In this prospective cohort of pregnant women, we observed that chocolate consumption, as measured by cord serum levels of the biomarker theobromine, was associated with lower risk of preeclampsia. As measured by self-reported maternal intake, increased chocolate consumption in both first and third trimesters was suggestive of reduced preeclampsia risk. Our findings are consistent with other studies that have investigated vascular and metabolic effects of chocolate. Grassi et al20
found that consumption of dark (vs. white) chocolate reduced blood pressure and insulin resistance, and improved nitric oxide-dependent vasorelaxation in men and women with untreated essential hypertension. In healthy men and women dark chocolate consumption lowered blood pressure and insulin sensitivity.21
Fisher and Hollenberg22
reported that consumption of flavanol-rich cocoa improved measures of endothelial function. A recent meta-analysis23
of 5 trials showed significant and clinically important drops in systolic and diastolic blood pressure after cocoa administration.
A major strength of this study is use of umbilical cord blood theobromine as a biomarker for cocoa and chocolate consumption. Flavanoids and magnesium are found in numerous other substances, but theobromine is primarily found in cocoa and tea leaves. Quantifying self-reported chocolate and cocoa consumption is extremely difficult due to considerable variation in the cocoa content of chocolate products. In addition, it is difficult to standardize self-reported chocolate consumption for serving size, or in any other way. Theobromine concentrations in chocolate also vary widely from 0.15% to 0.46%.6
Such sources of misclassification most likely drive effect estimates toward the null. These measurement issues may account for some of the differences in the magnitude of effects between reported consumption and cord serum theobromine. Umbilical cord blood levels of theobromine provide an objective indicator of recent maternal cocoa and chocolate intake since theobromine is rapidly absorbed from the gastrointestinal tract24
and freely crosses the placental barrier25
and are not hampered by possible recall bias of self-reported measurements.
One limitation of our study is the possibility of reverse causality. If women diagnosed with preeclampsia reduced their calorie intake (including chocolate) subsequent to their diagnosis, and if the reported third trimester consumption or cord theobromine concentration represented exposure after the time of diagnosis, reverse causality could explain some of our findings. (Reverse causality could not explain the first trimester findings.) We conducted several analyses to help elucidate the possible role of reverse causality in our data.
Examination of correlations between reported consumption in the first and third trimesters by preeclampsia status (rspearman = 0.34 for women who developed preeclampsia; rspearman = 0.35 for women who did not), suggested that women did not change consumption differentially based on preeclampsia diagnosis. Similarly, women diagnosed with preeclampsia were no more likely to change consumption than unaffected women. Restricting adjusted analyses to the 785 women whose category of chocolate consumption did not change from first to third trimester of pregnancy (, last column) produced estimates of associations of cord theobromine levels strikingly similar to the adjusted estimates in all women. Considering the possibility that women with preeclampsia consumed less chocolate because they were admitted to hospitals earlier than healthier women, we also analyzed times from hospitalization to delivery. Such times were essentially identical in mothers who had and had not developed preeclampsia (96% and 97% of women with or without preeclampsia, respectively, were admitted on the same or previous day as date of delivery). These analyses failed to support a role of reverse causation, although they cannot rule out this possibility.
Another potential limitation of our study is residual confounding by smoking or BMI. To address such confounding, we repeated analyses (1) restricting the sample to non-smoking women and (2) excluding obese women (but still controlling for BMI). In both analyses, we found no change in results. Results were similar when we further restricted the sample to women with normal BMI only. Finally, the small number of women with preeclampsia and the potential mis-classification of exposure may have reduced the precision of these estimates.
Our findings of an inverse relationship between cord serum theobromine concentrations and risk of preeclampsia may be due to a direct role of theobromine. During pregnancy, theobromine (or the other methylxanthines in chocolate) may improve placental circulation and inhibit xanthine oxidase, which, in the setting of hypoxia, increases production of reactive oxygen species and free radicals.26
Alternatively, theobromine concentrations could play an indirect role by (1) acting as a proxy for others chemicals (such as flavanols or magnesium) found in cocoa, (2) their correlation with other unmeasured dietary factors that influence risk of preeclampsia or (3) acting as a proxy for maternal metabolism of theobromine whereby enzymatic activity associated with metabolism, rather than actual theobromine concentrations, is responsible for influencing the risk of maternal outcomes.27
We repeated analyses (not shown) using a physician diagnosis of preeclampsia in the medical chart instead of our own designation based strictly on NHLBI preeclampsia criteria. Such analyses (n = 1907) consistently suggested an inverse relationship between all measures of chocolate consumption and preeclampsia risk. Interestingly, all the point estimates were practically unchanged, except that adjusted estimates of reported first trimester consumption were more strongly inversely associated with risk of preeclampsia (adjusted odds ratio 0.37 [95% CI = 0.13–1.08] for women consuming 5+ versus <1 weekly serving).
Our results raise the possibility that chocolate consumption by pregnant women may reduce the occurrence of preeclampsia. Because of the importance of preeclampsia as a major complication of pregnancy, replication of these results in other large prospective studies with a detailed assessment of chocolate consumption is warranted. Measurements of chocolate exposure should be designed to permit careful examination of the temporal relationship between chocolate consumption in pregnancy and subsequent risk of preeclampsia.