Is there a link between infertility, miscarriage, stillbirth, and premature or early menopause? Results from pooled analyses of 9 cohort studies.

BACKGROUND: Some reproductive factors (such as age at menarche and parity) have been shown to be associated with age at natural menopause, but there has been little quantitative analysis of the association between infertility, miscarriage, stillbirth, and premature (<40 years) or early menopause (40-44 years). In addition, it has been unknown whether the association differs between Asian and non-Asian women, although the age at natural menopause is younger among Asian women. OBJECTIVE: This study aimed to investigate the association of infertility, miscarriage, and stillbirth with age at natural menopause, and whether the association differed by race (Asian and non-Asian). STUDY DESIGN: This was a pooled individual participant data analysis from 9 observational studies contributing to the InterLACE consortium. Naturally postmenopausal women with data on at least 1 of the reproductive factors (ie, infertility, miscarriage, and stillbirth), age at menopause, and confounders (ie, race, education level, age at menarche, body mass index, and smoking status) were included. A multinomial logistic regression model was used to estimate relative risk ratios and 95% confidence intervals for the association of infertility, miscarriage, and stillbirth with premature or early menopause, adjusting for confounders. Between-study difference and within-study correlation were taken into account by including study as a fixed effect and indicating study as a cluster variable. We also examined the association with number of miscarriages (0, 1, 2, ≥3) and stillbirths (0, 1, ≥2), and tested whether the strength of association differed between Asian and non-Asian women. RESULTS: A total of 303,594 postmenopausal women were included. Their median age at natural menopause was 50.0 years (interquartile range, 47.0-52.0). The percentages of women with premature and early menopause were 2.1% and 8.4%, respectively. The relative risk ratios (95% confidence intervals) of premature and early menopause were 2.72 (1.77-4.17) and 1.42 (1.15-1.74) for women with infertility; 1.31 (1.08-1.59) and 1.37 (1.14-1.65) for women with recurrent miscarriages; and 1.54 (1.52-1.56) and 1.39 (1.35-1.43) for women with recurrent stillbirths. Asian women with infertility, recurrent miscarriages (≥3), or recurrent stillbirths (≥2) had higher risk of premature and early menopause compared with non-Asian women with the same reproductive history. CONCLUSION: Histories of infertility and recurrent miscarriages and stillbirths were associated with higher risk of premature and early menopause, and the associations differed by race, with stronger associations for Asian women with such reproductive history.

Menopause, hysterectomy, menopausal hormone therapy and cause-specific mortality: cohort study of UK Biobank participants.

STUDY QUESTION: What is the association between menopausal hormone therapy (MHT) and cause-specific mortality? SUMMARY ANSWER: Self-reported MHT use following early natural menopause, surgical menopause or premenopausal hysterectomy is associated with a lower risk of breast cancer mortality and is not consistently associated with the risk of mortality from cardiovascular disease or other causes. WHAT IS KNOWN ALREADY: Evidence from the Women's Health Initiative randomized controlled trials showed that the use of estrogen alone is not associated with the risk of cardiovascular mortality and is associated with a lower risk of breast cancer mortality, but evidence from the Million Women Study showed that use of estrogen alone is associated with a higher risk of breast cancer mortality. STUDY DESIGN, SIZE, DURATION: Cohort study (the UK Biobank), 178 379 women, recruited in 2006-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Postmenopausal women who had reported age at menopause (natural or surgical) or hysterectomy, and information on MHT and cause-specific mortality. Age at natural menopause, age at surgical menopause, age at hysterectomy and MHT were exposures of interest. Natural menopause was defined as spontaneous cessation of menstruation for 12 months with no previous hysterectomy or oophorectomy. Surgical menopause was defined as the removal of both ovaries prior to natural menopause. Hysterectomy was defined as removal of the uterus before natural menopause without bilateral oophorectomy. The study outcome was cause-specific mortality. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 178 379 women included, 136 790 had natural menopause, 17 569 had surgical menopause and 24 020 had hysterectomy alone. Compared with women with natural menopause at the age of 50-52 years, women with natural menopause before 40 years (hazard ratio (HR): 2.38, 95% CI: 1.64, 3.45) or hysterectomy before 40 years (HR: 1.60, 95% CI: 1.23, 2.07) had a higher risk of cardiovascular mortality but not cancer mortality. MHT use was associated with a lower risk of breast cancer mortality following surgical menopause before 45 years (HR: 0.17, 95% CI: 0.08, 0.36), at 45-49 years (HR: 0.15, 95% CI: 0.07, 0.35) or at ≥50 years (HR: 0.28, 95% CI: 0.13, 0.63), and the association between MHT use and the risk of breast cancer mortality did not differ by MHT use duration (<6 or 6-20 years). MHT use was also associated with a lower risk of breast cancer mortality following natural menopause before 45 years (HR: 0.59, 95% CI: 0.36, 0.95) or hysterectomy before 45 years (HR: 0.49, 95% CI: 0.32, 0.74). LIMITATIONS, REASONS FOR CAUTION: Self-reported data on age at natural menopause, age at surgical menopause, age at hysterectomy and MHT. WIDER IMPLICATIONS OF THE FINDINGS: The current international guidelines recommend women with early menopause to use MHT until the average age at menopause. Our findings support this recommendation. STUDY FUNDING/COMPETING INTEREST(S): This project is funded by the Australian National Health and Medical Research Council (NHMRC) (grant numbers APP1027196 and APP1153420). G.D.M. is supported by NHMRC Principal Research Fellowship (APP1121844), and M.H. is supported by an NHMRC Investigator Grant (APP1193838). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women.

