Table 1.
Characteristic study of effects of fertility drugs on cancer.
| References | Country | Design | Period |
Study population |
Mean age at entry (Year) |
Mean follow up (Year) |
Adjusting factor(s) |
Type of infertility treatment | Type of malignancy | Number of stimulated cycles | Effect estimates | Main finding(s) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Reigstad et al. (28) | Norway | Cohort | 1984–2010 | Total:808,834 Case: 16,626 Control: 792,208 |
Age range: Case: 29.7–35.3 Control: 22.9–29.9 |
16.0 (12,401,121) person- years |
Age Parity Age at first birth Region of residence |
IVF ICSI |
Breast | HR | Increased risk of breast cancer in women with ART. | |
| Burkman et al. (30) | US | Case-Control | 1994–1998 | Case: 4,575 Control: 4,682 |
Age range: 35–64 | Age Race Strata of study center |
Clomiphene citrate hMG |
Breast | <6-≥6 | OR | Increased risk of ductal breast cancer in women who use hMG. | |
| Williams et al. (32) | UK | Cohort | 1991–2002 | Total:255,786 | 34.5 | 8.8 (2,257,789 person- years) |
Breast Corpus uteri Ovary |
1.8 | SIR | No association between ART and corpus uteri and invasive breast cancer risk. Increased risks of in situ breast cancer and invasive and borderline ovarian tumors in women with ART. |
||
| Dor et al. (23) | Israel | Cohort | 1981–1992 | Total:5,026 | 34.0 | 3.6 (18,291 person- years) |
Clomiphene citrate hMG GnRH analogs |
Breast Ovary Cervix Endometrium |
1-≥6 | SIR | No association between fertility treatment and cancer risk. | |
| Luke et al. (33) | US | Cohort | 2004–2009 | Total:113,226 Case: Control: 53,872 |
Case: 37.8 Control:35.3 |
4.8 (263,457 person-years) |
Age at cycle start Parity Infertility diagnosis Number of ART cycles Cumulative FSH dosage ART outcome |
FSH clomiphene citrate | Endocrine Melanoma Breast Ovary Uterine Female genital |
1, 2, 3, 4, or ≥5 | SIR HR |
No association between fertility treatment and cancer risk. |
| Gauthier et al. (39) | France | Cohort | 1990–2000 | Total:92,555 Case: 6,602 Control: |
Age range: 40–65 | 9.7 | Education Smoking BMI Self and familial history of breast cancer Age at menarche Menopausal status Parity Age at first full term pregnancy |
Clomiphene citrate Gonadotropins |
Breast | Mean: 13 months | RR | No association between fertility treatment and breast cancer risk. |
| Jensen et al. (40) | Denmark | Cohort | 1965- 1998 |
Total:54,379 | 8.8 | Number of childbirth | FSHhCGhMGGnRH | Breast | RR | No association between fertility treatment and breast cancer risk. | ||
| Sanner et al. (47) | Swedan | Cohort | 1961–2004 | Total:2,768 Case: 1,153 Control:1,615 |
Age range: 16–45 |
33.0 | Indication of treatment Age OCP Parity Pelvic surgery before the infertility treatment Pregnancy with completed birth in the follow-up period |
Clomiphene citrate Gonadotropins |
Ovary | 1–4 cycles | SIR RR |
No association between hormonal infertility treatment and invasive ovarian epithelial cancer. |
| Silva et al. (48) | London | Cohort | 1963–1999 | Case:7,425 Control: 1,727 |
28.1 | 21.4 | Age Parity |
Clomiphene citrate Gonadotropinss |
Breast Uterine Ovary |
2–3 cycles | Period-age-standardized mortality (SMR) SIR |
No association between ovulation stimulation drugs and cancer risk. |
