The Effects of Caffeine On Reproductive Outcomes in Women

The effects of caffeine on reproductive outcomes in women
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http://www.uptodate.com.proxy.lib.ohio-state.edu/contents/the-effects-of...
Official reprint from UpToDate

www.uptodate.com 2014 UpToDate
Authors
Vicki Nisenblat, MD
Robert J Norman, MD
Section Editor
Charles J Lockwood, MD, MHCM
Deputy Editor
Kristen Eckler, MD, FACOG
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2014. | This topic last updated: Feb 06, 2014.
INTRODUCTION Caffeine is the most popular pharmacologically active substance consumed and one of the
most heavily researched commodities in the world. It is a stimulant, and is often used to enhance mental alertness.
Although there is no high quality evidence that a modest level of caffeine consumption has adverse effects on fertility
or pregnancy outcome, putative beliefs about a relationship between caffeine intake and adverse reproductive
outcomes are common, and caffeine consumption is often perceived to be an unhealthy habit. The consumption of
caffeinated beverages has been implicated in fertility problems, while consumption during pregnancy has been
associated with an increased risk of miscarriage, congenital malformations, fetal growth restriction, stillbirth, and
long-term behavioral effects in offspring. The biologic rationale for these associations is caffeine's ability to
accumulate in fetal tissues and produce diverse pharmacologic effects that could interfere with fetal growth and
development [1-3].
This topic will review the relationship between caffeine intake and reproductive issues in women. The physiological
effects of caffeine and caffeinated beverages and the effects of caffeine on specific disease processes, including
insulin resistance, cancer, cardiovascular disease, and mortality are discussed separately. (See "Cardiovascular
effects of caffeine and caffeinated beverages" and "Benefits and risks of caffeine and caffeinated beverages".)
SOURCES OF CAFFEINE Caffeine originates in more than 60 plants, occurs naturally in various food products
and beverages (including coffee, tea, chocolate, cocoa products, colas), and is added to some soft drinks and most
"energy" drinks. Caffeine is also present in some prescription and over-the-counter medications, such as cold and flu
remedies, allergy and headache treatments, diet pills, diuretics, and stimulants. Increasingly, caffeine is now present
as an additive in snack foods, sports performance supplements, and dietary supplements. Examples of the caffeine
content of various products can be found online (eg, http://www.cspinet.org/new/cafchart.htm) and in the table (table
1).
Coffee, tea, cocoa and carbonated soft drinks are the main sources of caffeine intake. Consumption varies
throughout the world, and is influenced by culture, individual preferences, availability, and advertising. Coffee
contains 50 to 70 percent more caffeine than tea and other products, accounting for the main source of caffeine in
many populations.
CAFFEINE CONSUMPTION IN WOMEN OF REPRODUCTIVE AGE Estimates of daily caffeine intake vary
widely, both worldwide and within individual countries, due to the many significant difficulties in ascertaining caffeine
consumption. (See 'Quality of existing evidence and methodological considerations' below.) In a study of data from a
United States Department of Agriculture (USDA) Survey of Food Intakes by Individuals, caffeine was consumed by
89 percent of women aged 18 to 34 years and their average intake was 164 mg per day [4]. In a study from the
United Kingdom, the average daily caffeine intake of women of childbearing age was estimated to be 174 mg per
day, with up to 18 percent consuming more than 300 mg per day [5]. A study from Japan reported the mean caffeine
intake of women aged 30 to 39 years was 213 mg/day, and 7 percent consumed more than 400 mg/day [6].
Although most women reduce their caffeine intake during pregnancy, in part because of nausea, pregnant women
have been reported to consume an average of 60 to 125 mg of caffeine per day [4,7], and 10 to 15 percent
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consumed more than 160 to 200 mg daily [7,8].

PHARMACOKINETICS, METABOLISM, AND PHYSIOLOGIC EFFECTS
General population Caffeine (methylated xanthine 1,3,7-trimethylxantine) is a highly soluble compound that
readily crosses cell membranes throughout the body. It is rapidly absorbed in the stomach and small intestine and
can be detected in human tissues 30 to 45 minutes after ingestion, with peak blood concentration reached within two
hours. Clearance values are 1 to 3 mL/kg/min in both men and women after low caffeine intake; however, clearance
is diminished with higher doses, largely because of saturable metabolism of caffeine metabolites that accumulate in
plasma and reduce caffeine clearance [9]. The volume of distribution of caffeine is 0.7 to 1.3 L/kg and elimination
half life is 4.1 to 6.4 hours.
Caffeine is metabolized in the liver by the cytochrome P450 family. Cytochrome P450 1A2 (CYP 1A2) is the
predominant isoform, accounting for 95 percent of primary caffeine metabolism [10]. CYP 2E1 and CYP 1B1 may
also make a minor contribution to the primary metabolism of caffeine [9].
