Download The relationship between infertility treatment and cancer including

DOI: 10.1111/tog.12040
2013;15:177–83
Review
The Obstetrician & Gynaecologist
http://onlinetog.org
The relationship between infertility treatment and cancer
including gynaecological cancers
Louay S Louis MRCOG,a,* Srdjan Saso
J Richard Smith MD FRCOGd
a
MRCS,
Sadaf Ghaem-Maghami
b
PhD MRCOG,
Hossam Abdalla
c
FRCOG,
a
Clinical Research Fellow, Division of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Imperial College London,
Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK
b
Consultant in Gynaecological Oncology, West London Gynaecological Cancer Centre, Queen Charlotte’s and Chelsea Hospital, Hammersmith
Hospital Campus, Imperial College London, Du Cane Road, London W12 0HS, UK
c
Consultant Gynaecologist and Lead Reproductive Medicine Specialist, Lister Fertility Centre, the Lister Hospital, Chelsea Bridge Road, London
SW1W 8RH, UK
d
Consultant Gynaecological Surgeon, West London Cancer Centre and Queen Charlotte’s and Chelsea Hospital, Hammersmith Hospital Campus,
Imperial College London, Du Cane Road, London W12 0HS, UK
*Correspondence: Louay S. Louis. Email: [email protected]
Accepted on 31 January 2013
Key content
Increasing availability and expanding usage of infertility treatment
is a concern with regard to a possible increase in the risk of future
malignancy development for women and their offspring.
Infertile women are at significantly increased risk of developing
ovarian and uterine cancers, especially nulliparous women.
Earlier studies pointed to a possible increase in the risk of ovarian
cancer following large doses and multiple cycles of clomiphene citrate.
Recent studies did not observe any increase in malignancy risk due
to infertility medications. Other confounding factors, such as
infertility itself, may well be the reason for the increased percentage
of cancer cases noted in earlier studies.
Uterine cancer risk is possibly increased following multiple cycles
and high doses of clomiphene citrate.
There is no strong evidence linking infertility treatment with
non-gynaecological or childhood cancers, with the possible
exception of melanoma.
Learning objectives
To highlight the available evidence linking infertility treatment
with gynaecological, non-gynaecological and childhood cancers.
How to counsel women about any possible risk of future neoplasia
after infertility treatment.
Ethical issues
Is it ethical to persevere with multiple fertility treatment cycles if it
might be associated with increased risk of neoplasia in the future?
Keywords: assisted conception / cancer / epidemiology / infertility
Please cite this paper as: Louis LS, Saso S, Ghaem-Maghami S, Abdalla H, Smith JR. The relationship between infertility treatment and cancer including
gynaecological cancers. The Obstetrician & Gynaecologist 2013;15:177–83.
Introduction
Debate has been continuing since the 1990s regarding the
association between infertility, infertility treatment, use of
assisted reproductive techniques (ART), and cancer,
especially gynaecological and breast cancers.
With approximately 1 in 7 couples affected by infertility,1
together with an annual increase in fertility treatment in the
UK and other developed countries, concerns have been raised
as to the possible impact of fertility treatments on the
development of cancer. A total of 39 879 women received
in vitro fertilisation (IVF) treatment in 2008 in the UK, an
increase of 8.2% on the previous year. These women had
50 687 cycles of treatment. There were 12 211 successful
births in 2008. Some of these births were twin or triplet
births, so a total of 15 082 babies were born.2
ª 2013 Royal College of Obstetricians and Gynaecologists
Ovulation-inducing agents have been widely used to treat
infertility problems, either alone such as anti-estrogens
(e.g. clomiphene citrate [CC] and less frequently tamoxifen),
or as part of IVF cycles including human menopausal
gonadotrophins (hMG) and recombinant follicle-stimulating
hormone (rFSH) and human chorionic gonadotrophins (hCG)
We will discuss whether there is an association between
infertility, its treatment, and cancer. This will help when
counselling patients—who suffer from infertility, awaiting
infertility treatment, or are concerned about the impact of
IVF on developing cancer.
