Reproductive longevity is essential for fertility and influences healthy ageing in women(1,2), but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here... Show moreReproductive longevity is essential for fertility and influences healthy ageing in women(1,2), but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause in approximately 200,000 women of European ancestry. These common alleles were associated with clinical extremes of age at natural menopause; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations(3). The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Show less
Spaan, M.; Belt-Dusebout, A.W. van den; Lambalk, C.B.; H.H. van boven; Schats, R.; Kortman, M.; ... ; Leeuwen, F.E. van 2021
Background: Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. Methods: This nationwide cohort study comprises 30 625 women who received ovarian... Show moreBackground: Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. Methods: This nationwide cohort study comprises 30 625 women who received ovarian stimulation for ART in 1983-2000 and 9988 subfertile women not treated with ART. Incident invasive and borderline ovarian tumors were ascertained through linkage with the Netherlands Cancer Registry and the Dutch Pathology Registry until July 2018. Ovarian tumor risk in ART-treated women was compared with risks in the general population and the subfertile non-ART group. Statistical tests were 2-sided. Results: After a median follow-up of 24 years, 158 invasive and 100 borderline ovarian tumors were observed. Ovarian cancer risk in the ART group was increased compared with the general population (standardized incidence ratio [SIR] = 1.43, 95% confidence interval [CI] = 1.18 to 1.71) but not when compared with the non-ART group (age- and parity-adjusted hazard ratio [HR] = 1.02, 95% CI = 0.70 to 1.50). Risk decreased with higher parity and with a larger number of successful ART cycles (resulting in childbirth, Ptrend = .001) but was not associated with the number of unsuccessful ART cycles. Borderline ovarian tumor risk was increased in ART-treated women compared with the general population (SIR = 2.20, 95% CI = 1.66 to 2.86) and with non-ART women (HR = 1.84, 95% CI = 1.08 to 3.14). Risk did not increase with more ART cycles or longer follow-up time. Conclusions: Increased ovarian cancer risk in ART-treated women compared with the general population is likely explained by nulliparity rather than ART treatment. The increased risk of borderline ovarian tumors after ART must be interpreted with caution because no dose-response relationship was observed. Show less
Windt, M. van der; Kleij, R.M. van der; Snoek, K.M.; Willemsen, S.P.; Dykgraaf, R.H.M.; Laven, J.S.E.; ... ; Steegers-Theunissen, R.P.M. 2020
Background: Periconception lifestyle behaviors affect maternal, paternal, offspring, and transgenerational health outcomes. Previous research in other target populations has shown that personalized... Show moreBackground: Periconception lifestyle behaviors affect maternal, paternal, offspring, and transgenerational health outcomes. Previous research in other target populations has shown that personalized lifestyle interventions, in which face-to-face counseling and eHealth ("blended care") are combined, may effectively target these lifestyle behaviors.Objective: We aimed to assess the effectiveness of a periconceptional lifestyle intervention on the improvement of specific lifestyle components.Methods: A blended periconception lifestyle care approach was developed, combining the outpatient lifestyle counseling service "Healthy Pregnancy" with the eHealth platform "Smarter Pregnancy" (www.smarterpregnancy.co.uk) in which lifestyle was coached for 24 weeks. All couples contemplating pregnancy or already pregnant (<= 12 weeks of gestation) who visited the outpatient clinics of the Department of Obstetrics and Gynecology at the Erasmus University Medical Center (Erasmus MC), Rotterdam, the Netherlands, between June and December 2018, were invited to participate. We measured changes in lifestyle behaviors at weeks 12 and 24 compared with baseline. Generalized estimating equations were used to analyze the changes in lifestyle behaviors over time. Subgroup analyses were performed for women with obesity (BMI >= 30 kg/m(2)), women pregnant at the start of the intervention, and those participating as a couple.Results: A total of 539 women were screened for eligibility, and 450 women and 61 men received the blended periconception intervention. Among the participating women, 58.4% (263/450) were included in the preconception period. Moreover, 78.9% (403/511) of the included participants completed the online lifestyle coaching. At baseline, at least one poor lifestyle behavior was present in most women (379/450, 84.2%) and