The primary metabolites of caffeine, paraxanthine (1,7 dimethylxanthine), theophylline (1,3 dimethylxanthine) and
theobromine (3,7 dimethylxanthine), share many of the biological activities of caffeine and also occur independently
in natural products [9]. Paraxanthine is the main metabolite in humans and is present in coffee beans; theophylline is
a significant xanthine in tea leaves; and theobromine, the weakest of xanthines, is present in cacao beans.
Metabolism of these metabolites leads to the formation of monomethylxanthines and methyluracils. Caffeine is
excreted by the kidneys, mainly in the form of different metabolites; only 5 to 10 percent is excreted unchanged [11].
Caffeine metabolism depends on numerous genetic and environmental factors. Individuals can be classified as slow
or fast metabolizers. The factors influencing caffeine metabolism primarily affect CYP 1A2 activity and include
cigarette smoking, pregnancy, oral contraceptive use, liver disease, certain medications, genetic polymorphism of
CYP 1A2, and ethnicity [1]. As an example, smoking accelerates caffeine metabolism and almost doubles its
clearance rate via induction of hepatic oxidative enzymes; this results in a two- to three-fold lower median plasma
caffeine concentration in smokers than in non-smokers at the same level of caffeine intake [12]. CYP 1A2 activity is
higher in adult males than in females; therefore, females, particularly non-smokers, are prone to more prolonged
exposure to caffeine.
Caffeine is a stimulant and is commonly used to enhance mental alertness; however, it has a wide range of
physiological effects. Chronic use is often associated with habituation and tolerance, while discontinuation may
produce withdrawal symptoms [1,9,11]. The physiological effects of caffeine in adults are reviewed in detail
separately. (See "Benefits and risks of caffeine and caffeinated beverages" and "Cardiovascular effects of caffeine
and caffeinated beverages".)
Maternal and fetal kinetics Caffeine and its metabolites readily cross the placenta and can be found in
substantial quantities in the amniotic fluid and fetal blood [13,14]. Maternal caffeine metabolism declines significantly
during pregnancy; the half life increases three-fold in the third trimester, reaching a t 1/2 of 11.5 to 18 hours. The fetus
metabolizes caffeine very slowly, mainly due to immaturity of caffeine-metabolizing hepatic microsome enzymes and
lack of CYP 1A2 activity in the placenta. Therefore, even low maternal caffeine consumption can be expected to lead
to prolonged fetal caffeine exposure, particularly when the mother is a genetically slow caffeine metabolizer. Infants
of smokers have lower umbilical cord blood caffeine concentrations and higher concentrations of caffeine
metabolites than infants of non-smokers, reflecting faster caffeine metabolism in smokers [1].
QUALITY OF EXISTING EVIDENCE AND METHODOLOGICAL CONSIDERATIONS Examining the association
between caffeine consumption and adverse reproductive outcomes presents a considerable challenge. The
consistency and quality of available data have generally been poor. Most studies have methodological shortcomings
and were based on epidemiologic research designs usually classified as level III or low quality evidence (ie,
comparative studies with concurrent controls but allocation not randomized, cohort studies, case-control studies, or
interrupted time series with a control group) [15]. A 2013 Cochrane systemic review on the effects of restricted
maternal caffeine intake on pregnancy outcomes concluded there was insufficient evidence to confirm or refute the
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effect of caffeine avoidance on pregnancy outcomes and neonatal health [16].

There are many potential reasons for inconsistent outcomes among studies, including but not limited to [1]:
Inaccurate estimation of caffeine consumption
Recall bias due to retrospective assessment of caffeine intake
Failure to allow for individual variations in caffeine metabolism
Inadequate control of confounding factors
Selection bias
Chemicals other than caffeine in dietary products, which may contribute to the observed outcome
Comprehensive reviews of these methodologic issues are available elsewhere [1,17,18], and will be reviewed briefly
here. In particular, caffeine consumption is likely to be lower in early than late pregnancy because of early pregnancy
nausea [19]. The majority of existent studies primarily capture the short-term effects of caffeine by assessing
consumption in the period shortly before the studied reproductive event or in individual trimesters rather than
throughout pregnancy, although many health-related conditions are likely to have multifactorial causes and a long
natural history. It has been difficult to document the long-term effects of caffeine because many new caffeinated
products appear in the marketplace and consumption patterns change as a result of dietary advice from a variety of
experts.
Assessment of caffeine intake Assessment of caffeine consumption is methodologically challenging due, in
part, to the wide variation of caffeine content in beverages and large differences in serving sizes. The amount of
caffeine varies according to source (coffee, tea, chocolate, soft drink), portion size (eg, cup size), brewing method
(for coffee and tea), and brand [11]. A standard cup of coffee is often assumed to provide 100 mg of caffeine;
however, an analysis of caffeine content of different coffees from various coffee shops revealed variations of 72 to
130 mg/cup [20]. For espresso, an analysis of caffeine content reported caffeine content of 200 to 322 mg/cup in 20
commercially available espresso products [21].