Fertility treatment and ovarian cancer
Ovarian cancer is the fifth commonest cancer in women in
England, with 5535 new cases diagnosed in 2010.3 Risk
177
Infertility treatment and cancer
factors include nulliparity, early menarche, late menopause,
and increasing age. Combined oral contraceptive (COC) pill
use, pregnancy, lactation, and tubal ligation are associated
with a reduced risk.4 Nulliparity increases the risk of
developing ovarian cancer by 1.5–2-fold (adjusted odds
ratio [OR] 2.71, 95% confidence interval [CI] 1.33–5.52) for
untreated, infertile nulliparous women;5 and nulligravidas
who received fertility treatment but failed to conceive are at
increased risk of ovarian malignancy compared with those
who did (OR 27.0, 95% CI 2.3–315.6).6,7 Furthermore,
unexplained infertility has been associated with an increased
risk of developing ovarian and uterine cancers (standardised
incidence ratio [SIR] 2.64, [95% CI 1.10–6.35] and 4.59 [95%
CI 1.91–11.0] respectively).8
COCs substantially decrease the risk of ovarian cancer even
after a few months of use.9,10 The longer a woman has used
COCs, the greater this effect, with the reduction in risk
persisting for more than 30 years after cessation of COCs.
However, its effect becomes attenuated11 with OR of developing
ovarian cancer as low as 0.21 for women who took the pill for
more than 10 years. It is estimated that each year of using the
pill brings an approximate 7% reduction in risk of ovarian
cancer.12 However, women who undergo fertility treatment
may have used COCs far less than the general population.13
Whittemore et al.7 first noted that a small fraction of the
excess in ovarian cancer risk among nulliparous women is
because of infertility, and that any increased risk associated
with infertility may be related to the use of fertility drugs.
Conclusions were derived from 12 case–control studies of
ovarian cancer, but only three of them reported data on
infertility, infertility treatment, and ovarian cancer
development. The treatments used were outdated and
included diethylstilbesterol and conjugated estrogen. A
follow-up analysis demonstrated an increased risk in
tumours of low malignant potential in comparison to
invasive tumours.14 Nonetheless, this conclusion was based
on only four ovarian cancer cases of low malignant potential
(OR 4.0, 95% CI 1.1–13.9). Neither of the above two studies
corrected for, nor took account of, confounding variables
such as family history or use of COCs.
Some historical as well as more recent cohort studies
showed an increased risk of ovarian cancer with the use of
infertility treatment, such as CC15 and gonadotrophins.16
This led some reviewers to conclude that the risk of ovarian
cancer, if such a risk exists, is two to three times higher than
the risk for the general population, with the lifetime risk of
ovarian cancer in the general population quoted at 1 in 70
(~1.43%)17; thus, an equivalent risk for patients treated with
fertility drugs may carry a 4–5% lifetime risk.18
The paper by Rossing et al.15 in 1994 led to significant
change in practice regarding the use of CC, as it concluded
that the latter increased the risk of borderline and invasive
ovarian cancer. This was even more so when CC was taken
178
for 12 or more cycles with a relative risk (RR) of 2.3 in
general and 11.1 (with 12 or more cycles) compared with
infertile women with no CC use (95% CI 0.5–11.4 and 1.5–
82.3 respectively). This cohort study included 3837 infertile
patients with a mean follow-up of 11.3 years. It reported 11
cases of invasive or borderline ovarian cancer (4.4 cases
expected). It was limited by the small number of tumours
and a heterogeneous histological mix.
More studies observed a stronger association between
fertility drug use and borderline tumours of the
ovary14,16,19,20 including hMG use.21 A recent large cohort
study by Sanner et al.16 reviewed 2768 infertile women; of
whom 1150 did receive treatment in the form of CC and/or
gonadotrophins, with a mean follow-up of 33 years.
Fourteen patients developed ovarian cancer, nine of them
were in the exposed group. The authors concluded that there
is an increased risk of ovarian cancer after gonadotrophins
(RR 5.28, 95% CI 1.91–13.75) and borderline tumours after
CC treatment (SIR 3.61, 95% CI 1.91–7.44).
