Laura B. Harrington

Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens

IMPORTANCEnLittle is known about the comparative cardiovascular safety of oral hormone therapy products, which impedes women from making informed safety decisions about hormone therapy to treat menopausal symptoms.nnnOBJECTIVEnTo compare the relative clinical cardiovascular safety of 2 commonly used oral estrogen drugs-conjugated equine estrogens (CEEs) and estradiol.nnnDESIGN, SETTING, AND PARTICIPANTSnPopulation-based, case-control study from January 1, 2003, to December 31, 2009, comparing cardiovascular event risk associated with current CEEs and estradiol use in a large health maintenance organization in which the preferred formulary estrogen changed from CEEs to estradiol during the course of data collection. Participants were 384 postmenopausal women aged 30 to 79 years using oral hormone therapy.nnnMAIN OUTCOMES AND MEASURESnIncident venous thrombosis was the primary clinical outcome, and incident myocardial infarction and ischemic stroke were secondary outcomes. As validation, an intermediate clotting phenotype, the endogenous thrombin potential-based normalized activated protein C sensitivity ratio, was measured in plasma of controls.nnnRESULTSnWe studied 68 venous thrombosis, 67 myocardial infarction, and 48 ischemic stroke cases, with 201 matched controls; all participants were current users of oral CEEs or estradiol. In adjusted analyses, current oral CEEs use compared with current oral estradiol use was associated with an increased venous thrombosis risk (odds ratio, 2.08; 95% CI, 1.02-4.27; P = .045) and an increased myocardial infarction risk that did not reach statistical significance (odds ratio, 1.87; 95% CI, 0.91-3.84; P = .09) and was not associated with ischemic stroke risk (odds ratio, 1.13; 95% CI, 0.55-2.31; P = .74). Among 140 controls, CEEs users compared with estradiol users had higher endogenous thrombin potential-based normalized activated protein C sensitivity ratios (P < .001), indicating a stronger clotting propensity.nnnCONCLUSIONS AND RELEVANCEnIn an observational study of oral hormone therapy users, CEEs use was associated with a higher risk of incident venous thrombosis and possibly myocardial infarction than estradiol use. This risk differential was supported by biologic data. These findings need replication and suggest that various oral estrogen drugs may be associated with different levels of cardiovascular risk.

Racial and ethnic differences in the risk of postpartum venous thromboembolism: a population-based, case-control study

Venous thromboembolism (VTE) is a major contributor of maternal morbidity and mortality. Whether maternal race/ethnicity is associated with the risk of postpartum VTE remains unclear.

The association of statin therapy with the risk of recurrent venous thrombosis

Essentials A lowered risk of recurrent venous thrombosis (VT) with statin treatment is controversial. Among observational inception cohort of 2,798 adults with incident VT, 457 had recurrent VT. Time‐to‐event models with time‐varying statin use and adjustment for potential confounders was used for analysis. Compared to nonuse, current statin use was associated with 26% lower risk of recurrent VT.

Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers

The risk of venous thrombosis (VT) associated with oral hormone therapy (HT) may differ by type of estrogen compound.

Hysterectomy and Bilateral Salpingo-Oophorectomy: Variations by History of Military Service and Birth Cohort.

INTRODUCTIONnLittle is known about hysterectomy and bilateral salpingo-oophorectomy (BSO), which are associated with both health risks and benefits, among women Veterans.nnnPURPOSE OF THE STUDYnTo compare the prevalence of hysterectomy with or without BSO, and early hysterectomy, between postmenopausal Veterans and non-Veterans.nnnDESIGN AND METHODSnWe used baseline data from the Womens Health Initiative Clinical Trial and Observational Study. Multinomial logistic regression models examined differences in the prevalence of hysterectomy (neither hysterectomy nor BSO, hysterectomy without BSO, and hysterectomy with BSO) between Veterans and non-Veterans. Generalized linear models were used to determine whether early hysterectomy (before age 40) differed between Veterans and non-Veterans. Analyses were stratified by birth cohort (<65, ≥65 years at enrollment).nnnRESULTSnThe unadjusted prevalence of hysterectomy without BSO was similar among Veterans and non-Veterans in both birth cohorts (<65: 22% vs 21%; ≥65: 22% vs 21%). The unadjusted prevalence of hysterectomy with BSO was equivalent among Veterans and non-Veterans in the >65 cohort (21%), but higher among Veterans in the <65 cohort (22% vs 19%). In adjusted analyses, although no differences were observed in the >65 cohort, Veterans in the <65 cohort had higher odds of hysterectomy without BSO (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03, 1.36) and with BSO (OR 1.26, 95% CI 1.10, 1.45), as well as elevated risk of early hysterectomy (relative risk 1.32, 95% CI 1.19, 1.47), compared with non-Veterans.nnnIMPLICATIONSnAging women Veterans may have higher prevalence of hysterectomy and BSO than non-Veterans. This information contributes to understanding the health needs and risks of women Veterans and can inform clinical practice and policy for this population.

