Use of data from two or more European birth cohorts - Is it worth?

1. Use of data from two or more European birth cohorts - Is it worth? Katrine Strandberg-Larsen Department of Public Health, University of Copenhagen E-mail: ksla@sund.ku.dk

2. Outline • Exploring educational disparities in risk of preterm birth: A comparative study of 12 European birth cohorts • Light drinking during pregnancy and preterm delivery • Caffeine intake in pregnancy and risk of cerebral palsy in offspring • The MOBAND ongoing work

3. Educational disparities in preterm birth – a comparative study of 12 European birth cohorts A CHICOS case study

4. Background & aim Background: An educational gradient in preterm birth has been observed in many countries The mechanisms behind this gradient are poorly understood Aim: Compare risk of preterm birth by maternal education in European birth cohorts Pedersen CB. Pediatric and Perinatal Epidemiology 2008

5. Identification of birth cohorts Cohort inventories: • www.birthcohorts.net • www.birthcohortsenrieco.net Other sources: • Publications on preterm birth • Cohort profiles • Cohort home pages August 2011

6. Included cohorts Results: • 65 birth cohorts identified • 19 satisfied eligibility criteria • 2 non responders • 2 declined to participate • 2 did not deliver data on time • 1 excluded recruitment too late in pregnancy Eligibility criteria: • ≥ 3,000 observations • Recruited either during pregnancy or at delivery • Sampling irrespective of pregnancy complications and/or outcome - except restrictions to: • Singletons and Non-ART pregnancies

7. Cohort characteristics -> Open/dynamic cohort – recruitmentcontinuously

8. Preterm birth • Live births (GA:>21 and <37 completedweeks) • GA recordeddifferently in the cohorts: • A combination of LMP, US and clinicalassessment • LMP measure, if <2 weeks variation from US measure – then US measure • Exclude observations with GA >43 weeks • Excludeimplausible GA-BW combinations

9. Classification of maternal education Group 1: Basic schooling (Primary or lower secondary school) or less Group 2:Intermediate education (Higher secondary school, lower vocational training, short further education) Group 3: Long education (university degree, or further education or vocational training corresponding to a bachelor degree)

11. Light drinking during pregnancy and preterm birth A CHICOS case study

12. Are there beneficial effects of light drinking? • Light drinking is < 1 drink/day • A ’J-shaped’ curve has been observed for: • Birth weight / SGA / IUGR • Preterm birth • Still birth • Behavioral problems • Cognitive problems

13. A healthy drinker effect Behavior modification bias Confounding Light drinkers are more likely than abstainers to be: From high income households Better educated Older Multiparous (Non-smokers) • Widespread consensus that alcohol is harmful during pregnancy • Women with a troublesome pregnancy experience will avoid drinking alcohol • Women with a high a-priori risk of reproductive failure will be over-represented among non-drinkers

14. Aim • To examine whether the observed beneficial effects of light drinking are attributable to behavior modification bias • Examine the association between light drinking during and preterm delivery, and: • - Restrict analysis to women unaware of their reproductive abilities

15. Included cohorts Results: • 65 birth cohorts identified • 15 satisfied eligibility criteria • 2 non responders • 1 declined to participate • 3 turned out not to have the mandatory data Eligibility criteria: • Enrolment during pregnancy and enrolment ongoing or terminated • Data on: • Average weekly alcohol consumption • Gestational age + birth weight • Gravidity • Time to pregnancy

16. Difficult to harmonize alcohol data • Great variation in questions and fixed response categories – we are still working on imputing data to compensate for differences caused by differences in categories

17. Lessons learned - positive • Willingness to do cross cohort collaboration • Able to transfer anonymised data across borders • Despite great differences between cohorts able to do similar analysis on e.g. educational disparities

18. Lessons learned – challenges • Difficult to establish contact, and time consuming • The information on the inventories is not up to date, e.g. contact information, the number of participants are exaggerated, the information on variables • Around 1/3 of the European cohorts include 3000+ observations • Great variation in the collected data – use of questionnaires/measurements • A lot of the cohorts do not have English translations of the data at hand • No formal instructions to follow when applying for data, and transfer data across borders • The number of cohorts is quickly reduced when you need information on specific variables • Very time consuming every time you add data from a cohort

19. Lessons learned Great diversity – too much? It is easier if…

20. Insert«Academic unit» on every page:1 Go to the menu «Insert»2 Choose: Date and time3 Write the name of your faculty or department in the field «Footer» 4 Choose «Apply to all" Caffeine intake in pregnancy and risk of cerebral palsy in offspring– a joint study in three large Nordic birth cohorts

21. Background – cerebral palsy (CP) • Prevalence: ~2 per 1000 liveborn • reliable diagnosis at 2-4 years of age • Several more or less distinct subtypes • Caused by damage to immature brain - aetiologies largely unknown • birth asphyxia – 10%? • preterm delivery strong risk factor • life style?

