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Clinical Epidemiology 2017:9 699–719

Clinical Epidemiology Dovepress

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Open Access Full Text Article

http://dx.doi.org/10.2147/CLEP.S146496

Association between coffee or caffeine consumption and fecundity and fertility: a systematic review and dose–response meta-analysis

Julie Lyngsø1

Cecilia Høst Ramlau-Hansen1

Bjørn Bay2

Hans Jakob ingerslev3

Adam Hulman1,4

Ulrik Schiøler Kesmodel5

1Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, 2The Fertility Clinic, Regional Horsens Hospital, Horsens, 3Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus, 4Danish Diabetes Academy, Odense, 5Department of Obstetrics and Gynaecology, Herlev and Gentofte Hospital, Herlev, Denmark

Objective: The aim was to investigate whether coffee or caffeine consumption is associated with reproductive endpoints among women with natural fertility (ie, time to pregnancy [TTP]

and spontaneous abortion [SAB]) and among women in fertility treatment (ie, clinical pregnancy

rate or live birth rate).

Design: This study was a systematic review and dose–response meta-analysis including data from case–control and cohort studies.

Methods: An extensive literature search was conducted in MEDLINE and Embase, with no time and language restrictions. Also, reference lists were searched manually. Two independent

reviewers assessed the manuscript quality using the Newcastle–Ottawa Scale (NOS). A two-

stage dose–response meta-analysis was applied to assess a potential association between coffee/

caffeine consumption and the outcomes: TTP, SAB, clinical pregnancy, and live birth. Hetero-

geneity between studies was assessed using Cochrane Q-test and I2 statistics. Publication bias

was assessed using Egger’s regression test.

Results: The pooled results showed that coffee/caffeine consumption is associated with a significantly increased risk of SAB for 300 mg caffeine/day (relative risk [RR]: 1.37, 95%

confidence interval [95% CI]: 1.19; 1.57) and for 600 mg caffeine/day (RR: 2.32, 95% CI: 1.62;

3.31). No association was found between coffee/caffeine consumption and outcomes of fertility

treatment (based on two studies). No clear association was found between exposure to coffee/

caffeine and natural fertility as measured by fecundability odds ratio (based on three studies)

or waiting TTP (based on two studies).

Conclusion: Results from this meta-analysis support the growing evidence of an association between coffee/caffeine intake and the risk of SAB. However, viewing the reproductive capac-

ity in a broader perspective, there seems to be little, if any, association between coffee/caffeine

consumption and fecundity. In general, results from this study are supportive of a precautionary

principle advised by health organizations such as European Food Safety Authority (EFSA) and

World Health Organization (WHO), although the advised limit of a maximum of two to three

cups of coffee/200–300 mg caffeine per day may be too high.

Keywords: coffee, caffeine, fecundity, fertility, spontaneous abortion, assisted reproduction

Plain language summary Coffee and other caffeinated beverages are widely consumed by women desiring to conceive as

well as pregnant women. Whether such consumption reduces the chance of achieving a preg-

nancy or may have harmful effects on the developing fetus is widely debated. As a contribution

to this debate and given the growing concern of subfecundity and infertility in public health,

Correspondence: Julie Lyngsø Department of Public Health, Section for Epidemiology, Aarhus University, Bartholins Allé 2, building 1260, 8000 Aarhus C, Denmark Tel +45 40 34 81 74 Email [email protected]

Journal name: Clinical Epidemiology Article Designation: Review Year: 2017 Volume: 9 Running head verso: Lyngsø et al Running head recto: Consumption of coffee or caffeine and fecundity and fertility DOI: http://dx.doi.org/10.2147/CLEP.S146496

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Lyngsø et al

we investigated the risk of coffee or caffeine consumption on the

ability to conceive a pregnancy and to carry the pregnancy to term.

Results from this study showed an increased risk of experiencing

a spontaneous abortion with increasing consumption of coffee/

caffeine during early pregnancy. No clear association was found

between coffee/caffeine consumption and the chance of achieving

a pregnancy among women/couples trying to conceive naturally

or by women/couples receiving fertility treatment. Results from

this study support the precautionary principle advised by health

organizations such as European Food Safety Authority (EFSA) and

World Health Organization (WHO), although the advised limit of a

maximum of two to three cups of coffee/200–300 mg caffeine per

day may be too high.

Introduction Subfecundity and infertility are multifactorial conditions

of growing concern in public health. Worldwide, one in six

couples experience fecundity problems during their repro-

ductive lifetime.1–3 While the cause often may be explained

by failure of ovulation, damages on the fallopian tubes, or

low sperm count, the reduced fecundity is still unexplained

in many cases. Thus, investigations of a potential effect of

modifiable exposures on longer waiting time to pregnancy

(TTP), increased rate of spontaneous abortion (SAB), or

reduced live birth rate are important.

Coffee consumption is common among people through-

out the world. Worldwide, Finland has the highest consump-

tion (12.0 kg coffee/person/year), with Denmark being the

fourth most coffee-consuming country (8.7 kg coffee/person/

year). Also, coffee and other caffeine-containing drinks and

foods are widely consumed by women desiring to conceive

and by pregnant women. On average, a cup of coffee contains

~100 mg of caffeine.4 Even small effects of coffee or caffeine intake on fecun-

dity could have considerable public health consequences,

considering the large consumption of these substances.

The European Food Safety Authority (EFSA) recommends

women desiring to conceive and pregnant women to keep

their daily caffeine consumption below 200 mg,5 while WHO

recommends a daily caffeine intake below 300 mg.6 Caffeine

is a central ingredient in coffee, while other sources of caffeine

include tea, soft drinks, chocolate, and some medications.

The association between caffeine intake and female

fecundity has been studied with inconsistent findings, in

studies with both retrospectively7–13 and prospectively col-

lected exposure data.14–19 A high level of coffee consumption

during pregnancy has been associated with an increased risk

of fetal death after 20 weeks of gestation20,21 and stillbirth.22

In meta-analyses, an increased risk of low birth weight and

small for gestational age was found,23 but no association was

found between caffeine intake during pregnancy and the risk

of preterm birth.23,24

Recently, a meta-analysis reported that an increment

in intake of 100 mg caffeine per day was associated with a

14% increased risk of SAB.23 However, the authors did not

account for the varying quality of the included studies, includ-

ing varying (or none) adjustment for potential confounders.

