Search

Alexandrosz Czira,1 Shoko Akiyama,2 Takeo Ishii,2 Robert P Wood,3 Lucinda J Camidge,3 Hannah Wallis,3 Thomas Jennison,3 Rosie AC Wild,3 Masao Yarita,2 Kenichi Hashimoto,2 Kieran J Rothnie,1 Afisi S Ismaila4,5 1Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, Middlesex, UK; 2Value Evidence and Outcomes, Japan Medical and Development, GSK, Tokyo, Japan; 3Real-World Evidence, Adelphi Real World, Bollington, UK; 4Value Evidence and Outcomes, R&D Global Medical, GSK, Collegeville, PA, USA; 5Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Kieran J Rothnie, Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, Middlesex, TW8 9GS, UK, Tel +44 7920 369573, Email kieran.j.rothnie@gsk.comPurpose: There is currently limited evidence for the optimal timing of triple therapy initiation in Japan, which is crucial for optimizing strategies for the effective treatment of chronic obstructive pulmonary disease (COPD). This study assessed the impact of prompt vs delayed initiation of triple therapy following a COPD exacerbation on clinical and economic outcomes in patients in Japan.Patients and Methods: Retrospective cohort study of patients in the Medical Data Vision Co., Ltd. database initiating triple therapy as single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol or budesonide/glycopyrronium/formoterol) or multiple-inhaler triple therapy within 180 days of a moderate-to-severe exacerbation (index). For the main analysis, patients were categorized as prompt or delayed initiators, initiating triple therapy within 0– 30 days or 31– 180 days of index, respectively. Inverse probability of treatment weighting based on propensity scores was used to adjust for measured confounders between prompt and delayed cohorts.Results: For the main analysis, 610 (60.3%) and 402 (39.7%) patients were prompt and delayed initiators, respectively. The rate of subsequent moderate-to-severe exacerbations following index exacerbation was numerically lower in prompt vs delayed initiators (weighted rate ratio 0.95, 95% confidence interval [CI]: 0.74– 1.21; P = 0.6603). Time-to-first subsequent moderate-to-severe exacerbation increased significantly in prompt vs delayed initiators (weighted hazard ratio 0.77, 95% CI: 0.64– 0.93; P = 0.0053). In patients indexed on a severe exacerbation, delayed initiation resulted in significantly higher 90-day all-cause readmissions vs prompt initiation (42.1% vs 30.6%; P = 0.0329 [weighted estimates]). Weighted healthcare resource utilization rates were numerically lower in prompt vs delayed initiators, and weighted direct costs (all cause and COPD-related) were significantly lower in prompt initiators.Conclusion: This real-world study demonstrated that earlier initiation of triple therapy resulted in several benefits in clinical outcomes for COPD and may also reduce the economic burden of COPD management in Japan.Plain Language Summary: Patients with chronic obstructive pulmonary disease (COPD) can experience flare-ups in their symptoms, known as exacerbations. If exacerbations continue despite patients taking either one or a combination of two respiratory medications, guidelines suggest that they should take a combination of three treatments, known as triple therapy. In Japan, the best timing for patients to start triple therapy following an exacerbation is currently unknown, therefore this study compared the impact on clinical and economic outcomes of patients starting triple therapy 0– 30 days (prompt initiators) or 31– 180 days (delayed initiators) after their first exacerbation. When looking at clinical outcomes for COPD, we found that prompt initiators had a significantly longer time period from starting triple therapy to experiencing their next moderate-to-severe exacerbation, and those who had an initial severe exacerbation had significantly fewer hospital readmissions during the 90 days that followed their initial exacerbation than delayed initiators. When looking at economic outcomes for COPD, we found that medical costs were significantly lower in prompt versus delayed initiators. Findings of this study suggest that starting triple therapy earlier following an exacerbation may lead to improved clinical outcomes for patients with COPD in Japan and can reduce the cost of managing this disease.Keywords: healthcare resource utilization, hospital readmissions, direct medical costs, inverse probability of treatment weighting, single inhaler triple therapy, multiple inhaler triple therapy

Objective: To examine the associations between estrogen use and levels of insulin and glucose as well as the effect of estrogen use on the risk of type 2 diabetes.Research Design and Methods: This report is based on 857 women who were both nondiabetic and postmenopausal at the baseline examination (1989-1992) and who completed a second examination (1993-1995) an average of 4 years later. The participants were divided into three groups: never, past, and current users based on their baseline estrogen use status. ANCOVA was used to compare the insulin and glucose levels among estrogen use groups. Logistic regression was used to evaluate the association between estrogen use and the incidence of type 2 diabetes.Results: Postmenopausal estrogen use was associated with lower fasting glucose (0.2 mmol/l lower) but higher 2-h glucose levels (0.4 mmol/l higher) compared with never users. It was not significantly associated with the risk of type 2 diabetes compared with past and never users, based on American Diabetes Association or World Health Organization definitions of diabetes or on only a 2-h glucose level > or = 11.1 mmol/l. However, the risk of type 2 diabetes increased with increasing duration of estrogen use among current users, with an odds ratio of 1.10 per year of use (95% CI: 1.01-1.19).Conclusions: The data suggest that estrogen use in American Indian postmenopausal women may relate to deterioration of glucose tolerance. Longer duration of estrogen use among current users may relate to an increased risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Context: Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus.Objective: To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT).Design: Double-blind, randomized, parallel trial.Setting: Eight sites in the United States.Participants: 390 healthy postmenopausal women recruited by advertisement.Intervention: Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo.Main Outcome Measures: Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment.Results: At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P < .001), similar to the 14% reduction with HRT (P < .001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P < .001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL2-C) by 15% to 17% (P < .05), less than the 33% increase with HRT (P < .001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P < .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P < .001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2.Conclusions: Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL2-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL2-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females, with a high prevalence. The etiology of this heterogeneous condition remains obscure, and its phenotype expression varies. Two widely cited previous ESHRE/ASRM sponsored PCOS consensus workshops focused on diagnosis (published in 2004) and infertility management (published in 2008), respectively. The present third PCOS consensus report summarizes current knowledge and identifies knowledge gaps regarding various women's health aspects of PCOS. Relevant topics addressed-all dealt with in a systematic fashion-include adolescence, hirsutism and acne, contraception, menstrual cycle abnormalities, quality of life, ethnicity, pregnancy complications, long-term metabolic and cardiovascular health, and finally cancer risk. Additional, comprehensive background information is provided separately in an extended online publication. [ABSTRACT FROM AUTHOR]

Objective: To compare reproductive history and postmenopausal health by birth status (preterm vs. full term) in a U.S. longitudinal study of postmenopausal women. Birth status was examined according to region of residence, household, and neighborhood socioeconomic status (SES)., Methods: In the Women's Health Initiative Observational Study, 2271 women were born prematurely (< 37 weeks). ANOVA and Chi-square determined birth status differences of reproductive history, pregnancy, and postmenopausal health. Odds ratios were calculated using either binary logistic or multinomial logistic regression. SES and U.S. region of residence were examined as potential effect modifiers., Results: Preterm-born women compared to term-born women had higher risk of delivering a premature infant (aOR 1.68, 95% CI [1.46, 1.93]), higher odds of later-age first pregnancy (aOR 1.27 95% CI [1.02, 1.58]), longer duration to become pregnant (> 1 year to pregnancy) (aOR 1.10 95% CI [1.01, 1.21]), more miscarriages (aOR 1.23 95% CI [1.11, 1.37]), and more pregnancy complications including hypertension (aOR 1.58 95% CI (1.13, 2.21)], preeclampsia (aOR 1.64 95% CI [1.24, 2.16]), and gestational diabetes (aOR 1.68 95% CI [1.11, 2.53]). Preterm-born women had higher odds of menopause before age 50 (aOR 1.09 95% CI [1.05, 1.14]). Post-menopause, they had higher rates of diabetes (p = .01), hypertension (p = .01), hysterectomy (p = .045), and higher Charlson Comorbidity Index scores (p = .01)., Conclusions: Preterm-born women had higher reproductive and pregnancy risks which when coupled with early menopause, may indicate a shorter childbearing period than term-born women. Guidelines for integration of preterm history in women's health care across the life course are needed to identify and manage their higher risk., (© 2024. The Author(s).)

