Previous discussions have indicated that the small increases of risk of venous thromboembolism (VTE) associated with newer combined oral contraceptives (third generation, containing desogestrel and gestodene) may be attributed to bias due to cohort effects. In a case-control analysis, this may produce an overestimate of risk of newer preparations. In 10 centres in Germany and the UK, the Transnational Study analysed data from 502 women aged 16-44 years with VTE, and from 1864 controls matched for 5-year age group and region. Information on lifetime exposure history from all subjects was added to the dataset used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person-years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of VTE for the comparison of current users of third-generation versus current users of second-generation (primarily levonorgestrel compounds) combined oral contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the Transnational Study data show no evidence for an increased risk of VTE with thirdcompared with second-generation combined oral contraceptives.
oral contraceptives venous thromboembolism third generation second generation risk, desogestrel gestodene VTE risk combined oral contraceptives, oral contraceptive generation comparison venous thromboembolism case-control, Cox regression time-dependent covariates oral contraceptive exposure history, levonorgestrel third generation pill thrombosis risk bias, Transnational Study oral contraceptives VTE Lewis Spitzer, cohort effect bias oral contraceptive venous thromboembolism studies, lifetime oral contraceptive exposure history VTE risk adjustment, combined oral contraceptive formulation safety comparison thrombosis, full exposure history oral contraceptive differential risk assessment
PMID 10359554 10359554 DOI 10.1093/humrep/14.6.1493 10.1093/humrep/14.6.1493
Cite this article
Lewis, M. A., MacRae, K. D., Kühl-Habichl, D., Bruppacher, R., Heinemann, L. A., & Spitzer, W. O. (1999). The differential risk of oral contraceptives: the impact of full exposure history. Human reproduction (Oxford, England), 14(6), 1493-1499. https://doi.org/10.1093/humrep/14.6.1493
Lewis MA, MacRae KD, Kühl-Habichl D, Bruppacher R, Heinemann LA, Spitzer WO. The differential risk of oral contraceptives: the impact of full exposure history. Hum Reprod. 1999;14(6):1493-1499. doi:10.1093/humrep/14.6.1493
Lewis, M. A., et al. "The differential risk of oral contraceptives: the impact of full exposure history." Human reproduction (Oxford, England), vol. 14, no. 6, 1999, pp. 1493-1499.
In October 1995 the Committee on Safety of Medicines advised UK doctors and pharmacists that oral contraceptives containing desogestrel and gestodene were associated with double the risk of venous thromboembolic events (VTE) compared to pills containing other progestogens. In 1997 data was analysed from the MediPlus database of UK general practitioner records, which reported odds ratios for desogestrel and gestodene lower than that for levonorgestrel. Here the results of a more stringent nested case control analysis on the MediPlus database are reported. The study was larger and cases were verified. A crude incidence of idiopathic VTE was found amongst users of combined oral contraceptives of 4.6 per 10 000 exposed women years. Using levonorgestrel 150 microg + ethinyloestradiol 30 microg as reference, non-significant odds ratios of 1.1 (0.5-2.6) for desogestrel 150 microg + ethinyloestradiol 30 microg and 1.1 (0.5-2.4) for gestodene 75 microg + ethinyloestradiol 30 microg were found. The results of this study show no significant difference in risk between different formulations of combined oral contraceptive.
Contraception/ComparisonVenous Thromboembolism RiskThird vs Second Generation ProgestagensConfounding and Bias in Observational Studies
Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary thrombosis, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding.
Are dietary patterns associated with age at menarche after accounting for BMI-for-age (BMIz) and height? We observed associations between both the Alternative Healthy Eating Index (AHEI) and the Empirical Dietary Inflammatory Pattern (EDIP) and age at menarche. Dietary patterns have been sparsely examined in relation to age at menarche and no studies have examined the association between the AHEI, a healthier diet, and EDIP, a pro-inflammatory diet, and menarche. STUDY DESIGN, SIZE, The Growing Up Today Study (GUTS) is a prospective cohort of children ages 9-14 years at study enrollment. GUTS enrolled in two waves with enrollment beginning in 1996 (GUTS1) and 2004 (GUTS2). For this analysis, GUTS1 and GUTS2 participants were followed through 2001 and 2008, respectively. PARTICIPANTS/MATERIALS, SETTING, We included 7530 participants who completed food frequency questionnaire(s) (FFQ) prior to menarche who then self-reported age at menarche during study follow-up. Cox proportional hazard models were used to calculate multivariable hazard ratios (HRs) and 95% CIs for the associations between two dietary patterns, the AHEI and EDIP, and age at menarche, with and without adjustment for time-varying BMIz and height. MAIN Six thousand nine hundred ninety-two participants (93%) reported menarche during the study period. On average, participants completed the baseline FFQ 1.75 years prior to menarche. Participants in the highest quintile of AHEI diet score (indicating a healthier diet) were 8% less likely to attain menarche within the next month compared to those in the lowest quintile (95% CI = 0.85-0.99; Ptrend = 0.03). This association remained after adjustment for BMIz and height (corresponding HR = 0.93; 95% CI = 0.86-1.00; Ptrend = 0.04). Participants in the highest quintile of the EDIP score (i.e. most inflammatory diet), were 15% more likely to attain menarche in the next month relative to those in the lowest quintile (95% CI = 1.06-1.25; Ptrend = 0.0004), and the association remained following adjustment for BMIz and height (corresponding HR = 1.15; 95% CI = 1.06-1.25; Ptrend = 0.0004). LIMITATIONS, Self-reported questionnaires are subject to some error; however, given our prospective study design it is likely this error is non-differential with respect to the outcome. Our findings of an association between both the AHEI and EDIP and age at menarche indicate that diet quality may play a role in age at menarche independent of BMI or height. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Breast Cancer Research Foundation. The GUTS is supported by the National Institutes of Health U01 HL145386. C.P.D. was supported by National Institutes of Health T32 CA094880. The authors have no conflicts of interest to disclose. N/A.