Coffee is reported as the only source of caffeine in 19 percent of pregnant caffeine consumers, with 26 percent of
caffeine intake solely from other non-coffee dietary sources [22,23]. Therefore, using coffee consumption as a proxy
for caffeine intake leads to gross underestimation of caffeine consumption. The majority of studies on caffeine and
reproductive outcomes neither made a comprehensive analysis of intake of all food, drinks, and drugs containing
caffeine, nor carefully accounted for the variation of caffeine content from individual portion size, brand, or
preparation method of these foods and drinks.
Furthermore, most epidemiological studies have relied on self-reported intake of caffeine instead of laboratory
assessment of biomarkers. The biomarkers of caffeine exposure (caffeine and its metabolites in blood, urine, and
saliva) are of limited use in large population samples, are highly dependent on the timing of the last caffeine intake,
and primarily indicate recent consumption rather than long-term exposure [8,24].
Although caffeine is detectable in amniotic fluid and in the nails of exposed newborns, studies have not used these
types of assays to monitor in utero caffeine exposure.
Recall bias Recall bias refers to differential recall between cases and controls and is of concern because it
distorts the internal validity of studies using self-reported data. It affects studies (both retrospective and prospective)
in which assessment of caffeine consumption is determined after, rather than before, the occurrence of the health
outcome of interest. Patients who have had an adverse event may be more likely to remember perceived unhealthy
habits and associate their consumption of coffee with the adverse event, and thus may overestimate their past
caffeine consumption compared with patients who have not experienced an adverse event.
The importance of recall bias was highlighted by a study that found the correlation between modest caffeine
consumption and pregnancy loss disappeared when pregnant women were interviewed about caffeine consumption
before, rather than after, they had miscarried [25].
Individual variations in caffeine metabolism The clearance rate of caffeine varies among individuals and
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depends on factors affecting cytochrome P450 enzymes, particularly genetic polymorphisms; smoking; and
exposure to other compounds that are metabolized by the same enzyme. As a result, despite equivalent caffeine
intake, slow metabolizers have higher caffeine concentrations and may be at higher caffeine-related risk than fast
metabolizers [26,27].
Potential confounders of caffeine consumption Heavy coffee consumption tends to be strongly associated
with increased age, cigarette smoking, alcohol consumption, a less health conscious lifestyle, and lower educational
level and household income [3]. Other potential confounders include ethnicity, stress, and sleeping pattern. Trying to
establish the independent health effects of coffee consumption by adjusting for these potential confounders is
difficult and can be inaccurate since their assessment is also affected by measurement error.
Nausea and other symptoms of a viable early pregnancy are sometimes called the pregnancy signal. A particular
concern in studies of the effects of caffeine intake during pregnancy is that pregnancy related nausea is common
and an important confounding factor [28]. Nausea in early pregnancy tends to cause dietary changes, such as an
aversion to coffee, but is also strongly predictive of fetal survival, presumably because nausea reflects hormonal
changes that support continued pregnancy [29]. For this reason, there has been a concern that the lower caffeine
consumption and more favorable pregnancy prognosis among women with nausea compared with those who do not
have nausea result in an artificial positive association between low caffeine consumption and better pregnancy
outcome. Well-designed studies of caffeine intake and pregnancy outcome attempt to control for the presence or
absence of pregnancy signal symptoms in their subjects.
Selection bias Many of the studies on the effect of caffeine on reproductive adversity are based on data obtained
from preconception counseling and prenatal health services. The patients attending these services are likely to be
more health conscious, which may be associated with lower coffee consumption and thus lead to selection bias, but
this would also tend to reduce the associated odds ratios.
Other components of caffeinated beverages that may contribute to health effects Coffee, tea, and cocoa
products contain hundreds of compounds other than caffeine that may contribute to the observed health effects of
caffeine consumption [30]. In addition, coffee and black tea are often consumed with a creamer. Non-dairy creamers
contain partially hydrogenated oils that, when used in large amounts, could be a significant dietary source of trans
fatty acids, which may have independent adverse effects on reproduction. Trans fatty acids may interfere with the
desaturation and elongation of n-3 (omega-3) fatty acids. These are important for the prevention of heart disease
and possibly some complications of pregnancy. (See "Nutrition in pregnancy", section on 'Macronutrients'.)
EFFECTS OF CAFFEINE ON REPRODUCTIVE OUTCOMES
Animal and in vitro studies Studies in animals can overcome many of the methodological limitations of studies
in humans, but pose additional methodological issues that prevent extrapolation to humans. First, humans are highly
unlikely to consume the high doses of caffeine used in animal studies. Second, although many metabolic and
pharmacokinetic factors related to caffeine are similar in humans and animals, there is not a direct correlation
between teratogenic effects in animals and in humans, and the dose/anomaly relationship may vary between the
species. Finally, in some animal studies, caffeine intake is by intravenous or intraperitoneal infusion or gavage
feeding, rather than by oral consumption in food/drink over the course of a day, as in humans. This difference may
result in different effects in laboratory animals versus humans. Indeed, when animals receive caffeine doses typically
consumed by humans, caffeine is not mutagenic, oncogenic, or cytotoxic [17]. However, it is possible that
subteratogenic doses of caffeine may have synergistic detrimental effects with other therapeutic agents consumed
by pregnant women.
