The to premature or low birth weight infants.

The American publicconsumes a wide array of caffeinated products including coffee, tea, chocolate,cola beverages, and caffeine-containing medication. Therefore, it seems ofvalue to inform both the scientific community and the consumer about thepotential effects of excessive caffeine consumption, particularly for pregnantwomen.

The results of this literature review suggest that heavy caffeine use(more than 300 mg per day) during pregnancy is associated with small reductionsin infant birth weight that may be especially detrimental to premature or lowbirth weight infants. Some researchers also document an increased risk ofspontaneous abortion associated with caffeine consumption prior to and duringpregnancy. However, overwhelming evidence indicates that caffeine is not ahuman teratogen, and that caffeine appears to have no effect on preterm laborand delivery. More research is needed before unambiguous statements about theeffects of caffeine on pregnancy outcome variables can be made, and todetermine the mechanisms by which caffeine can have these potential effects onthe fetus. Introduction Caffeine(1,3,7-trimethylxanthine) is a naturally occurring compound.

Its pharmacologicaland physiological effects, include central nervous system stimulation, cardiacmuscle stimulation, and smooth muscle relaxation, in addition to effectingmood, memory, alertness, and physical andcognitive performance. Caffeine is the most widely used stimulant for thecentral nervous system. Clinically, caffeine is effective in relaxing thebronchial muscle in patients with asthma, as well as increasing gastric acidsecretion and the concentrations of plasma free fatty acids and glucose (Instituteof Medicine, 2001).  Sourcesof Caffeine Coffee,tea, and soft drinks are the main sources of caffeine in the adult Americandiet (Table 1). Other dietary sources include cocoa and chocolate, sugars andsweets, and flavored dairy products.

Tea and cocoa also contain significantquantities of theophylline (1,3-dimethylxanthine) and theobromine(3,7-dimethylxanthine), respectively, which are caffeine derivatives that havenot been as widely researched (Frary, 2005). Caffeine is present in fiveclasses of nonprescription medications: analgesics, cold/allergy products,diuretic products, stimulants, and weight control agents. While each medicationhas a different suggested dose, chronic use may represent a significant sourceof caffeine for pregnant women who otherwise do not consume caffeinatedbeverages. For example, consuming a two-tablet dose of an over-the-counteranalgesic every 6 hours may result in daily consumption of up to 520 mg ofcaffeine (Table 2).  Demographicsof Caffeine Intake During Pregnancy Duringpregnancy, studies have shown women consume less caffeine than prior tobecoming pregnant, primarily 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).

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Colas, soft drinks, and foods containing chocolate contributeproportionally more to the total dietary intake of caffeine by pregnant womenthan non-pregnant women, but coffee and tea still make up the largest percentof their caffeine intake (Frary, 2005). Heavy caffeine consumption (more than300 mg per day) is noted among pregnant women with fewer years of formaleducation and consumers of large amounts of caffeine are also more likely tosmoke (Crozier, 2009a). Absorption,Distribution, and Clearance of the Methylxanthines  Absorption Caffeineand the other methylxanthines are readily 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.When consumed in a beverage, the caffeine is rapidly 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.

Peak plasma levels ofcaffeine occur between 15 minutes and 120 minutes after ingestion oradministration, there is considerable variation in the amount of time dependingupon the source of caffeine and individual metabolic differences (Institute ofMedicine, 2001). Distribution Thedistribution volume of caffeine within the body is 0.7 L/kg, suggesting thatcaffeine is hydrophilic and distributes freely into the intracellular tissuewater (Arnaud, 1993).

Caffeine is also amply lipophilic and can pass throughall biological membranes and freely crosses the blood-brain barrier (Instituteof Medicine, 2001). In pregnant women, the methylxanthines cross the placentato the fetus where an equilibrium is achieved between the maternal and fetalplasma. Caffeine achieves this equilibrium as early as 7-8 weeks of gestation(Goldstein, 1962). It has been estimated that the fetus can ingest severalmilligrams of caffeine each day in the approximately 500 mL of amniotic fluidswallowed daily. In addition, the fetal liver is able to methylate theophyllineto caffeine by week 12 of gestation (Brazier, 1981). Theophylline is alsoeliminated in the amniotic fluid, and the fetal elimination half-lives oftheophylline and caffeine are 30 and 150 hours, respectively.  Clearance Becausecaffeine is readily reabsorbed by the renal tubules, once it is filtered by theglomeruli only a small percentage is excreted unchanged in the urine. Itslimited appearance in urine indicates that caffeine metabolism is therate-limiting factor in its plasma clearance (Arnaud, 1993).