Background: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials., Methods: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status., Results: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m 2 ; p < .001)., Conclusions: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies., (© 2024 American Cancer Society.)

Study Question: What is the association between reproductive health history (e.g. age at menarche, menopause, reproductive lifespan) with abdominal adiposity in postmenopausal women?, Summary Answer: Higher visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) tissue levels were observed among women with earlier menarche, earlier menopause, and greater parity., What Is Known Already: Postmenopausal women are predisposed to accumulation of VAT and SAT. Reproductive health variables are known predictors of overall obesity status in women, defined by BMI., Study Design, Size, Duration: This study is a secondary analysis of data collected from the baseline visit of the Women's Health Initiative (WHI). The WHI is a large prospective study of postmenopausal women, including both a randomized trial and observational study. There were 10 184 women included in this analysis., Participants/materials, Setting, Methods: Data were collected from a reproductive health history questionnaire, dual-energy x-ray absorptiometry scans, and anthropometric measures at WHI baseline. Reproductive history was measured via self-report, and included age at menarche, variables related to pregnancy, and age at menopause. Reproductive lifespan was calculated as age at menopause minus age at menarche. Statistical analyses included descriptive analyses and multivariable linear regression models to examine the association between reproductive history with VAT, SAT, total body fat, and BMI., Main Results and the Role of Chance: Women who reported early menarche (<10 years) or early menopause (<40 years) had the highest levels of VAT. Adjusted multivariable linear regression results demonstrate women who experienced menarche >15 years had 23 cm2 less VAT (95% CI: -31.4, -14.4) and 47 cm2 less SAT (95% CI: -61.8, -33.4) than women who experienced menarche at age 10 years or earlier. A similar pattern was observed for age at menopause: compared to women who experienced menopause <40 years, menopause at 50-55 years was associated with 19.3 cm2 (95% CI: -25.4, -13.3) less VAT and 27.4 cm2 (-29.6, 10.3) less SAT. High parity (>3 pregnancies) was also associated with VAT and SAT. For example, adjusted beta coefficients for VAT were 8.36 (4.33, 12.4) and 17.9 (12.6, 23.2) comparing three to four pregnancies with the referent, one to two pregnancies., Limitations, Reasons for Caution: The WHI reproductive health history questionnaire may be subject to poor recall owing to a long look-back window. Residual confounding may be present given lack of data on early life characteristics, such as maternal and pre-menarche characteristics., Wider Implications of the Findings: This study contributes to our understanding of reproductive lifespan, including menarche and menopause, as an important predictor of late-life adiposity in women. Reproductive health has also been recognized as a sentinel marker for chronic disease in late life. Given established links between adiposity and cardiometabolic outcomes, this research has implications for future research, clinical practice, and public health policy that makes use of reproductive health history as an opportunity for chronic disease prevention., Study Funding/competing Interest(s): HRB and AOO are supported by the National Institute of Health National Institute of Aging (R01AG055018-04). JWB reports royalties from 'ACSM'S Body Composition Assessment Book' and consulting fees from the WHI. The remaining authors have no competing interests to declare., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited., Objective: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial., Design: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611)., Setting: A multicenter ( n = 40) trial across the United States., Participants: 36 282 postmenopausal women with no history of breast or colorectal cancer., Intervention: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D 3 daily or placebo., Measurements: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use., Results: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality., Limitation: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled., Conclusion: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality., Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2598.

Background: Although gestational diabetes mellitus and delivering high-birthweight infants are known to predict a higher risk of future type 2 diabetes mellitus, the association of hypertensive disorders of pregnancy and other adverse pregnancy outcomes with type 2 diabetes mellitus is not well established., Objective: This study aimed to examine the associations between different types of adverse pregnancy outcomes and incident type 2 diabetes mellitus among postmenopausal women., Study Design: The Women's Health Initiative, a nationwide cohort of postmenopausal women, collected self-reported history of adverse pregnancy outcomes, including gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm birth, and delivering low- birthweight (<2500 g) or high-birthweight (>4500 g) infants. Participants were followed up annually for self-reported incident type 2 diabetes mellitus treated with medication from baseline (1993-1998) to March 2021. This study used logistic regression to examine the associations of any and individual adverse pregnancy outcomes with diabetes mellitus. Stratified analyses were performed to assess effect modification by body mass index, race and ethnicity, education, parity, breastfeeding, and age at first birth., Results: This analysis included 49,717 women without a history of diabetes mellitus at enrollment who had a least 1 pregnancy and responded to the questionnaire about adverse pregnancy outcomes. After adjusting for body mass index, demographic, lifestyle, and reproductive factors, gestational diabetes mellitus (odds ratio, 2.26; 95% confidence interval, 1.94-2.63), high birthweight (odds ratio, 1.30; 95% confidence interval, 1.18-1.44), and hypertensive disorders of pregnancy (odds ratio, 1.18; 95% confidence interval, 1.08-1.30) were independently associated with higher odds of type 2 diabetes mellitus, whereas preterm birth and low birthweight were not associated with diabetes mellitus risk. A history of ≥2 adverse pregnancy outcomes was associated with higher odds of type 2 diabetes mellitus (odds ratio, 1.55; 95% confidence interval, 1.28-1.88). This study further observed higher odds of type 2 diabetes mellitus (odds ratio, 3.69; 95% confidence interval, 2.38-5.70) among women with a history of both gestational diabetes mellitus and hypertensive disorders of pregnancy than those without any adverse pregnancy outcomes., Conclusion: Postmenopausal women with a history of gestational diabetes mellitus, those delivering high-birthweight infants, or those with hypertensive disorders of pregnancy are at risk of future type 2 diabetes mellitus. In addition, women with ≥2 conditions had an augmented risk and might be prioritized for screening and prevention efforts for type 2 diabetes mellitus., (Copyright © 2023. Published by Elsevier Inc.)