Some examples of findings from animal studies are summarized below:
In rodents, a teratogenic effect was demonstrated at high caffeine doses (100 to 330 mg/kg); limb deficiencies,
cleft palate, and neural tube defects (NTDs) were among the most frequently observed caffeine-induced
congenital malformations [31-34]. The caffeine-induced NTD phenotype has been demonstrated by others in
various animal models [35-38].
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Caffeine injected into chicken eggs affected monoamine neurotransmitter synthesis in chick embryos and was
not metabolized in embryonic brains, which led to caffeine accumulation and magnification of the adverse
effects [35]. These changes have been implicated in subsequent neurobehavioral or neurophysiologic
deficiencies [39-41].
Rodents given a large bolus or parenteral dose of caffeine are at increased risk of growth restriction in pups;
however, no effect on birth weight has been observed when large doses of caffeine were consumed over the
course of the day in drinking water [17]. Caffeine boluses also delayed conception and decreased placental
weight and gain in maternal bodyweight; these effects were dose dependent [42]. Using a dose-conversion
correlation between humans and rats, the lowest dose of caffeine given to pregnant rats and associated with
the above effects appeared to be equivalent to 3.2 mg/kg per day in humans, which is equivalent to
consumption of 1.5 to 2.2 cups of coffee by a 70 kg woman.
Several basic research studies have assessed the effect of caffeine on trophoblast biology in vitro and suggested
molecular mechanisms for deleterious caffeine effect on pregnancy outcomes [43-45]. A detailed discussion of these
mechanisms is beyond the scope of this topic.
Human studies Data on the effects of caffeine in humans are largely obtained through epidemiological studies.
The bulk of available evidence is low quality and suggests that mild to moderate caffeine intake is not associated
with any adverse reproductive outcome [17,18]. Even a high level of caffeine intake is not always harmful. In a
unique case report, a pregnant woman who consumed a minimum of 5 to 6 cups of coffee per day and often as
much as 24 cups of coffee per day delivered an infant without congenital anomalies or growth restriction, but preterm
[46].
Physiological effects The physiological effects of caffeine exposure have not been studied extensively in
human pregnancy. Higher maternal plasma caffeine levels appear to be associated with a longer duration of fetal
arousal, but fetal tolerance to caffeine exposure also appears to occur [47-49]. Other fetal effects possibly related to
maternal caffeine consumption include increased fetal heart rate variability, lower basal heart rate [47,50], and
increased fetal breathing activity [49,50]. An increase in beat to beat variability and accelerations of the fetal heart
rate following maternal intake of even one cup of espresso coffee (60 mg caffeine) or 30 g of dark chocolate (70
percent cocoa) in the third trimester has been attributed to the pharmacological action of theobromine, present in
coffee and in chocolate [51].
Caffeine consumption may increase release of circulating catecholamines [52,53], which could cause uteroplacental
vasoconstriction leading to fetal hypoxia, but an increase in catecholamines has not been reported consistently [54].
Increases in maternal homocysteine, cholesterol, and cellular c-AMP concentrations [55-59] and changes in
maternal reproductive hormone levels [60] have also been reported, and potential adverse effects on pregnancy
outcome have been hypothesized, but not been proven.
Fecundability When adequately adjusted for other lifestyle factors related to fertility, particularly maternal age,
cigarette smoking, and alcohol intake, the bulk of evidence does not support a clear detrimental effect of caffeine on
fecundability (ie, probability of conception within a non-contracepting menstrual cycle) [18,61,62].
In 1988, a study of couples who failed to conceive within the first three months of trying to conceive observed that
consumption of at least one cup of coffee, two cups of tea, or 2.5 glasses of cola daily was associated with a marked
reduction in fecundability in subsequent cycles compared to women who consumed less caffeine, and a dose
response effect was noted [63]. This study prompted further investigation of a possible relationship between caffeine
and subfertility. Although some retrospective studies have also observed reduced fecundability, particularly with high
caffeine intake [64,65], most prospective epidemiological studies have not found a statistically significant association
between caffeine consumption and fecundability [66-71]. One of these studies was particularly strong because it was
the first to use daily, prospective information on caffeine intake and prospectively ascertained pregnancies, including
subclinical pregnancies, while controlling for frequency of intercourse, smoking, age, body mass index, frequency of
unprotected intercourse, and alcohol intake [67]. Another observed decreased fecundability among women who
consumed sodas and increased fecundability among women who drank tea [71]. This indicates that a caffeine
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exposure variable that does not take into account the specific source may not be appropriate and suggests that
these associations may reflect unmeasured confounding by diet or other lifestyle factors.
