1. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL ALSPAC AND CROSS-COHORT STUDIES Causal Effects of Breastfeeding on Child Health Outcomes Marie-Jo Brion Sir Henry Wellcome Postdoctoral Fellow MRC Centre for Causal Analyses in Translational Epidemiology School of Social and Community Medicine University of Bristol

2. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Cause and Effect in Observational Studies: Getting the Right Answer Examples where observational studies and RCTs fail to arrive at the same answer Protective effects on CVD from observational studies : Beta carotene Vitamin E supplements Vitamin C supplements Hormone replacement therapy Large RCTs showed no protective effect Likely explanation: confounding in particular, confounding by socioeconomic position ** NEED BETTER CAUSAL APPROACHES **

3. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL What are the causal effects of breastfeeding on IQ, obesity and blood pressure? Evidence from comparing high-income with middle-income cohorts Marie-Jo Brion, Debbie Lawlor, Alicia Matijasevich, Bernardo Horta, Luciana Anselmi, Ana Maria B Menezes, Cesar Victora, George Davey Smith Brion et al (2011) IJE 40(3): 670

4. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Objectives Explore novel approach for improving causal inference in observational studies Comparing associations from HIC to LMIC cohorts where associations of confounders with health outcomes are likely to differ between cohorts Assessing causal effects of breastfeeding on child BP, BMI and IQ

5. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL higher socioeconomic position healthy diet physical activity healthier families education Causal effects ?? less smoking better living conditions

6. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Methods ALSPAC, UK (N~5000) and Pelotas 1993, Brazil (N~1000) Meta-analyses of 5 LMIC (COHORTS consortium; N~11,000) Fall et al., IJE 2011 Randomised trial of breastfeeding promotion (PROBIT Belarus trial) Kramer et al., Arch Gen Psychiatry 2008; Kramer et al., AJCN 2007

7. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL

8. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL

9. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL

10. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Analyses Associations of indicators of SEP with breastfeeding Maternal education paternal education family income occupational social class Associations of breastfeeding duration with child outcomes: SBP/DBP ALSPAC N=5193 Pelotas N=1083 BMI ALSPAC N=4852 Pelotas N=1085 IQ ALSPAC N=4891 Pelotas N= 506

11. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Prevalence (%) Breastfeeding durationPelotasALSPAC 0 to <1 month15.6%36.8 % 1 to < 3 months25.4%15.6 % 3 to < 6 months23.6%13.7 % 6 months or more35.3%33.9 % Ever breastfed96.8%84.3% Exclusive breastfeeding at 2 months65.7%38.3%

12. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL

13. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Relative/Slope Index of Inequality Logistic regression: SEP indicator with binary outcomes Odds of outcome in highest SEP level (1) versus the lowest (0) Linear regression: SEP indicator with continuous outcomes Difference in outcome between highest SEP level (1) and the lowest (0) 30 40 50 60 70 Breastfeeding prevalence 0.2.4.6.81 Cumulative proportion of the population according to income ALSPACPelotas Breastfeeding by income

14. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL 0 1 2 3 4 5 6 7 8 9 10 OR ALSPACPelotas Cohort ORs for breastfeeding by income

15. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL BMI

16. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL higher socioeconomic position healthy diet physical activity healthier families education Causal effects ?? less smoking better living conditions Discordant ALSPAC-Pelotas

17. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Mean difference in outcome by breastfeeding category Outcome ALSPAC β (95% CI)P trend Pelotas β (95% CI)P trend SBP,-0.35 (-0.55, -0.14)0.001-0.13 (-0.83, 0.57)0.7 (mmHg) DBP-0.16 (-0.31, -0.01)0.040.05 (-0.50, 0.60)0.9 (mmHg) BMI-0.16 (-0.22, -0.09)<0.0010.14 (-0.07, 0.36)0.2 (kg/m 2 ) IQ0.97 (0.62, 1.32)<0.0011.97 (0.88, 3.05)<0.001 Breastfeeding categories: 0 to <1m; 1 to <3m; 3 to <6m; 6m or more Fully adjusted models

18. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL SBP (mmHg) ALSPAC Pelotas p hetero = 0.6 DBP (mmHg) ALSPAC Pelotas p hetero = 0.5 BMI (kg/m 2 ) ALSPAC Pelotas p hetero = 0.009 IQ ALSPAC Pelotas p hetero = 0.09 CHILD OUTCOME -0.35 (-0.55, -0.14) -0.13 (-0.83, 0.57) -0.16 (-0.31, -0.01) 0.05 (-0.50, 0.60) -0.16 (-0.22, -0.09) 0.14 (-0.07, 0.36) 0.97 (0.62, 1.32) 1.97 (0.88, 3.05) EFFECT SIZE (95% CI) 0-.50.511.522.533.5 ALSPAC-PELOTAS BREASTFEEDING ASSOCIATIONS

19. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL SBP (mmHg) ALSPAC Pelotas p hetero = 0.6 DBP (mmHg) ALSPAC Pelotas p hetero = 0.5 BMI (kg/m 2 ) ALSPAC Pelotas p hetero = 0.009 IQ ALSPAC Pelotas p hetero = 0.09 CHILD OUTCOME -0.35 (-0.55, -0.14) -0.13 (-0.83, 0.57) -0.16 (-0.31, -0.01) 0.05 (-0.50, 0.60) -0.16 (-0.22, -0.09) 0.14 (-0.07, 0.36) 0.97 (0.62, 1.32) 1.97 (0.88, 3.05) EFFECT SIZE (95% CI) 0-.50.511.522.533.5 ALSPAC-PELOTAS BREASTFEEDING ASSOCIATIONS SBP (mmHg) ALSPAC COHORT p hetero <0.001 DBP (mmHg) ALSPAC COHORT p hetero = 0.005 BMI (kg/m 2 ) ALSPAC COHORT p hetero <0.001 CHILD OUTCOME -0.35 (-0.55, -0.14) 0.12 (-0.01, 0.24) -0.16 (-0.31, -0.01) 0.10 (-0.01, 0.20) -0.16 (-0.22, -0.09) 0.04 (0.00, 0.08) EFFECT SIZE (95% CI) 0-.50.511.522.533.5 ALSPAC-LMIC COHORT CONSORTIUM BREASTFEEDING ASSOCIATIONS

20. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Comparison Method Validation ALSPAC Strong socioeconomic patterning in breastfeeding Pelotas Weak socioeconomic patterning in breastfeeding Belarus Randomised Trial Association with any breastfeeding (per category)* Effect of breastfeeding intervention Outcome β95% CIPβ PDifference in outcome 95% CI SBP, mmHg-0.35 -0.55, -0.14 0.001-0.13 -0.83, 0.57 0.70.2-2.9, 3.3 DBP, mmHg-0.16 -0.31, -0.01 0.040.05 -0.50, 0.60 0.90.2-1.8, 2.2 BMI, kg/m 2 -0.16 -0.22, -0.09<0.0010.14 -0.07, 0.36 0.20.1-0.2, 0.3 IQ0.97 0.62, 1.32<0.0011.97 0.88, 3.05<0.0015.9-1.0, 12.8 * Adjusted for all indicators of maternal education, paternal education, family income, occupational social class

21. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Using the totality of the evidence

22. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Integrating cross-cohorts and additional causal approaches Maternal prenatal smoking and child aggression: Exploring intrauterine effects in UK, Australian and Brazilian cohorts Marie-Jo Brion, Monique Robinson, Alicia Matijasevich, Colin Steer, Luciana Anselmi, Ana Menezes, Craig Pennell, Lyle Palmer, Cesar Victora, George Davey Smith, Debbie Lawlor Brion et al. (under review)

23. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Multi-method approach for assessing intrauterine mechanisms Conventional multivariable regression Cross-cohorts approach Maternal-paternal smoking comparisons Prenatal-postnatal smoking comparisons

24. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Multivariable Regression

25. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Cross-cohort confounders

26. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL

27. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Maternal-Paternal Comparisons

28. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Prenatal-Postnatal Comparisons

29. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Single Method Approach Conventional multivariable regression independent associations of maternal smoking and child aggression intrauterine effects as a possible explanation

30. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Totality of Evidence From Multiple Methods Total evidence for intrauterine effects is weak Not consistent with SEP being primary / sole determinant Confounding by other familial factors

31. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL ALSPAC and Cross-Cohort Studies ALSPAC integrated with additional cohorts to explore cross-cohort approach for improving causal inference based on conventional method alone Value of integrating multiple methods for assessing causal mechanisms to arrive at conclusions based on totality of evidence Breastfeeding and child BMI, BP and IQ Evidence supporting causal effects breastfeeding duration on greater IQ Maternal prenatal smoking and child aggression Weak evidence for intrauterine mechanisms Not consistent with SEP being the main explanation for the association Other family-level confounders are likely

32. School of SOCIAL AND COMMUNITY MEDICINE University of BRISTOL Acknowledgements CAiTE, University of Bristol Debbie Lawlor George Davey Smith Colin Steer Federal University of Pelotas Cesar Victora Alicia Matijasevich Bernardo Horta Other Co-authors: Monique Robinson, Craig Pennell, Lyle Palmer Luciana Anselmi, Ana Menezes Wellcome Trust UK Henry Wellcome Postdoctoral Fellowship