ORIGINAL ARTICLE Reproductive epidemiology
Risk of borderline and invasive ovarian
tumours after ovarian stimulation
for in vitro fertilization in a large
F.E. van Leeuwen1,*, H. Klip1,2, T.M. Mooij1, A.M.G. van de Swaluw1,3,
C.B. Lambalk4, M. Kortman5, J.S.E. Laven6, C.A.M. Jansen7,
F.M. Helmerhorst8, B.J. Cohlen9, W.N.P. Willemsen10,
J.M.J. Smeenk11, A.H.M. Simons12, F. van der Veen13, J.L.H. Evers14,
P.A. van Dop15, N.S. Macklon6,16, and C.W. Burger6
1Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands2Center of
Knowledge, Karakter, Horalaan 5, 6717 LX Ede, The Netherlands3Department of Gynaecology, Waterland Hospital, Postbus 250, 1440 AG
Purmerend, The Netherlands4Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Center, Postbus 7057, 1007 MB
Amsterdam, The Netherlands5Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht, Postbus 85500,
3508 GA Utrecht, The Netherlands6Department of Obstetrics and Gynaecology, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam,
The Netherlands7Department of Obstetrics and Gynaecology, Diaconessenhuis Voorburg, Postbus 998, 2270 AZ Voorburg, The Netherlands
8Department of Gynaecology and Reproductive Medicine and Department of Clinical Epidemiology, Leiden University Medical Center, Postbus
9600, 2300 RC Leiden, The Netherlands9Department of Obstetrics and Gynaecology, Isala Clinics, Dr van Heesweg 2, 8025 AB Zwolle, The
Netherlands10Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Center, Postbus 9101, 6500 HB Nijmegen,
The Netherlands11Department of Obstetrics and Gynaecology, St Elisabeth Hospital, Postbus 90151, 5000 LC Tilburg, The Netherlands
12Department of Obstetrics and Gynaecology, University Medical Center Groningen, Postbus 30001, 9700 RB Groningen, The Netherlands
13Department of Obstetrics and Gynaecology, Academic Medical Center, Postbus 22660, 1100 DD Amsterdam, The Netherlands
14Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Postbus 5800, 6202 AZ Maastricht, The Netherlands
15Department of Obstetrics and Gynaecology, Catharina Hospital, Postbus 1350, 5602 ZA Eindhoven, The Netherlands16Division of
Developmental Origins of Health and Disease, University of Southampton, Coxford Road, Southampton, SO16 5YA, UK
*Correspondence address. E-mail: email@example.com
Submitted on March 10, 2011; resubmitted on July 13, 2011; accepted on September 2, 2011
background: Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown.
methods: We identified a nationwide historic cohort of 19 146 women who received IVF treatment in the Netherlands between 1983
and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997–1999, data on reproductive risk factors
were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of
ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk
of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group.
results: After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared
with the general population [standardized incidence ratio (SIR) ¼ 1.76; 95% confidence interval (CI) ¼ 1.16–2.56]. The overall SIR for
invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P ¼ 0.02); the SIR was 3.54
(95% CI ¼ 1.62–6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group
were significantly increased compared with risks in the subfertile comparison group (hazard ratios ¼ 4.23; 95% CI ¼ 1.25–14.33 and
2.14; 95% CI ¼ 1.07–4.25, respectively, adjusted for age, parity and subfertility cause).
conclusions: Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More
large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.
Key words: ovarian stimulation / ovarian malignancies / fertility drugs / infertility / in vitro fertilization
& The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Human Reproduction, Vol.26, No.12 pp. 3456–3465, 2011
Advanced Access publication on October 26, 2011 doi:10.1093/humrep/der322
Currently, 1.2–2.3% of children born in the Western world are con-
ceived by assisted reproductive technologies (Kremer et al., 2008;
Wright et al., 2008). In the Netherlands, it has been estimated that
the number of treatment cycles increased by 40% from 1996 till
2005 (Kremer et al., 2008). Fertility drugs (FDs) used in IVF treatment
temporarily raise serum levels of exogenous gonadotrophins and
gonadal hormones, and consequently increase the chances of multiple
folliculogenesis and ovulations. The long-term effects of ovarian stimu-
lation are unknown. In view of the assumed role of ‘incessant ovu-
lation’ (Fathalla, 1972) and increased gonadotrophin levels in ovarian
cancer pathogenesis (Cramer and Welch, 1983; Risch, 1998; Vlahos
et al., 2010) concerns have been raised that ovarian stimulation and
multiple ovarian punctures as used in IVF may increase the risk of
ovarian malignancies (Fishel and Jackson, 1989). Invasive ovarian
cancer accounts for 6% of female cancer deaths in the USA (Jemal
et al., 2008).
