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Original Investigation |

Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer

Alexandra W. van den Belt-Dusebout, PhD1; Mandy Spaan, MSc1; Cornelis B. Lambalk, MD, PhD2; Marian Kortman, MD3; Joop S. E. Laven, MD, PhD4; Evert J. P. van Santbrink, MD, PhD5; Lucette A. J. van der Westerlaken, PhD6; Ben J. Cohlen, MD, PhD7; Didi D. M. Braat, MD, PhD8; Jesper M. J. Smeenk, MD, PhD9; Jolande A. Land, MD, PhD10; Mariëtte Goddijn, MD, PhD11; Ron J. T. van Golde, MD, PhD12; Minouche M. van Rumste, MD, PhD13; Roel Schats, MD, PhD2; Katarzyna Jóźwiak, PhD1; Michael Hauptmann, PhD1; Matti A. Rookus, PhD1; Curt W. Burger, MD, PhD4; Flora E. van Leeuwen, PhD1
[+] Author Affiliations
1Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
2Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, the Netherlands
3Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Utrecht, the Netherlands
4Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam, the Netherlands
5Department of Reproductive Medicine, Reinier de Graaf Hospital, Voorburg, the Netherlands
6Department of Obstetrics, Gynecology, and Reproductive Medicine, Leiden University Medical Center, Leiden, the Netherlands
7Department of Obstetrics and Gynecology, Isala Clinics, Zwolle, the Netherlands
8Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
9Department of Obstetrics and Gynecology, St Elisabeth Hospital, Tilburg, the Netherlands
10Department of Obstetrics and Gynecology, University Medical Center Groningen, University Groningen, Groningen, the Netherlands.
11Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, the Netherlands
12Department of Obstetrics and Gynecology, Maastricht University Medical Center, Maastricht, the Netherlands
13Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, the Netherlands
JAMA. 2016;316(3):300-312. doi:10.1001/jama.2016.9389.
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Importance  Previous studies of breast cancer risk after in vitro fertilization (IVF) treatment were inconclusive due to limited follow-up.

Objective  To assess long-term risk of breast cancer after ovarian stimulation for IVF.

Design, Setting, and Participants  Historical cohort (OMEGA study) with complete follow-up through December 2013 for 96% of the cohort. The cohort included 19 158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women starting other fertility treatments between 1980 and 1995 (non-IVF group) from all 12 IVF clinics in the Netherlands. The median age at end of follow-up was 53.8 years for the IVF group and 55.3 years for the non-IVF group.

Exposures  Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was collected from medical records and through mailed questionnaires.

Main Outcomes and Measures  Incidence of invasive and in situ breast cancers in women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Breast cancer risk in the IVF group was compared with risks in the general population (standardized incidence ratios [SIRs]) and the non-IVF group (hazard ratios [HRs]).

Results  Among 25 108 women (mean age at baseline, 32.8 years; mean number of IVF cycles, 3.6), 839 cases of invasive breast cancer and 109 cases of in situ breast cancer occurred after a median follow-up of 21.1 years. Breast cancer risk in IVF-treated women was not significantly different from that in the general population (SIR, 1.01 [95% CI, 0.93-1.09]) and from the risk in the non-IVF group (HR, 1.01 [95% CI, 0.86-1.19]). The cumulative incidences of breast cancer at age 55 were 3.0% for the IVF group and 2.9% for the non-IVF group (P = .85). The SIR did not increase with longer time since treatment (≥20 years) in the IVF group (0.92 [95% CI, 0.73-1.15]) or in the non-IVF group (1.03 [95% CI, 0.82-1.29]). Risk was significantly lower for those who underwent 7 or more IVF cycles (HR, 0.55 [95% CI, 0.39-0.77]) vs 1 to 2 IVF cycles and after poor response to the first IVF cycle (HR, 0.77 [95% CI, 0.61-0.96] for <4 vs ≥4 collected oocytes).

Conclusions and Relevance  Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, IVF treatment compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years. Breast cancer risk among IVF-treated women was also not significantly different from that in the general population. These findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women.

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Figure.
Identification of the OMEGA Study Cohort for Assessment of Breast Cancer Risk Following In Vitro Fertilization (IVF)

Adapted from Spaan et al.22

aAccording to the treatment center where these women were identified.

bWomen who were originally included in the non-IVF group but subsequently received IVF (eg, in another IVF clinic; n = 911 + 41 = 952) contributed person-time to both the non-IVF group and IVF group.

cWomen in this category contributed person-time from the first IVF treatment or first gynecological visit until date of death.

dFor unknown reasons, these women had originally not been identified as belonging in the IVF group; the women did not contribute person-time to the non-IVF group because IVF treatment was administered before 1989.

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