Association Between Newborn Birth Weight and the Risk of Postpartum Maternal Venous Thromboembolism A Population-Based Case–Control Study

Background— Postpartum venous thromboembolism (VTE) is a potentially fatal and preventable event leading to substantial short- and long-term morbidity. We sought to evaluate whether the delivery of term newborns of low or high birth weight was associated with greater risks of VTE. Methods and Results— In a population-based case–control study conducted in Washington State from 1987 through 2011, cases of hospitalized VTE within 3 months of delivery were identified by using selected International Classification of Diseases, Ninth Revision, Clinical Modification codes. Controls were randomly selected postpartum women without VTE, matched on birth year. Birth weight and other maternal and pregnancy characteristics were extracted from birth certificate data. Among term live singleton deliveries, we compared the risk of VTE for mothers of newborns of low and high birth weights (<2500 g and >4000 g, respectively) versus mothers of newborns of normal birth weight (2500–4000 g). Logistic regression models were adjusted for maternal age, race, education, body mass index, parity, delivery methods, gestational length, smoking, gestational diabetes mellitus, and preeclampsia. Patients with VTE (n=547) were older, had a higher body mass index, and experienced more pregnancy-related complications than controls (n=9482). In comparison with mothers of newborns with normal birth weight, mothers of newborns with low birth weight had a 3-fold increased risk of VTE, which persisted after multivariable adjustment (odds ratio, 2.98; 95% confidence interval, 1.80–4.93). Mothers of newborns with high birth weight had only a slightly increased risk of VTE, which was attenuated after multivariable adjustment (odds ratio, 1.26; 95% confidence interval, 0.99–1.61). Conclusions— The delivery of a newborn with low birth weight is associated with a 3-fold increased risk of maternal postpartum VTE. This should be considered when assessing VTE risk at delivery.

Vasomotor Symptoms and Quality of Life Among Veteran and Non-Veteran Postmenopausal Women

INTRODUCTIONnVasomotor symptoms (VMS), including hot flashes and night sweats, are common among postmenopausal women and are associated with reduced health related quality of life (HRQOL).nnnPURPOSE OF THE STUDYnTo determine whether Veterans are more likely to report VMS than non-Veterans, and whether the association of VMS with HRQOL varies by Veteran status.nnnDESIGN AND METHODSnWe used data from the Womens Health Initiative Observational Study, including self-reported baseline VMS presence and severity, and HRQOL at follow-up Year 3 (RAND Short Form 36-Item Health Survey). Employing generalized linear models we estimated whether Veteran status was associated with any VMS. We estimated the association between any VMS and HRQOL using linear regression, stratified by Veteran status. Interaction terms were added separately to determine whether the association varied by baseline depression, obesity, or smoking status.nnnRESULTSnThe final analyses included 77,153 postmenopausal women (2,004 Veterans). After adjustment, Veterans were no more likely than non-Veterans to report any VMS at baseline (relative risk [RR] 0.97, 95% confidence interval [CI] 0.90-1.04) or moderate to severe VMS (RR 1.03, 95% CI 0.89-1.18). Any VMS was associated with decreased HRQOL at Year 3, particularly among Veterans (mean difference range: Veterans -2.7 to -4.6, p-values < .001; non-Veterans -2.2 to -2.6, 95% CI -0.13 to -0.09, p values < .001). Baseline depression and obesity, but not smoking, amplified the negative association between VMS and HRQOL.nnnIMPLICATIONSnMulticondition care models for postmenopausal Veteran and non-Veteran women are needed that incorporate management strategies for VMS, weight, and depression.

Lack of strong effect modification by NFE2L2/CYP3A5/ABO of the risk of venous thrombosis associated with oral hormone therapy