Studies that fail to adjust for important risk factors associated

with SAB may over- or underestimate the risk associated

with caffeine consumption. Hence, taking adjustment status

into account would considerably improve the quality of a

meta-analysis. Moreover, other substances in coffee besides

caffeine might play an important role. Finally, applying a

broader view on fecundity through inclusion of different

reproductive endpoints among both women conceiving

naturally and following fertility treatment could extend the

use of the results and help general practitioners and fertility

clinics provide balanced information to women and couples

seeking advice or even fertility treatment. No meta-analysis

has previously reported on a possible association between

coffee/caffeine intake and TTP or endpoints among couples

in fertility treatment.

The aim of this systematic review and dose-response

meta-analysis was to investigate whether consumption of

coffee or caffeine is associated with reproductive endpoints

among women with natural fertility (ie TTP and SAB) and

among women in fertility treatment (ie clinical pregnancy

rate and live birth rate).

Methods A review protocol is available from the PROSPERO data-

base.25 The protocol was registered on June 9, 2015 (registra-

tion number: CRD42015020333).

Search strategy and selection We conducted a comprehensive literature search in MED-

LINE and Embase databases with the help of a medical

librarian on May 26, 2015. The following keywords and

medical subject headings were used to identify relevant

articles in the databases: ([“Fertility” or “Infertility, Female”

or “Reproduction” or “Preconception Care”) or [“Reproduc-

tive Techniques, Assisted” or “Reproductive Techniques” or

“fertility treatment”]) AND (“Caffeine/adverse effects” or

“Coffee”) AND (“Case-Control Studies” or “Cohort Stud-

ies”). To include non-indexed new literature, an additional

search was performed using free text terms. No restrictions

were made regarding study language or year of publication.

Further, the reference lists of retrieved articles and reviews

were searched manually for additionally relevant studies. The

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Consumption of coffee or caffeine and fecundity and fertility

first author reviewed all retrieved articles for eligibility by

title and abstract by consulting with at least one co-author in

cases of any doubt about the inclusion of a given study or not.

Potentially eligible articles were thoroughly read in full text to

check whether they fulfilled the following inclusion criteria:

1. Participants had to be either women/couples trying to

conceive naturally or women/couples trying to conceive

by medically assisted reproduction (MAR) treatment

2. Studies that reported a numerical exposure range of either

coffee or caffeine consumption

3. Studies that investigated at least one of the outcomes of

interest: TTP, SAB, clinical pregnancy, and live birth

4. Articles that reported data from original studies (ie, no

review articles)

5. Studies of which the design was a case-control study or

a cohort study (ie, no RCT)

Before finalizing the manuscript, the database search was

repeated on April 3, 2017.

Data extraction All included full text articles were read independently by at

least two authors. A data extraction form was developed a

priori, ensuring a standardized procedure. The following data

were extracted: lead author surname, study title, country of

origin, year of publication and journal, study design, study

population (size and selection), exposure and outcome assess-

ment, covariates adjusted for, main results, study limitations,

and assessment of quality scoring.

We assessed the quality of all included studies using the

Newcastle–Ottawa Scale (NOS).26 Thus, the selection process

and comparability of the study groups as well as the ascertain-

ment of exposure or outcome of interest of the included stud-

ies were evaluated for either cohort or case–control studies

(please see scoring details in the Supplementary material). In

addition to the NOS scheme, we constructed an explanatory

form ensuring a standardized scoring among the authors with

regard to the specific scope of this review (Supplementary

material). When using NOS to evaluate study comparability,

one has to choose the two most important covariates. Hence,

based on the current knowledge, maternal age was chosen

as the most important factor to adjust for. As additionally

important adjustment factors, smoking was chosen for

studies evaluating TTP and MAR treatment, while maternal

alcohol consumption was chosen for those investigating

SAB. All studies were allocated a total score between 0 and

9 independently by a minimum of two authors. Any incon-

sistency was resolved by discussion, leading to a uniform

decision. Studies with a total score of ≥7 were considered as “ high-quality studies”, and in a sub-analysis, studies were

stratified according to this selected cut-off value. Regardless

of total NOS score, all studies were included in the review.

This review is reported in accordance with the PRISMA

statement27 for reporting of systematic review and meta-

analysis. Supplementary material regarding the full search

strategy for MEDLINE, elaborated reasons for exclusion, and

NOS explanatory form are all available online.

Outcomes The ability to naturally conceive was investigated by two

broad fecundability measures including TTP (ie, the number

of months or cycles taken by a couple to conceive, when

being sexually active and not using birth control) and fecund-

ability odds ratio (FOR) (ie, the ratio of couple’s probability

of conceiving in one menstrual cycle).28 The capability of

maintaining a pregnancy after conception was evaluated by

the risk of experiencing an SAB (yes/no). Among couples

receiving MAR treatment, a possible association was inves-

tigated using different endpoints to evaluate a successful

fertility treatment (ie, achieving a pregnancy or live birth

after fertility treatment; yes/no).

Statistical analysis Although still included in the review, studies were excluded

from the meta-analyses if they did not provide information on

the number of cases and total number of subjects within each

exposure category and whose corresponding author did not

respond to emails asking for additional data to calculate these

numbers.7,9,10,14,15,17,29–33 Also, we excluded studies that did not

report on three or more quantitative categories of coffee/caf-

feine consumption,34–37 as these cannot contribute sufficient

data when performing a dose–response meta-analysis.38

We applied a two-stage dose–response meta-analysis

to assess a potential association between coffee/caffeine

consumption and our outcomes.39 For fecundability and

MAR treatment, we included only fixed effects in the meta-

analysis due to the low number of included studies,40 while

for SAB, we conducted a random-effects meta-analysis after

considering heterogeneity between studies. As coffee/caffeine

consumption was reported on various scales, we converted

exposure data into a uniform measurement (mg/day). Studies

reporting consumption in cups of coffee were recalculated

into an approximate caffeine content, assuming that one

cup of coffee in general contains 100 mg caffeine.4,41 As the

approximation of caffeine content per cup of coffee might

be imprecise, a sensitivity analysis was performed, assuming

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Lyngsø et al

that one cup of coffee contained 150 mg caffeine. Coffee/

caffeine consumption was modeled using restricted cubic

splines with three knots at the 10th, 50th, and 90th percentiles

of the distribution of doses.38,42,43 For each model, we present

an overall p-value testing that the two regression coefficients

describing the nonlinear relationship were simultaneously

equal to zero. Also, upon finding a statistical significant

association, we present a p-value testing the linear versus

nonlinear relationship.44 When analyzing risk of SAB, we

performed stratified analyses by type of consumption (caf-

feine vs coffee), adjustment status (crude vs any adjustment),

study quality (NOS>7 vs NOS<7), and study design (cohort vs case–control). Similar analyses were not possible for other

outcomes due to the low number of studies. Heterogeneity

between studies was assessed using the Cochrane Q-test and

the I2 statistic. Low heterogeneity was defined by I2 values

<25%, while a I2 value >75% was considered an indicator of substantial heterogeneity.45 Publication bias was assessed for

