The risk of breast cancer and gynecologic malignancies after ovarian stimulation: Meta-analysis of cohort study

For decades, the use of ovarian stimulation continues to increase with the number of infertile population (Skakkebaek et al., 2006, te Velde et al., 2012) and advances in infertility treatment techniques (Wyns et al., 2021). Cancer is a great threat to health nowadays, and although the overall incidence and mortality rate of cancer has declined in the long run (Siegel et al., 2022), it has not reduced people's fear of it because there's no denying that some cancers, such as breast cancer, have a risk of recurrence for up to two or three decades (Fillon, 2022). Concern has been expressed that exposure to ovarian stimulation might be associated with a risk of breast and gynecologic cancers.

Ovarian stimulation involved in Assisted Reproductive Technology (ART) and infertility treatment has brought many short-term complications, such as ovarian hyperstimulation syndrome (OHSS) (Delvigne and Rozenberg, 2002, Myrianthefs et al., 2000, Schirmer et al., 2020) and endometrial lesion (Guo et al., 2022). Assisted Reproductive Technology and infertility treatment has been carried out for many years, and the long-term risk it brings has also attracted the interest of many researchers around the world. According to previous research results, various cancers such as melanoma (Spaan et al., 2015, Del Pup et al., 2018), colorectal cancer (Althuis et al., 2005a, Spaan et al., 2016), breast cancer (MacHtinger et al., 2022, Fredriksson et al., 2021, van den Belt-Dusebout et al., 2016) and gynecological cancers (Silva Idos et al., 2009, Guleria et al., 2021) have become issues of public concern and research hotspots. Because a large number of hormone-related drugs are used and can affect hormone levels in the body (Beckers et al., 2000), the meta-analysis mainly focuses on breast cancer (Folkerd et al., 2012, Tworoger et al., 2014) and gynecological tumors (Cole, 1980, den Boon et al., 2015, Rao and Slotman, 1991) that are closely related to hormone levels.

A systematic review and meta-analysis of the risks associated with breast cancer and gynecological tumors after ovarian stimulation has great clinical significance, then several studies (van den Belt-Dusebout et al., 2016, Venn et al., 1995, Yli-Kuha et al., 2012, Venn et al., 1999) showed that there was no statistically significant difference in the risk of breast cancer before and after ovarian stimulation related drugs, while these studies (Vassard et al., 2021, Reigstad et al., 2015) concluded that ovarian stimulation is a hazard factor for breast cancer. In addition, the incidence of ovarian cancer (Spaan et al., 2021), endometrial cancer (Reigstad et al., 2017) and cervical cancer after ovarian stimulation is also controversial and some meta-analysis have reported inconclusive results regarding the effect of ovarian stimulation on cancers risk (Sergentanis et al., 2014). So there is still a lot of controversy (Siristatidis et al., 2013, Barcroft et al., 2021) about whether the incidence of related cancers is related to ovarian stimulation. Perhaps many previous studies were not all cohort studies, resulting in many biases and confounders, and to elevate the level of evidence (Durieux et al., 2013), this meta-analysis included cohort studies. This meta-analysis can make doctors and patients have a clearer understanding of the risks of ovarian stimulation, and the correct use and publicity of assisted reproduction are also more scientific.

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