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Cancer risk for the
patients undergoing ART
Is there still a problem?
M. Aboulghar
Cairo - Egypt
Women are delaying their first
By the year 2025, between 5.4-7.7
million women aged 15-44 will be
diagnosed in the USA with infertility
(Stephen and Chandra, 1998).
Consequently, ovulation-stimulating
drugs are among the fastest growing
groups of drugs (Wysowski, 1993).
Ovulation inducing drugs and
cancer risk
Studies addressing ovulation
inducing drugs and cancer risk have
limitations due to small sample size,
short follow up, imprecise
information on drug exposure,
indications for usage, absence of
information of drug exposure that
could influence cancer and recall
The results of case control studies are
limited by the fact that information on
prior drug use is based on patient
Most have been further limited by
small numbers of ovarian cancer cases
reporting prior drug usage.
For example, in the largest casecontrol study (Parazzini et al 2001).
Only 15 cases and 26 controls with
relevant exposures were reported for
Ovulation inducing drugs and
cancer risk
The principal shortcoming of these casecontrol and retrospective cohort studies is
that infertile women, usually anovulatory
are being compared with the experience of
the general population.
This is done using the calculation of
standardized incidence ratios (SIRs). SIRs
compare the numbers of observed cancers
in the cohort of interest to the number
expected on the basis on incidence rates
in the general populations.
Fertility drugs and ovarian cancer
The life time risk that a woman develops
ovarian cancer is between 1.4-1.8%.
In 1992 Whittmore and colleagues
conducted a systematic review of 12 casecontrol studies related to the etiology of
ovarian cancer.
The data from Whittmore and colleagues
was based upon a comparison of users
(fertility drugs) with the general
The risk of ovarian cancer and the
use of fertility medications was
heightened by a series of
publications, Whittemore et al. (1992)
from the Collaborative Ovarian
Cancer Group, which reported that
infertile women using fertility
drugs had almost three times the
risk (RR = 2.8, 95% CI = 1.3 to
6.1) for invasive epithelial ovarian
Critics of this report have cited:
Selection bias
Wide confidence intervals
Lack of a uniform etiology of infertility
Temporal incompatibility between
treatment for infertility and licensing of
modern fertility drugs in the subjects
Because of these limitation, the
conclusion of a causal link between
fertility medications and ovarian cancer
cannot be drawn confidently from these
Ovulation induction treatment and risk of
borderline ovarian tumors (Cusido et al. 2007)
This was a case-control study in which the
study group comprised 42 women with a
borderline ovarian tumor and the control group
comprised 257 women with benign ovarian
No differences were found between the
borderline tumor and control groups (14.3% vs
27.2%, respectively) in terms of infertility
history. And type of drug used whether CC
(9.5% vs 6.2%, respectively or gonadotropins
(7.1% vs 10.1% respectively). Analysis in
terms of the number of cycles administered
also failed to reveal any differences. This series
produced no evidence that ovulation induction
treatment predisposes women to the
development of borderline ovarian tumors.
Potashnik et al. (1999) in a prospective
cohort study followed 1197 infertile
women for a mean of 17.9 years. No
increased risk of ovarian cancer was
noted among those who had used
fertility drugs compared with the
unexposed group.
In a cohort of 29700 women, 20656
were exposed to fertility drugs and
9044 were not. For breast and
ovarian cancer the incidence was no
greater than expected (SIR 0.91
[95% CI 0.74-1.13] for breast cancer
and 0.88 [0.42-1.841] for ovarian
cancer in the exposed group and
0.95 [0.73-1.23] for breast cancer
and 1.16 [0.52-2.59] for ovarian
cancer in the unexposed group)
(Venn et al 1999).
Venn et al (1999) had a follow-up of 7
years for the exposed group and 10
years for unexposed group. Women
who underwent IVF were not at an
increased risk for ovarian cancer
compared to the general population.
Again, women with unexplained
infertility had significantly more ovarian
cancers than expected (SIR = 2.6).
A meta-analysis of eight studies involving
data on 1060 cases and 1337 controls
(Ness et al. 2002) also showed no risk
associations with fertility drug use.
In this study, after adjustment for types of
infertility, the risk associated with drug
usage was somewhat higher among
nulligravid women (1.8) and among those
who had more than 4 months of exposure
(relative risk (RR) 1.5-1.7), but none of
these risks was statistically significant.
