PROFESSOR ULRIK SCHIØLER KESMODEL (Orcid ID : 0000-0003-3868-106X)

DR MARIE HARGREAVE (Orcid ID : 0000-0001-6821-9242)

Accepted Article
Article type : Original Research Article

Coffee, tea and caffeine consumption and risk of primary infertility in women: a Danish
cohort study

Running title: Coffee, tea and caffeine use and infertility

Lív í Soylu1, Allan Jensen1, Kirsten Egebjerg Juul1, Ulrik S. Kesmodel2, Kirsten
Frederiksen3, Susanne K. Kjaer1,4& Marie Hargreave1

1
Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen,
2
Department of Obstetrics and Gynecology, Herlev Hospital, Herlev, 3Statistics,
Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen,
4
Department of Gynaecology, Rigshospitalet University Hospital, Copenhagen, Denmark

Corresponding author:
Marie Hargreave
Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden
49, 2100, Copenhagen, Denmark
E-mail: mariehar@cancer.dk
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1111/aogs.13307
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 Declaration of interest
The authors report no conflict of interest. The authors alone are responsible for the content
Accepted Article
and writing of the paper.

Abstract

Introduction: The aim of this study was to investigate whether consumption of coffee, tea
and caffeine affects the risk of primary infertility in women. Material and methods: We
selected nulliparous Danish women aged 20–29 years from a prospective cohort and
retrieved information on coffee and tea consumption from a questionnaire and an
interview at enrollment. We assessed the women’s fertility by linkage to the Danish
Infertility Cohort and retrieved information on children and vital status from the Civil
Registration System. All 7574 women included for analysis were followed for primary
infertility from the date of enrollment (1991–1993) until 31 December 2010. Analyses
were performed with Cox proportional hazard models. Results: During follow-up, primary
infertility was diagnosed in 822 women. Compared to never consumers, the risk of
primary infertility among women who drank coffee or tea was not affected. The risk of
primary infertility was neither associated with an increasing number of daily servings of
coffee (hazard ratio 1.00; 95% confidence interval (CI), 0.97–1.03) or tea (hazard ratio
1.01; 95% CI, 0.99–1.03) in consumers only. Concerning total caffeine consumption (from
coffee and tea), the risk of infertility was similar among consumers compared to never
consumers. Finally, each additional daily 100 mg of caffeine did not affect the risk among
consumers only (hazard ratio 1.00; 95% CI, 0.98–1.02). Conclusions: In this population-
based cohort study, not restricted to women seeking pregnancy, we found no association
between coffee, tea or total caffeine consumption and the risk of primary infertility in
women.

Key words
infertility; caffeine; coffee; tea; population-based

Abbreviations
CI, confidence interval

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 Key message
In this large Danish cohort study, the risk of primary infertility in women was not
associated with consumption of coffee, tea or total caffeine.
Accepted Article
Introduction

It has been suggested that drinking caffeine-containing beverages, including coffee and
tea, affects the risk for female infertility (1). Coffee and tea are widely consumed
worldwide; in Denmark, 80% of the population aged 15–75 years drinks coffee regularly,
with an average consumption of three to four cups a day (2). No clear mechanism for a
putative effect of coffee or tea on female fertility has been proposed, but caffeine has been
suggested to adversely affect ovulation (1). In contrast, caffeine has been associated with
increased insulin sensitivity (3), which has been shown to improve ovulatory function in
women with polycystic ovary syndrome, one of the leading causes of poor fertility (4).
Even if small effects of coffee and tea on female fertility exist, it may have large public
health implications due to the widespread use of these beverages.

The first epidemiological study on female fertility and caffeine consumption, published in
1988, showed that women who consumed a quantity of caffeine equivalent to more than
one cup of coffee a day were half as likely to become pregnant per ovulation cycle than
women who consumed less (5). Although other studies on this subject were published
subsequently, the results are inconclusive. Many studies showed a detrimental effect of
either coffee, tea or total caffeine consumption on female fertility (5-15), while others
showed no association (16-21) or a beneficial effect (22-25). One reason for the
inconsistency of the results may be the limited statistical power of most studies.
Furthermore, most of the studies were of women who were aware of their poor fertility or
who were trying to conceive and reported their caffeine consumption retrospectively. Such
studies are subject to recall and other types of bias, and their design makes it difficult to
estimate long-term effects.

