1. EUROCAT: Surveillance of Environmental Impact Dr Martine Vrijheid (Lyon, France) for EUROCAT Prof Helen Dolk, University of Ulster WHO Collaborating Centre for the Epidemiological Surveillance of Congenital Anomalies Supported by the EU-Commission Public Health Directorate Programme of Community Action on Rare Diseases

2. AREHNA, Kos, 9-11 June 2005 EUROCAT: Surveillance of environmental impact What is EUROCAT? Environmental causes of congenital anomalies What is surveillance? Approaches to surveillance of environmental impacts in causation of congenital anomalies 1.Routine monitoring 2.Detection and response to temporal and spatial clusters 3.Evaluation of specific hypotheses Conclusions

3. AREHNA, Kos, 9-11 June 2005 What is EUROCAT? European network of registries for the epidemiologic surveillance of congenital anomalies. Started in 1979 More than 1 million births surveyed per year in Europe (25% of European birth population) 40 registries in 19 countries of Europe Standardised database on >350,000 cases of congenital anomaly among livebirths, stillbirths and terminations of pregnancy since 1980 – updated annually

4. AREHNA, Kos, 9-11 June 2005 EUROCAT Registries European network of population-based registries for the epidemiologic surveillance of congenital anomalies. Started in 1979 More than 1 million births surveyed per year in Europe 40 registries in 19 countries of Europe Standardised database on >350,000 cases of congenital anomaly among livebirths, stillbirths and terminations of pregnancy since 1980 – updated annually

5. AREHNA, Kos, 9-11 June 2005 EUROCAT Objectives u To provide essential epidemiologic information on congenital anomalies in Europe u To facilitate the early warning of teratogenic exposures u To act as an information and resource centre for the population and health professionals regarding clusters or exposures or risk factors of concern u To provide a ready collaborative network and infrastructure for research related to the causes and prevention of congenital anomalies

6. AREHNA, Kos, 9-11 June 2005 EUROCAT Registries provide high data quality: u Population-based u Multiple sources of ascertainment u Follow-up cases for diagnostic information u Ascertain anomalies diagnosed after the early neonatal period u Ascertain terminations of pregnancy following prenatal diagnosis Quality at the expense of completeness of geographical coverage

7. AREHNA, Kos, 9-11 June 2005 Environmental causes : Potential adverse outcomes of embryonic/fetal exposure Congenital anomalies (2-4% of births) congenital heart disease 25% limb anomaly 17% central nervous system anomaly (e.g. neural tube defects incl spina bifida) 9% cleft palate or cleft lip 6% chromosomal syndrome (incl Down Syndrome) 12% Spontaneous abortion (15% of recognized pregnancies) or stillbirth (<1% of births) Low birthweight (6-7% of births) – preterm and/or growth retarded in utero Poor neurodevelopmental outcomes, including motor, cognitive and behavioural outcomes Effects later in childhood/ adult life (cancer, fertility, etc)

8. AREHNA, Kos, 9-11 June 2005 Environmental causes of congenital anomalies: 3 important principles Susceptibility to an environmental agent (and type of effect) depends on the developmental stage at the time of exposure (“sensitive period”) u Before pregnancy recognized (later for other outcomes) The effect of an environmental agent increases in frequency and degree as dosage increases and there may be a practical “threshold” dose Susceptibility to an environmental agent depends on the background of other genetic and environmental factors

9. AREHNA, Kos, 9-11 June 2005 Environmental pollution as a cause of congenital anomalies? Disasters/accidental or deliberate high exposure incidents: u Radiation: Hiroshima – microcephaly, mental retardation u Methylmercury: Minamata – cerebral palsy u PCB contaminated oil: Taiwan, Japan –skin, nail, teeth, growth, neurodevelopment Chronic exposures: u Water disinfection/chlorination byproducts? u Residence near (hazardous) waste landfill sites?? u Endocrine disrupting chemicals?? u Pesticides? Dolk & Vrijheid 2004 EUROCAT Special Report “A review of Environmental Risk Factors for Congenital Anomalies” www.eurocat.ulster.ac.uk/pubdata

10. AREHNA, Kos, 9-11 June 2005 Public Health Surveillance The continuous scrutiny of the distribution of disease in a population in order to take and evaluate control measures. As opposed to epidemiologic research, tends to be (Thacker and Berkelman 1988) u Problem detection/hypothesis generating rather than hypothesis testing u Ongoing, using routine data collection systems, with minimal often incomplete data as opposed to time limited, tailored, extensive and complete data collection u Simple and descriptive analysis with timely and targeted communication to agencies involved with policy and intervention, as opposed to complex analysis with sporadic communication to clinical or academic audience

11. AREHNA, Kos, 9-11 June 2005 EUROCAT Approaches to Surveillance 1.Routine monitoring of temporal trends 2.Detection and response to temporal and spatial clusters 3.Evaluation of specific hypotheses

12. AREHNA, Kos, 9-11 June 2005 1. Routine monitoring EUROCAT Reports / web Effects of folic acid supplementation on trends in neural tube defects throughout Europe; Reports of rising prevalence of hypospadias; Increasing prevalence of gastroschisis.