Background: Associations of weight changes and intentionality of weight loss with longevity are not well described., Methods: Using longitudinal data from the Women's Health Initiative (N = 54 437; 61-81 years), we examined associations of weight changes and intentionality of weight loss with survival to ages 90, 95, and 100. Weight was measured at baseline, year 3, and year 10, and participants were classified as having weight loss (≥5% decrease from baseline), weight gain (≥5% increase from baseline), or stable weight (<5% change from baseline). Participants reported intentionality of weight loss at year 3., Results: A total of 30 647 (56.3%) women survived to ≥90 years. After adjustment for relevant covariates, 3-year weight loss of ≥5% vs stable weight was associated with lower odds of survival to ages 90 (OR, 0.67; 95% CI, 0.64-0.71), 95 (OR, 0.65; 95% CI, 0.60-0.71), and 100 (OR, 0.62; 95% CI, 0.49-0.78). Compared to intentional weight loss, unintentional weight loss was more strongly associated with lower odds of survival to age 90 (OR, 0.83; 95% CI, 0.74-0.94 and OR, 0.49; 95% CI, 0.44-0.55, respectively). Three-year weight gain of ≥5% vs stable weight was not associated with survival to age 90, 95, or 100. The pattern of results was similar among normal weight, overweight, and obese women in body mass index (BMI)-stratified analyses., Conclusions: Weight loss of ≥5% vs stable weight was associated with lower odds of longevity, more strongly for unintentional weight loss than for intentional weight loss. Potential inaccuracy of self-reported intentionality of weight loss and residual confounding were limitations., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Advancements in medical technology and pharmacologic interventions have drastically improved survival of infants born preterm and low birth weight, but knowledge regarding the long-term health impacts of these individuals is limited and inconsistent., Aim: To investigate whether an individual's birthweight or history of being born preterm increases the risk of an adverse reproductive outcome., Study Design: Nested case-control study within the Women's Health Initiative., Subjects: 79,934 individuals who self-reported their personal birthweight category and/or preterm birth status., Outcomes Measures: Self-reported pregnancy outcomes: subfertility, miscarriage, stillbirth, preeclampsia, gestational diabetes, gestational hypertension, preterm birth, low birthweight infant, high birthweight infant. Logistic regression models were used to estimate unadjusted and adjusted odds ratios (OR)., Results: After adjustments, individuals reporting their birthweight <6lbs. were 20 % more likely to have a stillbirth or 70 % more likely to have a low birthweight infant and were less likely to have a full-term birth or high birthweight infant during their pregnancy. Individuals reporting a birthweight ≥10 lbs. were more likely to have a high birthweight infant (OR 3.49, 95 % CI 2.73-4.39) and less likely to have a low birthweight infant (OR 0.64, 95 % CI 0.47-0.82). Individuals born preterm were at increased risk for infertility, miscarriage, preeclampsia, gestational diabetes, and delivering a preterm or low birthweight infant., Conclusions: As more individuals born preterm and/or low birthweight survive to adulthood, the incidence and prevalence of poor reproductive outcomes may increase. Women born at extremes of birthweight and prematurity may need to be monitored more closely during their own pregnancies., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Published studies have demonstrated inconclusive relationships between serum lipid levels and mortality after cancer., Methods: The primary objective was to evaluate the relationship between fasting lipid levels and mortality after cancer. Data were obtained on baseline lipids and outcomes after cancer from 1263 postmenopausal women diagnosed with 13 obesity-related cancers who were part of the Women's Health Initiative (WHI) lipid biomarkers cohort. Obesity-related cancers included incident invasive cancers of the breast, colorectum, endometrium, esophagus (adenocarcinoma), kidney, liver, gallbladder, pancreas, ovaries, small intestine, thyroid, stomach, as well as multiple myeloma. Baseline lipid measurements included high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and non-HDL-cholesterol. Outcomes were all cause, cancer-specific, and CVD mortality. Multivariable Cox proportional hazards models were used to measure associations between lipid levels and mortality (all cause, cancer, and CVD) after a cancer diagnosis, with lipids analyzed as continuous variables., Results: Among women with obesity-related cancer, there were 707 deaths, of which 379 (54%) were due to cancer and 113 (16%) were due to CVD. Mean time from blood draw to cancer diagnosis was 5.1 years (range: 0.05-10 years). LDL-C values above the 95th percentile were associated with higher risk of all-cause mortality (p < 0.001), and cancer-specific mortality (p < 0.001), but not mortality due to CVD. Non-HDL-C values above the 65th percentile were associated with higher risk of all-cause mortality (p = 0.01) and mortality due to CVD (p = 0.003), but not cancer-specific mortality (p = 0.37). HDL-C values above the 95th percentile were associated with lower all-cause mortality (p = 0.002), and above the 65th percentile with lower cancer-specific mortality (p = 0.003), but no significant relationship with mortality due to CVD was observed., Conclusions: The relationship between pre-diagnosis fasting lipid levels and mortality after cancer diagnosis is complex. These results suggest that improved lipid control through lifestyle and anti-lipid medications could have a meaningful impact on outcomes after cancer., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Atherogenic dyslipidemia-before or during pregnancy-may contribute to preeclampsia and subsequent cardiovascular disease risk. We performed a nested case-control study to further understand dyslipidemia associated with preeclampsia. The cohort consisted of participants in the randomized clinical trial "Improving Reproductive Fitness Through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility" (FIT-PLESE). FIT-PLESE was designed to study the effect of a pre-fertility treatment 16-week randomized lifestyle intervention program (Nutrisystem diet + exercise + orlistat vs. training alone) on improvement in live birth rate among obese women with unexplained infertility. Of the 279 patients in FIT-PLESE, 80 delivered a viable infant. Maternal serum was analyzed across five visits: before and after lifestyle interventions and also at three pregnancy visits (16, 24, and 32 weeks gestation). Apolipoprotein lipids were measured in a blinded fashion using ion mobility. Cases were those who developed preeclampsia. Controls also had a live birth but did not develop preeclampsia. Generalized linear and mixed models with repeated measures were used to compare the mean lipoprotein lipid levels of the two groups across all visits. Complete data were available for 75 pregnancies, and preeclampsia developed in 14.5% of the pregnancies. Cholesterol/high-density lipoprotein (HDL) ratios (p < 0.003), triglycerides (p = 0.012), and triglyceride/HDL ratios, all adjusted for BMI, were worse in patients with preeclampsia (p < 0.001). Subclasses a, b, and c of highly atherogenic, very small, low-density lipoprotein (LDL) particles were higher during pregnancy for the preeclamptic women (p < 0.05). Very small LDL particle subclass d levels were significantly greater only at 24 weeks (p = 0.012). The role of highly atherogenic, very small LDL particle excess in the pathophysiology of preeclampsia awaits further investigation., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Background A lifestyle comprising a healthy diet, light alcohol consumption, no smoking, and moderate or intense physical activity has been associated with reduced risk of cardiovascular disease (CVD). We examined the association of a healthy lifestyle index (HLI), derived from scores for each of these components plus waist circumference, with the risk of incident CVD and CVD subtypes in postmenopausal women with normal body mass index (18.5-<25.0 kg/m 2 ). Methods and Results We studied 40 118 participants in the Women's Health Initiative, aged 50 to 79 years at enrollment, with a normal body mass index and no history of CVD. The HLI score was categorized into quintiles. We estimated multivariable adjusted hazard ratios (HR) and 95% CIs for the association of HLI with risk of CVD and CVD subtypes using Cox regression models. A total of 3821 cases of incident CVD were ascertained during a median follow-up of 20.1 years. Compared with the lowest quintile (unhealthiest lifestyle), higher HLI quintiles showed inverse associations with the risk of CVD (HR quintile-2 =0.74 [95% CI, 0.67-0.81]; HR quintile-3 =0.66 [95% CI, 0.60-0.72]; HR quintile-4 =0.57 [95% CI, 0.51-0.63]; and HR quintile-5 =0.48 [95% CI, 0.43-0.54], P-trend =<0.001). HLI was also inversely associated with risks of stroke, coronary heart disease, myocardial infarction, angina, and coronary revascularization. Subgroup analyses, stratified by age (≤63 years vs >63 years), body mass index (2 ), and general health status (absence/presence of hypertension, diabetes, or lipid-lowering drug use) also showed inverse associations between HLI and risk of CVD. Conclusions Among postmenopausal women with a normal body mass index, adherence to a healthy lifestyle is associated with a reduced risk of clinical CVD and CVD subtypes, underscoring the cardiovascular benefits of maintaining a healthy lifestyle, even for women with a healthy weight.

