American Journal of Epidemiology Vol. 155, No.

3
Copyright © 2002 by the Johns Hopkins Bloomberg School of Public Health Printed in U.S.A.
All rights reserved

Infertility and Ovarian Cancer Ness et al.

Infertility, Fertility Drugs, and Ovarian Cancer: A Pooled Analysis of Case-
Control Studies

Roberta B. Ness,1 Daniel W. Cramer,2 Marc T. Goodman,3 Susanne Krûger Kjaer,4 Kathy Mallin,5 Berit Jul
Mosgaard,6 David M. Purdie,7 Harvey A. Risch,8 Ronald Vergona,1 and Anna H. Wu9

Downloaded from https://academic.oup.com/aje/article-abstract/155/3/217/63390 by guest on 31 August 2019

Controversy surrounds the relations among infertility, fertility drug use, and the risk of ovarian cancer. The
authors pooled interview data on infertility and fertility drug use from eight case-control studies conducted
between 1989 and 1999 in the United States, Denmark, Canada, and Australia. Odds ratios and 95% confidence
intervals were calculated, adjusting for age, race, family history of ovarian cancer, duration of oral contraception
use, tubal ligation, gravidity, education, and site. Included in the analysis were 5,207 cases and 7,705 controls.
Among nulligravid women, attempts for more than 5 years to become pregnant compared with attempts for less
than 1 year increased the risk of ovarian cancer 2.67-fold (95% confidence interval (CI): 1.91, 3.74). Among
nulliparous, subfertile women, neither any fertility drug use (odds ratio (OR) = 1.60, 95% CI: 0.90, 2.87) nor more
than 12 months of use (OR = 1.54, 95% CI: 0.45, 5.27) was associated with ovarian cancer. Fertility drug use
in nulligravid women was associated with borderline serous tumors (OR = 2.43, 95% CI: 1.01, 5.88) but not with
any invasive histologic subtypes. Endometriosis (OR = 1.73, 95% CI: 1.10, 2.71) and unknown cause of infertility
(OR = 1.19, 95% CI: 1.00, 1.40) increased cancer risk. These data suggest a role for specific biologic causes of
infertility, but not for fertility drugs in overall risk for ovarian cancer. Am J Epidemiol 2002;155:217–24.

fertility agents, female; infertility; ovarian neoplasms

Considerable public attention and patient anxiety during
the past decade have focused on the possible link between
fertility drugs and ovarian cancer risk. Some studies sug-
gested that women who took fertility drugs, yet did not
become pregnant, as well as women with longer durations of
fertility drug exposure, are at substantially elevated risk of
ovarian cancer (1, 2). However, results from other studies
have not been consistent, even among potentially high-risk
subgroups of women with high lifetime exposures to fertil-
ity drugs (3–10).
Interpretation of an association between fertility drugs
and ovarian cancer is complicated by the fact that infertility
Received for publication December 6, 2000, and accepted for
publication July 31, 2001.
Abbreviations: CI, confidence interval; OR, odds ratio.
1
University of Pittsburgh School of Public Health, Pittsburgh, PA.
2
Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA.
3
Cancer Research Center, University of Hawaii, Honolulu, HI.
4
Danish Cancer Society, Institute of Cancer Epidemiology,
Copenhagen, Denmark.
5 University of Illinois at Chicago, Chicago, IL.
6
Department of Obstetrics and Gynecology, Herlev Hospital,
University of Copenhagen, Copenhagen, Denmark.
7
Queensland Institute of Medical Research, Royal Brisbane
Hospital, Queensland, Australia.
8
Yale University School of Medicine, New Haven, CT.
9
University of Southern California, Los Angeles, CA.
Reprint requests to Dr. Roberta B. Ness, University of Pittsburgh,
130 DeSoto Street, 517 Parran Hall, Pittsburgh, PA 15261 (e-mail:
repro@vms.cis.pitt.edu).
may elevate ovarian cancer risk (1–3, 6–9, 11–16).
Infertility is a heterogeneous end product of a number of
biologically distinct conditions. There have been several
attempts to segregate infertility by type and to examine each
infertility type separately as it relates to ovarian cancer risk.
These studies have been inconclusive, with some showing
an association to ovarian cancer and ovulatory infertility (2,
16) and some to infertility of unknown cause (3, 7).
The increasing use of fertility drugs in many countries
suggests an emerging need to separate an association of
infertility with ovarian cancer from that of infertility treat-
ment. Key obstacles to studying this question include the
rarity of the disease and the relatively infrequent prescrip-
tion of ovulation-inducing drugs.
We report the results of an international pooled analysis
of infertility and fertility drug use in eight ovarian cancer
case-control investigations. Our analysis included a large
sample of subjects in which to 1) determine whether specific
infertility diagnoses were associated with ovarian cancer
and 2) examine whether, among women with subfertility,
fertility drugs elevated ovarian cancer risk.
MATERIALS AND METHODS
Data collection
Table 1 summarizes the characteristics of the eight case-
control studies included in this analysis. All of the studies
were conducted between 1989 and 1999, and each used pop-
ulation-based case and control selection. Four studies were

217
218 Ness et al.

