1. EUROCAT CCASN Stakeholders meeting Ottawa, November 2008 Ester Garne

2. Agenda  What is EUROCAT?  Methods and surveillance  European differences  EUROCAT studies

3. European Surveillance of Congenital Anomalies Supported by the EU Public Health Programme WHO Collaborating Centre for the Epidemiological Surveillance of Congenital Anomalies

4. What is EUROCAT?  European network of population-based registries for the epidemiologic surveillance of congenital anomalies.  Started in 1979  More than 1.4 million births surveyed per year in Europe  39 registries in 20 countries  26% of European birth population covered  High quality multiple data source registries, ascertaining terminations of pregnancy as well as births.

5. Full Member Associate Member < 10,000 births per year 10,000 – 40,000 births per year > 40,000 births per year

6. EUROCAT Objectives  Provide essential epidemiologic information on congenital anomalies in Europe  Co-ordinate the establishment of new registries throughout Europe collecting comparable, standardised data  Co-ordinate the detection and response to clusters and early warning of teratogenic exposures

7. EUROCAT Objectives cont.  evaluate the effectiveness of primary prevention  assess the impact of developments in prenatal screening  provide an information and resource centre and ready collaborative research network to address the causes and prevention of congenital anomalies and the treatment, care and outcome of affected individuals

8. Methods  Livebirths, fetal deaths with GA  20 weeks and terminations of pregnancy (TOPFA) after prenatal diagnosis of malformation  Follow-up during first year of life for late diagnosed cases in most registries  All registries are population based  Multiple sources of ascertainment  ICD10 Q chapter for inclusion and list of minor anomalies for exclusion (codes and/or text)  Central database at University of Ulster

11. Local and central data  Data send to Central Registry once per year (2 deadlines)  Local and central datavalidation  Local approval of data before published on the website  No data used without local approval for the specific purpose (research)  Data owned by local registry  Only year of birth for data send outside Central Registry

12. Size of EUROCAT registries  Large difference in number of births covered: from 4.000 births per year til 65.000 births per year  For full membership: Recommend minimum 5000 births per year At least 15.000 births before prevalence data is placed on the website Optimal size of a EUROCAT registry is 10.000- 20.000 births per year

13. Distribution of type of malformation All full member registries 2000-2005

14. All Anomalies, Full Member Registries, 1992-2004

15. For most malformations there is no clear limit between the normal situation and the malformation Therefore strict definitions and inclusion or exclusion criteria are needed before comparison of data

16. Discharge diagnosis cannot be the only source of data - examples from Odense Discharge diagnosisReviewed diagnosis HypospadiaHooded foreskin Malformation of handReduction defect of hand Unspecified malformationGastroschisis Choanal atresiaOnly suspected – not confirmed Patent ductusTerm baby with pulmonary hypertension HydronephrosisMulticystic renal dysplasia Malformation of circulatory system Pulmonary valve atresia

17. Statistical surveillance  The main aim of EUROCAT and what EU is funding us for  Looking for new teratogenes – including drugs  Surveillance is to detect clusters and trends and to act as early warning system  Clustering in space and time

18. Monitoring – Surveillance Detection of clusters – New teratogens  Based on the malformation codes  Statistical noise from  Different doctors code differently  Specified versus unspecified  Number of digits used  Malformation / syndrome feature  Inclusion of genetic syndromes (diagnosed or undiagnosed)  Other known etiology (fetal alcohol syndrome etc)

19. Methods  Statistical software developed for use at both central and local level  Cluster analysis: requiring minimum 7 cases over a 5 year period and aim to detect clusters of less than 18 months within the last 2 years of the period  Trends: 10 years data using number of cases per year and number of births per year

20. Detection of clusters and trends  Annual statistical surveillance done at central registry after February deadline for sending data  Preliminary discussion at the spring PMC meeting  Results send to local registries one month before the annual meeting  Session at the annual meeting in June to discuss local clusters and trends  Statistical monitoring report published 3-6 months after the meeting – next time with a press release