SAB studies, using Egger’s regression test.46 As meta-analysis

for fecundity and MAR endpoints only included a maximum

of three studies, tests of heterogeneity and publication bias

were irrelevant for these outcomes.47 All statistical analyses

were performed using the “dosresmeta” and “metafor” pack-

ages in R version 3.3.1.48,49 p-values <0.05 were considered statistically significant.

Results Characteristics of the included studies A total number of 379 articles were identified through the

systematic literature search, and an additional 68 articles

were identified through a manual search of their references

( Figure 1). Of the total 447 articles, 136 were duplicates

and thus excluded. The remaining 311 unique articles were

screened by title and, if necessary, by abstract, and 195 did

not meet the eligibility criteria. Full-texts were assessed

for the remaining 116 articles. Of these, 68 articles were

excluded due to not meeting the eligibility criteria, and

one article was excluded due to insufficient data reporting.

Thus, a total of 47 studies were included in the systematic

review. Of these, 35 studies had dose–response information

(ie, reporting at least three or more quantitative exposure

categories) and were included in our meta-analyses. Of

these 35 studies, 5 studies reported about the endpoints of

fecundity9,10,16,19,50, 27 studies reported about SAB,21,32,34,51–73

and 3 studies reported on the outcomes of MAR.74–76 Results

from the remaining 12 studies that did not provide sufficient

data to be included in the meta-analysis are included as a

narrative description.

All included studies were published between 1988

and 2015. Thirty-one were cohort studies, while 16 were

case–control studies. Study characteristics, results, and the

assigned total NOS scores are presented in Tables 1–3 (for

NOS elaborations, please see the Table S1). The presented

results cover a variety of countries with large differences in

exposure levels ranging from non-consumers to those who

consume over 1,200 mg/day (corresponding to 12 cups of cof-

fee/day). Also, adjustment for potential confounders varied

considerably between studies (Tables 1–3).

FOR In the three cohort studies providing sufficient data to be

included in the meta-analysis, we found no indication of an

association between caffeine intake up to 400 mg/day and

altered FOR (overall p=0.76; Figure 2A). Compared with no caffeine intake, the pooled odds ratios for altered fecund-

ability were 1.03 (95% confidence interval [CI]: 0.83; 1.28)

for 100 mg caffeine/day and 1.09 (95% CI: 0.86; 1.37) for

400 mg caffeine/day.

Studies not eligible for meta-analysis Five other studies have addressed a possible association

between coffee/caffeine consumption and fecundability with

contradicting findings. Two studies from the US13,15 includ-

ing a total of 104 and 6,303 women, respectively reported

reduced fecundability with higher caffeine consumption in

the late 1980s. However, results by three later studies (two

European studies and one US study)14,17,30 including 259 and

423, and 470 women, respectively, support the findings of no

association between caffeine consumption on fecundability.

TTP Only two cohort studies provided sufficient data on TTP, to

be included in the dose–response meta-analysis. The results

did not indicate an association (p=0.43 for TTP >6 months and p=0.98 for TTP >12 months) (Figure 2B and 2C).

Compared with no caffeine intake, the pooled relative

risks for TTP >6 months were 0.92 (95% CI: 0.79; 1.07) for 100 mg caffeine/day and 0.76 (95% CI: 0.49; 1.18) for 600

mg caffeine/day. For TTP >12 months, the pooled relative risks were 0.99 (95% CI: 0.88; 1.11) for 100 mg caffeine/

day and 0.97 (95% CI: 0.71; 1.33) for 600 mg caffeine/day,

compared with no caffeine intake.

Studies not eligible for meta-analysis Two studies that were not included in the meta-analysis

have investigated a possible association between caffeine

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Consumption of coffee or caffeine and fecundity and fertility

consumption and TTP. Bolúmar et al7 reported on 3,146

European women and found an increased risk of TTP >9.5 months with a caffeine intake of >500 mg/day when reporting retrospectively on their first pregnancy. However, no associa-

tion was found when reporting on the most recent waiting

time. Another study including 66 American women29 did not

find an association between caffeine consumption and TTP.

SAB We found that higher intake of caffeine was associated with

higher risk of spontaneous abortion (overall association

p<0.0001; p for non-linearity <0.01), based on 27 studies providing sufficient data to be included in the meta-analysis

(Figure 2D). Compared with no caffeine intake, the pooled

relative risks for SAB were 1.08 (95% CI: 1.03; 1.13) for

Figure 1 Flow diagram. Abbreviations: SAB, spontaneous abortion; MAR, medically assisted reproduction.

Total number of records identified (n = 447)

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Total number of unique records identified (n = 311)

Unique full-text articles assessed for eligibility (n = 116)

Studies included in review (n = 47)

Studies included in meta-analyses (n = 35)

Fecundity studies (n = 5)

SAB studies (n = 27)

MAR studies (n = 3)

Exclusion of duplicate records (n = 136)

Exclusion of non-relevant records based on title and abstract

(n = 195)

Studies only included in the review (n = 12) Reporting insufficient data (n = 9) Only two exposure categories (n = 3)

- -

Full-text articles excluded Lack of relevance (n = 68)-

- Insufficient data reporting (n = 1)

Total number of records identified through search of References (n = 68)-

Total number of records identified through database searching

MEDLINE/PubMed (n = 140)- - -

Embase (n= 238) Repeated database search (n=1)

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Table 1 Characteristics and results of publications on coffee/caffeine and fecundity endpoints

Author and year

Country Design Study groups included in the analyses

Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

wilcox et al, 198815

US Cohort N=104 volunteering healthy women who did not become pregnant in the first 3 months of trying to conceive