TABLE 1. Study sites and their characteristics included in the pooled analysis of eight case-control studies, 1989–1999
Cases Controls Age
Authors Period of Case Control Matching
Location % % range
(reference no.) ascertainment selection selection No. No. parameters
recruited recruited (years)

Cramer et al. (18) Massachusetts and 1992–1997 Treatment Random digit 563 70 523 72 17–75 Individual age,
New Hampshire centers dialing and residence
town lists

Mallin et al.* Cook County, Illinois 1994–1998 Hospitals Random digit, 351 39 501 50 18–74 Frequency age,
HCFA† for race
≥64 years

Goodman et al. Hawaii and Los 1993–1999 SEER† Population 606 66 613 75‡ 18–87 Frequency age,
(17) Angeles County, registries register, 65 72§ race, and
California HCFA files location

Downloaded from https://academic.oup.com/aje/article-abstract/155/3/217/63390 by guest on 31 August 2019

(Hawaii, Los
Angeles)

Kjaer et al.* Denmark, selected 1995–1999 Hospitals Population 764 85 1,562 61 35–79 Frequency age
counties register

Mosgaard et al. Denmark 1989–1994 National Population 915 82 1,721 80 18–59 Individual age,
(8) register register residence

Ness et al. (19) Philadelphia, 1993–1998 Hospitals Random digit 767 88 1,367 72 20–69 Frequency age,
Pennsylvania dialing, residence
HCFA files

Purdie et al. (21) Australia 1990–1993 Treatment Population 793 90 855 73 16–79 Frequency age,
centers register urban/rural

Risch et al. (20) Ontario, Canada 1989–1992 Cancer Population 450 71 564 65 35–79 Frequency age
registry register

* Unpublished data.
† HCFA, Health Care Financing Administration; SEER, Surveillance, Epidemiology, and End Results.
‡ Percent recruited in Hawaii.
§ Percent recruited in Los Angeles, California.

conducted among women living on the mainland United
States (17–19) (one of which included women living in
Hawaii (17)), two were conducted in Denmark (8) (Kjaer et
al., Danish Cancer Society, unpublished data), one in Canada
(20), and one in Australia (21). Only one study separately
published an analysis of fertility drug use and ovarian can-
cer (8). Six additional studies were excluded from consider-
ation in this pooled analysis because they did not meet the
timing criteria of conduct on or after 1989 or did not collect
data on fertility drugs or both (five studies) or because they
had not completed data collection (one study). All data in
this report were analyzed in Pittsburgh, Pennsylvania, using
datasets stripped of individual identifiers.
Infertility and fertility drug use
Standardized in-person interviews were conducted in all
but one (8) of the studies. That study mailed self-administered
questionnaires. In four of the studies (17, 19) (Kjaer et al.,
Danish Cancer Society, and Mallin et al., University of
Illinois at Chicago, unpublished data) a modification of a sin-
gle questionnaire was used. This questionnaire based recall
for reproductive events on a “life” calendar approach in
which each woman marked a calendar with important events
during her life and used these to enhance her memory for
date-related information. The studies by Risch et al. (20) and
Purdie et al. (21) also used a life calendar as a memory aid.
Data were checked for internal consistency, and when neces-
sary, clarifications were requested from the investigators.
We requested that each study provide data on the follow-
ing independent variables in the following format: sought
medical attention for infertility (yes/no), infertility tests done
(partner/self/both/neither), infertility diagnosis (type), fertil-
ity drug use (duration), specific fertility drug used (duration),
and histology (cases only). Time spent attempting pregnancy
(continuous) was also obtained. In most studies, this had
been collapsed into a single variable encompassing cumula-
tive duration of trying over a lifetime.
Covariates
Each study also provided data on potentially important
covariates that we have previously found to be significantly
related to ovarian cancer risk (22): age (continuous), gra-
vidity (continuous), first-degree family history of ovarian
cancer (yes/no), race (Black, White, Hispanic, Asian,
other), educational attainment (less than high school, high
school, more than high school), tubal ligation (ever/never),
oral contraceptive use duration (continuous), and study
code (categorical).
Statistical analysis
Pooled odds ratios, with corresponding 95 percent confi-
dence intervals, were calculated as the primary measure of
effect size. Because most studies used frequency rather than
individual matching and matched on the basis of broad cri-
teria, such as age within 5- to 10-year intervals, we used