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population. Baseline and incident data (>16 years of follow-up) from the Women's Health Initiative ( n = 85,356) were used to examine the association between personal history of being born preterm (born 1910-1940s) and prevalent (baseline enrollment; cross-sectional) or incident (prospective cohort) cases of type 2 diabetes. Logistic and Cox proportional hazards regression models were used to estimate odds and hazards ratios. Being born preterm was significantly, positively associated with odds for prevalent type 2 diabetes at enrollment (adjOR = 1.79, 95% CI 1.43-2.24; P < 0.0001). Stratified regression models suggested the positive associations at baseline were consistent across race and ethnicity groups. However, being born preterm was not significantly associated with risk for incident type 2 diabetes. Regression models stratified by age at enrollment suggest the relationship between being born preterm and type 2 diabetes persists only among younger age groups. Preterm birth was associated with higher risk of type 2 diabetes but only in those diagnosed with type 2 diabetes prior to study enrollment, suggesting the association between preterm birth and type 2 diabetes may exist at earlier age of diagnosis but wane over time.

Background: Abdominal adiposity, including visceral and subcutaneous abdominal adipose tissue (VAT and SAT), is recognized as a strong risk factor for cardiometabolic disease, cancer, and mortality., Objective: The primary aim of this analysis is to describe longitudinal patterns of change in abdominal adipose tissue in postmenopausal women, overall and stratified by age, race/ethnicity, and years since menopause., Methods: The data are from six years of follow up on 10,184 postmenopausal women (7828 non-Hispanic White women, 1423 non-Hispanic Black women, and 703 Hispanic women) who participated in the Women's Health Initiative (WHI). The WHI is a large prospective cohort study of postmenopausal women across the United States. All participants in this analysis had DXA scans in the 1990s as part of the WHI protocol. Hologic APEX software was used to re-analyze archived DXA scans and obtain measures of abdominal adipose tissue. Analyses examined differences in abdominal adipose tissue, overall adiposity, and anthropometric variables., Results: There were important differences in VAT and SAT by age and race/ethnicity. In women <60 years, VAT increased over the follow-up period, while in women ≥70 years, VAT decreased. Non-Hispanic Black women had the highest levels of SAT. Hispanic women had the highest VAT levels. Women more than ten years since menopause had less SAT and more VAT than women less than ten years since menopause, resulting in a higher VAT/SAT ratio. There was a moderate to strong correlation between measures of abdominal adipose tissue and anthropometric measurements of body size. Still, there were substantial differences in the quantity of VAT and SAT within BMI and waist circumference categories., Conclusions: These results demonstrate differences in VAT and SAT according to age, race/ethnicity, time since menopause, and compared to standard measures of body composition in a large and diverse cohort of postmenopausal women., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Increasing evidence suggests preterm birth is a risk factor for hypertension and cardiovascular disease (CVD) in adulthood. Whether there is effect modification by hypertension on CVD risk is unknown. To investigate the associations between preterm birth, hypertension, and incident CVD, we identified 2,303 women aged 50 to 79 years who self-reported being born preterm from the Women's Health Initiative. Using multivariable logistic regression, prevalent hypertension at enrollment, age at hypertension diagnosis, and antihypertensive medication use were compared by birth status (preterm, full-term). Risk of incident hypertension, coronary heart disease, and CVD were analyzed using multivariable Cox proportional-hazard models. Both models adjusted for age, race/ethnicity, education, smoking, physical activity, body mass index, and diabetes mellitus. Significant associations were found between preterm birth and prevalent hypertension (37% vs 33.1%; adjusted odds ratio 1.26 [95% confidence interval (CI) 1.15 to 1.28] p = <0.0001), early-onset hypertension (<50 years) (14.7% vs 11.7%; adjusted odds ratio 1.31, 95% CI 1.15 to 1.48, p = <0.0001), and incident hypertension (53.2% vs 51%; ajusted hazard ratio 1.10, 95% CI 1.03 to 1.19, p = 0.008). Preterm-born women reported taking more antihypertensive medications (2.9% vs 2.6%, p = 0.04). Preterm birth had a nonsignificant association with CVD risk, but when stratified by prevalent hypertension, women born preterm without hypertension had elevated CVD risk compared with women born full-term without prevalent hypertension. Women with prevalent hypertension, preterm and full-term, had similar magnitudes of elevations in CVD risk. In conclusion, preterm birth increases the risk of hypertension and coronary heart disease. With 10% of the population born preterm, birth history should be assessed as a CVD risk factor., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Previous studies have demonstrated an increased risk of cardiovascular disease (CVD) in women with a history of pregnancy loss. Less is known about whether pregnancy loss is associated with age at the onset of CVD, but this is a question of interest, as a demonstrated association of pregnancy loss with early-onset CVD may provide clues to the biological basis of the association, as well as having implications for clinical care. We conducted an age-stratified analysis of pregnancy loss history and incident CVD in a large cohort of postmenopausal women aged 50-79 years old., Methods: Associations between a history of pregnancy loss and incident CVD were examined among participants in the Women's Health Initiative Observational Study. Exposures were any history of pregnancy loss (miscarriage and/or stillbirth), recurrent (2+) loss, and a history of stillbirth. Logistic regression analyses were used to examine associations between pregnancy loss and incident CVD within 5 years of study entry in three age strata (50-59, 69-69, and 70-79). Outcomes of interest were total CVD, coronary heart disease (CHD), congestive heart failure, and stroke. To assess the risk of early onset CVD, Cox proportional hazard regression was used to examine incident CVD before the age of 60 in a subset of subjects aged 50-59 at study entry., Results: After adjustment for cardiovascular risk factors, a history of stillbirth was associated with an elevated risk of all cardiovascular outcomes in the study cohort within 5 years of study entry. Interactions between age and pregnancy loss exposures were not significant for any cardiovascular outcome; however, age-stratified analyses demonstrated an association between a history of stillbirth and risk of incident CVD within 5 years in all age groups, with the highest point estimate seen in women aged 50-59 (OR 1.99; 95% CI, 1.16-3.43). Additionally, stillbirth was associated with incident CHD among women aged 50-59 (OR 3.12; 95% CI, 1.33-7.29) and 60-69 (OR 2.06; 95% CI, 1.24-3.43) and with incident heart failure and stroke among women aged 70-79. Among women aged 50-59 with a history of stillbirth, a non-significantly elevated hazard ratio was observed for heart failure before the age of 60 (HR 2.93, 95% CI, 0.96-6.64)., Conclusions: History of stillbirth was strongly associated with a risk of cardiovascular outcomes within 5 years of baseline in a cohort of postmenopausal women aged 50-79. History of pregnancy loss, and of stillbirth in particular, might be a clinically useful marker of cardiovascular disease risk in women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wright, Enquobahrie, Prager, Painter, Kooperberg, Wild, Park, Sealy-Jefferson and Kernic.)