men (58/61, 95.1%). In the total group, median fruit intake increased from 1.8 to 2.2 pieces/day (P<.001) and median vegetable intake increased from 151 to 165 grams/day (P<.001) after 24 weeks of online coaching. The probability of taking folic acid supplementation among women increased from 0.97 to 1(P<.001), and the probability of consuming alcohol and using tobacco in the total group decreased from 0.25 to 0.19 (P=.002) and from 0.20 to 0.15 (P=.63), respectively. Overall, the program showed the strongest effectiveness for participating couples. Particularly for vegetable and fruit intake, their consumption increased from 158 grams/day and 1.8 pieces/day at baseline to 190 grams/day and 2.7 pieces/day at the end of the intervention, respectively.Conclusions: We succeeded in including most participating women in the preconception period. A high compliance rate was achieved and users demonstrated improvements in several lifestyle components. The blended periconception lifestyle care approach seems to be an effective method to improve lifestyle behaviors. The next step is to further disseminate this approach and to perform a randomized trial to compare the use of blended care with the provision of only eHealth. Additionally, the clinical relevance of these results will need to be substantiated further. Show less
BackgroundPreeclampsia is a female-specific risk factor for the development of future cardiovascular disease. Whether early preventive cardiovascular disease risk screenings combined with risk... Show moreBackgroundPreeclampsia is a female-specific risk factor for the development of future cardiovascular disease. Whether early preventive cardiovascular disease risk screenings combined with risk-based lifestyle interventions in women with previous preeclampsia are beneficial and cost-effective is unknown.MethodsA micro-simulation model was developed to assess the life-long impact of preventive cardiovascular screening strategies initiated after women experienced preeclampsia during pregnancy. Screening was started at the age of 30 or 40 years and repeated every five years. Data (initial and follow-up) from women with a history of preeclampsia was used to calculate 10-year cardiovascular disease risk estimates according to Framingham Risk Score. An absolute risk threshold of 2% was evaluated for treatment selection, i.e. lifestyle interventions (e.g. increasing physical activity). Screening benefits were assessed in terms of costs and quality-adjusted-life-years, and incremental cost-effectiveness ratios compared with no screening.ResultsExpected health outcomes for no screening are 27.35 quality-adjusted-life-years and increase to 27.43 quality-adjusted-life-years (screening at 30 years with 2% threshold). The expected costs for no screening are euro9426 and around euro13,881 for screening at 30 years (for a 2% threshold). Preventive screening at 40 years with a 2% threshold has the most favourable incremental cost-effectiveness ratio, i.e. euro34,996/quality-adjusted-life-year, compared with other screening scenarios and no screening.ConclusionsEarly cardiovascular disease risk screening followed by risk-based lifestyle interventions may lead to small long-term health benefits in women with a history of preeclampsia. However, the cost-effectiveness of a lifelong cardiovascular prevention programme starting early after preeclampsia with risk-based lifestyle advice alone is relatively unfavourable. A combination of risk-based lifestyle advice plus medical therapy may be more beneficial. Show less
ObjectiveWomen with premature ovarian insufficiency (POI) enter menopause before age 40. Early menopause was associated with increased risk for coronary artery disease (CAD), death from... Show moreObjectiveWomen with premature ovarian insufficiency (POI) enter menopause before age 40. Early menopause was associated with increased risk for coronary artery disease (CAD), death from cardiovascular disease and all-cause mortality. We compared the prevalence of CAD between middle-aged women on average 10years following the initial POI diagnosis, with a population-based cohort.DesignCross-sectional case-control study.ParticipantsWomen from two Dutch University Medical Centers above 45years of age previously diagnosed with POI (n=98) were selected and compared with age- and race-matched controls from the Multi-Ethnic Study of Atherosclerosis (MESA).MeasurementsThe primary outcome was detectable coronary artery calcium (CAC) determined by coronary computed tomography (CCT).ResultsWomen with POI had significantly higher blood pressure, cholesterol and glucose, despite lower BMI compared to controls. Similar proportions of detectable CAC (CAC score >0 Agatston Units) were observed in women with POI and controls (POI n=16 (16%), controls n=52 (18%), P=0.40 and P-adj=0.93). In women with POI separately, we were not able to identify associations between CVD risk factors and CAC. The following CVD risk factors in controls were positively associated with CAC: age, diabetes mellitus, hypertension and LDL cholesterol. HRT use was negatively associated with CAC in controls.ConclusionsThe presence of CAC did not differ significantly in women with POI around 50years of age, compared to an age- and race-matched control group. We observe no increased calcified coronary disease in POI patients, despite the presence of unfavourable cardiovascular risk factors in these women. Show less
