Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study.

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

Prevalence of Down's Syndrome in England, 1998-2013: Comparison of linked surveillance data and electronic health records.

INTRODUCTION: Disease registers and electronic health records are valuable resources for disease surveillance and research but can be limited by variation in data quality over time. Quality may be limited in terms of the accuracy of clinical information, of the internal linkage that supports person-based analysis of most administrative datasets, or by errors in linkage between multiple datasets. OBJECTIVES: By linking the National Down Syndrome Cytogenetic Register (NDSCR) to Hospital Episode Statistics for England (HES), we aimed to assess the quality of each and establish a consistent approach for analysis of trends in prevalence of Down's syndrome among live births in England. METHODS: Probabilistic record linkage of NDSCR to HES for the period 1998-2013 was supported by linkage of babies to mothers within HES. Comparison of prevalence estimates in England were made using NDSCR only, HES data only, and linked data. Capture-recapture analysis and quantitative bias analysis were used to account for potential errors, including false positive diagnostic codes, unrecorded diagnoses, and linkage error. RESULTS: Analyses of single-source data indicated increasing live birth prevalence of Down's Syndrome, particularly in the analysis of HES. Linked data indicated a contrastingly stable prevalence of 12.3 (plausible range: 11.6-12.7) cases per 10 000 live births. CONCLUSION: Case ascertainment in NDSCR improved slightly over time, creating a picture of slowly increasing prevalence. The emerging epidemic suggested by HES primarily reflects improving linkage within HES (assignment of unique patient identifiers to hospital episodes). Administrative data are valuable but trends should be interpreted with caution, and with assessment of data quality over time. Data linkage with quantitative bias analysis can provide more robust estimation and, in this case, stronger evidence that prevalence is not increasing. Routine linkage of administrative and register data can enhance the value of each.

Correction to: EUROCAT: an update on its functions and activities.

The published online version contains the following errors: On the cover page "JRC Management Committee" - should be corrected to JRC-EUROCAT Management Committee. In the authors list under the title, same as above, "JRC Management Committee" should be corrected to JRC-EUROCAT Management Committee.

Estimating the birth prevalence and pregnancy outcomes of congenital malformations worldwide.

Congenital anomaly registries have two main surveillance aims: firstly to define baseline epidemiology of important congenital anomalies to facilitate programme, policy and resource planning, and secondly to identify clusters of cases and any other epidemiological changes that could give early warning of environmental or infectious hazards. However, setting up a sustainable registry and surveillance system is resource-intensive requiring national infrastructure for recording all cases and diagnostic facilities to identify those malformations that that are not externally visible. Consequently, not all countries have yet established robust surveillance systems. For these countries, methods are needed to generate estimates of prevalence of these disorders which can act as a starting point for assessing disease burden and service implications. Here, we describe how registry data from high-income settings can be used for generating reference rates that can be used as provisional estimates for countries with little or no observational data on non-syndromic congenital malformations.

EUROCAT: an update on its functions and activities.

This paper provides an outline of the development and growth of EUROCAT, the European network of congenital anomaly registers. In recent years the network has been through a period of transition and change. The Central Register of data has transferred from the Ulster University to the EU Joint-Research-Centre, Ispra, Italy.The benefits of combining data from across Europe, from different populations and countries are described by the uses to which these data can be put. These uses include:. surveillance of anomalies at a local, regional or pan-European level. pharmacovigilance. registration of rare diseasesNew studies and projects are underway, including EUROlinkCAT (a Horizon 2020 funded data-linkage project), promising a fruitful future in further research of congenital anomalies.

Mortality from aortic stenosis: prospective study of serum calcium and phosphate.

