Introduction to 520 mg of caffeine when taken

Introduction Caffeine(1,3,7-trimethylxanthine) is a naturally occurring compound. Itspharmacological and physiological effects, include stimulation of the centralnervous system and cardiac muscle, and relaxation of smooth muscle.

Caffeinehas been shown to have effects on physical and cognitive performance, as well asmood, memory, and alertness. Caffeine is the most widely used stimulant for thecentral nervous system. Clinically, caffeine is useful for relaxing thebronchial muscle in asthmatic patients, and increasing secretion of gastricacid and the concentrations of plasma free fatty acids and glucose (Instituteof Medicine, 2001).  Sourcesof Caffeine The mainsources of caffeine in the adult American diet are coffee, tea, and soft drinks(Table 1). Other dietary sources include cocoa and chocolate, sugars and sweets,and flavored dairy products.

Tea also contains a significant amount oftheophylline (1,3-dimethylxanthine), as cocoa also contains theobromine(3,7-dimethylxanthine), both being caffeine derivatives that have not been aswidely researched (Frary, 2005). Many classes of nonprescription medicationsincluding analgesics, cold/allergy products, diuretic products, stimulants, andweight control agents have some caffeine content. All medications have asuggested dose, but consistent usage may lead to the medication becoming a significantsource of caffeine consumption.

For instance, a two-tablet dose of anover-the-counter analgesic may constitute a daily intake of up to 520 mg ofcaffeine when taken every 6 hours.  (Table2).  Demographicsof Caffeine Intake During Pregnancy Studieshave shown most women’s daily caffeine intake during pregnancy is lower than priorto becoming pregnant, predominantly due to a decline in coffee and tea intake(Crozier, 2009a). Before pregnancy 39 percent of women consume more than 300 mgof caffeine every day, which is considered heavy caffeine intake, but only 16percent of women consume more than 300 mg per day during pregnancy (Crozier,2009b). Proportionally, colas, soft drinks, and foods containing chocolatecontribute more to the total dietary intake of caffeine of pregnant women than non-pregnantwomen, but coffee and tea still make up the largest percent of their caffeineintake (Frary, 2005). Fewer years of formal education, and smoking are both associatedwith women who are more likely to consume more than 300 mg of caffeine dailyduring pregnancy. (Crozier, 2009a).

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 Absorption,Distribution, and Clearance of the Methylxanthines  Absorption Caffeineand the other methylxanthines are quickly absorbed in humans, as much as 99percent is absorbed within the 45 minutes after ingestion. Oral, rectal, andparenteral administration is possible, with the oral route being most common. Whenconsumed in a beverage, the caffeine is quickly absorbed from thegastrointestinal tract and distributed throughout body water. More rapidabsorption is possible for caffeine in preparations that allow absorptionthrough oral mucosa, such as caffeinated chewing gum. Depending on the sourceof the caffeine and the individual’s metabolism, peak plasma levels of caffeineappear between 15 minutes and 120 minutes after ingestion or administration(Institute of Medicine, 2001). Distribution Thedistribution volume of caffeine within the body is 0.

7 L/kg, demonstratingcaffeine’s hydrophilic quality and ability to distribute freely intointracellular tissue water (Arnaud, 1993). Caffeine is also amply lipophilicand can pass through all biological membranes and freely crosses theblood-brain barrier (Institute of Medicine, 2001). In pregnant women, themethylxanthines consumed cross the placenta to the fetus. As early as 7-8 weeksgestation, an equilibrium is achieved between the maternal and fetal plasma (Goldstein,1962). A fetus swallows approximately 500 mL of amniotic fluid daily, and studiessuggest that several milligrams of caffeine can be ingested along with thefluids.

