Introduction to 520 mg of caffeine when taken



(1,3,7-trimethylxanthine) is a naturally occurring compound. Its
pharmacological and physiological effects, include stimulation of the central
nervous system and cardiac muscle, and relaxation of smooth muscle. Caffeine
has been shown to have effects on physical and cognitive performance, as well as
mood, memory, and alertness. Caffeine is the most widely used stimulant for the
central nervous system. Clinically, caffeine is useful for relaxing the
bronchial muscle in asthmatic patients, and increasing secretion of gastric
acid and the concentrations of plasma free fatty acids and glucose (Institute
of Medicine, 2001).


of Caffeine


The main
sources 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 of
theophylline (1,3-dimethylxanthine), as cocoa also contains theobromine
(3,7-dimethylxanthine), both being caffeine derivatives that have not been as
widely researched (Frary, 2005). Many classes of nonprescription medications
including analgesics, cold/allergy products, diuretic products, stimulants, and
weight control agents have some caffeine content. All medications have a
suggested dose, but consistent usage may lead to the medication becoming a significant
source of caffeine consumption. For instance, a two-tablet dose of an
over-the-counter analgesic may constitute a daily intake of up to 520 mg of
caffeine when taken every 6 hours.  (Table



of Caffeine Intake During Pregnancy


have shown most women’s daily caffeine intake during pregnancy is lower than prior
to becoming pregnant, predominantly due to a decline in coffee and tea intake
(Crozier, 2009a). Before pregnancy 39 percent of women consume more than 300 mg
of caffeine every day, which is considered heavy caffeine intake, but only 16
percent of women consume more than 300 mg per day during pregnancy (Crozier,
2009b). Proportionally, colas, soft drinks, and foods containing chocolate
contribute more to the total dietary intake of caffeine of pregnant women than non-pregnant
women, but coffee and tea still make up the largest percent of their caffeine
intake (Frary, 2005). Fewer years of formal education, and smoking are both associated
with women who are more likely to consume more than 300 mg of caffeine daily
during pregnancy. (Crozier, 2009a).


Distribution, and Clearance of the Methylxanthines




and the other methylxanthines are quickly absorbed in humans, as much as 99
percent is absorbed within the 45 minutes after ingestion. Oral, rectal, and
parenteral administration is possible, with the oral route being most common. When
consumed in a beverage, the caffeine is quickly absorbed from the
gastrointestinal tract and distributed throughout body water. More rapid
absorption is possible for caffeine in preparations that allow absorption
through oral mucosa, such as caffeinated chewing gum. Depending on the source
of the caffeine and the individual’s metabolism, peak plasma levels of caffeine
appear between 15 minutes and 120 minutes after ingestion or administration
(Institute of Medicine, 2001).




distribution volume of caffeine within the body is 0.7 L/kg, demonstrating
caffeine’s hydrophilic quality and ability to distribute freely into
intracellular tissue water (Arnaud, 1993). Caffeine is also amply lipophilic
and can pass through all biological membranes and freely crosses the
blood-brain barrier (Institute of Medicine, 2001). In pregnant women, the
methylxanthines consumed cross the placenta to the fetus. As early as 7-8 weeks
gestation, an equilibrium is achieved between the maternal and fetal plasma (Goldstein,
1962). A fetus swallows approximately 500 mL of amniotic fluid daily, and studies
suggest that several milligrams of caffeine can be ingested along with the
fluids. Additionally, by week 12 of gestation the fetal liver is able to
methylate theophylline to caffeine (Brazier, 1981). Both caffeine and
theophylline are eliminated in the amniotic fluid, the fetal elimination
half-life of caffeine is 150 hours, while that of theophylline is 30 hours.




The small
fraction of caffeine that is excreted unchanged in urine, suggests that
caffeine metabolism is the rate-limiting factor in its plasma clearance. Its
limited appearance in urine is due to caffeine being readily reabsorbed by the
renal tubules and filtered by the glomeruli. (Arnaud, 1993). In healthy humans,
repeated caffeine ingestion does not alter its absorption or metabolism. Caffeine
metabolism transpires primarily in the liver, catalyzed by hepatic microsomal
enzyme systems (Grant, 1987). In the liver, caffeine is metabolized to dimethylxanthines,
uric acids, di- and trimethylallantoin, and uracil derivatives. 3-ethyl
demethylation to paraxanthine is the primary route of caffeine metabolism in
humans (Arnaud, 1987). This is first step in caffeine metabolism and accounts
for approximately 75–80 percent of the process (Arnaud, 1993). Being the chief
metabolite in humans, paraxanthine is found to have a plasma concentration ten
times higher than those of theophylline and theobromine. Eight to ten hours
after ingestion, paraxanthine levels in plasma exceed caffeine levels, as
caffeine is cleared more rapidly than paraxanthine (Arnaud, 1993). During the
second and third trimesters of pregnancy, there is decreased rate of maternal
elimination of caffeine, due to changes in progesterone and estrogen levels, with
the half-life of caffeine changing from 5.3 hours to 18.1 hours (Aldridge,
1981). Maternal clearance of caffeine during pregnancy can be further influenced
by other factors including age, disease, and personal habits such as smoking
and long-term use of oral contraceptives prior to becoming pregnant. These
factors may result in prolonged maternal and fetal exposure to caffeine. Within
a few weeks after giving birth, the maternal rate of caffeine elimination
returns to original levels (Aldrige, 1981).