PURPOSE: To investigate the associations between levels of serum calcium and phosphate and subsequent death from aortic stenosis, and the implications for prevention. METHODS: A prospective (nested case-control) analysis of serum calcium and phosphate levels was performed in stored samples from the British United Provident Association prospective study of 21 520 men aged 35-64, followed for up to 32 years. There were 49 men without baseline valvular heart disease who subsequently died of aortic stenosis. Each was matched, for age, duration of sample storage and number of freeze-thaw cycles, with four unaffected control subjects. Odds ratios for death from aortic stenosis were estimated by logistic regression. RESULTS: Mean serum calcium concentration was higher in men who died of aortic stenosis than in those who did not (2.44 vs. 2.39 mmol L-1 ; P = 0.01). The risk of death from aortic stenosis in the highest calcium tertile was 2.87-fold higher than in the lowest tertile (95% confidence interval 1.22-6.76). There was a continuous dose-response relationship; risk of death from aortic stenosis increased by 51% (11-105%) per 0.1 mmol L-1 increase in serum calcium, equivalent to a 34% (10-52%) lower risk per 0.1 mmol L-1 decrease. Serum phosphate was not significantly higher in men who died of aortic stenosis than in those who did not (1.0 vs. 0.99 mmol L-1 ; P = 0.76). CONCLUSIONS: The association between serum calcium and subsequent mortality from aortic stenosis is of potential preventive significance. If confirmed quantitatively in other similar cohort studies, the results suggest that a very small reduction in serum calcium (about 5%) could translate into a large (about one-third) reduction in aortic stenosis.

The association between Ehlers-Danlos syndrome-hypermobility type and gastrointestinal symptoms in university students: a cross-sectional study.

BACKGROUND: Patients with Ehlers-Danlos syndrome-hypermobility type (EDS-HT) have increased prevalence of gastrointestinal (GI) symptoms, particularly reflux and dyspepsia. EDS-HT is associated with dysautonomia, psychopathology, and chronic pain which can be associated with GI symptoms. The association between GI symptoms and EDS-HT in a 'non-patient' population and the effect of the above-mentioned factors has never been studied. METHODS: In a cross sectional study, a hypermobility questionnaire was used to screen university students; further clinical examination established the diagnosis of EDS-HT. Validated questionnaires assessed for GI, somatic, pain and autonomic symptoms, psychopathology and quality of life (QOL). These were compared in students with and without EDS-HT; logistic regression analysis examined associations between EDS-HT, GI symptoms and other variables. KEY RESULTS: Of 1998 students screened, 162 were included: 74 EDS-HT (21.0 years, 53% female) vs 88 Non-EDS-HT (21.5 years, 65% female). Compared to non-EDS-HT students, EDS-HT students were more likely to have multiple GI symptoms (41.9% vs 27.3% P=.05), particularly postprandial fullness (34.4% vs 15.9%, P=.01) and early satiety (32% vs 17%, P=.03), greater autonomic (P<.001) and somatic symptoms (P=.04) but not psychopathology (P>.8). The association between EDS-HT and postprandial symptoms was dependent on autonomic factors but independent of pain and psychopathology. Pain-related QOL scores were reduced in the EDS-HT group (80 vs 90, P=.03). CONCLUSIONS AND INFERENCES: The previously described association between EDS-HT, dyspepsia, pain and autonomic symptoms in patients is also present in non-patient groups. Future studies are necessary to explore the etiological role of connective tissue in GI and extra intestinal symptoms.

Prevention of neural tube defects in the UK: a missed opportunity.

OBJECTIVE: In 1991, the Medical Research Council (MRC) Vitamin Study demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). We aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in the UK from 1998 as it had been in the USA. DESIGN: Estimates of NTD prevalence, the preventive effect of folic acid and the proportion of women taking folic acid supplements before pregnancy were used to predict the number of NTD pregnancies that would have been prevented if folic acid fortification had been implemented. SETTING: Eight congenital anomaly registers in England and Wales. MAIN OUTCOME MEASURES: The prevalence of pregnancies with an NTD in the UK and the number of these pregnancies that would have been prevented if folic acid fortification had been implemented. RESULTS: From 1991 to 2012, the prevalence of NTD pregnancies was 1.28 (95% CI 1.24 to 1.31) per 1000 total births (19% live births, 81% terminations and 0.5% stillbirths and fetal deaths ≥20 weeks' gestation). If the USA levels of folic acid fortification from 1998 onwards had been adopted in the UK, an estimated 2014 fewer NTD pregnancies would have occurred. CONCLUSIONS: Failure to implement folic acid fortification in the UK has caused, and continues to cause, avoidable terminations of pregnancy, stillbirths, neonatal deaths and permanent serious disability in surviving children.

Cardiorespiratory fitness and white matter integrity in Alzheimer's disease.