Over the past decades, several studies reported a significant
increase of ovarian cancer risk after FD use (Whittemore et al.,
1992; Rossing et al., 1994; Brinton et al., 2005; Sanner et al., 2009;
Ka ¨lle ´n et al., 2011), but others did not observe such an elevated
risk (Franceschi et al., 1994; Bristow and Karlan, 1996; Mosgaard
et al., 1997; Modan et al., 1998; Venn et al., 1999; Parazzini et al.,
2001; Dor et al., 2002; Doyle et al., 2002; Ness et al., 2002;
Rossing et al., 2004; Dos Santos Silva et al., 2009; Jensen et al.,
2009), or reported non-significant risk increases for subgroups
(Shushan et al., 1996; Ness et al., 2002; Brinton et al., 2004). Some
studies noted an elevated risk of borderline ovarian tumours following
the use of FDs (Harris et al., 1992; Rossing et al., 1994; Shushan et al.,
1996; Parazzini et al., 1998; Ness et al., 2002; Sanner et al., 2009).
Borderline ovarian tumours are low-grade ovarian malignancies with
far less aggressive behaviour than invasive ovarian cancer (Bell,
2005; Hart, 2005).
Short follow-up, low statistical power and lack of control for impor-
tant confounders, such as cause of subfertility and parity, have limited
the conclusions from previous studies. We report here on a large
nationwide cohort study in the Netherlands (the OMEGA study)
that was designed to examine long-term risk of ovarian malignancies
(both invasive ovarian cancer and borderline ovarian tumours) after
ovarian stimulation for IVF. A unique feature of our study is that
data on reproductive factors were obtained from the participating
women, whereas detailed information on subfertility cause and
treatment was abstracted from the medical files.
Patients and Methods
In 1995–1996, we identified a nationwide historical cohort of 19 861 sub-
fertile women who received at least one IVF cycle with ovarian stimulation
between 1983 and 1995 in 1 of the 12 IVF hospitals with legal permission
to provide IVF treatment in the Netherlands. Since the registration of IVF
treatment was obligatory by law, all IVF clinics in the Netherlands could
provide a minimal data set with names, birth dates and addresses of
eligible women. The institutional ethics committees of all IVF clinics
approved the study procedures, which have been described previously
(Klip et al., 2001; Klip, 2002; de Boer et al., 2003).
To obtain a large enough comparison group of subfertile women not
treated with IVF, we identified women who were diagnosed with fertility
problems shortly before IVF became a routine procedure for subfertile
patients. The non-IVF comparison group consisted of 6604 women
whose subfertility was diagnosed in the four participating clinics that had
a computerized registry of all subfertile women evaluated during 1980–
1995. We attempted to frequency match the non-IVF comparison
group according to the distribution of subfertility diagnoses in the IVF
group. Most women in the non-IVF group registered for their first consul-
tation in the 1980s (before IVF became a routine procedure) and under-
went tubal surgery and/or hormonal treatments. The majority of those
who registered after 1990 withdrew from the waiting list for IVF
because they pursued other treatment options, reached the age of
40 years (the upper age limit for IVF at the time), became pregnant or
decided to refrain from IVF for various reasons, such as divorce. When
the non-IVF group was compared with the IVF group, it turned out that
911 women selected into the non-IVF comparison group subsequently
received IVF. These women had subfertility treatments other than IVF in
one centre and subsequently received IVF in a second centre. In the
description of the cohort, these women are included in the IVF group
(Table I) (see also section ‘Statistical analysis’).
Based on names, birth dates and addresses at the time of subfertility
treatment all cohort members were traced. Given that the subjects’ last
visit to the fertility clinic could date back to 1980, extensive tracing tech-
niques were required to obtain current addresses of all women (Klip et al.,
2001; Klip, 2002; de Boer et al., 2003), using the municipal population
offices that fully cover the Netherlands. From the initial 26465 women,
4.2% was not approached (the OMEGA cohort study, Fig. 1).
Risk factor questionnaire
Between 1997 and 1999, 25 353 women received a risk factor question-
naire, a study information letter, and a brochure. Each participant was
asked written informed consent for medical record data abstraction and
future linkage with disease registries. The study information letter was
signed by the treating gynaecologist or, if he/she had left, the current
head of the IVF department. In the study information letter as well as in
the brochure, women were informed about the purpose, the design and
the privacy aspects of the study. The purpose of the study was stated
as follows: ‘to examine whether women who underwent an IVF treatment
more frequently report gynaecological health problems compared with
women who did not have an IVF treatment’. After 4–6 weeks, non-
responders were sent a reminder. Non-responders to the second letter
were approached by telephone. The 23 page questionnaire ascertained
information on the women’s reproductive histories, subfertility treatment,
use of exogenous hormones, lifestyle factors and family history of cancer.
A total of 16 343 women returned the questionnaire (response rate
65.2%). The response rate was substantially lower in the non-IVF group
(48.7%) than in the IVF group (71.1%).
Trained abstractors collected information on cause of subfertility and all
fertility treatments. Cause of subfertility was classified as tubal, male
factor, endometriosis, ovarian disorders, cervical factor, uterine abnormal-
ities or unexplained. Multiple causes of subfertility were registered if
For each IVF and insemination cycle, we recorded date, dosage and type
of FDs used in each phase of the menstrual cycle (hMG, FSH, clomiphene,
hCG, GnRH and progesterone), number of oocytes collected and outcome.