OBJECTIVE: To examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes. DESIGN: Individual participant pooled analysis of eight prospective cohort studies. SETTING: Cohort studies across seven countries (Australia, China, Japan, Netherlands, Sweden, the United Kingdom, and the United States) participating in the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium, which was established in June 2012. PARTICIPANTS: 618 851 women aged 32.0-73.0 years at baseline with data on infertility, miscarriage, or stillbirth, at least one outcome event (non-fatal or fatal stroke), and information on covariates were included; 93 119 women were excluded. Of the participants, 275 863 had data on non-fatal and fatal stroke, 54 716 only had data on non-fatal stroke, and 288 272 only had data on fatal stroke. MAIN OUTCOME AND MEASURES: Non-fatal strokes were identified through self-reported questionnaires, linked hospital data, or national patient registers. Fatal strokes were identified through death registry data. RESULTS: The median follow-up for non-fatal stroke and fatal stroke was 13.0 years (interquartile range 12.0-14.0) and 9.4 years (7.6-13.0), respectively. A first non-fatal stroke was experienced by 9265 (2.8%) women and 4003 (0.7%) experienced a fatal stroke. Hazard ratios for non-fatal or fatal stroke were stratified by hypertension and adjusted for race or ethnicity, body mass index, smoking status, education level, and study. Infertility was associated with an increased risk of non-fatal stroke (hazard ratio 1.14, 95% confidence interval 1.08 to 1.20). Recurrent miscarriage (at least three) was associated with higher risk of non-fatal and fatal stroke (1.35, 1.27 to 1.44, and 1.82, 1.58 to 2.10, respectively). Women with stillbirth were at 31% higher risk of non-fatal stroke (1.31, 1.10 to 1.57) and women with recurrent stillbirth were at 26% higher risk of fatal stroke (1.26, 1.15 to 1.39). The increased risk of stroke (non-fatal or fatal) associated with infertility or recurrent stillbirths was mainly driven by a single stroke subtype (non-fatal ischaemic stroke and fatal haemorrhagic stroke), while the increased risk of stroke (non-fatal or fatal) associated with recurrent miscarriages was driven by both subtypes. CONCLUSION: A history of recurrent miscarriages and death or loss of a baby before or during birth could be considered a female specific risk factor for stroke, with differences in risk according to stroke subtypes. These findings could contribute to improved monitoring and stroke prevention for women with such a history.

Associations Between Socioeconomic Status, Patient Risk, and Short-Term Intensive Care Outcomes.

