Abstract

Infertility is considered to influence the risk of breast cancer and gynecologic cancers. To assess this association, the authors used data from a large cohort of 54,362 women with a diagnosis of infertility who were referred to Danish fertility clinics between 1963 and 1998. Through 2003, 1,975 cancers were identified by linkage to the Danish Cancer Registry. Cancer risk was assessed through standardized incidence ratios (SIRs) and corresponding 95% confidence intervals, using general and parity-specific cancer incidence rates in the general population of Denmark as a reference. After adjustment for parity status, significantly increased SIRs were observed for breast (SIR = 1.08, 95% confidence interval: 1.01, 1.16) and ovarian (SIR = 1.46, 95% confidence interval: 1.24, 1.71) cancer. The risk of breast cancer increased with follow-up time. Similar risk patterns were observed for the different histologic types of breast cancer and all nonmucinous types of ovarian cancer, whereas the risk of mucinous ovarian cancers seemed not to be increased. These data thus suggest higher risks of breast and ovarian cancer among infertile women. However, since these results could not distinguish the effects of underlying infertility from the effects of fertility treatment, additional studies are needed to disentangle the effects of these two factors.

Breast cancer and gynecologic cancers are known to be of multifactorial etiology. One of the most well-established risk factors for breast, ovarian, and endometrial cancer is parity: Nulliparous women have an increased risk in comparison with parous women (1–6). A diagnosis of infertility and infertility treatment are related factors also considered to influence risk of these cancers (7–10). The question of whether infertility and infertility treatment increase the risk of breast and gynecologic cancers is a matter of great public health concern, considering the large and constantly growing number of women requesting infertility treatment and the high incidence of these cancers in most Western countries.

A number of epidemiologic studies have examined the risks of breast (11–27), ovarian (12, 15, 17, 27–37), endometrial (12, 15, 17, 24, 27, 38, 39), and cervical (18, 40, 41) cancer in populations of infertile women. Results have been inconsistent. The majority of studies have found no convincing relation to risk, but the results in some may have been influenced by various methodological limitations, such as low statistical power due to small numbers of cases, short follow-up periods, loss to follow-up, and inability to control for potential confounders.

Concerning confounders, it is of particular importance to take parity into account, as the frequency of nulliparity is higher among infertile women than among fertile women. Otherwise, the cancer risk among infertile women will be overestimated as a consequence of the increased risk in nulliparous women. The availability of appropriate comparison groups is therefore of fundamental importance in cohort studies examining the association between infertility and cancer. Researchers in several cohort studies have used standardized incidence ratios (SIRs) to compare cancer risk in infertile women with that in the general population (11, 12, 14, 15, 17–20, 22, 24, 26, 28, 29, 39). However, use of general-population cancer incidence rates for comparisons makes it difficult to adjust for differences in cancer predictors, except age and calendar time. None of the previous studies using SIRs to compare cancer risk in cohorts of infertile women with that in the general population have been able to stratify or adjust for parity; therefore, the SIRs in these studies may have overestimated cancer risk and are thus difficult to interpret.

In Denmark, however, we have the opportunity to calculate parity-specific and parity-adjusted SIRs in cohorts of infertile women, since parity status for the infertility cohort and parity-specific cancer incidence rates for the general population can be calculated on the basis of information contained in the Danish Civil Registration System and the Danish Cancer Register, both of which are nationwide population-based registries. We have established a cohort including 54,362 Danish women diagnosed with infertility during the period 1963–1998. To our knowledge, this infertility cohort involves the largest number of breast and gynecologic cancer cases compiled to date. Furthermore, practically no women from the cohort are lost to follow-up, and there is almost complete ascertainment of cancer diagnoses, since the personal identification number assigned in Denmark allows precise linkage between the infertility cohort and the Danish population-based registries. Through the use of these data, we designed the present study to evaluate the risk (measured as parity-specific and parity-adjusted SIR estimates) of breast and gynecologic cancers after a diagnosis of infertility.

MATERIALS AND METHODS

Study population

A cohort of women with a diagnosis of infertility who had been referred to Danish public hospitals or private fertility clinics during the period 1963–1998 was established. All public gynecologic departments and private fertility clinics in Denmark were included. Patients were identified from medical files or index cards. In addition, we included patients with an infertility diagnosis (International Classification of Diseases, Eighth Revision, code 628; International Classification of Diseases, Tenth Revision, code DN97) recorded in the National Patient Register, a nationwide register of virtually all somatic discharges from Danish hospitals since 1977. Both women with primary infertility and women with secondary infertility were included in the study. A total of 54,362 women were included in the infertility cohort, and all data were merged into a single database with one record for each woman. Each record contained the woman's Danish personal identification number, the name of the infertility clinic, and the first date of infertility evaluation. The Scientific Ethical Committee and the Data Protection Board in Denmark approved the study.

Since April 1, 1968, all residents of Denmark have been recorded in the nationwide computerized Civil Registration System and assigned a unique personal identification number that contains information on date of birth and gender. The personal identification number is used universally in Danish society and is included in numerous health registries, ensuring accurate linkage of information between registries. The Civil Registration System also contains information about place of birth, continuously updated information on vital status (date of death and data on migration), and identifiable information about parents and liveborn offspring.

