Fertility Treatment and Risk of Cancer

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.



Fertility and Female Age

Social trends have led to deferring the age of child bearing not only in the developed countries but also in developing countries.

It is well understood that the number of oocytes in the ovaries decline naturally and spontaneously through process of programmed cell death.Hence chances of achieving pregnancy not only decline through natural conception but also through assisted reproductive technologies (IUI/IVF/ICSI)

This has been re-enforced by research led by Prof Siladitya Bhattacharya, of the Reproductive Medicine team at the University of Aberdeen (UK) who found that the chances of a woman having a baby following IVF go "very rapidly downhill" from the age of 37.Data was obtained from 121,744 women from across the UK.

They found the chances of having a baby following IVF start to decline by the time the woman reaches her mid-30s, but especially from 37.The team used data from women who underwent their very first cycle of IVF using their own eggs.The research also found that even after a pregnancy has been confirmed, women aged 38-39 were 43% more likely to have a miscarriage than women aged 18-34, while women aged 40-42 were almost twice as likely to lose the baby as the younger age group.

To conclude, age is amongst one of the most important factors which determines the success to achieving conception. Hence awareness of effect of age on fertility is important when counselling couples with infertility.