13. AREHNA, Kos, 9-11 June 2005 Trends in the prevalence of congenital anomalies per 10,000 births: all and cardiac anomalies, all EUROCAT registries combined, 1980-2002

14. AREHNA, Kos, 9-11 June 2005 NTD Prevalence per 10,000 births 1980-2001 (LB + SB + TOP) UK and Ireland Continental Europe

15. AREHNA, Kos, 9-11 June 2005 Hypospadias Prevalence Rates by Year of Birth in England and Wales, 1964-1996 (NCAS Data)

16. AREHNA, Kos, 9-11 June 2005 Gastroschisis per 10,000 births, all European registers combined, 1980-2002

17. AREHNA, Kos, 9-11 June 2005 2. Detection and response to temporal and spatial clusters  Clusters arising through surveillance  Cluster concerns from local community Routine statistical monitoring to detect temporal clusters carried out by EUROCAT; Empirical investigations: geographic heterogeneity of congenital anomalies in the UK Geographical clustering of anophthalmia in England; EUROCAT Cluster Advisory Service: www.eurocat.ulster.ac.uk. www.eurocat.ulster.ac.uk

18. AREHNA, Kos, 9-11 June 2005 Clusters under random pattern

19. AREHNA, Kos, 9-11 June 2005 Routine Statistical Monitoring Statistical tests for detection of clusters Eg. Kulldorf techniques, adjusting for multiple testing: scan moving window Would routine detection of clusters overwhelm our capacity to respond? Main problems are u not random variation, but ascertainment variation u Lack of sensitivity in picking up exposure related variation

20. AREHNA, Kos, 9-11 June 2005 Empirical clustering observations  Anophthalmia in England (Dolk 98) 444 cases born 1988-94, prevalence 1.0 per 10,000 births “Clustering” consistent with random distribution  Geographical variation in congenital anomalies in Britain (Dolk 2003) 5 regions over 9 year period 6,959 non-chromosomal anomalies; 1611 Down syndrome cases. “Clustering” consistent with random variation

21. AREHNA, Kos, 9-11 June 2005 3. Evaluation of specific environmental exposure hypotheses  Chernobyl Conclusion: no detectable effect of Chernobyl on overall prevalence of congenital anomalies in Europe (Dolk 1999)  Hazardous Waste Landfill Sites Population covered approx 100,000 births within 7 km of 26 hazardous waste landfill sites in seven regions 1089 non-chromosomal cases, 270 chromosomal cases, 2508 controls Residence within 3 km vs 3-7 km Non-chromosomal anomalies OR 1.33 (95%CI 1.11-1.59) near sites (Dolk, Vrijheid 1998); Chromosomal anomalies OR 1.41 (95%CI 1.00-1.99) (Vrijheid, Dolk, 2002)

22. AREHNA, Kos, 9-11 June 2005 Evaluation of specific environmental exposure hypotheses  Risk of hypospadias in relation to maternal occupational exposures to endocrine disrupting chemicals Routine data UK-NCAS, 1980-96 Includes code for maternal occupation at time of birth registration Job-exposure matrix to classify exposure to potential EDCs (van Tongeren 2002): 7 chemical groups (phthalates, pesticides, alkyl phenolics, heavy metals, etc); 8% of cases classified with probable exposure Results: (Vrijheid, Armstrong et al 2003) No increase in risk of hypospadias in categories of “possible” or “probably” exposure to EDCs Increased risk for hair dressers / exposure to phthalates in one time period, before adjustment for socio-economic status

23. AREHNA, Kos, 9-11 June 2005 Evaluation of specific environmental exposure hypotheses Will we be overwhelmed with associations with environmental pollution beyond our capacity to respond? u Missing what is real: Exposure misclassification tends to dilute real associations u Finding what is not real: Ascertainment variation and confounding can exaggerate or reduce real associations or produce spurious associations where none exists

24. AREHNA, Kos, 9-11 June 2005 Advantages of congenital anomaly surveillance Short time lapse between exposure and diagnosis Continuously updated (spatially referenced) denominator statistics (births) Network of established registers with harmonised data collection

25. AREHNA, Kos, 9-11 June 2005 Methodological challenges in environmental surveillance  Relating to congenital anomaly data: u Classification: lumping and splitting u Adjustment for terminations of pregnancy u Diagnostic and ascertainment variation  Relating to other data sources: u Easily accessible systems of georeferencing of cases and births across Europe u Easily accessible information on environmental exposures in Europe How to defined “similar” exposures?: lumping and splitting again Exposure modelling/exposure surrogates/biomarkers? u Easily accessible information on socioeconomic status across Europe  Integration of systems, including expertise

26. AREHNA, Kos, 9-11 June 2005 Conclusions  Fetal life is an especially sensitive period to environmental exposures  Crucial fetal exposure occurs before the pregnancy is recognized  The proportion of congenital anomalies attributable to environmental pollution may not be high, but any excess cases would represent a failure of our environmental health protection system  EUROCAT, covering a quarter of European births, can play an important part in a European environmental health surveillance strategy