The use of oral, estrogen-based hormone therapy (HT) among postmenopausal women increases the risk of venous thrombosis (VT) compared with placebo or non-use [1, 2]. However, HT remains an effective therapy to reduce burdensome climacteric symptoms present in at least 40% of women during the menopausal transition [3]. Genetic variants may modify the association between HT and VT risk and increase this risk for specific alleles. Three such gene-drug interactions have been previously reported, for which women carrying a risk allele had greater risks of VT due to HT than non-carriers [4–6]. The 3 loci include: nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), involved in the expression levels of genes for phase II metabolism (rs6721961 allele A, minor allele frequency (MAF) 0.10); cytochrome P450 3A5 (CYP3A5), involved in the phase I metabolism of estrogens (rs776746 allele A, MAF 0.09); and blood group antigen (ABO, rs8176719 allele G defining a non-O blood group, MAF 0.36). Our aim was to replicate these findings in a larger, population-based, case-control study of incident VT. n nOur study is part of the Heart and Vascular Health (HVH) study, a set of case-control studies of major cardiovascular outcomes among members of Group Health Cooperative (GHC), a large, integrated healthcare system in Washington State. VT cases were women who suffered a first VT (deep-vein thrombosis [DVT] and/or pulmonary embolism [PE]) from 1995 through 2009. An objective imaging test was present and confirmatory in greater than 97% of cases. Controls were randomly selected women without any history of VT who were matched to HVH cases on year of index, hypertension status, and age. n nCurrent oral HT use was determined by computerized GHC pharmacy records under the assumption of 80% compliance with prescribed use. As previously reported, greater than 95% of GHC enrollees fill all prescriptions at a GHC pharmacy, suggesting near complete information on oral HT use from GHC records [7]. Use of transdermal estrogen HT was uncommon and users were excluded. Data on covariates were collected through a standardized review of the medical records by trained abstractors and through a telephone interview. DNA was collected from those consenting to phlebotomy. Genetic variation was characterized using information from candidate and genome-wide genotyping panels previously conducted in the HVH study. Two variants (rs6721961 and rs8176719) were not measured or imputed (missing from the Hap Map 3 imputation panels); for these, we estimated the genotype using available tag-SNPs in high linkage disequilibrium with the targeted variant: rs2001350 for NFE2L2 rs6721961 (r2=1.0) and rs514659 for ABO rs8176719 (r2=0.72). n nThe analytic population was restricted to post-menopausal women of European ancestry with available genetic information. Further, to best approximate the characteristics of the discovery population for this replication study, we excluded 803 women who had the following risk factors for incident VT: recent cancer (diagnosis within 5 years of index date), cardiovascular disease, recent hospitalization, surgery, trauma or cast (within 1 month of index date). n nWe first characterized associations between the genetic variants and incident VT in our data using logistic regression that adjusted for age, hypertension and index year (matching factors). Then, to attempt replication, we tested for effect modification between the genetic variants and HT use and used logistic regression including a multiplicative interaction term, adjusted for the matching factors and BMI (a priori selected confounding variable). P-value less than 0.05 determined statistical significance. n nThe analytic population included up to 381 incident cases of VT and 1634 controls. Among controls, mean age was 68 years (standard deviation [SD] 8.3) and mean BMI was 28.6 kg/m2 (SD 6.5). The average duration of HT, used by 35.6% of controls, was 10 years. Greater than 90% of HT preparations were conjugated equine estrogens (CEE) and esterified estrogens. Among cases, 48.8% had experienced a PE (with or without a DVT) and 51.2% an isolated DVT. n nAmong controls, the minor allele frequencies of NFE2L2 rs2001350, CYP3A5 rs776746 and ABO rs514659 were 0.10, 0.08 and 0.34, respectively. Overall, NFE2L2 rs2001350 and CYP3A5 rs776746 were not associated with an increased risk of VT (odds ratio [OR] 1.0 [95%CI 0.8–1.4] and OR 1.1 [95%CI 0.7–1.5], additive genetic models adjusted for matching factors, respectively). A non-O blood group was associated with a greater risk of VT than O (OR 1.6 [95%CI 1.2–2.0], dominant model adjusted for matching factors). n nOverall, the use of oral HT was associated with a 70% increased risk of incident VT (adjusted OR 1.7 [95%CI 1.2–2.2] p 0.44. For ABO, a supra-multiplicative effect modification was also excluded. We could not confirm or exclude a departure from an additive association between ABO and HT due to the imprecision of estimates (combined OR of 2.4 [95%CI 1.7–3.5] vs. an expected OR of 1.7 based on individual ORs of 1.4 for ABO and 1.3 for HT). Finally, we conducted analyses stratified by the use of progestogen and found no interactions between the genetic variants and the use of unopposed HT or opposed HT (data not shown). n n n nTable n nAssociation between oral hormone therapy and VT in postmenopausal women, by SNP strata (dominant model). n n n nIn this population-based study, we found no evidence of gene-drug interaction of oral HT with variants in NFE2L2 and CYP3A5 on the risk of VT in postmenopausal women. Our findings contrast with those of the ESTHER study (Table), where associations between oral HT and VT differed markedly by these variants. Our data cannot exclude a modest supra-additive interaction between non-O blood group and the use of HT, however much smaller than reported in the ESTHER study. n nHypothesized gene-environment interactions have not been readily identified or validated in most settings, including genetic modifications of VT risk by HT. A limitation in the identification and validation of gene-environment interactions has been modest sample sizes, which produce unstable estimates with large confidence intervals. This is the likely explanation of the difference in findings between discovery and replication efforts such as those in the HVH and ESTER studies where there were 2–3 times more cases and 2-–5 times more controls in the former compared with the latter. There were also methodologic differences including population-based versus mostly hospitalized-based study designs. The risk of VT associated with oral HT was lower in our sample than in the ESTHER study [2, 4]. Apart from study design, this lower estimated risk may be due to the prescription of esterified estrogens and of unopposed estrogens in >60% of HT users, known to be less thrombogenic than CEE and opposed estrogens, respectively [2, 7], the lower estrogen dose (CEE 0.625mg or lower for >90% of HT users), and the high proportion of prevalent users. A limitation of this study is the use of tag-SNPs for the NFE2LE SNP (r2=1.0) and the blood group determination (r2=0.72), whose associated measurement error may induce bias. n nIn conclusion, our data do not support previous findings of strong effect modification between genetic variants in NFE2LE, CYP3A5, or ABO and the use of oral HT on the risk of VT. A modest supra-additive interaction between oral HT and ABO cannot be excluded and should be further investigated.

