Keywords
caffeine - pregnancy - cohort studies - low birth weight - preterm birth
Palavras-chave
cafeína - gestação - estudo de coorte - baixo peso ao nascer - nascimento pré-termo
Introduction
Maternal exposures, such as excessive caffeine consumption during pregnancy, are likely
associated to low birth weight (LBW) and preterm birth. This issue has been the subject
of several epidemiological studies.[1]
[2]
[3]
[4] However, the results of these studies are contradictory, which is partly explained
by the heterogeneity in study design, by the measurement of caffeine intake, and by
the identification of confounders.[3]
[5]
[6]
[7]
Caffeine (1,3,7- trimethylxanthine), an alkaloid contained in coffee, tea, cocoa,
soft drinks with cola, some medications, and stimulants, is a substance generally
socially accepted in the whole world that acts as a psychoactive stimulant.[1] In pregnant women, caffeine passes the placenta freely, where the immature fetal
liver enzyme CYP3A4 is unable to metabolize it,[8] resulting in the accumulation of caffeine in the fetus;[9]
[10]
[11] substantial quantities of caffeine pass into the amniotic fluid and into the umbilical
cord blood, being distributed to all of the tissues of the fetus. Therefore, this
may increase the concentration of cellular cyclic adenosine monophosphate (cAMP),
interfering in fetal cell growth and development.[12] Moreover, caffeine causes most of its biological effects via antagonizing all types
of adenosine receptors and increasing epinephrine concentrations in the mother and
in the fetus, resulting in decreased placental blood flow and hypoxia.[13]
Studies showed that the amount of caffeine intake during pregnancy is relatively high.
The prevalence in women who had preterm birth was 68.1%,[5] whereas, in Brazil, the prevalence was 75% during pregnancy.[14]
Several studies showed an increased risk of adverse perinatal outcomes when caffeine
consumption was ≥300 mg/day,[1]
[9]
[15] between 150 and 300 mg/day,[16] or < 150 mg/day.[5] Other studies did not find any association,[17]
[18] but most of the studies consider high caffeine intake as ≥300 mg/day.[1]
[9]
[15]
[19]
[20]
[21]
[22]
In Ribeirão Preto, state of São Paulo, Brazil, a birth cohort started in January 2010,
which included 7,702 mothers and newborns (NB) in facilities right after childbirth.
Cohort studies are considered paramount in understanding the effects of intrauterine
life and of childhood conditions on adult health.[23]
Thus, the objectives of the present study were to describe caffeine intake during
pregnancy and estimate the risks between high caffeine consumption with LBW and preterm
birth, on the 2010 birth cohort of Ribeirão Preto, state of São Paulo, Brazil.
Methods
This cohort is part of the Brazilian Ribeirão Preto and São Luís Birth Cohort Studies
(BRISA, in the Portuguese acronym,), with the main objectives of evaluating new preterm
birth risk factors (neuroendocrine, immunoinflammatory, and medical intervention hypothesis),
perinatal health indicators, and impact on later preterm birth growth. The cohort
included 7,702 mothers and their NBs between January 1st and December 31th, 2010; 95 twin pregnancies were excluded, remaining 7,607 mothers and NBs evaluated.
Childbirth took place in eight maternity hospitals of Ribeirão Preto and, during the
study period, trained personnel visited these facilities to interview the mothers
and collect information about the NBs from medical records.
The dependent variables were low birth weight (LBW) (birth weight [BW] < 2,500 g)
and preterm birth (gestational age < 37+0 weeks), and the independent variable was caffeine intake (only from coffee). Information
about daily and weekly frequency of caffeine consumption during each trimester of
gestation (days/week), and type of container used were collected. No information about
tea, chocolates, sodas and other sources of caffeine were recorded. Caffeine consumption
from coffee during pregnancy was categorized as none, low (< 300 mg/day) and high
(≥300 mg/day), according to the Care Study Group.[24] The daily frequency of caffeine consumption in milliliters was calculated by multiplying
the daily quantity (times/day) by the daily frequency (days/week) and the type of
container (50 or 200 ml) in each trimester. Then, the result was divided by 7 days
of the week. Since 125 ml of coffee corresponded to 90 mg of caffeine,[7] each ml of coffee intake contained 0.72 mg of caffeine.
The questionnaires included mother variables (demographic, social and reproductive
health, life habits, pregnancy complications, and coffee intake) and NB variables
(gender, BW, gestational age [GA], morbidities, and stillborn). Newborn anthropometry
included BW and length.