We linked the infertility cohort to the Civil Registration System to obtain information about place of birth, dates of death and migration, and parity. For the present analysis, we included only women born in Denmark during the period January 1, 1936–January 1, 1992, who were alive on April 1, 1968, and women who were born after that date (totaling 49,799 women). To obtain information about parity status, we extracted information on all children born to these women before December 31, 2003 (totaling 73,661 children). In the Civil Registration System, it is not possible to distinguish children with a link to their biologic mother from children with a link to their adoptive mother. Therefore, to exclude adopted children, we excluded 7,992 children who had not been born in Denmark, since we assumed that the vast majority of these children had been adopted. Thus, the study cohort for further analysis consisted of 49,799 infertile women with 65,669 children. On December 31, 2003, 14,103 of these women were nulliparous and 35,696 women were parous.

Follow-up for cancer

In the study cohort, the following analysis groups were established: 1) the total cohort of infertile women, irrespective of parity status; 2) parous infertile women (one or more liveborn children); and 3) nulliparous infertile women. In order to ascertain incident cases of cancer, we linked all persons to the Danish Cancer Register through the use of the personal identification number. The Danish Cancer Register contains nationwide information about all incident cases of invasive cancer diagnosed in Denmark since 1943. It is supplemented by linkage to the Death Certificate Register and the National Patient Register to ensure complete data (42). Person-years of observation within each analysis group were calculated from the first date of infertility evaluation, April 1, 1968, or the date of the first livebirth after infertility evaluation (parous infertile women only), whichever came first, to the date of cancer diagnosis, the date of the first livebirth (parous infertile women only), the date of emigration, the date of death, or December 31, 2003, whichever came first. Women with primary infertility who gave birth to a live child after the date of the first infertility evaluation would contribute person-years of observation both in the analysis group of nulliparous women and in the analysis group of parous women.

Statistical analysis

The number of cancers observed in each analysis group was compared with the number expected. The expected numbers were calculated by multiplying the accumulated person-years of observation in each analysis group by calculated overall and parity-specific cancer incidence rates in the general female population of Denmark, in 5-year age groups and 5-year calendar periods of observation. Parity-specific cancer incidence rates in the general female population of Denmark were calculated on the basis of information extracted from the Danish Civil Registration System and the Danish Cancer Register. Parity status in the general population of Denmark was calculated from the Danish Civil Registration System using the same criteria as those used to calculate parity status in the infertility cohort.

SIRs (the observed number of cancers divided by the expected number) for cancer and 95 percent confidence intervals were calculated on the assumption that the observed number of cancers followed a Poisson distribution for 1) the total cohort of infertile women, adjusted for age and calendar time; 2) the total cohort of infertile women, adjusted for age, calendar time, and parity status; 3) parous infertile women, adjusted for age and calendar time; and 4) nulliparous infertile women, adjusted for age and calendar time. For all four infertility cohorts, we also calculated SIRs associated with years of follow-up since the first date of infertility evaluation (latency). Two-sided ptrend values in the analysis of years since first date of infertility evaluation were calculated using the Poisson linear trend statistic; ptrend < 0.05 was considered statistically significant. Finally, SIRs were calculated for different histologic types of breast and epithelial ovarian cancer. Based on the International Classification of Diseases for Oncology codes from the Danish Cancer Register, breast tumors were classified into three histologic types (ductal, lobular, or other) and epithelial ovarian tumors were classified into four histologic types (serous, mucinous, endometrioid, or other).

RESULTS

The distributions of entry period and entry age in the infertility cohort are shown in table 1. The median year at entry in the cohort and age at first infertility evaluation were 1989 and 29 years, respectively, whereas the median age at the end of follow-up was 45 years. The median length of follow-up was 13.0 years (range, 0–40 years), with 25 percent of the women being followed for more than 21 years. In total, the 49,799 women contributed 782,598 person-years of observation. Tumors were diagnosed an average of 13.9 years after enrollment in the cohort (range, 1–35 years). Women ranged in age from 21 years to 66 years at the time of cancer diagnosis (median, 44 years). A total of 1,975 invasive cancers (in situ tumors and nonmelanoma skin cancers excluded) were observed in the infertility cohort during the follow-up period; 1,202 cancers were observed among parous women and 773 cancers were observed among nulliparous women.

TABLE 1.

Calendar period of study entry and age at entry into the study cohort* among 49,799 Danish women evaluated for infertility during the years 1963–1998

Period of study entry Age group (years) at cohort entry Total 
18–26 27–30 31–36 ≥37 No. 
1963–1967 75 42 118 0.2 
1968–1972 447 400 177 1,024 2.1 
1973–1977 1,618 1,403 809 78 3,908 7.9 
1978–1982 3,327 2,843 2,010 321 8,501 17.1 
1983–1987 2,453 2,662 2,114 369 7,598 15.3 
1988–1992 2,762 4,471 4,523 1,059 12,815 25.7 
1993–1998 2,782 5,377 5,899 1,777 15,835 31.8 
Total 13,464 (27.0)† 17,198 (34.5) 15,533 (31.2) 3,604 (7.2) 49,799 100.0 
Period of study entry Age group (years) at cohort entry Total 
18–26 27–30 31–36 ≥37 No. 
1963–1967 75 42 118 0.2 
1968–1972 447 400 177 1,024 2.1 
1973–1977 1,618 1,403 809 78 3,908 7.9 
1978–1982 3,327 2,843 2,010 321 8,501 17.1 
1983–1987 2,453 2,662 2,114 369 7,598 15.3 
1988–1992 2,762 4,471 4,523 1,059 12,815 25.7 
1993–1998 2,782 5,377 5,899 1,777 15,835 31.8 
Total 13,464 (27.0)† 17,198 (34.5) 15,533 (31.2) 3,604 (7.2) 49,799 100.0 
*

Age at initial hospital/clinic evaluation.

Numbers in parentheses, percentage.