For FDs used prior to inseminations/IVF, we also coded date, dosage and
type of FDs used per cycle. We made special attempts to collect infor-
mation on subfertility treatments provided outside the participating IVF
Risk of ovarian malignancies after in vitro fertilization
clinics, by screening intake forms and letters from other treating physicians.
Due to limited funding, we could only complete medical record abstraction
for 9 out of 12 centres, i.e. 13807 women (76% of women in the IVF
group) (Klip et al., 2001; Klip, 2002; de Boer et al., 2003).
Incidence of ovarian malignancies
Cancer incidence in the period 1989–2003 was ascertained through
linkage with the population-based Netherlands Cancer Registry (NCR)
(International Agency for Research on Cancer, 2003), and incidence of
ovarian malignancies (including borderline ovarian tumours) through June
2007 was ascertained through linkage with the Dutch nationwide
network and registry of histo- and cytopathology (PALGA). PALGA con-
tains records of all histological diagnoses made in the Netherlands, with
computerized data submission by all pathology laboratories, and nation-
wide coverage since 1989 (Casparie et al., 2007). We linked with
PALGA since the NCR had incomplete data on borderline ovarian
tumours; in addition PALGA case ascertainment is complete till 2 weeks
prior to linkage, while the NCR lags a few years behind. We used a
record linkage protocol developed previously (van den Brandt et al.,
1990), which was based on the first four characters of the family name,
gender and date of birth. All positive matches were checked for adminis-
trative twins by place of birth, postal code at cancer diagnosis and first
initial. The NCR and PALGA granted us permission to not only link
responders who gave permission, but also non-responders and deceased
women, under additional privacy regulations. Only women who explicitly
refused future linkage with disease registries (n ¼ 1017; 4.0% of all
women) were excluded from linkage. For each ovarian malignancy, we
received information on date of diagnosis and morphology. Vital status
as of June 2007 was obtained by linkage with the Central Bureau for
Genealogy, which keeps computerized records of all deceased persons
in the Netherlands since 1994.
The analytic study cohort consisted of 25 152 women; 19 146 women in
the IVF group and 6006 women in the non-IVF group (Fig. 1). Because the
NCR and PALGA did not fully cover the Netherlands before 1989, the
observation time for each participant started on 1 January 1989 or
the date of first IVF treatment (IVF group), or clinic visit for subfertility
evaluation (non-IVF group), whichever came last. Person-years of obser-
vation were calculated to the date PALGA follow-up ended (June 2007),
date of ovarian cancer diagnosis or date of death, whichever came first.
Women selected into the non-IVF comparison group who subsequently
received IVF contributed person-time to the non-IVF group until the
date of first IVF treatment, and switched to the IVF group after this
date, according to standard cohort methodology regarding time-
dependant allocation of person-years in case of changing exposure
(Breslow and Day, 1987). Women diagnosed with ovarian cancer
before entering the cohort (n ¼ 14) or before 1989 (n ¼ 13), were
excluded from the analysis.
First, we compared ovarian cancer incidence in the IVF group and
non-IVF group with incidence in the general population. We determined
the standardized incidence ratio (SIR) as the ratio of the observed (O)
and expected (E) number of cancers in the cohort. Expected numbers
were based on age- and calendar period-specific reference rates for inva-
sive ovarian cancer and borderline ovarian tumours from the NCR and
PALGA, respectively (International Agency for Research on Cancer,
2003). Incidence rates for borderline ovarian tumours were calculated
by the authors (T.M.M. and F.E.v L.), based on annual numbers of border-
line ovarian tumour diagnoses obtained from PALGA. In all analyses, the
subfertility cause(s) and treatments were preferably based on the
medical records, and only derived from the woman’s questionnaire if
the records had not been abstracted. Information on reproductive
factors was derived from the women’s questionnaires, since these vari-
ables could change after IVF treatment. For non-responding women infor-
mation from hospital databases was added when available. Previous FD
use was defined as a combined variable relating to FD use during insemi-
nations and FD use prior to inseminations/IVF, and was based on infor-
mation from the medical records combined with the risk factor
................... ................. ...................
Year of birth
Age at first IVF treatment or visit (years)
Endometriosis 1970 10.3
Male factor5492 28.7
Other factors912 4.8
Number of IVF treatmentsb
3–4 cycles6271 32.8
5 or more cycles3352 17.5
Time since first treatment or visit (years)
5–9 years689 3.6
10–14 years10 343 54.0
Table I Population characteristics of the OMEGA
cohort by exposure status.
(n 5 19 146)
(n 5 6006)
(n 5 25 152)
11 923 7621
aWomen could have more than one cause of subfertilly, except for unexplained and
missing, which were unique classifications.
bInformation based on medical records; for women without medical record data,
information was added from health questionnaire survey.
cIncluded ovulation disorders, polycystic ovary syndrome and premature
van Leeuwen et al.
Cox proportional hazards models were used to compare cancer risk
between the IVF group and the non-IVF group, adjusting for age and
potential confounders such as parity and subfertility cause. Forward step-
wise confounder selection, in which the effect of adding one confounder at
a time was evaluated, was based on a .10% change in the risk estimate of
the exposure variable of interest, irrespective of significance values.