Maternal age was categorized as ≤ 19, between 20 and 34, and ≥ 35 years old. Maternal
education was categorized as ≤ 8, between 9 and 11, and ≥ 12 years of study. Skin
color was self-referenced as either white or not white. Marital status was categorized
as with or without partner. The occupation of the head of the family[25] was categorized as no manual, qualified, semi qualified, and not qualified workers.
Parity was categorized as 1, between 2 and 3, and ≥ 4 childbirths. Information was
collected regarding previous preterm birth, abortion, and stillbirth; hypertension,
diabetes, urinary tract infection and odontological treatments during pregnancy; threatened
abortion and preterm delivery; as well as alcohol consumption and maternal smoking.
For improving the presentation of the results, we followed the strengthening the reporting
of observational studies in epidemiology (STROBE) initiative.[26]
Data analysis included mean (standard deviation [SD]), median (interquartile range
[IQR]) or proportions (95% confidence interval [CI]). A univariate risk analysis between
LBW and preterm birth, high caffeine consumption and covariates were performed. Then,
four adjusted polytomous logistic regression models (relative risk [RR] and 95% confidence
interval [95% CI]) were fit. The first one was adjusted for biological and sociodemographic
conditions (age, maternal education, skin color, marital status, occupation of the
head of the family); the second included obstetric history (parity, previous preterm
birth, abortion and stillbirth); the third was adjusted for current gestational conditions
(gestational hypertension and diabetes, threatened abortion and preterm delivery,
alcohol consumption, maternal smoking, urinary tract infection, and odontological
treatments during pregnancy); and the last was adjusted for all variables included
in the previous models. The reference value was the absence of caffeine consumption.
The goodness of fit was tested using the Hosmer-Lemeshow test. All analyses were performed
with Stata software, version 13.0 (Stata Corp., College Station, TX, USA) and SAS
software, version 9.2 (SAS Institute, Cary, NC, USA). Statistically significant difference
was set at p < 0.05. The present study was approved by the Research Ethic Committee of the Ribeirão
Preto Medical School of the Universidade de São Paulo (process n° 10400/2012), and
all participants received and signed the informed consent form.
Results
A total of 7,607 mothers and their NBs were included. Of these, 4,908 (64.5%; 95%
CI: 63–65) consumed caffeine from coffee during pregnancy, 143 of whom (2.9%; 95%
CI: 25–34) ingested ≥300 mg/day. The mean BW was 3,143 g (SD = 553); 8.7% were LBW,
and 1.7% were very low birth weight (VLBW [< 1,500 g]). The mean GA was 285 (SD = 104)
days, and 14.5% of the childbirths were preterm (< 259 days).
The majority of the total population studied ingested up to 500 mg of caffeine per
day, with a median caffeine intake of 91.5 mg/day (IQR = 143.8); there was no difference
per trimester of caffeine intake (data not shown).
High caffeine intake was significantly associated with reduced maternal education,
occupation of the head of the family, nonwhite skin color, and not having a partner
([Table 1]).
Table 1
Selected sociodemographic maternal characteristics of the Ribeirão Preto Birth Cohort
of 2010 in terms of caffeine consumption
|
Characteristic
|
< 300 mg/day
n (%)
|
≥300 mg/day
n (%)
|
p-value
|
|
Maternal age (years old)
|
|
|
0.153
|
|
20–34
|
3,543 (74.4)
|
111 (77.6)
|
|
< 20
|
526 (11.0)
|
19 (13.3)
|
|
≥35
|
696 (14.6)
|
13 (9.1)
|
|
Maternal education (years)*
|
|
|
< 0.001
|
|
≥ 12
|
1,099 (23.6)
|
8 (5.7)
|
|
≤ 8
|
1,197 (25.7)
|
76 (54.7)
|
|
9–11
|
2,358 (50.7)
|
55 (39.6)
|
|
Occupation of the head of the family*
|
|
|
< 0.001
|
|
No manual workers
|
711 (15.4)
|
2 (1.5)
|
|
Qualified workers
|
702 (15.2)
|
8 (5.9)
|
|
Semi-qualified workers
|
2,072 (45.0)
|
68 (50.4)
|
|
Not qualified workers
|
1,122 (24.4)
|
57 (42.2)
|
|
Skin Color*
|
|
|
< 0.001
|
|
White
|
2,814 (59.5)
|
56 (40.3)
|
|
Not white
|
1,915 (40.5)
|
83 (59.7)
|
|
Marital status*
|
|
|
< 0.001
|
|
With partner
|
4,182 (87.8)
|
105 (73.4)
|
|
Without partner
|
581 (12.2)
|
38 (26.6)
|
|
Total
|
4,765 (100)
|
143 (100)
|
|
*Excluded cases.