Am J Epidemiol Vol. 155, No. 3, 2002


unconditional logistic regression models to adjust for any
additional effects of age as well as for gravidity, race, edu-
cation, history of ovarian cancer in any first-degree relative,
tubal ligation, oral contraceptive use duration, and study, as
indicated above. We checked the reasonableness of pooling
estimates by calculating odds ratios within individual stud-
ies and calculating a Woolf test for heterogeneity among
studies for all major results (23). In none of the significant
associations between infertility type and ovarian cancer and
in none of the fertility drug and ovarian cancer analyses did
we find statistically significant heterogeneity among stud-
ies. We did find heterogeneity when comparing four or more
pregnancies with zero pregnancies and in comparing never-
pregnant women trying for less than 1 year to get pregnant
with those trying for more than 5 years. In both situations,
we provide the heterogeneity statistic and range of odds
ratios in Results.
In evaluating risk associated with fertility drugs, we
restricted analyses to women who had a history of 2 or more
years of trying to conceive over a lifetime and/or of seeking
medical attention for infertility. Both seeking infertility
treatment and prolonged episodes of trying to conceive
without success (typically for at least a 1-year period) are
standard markers of infertility. The term “subfertility” rather
than infertility is used here to describe women who tried to
conceive for 2 or more years and/or sought medical atten-
tion because our data on trying comprises a cumulative
period over a lifetime rather than the duration of a single
episode. Confining our analyses solely to care seekers might
have focused on an unrepresentative group of women with
enhanced access to health care and higher socioeconomic
status. Furthermore, preliminary analyses revealed that,
although almost all women using fertility drugs tried for 2 or
more years to get pregnant, 29.9 percent of the controls and
33.5 percent of the cases used fertility drugs yet did not
report seeking medical attention specifically for infertility.
One data set (Mallin et al., unpublished data) did not capture
length of pregnancy attempts, but instead asked about trying
for at least 1 year; that definition was used to identify sub-
fertility among those women. We analyzed use and duration
of use of fertility drugs in general and then duration of the
specific drugs clomiphene and human menopausal
gonadotrophin. Too few women reported exposure to other
specific drugs to present those results.
Logistic regression was used to explore the interaction of
infertility and fertility drug use by modeling each level of
interaction between the pairs of variables infertility (yes/no)
and fertility drug use (yes/no) using subjects who were fertile
and who never used fertility drugs as the reference category.
Although other variables were fairly readily combined
across studies, the variable for which categorization differed
most between studies was type of infertility. One study (8)
had no data on infertility types and, therefore, was not
included in these analyses. For other datasets, whenever
possible, we collapsed medically similar categories, but for
some categories we could not include datasets in which
information was unavailable. Datasets that were not
included in specific analyses were as follows: uterus devel-
opment problems (18, 21), menstruation problems (18), and
Am J Epidemiol Vol. 155, No. 3, 2002
Infertility and Ovarian Cancer 219
cervical mucous/inflamed cervix (21). We also defined a
group of women as having an unknown cause of infertility
by taking all women so designated in the data and adding
any women who had infertility tests, but did not report a
specific diagnosis. To account for multiple infertility diag-
noses, we limited the comparison group to women with no
infertility diagnosis and present analyses adjusted for stan-
dard confounders plus all types of infertility beyond the one
of interest.
Finally, for infertility types that appeared to elevate ovar-
ian cancer risk and for fertility drug use, we separately ana-
lyzed histologic subtypes, including borderline serous (n 
489), invasive serous (n  1,782); mucinous (n  773),
Downloaded from https://academic.oup.com/aje/article-abstract/155/3/217/63390 by guest on 31 August 2019
endometrioid and clear cell (n  985), and undifferentiated
and all other types (n  420).
RESULTS
Among the 7,705 controls, 10.2 percent were never preg-
nant, and among the 5,207 cases, 19.6 percent were never
pregnant. In adjusted analyses, women who had never been
pregnant were 2.42 times (95 percent confidence interval
(CI): 1.86, 3.14) as likely to have ovarian cancer as were
those with four or more pregnancies (table 2). Estimates of
this association were heterogeneous between studies (p <
0.005), with odds ratios ranging from 1.69 (95 percent CI:
1.25, 2.29) to 3.75 (95 percent CI: 2.80, 5.01). Seeking med-
ical attention for fertility problems was a modest risk factor
for ovarian cancer, with the same odds ratio, 1.2, among
ever pregnant and never pregnant women. Prolonged
episodes of trying also elevated ovarian cancer risk, partic-
ularly among never pregnant women, wherein trying for
more than 5 years versus less than 1 year without achieving
pregnancy elevated the risk of ovarian cancer 2.7-fold (95
percent CI: 1.91, 3.74). Estimates for more than 5 years ver-
sus less than 1 year of trying among nulligravid women
were also heterogeneous (p < 0.005), with odds ratios rang-
ing from 0.85 (95 percent CI: 0.28, 2.59) to 15.96 (95 per-
cent CI: 8.91, 28.60). In those trying for more than 5 years
who became pregnant, the risks were 1.20–1.39 times higher
than among women trying for less than 1 year and were not
significant.
Two types of infertility (table 3), endometriosis (odds
ratio (OR)  1.73, 95 percent CI: 1.10, 2.71) and unknown
cause of infertility (OR  1.19, 95 percent CI: 1.00, 1.43),
were independently associated with elevations in risk after
adjustment for standard confounding factors. Further adjust-
ment for each of the other types of infertility did not greatly
alter the strength of these associations (table 3); however,
with reduced power, only unknown cause of infertility con-
tinued to be significant.
Fertility drug use overall did not raise the risk of ovarian
cancer in adjusted analyses (table 4). Among the 2,397
women defined as subfertile (those who sought medical
attention for infertility or tried for at least 2 years to get
pregnant), 14.6 percent took fertility drugs. The odds ratio
of ovarian cancer for subfertile women ever taking these
medications versus not taking them was 0.97 (95 percent CI:
0.76, 1.25). Among never pregnant women, the risk for ever
220 Ness et al.