In table 2, SIRs are presented for all cancers, breast cancer, gynecologic cancers (cervical, endometrial, and ovarian cancer), and cancers at other major sites. The overall risk in the cohort of infertile women was significantly increased in comparison with that in the general population of Denmark, both when results were unadjusted (SIR = 1.08, 95 percent confidence interval (CI): 1.03, 1.12) (data not shown) and when results were adjusted for parity status (SIR = 1.04, 95 percent CI: 1.00, 1.09). The risks of breast, ovarian, endometrial, and thyroid cancer seemed to contribute the most to the higher risk of all cancers. However, only the risk of breast cancer (unadjusted for parity status: SIR = 1.12, 95 percent CI: 1.04, 1.20 (data not shown); adjusted for parity status: SIR = 1.08, 95 percent CI: 1.01, 1.16) and the risk of ovarian cancer (unadjusted for parity status: SIR = 1.69, 95 percent CI: 1.44, 1.98 (data not shown); adjusted for parity status: SIR = 1.46, 95 percent CI: 1.24, 1.71) reached statistical significance. For ovarian cancer, the risk was increased for both parous women (SIR = 1.33, 95 percent CI: 1.04, 1.68) and nulliparous women (SIR = 1.60, 95 percent CI: 1.28, 1.99), whereas only parous women had a significantly increased breast cancer risk (SIR = 1.12, 95 percent CI: 1.02, 1.22). In contrast, cervical cancer occurred less frequently than expected in the infertility cohort (adjusted for parity status: SIR = 0.73, 95 percent CI: 0.61, 0.87), and the decreased risk was primarily found in parous women. For all other cancer sites, the risk was not significantly altered by infertility status, except for a lower risk of stomach cancer in parous women (SIR = 0.32, 95 percent CI: 0.07, 0.95).

TABLE 2.

Parity-adjusted and parity-specific standardized incidence ratios for all cancers, breast cancer, gynecologic cancers (cervical, endometrial, and ovarian cancer), and specified groups of nongynecologic cancers among 49,799 Danish women evaluated for infertility during the period 1963–1998

Cancer site All women (adjusted for parity status) Parous women Nulliparous women 
Obs* Exp* SIR* 95% CI* Obs Exp SIR 95% CI Obs Exp SIR 95% CI 
All† 1,975 1,896.1 1.04 1.00, 1.09 1,202 1,178.2 1.02 0.96, 1.08 773 717.8 1.08 1.00, 1.16 
Breast 796 735.3 1.08 1.01, 1.16 516 461.6 1.12 1.02, 1.22 280 273.6 1.02 0.91, 1.15 
Cervix 132 180.1 0.73 0.61, 0.87 72 116.5 0.62 0.48, 0.78 60 63.6 0.94 0.72, 1.21 
Endometrium 64 59.1 1.08 0.83, 1.38 29 29.3 0.99 0.66, 1.42 35 29.8 1.17 0.82, 1.63 
Ovary 155 105.8 1.46 1.24, 1.71 71 53.4 1.33 1.04, 1.68 84 52.4 1.60 1.28, 1.99 
Stomach 14.9 0.60 0.28, 1.14 9.3 0.32 0.07, 0.95 5.7 1.06 0.39, 2.30 
Colon 67 66.0 1.02 0.79, 1.29 42 42.4 0.99 0.71, 1.34 25 23.6 1.06 0.68, 1.56 
Rectum 34 29.9 1.14 0.79, 1.59 23 20.0 1.15 0.73, 1.72 11 9.8 1.12 0.56, 2.00 
Pancreas 18 19.7 0.91 0.54, 1.44 14 12.7 1.10 0.60, 1.85 7.0 0.57 0.15, 1.46 
Lung 115 113.1 1.02 0.84, 1.22 77 75.4 1.02 0.81, 1.28 38 37.7 1.01 0.71, 1.38 
Kidney 19 18.3 1.04 0.62, 1.62 10 12.3 0.81 0.39, 1.49 6.0 1.50 0.69, 2.85 
Bladder 25 24.7 1.01 0.66, 1.49 13 15.3 0.85 0.45, 1.45 12 9.4 1.28 0.66, 2.24 
Skin (melanoma) 162 156.8 1.03 0.88, 1.20 101 101.4 1.00 0.81, 1.21 61 55.4 1.10 0.84, 1.41 
Brain 104 101.0 1.03 0.84, 1.25 60 63.7 0.94 0.72, 1.21 44 37.3 1.18 0.86, 1.58 
Thyroid 41 30.8 1.33 0.96, 1.81 27 20.2 1.34 0.88, 1.94 14 10.6 1.33 0.72, 2.22 
Lymphatic/hematopoietic system 91 100.0 0.91 0.73, 1.12 55 62.8 0.88 0.66, 1.14 36 37.2 0.97 0.68, 1.34 
Cancer site All women (adjusted for parity status) Parous women Nulliparous women 
Obs* Exp* SIR* 95% CI* Obs Exp SIR 95% CI Obs Exp SIR 95% CI 
All† 1,975 1,896.1 1.04 1.00, 1.09 1,202 1,178.2 1.02 0.96, 1.08 773 717.8 1.08 1.00, 1.16 
Breast 796 735.3 1.08 1.01, 1.16 516 461.6 1.12 1.02, 1.22 280 273.6 1.02 0.91, 1.15 
Cervix 132 180.1 0.73 0.61, 0.87 72 116.5 0.62 0.48, 0.78 60 63.6 0.94 0.72, 1.21 
Endometrium 64 59.1 1.08 0.83, 1.38 29 29.3 0.99 0.66, 1.42 35 29.8 1.17 0.82, 1.63 
Ovary 155 105.8 1.46 1.24, 1.71 71 53.4 1.33 1.04, 1.68 84 52.4 1.60 1.28, 1.99 
Stomach 14.9 0.60 0.28, 1.14 9.3 0.32 0.07, 0.95 5.7 1.06 0.39, 2.30 
Colon 67 66.0 1.02 0.79, 1.29 42 42.4 0.99 0.71, 1.34 25 23.6 1.06 0.68, 1.56 
Rectum 34 29.9 1.14 0.79, 1.59 23 20.0 1.15 0.73, 1.72 11 9.8 1.12 0.56, 2.00 
Pancreas 18 19.7 0.91 0.54, 1.44 14 12.7 1.10 0.60, 1.85 7.0 0.57 0.15, 1.46 
Lung 115 113.1 1.02 0.84, 1.22 77 75.4 1.02 0.81, 1.28 38 37.7 1.01 0.71, 1.38 
Kidney 19 18.3 1.04 0.62, 1.62 10 12.3 0.81 0.39, 1.49 6.0 1.50 0.69, 2.85 
Bladder 25 24.7 1.01 0.66, 1.49 13 15.3 0.85 0.45, 1.45 12 9.4 1.28 0.66, 2.24 
Skin (melanoma) 162 156.8 1.03 0.88, 1.20 101 101.4 1.00 0.81, 1.21 61 55.4 1.10 0.84, 1.41 
Brain 104 101.0 1.03 0.84, 1.25 60 63.7 0.94 0.72, 1.21 44 37.3 1.18 0.86, 1.58 
Thyroid 41 30.8 1.33 0.96, 1.81 27 20.2 1.34 0.88, 1.94 14 10.6 1.33 0.72, 2.22 
Lymphatic/hematopoietic system 91 100.0 0.91 0.73, 1.12 55 62.8 0.88 0.66, 1.14 36 37.2 0.97 0.68, 1.34 
*

