The to premature or low birth weight infants.

The American public
consumes a wide array of caffeinated products including coffee, tea, chocolate,
cola beverages, and caffeine-containing medication. Therefore, it seems of
value to inform both the scientific community and the consumer about the
potential effects of excessive caffeine consumption, particularly for pregnant
women. The results of this literature review suggest that heavy caffeine use
(more than 300 mg per day) during pregnancy is associated with small reductions
in infant birth weight that may be especially detrimental to premature or low
birth weight infants. Some researchers also document an increased risk of
spontaneous abortion associated with caffeine consumption prior to and during
pregnancy. However, overwhelming evidence indicates that caffeine is not a
human teratogen, and that caffeine appears to have no effect on preterm labor
and delivery. More research is needed before unambiguous statements about the
effects of caffeine on pregnancy outcome variables can be made, and to
determine the mechanisms by which caffeine can have these potential effects on
the fetus.

 

Introduction

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

 

Sources
of Caffeine

 

Coffee,
tea, and soft drinks are the main sources of caffeine in the adult American
diet (Table 1). Other dietary sources include cocoa and chocolate, sugars and
sweets, and flavored dairy products. Tea and cocoa also contain significant
quantities of theophylline (1,3-dimethylxanthine) and theobromine
(3,7-dimethylxanthine), respectively, which are caffeine derivatives that have
not been as widely researched (Frary, 2005). Caffeine is present in five
classes of nonprescription medications: analgesics, cold/allergy products,
diuretic products, stimulants, and weight control agents. While each medication
has a different suggested dose, chronic use may represent a significant source
of caffeine for pregnant women who otherwise do not consume caffeinated
beverages. For example, consuming a two-tablet dose of an over-the-counter
analgesic every 6 hours may result in daily consumption of up to 520 mg of
caffeine (Table 2).

 

 

Demographics
of Caffeine Intake During Pregnancy

 

During
pregnancy, studies have shown women consume less caffeine than prior to
becoming pregnant, primarily 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). Colas, soft drinks, and foods containing chocolate contribute
proportionally more to the total dietary intake of caffeine by pregnant women
than non-pregnant women, but coffee and tea still make up the largest percent
of their caffeine intake (Frary, 2005). Heavy caffeine consumption (more than
300 mg per day) is noted among pregnant women with fewer years of formal
education and consumers of large amounts of caffeine are also more likely to
smoke (Crozier, 2009a).

 

Absorption,
Distribution, and Clearance of the Methylxanthines

 

Absorption

 

Caffeine
and the other methylxanthines are readily 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 rapidly 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. Peak plasma levels of
caffeine occur between 15 minutes and 120 minutes after ingestion or
administration, there is considerable variation in the amount of time depending
upon the source of caffeine and individual metabolic differences (Institute of
Medicine, 2001).

 

Distribution

 

The
distribution volume of caffeine within the body is 0.7 L/kg, suggesting that
caffeine is hydrophilic and distributes freely into the 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 cross the placenta
to the fetus where an equilibrium is achieved between the maternal and fetal
plasma. Caffeine achieves this equilibrium as early as 7-8 weeks of gestation
(Goldstein, 1962). It has been estimated that the fetus can ingest several
milligrams of caffeine each day in the approximately 500 mL of amniotic fluid
swallowed daily. In addition, the fetal liver is able to methylate theophylline
to caffeine by week 12 of gestation (Brazier, 1981). Theophylline is also
eliminated in the amniotic fluid, and the fetal elimination half-lives of
theophylline and caffeine are 30 and 150 hours, respectively.

 

Clearance

 

Because
caffeine is readily reabsorbed by the renal tubules, once it is filtered by the
glomeruli only a small percentage is excreted unchanged in the urine. Its
limited appearance in urine indicates that caffeine metabolism is the
rate-limiting factor in its plasma clearance (Arnaud, 1993). Caffeine
metabolism occurs primarily in the liver, catalyzed by hepatic microsomal
enzyme systems (Grant, 1987). In healthy humans, repeated caffeine ingestion
does not alter its absorption or metabolism. Caffeine is metabolized in the
liver to dimethylxanthines, uric acids, di- and trimethylallantoin, and uracil
derivatives. In humans 3-ethyl demethylation to paraxanthine is the primary
route of metabolism (Arnaud, 1987). This first metabolic step accounts for
approximately 75–80 percent of caffeine metabolism (Arnaud, 1993). Paraxanthine
is the dominant metabolite in humans, rising in plasma to concentrations 10
times those of theophylline or theobromine. Caffeine is cleared more quickly
than paraxanthine, so 8 to 10 hours after caffeine ingestion, paraxanthine
levels exceed caffeine levels in plasma (Arnaud, 1993). Formation of paraxanthine and its excretion in the urine
appears to be the major pathway for caffeine metabolism. During the second and
third trimesters of pregnancy, there is decreased maternal elimination of
caffeine (Aldridge, 1981). The half-life of caffeine in pregnant women changes
from 5.3 hours to 18.1 hours during the second and third trimesters of
pregnancy, which is attributed to changes in plasma progesterone and estrogen
levels. Maternal clearance of caffeine is also influenced by age, disease, and
personal habits such as smoking and long-term use of oral contraceptives prior
to pregnancy. These factors may result in prolonged maternal and fetal exposure
to caffeine and may be especially significant to the fetus during the rapid
growth of the third trimester. A few weeks after giving birth, the rate of
maternal caffeine elimination returns to non-pregnant levels (Aldrige, 1981).

