Does caffeine consumption during pregnancy increase the risk of fetal mortality? A literature review O consumo de cafeína durante a gestação aumenta o risco de mortalidade fetal? Uma revisão da literatura

The aim of this study was to evaluate the available epidemiological evidence of the effect of caffeine consumption during pregnancy on fetal mortality. A systematic qualitative review of observational studies that referred to any source of exposure to caffeine from food in pregnancy and to fetal mortality as the outcome was conducted in the databases MEDLINE and LILACS. Studies published between January 1966 and September 2004 were searched. The following descriptors were used: “caffeine”, “coffee”, “tea”, “cola”, and “cacao” to define the exposure and “fetal death”, “stillbirth”, “fetal demise”, and “fetal loss” to define the outcome. The search strategy retrieved 32 publications, but only six met the inclusion criteria and three were included. One more article was found using “see related articles” feature in PubMed. A total of four publications were included in the review. The small number of publications addressing this subject, methodological limitations, inaccurate exposure assessment in all the studies, overall risks only marginally significant in most cases, and the possibility of publication bias preclude stating with certainty that caffeine consumption is actually associated with fetal death. Caffeine; Fetal Death; Pregnancy Introduction Caffeine (1,3,7-trimetylxanthine) is a plant alkaloid, structurally related to DNA purine bases. It is probably the most frequently ingested pharmacologically active substance in the world. The most commonly known sources of caffeine are coffee, cocoa beans, cola nuts, and tea leaves. Caffeine constitutes a substantial portion of many over-the-counter medications, such as cold tablets, allergy or analgesic preparation, appetite suppressants, diuretics, and stimulants 1. At doses relevant to general human consumption, caffeine exerts most of its pharmacological effects by acting as an antagonist of adenosine receptors 2. Following studies in animals, caffeine intake during pregnancy has been suggested as a risk factor for adverse reproductive outcomes. This hypothesis is biologically plausible based on the fact that caffeine ingested by the mother is rapidly absorbed from the gastrointestinal tract into the bloodstream, readily crosses the placenta, and is distributed to all fetal tissues, including the central nervous system. Potential effects of caffeine on fetal development may follow prolonged accumulation of caffeine in pregnant women (metabolic half life increases steadily from 4 hours during the first trimester to 18 hours during the third trimester) and passage to the fetus which lacks the necessary enzymes to metabolize it 3,4. CAFFEINE CONSUMPTION AND FETAL MORTALITY 1677 Cad. Saúde Pública, Rio de Janeiro, 21(6):1676-1684, nov-dez, 2005 Although much epidemiological work has been conducted, results from studies investigating the association between caffeine consumption and outcomes such as decreased fetal growth, preterm delivery, and spontaneous abortion have been conflicting and the available information is incomplete and remains controversial 5,6,7,8,9. Regarding fetal mortality, studies in monkeys after chronic caffeine exposure showed that those treated with caffeine in their drinking water had an increased rate of stillbirths. Although the experiment attempted to mimic human caffeine consumption, it is difficult to extrapolate these results to human beings due to differences in the caffeine dose and exposure regimen as well as metabolic and physiological differences between species 10. In humans, although epidemiological studies examining the relationship between caffeine consumption and fetal mortality have been published since 1977 11, the available information is still scarce and the overall evidence for such a relationship remains uncertain. With the aim of evaluating the available epidemiological evidence of the effect of caffeine consumption during pregnancy on fetal mortality, a systematic qualitative review was conducted.