A study on a total of 12193
infertile women in five fertility
centers in the USA, showed that
the increase in the risk of
ovarian cancer was similar for
women who received fertility
drugs and those who did not.
(Brinton et al., 2004).
Based on the evidence to date, there is
no conclusive link between fertility drugs
use and ovarian cancer. Additional
studies should continue to monitor longterm effects and assess whether there
may be distinctive relationships for
borderline ovarian tumors and certain
tumor histologies. Specific attention
should also be focused on effects among
nulligravidas. (Brinton et al 2005).
The recent multicenter US study of
gonadotropin and clomid users did
not find an increase in ovarian cancer
in this cohort (Althius et al 2005;
Brinton et al 2004).
A pooled analysis of 8 case controled
studies by Ness et al 2002 suggested
that infertility per se, but not the use
of fertility medications, elevates the
overall risk of ovarian cancer.
Case control studies of ovarian cancer
risk and fertility drugs versus no drugs
(Mahdavi 2006)
Whittemore et al. (1992)
No. of cases
(% treated)
No. of controls OR (95% CI)
(% treated)
718 (2.8)
1,236 (0.9)
2.8 (1.3-6.1)
1,060 (14.1)
1,337 (15.0)
1.0 (0.8 –
Franceschi et al. (1994)
195 (1.0)
1,339 (1.1)
0.7 (0.2-3.3)
Shushan et al. (1996)
164 (12)
408 (7.1)
1.3 (0.6278)
Mosgaard et al. (1997)
684 (20.7)
1,721 (23.8)
0.8 (0.4-2.0)
Parazzini et al. (1997)
971 (0.5)
2758 (0.4)
1.1 (0.4-3.3)
Parazzini et al. (2001)
10.31 (1.5)
2,411 (1.1)
1.3 (0.7-2.5)
Ness et al. (2002)
Rossing et al (1994) examined a
cohort of 3837 infertile women from
1974 to 1985.
The ratio of the observed to the
expected new cases for invasive
epithelial ovarian cancer was 1.5
(95% CI 0.4-3.7) and was 3.3 (95%
CI 1.1-7.8) for borderline tumors.
Fertility drugs and breast cancer
Among 92555 women from the study
population 6602 women were treated for
infertility. During the 10 year follow-up
period, 2571 cases of primary invasive
breast cancer were diagnosed (183 in
treated women). The study showed no
overall significant association between
breast cancer risk and treatment for
infertility (RR = 0.85, confidence interval
0.82-1.11). (Gauthier et al 2004)
Overall, the findings on ovarian
cancer (especially invasive
epithelial and non-epithlial) risk
associated with fertility drug
treatment are reassuring. However,
a stronger association between
fertility drug use and borderline
tumors of the ovary has been
observed. (Mahdavi et al 2006)
That ovulation-stimulating drugs
might preferentially affect the risk of
borderline ovarian tumours is also
suggested by several studies (Ness
et al 2002).
Ovarian stimulation may induce
growth in existing highly
differentiated indolent tumours.
Alternatively, the findings simply
could reflect more intensive medical
surveillance among infertile women.
Among women who participated in the
Nurses’ Health Study II, Terry et al (1006)
observed an inverse association between
infertility due to ovulatory disorder and
breast cancer incidence. We observed the
greatest reduction in the incidence of breast
cancer for women who reported ovulatory
disorder and use of ovulation induction
therapy, but these results should be
interpreted with caution because these
women may be the most infertile.
Infertile patients had a significantly higher
breast cancer risk than the general population
[SIR = 1.29, 95% confidence interval 1.1 -1.4].
Analysis within the cohort showed adjusted RRs
of 1.02 for clomiphene citrate and 1.07 for
gonadotrophins, and no substantial
relationships to dosage or cycles of use.
Although there was no overall increase in breast
cancer risk associated with use of ovulationstimulation drugs, long-term effects should
continue to be monitored (Brinton et al 2004).
Infertility, ovulation induction treatments and
the incidence of breast cancer--a historical
prospective cohort of Israeli women
The study cohort included 120,895 women
years of follow-up. Compared to 115.2
expected breast cancer cases, 131 cases
were observed (SIR = 1.1; 95% CI 0.91.4). Risk for breast cancer was significantly
higher for women treated with clomiphene
citrate (SIR = 1.4; 95% CI 1.0-1.8).