 

Methods

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.

 

Caffeine
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

 

An infant who weighs less
than 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 shortened
gestational period (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 aged between 18 and 45 years,
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 association found with
increased risk of fetal growth restriction, and this risk was maintained
throughout pregnancy. They found that an average caffeine consumption of
greater than 100 mg per day was associated 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
(after adjustment for smoking status and alcohol intake). Although the overall
size of the reduction in birth weight may be seen as small, an extra 60-70 g in
weight could reduce perinatal morbidity and mortality in an already compromised
fetus. There was steep decline in risk observed associated with caffeine
intakes of less than 30 mg per day, but this may be attributable to unmeasured
confounding. Furthermore, women who consume little or no caffeine may be
generally more health conscious than 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. 53 of the women consumed
greater than five cups of coffee daily, and the study determined that the 53
women had a significantly higher prevalence (13.2%) of fetuses who were SGA
(Fuhurhashi, 1985).

 

The Norwegian Mother and
Child Cohort Study conducted by the Norwegian Institute of Public Health,
followed a total of 59,123 women with uncomplicated pregnancies giving birth to
a live singleton. Caffeine intake from different sources was self-reported at
gestational weeks 17, 22, and 30. 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).

 

Because gestational age
was not related to caffeine consumption in these studies, it appears that maternal
caffeine consumption has an effect on birth weight through IUGR. Two mechanisms
may be responsible for this effect. Caffeine is structurally similar to adenine
and guanine and may interfere with cell division and metabolism. In addition,
caffeine has a vasoconstrictive effect on placental intervillous blood flow
that may also contribute to the potential risk of IUGR (Kirkinen, 1983).

 

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 also reduced their risk of delivering LBW
infants compared with women who did not reduce their intake early in their
pregnancies. Women who reduced their caffeine intake to less than 300 mg within
6 weeks of their last menstrual period also had a lower risk of delivering
infants with IUGR. This study was controlled for gestational age (Fenster,
1991).

 

In general, there is a
consistent negative correlation between infant singleton birth weight and
caffeine consumption above 300 mg, the data for intakes between 151 mg and 300
mg are conflicting, and few adverse effects have been documented below 150 mg.
Therefore, to mitigate the effect of small reductions in birth weight that
might be especially significant to premature infants, women should limit their
daily caffeine intake to less than 300 mg daily. In addition, further research
is needed to elucidate the mechanism(s) that allow caffeine to exert an effect
on fetal growth.

 

Effects of Caffeine Consumption
on Preterm Labor and Delivery

 

The association between
caffeine consumption and preterm births is, at best, weak. In a case-control
study of 408 preterm (less than 37 weeks gestation) infants, caffeine intake in
the third trimester showed a nonsignificant relationship with preterm delivery
(Pastore, 1995).

 

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).
Coffee caffeine, but not caffeine from other sources, was actually associated
with prolonged gestation but neither total nor coffee caffeine was associated
with spontaneous preterm delivery risk (Sengpeil, 2013).

 

Other studies as well
found no effect on gestational age indicating that caffeine influences fetal
growth, not gestational age at delivery. In 1996–2000, Bracken et. al evaluated
2,291 mothers with singleton livebirths in Connecticut and Massachusetts after
their first prenatal visit and questioned them about caffeine consumption and
important confounding factors. Urine samples were provided to analyze urinary
caffeine, cotinine, and creatinine levels. Mothers were followed throughout
pregnancy to monitor changes in consumption and medical records were obtained
to confirm pregnancy outcomes. Mean birth weight was reduced by reported
caffeine consumption (–28 g per 100 mg of caffeine consumed daily) but not mean
gestational age (CARE Study Group, 2008)

 

In a population-based
study of 7,855 livebirths in California’s San Joaquin Valley, 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. (Those who consumed both caffeinated and decaffeinated
coffee showed a reduction in adjusted mean birth weight of ?3.0 g per cup per
week for caffeinated coffee and an increase of +0.4 g per cup per week for decaffeinated
coffee) (Eskenzai, 1999). This study has not been replicated, and other
analyses did not support it.

 

Gestational age is difficult
to assess accurately, and misclassification may account for some null results.
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, but not all. High caffeine
consumption during pregnancy has been shown to significantly increase the risk
of spontaneous abortions. In a prospective cohort study of 3,135 pregnant women
who miscarried late in the first trimester or in the second trimester, women
who consumed more than 151 mg of caffeine per day were significantly more
likely to abort spontaneously compared with women who consumed less than 150 mg
of caffeine daily (Srisuphan, 1986).