TABLE 2. Fertility measures among cases and controls, crude and adjusted odds ratios for ovarian cancer for eight case-control
studies, 1989–1999
Variable No. of cases No. of controls Crude OR* 95% CI† Adjusted OR 95% CI

No. of pregnancies
≥4 1,143 2,224 1.0 1.0
3 989 1,830 1.05 0.95, 1.17 1.13 0.98, 1.31
2 1,300 2,099 1.21 1.09, 1.33 1.37 1.15, 1.63
1 755 764 1.92 1.70, 2.18 2.11 1.68, 2.65
0 1,020 788 2.52 2.24, 2.83 2.42 1.86, 3.14

Sought medical attention‡

Never pregnant
No 696 583 1.0 1.0

Downloaded from https://academic.oup.com/aje/article-abstract/155/3/217/63390 by guest on 31 August 2019

Yes 175 121 1.21 0.94, 1.57 1.19 0.91, 1.55
Ever pregnant
No 3,262 5,741 1.0 1.0
Yes 493 710 1.22 1.08, 1.38 1.16 1.02, 1.31

Time spent trying to get

pregnant (years)§
Never pregnant
<1 412 423 1.0 1.0
1–2 23 14 1.68 0.86, 3.32 1.55 0.77, 3.13
>2–5 54 28 1.98 1.23, 3.19 2.03 1.24, 3.32
>5 156 69 2.32 1.70, 3.18 2.67 1.91, 3.74

One pregnancy (years)

<1 384 421 1.0 1.0
1–2 41 42 1.07 0.68, 1.68 1.03 0.65, 1.63
>2–5 44 41 1.18 0.75, 1.84 1.12 0.71, 1.78
>5 95 69 1.51 1.08, 2.12 1.39 0.98, 1.96

Two pregnancies (years)

<1 774 1,371 1.0 1.0
1–2 90 151 1.06 0.80, 1.39 1.09 0.82, 1.44
>2–5 81 117 1.23 0.91, 1.65 1.19 0.88, 1.61
>5 57 77 1.31 0.92, 1.87 1.20 0.84, 1.72

Three or more pregnancies

(years)
<1 1,274 2,429 1.0 1.0
1–2 130 272 0.91 0.73, 1.14 0.92 0.74, 1.15
>2–5 101 243 0.79 0.62, 1.01 0.79 0.62, 1.01
>5 69 101 1.30 0.95, 1.80 1.22 0.88, 1.68
* Odds ratios (OR) of 1.0 represent the referent categories. They are adjusted for age, gravidity, race, education, history of ovarian
cancer, tubal ligation, oral contraceptive use duration and research site.
† CI, confidence interval.
‡ Excludes Cramer et al. (18).
§ Excludes Cramer et al. (18) and Mallin et al. (unpublished data).

taking fertility drugs was elevated, but not significantly so
(OR  1.60, 95 percent CI: 0.90, 2.87), and among ever
pregnant women, the risk was less than 1.0 (OR  0.82, 95
percent CI: 0.62, 1.09). Further adjustment for each of the
types of infertility resulted in odds ratios of 1.75 (95 percent
CI: 0.73, 4.21) for nulligravid women and 0.69 (95 percent
CI: 0.48, 1.00) for gravid women. Longer duration (>12
months) of fertility drug exposure did not significantly ele-
vate ovarian cancer risk, even among nulligravid women
(OR  1.54, 95 percent CI: 0.45, 5.27), nor did longer dura-
tion of specific drugs (i.e., clomiphene or human
menopausal gonadotrophin) significantly elevate risk.
Separate results for histologic subtypes of ovarian cancers
did not reveal any additional associations, with the follow-
ing exceptions. Among nulligravid women, fertility drug use
was significantly associated with borderline serous tumors
(OR  2.43, 95 percent CI: 1.01, 5.88), but not with inva-
sive serous tumors (OR  1.11, 95 percent CI: 0.51, 2.42)
or with borderline or invasive mucinous tumors, endometri-
oid or clear cell tumors, or undifferentiated or other tumors.
Among gravid women, fertility drugs were not significantly
associated with any of these histologic types. Serous bor-
derline tumors were associated with ovarian cysts (OR 
3.75, 95 percent CI: 2.15, 6.51), uterine development prob-

Am J Epidemiol Vol. 155, No. 3, 2002

 Infertility and Ovarian Cancer 221

TABLE 3. Infertility types and ovarian cancer risk for eight case-control studies, 1989–1999
No. of No. of Crude 95% Adjusted 95% Adjusted 95%
Variable
cases controls OR* CI* OR† CI OR‡ CI

Low sperm count§

No 3,627 5,229 1.0 1.0 1.0
Yes 131 126 1.50 1.17, 1.92 1.30 0.99, 1.71 1.28 0.93, 1.75

Ovulation problems§
No 3,627 5,229 1.0 1.0 1.0
Yes 48 84 0.82 0.58, 1.18 0.80 0.54, 1.18 0.66 0.34, 1.26