High caffeine intake was significantly associated with higher parity, previous abortion
and preterm birth, urinary tract infection, threatened abortion, alcohol consumption,
and smoking ([Table 2]).
Table 2
Selected obstetric characteristics of the Ribeirão Preto Birth Cohort of 2010 in terms
of caffeine consumption
|
Characteristic
|
< 300 mg/day
n (%)
|
≥300 mg/day
n (%)
|
p-value
|
|
Parity (childbirths)*
|
|
|
< 0.001
|
|
1
|
2,242 (47.1)
|
41 (28.7)
|
|
2–3
|
2,152 (45.2)
|
69 (48.2)
|
|
≥4
|
364 (7.7)
|
33 (23.1)
|
|
Previous abortion*
|
|
|
0.023
|
|
No
|
3,859 (81.0)
|
105 (73.4)
|
|
Yes
|
903 (19.0)
|
38 (26.6)
|
|
Previous preterm birth*
|
|
|
0.003
|
|
No
|
4,079 (86.5)
|
109 (78.4)
|
|
Yes
|
639 (13.5)
|
30 (21.6)
|
|
Previous stillbirth*
|
|
|
0.404
|
|
No
|
4,688 (98.4)
|
142 (99.3)
|
|
Yes
|
75 (1.6)
|
1 (0.7)
|
|
Gestational hypertension*
|
|
|
0.680
|
|
No
|
4,163 (87.7)
|
127 (88.8)
|
|
Yes
|
586 (12.3)
|
16 (11.2)
|
|
Gestational diabetes*
|
|
|
0.999
|
|
No
|
4,450 (93.7)
|
134 (93.7)
|
|
Yes
|
299 (6.3)
|
9 (6.3)
|
|
Urinary tract infection*
|
|
|
0.049
|
|
No
|
3,256 (68.6)
|
87 (60.8)
|
|
Yes
|
1,489 (31.4)
|
56 (39.2)
|
|
Odontological treatments*
|
|
|
0.222
|
|
No
|
3,315 (70.7)
|
93 (66.0)
|
|
Yes
|
1,373 (29.3)
|
48 (34.0)
|
|
Threatened abortion*
|
|
|
0.049
|
|
No
|
4,427 (93.0)
|
127 (88.8)
|
|
Yes
|
329 (7.0)
|
16 (11.2)
|
|
Threatened preterm birth*
|
|
|
0.275
|
|
No
|
4,129 (86.9)
|
119 (83.8)
|
|
Yes
|
620 (13.1)
|
23 (16.2)
|
|
Alcohol consumption*
|
|
|
< 0.001
|
|
No
|
3,578 (75.1)
|
86 (60.1)
|
|
Yes
|
1,185 (24.9)
|
57 (39.9)
|
|
Smoking
|
|
|
< 0.001
|
|
No
|
4,213 (88.4)
|
88 (61.5)
|
|
Yes
|
552 (11.6)
|
55 (38.5)
|
|
TOTAL
|
4,765 (100)
|
143 (100)
|
|
*Excluded cases.
Low birth weight was the only condition significantly associated with high caffeine
consumption ([Table 3]).
Table 3
Selected neonatal characteristics of the Ribeirao Preto Birth Cohort of 2010in terms
of caffeine consumption
|
Characteristic
|
< 300 mg/day
n (%)
|
≥300 mg/day
n (%)
|
p-value
|
|
Gender*
|
|
|
0.928
|
|
Male
|
2,394 (50.3)
|
72 (50.3)
|
|
Female
|
2,366 (49.7)
|
71 (49.6)
|
|
Low birth weight
|
|
|
0.034
|
|
No
|
4,370 (91.7)
|
124 (86.7)
|
|
Yes
|
395 (8.3)
|
19 (13.3)
|
|
Preterm Birth
|
|
|
0.424
|
|
No
|
4,079 (85.6)
|
119 (83.2)
|
|
Yes
|
686 (14.4)
|
24 (16.8)
|
|
Congenital Malformations*
|
|
|
0.290
|
|
No
|
4,701 (98.9)
|
140 (97.9)
|
|
Yes
|
54 (1.1)
|
3 (2.1)
|
|
Total
|
4,765 (100)
|
143 (100)
|
|
Low birth weight: birth weight < 2500 g. Preterm birth: gestational age < 259 days.
*Excluded cases.