Objective: The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension., Methods: The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits., Results: Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P < 0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P < 0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years., Conclusion: There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo., Competing Interests: Financial disclosure/conflicts of interest: Dr Lisa Warsinger Martin is paid for work on the Presentations and Publications committee, from the Women's Health initiative from the National Institutes of Health. The other authors have nothing to disclose., (Copyright © 2022 by The North American Menopause Society.)

Objective: To determine if premature menopause and early menarche are associated with increased risk of AAA, and to explore potential effect modification by smoking history., Summary of Background Data: Despite worse outcomes for women with AAA, no studies have prospectively examined sex-specific risk factors, such as premature menopause and early menarche, with risk of AAA in a large, ethnically diverse cohort of women., Methods: This was a post-hoc analysis of Women's Health Initiative participants who were beneficiaries of Medicare Parts A&B fee-for-service. AAA cases and interventions were identified from claims data. Follow-up period included Medicare coverage until death, end of follow-up or end of coverage inclusive of 2017., Results: Of 101,119 participants included in the analysis, the mean age was 63 years and median follow-up was 11.3 years. Just under 10,000 (9.4%) women experienced premature menopause and 22,240 (22%) experienced early men-arche. Women with premature menopause were more likely to be overweight, Black, have >20 pack years of smoking, history of cardiovascular disease, hypertension, and early menarche. During 1,091,840 person-years of follow-up, 1125 women were diagnosed with AAA, 134 had premature menopause (11.9%), 93 underwent surgical intervention and 45 (48%) required intervention for ruptured AAA. Premature menopause was associated with increased risk of AAA [hazard ratio 1.37 (1.14, 1.66)], but the association was no longer significant after multivariable adjustment for demographics and cardiovascular disease risk factors. Amongst women with ≥20 pack year smoking history (n = 19,286), 2148 (11.1%) had premature menopause, which was associated with greater risk of AAA in all models [hazard ratio 1.63 (1.24, 2.23)]. Early menarche was not associated with increased risk of AAA., Conclusions: This study finds that premature menopause may be an important risk factor for AAA in women with significant smoking history. There was no significant association between premature menopause and risk of AAA amongst women who have never smoked. These results suggest an opportunity to develop strategies for better screening, risk reduction and stratification, and outcome improvement in the comprehensive vascular care of women., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of this study was to examine the association between common menopausal symptoms (MS) and long-term cardiovascular disease (CVD) and all-cause mortality., Methods: In an observational cohort of 80,278 postmenopausal women with no known CVD at baseline from the Women's Health Initiative, we assessed individual MS severity (mild vs none; moderate/severe vs none) for night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating. Outcomes included total CVD events (primary) and all-cause mortality (secondary). Associations between specific MS, their severity, and outcomes were assessed during a median of 8.2 years of follow-up. All results were multivariable adjusted, and individual associations were Bonferroni corrected to adjust for multiple comparisons. A machine learning approach (least absolute shrinkage and selection operator) was used to select the most parsimonious set of MS most predictive of CVD and all-cause mortality., Results: The severity of night sweats, waking up several times at night, joint pain or stiffness, heart racing or skipping beats, dizziness, feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were each significantly associated with total CVD. The largest hazard ratio (HR) for total CVD was found for moderate or severe heart racing or skipping beats (HR, 1.55; 95% confidence interval [CI], 1.29-1.86). The individual severities of heart racing or skipping beats, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were associated with increased all-cause mortality. Moderate or severe dizziness had the largest HR (1.58; 95% CI, 1.24-2.01). Multiple symptom modeling via least absolute shrinkage and selection operator selected dizziness, heart racing, feeling tired, and joint pain as most predictive of CVD, whereas dizziness, tremors, and feeling tired were most predictive of all-cause mortality., Conclusion: Among postmenopausal women with no known CVD at baseline, the severity of specific individual MS was significantly associated with incident CVD and mortality. Consideration of severe MS may enhance sex-specific CVD risk predication in future cohorts, but caution should be applied as severe MS could also indicate other health conditions., Competing Interests: Financial disclosure/conflicts of interest: Michelle J. Naughton received funding from the Merck Foundation to her institution (The Ohio State University) for a research project unrelated to this manuscript topic. The other authors have nothing to disclose., (Copyright © 2022 by The North American Menopause Society.)

Context: Ovarian stimulation (OS) increases pregnancy rates but can cause multiple folliculogenesis and multiple pregnancy., Objective: To determine whether the probability of pregnancy differs in OS cycles with mono- vs multifolliculogenesis in women with unexplained infertility (UI)., Design: Secondary analysis of a multicenter, randomized controlled trial: Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation with 3 treatment arms: gonadotropins, clomiphene, or letrozole, combined with intrauterine insemination. Women were categorized as having either 1 or ≥ 2 mature follicles (≥ 16 mm). Relative risk (RR) and 95% CIs for clinical pregnancy and live birth by number of follicles were estimated using generalized linear models adjusted for age, body mass index, years of infertility, and history of prior live birth., Setting: 12 US-based clinical sites., Participants: Normally cycling women aged 18 to 40 years with a normal uterine cavity and at least 1 patent fallopian tube. Male partners with ≥ 5 million total motile sperm., Interventions: Gonadotropins, clomiphene, or letrozole with insemination., Main Outcome Measures: Clinical pregnancy rates (CPR) and live birth rates (LBR)., Results: A single mature follicle > 16 mm resulted in lower CPR (RR, 0.70; 95% CI, 0.54-0.90) and LBR (RR, 0.67; 95% CI, 0.51-0.89) compared with ≥ 2 mature follicles. When stratified by treatment modality, no association of follicle number with CPR or LBR was observed for letrozole or clomiphene, but women using gonadotropins had lower CPR and LBR with monofolliculogenesis., Conclusion: In couples undergoing gonadotropin treatment for UI, monofolliculogenesis following OS is related to a lower rate of live birth., (Published by Oxford University Press on behalf of the Endocrine Society 2022.)