Critical analysis of peer reviewed journal articles and
original clinical research papers was used to write this review. The articles
and papers from which the research was gathered were obtained with access to
online publications through the Touro college library. Additional references
were obtained through Pubmed and Google Scholar.


and Pregnancy Outcome Variables


There are
several clinical measures of adverse pregnancy outcome, which include low
infant birth weight, premature labor and delivery, spontaneous abortion, and
congenital malformations.


Effects of Caffeine
Consumption 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 birth
weight can be caused by a shortened gestational period, also known as
prematurity, or the result of intrauterine growth retardation (IUGR), which
results in a small for gestational age (SGA) infant. Intrauterine growth
retardation is classified as less than the 10th percentile of birth weight for
gestational age in comparison to an external standard of birth weight for
gestational age, adjusted for gender and ethnicity, that was developed from all
1999 singleton births in the United States, and updated in 2014 (Talge, 2014).
Many studies have shown a strong correlation between caffeine intake during
pregnancy and reduced birth weights. For pregnant women who consume more than
300 mg of caffeine daily, a high risk of SGA and IUGR have been found. Intake
between 150 mg and 300 mg daily has also been linked to such risks, however,
the data is not as consistent. 


From 2003-2006, a
perspective cohort study following pregnant women between the ages of 18 and 45,
with singleton pregnancies was implemented. The caffeine intake of these women
was monitored, and the relationship between caffeine and fetal growth was
evaluated. At any level of caffeine intake there was an associated risk of
fetal growth retardation found, and this risk was maintained throughout
pregnancy. They found that after adjustment for smoking and alcohol intake, an
average caffeine consumption of more than 100 mg per day was correlated with a
reduction 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 can
make all the difference for an already compromised fetus, and can help avoid
perinatal morbidity and mortality. The study did observe a steep decline in
risk for caffeine intakes of less than 30 mg per day, but this may be due to
unmeasured confounding, or simply because women who consume little or no
caffeine may be more health conscious in general, compared to those who consume
more. (CARE Study Group, 2008)


In a second prospective
study, Fuhurhashi et al. observed the caffeine intake of 9,921 healthy pregnant
women with a gestational age of at least 24 weeks. Among the 53 of the women
who consumed more than five cups of coffee daily, a 13.2% higher prevalence of
fetuses who were SGA was observed (Fuhurhashi, 1985).


The Norwegian Mother and
Child 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 customized
growth curves. Based on the three scales, an average of 25 g weight reduction
was associated with every additional 100 mg of maternal caffeine intake per day
for a baby with an expected birth weight of 3,600 g. The findings of this study
were strengthened by coinciding results for caffeine sources, time of survey,
and different SGA definitions. Even caffeine consumption below the recommended
maximum such as 200 mg per day, compared to the recommended 300 mg per day was
consistently associated with increased risk for SGA (Sengpiel, 2013).


Gestational age was not linked
to caffeine intake in these studies, suggesting that the effect maternal
caffeine consumption has on fetal birth weight occurs through IUGR. Possible
mechanisms responsible for this effect include caffeine’s similar structure to
adenine and guanine which may allow it to interfere with cell division and
metabolism. Additionally, caffeine has a vasoconstrictive effect on placental
intervillous blood flow that may also contribute to the potential risk of IUGR
(Kirkinen, 1983).


During the first trimester
of pregnancy, the embryo first starts developing it’s organs, heart beat, brain
waves, and the rest of it’s body parts. As this is such a crucial time of
development, caffeine intake should be limited especially in this time. In
fact, Fenster et. al have shown that women who reduced their caffeine intake to
less than 300 mg a day within 6 weeks of their last menstrual period further
reduced their risk of delivering LBW infants and infants with IUGR compared
with women who did not reduce their intake early in their pregnancies. This
study was controlled for gestational age (Fenster, 1991).