Ovarian cysts§
No 3,627 5,229 1.0 1.0 1.0

Downloaded from https://academic.oup.com/aje/article-abstract/155/3/217/63390 by guest on 31 August 2019

Yes 69 73 1.36 0.98, 1.90 1.29 0.80, 2.07 1.92 0.83, 4.46

Blocked tubes§
No 3,627 5,229 1.0 1.0 1.0
Yes 84 95 1.28 0.95, 1.72 1.14 0.82, 1.59 1.04 0.67, 1.62

Uterine development problems¶

No 2,490 4,032 1.0 1.0 1.0
Yes 29 41 1.15 0.71, 1.85 1.06 0.63, 1.76 0.75 0.35, 1.63

Cervical mucous and/or

inflamed cervix#
No 2,977 4,483 1.0 1.0 1.0
Yes 23 40 0.87 0.52, 1.45 1.14 0.57, 2.26 0.83 0.25, 2.69

Menstrual problems**
No 3,140 4,778 1.0 1.0 1.0
Yes 81 122 1.01 0.76, 1.34 1.07 0.72, 1.59 1.08 0.55, 2.14

Endometriosis§
No 3,627 5,229 1.0 1.0 1.0
Yes 51 39 1.89 1.24, 2.87 1.73 1.10, 2.71 1.52 0.81, 2.83

Unknown cause of infertility§

No 3,627 5,229 1.0 1.0 1.0
Yes 294 285 1.49 1.26, 1.76 1.19 1.00, 1.43 1.22 1.01, 1.46
* OR, odds ratio; CI, confidence interval.
† Odds ratios were adjusted for age, gravidity, race, education, history of ovarian cancer, tubal ligation, duration of oral contraceptive use,
and research site.
‡ Odds ratios were adjusted for age, gravidity, race, education, history of ovarian cancer, tubal ligation, duration of oral contraceptive use,
and research site plus each other infertility type.
§ Excludes Mosgaard et al. (8).
¶ Excludes Mosgaard et al. (8), Cramer et al. (18), and Purdie et al (21).
# Excludes Mosgaard et al. (8) and Purdie et al. (21).
** Excludes Mosgaard et al. (8) and Cramer et al. (18).

lems (OR  2.73, 95 percent CI: 1.07, 7.00), menstrual
problems (OR  2.34, 95 percent CI: 1.33, 4.14),
endometriosis (OR  2.63, 95 percent CI: 1.10, 6.26), and
unknown cause of infertility (OR  1.86, 95 percent CI:
1.26, 2.74). Beyond this effect, which may well represent a
surveillance bias, we found endometrioid/clear cell tumors
associated with endometriosis (OR  3.41, 95 percent CI:
1.94, 5.99) and unknown cause of infertility (OR  1.94, 95
percent CI: 1.49, 2.54). Furthermore, unknown cause of
infertility related to serous invasive ovarian cancer (OR 
1.86, 95 percent CI: 1.26, 2.74).
We further assessed the independent and joint relations
among infertility, fertility drug use, and ovarian cancer in a
logistic regression model that adjusted for standard con-
founders. Infertility was significantly related to ovarian can-
cer (OR  1.26, 95 percent CI: 1.14, 1.39). Fertility drug
use was not related to ovarian cancer (OR  1.13, 95 per-
cent CI: 0.56, 2.29) nor was the multiplicative interaction
between infertility and fertility drugs (OR  0.79, 95 per-
cent CI: 0.37, 1.66) related to ovarian cancer.
DISCUSSION
In our pooled analysis, we found no association between
fertility drug use and the overall risk of ovarian cancer.
Neither longer duration of fertility drug use nor unsuccess-
ful fertility drug use was independently associated with sig-
nificant elevations in adjusted cancer risk. We did find that,

Am J Epidemiol Vol. 155, No. 3, 2002

222 Ness et al.

TABLE 4. Fertility drug use and ovarian cancer risk* for eight case-control studies, 1989–1999
Variable No. of cases No. of controls Crude OR† 95% CI‡ Adjusted OR 95% CI

Fertility drugs (all)

No 911 1,137 1.0 1.0
Yes 149 200 0.93 0.74, 1.17 0.97 0.76, 1.25

Fertility drugs
Never pregnant
No 191 147 1.0 1.0
Yes 54 22 1.89 1.10, 3.24 1.60 0.90, 2.87
Ever pregnant
No 720 990 1.0 1.0

Downloaded from https://academic.oup.com/aje/article-abstract/155/3/217/63390 by guest on 31 August 2019

Yes 95 178 0.73 0.56, 0.96 0.82 0.62, 1.09

Duration of fertility drug use

(months)§
Never pregnant
Never 191 147 1.0 1.0
1–3 14 7 1.54 0.61, 3.91 1.56 0.59, 4.10
4–12 30 11 2.10 1.02, 4.33 1.67 0.78, 3.57
>12 10 4 1.92 0.59, 6.26 1.54 0.45, 5.27
Ever pregnant
Never 720 990 1.0 1.0
1–3 34 65 0.72 0.47, 1.10 0.81 0.54, 1.25
4–12 41 73 0.77 0.52, 1.15 0.84 0.56, 1.26
>12 20 40 0.69 0.40, 1.19 0.82 0.46, 1.44

