Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort

Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Human Reproduction (Impact Factor: 4.57). 12/2011; 26(12):3456-65. DOI: 10.1093/humrep/der322
Source: PubMed


Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown.
We identified a nationwide historic cohort of 19,146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997-1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group.
After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16-2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62-6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25-14.33 and 2.14; 95% CI = 1.07-4.25, respectively, adjusted for age, parity and subfertility cause).
Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

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    • "It is not clear what biological mechanisms can explain this association. One of the major and unavoidable shortcomings of the reviewed studies is short follow-up periods and only two studies (vanLeeuwen et al., 2011;Bjornholt et al., 2015) have provided longer follow-up periods. So this condition seems indispensable for evaluating the impact of ovarian stimulation drugs on the risk of gynaecological cancer. "
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    ABSTRACT: Background: The trend toward late childbearing has made fertility preservation a major issue for women who face gynecological cancer. New techniques in assisted reproductive medicine enable conception after primary treatment of these cancers. Here, we aimed to review the efficacy and safety of assisted reproductive techniques (ART) after fertility-preserving treatment of gynaecological cancers. Methods: We conducted a systematic literature review of both prospective and retrospective studies in the PubMed, EMBASE, CENTRAL and SciSearch databases. In the retrieved studies, we evaluated live births, clinical pregnancies, overall survival and disease-free survival. Results: We identified many prospective and retrospective studies on this topic, but no relevant randomized clinical trials. Fertility-sparing treatments with safe oncological outcomes are feasible in endometrial, cervical and ovarian cancer cases. After cancer treatment, ART seem safe and show variable obstetrical outcomes. Conclusions: After fertility-preserving treatment for gynaecological cancers, ART can enable pregnancy to be achieved with apparent oncological safety. The success of such procedures should directly impact clinical practice and management of those patients who require fertility-sparing treatment.
    Full-text · Article · Jan 2016 · Human Reproduction Update
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    • "Although some studies have indicated that women treated with fertility hormones are at an increased risk of ovarian tumors (Whittemore et al., 1992; Rossing et al., 1994; Lerner-Geva et al., 2003; van Leeuwen et al., 2011) or breast cancer (Jensen et al., 2007; Orgeas et al., 2009; Silva Idos et al., 2009; Brinton et al., 2014), a recent meta-analysis concluded that controlled ovarian hyperstimulation for IVF resulted in no increased risks of ovarian, uterine or cervical cancers, once confounding effects were taken into account (Siristatidis et al., 2013). Studies have also focused on possible associations of ART with tumors of the CNS (Kallen et al., 2011; Yli-Kuha et al., 2012), CRC (Althuis et al., 2005; Kallen et al., 2011; Yli-Kuha et al., 2012), thyroid (Althuis et al., 2005; Hannibal et al., 2008b; Pazaitou-Panayiotou et al., 2014) and CMM (Rossing et al., 1994; Althuis et al., 2005; Hannibal et al., 2008a; Stewart et al., 2013), with discrepant results. "
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    ABSTRACT: Do women who give birth after assisted reproductive technology (ART) have an increased risk of cancer compared with women who give birth without ART? Without correction, the results indicate an increase in overall cancer risk, as well as a 50% increase in risk of CNS cancer for women giving birth after ART, however the results were not significant after correcting for multiple analyses. Studies regarding the effects of hormonal treatments involved with ART on subsequent cancer risk have provided inconsistent results, and it has also been suggested that infertility itself could be a contributory factor. A population-based cohort consisting of all women registered in the Medical Birth Registry of Norway as having given birth between 1 January 1984 and 31 December 2010 was assembled (n = 812 986). Cancers were identified by linkage to the Cancer Registry of Norway. Study subjects were followed from start of first pregnancy during the observational period until the first cancer, death, emigration, or 31 December 2010. Of the total study population (n = 806 248), 16 525 gave birth to a child following ART. Cox regression analysis computed hazard ratios (HR) and 95% confidence intervals (CI) comparing cancer risk between ART women and non-ART women; for overall cancer, and for cervical, ovarian, uterine, central nervous system (CNS), colorectal and thyroid cancers, and for malignant melanoma. A total of 22 282 cohort members were diagnosed with cancer, of which 338 were ART women and 21 944 non-ART women. The results showed an elevated risk in one out of seven sites for ART women. The HR for cancer of the CNS was 1.50 (95% CI 1.03- 2.18), and among those specifically subjected to IVF (without ICSI) the HR was 1.83 (95% CI 1.22-2.73). Analysis of risk of overall cancer gave an HR of 1.16 (95% CI 1.04-1.29). Among those who had delivered only one child by the end of follow-up, the HR for ovarian cancer was 2.00 (95% CI 1.08-3.65), and for those nulliparous at entry the HR was 1.80 (95% CI 1.04-3.11). However, all findings became non-significant after correcting for multiple analyses. The results of elevated risk of overall cancer and CNS cancer lost significance when adjusting for multiple analyses, implying an important limitation of the study. The follow-up time was relatively short, especially for ART women. In addition, as the cohort was relatively young, there were few incident cancers, especially for some rarer cancer forms, such as uterine cancer. Risk assessments according to different causes of infertility could not be done. In light of the findings in the present study, further studies should be made on risk of CNS and ovarian cancer, and continued monitoring of all those treated with ART is encouraged. Our findings may only be generalizable to women who give birth after ART, and the risk for women who remain nulliparous after ART remains to be assessed. The study was funded by the Norwegian National Advisory Unit on Women's Health. All authors claim no competing interests. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
    Full-text · Article · Jun 2015 · Human Reproduction
    • "In the IVF group 32% had one to two stimulated cycles, 33% had three to four stimulated cycles and 22% had five or more stimulated cycles. IVF stimulation regimens used in the cohort have been described in detail previously (De Boer et al., 2004; van Leeuwen et al., 2011). In the IVF group more women remained nulliparous (36%) compared with the non-IVF group (27%). "
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    ABSTRACT: Do women treated with ovarian stimulation for IVF have an increased risk of melanoma? Ovarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up. Although exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group. In 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses. The cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database. 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 was 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). Despite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses. Our results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence. This study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
    No preview · Article · Mar 2015 · Human Reproduction
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