Women who reported regular chocolate consumption of ≥1-3 servings/week had a 50% or greater reduced risk of preeclampsia, which did not appear to be dose-dependent. Analysis by timing of exposure suggested that regular chocolate intake during the 1st or 3rd trimester was equally protective against preeclampsia. The highest rate of preeclampsia (4.5%) occurred among women who did not regularly consume chocolate in the 1st and 3rd trimesters of pregnancy. In contrast, only women who regularly consumed chocolate during the first trimester had a reduced risk of GH.
Given our current understanding of the pathophysiology of preeclampsia as a “2-stage disease process”, it is biologically plausible that trimesters 1 and 3 would be “critical windows” for exposure and possible intervention. Defective placentation of preeclampsia is initiated in the first trimester of pregnancy (16
). The resulting placental oxidative stress and inflammation is hypothesized to trigger the release of pro-inflammatory syncytiotrophoblast-derived factors (eg. sFlt-1), which lead to maternal systemic vascular endothelial disruption and the eventual clinical manifestation of preeclampsia in the 3rd
trimester of pregnancy (16
Triche et al. (2008) also found that self-reported, regular consumption in the 3rd
trimester was protective against preeclampsia; however, they did not find a protective effect of 1st
trimester consumption (10
). Our findings are also consistent with their report of a 60% reduction in preeclampsia associated with levels of cord blood theobromine at or above the 2nd
quartile of exposure (9
). In contrast, our findings are not consistent with those of Klebanoff et al. (2009) who found no protective effect of theobromine measured in maternal serum after the 26th
week of gestation for preeclampsia (9
). They found also reported that preeclampsia risk increased in a dose-response fashion with increasing levels of theobromine measured in maternal serum collected before 20 weeks gestation. Possible explanations for the disparate findings include the very different study populations; differences in the length of storage of the serum specimens;; different definitions of preeclampsia; and differences in the possible sources of theobromine over the 40-year period separating these studies.
Although Triche et al found evidence of an inverse dose-response relationship of theobromine levels in cord serum with preeclampsia risk (Triche et al, 2008), our questionnaire assessment of dietary chocolate intake was not adequately robust to detect a dose-response effect. Different chocolate products and sources contain varying amounts of cocoa; such heterogeneity in cocoa content makes it very difficult to assess for dose-response relationships using food frequency questionnaires. This is not an unusual problem in epidemiology; even in a recent study of the association of vitamin D intake with risk of preeclampsia, no association was observed based on food frequency dietary measurements of Vitamin D intake; however, a 27% reduced risk of preeclampsia was detected when analyses were restricted to assessments of vitamin D intake from supplements alone (10-15 microg/d vs no supplementation)(18
There is considerable pathophysiologic and epidemiologic support for our findings from literature examining the cardiovascular effects of chocolate intake in adult populations. A recent review reported findings from eleven human studies of direct, beneficial effects of cocoa exposure on endothelial function, including improvements in vasodilation, coronary circulation, nitric oxide levels, blood pressure, and platelet function (8
). Endothelial dysfunction is implicated as a central feature in the pathogenesis of preeclampsia. A recent 16-year epidemiologic follow-up study of post-menopausal participants in the Iowa Women’s Health Study revealed chocolate intake was associated with reduced rates of cardiovascular disease mortality (19
A recent systematic review of 10 RCTs assessed the antihypertensive effects of flavinol-rich cocoa reported significant declines in systolic (−4.5 mmHg) and diastolic (−2.5 mmHg) blood pressure (20
). Most of the reviewed trials used relatively high doses of cocoa for periods of 2-18 weeks. One trial examined very low doses of dark chocolate (6.3g/d) over 18 weeks but still found highly significant reductions in blood pressure (−2.9 mmHg systolic and −1.9 mmHg diastolic (21
). Two new trials of low dose chocolate intake report similar drops in systolic and diastolic blood pressure (22
). Desch et al compared low-dose (6g/d) versus high dose (25g/d) intakes over 3 months but found no difference in blood pressure changes between the two groups (20
). In an adult German population, significant reductions in blood pressure were also observed with low-dose consumption (6g/d), with a larger reduced risk for MI and stroke (22