There is a steady negative
correlation 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, and
occasionally, even for daily intakes lower than 150 mg. Pregnant women should
be sure to limit their caffeine intake as much as possible to lessen the probability
of small reductions in birth weight that might be especially harmful to premature
infants. Further research is needed to clarify the mechanisms by which caffeine
exercise’s an effect on fetal growth.


Effects of Caffeine Consumption
on Preterm Labor and Delivery


Caffeine has not been
found to be a strong factor in increasing for preterm labor and delivery. In
1996–2000, Bracken et. al questioned 2,291 mothers with singleton pregnanices
in Connecticut and Massachusetts about caffeine consumption and other important
confounding factors after their first prenatal visit. Urine samples were taken
to analyze urinary caffeine, cotinine, and creatinine levels. The mothers were
followed throughout pregnancy to monitor changes in consumption, and medical
records were obtained to confirm pregnancy outcomes. While mean birth weight
was found to be reduced by 28 g per 100 mg of daily caffeine intake, mean
gestational age was not found to be affected at all. (CARE Study Group, 2008)


In the Norwegian Mother
and Child Cohort Study spontaneous preterm delivery was defined as “spontaneous
onset of delivery between 22+0 and 36+6 weeks (n = 1,451)” (Sengpiel, 2013). Caffeine
from coffee, but not from other sources, was actually associated with prolonged
gestation, but no association of increased risk of spontaneous preterm delivery
was found with caffeine consumption. (Sengpeil, 2013).


Other studies as well
found no effect on gestational age indicating that caffeine influences fetal
growth, not gestational age at delivery. Pastor et. al performed a case control
study of 408 preterm (less than 37 weeks gestation) infants, and caffeine
intake in the third trimester showed a nonsignificant relationship with preterm
delivery (Pastore, 1995).



Alternatively, in a
population-based study of 7,855 livebirths in San Joaquin Valley, California, increased
preterm birth among women who drank caffeinated coffee was found compared with
women who drank neither decaffeinated nor caffeinated coffee. Those who
consumed only decaffeinated coffee showed no increased odds of SGA birth, LBW,
or preterm delivery, while women who consumed caffeinated coffee alone had a
higher association with preterm delivery. (Eskenzai, 1999). This study has not
been replicated, and other analyses did not support it.


Gestational age is difficult
to calculate and assess, making this topic more difficult to analyze accurately.
Generally, there appears to be no relationship between caffeine consumption
during pregnancy and premature labor and delivery in humans.


Effects of Caffeine
Consumption on Spontaneous Abortions


Most studies report
effects of caffeine on spontaneous abortion, however, there are some who
suggest otherwise. In one study, 2,967 pregnant women who delivered at Yale-New
Haven hospital between 1988 and 1992 were evaluated for caffeine intake the
first month of pregnancy. After studying the effect of the caffeine on
pregnancy outcomes, it was concluded that increased risk of spontaneous
abortions was linked to drinking more than 3 cups of tea or coffee daily. The
association of risk with tea and coffee intake showed to be stronger than with
caffeine in general, and was primarily correlated with abortions which took
place in later trimesters (Dlugosz,1996).


A prospective cohort study
of 3,135 pregnant women found that those who consumed more than 151 mg of
caffeine daily were more likely to spontaneously abort, in the second or third
trimester, in comparison to those who had a daily intake of less than 150 mg of
caffeine. (Srisuphan, 1986).


Fuhurhashi et al. studied
healthy, pregnant women, all of whom were beyond 24 weeks of gestation.
Caffeine consumption of more than 600 mg daily was significantly associated with
impending abortion, with a higher prevalence of 17% found. (Fuhurhashi,1985).  


Another study of 1324
women demonstrated associations between caffeine intake prior to, and during
pregnancy with spontaneous abortions in 331 of the 1324 women. The risk of
fetal loss increased for each 100 mg of caffeine ingested daily during
pregnancy, as well as smaller increases in risk for each 100 mg of caffeine
ingested daily prior to becoming pregnant. (Infante-Rivard, 1993).


Dominguez-Rojas et. al
conducted a retrospective cohort study of 711 pregnant women, monitoring their
caffeine intake, and found caffeine to be a clear risk factor for spontaneous
abortion. They determined that the adjusted odds ratio (a measure of
association between exposure and outcome) of spontaneous abortion by caffeine
consumption 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,


Alternatively, different
studies found no association between maternal caffeine intake and spontaneous
abortions. 431 women were enrolled in a multicenter study within 21 days of
conception. Throughout pregnancy, they were monitored for caffeine intake, and
exposure to other risk factors, and the effects on pregnancy outcome. The
investigators found no connection between caffeine intake, neither above or
below 30 mg daily, increased risk of spontaneous abortions (Mills, 1993).