Multiple Yes Yes Age, frequency of intercourse, age at menarche, woman’s prenatal exposure to mother’s smoking. Subanalysis resticted to non-smokers

women with a caffeine intake had a decreased fecundability FOR: 0.51 (95% Ci 0.35; 0.75)

Christianson et al, 198913

US Cohort N=6,303 pregnant women Coffee No Yes Ethnicity, parity, smoking women with a coffee intake of >7 cups/day had an increased risk of experiencing difficulties in becoming pregnant RR: 1.96*

Olsen, 19919 Denmark Cohort N=5,309 non-smoking pregnant Danish women who had reached their 3rd trimester Cases: 523

Multiple Yes Yes Main analysis – data stratified on smoking status. Adjusted for number of pregnancies, father’s age, mother’s and father’s alcohol drinking habits, shift work, mother’s education, mother’s and father’s smoking habits

Among nonsmokers, there was no association between coffee/tea intake >8 cups/day and TTP >6 or TTP >12 months OR: 0.92 (95% Ci 0.71; 1.19) and OR: 0.98 (95% Ci 0.70; 1.37) Among smokers, an intake of >8 cups/day was associated with TTP >12 months OR: 1.35 (95% Ci 1.02; 1.48)

Florack et al, 199417

The Netherlands

Cohort N=259 Dutch women planning a pregnancy within a year, hospital workers

Coffee No No Main analysis = crude analysis. Subanalysis: controling for smoking and partners behavioral risk factors

women with a caffeine intake of 400–700 mg/day had an increased fecundability FOR: 2.10 (95% Ci 1.20; 3.70)

Alderete et al, 199510

US Cohort N=787 Primigravidas and married American women

Coffee Yes Yes Stratification by smoking status. Adjusted for age, race, BMi, education, prior use of contraceptive pills, alcohol consumption, husband’s smoking habits, income, whether pregnancy was planned, abnormal reproductive conditions, immune and endocrine disorders

Nonsmoking women with a coffee intake >3 cups/day had no increased risk of TTP >3 months (187 cases) OR: 1.10 (95% Ci 0.70; 1.80) TTP >6 months (104 cases) OR: 1.00 (95% Ci 0.60; 1.80) or TTP >12 months (56 cases) OR: 1.00 (95% Ci 0.50; 1.70)

Bolúmar et al, 19977

Spain Cohort N=3,146 European women in the fertile age, planning their first pregnancy

Multiple Yes Yes Age, parity, smoking, alcohol consumption, frequency of intercourse, educational level, working status, use of oral contraceptives, and country

Women with a caffeine intake during the first pregnancy of >500 mg/day had an increased risk of TTP >9.5 months OR: 1.45 (95% Ci 1.03; 2.04) No association between total caffeine intake >500 mg/day or coffee intake >5 cups/day and TTP >9.5 months (N=3.053) OR: 1.32 (95% Ci 0.94; 1.86) and OR: 1.26 (95% Ci 0.91; 1.74) during the most recent waiting time

Caan et al, 199816 US Cohort N=187 volunteering American women, pregnancy planners who had been trying for 3 months or less to conceive in total 737 cycles; 115 pregnant cycles and 622 non- pregnant cycles

Multiple/ coffee

Yes Yes Age, BMi, gravidity, frequency of intercourse, smoking, and alcoholic beverage

No risk of reduced fecundability with total caffeine intake >106.8 mg/day OR: 1.09 (95% Ci 0.63; 1.89) or coffee intake >1 cup/day OR: 0.77 (95% Ci 0.43; 1.37)

Hakim et al, 199819

US Cohort N=98 volunteering American women in the reproductive age, employed at two semiconductor plants No. of conceptions: 90 No. of menstrual cycles: 536

Coffee Yes Yes Participants’ age, number of occurrences of sexual intercourse in each month, alcohol consumption. The analysis was restricted to nonsmoking women

Nonsmoking women had no risk of reduced fecundability with caffeine intake >300 mg/day OR: 0.83 (95% Ci 0.34; 2.01)

Jensen et al, 199814

Denmark Cohort N=423 volunteering Danish couples, nulliparous and pregnancy planners with 1,596 cycles

Multiple/ coffee

No Yes Stratification by smoking. Total caffeine adjusted for female BMi, alcohol intake, deseases of the reproductive organs, semen quality, duration of menstrual cycle

Nonsmoking women had no risk of reduced fecundability with total caffeine intake >700 mg/day FOR: 0.63 (95% Ci 0.25; 1.60) or caffeine intake from coffee >300 mg/day FOR: 0.87 (95% Ci 0.32; 2.37) Among smokers, a total intake of caffeine 0–299 mg/day and a caffeine intake from coffee >300 mg/day were associated with reduced fecundability (FOR: 0.55 [95% Ci 0.32; 0.98] and FOR: 0.34 [95% Ci 0.12; 0.98], respectively)

Pollack et al, 201029

US Cohort N=66 American pregnancy planners Cases: 14

Multiple Yes Yes Age, average alcohol consumption and cigarette consumption per standardized 28-day cycle, and prior history of SAB

No risk of longer TTP with total caffeine intake (RR: 1.00 [95% Ci 0.99; 1.01])

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Table 1 Characteristics and results of publications on coffee/caffeine and fecundity endpoints

Author and year

Country Design Study groups included in the analyses

Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

wilcox et al, 198815

US Cohort N=104 volunteering healthy women who did not become pregnant in the first 3 months of trying to conceive

Multiple Yes Yes Age, frequency of intercourse, age at menarche, woman’s prenatal exposure to mother’s smoking. Subanalysis resticted to non-smokers

women with a caffeine intake had a decreased fecundability FOR: 0.51 (95% Ci 0.35; 0.75)

Christianson et al, 198913

US Cohort N=6,303 pregnant women Coffee No Yes Ethnicity, parity, smoking women with a coffee intake of >7 cups/day had an increased risk of experiencing difficulties in becoming pregnant RR: 1.96*

Olsen, 19919 Denmark Cohort N=5,309 non-smoking pregnant Danish women who had reached their 3rd trimester Cases: 523