Using two population-based Danish cohorts, we here perform a large cohort study to
further clarify the association between coffee, tea and caffeine consumption and primary
infertility (i.e. infertility with no previous live birth). Information on coffee and tea

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 consumption was obtained prospectively, thus eliminating the risk for recall bias, and
detailed information on lifestyle factors made it possible to account for several potential
confounders. Finally, the women were followed for up to 20 years, which gave us a unique
Accepted Article
opportunity to investigate any effect of coffee, tea and caffeine consumption on the
fertility of women followed virtually throughout their fertile period.

Material and methods

Study population
The study population was based on women in a Danish prospective cohort initially
designed to examine the association between human papillomavirus and cervical
neoplasia. This cohort comprised 11 088 young women (aged 20–29 years) randomly
selected from the general female population living in the Greater Copenhagen area
through the Danish Civil Registration System and enrolled in the period May 1991 to
January 1993. During enrollment, the women filled in a detailed food-frequency
questionnaire and responded to a structured interview on lifestyle. The procedures for
enrollment and data collection are described in more detail elsewhere (26). For the present
study, we excluded women with an invalid personal identification number or a missing
enrollment date, women who were parous or pregnant at the time of enrollment or had had
a hysterectomy or oophorectomy prior to enrollment and women who failed to return the
food-frequency questionnaire or for whom information on tea or coffee consumption or
preselected potential confounders was missing, leaving 7646 nulliparous women in the
study population (Figure 1).

Assessment of coffee, tea and caffeine consumption

In the food-frequency questionnaire, consumption of coffee and tea was recorded as
typical consumption of specific numbers of cups and mugs of each beverage in 12
predefined response categories, from “never” to “8 or more a day”. For the analyses, we
defined a cup as containing 150 ml and a mug as containing 250 ml, and we defined “a
serving” of each beverage as 200 ml. To assess total caffeine consumption from both
coffee and tea, we used a standardized measure of the caffeine content of coffee and tea
recently applied in a Danish study by Gosvig et al. (27). Based on information from the
Danish Veterinary and Food Administration, Gosvig et al. (27) estimated the caffeine
content of a 200-ml serving of coffee to be 132 mg and that of a 200-ml serving of tea to

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 be 52 mg. The total daily consumption of caffeine was calculated as the sum of those from
both coffee and tea.
Accepted Article
Follow-up for infertility
Since 1968, all residents of Denmark have been assigned a personal identification number,
which contains date of birth and sex and is used in all Danish registries. To assess
infertility in the study population, we used the personal identification numbers to link the
study population to the Danish Infertility Cohort, which contains data on all women
referred to public hospitals or private fertility clinics for infertility in the period 1963–
1998, all women with a recorded diagnosis of infertility (codes 628 and N97, excluding
N97.4: female infertility due to male factor, International Classification of Disease 8th and
10th revisions, respectively) in the National Patient Registry in the period 1977–2012 and
all women with recorded female infertility in the Danish IVF Registry (which contains
mandated information on all treatment for infertility in public and private clinics in
Denmark since 1994) between 1994 and 2011. At present, the Danish Infertility Cohort
comprises 131 692 women in whom infertility was diagnosed between 1 September 1963
and 31 December 2012. The cohort is described in further detail elsewhere (28). All
women with a diagnosis of infertility prior to the enrollment date were excluded (n = 72),
leaving 7574 women in the study population for analysis (Figure 1). The women were
followed from the date of enrollment until a diagnosis of infertility (n = 822) or censoring,
whichever came first. Censoring was performed on the date of emigration (n = 238), date
of death (n = 22), date of disappearance (n = 1), date of conception (n = 5375) or 31
December 2010 (n = 1116). Vital status (emigration, death or disappearance) and date of
giving birth were retrieved from the Civil Registration System. The date of the last
menstrual period was estimated by extracting the mean gestational age (280 days) from the
child’s date of birth. In the present study, women registered in the Danish Infertility
Cohort were considered infertile, and women not registered in the Cohort were considered
to be fertile.

Statistical analyses
We used a Cox proportional hazard model to estimate hazard ratios and corresponding
95% confidence intervals (CIs) for associations between coffee, tea and caffeine
consumption and a diagnosis of primary infertility. Age was used as the underlying time
scale, and women were entered according to their age at enrollment. We categorized daily

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 servings of coffee and tea consumption into four levels (never, ≤ 1 serving/day, 2–4
servings/day or ≥ 5 servings/day). Daily caffeine consumption was categorized into
quartiles on the basis of the distribution in the study population (Q1 = 1–168; Q2 = 169–
Accepted Article
333; Q3 = 334–579; and Q4 ≥ 580 mg of caffeine/day); “never consumers” were
categorized in a separate group. We analysed the association between coffee, tea and total
caffeine consumption and primary infertility in women as the number of servings or mg
caffeine per day (in the predefined categories) as compared with no consumption and as
the risk accrued by each additional daily serving or additional 100 mg/day caffeine per day
among consumers only.