Caffeinemetabolism occurs primarily in the liver, catalyzed by hepatic microsomalenzyme systems (Grant, 1987). In healthy humans, repeated caffeine ingestiondoes not alter its absorption or metabolism. Caffeine is metabolized in theliver to dimethylxanthines, uric acids, di- and trimethylallantoin, and uracilderivatives. In humans 3-ethyl demethylation to paraxanthine is the primaryroute of metabolism (Arnaud, 1987). This first metabolic step accounts forapproximately 75–80 percent of caffeine metabolism (Arnaud, 1993).

Paraxanthineis the dominant metabolite in humans, rising in plasma to concentrations 10times those of theophylline or theobromine. Caffeine is cleared more quicklythan paraxanthine, so 8 to 10 hours after caffeine ingestion, paraxanthinelevels exceed caffeine levels in plasma (Arnaud, 1993). Formation of paraxanthine and its excretion in the urineappears to be the major pathway for caffeine metabolism. During the second andthird trimesters of pregnancy, there is decreased maternal elimination ofcaffeine (Aldridge, 1981). The half-life of caffeine in pregnant women changesfrom 5.3 hours to 18.1 hours during the second and third trimesters ofpregnancy, which is attributed to changes in plasma progesterone and estrogenlevels. Maternal clearance of caffeine is also influenced by age, disease, andpersonal habits such as smoking and long-term use of oral contraceptives priorto pregnancy.

These factors may result in prolonged maternal and fetal exposureto caffeine and may be especially significant to the fetus during the rapidgrowth of the third trimester. A few weeks after giving birth, the rate ofmaternal caffeine elimination returns to non-pregnant 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 An infant who weighs lessthan 2,500 g (5 lbs, 8 oz) at birth is classified as low birth weight (LBW).

 Low birth weight may be the result of a shortenedgestational period (prematurity) or the result of intrauterine growthretardation (IUGR), which results in a small for gestational age (SGA) infant.Intrauterine growth retardation is classified as less than the 10th percentileof birth weight for gestational age in comparison to an external standard ofbirth weight for gestational age, adjusted for gender and ethnicity, that wasdeveloped from all 1999 singleton births in the United States, and updated in2014 (Talge, 2014). Many studies have shown a strong correlation betweencaffeine intake during pregnancy and reduced birth weights. For pregnant womenwho consume more than 300 mg of caffeine daily, a high risk of SGA and IUGRhave been found. Intake between 150 mg and 300 mg daily has also been linked tosuch risks, however, the data is not as consistent.   From 2003-2006, aperspective cohort study following pregnant women aged between 18 and 45 years,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 association found withincreased risk of fetal growth restriction, and this risk was maintainedthroughout pregnancy. They found that an average caffeine consumption ofgreater than 100 mg per day was associated with a reduction in birth weight of34-59 g in the first trimester, 24-74 g in the second, and 66-89 g in the third(after adjustment for smoking status and alcohol intake). Although the overallsize of the reduction in birth weight may be seen as small, an extra 60-70 g inweight could reduce perinatal morbidity and mortality in an already compromisedfetus. There was steep decline in risk observed associated with caffeineintakes of less than 30 mg per day, but this may be attributable to unmeasuredconfounding. Furthermore, women who consume little or no caffeine may begenerally more health conscious than those who consume more.

(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. 53 of the women consumedgreater than five cups of coffee daily, and the study determined that the 53women had a significantly higher prevalence (13.2%) of fetuses who were SGA(Fuhurhashi, 1985). The Norwegian Mother andChild Cohort Study conducted by the Norwegian Institute of Public Health,followed a total of 59,123 women with uncomplicated pregnancies giving birth toa live singleton.

Caffeine intake from different sources was self-reported atgestational weeks 17, 22, and 30. SGA was defined according to ultrasound-based,population-based, and customized growth curves. Based on the three scales, an averageof 25 g weight reduction was associated with every additional 100 mg ofmaternal caffeine intake per day for a baby with an expected birth weight of3,600 g. The findings of this study were strengthened by coinciding results forcaffeine sources, time of survey, and different SGA definitions.

Even caffeineconsumption below the recommended maximum such as 200 mg per day, compared tothe recommended 300 mg per day was consistently associated with increased riskfor SGA (Sengpiel, 2013). Because gestational agewas not related to caffeine consumption in these studies, it appears that maternalcaffeine consumption has an effect on birth weight through IUGR. Two mechanismsmay be responsible for this effect. Caffeine is structurally similar to adenineand guanine and may interfere with cell division and metabolism. In addition,caffeine has a vasoconstrictive effect on placental intervillous blood flowthat may also contribute to the potential risk of IUGR (Kirkinen, 1983).  Fenster et al. have shownthat women who reduced their caffeine intake to less than 300 mg a day within 6weeks of their last menstrual period also reduced their risk of delivering LBWinfants compared with women who did not reduce their intake early in theirpregnancies.

