Risk of breast cancer for women who give birth after conception by assisted reproductive technology versus natural conception - a Nordic cohort study

Abstract Study question Are women who give birth after assisted reproductive technology (ART) at higher risk of breast cancer than women who give birth after natural conception? Summary answer Risk of breast cancer was similar or lower for women who gave birth after ART-conception compared to women who gave birth after natural conception. What is known already Most studies indicate no increase in breast cancer risk after use of ART, but results have been conflicting and with limited confounder control. Interpretation of existing knowledge is further complicated by the well-established dual effect of pregnancy on breast cancer risk, with short-term increase in risk and long-term protection. The population of ART-treated women is still relatively young and further studies are needed to understand how fertility treatment, pregnancy and causes of infertility collectively influence breast cancer risk in women treated with ART. Study design, size, duration Cohort study based on data linkage between the Medical Birth Registries, ART Registries, Population and Cause of Death Registries in Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015) and Sweden (1985-2015) and the Cancer Registries in each country (1958-2014, 1954-2014, 1953-2015, 1958-2015, respectively). We included 2,283,592 women who gave their first birth during the study period, at age ≥25 years. Among these, 111,781 women had at least one birth after ART conception. Participants/materials, setting, methods Women without prior cancer were followed from first birth to date of first cancer, death, emigration, or end of follow-up. We compared risk of breast cancer in Cox regression for women who ever gave birth after ART (time-dependent) vs women with birth(s) after natural conception only, using age as the time scale. We included age at first birth, parity (time-dependent), country and year of delivery as covariates. Sub-analyses included height, body mass index and smoking. Main results and the role of chance Women who gave birth after ART were on average 3 years older than women who gave birth after natural conception. Among women who gave birth after ART, 1,101 were diagnosed with breast cancer during a median follow-up of 8.8 years (incidence rate 101/100,000 person-years), compared to 26,984 cases during a median follow-up of 12.7 years (incidence rate 91/100,000 person-years) among women with naturally conceived pregnancies. Age-specific rates were similar. After covariate adjustment, risk was slightly lower for women with ART vs natural conception (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.87 - 0.99). Further adjustment for height, body mass index and smoking gave similar results. Age at first birth was not clearly associated with breast cancer risk for women with either conception method. Women with ART-conception in their first two pregnancies had lower risk (HR 0.83, 95% CI 0.70 - 0.98), whereas no clear differences were found for women with both conception methods, compared to women with two naturally conceived pregnancies. Associations according to ART indication (male, ovarian, other female and unexplained infertility) were consistent with the main findings, as were results for treatment type (IVF, ICSI, fresh and frozen transfer, and single or double embryo transfer). Limitations, reasons for caution We had no data on unsuccessful ART treatments, number or type of stimulation cycles. Because only women who gave birth were included, and because a large proportion of ART-treated women had unknown cause of infertility, we cannot exclude residual confounding from causes or severity of infertility. Wider implications of the findings Women with successful ART treatment had similar or slightly lower risk of breast cancer compared to women who gave birth after natural conception. Although this study could not completely rule out adverse effects of ART on breast cancer risk, we found no evidence to support strong adverse effects. Trial registration number Not applicable