Determining a definite
causal connection between caffeine intake and occurrence of spontaneous abortions
is complicated by the fact that many of the studies reviewed failed to control
adequately for smoking, alcohol intake, or parity. There seems to be a strong association
between caffeine consumption and fetal loss, but more research must be done
before unambiguous statements can be made.


Effects of Caffeine
Consumption on Congenital Malformations


Caffeine can perhaps act
as a teratogen due to its chemical structure as a purine, one of the components
of DNA. After maternal consumption, caffeine can cross the placenta to the developing
embryo. If the molecule were to become incorporated into DNA, there is a
possibility that it could induce the production of abnormal proteins (Goldstein,
1962). The literature reviewed showed no significant evidence linking human maternal
caffeine intake during pregnancy to major congenital malformations.


In a study performed to
analyze information from the Finnish Registry of Congenital Malformation, mothers
who had given birth to infants with the same defects were matched according and
place and time of birth. One mother in each pair consumed coffee during
pregnancy, while the other did not. To evaluate the hypothesis that coffee
consumption during pregnancy is teratogenic, the 706 pairs of mothers of
malformed children and their controls were interviewed soon after delivery. The
subjects of the study subjects included 112 mothers of children with defects of
the central nervous system, 241 mothers of children with orofacial clefts, 210
mothers of children with structural defects of the skeleton, and 143 mothers of
children cardiovascular malformations. The study determined that coffee intake
does not appear to increase risk for any of the defects that were studied. Even
mothers who consumed more than six cups of coffee per day had no higher risk of
giving birth to an infant with congenital malformations. The study also paired
these mothers with women who gave birth to non-defective infants, in the same
time and place, and consumed an equivalent amount of caffeine daily during pregnancy.
The amount of coffee consumed during pregnancy was similar for the mothers of
malformed and non-malformed children, with the broad range of maternal intake
being 0-10 cups daily, demonstrating that excessive coffee intake does not
increase risk of congenital malformations (Kurppa, 1983).


Mcdonald et al.
investigated the relationships between smoking, alcohol intake, and caffeine
consumption, and congenital malformations using data from a survey conducted in
Montreal from 1982-1984. A weak association between caffeine consumption and
heart defects was found, but the evidence was not strong. There was no
connection found between caffeine intake and club foot, musculoskeletal,
renal/urinary, gastrointestinal or respiratory, clefts or neural tube defect
abnormalities (Mcdonald et al., 1992).


Similarly, a study was performed to determine the possible effects
of different chemical and physical factors during pregnancy on the occurrence of cardiovascular
malformations, specifically hypoplastic left heart syndrome.  573 cases and
1,055 controls were interviewed approximately 3 months after delivery using a
standard questionnaire. An increased risk
of cardiovascular malformations was not found to be associated with coffee, tea, or cola
consumption. (Tikkanen et al., 1994)


One study did show an
increased risk for malformations due to caffeine. A retrospective case-control
study was executed in which 558 women in England who had delivered an
anencephalic stillbirth, were matched with 2232 control women based on maternal
age, parity, and date of delivery. Based on a structured questionnaire completed
by the cases and controls, it was shown that the women who drank 3 or more cups
of tea daily were more likely to give birth an anencephalic stillborn. (Fedrick,
1974). However, the results of this study may not be completely accurate, and
the authors themselves wrote that caution should be taken when interpreting
their results.


Most studies agree that
there is no connection between caffeine intake during pregnancy and congenital
abnormalities. Any connections that were found, have been deemed weak at best.




Based on the literature
reviewed, maternal caffeine intake during pregnancy should be limited to
between 150 mg and 300 mg per day, to mitigate negative effect caffeine has
been shown to have on birth weight, risk of IUGR, and risk of spontaneous
abortion. More studies must be done to confirm correlation between caffeine and
spontaneous abortion, and based on current data, there does not seem to be a
significant risk of preterm labor or congenital malformations related to
caffeine intake.


Pregnancy is a time when
motherly instincts begin to kick in, and women are likely to be receptive to
counseling about lifestyle changes. Many women are unaware of the real risk
that their caffeine intake can create for their unborn child. Doctors and
prenatal counselors should be sure to discuss the matter with soon-to-be
mothers so they can make informed decisions when consuming caffeine during
pregnancy. In addition, having a health care provider monitor caffeine intake may
help establish the degree of risk for use of other drugs or high-risk behaviors
during pregnancy.


 List of Acronyms


LBW- Low Birth Weight

SGA- Small for Gestational Age

IUGR-Intrauterine Growth Retardation