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

Abstract

BACKGROUNDLong-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown.METHODSWe 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.RESULTSAfter 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).CONCLUSIONSOvarian 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.

Diagnosis, Treatment, and Follow-Up of Borderline Ovarian Tumors

“…In particular, there are studies showing no protective effect of hormonal contraceptives against BOTs as opposed to ovarian cancers [3,7]; however, the results of further studies concerning BOTs and hormonal contraceptives are controversial, as discussed later. The increased risk of BOTs may also be associated with the use of fertility drugs [8].…”

Repeated ovarian stimulation does not affect the expression level of proteins involved in cell cycle control in mouse ovaries and fallopian tubes

“…By considering that human ovarian carcinoma tissues have an estimated +46 % of cyclin D1 overexpression, that has been correlated with an ascending clinical stage and poor prognosis [37], we can hypothesize that such a more limited increase might highlight a latent precursor phase, that predisposes to potential cancer development. Indeed, epidemiological data evidenced an increased risk for borderline ovarian tumors in infertile women treated with IVF [10], and it is noteworthy that about 2/3 of serous borderline ovarian tumors are characterized by kras mutations that determines a significant increase of cyclin D1 expression [38]. On the other hand, we cannot exclude the possibility that, in our experimental model, cyclin D1 increase could be a hypertrophic response of epithelial cells of the FT to supraphysiological gonadotropin stimulation, without any established role in the causation of OC.…”

“…Indeed, infertility per se increases the risk for OC [4], and nulliparous women or women who used fertility drugs to achieve pregnancy seem to have a higher risk of developing OC than women with children and/or those that have used oral contraceptives [8]. Large epidemiological studies evidenced a weak but not significant association between infertility drugs and OC risk [5,[9][10][11], even if an increased risk of borderline ovarian tumors in IVF groups compared with the general population has been reported [10]. As a consequence, it is necessary to evaluate how the need of motherhood could reconcile with the side effects of these therapies.…”

Ovarian tumours, their characterisation and origins and ovarian screening

“…Th is was further supported by publications from Whittemore et al (1992) and Rossing et al (1994) in which the use of gonadotrophins and clomiphene were implicated. Subsequent analyses (Venn et al 1995(Venn et al , 1999Klip et al 2000) including one with the editor ' s collaborators (dos Santos Silva et al 2009) could not fi nd an increased incidence or mortality from ovarian cancer among women with infertility or aft er ovarian/ovulation stimulation, although a most recent report from the Dutch group (van Leeuwen et al 2011) describes an increased risk of borderline and invasive ovarian tumours aft er ovarian stimulation for in vitro fertilisation.…”

“…Th ey were reported by Rossing et al (1994) among women with ovarian tumours following treatment with clomiphene, and the review by Ness et al (2002) of eight case -control studies demonstrated an increased incidence of borderline tumours among nulligravid women who had used fertility drugs. Th e study by van Leeuwen et al (2011) reported fi nding borderline tumours in women who had undergone IVF. Th e report by Menon et al (2009) suggests these tumours are more likely to be detected among women undergoing ultrasound screening as compared with those in their multimodal screening group.…”