The relationship between caffeine consumption and success of in vitro fertilization (IVF) has not been studied as
extensively. In one study, recent caffeine intake by women undergoing IVF did not affect rates of oocyte retrieval,
fertilization, embryo transfer, or pregnancy, but more remote caffeine intake seemed to have a negative effect on
achieving and maintaining pregnancy [72]; this was a small study and the confidence intervals around the point
estimates were wide. Another study concluded caffeine consumption did not affect overall IVF pregnancy rates;
however, higher coffee/tea consumption was negatively associated with the number of eggs retrieved and the
number of good quality embryos [73]. Caffeine was detected in follicular fluid; its actions there are unknown.
The available data are not definitive; therefore, reproductive endocrinologists suggest that it may be prudent for
women who are having difficulty conceiving to limit caffeine consumption to less than 200 to 300 mg per day, in
addition to eliminating tobacco use and decreasing alcohol consumption [61,62,74,75].
Caffeine consumption by the male partner does not appear to affect male fertility potential [65,76-79].
Spontaneous abortion A 2011 systematic review of both human and animal studies of the risk of
spontaneous abortion from caffeine exposure concluded there was fair to good evidence that consumption of
caffeinated beverages during pregnancy at a level 5 to 6 mg/kg body weight/day does not increase the risk of
spontaneous abortion [17]. Although very, very high caffeine intake in some animal studies increased the risk
minimally, even a woman who consumed 10 cups of coffee over a period of 8 to 10 hours (approximately 1000 mg of
caffeine) would not reach this harmful level of intake.
Findings among the 17 epidemiologic studies in this review were inconsistent [17]. Many studies did not observe an
association at any level of reported exposure. Studies that noted a link between caffeine intake and spontaneous
abortion generally reported a dose-response relationship, but differed in their conclusions about a threshold for a
safe amount of caffeine consumption. In studies that relied upon self-reported caffeine intake, an increased risk of
spontaneous abortion generally was not observed until intake levels were 3 cups or 300 mg caffeine per day. By
comparison, a study using an objective assessment of caffeine exposure, serum paraxanthine concentration,
observed an increased risk beginning at caffeine doses 600 mg [80]. In addition, an analysis within the Danish
national birth cohort, which included 565 women who periconceptionally consumed a prescription diet drug (Letigen)
containing 200 mg of caffeine per pill, ie, about 600 mg/treatment day, found no association between miscarriage
and high dose periconceptional caffeine exposure [81].
The methodological issues and limitations previously discussed apply to the association reported in these studies,
and include confounding by the inverse relationship between maternal nausea and both coffee consumption and
miscarriage rate; recall bias; and imprecise ascertainment of caffeine intake [25,29]. Other potentially distorting
factors include using controls that were not well-matched for gestational age to the study population, lack of
ascertainment of the multiple known causes of abortion, a tendency of women to report induced terminations as
spontaneous abortions, and inadequate adjustment for multiple known confounders [17].
Congenital anomalies Analysis of data from the National Birth Defects Prevention Study (NBDPS) suggested
that maternal dietary caffeine consumption was associated with a slightly increased risk of congenital limb defects
(OR 1.4-1.7) [82], NTDs (OR 1.1-1.4) [83], as well as anotia/microtia, esophageal atresia, small intestinal atresia,
and craniosynostosis (OR 1.31.8) [84]. The increased risk was observed with even small amounts of caffeine
consumption (above 10 mg/day) and did not appear to be dose-dependent. The highest caffeine intake (above 300
mg/day) was associated with anorectal atresia (OR 1.5, 95% CI 1.0-2.2) and remained unchanged after adjustment
for covariates [85]. There was no evidence of an increased risk of cardiovascular malformations [86], orofacial clefts
[87], bilateral renal agenesis or hypoplasia [88], diaphragmatic hernia, omphalocele, and gastroschisis [84].
Although some of these epidemiologic studies reported an association between caffeine intake and certain
congenital anomalies, the results should be interpreted with caution due to the methodological flaws of these studies
(eg, lack of correction for multiple comparisons, poor ascertainment of caffeine intake, etiologic heterogeneity for
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some malformations, biased exposure data, biased ascertainment of congenital anomalies) or because the findings
were inconsistent with basic teratological principles (eg, lack of dose effect, lack of increasing risk with increasing
exposure, lack of consistent association with a specific defect or constellation of defects). Several narrative reviews
and a systematic review concluded that caffeine is unlikely to cause congenital anomalies at doses consumed by
humans (eg, fractional doses totaling <5 mg/kg body weight/day) [17,18,89,90].
Fetal growth restriction Although the relationship between caffeine consumption in pregnancy and fetal
growth requires further clarification, a 2011 systematic review concluded it is unlikely that caffeine intake <300
mg/day has a significant adverse effect on fetal growth in non-smoking women [17].