Objectives Compare the predictive performance of Framingham Risk Score (FRS), Pooled Cohort Equations (PCEs) and Systematic COronary Risk Evaluation (SCORE) model between women with and without a... Show moreObjectives Compare the predictive performance of Framingham Risk Score (FRS), Pooled Cohort Equations (PCEs) and Systematic COronary Risk Evaluation (SCORE) model between women with and without a history of hypertensive disorders of pregnancy (hHDP) and determine the effects of recalibration and refitting on predictive performance. Methods We included 29 751 women, 6302 with hHDP and 17 369 without. We assessed whether models accurately predicted observed 10-year cardiovascular disease (CVD) risk (calibration) and whether they accurately distinguished between women developing CVD during follow-up and not (discrimination), separately for women with and without hHDP. We also recalibrated (updating intercept and slope) and refitted (recalculating coefficients) the models. Results Original FRS and PCEs overpredicted 10-year CVD risks, with expected:observed (E:O) ratios ranging from 1.51 (for FRS in women with hHDP) to 2.29 (for PCEs in women without hHDP), while E:O ratios were close to 1 for SCORE. Overprediction attenuated slightly after recalibration for FRS and PCEs in both hHDP groups. Discrimination was reasonable for all models, with C-statistics ranging from 0.70-0.81 (women with hHDP) and 0.72-0.74 (women without hHDP). C-statistics improved slightly after refitting 0.71-0.83 (with hHDP) and 0.73-0.80 (without hHDP). The E:O ratio of the original PCE model was statistically significantly better in women with hHDP compared with women without hHDP. Conclusions SCORE performed best in terms of both calibration and discrimination, while FRS and PCEs overpredicted risk in women with and without hHDP, but improved after recalibrating and refitting the models. No separate model for women with hHDP seems necessary, despite their higher baseline risk. Show less
AimTo provide a comprehensive overview of cardiovascular disease (CVD) risk prediction models for women and models that include female-specific predictors.MethodsWe performed a systematic review of... Show moreAimTo provide a comprehensive overview of cardiovascular disease (CVD) risk prediction models for women and models that include female-specific predictors.MethodsWe performed a systematic review of CVD risk prediction models for women in the general population by updating a previous review. We searched Medline and Embase up to July 2017 and included studies in which; (a) a new model was developed, (b) an existing model was validated, or (c) a predictor was added to an existing model.ResultsA total of 285 prediction models for women have been developed, of these 160 (56%) were female-specific models, in which a separate model was developed solely in women and 125 (44%) were sex-predictor models. Out of the 160 female-specific models, 2 (1.3%) included one or more female-specific predictors (mostly reproductive risk factors). A total of 591 validations of sex-predictor or female-specific models were identified in 206 papers. Of these, 333 (56%) validations concerned nine models (five versions of Framingham, SCORE, Pooled Cohort Equations and QRISK). The median and pooled C statistics were comparable for sex-predictor and female-specific models. In 260 articles the added value of new predictors to an existing model was described, however in only 3 of these female-specific that no competing interests exist. predictors (reproductive risk factors) were added.ConclusionsThere is an abundance of models for women in the general population. Female-specific and sex-predictor models have similar predictors and performance. Female-specific predictors are rarely included. Further research is needed to assess the added value of female-specific predictors to CVD models for women and provide physicians with a well-performing prediction model for women. Show less
Berg, M.H. van den; Overbeek, A.; Lambalk, C.B.; Kaspers, G.J.L.; Bresters, D.; Heuvel-Eibrink, M.M. van den; ... ; DCOG LATER-VEVO Study Grp 2018