < 0.01) and associated comorbidity (auto-immune, 69%, haematological malignancy 28%, any other malignancy, 37% p < 0.01). Those aged < 54 years had a threefold increased risk of death at 1-year amongst HLH associated with malignancy compared to auto-immune. However, predicted 1-year survival decreased markedly with age in those with auto-immune (age 0-14, 84%; 15-54, 73%; > 55, 27%) such that among those > 55 years, survival was as poor as for patients with haematological malignancy. One-year survival following a diagnosis of HLH varies considerably by age, gender and associated comorbidity. Survival was better in those with auto-immune diseases among the young and middle age groups compared to those with an underlying malignancy, whereas in older age groups survival was uniformly poor regardless of the underlying disease process.

Antibody prevalence after three or more COVID-19 vaccine doses in individuals who are immunosuppressed in the UK: a cross-sectional study from MELODY.

BACKGROUND: In the UK, additional COVID-19 vaccine booster doses and treatments are offered to people who are immunosuppressed to protect against severe COVID-19, but how best to choose the individuals that receive these vaccine booster doses and treatments is unclear. We investigated the association between seropositivity to SARS-CoV-2 spike protein with demographic, disease, and treatment-related characteristics after at least three COVID-19 vaccines in three cohorts of people who are immunosuppressed. METHODS: In a cross-sectional study using UK national disease registries, we identified, contacted, and recruited recipients of solid organ transplants, participants with rare autoimmune rheumatic diseases, and participants with lymphoid malignancies who were 18 years or older, resident in the UK, and who had received at least three doses of a COVID-19 vaccine. The study was open to recruitment from Dec 7, 2021, to June 26, 2022. Participants received a lateral flow immunoassay test for SARS-CoV-2 spike antibodies to complete at home, and an online questionnaire. Multivariable logistic regression was used to estimate the mutually adjusted odds of seropositivity against each characteristic. FINDINGS: Between Feb 14 and June 26, 2022, we screened 101 972 people (98 725 invited, 3247 self-enrolled) and recruited 28 411 (27·9%) to the study. 23 036 (81·1%) recruited individuals provided serological data. Of these, 9927 (43·1%) were recipients of solid organ transplants, 6516 (28·3%) had rare autoimmune rheumatic diseases, and 6593 (28·6%) had lymphoid malignancies. 10 485 (45·5%) participants were men and 12 535 (54·4%) were women (gender was not reported for 16 [<0·1%] participants), and 21661 (94·0%) participants were of White ethnicity. The median age of participants with solid organ transplants was 60 years (SD 50-67), with rare autoimmune rheumatic diseases was 65 years (54-73), and with lymphoid malignancy was 69 years (61-75). Of the 23 036 participants with serological data, 6583 (28·6%) had received three vaccine doses, 14 234 (61·8%) had received four vaccine doses, and 2219 (9·6%) had received five or more vaccine doses. IgG anti-spike antibodies were undetectable in 2310 (23·3%) of 9927 patients with solid organ transplants, 922 (14·1%) of 6516 patients with rare autoimmune rheumatic diseases, and 1366 (20·7%) of 6593 patients with lymphoid malignancies. In all groups, seropositivity was associated with younger age, higher number of vaccine doses (ie, five vs three), and previous COVID-19. Immunosuppressive medication reduced the likelihood of seropositivity: the lowest odds of seropositivity were found in recipients of solid organ transplants receiving a combination of an anti-proliferative agent, a calcineurin inhibitor, and steroids, and those with rare autoimmune rheumatic diseases or lymphoid malignancies treated with anti-CD20 therapies. INTERPRETATION: Approximately one in five recipients of solid organ transplants, individuals with rare autoimmune rheumatic diseases, and individuals with lymphoid malignancies have no detectable IgG anti-spike antibodies despite three or more vaccine doses, but this proportion decreases with sequential booster doses. Choice of immunosuppressant and disease type is strongly associated with serological response. Antibody testing using lateral flow immunoassay tests could enable rapid identification of individuals who are most likely to benefit from additional COVID-19 interventions. FUNDING: UK Research and Innovation, Kidney Research UK, Blood Cancer UK, Vasculitis UK and the Cystic Fibrosis Trust.

Deaths in preterm infants: changing pathology over 2 decades.