Obs, no. observed; Exp, no. expected; SIR, standardized incidence ratio; CI, confidence interval.

Excluding nonmelanoma skin cancers (428 cases).

For breast cancer, the SIR increased statistically significantly with increasing length of follow-up both for all women and for parous women (p = 0.01) but not for nulliparous women (table 3). For cervical cancer, there was a borderline-significant trend of lower SIRs with increasing time of follow-up (p = 0.05). For endometrial cancer, the SIRs increased with increasing length of follow-up only for parous women (p = 0.03). No consistent trend in SIRs with increasing length of follow-up was observed for ovarian cancer.

TABLE 3.

Parity-adjusted and parity-specific standardized incidence ratios for breast cancer and gynecologic cancers (cervical, endometrial, and ovarian cancer), by length of follow-up (latency), among 49,799 Danish women evaluated for infertility during the period 1963–1998

Cancer site and length (years) of follow-up All women (adjusted for parity status) Parous women Nulliparous women 
Obs* Exp* SIR* 95% CI* Obs Exp SIR 95% CI Obs Exp SIR 95% CI 
Breast             
    <1 10.4 0.67 0.27, 1.38 4.2 0.24 0.00, 1.32 6.2 0.96 0.35, 2.10 
    1–4 57 67.1 0.85 0.64, 1.10 31 38.4 0.81 0.55, 1.15 26 28.7 0.91 0.59, 1.33 
    5–9 146 148.5 0.98 0.83, 1.16 101 95.9 1.05 0.86, 1.28 45 52.6 0.86 0.62, 1.14 
    10–14 182 166.2 1.10 0.94, 1.27 118 105.2 1.12 0.93, 1.34 64 60.9 1.05 0.81, 1.34 
    15–19 166 158.3 1.05 0.90, 1.22 99 100.0 0.99 0.80, 1.21 67 58.3 1.15 0.89, 1.46 
    ≥20 238 184.8 1.29 1.13, 1.46 166 117.7 1.41 1.20, 1.64 72 67.1 1.07 0.84, 1.35 
        ptrend†   0.01   0.01   0.19 
Cervix             
    <1 10 8.6 1.16 0.55, 2.13 3.3 0.61 0.07, 2.20 5.3 1.50 0.64, 2.95 
    1–4 34 42.2 0.81 0.56, 1.13 17 24.7 0.69 0.40, 1.10 17 17.6 0.97 0.56, 1.55 
    5–9 41 54.8 0.75 0.54, 1.01 25 37.9 0.66 0.43, 0.97 16 16.9 0.95 0.54, 1.54 
    10–14 27 37.6 0.72 0.47, 1.05 16 25.8 0.62 0.35, 1.01 11 11.8 0.93 0.47, 1.67 
    15–19 13 22.0 0.59 0.31, 1.01 14.8 0.54 0.23, 1.07 7.3 0.69 0.22, 1.61 
    ≥20 14.8 0.47 0.19, 0.98 10.0 0.40 0.11, 1.02 4.7 0.63 0.13, 1.85 
        ptrend   0.05   0.33   0.16 
Endometrium             
    <1 0.5   0.1   0.4   
    1–4 3.3 0.92 0.18, 2.68 1.2   2.1 1.42 0.29, 4.15 
    5–9 8.0 1.00 0.43, 1.96 3.4 0.58 0.07, 2.10 4.6 1.31 0.48, 2.85 
    10–14 10.9 0.73 0.32, 1.45 5.0 0.80 0.22, 2.06 5.9 0.67 0.18, 1.73 
    15–19 17 13.2 1.28 0.75, 2.06 6.8 0.73 0.24, 1.71 12 6.4 1.88 0.97, 3.28 
    ≥20 28 23.1 1.21 0.80, 1.75 18 12.8 1.41 0.84, 2.23 10 10.4 0.96 0.46, 1.77 
        ptrend   0.19   0.03   0.98 
Ovary             
    <1 2.5 2.01 0.65, 4.70 0.6 1.70 0.02, 9.45 1.9 2.11 0.57, 5.41 
    1–4 13 11.9 1.09 0.58, 1.86 4.8 0.63 0.13, 1.84 10 7.2 1.39 0.67, 2.57 