OBJECTIVES: To investigate the association of socioeconomic status as measured by the average socioeconomic status of the area where a person resides on short-term mortality in adults admitted to an ICU in Queensland, Australia. DESIGN: Secondary data analysis using de-identified data from the Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation linked to the publicly available area-level Index of Relative Socioeconomic Advantage and Disadvantage from the Australian Bureau of Statistics. SETTING: Adult ICUs from 35 hospitals in Queensland, Australia, from 2006 to 2015. PATIENTS: A total of 218,462 patient admissions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The outcome measure was inhospital mortality. The main study variable was decile of Index of Relative Socioeconomic Advantage and Disadvantage. The overall crude inhospital mortality was 7.8%; 9% in the most disadvantaged decile and 6.9% in the most advantaged decile (p < 0.001). Increasing socioeconomic disadvantage was associated with increasing severity of illness as measured by Acute Physiology and Chronic Health Evaluation III score, admission with a diagnosis of sepsis or trauma, cardiac, respiratory, renal, and hepatic comorbidities, and remote location. Increasing socioeconomic advantage was associated with elective surgical admission, hematological and oncology comorbidities, and admission to a private hospital (all p < 0.001). After excluding patients admitted after elective surgery, in the remaining 106,843 patients, the inhospital mortality was 13.6%, 13.3% in the most disadvantaged, and 14.1% in the most advantaged. There was no trend in mortality across deciles of socioeconomic status after excluding elective surgery patients. In the logistic regression model adjusting for severity of illness and diagnosis, there was no statistically significant difference in the odds ratio of inhospital mortality for the most disadvantaged decile compared with other deciles. This suggests variables used for risk adjustment may lie on the causal pathway between socioeconomic status and outcome in ICU patients. CONCLUSIONS: Socioeconomic status as defined as Index of Relative Socioeconomic Advantage and Disadvantage of the area in which a patient lives was associated with ICU admission diagnosis, comorbidities, severity of illness, and crude inhospital mortality in this study. Socioeconomic status was not associated with inhospital mortality after excluding elective surgical patients or when adjusted for severity of illness and admission diagnosis. Commonly used measures for risk adjustment in intensive care improve understanding of the pathway between socioeconomic status and outcomes.

Consistency and Inconsistency of Young Women's Reporting of Intimate Partner Violence in a Population-Based Study.

We examined reporting of lifetime intimate partner violence (IPV) among 7,917 young women who completed two surveys, 12 months apart. At the first survey, 32% reported a history of IPV with a current or former partner. Of these, one third of women did not report IPV 12 months later (inconsistently reported IPV). Compared with women who consistently reported a history of IPV, women who inconsistently reported a history of IPV were less likely to report suicidal ideation, self-harm, illicit drug use, and smoking at the 12-month follow-up. A deeper understanding of what influences young women's reporting of IPV is needed.

Combined Influence of Waist and Hip Circumference on Risk of Death in a Large Cohort of European and Australian Adults.

Background Waist circumference and hip circumference are both strongly associated with risk of death; however, their joint association has rarely been investigated. Methods and Results The MONICA Risk, Genetics, Archiving, and Monograph (MORGAM) Project was conducted in 30 cohorts from 11 countries; 90 487 men and women, aged 30 to 74 years, predominantly white, with no history of cardiovascular disease, were recruited in 1986 to 2010 and followed up for up to 24 years. Hazard ratios were estimated using sex-specific Cox models, stratified by cohort, with age as the time scale. Models included baseline categorical obesity measures, age, total and high-density lipoprotein cholesterol, systolic blood pressure, antihypertensive drugs, smoking, and diabetes mellitus. A total of 9105 all-cause deaths were recorded during a median follow-up of 10 years. Hazard ratios for all-cause death presented J- or U-shaped associations with most obesity measures. With waist and hip circumference included in the same model, for all hip sizes, having a smaller waist was strongly associated with lower risk of death, except for men with the smallest hips. In addition, among those with smaller waists, hip size was strongly negatively associated with risk of death, with ≈20% more people identified as being at increased risk compared with waist circumference alone. Conclusions A more complex relationship between hip circumference, waist circumference, and risk of death is revealed when both measures are considered simultaneously. This is particularly true for individuals with smaller waists, where having larger hips was protective. Considering both waist and hip circumference in the clinical setting could help to best identify those at increased risk of death.