OBJECTIVE: To establish how cause of death for live-born preterm infants (24-31 weeks gestation) has changed in a single large UK population over 2 decades. STUDY DESIGN: This was an interrogation of a population-based survey of >680, 000 live births (between 1988 and 2008) for deaths in the first postnatal year. We collected cause of death grouped into major etiologies: respiratory, infection, malformation, necrotizing enterocolitis (NEC), and other. Data were analyzed in three 7-year epochs and 2 gestational groups (<27 and 28-31 weeks). Numbers, rates per 1000 live births, and proportional contributions to each epoch were analyzed. RESULTS: A total of 1504 deaths occurred. The infants who died had a median gestational age of 26 weeks (IQR, 25-28 weeks) and a median birth weight of 880 g (IQR, 700-1170 g). The number of deaths decreased with each later epoch (from 671 to 473 and then to 360), as did the proportion of deaths from respiratory causes (64% to 62% and then to 49%). The proportion of deaths occurring after 40 weeks postmenstrual age remained stable across the 3 epochs (8.8%, 8%, and 8%). Deaths from infection and NEC increased with time (from 11% to 13% and then to 21%), as did median time to death (from 2.7 to 3.8 days). CONCLUSION: Infection and NEC are increasingly prevalent causes of death in preterm infants.

Hirschsprung's disease in the North of England: prevalence, associated anomalies, and survival.

INTRODUCTION: Hirschsprung's disease is the commonest congenital gut motility disorder, characterized by the absence of the enteric ganglion cells along the distal gut, which causes intestinal obstruction. Few publications report its epidemiology and temporal trends. METHODS: Cases of Hirschsprung's disease delivered during 1990 to 2008 in the North of England reported to the Northern Congenital Abnormality Survey (NorCAS) formed this population-based case series. RESULTS: Of 612,916 live births, 105 cases were reported to NorCAS. After excluding one diabetic and four multiple pregnancies, the live birth prevalence was 1.63 (95% confidence interval [CI], 1.33-1.98) per 10,000 live births. There was a significant temporal increase in the prevalence of Hirschsprung's disease (p = 0.020), from 1.26 (95% CI, 0.80-1.89) in 1990 to 1994 to 2.29 (95% CI, 1.53-3.29) in 2005 to 2008. The ratio of male to female cases was 2:1. Ten (10.0%) cases occurred with Down syndrome, one with Smith-Lemli-Opitz Syndrome, and six (6.0%) with associated structural anomalies. The remaining 83 (83.0%) cases were isolated. All cases were live born, but nine (9.0%) died in the first year of life. Hirschsprung's disease was not prenatally suspected in any case. Half the cases were diagnosed within 5 days postpartum, but time of diagnosis ranged from birth to 5 years of age. CONCLUSION: This study confirmed a male predominance and an association with Down syndrome, but also found a temporal increase in Hirschsprung's disease prevalence. No cases were suspected prenatally, but half were diagnosed within 5 days of life.

Temporal Trends in the Incidence of Hemophagocytic Lymphohistiocytosis: A Nationwide Cohort Study From England 2003-2018.

Hemophagocytic lymphohistiocytosis (HLH) is rare, results in high mortality, and is increasingly being diagnosed. We aimed to quantify the incidence of diagnosed HLH and examine temporal trends in relation to age and associated diseases. Using national linked electronic health data from hospital admissions and death certification cases of HLH that were diagnosed in England between January 1, 2003, and December 31, 2018. We calculated incidence rates of diagnosed HLH per million population by calendar year, age group, sex, and associated comorbidity (hematological malignancy, inflammatory rheumatological or bowel diseases [IBD]). We modeled trends in incidence and the interactions between calendar year, age, and associated comorbidity using Poisson regression. There were 1674 people with HLH diagnosed in England between 2003 and 2018. The incidence rate quadrupled (incidence rate ratio [IRR] 2018 compared to 2003: 3.88, 95% confidence interval [CI] 2.91 to 5.28), increasing 11% annually (adjusted IRR 1.11, 95% CI 1.09 to 1.12). There was a transition across age groups with greater increases in those aged 5-14 years of HLH associated with rheumatological disease/IBD compared with hematological malignancy, with similar increases in HLH associated with both comorbidities for those 15-54, and greater increases in HLH associated with hematological malignancies for those 55 years and older. The incidence of HLH in England has quadrupled between 2003 and 2018. Substantial variation in the incidence occurred with inflammatory rheumatological diseases/IBD-associated HLH increasing more among the younger age groups, whereas in older age groups, the largest increase was seen with hematological malignancy-associated HLH.

