Theophylline
Sources: Tea
Effects: Cardiac stimulant, smooth muscle relaxant, diuretic, vasodilator.
Theobromine:
Sources: Cacao, also present in traces in cola nuts and tea.
Effects: Diuretic, smooth muscle relaxant, cardiac stimulant, vasodilator.
Caffeine and Birth Defects
The nature of caffeine’s effects on birth abnormalities and fertility is probably the most urgent unresolved question that remains to be addressed by future researchers. In this section we present what is known today about these effects and, in Appendix D, explain the formidable methodological confounders—that is, factors that confuse the interpretation of the data— that researchers in this area must surmount before these effects can be understood.
The consensus of the medical and scientific community is that, to avoid risk to the fetus, women ought to curtail caffeine use during pregnancy, although authorities differ about the nature or extent of the dangers of failing to do so. But the worrisome fact is that, despite this admonition, most women using caffeine continue throughout pregnancy, with an average intake among users of more than 200 mg a day. As a result, the great majority of babies begin life with detectable levels of the drug in their blood.49,50 Because fetal exposur to caffeine is so pervasive, any unfavorable effect on the health of the newborn, even one with a very low incidence, could mean tens of thousands of defective births a year in the United States alone. It is therefore critical to investigate the effect of caffeine exposure on the outcomes of pregnancy as exhaustively as possible.
Two facts about caffeine metabolism increase concern over the harm that could be posed by maternal caffeine use.
First, caffeine metabolism dramatically slows during gestation. The metabolic rate drops progressively, falling to one-half normal during the second trimester, and to one-third normal during the third trimester,51 before returning to normal within the week following delivery. This means that caffeine that is ingested by the woman in the last few months of pregnancy will remain in her system three times longer than usual, and, consequently, that the exposure of her unborn child to caffeine will last three times longer.52
Second, the livers of the fetus and newborn are unable to metabolize caffeine. Because of the incapacity of their hepatic enzyme systems, their livers cannot transform caffeine into its metabolites, so the drug lingers in their systems much longer than in either children or adults, until it is finally excreted, virtually unchanged, in the urine.53 One researcher found the mean elimination time in infants being treated for apnea with caffeine was one hundred hours, fifteen times the adult average, and other scientists report a range up to about 350 hours in premature infants.54 These dramatic metabolic decrements, however, are short-lived. The infant’s capacity to metabolize caffeine progressively increases in the first months of life until it reaches the adult level of three to seven hours by the eighth month,55 though full maturity of the metabolic pathways of caffeine may not be achieved until the end of the first year.56
Because the risk of gross morphological abnormalities is high only in the first trimester, one would not expect that a decrease in the mother’s ability to metabolize caffeine occurring later in the pregancy could significantly increase the risk of these abnormalities. Happily, the latest studies convincingly exclude maternal caffeine use as a cause of such gross morphological abnormalities in human infants.
Caffeine and Morphological Abnormalities
Teratology, from the Greek roots meaning “the study of monsters,” is the examination of congenital abnormalities and defects. Teratologies are often associated with maternal exposure to drugs or chemicals, because the fetus is much more vulnerable than either a child or an adult to their adverse effects, with different risks attaching to different stages of fetal development. As we have seen, the greatest risk for gross morphological defects, which is to say, for obvious deformations of the skeleton, face, or major organs, is associated with the first trimester. Although all drugs and chemicals come under scrutiny with regard to such dangers, there are special reasons caffeine has been singled out for concern.
The structural similarity between caffeine and some of the building blocks of DNA—that is, the DNA base pairs adenine and guanine57—sometimes called the “DNA purines,” raised the ominous possibility that caffeine may interfere with the functioning or replication of genetic material. This threat spurred extensive laboratory investigations and epidemiological studies, for if caffeine does interfere with DNA, there is no limit to the severity or extent of the dangers it would pose. Nowhere would these dangers be more acute than in the first weeks following conception, when each cell is a repository of information needed for the development of a major bodily system, and when damage to the DNA of any one cell could result in a gross malformation. According to a 1992 review of the literature published by the Johns Hopkins University School of Hygiene and Public Health, scientists posit several mechanisms by which caffeine could inflict genetic damage:58
Caffeine may be an intercalator; that is, it may interpose itself into the DNA sequence
Caffeine may inhibit enzymes that catalyze DNA
Caffeine may damage DNA
Caffeine potentiates the toxic effects on cells of ionizing radiation, alkylators (drugs used in the chemotherapeutic treatment of cancer), and other mutagens on eucaryotic cells (cells with true nuclei)
Despite this menacing list of hypothetical mechanisms and a clear determination that caffeine is “mutagenic in bacteria, fungi, plants and human cell cultures,”59 no epidemiological association has been demonstrated between caffeine use and adverse outcomes of pregnancy, with particularly reassuring exclusionary findings with regard to major malformations. Although gross morphological defects can consistently be induced in laboratory animals by administering toxic doses of caffeine, producing serum levels that would be fatal in people, no relationship between maternal caffeine consumption and congenital skeletal malformations or malformations of any organs has been found in human beings.60 Studies suggesting caffeine’s harmful effects on the fetus prompted the FDA, in 1980, to institute a recommendation that pregnant women should eliminate caffeine intake or keep it as low as possible. However, a shift in the scientific estimate of caffeine’s reproductive dangers is represented by the reassessment of this warning made by the FDA in 1984. At that time, Dr. Sanford Miller, director of the FDA’s Bureau of Foods, said that caffeine during gestation is probably acceptable if limited to the amount in two or three cups of coffee daily, and that fears about its effects were based on animal studies in which enormous amounts were given to pregnant rats in a single dose. Today, although caffeine is no longer suspect in major teratologies, the original FDA warning remains in place, and has been recently reaffirmed, because of fears relating to less obvious injuries.61