 

In Fuhurhashi et al. study
of healthy pregnant women beyond 24 weeks of gestation, ingestion of more than 600
mg per day of caffeine was significantly associated with a high prevalence
(17%) of impending abortion (Fuhurhashi,1985).  

 

In one study, 2,967
pregnant women planning to deliver 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 drinking more than 3 cups of tea or coffee was associated with elevated
risks of spontaneous abortion. The association appeared stronger for tea and
coffee than caffeine in general and was primarily found with abortions which
took place in later trimesters (Dlugosz,1996).

 

Infante-Rivard et al. also
demonstrated associations between caffeine intake prior to and during pregnancy
with 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, and
increased by 1.10 (1.001.22) for each 100 mg of caffeine intake prior to
pregnancy (Infante-Rivard, 1993).

 

Similarly, a retrospective
cohort study design of 711 women determined the adjusted odds ratios of
spontaneous 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); indicating
that caffeine is a clear risk factor for spontaneous abortion (Dominguez-Rojas,
1994).

 

Alternatively, an
additional study found a weak association between maternal caffeine intake and
spontaneous abortions. A cohort of 431 women, enrolled in a multicenter study
within 21 days of conception, was monitored throughout pregnancy to determine
caffeine exposure, and exposure to other risk factors, and the effect on
pregnancy outcome. The investigators found no association between spontaneous
abortions and caffeine intake either above or below 300 mg a day (Mills, 1993).

 

This issue is complicated
by the fact that many of the studies reviewed failed to control adequately for
smoking, alcohol intake, or parity. Further research is needed to determine
whether there is a definite causal relationship between caffeine and/or coffee
intake and the incidence of spontaneous abortion.

 

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
constituents of DNA. Caffeine can cross the human placenta and enter the fetal
gonad. If the caffeine molecule were incorporated into DNA, there is a
possibility that it could give rise to abnormal proteins important in health
(Goldstein, 1962). Based on the literature reviewed, there is no significant
evidence that links human maternal caffeine intake during pregnancy to major infant
birth defects.

 

In an analysis of
information from the Finnish Registry of Congenital Malformation, pairs of
coffee-drinking mothers who had given birth to infants with defects were
matched (according to daily maternal coffee consumption and place and time of
birth) with an equal number of non-coffee drinking mothers with defective infants
(controls). To evaluate the hypothesis that coffee consumption during pregnancy
is teratogenic, 706 pairs of mothers of malformed children and their controls
were personally interviewed soon after delivery. Study subjects consisted of
mothers of children with 112 defects of the central nervous system, 241
orofacial clefts, 210 structural defects of the skeleton, and 143
cardiovascular malformations. Kurppa et al. determined that even mothers who
consumed at least six cups of coffee per day were no more likely to give birth
to children with congenital malformations. The coffee consumption during
pregnancy was similar for the mothers of malformed or non-malformed children
(Kurppa, 1983). This finding is especially relevant in light of the wide range
of maternal coffee intake (0-10 cups daily), suggesting that there is no
association between excessive coffee intake and congenital defects.

 

Mcdonald et al.
investigated the relationships between cigarette, alcohol, and coffee
consumption, and congenital defects using data from a survey of occupational
factors in pregnancy conducted in Montreal from 1982-1984. Coffee consumption
was associated only with heart defects and 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, the possible effect of chemical and physical factors during pregnancy on the occurrence of cardiovascular
malformations, specifically hypoplastic left heart syndrome in offspring was studied in 573 cases and 1,055 controls. Case and control mothers were interviewed by
midwives approximately 3 months after delivery using a structured questionnaire. The risk
of cardiovascular malformations was not associated with coffee, tea, or cola consumption, and
was equal in urban and rural areas. The causes of the majority of cardiovascular malformations remain unknown. (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 resident in England and Wales who had
delivered an anencephalic stillbirth, and 2232 control women matched for
maternal age, parity, area of the country, and date of delivery, were sent a
questionnaire. It was shown that the women who had given birth to anencephalic
stillbirths 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, 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.

 

Smoking and Caffeine

 

The interaction between
caffeine and smoking is particularly important. It is possible that smoking and
caffeine interact with each other to reduce fetal growth, but the mechanisms by
which caffeine may reduce fetal growth are unclear and may differ from those by
which smoking induces its effects. Women who drink caffeine also tend to smoke,
and women who smoke metabolize caffeine more quickly, which may protect the
fetus from developmental effects. Evidence of any interaction between smoking
and caffeine exposure is mixed; some studies reported effects (Fortier et
al.,1993), but others found none (Fenster, 1991, McDonald, 1992).

 

Conclusion

 

Based on the literature
reviewed, caffeine intake should be limited to between 150 mg and 300 mg per
day, particularly because of the potential negative effects of caffeine on
birth weight, 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 women are likely to be receptive to counseling about lifestyle
changes, including use of licit and illicit substances. An initial discussion
about caffeine intake may provide a basis for an honest exchange about
lifestyle practices that place the fetus and mother at risk, because caffeine
is less likely to be perceived as a substance of abuse. In addition, assessment
of caffeine intake by the health care provider may help ascertain the degree of
risk for use of other drugs or high-risk behaviors during pregnancy.

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