    5–9 29 20.9 1.39 0.93, 1.99 12 10.3 1.17 0.60, 2.04 17 10.6 1.60 0.93, 2.56 
    10–14 30 22.3 1.35 0.91, 1.92 16 11.3 1.42 0.81, 2.30 14 11.0 1.28 0.70, 2.14 
    15–19 45 21.7 2.08 1.52, 2.78 21 11.6 1.81 1.12, 2.77 24 10.1 2.38 1.52, 3.54 
    ≥20 33 26.6 1.24 0.85, 1.74 18 14.9 1.21 0.71, 1.91 15 11.6 1.29 0.72, 2.12 
        ptrend   0.66   0.39   0.95 
Cancer site and length (years) of follow-up All women (adjusted for parity status) Parous women Nulliparous women 
Obs* Exp* SIR* 95% CI* Obs Exp SIR 95% CI Obs Exp SIR 95% CI 
Breast             
    <1 10.4 0.67 0.27, 1.38 4.2 0.24 0.00, 1.32 6.2 0.96 0.35, 2.10 
    1–4 57 67.1 0.85 0.64, 1.10 31 38.4 0.81 0.55, 1.15 26 28.7 0.91 0.59, 1.33 
    5–9 146 148.5 0.98 0.83, 1.16 101 95.9 1.05 0.86, 1.28 45 52.6 0.86 0.62, 1.14 
    10–14 182 166.2 1.10 0.94, 1.27 118 105.2 1.12 0.93, 1.34 64 60.9 1.05 0.81, 1.34 
    15–19 166 158.3 1.05 0.90, 1.22 99 100.0 0.99 0.80, 1.21 67 58.3 1.15 0.89, 1.46 
    ≥20 238 184.8 1.29 1.13, 1.46 166 117.7 1.41 1.20, 1.64 72 67.1 1.07 0.84, 1.35 
        ptrend†   0.01   0.01   0.19 
Cervix             
    <1 10 8.6 1.16 0.55, 2.13 3.3 0.61 0.07, 2.20 5.3 1.50 0.64, 2.95 
    1–4 34 42.2 0.81 0.56, 1.13 17 24.7 0.69 0.40, 1.10 17 17.6 0.97 0.56, 1.55 
    5–9 41 54.8 0.75 0.54, 1.01 25 37.9 0.66 0.43, 0.97 16 16.9 0.95 0.54, 1.54 
    10–14 27 37.6 0.72 0.47, 1.05 16 25.8 0.62 0.35, 1.01 11 11.8 0.93 0.47, 1.67 
    15–19 13 22.0 0.59 0.31, 1.01 14.8 0.54 0.23, 1.07 7.3 0.69 0.22, 1.61 
    ≥20 14.8 0.47 0.19, 0.98 10.0 0.40 0.11, 1.02 4.7 0.63 0.13, 1.85 
        ptrend   0.05   0.33   0.16 
Endometrium             
    <1 0.5   0.1   0.4   
    1–4 3.3 0.92 0.18, 2.68 1.2   2.1 1.42 0.29, 4.15 
    5–9 8.0 1.00 0.43, 1.96 3.4 0.58 0.07, 2.10 4.6 1.31 0.48, 2.85 
    10–14 10.9 0.73 0.32, 1.45 5.0 0.80 0.22, 2.06 5.9 0.67 0.18, 1.73 
    15–19 17 13.2 1.28 0.75, 2.06 6.8 0.73 0.24, 1.71 12 6.4 1.88 0.97, 3.28 
    ≥20 28 23.1 1.21 0.80, 1.75 18 12.8 1.41 0.84, 2.23 10 10.4 0.96 0.46, 1.77 
        ptrend   0.19   0.03   0.98 
Ovary             
    <1 2.5 2.01 0.65, 4.70 0.6 1.70 0.02, 9.45 1.9 2.11 0.57, 5.41 
    1–4 13 11.9 1.09 0.58, 1.86 4.8 0.63 0.13, 1.84 10 7.2 1.39 0.67, 2.57 
    5–9 29 20.9 1.39 0.93, 1.99 12 10.3 1.17 0.60, 2.04 17 10.6 1.60 0.93, 2.56 
    10–14 30 22.3 1.35 0.91, 1.92 16 11.3 1.42 0.81, 2.30 14 11.0 1.28 0.70, 2.14 
    15–19 45 21.7 2.08 1.52, 2.78 21 11.6 1.81 1.12, 2.77 24 10.1 2.38 1.52, 3.54 
    ≥20 33 26.6 1.24 0.85, 1.74 18 14.9 1.21 0.71, 1.91 15 11.6 1.29 0.72, 2.12 
        ptrend   0.66   0.39   0.95 
*

Obs, no. observed; Exp, no. expected; SIR, standardized incidence ratio; CI, confidence interval.

Calculated using the Poisson linear trend statistic (two-sided test).