On the other hand, larger cohort and case–control studies
reported no association between fertility treatment and
ovarian cancer.22–27
Modan et al.22 reviewed a cohort of 2496 infertile patients
with a mean follow-up of 21.4 years. In all, 143 cancer cases
were observed; 12 were ovarian (7.2 expected, 95% CI 0.6–
3.8). However, the latter result was not significant (SIR 1.7 vs
1.6, v2 = 0.34) after correcting for nulliparity.
A historical cohort analysis by Dor et al.23 of 5026 patients
who had IVF using either CC with hMG, hMG alone, or
gonadotrophin-releasing hormone (GnRH) agonist observed
27 cases of cancer (35.6 expected). No excess cancer risk was
noted, but the mean follow-up period was 3.6 years only. A
similar cohort study was performed by Doyle et al.24 on 5556
patients, 75% of whom had CC either alone or in
combination with gonadotrophins. After a mean follow-up
period of 15.5 years, 118 cancers were identified (55 breast,
four uterine, and six ovarian). There was no significant
difference noted in the observed and expected incidence of
breast, uterine and ovarian cancers.
Brinton et al.25 reported on a retrospective cohort of
12 193 patients treated with CC and/or hMG. The mean
follow-up period was 19.4 years. A total of 581 cases of
cancer, including 45 cases of ovarian cancers, were identified.
After adjusting for patients’ characteristics, no strong link
was observed between ovulation-stimulating drugs and
ovarian cancer (SIR 0.82 [95% CI 0.4–1.5] for CC and 1.09
[95% CI 0.4–2.8] for gonadotrophins).
Four large studies since 2009 have sought to determine
whether there is an association between fertility treatment
and ovarian cancer. The first was a large Danish case–control
study by Jensen et al.26 who reviewed 54 362 patients during
a 16 year (median) follow-up. Patients were treated with four
different categories of fertility drugs including CC,
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Louis et al.
gonadotrophins, hCG and GnRH. The authors concluded
that there was no convincing association between fertility
treatment and ovarian cancer, including different drug
groups, length of follow-up or parity (rate ratios:
gonadotrophins [0.83, 95% CI 0.50–1.37], CC [1.14, CI
0.79–1.64], hCG [0.89, CI 0.62–1.29] and GnRH [0.80, CI
0.42–1.51]). The second study by Calderon-Margalit et al.27
was a historical cohort study of 15 030 parous women treated
with CC and gonadotrophins, with a mean follow-up of
29 years. The authors found no association between fertility
treatment and ovarian cancer (age-adjusted hazard ratio
[HR] of 0.61, 95% CI 0.08–4.42).
K€allen et al.28 reported an increased risk in ovarian cancer
following IVF treatment. The risk nonetheless was lower than
that before treatment. This was a large study based on a cohort
of 24 058 patients matched to a control group with all patients
having undergone IVF. A total of 1279 patients developed
cancer, 26 of which were ovarian cancers. There was a
statistically generalised decrease in cancer risk following IVF
compared with prior to treatment (OR 0.74, 95% CI 0.67–
0.82). This was even more so in women who had more than
one delivery. Van Leeuwen et al.29 reported on a historic
Dutch cohort of 19 146 subfertile women who received at least
one cycle of IVF between 1983 and 1995. This was compared
with 6006 women who did not undergo IVF treatment, and to
the general population. After a mean follow-up period of
14.3 years for the treatment group, the authors concluded that
ovarian stimulation using IVF may increase the risk of ovarian
malignancies. The risk of borderline ovarian tumours (but not
invasive ovarian cancer) was higher in the IVF-treated group
compared with the general population (SIR 1.76, 95% CI 1.16–
2.56), whereas the risk of all ovarian malignancies was higher
compared with the untreated subfertile cohort (adjusted HR
2.14, 95% CI 1.07–4.24).
In conclusion, the increased risk in borderline and invasive
ovarian cancer noted in earlier studies following high doses
and multiple cycles of CC was not confirmed in larger and
more recent studies, the results of which are more reassuring
with respect to any increase in malignancy risk due to
infertility medications (Table S1).