In all analyses missing values were included as a separate category. Data
were analysed with SPSS software (SPSS Inc., Chicago, IL, USA).
Characteristics of 19146 IVF-treated women and 6006 women not
treated with IVF are presented in Table I. Women in the non-IVF
group had a slightly longer median duration of follow-up than
women in the IVF group (16.4 versus 14.3 years) and they were
also older at the end of follow-up (mean age 49.4 versus 47.5
years). These differences reflect the initial inclusion criteria for the
IVF and the non-IVF groups, with an over-representation of women
in the non-IVF group seeking subfertility treatment in the years
before IVF treatment became a routine procedure. Cause of
subfertility was related to tubal problems in 32% of women, 25%
had male-factor subfertility, 9% endometriosis, 7% hormonal subferti-
lity, 16% unexplained subfertility and 23% was missing (percentage add
up to .100% due to multiple causes of subfertility). A total of 42% of
the cohort was nulliparous at questionnaire completion. In the IVF
group, 40% of women had one to two stimulated IVF cycles, 39%
had three to four cycles and 21% received five or more cycles. IVF
stimulation regimens used in the cohort have been described in
detail previously (de Boer et al., 2004). In brief, clomiphene/hMG
or FSH/hMG stimulation protocols were used till 1988–1989,
whereas stimulation with GnRH agonists became common after
1990 (from 20% in 1986 to about 90% after 1990). Furthermore,
from 1984 to 1994, the number of ampoules of gonadotrophins
strongly increased, as did the number of retrieved oocytes at the
first IVF cycle (from 5.4 in 1986 to 10.7 in 1994) (de Boer et al., 2004).
Comparisons with external reference rates
After a median follow-up time of 14.7 years, 77 ovarian malignancies
were observed in the full cohort [SIR ¼ 1.43; 95% confidence interval
Figure 1 Identification of the OMEGA study cohort.aWomen in this category contributed person time till date of questionnaire completion.
bIncluding women who returned an empty questionnaire (n ¼ 66) and questionnaires that were returned to sender (n ¼ 656).
Risk of ovarian malignancies after in vitro fertilization
(CI) ¼ 1.12–1.78]; 42 invasive ovarian cancers and 35 borderline
ovarian tumours (Table II). Sixty-one ovarian malignancies were
observed in the IVF group (SIR ¼ 1.59; 95% CI ¼ 1.21–2.04) and
16 in the non-IVF group (SIR ¼ 1.02; 95% CI ¼ 0.59–1.66). Com-
pared with the general population rates, we observed a significantly
increased risk for borderline ovarian tumours in the IVF group
(SIR ¼ 1.93; 95% CI ¼ 1.31–2.73) and no increase in the non-IVF
group (SIR ¼ 0.67; 95% CI ¼ 0.18–1.71). The SIRs for invasive
ovarian cancer were not significantly raised in either IVF-treated
women (1.35; 95% CI ¼ 0.91–1.92) or non-IVF women (1.24; 95%
CI ¼ 0.64–2.17). The morphologies of the invasive ovarian cancers
were serous (60%), mucinous (7%), clear-cell (7%), endometrioid
(21%) and other (5%). Of the borderline ovarian tumours, 63%
were serous and 37% were mucinous. Serous borderline ovarian
tumours and invasive ovarian cancers occurred more frequently in
the IVF group than in the non-IVF group (P ¼ 0.04).
The SIRs in both the IVF group and non-IVF group were strongly
increased in the first year of follow-up (3- to 18-fold), possibly related
towork-up for subfertility diagnosis and treatment. When we excluded
the first year of follow-up, the SIR for all ovarian malignancies was 1.49
(95%CI ¼ 1.12–1.94)intheIVFgroupand0.85(95%CI ¼ 0.45–1.45)
cancer in the IVF group was 3.54 (95% CI ¼ 1.62–6.72, P for trend ¼
0.02), whereas the SIR in the non-IVF group was close to unity
(Table II). No clear increasewith longer follow-up wasseen for border-
line ovarian tumours (P for trend ¼ 0.49).
Within the IVF group, SIRs of ovarian malignancy did not
increase with a greater number of IVF cycles or ampoules of
gonadotrophins (Table III). The mean number of oocytes harvested
per stimulated cycle and the maximum number over all treatment
cycles were used as a proxy for a woman’s responsiveness to
ovarian stimulation; the total number of oocytes collected over all
cycles was used as a proxy for the amount of damage to the
ovarian epithelium. The SIRs did not appear to be associated with
any of these variables. FD use prior to IVF treatment was not
associated with an increased SIR for all ovarian malignancies com-
bined; for invasive ovarian cancer the SIR was non-significantly
increased (SIR ¼ 1.69; 95% CI ¼ 0.95–2.79), while for borderline
ovarian tumours the SIR was increased for women who did not use
FDs prior to IVF treatment (SIR ¼ 2.93; 95% CI ¼ 1.71–4.69).