Florack et al, 199417

The Netherlands

Cohort N=259 Dutch women planning a pregnancy within a year, hospital workers

Coffee No No Main analysis = crude analysis. Subanalysis: controling for smoking and partners behavioral risk factors

women with a caffeine intake of 400–700 mg/day had an increased fecundability FOR: 2.10 (95% Ci 1.20; 3.70)

Alderete et al, 199510

US Cohort N=787 Primigravidas and married American women

Bolúmar et al, 19977

Spain Cohort N=3,146 European women in the fertile age, planning their first pregnancy

Multiple Yes Yes Age, parity, smoking, alcohol consumption, frequency of intercourse, educational level, working status, use of oral contraceptives, and country

Multiple/ coffee

Yes Yes Age, BMi, gravidity, frequency of intercourse, smoking, and alcoholic beverage

No risk of reduced fecundability with total caffeine intake >106.8 mg/day OR: 1.09 (95% Ci 0.63; 1.89) or coffee intake >1 cup/day OR: 0.77 (95% Ci 0.43; 1.37)

Hakim et al, 199819

US Cohort N=98 volunteering American women in the reproductive age, employed at two semiconductor plants No. of conceptions: 90 No. of menstrual cycles: 536

Coffee Yes Yes Participants’ age, number of occurrences of sexual intercourse in each month, alcohol consumption. The analysis was restricted to nonsmoking women

Nonsmoking women had no risk of reduced fecundability with caffeine intake >300 mg/day OR: 0.83 (95% Ci 0.34; 2.01)

Jensen et al, 199814

Denmark Cohort N=423 volunteering Danish couples, nulliparous and pregnancy planners with 1,596 cycles

Multiple/ coffee

No Yes Stratification by smoking. Total caffeine adjusted for female BMi, alcohol intake, deseases of the reproductive organs, semen quality, duration of menstrual cycle

Pollack et al, 201029

US Cohort N=66 American pregnancy planners Cases: 14

Multiple Yes Yes Age, average alcohol consumption and cigarette consumption per standardized 28-day cycle, and prior history of SAB

No risk of longer TTP with total caffeine intake (RR: 1.00 [95% Ci 0.99; 1.01])

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Author and year

Country Design Study groups included in the analyses

Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

Taylor et al, 201130

US Cohort N=470 American women who were sexually active and with no history of infertility

Multiple Yes Yes Age, trying to get pregnant, frequency of unprotected intercourse, BMi, average alcohol intake, smoking

No risk of reduced fecundability among women with a caffeine intake >300 mg/day (FOR: 0.89 [95% Ci 0.58; 1.38])

Hatch et al, 201250

US Cohort N=2,484 Danish women, planning a pregnancy who had not been trying to conceive for >6 cycles at study entry No. of pregnancies: 2,484 Cycles at risk: 15,225

Multiple/ coffee

Yes Yes Age, partner’s age, BMi, pack-years of smoking, number of alcoholic beverages consumed per week, physical activity (METs/week), and frequency of intercourse (also adjusted for tea and cola in analyses concerning coffee)

No risk of reduced fecundability among women with a caffeine intake >300 mg/day (FOR: 1.06 [95% Ci 0.92; 1.23]) or coffee intake >3 cups/day (FOR: 1.01 [95% Ci 0.80; 1.27])

Notes: *No 95% Ci provided. Abbreviations: 95% CI, 95% confidence interval; FOR, fecundability odds ratio; NOS, Newcastle–Ottawa scale; TTP, time to pregnancy; SAB, spontaneous abortion; BMi, body mass index.

Table 1 (Continued)

Table 2 Characteristics and results of publications on coffee/caffeine and spontaneous abortion (SAB)

Author and year Country Design Study groups included in the analyses Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

Srisuphan and Bracken, 198634

US Cohort N=2,188 pregnant American women attending care at 29 private hospitals Cases: 345

Multiple Yes No Gestational age at the interview, maternal age, prior gynecologic surgery, member of Jewish religion, SAB in last pregnancy

women consuming ≥151 mg caffeine/day had an increased risk of SAB RR: 1.73*

Axelsson and Rylander, 198931

Sweden Cohort N=654 Swedish shift-working women, including 970 pregnancies

Coffee Yes No Age women with a coffee intake of >3 cups/day had an increased risk of miscarriage RR: 1.56 (95% Ci 1.06; 2.30)

wilcox et al, 199066 US Cohort N=104 healthy volunteering American women, who did not become pregnant in the first 3 months of trying to conceive with 171 pregnancies Cases: 43

Multiple Yes No Age No increased risk of early pregnancy loss with caffeine consumption >3,500 mg/month RR: 2.40 (95% Ci 0.80; 7.00)

Fenster et al, 199151 US Case– control

N=1,891 Cases: 607 American women with SAB within the first 20 weeks of gestation Controls: 1,284 women, frequency matched by last menstrual period and hospital, selected two per case from county live births

Multiple Yes Yes Age, race marital status, insurance coverage, cigarette and alcohol consumption, previous spontaneous abortions and previous therapeutic abortions

No increased risk of SAB with total caffeine intake >300 mg/day OR: 1.22 (95% Ci 0.80; 1.87) Among heavy users, nausea modified the risk of SAB OR: 2.10 (95% Ci 1.20; 3.70)

Kline et al, 199160 US Case– control

N=2,441 Cases: 1,135 American women with SAB within the first 28 weeks of gestation Controls: 1,306 pregnant women, matched by age and payment group

Multiple Yes No Adjusted for maternal age in the article (not able to include this in the meta-analysis, using crude estimates)

women with a perifertilization caffeine intake of 28–124 mg/day had a decreased risk of SAB OR: 0.66 (95% Ci 0.52; 0.83) women with a caffeine intake of 225–1,308 mg/day during pregnancy had an increased risk of SAB OR: 1.71 (95% Ci 1.29; 2.26)

Parazzini et al, 199136 italy Case– control

N=260 Cases: 94 italian women with two or more unexplained miscarriages and no full-term pregnancy Controls: 176 women with normal delivery

Coffee Yes No Age (adjustment for alcohol was not done in the presented analysis)

No significant increased risk of SAB with coffee intake OR: 1.40 (95% Ci 0.70; 2.60)

Armstrong et al, 199253

US Cohort N=35,848 American women with previous pregnancy ending in either delivery or SAB Cases: 7,606