Fertility treatment and uterine cancer
Uterine cancer is the fourth commonest cancer in women in
the UK with 6834 new cases diagnosed in 2010.3 As stated
above, unexplained infertility has been associated with a
diagnosis of uterine cancer (including both endometrial
carcinoma and sarcoma).8 The main concern regarding the
increased risk of uterine cancer with infertility treatment is the
fact that the latter is associated with unopposed
supraphysiological levels of estrogen which may lead to
endometrial hyperplasia and possibly endometrial cancer.
This is true in the case of tamoxifen.30 As for CC, there is
ª 2013 Royal College of Obstetricians and Gynaecologists
evidence that endometrial thickness is significantly reduced in
cycles using CC for ovulation induction compared with that in
non-CC cycles.31 Nonetheless, it is believed that CC increases
serum estradiol levels during the follicular phase of menstrual
cycles of induced ovulation,30 leading to the endometrium
being exposed to increasing levels of estrogen, and hence
increased mitotic activity, DNA replication errors, somatic
mutations, and the possible development of malignancy.19
This is a specific concern with regard to cases of anovulatory
infertility, a large number of which are due to polycystic ovary
syndrome (PCOS). However, contrary to general belief, the
evidence linking PCOS as an independent risk factor for
developing endometrial cancer is not conclusive.32
Interestingly, in one study, patients with primary infertility
due to anovulation seemed to be particularly predisposed to
uterine cancers (RR 2.42, 95% CI 1.0–5.8). However, only 5%
of women in that study would be classified as PCOS.33
Reviewing the literature yields few relevant studies but they
mostly demonstrate a persistent trend to an increased risk of
uterine cancer, mainly with CC8,22,27,30,34,35 ChalderonMalgarit et al.27 reported an increased risk of uterine cancer
with fertility treatment (adjusted HR: 3.39, 95% CI 1.28–8.97),
and the risk further increased with CC (HR 4.56, 95% CI 1.56–
13.34). However, it is worth noting that ‘uterine cancer’ was
not strictly defined in this study, though it implied cases of
endometrial carcinoma only.
A study by Venn et al.8 of a large Australian cohort of
29 700 patients in total (20 656 were exposed to fertility
drugs including CC, hMG and GnRH agonist, whereas 9044
patients were not) noted a transient increase in the risk of
uterine cancer diagnosed in the first year after treatment,
though the incidence overall was no greater than expected
(SIR 1.09, 95% CI 0.45–2.61). This observation was based on
12 cases with only 7 years of follow-up. Four of those cases
were sarcomas and occurred in the unexposed group.
In a retrospective case–control study by Althuis et al.,30
8431 patients had been treated with CC and gonadotrophins,
with an average follow-up of 20 years. The authors identified
39 uterine cancers (almost all of endometrial type), and
concluded that CC may increase the risk of uterine cancer
(RR 1.79, 95% CI 0.9–3.4) in a dose-related fashion especially
when coupled with nulliparity (RR 3.49, 95% CI 1.3–9.3) and
obesity (RR 6.02, 95% CI 1.2–30.0). This conclusion was
more evident with doses of ≥900 mg (RR 1.93, 95% CI 0.9–
4.0), six or more menstrual cycles of CC (RR 2.16, 95% CI
0.9–5.2) and time elapsed since the initial use (RR 2.5, 95%
CI 0.9–7.2). Adjustments for anovulatory disorders in
multivariate models did not change the estimates of uterine
cancer risk associated with CC.
Jensen et al.34 concluded that gonadotrophins, and
possibly CC and hCG, may increase the risk of uterine
cancer. The higher the dose and the longer the follow-up, the
greater was the risk especially after more than 10 years of
179
Infertility treatment and cancer
follow-up. This was based on the same large Danish cohort of
54 362 patients mentioned above who were treated with four
drug groups of CC, hCG, gonadotrophins and GnRH.
Eighty-three uterine cancers were identified, with the
majority (79) being of the epithelial (endometrial) type.
This study also concluded that six or more cycles of hCG or
CC may increase the risk of uterine cancer (RR 1.96, 95% CI
1.03–3.72, and RR 2.18, 95% CI 1.16–4.08 respectively). The
main limitation of this study was the patients’ mean age at
the end of the follow-up period being only 47 years. This is
well below the average age of 60 years for developing uterine
cancer.36 Other limitations included not adjusting for other
confounding factors such as histological subtype, obesity,
COC use or menopausal status, although adjustment of the
RR with causes of infertility (when the results were available)
did not significantly change that risk.