Introduction: Little is known about the relationships between annual visit-to-visit blood pressure variability and heart failure subphenotypes. The aim of this analysis was to examine the association between blood pressure variability and incident heart failure with preserved and reduced ejection fraction., Methods: Data from 23,918 postmenopausal women enrolled in the Women's Health Initiative Hormone Therapy Trials were analyzed. Blood pressure was measured at baseline (1993‒1998) and then annually through 2005. Variability was defined as the SD of the mean blood pressure across visits or the SD of the participant's regression line for blood pressure across visits. The outcome was the first heart failure hospitalization. Heart failure ascertainment and adjudications were through March 31, 2018., Results: During a mean follow-up of 15.8 years, 913 incident cases of heart failure with preserved ejection fraction and 421 cases of heart failure with reduced ejection fraction were identified. In fully adjusted models, including mean longitudinal systolic and diastolic blood pressure and time-varying coronary events interim to heart failure hospitalization, women in the highest versus in the lowest quartile of SD of the mean systolic blood pressure were at a statistically significantly higher risk of heart failure with preserved ejection fraction (hazard ratio [95% CI]=1.61 [1.12, 2.31]) but not of heart failure with reduced ejection fraction (1.18 [0.70,1.96]). Conversely, the hazard ratio (95% CI) for the highest versus lowest quartile of SD of the mean diastolic blood pressure was 1.56 (0.89, 2.74) for heart failure with reduced ejection fraction and 1.19 (0.85,1.65) for heart failure with preserved ejection fraction. Results attenuated for SD of the participant's regression line when additionally adjusted for the temporal trend of systolic and diastolic blood pressure., Conclusions: Greater systolic blood pressure variability was associated with a higher risk of heart failure with preserved ejection fraction independent of mean blood pressure and coronary events interim to heart failure hospitalization., (Copyright © 2022 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Serum lipids, including total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c), increase during pregnancy. Serum Proprotein Convertase Subtilisin Kexin 9 (PCSK9) is a vital regulator in lipoprotein metabolism. Circulating PCSK9 downregulates the LDL receptor on the surface of liver cells inhibiting clearance of LDL-c., Objective: To determine the influence of weeks of pregnancy and obesity on circulating levels of essential lipid lipoproteins and PCSK9 in women with normal, uncomplicated pregnancies and deliveries., Methods: We performed a comprehensive lipid and lipoprotein profile during each trimester of pregnancy in 70 mostly Caucasian women with uncomplicated normal pregnancies and deliveries. Based on their first trimester BMI, we placed them into one of three categories: (<25 kg/m 2 n=23, 25-30 kg/m 2 n=25, or >30 n=22) kg/m 2 . Cholesterol, triglycerides, LDL cholesterol (LDL-c), non-HDL particles, and lipoprotein(a) were measured by spectrophotometry, ion mobility, and immunoturbidimetric assays. Elisa assay determined PCSK9 (active and total). Homeostatic Model Assessment (HOMA-IR) assessed insulin resistance in the second and third trimesters of pregnancy., Results: Total and active PCSK9, LDL-c, and nonHDL particle concentrations were higher than reported for non-pregnant normal values, increased after the first trimester of pregnancy, and were highest from mid-gestation to the last trimester of pregnancy in the overweight and the obese., Conclusion: PCSK9 levels rise as normal pregnancy progresses. Levels are higher in persons who are obese, even after adjustment for insulin resistance. Defining normal PCSK9 levels during pregnancy must adjust for gestational age and BMI., Competing Interests: Declaration of Competing Interest We confirm no known conflicts of interest associated with this publication, and there has been no financial support for this work that could have influenced the outcome. Dr Wren is Medical Director at Quest and Dr Lopez has a registered patent for the PCSK9 assay. Analysis and reporting was blind to the clinical data. We also confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that all have approved the order of our authors., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To determine whether successful weight loss before ovarian stimulation with intrauterine insemination (OS-IUI) affects the risk of future pregnancy complications among women with obesity and unexplained infertility after fertility treatment., Design: Secondary analysis of the randomized controlled clinical trial Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility (FIT-PLESE)., Setting: Multiple academic health centers in the United States., Patients: Three hundred seventy-nine women with obesity and unexplained infertility who underwent standard infertility treatment after a lifestyle intervention., Interventions: The FIT-PLESE trial evaluated whether prepregnancy lifestyle interventions (diet with weight loss medication and exercise vs. exercise alone) before OS-IUI improved the live birth rate among women with obesity and unexplained infertility. Although the primary outcome of FIT-PLESE was live birth rate, we compared the demographics and subsequent pregnancy complications of women who successfully lost some weight with those of women who did not lose any during the interventions., Main Outcome Measures: Obstetric complications by groups were compared using χ 2 and Fisher's exact tests, and continuous variables were compared using Student's t -tests. Logistic regression was used to assess the odds of preeclampsia after adjustment for the randomized treatment arm in FIT-PLESE., Results: There was a nonsignificant trend toward a lower risk of intrauterine growth restriction (4% vs. 16%, P = .124) and preterm delivery (6% vs. 15%, P = .343) among patients who lost at least some weight. The risk of preeclampsia was significantly lower (6% vs.35%, P = .002) in the weight loss group (odds ratio, 0.09; 95% confidence interval, 0.016-0.505; P = .006) after adjustment for treatment assignment., Conclusions: Among women with obesity and unexplained infertility who had live births after fertility treatment, prepregnancy weight loss due to lifestyle interventions before OS-IUI was associated with a lower risk of preeclampsia., (© 2022 The Authors.)

Hypertensive disorders of pregnancy are among the leading causes of maternal morbidity and mortality in the US. Preeclampsia (PreE) which includes hypertension and proteinuria during pregnancy, is thought to result from placental ischemia. Risk factors for PreE parallel those for cardiovascular disease, and recent studies point to hyperlipidemia specifically, hypertriglyceridemia, as a risk factor for PreE. Current practice does not routinely include lipid testing pre-conception or during pregnancy. Professional, societal recommendations should advocate for hyperlipidemia screening, followed by appropriate management, pre-conception and during pregnancy., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To investigate the association of infertility with atherosclerotic cardiovascular disease (ASCVD) among postmenopausal participants in the Women's Health Initiative (WHI). We hypothesized that nulliparity and pregnancy loss may reveal more extreme phenotypes of infertility, enabling further understanding of the association of infertility with ASCVD., Design: Prospective cohort study., Setting: Forty clinical centers in the United States., Patient(s): A total of 158,787 postmenopausal participants in the Women's Health Initiative cohort., Intervention(s): Infertility, parity, and pregnancy loss., Main Outcome Measure(s): The primary outcome was risk of ASCVD among women with and without a history of infertility, stratified by history of live birth and pregnancy loss. Cox proportional-hazards models were adjusted for demographics and risk factors for ASCVD., Result(s): Among 158,787 women, 25,933 (16.3%) reported a history of infertility; 20,427 (80%) had at least 1 live birth; and 9,062 (35%) had at least 1 pregnancy loss. There was a moderate overall association between infertility and ASCVD (adjusted hazard ratio, 1.02; 95% confidence interval [CI], 0.99-1.06) over 19 years of follow-up. Among nulliparous women, infertility was associated with a 13% higher risk of ASCVD (95% CI, 1.04-1.23). Among nulliparous women who had a pregnancy loss, infertility was associated with a 36% higher risk of ASCVD (95% CI, 1.09-1.71)., Conclusion(s): Women with a history of infertility overall had a moderately higher risk of ASCVD compared with women without a history of infertility. Atherosclerotic cardiovascular disease risk was much higher among nulliparous infertile women and among nulliparous infertile women who also had a pregnancy loss, suggesting that in these more extreme phenotypes, infertility may be associated with ASCVD risk., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Lower grip strength and measures of physical functioning are associated with all-cause mortality. Relationships among long-term weight loss, physical functioning, and mortality in older women are understudied., Methods: Participants were 5039 women who were part of the Long Life Study (LLS) ancillary study to the Woman's Health Initiative (WHI). Average age was 78.76 ± 6.92. We defined long-term weight loss or gain as a decrease or increase of 5% or more of baseline body weight. Our primary outcome was all-cause mortality and our secondary outcomes were vascular death, and coronary heart disease (CHD). The mean follow-up time was 5.4 years. Cox regression modeling was performed for each outcome of interest. Variables of interest were weight change, grip strength, and functional status as measured by the Short Physical Performance Battery (SPPB) controlling for multiple potential confounders., Results: Weight loss of 5% or more percent body weight was associated with a hazard ratio of 1.66 (1.37-2.01) for all-cause mortality. Weight gain was not related to mortality or cardiovascular outcomes. Those in the highest grip strength quartile had a hazard ratio of 0.51 (0.39-0.66) for all-cause mortality. For the SPPB the hazard ratio was 0.29 (0.21-0.40), adjusting for changes in weight, race, smoking, history CHD, smoking, and diabetes. Higher grip strength and SPPB were associated with lower risks for vascular death, and CHD, independently of weight change., Conclusions: Weight loss was associated with increased mortality. Stronger grip strength and higher SPPB scores were associated with lower mortality risk independent of weight change., (© 2022 The American Geriatrics Society.)