Coffee Yes Yes Maternal age (at pregnancy outcome), pregnancy history, educational level, ethnic group, employment during pregnancy, cigarettes, alcohol

women with a coffee intake of 5–9 cups/day had an increased risk of SAB OR: 1.17 (95% Ci i.03; 1.32)

infante-Rivard et al, 199361

Canada Case– control

N=1,323 Cases: 331 Canadian women admitted for fetal loss Controls: N=992 pregnant women expected to deliver at the same hospital, matched 3:1 on periods of pregnancy

Coffee Yes Yes Period of pregnancy, age, educational level, smoking and alcohol use during pregnancy, uterine abnormality, and work schedule

women with a pre-pregnancy caffeine intake >321 mg/day had an increased risk of SAB OR: 1.85 (95% Ci i.18; 2.89) women with a caffeine intake of >321 mg/day during pregnancy had an increased risk of SAB OR: 2.62 (95% Ci i.38; 5.01)

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Consumption of coffee or caffeine and fecundity and fertility

Author and year

Country Design Study groups included in the analyses

Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

Taylor et al, 201130

US Cohort N=470 American women who were sexually active and with no history of infertility

Multiple Yes Yes Age, trying to get pregnant, frequency of unprotected intercourse, BMi, average alcohol intake, smoking

No risk of reduced fecundability among women with a caffeine intake >300 mg/day (FOR: 0.89 [95% Ci 0.58; 1.38])

Hatch et al, 201250

US Cohort N=2,484 Danish women, planning a pregnancy who had not been trying to conceive for >6 cycles at study entry No. of pregnancies: 2,484 Cycles at risk: 15,225

Multiple/ coffee

No risk of reduced fecundability among women with a caffeine intake >300 mg/day (FOR: 1.06 [95% Ci 0.92; 1.23]) or coffee intake >3 cups/day (FOR: 1.01 [95% Ci 0.80; 1.27])

Table 2 Characteristics and results of publications on coffee/caffeine and spontaneous abortion (SAB)

Author and year Country Design Study groups included in the analyses Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

Srisuphan and Bracken, 198634

US Cohort N=2,188 pregnant American women attending care at 29 private hospitals Cases: 345

Multiple Yes No Gestational age at the interview, maternal age, prior gynecologic surgery, member of Jewish religion, SAB in last pregnancy

women consuming ≥151 mg caffeine/day had an increased risk of SAB RR: 1.73*

Axelsson and Rylander, 198931

Sweden Cohort N=654 Swedish shift-working women, including 970 pregnancies

Coffee Yes No Age women with a coffee intake of >3 cups/day had an increased risk of miscarriage RR: 1.56 (95% Ci 1.06; 2.30)

wilcox et al, 199066 US Cohort N=104 healthy volunteering American women, who did not become pregnant in the first 3 months of trying to conceive with 171 pregnancies Cases: 43

Multiple Yes No Age No increased risk of early pregnancy loss with caffeine consumption >3,500 mg/month RR: 2.40 (95% Ci 0.80; 7.00)

Fenster et al, 199151 US Case– control

Multiple Yes Yes Age, race marital status, insurance coverage, cigarette and alcohol consumption, previous spontaneous abortions and previous therapeutic abortions

No increased risk of SAB with total caffeine intake >300 mg/day OR: 1.22 (95% Ci 0.80; 1.87) Among heavy users, nausea modified the risk of SAB OR: 2.10 (95% Ci 1.20; 3.70)

Kline et al, 199160 US Case– control

N=2,441 Cases: 1,135 American women with SAB within the first 28 weeks of gestation Controls: 1,306 pregnant women, matched by age and payment group

Multiple Yes No Adjusted for maternal age in the article (not able to include this in the meta-analysis, using crude estimates)

Parazzini et al, 199136 italy Case– control

N=260 Cases: 94 italian women with two or more unexplained miscarriages and no full-term pregnancy Controls: 176 women with normal delivery

Coffee Yes No Age (adjustment for alcohol was not done in the presented analysis)

No significant increased risk of SAB with coffee intake OR: 1.40 (95% Ci 0.70; 2.60)

Armstrong et al, 199253

US Cohort N=35,848 American women with previous pregnancy ending in either delivery or SAB Cases: 7,606

Coffee Yes Yes Maternal age (at pregnancy outcome), pregnancy history, educational level, ethnic group, employment during pregnancy, cigarettes, alcohol

women with a coffee intake of 5–9 cups/day had an increased risk of SAB OR: 1.17 (95% Ci i.03; 1.32)

infante-Rivard et al, 199361

Canada Case– control

N=1,323 Cases: 331 Canadian women admitted for fetal loss Controls: N=992 pregnant women expected to deliver at the same hospital, matched 3:1 on periods of pregnancy

Coffee Yes Yes Period of pregnancy, age, educational level, smoking and alcohol use during pregnancy, uterine abnormality, and work schedule

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Author and year Country Design Study groups included in the analyses Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

Mills et al, 199362 US Cohort N=423 American pregnancy planners (24% enrolled no later than 21 days after conception) Cases: 59

Multiple Yes Yes Smoking, maternal age, parity, prior SAB, alcohol use, maternal education, and income

No increased risk of SAB with caffeine intake OR: 1.15 (95% Ci 0.89; 1.49)

Dominguez-Rojas et al, 199454

Spain Cohort N=691 Spanish women who were primipara Cases: 169

Coffee Yes No Age, previous SAB, menarcheal age, and marital status

women with a caffeine intake of 141–280, 281–420, and >420 mg/day had an increased risk of SAB OR: 2.20 (95% Ci i.22; 3.96), OR: 4.81 (95% Ci 2.28; 10.14), and OR: 15.43 (95% Ci 7.34; 32.43)

Lubna and Al-Ansary, 199437

Saudi Arabia Case– control

N=452 Cases: 226 Saudi women hospitalized for SAB within the first 4 weeks of gestation Controls: 226 women admitted for normal delivery

Multiple No No No women with a caffeine intake of >150 mg/day had an increased risk of SAB RR: 1.90 (95% Ci 1.20; 3.00)

Dlugosz et al, 199655 US Cohort N=2,849 pregnant American women recruited from private clinics Cases: 135

Multiple/ coffee

Yes Yes Maternal age, gestational age at the interview, cigarette smoking, and alcoholic beverage consumption (also adjusted for tea and soda intake when reporting results on coffee intake)

women with a coffee intake of >3 cups/day had an increased risk of SAB OR: 2.63 (95% Ci 1.29; 5.34)