22. Caffeine and cerebral palsy • Caffeine in pregnancy has been linked to adverse outcomes, such as: • spontaneous abortion • fetal death • fetalgrowth restriction • birth defects • Caffeine citrate is used to prevent episodes of apnea in premature infants. Infants treated with caffeine have • lower risk of cerebral palsy (OR=0.6, CI:0.4-0.9) 1 • greater chance of survival without neurodevelopmental disabilities • 1Long-term effects of caffeine therapy for apnea of prematurity, Schmidt B et al, NEJM, 2007

23. Research question Does caffeine intake during pregnancy affect the risk of cerebral palsy in offspring?

24. The three large Nordic birth cohorts • Rare disease so great sample size is need • Prospectively collected information on intake of caffeinated beverages • Similar data collection will ease the data harmonization or at least comparability of the results

25. Early pregnancy Mid-pregnancy Late pregnancy ABC(1990-) Questionnaire Week 12-16 Recruitment Week 6-10 1st interview Week 16 FFQ Week 24 2nd interview Week 31 Recruitment Week 8+ DNBC (1996-2002) Birth Birth Recruitment and 1st questionnaire ,Week 17 3rd questionnaire Week 30 FFQ Week 22 MoBa (1999-2008) Birth

26. Data material • Study populations • Denmark: 104,367 liveborn • Norway: 60,953 liveborn • Identification of CP cases • Denmark: national cerebral palsy registry, 198 cases • Norway: maternal report at age 3/5 years, 109 cases • Intake of caffeinated beverages collected in early, mid- and late pregnancy

27. Risk of CP by consumption of coffee Early pregnancy Mid-pregnancy Late pregnancy P-value=0.001 Adjusted for maternal age, social status, smoking, medically assisted reproduction and tea/cola consumption

28. Risk of CP by consumption of tea Early pregnancy Mid-pregnancy Late pregnancy P-value=0.016 Adjusted for maternal age, social status, smoking, medically assisted reproduction and coffee/cola consumption

29. Risk of CP by consumption of cola Early pregnancy Mid-pregnancy Late pregnancy SOFT DRINKS P-value=0.016 P-value<0.001 P-value=0.002 Adjusted for maternal age, social status, smoking, medically assisted reproduction and coffee/tea consumption

30. Risk of CP by total caffeine consumption Early pregnancy Mid-pregnancy Late pregnancy P-value=0.005 Adjusted for maternal age, social status, smoking, medically assisted reproduction

31. Conclusions • Negative associations between caffeinated beverages in early pregnancy and CP • coffee and total caffeine in Danish cohorts • cola in ABC (Danish) and MoBa (Norwegian) • who are the cola consumers? • No evidence of protective effect of caffeine in late pregnancy • negative association coffee-CP in Norway

32. Is it worth? YES – definitely Easiest when the number of cohort is small

33. Insert«Academic unit» on every page:1 Go to the menu «Insert»2 Choose: Date and time3 Write the name of your faculty or department in the field «Footer» 4 Choose «Apply to all" MOBAND(MOthers and BAbies in Norway and Denmark) An epidemiologic study of cerebral palsy in the Norwegian and Danish birth cohorts

34. Thank youAcknowledgements: The CHICOS work • Gry Poulsen (DK) • Anne-Marie Nybo Andersen (DK) • Pernille Stemann Larsen • All CHICOS collaborators The MOBAND work • Mette C Tollånes (N) • Gitte Lindved Pedersen (DK) • Tine Brink Henriksen • Allen J Wilcox • All MOBAND collaborators

35. Explanations • Lower proportion of high caffeine consumers in Norway • The observed association is attributable to confounding – and the confounding structure may be different in the two countries – the coffee consumers have same characteristics on the measured variables • Difference in case definition and more chance of selection bias in MoBa – as cerebral palsy is self-reported • Too few cases, especially in the MoBa study

36. Thank you for your attention Acknowledgments goes to: Mette C Tollånes Allen Wilcox Kacey Eichelberger Camilla Stoltenberg Dag Moster Denmark Norway • Gitte Lindved Petersen • Bodil Hammer Beck • Jørn Olsen • Morten Søndergaard Jensen • Tine Brink Henriksen • Peter Uldall