Infertility and usage of infertility drugs in
general are not associated with increased
risk for breast cancer. However, for infertile
women treated with clomiphene citrate,
breast cancer risk is elevated.
IVF and breast cancer
(Salhab et al 2005)
Fifteen studies were identified, of
these, 11 were cohort studies and 4
were case-control studies. None of the
individual studies showed an overall
significant association between IVF
and breast cancer and, in fact, one
study showed that treatment with hCG
significantly reduced the risk of breast
cancer in women whose maximum
non-pregnant body mass index was
less than 27.5.
IVF and breast cancer
(Salhab et al 2005)
CONCLUSION: Overall, there is no
clear evidence that ovulation
induction or IVF increases the risk of
breast cancer. However, there may
be a transient increase in the
incidence of breast cancer in the first
year due to earlier diagnosis.
Furthermore, the risk may be
increased in women with a positive
family history.
IVF and breast cancer
(Salhab et al 2005)
A combined analysis of the cohort studies
including a total of 60,050 women treated
with ovulation induction/IVF showed no
significant association between these
treatments and increased risk of breast
cancer (observed vs. expected: 601 vs. 568,
pooled relative risk [RR] = 1.06, P = 0.337).
The case-control studies included a total of
11,303 women in the breast cancer groups
and 10,930 controls. Women in the breast
cancer groups were slightly less likely to
have received IVF (2.2% vs. 2.5%, pooled
RR = 0.88, P = 0.231).
Fertility drugs and endometrial cancer
The most recently published study was a
multicenter retrospective cohort conducted in 5
US centers.
This study initiated from medical records
followed 12193 infertile women for a median of
18.8 years of follow up. The multicenter US
cohort study which detected 39 cases of
endometrial cancer among a cohort of clomid
users found a non-significant increase in
relative risk (RR = 1.79 CI 0.9-3.4)
The data from this study was based primarily
upon a comparison of fertiltiy drug users with
the general population.
An accurate assessment requires a randomized
placebo controlled trial in a uniform population
of anovulatory women (Athuis et al 2005).
Risk of thyroid cancer after exposure to
fertility drugs: results from a large
Danish cohort study (Hannibal et al. 2008)
A cohort of 54362 women with infertility
problems calculated rate ratios (RRs) of
thyroid cancer associated with different
fertility drugs after adjustment for age at
first live birth.
Use of clomiphene [RR= 2.28; 95% CI:
1.08-4.82] or progesterone [RR=10.14;
95% CI: 1.93-53.33] was associated with
an increased thyroid cancer risk.
Longer follow-up is needed to confirm
these findings.
Need more thoughtful planning
Need to link data bases in
different countries.
Need improved long-term followup
Need continued investigation of
fertility drugs and ovarian cancer
among nulligravida women.
The Egyptian IVF-ET Center
 Clinical directors:
• M. Aboulghar, M. D.
• G. Serour, M. D.
- Clinical associates:
• Y. Amin, M. D.
• M. Sattar, M. D.
• A. Ramzy, M. D.
• L. Mansour, M. D.
• M. Metwally, M. D.
• H. Aboulghar, M. D.
• M. Aboulghar, M. D.
• H. Al Inany, M. D.
• A. Abou-Setta, M. D.
- Andrology:
• I. Fahmy, M. D.
• A. El-Gindy
 Scientific director & Program manager:
• Ragaa Mansour, M. D., Ph. D.
- Embryology and micromanipulation
• S. Mansour, M. D.
• A. Kamal, M. D.
• A. Mostafa, M. D.
• N. Tawab, B.Sc.
• M. Serour, B.Sc.
• G. Afifi, B.Sc.
• M. Hammam, B.A.
- Cytogenetics - Cryobiology & andrrology
H. Fayek, Ph. D.
• D. Saad, B.Sc.
A. Abdel-Razek, M. D. • Y. Demery, B.Sc.
A. Amer, B.Sc.
• A. Barakat, B.Sc.
A. Khalil, Ph. D.
• M. Serour , B.Sc.
A. Naser, Ph. D.
• N. Salah , B.Sc.
O. Kamal, B.S.
• H. Fanous , B.Sc.
S. Mostafa
• A. Mohamed , B.Sc.