Treatment of Infertility and Cancer Risk : Is there any association?

The use of assisted reproductive technologies is increasing. With advancement in the understanding of reproductive physiology and advancements in the techniques of reproductive medicine, its use is now extended to link this specialty with cancer treatment as well in the form of preserving fertility.

On the other hand, the possible link between fertility drugs and cancer of reproductive organs remains controversial and there is still an ongoing debate on the long-term effects of assisted reproductive technology techniques such as ovulation induction, in-vitro fertilization on the risk of ovarian, endometrial, cervical and breast cancer and also on risk of melanoma.

Here we discuss few studies which have been conducted worldwide to look into his ongoing controversial issue-

Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large US infertility cohort

Britton Trabert et al, Fertil Steril. 2013 December; 100(6)

 

A retrospective cohort of 9,825 women were evaluated for infertility at five clinical sites in the United States between 1965 and 1988 with follow-up through 2010.

Among women evaluated for infertility, there was no association of ovarian cancer risk with ever use of clomiphene citrate (adjusted RR 1.34, 95% CI 0.86–2.07) or gonadotropins (RR 1.00, 95% CI 0.48–2.08) and no evidence that any of several more detailed subgroups of usage were related to an increased risk. Though it was found in the analysis that women who used Clomiphene citrate and remained nulligravid did demonstrate much higher risks than those who successfully conceived compared with nonusers (respectively, RR 3.63, 95% CI 1.36–9.72 vs. RR 0.88, 95% CI 0.47– 1.63).

IVF and breast cancer: a systematic review and meta-analysis

Theodoros N. et al Human Reproduction Update, Vol.20, No.1 pp. 106–123, 2014

Eight cohort studies were analyzed with a total cohort size of

1 554 332 women among whom 14 961 incident breast cancer cases occurred, encompassing 576 incident breast cancer cases among women exposed to IVF. No significant association between IVF and breast cancer was observed either in the group of studies treating the general population (RR 1⁄4 0.91, 95% confidence interval (CI): 0.74 – 1.11) or infertile women (RR 1⁄4 1.02, 95% CI: 0.88 – 1.18), as a reference group. Though it was noticed that pregnant and/or parous women after IVF (pooled effect estimate 1⁄4 0.86, 95% CI: 0.73–1.01) were marginally protected but it was not protective with those who were 30 years at first IVF treatment (pooled effect estimate 1⁄4 1.64, 95% CI: 0.96–2.80).

the conclusion from this analysis was that in the current scenario COH for IVF does not seem to impart increased breast cancer risk, but still what is needed is longer follow-up periods, comparisons versus infertile women, subgroup analyses aiming to trace vulnerable subgroups, adjustment for various confounders and larger informative data sets before conclusive statements for the safety of the procedure are reached.

Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer—a systematic review and meta-analysis

Charalampos Siristatidis et al , Human Reproduction Update, Vol.19, No.2 pp. 105–123, 2013

Nine cohort studies were synthesized, corresponding to a total size of 109 969 women exposed to IVF, among whom 76 incident cases of ovarian, 18 of endometrial and 207 cases of cervical cancer were studied. The synthesis of studies with general population as the reference group pointed to a statistically significant positive association between IVF and increased risk for ovarian (RR 1⁄4 1.50, 95%

The conclusion from this analysis was that IVF does not seem to be associated with elevated cervical cancer risk, nor with ovarian or endometrial cancer when the confounding effect of infertility was neutralized . Of importance is only one study provided follow-up longer than 10 years for the group exposed to IVF. Hence what is needed is future cohort studies preferably using infertile women as the reference group, rely on IVF-registered valid exposure data, adjust for a variety of meaningful confounders and adopt relatively longer follow-up periods before sound conclusions are drawn.

Melanoma risk after ovarian stimulation for in vitro fertilization.

Spaan M et al. Hum Reprod. 2015 May;30(5):1216-28.

This study was part of OMEGA project group looking into association of ovarian stimulation on development of cancer. The cohort comprised of 19158 women who received IVF between 1983-1995 and a comparison group of 5950 womenwho underwent subfertility treatment other than IVF. . In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles were associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21).

Conclusion – the above reviews have tried to address an important aspect and so far infer that treatment of infertility in the form of ovulation induction, in-vitro fertilization does not confer high risk for cancer in reproductive system. Interestingly studies have also highlighted that patients who remain infertile despite these treatments have shown some increased risk in cancer development though numbers studies in these sub-groups were small and properly designed studies to answer these questions further. Extrapolation of these global studies to Indian context has also to be considered when counseling our patients.