Crude risks for LBW and preterm birth were 1.45 (95% CI: 0.91–2.32) and 1.16 (95%
CI: 0.77–1.75), respectively. For LBW, the RR increased slightly after the adjustment,
but no differences were observed ([Table 4]). For preterm birth, the RR decreased slightly after the adjustment in the four
models, but without association with high caffeine intake during pregnancy ([Table 5]).
Table 4
Crude and adjusted risks of low birth weight, according to caffeine consumption. Ribeirão
Preto Birth Cohort of 2010
|
Caffeine consumption
|
Crude Relative Risk
|
Adjusted Relative Risk
|
|
Model 1
|
Model 2
|
Model 3
|
Model 4
|
|
RR (95% CI)
|
RR1 (95% CI)
|
RR2 (95% CI)
|
RR3 (95% CI)
|
RR4 (95% CI)
|
|
Not consumed
|
1
|
1
|
1
|
1
|
1
|
|
< 300 mg/day
|
0.91 (0.77–1.06)
|
1.10 (0.93–1.32)
|
1.07 (0.91–1.27)
|
1.08 (0.91–1.27)
|
1.10 (0.92–1.32)
|
|
≥ 300 mg/day
|
1.45 (0.91–2.32)
|
1.52 (0.92–2.52)
|
1.56 (0.97–2.50)
|
1.34 (0.53–2.16)
|
1.42 (0.85–2.38)
|
Abbreviations: CI, confidence interval; RR, relative risk.
Model 1 adjusted for maternal age, education and skin color, marital status, and occupation
of the head of the family.
Model 2 adjusted for parity, previous preterm birth, abortion, and stillbirth.
Model 3 adjusted for gestational hypertension and diabetes, threatened abortion and
preterm delivery, alcohol consumption, maternal smoking, and urinary tract infection.
Model 4 adjusted for all variables included in the previous models.
Table 5
Crude and adjusted risks of preterm birth according to caffeine consumption. Ribeirão
Preto Birth Cohort of 2010
|
Caffeine consumption
|
|
Crude Relative Risk
|
Adjusted Relative Risk
|
|
Model 1
|
Model 2
|
Model 3
|
Model 4
|
|
RR (95% CI)
|
RR1 (95% CI)
|
RR2 (95% CI)
|
RR3 (95% CI)
|
RR4 (95% CI)
|
|
Not consumed
|
|
1
|
1
|
1
|
1
|
1
|
|
< 300 mg/day
|
|
0.99 (0.87–1.13)
|
1.07 (0.94–1.22)
|
1.10 (0.97–1.25)
|
1.11 (0.97–1.26)
|
1.10 (0.96–1.26)
|
|
≥ 300 mg/day
|
|
1.16 (0.77–1.75)
|
1.16 (0.74–1.80)
|
1.12 (0.73–1.69)
|
1.12 (0.72–1.73)
|
1.03 (0.65–1.63)
|
Abbreviations: CI, confidence interval; RR, relative risk.
Model 1 adjusted for maternal age, education and skin color, marital status, and occupation
of the head of the family.
Model 2 adjusted for parity, previous preterm birth, abortion, and stillbirth.
Model 3 adjusted for gestational hypertension and diabetes, threatened abortion and
preterm delivery, alcohol consumption, maternal smoking, urinary tract infection and
odontological treatments during pregnancy.
Model 4 adjusted for all variables included in the previous models.
Discussion
In the present study, 64.5% of the pregnant women drank coffee and there was no difference
per trimester of caffeine intake. Only 2.9% of these women reported high caffeine
intake, without association with LBW or preterm birth.
Similarly to the present study, large studies that incorporated trimester-specific
questionnaires showed no difference between the trimesters.[24]
In other studies, the incidence of high caffeine consumption was higher than in Ribeirão
Preto (18.9%,[11] 13.5%,[9] 12%,[2] and 8.3%[27]), possibly by including other sources of caffeine. Another explanation is that when
other health risks are present, doctors might discourage caffeine consumption, resulting
in a lower coffee intake in contrast with the healthier women. This is supported by
the elevated rate of gestational hypertension, diabetes, and urinary tract infection
observed in the studied population.
Caffeine consumption from coffee, tea, soft drinks with cola, chocolate, and some
medications is frequently described,[19] including in pregnant women. Previous studies found that a high caffeine intake
could be harmful during pregnancy because caffeine crosses the placenta and accumulates
in the fetus, decreases blood flow and produces biochemical changes, with smaller
BW or shorter GA, and increases abortions and the risk of congenital anomalies.[10]
[13]
In the present cohort, high caffeine consumption during pregnancy was not associated
with LBW or preterm birth, in crude and adjusted models. To study the associations
between the independent variables and LBW and preterm birth, odds ratios (ORs) were
estimated by using a hierarchized (polytomous) logistic regression model.