We observed similarly increased risk estimates for ductal, lobular, and other histologic types of breast cancer (table 4). The overall increase in epithelial ovarian cancer risk was primarily due to a statistically significant increased risk of serous tumors (SIR = 2.01, 95 percent CI: 1.60, 2.49). In contrast, we observed a nonsignificantly decreased risk of mucinous ovarian cancers (SIR = 0.65, 95 percent CI: 0.30, 1.23). This pattern was also found in both parous and nulliparous women. The risk estimates for all four histologic groups of epithelial ovarian cancer were generally higher in nulliparous women than in parous women.

TABLE 4.

Parity-adjusted and parity-specific standardized incidence ratios for epithelial ovarian cancer and breast cancer, by histologic subtype, among 49,799 Danish women evaluated for infertility during the period 1963–1998

Cancer site and histologic subtype All women (adjusted for parity status) Parous women Nulliparous women 
Obs* Exp* SIR* 95% CI* Obs Exp SIR 95% CI Obs Exp SIR 95% CI 
Breast†             
    Ductal 582 540.0 1.08 0.99, 1.17 365 339.7 1.07 0.97, 1.19 217 200.3 1.08 0.94, 1.24 
    Lobular 79 73.5 1.08 0.85, 1.34 57 48.2 1.18 0.90, 1.53 22 25.3 0.87 0.55, 1.32 
    Other 133 119.5 1.11 0.93, 1.32 93 72.6 1.28 1.03, 1.57 40 46.9 0.85 0.61, 1.16 
Ovary‡             
    Serous 83 41.3 2.01 1.60, 2.49 42 21.8 1.93 1.39, 2.60 41 19.5 2.10 1.51, 2.85 
    Mucinous 13.9 0.65 0.30, 1.23 7.7 0.52 0.14, 1.33 6.2 0.81 0.26, 1.89 
    Endometrioid 20 15.9 1.26 0.77, 1.94 6.3 1.11 0.45, 2.29 13 9.6 1.35 0.72, 2.31 
    Other 33 28.4 1.16 0.80, 1.63 14 14.2 0.99 0.54, 1.66 19 14.2 1.33 0.80, 2.08 
Cancer site and histologic subtype All women (adjusted for parity status) Parous women Nulliparous women 
Obs* Exp* SIR* 95% CI* Obs Exp SIR 95% CI Obs Exp SIR 95% CI 
Breast†             
    Ductal 582 540.0 1.08 0.99, 1.17 365 339.7 1.07 0.97, 1.19 217 200.3 1.08 0.94, 1.24 
    Lobular 79 73.5 1.08 0.85, 1.34 57 48.2 1.18 0.90, 1.53 22 25.3 0.87 0.55, 1.32 
    Other 133 119.5 1.11 0.93, 1.32 93 72.6 1.28 1.03, 1.57 40 46.9 0.85 0.61, 1.16 
Ovary‡             
    Serous 83 41.3 2.01 1.60, 2.49 42 21.8 1.93 1.39, 2.60 41 19.5 2.10 1.51, 2.85 
    Mucinous 13.9 0.65 0.30, 1.23 7.7 0.52 0.14, 1.33 6.2 0.81 0.26, 1.89 
    Endometrioid 20 15.9 1.26 0.77, 1.94 6.3 1.11 0.45, 2.29 13 9.6 1.35 0.72, 2.31 
    Other 33 28.4 1.16 0.80, 1.63 14 14.2 0.99 0.54, 1.66 19 14.2 1.33 0.80, 2.08 
*

Obs, no. observed; Exp, no. expected; SIR, standardized incidence ratio; CI, confidence interval.

Two breast cancer cases (one in a parous woman and one in a nulliparous woman) were excluded from the analysis, since information about histologic type was missing from the Danish Cancer Registry.

Seven cases of nonepithelial invasive ovarian cancer (four in parous women and three in nulliparous women) were excluded from the analysis. In addition, three cases of epithelial ovarian cancer (all in nulliparous women) for which information on histologic type was missing from the Danish Cancer Registry were excluded.

DISCUSSION

Based on the largest cohort of infertile women compiled to date, our results showed a slightly increased overall cancer risk in infertile women compared with that in the general population. Infertile women had significantly increased risks of breast and ovarian cancer both unadjusted and adjusted for parity, and these two cancers contributed the most to the higher overall cancer risk in the cohort of infertile women. Since the parity-adjusted increases in risk for breast (8 percent) and ovarian (46 percent) cancer were lower than the unadjusted risk estimates (12 percent and 69 percent, respectively), our results clearly show the importance of taking parity into account when evaluating these cancers.

Investigators in most previous studies found no statistically significant increased risks of breast and ovarian cancer in cohorts of infertile women (11, 12, 14, 15, 17–20, 24, 26, 28, 43). However, our results for breast and ovarian cancer are in line with a recent large cohort study that included more than 12,000 infertile women (22, 29). Brinton et al. (22, 29) reported a 30 percent increased risk of breast cancer (unadjusted for parity status) and a 100 percent increased risk of ovarian cancer (unadjusted for parity status) in a cohort of infertile women when compared with the general population. Furthermore, Brinton et al. also assessed ovarian cancer risk according to different causes of infertility (10, 44) and showed that women with a diagnosis of endometriosis had the highest ovarian cancer risk. This result suggests that determination of ovarian cancer risk should take into account the type of infertility. Unfortunately, this was not possible in our study, as the specific type of infertility was only registered for a minority of the infertile women.