The objective of this study was to investigate the relationship between cardiorespiratory (CR) fitness and the brain's white matter tract integrity using diffusion tensor imaging (DTI) in the Alzheimer's disease (AD) population. We recruited older adults in the early stages of AD (n = 37; CDR = 0.5 and 1) and collected cross-sectional fitness and diffusion imaging data. We examined the association between CR fitness (peak oxygen consumption [VO2peak]) and fractional anisotropy (FA) in AD-related white matter tracts using two processing methodologies: a tract-of-interest approach and tract-based spatial statistic (TBSS). Subsequent diffusivity metrics (radial diffusivity [RD], mean diffusivity [MD], and axial diffusivity [A × D]) were also correlated with VO2peak. The tract-of-interest approach showed that higher VO2peak was associated with preserved white matter integrity as measured by increased FA in the right inferior fronto-occipital fasciculus (p = 0.035, r = 0.36). We did not find a significant correlation using TBSS, though there was a trend for a positive association between white matter integrity and higher VO2peak measures (p < 0.01 uncorrected). Our findings indicate that higher CR fitness levels in early AD participants may be related to preserved white matter integrity. However to draw stronger conclusions, further study on the relationship between fitness and white matter deterioration in AD is necessary.

Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study.

BACKGROUND: The overlap of unexplained gastrointestinal (GI) and somatic symptoms is well established in patients with functional gastrointestinal disorders (FGID). Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder associated with GI and somatic symptoms. We aimed to determine whether there is an association between diagnosis of JHS and FGID and the impact of this association on comorbidities and quality of life (QOL). METHODS: Prospective case-control study in secondary care GI clinics over 2 years. JHS was assessed by the first author prior to consultation in 641 consecutive new patients. Diagnosis of FGID (cases, n = 336) or organic disorders (controls, n = 305) was established blind to JHS status. JHS prevalence was compared in cases (FGID patients) and controls (organic disorders patients). Extra-intestinal comorbidity and QOL were compared in FGID patients with and without JHS. KEY RESULTS: JHS prevalence was higher in FGID compared to organic GI disorders (39.0% vs 27.5%, ORadj: 1.51, CI: 1.07-2.12, p = 0.02), and particularly associated with functional gastroduodenal disorders (44.1%, ORadj: 2.08, CI: 1.25-3.46, p = 0.005), specifically postprandial distress syndrome (51%, ORadj: 1.99, CI: 1.06-3.76, p = 0.03). FGID patients with JHS had increased chronic pain (23.2% vs 11.9%, p = 0.01), fibromyalgia (10.5% vs 3.1%, p = 0.01), somatization scores (13 vs 10, p < 0.001), urinary autonomic scores (30.5 vs 20.7, p = 0.03), and worse pain-related QOL scores (45.0 vs 63.5, p = 0.004). CONCLUSIONS & INFERENCES: JHS is significantly associated with FGID, and this subgroup of patients have increased comorbidity and decreased QOL. Further research is required to understand the pathophysiological basis of this association.

In vivo and in vitro ketamine exposure exhibits a dose-dependent induction of activity-dependent neuroprotective protein in rat neurons.

Anesthetic doses of ketamine induce apoptosis, as well as gene expression of activity-dependent neuroprotective protein (ADNP), a putative homeodomain transcription factor in rat pups (P7). This study investigated if ketamine induced ADNP protein in a dose-dependent manner in vitro and in vivo using primary cultures of cortical neurons and neonatal pups (P7). In vivo immunohistochemistry demonstrated a sub-anesthetic dose of ketamine increased ADNP in the somatosensory cortex (SCC) which was previously identified to be damaged by repeated exposure to anesthetic doses of ketamine. Administration of low-dose ketamine prior to full sedation prevented caspase-3 activation in the hippocampus and SCC. Primary cultures of cortical neurons treated with ketamine (10 µM-10mM) at 3 days-in vitro (3 DIV) displayed a concentration-dependent decrease in expanded growth cones. Furthermore, neuronal production and localization of ADNP varied as a function of both ketamine concentration and length of exposure. Taken together, these data support the model that ADNP induction may be partially responsible for the efficacy of a low-dose ketamine pre-treatment in preventing ketamine-induced neuronal cell death.

Insulin resistance and gray matter volume in neurodegenerative disease.