Type of menopause, age of menopause and variations in the risk of incident cardiovascular disease: pooled analysis of individual data from 10 international studies.

STUDY QUESTION: How does the risk of cardiovascular disease (CVD) vary with type and age of menopause? SUMMARY ANSWER: Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause. WHAT IS KNOWN ALREADY: Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear. STUDY DESIGN, SIZE, DURATION: Pooled individual-level data of 203 767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35-39, 40-44, 45-49, 50-54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16-1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50-54 years, women with surgical menopause before 35 (2.55, 2.22-2.94) and 35-39 years (1.91, 1.71-2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23-2.05 and 1.51, 1.33-1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT. LIMITATIONS, REASONS FOR CAUTION: Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results. WIDER IMPLICATIONS OF THE FINDINGS: In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD. STUDY FUNDING/COMPETING INTEREST(S): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests.

How rates of perinatal mental health screening in Australia have changed over time and which women are missing out.

OBJECTIVES: To report rates of perinatal mental health screening from 2000 to 2017 and investigate factors associated with not being screened both antenatally and postnatally more recently (2013-2017). METHODS: A longitudinal community-based study of self-reported perinatal mental health screening with a national sample of 7,566 mothers from the Australian Longitudinal Study on Women's Health reporting on 9,384 children. The main outcome measure was whether mothers were asked about their emotional wellbeing by a health professional, including completing a questionnaire. RESULTS: From 2000 to 2017, the percentage of women not screened decreased from 40.6% to 1.7%. The percentage of women screened both antenatally and postnatally increased from 21.3% to 79.3%. From 2013 to 2017, women who were older (aOR, 0.65; 95%CI, 0.52-0.81) or had reported emotional distress (aOR, 0.77; 95%CI, 0.60-0.99) were less likely to have been screened both antenatally and postnatally. CONCLUSIONS: Despite improvements, perinatal mental health screening is not yet universal. One-in-five women are not screened both antenatally and postnatally, including women in high-risk populations such as those who have reported emotional distress. Implications for public health: Women are in regular contact with health professionals in the perinatal period. This opportunity to detect women at risk of perinatal mental health issues is too important to be missed.

Obesity, smoking, and risk of vasomotor menopausal symptoms: a pooled analysis of eight cohort studies.

BACKGROUND: Frequent and severe vasomotor symptoms during menopause are linked with adverse health outcomes. Understanding modifiable lifestyle factors for the risk of vasomotor menopausal symptoms is important to guide preventive strategies. OBJECTIVE: We investigated the associations between body mass index and smoking, their joint effects with the risk of vasomotor symptoms, and whether the associations differed by menopausal stage. STUDY DESIGN: The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events pooled data on 21,460 midlife women from 8 studies (median age, 50 years; interquartile range, 49-51 years) for the cross-sectional analysis. Four studies provided data for the prospective analysis (n=11,986). Multinomial logistic regression models with 4 categories of frequency/severity for the outcome of vasomotor symptoms were used to estimate relative risk ratios and 95% confidence intervals that were adjusted for within-study correlation and covariates. RESULTS: At baseline, nearly 60% of the women experienced vasomotor symptoms. One-half of them were overweight (30%) or obese (21%), and 17% were current smokers. Cross-sectional analyses showed that a higher body mass index and smoking more cigarettes with longer duration and earlier initiation were all associated with more frequent or severe vasomotor symptoms. Never smokers who were obese had a 1.5-fold (relative risk ratio, 1.52; 95% confidence interval, 1.35-1.73) higher risk of often/severe vasomotor symptoms, compared with never smokers who were of normal-weight. Smoking strengthened the association because the risk of often/severe vasomotor symptoms was much greater among smokers who were obese (relative risk ratio, 3.02; 95% confidence interval, 2.41-3.78). However, smokers who quit at <40 years of age were at similar levels of risk as never smokers. Prospective analyses showed a similar pattern, but the association attenuated markedly after adjustment for baseline vasomotor symptoms. Furthermore, we found that the association between body mass index and vasomotor symptoms differed by menopausal status. Higher body mass index was associated with increased risk of vasomotor symptoms in pre- and perimenopause but with reduced risk in postmenopause. CONCLUSION: High body mass index (≥25 kg/m2) and cigarette smoking substantially increased women's risk for experiencing frequent or severe vasomotor symptoms in a dose-response manner, and smoking intensified the effect of obesity. However, the effect of body mass index on the risk of vasomotor symptoms was opposite among postmenopausal women. Maintaining a normal weight before the menopausal transition and quitting smoking at <40 years of age may mitigate the excess risk of vasomotor symptoms in midlife.