Caffeine and Non-Morphological Abnormalities: From Low Birthweight to Behavioral Dysfunction
Much less attention has been paid to the effects of caffeine on premature births, spontaneous abortions, or the comparatively subtle processes of intrauterine development. Because the risks of low birthweight and other less obvious abnormalities increase throughout pregnancy, the progressively slowing metabolic passage of caffeine poses a greater threat of these dangers than of gross morphological defects. Unfortunately, there is still considerable uncertainty about caffeine’s effect on such subtler defects. However, widespread experience treating newborns with caffeine for apnea, which provides an unusual opportunity to study its possible toxic effects, strongly suggests that “the fetus during the later states of pregnancy…should be fairly robust to the systemic levels associated with typical patterns of maternal caffeine consumption.”62
Virtually all of the larger and better constructed studies demonstrate no correlation of prematurity with caffeine use.63,64 However, the literature remains contradictory as to whether caffeine has any correlation with spontaneous abortions. A number of major studies 65,66 found no significant as
sociation. In contrast, a 1992 study of more than fifty thousand pregnant women 67 reported a small but significant dose-dependent increase in spontaneous abortions. Those who believe the increase in the miscarriage rate is real explain it by offering an unsubstantiated conjecture that caffeine enters the egg just before the opportunity for implantation and may interfere with implantation, so that the blastocyst, or fertilized egg, is lost or develops abnormally.68
Almost forty years ago, two scientists issued a warning about the potential dangers to fetal development resulting from paternal caffeine consumption immediately prior to conception. Noting that the concentration in sperm cells is virtually identical to the serum levels, they stated, “germ cells are bathed in a caffeine solution of fluctuating concentration.”69 The significance of this effect is still unknown today.
Since 1980, a few animal studies have apparently confirmed an association between behavioral abnormalities in the fetus and maternal use of caffeine, raising concerns that similar effects may obtain in people. However, there have been few studies of neurobehavioral effects in humans, and these have conflicting results. One prospective study, which followed children from before birth to age seven, showed caffeine had no effects on the neurodevelopment of infants or children.70 In contrast, another showed “poor neuromuscular development and greater arousal and irritability in neonates.”71
Dr. Leo Leader of the School of Obstetrics and Gynecology at the University of New South Wales has also investigated the effect coffee has on unborn babies. His early findings suggest that, within about twenty minutes after the mother drinks a cup of coffee, the caffeine stimulates fetal movement. Other studies have already shown that caffeine intensifies the contraction of the heart and that even moderate doses of caffeine (200 mg) decrease placental blood flow.72
In a more speculative vein, generalized prenatal learning ability has been purportedly measured by determining how long a fetus takes to stop reacting to the repeated buzzing of an electric toothbrush pressed to the outside of a mother’s stomach. Initially, the fetal heart rate increases and the fetus demonstrates increased movement. Then, through a basic learning response called “habituation,” normal babies stop reacting between ten and fifty buzzes. Leader has demonstrated that fetuses who were able to demonstrate habituation did significantly better in tests of movement, socialization, language, and behavior between a year and two years after birth than those who were not. Chemicals ingested by the mother can cause an immediate reaction in the fetus’s ability to learn. For example, for about two hours after a mother smoked a cigarette, the fetal ability to respond to the buzzing was found to be absent or impaired. Dr. Leader intends to test if caffeine accelerates or slows the fetal response to the buzzing toothbrush.
Can a pregnant woman addict a fetus to caffeine? In other words, if a woman uses coffee, tea, or caffeinated soft drinks during pregnancy, can her baby be born with the symptoms of caffeine withdrawal? A 1988 study identified five babies who were born suffering from withdrawal syndrome; however, the levels of caffeine used by their mothers were remarkably large, averaging fifteen cups of coffee or two quarts of cola each day.73 Another study, completed the same year, found that eight children of heavy-caffeine-using mothers demonstrated unusual levels of irritability, jitteriness, and vomiting, with an absence of any of the usual causes for such symptoms.74 Some investigators have speculated that caffeine withdrawal could be implicated in neonatal apnea (an idea bolstered by the fact that caffeine is an effective treatment for apnea) and sudden infant death syndrome (SIDS), while others suggest the possibility that maternal caffeine use during pregnancy may be associated with childhood diabetes.75
If a woman continues drinking caffeinated beverages while nursing, the caffeine from her breast milk enters the infant’s system at a time when the child metabolizes it imperfectly or not at all. Thus the effect on the infant is multiplied many times during a period in which its neurodevelopment can still be affected.76 Despite the obvious possibility of a hazard, the Association of Women’s Health, Obstetric & Neonatal Nurses published a pamphlet in cooperation with IFIC, the public relations arm of a food industry-sponsored scientific organization, advising:
The American Academy of Pediatrics Committee on Drugs has reviewed the effects of caffeine on breast feeding and reported that moderate caffeine consumption has no effect on breast feeding.