Validation of methods to identify people with idiopathic inflammatory myopathies using hospital episode statistics.

Objective: Hospital episode statistics (HES) are routinely recorded at every hospital admission within the National Health Service (NHS) in England. This study validates diagnostic ICD-10 codes within HES as a method of identifying cases of idiopathic inflammatory myopathies (IIMs). Methods: All inpatient admissions at one NHS Trust between 2010 and 2020 with relevant diagnostic ICD-10 codes were extracted from HES. Hospital databases were used to identify all outpatients with IIM, and electronic care records were reviewed to confirm coding accuracy. Total hospital admissions were calculated from NHS Digital reports. The sensitivity and specificity of each code and code combinations were calculated to develop an optimal algorithm. The optimal algorithm was tested in a sample of admissions at another NHS Trust. Results: Of the 672 individuals identified by HES, 510 were confirmed to have IIM. Overall, the positive predictive value (PPV) was 76% and sensitivity 89%. Combination algorithms achieved PPVs between 89 and 94%. HES can also predict the presence of IIM-associated interstitial lung disease (ILD) with a PPV of 79% and sensitivity of 71%. The optimal algorithm excluded children (except JDM code M33.0), combined M33.0, M33.1, M33.9, M36.0, G72.4, M60.8 and M33.2, and included M60.9 only if it occurred alongside an ILD code (J84.1, J84.9 or J99.1). This produced a PPV of 88.9% and sensitivity of 84.2%. Retesting this algorithm at another NHS Trust confirmed a high PPV (94.4%). Conclusion: IIM ICD-10 code combinations in HES have high PPVs and sensitivities. Algorithms tested in this study could be applied across all NHS Trusts to enable robust and cost-effective whole-population research into the epidemiology of IIM.

20-year survival of children born with congenital anomalies: a population-based study.

BACKGROUND: Congenital anomalies are a leading cause of perinatal and infant mortality. Advances in care have improved the prognosis for some congenital anomaly groups and subtypes, but there remains a paucity of knowledge about survival for many others, especially beyond the first year of life. We estimated survival up to 20 years of age for a range of congenital anomaly groups and subtypes. METHODS: Information about children with at least one congenital anomaly, delivered between 1985 and 2003, was obtained from the UK Northern Congenital Abnormality Survey (NorCAS). Anomalies were categorised by group (the system affected), subtype (the individual disorder), and syndrome according to European Surveillance of Congenital Anomalies (EUROCAT) guidelines. Local hospital and national mortality records were used to identify the survival status of liveborn children. Survival up to 20 years of age was estimated by use of Kaplan-Meier methods. Cox proportional hazards regression was used to examine factors that affected survival. FINDINGS: 13,758 cases of congenital anomaly were notified to NorCAS between 1985 and 2003. Survival status was available for 10 850 (99.0%) of 10 964 livebirths. 20-year survival was 85.5% (95% CI 84.8-86.3) in individuals born with at least one congenital anomaly, 89.5% (88.4-90.6) for cardiovascular system anomalies, 79.1% (76.7-81.3) for chromosomal anomalies, 93.2% (91.6-94.5) for urinary system anomalies, 83.2% (79.8-86.0) for digestive system anomalies, 97.6% (95.9-98.6) for orofacial clefts, and 66.2% (61.5-70.5) for nervous system anomalies. Survival varied between subtypes within the same congenital anomaly group. The proportion of terminations for fetal anomaly increased throughout the study period (from 12.4%, 9.8-15.5, in 1985 to 18.3%, 15.6-21.2, in 2003; p<0.0001) and, together with year of birth, was an independent predictor of survival (adjusted hazard ratio [HR] for proportion of terminations 0.95, 95% CI 0.91-0.99, p=0.023; adjusted HR for year of birth 0.94, 0.92-0.96, p<0.0001). INTERPRETATION: Estimates of survival for congenital anomaly groups and subtypes will be valuable for families and health professionals when a congenital anomaly is detected, and will assist in planning for the future care needs of affected individuals. FUNDING: BDF Newlife.

Residential mobility during pregnancy in the north of England.