EndometriosisMenopause TimingEndometriosis HistoryPooled Cohort Analysis
Open Access
What is the association between endometriosis and the type and age of menopause? Women with endometriosis had a 7-fold increased risk of undergoing surgical menopause rather than natural menopause and were more likely to experience premature or early menopause, both surgically and naturally. Endometriosis is associated with reduced ovarian reserve, but evidence on its relationship with the type of menopause (surgical vs natural) and timing (especially premature and early menopause) is limited. Women with endometriosis are more likely to undergo hysterectomy and/or oophorectomy (either unilateral or bilateral), but the average age of these surgeries remains unclear. STUDY DESIGN, SIZE, The study analysed individual-level data from 279 948 women in five cohort studies conducted in the UK, Australia, Sweden, and Japan between 1996 and 2022. PARTICIPANTS/MATERIALS, SETTING, Women whose menopause type and age could not be determined due to premenopausal hysterectomy with ovarian preservation or use of menopausal hormone therapy were excluded. Endometriosis was identified through self-reports and administrative data. Surgical menopause was defined as premenopausal bilateral oophorectomy. Fine-Gray subdistribution hazard models estimated hazard ratios (HRs) for surgical and natural menopause. Age at menopause was determined by the ages at the final menstrual period or bilateral oophorectomy. Linear regression assessed mean differences in menopause age, while multinomial logistic regression estimated odds ratios (ORs) <40 (premature), 40-44 (early), 45-49, 50-51 (reference), 52-54, and ≥55 years. Spontaneous premature ovarian insufficiency (POI) was defined as natural menopause before age 40 years. MAIN Endometriosis was identified in 3.7% of women. By the end of follow-up, 7.9% had surgical menopause and 58.2% experienced natural menopause. Using a competing risk model, women with endometriosis had a 7-fold increased risk of surgical menopause (HR: 7.54, 95% CI 6.84, 8.32) and were less likely to experience natural menopause (HR: 0.40, 95% CI 0.33, 0.49). On average, surgical menopause occurred 1.6 years (19 months) earlier (β: -1.59, 95% CI -1.77, -1.42) in women with endometriosis. Among women who experienced natural menopause, it was 0.4 years (5 months) earlier (β: -0.37, 95% CI -0.46, -0.28) for those with endometriosis. Women with endometriosis were twice as likely to experience premature surgical menopause (<40 years) (OR: 2.11, 95% CI 2.02, 2.20) or 1.4 times more likely to develop spontaneous POI (OR: 1.36, 95% CI 1.17, 1.59). They were also at increased odds of early surgical and natural menopause (40-44 years). LIMITATIONS, This study could not differentiate between subtypes and stages of endometriosis or assess treatments for ovarian endometrioma, which may impact ovarian reserve. Self-reported menopause type and age could introduce recall bias. Given the consistent findings across individual studies, our results are likely to be generalizable to different populations, highlighting the need for tailored management of endometriosis to prevent medically induced or premature menopause. Long-term monitoring of women with endometriosis is recommended, given their elevated risk of surgical menopause and premature or early menopause, which are associated with adverse health outcomes in later life. STUDY FUNDING/COMPETING INTEREST(S): The InterLACE Consortium is funded by the Australian National Health and Medical Research Council project grant (APP1027196) and Centres of Research Excellence (APP1153420). G.D.M. is funded by the Australian National Health and Medical Research Council Leadership Fellowship (APP2009577). This research is funded in part by the Japan Society for the Promotion of Science (JSPS 19KK0235, 23KK0167). The authors have no conflict of interest. Where authors are identified as personnel of the International Agency for Research on Cancer or WHO, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO. N/A.