The association between the reproductive health of young women and cardiovascular disease across the lifespan

Background: In women, cardiovascular disease (CVD) is the leading cause of death, accounting for one-third of all deaths worldwide. Traditionally, CVD has been perceived as a male-dominated condition, with reproductive-age group women perceived to be protected from CVD. Recent analyses of age-and sex-specific data from high-income countries have revealed that the observed ongoing decline in CVD mortality was sustained in older adults (> 55 years) but had slowed in young adults (< 55 years). The rate of decline was slowest in young women. Contemporary data describing CVD trends among young adults from the United Kingdom (UK) are scarce. Several lines of evidence suggest that reproductive factors (adverse pregnancy outcomes and fertility-related endocrine factors) in young women may serve as markers of their cardiometabolic health throughout the lifespan (young adulthood, midlife, and old age). The breadth, level, and quality of evidence on the relationship between reproductive factors and CVD is unclear. Also, awareness of these reproductive factors as factors that enhance CVD is low among healthcare providers and women themselves. Aim: The aim of this thesis was to examine the association between female reproductive factors and cardiovascular disease across the lifespan. Methods: A series of annual cohort and cross-sectional studies (1998-2017) were constructed to estimate incidence rates and prevalence among 16-50-year-old men and women (Objective 1). An umbrella review (tertiary level review of existing systematic reviews and meta-analyses) was conducted to consolidate higher-level evidence on the association between female reproductive factors and CVD (Objective 2). Cochrane, Medline and Embase were searched for relevant systematic reviews and meta-analyses from inception until 31st August 2019. Three separate retrospective matched cohort studies were conducted using UK primary care data. Cox proportional hazard models were fitted to estimate adjusted hazard ratio’s (aHR) and corresponding 95% confidence interval (95% CI) for CVD in women with (i) endometriosis (Objective 3), (ii) pelvic inflammatory disease (Objective 4), (iii) menstrual cycle characteristics including irregular and frequent or infrequent cycles (Objective 5) versus a matched comparator group. Results: Overall, from 1998 to 2017, the incidence and prevalence of ischaemic heart disease (IHD) and angina decreased, while coronary revascularisation, stroke/transient ischaemic attack (TIA), and heart failure (HF) increased in both sexes. (P for trend <0.05 for all except MI incidence and prevalence in men, revascularisation incidence in men, and stroke/TIA incidence in women). The umbrella review analysis included a total of 32 reviews evaluating multiple reproductive factors. The average period of follow-up was 7 to 10 years. All reviews were rated moderate in quality except three. In summary, the effect sizes for CVD ranged from 1.01 to 4-fold. The effect sizes were greatest (2-fold) for stillbirth, gestational diabetes, pre-term birth, current use of oral contraceptives (combined oral contraceptives or progesterone only pill), pre-eclampsia and recurrent pre-eclampsia. The effect size for HF was 4-fold in pre-eclampsia. The aHR for composite CVD were: 1.24 (95% CI 1.13–1.37) for endometriosis; 1.10 (95% CI 0.93-1.30) for pelvic inflammatory disease; 1.08 (95% CI 1.00-1.19) for irregular menstrual cycles; and 1.24 (1.02-1.52) for frequent or infrequent menstrual cycles. Conclusion: Overall, among young adults in the UK, the incidence and prevalence (1998-2017) of IHD and angina exhibited a downward trend while stroke/TIA, HF, and revascularisation, exhibited an upward trend. MI incidence increased in women but remained stable in men. From menarche to menopause, female reproductive factors were associated with CVD throughout the lifespan. Physicians addressing health indicators should consider the adverse impact of female reproductive factors on CVD. Policymakers should consider including female reproductive risk factors in clinical guidelines as part of CVD risk evaluation

Systematic approach to outcome assessment from coded electronic healthcare records in the DaRe2THINK NHS-embedded randomized trial