Though studies have observed inverse associations between use of analgesics (aspirin, NSAIDs, and acetaminophen) and the risk of several cancers, the potential biological mechanisms underlying these associations are unclear. We investigated the relationship between analgesic use and serum concentrations of estrogens, androgens, and their metabolites among postmenopausal women to provide insights on whether analgesic use might influence endogenous hormone levels, which could in turn influence hormone-related cancer risk. The study included 1,860 postmenopausal women from two case-control studies nested within the Women's Health Initiative Observational Study. Analgesic use was reported at study baseline. Fifteen estrogens and estrogen metabolites and 12 androgens and androgen metabolites were quantified in baseline serum by LC/MS-MS. Linear regression with inverse probability weighting, stratified by menopausal hormone therapy (MHT) use, was used to estimate adjusted geometric mean concentrations of each hormone by analgesic use. Among women not currently using MHT (n = 951), low-dose aspirin (<100 mg) use was associated with a higher serum concentration of estrone, estradiol, and 2, 4, and 16 hydroxylated metabolites. Use of regular-dose aspirin (≥100 mg), non-aspirin NSAIDs, and acetaminophen was not associated with serum concentrations of estrogens, androgens, or their metabolites. This study highlights the importance of examining aspirin use by dose and suggests that low-dose aspirin may influence endogenous estrogen concentrations., Prevention Relevance: This study explores a potential pathway by which analgesic medications such as aspirin may prevent hormone-related cancers. The findings support a positive association between low-dose aspirin use and endogenous estrogens, indicating that further elucidation of the interplay between low-dose aspirin, estrogen concentrations, and cancer risk is needed., (©2021 American Association for Cancer Research.)

Objective: To estimate the probability of clinical or multiple pregnancy during ovulation induction (OI)/ovarian stimulation (OS)., Design: Secondary analysis of two multicenter randomized clinical trials (combined)., Setting: Multicenter., Patients: A total of 750 women with polycystic ovary syndrome and 900 women with unexplained infertility., Interventions: Ovulation induction/OS with either timed intercourse (polycystic ovary syndrome) or intrauterine insemination., Main Outcome Measures: Clinical and multiple pregnancy rates/cycle, cumulative pregnancy rates. Age, body mass index, parity, diagnosis, medication, markers of ovarian reserve, and ovarian response were considered in multivariable regression models for clinical, multiple, and cumulative pregnancy rates. Receiver operating characteristic curves were created for clinical and multiple pregnancy rates., Results: Younger patient and partner age, treatment type, lower body mass index, and medication dose were all associated with clinical pregnancy. Variables associated with multiple pregnancy included the abovementioned variables (except age), in addition to diagnosis, parity, higher antral follicle count, antimüllerian hormone levels, and ovarian response. Gonadotropin use was associated with multiple pregnancy, with progressively increasing odds ratios (cycles 1-4). Receiver operating characteristic curves indicated the model's predictive power to be fair for clinical pregnancy (areas under the curve [95% confidence interval {CI}]: 0.78 [0.75-0.81] for cycle 1 and 0.70 [0.64-0.75] for cycle 4) and good-to-excellent for multiple pregnancy (areas under the curve [95% CI]: 0.78 [0.72-0.84] for cycle 1 and 0.86 [0.78-0.93] for cycle 4). Partner age, lower medication dose, parity, antimüllerian hormone levels, and diagnosis were associated with cumulative pregnancy rates., Conclusions: Using the majority of the factors known to predict the outcome of OI/OS cycles, we constructed an easy-to-use formula that may predict individualized chances of clinical and multiple pregnancy for commonly used fertility treatments (https://pregnancyprediction.medicine.yale.edu/CalDirect.html)., Clinical Trial Registration Numbers: Assessing Multiple Intrauterine Gestations after Ovulation Stimulation NCT01044862; PPCOSII NCT00719186., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Mechanisms underlying the adiposity-cancer relationship are incompletely understood. We quantified the mediating roles of C-reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)-positive breast, endometrial, and colorectal cancer risk in postmenopausal women., Methods: We used a case-cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case-control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis., Results: For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5-<25 kg/m 2 was 1.87 (95%CI,1.11-3.13). The indirect effect RRs were 1.38 (0.79-2.33) through leptin and CRP, 1.58 (1.17-2.43) through insulin, and 1.11 (0.98-1.30) through estradiol. The direct effect RR was 0.82 (0.39-1.68). For endometrial cancer, the total effect RR was 2.12 (1.12-4.00). The indirect effect RRs were 1.72 (0.85-3.98) through leptin and CRP, 1.42 (0.96-2.26) through insulin, and 1.24 (1.03-1.65) through estradiol. The direct effect RR was 0.70 (0.23-2.04). For colorectal cancer, the total effect RR was 1.70 (1.03-2.79). The indirect effect RRs were 1.04 (0.61-1.72) through leptin and CRP, 1.36 (1.00-1.88) through insulin, and 1.02 (0.88-1.17) through estradiol. The direct effect RR was 1.16 (0.58-2.43)., Conclusion: Leptin, CRP, fasting insulin, and estradiol appear to mediate the effect of high BMI on cancer risk to different extents, with likely varying degrees of importance between cancers. These insights might be important in developing interventions to modify obesity-associated cancer risk in postmenopausal women., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth., Methods and Findings: In this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m2) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (-6.6 ± 5.4% versus -0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful., Conclusions: A preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity., Trial Registration: ClinicalTrials.gov NCT02432209., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.S.L reports consulting fees from InSupp, Ferring, Bayer, Abbvie and Fractyl and research sponsorship from Guerbet and the NIH (U10 HD38992). K.R.H. reports research support from Roche Diagnostics, Ferring and Ablacare and the NIH (U10HD077680). M.P.D reports institutional grants/contracts from Bayer, ObsEva, and AbbVie; serving as a member of the Board of Directors and a stockholder of Advanced Reproductive Care; and serving as a Consultant for Seikagaku, Actamax, AEGEA, Temple Therapeutics, and ARC Medical Devices as well as receiving funding from the NIH(U10 HD39005). A.Z.S. reports consulting fees from Seikagaku and Prima-Temp and research funding from the NIH. M.I.C. reports research funding from Ferring Pharmaceuticals and the NIH (U10HD077844). C.C. reports research funding from the NIH (U10 HD27049). R.A.W. reports Ablacare PCOS, Amgen Repatha in Pg and Partners Mass General Menopause Reviews, grants from NICHD. S.A.K. reports research grant from Merck. D.B.S. reports grants from National Institute of Diabetes, Digestive and Kidney Disease, National Institute of Dental and Craniofacial Research, Department of Defense and Commonwealth of Pennsylvania (PA CURE), consulting fees from Ethicon and NovoNordisk. N.S. reports consulting for Ansh Labs, and is a Scientific Advisor to Astellas and Menogenix, Inc. H.Z. reports research funding from the NIH (U10HD055925).