Zhang and Bracken, 199667

US Cohort N=2,849 pregnant American women recruited from private clinics Cases: 135

Coffee No No No women consuming ≥3 cups of coffee/day during the first month of pregnancy had an increased risk of SAB RR: 2.45 (95% Ci 1.38; 4.35)

Agnesi et al, 199757 italy Case– control

N=216 Cases: 108 italian women with clinically recognized SAB Controls: 108 women admitted for normal delivery; matched by age, year, and residence

Coffee Yes Yes Gravidity, previous abortions, level of education, smoking habits, consumption of alcohol, medicines and marital status, solvent exposure

women with a coffee intake had an increased risk of SAB RR: 1.36 (95% Ci 1.06; 1.76)

Fenster et al, 199752 US Cohort N=5,142 pregnant American women enrolled from three private facilities Cases: 498

Multiple Yes Yes Maternal age, pregnancy history, cigarette smoking, alcohol consumption, employment, race, gestational age at interview, marital and socioeconomic status (also adjusted for tea, soda, and decaffeinated coffee when analyzing caffeinated coffee)

No increased risk of SAB with a prepregnancy intake of total caffeine >300 mg/day before pregnancy OR: 1.25 (95% Ci 0.90; 1.73) or coffee >3 cups/day OR: 1.13 (95% Ci 080; 1.60) During first trimester, there were no increased risk of SAB with total caffeine intake >300 mg/day OR: 1.29 (95% Ci 0.80; 2.06) or coffee intake >3 cups/day OR: 0.84 (95% Ci 0.41; 1.68)

Parazzini et al, 199863 italy Case– control

N=2,325 Cases: 782 italian women admitted for SAB within the first 12 weeks of gestation Controls: 1,543 women who gave birth at term (>37 weeks of gestation)

Coffee Yes Yes Age, education, previous live births, and SAB, maternal alcohol consumption and smoking in the first trimester, nausea intensity in the first trimester of pregnancy

women with a coffee consumption of 2–3 and ≥4 cups/day before conception had an increased risk of SAB OR: 1.34 (95% Ci 1.04; 1.73) and OR: 1.47 (95% Ci 1.07; 2.02) women with a coffee consumption of 2–3 and ≥4 cups/day during the first trimester had an increased risk of SAB OR: 1.75 (95% Ci 1.23; 2.29) and OR: 3.98 (95% Ci 2.55; 6.21)

Cnattingius et al, 200032

Sweden Case– control

N=1,515 Cases: 562 Swedish women admitted with SAB within 6–12 weeks of gestation Controls: 953 pregnant women, frequency- matched on weeks of gestation and area of residence

Multiple Yes Yes Smoking status, age, number of previous pregnancies, history of SAB, consumption of alcohol during pregnancy (yes/no), presence or absence of nausea, vomiting, and fatigue

No increased risk of early SAB with total caffeine intake ≥500 mg/day during pregnancy OR: 1.40 (95% Ci 0.90; 2.20) when stratifying on smoking status, nonsmokers with a caffeine intake ≥500 mg/day had an increased risk of SAB OR: 2.20 (95% Ci 1.30; 3.80) No association was found among smokers

wen et al, 200168 US Cohort N=550 American women planning to become pregnant and who had not been trying for more than 3 months at enrolment Cases: 70

Multiple No No No No increased risk for SAB with total caffeine intake of ≥300 mg/day before pregnancy RR: 1.10 (95% Ci 0.50; 2.40) A tendency of increased risk for SAB with total caffeine intake ≥300 mg/day during first trimester RR: 2.50 (95% Ci 1.00; 6.40)

Table 2 (Continued)

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Consumption of coffee or caffeine and fecundity and fertility

Author and year Country Design Study groups included in the analyses Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

Mills et al, 199362 US Cohort N=423 American pregnancy planners (24% enrolled no later than 21 days after conception) Cases: 59

Multiple Yes Yes Smoking, maternal age, parity, prior SAB, alcohol use, maternal education, and income

No increased risk of SAB with caffeine intake OR: 1.15 (95% Ci 0.89; 1.49)

Dominguez-Rojas et al, 199454

Spain Cohort N=691 Spanish women who were primipara Cases: 169

Coffee Yes No Age, previous SAB, menarcheal age, and marital status

women with a caffeine intake of 141–280, 281–420, and >420 mg/day had an increased risk of SAB OR: 2.20 (95% Ci i.22; 3.96), OR: 4.81 (95% Ci 2.28; 10.14), and OR: 15.43 (95% Ci 7.34; 32.43)

Lubna and Al-Ansary, 199437

Saudi Arabia Case– control

N=452 Cases: 226 Saudi women hospitalized for SAB within the first 4 weeks of gestation Controls: 226 women admitted for normal delivery

Multiple No No No women with a caffeine intake of >150 mg/day had an increased risk of SAB RR: 1.90 (95% Ci 1.20; 3.00)

Dlugosz et al, 199655 US Cohort N=2,849 pregnant American women recruited from private clinics Cases: 135

Multiple/ coffee

Yes Yes Maternal age, gestational age at the interview, cigarette smoking, and alcoholic beverage consumption (also adjusted for tea and soda intake when reporting results on coffee intake)

women with a coffee intake of >3 cups/day had an increased risk of SAB OR: 2.63 (95% Ci 1.29; 5.34)

Zhang and Bracken, 199667

US Cohort N=2,849 pregnant American women recruited from private clinics Cases: 135

Coffee No No No women consuming ≥3 cups of coffee/day during the first month of pregnancy had an increased risk of SAB RR: 2.45 (95% Ci 1.38; 4.35)

Agnesi et al, 199757 italy Case– control

N=216 Cases: 108 italian women with clinically recognized SAB Controls: 108 women admitted for normal delivery; matched by age, year, and residence

Coffee Yes Yes Gravidity, previous abortions, level of education, smoking habits, consumption of alcohol, medicines and marital status, solvent exposure

women with a coffee intake had an increased risk of SAB RR: 1.36 (95% Ci 1.06; 1.76)

Fenster et al, 199752 US Cohort N=5,142 pregnant American women enrolled from three private facilities Cases: 498

Parazzini et al, 199863 italy Case– control

N=2,325 Cases: 782 italian women admitted for SAB within the first 12 weeks of gestation Controls: 1,543 women who gave birth at term (>37 weeks of gestation)

