EUROCAT

CCASN Stakeholders meetingOttawa, November 2008

Ester Garne

Agenda

What is EUROCAT? Methods and surveillance European differences EUROCAT studies

European Surveillance of Congenital Anomalies

Supported by the EU Public Health Programme

WHO Collaborating Centre for the Epidemiological Surveillance of Congenital Anomalies

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.

Full Member

Associate Member

< 10,000 births per year

10,000 – 40,000 births per year

> 40,000 births per year

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

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

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

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

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

Distribution of type of malformation

0

5

10

15

20

25

30

% o

f to

tal

All full member registries 2000-2005

All Anomalies, Full Member Registries, 1992-2004

0

50

100

150

200

250

300

199

2

199

3

199

4

199

5

199

6

199

7

199

8

199

9

200

0

200

1

200

2

200

3

200

4

Years

Pre

vale

nce

per

10,0

00 b

irth

s

All Anomalies LB Prevalence All Anomalies TOPFA PrevalenceAll Anomalies Total Prevalence Cardiac Anomalies Total Prevalence

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

Discharge diagnosis cannot be the only source of data - examples from Odense

Discharge diagnosis Reviewed diagnosis

Hypospadia Hooded foreskin

Malformation of hand Reduction defect of hand

Unspecified malformation Gastroschisis

Choanal atresia Only suspected – not confirmed

Patent ductus Term baby with pulmonary hypertension

Hydronephrosis Multicystic renal dysplasia

Malformation of circulatory system

Pulmonary valve atresia

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

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)

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

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

Statistical problemsProblem Solution

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 area

No solution yet

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

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

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

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

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

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

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

European laws and recommendations

Different recommendations on prenatal screening – ultrasound and invasive tests

Different laws on terminations of pregnancy

Prevalence of hydronephrosis -

all cases and prenatally diagnosed

0

5

10

15

20

25

30

35

pr 1

0,00

0 bi

rth

s

prevalence prev prenatal

Garne et al. Journal of Paediatric Urology, in press

Distribution of type of birth - 2000-2006

Registry Country LB FD TOPFA

Paris France 64% 1% 34%

Northern Region

UK 76% 2% 21%

Tuscany Italy 82% 1% 17%

Odense Denmark 83% 2% 15%

Mainz Germany 87% 3% 10%

Groningen Netherlands 90% 3% 6%

Dublin Ireland 94% 6% 0%

Wielkopolska Poland 99% 1% -

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

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

The opportunity for pooling of data

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

Prevalence of gastroschisis in Europe, by maternal age

0

2

4

6

8

10

12

1980-1984 1985-1989 1990-1994 1995-2000 2000-2002

time period

Pre

vale

nce

per

10,

000

bir

ths

<20

20-24

25-29

30-34

35+

all ages

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.

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

Cerebral palsy and congenital malformations

SCPE database

1976-1996

EUROCAT 1980-1992Livebirths

only

RatioSCPE/

EUROCAT

Cerebral malformations excl NTD

859.5 7.8 110

Microcephaly 222.5 2.7 82

Hydrocephaly 161.4 2.7 60

Eye 17.5 5.7 3.1

Facial clefts 39.3 13.6 2.9

Congenital heart disease 63.3 48.1 1.3

Digestive and abdominal wall

17.5 14.2 1.2

Malformations of diaphragm 6.5 2.5 2.6

Renal 10.9 18.1 0.6

Hypospadia and other genital

10.9 15.9 0.7Garne E et al. Cerebral palsy and congenital malformations. Eur J Peadiatr Neurology 2007

The opportunity for opportunity for comparison of datacomparison of data

Neural tube defects in Europe

0

10

20

30

40

50

60

1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Year

Pre

vale

nce

per

100

00 b

irth

s

UK & Ireland Rest of Europe

Common response to public health questions

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

O O/E 95%CI

Down Syndrome 24 0.94 0.60 - 1.40

Neural Tube Defects British isles (5 regs) Cont Europe (11 regs)

29

25

0.61

1.21

0.41 - 0.88

0.78 - 1.79

Hydrocepahly 36 0.83 0.58 - 1.14

Microcephaly 26 0.87 0.57 - 1.28

An/Microphthalmia 11 1.03 0.51 - 1.85

Congenital cataract 7 0.72 0.29 - 1.49

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

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

Ethical problems problems

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 pregnancyBoyd BJOG 2008

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