European Journal of Cancer (Oxford, England : 1990), 215, 115168, 2024
Maternal use of hormonal contraception and risk of childhood leukemia: A Scandinavian population-based cohort study
Caroline H Hemmingsen, Susanne K Kjaer, Sarah Hjorth
Ulrika Nörby, Anton Pottegård, Justine Bénévent, Kjeld Schmiegelow, Charlotte Wessel Skovlund, Maarit K Leinonen, Hedvig Nordeng, Lina Steinrud Mørch, Marie Hargreave, Anne Broe
Virus, Lifestyle and Genes, Danish Cancer Institute, Copenhagen, Denmark; Department of Gynaecology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. Electronic address: susanne@...
Maternal hormonal contraception use has been associated with childhood leukemia risk. However, studies are few and often based on self-reported information.
Methods
Using registry data from Denmark, Norway, and Sweden, we identified 3,183,316 children (born 1996-2018) and followed them from birth until leukemia diagnosis, censoring (death, emigration, other cancer, 20th birthday) or study closure (December 31st, 2017, 2018 or 2020). We estimated hazard ratios (HRs) and 95 % confidence intervals (CIs) for childhood leukemia (any, lymphoid and non-lymphoid) associated with maternal recent use (≤ 3 months before or during pregnancy) or previous use (before recent use) of hormonal contraception overall and by type, compared to no use.
Results
During 29,455,528 person-years, 1701 children developed leukemia (no use: 518, previous use: 974, recent use: 209). Maternal recent use of hormonal contraception was associated with an increased leukemia risk in children (HR 1.22, 95 % CI 1.04-1.44; incidence rate per 1,000,000 person-years [IR] 65), compared to no use (IR 53). The association was strongest for non-lymphoid leukemia (HR 1.69, 95 % CI 1.20-2.37) and mainly driven by the oral combined products, both for any leukemia (HR 1.29, 95 % CI 1.05-1.59) and non-lymphoid leukemia (HR 1.75, 95 % CI 1.17-2.62). Additionally, non-lymphoid leukemia was associated with recent use of the non-oral progestin-only products (HR 2.10, 95 % CI 1.28-3.44).
Conclusions
Although the absolute risk was low, maternal hormonal contraception use up to or during pregnancy was associated with an increased childhood leukemia risk, particularly non-lymphoid leukemia, and mainly driven by oral combined and non-oral progestin-only products.
maternal hormonal contraception childhood leukemia risk, oral combined contraceptive pregnancy childhood cancer Scandinavian cohort, hormonal contraception periconceptional exposure childhood leukemia, Hemmingsen Mørch contraception leukemia Scandinavian registry, progestin-only contraceptive non-lymphoid leukemia offspring risk, ethinylestradiol progestin preconception childhood leukemia population cohort, maternal contraceptive use before pregnancy cancer risk children, combined oral contraceptive periconceptional childhood acute leukemia, hormonal contraception pregnancy non-lymphoid lymphoid leukemia offspring, Scandinavian population cohort registry study contraceptive safety childhood cancer
PMID 39667251 39667251 DOI 10.1016/j.ejca.2024.115168 10.1016/j.ejca.2024.115168 Hemmingsen et al. 2024, Hemmingsen 2024
Cite this article
Hemmingsen, C. H., Kjaer, S. K., Hjorth, S., Nörby, U., Broe, A., Pottegård, A., Bénévent, J., Schmiegelow, K., Skovlund, C. W., Leinonen, M. K., Nordeng, H., Mørch, L. S., & Hargreave, M. (2025). Maternal use of hormonal contraception and risk of childhood leukemia: A Scandinavian population-based cohort study. European journal of cancer (Oxford, England : 1990), 215, 115168. https://doi.org/10.1016/j.ejca.2024.115168
Hemmingsen CH, Kjaer SK, Hjorth S, Nörby U, Broe A, Pottegård A, et al. Maternal use of hormonal contraception and risk of childhood leukemia: A Scandinavian population-based cohort study. Eur J Cancer. 2025;215:115168. doi:10.1016/j.ejca.2024.115168
Hemmingsen, C. H., et al. "Maternal use of hormonal contraception and risk of childhood leukemia: A Scandinavian population-based cohort study." European journal of cancer (Oxford, England : 1990), vol. 215, 2025, pp. 115168.