The goal of this study was to compare insulin resistance in aging and aging-related neurodegenerative diseases, and to determine the relationship between insulin resistance and gray matter volume (GMV) in each cohort using an unbiased, voxel-based approach. Insulin resistance was estimated in apparently healthy elderly control (HC, n=21) and neurodegenerative disease (Alzheimer's disease (AD), n=20; Parkinson's disease (PD), n=22) groups using Homeostasis Model Assessment of Insulin Resistance 2 (HOMA2) and intravenous glucose tolerance test (IVGTT). HOMA2 and GMV were assessed within groups through General Linear Model multiple regression. We found that HOMA2 was increased in both AD and PD compared to the HC group (HC vs. AD, p=0.002, HC vs. PD, p=0.003), although only AD subjects exhibited increased fasting glucose (p=0.005). Furthermore, our voxel-based morphometry analysis revealed that HOMA2 was related to GMV in all cohorts in a region-specific manner (p<0.001, uncorrected). Significant relationships were observed in the medial prefrontal cortex (HC), medial temporal regions (AD), and parietal regions (PD). Finally, the directionality of the relationship between HOMA2 and GMV was disease-specific. Both HC and AD subjects exhibited negative relationships between HOMA2 and brain volume (increased HOMA2 associated with decreased brain volume), while a positive relationship was observed in PD. This cross-sectional study suggests that insulin resistance is increased in neurodegenerative disease, and that individuals with AD appear to have more severe metabolic dysfunction than individuals with PD or PD dementia.

Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening.

OBJECTIVE: To determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome. DESIGN: Population-based prevalence study based on EUROCAT congenital anomaly registries. SETTING: Eight European countries. POPULATION: 14.8 million births 1990-2009; 2.89% multiple births. METHODS: DS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases. MAIN OUTCOME MEASURES: Relative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome. STATISTICAL ANALYSIS: Poisson and logistic regression stratified for maternal age, country and time. RESULTS: Overall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53-0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25-0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23-1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50-0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27-0.59]). CONCLUSIONS: The risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening.

Effects of unilateral nigrostriatal dopamine depletion on peripheral glucose tolerance and insulin signaling in middle aged rats.

Clinical studies indicate an increased incidence of impaired glucose tolerance in individuals with Parkinson's disease (PD). The mechanisms that underlie this co-morbidity are currently unknown. The purpose of this study was to analyze peripheral glucose tolerance following severe unilateral nigrostriatal dopamine (DA) depletion, and to determine whether central and peripheral insulin signaling was affected in the 6-hydroxydopamine (6-OHDA) middle-aged rat model of PD. Although serum insulin levels differed significantly between the 6-OHDA and sham groups over the course of a glucose tolerance test six weeks post-lesion, no significant effect on glucose tolerance or insulin signaling in skeletal muscle was observed. In contrast, markers of striatal insulin resistance were evident in the rats. These data suggest that while 6-OHDA may affect serum insulin levels and striatal insulin signaling, the unilateral 6-OHDA lesion model does not induce glucose intolerance or peripheral insulin resistance, at least at the six-week post-lesion timepoint.

Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy.

Insulin signaling depends on tyrosine phosphorylation of insulin receptor substrates (IRSs) to mediate downstream effects; however, elevated serine phosphorylation of IRS impairs insulin signaling. Here, we investigated IRS protein expression patterns in dorsal root ganglia (DRG) of mice and whether their signaling was affected by diabetes. Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. Phosphorylation of Ser(731)IRS2 was significantly elevated in DRG neurons from type 1 and type 2 diabetic mice. Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. These results suggest that DRG neurons express IRS proteins that are altered by diabetes similar to other peripheral tissues, and insulin signaling downstream of the insulin receptor may be impaired in sensory neurons and contribute to the pathogenesis of diabetic neuropathy.

Insulin resistance impairs nigrostriatal dopamine function.

Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function.

Case-control analysis of paternal age and trisomic anomalies.

OBJECTIVES: To determine whether older paternal age increases the risk of fathering a pregnancy with Patau (trisomy 13), Edwards (trisomy 18), Klinefelter (XXY) or XYY syndrome. DESIGN: Case-control: cases with each of these syndromes were matched to four controls with Down syndrome from within the same congenital anomaly register and with maternal age within 6 months. SETTING: Data from 22 EUROCAT congenital anomaly registers in 12 European countries. PARTICIPANTS: Diagnoses with observed or (for terminations) predicted year of birth from 1980 to 2005, comprising live births, fetal deaths with gestational age ≥ 20 weeks and terminations after prenatal diagnosis of the anomaly. Data include 374 cases of Patau syndrome, 929 of Edwards syndrome, 295 of Klinefelter syndrome, 28 of XYY syndrome and 5627 controls with Down syndrome. MAIN OUTCOME MEASURES: Odds ratio (OR) associated with a 10-year increase in paternal age for each anomaly was estimated using conditional logistic regression. Results were adjusted to take account of the estimated association of paternal age with Down syndrome (1.11; 95% CI 1.01 to 1.23). RESULTS: The OR for Patau syndrome was 1.10 (95% CI 0.83 to 1.45); for Edwards syndrome, 1.15 (0.96 to 1.38); for Klinefelter syndrome, 1.35 (1.02 to 1.79); and for XYY syndrome, 1.99 (0.75 to 5.26). CONCLUSIONS: There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age. The larger positive associations of Klinefelter and XYY syndromes with paternal age compared with Patau and Edwards syndromes are consistent with the greater percentage of these sex chromosome anomalies being of paternal origin.

