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Keywords:

  • assisted conception;
  • cancer;
  • epidemiology;
  • infertility

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

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?

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

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]

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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

Ovarian cancer is the fifth commonest cancer in women in England, with 5535 new cases diagnosed in 2010.[3] Risk 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 attenuated[11] 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 CC[15] 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 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 ovary[14, 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, χ2 = 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, 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).

Källén 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

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 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 CC[8, 22, 27, 30, 34, 35] Chalderon-Malgarit 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 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

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 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 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

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 (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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

Several sporadic case reports[53, 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 reports[55] 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 reassuring[57-60] 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).

Another large record linkage study[61] 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.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

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 cycles[1]; 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 years[2] 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.

Disclosure of interests

None to declare

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fertility treatment and ovarian cancer
  5. Fertility treatment and uterine cancer
  6. Fertility treatment and breast cancer
  7. Fertility treatment and other cancers
  8. Fertility treatment and childhood cancers
  9. Conclusion
  10. References
  11. Supporting Information
FilenameFormatSizeDescription
tog12040-sup-0001-TableS1.docxWord document36KTable S1. Principal studies examining infertility treatment and risk of ovarian cancer.
tog12040-sup-0002-TableS2.docxWord document31KTable S2. Principal studies examining infertility treatment and risk of uterine cancer.
tog12040-sup-0003-TableS3.docxWord document36K

Table S3. Principal studies examining infertility treatment and risk of breast cancer.

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