In all analyses, we adjusted for educational level (≤ 9, 10–11 or ≥ 12 years of schooling),

smoking (yes or no), marital status (married/cohabiting or single), number of alcohol-
containing drinks per week and year of birth. These potential confounding factors were
derived from the current literature and were included in all models a priori. The
quantitative variables (number of alcohol-containing drinks per week and year of birth)
were included as restricted cubic splines and tested for linearity in a joint Wald test. The
proportional hazard assumption was tested with Schoenfeld residuals and was fulfilled for
all models. All statistical analyses were performed with the stset procedure in the
Stata/MP software package (version 11.2; StataCorp LP, College Station, TX, USA).

Ethical approval
The study was approved by the Danish Data Protection Agency (j. nr. 2012–41–0274, 15
January, 2012 and j. nr. 2012–41–0770, 7 September 2015).

Results

The median follow-up time for the 7574 women in the study population was 5.8 years
(range, 0–19.6 years), resulting in 57 051 person-years of observation. During follow-up,
primary infertility was diagnosed in 822 (11%) women, of whom 610 (74%) reported
drinking coffee and 758 (92%) reported drinking tea. Of the fertile women (n = 6752),
5202 (77%) reported drinking coffee, and 6276 (93%) reported drinking tea.

The baseline characteristics of the women differed slightly according to coffee and tea
consumption patterns (Table 1). Women who drank coffee (> 0 servings/day) were

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 generally older at enrollment, had a higher intake of alcohol, were more likely to smoke
and had a higher educational level than women who never drank coffee. Women who
drank tea (> 0 servings/day) were slightly younger at enrollment, drank more alcohol,
Accepted Article
were less likely to smoke, had a higher educational level and were more likely to be single
than women who never drank tea.

Table 2 shows the relative risks of women for primary infertility according to their coffee,
tea and caffeine consumption. Overall, we found no association between coffee, tea and
caffeine consumption and primary infertility in women. As compared with women who
never drank coffee, women in all categories of daily coffee consumption (≤ 1, 2–4 and ≥ 5
servings/day) had a lower but statistically nonsignificant risk for primary infertility. In
addition, the risk of primary infertility was not affected by an increasing number of daily
coffee servings in consumers only (hazard ratio 1.00; 95% CI, 0.97–1.03). The risk of
women who drank tea was higher, although not statistically significantly, for all categories
of daily servings (≤ 1, 2–4 and ≥ 5 servings/day) as compared with women who did not
drink tea. Furthermore, an increasing number of tea servings per day, among consumers
only, did not affect the risk of primary infertility (hazard ratio 1.01; 95% CI, 0.99–1.03).
Women in all categories of daily caffeine consumption (1–168, 169–333, 334–579 and ≥
580 mg/day) had a statistically nonsignificantly lower risk for primary infertility than
women who did not consume caffeine. Finally, each additional 100 mg of caffeine
consumed per day did not affect the risk for primary infertility among consumers only
(hazard ratio 1.00; 95% CI, 0.98–1.02).

Discussion

In this large population-based cohort study of 7574 Danish women, we observed no

association between the risk for primary infertility and consumption of coffee, tea and
total caffeine.

Several other studies showed associations between decreased fertility and coffee or total
caffeine consumption (5-8, 10-15). For example, in a North American case–control study
with 4883 women in 1993, Grodstein et al. (10) found that caffeine consumption increased
their risk for infertility due to tubal disease or endometriosis. A beneficial effect of coffee
and caffeine consumption on female fertility has also been shown (22, 23). In line with our

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 results, however, a number of other studies have shown no association between coffee and
total caffeine consumption and female fertility (9, 16, 17, 19-21, 24, 25). Thus, the results
of a large cohort study of 18 555 women in North America followed from 1991 to 1999
Accepted Article
showed no association between the consumption of coffee and total caffeine (from coffee,
tea and caffeinated soft drinks) and the risk for ovulatory disorders (21). Three cohort
studies on tea consumption showed a protective effect on female fertility (22, 24, 25),
while three other cohort studies indicated an increased risk for delayed conception among
women who drank tea (6, 7, 9). Nonetheless, in agreement with our results, the majority of
studies on tea consumption and fertility showed no association (8, 11, 16, 18, 21, 23).