Additionally, by week 12 of gestation the fetal liver is able tomethylate theophylline to caffeine (Brazier, 1981). Both caffeine andtheophylline are eliminated in the amniotic fluid, the fetal eliminationhalf-life of caffeine is 150 hours, while that of theophylline is 30 hours.  Clearance The smallfraction of caffeine that is excreted unchanged in urine, suggests thatcaffeine metabolism is the rate-limiting factor in its plasma clearance. Itslimited appearance in urine is due to caffeine being readily reabsorbed by therenal tubules and filtered by the glomeruli. (Arnaud, 1993).

In healthy humans,repeated caffeine ingestion does not alter its absorption or metabolism. Caffeinemetabolism transpires primarily in the liver, catalyzed by hepatic microsomalenzyme systems (Grant, 1987). In the liver, caffeine is metabolized to dimethylxanthines,uric acids, di- and trimethylallantoin, and uracil derivatives. 3-ethyldemethylation to paraxanthine is the primary route of caffeine metabolism inhumans (Arnaud, 1987).

This is first step in caffeine metabolism and accountsfor approximately 75–80 percent of the process (Arnaud, 1993). Being the chiefmetabolite in humans, paraxanthine is found to have a plasma concentration tentimes higher than those of theophylline and theobromine. Eight to ten hoursafter ingestion, paraxanthine levels in plasma exceed caffeine levels, ascaffeine is cleared more rapidly than paraxanthine (Arnaud, 1993). During thesecond and third trimesters of pregnancy, there is decreased rate of maternalelimination of caffeine, due to changes in progesterone and estrogen levels, withthe half-life of caffeine changing from 5.

3 hours to 18.1 hours (Aldridge,1981). Maternal clearance of caffeine during pregnancy can be further influencedby other factors including age, disease, and personal habits such as smokingand long-term use of oral contraceptives prior to becoming pregnant. Thesefactors may result in prolonged maternal and fetal exposure to caffeine. Withina few weeks after giving birth, the maternal rate of caffeine eliminationreturns to original levels (Aldrige, 1981). MethodsCritical analysis of peer reviewed journal articles andoriginal clinical research papers was used to write this review. The articlesand papers from which the research was gathered were obtained with access toonline publications through the Touro college library.

Additional referenceswere obtained through Pubmed and Google Scholar.  Caffeineand Pregnancy Outcome Variables There areseveral clinical measures of adverse pregnancy outcome, which include lowinfant birth weight, premature labor and delivery, spontaneous abortion, andcongenital malformations. Effects of CaffeineConsumption on Birth Weight A low birth weight (LBW)infant is one who weighs less than 2,500 g (5 lbs, 8 oz) at birth. Low birthweight can be caused by a shortened gestational period, also known asprematurity, or the result of intrauterine growth retardation (IUGR), whichresults in a small for gestational age (SGA) infant. Intrauterine growthretardation is classified as less than the 10th percentile of birth weight forgestational age in comparison to an external standard of birth weight forgestational age, adjusted for gender and ethnicity, that was developed from all1999 singleton births in the United States, and updated in 2014 (Talge, 2014).

Many studies have shown a strong correlation between caffeine intake duringpregnancy and reduced birth weights. For pregnant women who consume more than300 mg of caffeine daily, a high risk of SGA and IUGR have been found. Intakebetween 150 mg and 300 mg daily has also been linked to such risks, however,the data is not as consistent.

   From 2003-2006, aperspective cohort study following pregnant women between the ages of 18 and 45,with singleton pregnancies was implemented. The caffeine intake of these womenwas monitored, and the relationship between caffeine and fetal growth wasevaluated. At any level of caffeine intake there was an associated risk offetal growth retardation found, and this risk was maintained throughoutpregnancy. They found that after adjustment for smoking and alcohol intake, anaverage caffeine consumption of more than 100 mg per day was correlated with areduction in birth weight of 34-59 g in the first trimester, 24-74 g in the second,and 66-89 g in the third.

