Infertility and risk of ovarian cancer: A systematic review and meta analysis

Millions of people around the world struggle with infertility. Globally, 186 million people and 48 million couples struggle with infertility.[ 1 ] A diagnosis of infertility is like a battle spearheaded by couples and healthcare professionals that begins with a series of investigations and exploration of treatment. To assess the efficacy of alternative interventions for the condition, agreement on the criteria used to make the diagnosis is also critical. For reproductive health care providers, appropriate experience and understanding of the prevalence of infertility, awareness of new and existing systems, and geographic differences are critical.[ 2 ] The World Health Organization (WHO) estimates that 3.9%–16.8% of Indian women experience primary infertility.[ 3 ] Infertility is estimated to affect men 35%–40% of the time, women 35%–40% of the time, and to be related to a combination of other factors in 20%–30% of cases.[ 4 ] Infertility diagnosis and treatment and recurrent treatment failures are critical incidents that occur suddenly and unexpectedly and aggressively dominate a person’s ability to adapt.[ 5 ] Numerous infertility clinics have emerged, and assisted reproduction technologies (ART) have become more prevalent. Over the past three decades, ART has assisted in the birth of over five million children around the world.[ 6 ] There is more chance of developing cancer in women’s advanced age after taking ART treatments.[ 7 ] Knowledge about the biological process of reproduction, causes of infertility, and treatment available for infertility are crucial for people to understand the importance of reproductive health. Cancer is the second leading cause of death worldwide, and ovarian cancer is the seventh most prevalent cancer in women, accounting for 9.6 million deaths in 2018, or one in six deaths.[ 8 ] The deadliest gynecologic cancer is ovarian cancer. This malignancy does not have an easily clinically identifiable premalignant phase for many cancers, such as cervical, breast, and colon cancers, making early detection difficult. The American Cancer Society reports that ovarian cancer is the most frequently diagnosed cancer worldwide and the fifth leading cause of death in women, killing more people than any other reproductive cancer.[ 9 ] “In 2017, the World Health Assembly passed the Resolution Cancer prevention and control in the context of an integrated approach, which calls on governments and the WHO to take instant action to meet the goals set out in the Global Action Plan for the Prevention and Control of NCDs 2013-2020 and the 2030 UN Agenda for Sustainable Development to reduce cancer-related premature mortality.”[ 10 ] Simultaneously, ovarian cancer poses a significant threat as the world’s fifth-leading cause of cancer-related deaths in women. Its hidden nature frequently results in a late-stage diagnosis and a poor prognosis, highlighting the critical need for methods of early detection and prevention. Age, family history, genetic predispositions such as BRCA mutations, and other factors have been identified as risk factors for ovarian cancer; however, new research indicates that infertility may potentially be a component in ovarian cancer risk modulation. Many studies have been undertaken to shed light on the complex relationship between ovarian cancer and infertility as this relationship has drawn the interest of researchers and physicians alike. Conclusive insights are hampered by methodological limitations and inconsistent findings in the current literature, which is still fragmented. Therefore, to compile the existing data, assess the strength of the link, and pinpoint prospective directions for further study and therapeutic application, a systematic review and meta-analysis are necessary. Infertility is associated with an increased risk of ovarian, breast, and endometrial cancers.[ 11 ] In the past 10 years, there has been a lot of focus on the potential contributing factor between fertility treatments and the risk of ovarian cancer. Many factors are associated with developing ovarian cancer, but some causes are unknown. Identifying women at a greater risk of ovarian cancer and recognizing disease-related early symptoms is critical and urgent; plans can be developed to prevent and/or detect the disease. The purpose of this study is to determine the pooled risk of association between infertility, infertility treatments, and ovarian cancer in women.

Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed for this systematic review. Scientific databases such as PubMed and Scopus were used to conduct a systematic literature search from which the pertinent articles were extracted. The Joanna Briggs Institute (JBI) scale was utilized to evaluate the risk of bias. This systematic review has been registered with the International Prospective Registry of Systematic Reviews (PROSPERO) (CRD CRD42021288860). The MeSH terms associated with PICO were used to locate literature sources. To find the association between infertility and ovarian cancer, the search strategy used in this review included the combination of the following subheadings: “ovarian cancer,” “ovarian tumor,” ovarian neoplasm,” “ovarian malignancy,” “infertility,” “primary infertility,” “secondary infertility,” “null parity,” “nulliparous,” “sub-fertility,” and “sterility.” During the search, we used truncation “*” to minimize errors in spelling, and Medical Subject Heading (MeSH) terms were used during the articles search. The key terms were repeated to find the steadiness of the research terms and the result. Authors (GJ and IS) independently reviewed the literature search for collecting the articles from August 5, 2021, until October 26, 2022. The systematic search was filtered to the articles published in the last 20 years. The articles account for fertility drug use or exposure to any fertility treatment and ovarian cancer to find the association between infertility, infertility treatment, and ovarian cancer. The participants diagnosed with infertility and undergoing fertility treatment such as hormonal therapy, medications, surgery, and reproductive assistance were included. The articles published from 2001 to 2021 were included in this review. Only observational studies were included. Initially, titles and abstracts were screened to find relevant articles. After the initial screening, full-text articles were reviewed further. The results of the included articles are summarized in Table 1 . In this review, articles and conference abstracts were excluded. Study characteristics of the included articles The authors (IS and SC) screened articles by screening the title and abstract. After the initial screening, the controversies that arose were discussed and resolved with the help of a third author (GJ). Based on the inclusion criteria, full-text articles were reviewed further. The articles collected from each database were selected and analyzed [ Figure 1 ]. PRISMA flowchart Using the JBI scale, the quality of the articles was assessed. Two authors evaluated the quality of articles separately to determine the risk of bias. Different checklists (10 items) were used for cross-sectional, case-control, and cohort studies (10 items). All included articles exhibited a moderate to high risk of bias. A standardized extraction form was utilized to obtain data from all papers. The following data were collected. Information regarding authors, year of publication, region, country of the study population, follow-up period, study design, sample size, and the effect size estimates with the 95% CI for the risk of ovarian cancer and the associated risk factor were extracted. One author extracted the data, while the other verified its accuracy. The dispute was settled through dialogue with the third author. Through a search strategy with world builders, four articles were found on the relationship between infertility and ovarian cancer [ Table 1 ]. This search was restricted to electronic databases, with no other sources considered for the additional search. The article selection process is described in detail in Figure 1 .

There are limited studies available in India to find the association between cancer and infertility; the articles were collected worldwide. We included 25 studies for systematic review and four studies for meta-analysis. The characters of the included study are described in detail in Table 1 . We included four eligible studies and performed a meta-analysis by using the RevMan software. Due to the anticipated heterogeneity, a random-effects model was employed. The concluding data were reported as a pooled odd ratio with a 95% confidence interval (CI). A forest plot was utilized to visually represent the estimated pooled prevalence, whereas a funnel plot was utilized to evaluate and visually represent publication bias. Egger’s test was also utilized to determine the asymmetry of the plot. In terms of publication bias, P values of 0.10 were regarded as statistically significant. The funnel plot of the pooled odd ratio did not reveal any conclusive proof of publication bias [ Figure 2 ]. Funnel plot A total of 10,061 individuals were examined across four studies. The calculated OR of developing ovarian cancer as a result of infertility was 1.35 (95% CI: 0.92–1.97) [ Figure 3 ]. However, there was substantial heterogeneity (I 2 = 88%; Chi-square test for heterogeneity: P <0.0001) for infertility and risk of ovarian cancer. The pooled odds ratio of developing ovarian cancer as a result of infertility drug use was 0.93 (95% CI: 0.94–2.46) [ Figure 4 ]. However, there was no heterogeneity (I 2 = 0%; Chi-square test for heterogeneity: P <0.55) for infertility drug use and risk of ovarian cancer. Pooled effect