These observations must be interpreted with caution since infor-
mation on previous FD use was missing for 27% of women.
All ovarian malignancies
,1 years6 1.523.94 1.44–8.573
1–4 years9 7.521.20 0.55–2.271
5–9 years16 12.411.29 0.74–2.093
10–14 years 1813.22 1.360.81–2.154
All intervals61 38.41 1.591.21–2.04 16
All intervals excl. first year5536.88 1.49 1.12–1.9413
Invasive ovarian cancer
,1 years2 0.78 2.57 0.31–9.263
1–4 years5 3.941.27 0.41–2.961
5–9 years4 6.90 0.580.16–1.482
10–14 years10 8.13 1.230.59–2.262
All intervals30 22.30 1.350.91–1.92 12
All intervals excl. first year28 21.52 1.300.86–1.889
Borderline ovarian tumours
,1 years4 0.745.381.46–13.770
1–4 years4 3.58 1.120.03–2.860
5–9 years125.512.18 1.13–3.811
10–14 years8 5.09 1.57 0.68–3.102
All intervals 31 16.10 1.93 1.31–2.734
All intervals excl. first year27 15.36 1.761.16–2.564
Table II Incidence of ovarian malignancies by years of follow up and exposure status.
Follow-up IVF groupNon-IVF groupTotal
95% CI 95% CI95% CI
123.73 3.22 1.66–5.625
9 2.543.54 1.62–6.724
3 1.182.53 0.52–7.401
Obs, observed; Exp, expected; SIR, standardized incidence ratio; CI, confidence interval.
van Leeuwen et al.
Obs Exp SIR
Obs Exp SIR
Total number of IVF cyclesa,b
1–2 cycle(s)82599 2113.991.50 0.93–2.29
3–4 cycles84025 2214.46 1.520.95–2.30
Tubal 848223514.96 2.34 1.63–3.25
Endometriosis2685314 4.593.05 1.67–5.12
Male factor70793 1611.53 1.39 0.79–2.25
168733 2.64 1.140.23–3.32
Unexplained 458465 7.97 0.63 0.20–1.46
Other factors 120054 2.02 1.980.54–5.07
Previous FD usec,f
No 957822614.151.84 1.20–2.69
Yes 10914920 15.41 1.300.79–2.01
Missing 4929797.33 1.23 0.56–2.33
Nulliparous86058 24 12.821.87 1.20–2.79
Parous 1232422117.38 1.210.75–1.85
Missing44928 106.681.50 0.72–2.75
Total no. of ampoules hMG/FSHg
1–40 ampoules 4803310 6.851.46 0.70–2.69
41–80 ampoules 49345 117.081.55 0.78–2.78
Missing 9910120 14.351.39 0.85–2.15
Total no. of oocytesg
0–19 oocytes899292013.84 1.45 0.88–2.23
Missing85113 1912.42 1.530.92–2.39
Mean no. of oocytesg
0–3 oocytes214686 3.81 1.570.58–3.43
4–6 oocytes46899 14 7.311.91 1.05–3.21
Missing 851132012.411.61 0.98–2.49
Maximum no. of oocytesg
0–5 oocytes338199 5.75 1.56 0.72–2.97
6–10 oocytes 58581 13 8.751.490.79–2.54
Missing 8511320 12.41 1.610.98–2.49
Table III Incidence of ovarian malignancies in IVF-treated women, according to IVF treatment characteristics,
subfertility and parity.
IVF groupPerson years All ovarian malignancies Invasive ovarian cancer Borderline ovarian tumours
95% CI 95% CI 95% CI
0.47–3.384766112 8.43 1.42 0.74–2.49
57749 148.60 1.630.89–2.73
10074715 13.351.12 0.63–1.85
76714 13 9.971.30 0.69–2.23
Obs, observed; Exp, expected; SIR, standardized incidence ratio; CI, confidence interval.
aInformation based on health questionnaire survey; for non-responding women information was added from the medical records.
bMissing values of this variable were retrospectively completed for all cases; among non-cases with missing values, we distributed person time according to the distribution of
person-years over categories of this variable.
cInformation based on medical records; for women without medical record data, information was added from health questionnaire survey.
dWomen may contribute person-years to more than one type of subfertility except for the categories unexplained and missing, which were unique classifications.
eHormonal factors included ovulation disorders, polycystic ovary syndrome and premature menopause.
fPrevious FD use was defined as a combined variable relating to FD use during inseminations and FD use prior to inseminations/IVF.
gInformation based solely on medical records; no data abstraction could be done for 24% of the cohort that did give informed consent to do so.
Risk of ovarian malignancies after in vitro fertilization
Endometriosis was associated with significantly increased risk of inva-
sive ovarian cancer, whereas tubal problems significantly increased the
SIR for borderline ovarian tumours.
Comparisons within the cohort
Direct comparison of the IVF group with the non-IVF group (Table IV)
yielded an adjusted hazard ratio (HR) for all ovarian malignancies of
2.14 (95% CI ¼ 1.07–4.25), excluding the first year of follow-up.