Objective: To determine if chronic inflammation, assessed by basal high-sensitivity C-reactive protein (hs-CRP) levels, is associated with pregnancy outcomes in women with unexplained infertility undergoing ovarian stimulation with intrauterine insemination., Design: Prospective cohort analysis of the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) randomized controlled trial., Setting: Multicenter university-based randomized controlled trial., Patients: A total of 781 couples with unexplained infertility., Interventions: Secondary analysis., Main Outcome Measures: Adjusted risk ratios of live birth, clinical pregnancy, and pregnancy loss rates by hs-CRP levels., Results: Associations between hs-CRP levels and clinical pregnancy rates were not observed after adjustment for baseline body mass index. There were fewer live births among women with higher hs-CRP levels, although confidence intervals crossed 1.0. The risk of pregnancy loss was greater in women with increased hs-CRP levels (1-3 mg/L: risk ratio [RR], 1.67; 95% confidence interval [CI], 1.00-2.79; >3-10 mg/L: RR, 1.84; 95% CI, 1.06-3.20; and >10 mg/L: RR, 2.14; 95% CI, 1.05-4.36 compared to women with hs-CRP <1 mg/L)., Conclusions: This investigation suggests that chronic inflammation may increase the risk of pregnancy loss but not impact the clinical pregnancy rate in women with unexplained infertility undergoing ovarian stimulation with intrauterine insemination. Associations between inflammation and pregnancy outcomes in women with infertility merit further investigation., Clinical Trial Registration Number: clinicaltrials.gov NCT01044862., (© 2022 Published by Elsevier Inc. on behalf of American Society for Reproductive Medicine.)

Background: Prolonged sitting and physical inactivity are associated with higher circulating levels of estrogens. It is unknown whether these risk factors are associated with circulating androgens/androgen metabolites, another set of hormones implicated in the etiology of cancers in postmenopausal women., Methods: We conducted a cross-sectional analysis of 1,782 postmenopausal women in the Women's Health Initiative Observational Study. Serum concentrations of 12 androgens/androgen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting time were self-reported at baseline. We performed linear regression to estimate geometric means (GM) of androgen/androgen metabolite concentrations (pmol/L) according to physical activity and sitting time, adjusting for potential confounders and stratified by menopausal hormone therapy (MHT) use., Results: Physical activity (≥15 vs. 0 MET-h/wk) was inversely associated with estrogen-to-androgen ratios among never/former MHT users (adj-GM = 37.5 vs. 49.6 unconjugated estrone:androstenedione; 20.2 vs. 30.3 unconjugated estradiol:testosterone; all P trend ≤ 0.03) but was not associated among current MHT users. Prolonged sitting (≥10 vs. ≤5 h/d) was positively associated with these ratios among both never/former (adj-GM = 44.2 vs. 38.3, P trend = 0.10; adj-GM = 23.4 vs. 20.2, P trend = 0.17; respectively) and current MHT users (adj-GM = 197 vs. 147; 105 vs. 75.5; respectively; all P trend ≤0.02), but the associations were statistically significant among current MHT users only. The associations persisted after adjustment for BMI. After adjustment for adrenal androgens, physical activity and sitting were not associated with androgen metabolites., Conclusions: Physical activity and sitting were associated with serum estrogen-to-androgen ratios but not androgen metabolites., Impact: This study contributes to our understanding of the link between physical activity, sitting, and cancer risk in postmenopausal women., (©2021 American Association for Cancer Research.)

Objective: To assess the relationship between body fat distribution and incident lower-extremity arterial disease (LEAD)., Research Design and Methods: We included 155,925 postmenopausal women with anthropometric measures from the Women's Health Initiative who had no known LEAD at recruitment. A subset of 10,894 participants had body composition data quantified by DXA. Incident cases of symptomatic LEAD were ascertained and adjudicated through medical record review., Results: We identified 1,152 incident cases of LEAD during a median 18.8 years follow-up. After multivariable adjustment and mutual adjustment, waist and hip circumferences were positively and inversely associated with risk of LEAD, respectively (both P-trend < 0.0001). In a subset (n = 22,561) where various cardiometabolic biomarkers were quantified, a similar positive association of waist circumference with risk of LEAD was eliminated after adjustment for diabetes and HOMA of insulin resistance (P-trend = 0.89), whereas hip circumference remained inversely associated with the risk after adjustment for major cardiometabolic traits (P-trend = 0.0031). In the DXA subset, higher trunk fat (P-trend = 0.0081) and higher leg fat (P-trend < 0.0001) were associated with higher and lower risk of LEAD, respectively. Further adjustment for diabetes, dyslipidemia, and blood pressure diminished the association for trunk fat (P-trend = 0.49), yet the inverse association for leg fat persisted (P-trend = 0.0082)., Conclusions: Among U.S. postmenopausal women, a positive association of upper-body fat with risk of LEAD appeared to be attributable to traditional risk factors, especially insulin resistance. Lower-body fat was inversely associated with risk of LEAD beyond known risk factors., (© 2021 by the American Diabetes Association.)

Importance: Some prior evidence suggests that adverse pregnancy outcomes (APOs) may be associated with heart failure (HF). Identifying unique factors associated with the risk of HF and studying HF subtypes are important next steps., Objective: To investigate the association of APOs with incident HF overall and stratified by HF subtype (preserved vs reduced ejection fraction) among postmenopausal women in the Women's Health Initiative (WHI)., Design, Setting, and Participants: In 2017, an APO history survey was administered in the WHI study, a large multiethnic cohort of postmenopausal women. The associations of 5 APOs (gestational diabetes, hypertensive disorders of pregnancy [HDP], low birth weight, high birth weight, and preterm delivery) with incident adjudicated HF were analyzed. In this cohort study, the association of each APO with HF was assessed using logistic regression models and with HF subtypes using multinomial regression, adjusting for age, sociodemographic characteristics, smoking, randomization status, reproductive history, and other APOs. Data analysis was performed from January 2020 to September 2021., Exposures: APOs (gestational diabetes, HDP, low birth weight, high birth weight, and preterm delivery)., Main Outcomes and Measures: All confirmed cases of women hospitalized with HF and HF subtype were adjudicated by trained physicians using standardized methods., Results: Of 10 292 women (median [IQR] age, 60 [55-64] years), 3185 (31.0%) reported 1 or more APO and 336 (3.3%) had a diagnosis of HF. Women with a history of any APO had a higher prevalence of hypertension, diabetes, coronary heart disease, or smoking. Of the APOs studied, only HDP was significantly associated with HF with a fully adjusted odds ratio (OR) of 1.75 (95% CI, 1.22-2.50), and with HF with preserved ejection fraction in fully adjusted models (OR, 2.06; 95% CI, 1.29-3.27). In mediation analyses, hypertension explained 24% (95% CI, 12%-73%), coronary heart disease 23% (95% CI, 11%-68%), and body mass index 20% (95% CI, 10%-64%) of the association between HDP and HF., Conclusions and Relevance: In this large cohort of postmenopausal women, HDP was independently associated with incident HF, particularly HF with preserved ejection fraction, and this association was mediated by subsequent hypertension, coronary heart disease, and obesity. These findings suggest that monitoring and modifying these factors early in women presenting with HDP may be associated with reduced long-term risk of HF.