Coffee Yes Yes Age, education, previous live births, and SAB, maternal alcohol consumption and smoking in the first trimester, nausea intensity in the first trimester of pregnancy

Cnattingius et al, 200032

Sweden Case– control

N=1,515 Cases: 562 Swedish women admitted with SAB within 6–12 weeks of gestation Controls: 953 pregnant women, frequency- matched on weeks of gestation and area of residence

Multiple Yes Yes Smoking status, age, number of previous pregnancies, history of SAB, consumption of alcohol during pregnancy (yes/no), presence or absence of nausea, vomiting, and fatigue

wen et al, 200168 US Cohort N=550 American women planning to become pregnant and who had not been trying for more than 3 months at enrolment Cases: 70

(Continued)

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Author and year Country Design Study groups included in the analyses Source of caffeine

Controls for maternal age

Controls for other important covariates

Confounding factors Main results Total NOS score

Giannelli et al, 200358 UK Case– control

N=469 Cases: 159 nulliparous English women with a clinically recognized miscarriage Controls: 310 nulliparous pregnant women, without a SAB in 1st and 2nd trimesters

Multiple Yes No Maternal age, nausea in pregnancy, and gestational age

women with a caffeine intake of 301–500 and >500 mg/day during pregnancy had an increased risk of miscarriage OR: 1.94 (95% Ci 1.04; 3.63) and OR: 2.18 (95% Ci 1.08; 4.40). women with a coffee intake of 107–321 and >321 mg/day during pregnancy had an increased risk of miscarriage OR: 2.19 (95% Ci 1.31; 3.64) and OR: 2.31 (95% Ci 1.21; 4.41)

Rasch, 200377 Denmark Case– control

N=1,459 Cases: 320 Danish women with an SAB in gestational week 6–16 Controls: 1,139 pregnant women with a live fetus at gestational week 6–16

Multiple Yes Yes Age, parity, occupation, cigarette smoking, and alcohol consumption

women with a caffeine intake of ≥375 mg/day had an increased risk of SAB OR: 2.21 (95% Ci 1.53; 3.18)

Tolstrup et al, 200369 Denmark Case– control

N=1,712 Cases: 303 Danish women who reported an SAB or registered with a diagnosis of SAB Controls: 1,409 women reporting giving birth or being pregnant for >28 weeks

Multiple Yes Yes Maternal age, marital status, smoking, and alcohol intake

A tendency of increased risk for SAB with total caffeine intake of >900 mg/day OR: 1.72 (95% Ci 1.00; 2.96) No interaction between caffeine and smoking

Khoury et al, 200435 US Cohort N=191 pregnant American women with type 1 diabetes planning a pregnancy or enrolled after conception Cases: 23

Multiple Yes No Maternal age, years since diagnosis of diabetes, previous SAB, nephropathy and retinopathy, glycemic control, and cigarette smoking

Women who consumed caffeine early in the first trimester had an increased risk of SAB 4.50 (95% Ci 1.20; 16.80) compared to women not consuming caffeine

Bech et al, 200521 Denmark Cohort N=86,282 pregnant Danish women recruited by their GP Cases: 616

Coffee Yes Yes Age, parity, smoking, prepregnancy BMi, alcohol consumption, and socio- occupational status

women with a coffee intake of ≥8 cups/day had an increased risk of fetal death (gestation length <140 days) HR: 1.48 (95% Ci 1.01; 2.17)

Sata et al, 200570 Japan Case– control

N=205 Cases: 58 Japanese women with a history of recurrent pregnancy loss Controls: 147 fertile women whose pregnancies ended in live births

Multiple Yes No Age and smoking status during pregnancy No statistical significant increased risk of RPL with a caffeine intake of ≥300 mg/day during pregnancy when compared to women with a caffeine intake of 0–99 mg/day OR: 1.82 (95% Ci 0.72; 4.58) women with homozygous CYP1A2*1F alleles had an increased risk of RPL with a caffeine intake of ≥300 mg/day OR: 5.23 (95% Ci 1.05; 25.90)

George et al, 200659 Sweden Case– control

N=691 Cases: 108 Swedish women admitted with two or more consecutive miscarriages Controls: 583 pregnant women with at least two pregnancies, frequency-matched on weeks of gestation and area of residence

Multiple Yes Yes Maternal age, obstetric history, induced abortions, myoma, time to concieve, marital status, smoking, alcohol intake during pregnancy, amd plasma folate levels

No statistical significant increased risk of RPL with a caffeine intake of ≥300 mg/day during pregnancy OR: 1.80 (95% Ci 0.80; 2.90) Nonsmokers had an increased risk of RPL with a caffeine intake of ≥300 mg/day OR: 2.70 (95% Ci 1.10; 6.20)

Maconochie et al, 200764

UK Case– control

N=6,167 Cases: 546 English women whose most recent pregnancy had ended in first trimester miscarriage (<13 weeks of gestation) or who had a miscarriage since 1995 Controls: N=5,621 women whose most recent pregnancy progressed beyond 13 weeks of gestation

Multiple Yes No Year of conception, maternal age at conception, pregnancy order, history of miscarriage, history of live birth (further adjusted for nausea in one analysis)

women consuming 301–500 and >500 mg caffeine/day had an increased risk of miscarriage OR: 1.51 (95% Ci 1.06; 2.17) and OR: 1.70 (95% Ci 1.19; 2.43)

Savitz et al, 200871 US Cohort N=2,370 pregnant American women enrolled before 12 weeks of gestation and who had not been trying to conceive for >6 months Cases: 258

Multiple/ coffee

Yes Yes Maternal age, race/etnicity, maternal education, marital status, alcohol use, vitamin use and symptoms of nausea, and vomiting during early pregnancy

No increased risk of SAB with a prepregnancy coffee intake of >696 mg/day OR: 0.90 (95% Ci 0.50; 1.50) or total caffeine intake of >513.2 mg/day OR: 0.80 (95% Ci 0.50; 1.20) No increased risk of SAB with a coffee intake of >372.9 mg/day at the time of the telephone interview OR: 0.70 (95% Ci 0.30; 1.80) or total caffeine intake of >273.2 mg/day OR: 1.30 (95% Ci 0.90; 1.19)

Table 2 (Continued)

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