The adjusted HRs for invasive ovarian cancer and borderline ovarian
tumours were 1.51 (95% CI ¼ 0.65–3.54) and 4.23 (95% CI ¼
1.25–14.33), respectively. No trends emerged with number of IVF
cycles or other IVF treatment characteristics, but numbers in subcate-
gories were small. Clomiphene use prior to IVF was not associated
with increased risk of ovarian malignancies (HRs for all malignancies,
invasive ovarian cancer and borderline ovarian tumours were 0.89
(95% CI ¼ 0.45–1.77), 1.22 (95% CI ¼ 0.50–2.99) and 0.62 (95%
CI ¼ 0.21–1.83), respectively). Finally, we compared the risk of all
ovarian malignancies between the IVF group and women in the
non-IVF group who never used FDs (HR ¼ 1.83; 95% CI ¼ 0.70–
4.82, based on five cases in 2115 unexposed women).
This large nationwide cohort study with a median follow-up of
15 years shows that women treated with ovarian stimulation for IVF
have a 2-fold increased risk of ovarian malignancies compared with
subfertile women not treated with IVF. The excess risk was mostly
due to borderline ovarian tumours, but 15 or more years after IVF
treatment we also observed a SIR of 3.5 for invasive ovarian cancer.
Surprisingly, we observed that a high proportion (46%) of all ovarian
malignancies in the IVF group concerned borderline ovarian tumours,
whereas in the general population (below the age of 50 years) border-
line ovarian tumours account only for 15–30% (Hart, 2005) of
epithelial ovarian malignancies. So far only few studies examined FD
use in relation to risk of borderline ovarian tumours, related to the
fact that most population-based cancer registries do not record bor-
derline ovarian tumours. Our cohort study is the first one examining
the risk of borderline ovarian tumours following IVF treatment. Strik-
ingly, the few case–control studies that examined the risk of border-
line ovarian tumours after FD use found 2- to 4-fold increased risks
(Harris et al., 1992; Rossing et al., 1994; Shushan et al., 1996; Parazzini
et al., 1998; Ness et al., 2002), though based on small numbers. In a
case–cohort study (Rossing et al., 1994) reporting an 11-fold risk
increase of ovarian malignancies after 12 or more cycles of clomi-
phene, 5 of the 11 ovarian tumours were borderline ovarian
tumours. Although screening for ovarian tumours in IVF-treated
women has never been recommended in the Netherlands, we con-
sidered whether the increased risk of borderline ovarian tumours in
the IVF group might be due to increased medical surveillance. We
sent a questionnaire about diagnostic procedures to the gynaecologists
of all case subjects with a borderline ovarian tumour who had given
permission to approach their physician (n ¼ 18). We received infor-
mation for 14 subjects; in all cases, the diagnosis was made subsequent
to complaints for which the woman visited her gynaecologist, render-
ing surveillance bias an unlikely explanation of our findings. Remark-
ably, we observed a high proportion of serous borderline ovarian
tumours (63%), which was also seen in one case–control study
(Ness et al., 2002). Mucinous borderline ovarian tumours are more
frequent in the general population (Verbruggen et al., 2009).
Risk of borderline ovarian tumours was particularly strongly elevated
in the first year after IVF, which is in line with several case reports of
borderline ovarian tumours developing during or shortly after ovarian
stimulation treatments (Atlas and Menczer, 1982; Goldberg et al.,
1992; Nijman et al., 1992), providing support for speculations that
ovarian stimulation may induce growth in existing highly differentiated
tumours(Brinton etal.,2005). Weexcluded ovariantumoursoccurring
in the first year after IVF, because of concern that their diagnosis might
be related to diagnostic and treatment procedures for infertility. The
early increase in risk was followed by a SIR close to unity in the 1–4
year follow-up interval; subsequently, risk of borderline ovarian
tumours remained elevated up to more than 15 years after first IVF
treatment. Hence, our data suggest that IVF treatment may be causally
related to a prolonged increase of the risk of highly differentiated
tumours. The natural history of borderline ovarian tumours is unclear
and it is unknown which part of borderline ovarian tumours, if unde-
tected, would develop into invasive ovarian cancer (Singer et al.,
2003; Sherman et al., 2004; Shih and Kurman, 2004).
A concerning finding of our study is the increased SIR of invasive
ovarian cancer in the IVF group after more than 15 years of follow-up,
whichwasnot observedin the non-IVFgroup. We cannotcomparethis
result with findings from others since our study is the first reporting on
cancer risk more than 10 years after IVF treatment. However, Brinton
et al. (2004) followed a large cohort of 12 193 women treated for infer-
tility prior to the IVF era. After 15 or more years of follow-up they
reported non-significantly elevated rate ratios of ovarian cancer, 1.48
(95% CI ¼ 0.7–3.2) for clomiphene and 2.46 (95% CI ¼ 0.7–8.3) for
gonadotrophins (when compared with never use of these drugs).