Women who reduced their caffeine intake to less than 300 mg within6 weeks of their last menstrual period also had a lower risk of deliveringinfants with IUGR. This study was controlled for gestational age (Fenster,1991). In general, there is aconsistent negative correlation between infant singleton birth weight andcaffeine consumption above 300 mg, the data for intakes between 151 mg and 300mg are conflicting, and few adverse effects have been documented below 150 mg.Therefore, to mitigate the effect of small reductions in birth weight thatmight be especially significant to premature infants, women should limit theirdaily caffeine intake to less than 300 mg daily. In addition, further researchis needed to elucidate the mechanism(s) that allow caffeine to exert an effecton fetal growth. Effects of Caffeine Consumptionon Preterm Labor and Delivery The association betweencaffeine consumption and preterm births is, at best, weak.

In a case-controlstudy of 408 preterm (less than 37 weeks gestation) infants, caffeine intake inthe third trimester showed a nonsignificant relationship with preterm delivery(Pastore, 1995).  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).Coffee caffeine, but not caffeine from other sources, was actually associatedwith prolonged gestation but neither total nor coffee caffeine was associatedwith spontaneous preterm delivery risk (Sengpeil, 2013). Other studies as wellfound no effect on gestational age indicating that caffeine influences fetalgrowth, not gestational age at delivery.

In 1996–2000, Bracken et. al evaluated2,291 mothers with singleton livebirths in Connecticut and Massachusetts aftertheir first prenatal visit and questioned them about caffeine consumption andimportant confounding factors. Urine samples were provided to analyze urinarycaffeine, cotinine, and creatinine levels. Mothers were followed throughoutpregnancy to monitor changes in consumption and medical records were obtainedto confirm pregnancy outcomes.

Mean birth weight was reduced by reportedcaffeine consumption (–28 g per 100 mg of caffeine consumed daily) but not meangestational age (CARE Study Group, 2008) In a population-basedstudy of 7,855 livebirths in California’s San Joaquin Valley, increased pretermbirth among women who drank caffeinated coffee was found compared with womenwho drank neither decaffeinated nor caffeinated coffee. Those who consumed onlydecaffeinated coffee showed no increased odds of SGA birth, LBW, or pretermdelivery, while women who consumed caffeinated coffee alone had a higher associationwith preterm delivery. (Those who consumed both caffeinated and decaffeinatedcoffee showed a reduction in adjusted mean birth weight of ?3.0 g per cup perweek for caffeinated coffee and an increase of +0.4 g per cup per week for decaffeinatedcoffee) (Eskenzai, 1999). This study has not been replicated, and otheranalyses did not support it.  Gestational age is difficultto assess accurately, and misclassification may account for some null results.

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, but not all. High caffeineconsumption during pregnancy has been shown to significantly increase the riskof spontaneous abortions. In a prospective cohort study of 3,135 pregnant womenwho miscarried late in the first trimester or in the second trimester, womenwho consumed more than 151 mg of caffeine per day were significantly morelikely to abort spontaneously compared with women who consumed less than 150 mgof caffeine daily (Srisuphan, 1986).  In Fuhurhashi et al. studyof healthy pregnant women beyond 24 weeks of gestation, ingestion of more than 600mg per day of caffeine was significantly associated with a high prevalence(17%) of impending abortion (Fuhurhashi,1985).   In one study, 2,967pregnant women planning to deliver at Yale-New Haven hospital between 1988 and1992 were evaluated for caffeine intake the first month of pregnancy.

Afterstudying the effect of the caffeine on pregnancy outcomes, it was concludedthat drinking more than 3 cups of tea or coffee was associated with elevatedrisks of spontaneous abortion. The association appeared stronger for tea andcoffee than caffeine in general and was primarily found with abortions whichtook place in later trimesters (Dlugosz,1996). Infante-Rivard et al.

alsodemonstrated associations between caffeine intake prior to and during pregnancywith fetal loss in 331 of 1324 women. The adjusted odds ratio increased by 1.22(1.10-1.

34) for each 100 mg of caffeine intake per day during pregnancy, andincreased by 1.10 (1.001.22) for each 100 mg of caffeine intake prior topregnancy (Infante-Rivard, 1993).  Similarly, a retrospectivecohort study design of 711 women determined the adjusted odds ratios ofspontaneous abortion by caffeine consumption to be 2.20 (141-280 mg per day),4.