Age at natural menopause and risk of incident cardiovascular disease: a pooled analysis of individual patient data.

BACKGROUND: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease. METHODS: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40-44 years (early menopause), 45-49 years (relatively early), 50-51 years (reference category), 52-54 years (relatively late), and 55 years or older (late menopause). FINDINGS: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50-51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38-1·73; p<0·0001), early menopause (age 40-44 years; 1·30, 1·22-1·39; p<0·0001), and relatively early menopause (age 45-49 years; 1·12, 1·07-1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62-2·20; p<0·0001) and early menopause (1·40, 1·27-1·54; p<0·0001), but were attenuated at age 60-69 years, with no significant association observed at age 70 years and older. INTERPRETATION: Compared with women who had menopause at age 50-51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women. FUNDING: Australian National Health and Medical Research Council.

Longitudinal associations between lifestyle, socio-economic position and physical functioning in women at different life stages.

Women's physical functioning declines with age and the rate of decline increases with age, but substantial disparities exist in trajectories over time. To inform development of interventions to optimise physical functioning across the adult life span, the aim is to explore which lifestyle and socio-economic position (SEP) factors contribute to disparities in physical functioning across the adult life span in women. Younger (born 1973-1978, n = 14,247), middle-aged (born 1946-1951, n = 13,715) and older (born 1921-1926, n = 12,432) participants from the Australian Longitudinal Study on Women's Health completed six questionnaires between 1996 and 2012 at approximate 3-year intervals. Physical functioning was measured with a 10-item subscale of the Short-Form Health Survey (score 1-100). Relationships between age and physical functioning were modelled using spline regression, stratified by baseline categories of physical activity, alcohol intake, smoking status, level of education, managing on income and index of neighbourhood socio-economic disadvantage for area. Multivariable models excluding one of the six factors were compared with models including all six factors to examine the relative importance of each factor. Women with unhealthy lifestyles (inactive, smokers or risky alcohol intake) and lower SEP had lower levels of physical functioning and more rapid declines across the adult life span. The variables with the greatest relative contribution to the models for physical functioning differed by age cohort: i.e. education and physical activity in younger women, managing on income and physical activity in middle-aged women and physical activity in older women. For optimal physical functioning, socio-economic factors seemed particularly important in younger and middle-aged women, while physical activity seemed important at all ages.

Premenopausal cardiovascular disease and age at natural menopause: a pooled analysis of over 170,000 women.

Early menopause is associated with an increased risk of subsequent cardiovascular disease (CVD). Few studies have investigated the converse. We examined whether premenopausal CVD events are associated with early age at menopause. We pooled the individual data of 177,131 women from nine studies. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRR) and 95% confidence intervals (CI) for the associations between age at onset of premenopausal CVD events-including coronary heart disease (CHD) and stroke-and age at natural menopause. Altogether 1561 (0.9%) premenopausal participants reported CVD events (including 1130 CHD and 469 stroke) at a mean age of 41.3 years. Compared with women without any premenopausal CVD events, women who experienced a first CVD event before age 35 years had a twofold risk of menopause before age 45 years (early menopause); adjusted RRR (95% CI) of 1.92 (1.17, 3.14) for any CVD, 1.86 (1.01, 3.43) for CHD and 2.17 (1.43, 3.30) for stroke. Women who experienced a first premenopausal CVD event after age 40 years underwent a natural menopause at the expected age (around 51 years). These associations were robust to adjustment for smoking status, BMI, educational level, race/ethnicity, age at menarche, parity, hypertension and family history of CVD. For premenopausal women, a first CVD event before age 35 years is associated with a doubling of the risk of an early menopause, while a first CVD event occurred after 35 years indicates a normal menopause at around 51 years. Shared genetic and environmental factors (such as smoking), as well as compromised vasculature following CVD events, may contribute to this outcome.

Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies.

BACKGROUND: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause. METHODS AND FINDINGS: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias. CONCLUSIONS: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.

Progression of diabetes, heart disease, and stroke multimorbidity in middle-aged women: A 20-year cohort study.

BACKGROUND: The prevalence of diabetes, heart disease, and stroke multimorbidity (co-occurrence of two or three of these conditions) has increased rapidly. Little is known about how the three conditions progress from one to another sequentially through the life course. We aimed to delineate this progression in middle-aged women and to determine the roles of common risk factors in the accumulation of diabetes, heart disease, and stroke multimorbidity. METHODS AND FINDINGS: We used data from 13,714 women aged 45-50 years without a history of any of the three conditions. They were participants in the Australian Longitudinal Study on Women's Health (ALSWH), enrolled in 1996, and surveyed approximately every 3 years to 2016. We characterized the longitudinal progression of the three conditions and multimorbidity. We estimated the accumulation of multimorbidity over 20 years of follow-up and investigated their association with both baseline and time-varying predictors (sociodemographic factors, lifestyle factors, and other chronic conditions). Over 20 years, 2,511 (18.3%) of the women progressed to at least one condition, of whom 1,420 (56.6%) had diabetes, 1,277 (50.9%) had heart disease, and 308 (12.3%) had stroke; 423 (16.8%) had two or three of these conditions. Over a 3-year period, the age-adjusted odds of two or more conditions was approximately twice that of developing one new condition compared to women who did not develop any new conditions. For example, the odds for developing one new condition between Surveys 7 and 8 were 2.29 (95% confidence interval [CI], 1.93-2.72), whereas the odds for developing two or more conditions was 6.51 (95% CI, 3.95-10.75). The onset of stroke was more strongly associated with the progression to the other conditions (i.e., 23.4% [95% CI, 16.3%-32.2%] of women after first onset of stroke progressed to other conditions, whereas the percentages for diabetes and heart disease were 9.9% [95% CI, 7.9%-12.4%] and 11.4% [95% CI, 9.1%-14.4%], respectively). Being separated, divorced, or widowed; being born outside Australia; having difficulty managing on their available income; being overweight or obese; having hypertension; being physically inactive; being a current smoker; and having prior chronic conditions (i.e., mental disorders, asthma, cancer, osteoporosis, and arthritis) were significantly associated with increased odds of accumulation of diabetes, heart disease, and stroke multimorbidity. The main limitations of this study were the use of self-reported data and the low number of events. CONCLUSIONS: Stroke was associated with increased risk of progression to diabetes or heart disease. Social inequality, obesity, hypertension, physical inactivity, smoking, or having other chronic conditions were also significantly associated with increased odds of accumulating multimorbidity. Our findings highlight the importance of awareness of the role of diabetes, heart disease, and stroke multimorbidity among middle-aged women for clinicians and health-promotion agencies.

Corrigendum to: Changes in smoking, drinking, overweight and physical inactivity in young Australian women 1996-2013.

Issue addressed: Smoking, risky drinking, overweight and obesity, and physical inactivity are health-risk factors (HRFs) that contribute significantly to morbidity worldwide. Several initiatives have been introduced over the past two decades to reduce these HRFs. This paper examines changes in the prevalence of HRFs in young women (aged 18-23 years) between 1996 and 2013, overall and within demographic groups.Methods: Data from two cohorts of the Australian Longitudinal Study on Women's Health, born in 1973-78 (n=14247) and 1989-95 (n=17012) were weighted to provide national estimates. Prevalence ratios were used to compare HRFs in 2013 relative to 1996.Results: In 1996, 32% were current smokers, 38% were risky drinkers, 22% were overweight or obese and 7% were physically inactive. In 2013, corresponding estimates were 19%, 35%, 33% and 6%. Between 1996 and 2013, overall smoking prevalence decreased, but remained over 43% among least educated women. Overweight and obesity increased in all demographic groups.Conclusions: The findings suggest that only smoking, which has been the subject of changes in taxation, legislation and regulation, declined significantly, in all except the least educated women. In contrast, the prevalence of overweight and obesity, which has largely been addressed through awareness campaigns and voluntary actions by the food industry, increased markedly in all demographic sub-groups.So what?: The findings show that comprehensive health promotion interventions, such as those for tobacco control, are successful (but may still be ineffective among less educated women). In contrast the measures to control population weight gain among young women have been futile so far.