As with all foods, pregnant and lactating women should apply the principle of moderation.... A reasonable guideline is around 300 mg daily.77
Caffeine and Fertility
Perhaps no area of concern over caffeine’s effect on health has a longer history or has been the subject of more confusion than fertility. Long before caffeine had been isolated, coffee was charged with reducing fertility in both men and women and with reducing the sexual appetites of men. As we saw, the latter effect was the subject of heated broadsides against coffeehouses from the distaff side in seventeenth-century London.
Repeated studies have failed to find a dose-related correlation between caffeine consumption and the risk of either delayed conception or persistent infertility in women. A typical example is a retrospective study of more than two thousand postdelivery women that found no association with delayed conception.78 It concluded that the average time to conception (four or five months) for women who consumed the equivalent of one cup of coffee a week was similar to the time to conception for those who consumed more than two cups a day. In addition, the study found that caffeine consumption was not a risk factor for primary infertility. However, because other studies suggest that caffeine intake can contribute to delaying conception, perhaps the best advice for women who are intending to become pregnant is to minimize or eliminate caffeine intake, at least until more proof of its consequences has been gathered.79
Because caffeine permeates every cell of the body with ease, the concentrations of caffeine in male gonadal tissue and seminal fluid are virtually identical to those that occur in the blood. Therefore it has been widely conjectured that caffeine has doserelated effects on the number and structure of spermatozoa. Its varying effects on sperm motility are well-documented.80 When semen is exposed to high concentrations of caffeine immediately prior to artificial insemination, the increased motility is sufficient to double a woman’s chances of getting pregnant. It is not known if there are deleterious effects on the sperm that may later increase the likelihood of miscarriage. Oddly enough, the profile of some of caffeine’s effects on sperm observed both in vitro and in vivo closely resembles that predicted by the Yerkes-Dodson principle, enunciated in 1908, that the “relationship between arousal and performance efficiency takes the form of an inverted-U,”81 which is to say that performance is best at intermediate arousal levels and drops off in states of low arousal, such as when a person is bored or tired, or in states of high arousal, as when a person is anxious or under stress. This means that the effects of caffeine on sperm cells increase with the dose until a certain level is reached, whereupon additional doses of the drug have less and less impact, and still higher doses progressively reverse its initial effects.
Researchers L.Dlugosz and M.B.Bracken comment on these findings:
In several in vitro assays, human sperm motility and sperm progression increased with the addition of caffeine. However in other assays, more detrimental effects on spermatozoa ultrastructure and penetrating ability were observed at high concentrations than at low concentrations of caffeine. In a study of 446 men attending an infertility clinic, men who drank 1–2 cups of coffee per day had increased sperm motility and density compared with subjects who drank no coffee. However, men who drank more than 2 cups per day had decreased sperm motility and density…. Current data are too sparse to draw conclusions about the effects of caffeine consumption on male infertility.82
Thus, although the effect of large doses on fertility in men is still undetermined, moderate doses of caffeine may even help a man to father a child, and the dynamics of caffeine’s effects on sperm seem to resemble those
ascribed to alcohol on sexual performance in the traditional aphorism, “A little stimulates; a lot depresses.”
Caffeine and Weight Loss
Once upon a time, men who wished to set themselves on a thorny quest chose to pursue the Holy Grail, the cup used by Christ at the Last Supper, a draught from which would confer all earthly and heavenly benisons. Today the quest for the Grail has been replaced by the quest for a “fat pill,” a safe, pharmacologically active chemical that a person can ingest to reduce and keep off excess fat. Presumably the scientist who discovers and the first company that markets such a wondrous medicament will eclipse Bill Gates and Microsoft as the greatest financial success story in modern times.
The key words here are “safe” and “reduce and keep off.” Many stimulants, especially powerful ones such as amphetamines and cocaine, effectively suppress appetite and increase metabolic rates. In other words, they help burn fat at a faster rate than normal. The problem is that their use is not safe and that, irrespective of their dangers, the capacity, at least of cocaine, to reduce your appetite seems to wear off as usage continues. A full range of amphetamine derivatives have been legal prescription drugs for decades, but they are rarely prescribed today, as some of them once were, as treatments for obesity or aids for weight loss. To fill the void left by their removal, natural medicine enthusiasts have marketed a variety of quack nostrums promising to “burn fat” or “speed up metabolism.”
Despite repeated claims of tabloid headlines touting these breakthroughs, few people believe that such a fat-burning substance actually exists or is even in the early stages of development. The amazing truth, however, is that common caffeine might be the fat-burning wonder drug everyone has been looking for all along.
The World of Caffeine Page 42