Association Between Newborn Birth Weight and the Risk of Postpartum Maternal Venous ThromboembolismCLINICAL PERSPECTIVE: A Population-Based Case–Control Study

Background— Postpartum venous thromboembolism (VTE) is a potentially fatal and preventable event leading to substantial short- and long-term morbidity. We sought to evaluate whether the delivery of term newborns of low or high birth weight was associated with greater risks of VTE. Methods and Results— In a population-based case–control study conducted in Washington State from 1987 through 2011, cases of hospitalized VTE within 3 months of delivery were identified by using selected International Classification of Diseases, Ninth Revision, Clinical Modification codes. Controls were randomly selected postpartum women without VTE, matched on birth year. Birth weight and other maternal and pregnancy characteristics were extracted from birth certificate data. Among term live singleton deliveries, we compared the risk of VTE for mothers of newborns of low and high birth weights (<2500 g and >4000 g, respectively) versus mothers of newborns of normal birth weight (2500–4000 g). Logistic regression models were adjusted for maternal age, race, education, body mass index, parity, delivery methods, gestational length, smoking, gestational diabetes mellitus, and preeclampsia. Patients with VTE (n=547) were older, had a higher body mass index, and experienced more pregnancy-related complications than controls (n=9482). In comparison with mothers of newborns with normal birth weight, mothers of newborns with low birth weight had a 3-fold increased risk of VTE, which persisted after multivariable adjustment (odds ratio, 2.98; 95% confidence interval, 1.80–4.93). Mothers of newborns with high birth weight had only a slightly increased risk of VTE, which was attenuated after multivariable adjustment (odds ratio, 1.26; 95% confidence interval, 0.99–1.61). Conclusions— The delivery of a newborn with low birth weight is associated with a 3-fold increased risk of maternal postpartum VTE. This should be considered when assessing VTE risk at delivery.

Association Between Newborn Birth Weight and the Risk of Postpartum Maternal Venous ThromboembolismCLINICAL PERSPECTIVE

Background— Postpartum venous thromboembolism (VTE) is a potentially fatal and preventable event leading to substantial short- and long-term morbidity. We sought to evaluate whether the delivery of term newborns of low or high birth weight was associated with greater risks of VTE. Methods and Results— In a population-based case–control study conducted in Washington State from 1987 through 2011, cases of hospitalized VTE within 3 months of delivery were identified by using selected International Classification of Diseases, Ninth Revision, Clinical Modification codes. Controls were randomly selected postpartum women without VTE, matched on birth year. Birth weight and other maternal and pregnancy characteristics were extracted from birth certificate data. Among term live singleton deliveries, we compared the risk of VTE for mothers of newborns of low and high birth weights (<2500 g and >4000 g, respectively) versus mothers of newborns of normal birth weight (2500–4000 g). Logistic regression models were adjusted for maternal age, race, education, body mass index, parity, delivery methods, gestational length, smoking, gestational diabetes mellitus, and preeclampsia. Patients with VTE (n=547) were older, had a higher body mass index, and experienced more pregnancy-related complications than controls (n=9482). In comparison with mothers of newborns with normal birth weight, mothers of newborns with low birth weight had a 3-fold increased risk of VTE, which persisted after multivariable adjustment (odds ratio, 2.98; 95% confidence interval, 1.80–4.93). Mothers of newborns with high birth weight had only a slightly increased risk of VTE, which was attenuated after multivariable adjustment (odds ratio, 1.26; 95% confidence interval, 0.99–1.61). Conclusions— The delivery of a newborn with low birth weight is associated with a 3-fold increased risk of maternal postpartum VTE. This should be considered when assessing VTE risk at delivery.