An extra 60-70 g may seem insignificant, but it canmake all the difference for an already compromised fetus, and can help avoidperinatal morbidity and mortality. The study did observe a steep decline inrisk for caffeine intakes of less than 30 mg per day, but this may be due tounmeasured confounding, or simply because women who consume little or nocaffeine may be more health conscious in general, compared to those who consumemore. (CARE Study Group, 2008) In a second prospectivestudy, Fuhurhashi et al. observed the caffeine intake of 9,921 healthy pregnantwomen with a gestational age of at least 24 weeks. Among the 53 of the womenwho consumed more than five cups of coffee daily, a 13.2% higher prevalence offetuses who were SGA was observed (Fuhurhashi, 1985).

 The Norwegian Mother andChild Cohort Study conducted by the Norwegian Institute of Public Health,followed of 59,123 women with uncomplicated singleton pregnancies. At weeks 17,22, and 30, the women reported their caffeine intakes from different sources.SGA was defined according to ultrasound-based, population-based, and customizedgrowth curves. Based on the three scales, an average of 25 g weight reductionwas associated with every additional 100 mg of maternal caffeine intake per dayfor a baby with an expected birth weight of 3,600 g. The findings of this studywere strengthened by coinciding results for caffeine sources, time of survey,and different SGA definitions.

Even caffeine consumption below the recommendedmaximum such as 200 mg per day, compared to the recommended 300 mg per day wasconsistently associated with increased risk for SGA (Sengpiel, 2013). Gestational age was not linkedto caffeine intake in these studies, suggesting that the effect maternalcaffeine consumption has on fetal birth weight occurs through IUGR. Possiblemechanisms responsible for this effect include caffeine’s similar structure toadenine and guanine which may allow it to interfere with cell division andmetabolism.

Additionally, caffeine has a vasoconstrictive effect on placentalintervillous blood flow that may also contribute to the potential risk of IUGR(Kirkinen, 1983).  During the first trimesterof pregnancy, the embryo first starts developing it’s organs, heart beat, brainwaves, and the rest of it’s body parts. As this is such a crucial time ofdevelopment, caffeine intake should be limited especially in this time. Infact, Fenster et.

al have shown that women who reduced their caffeine intake toless than 300 mg a day within 6 weeks of their last menstrual period furtherreduced their risk of delivering LBW infants and infants with IUGR comparedwith women who did not reduce their intake early in their pregnancies. Thisstudy was controlled for gestational age (Fenster, 1991). There is a steady negativecorrelation between LBW infants and maternal caffeine consumption above 300 mg.Risk has been observed for intakes between 151 mg and 300 mg in many cases, andoccasionally, even for daily intakes lower than 150 mg.

Pregnant women shouldbe sure to limit their caffeine intake as much as possible to lessen the probabilityof small reductions in birth weight that might be especially harmful to prematureinfants. Further research is needed to clarify the mechanisms by which caffeineexercise’s an effect on fetal growth. Effects of Caffeine Consumptionon Preterm Labor and Delivery Caffeine has not beenfound to be a strong factor in increasing for preterm labor and delivery. In1996–2000, Bracken et. al questioned 2,291 mothers with singleton pregnanicesin Connecticut and Massachusetts about caffeine consumption and other importantconfounding factors after their first prenatal visit. Urine samples were takento analyze urinary caffeine, cotinine, and creatinine levels. The mothers werefollowed throughout pregnancy to monitor changes in consumption, and medicalrecords were obtained to confirm pregnancy outcomes. While mean birth weightwas found to be reduced by 28 g per 100 mg of daily caffeine intake, meangestational age was not found to be affected at all.

(CARE Study Group, 2008) In the Norwegian Motherand Child Cohort Study spontaneous preterm delivery was defined as “spontaneousonset of delivery between 22+0 and 36+6 weeks (n = 1,451)” (Sengpiel, 2013). Caffeinefrom coffee, but not from other sources, was actually associated with prolongedgestation, but no association of increased risk of spontaneous preterm deliverywas found with caffeine consumption. (Sengpeil, 2013). Other studies as wellfound no effect on gestational age indicating that caffeine influences fetalgrowth, not gestational age at delivery. Pastor et. al performed a case controlstudy of 408 preterm (less than 37 weeks gestation) infants, and caffeineintake in the third trimester showed a nonsignificant relationship with pretermdelivery (Pastore, 1995).

