European Birth CohortsEuropean Birth Cohorts

- OverviewOverview- Some lessons from data Some lessons from data poolingpooling

Martine Vrijheid

BackgroundBackground

Foetus and infant are especially vulnerable to the effects of environmental contaminants, and that these effects may manifest themselves throughout the lifetime and even over generations.

In Europe, there are many pregnancy and birth cohorts currently collecting a wealth of information on environmental exposure and child outcomes.

Pregnancy and birth cohort studies have played an important role in studying these effects.

Data are often of fragmented nature and there is relatively little coordination to structure and consolidate scattered research.

Aim

Coordination of European birth cohort research in the area of environmental exposures.

Objectives

• Inventory of birth cohort data

• Evaluate exposure, health and exposure-response data

• Attempt to combine data from various cohorts

• Make recommendations

Methods

• Inventory questionnaires to cohorts

• Working Groups – expert evaluation of cohort data

• Workshops involving all cohorts

ENRIECOENRIECO

Objectives1. Inventory of data from cohorts and registries

2. Evaluation of existing information

3. Recommendations for research action in key areas of policy concern

4. Recommendations for improved contribution of mother-child cohort research to policy at European level

5. Dissemination

AimTo develop a strategy for mother-child cohort research in Europe through the coordination of European cohorts.

Faroes

DNBC

Co.N.ER

INUENDO

Duisburg

EDEN

Generation XXI

FLEHS I

HUMIS

INMA-old

REPRO_PL

KANC

LUKAS

PCB cohortINUENDO

RHEA

Czech

Leicester MAS

NINFEA

GASPII

INUENDO

GINIplus

BAMSE

PÉLAGIE

MoBa

ABCDGeneration R

KOALAPIAMA

LISAplusALSPAC

BiB

Size of circle:

< 1,000

1-5,000

5-20,000

100,000

INMA-new

DARC

PARIS

ArcRisk-Norway

Krákow

37 birth cohorts

T1 T2 T3

Leicester I 1985Faroes 1 1986

MAS 1990ALSPAC 1991

Leicester II 1993BAMSE 1994Faroes 2 1994

Czech 1994GINIplus 1995

DNBC 1996PIAMA 1996Faroes 3 1997

INMA old 1997LISAplus 1997

DARC 1998MoBa 1999

Duisburg 2000KOALA 2000Krákow 2000

Generation R 2001PCB cohort 2001

FLEHS I 2002HUMIS 2002

INUENDO 2002LUKAS 2002

PÉLAGIE 2002ABCD 2003EDEN 2003

GASPII 2003PARIS 2003

Co.N.ER 2004Generation XXI 2004

INMA new 2004NINFEA 2005

ArcRisk-Norway 2007BiB 2007

Faroes 5 2007KANC 2007

REPRO_PL 2007RHEA 2007ELFE 2011

Cohort 18m-5yr 5-10yr 10+ yrStart Pregnancy Birth 1-6m 6-18m

www.birthcohortsenrieco.net

B: blood, CB: cord blood, U: urine, P: placenta, BM: breastmilk, S: saliva, H: hair,

ExposuresExposures

Cohort Metals Persistent Organic Pollutants and other pesticides Tobacco smoking Other chemicals

ALSPAC As, Cd, Hg, Mn, Pb, Se*, TMS

PFCs* cotinine -

ArcRisk-Norway As, Cd, Co, Hg, Mb, Mn , Pb chlordane, DDT/DDE, HCB, PCBs - planned

BAMSE - - cotinine -

Czech - - cotinine PAHs

DNBC - PFCs - -

Duisburg Cd, Hg, Pb, Se DDT/DDE, HCB*, HCH, PCBs, PCDDs, PCDFs, PFCs cotinine* BPA, phthalates

EDEN B, Cd, Mn, Hg, Pb - cotinine phthalates, phenols (incl BPA)

ELFE Al*, As*, Cd*, Hg*, Pb* BFRs*, organochlorines*, PFCs*, PCBs*, PCDDs*, PCDFs*, organophosphates*, pyrethroids*

cotinine* BPA*, phthalates*

Faroes Hg, Pb, Se BFRs*, chlordane, DDT/DDE, dieldrin/endrin, heptachlor, HCB, β-HCH, mirex, organometallic compounds, PCBs, PFCs*, toxaphene

- BPA*, phthalates*

FLEHS I Cd, Pb DDT/DDE, dioxin-like compounds, HCB, PCBs - -

Generation R - organochlorines*, organophosphates - BPA, phthalates

GINIplus - - cotinine -

HUMIS Hg*, Pb* BFRs, DDT/DDE, HCB, HCH, mirex, PCBs, PCDDs, PCDFs, PFCs, toxaphene

- phthalates

INMA old Hg, Pb*, TMS* aldrin/dieldrin/endrin, BFRs, DDT/DDE, endosulphan, lindane, methoxychlor, mirex, HCB, HCH, PCBs

cotinine phthalates, phenols (incl BPA)

