Maternal Exposure to Caffeine and Risk of Congenital Anomalies.

Caffeine is a natural component of coffee, tea, and cocoa products. It is added to many soft drinks and to certain prescription and over-the-counter medications. Caffeine's pharmacologic effects include central nervous system stimulation, bronchodilation, and higher blood pressure, most likely through antagonism of adenosine receptors in the brain, heart, lungs, and blood vessels. Based on a recent survey by the U.S. Department of Agriculture, coffee, soft drinks, and tea (in that order) are the major sources of caffeine among adults. Average caffeine intake is estimated to be 164 mg per day among women 18–34 years and 125 mg per day among pregnant women. In a prospective cohort study conducted in Connecticut during 1988–1992, caffeine consumption during the first month of pregnancy was reported by 60% of study participants, with 16% consuming 150 mg or more of caffeine per day.

In their review of the animal literature, Nehlig and Debry note that teratogenic effects have generally been observed after once-per-day administration of caffeine at doses much higher than human consumption levels. However, when administered in combination with substances such as nicotine or alcohol, teratogenic effects of caffeine were observed at somewhat lower doses. In humans, caffeine and its metabolites easily cross the placenta and reach the fetus. Decreases in fetal heart rate and placental blood flow have been observed after maternal caffeine ingestion. Human studies have also demonstrated increased homocysteine levels and decreases in insulin sensitivity after intake of caffeine or coffee. Vascular disruption, increased levels of homocysteine, and oxidative stress associated with hyperglycemia are postulated mechanisms for various congenital malformations. Given the prevalence of caffeine use during pregnancy, even a small increase in the risk of congenital anomalies would have an important effect on public health.

A number of published reports have reviewed the scientific literature regarding maternal caffeine consumption and congenital anomalies. However, a systematic review of the epidemiologic literature on this topic has not been published. In a systematic review, specific well-defined criteria are used in searching for papers, selecting studies for inclusion, critically appraising study methods, and summarizing study findings. The methods for this systematic review were based on Mulrow's and Weed's guidelines.

DISCUSSION

Studies with extensive grouping by exposure and outcome were not selected for review. Classifying caffeine intake as “any versus none” is problematic because grouping low exposures with high exposures could hide a true effect that happens only at high levels of exposure. Different types of congenital anomalies have diverse etiologies; grouping all anomalies as a single outcome can mask an effect that occurs for only particular categories of anomalies. With a few exceptions, the studies excluded for these reasons did not find associations between caffeine intake and congenital anomalies. In the few instances in which a positive association was observed, selection bias and confounding were possible alternative explanations.

The 7 included studies were well-conducted studies and provide the best available epidemiologic evidence about caffeine teratogenicity. Inaccuracies in exposure assessment and the relatively small number of specific exposure–outcome relationships that have been studied limit conclusions based on these data. Meta-analysis was possible for associations between coffee and oral clefts, coffee and cardiovascular malformations, and tea and cardiovascular malformations. Summary estimates could not be calculated for total caffeine intake (versus coffee or tea consumption) because only one of the 7 included studies reported findings for caffeine exposure from multiple sources. The few exposure–outcome combinations suitable for quantitative synthesis emphasize the relative scarcity of published research on this topic. The possibility of publication bias is a concern in interpreting the results restricted to published reports. Findings of little or no increased risk in early studies of this topic may have reduced interest on the part of both investigators and editors in publishing additional studies with null results.

The results of the studies included in this review suggest that a large increase in the risk of congenital anomalies is unlikely to result from consumption of caffeinated beverages during pregnancy. The 10% to 20% excess risk associated with coffee intake suggested by the summary estimates for cardiovascular malformations and oral clefts would be important if the relative risks reflected a true effect of coffee consumption. However, these small increases might also be explained by recall bias or confounding. Conversely, sources of nondifferential exposure misclassification were likely to have attenuated risk estimates. Therefore, these slight increases and the null results for other anomaly categories may warrant further attention. The few available studies for each anomaly category do not provide adequate negative evidence regarding risk.

Misclassification of exposure is a special concern in studies of caffeine exposure. Wide variations in the caffeine content of a beverage serving and changes in caffeine consumption during pregnancy are 2 prominent difficulties. In addition, interindividual differences in caffeine metabolism represent a source of error in measuring caffeine exposure. The rate of caffeine clearance among smokers is approximately twice that in nonsmokers as a result of metabolic enzyme induction by cigarette smoke. Grosso and Bracken recently provided a detailed description of sources of misclassification in measuring caffeine intake during pregnancy. The authors proposed measurement of caffeine biomarkers as a remedy to the deficiencies of questionnaire-based methods. Unfortunately, prospective study methods are not practical in studies of congenital anomalies. However, validation studies comparing prospectively measured exposure information with questionnaire-based estimates collected after delivery would be helpful in estimating uncertainty in retrospective study results and in guiding development of improved exposure assessment methods.

A list of recommendations for future research follows:

* Collect information on multiple sources of caffeine. To separate any effect of caffeine from that of other components of coffee, tea, and soda, analyze exposure–outcome relationships for individual caffeinated beverages in addition to total caffeine.
* Avoid extensive grouping of different malformations; define malformation outcome categories that are “embryologically or pathogenetically meaningful.”
* Through validation studies, identify questionnaire methods that could improve exposure assessment accuracy. For example, questions on brew strength (tea and coffee), portion size, and changes in caffeine consumption during the period starting before pregnancy through the first trimester.
* In the analysis, form categories of exposure that allow assessment of dose–response; avoid grouping high exposures with low exposures.
* Assess potential effect modification by smoking status and other factors that affect caffeine metabolism.
* To reduce concerns about spurious findings from multiple analyses, use a priori relationships and mechanisms to guide the choice of outcome categories and potential effect modifiers. However, exploratory analyses in the absence of mechanistic hypotheses, when reported as such, are also useful in guiding subsequent research efforts.

SUMMARY

The 7 studies included in this review do not provide adequate evidence on which to base conclusions about the safety of maternal caffeine consumption during pregnancy. There is no evidence that caffeine intake causes a large increase in the risk of various types of congenital anomalies, but there is greater uncertainty about small elevations in risk. Given the relatively high prevalence of maternal caffeine exposure, even a small increase in the risk of congenital anomalies would have an important effect on public health. Large study populations and improved exposure assessment methods would be necessary to rule out small risks for specific categories of congenital anomalies after maternal exposure to caffeine.

Conclusions:

There is no evidence to support a teratogenic effect of caffeine in humans. Current epidemiologic evidence is not adequate to assess the possibility of a small change in risk of congenital anomalies resulting from maternal caffeine consumption.