In addition, two other large studies found significant associations between a diagnosis of infertility and the risks of breast and ovarian cancer. Tworoger et al. (45), using data from the Nurses' Health Study, found a modestly increased ovarian cancer risk among women reporting infertility (rate ratio = 1.36, 95 percent CI: 1.07, 1.75). In contrast, using prospective data from Nurses' Health Study II, Terry et al. (46) found a significantly lower breast cancer risk in women reporting infertility than in women who did not report infertility. For endometrial cancer, we found a 29 percent borderline-significant crude increased risk, but the risk was not significantly increased when results were adjusted for parity. Investigators in most other cohort studies found no increased risk of endometrial cancer among infertile women compared with that in the general population (12, 14, 15, 17, 18, 20, 24). The exception is Althuis et al. (39), who reported a significant 60 percent increased risk (unadjusted for parity status). In line with results from three previous cohort studies (18, 40, 41), we found cervical cancer to be less frequently diagnosed among infertile women.

In general, discrepancies in the above results may be explained by differences in study designs and study populations and various methodological limitations, such as low statistical power and inability to control for potential confounders. The risk estimates in our study had a high level of precision, since the study included 796 breast cancers, 155 ovarian cancers, 64 endometrial cancers, and 132 cervical cancers. Most previous cohort studies examining the association between cancer risk and infertility have been limited by markedly smaller numbers of breast cancers (n = 5–243) (11, 12, 14, 15, 17–19, 22, 24, 26, 46), ovarian cancers (n = 1–75) (12, 14, 15, 17, 18, 20, 24, 28, 29, 45), endometrial cancers (n = 2–39) (12, 14, 15, 17, 18, 20, 24, 39), and cervical cancers (n = 3–36) (18, 40, 41). The register-based, individually identifiable information on vital status, parity, and cancer enabled us to calculate parity-specific cancer incidence rates in the general Danish population and thereby gave us the ability to calculate parity-adjusted SIRs in our infertility cohort. None of the previous cohort studies that have used SIRs to compare cancer risk in cohorts of infertile women with that in the general population have been able to adjust for parity (11, 12, 14, 15, 17–20, 22, 24, 26, 28, 29, 39), and therefore the SIRs in these studies may be difficult to interpret. Since nulliparity is one of the most established risk factors for breast cancer and most gynecologic cancers (1–3) and because the frequency of nulliparity in cohorts of infertile women is higher than the frequency of nulliparity in the general population, the cancer risk among infertile women will tend to be overestimated if the risk estimates are not adjusted for parity. The availability of appropriate comparison groups is therefore of fundamental importance in cohort studies examining the association between infertility and cancer. This has clearly been emphasized by our results.

The increased risks of breast and ovarian cancer that remain after adjustment for parity indicate that other infertility-related factors may have the potential to increase the risk of these cancers. Two likely candidates are a shared genetic/biologic susceptibility to both cancer and infertility and/or the use of fertility drugs, which has held an important place in infertility treatment during approximately the last 30 years. The association between use of fertility drugs and breast and ovarian cancer has been evaluated in several epidemiologic studies. Although the results are generally reassuring in not confirming a strong link between use of fertility drugs and the risk of breast (11–21, 24) or ovarian (12, 15, 17, 27–37) cancer, there are indications that certain user subgroups might experience slight elevations in risk of both breast (22, 23) and ovarian (28, 30) cancer.

Results from the present study do not distinguish the effects of underlying infertility from the effects of fertility treatment, since information about use of fertility drugs was not available for the entire infertile cohort. However, in order to separate the effects of these two factors, within-cohort studies have also been performed (47–49). Information about the use of fertility drugs has been abstracted from collected hospital files and medical records on all available infertility-related medical visits for all infertile women developing cancer (cases) and all members of a randomly selected subcohort. In the case-cohort design, cancer risk among infertile women who have used fertility drugs is compared with that among infertile women who have not used fertility drugs, thereby providing an estimate of the effect of fertility drugs on cancer risk that is separate from the effect of the underlying infertility diagnosis.

At present, three within-cohort studies examining the association between use of fertility drugs and risks of breast cancer (47), thyroid cancer (48), and malignant melanoma (49) have been published. Concerning breast cancer and malignant melanoma (47, 49), the results were generally assuring that treatment with fertility drugs does not cause these cancers, as risk was not related to the use of most fertility drugs (gonadotropins, clomiphene, human chorionic gonadotropin, or gonadotropin-releasing hormone). Subgroup findings based on a small number of cases indicated a stronger effect of gonadotropins on breast cancer risk among nulliparous women and a stronger effect of gonadotropins and gonadotropin-releasing hormone on malignant melanoma risk among parous women. However, since no strong overall association between breast cancer risk and use of fertility drugs was found when infertile women who used fertility drugs were compared with a control group of infertile women who had not been exposed to fertility drugs, those results indicate that the generally increased risk of breast cancer found for the total cohort of infertile women in the present study may mostly be due to genetic or biologic factors related to the underlying infertility diagnosis. In contrast, thyroid cancer may be more related to use of fertility drugs, since infertile women who were treated with clomiphene had an increased risk of thyroid cancer (rate ratio = 2.28, 95 percent CI: 1.08, 4.82) (48).

Because clomiphene was the most commonly used fertility drug in Denmark during the study period (50; Vibeke Dahl Jensen, Danish Medicines Agency, unpublished data, 2006), it is likely that the increased thyroid cancer risk associated with this type of fertility drug may partly explain the borderline-significantly increased thyroid cancer risk (SIR = 1.33, 95 percent CI: 0.96, 1.81) found for the total cohort of infertile women in the present study. Similar within-cohort studies of the association between use of fertility drugs and risks of ovarian and endometrial cancer are under way.