Aims Improving the efficiency of clinical trials is key to their continued importance in directing evidence-based patient care. Digital innovations, in particular the use of electronic healthcare records (EHRs), allow for large-scale screening and follow up of participants. However, it is critical these developments are accompanied by robust and transparent methods that can support high-quality and high clinical value research. Methods and results The DaRe2THINK trial includes a series of novel processes, including nationwide pseudonymized pre screening of the primary-care EHR across England, digital enrolment, remote e-consent, and ‘no-visit’ follow up by linking all primary- and secondary-care health data with patient-reported outcomes. DaRe2THINK is a pragmatic, healthcare-embedded randomized trial testing whether earlier use of direct oral anticoagulants in patients with prior or current atrial fibrillation can prevent thromboembolic events and cognitive decline (www.birmingham.ac.uk/dare2think). This study outlines the systematic approach and methodology employed to define patient information and outcome events. This includes transparency on all medical code lists and phenotypes used in the trial across a variety of national data sources, including Clinical Practice Research Datalink Aurum (primary care), Hospital Episode Statistics (secondary care), and the Office for National Statistics (mortality). Conclusion Co-designed by a patient and public involvement team, DaRe2THINK presents an opportunity to transform the approach to randomized trials in the setting of routine healthcare, providing high-quality evidence generation in populations representative of the community at risk

Postpartum haemorrhage and risk of long-term hypertension and cardiovascular disease : an English population-based longitudinal study using linked primary and secondary care databases

Objective To investigate the long-term risk of developing hypertension and cardiovascular disease (CVD) among those women who suffered a postpartum haemorrhage (PPH) compared with those women who did not. Design Population-based longitudinal open cohort study. Setting English primary care (The Health Improvement Network (THIN)) and secondary care (Hospital Episode Statistics (HES)) databases. Population Women exposed to PPH during the study period matched for age and date of delivery, and unexposed. Methods We conducted an open cohort study using linked primary care THIN and HES Databases, from 1 January 1997 to 31 January 2018. A total of 42 327 women were included: 14 109 of them exposed to PPH during the study period and 28 218 matched for age and date of delivery, and unexposed to PPH. HRs for cardiovascular outcomes among women who had and did not have PPH were estimated after controlling for covariates using multivariate Cox regression models. Outcome measures Risk of hypertensive disease, ischaemic heart disease, heart failure, stroke or transient ischaemic attack. Results During a median follow-up of over 4 years, there was no significant difference in the risk of hypertensive disease after adjustment for covariates (adjusted HR (aHR): 1.03 (95% CI: 0.87 to 1.22); p=0.71). We also did not observe a statistically significant difference in the risk of composite CVD (ischaemic heart disease, heart failure, stroke or transient ischaemic attack) between the exposed and the unexposed cohort (aHR: 0.86 (95% CI: 0.52 to 1.43; p=0.57). Conclusion Over a median follow-up of 4 years, we did not observe an association between PPH and hypertension or CVD

Postpartum haemorrhage and risk of mental ill health : a population-based longitudinal study using linked primary and secondary care databases

There is a gap in the literature investigating the impact of obstetric complications on subsequent mental ill health outcomes. The aim of this study was to establish the association between post-partum haemorrhage (PPH) and mental ill health. We conducted a retrospective open cohort study utilizing linked primary care (The Health Improvement Network (THIN)) and English secondary care (Hospital Episode Statistics (HES)) databases, from January 1, 1990 to January 31, 2018. A total of 42,327 women were included: 14,109 of them were exposed to PPH during the study period and 28,218 unexposed controls were matched for age and date of delivery. Hazard ratios (HRs) for mental illness among women with and without exposure to PPH were estimated after controlling for covariates. Women who had had PPH were at an increased risk of developing postnatal depression (adjusted HR: 1·10, 95%CI: 1·01–1·21) and post–traumatic stress disorder (PTSD) (adjusted HR: 1·17, 95%CI: 0·73–1·89) compared to women unexposed to PPH. When restricting the follow–up to the first year after childbirth, the adjusted HR for PTSD was 3·44 (95% CI 1·31–9·03). No increase in the overall risk was observed for other mental illnesses, including depression (adjusted HR: 0·94, 95%CI: 0·87–1·01), severe mental illness (adjusted HR: 0·65, 95%CI: 0·40–1·08, p = 0·239) and anxiety (adjusted HR: 0·99, 95%CI: 0·90–1·09). PPH is associated with a significant increase in the risk of developing postnatal depression and PTSD in the first year after delivery. Active monitoring for mental illness should form an integral part of the follow–up in women who suffered a PPH

Association of pregnancy complications/risk factors with the development of future long-term health conditions in women : overarching protocol for umbrella reviews

Acknowledgments Patient representatives and MuM-PreDiCT team. Funding This work was funded by the Strategic Priority Fund 'Tackling multimorbidity at scale' programme (grant number-MR/W014432/1) delivered by the Medical Research Council and the National Institute for Health and Care Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council.Peer reviewedPublisher PD