21. Statistical problems ProblemSolution Subgroups may be heterogenous and inflated by genetic conditions We have revised the subgroups to make them more specified and clinically relevant Chromosomal cases often have several major malformations Chromosomal cases deleted from non-chromosomal subgroups Surveillance based on date of birth problematic when adding livebirths and TOPFA Surveillance based on calculated date of conception (using GA) Surveillance of multiple malformations Flow-chart developed but not yet implemented in routine surveillance Change in registry uptake areaNo solution yet

22. Local registry investigations of clusters 2006 data surveillance  Apparent cluster with cause for concern, investigation ongoing (n = 0)  Not “true” cluster as associated with aetiologic hetero- geneity, change in diagnosis, familial recurrence (n = 1)  Excess of cases confirmed but no further investigation proposed other than further surveillance (n = 5)  Increase in cases due to increasing use of invasive diagnostic procedures or improvements in prenatal ultrasound detection rates or better ascertainment (n = 2)  Data quality issues found to explain cluster (n = 4)  No report of preliminary investigations send to Central registry (n = 5) 17 clusters in 2002-2006

23. Cluster - Dublin  Ventricular septal defect  Date of conception  1.5 months (06-07-04 – 26-08-04): 18 cases  Expected: 4.6, p = 0.012  Decreasing trend of VSD in same time period  Local investigation: no obvious reason. Registry will monitor VSD rates with paediatric cardiology department

24. Cluster - Odense  Edward syndrome/trisomy 18  Date of conception  03/09/02 – 11/02/03: 6 cases  Expected: 1,14, p = 0,033  Local investigation: one was a familial translocation. After exclusion of this case, the cluster disappeared

25. Personal unique ID numbers in Scandinavia  Given at birth and is used in every contact to official authorities until death  051108 – 5689 boy born today  051108 – 6708 girl born today  051198 – 3478 girl 10 years today  Sweden add five digits

26. European differences  Some differences are related to acces to datasources  Some differences are related to difference in diagnostic methods  Some differences are related to laws and recommendations

27. Access to data sources  Active or passive case ascertainment  Length of follow-up of late diagnosed cases in childhood  Main data-sources: prenatal, postnatal, genetic, obstetric or paediatric

28. Diagnostic methods - examples  Hip dislocation: routine ultrasound after birth or clinical diagnosis  Access to MR scan: many cerebral malformations only visible at MR  Access to echocardiography: small muscular VSD’s may close spontaneously or may not be diagnosed if access to echo is restricted or waiting time for echo is long

30. European laws and recommendations  Different recommendations on prenatal screening – ultrasound and invasive tests  Different laws on terminations of pregnancy

31. Garne et al. Journal of Paediatric Urology, in press

32. Distribution of type of birth - 2000-2006 RegistryCountryLBFDTOPFA ParisFrance64%1%34% Northern RegionUK76%2%21% TuscanyItaly82%1%17% OdenseDenmark83%2%15% MainzGermany87%3%10% GroningenNetherlands90%3%6% DublinIreland94%6%0% WielkopolskaPoland99%1%-

34. European differences  In Paris very high level of prenatal diagnosis and TOPFA allowed at all GA - In Poland mainly malformations visible at birth, TOPFA only on very limited indications  In many European countries livebirths are a selected group of all pregnancies  European differences are a challenge in surveillance and research – not a limitation

35. Why European collaboration?  Sharing of expertise and resources  Pooling of data  Comparison of data  Common response to public health questions  www.eurocat.ulster.ac.uk www.eurocat.ulster.ac.uk