| Potashnik et al. (49) | Israel | Cohort | 1960–1984 | Total:1,197 Case: 780 Control: 417 |
27.5 | 17.9 (21,407 person-years) |
Clomiphene citrate hMG |
Breast Ovary Uterine Cervix |
SIR | No association between fertility drugs and cancer risk. | ||
| Venn et al. (50) | Australia | Cohort | 1978–1992 | Total:10,358 Case: 5,564 Control: 4,794 |
Case: 32 Control: 31 |
Case: 5.2 Control: 7.6 (31,272 person-yers) |
Age Infertility type |
IVF | Breast Ovary |
Median: 2 cycles | SIR | No association between IVF and cancer risk. |
| Franceschi et al. (51) | Italy | Case-Control | 1992 | Case: 195 Control: 1,339 |
Case: 55 Contol: 56 | Ovary | OR | No association between ovulation stimulation drugs and cancer risk. | ||||
| Modan et al. (85) | Israel | Cohort | 1964–1974 | Total:2,496 | 28.7 | 21.4 (54,413 person- years) |
Clomiphene citrate hMG |
Ovary Endometrium Breast Melanoma Thyroid |
SIR | No association between ovulation stimulation drugs and ovarian cancer risk. | ||
| Trabert et al. (53) | US | Cohort | 1965–1988 | Total:9,825 | 30.1 | 17.6 (256,448 person- years) |
Study site Age Gravidity |
Clomiphene citrate gonadotropins |
Ovary | ≥6 | RR | No association between ovulation stimulation drugs and cancer risk. (exception: Use of Clomiphene citrate and failure to pregnancy was related to ovarian cancer risk) |
| Jensen et al. (54) | Denmark | Cohort | 1963– 1998 |
Total:54,362 | 30 | 16.0 (957,454 person-years) |
Parity | Clomiphene citrate Gonadotropins hCG GnRH |
Ovary | 1-≥10 | RR | No association between fertility drugs and cancer risk. |
| Doyle (86) | UK | Cohort | 1975–1989 | Total:5,556 | 43,811 person-years | Age Calendar year Parity following the last treatment cycle |
Breast Uterine Ovary |
SIR | No association between fertility drugs and cancer risk. | |||
| Stewart et al. (87) | Australia | Cohort | 1982–2002 | Total:21,639 Case: 7,544 Control: 14,095 |
31.2 | 16.5 (365,775 person- years) |
Age Socioeconomic status |
IVF | Ovary | HR | Increased risk of borderline ovarian tumors in women with IVF | |
| Mosgaard et al. (58) | Denmark | Case-Control | 1989–1994 | Case: 231 Control: 1,721 |
Case: 43.6 Control: 46.0 |
Age Region of residence Use of oral contraceptives Use of hormone replacement therapy Smoking |
Clomiphene citrate hCG hMG |
Ovary | OR | No association between fertility drugs and borderline ovarian cancer risk. | ||
| Bjørnholt et al. (59) | Denmark | Cohort | 1963–2006 | Total:96,545 | 30.3 | 11.3 (1,222,252 person- years) |
Parity Cause of infertility |
hCG clomiphene citrate Gonadotropins GnRH analogs |
Ovary | 1-≥4 | RR | No association between fertility drugs and borderline ovarian cancer risk. |
| Liat et al. (24) | Israel | Cohort | 1964–1974 | Total:2,431 | 28.6 | 33.8 (88,186 person- years) |
Clomiphene citrate hMG |
Ovary Breast Endometrium |
SIR | No association between fertility drugs and borderline ovarian cancer risk. Uncertain association between fertility drugs and breast and endometrial cancer risk. |
||
| Althuis et al. (69) | US | Cohort | 1965–1988 | Total:8,431 | 30 | 18.8 (155,658 person- years) |
Calendar year Age Study site |
clomiphene citrate Gonadotropins |
Uterine | <6-≥6 | RR | Increased risk of uterine cancer in women who use clomiphene citrate |
| Jensen et al. (70) | Denmark | Cohort | 1965–1998 | Total:54362 | 30 | 16.0 (957,887 person- years) |