A study by Silva et al.35 of a British cohort of 7355 patients,
of whom 43% had received ovarian stimulatory drugs,
reported that CC conferred a 2.6-fold increase in the risk of
developing cancer of the corpus uteri with a total dose of
≥2250 mg (RR 2.62, 95% CI 0.94–6.82). There were no clear
trends with time since first treatment, i.e. latency, but there was
possibly an association with the number of cycles of CC (RR
2.2, 95% CI 0.24–9.80 with 10 or more cycles). Although high
doses of CC may have been preferentially given to women with
PCOS, adjustments for underlying diagnosis of the latter only
slightly reduced the magnitude of the estimated risk. The
follow-up in this study was more than 20 years; but with only
31 uterine cancer cases, and histology not ascertained, it is
quite difficult to draw any concrete conclusions.
In conclusion, multiple cycles and high doses of
clomiphene citrate may be associated with an increased risk
of uterine cancers, but the evidence for this being an
independent risk factor is inconclusive (see Table S2).
Fertility treatment and breast cancer
Breast cancer is the commonest cancer in women in England
and worldwide, with 41 259 new cases diagnosed in 2010.3
Estrogen and progesterone play an important role in
tumorigenesis. As there is an increased risk of breast cancer
for infertile nulliparous women anyway, it is interesting to
focus on the role of ART and ovulation induction treatments
as a risk factor for breast cancer, with ART being associated
with supraphysiological and unopposed levels of estrogen.
As early as 1977, Bolton published the first case report of
bilateral breast cancer associated with CC.37 Since then, a few
cohort and case–control studies have been published with
contradictory conclusions. Some studies observed no
confirmatory association between fertility drugs and breast
cancer.8,38–40 Other studies found an increased risk in the
first year after fertility treatment which was attributed to the
probable presence of an occult lesion at the time of
180
treatment.41 However, a few other studies did report an
increased risk following IVF.27,42,43
A 1995 study by Venn et al.,40 extended in 1999 to include
29 700 patients, of whom 20 656 were exposed to fertility
drugs with a mean follow-up of 7 years,8 reported 143 cases
of breast cancer. The authors concluded that women exposed
to fertility drugs have a transient increase in the risk of breast
cancer diagnosed in the first year after treatment (SIR 1.96,
95% CI 1.22–3.15). However, the overall incidence was no
greater than expected.
A large cohort study from Denmark by Jensen et al.44 did
not demonstrate an association between breast cancer and use
of fertility drugs. Using the same cohort they had followed for
the ovarian and uterine cancer mentioned earlier, they
identified 331 cases of breast cancer after a mean follow-up
period of 8.8 years. Nonetheless, there was some evidence of an
increased risk of breast cancer in a subgroup of patients who
had used progesterone (RR 3.36, 95% CI 1.3–8.6).
Three studies from Israel reported an association between
fertility treatment including IVF and breast cancer. Pappo
et al.42 reported a possible association between IVF therapy
and breast cancer in a cohort of 3375 IVF-treated women.
This was evident in: women aged ≥40 years at first IVF cycle,
those with hormonal infertility, and those undergoing four or
more IVF cycles. This was all in comparison to the general
population (SIR of 1.9, 95% CI 0.97–3.30; 3.1, 95% CI 0.99–
7.22; and 2.0; 95% CI 1.15–3.27 respectively). The limitations
of this study include: small sample, relatively short follow-up
period of 8.1 years with only 35 cases identified, of whom
29% had a positive family history. The second study by Katz
et al.43 reported an increased risk of breast cancer in women
who started their IVF treatment after age 30 years (RR 1.24,
95% CI 1.03–1.48). This was based on a cohort study of 7162
patients from a single centre and only 41 cases of breast
cancer. The mean follow-up period was 12.9 years. Finally, a
historical cohort study by Chalderon-Malgarit et al.
including 15 030 parous women who were treated with CC
or gonadotrophin, and followed-up for 29 years, noted an
increased risk of breast cancer of borderline significance
(multivariate hazard ratio [HR] 1.42, 95% CI 0.99–2.05). The
risk was higher for patients who waited ≥12 months to
conceive (HR 2.36, 95% CI 1.30–4.27).27
A study by Orgeas et al.45 reported no association between
fertility treatment and breast cancer. Even so, they did note
that women with non-ovulatory causes treated with
high-dose CC therapy may have an elevated risk (SIR 1.9,
95% CI 1.08–3.35). The cohort sample was small with only
1135 patients, but the median time from fertility treatment to
breast cancer diagnosis was 26 years.