Other studies reinforced this finding;[2]
[3]
[6]
[11]
[17]
[28]
[29]
[30] recently, two meta-analyses reported a higher risk of delivering LBW newborns, while
no association with preterm delivery was found.[31]
[32]
However, some authors found an association with different caffeine levels (consumption
between 70–92 mg/day,[30] > 300 mg/day,[16]
[21]
[22]
[33] ≥140 mg/day,[9] and ≥ 6 cups, with 90 mg/cup),[7] but most of the associations were found with the highest levels of consumption.[31]
Associations between lower values of caffeine intake and LBW were found in some studies,
which divided the cutoff points into between 1 and 100 mg/day, between 101 and 200
mg/day, and between 201 and 300 mg/day.[16]
[21]
The only existing randomized controlled trial that studied the effect of caffeine
on a Danish cohort of 1,207 women during the second half of pregnancy observed no
effect on BW or GA at birth.[34] Another case control study with 502 mothers did not find any association between
caffeine intake and preterm birth.[3]
Several recognized maternal conditions were statistically associated with LBW and
preterm birth, such as not having a partner, highest parity, previous preterm birth
or stillbirth, gestational hypertension, threatened preterm birth, and smoking, in
accordance with other studies.[27]
[28]
High caffeine intake was significantly associated with reduced education, occupation
of the head of the family, nonwhite skin color, not having a partner, higher parity,
previous abortion and preterm birth, urinary tract infection, threatened abortion,
alcohol consumption, and smoking.
Pacheco et al[27] found that high caffeine intake was associated with reduced education, higher parity,
alcohol consumption, and smoking. No association with age, previous preterm birth,
and body mass index (BMI) was found.
Another study with 7,025 women found similar results: women without partner, reduced
education, higher parity, history of preterm birth, and smoking presented a higher
caffeine intake.[30]
The main differences with other studies were the heterogeneity of the caffeine exposure
in different concentrations, of the diversity of brands, of the preparation according
to each region and country, of the different methods for the assessment of caffeine
consumption (postpartum questionnaires or caffeine concentration in plasma and in
saliva measured by swab), of the inadequate measures of caffeine intake, of the insufficient
statistical power and control of confounding variables. In some studies, higher consumption
of caffeine intake was found with a similar cutoff (> 300 mg/day), but including tea,
chocolate and other sources of caffeine.[15]
[27]
Some studies suggest a possible effect of chemicals present in coffee and tea other
than caffeine, such as polyphenols, which contribute to adverse pregnancy outcomes
including preterm delivery and preeclampsia.[35] Therefore, studies investigating the effect of caffeine tend to overlook the fact
that other components in coffee and tea may be contributing factors.
Several limitations of the present study should be mentioned. First, the sample size
was originally not computed for caffeine consumption and, therefore, a type I error
cannot be ruled out. Second, caffeine intake during pregnancy was measured on a self-reported
basis only after birth, a fact known to underestimate the frequency and amount of
caffeine ingested by pregnant women; consequently, our study is subjected to recall
bias. The information about caffeine intake were obtained by questionnaires; therefore,
it was not possible to quantify neither the concentration, the brand of coffee, nor
the method of preparation (strong, medium, weak). The questionnaires employed did
not have information about other sources of caffeine, such as tea, soft drinks with
cola, chocolate, or some medications, which can influence the lower prevalence of
consumption of caffeine compared with the aforementioned studies. Third, the present
study was performed in a cohort of relatively healthy pregnant women with singleton
pregnancies. Therefore, the findings can only be generalized to an obstetric population
with a similar risk of complications. Finally, we cannot exclude the possibility of
residual confounding variables.
The strength of the present study was the assessment of a birth cohort followed-up
since the prenatal period with a high response rate (96%). Since the data were collected
at two different periods, we were able to confirm the information and to adjust the
outcomes for a wide range of known confounders, such as maternal behaviors and sociodemographic
factors, and possible risk factors of adverse perinatal outcomes could be registered.
Therefore, more detailed studies analyzing sources of caffeine are necessary, and
also to verify if any specific trimester of gestation can be more vulnerable to caffeine
exposure.
Conclusion
High caffeine intake during pregnancy was not associated with an increased risk of
LBW and preterm risk in the birth cohort of Ribeirão Preto.