81 (281-420 mg per day), and 15.43 (greater than 421 mg per day); indicatingthat caffeine is a clear risk factor for spontaneous abortion (Dominguez-Rojas,1994). Alternatively, anadditional study found a weak association between maternal caffeine intake andspontaneous abortions. A cohort of 431 women, enrolled in a multicenter studywithin 21 days of conception, was monitored throughout pregnancy to determinecaffeine exposure, and exposure to other risk factors, and the effect onpregnancy outcome. The investigators found no association between spontaneousabortions and caffeine intake either above or below 300 mg a day (Mills, 1993). This issue is complicatedby the fact that many of the studies reviewed failed to control adequately forsmoking, alcohol intake, or parity. Further research is needed to determinewhether there is a definite causal relationship between caffeine and/or coffeeintake and the incidence of spontaneous abortion. Effects of CaffeineConsumption on Congenital Malformations Caffeine can perhaps actas a teratogen due to its chemical structure as a purine, one of theconstituents of DNA.

Caffeine can cross the human placenta and enter the fetalgonad. If the caffeine molecule were incorporated into DNA, there is apossibility that it could give rise to abnormal proteins important in health(Goldstein, 1962). Based on the literature reviewed, there is no significantevidence that links human maternal caffeine intake during pregnancy to major infantbirth defects.  In an analysis ofinformation from the Finnish Registry of Congenital Malformation, pairs ofcoffee-drinking mothers who had given birth to infants with defects werematched (according to daily maternal coffee consumption and place and time ofbirth) with an equal number of non-coffee drinking mothers with defective infants(controls). To evaluate the hypothesis that coffee consumption during pregnancyis teratogenic, 706 pairs of mothers of malformed children and their controlswere personally interviewed soon after delivery. Study subjects consisted ofmothers of children with 112 defects of the central nervous system, 241orofacial clefts, 210 structural defects of the skeleton, and 143cardiovascular malformations.

Kurppa et al. determined that even mothers whoconsumed at least six cups of coffee per day were no more likely to give birthto children with congenital malformations. The coffee consumption duringpregnancy was similar for the mothers of malformed or non-malformed children(Kurppa, 1983). This finding is especially relevant in light of the wide rangeof maternal coffee intake (0-10 cups daily), suggesting that there is noassociation between excessive coffee intake and congenital defects. Mcdonald et al.investigated the relationships between cigarette, alcohol, and coffeeconsumption, and congenital defects using data from a survey of occupationalfactors in pregnancy conducted in Montreal from 1982-1984. Coffee consumptionwas associated only with heart defects and the evidence was not strong.

Therewas no connection found between caffeine intake and club foot, musculoskeletal,renal/urinary, gastrointestinal or respiratory, clefts or neural tube defectabnormalities (Mcdonald et al., 1992).  Similarly, the possible effect of chemical and physical factors during pregnancy on the occurrence of cardiovascularmalformations, specifically hypoplastic left heart syndrome in offspring was studied in 573 cases and 1,055 controls.

Case and control mothers were interviewed bymidwives approximately 3 months after delivery using a structured questionnaire. The riskof cardiovascular malformations was not associated with coffee, tea, or cola consumption, andwas equal in urban and rural areas. The causes of the majority of cardiovascular malformations remain unknown. (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 resident in England and Wales who haddelivered an anencephalic stillbirth, and 2232 control women matched formaternal age, parity, area of the country, and date of delivery, were sent aquestionnaire. It was shown that the women who had given birth to anencephalicstillbirths were more likely to drink 3 or more cups of tea per day (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.  Smoking and Caffeine The interaction betweencaffeine and smoking is particularly important. It is possible that smoking andcaffeine interact with each other to reduce fetal growth, but the mechanisms bywhich caffeine may reduce fetal growth are unclear and may differ from those bywhich smoking induces its effects. Women who drink caffeine also tend to smoke,and women who smoke metabolize caffeine more quickly, which may protect thefetus from developmental effects.

Evidence of any interaction between smokingand caffeine exposure is mixed; some studies reported effects (Fortier etal.,1993), but others found none (Fenster, 1991, McDonald, 1992). Conclusion Based on the literaturereviewed, caffeine intake should be limited to between 150 mg and 300 mg perday, particularly because of the potential negative effects of caffeine onbirth weight, IUGR, and risk of spontaneous abortion.

More studies must be doneto confirm correlation between caffeine and spontaneous abortion, and based oncurrent data, there does not seem to be a significant risk of preterm labor orcongenital malformations related to caffeine intake.  Pregnancyis a time when women are likely to be receptive to counseling about lifestylechanges, including use of licit and illicit substances. An initial discussionabout caffeine intake may provide a basis for an honest exchange aboutlifestyle practices that place the fetus and mother at risk, because caffeineis less likely to be perceived as a substance of abuse. In addition, assessmentof caffeine intake by the health care provider may help ascertain the degree ofrisk for use of other drugs or high-risk behaviors during pregnancy.