Gauthier et al.,46 in a prospective cohort study involving
6602 patients treated for infertility, reported a possible
increased risk of breast cancer after fertility treatment in
women with a family history of the disease. However, no
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Louis et al.
overall significant association between treatment and breast
cancer was observed (RR 0.95, 95% CI 0.82–1.11) despite
almost 10 years of follow-up. Furthermore, the association
between IVF and familial breast cancer was disputed in a
case–control study by Kotsopoulos et al.47 who concluded
that fertility treatment, including IVF, did not increase the
risk of breast cancer among patients with BRCA mutation
(OR 1.21, 95% CI 0.81–1.82).
It has been observed that women who gave birth after IVF
treatment had a decreased incidence of breast cancer, but this
was not statistically significant (rate ratio 0.93, 95% CI 0.58–
1.43). This was a cohort of 8716 patients who gave birth
following IVF and were followed up for a mean of
6.2 years.48 The large British cohort study by Silva et al.35
reported an increased risk of breast cancer compared with the
general population (RR 1.13, 95% CI 0.97–1.30).
Nevertheless, no significant differences between the exposed
and non-exposed infertile cohort after mean follow up of
21.4 years were observed. Evidently this implies that it may
well be infertility that is the cause for the increased risk;
furthermore, a case–cohort study by Rossing et al. concluded
that using CC as a treatment for infertility lowers the risk of
breast cancer (adjusted RR 0.5, 95% CI 0.2–1.2).49
In conclusion, there is no strong evidence linking fertility
treatment with breast cancer (Table S3).
Fertility treatment and other cancers
A few studies have reported an increased risk of developing
non-gynaecological cancer after fertility treatment. However,
the numbers are generally very small and one is unable to reach
any reliable conclusions. This is also partly due to the lower
incidence of some of these cancers. One must note that the
effects of infertility may well extend beyond gynaecological
cancers, especially with thyroid cancers and melanomas,
particularly when the cause of infertility is secondary to
endometriosis, although the association is likely to be casual.33
In 2010, a total of 5505 new cases were diagnosed with thyroid
cancer and 1578 with malignant melanoma.3
The aetiology of malignant melanoma, and to a lesser
extent that of thyroid cancer, is known to involve
endogenous and exogenous hormones. It is also associated
with parity and COCs.50,51 It was therefore hypothesised that
the exogenous hormones administered for fertility treatment
might be linked with both cancers.
The study by Silva et al. observed higher than expected
incidence of liver and biliary tract cancer but the results
showed no statistical significance.35
Linkage of the large Danish cohort mentioned earlier to
different cancer registries yielded no strong association
between use of fertility drugs and malignant melanoma.
However, the results did indicate that use of gonadotrophins
or GnRH might increase melanoma risk in parous women
ª 2013 Royal College of Obstetricians and Gynaecologists
(RR 2.29, 95% CI 1.16–5.52, and RR 3.26, 95% CI 1.50–7.09
respectively).50 The same group also reported that, for the
same cohort, CC and possibly progesterone may increase
thyroid cancer risk particularly among parous women (RR
3.09, 95% CI 1.21–7.88). This was based on only 29 cases of
thyroid cancers out of a cohort of 54 362 women.51
Another retrospective cohort study by Althuis et al. of
8422 patients evaluated for infertility (1965–1998) and
followed up for a mean of 18.8 years reported that the risk
of cancer after CC or gonadotrophins did not increase
significantly for melanoma, thyroid, cervical, or colon cancer
with either drug. However, CC may impart stronger effects
on risks of melanoma (RR 2.0, 95% CI 0.9–4.6) and thyroid
cancer (RR 4.32, 95% CI 1.0–17.1) among women who
remained nulliparous.52
In conclusion, there is no strong evidence linking infertility
treatment with non-gynaecological cancers. Further studies
are needed to evaluate any association between infertility,
fertility treatment and melanoma.