To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism. Nationwide cohort study. Denmark through national registries. All 15-49 year old women living in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment (n=2 029 065). A first time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism. Among 2.0 million women followed for 21.0 million person years, 8710 venous thromboembolic events occurred. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 7.2 (95% confidence interval 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception. NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age. The number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception. Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.
Increasing numbers of BReast CAncer (BRCA) 1 or 2 pathogenic variant (PV) carriers, who have an inherited predisposition to breast and ovarian cancer, are being identified. Among these women, data regarding the effects of contraception on cancer risks are unclear and various guidelines provide various recommendations. We aim to optimize counselling regarding contraception for BRCA1/2-PV carriers. Therefore, we performed a systematic review and meta-analysis. We investigated the risk ratio for developing breast cancer or ovarian cancer in BRCA1/2-PV carriers who have used any form of contraception versus non-users. Second, we analysed breast and ovarian cancer risk among BRCA1/2-PV carriers as influenced by the duration of contraceptive use and by the time since last use. In addition, we provide an overview of all relevant international guidelines regarding contraceptive use for BRCA1/2-PV carriers. A systematic search in the Medline database and Cochrane library identified studies describing breast and/or ovarian cancer risk in BRCA1/2-PV carriers as modified by contraception until June 2021. The search included medical subject headings, keywords and synonyms related to BRCA and contraceptives (any kind). PRISMA guidance was followed. Risk Of Bias In Non-randomized Studies of Interventions and Grading of Recommendations, Assessment, Development and Evaluations assessments were performed. Random-effects meta-analyses were used to estimate pooled effects for breast and ovarian cancer risk separately. Subgroup analyses were conducted for BRCA1 versus BRCA2 and for the various contraceptive methods. Outcomes: Results of the breast cancer risk with oral contraceptive pill (OCP) analysis depended on the outcome measure. Meta-analyses of seven studies with 7525 women revealed a hazard ratio (HR) of 1.55 (95% CI: 1.36-1.76) and of four studies including 9106 women resulted in an odds ratio (OR) of 1.06 (95% CI: 0.90-1.25), heterogeneity (I2) 0% and 52%, respectively. Breast cancer risk was still increased in ever-users compared with never-users >10 years after last OCP use. In contrast, ovarian cancer risk was decreased among OCP users: HR 0.62 (95% CI: 0.52-0.74) based on two studies including 10 981 women (I2: 0%), and OR 0.49 (95% CI: 0.38-0.63) based on eight studies including 10 390 women (I2: 64%). The protective effect vanished after cessation of use. Tubal ligation also protects against ovarian cancer: one study including 3319 women (I2: 0%): HR: 0.44 (95% CI: 0.26-0.74) and three studies with 7691 women (I2: 44%): OR: 0.74 (95% CI: 0.53-1.03). Data regarding other contraceptives were unavailable. No differences were observed between BRCA1 and BRCA2-PV carriers. The quality of evidence was either low or very low. The OCP potentially increases breast cancer risk, while ovarian cancer risk decreases with either the OCP and tubal ligation in BRCA1/2-PV carriers. Counselling of BRCA1/2-PV carriers should be personalized; the genetic and non-genetic factors (like prior risk-reducing surgeries, prior breast cancer and age) and patients' preferences (reversibility, ease of use, reliability and effect on menstrual cycle) should be balanced. To further optimize counselling for high-risk women, future research should focus on other (commonly used) contraceptive methods and cancer risks in this specific population, and on the potential impact of changing formulations over time.