was shown to be stable and reliable by cumulative meta-analysis. However, publication bias was found by the Egger’s ( P = 0.0001) and Harbord ( P = 0.0002) tests. Infertility and risk of ovarian cancer Infertility treatment and risk of ovarian cancer Ovarian cancer risk can escalate as a result of undergoing infertility treatment. The use of Clomiphene Citrate has a 0.94 times risk of developing ovarian cancer (95% CI: 0.66–1.34). Use of oral contraceptives has a 0.66 times risk of developing ovarian cancer with P = 0.005. Data were inadequate to perform sub-group analysis. We included 25 studies for systematic review and found that certain risk factors were associated in their studies [ Figure 5 ]. With increasing age, fertility declines and they seek fertility treatment. When compared to other countries, women who have experienced infertility in the past and who seek medical care for longer periods of time as they get older are at an increased risk of developing ovarian cancer. Brinton L. A., et al mentioned that ovarian cancer risk was higher in nulliparous women than in parous women diagnosed with infertility after 30 years. The disease is more likely to affect women who have a family history of ovarian cancer. According to a study by Rossing et al. ,[ 13 ] ovarian cancer risk was increased in families with a history of carcinoma (OR: 2.7 (1.2, 6.0)). Pregnancy and fertility treatments need to be carefully planned for women with ovarian cancer in their families. Studies report that the use of oral contraceptives for a longer duration has an increased risk of developing ovarian cancer. According to Tworoger et al. ,[ 16 ] women with infertility who use oral contraceptives have an increased risk of developing ovarian cancer and an intrauterine device OR 1.76 (1.08, 2.85) which is less than or equal to 3 years of contraceptive use. Risk factors

The current meta-analysis showed that women who used infertility drugs had a higher risk of developing OC. However, ovarian cancer risk may be higher in women who remain nulligravid despite receiving infertility evaluations and taking fertility drugs. Hence, there is limited data on the history of infertility treatments and the risk of ovarian cancer among couples in the reproductive age group. More studies are needed to address medications used for fertility treatment and their risks in both genders. Additional large-scale observational studies are necessary to confirm these results in other regions to gain more insight because the majority of studies have been conducted in Western countries. There are no conflicts of interest.

Infertility has been an emerging problem in recent years. There are various treatment options available for infertility, and numerous infertility clinics are readily accessible. The prolonged exposure to infertility treatment results in cancer development among women in the reproductive age group. Women who have a history of endometriosis and who have been diagnosed with infertility are at an increased risk of developing ovarian cancer. Stewart L et al .[ 17 ] reported that ovarian cancer was three times more common in women with endometriosis who are still nulliparous. (hazard ratio: 3.11; 95% CI: 1.13–8.57). Women who have endometriosis have a three- to eight-fold increased risk of developing ovarian tumors, as reported by Buis et al .[ 18 ] in their study. The hazard ratio for developing ovarian tumors is 12.4 (2.8–54.2). A similar report by Vassard et al .[ 19 ] mentioned that women with endometriosis have a greater risk for ovarian cancer. Many people actively seek medical assistance to address issues related to their fertility problems. Delay in conception was one of the main reasons for fertility issues. After taking ART treatment, many women conceived after a short or long duration. Some studies reported that women who experience a delay in conception despite receiving fertility treatment are at an increased risk of developing ovarian cancer.[ 17 19 20 ] At the first clinic visit, significantly fewer ovarian cancer patients had ever been pregnant than non-cancer patients ( P = 0.04).[ 21 ] Despite seeking medical help for infertility problems, women who are still nulligravid had a statistically significantly greater risk of ovarian cancer (OR: 3.13; CI: 1.01–9.67).[ 14 ] There was no relationship between getting professional treatment for infertility and an increased risk of ovarian cancer.[ 22 ] Tworoger SS et al .[ 16 ] mentioned that infertility is correlated with ovarian cancer by 1.36 (1.07, 1.75) after 28 years of follow-up. Similar reports by Rossing M A et al. ,[ 13 ] in a population-based case-control study, stated that women who have been previously diagnosed with infertility are linked to an increased risk of developing ovarian cancer. (RR: 1.65 (1.0, 2.6)). After 14.7 years of median follow-up, Brinton LA et al .[ 21 ] reported in a cohort study that ovarian stimulation for IVF is linked to a 2-fold increased risk of ovarian cancers when compared to subfertile women who are not treated with IVF. Longer duration, 15 years following IVF treatment, strongly correlates with ovarian cancer.[ 23 ] Similar results were reported by Stewart et al. ,[ 17 ] who found that women undergoing IVF treatment have a higher chance of developing borderline ovarian tumors (HR: 2.16 (1.20, 5.04)). Bjornholt et al .