INMA new Hg, Pb, TMS* BFRs, DDT/DDE, HCB, HCH, PCBs cotinine phthalates, phenols (incl BPA)

INUENDO Cd*, Hg*, Pb* BFRs*, DDT/DDE, HCB*, PCBs, PFCs* - BPA*, phthalates*

Krákow Cd, Hg, Pb - cotinine Phthalates, PAHs, benzo[a]pyrene-adducts

LISA - - cotinine -

LUKAS As, Cd, Hg, Pb, Se BFRs, DDT/DDE, organometallic compounds, PCBs, PCDDs, PCDFs, polychlorinated naphthalene

- phthalates*

MAS - - cotinine -

MoBa planned BFRs*, DDT/DDE*, PCBs*, organophosphates - BPA, phthalates

NINFEA - - - -

PCB cohort Hg, Pb DDT/DDE, HCB, HCH, PCBs, PFCs* - phthalates*

PÉLAGIE Hg aldrin, BFRs, DDT/DDE, dieldrin/endrin, heptachlor, HCB, PCBs, acetolachlore, alachlore, metolachlore, organophosphorous, propoxur, triazines

- phthalates

REPRO_PL Cd, Hg, Pb, Se, Zn, Cu PCBs, PCDDs, PCDFS cotinine PAHs (1-hydroxypyrene)

RHEA As, Cd, Hg, Mn, Pb DDT/DDE*, HCB*, PCBs*, PCDDs*, PFCs* NNAL, cotinine phthalates*

Exposure BiomarkersExposure Biomarkers

0 5 10 15 20 25 30 35 40

SEXUAL MATURATION

METABOLIC SYNDROME

GROWTH & OBESITY

CANCER

Food allergies

Respiratory infections

Eczema

Allergic rhinitis

Allergies

Asthma

ALLERGIES & ASTHMA

Personality

Mental health

School achievements/performance

Hyperactivity disorders

Autism symptoms

Behaviour

Cognitive function

NEURODEVELOPMENT

Ultrasound measurement

Mode of delivery

Birth weight

Gestational age

Spontaneous abortion/stillbirths/terminations

Congenital anomalies

Time to pregnancy

BIRTH OUTCOMES

Number of cohorts

doneongoingplanned

www.birthcohorts.net

Combining data – ongoing:Combining data – ongoing:

POPs & birth outcomes

Smoking, SHS & asthma and allergies

Alcohol consumption & birth outcomes

Socioeconomic inequalities & birth outcomes

Maternal occupation & birth outcomes

Fish consumption & birth outcomes

Maternal complications & asthma and allergies

Obesity – BMI as predictor of body fat

Other EU projects: air pollution, water DBPs, biological agents, etc.

Govarts et al. 2011. EHP. In Press. Prenatal exposure to polychlorinated biphenyls (PCB) and dichlorodiphenyldichloroethylene (DDE) and fetal growth: a meta-analysis within 12 European birth cohorts.

Association of cord serum concentrations of PCB 153 (ng/L) with birth weight (grams

Case studies to evaluate combined data analyses…

…using the original raw data from European birth cohorts on allergy / asthma

to examine associations between:

indoor environmental exposures (a. dampness/mould; b. second hand tobacco smoke)

allergies

(asthma, allergic rhinitis, eczema)Courtesy: Thomas Keil

Step 1: Willingness to participate

Step 2: Assess eligibility of cohorts

Step 3: Collect individual participant data

Step 4: Harmonise data

Step 5: Perform analyses (indiv. cohorts and meta-a.)

Courtesy: Thomas Keil

Step 1: Willingness to participate

Trust building

- Personal contact, if possible

- Transparency throughout (propose analysis strategy,

discuss analysis plan, agree!, abstracts, publications)

- Regular information on progress

Courtesy: Thomas Keil

Cohorts in WG 1 (dampness/mould)

1. ALSPAC2. BAMSE3. CO.N.ER4. DARC5. GINI6. KOALA7. Leicester8. LISA9. MAS10. NINFEA11. PIAMA-NHS

Cohorts in WG 2 (smoke+asthma 4-6y)

1. ALSPAC2. AMICS3. BAMSE4. DARC5. GINI6. PIAMA-NHS7. KOALA8. Leicester9. LISA10. MAS

Cohorts in WG 3(smoke+wheeze 0-2y)

1. ALSPAC2. AMICS3. BAMSE4. CO.N.ER5. DARC6. Generation R7. GINI8.-11. INMA A, G, S, V 12. KOALA13. Leicester14. LISA15. MAS16. NINFEA17. PIAMA-NHS18. EDEN19. RHEA

Step 2: Eligibility of Cohorts

Courtesy: Thomas Keil

Step 3: Delays in data collection process because of

• Variables not send in correct order• Labels did not often include the whole translated

questions• Half of the variables were wrongly or not

translated at all• Plausibility checks showed categories were

sometimes wrong (eg non-smokers with 10 cig/day)

Courtesy: Thomas Keil

Step 4: Data Harmonization

Homogeneous data only for some outcome variables (ISAAC questions were often modified)

Very heterogeneous data for:- Main exposures (mould/dampness, smoking)- Potential confounders (breast feeding, smoking, educational level etc)

- Variation in time points of exposure and follow-up assessment

Courtesy: Thomas Keil

Adjusted for sex, parental asthma, parental education, birth weight and older siblings.