Results of epidemiological studies examining the effect of maternal caffeine consumption on the risk of low birth
weight (less than 2500 grams) or fetal growth restriction (less than the 10th percentile of birth weight for gestational
age) are conflicting [17]. Several studies observed that maternal caffeine intake ranging from 200 to 400 mg per day
was associated with a mean decrease in birth weight of about 100 grams [91-93], while other studies either were not
able to show any significant association with birth weight or demonstrated reduction in mean birth weight only at
caffeine intake exceeding 600 mg per day [94-98]. Many of the available epidemiologic studies have been criticized
for inadequately controlling for important risk factors for low birth weight, particularly smoking [18,74,89]. The
following studies exemplify research in this area:
One well-designed large prospective study assessed caffeine consumption from all known sources, objectively
quantified intake, and adjusted for smoking and alcohol use [23]. This study included 2635 women in whom
caffeine consumption was assessed using a detailed questionnaire and was validated throughout pregnancy by
repeated objective measures using saliva samples. Mean caffeine consumption >200 mg/day over the course
of pregnancy was associated with reduction in birth weight of 60 to 70 grams. The risk of fetal growth restriction
increased linearly in a dose-response relationship, yielding odds ratios of 1.2 to 1.5 compared to women who
consumed less than 100 mg caffeine per day. Although statistically significant, the small differences in birth
weight observed in this study are not clinically important. In all trimesters, active smokers had nearly twice the
risk of fetal growth restriction compared to non-smokers.
A population-based prospective cohort study from the Netherlands including 7346 women reported a statistical
trend between increasing caffeine intake and the risk of delivering a small-for-gestational-age (SGA) neonate
[99]. Compared with mothers who consumed fewer than two cups of coffee per day, the adjusted odds ratios
(OR) for mothers who consumed two to three, four to five, and six or more cups of coffee per day were 1.38,
1.50, and 1.87, (p-value trend <0.01). However, the adjusted OR of delivering an SGA infant did not achieve
statistical significance at any level of caffeine intake. Impaired fetal growth was mainly associated with fetal
length measures with no significant effect on other parameters, suggesting that high caffeine intake in
pregnancy may predominantly affect fetal skeletal growth; this observation requires additional research for
confirmation.
The only randomized double blind trial that analyzed the effect of reducing caffeine intake on birth weight and
length of gestation found that reducing caffeine intake by greater than 50 percent had no significant effect on
these outcomes [100]. In this trial, 1207 pregnant women who drank at least three cups of coffee per day were
randomly assigned to receive unmarked jars of caffeinated or decaffeinated instant coffee for consumption after
20 weeks of gestation. Mean caffeine intake in the decaffeinated and caffeinated coffee groups was 117 and
317 mg/day, respectively. Mean birth weight and mean length of gestation were similar for women in the
decaffeinated and caffeinated coffee groups (mean birth weight 3519 versus 3539 grams; mean length of
gestation 279.3 versus 280.2 days). However, among women who smoked more than 10 cigarettes a day at
study entry, those in the caffeinated coffee group delivered infants 263 grams lower mean birthweight than
those in the decaffeinated coffee group.
A prospective, longitudinal observational study assessed the relationship between nausea, maternal caffeine
intake, caffeine metabolism, and fetal growth restriction in a cohort of 2643 pregnant women recruited in the
first trimester [101]. A validated caffeine assessment tool (CAT) was implemented to record habitual caffeine
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intake, a caffeine challenge test was used to assess a caffeine half-life, and the data were adjusted for smoking
and alcohol intake. There was no evidence that nausea and vomiting modified associations between fetal
growth restriction and maternal caffeine intake or metabolism.
Preterm delivery A systematic review and meta-analysis that combined 15 cohort and 7 case-control studies
did not find a significant association between maternal caffeine intake anytime in pregnancy and preterm birth [102].
The lack of association was observed when comparing any versus no caffeine consumption and for high versus
low/no caffeine consumption. For the highest versus the lowest level of caffeine intake (or no intake) during the first,
second, and third trimesters, the odds ratios for preterm birth in cohort studies were 1.11 (95% CI 0.96-1.28), 1.10
(95% CI 1.01-1.19), and 1.08 (95% CI 0.93-1.27), respectively. For case-control studies, the odds ratios were 1.07
(95% CI 0.84-1.37), 1.17 (95% CI 0.94-1.45), and 0.94 (95% CI 0.79-1.12), respectively.
Fetal death A systematic review of observational studies that examined the association between any source
of exposure to caffeine from food in pregnancy and fetal mortality concluded that "the small number of publications,
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" [103].
Gestational diabetes mellitus In a prospective cohort study, preconceptional moderate caffeine intake from
coffee appeared to protect against development of gestational diabetes mellitus (GDM) (adjusted RR 0.50; 95% CI
0.29-0.85); there was no risk reduction associated with consumption of decaffeinated coffee or caffeinated tea or
soda [104]. These results are consistent with results from epidemiological studies of coffee consumption and risk of
type 2 diabetes mellitus, which show that long-term coffee consumption is associated with reduced risk of diabetes.
