Risk of Ovarian Tumors After Ovarian Stimulation for IVF
Risk of Ovarian Tumors After Ovarian Stimulation for IVF
BACKGROUND Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown.
METHODS 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.
RESULTS 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).
CONCLUSIONS 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.
Currently, 1.2-2.3% of children born in the Western world are conceived by assisted reproductive technologies (Kremer et al., 2008; Wright et al., 2008). In the Netherlands, it has been estimated that the number of treatment cycles increased by 40% from 1996 till 2005 (Kremer et al., 2008). Fertility drugs (FDs) used in IVF treatment temporarily raise serum levels of exogenous gonadotrophins and gonadal hormones, and consequently increase the chances of multiple folliculogenesis and ovulations. The long-term effects of ovarian stimulation are unknown. In view of the assumed role of 'incessant ovulation' (Fathalla, 1972) and increased gonadotrophin levels in ovarian cancer pathogenesis (Cramer and Welch, 1983; Risch, 1998; Vlahos et al., 2010) concerns have been raised that ovarian stimulation and multiple ovarian punctures as used in IVF may increase the risk of ovarian malignancies (Fishel and Jackson, 1989). Invasive ovarian cancer accounts for 6% of female cancer deaths in the USA (Jemal et al., 2008).
Over the past decades, several studies reported a significant increase of ovarian cancer risk after FD use (Whittemore et al., 1992; Rossing et al., 1994; Brinton et al., 2005; Sanner et al., 2009; Källén et al., 2011), but others did not observe such an elevated risk (Franceschi et al., 1994; Bristow and Karlan, 1996; Mosgaard et al., 1997; Modan et al., 1998; Venn et al., 1999; Parazzini et al., 2001; Dor et al., 2002; Doyle et al., 2002; Ness et al., 2002; Rossing et al., 2004; Dos Santos Silva et al., 2009; Jensen et al., 2009), or reported non-significant risk increases for subgroups (Shushan et al., 1996; Ness et al., 2002; Brinton et al., 2004). Some studies noted an elevated risk of borderline ovarian tumours following the use of FDs (Harris et al., 1992; Rossing et al., 1994; Shushan et al., 1996; Parazzini et al., I998; Ness et al., 2002; Sanner et al., 2009). Borderline ovarian tumours are low-grade ovarian malignancies with far less aggressive behaviour than invasive ovarian cancer (Bell, 2005; Hart, 2005).
Short follow-up, low statistical power and lack of control for important confounders, such as cause of subfertility and parity, have limited the conclusions from previous studies. We report here on a large nationwide cohort study in the Netherlands (the OMEGA study) that was designed to examine long-term risk of ovarian malignancies (both invasive ovarian cancer and borderline ovarian tumours) after ovarian stimulation for IVF. A unique feature of our study is that data on reproductive factors were obtained from the participating women, whereas detailed information on subfertility cause and treatment was abstracted from the medical files.
Abstract and Introduction
Abstract
BACKGROUND Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown.
METHODS 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.
RESULTS 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).
CONCLUSIONS 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.
Introduction
Currently, 1.2-2.3% of children born in the Western world are conceived by assisted reproductive technologies (Kremer et al., 2008; Wright et al., 2008). In the Netherlands, it has been estimated that the number of treatment cycles increased by 40% from 1996 till 2005 (Kremer et al., 2008). Fertility drugs (FDs) used in IVF treatment temporarily raise serum levels of exogenous gonadotrophins and gonadal hormones, and consequently increase the chances of multiple folliculogenesis and ovulations. The long-term effects of ovarian stimulation are unknown. In view of the assumed role of 'incessant ovulation' (Fathalla, 1972) and increased gonadotrophin levels in ovarian cancer pathogenesis (Cramer and Welch, 1983; Risch, 1998; Vlahos et al., 2010) concerns have been raised that ovarian stimulation and multiple ovarian punctures as used in IVF may increase the risk of ovarian malignancies (Fishel and Jackson, 1989). Invasive ovarian cancer accounts for 6% of female cancer deaths in the USA (Jemal et al., 2008).
Over the past decades, several studies reported a significant increase of ovarian cancer risk after FD use (Whittemore et al., 1992; Rossing et al., 1994; Brinton et al., 2005; Sanner et al., 2009; Källén et al., 2011), but others did not observe such an elevated risk (Franceschi et al., 1994; Bristow and Karlan, 1996; Mosgaard et al., 1997; Modan et al., 1998; Venn et al., 1999; Parazzini et al., 2001; Dor et al., 2002; Doyle et al., 2002; Ness et al., 2002; Rossing et al., 2004; Dos Santos Silva et al., 2009; Jensen et al., 2009), or reported non-significant risk increases for subgroups (Shushan et al., 1996; Ness et al., 2002; Brinton et al., 2004). Some studies noted an elevated risk of borderline ovarian tumours following the use of FDs (Harris et al., 1992; Rossing et al., 1994; Shushan et al., 1996; Parazzini et al., I998; Ness et al., 2002; Sanner et al., 2009). Borderline ovarian tumours are low-grade ovarian malignancies with far less aggressive behaviour than invasive ovarian cancer (Bell, 2005; Hart, 2005).
Short follow-up, low statistical power and lack of control for important confounders, such as cause of subfertility and parity, have limited the conclusions from previous studies. We report here on a large nationwide cohort study in the Netherlands (the OMEGA study) that was designed to examine long-term risk of ovarian malignancies (both invasive ovarian cancer and borderline ovarian tumours) after ovarian stimulation for IVF. A unique feature of our study is that data on reproductive factors were obtained from the participating women, whereas detailed information on subfertility cause and treatment was abstracted from the medical files.
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