Changes in smoking, drinking, overweight and physical inactivity in young Australian women 1996-2013.

Issue addressed Smoking, risky drinking, overweight and obesity, and physical inactivity are health-risk factors (HRFs) that contribute significantly to morbidity worldwide. Several initiatives have been introduced over the past two decades to reduce these HRFs. This paper examines changes in the prevalence of HRFs in young women (aged 18-23 years) between 1996 and 2013, overall and within demographic groups. Methods Data from two cohorts of the Australian Longitudinal Study on Women's Health, born in 1973-78 (n=14247) and 1989-95 (n=17012) were weighted to provide national estimates. Prevalence ratios were used to compare HRFs in 2013 relative to 1996. Results In 1996, 32% were current smokers, 38% were risky drinkers, 22% were overweight or obese and 7% were physically inactive. In 2013, corresponding estimates were 19%, 35%, 33% and 6%. Between 1996 and 2013, overall smoking prevalence decreased, but remained over 43% among least educated women. Overweight and obesity increased in all demographic groups. Conclusions The findings suggest that only smoking, which has been the subject of changes in taxation, legislation and regulation, declined significantly, in all except the least educated women. In contrast, the prevalence of overweight and obesity, which has largely been addressed through awareness campaigns and voluntary actions by the food industry, increased markedly in all demographic sub-groups. So what? The findings show that comprehensive health promotion interventions, such as those for tobacco control, are successful (but may still be ineffective among less educated women). In contrast the measures to control population weight gain among young women have been futile so far.

Improvements in physical function and pain sustained for up to 10 years after knee or hip arthroplasty irrespective of mental health status before surgery.

Background and purpose - There are concerns that mental health (MH) may influence outcomes of total knee arthroplasty (TKA) or total hip arthroplasty (THA). We examined effects of poor MH before surgery on long-term outcomes of osteoarthritis-related TKA or THA in women. Patients and methods - The data were from 9,737 middle-aged participants (47-52 years) and 9,292 older participants (73-78 years) in the Australian Longitudinal Study on Women's Health who completed surveys between 1998 and 2013. Dates of arthroplasties were obtained from the Australian Orthopaedics Association National Joint Replacement Registry. Participants without procedures were matched with participants with procedures. Trajectories of the Short-Form 36 scores for physical functioning, bodily pain, social functioning, and mental health based on mixed modeling were plotted for participants with and without surgery (stratified according to mental health, separately for TKA and THA, and for middle-aged and older participants). Results - In middle-aged women with poor and good MH, TKA improved physical function and reduced bodily pain, with improvements sustained up to 10 years after surgery. TKA contributed to restoration of social function in women with good MH, but this was less clear in women with poor MH. In both MH groups, mental health appeared to be unaffected by TKA. Similar patterns were observed after THA, and in older women. Interpretation - Recovery of physical and social function and reductions in pain were sustained for up to 10 years after surgery. Improvements in physical function and pain were also observed in women with poor mental health. Thus, in our view poor mental health should not be a contraindication for arthroplasty.

The InterLACE study: Design, data harmonization and characteristics across 20 studies on women's health.