gynecology/breast-health/breast-cancer-riskcontraception/adverse-effects/venous-thromboembolismtherapeutics/hormonal-agents/progesterone-and-progestins
Open Access
Niemeyer Hultstrand J et al., 2022·Lancet Reg Health Eur
Evidence on a possible association between newer hormonal contraceptives (HC) and risk of breast cancer remains inconclusive, especially as concerns progestogen-only methods. In this nationwide prospective cohort study, all Swedish women aged 15-34 at study start on January 1(st) 2005, or who turned 15 years during the study period, were followed until December 31(st) 2017. Using information from seven National Registers, we assessed the risk ratio of developing breast cancer and breast cancer in situ in relation to different HC using Poisson regression. We adjusted the analyses for several known confounders of breast cancer. Findings: This cohort included 1.5 million women providing more than 14 million person-years. During the study period, 3842 women were diagnosed with breast cancer. Compared with never users of any HC, we found no increased risk of developing breast cancer among current users of any combined HC, IRR 1.03 (0.91-1.16), whereas current users of progestogen-only methods had an increased risk of developing breast cancer, IRR 1.32 (1.20-1.45). Across all types of HC, the risk of developing breast cancer appeared to be highest the first five years of use (combined HC IRR 1.39 (1.14-1.69); progestogen-only methods IRR 1.74 (1.44-2.10). The risk disappeared ten years after the women stopped using HC. The absolute risk of breast cancer per 100,000 women-years was 22.4 for never users, 10.9 for current users of combined HC, and 29.8 for current users of progestogen-only methods. Interpretation: Current use of progestogen-only methods is associated with a small increased risk of developing breast cancer, whereas we could only detect an increased risk among users of combined HC during the first five years of use. This may partly be explained by a selective prescription of progestogen-only methods to women with risk factors for breast cancer, like smoking or obesity. As the absolute risk of breast cancer was small, the many health benefits associated with HC must also be taken into account in contraceptive counselling. This study was funded by the Swedish Cancer Society and by the Uppsala County Council, the Faculty of Medicine at Uppsala University.
Hormonal contraception (HC) is widely used throughout the world and has been associated with venous thrombosis (VT) such as deep vein thrombosis, pulmonary emboli, and cerebral VT. To provide a current comprehensive overview of the risk of objectively confirmed VT with HC in healthy women compared to nonusers. PubMed was searched from inception to April 2018 for eligible studies in the English language, with hand searching from past systematic reviews.
Selection Criteria: We selected original research evaluating risk of objectively confirmed VT in healthy women taking oral or nonoral HC compared with nonusers. The primary outcome of interest was a fatal or nonfatal VT in users of HC compared to nonusers or past users. Studies with at least twenty events were eligible. Adjusted relative risks with 95 percent confidence intervals were reported. Three independent reviewers extracted data from selected studies. 1,962 publications were retrieved through the search strategy, with 15 publications included. Users of oral contraception with levonorgesterol had increased risk of VT by a range of 2.79-4.07, while other oral hormonal preparations increased risk by 4.0-48.6. Levonorgestrel intrauterine devices did not increase risk. Etonogestrel/ethinyl estradiol vaginal rings increased the risk of VT by 6.5. Norelgestromin/ethinyl estradiol patches increased risk of VT by 7.9. Etonogestrel subcutaneous implants by 1.4 and depot-medroxyprogesterone by 3.6. The risk of fatal VT was increased in women aged fifteen to twenty-four by 18.8-fold. Users of HC have a significant increased risk of VT compared to nonusers. Current risks would project at least 300-400 healthy young women dying yearly in the United States due to HC. Women should be informed of these risks and offered education in fertility-awareness-based methods with comparable efficacy for family planning.
HC is widely used throughout the world and has been associated with blood clots in the legs and lungs. We searched the literature and found the risks of currently used forms of birth control increased between threeand ninefold for blood clots for healthy women. The risks found would project 300-400 women dying from using HC each year in the United States.