). The difference between a small effect on blood pressure and a larger clinical effect may result from the influence of cocoa on other cardiovascular risk factors, particularly those influencing inflammation. A diet of 6.7 g/d of dark chocolate has been associated with decreased serum C-reactive proteins, a marker of inflammation (24
Several recent studies conducted in various patient populations suggest there are sustained benefits in vascular function following a single dose intake of flavanol-rich cocoa (25
). A recent study of oral intake of cocoa found that the highest plasma levels of flavanols peak 2-3 hours after ingestion -- but are still measurable 8 hours following ingestion (27
There are several strengths of the current study analysis. Data are derived from a large cohort of women interviewed early in pregnancy for risk factors relating to adverse pregnancy outcomes. First trimester exposure data were obtained prospectively with respect to the outcomes. Furthermore, recall bias is unlikely to influence third trimester exposure self-reports because chocolate was not recognized as having anti-hypertensive properties during the study period (1988-1991). Classification of preeclampsia and GH was based on abstraction of blood pressure and urinary protein readings from both prenatal and hospital delivery chart data, and strict research definitions were uniformly applied to reduce misclassification and increase specificity of case diagnoses. We were also able to consider timing of regular chocolate intake during pregnancy, and had extensive data on a number of potentially confounding variables. The study utilized both self-report and medical chart data in the assessment of exposure, outcome, and confounding variables. In addition, this is the first study to examine the association between chocolate consumption and risk of GH.
There are some limitations of the current research. The self-reported exposure data may have led to misclassification as it is very difficult to accurately quantify serving sizes and cocoa content of different products. In addition, our questionnaire did not differentiate between dark and other types of chocolate. Because the data were collected prospectively with respect to the outcome, we would expect that the misclassification would be non-differential and lead to attenuation of risk estimates. Our study would have been enhanced by having biomarker data (e.g., theobromine) to validate associations between self-reported chocolate consumption and risk of preeclampsia and GH.
As we did not assess other dietary constituents other than caffeinated beverages, it is possible that our results are subject to unmeasured confounding. While there are very few well established risk factors for preeclampsia, we have controlled for many of these. To date, there are no dietary factors that have been consistently associated with preeclampsia, providing support that our study findings would be unlikely to change with additional information about diet during pregnancy (29
Another potential bias is that overweight women may underreport their chocolate intake. We re-ran the analyses, restricted to women with normal pre-pregnancy BMI, to address this potential bias and found nearly identical risk estimates as those for all women. Similarly, to address the possibility of residual confounding by smoking during pregnancy, which has been associated with a reduced risk of preeclampsia, we re-ran the final models among only non-smokers and found no change in the risk estimates.
We also considered the possibility of reverse causality whereby women who developed high blood pressure might be less likely to consume chocolate after diagnosis. However, we excluded from analysis women who had elevated blood pressure prior to 20 weeks gestation. Furthermore, the protective influence of regular chocolate consumption was apparent with first trimester exposure, which, by definition, preceded all diagnoses of preeclampsia, GH or high blood pressure readings in this study population. We also noted that women with gestational diabetes reported reduced chocolate consumption, particularly later in pregnancy. There was no evidence, however, that gestational diabetes was a confounder of the association of chocolate consumption and risk of either hypertensive outcome. Further, when models were restricted to non-diabetic women, no changes in risk estimates were noted.
In conclusion, these findings provide additional evidence of the potential benefits of chocolate consumption. Prospective studies are needed to confirm and delineate protective effects of chocolate intake on risk of preeclampsia. Such studies require detailed assessments of dietary chocolate intake and its metabolites over the course of pregnancy.