Parity | Clomiphene citrate Gonadotropins hCG GnRH |
Uterine | 1-≥10 | RR | Increased risk of uterine cancer in women who use gonadotropins, clomiphene and human chorionic gonadotropin |
| Hannibal et al. (88) | Denmark | Cohort | 1963– 1998 |
Total:54,362 | 30 | 8.8 | Age at first live birth Use of OCP Parity |
Clomiphene citrate Gonadotropins hCG GnRH |
Thyroid | 1-≥6 | RR | Increased risk of thyroid cancer in women who use clomiphene |
| Calderon-Margalit. (29) | Israel | Cohort | 1974–2004 | Total:14,463 | Case: 28.1 Control:27.5 |
29.0 (424,193 person- years) |
Age Socioeconomic status Mother's geographic origin Body mass index Parity |
Clomiphene citrate | Breast Uterus Ovary Cervix Non-Hodgkin lymphoma Malignant melanoma Thyroid Colon |
HR | No association between fertility drugs and ovarian cancer risk. Increased risk of uterine and borderline breast cancer, malignant melanoma and non-Hodgkin lymphoma in women who use ovulation induction |
|
| Kallen et al. (84) | Swedan | Case-Control | 1982–2006 | Case:24,058 Control: 1,394,061 |
32.0 | Year of delivery Maternal age Parity Smoking |
IVF | Breast Cervix Ovary Placenta CNS Malignant melanoma Thyroid Colon |
OR | Decreased risk of breast and cervical cancer in women with IVF | ||
| Leeuwen et al. (63) | Netherlands | Cohort | 1983–2007 | Case: 19,146 Control:6,006 |
At end of follow up Case:47.5 Control:49.4 |
14.7 | Age Parity Subfertility cause |
IVF | Ovary | 1-≥5 | SIR | Increased risk of borderline ovarian cancer in women with IVF |
| Orgéas et al. (89) | Sweden | Cohort | 1961–2004 | Total:1,135 | 27 | 35,092 person- years | Age Calendar period of breast cancer diagnosis Age at first birth Parity |
Clomiphene citrate Gonadotropins |
Breast | 1-≥4 | SIR | No association between fertility drugs and breast cancer risk. |
| Lundburg et al. (90) | Sweden | Cohort | 1982–2012 | Total:1,340,211 | Case: 9.6 Control: 14.6 |
Age Parity Calendar time Educational level Country of birth Family history of breast cancer Age at first birth |
Clomiphene citrate Gonadotropins |
Breast | HR | No association between ovarian stimulation and breast cancer risk. | ||
| Kessous et al. (46) | Israel | Cohort | 1988–2013 | Total:10,6031 | Case: 30.4 Control: 28.3 |
11.6 | Maternal age Obesity |
Ovary Uterine Cervix Breast |
HR | Increased risk of ovarian and uterine cancer in women who used fertility treatment | ||
| Kristiansson et al. (91) | Sweden | Cohort | 1981–2001 | Case: 8,716 Control: 64,0059 |
Age range:21–43 | Case: 6.2 Control: 7.8 |
Age at follow-up Calendar year at follow-up Number of siblings and multiple births Age at first conception |
IVF | Ovary Uterine Cervix Breast |
RR | decreased incidence of carcinoma in situ of the cervix and breast cancer in women who used fertility treatment | |
| Pappo et al. (92) | Israel | Cohort | 1986–2003 | Total:3,375 | 32.1 | 8.1 (27,327 person-years) |
Age Continent of birth |
Breast | 1–18 | SIR | Increased risk of breast cancer in women who used fertility treatment | |
| Spaan et al. (81) | Netherlands | Cohort | 1989–2013 | Case: 19,157 Control:5,950 |
Case: 20.7 Control: 23.5 |
Age Parity IVF cycles |
IVF | Colon | 1-≥7 | SIR | No association between IVF and colorectal cancer risk. |