(See "Benefits and risks of caffeine and caffeinated beverages", section on 'Type 2 diabetes mellitus'.)
Paradoxically, several studies have shown that exposure to caffeine in experimental settings mildly reduced insulin
sensitivity in humans [105-107]. This may be due to combination of an indirect effect of caffeine via increasing levels
of circulating epinephrine or to direct antagonism of adenosine receptors. Overall, the effect of caffeine on insulin
resistance appears to be mild and has been mainly related to acute exposure. Moreover, the researchers in these
studies predominantly implemented alkaloid caffeine, which may cause a different physiological response than
caffeine from dietary sources. The significance of caffeines acute effect on the physiological release of insulin in the
natural setting, as well as the degree of tolerance to its metabolic effects during chronic consumption, remains
unclear [108]. Pregnant women in whom there are physiological changes in glucose metabolism and a pregnancyinduced state of peripheral insulin resistance may be more likely to show the acute effects of caffeine observed in
experimental settings. A retrospective study on banked blood samples of 251 women in the second trimester (mean
gestational age of 20.3 weeks) showed a positive association between the risk of insulin resistance (estimated by
homeostasis model assessment) and higher levels of caffeine and its metabolite paraxanthine in the blood [109].
Caffeine concentrations >266 ng/mL and paraxanthine concentrations >392 ng/mL were associated with three-fold
higher odds of having higher insulin resistance [109]. The clinical significance of these findings was not studied and
requires further investigation.
Gestational hypertension A group from the Netherlands assessed the effect of caffeine consumption on
maternal cardiovascular changes in a cohort of 7890 pregnant women [110]. Although higher caffeine intake was
associated with elevated systolic blood pressure in the first and third trimesters, there was no effect on diastolic
blood pressure levels and caffeine consumption appeared to be protective against preeclampsia.
Postpartum depression A study of 662 women recruited within 24 hours of giving birth did not observe an
association between prenatal caffeine intake and depressive symptoms postpartum [111].
Long-term health consequences of intrauterine exposure Associations between in utero caffeine exposure
and attention deficit disorder, cognitive development, behavioral problems, leukemia, testicular cancer, and sudden
infant death syndrome in offspring have been evaluated, but the available data are inconclusive [3,112-120].
LACTATION Caffeine is detectable in breast milk within 15 minutes of consumption and levels peak after about
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one hour. Maternal caffeine consumption of 500 mg/day results in daily infant caffeine intake ranging from 0.3 to 1.0
mg/kg body weight and caffeine levels 1 percent of maternal levels [74]. Adverse effects have not been reported in
term infants whose mothers had moderate intake of up to five cups of coffee daily, but some case reports have
described an increase in infant irritability, jitteriness, or sleep disturbance at this level of maternal caffeine
consumption [121,122]. In one of the larger series (n = 885 infants), heavy (300 mg/day) maternal caffeine
consumption during pregnancy and three months postpartum by breastfeeding mothers was associated with an
increase in the percentage of infants with frequent (>3 times per night) nocturnal wakening (19.5 versus 13.3 percent
with non-heavy or no maternal caffeine consumption; RR 1.65, 95% CI 0.86-3.17), but the difference was not
statistically significant [123].
RECOMMENDATIONS OF SOCIETIES No uniform counseling guidelines or evidence-based recommendations
for caffeine intake are available.
The March of Dimes recommends that women who are pregnant or trying to become pregnant consume no
more than 200 mg of caffeine per day [124].
Health Canada suggests daily caffeine intake of no more than 300 mg/day in women who are planning to
become pregnant, pregnant women, and breastfeeding mothers [125].
The United Kingdom Food Standards Agency (FSA) does not provide any guidelines on caffeine consumption
in the general population, but suggests limiting caffeine intake in pregnancy to 200 mg per day [126].
A Committee Opinion by the American College of Obstetricians and Gynecologists (ACOG) concluded that
moderate caffeine consumption (<200 mg/day) did not appear to be a contributing factor to miscarriage or
preterm birth, and the relationship with fetal growth restriction was unclear [127]. Specific recommendations
about caffeine intake in pregnancy were not provided.
The American Dietetic Association (ADA) recommends that pregnant women avoid caffeine intakes above 300
mg/day [128].
SUMMARY AND RECOMMENDATIONS
In many countries, the main source of caffeine is coffee, followed by tea and caffeinated beverages. (See
'Sources of caffeine' above.)
Maternal caffeine metabolism declines significantly during pregnancy. Caffeine and its metabolites readily cross
the placenta and can be found in substantial quantities in the amniotic fluid and fetal blood. Higher maternal
plasma caffeine levels appear to be associated with a longer duration of fetal arousal, increased fetal heart rate
variability, lower basal fetal heart rate, increased fetal breathing activity, and inconsistent effects on fetal and
placental blood flow. (See 'Maternal and fetal kinetics' above.)