Prenatal second hand smoke exposure and asthma age 4-6 years

NOTE: Weights are from random effects analysis

Overall (I-squared = 0.0%, p = 0.444)

LISA

PIAMA

MAS

DARC

BAMSE

AMICS-M

cohort

1.47 (1.22, 1.78)

1.67 (0.90, 3.10)

1.10 (0.73, 1.66)

2.83 (1.29, 6.19)

1.55 (0.56, 4.29)

1.50 (1.16, 1.94)

1.48 (0.71, 3.08)

ES (95% CI)

100.00

9.32

20.83

5.82

%

3.44

53.93

6.65

Weight

1.47 (1.22, 1.78)

1.67 (0.90, 3.10)

1.10 (0.73, 1.66)

2.83 (1.29, 6.19)

1.55 (0.56, 4.29)

1.50 (1.16, 1.94)

1.48 (0.71, 3.08)

ES (95% CI)

100.00

9.32

20.83

5.82

%

3.44

53.93

6.65

Weight

1.162 1 6.19

Step 5: Data Analyses

Courtesy: Thomas Keil

What went well?• Kick-Off Meeting successful to establish personal contacts

and interest in case studies.

• Key responsibility for coordination and communication

concentrated in one institution; with a single data

collection and harmonization process.

• Complex data questions solved by telephone contacts with

most cohorts in a fast and uncomplicated way.

Courtesy: Thomas Keil

What were the challenges?

- Time and effort for data management were

underestimated

- Heterogeneity of outcome data

- Heterogeneity of exposure data

- Frequent meetings and personal contacts essential

Compromises for outcome and exposure variables result in loss of information in harmonized datasets.

Courtesy: Thomas Keil

LessonsLessons More than 35 birth cohorts in Europe, studying more than 350 000 mother-child pairs

Data and methods are fragmented

Combining information is possible and scientifically beneficial

Combining data from existing cohorts requires careful consideration of the aims, protocols, data, ethical issues, analyses and management

it is time and labour intensive.

Future??Future??

Flexible and long-term platform/network/infrastructure for combined studies for exchange of methods/expertise

Flexible to inclusion of new cohorts

Expansion to countries outside Europe

This will only be possible with continued support for coordination.

CollaboratorsCollaboratorsProject PI: Mark Nieuwenhuijsen (CREAL)Postdoc: Maribel Casas (CREAL)WP leaders: Martine Vrijheid, Ulrike Gehring, Remy Slama, Joachim

Heinreich, Thomas Keil, Manolis Kogevinas

Cohort representatives: Anna Bergström, Amanda Carmichael, Sylvaine Cordier, Merete Eggesbø, Esben Eller, Maria P Fantini, Marieta F Fernández, Ana Fernández-Somoano, Regina Grazuleviciene, Cynthia Hohmann, Anne M Karvonen, Gudrun Koppen, Ursula Krämer, Claudia E Kuehni, Per Magnus, Renata Majewska, Anne Marie Nybo Andersen, Evridiki Patelarou, Maria Skaalum Petersen, Frank H Pierik, Kinga Polanska, Daniela Porta, Lorenzo Richiardi, Ana Cristina Santos, Radim J Sram, Carel Thijs, Christina Tischer, Gunnar Toft, Tomáš Trnovec, Stephanie Vandentorren, Tanja GM Vrijkotte, Michael Wilhelm, John Wright

The full evaluation reports are publically available through the ENRIECO website: www.enrieco.orgInventory: www.birthcohortsenrieco.net

www.chicosproject.eu

Project PI: - Martine VrijheidPartners: • ALSPAC cohort (Bristol, UK) - Debbie Lawlor, Particia Lucas

• Danish National Birth Cohort - Anne-Marie Nybo Andersen

• Generation R cohort (Netherlands) - Vincent Jaddoe, Hein Raat, Johan de Jongste, Liesbeth Duijts

• INMA cohort (Spain) - Jordi Sunyer, Mark Nieuwenhuijsen

• MoBa cohort (Norway) - Camilla Stoltenberg, Per Magnus

• NINFEA cohort (Turin) - Franco Merletti, Lorenz Richiardi

• RHEA cohort (Crete) - Manolis Kogevinas, Leda Chatzi