Fertility treatment and childhood cancers
Several sporadic case reports53,54 highlighted a possible link
between IVF and childhood cancer starting in 2001 with
a report of unilateral retinoblastoma in one child among a
cohort of 47 children born after ART.53 Retinoblastoma is a
rare childhood cancer with only 41 new cases diagnosed in
England in 2010.3
In 2003 a small series of case reports55 noted an increased
risk of developing retinoblastoma in babies born following
IVF. This was based on five cases of retinoblastoma and the
estimation that 1–1.5% of babies in the general population
were born as a result of IVF (RR 7.2, 95% CI 2.4–17.1for 1%
estimate, and RR 4.9, 95% CI 1.6–11.3 for 1.5% estimate).
Though the same researchers observed no increase in risk
over an expanded study period of 5 years, they still found an
increased risk of retinoblastoma based on the calculations
from the earlier cohort.56 The study provided no firm link
between IVF treatment and retinoblastoma, other than
perhaps to question whether a change in the IVF
procedure itself (such as the culture medium) had been
influential, or to speculate on some undefined genetic factors
linking both infertility and retinoblastoma. This is in
addition to the possibility that the association may be a
chance finding.55
Other larger studies were more reassuring57–60 and found
that children conceived using IVF and related procedures did
not have a significantly increased incidence of cancer
compared with the general population. In the largest of
these studies by Bruinsma et al.57 who reviewed a cohort of
5249 births with a median follow-up of 45 months, the
authors expected 4.33 cases of cancer and six cases were
observed (SIR 1.39, 95% CI 0.62–3.09).
181
Infertility treatment and cancer
Another large record linkage study61 of 30 364 Danish
women evaluated for fertility concluded that there was no
increase in the risk of any childhood malignancy. However,
it advised to continue monitoring the effects of
ovulation-stimulating drugs on future tumour incidence.
In conclusion, there is no strong evidence linking infertility
treatment with childhood cancers.
Table S2. Principal studies examining infertility treatment
and risk of uterine cancer.
Table S3. Principal studies examining infertility treatment
and risk of breast cancer.
Please access TOG online here: http://onlinetog.org.
RCOG fellows and members can access TOG via the RCOG
website.
Conclusion
References
Despite the increasing numbers and the wide availability of
ART, particularly IVF, the number of gynaecological cancers
(ovarian and uterine) as well as breast and other cancers
remains relatively small—as per expectation from various
studies, including more recent and large ones, that corrected
for confounding factors, namely infertility and nulliparity.
There is some reliable evidence to suggest that CC when
given in large doses and with multiple cycles increases the
risks of the gynaecological cancers, and probably breast
cancer. However, guidelines for current practice recommend
not to use CC for more than 12 cycles1; furthermore, CC is
only licensed for a maximum use of six cycles.
There is also some weak evidence to suggest that multiple
IVF cycles might be associated with an increased risk of
breast cancer. While pointing out that all the studies have
methodological limitations, it will be sensible to ensure that
women who have had multiple IVF cycles (regardless of the
outcome) are informed of this possible risk as part of their
counselling. The decision to proceed with IVF subsequently
should be patient-centred and must respect the patient’s
informed choice.
One should remember that since the average age of
IVF patients is 35 years2 and that the average age for
ovarian and uterine cancer diagnosis is around 60 years,17,36
most of the treated patients have not yet reached that
stage; therefore vigilance is paramount to determine any
future trends.
When counselling, patients in general should be reassured
about the current data: that there is no significant increase in
risk of cancer with IVF treatment for them or their offspring.
We should also remember that infertile patients are at
significantly higher risk of cancer due to their infertility and
other confounding factors. Nevertheless, future data may
indicate otherwise.
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Disclosure of interests
None to declare
Supporting information
Additional supporting information may be found in the
online version of this article:
Table S1. Principal studies examining infertility treatment
and risk of ovarian cancer.
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