  Alternatively, in apopulation-based study of 7,855 livebirths in San Joaquin Valley, California, increasedpreterm birth among women who drank caffeinated coffee was found compared withwomen who drank neither decaffeinated nor caffeinated coffee. Those whoconsumed only decaffeinated coffee showed no increased odds of SGA birth, LBW,or preterm delivery, while women who consumed caffeinated coffee alone had ahigher association with preterm delivery. (Eskenzai, 1999). This study has notbeen replicated, and other analyses did not support it.  Gestational age is difficultto calculate and assess, making this topic more difficult to analyze accurately.

Generally, there appears to be no relationship between caffeine consumptionduring pregnancy and premature labor and delivery in humans.  Effects of CaffeineConsumption on Spontaneous Abortions Most studies reporteffects of caffeine on spontaneous abortion, however, there are some whosuggest otherwise. In one study, 2,967 pregnant women who delivered at Yale-NewHaven hospital between 1988 and 1992 were evaluated for caffeine intake thefirst month of pregnancy. After studying the effect of the caffeine onpregnancy outcomes, it was concluded that increased risk of spontaneousabortions was linked to drinking more than 3 cups of tea or coffee daily. Theassociation of risk with tea and coffee intake showed to be stronger than withcaffeine in general, and was primarily correlated with abortions which tookplace in later trimesters (Dlugosz,1996). A prospective cohort studyof 3,135 pregnant women found that those who consumed more than 151 mg ofcaffeine daily were more likely to spontaneously abort, in the second or thirdtrimester, in comparison to those who had a daily intake of less than 150 mg ofcaffeine. (Srisuphan, 1986).  Fuhurhashi et al.

studiedhealthy, pregnant women, all of whom were beyond 24 weeks of gestation.Caffeine consumption of more than 600 mg daily was significantly associated withimpending abortion, with a higher prevalence of 17% found. (Fuhurhashi,1985).   Another study of 1324women demonstrated associations between caffeine intake prior to, and duringpregnancy with spontaneous abortions in 331 of the 1324 women. The risk offetal loss increased for each 100 mg of caffeine ingested daily duringpregnancy, as well as smaller increases in risk for each 100 mg of caffeineingested daily prior to becoming pregnant. (Infante-Rivard, 1993).  Dominguez-Rojas et.

alconducted a retrospective cohort study of 711 pregnant women, monitoring theircaffeine intake, and found caffeine to be a clear risk factor for spontaneousabortion. They determined that the adjusted odds ratio (a measure ofassociation between exposure and outcome) of spontaneous abortion by caffeineconsumption was significant for 141-280 mg daily, doubled for 281-420 mg daily,and then almost tripled for intake of greater than 421 mg daily. (Dominguez-Rojas,1994). Alternatively, differentstudies found no association between maternal caffeine intake and spontaneousabortions. 431 women were enrolled in a multicenter study within 21 days ofconception.

Throughout pregnancy, they were monitored for caffeine intake, andexposure to other risk factors, and the effects on pregnancy outcome. Theinvestigators found no connection between caffeine intake, neither above orbelow 30 mg daily, increased risk of spontaneous abortions (Mills, 1993). Determining a definitecausal connection between caffeine intake and occurrence of spontaneous abortionsis complicated by the fact that many of the studies reviewed failed to controladequately for smoking, alcohol intake, or parity. There seems to be a strong associationbetween caffeine consumption and fetal loss, but more research must be donebefore unambiguous statements can be made.  Effects of CaffeineConsumption on Congenital Malformations Caffeine can perhaps actas a teratogen due to its chemical structure as a purine, one of the componentsof DNA. After maternal consumption, caffeine can cross the placenta to the developingembryo. If the molecule were to become incorporated into DNA, there is apossibility that it could induce the production of abnormal proteins (Goldstein,1962).