Chlomiphene duration
(months)¶
Never 892 1,070 1.0 1.0
1–3 17 25 0.82 0.44, 1.52 0.92 0.48, 1.74
4–12 16 29 0.66 0.36, 1.23 0.76 0.40, 1.43
>12 9 10 1.08 0.44, 2.67 1.20 0.47, 3.05

HMG‡ duration (months)¶

Never 916 1,110 1.0 1.0
1–3 10 10 1.21 0.50, 2.92 1.47 0.60, 3.59
4–12 6 13 0.56 0.21, 1.47 0.60 0.22, 1.64
>12 3 1 3.64 0.38, 35.0 4.51 0.46, 44.12
* Includes only women who tried to get pregnant for 2 or more years and/or sought medical attention for infertility.
† Odds ratios (OR) were adjusted for age, gravidity, race, education, history of ovarian cancer, tubal ligation, duration of oral
contraceptive use, and research site.
‡ CI, confidence interval; HMG, human menopausal gonadotropin.
§ Excludes Purdie et al. (21).
¶ Excludes Mosgaard et al. (8) and Purdie et al. (21).

among women who never achieved a pregnancy, fertility
drugs were related to an elevated risk of borderline serous
tumors but not to invasive tumors. Although the association
between fertility drugs and borderline serous tumors may be
real and important, it might also be a significant result aris-
ing from multiple comparisons. Furthermore, the associa-
tion may reflect surveillance or diagnostic bias with
enhanced surveillance occurring among young women who
have invasive, fertility-related procedures; borderline
tumors generally arise among younger women who have an
excellent life expectancy after tumor excision (24, 25). This
assertion is strengthened by the many nonspecific associa-
tions between serous borderline tumors and various infertil-
ity types. Overall, our findings conflict with some previous
reports (1, 2, 9) but not with others (3, 6, 7, 10), suggesting
that it may be premature to ascribe a causal link between fer-
tility drug use and the subsequent development of ovarian
cancer (26–29).
We did find strong relations among nulligravidity, pro-
longed attempts to become pregnant (although these results
were heterogeneous among studies), and ovarian cancer
risk, suggesting that subfertile women are at increased risk
of ovarian cancer even after adjustment for contraception
and pregnancies. Both lack of gravidity and attempts at
pregnancy were more strongly related to risk than seeking
medical attention for infertility among nulligravid women.
These results may be explained by the observation that most
women who sought medical attention subsequently became
pregnant. At the same time, many women who were nul-
ligravid never sought medical attention (table 2).