BACKGROUND: Many epidemiological studies assign exposure to an individual's residence at a single time point, such as birth or death. This approach makes no allowance for migration and may result in exposure error, leading to reduced study power and biased risk estimates. Pregnancy outcomes are less susceptible to this bias, however data from North American populations indicate that pregnant women are a highly mobile group. We assessed mobility in pregnant women in the north of England using data from the Northern Congenital Abnormality Survey (NorCAS). METHODS: Data were extracted from NorCAS for 1985 to 2003. Eligible cases had a gestational age at delivery of > or = 24 weeks (a viable delivery) (n = 11 559). We assessed mobility between booking appointment (average gestational age 13 weeks) and delivery for pregnancies where the address at booking appointment and delivery were known. The impacts on mobility of maternal age and area-level socio-economic indicators were explored using standard descriptive statistics. A sensitivity analysis and a small validation exercise were undertaken to assess the impact of missing data on the estimate of mobility. RESULTS: Out of 7 919 eligible cases for whom addresses at booking and delivery were known, 705 (8.9% (95% CI 8.3 - 9.5)) moved between booking and delivery; the mean and median moving distance was 9.7 and 1.4 km respectively. Movers were significantly younger (25.4 versus 27.3 years, p < 0.01) and lived in more deprived areas (index of multiple deprivation score 38.3 versus 33.7, p < 0.01) than non movers. CONCLUSION: Mobility in the north of England (9%) is considerably lower than that reported in North America and the only other study from the UK (23%). Consistent with other studies, mobility was related to maternal age and socio-economic status, and the majority of moves were over a relatively short distance. Although this population appears relatively stable, the mobility we have observed may still introduce misclassification or error into an exposure assessment relying solely on postcode at delivery, and migration should still therefore be considered a potential source of bias in future studies.

Exposure misclassification due to residential mobility during pregnancy.

OBJECTIVES: Pregnant women are a highly mobile group, yet studies suggest exposure error due to migration in pregnancy is minimal. We aimed to investigate the impact of maternal residential mobility on exposure to environmental variables (urban fabric, roads and air pollution (PM10 and NO2)) and socio-economic factors (deprivation) that varied spatially and temporally. METHODS: We used data on residential histories for deliveries at ≥ 24 weeks gestation recorded by the Northern Congenital Abnormality Survey, 2000-2008 (n=5399) to compare: (a) exposure at conception assigned to maternal postcode at delivery versus maternal postcode at conception, and (b) exposure at conception assigned to maternal postcode at delivery versus mean exposure based on residences throughout pregnancy. RESULTS: In this population, 24.4% of women moved during pregnancy. Depending on the exposure variable assessed, 1-12% of women overall were assigned an exposure at delivery >1 SD different to that at conception, and 2-25% assigned an exposure at delivery >1 SD different to the mean exposure throughout pregnancy. CONCLUSIONS: To meaningfully explore the subtle associations between environmental exposures and health, consideration must be given to error introduced by residential mobility.

Predictors of survival in children born with Down syndrome: a registry-based study.

OBJECTIVE: To examine the influence of fetal and maternal characteristics on the survival of children born with Down syndrome. METHODS: We used prospectively collected population-based data on Down syndrome extracted from the UK Northern Congenital Abnormality Survey (NorCAS), January 1, 1985-December 31, 2003, matched to hospital and national mortality records to January 29, 2008, to determine survival status of liveborn children. Survival to 20 years was estimated by using Kaplan-Meier methods. Cox proportional hazards regression was used to examine factors that predict survival. RESULTS: A total of 1115 Down syndrome pregnancies were notified to NorCAS during the 19 years, a total prevalence of 16.8 (95% CI, 15.8-17.8) per 10,000 live births and stillbirths. Of these, 5.4% resulted in a spontaneous fetal loss (late miscarriage ≥ 20 weeks and stillbirth), 31.7% in a termination of pregnancy, and 63.0% in a live birth. Survival status was known for 95.3% of live births; 16.6% resulted in a death. Year of birth (P < .001), gestational age at delivery (P < .001), standardized birth weight (P < .001), karyotype (P < .01), and presence of additional structural anomalies (P < .001) were significant predictors of survival. Infant gender, plurality, maternal age, and maternal deprivation were not significant predictors of survival. CONCLUSIONS: These robust estimates of predictors of survival are important for the prenatal counseling of parents whose pregnancy is affected by Down syndrome and for health care planning for the future care needs of these children.