Our study has several strengths, one of which is the size (n = 7574), which makes it one of
the largest population-based cohort studies to date on the association between coffee, tea
and caffeine consumption and the risk of women for primary infertility. Unlike most other
published studies, which are based on self-reported information on fertility, we had access
to information on fertility from a nationwide registry. Furthermore, information on coffee
and tea consumption was obtained at enrollment, eliminating the risk for recall bias. The
availability of information on vital status and emigration minimized loss to follow-up,
population-based data increased the generalizability of the study and detailed information
on the women’s lifestyle made it possible to adjust for several potential confounders.
Finally, the long follow-up period of up to 20 years gave us the opportunity to follow the
women almost throughout their fertile years (median age at end of follow-up: 44 years;
range 38–49).

The difference between our findings and those of several previous studies that reported an
increased risk for fertility problems associated with coffee and caffeine consumption may
have several explanations. First, in the vast majority of previous studies, female infertility
was measured as the chance of conceiving per menstrual cycle over 12 months. We did
not have information on pregnancy wish or the number of cycles that the women had been
trying to conceive, but used a diagnosis of infertility, which may reflect more severe forms
of infertility. Secondly, we had no information on the consumption of other caffeinated
beverages and foods (e.g. soft drinks and chocolate). Consequently, although coffee and
tea are the two main sources of caffeine in Denmark (29), we may have slightly
underestimated total caffeine. Thirdly, in contrast to our study, several other studies
recorded consumption of caffeinated beverages at the same time as fertility status. This

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 might result not only in recall bias but also reverse causality, as it is reasonable to assume
that women who are unsuccessful in becoming pregnant change their behavior
accordingly, hence making it difficult to determine any time–cause relation. Fourthly,
Accepted Article
although we adjusted for several potential confounders such as smoking and educational
level, we did not adjust for body mass index, as this information was available for only a
subset of women (~70%) in the study population. A sub-analysis of women for whom
information on body mass index was available did not, however, markedly change our
results (data not shown). Fifthly, as a number of nulliparous women were initially
excluded from the study, mainly because of missing information (n=1567), our results
may be somewhat affected by selection bias. Such bias would, however, be of limited
importance, as the women who were excluded did not differ systematically according to
rate of infertility, age at enrollment, year of birth, year of enrollment, alcohol consumption
or marital status from the main cohort, although they did differ slightly by smoking status
and educational level (data not shown). Furthermore, the number of women who were
followed to the end of follow-up without either infertility or pregnancy might include
women who were not aspiring to be pregnant and thus at lower risk for a diagnosis of
infertility; however, a sensitivity analysis only of women with diagnosed infertility and
women who became pregnant during follow-up gave similar risk estimates (data not
shown). Sixthly, consumption of coffee and tea was recorded only at the time of
enrollment (1991–1993). As drinking habits may change over time, this initial
measurement may not adequately reflect consumption at the time of diagnosis of
infertility. It has been shown, however, that the majority of women who begin drinking
coffee at around the age of 20 continue their daily intake (30); therefore, we consider the
early measure an adequate indicator of later consumption. Finally, we had no information
on the specific type of coffee or tea consumed or the brewing methods used. As the vast
majority of tea sold in Denmark in the mid- to early 1990s was black tea, and the standard
coffee-brewing method was drip or filtered, our results may be generalizable only to these
types.

In conclusion, in this population-based cohort study (i.e. not restricted to women seeking
pregnancy), we found no evidence that coffee, tea or total caffeine consumption affects the
risk of Danish women for primary infertility. This finding is reassuring, as even small
effects of coffee and tea on female fertility could have a large health impact because of the
widespread consumption of these beverages.

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 Funding
The project was supported by funding from Rigshospitalet, Copenhagen University
Accepted Article
Hospital.

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LEGENDS

Figure 1. Identification of the study population.

Table 1. Baseline characteristics of the study population (n=7574) according to coffee and
tea consumption.

Table 2. Coffee, tea and caffeine consumption and the risk of infertility.

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ccepted Articl
TABLE 1. Baseline characteristics of the study population (n = 7574) according to coffee and tea consumption

Coffee consumption Tea consumption

Never ≤1 serving/day 2–4 servings/day ≥5 servings/day Never ≤1 serving/day 2–4 servings/day ≥5 servings/day

n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

175 (100 166 (100 258 (100 (100 275 (100 247 180
(100) 1568 540 (100) (100)
Total consumption 8 ) 1 ) 7 ) ) 5 ) 7 2
Age at enrollment
104
855 (49) 720 (43) 856 (33) 422 (27) 186 (34) (38) 984 (40) 642 (36)
20–23 1
24–26 559 (32) 571 (34) 897 (35) 569 (36) 187 (35) 967 (35) 826 (33) 616 (34)
27–30a 344 (20) 370 (22) 834 (32) 577 (37) 167 (31) 747 (27) 667 (27) 544 (30)
Mean 23.8 24.1 24.9 25.3 24.8 24.5 24.4 24.7
Year of birth
1961–1964 301 (17) 335 (20) 751 (29) 523 (33) 154 (28) 677 (25) 589 (24) 490 (27)
119 125 111
765 (44) 736 (44) (46) 732 (47) 235 (44) (46) (45) 822 (46)
1965–1968 4 5 5
1969–1972 692 (39) 590 (36) 642 (25) 313 (20) 151 (28) 823 (30) 773 (31) 490 (27)
196 196 196 196 196 196 196
1966
Median 8 7 6 6 7 7 7
Alcohol consumption