Sanner et al. (2009) reported on a Swedish cohort treated for infertility
in the 1960s–1970s, with a median follow-up of 33 years. Gonado-
trophins were associated with increased risk of invasive ovarian cancer
(relative risk ¼ 5.28, 95% CI ¼ 1.70–16.47) but clomiphene was
not (when compared with never use of these drugs) (Sanner et al.,
2009). Ovulation stimulating drugs such as clomiphene were intro-
duced in the late 1960s and IVF treatment with gonadotrophins,
..................... ..................... .....................
HR 95% CIHR95% CI
Table IV Adjusted HRs for cancer risk in IVF group
versus non-IVF group.
≥ ≥1 year
≥ ≥10 years
2.05 1.10–3.822.14 1.07–4.252.08 0.86–5.00
1.14 0.54–2.41 1.51 0.65–3.542.26 0.78–6.55
6.38 2.05–19.84 4.23 1.25–14.33 2.26 0.46–11.05
HR, hazard ratio; CI, confidence interval.
aAdjusted for age at end of follow-up, endometriosis, tubal problems.
bAdjusted for age at end of follow-up, endometriosis.
cAdjusted for age at end of follow-up, tubal problems, parity.
van Leeuwen et al.
resulting in much stronger ovarian stimulation, did not become widely
available until the late 1980s. Consequently, women exposed to clo-
miphene have just recently reached the age range at which ovarian
cancer frequently occurs (.70 years), while the oldest IVF-treated
women have only recently reached their 50s. Since the induction
period of ovarian cancer with respect to established risk factors
amounts to 25 years or more (Risch, 1998), much longer follow-up
is needed to fully evaluate the effects of gonadotrophins.
If ovarian stimulation were causally related to the risk of ovarian
malignancy, we would expect increasing risks with greater number
of IVF cycles or number of oocytes harvested. No such dose–
response trends emerged. However, numbers in relevant dose cat-
egories were small, and data were missing for 17% of subjects,
which reduced power for these analyses. In addition, the number of
IVF cycles and number of harvested oocytes are only proxies for
the number of ovarian punctures, which may have reduced the
power to detect a dose–response relationship.
Case–control studies of the association between ovarian cancer
risk and FD use have shown inconsistent results, with some studies
reporting increased risks for subgroups (e.g. nulliparous women)
(Ness et al., 2002; Rossing et al., 2004) and some suggesting a
dose–response effect for clomiphene (Ness et al., 2002; Rossing
et al., 2004). Treatment with hMG or FSH, as in IVF, may increase
the number of ovulations to approximately six to nine times that of
untreated women (Fishel and Jackson, 1989), which is a much stronger
increase than the doubling of ovulations with clomiphene (Glasier,
1990; Derman and Adashi, 1994).
Nationwide cohort studies of IVF-treated women have only been
reported from Australia (Venn et al., 1999), Israel (Lerner-Geva
et al., 2003) and Sweden (Ka ¨lle ´n et al., 2011). The first two cohort
studies did not show increased risk of ovarian cancer in the IVF
group compared with the general population (Venn et al., 1999;
Lerner-Geva et al., 2003), while the recent Swedish study reported
for parous women increased risk of ovarian cancer after IVF, com-
pared with all other Swedish women who gave birth in the study
period (HR ¼ 2.09; 95% CI ¼ 1.39–3.12) (Ka ¨lle ´n et al., 2011).
However, this study had no information on subfertility cause; there-
fore it is not clear whether the risk increase is attributable to IVF or
subfertility. Of all cohort studies including IVF-treated women, our
study includes the largest number of ovarian malignancies (n ¼ 77
versus 13, 3 and 26 cases in the cohort studies from Australia,
Israel and Sweden) (Venn et al., 1999; Lerner-Geva et al., 2003;
Ka ¨lle ´n et al., 2011).
Our study design had several strengths and weaknesses. Advantages
include the large size of our cohort and the long-term follow-up. Selec-
tion bias can be ruled out since we were able to link 96% of our
cohort with the population-based cancer and pathology registries,
enabling us to also evaluate the occurrence of borderline ovarian
tumours. All ovarian malignancies were histologically confirmed. Fur-
thermore, we collected reproductive variables after IVF directly
from the participating women, whereas for the majority of women
information on subfertility cause and treatment could be abstracted
from the medical files. Our data also include information on FD use
prior to IVF, although this was incomplete for 27% of women. A limit-
ation of our study is, however, that the comparison group of women
unexposed to IVF treatment was relatively small, and that a proportion
of these women (40%), had used FDs (clomiphene) outside the IVF
setting (as did 54% of women in the IVF group), thus restricting the
power for comparisons with a truly unexposed reference group.
However, if multiple ovarian punctures rather than hormonal stimu-
lation would induce ovarian malignancy, potential differences in FD
use outside the IVF setting are not relevant.
Unfortunately, the response rate to the questionnaire was lower in
the non-IVF group (49 versus 71% in the IVF group). Since we were
allowed to link non-responders with the NCR and PALGA, differential
non-response could not affect our overall risk estimates. However, the
larger proportion of missing values for potential confounders (repro-
ductive factors, cause of subfertility) among controls complicated
our multivariable analyses. Adjustment for potential confounders did
not materially affect our risk estimates, however.