The literature reviewed showed no significant evidence linking human maternalcaffeine intake during pregnancy to major congenital malformations.  In a study performed toanalyze information from the Finnish Registry of Congenital Malformation, motherswho had given birth to infants with the same defects were matched according andplace and time of birth. One mother in each pair consumed coffee duringpregnancy, while the other did not. To evaluate the hypothesis that coffeeconsumption during pregnancy is teratogenic, the 706 pairs of mothers ofmalformed children and their controls were interviewed soon after delivery. Thesubjects of the study subjects included 112 mothers of children with defects ofthe central nervous system, 241 mothers of children with orofacial clefts, 210mothers of children with structural defects of the skeleton, and 143 mothers ofchildren cardiovascular malformations. The study determined that coffee intakedoes not appear to increase risk for any of the defects that were studied.

Evenmothers who consumed more than six cups of coffee per day had no higher risk ofgiving birth to an infant with congenital malformations. The study also pairedthese mothers with women who gave birth to non-defective infants, in the sametime and place, and consumed an equivalent amount of caffeine daily during pregnancy.The amount of coffee consumed during pregnancy was similar for the mothers ofmalformed and non-malformed children, with the broad range of maternal intakebeing 0-10 cups daily, demonstrating that excessive coffee intake does notincrease risk of congenital malformations (Kurppa, 1983).  Mcdonald et al.investigated the relationships between smoking, alcohol intake, and caffeineconsumption, and congenital malformations using data from a survey conducted inMontreal from 1982-1984. A weak association between caffeine consumption andheart defects was found, but the evidence was not strong. There was noconnection found between caffeine intake and club foot, musculoskeletal,renal/urinary, gastrointestinal or respiratory, clefts or neural tube defectabnormalities (Mcdonald et al.

, 1992).  Similarly, a study was performed to determine the possible effectsof different chemical and physical factors during pregnancy on the occurrence of cardiovascularmalformations, specifically hypoplastic left heart syndrome.  573 cases and1,055 controls were interviewed approximately 3 months after delivery using astandard questionnaire. An increased riskof cardiovascular malformations was not found to be associated with coffee, tea, or colaconsumption. (Tikkanen et al., 1994) One study did show anincreased risk for malformations due to caffeine. A retrospective case-controlstudy was executed in which 558 women in England who had delivered ananencephalic stillbirth, were matched with 2232 control women based on maternalage, parity, and date of delivery.

Based on a structured questionnaire completedby the cases and controls, it was shown that the women who drank 3 or more cupsof tea daily were more likely to give birth an anencephalic stillborn. (Fedrick,1974). However, the results of this study may not be completely accurate, andthe authors themselves wrote that caution should be taken when interpretingtheir results. Most studies agree thatthere is no connection between caffeine intake during pregnancy and congenitalabnormalities. Any connections that were found, have been deemed weak at best.

 Conclusion Based on the literaturereviewed, maternal caffeine intake during pregnancy should be limited tobetween 150 mg and 300 mg per day, to mitigate negative effect caffeine hasbeen shown to have on birth weight, risk of IUGR, and risk of spontaneousabortion. More studies must be done to confirm correlation between caffeine andspontaneous abortion, and based on current data, there does not seem to be asignificant risk of preterm labor or congenital malformations related tocaffeine intake.  Pregnancy is a time whenmotherly instincts begin to kick in, and women are likely to be receptive tocounseling about lifestyle changes.

Many women are unaware of the real riskthat their caffeine intake can create for their unborn child. Doctors andprenatal counselors should be sure to discuss the matter with soon-to-bemothers so they can make informed decisions when consuming caffeine duringpregnancy. In addition, having a health care provider monitor caffeine intake mayhelp establish the degree of risk for use of other drugs or high-risk behaviorsduring pregnancy.  List of Acronyms LBW- Low Birth WeightSGA- Small for Gestational AgeIUGR-Intrauterine Growth Retardation               References