Down's syndrome: screening and antenatal diagnosis regionally in England and Wales 1989-2008.

OBJECTIVE: To illustrate regional changes that occurred in screening for Down's syndrome (trisomy 21) in England and Wales from 1989 to 2008. METHODS: The National Down Syndrome Cytogenetic Register has collected data on all ante- and postnatal diagnoses of Down's syndrome in England and Wales since 1989 (n = 27,954). The percentages of (i) diagnoses made antenatally, (ii) antenatal diagnoses that had nuchal translucency (NT) measured, and (iii) antenatal diagnoses in mothers aged 37 and over with advanced maternal age as the sole recorded indication for diagnosis are presented according to where the mother lived (Government Office Region), year of diagnosis (1989-1994, 1995-2000, 2001-2006, 2007-2008), and maternal age (<37 years, ≥37 years). RESULTS: The percentage of cases diagnosed antenatally has increased in younger women but varies between regions. It remained relatively constant at approximately 70% in older women. The use of NT measurement in antenatal screening has expanded rapidly but varies regionally, being most common in London and the South East where, in 2007-2008, over 75% of antenatal diagnoses in older women had NT measured. The sole indication of advanced maternal age has substantially reduced, and was less than 10% in older mothers in all regions in 2007-2008. CONCLUSIONS: There are regional and maternal age variations in Down's syndrome screening and diagnosis. Some regions used NT measurements, and eliminated advanced maternal age as sole reason for antenatal diagnostic testing more quickly than others. The reasons for variations need to be identified and addressed to ensure that when new screening techniques become available, regional differences are minimized.

Maternal age-specific risk of non-chromosomal anomalies.

OBJECTIVES: To determine the excess risk of non-chromosomal congenital anomaly (NCA) among teenage mothers and older mothers. DESIGN AND SETTING: Population-based prevalence study using data from EUROCAT congenital anomaly registers in 23 regions of Europe in 15 countries, covering a total of 1.75 million births from 2000 to 2004. PARTICIPANTS: A total of 38,958 cases of NCA that were live births, fetal deaths with gestational age > or = 20 weeks or terminations of pregnancy following prenatal diagnosis of a congenital anomaly. MAIN OUTCOME MEASURES: Prevalence of NCA according to maternal age, and relative risk (RR) of NCA and 84 standard NCA subgroups compared with mothers aged 25-29. RESULTS: The crude prevalence of all NCA was 26.5 per 1000 births in teenage mothers (<20 years), 23.8 for mothers 20-24 years, 22.5 for mothers 25-29 years, 21.5 for mothers 30-34 years, 21.4 for mothers 35-39 years and 22.6 for mothers 40-44 years. The RR adjusted for country for teenage mothers was 1.11 (95% CI 1.06-1.17); 0.99 (95% CI 0.96-1.02) for mothers 35-39; and 1.01 (95% CI 0.95-1.07) for mothers 40-44. The pattern of maternal age-related risk varied significantly between countries: France, Ireland and Portugal had higher RR for teenage mothers, Germany and Poland had higher RR for older mothers. The maternal age-specific RR varied for different NCAs. Teenage mothers were at a significantly greater risk (P < 0.01) of gastroschisis, maternal infection syndromes, tricuspid atresia, anencephalus, nervous system and digestive system anomalies while older mothers were at a significantly greater risk (P < 0.01) of fetal alcohol syndrome, encephalocele, oesophageal atresia and thanatophoric dwarfism. CONCLUSIONS: Clinical and public health interventions are needed to reduce environmental risk factors for NCA, giving special attention to young mothers among whom some risk factors are more prevalent. Reassurance can be given to older mothers that their age in itself does not confer extra risk for NCA.