We observed a higher risk of ovarian cancer associated with infertility among nulliparous women than among parous women. This observation has also been reported in two large pooled analyses of case-control study results (30, 35), a large prospective cohort study (43), and, most recently, a case-control study by Rossing et al. (37), who found a 60 percent increased risk of ovarian cancer among nulliparous women with a history of infertility. Althuis et al. (39) have suggested that the higher estrogen levels found in nulliparous women may act in synergy with fertility drugs to increase cancer risk. On the other hand, it is also possible that the increased cancer risk among nulliparous infertile women is due to the fact that these women receive larger amounts of fertility drugs during treatment in order to become pregnant, as compared with infertile women who succeed in becoming pregnant. However, these hypotheses have not yet been confirmed and will require assessment in future investigations.

Breast cancer risk increased with increasing follow-up time, whereas cervical cancer risk decreased with increasing follow-up time. It is possible that the lower cervical cancer risk in general and the decreased cervical cancer risk with increased follow-up may be explained by surveillance bias, because infertile women are under closer medical scrutiny than women in the general population. Risks of endometrial and ovarian cancer were not strongly associated with increased follow-up time. When ovarian cancers with the lowest (<1 year) and highest (≥20 years) latency periods were excluded from the analysis, the SIR increased with increasing follow-up time for all three groups of women. However, the increase was statistically significant only for all women (p = 0.02) and for parous women (p < 0.05). As for cervical cancer, the high ovarian cancer risk observed within 1 year after infertility diagnosis may be explained by surveillance bias, whereas the drop in ovarian cancer risk after 20 or more years of follow-up is more difficult to explain. Longer follow-up time is certainly needed to further study latency effects on cancer risk after a diagnosis of infertility.

The large number of ovarian cancer and breast cancer cases in our cohort enabled us to analyze potential differences in risk according to histologic subtype. For breast cancer, no marked differences in the risk profiles for ductal, lobular, or other types of tumors were found. In contrast, the overall increase in epithelial ovarian cancer risk was primarily due to an increased risk of nonmucinous tumors, notably serous carcinomas, whereas we observed a nonsignificantly lower risk of mucinous ovarian cancers. To our knowledge, no previous cohort studies have evaluated the association between infertility and the risks of breast and ovarian cancer according to histologic type. However, several investigators have suggested that mucinous ovarian cancers are less influenced by hormonal (i.e., use of oral contraceptives) and parity-related factors than are nonmucinous ovarian tumors (51–57). It is therefore plausible that a cancer-related effect of infertility would also be less pronounced for mucinous ovarian tumors. Indeed, the results of our study support differences in the risk profile between the mucinous and serous types of epithelial ovarian cancer, and hence different etiologies.

Apart from its large size, the large number of cancer cases, and the ability to adjust the analyses for parity status, our study had two other important strengths. First, because of the unique nature of the Danish personal identification number, which permitted precise linkage between our infertility cohort and the Danish population-based registries, practically no women were lost to follow-up, thus allowing precise estimation of the numbers of person-years of risk. Furthermore, we had almost complete ascertainment of cancer diagnoses through linkage with the Danish Cancer Register.

Our study also had some important limitations. Both the median age at the end of follow-up (45 years) and the median age at cancer diagnoses (44 years) were below the ages at which incidence of breast and gynecologic cancers peaks. As such, the present analysis might have only partially represented the true long-term cancer risk associated with infertility. Furthermore, the fact that we were not able to adjust for potential risk factors (i.e., use of oral contraceptives, body mass index, smoking, and alcohol consumption), other than age, calendar time, and parity status, may have confounded our results slightly. It is well-known that oral contraceptives have a protective effect on ovarian cancer risk (55, 58). It is likely that the use of oral contraceptives might have differed between our cohort of infertile women and women in the general population; thus, we cannot rule out the possibility that the lack of adjustment for oral contraceptive use may have confounded our risk estimates.

Another limitation is that only women who had borne one or more live children were treated as parous in the present study, since only liveborn children are assigned a personal identification number in the Civil Registration System. It would have been more optimal to adjust for pregnancy status, since pregnancy itself affects the risk of cancer and because the proportion of unsuccessful pregnancies/terminations will be different in the infertility cohort as compared with the general population.

Finally, because our infertility cohort comprised data from all public gynecology departments and private fertility clinics in Denmark from 1963 to 1998 and was further supplemented with patients who had an infertility diagnosis recorded in the National Patient Register during that period, it is likely that the vast majority of women diagnosed with infertility in Denmark during that period were included in our cohort. However, our risks might have been slightly underestimated, since some women in the general population of Denmark will have had undiagnosed infertility and because some infertile women are referred only to private gynecologists (who nevertheless are rare in Denmark).

In summary, to our knowledge, our large nationwide cohort study has been the first to determine parity-specific and parity-adjusted SIRs for breast cancer and gynecologic cancers in a cohort of infertile women. The results revealed that infertile women have increased risks of ovarian cancer and breast cancer, even when results are adjusted for parity status. Our results clearly show the importance of taking parity into account for these cancers but also indicate that other infertility-related factors, such as use of fertility drugs or a shared genetic/biologic susceptibility to both cancer and infertility, may contribute to the increased risks of breast and ovarian cancer. Thus, further within-cohort studies are in progress to disentangle the effects of underlying infertility and infertility treatment on cancer risk. Furthermore, since our results were based primarily on cancers occurring at a relatively young age, additional follow-up studies are needed to further explore the long-term risks of breast cancer and ovarian cancer among infertile women.

Abbreviations

    Abbreviations
  • CI

    confidence interval

  • SIR

    standardized incidence ratio

This research was supported by the Danish Cancer Society.

The authors gratefully acknowledge Svend Bang for help with data management. They also thank Dr. Kirsten Frederiksen for useful discussions and suggestions.

Conflict of interest: none declared.

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