[ 24 ] reported an increase in the number of treatment cycles (RR: 2.63 (1.04, 6.64)) significantly associated with ovarian cancer. Women receiving ART treatment had ovarian cancer risk ( P = 0.05).[ 20 ] Women treated with ART (HR: 1.20 (1.10, 1.31)) had a greater risk of ovarian cancer.[ 19 ] In this review, infertility had a 35% similar effect in developing ovarian cancer when compared with the general population. Several studies reported that infertility patients had a significantly greater risk of developing ovarian cancer. A study by Jiang et al . reported that women who are infertile have an increased risk of ovarian cancer by 51%.[ 25 ] As more women wait until they are over 35 to get pregnant, the use of fertility drugs has dramatically increased in developing nations over the past few years. The use of fertility drugs is strongly associated with numerous other risk factors for ovarian cancer, making it difficult to isolate the role of fertility drug treatments. The results of this review indicate that the use of infertility medications is significantly associated with the development of ovarian cancer. In our study, those who use infertility medications have a 9.3% higher risk of developing ovarian cancer than the general population. The author found a statistically significant positive association between infertility medications and a higher risk for BOTs, but for particular medications, only CC plus Gn was statistically significant.[ 26 ] In the present study, there was no relationship between the use of fertility medications and overall risk of ovarian cancer. Clomiphene citrate, follicle-stimulating hormone, and gonadotropin-releasing hormone are all common fertility drugs. Depending on the cause of infertility, these drugs may be used singly or in combination.[ 27 ] In our study, the risk of developing ovarian cancer from using clomiphene citrate was 0.66 (95% CI: 0.66–1.34), which is comparable to the risk for the general population. According to Moorman et al. ,[ 28 ] the associations between ever using OCs and developing ovarian cancer are similar among women who carry the BRCA1 or BRCA2 mutations to those found in the general population. In another study, clomiphene was recommended to 3277 (38.4%) of the study participants, while gonadotropins were given to 866 (10.3%). The risks for both non-exposed and exposed subjects seem to have been similar.[ 22 ] Our study’s findings support those of Barcroft et al. ,[ 29 ] who found that CC treatment was linked to a noticeably higher incidence of ovarian cancer. The findings suggest that after 20 years of use, the protective effect of oral contraceptives against ovarian cancer risk declines.[ 16 ] Similar findings demonstrated that oral contraceptives reduce the risk of ovarian cancer.[ 30 ] In our research, we found that women who use oral contraceptives have a 66% higher risk of ovarian cancer than women in the general population. Oral contraceptives are a significant contributor to the risk of developing ovarian cancer, and this contribution holds true regardless of the use of fertility drugs. A study by Mitchell S et al .[ 31 ] reported that artificial intelligence has significant potential to enhance the preoperative assessment of ovarian cancer on an ultrasound test, as indicated by encouraging outcomes in existing research. Given the devastating impact of ovarian cancer on the reproductive health of women, prevention, control, health education, and early identification of women at high risk are strongly recommended. Although some risk factors are unavoidable, focusing on risk factors that can be avoided may help reduce ovarian cancer risk. Our findings suggest that the doctor ultimately bears the duty for decision making, but a synergistic collaboration between the clinician and AI could enhance early diagnosis as well as improve outcomes. Healthcare workers need to focus on the long-term health impacts of infertility treatments. Married couples must be aware about the long-term health effects before deciding to take infertility treatments. More awareness is needed among the individuals as well as among the primary care health workers. Our review contributes to the limited understanding of the relationship between infertility and ovarian cancer risk. In addition, we observed the relationship between the use of oral contraceptives, infertility drug use, and the risk of developing ovarian cancer. The cumulative meta-analysis revealed that the pooled effects were reliable and consistent. The studies showed significant heterogeneity. The review adheres to PRISMA guidelines and is registered in PROSPERO. A JBI quality assessment was conducted to determine which studies would be included in the review. Only studies published in English that could significantly contribute to language bias were included in this systematic review. The reliability is questioned because most studies reported hazard and standardized incidence ratios. Subgroup analysis, and sensitivity analysis were not performed. Unpublished research articles, small sample size, inadequate results, poor quality facts due to an ambiguous risk of bias, and observable heterogeneity among trials included were also concerns.