We wondered whether the increased SIR of invasive ovarian cancer
observed in the IVF group after 15 years might be due to less oral con-
traceptive (OC) use and/or lower parity in IVF-treated women.
However, in the non-IVF group no increased SIR after long-term
follow-up was seen. The proportion of long-term (≥7 years) OC
users was high in our cohort and very similar in the IVF group and
the non-IVF group (39.2 and 38.1%, respectively). Dutch women
start OC use early and have a late age at first birth (mean 1985–
1995: 28 years (Statistics Netherlands; www.cbs.nl, 2011) and only
19.1% of the IVF group and 22.5% of the non-IVF group never used
OC or used them ,1 year. Consequently, OC use was not a con-
founder in our multivariable Cox analysis. IVF-treated women
remained more often nulliparous then the non-IVF group (44 versus
35%), but adjustment for parity only affected our results for borderline
ovarian tumours, not for invasive ovarian cancer.
Our study is the only IVF cohort including a comparison group of
subfertile women not treated with IVF, in addition to a comparison
with the general population. Such a comparison group is important
since IVF-treated women differ from the general population with
respect to several risk factors for ovarian malignancies, e.g. subfertility
and nulliparity. We cannot exclude the possibility, however, that the
severity of certain causes of subfertility in the IVF group was not the
same as in the non-IVF group. Since adjustment for individual causes
of subfertility only slightly affected our estimates of the risk associated
with IVF (data not shown), residual confounding by severity of certain
subfertility causes seems unlikely, however.
Another limitation of our study is that our results are based on IVF
treatment protocols used until 1995, prior to the adoption of
currently applied milder stimulation regimens.
In conclusion, our results suggest that ovarian stimulation for IVF
may increase the risk of ovarian malignancies, especially borderline
ovarian tumours. Knowledge about the magnitude of the risks associ-
ated with ovarian stimulation is important for women considering
starting or continuing IVF treatment, as well as their treating phys-
icians. Clearly, the outcome of weighing a wish to conceive against
the potential risks associated with IVF may differ among couples con-
sidering fertility treatment. In the Netherlands the cumulative risk of
ovarian malignancy (including borderline ovarian tumours) is small,
i.e. 0.45% at the age of 55 years. If our results are true, we would esti-
mate a 0.71% risk for women who underwent IVF. It should be
explained to women opting for IVF treatment that a borderline
ovarian tumour does not constitute a lethal disease, although it may
require extensive surgery and cause substantial morbidity. Ovarian
cancer, however, is a disease with a high case fatality rate, for which
Risk of ovarian malignancies after in vitro fertilization
effective screening methods are not available (Hermsen et al., 2007).
Although our findings give reason for some concern, they are still
based on rather small numbers, no dose–response relationship was
found and the risk increase for invasive ovarian cancer was not statisti-
cally significant in multivariable analyses. Even larger prospective
cohort studies of IVF-treated women, with prolonged follow-up and
a subfertile comparison group not treated with IVF, are needed to
confirm or refute our findings and to conduct dose–response analyses
with more power.
F.E.v L. and C.W.B. designed the OMEGA study and were principal
investigators of the study. F.E.v L. also coordinated statistical analyses,
contributed to interpretation of the data and drafted the paper.
C.W.B. contributed to interpretation of the data and drafting of the
manuscript. H.K. contributed to the design of the study, coordinated
identification of the cohort and data collection, did statistical analyses
and contributed to interpretation of data. T.M.M. coordinated data
collection, did the statistical analyses, contributed to study design,
interpretation of the data and drafting of the manuscript. A.M.G.vd
S. contributed to data collection and statistical analysis. C.B.L., M.K.,
J.S.E.L., C.A.M.J., F.M.H., B.J.C., W.N.P., J.M.J.S., A.H.M.S., F.vd V.,
J.L.H.E., P.A.v D. and N.S.M. provided IVF patient data and contribu-
ted to interpretation of the data. All authors contributed to critical
revisions of the draft manuscript. All authors saw and approved the
final version of the report.
The authors thank the participants of the OMEGA project, without
whom this study would not have been possible. We thank the
medical registries of the participating clinics for making patient
selection possible, and all attending physicians for providing access
to their patients’ medical files. We are especially grateful to the
research assistants M.Schippers, E.J. de Boer, I.M. Versteegden,
S. Braak, G.M. Plas, I. van Gils and I. Verburg for abstracting data
from the medical files in the participating hospitals. The authors
offer special thanks to A.W. van den Belt-Dusebout for all her contri-
butions to the OMEGA project. The authors also acknowledge the
Netherlands Cancer Registry (in particular O.Visser and J. van Dijck)
and PALGA (M. Casparie) for providing the follow-up cancer data
and W.J. Klokman for his support with the person-year analysis
Conflict of interest
J.L.H.E. declares that he works in a department that has received
unrestricted research grants from MSD and Ferring.
This study was supported by grants from the Health Research and
Development Counsel (28–2540) and the Dutch Ministry of Health.
Funding to pay the Open Access publication charges for this article
was provided by the Netherlands Cancer Institute.
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