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ccepted Articl 156
≤7 drinks per week 3
(89)
138
0
(83)
195
8
(76) 1161 (74) 448 (83)
219
9
(80)
198
9
(80)
142
6
(79)

>7 drinks per week 195 (11) 281 (17) 629 (24) 407 (26) 92 (17) 556 (20) 488 (20) 376 (21)
Median 1.9 3.5 4.3 4.0 2.3 3.6 3.6 3.9
Smoking
117 115 139 142 150 113
(67) (70) (54) 591 (38) 246 (46) (52) (61) (63)
No 6 5 1 2 2 1
120 133
584 (33) 508 (31) (47) 988 (63) 294 (54) (48) 975 (39) 671 (37)
Yes 8 3
Educational level
≤9 years 113 (6) 60 (4) 99 (4) 77 (5) 39 (7) 139 (5) 110 (4) 61 (3)
10–11 years 462 (26) 293 (18) 434 (17) 376 (24) 170 (31) 645 (23) 421 (17) 329 (18)
118 130 205 197 194 141
(67) (79) (79) 1115 (71) 331 (61) (72) (79) (78)
≥12 years 3 8 4 1 6 2
Marital status
144 151 136
944 (54) 882 (53) (56) 873 (56) 268 (50) (55) (55) 993 (55)
Single 1 1 8
114 124 110
814 (46) 779 (47) (44) 695 (44) 272 (50) (45) (45) 809 (45)
Married/cohabiting 6 4 9
Does not sum up to 100% since rounding is used. One serving contains 200 ml.
a
Sixty nine women turned thirty years of age prior to enrollment

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ccepted Articl
TABLE 2. Coffee, tea and caffeine consumption and the risk of infertility

No. of women diagnosed

No. of women HRa (95% CI)
with infertility

Total 7574 822

Coffee (servings/day)
Never 1758 212 1.00 –

≤1 1661 171 0.86 (0.70–1.06)

2–4 2587 269 0.88 (0.73–1.06)
≥5 1568 170 0.89 (0.72–1.10)
Per daily serving in consumers only 7574 822 1.00b (0.97–1.03)
Tea (servings/day)
Never 540 64 1.00 –
≤1 2755 303 1.10 (0.84–1.44)
2–4 2477 260 1.10 (0.84–1.46)
≥5 1802 195 1.15 (0.87–1.53)
Per daily serving in consumers only 7574 822 1.01b (0.99–1.03)
Caffeine (mg/day)c
Never 134 19 1.00 –

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ccepted Articl Q1 (1–168)
Q2 (169–333)
1625
1558
183
155
0.93
0.91
(0.58–1.49)
(0.57–1.47)
Q3 (334–579) 2188 237 0.97 (0.60–1.55)
Q4 (≥580) 2069 228 0.93 (0.58–1.50)
Per daily 100 mg in consumers only 7574 822 1.00b (0.98–1.02)
One serving contains 200 ml.
a
Adjusted for educational level (≤9, 10–11 or ≥12 years of schooling), smoking (yes or no), marital status (married/cohabiting or single), weekly alcohol intake and year of birth
b
Further adjusted for never consumption (never/ever)
c
Total caffeine calculated from consumption of both coffee and tea

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 Figure. 1. Identification of the study population

The Danish Human Papilloma Virus Cohort

Accepted Article
11 088 women aged 20 to 29 enrolled in 1991–1993

- Invalid personal identification number (30)

3442 women excluded due to
- Missing date of enrollment (5)
- Pregnant or parous at enrollment (1817)
- Hysterectomy or oophorectomy prior to enrollment (58)
- Failed to return food-frequency questionnaire (1459)
- Missing information on coffee or tea (54)
- Missing information on preselected confounders (19)

The Danish Infertility Cohort

7646 nulliparous women
Infertility in Denmark in 1963–2012

72 women diagnosed with infertility prior to enrollment

7574 nulliparous women

without a history of infertility

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