36. The opportunity for pooling of data

37. Risk of congenital anomalies near hazardous-waste landfill sites in Europe: the EUROHAZCON study. Multicentre case-control study in seven regions, 1089 cases of non-chromosomal anomaly and 2366 controls. Dolk H, Vrijheid M, Armstrong B, Abramsky L, Bianchi F, Garne E, Nelen V, Robert E, Scott JES, Stone D, Tenconi R.. Risk of congenital anomalies near hazardous waste landfill sites in Europe: the EUROHAZCON study. Lancet 1998; 352: 423-27

38. Prevalence of gastroschisis in Europe, by maternal age Loane, Dolk, Bradbury and EUROCAT Working group: Increasing prevalence of gastroschisis in Europe 1980-2002: a phenomenon restricted to younger mothers? Paediatr Perinat Epidemiol. 2007 Jul;21(4):363-9.

39. Exposure to anti-epilectic drugs during pregnancy  Concern about Lamotrigine has recently centered on a signal regarding a 14-fold higher rate of isolated orofacial clefts in infants exposed during pregnancy (FDA alert September 2006)  EUROCAT decided in December 2006 to do a study on lamotrigine exposure during pregnancy to confirm this finding  Population-based case-control study with malformed controls based on EUROCAT data  19 registries contributed to the study with data for some or all of the period 1995-2005  The study population covered a total of 3.9 million births  Nearly 500 cases exposed to any anti-epilectic drug  We could not confirm the increased risk of facial clefts after lamotrigine expoure Dolk et al. "Does Lamotrigine Use in Pregnancy Increase Orofacial Cleft Risk Relative to Other Malformations", Neurology 2008

40. Cerebral palsy and congenital malformations SCPE database 1976-1996 EUROCAT 1980-1992 Livebirths only Ratio SCPE/ EUROCA T Cerebral malformations excl NTD 859.57.8110 Microcephaly222.52.782 Hydrocephaly161.42.760 Eye17.55.73.1 Facial clefts39.313.62.9 Congenital heart disease63.348.11.3 Digestive and abdominal wall17.514.21.2 Malformations of diaphragm6.52.52.6 Renal10.918.10.6 Hypospadia and other genital10.915.90.7 Garne E et al. Cerebral palsy and congenital malformations. Eur J Peadiatr Neurology 2007

41. opportunity for The opportunity for comparison of data comparison of data

42. Neural tube defects in Europe

43. Common response to public health questions

44. Evaluation of the impact of Chernobyl on the prevalence of congenital anomalies in 16 regions of Europe. Observed and expected cases among pregnancies exposed in the first month following Chernobyl Source: Dolk H, Nichols R and a EUROCAT Working Group. Evaluation on the impact of Chernobyl on the prevalence of congenital anomalies in 16 regions of Europe. Int J Epid 1999; 28: 941-948

45. Pharmacovigilance  The lamotrigine study has shown that the EUROCAT database can be used to answer questions of public concern on drug exposure during pregnancy  The largest existing database in the world for studying exposure to anti-epileptic drugs  Studies on drugs for other chronic maternal diseases possible  Controls inside the EUROCAT database  Answer possible in less than one year  Our method can answer questions on increased risk of a specific malformation but cannot give the exact risk of malformations in exposed pregnancies  We hope to expand the network by getting information on non- malformed controls - if we can find funding

47. problems Ethical problems

48. Terminations of pregnancy  Different laws on termination of pregnancy  TOP after prenatal detection of malformation is a major burden for the couple  The future goal should be primary prevention of malformations – not to diagnose prenatally and terminate (secondary prevention)  2000 late TOPFA (GA ≥ 24 weeks) in the EUROCAT database for the latest 5 year period  If primary prevention is not possible: early prenatal diagnosis of severe malformations very important to avoid the very difficult situation with a late TOPFA EUROCAT paper published on European policies on prenatal diagnosis and termination of pregnancy Boyd BJOG 2008

49. Collaboration creates a whole that is greater than the sum of its part Epidemiology 1997 The strenght of EUROCAT collaboration www.eurocat.ulster.ac.uk