1. Is Prenatal Caffeine Exposure Related to Neurodevelopment? Author 1 Author 2 PH251A: Practicum in Epidemiologic Methods 12/5/2007

2. Description of Question zDoes prenatal coffee exposure increase the risk of poor neurodevelopment at ages 9 to 11?

3. Reasons to Study Caffeine and Neurodevelopment z71% of the caffeine in the US is consumed in the form of coffee (Faray, 2005) zAverage American consumes 1.2 cups of coffee per day (FAS/USDA, 2002) z Widely ingested by pregnant women (Sobotka, 1989) z Can cross the placenta and reach the fetus; is metabolized more slowly during pregnancy z Associated with spontaneous abortion and low- birth weight in humans z Little information is available on the long-term effects of prenatal coffee exposure

4. Summary of Background Literature Two studies directly address this question: z Jacobson et al (1984): Caffeine exposure predicted negative behavioral effects (p<0.05) zBarr et al (1989): Long term effects of caffeine on IQ at 4 and 7 years are null -- but they should conclude that they fail to find an effect

5. Public Health Significance z Long-term effect or prenatal coffee exposure is still unknown z Because of the popularity of coffee, negative long-term effects would mandate wide-scale interventions to decrease prenatal consumption

6. Primary Variables zExposure Variable: Number of cups of prenatal coffee per day: y None or <1 a week y 1 to 2 cups/ day y 3 to 4 cups/ day y >4 cups/ day zOutcome Variable: y Peabody Picture Vocabulary Test: - Test for Verbal Intelligence - Scores range from 27 to 147 yRaven Colored Progressive Matrices - Test for perceptual reasoning - Scores range from 0 to 77

7. Key Covariates zMaternal Characteristics: - Age - BMI - Prenatal Smoking - Prenatal Alcohol - Prenatal Work - Marital Status - Peabody Score zPaternal Age zTotal Family Income zChild Characteristics - Age - Sex - Race - Birth weight - Gestational Length - Glasses Use

8. Methods z Univariate and multivariate analyses were conducted to address the relationship between prenatal coffee exposure and Peabody and Raven Scores at ages 9 – 11. z Adjusted for confounders in the analyses. z Used restricted vs. full F-tests to help with model selection. z Looked at statistically significant interactions in the final model.

9. Figure 1 ( Subject Exclusion Flow Chart) Prospective Study Group – Total Number of Pregnancies N= 20,754 -4,826 Interview Before Delivery N= 15,928 -1,330 Live Births N= 14,899 - 301 Singleton Births N= 14,598 -451 No Severe Birth Anomalies N=14,147 -10,410 At Nine to Eleven Year Old Exam Total Children Examined N=3,737

10. Results- Outline zSummary Statistics zUnivariate Analysis yCrude RR zMultivariate Analysis y Included statistically significant (found in univariate analysis)and biologically relevant covariates. y Model selection: Checked different models, compared them using F-tests y Checked for normality assumptions yChecked for the effect of outliers in the final model

11. Select Variables - Univariate Analysis

12. Outcome by Exposure – Crude RRs

13. Final Model – Key Results zEffect of prenatal coffee intake on child’s Peabody scores: statistically significant negative effect after controlling for the effect of other relevant covariates zIntake of 3-4 cups of coffee compared to no coffee is associated with 1.57 point reduction in Peabody scores: Effect is small but highly statistically significant.

14. Final Model – Key Results zSimilar Results if Raven Scores are used as an independent variable: Provide more confidence about the overall finding

15. Final Model

16. Comparison with previous studies zBarr et al (1991) fail to find an effect of prenatal caffeine exposure on child’s IQ at ages 4 and 7 -- However, this study does not control for the effect of mother’s IQ or its equivalent zIn our analysis we find that mother’s IQ (measured as mother’s Peabody score) is a confounder. Mother’s Peabody score is positively correlated with both Child’s Peabody score and prenatal coffee intake. z If we do not control for this confounder, we fail to see an effect of prenatal coffee on child’s Peabody and Raven Scores.

17. Other Findings zWe explored the possibilities of interactions (effect modifications) of different independent variables such as: alcohol intake and coffee intake, alcohol intake and smoking, smoking and alcohol intake, race and coffee intake, mother’s Peabody scores and coffee intake, SES and coffee intake zWe do not find statistically significant effect of interactions

18. Other Findings zOther variables that were significant and that were positively associated with child’s peabody scores: ymother’s age, father’s occupation, mother’s peabody scores, high prenatal alcohol intake, child did not wear glasses, mother’s occupation, mother’s education, Child’s race (other), age of child at exam yOther studies that use the CHDS dataset do not use alcohol variable as covariate?? yExcluding alcohol variable do not affect the result of caffeine intake zOther variables that were significant and that were negatively associated with child’s peabody scores: y Female child, black race, 2-4 cups of coffee per day

19. Conclusions zPrenatal coffee intake has a small negative effect on child’s neurodevelopment as assessed by Peabody (2% reduction) and Raven scores (4.3% reduction) zEffects precisely estimated zCaution in drinking 3-4 cups of coffee/ day during pregnancy is warranted

20. Limitations and Future Research z Coffee is the only source of caffeine included z Milligrams of caffeine in each cup of coffee was unspecified in the CHDS dataset z No possible explanation for the counterintuitive effect of alcohol on child’s Peabody and Raven scores

21. Bibliography zBarr HM and Streissguth AP. Caffeine Use During Pregnancy and Child Outcome: A 7-Year Prospective Study. Neurotoxicology and Teratology. 13:441-448; 1989. zFAS/USDA, Horticulture and Tropical Products Division. US Coffee Consumption. 2002. Accessed on 9/17/07. Available at: http://www.fas.usda.gov/htp/tropical/2002/06-02/coffusco.pdf. zJacobson SW, Fein GG, Jacobson JL, Schwartz PM, Dowler JK. Neonatal Correlates of Prenatal Exposure to Smoking, Caffeine, and Alcohol. Infant Behavior and Development. 7:253-265; 1984. zStreissguth AP, Barr HM, Martin DC. Maternal Alcohol Use and Neonatal Habituation Assessed with the Brazelton Scale. Child Development. 54(5): 1109-1118; 1983. zStreissguth AP, Barr HM, Sampson PD. Moderate Prenatal Alcohol Exposure: Effects on Child IQ and Learning Problems and Age 7.5 Years. Alcoholism: Clinical and Experimental Research. 14(5): 662-669; 1990.