OBJECTIVES: The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of women's reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE. STUDY DESIGN: InterLACE is an individual-level pooled study of 20 observational studies (12 of which are longitudinal) from ten countries. Variables were harmonized across studies to create a new and systematic synthesis of life-course data. MAIN OUTCOME MEASURES: Harmonized data were derived in three domains: 1) socio-demographic and lifestyle factors, 2) female reproductive characteristics, and 3) chronic disease outcomes (cardiovascular disease (CVD) and diabetes). RESULTS: InterLACE pooled data from 229,054 mid-aged women. Overall, 76% of the women were Caucasian and 22% Japanese; other ethnicities (of 300 or more participants) included Hispanic/Latin American (0.2%), Chinese (0.2%), Middle Eastern (0.3%), African/black (0.5%), and Other (1.0%). The median age at baseline was 47 years (Inter-quartile range (IQR): 41-53), and that at the last follow-up was 56 years (IQR: 48-64). Regarding reproductive characteristics, half of the women (49.8%) had their first menstruation (menarche) at 12-13 years of age. The distribution of menopausal status and the prevalence of chronic disease varied considerably among studies. At baseline, most women (57%) were pre- or peri-menopausal, 20% reported a natural menopause (range 0.8-55.6%) and the remainder had surgery or were taking hormones. By the end of follow-up, the prevalence rates of CVD and diabetes were 7.2% (range 0.9-24.6%) and 5.1% (range 1.3-13.2%), respectively. CONCLUSIONS: The scale and heterogeneity of InterLACE data provide an opportunity to strengthen evidence concerning the relationships between reproductive health through life and subsequent risks of chronic disease, including cross-cultural comparisons.

Lifestyle and Socioeconomic Determinants of Multimorbidity Patterns among Mid-Aged Women: A Longitudinal Study.

BACKGROUND: Little is known about patterns of associative multimorbidity and their aetiology. We aimed to identify patterns of associative multimorbidity among mid-aged women and the lifestyle and socioeconomic factors associated with their development. METHODS: Participants were from the Australian Longitudinal Study on Women's Health. We included 4896 women born 1946-51, without multimorbidity in 1998. We identified multimorbidity patterns at survey 6 (2010) using factor analysis, and related these patterns to baseline lifestyle and socioeconomic factors using logistic regression. We dichotomised factor scores and determined odds ratios (ORs) with 95% confidence intervals (CIs) for associations between characteristics and odds of a high versus low factor score. RESULTS: We identified five multimorbidity patterns: psychosomatic; musculoskeletal; cardiometabolic; cancer; and respiratory. Overweight and obesity were respectively associated with increased odds of having a high score for the musculoskeletal (adjusted ORs 1.45 [95% CI 1.23, 1.70] and 2.14 [95% CI 1.75, 2.60]) and cardiometabolic (adjusted ORs 1.53 [95% CI 1.31, 1.79] and 2.46 [95% CI 2.02, 2.98]) patterns. Physical inactivity was associated with increased odds of a high score for the psychosomatic, musculoskeletal and cancer patterns (adjusted ORs 1.41 [95% CI 1.13, 1.76]; 1.39 [95% CI 1.11, 1.74]; and 1.35 [95% CI 1.08, 1.69]). Smoking was associated with increased odds of a high score for the respiratory pattern. Education and ability to manage on income were associated with increased odds of a high score for the psychosomatic pattern (adjusted ORs 1.34 [95% CI 1.03, 1.75] and 1.73 [95% CI 1.37, 1.28], respectively) and musculoskeletal pattern (adjusted ORs 1.43 [95% CI 1.10, 1.87] and 1.38 [1.09, 1.75], respectively). CONCLUSIONS: Distinct multimorbidity patterns can be identified among mid-aged women. Social inequality, physical activity and BMI are risk factors common to multiple patterns and are appropriate targets for reducing the risk of specific multimorbidity groups in mid-life women.

Cohort Profile Update: Australian Longitudinal Study on Women's Health.

In 1996 the Australian Longitudinal Study on Women's Health recruited a nationally representative sample of more than 40,000 women in three age cohorts, born in 1973-78, 1946-51 and 1921-26. At least six waves of 3-yearly surveys have been completed. Although the focus remains on factors affecting the health and well-being of women and their access to and use of health services across urban, rural and remote areas of Australia, the study has now been considerably expanded by linkage to other health data sets. For most women who have ever participated in the study, linked records are now available for: government-subsidized non-hospital services (e.g. all general practitioner visits); pharmaceutical prescriptions filled; national death index, including codes for multiple causes of death; aged care assessments and services; cancer registries; and, for most states and territories, hospital admissions and perinatal data. Additionally, a large cohort of women born in 1989-95 have been recruited. The data are available to approved collaborators, with more than 780 researchers using the data so far. Full details of the study materials and data access procedures are available at [http://www.alswh.org.au/].