Am J Epidemiol Vol. 155, No. 3, 2002


Endometriosis and unknown cause of infertility have been
linked to ovarian cancer in a variety of clinical and epidemio-
logic studies, including our own (3, 4, 7, 22, 30–33). Indeed,
endometriosis has specifically been linked to endometrioid
and clear cell tumors, perhaps as part of a natural progression.
That we did not have data on time between infertility workup
and ovarian cancer diagnosis introduces the possibility that
endometriosis may represent a precursor of ovarian cancer. It
is also possible that inflammation plays a role in ovarian car-
cinogenesis. This may explain the link between ovarian cancer
and endometriosis, with its marked local inflammation (34,
35). It may further explain the link to infertility of unknown
origin, perhaps through abnormal prostaglandin responses,
which mediate both ovulation and inflammation (36, 37).
We did not find that either ovulatory infertility or men-
strual infertility (perhaps a surrogate marker for anovula-
tion) elevated invasive ovarian cancer risk. Although such
relations have been reported in the past (2, 16), current
hypotheses regarding the etiology of ovarian cancer do not
predict a causal association. Both the ovulation hypothesis
and the gonadotrophin hypothesis postulate that fewer ovu-
lations resulting from ovulatory infertility and/or lower-
peak estrogen and progesterone levels associated with
anovulation would reduce, not elevate, ovarian cancer risk.
Strengths of this pooled analysis include its size, generaliz-
ability, population-based ascertainment strategy, and the use
of structured, detailed data collection methods, including data
on infertility and fertility drug use. Weaknesses include the
relatively small proportion of women using fertility drugs
among the entire population (2.7 percent), even among sub-
fertile women (14.6 percent), and the even smaller number of
women on whom we had specific information regarding spe-
cific types of fertility drugs used. Another study weakness is
reliance on self-reports for fertility evaluations and fertility
drug use. We know of no data regarding distant recall of infer-
tility type or fertility drugs per se, but there are data on distant
recall of contraceptive hormones that suggest women were
unlikely to err in recall of ever versus never use of oral con-
traceptives (38–42). Typically, women with medical record
documentation of use reported utilizing these medications 80
percent of the time or more. However, duration of oral con-
traceptive use and type of oral contraceptives used were less
likely to be recalled correctly. On a related topic, it is likely
that diagnosis and classification of fertility type may have
varied by study site. We did observe variability in the propor-
tion of women with specific fertility diagnoses by study site,
yet we did not observe significant heterogeneity in the asso-
ciation between type of infertility and ovarian cancer by site.
Nevertheless, these case-control data suggest that infertil-
ity per se, but not the use of fertility medications, elevates
the overall risk of ovarian cancer.
ACKNOWLEDGMENTS
The studies involved in this pooled analysis received
grant support, and the authors wish to acknowledge contrib-
utors as follows: Goodman et al.: grants R01-CA-58598 and
N01-CN-67001 from the National Cancer Institute, Castle
Am J Epidemiol Vol. 155, No. 3, 2002
Infertility and Ovarian Cancer 223
Memorial Hospital, Kaiser Foundation Hospital, Kapiolani
Medical Center, Kuakini Medical Center, Queens Medical
Center, Straub Clinic and Hospital, St. Francis Hospital,
Tripler Army Hospital, and Wahiawa General Hospital; Ness
et al.: grant R01-CA63748 from the National Cancer
Institute; Cramer et al.: grant RO1-CA 54419 from the
National Cancer Institute; Risch et al.: grant 6613–1415–53
from the National Health Research and Development
Program of Health Canada; Purdie et al.: Australian
National Health and Medical Research Council and the
Queensland Cancer Fund; Mallin et al.: grant R01-CA61093
from the National Cancer Institute; Kjaer et al.: grant R01-
Downloaded from https://academic.oup.com/aje/article-abstract/155/3/217/63390 by guest on 31 August 2019
CA-61107 from the National Cancer Institute; Mosgaard et
al.: grants from Løvens Kemiske Fabriks Forskningsfond,
Stud. Med. Karsten Hansens Grant, NovoCare, Fabrikant
Einar Willumsens Grant, Danish Hospital Foundation for
Medical Research, Region of Copenhagen, The Faroe Island
and Greenland (J77/94), Minister Erna Hamiltons Grant for
Science and Art, Agnes og Poul Friis-Fund, The Danish
Medical Association Research Fund (J086.51), and Max and
Anna Friedmanns Grant, Copenhagen, Denmark.
The authors also acknowledge the contributions of the
following persons: Ness et al.: Jeanne Anne Grisso and
Jennifer Klapper; Purdie et al.: Adele Green, Christopher
Bain, Victor Siskind, Bruce Ward, Neville Hacker, Michael
Quinn, Peter Russell, Gordon Wright, and Beatrice Susil;
Mallin et al.: coinvestigators Karin Rosenblatt, Faith Davis,
Viswanath, and Candice Zahora; Kjaer et al.: coinvestigator
Eva Glud, Jan Blaakaer, and Claus Hoegdall.
REFERENCES
1. Whittemore AS, Harris R, Itnyre J. Characteristics relating to
ovarian cancer risk: collaborative analysis of 12 US case-
control studies. II. Invasive epithelial ovarian cancer in white
women. Am J Epidemiol 1992;136:1184–1203.
2. Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a
cohort of infertile women. N Engl J Med 1994;331:771–6.
3. Ron E, Lunenfeld B, Menczer J, et al. Cancer incidence in a
cohort of infertile women. Am J Epidemiol 1987;125:780–
90.
4. Shu WO, Brinton LA, Gao YT, et al. Population-based case-
control study in Shanghai. Cancer Res 1989;49:3670–4.