The consistency and quality of available data regarding the effects of caffeine on fertility and pregnancy
outcomes have generally been poor. Most studies have methodological shortcomings. (See 'Quality of existing
evidence and methodological considerations' above.)
At typical levels of caffeine intake, there does not appear to be an association between caffeine consumption
and fecundability or adverse reproductive events, including congenital anomalies, spontaneous abortion, fetal
growth restriction, and preterm birth. (See 'Effects of caffeine on reproductive outcomes' above.)
Preconceptional moderate coffee intake appears to protect against development of gestational diabetes
mellitus. (See 'Gestational diabetes mellitus' above.)
Given the limitations and inconsistencies of available data, we suggest women who are attempting to conceive
or who are pregnant or breastfeeding limit caffeine consumption to less than 200 to 300 mg per day (Grade
2C). Examples of the caffeine content of various beverages are shown in the table (table 1) and available at
http://www.cspinet.org/new/cafchart.htm. (See 'Recommendations of societies' above and 'Quality of existing
evidence and methodological considerations' above and 'Effects of caffeine on reproductive outcomes' above
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and 'Lactation' above.)

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Topic 406 Version 16.0
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GRAPHICS
Caffeine content in foods and beverages
Coffees
Serving size
Caffeine (mg)
(oz)
Coffee, brewed
133 (range: 102 to

200)
Coffee, generic instant
93 (range: 27 to 173)
Coffee, generic decaffeinated
5 (range: 3 to 12)
Espresso
40 (range: 30 to 90)
Espresso decaffeinated
Serving size
(oz)
Caffeine (mg)
Tea, brewed
53 (range: 40 to 120)
Starbucks Tazo Chai Tea Latte (Grande)
16
100
Snapple, Lemon, Peach, or Raspberry
16
42
Arizona Iced Tea, black
16
32
Nestea
12
26
Snapple, Just Plain Unsweetened
16
18
Arizona Iced Tea, green
16
15
Snapple, Kiwi Teawi
16
10
Serving size
(oz)
Caffeine (mg)
12
71
Jolt Cola
12
72
Mountain Dew MDX, regular or diet
12
71 (20 oz = 118)
Mountain Dew, regular or diet
12
54 (20 oz = 90)
Pepsi, regular or diet
12
36 to 38
Mellow Yellow
12
53
Coke, regular or diet
12
35 to 47
TAB
12
46.5
Dr. Pepper, regular or diet
12
42 to 44
Barq's Diet Root Beer
12
Barq's Root Beer
12
22
7-Up, regular or diet
12
Fanta, all flavors
12
Fresca, all flavors
12
Teas
Soft drinks
FDA official limit for cola and pepper soft
drinks
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Mug Root Beer, regular or diet
12
Sierra Mist, regular or free
12
Sprite, regular or diet
12
Serving size
Caffeine (mg)
Energy drinks
(oz)
Spike Shooter
8.4
300
Cocaine
8.4
288
Monster Energy
16
160
Full Throttle
16
144
Rip It, all varieties
100
Enviga
12
100
Tab Energy
10.5
95
SoBe No Fear
83
Red Bull
8.3
80
Red Bull Sugarfree
8.3
80
Rockstar Energy Drink
80
SoBe Adrenaline Rush
8.3
79
Amp
8.4
74
Glaceau Vitamin Water Energy Citrus
20
50
SoBe Essential Energy, Berry or Orange
48
5 Hour Energy
215*
Serving size
(oz)
Caffeine (mg)
Ben & Jerry's Coffee Ice Cream
68 to 84
Haagen-Dazs Coffee Ice Cream or Yogurt
58
Starbucks Coffee Ice Cream
50 to 60
Serving size
Caffeine (mg)
Hershey's Special Dark Chocolate Bar
1.45 oz
31
Hershey's Chocolate Bar
1.55 oz
Hershey's Kisses
41 g (9 pieces)
Hot Cocoa
8 oz
3 to 13
1/16 tsp
200
Frozen desserts
Chocolates/candies/other
Powdered caffeine
* reported by Consumer Reports
References:
1. Harland BF. Caffeine and nutrition. Nutrition 2000; 16:522.

2. Juliano LM, Griffiths RR. Caffeine. In: Substance Abuse: A Comprehensive Textbook, Fourth Edition,
Lowinson JH, Ruiz P, Millman RB, Langrod JG (Eds), Baltimore: Lippincott Williams, & Wilkins, 2005.
3. Center for Science in the Public Interest. Caffeine Content of Food and Drugs.
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Disclosures
Disclosures: Vicki Nisenblat, MD Nothing to disclose. Robert J Norman, MD Nothing to disclose. Charles J Lockwood, MD, MHCM
Nothing to disclose. Kristen Eckler, MD, FACOG Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
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The Effects of Caffeine On Reproductive Outcomes in Women

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The effects of caffeine on reproductive outcomes in women

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