5. Franceschi S, La Vecchia C, Negri E, et al. Fertility drugs and
risk of epithelial ovarian cancer in Italy. Hum Reprod 1994;9:
1673–5.
6. Modan B, Ron E, Lerner-Geva L, et al. Cancer incidence in a
cohort of infertile women. Am J Epidemiol 1998;147:1038–42.
7. Venn A, Watson L, Lumley J, et al. Breast and ovarian cancer
incidence after infertility and in vitro fertilization. Lancet 1995;
346:995–1000.
8. Mosgaard BJ, Lidegaard O, Kjaer SK, et al. Infertility, fertility
drugs, and invasive ovarian cancer: a case-control study. Fertil
Steril 1997;67:1005–12.
9. Shushan A, Paltiel O, Iscovich J, et al. Human menopausal
gonadotropin and the risk of epithelial ovarian cancer. Fertil
Steril 1996;65:13–18.
10. Potashnik G, Lerner-Geva L, Genkin L, et al. Fertility drugs
and the risk of breast and ovarian cancers: results of a long-
term follow-up study. Fertil Steril 1999;71:853–9.
11. Cramer DW, Hutchison GB, Welch WR, et al. Determinants of
ovarian cancer risk. I. Reproductive experiments and family
history. J Natl Cancer Inst 1983;71:711–16.
224 Ness et al.
12. Hartge P, Schiffman MH, Hoover R, et al. A case-control study
of epithelial ovarian cancer. Am J Obstet Gynecol 1989;161:
10–16.
13. Booth M, Beral V, Smith P. Risk factors for ovarian cancer: a
case-control study. Br J Cancer 1989;60:592–8.
14. Nasca PC, Greenwald P, Chorost S, et al. An epidemiologic
case-control study of ovarian cancer and reproductive factors.
Am J Epidemiol 1984;119:705–13.
15. Rodriguez C, Tatham LM, Calle EE, et al. Infertility and risk
of fatal ovarian cancer in a prospective cohort of US women.
Cancer Causes Control 1998;9:645–51.
16. Brinton LA, Melton LJ 3rd, Malkasian GD Jr, et al. Cancer
risk after evaluation for infertility. Am J Epidemiol 1989;129:
712–22.
17. Goodman MT, McDuffie K, Kolonel LN, et al. Case-control
study of ovarian cancer and polymorphisms in genes involved
in catecholestrogen formation and metabolism. Cancer
Epidemiol Biomarkers Prev 2001;10:209–16.
18. Cramer DW, Harlow BL, Titus Ernstoff L, et al. Over-the-
counter analgesics and risk of ovarian cancer. Lancet 1998;351:
104–7.
19. Ness RB, Grisso JA, Klapper J, et al. Risk of ovarian cancer in
relation to estrogen and progestin dose and use characteristics
of oral contraceptives. Am J Epidemiol 2000;152:233–41.
20. Risch HA, Marrett LD, Howe GR. Parity, contraception, infer-
tility, and the risk of epithelial ovarian cancer. Am J Epidemiol
1994;140:585–97.
21. Purdie D, Green A, Bain C, et al. Reproductive and other fac-
tors and risk of epithelial ovarian cancer: an Australian case-
control study. Int J Cancer 1995;62:678–84.
22. Ness RB, Grisso JA, Cottreau C, et al. Factors related to
inflammation of the ovarian epithelium and risk of ovarian
cancer. Epidemiology 2000;11:111–17.
23. Woolf B. On estimating the relation between blood group and
disease. Ann Hum Genet 1955:19:251–3.
24. Kehoe S, Powell J. Long-term follow-up of women with bor-
derline ovarian tumors. Int J Gynecol Obstet 1996;53:139–43.
25. Barnhill DR, Kurman RJ, Brady MF, et al. Preliminary analy-
sis of the behavior of stage I ovarian serous tumors of low
malignant potential: a Gynecologic Oncology Group study. J
Clin Oncol 1995;13:2752–6.
26. Glud E, Kjaer SK, Troisi R, et al. Fertility drugs and ovarian
cancer. Epidemiol Rev 1998;20:237–57.
27. Artini PG, Fasciani A, Cela V, et al. Fertility drugs and ovarian
cancer. Gynecol Endocrinol 1997;11:59–68.
28. Bristow RE, Karlan BY. Ovulation induction, infertility, and
ovarian cancer risk. Fertil Steril 1996:66:499–507.
29. Kaufman SC, Spirtas R, Alexander NJ. Do fertility drugs cause
ovarian tumors? J Womens Health 1995;4:247–59.
30. Heaps JM, Nieberg RK, Berek JS. Malignant neoplasms aris-
ing in endometriosis. Obstet Gynecol 1990;75:1023–8.
31. Sainz de la Cuesta R, Eichhom JH, Rice LW, et al. Histologic
transformation of benign endometriosis to early epithelial
ovarian cancer. Gynecol Oncol 1996;60:238–44.
32. Moll CM, Chumas JC, Chalas E, et al. Ovarian carcinoma aris-
ing in atypical endometriosis. Obstet Gynecol 1990;75:537–9.
33. Brinton LA, Gridley G, Persson I, et al. Cancer risk after a hos-
Downloaded from https://academic.oup.com/aje/article-abstract/155/3/217/63390 by guest on 31 August 2019
pital discharge diagnosis of endometriosis. Am J Obstet Gynecol
1997;176:572–9.
34. Ness RB, Cottreau C. Possible role of ovarian epithelial inflam-
mation in ovarian cancer. J Natl Cancer Inst 1999;91:1459–67.
35. Risch HA, Howe GR. Pelvic inflammatory disease and the risk
of epithelial ovarian cancer. Cancer Epidemiol Biomarkers
Prev 1995;4:447–51.
36. Fosslien E. Biochemistry of cyclooxygenase (COX)-2
inhibitors and molecular pathology of COX-2 in neoplasia.
Crit Rev Clin Lab Sci 2000;37:431–502.
37. Hillier SG, Tetsuka M. An anti-inflammatory role for gluco-
corticoids in the ovaries. J Reprod Immunol 1998;39:21–7.
38. West SL, Savitz DA, Koch G, et al. Recall accuracy for pre-
scription medications: self-reported compared with database
information. Am J Epidemiol 1995;142:1103–12.
39. Coulter A, Vessey M, McPherson K. The ability of women to
recall their oral contraceptive histories. Contraception 1986;
33:127–37.
40. Harlow SD, Linet MS. Agreement between questionnaire data
and medical records: the evidence for accuracy of recall. Am J
Epidemiol 1989;129:233–48.
41. Stolley PD, Tonascia JA, Sartwell PE, et al. Agreement rates
between oral contraceptive users and prescribers in relation to
drug use histories. Am J Epidemiol 1978;107:226–35.
42. Wingo PA, Lee NC. Use of a life-calendar to enhance the qual-
ity of exposure and risk factors histories. (Abstract). Am J
Epidemiol 1988;128:921.
Am J Epidemiol Vol. 155, No. 3, 2002