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Jceme114.Pdf JCEM ONLINE Brief Report—Endocrine Research Menstrual Irregularity and Cardiovascular Mortality Erica T. Wang, Piera M. Cirillo, Eric Vittinghoff, Kirsten Bibbins-Domingo, Barbara A. Cohn, and Marcelle I. Cedars Center for Research on Women’s and Children’s Health, Public Health Institute, University of California San Francisco, San Francisco, California 94115 Downloaded from https://academic.oup.com/jcem/article/96/1/E114/2833816 by guest on 29 September 2021 Background: Polycystic ovary syndrome, the most common cause of irregular menstrual cycles, is associated with an adverse cardiovascular risk profile. However, there are limited prospective studies confirming the link between polycystic ovary syndrome and cardiovascular mortality. Methods: We studied 15,005 pregnant women recruited from the Kaiser Foundation Health Plan in California between 1959 and 1966. The menstrual cycle pattern was assessed at baseline ac- cording to self-report, physician report, and medical record abstraction. Participants were matched to California Vital Status files annually until 2007 to identify deaths due to overall cardiovascular disease (CVD) and subsets of coronary heart disease (CHD) and cerebrovascular disease based on International Classification of Diseases codes. Cox proportional hazards models were used to es- timate the association between irregular cycles and cardiovascular mortality. Missing covariate data were multiply imputated using standard methods. Results: During 456,298.5 person-years of follow-up, there were 666 CVD deaths, including 301 CHD deaths and 149 cerebrovascular deaths. Compared with women with regular cycles, women with irregular cycles had an increased risk for CHD mortality [age adjusted hazards ratio (HR) 1.42, 95% confidence interval (CI) 1.03–1.94]; however, the association was not statistically significant after adjustment for body mass index (adjusted HR 1.35, 95% CI 0.98–1.85). There was a nonsig- nificant increase in CVD mortality (age adjusted HR 1.21, 95% CI 0.97–1.52) but not cerebrovascular mortality (age adjusted HR 0.85, 95% CI 0.49–1.47). Conclusions: In this large prospective cohort of pregnant women, we found an increase in age- adjusted risk for CHD mortality in women with irregular menstrual cycles. This risk was attenuated after adjustment for body mass index. (J Clin Endocrinol Metab 96: E114–E118, 2011) olycystic ovary syndrome (PCOS) is a heterogeneous from the East Bay Area of California (1959–1967) and P syndrome among reproductive-aged women charac- followed up for approximately 40 yr, we aimed to deter- terized by irregular menstrual cycles due to anovulation, mine whether menstrual cycle irregularity is associated hyperandrogenism, and/or polycystic ovaries on ultra- with increased cardiovascular mortality. sound (1, 2). PCOS is associated with an adverse cardio- vascular risk profile (3); however, the literature lacks pro- spective studies based on a well-defined population to Materials and Methods confirm the link between PCOS and cardiovascular Study design and sample mortality. The Child Health and Development Studies (CHDS) was ini- Among healthy reproductive-aged women, PCOS ac- tiated in 1959 to investigate events of pregnancy and childhood counts for 87% of women with irregular cycles (4). Using development. The recruitment procedures and characteristics of data from a large cohort of pregnant women recruited the cohort have been previously described (5). The target pop- ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BMI, Body mass index; CHD, coronary heart disease; CHDS, Child Health Printed in U.S.A. and Development Studies; CI, confidence interval; CVD, cardiovascular disease; DMV, Copyright © 2011 by The Endocrine Society Department of Motor Vehicles; HR, hazards ratio; ICD, International Classification of Dis- doi: 10.1210/jc.2010-1709 Received July 26, 2010. Accepted September 27, 2010. eases; ICD-8, ICD, eighth revision; ICD-9, ICD, ninth revision; PCOS, polycystic ovary First Published Online October 27, 2010 syndrome. E114 jcem.endojournals.org J Clin Endocrinol Metab, January 2011, 96(1):E114–E118 J Clin Endocrinol Metab, January 2011, 96(1):E114–E118 jcem.endojournals.org E115 ulation for the CHDS included all members of the Kaiser Foun- ceptive use was dichotomized based on participants’ self-report dation Health Plan residing in the East Bay of the San Francisco of using oral contraceptive pills since their last pregnancy or Bay Area. Women were invited to enroll in the CHDS when they indication of oral contraceptive use in the medical records. Parity contacted participating Kaiser facilities regarding a confirmed was defined as the count of previous live-born births. Tobacco pregnancy. Recruitment efforts resulted in enrollment of more use was categorized as never, past, or current. Personal history of than 98% of eligible women. In all, 15,528 women, aged 14–48 diabetes was obtained from physician diagnosis or medical yr, were enrolled between 1959 and 1966. The institutional re- records; this condition was not specified as pregestational or view board approved the study protocol; informed consent was gestational. obtained from all participants. At the time of enrollment, base- Weight and height were measured at first interview. Weight line demographic and pregnancy history information was col- was adjusted to compensate for variation in gestational age by lected by in-person interviews. Clinical measures and informa- regressing weight on gestational age using the locally weighted tion about maternal medical conditions were abstracted from scatterplot smoothing technique (7). Adjusted weight was then medical records beginning 6 months before pregnancy through imputed as the fitted mean weight at 104 d of gestation, the Downloaded from https://academic.oup.com/jcem/article/96/1/E114/2833816 by guest on 29 September 2021 labor and delivery. The present investigation included 15,005 median value at first interview, plus her residual from the locally women from the cohort with known follow-up status. weighted regression and scatterplot smoothing technique fit. This procedure removes differences in weight due to differences Menstrual cycle regularity in gestational age at first interview. Menstrual cycle pattern was assessed at baseline according to the following factors: 1) self-report at the interview and 2) phy- Statistical analyses sician report and diagnosis from medical record abstraction. Par- We compared women with irregular and regular cycles using ticipants were asked, “Would you say your periods have been unadjusted linear regression for continuous variables and logis- regular?” If the participants responded no, they were considered tic regression for categorical variables. The independent associ- to have irregular cycles. If the participants indicated regular cy- ations of irregular cycles with CVD, CHD, and cerebrovascular cles, they were asked, “What is the usual interval between the disease mortality were then assessed using Cox proportional haz- beginning of one period to the next?” A participant was defined ards models, adjusting for age, race, body mass index (BMI), oral as having irregular cycles if one of the following criteria was met: contraceptive use, parity, and tobacco use. self-report or physician report of irregular cycles; self-report or We dealt with missing covariate values using multiple impu- physician report of cycle length 36 d or longer; or physician- tation (8, 9), as implemented in the imputation by chained equa- coded oligomenorrhea, anovulatory cycles, or irregular menses. tions package in STATA (StataCorp., College Station, TX) (10). Among 15,005 women, 167 had missing values for age, 282 for Vital Status surveillance and mortality data race, 2013 for BMI, 122 for parity, and 2912 for tobacco use. After active follow-up of the cohort ended in 1972, Vital The chained equation for each missing covariate was fully spec- Status surveillance was conducted annually. Cohort members ified to capture nonlinearities and interactions in its associations were matched to the California Department of Motor Vehicles with other covariates. Age was modeled using a cubic spline. (DMV) files and California Vital Status records using name and There were no missing follow-up times for women who died, and birth date. The DMV files provided both residence and date at we did not attempt to impute 523 missing censoring times. Thus, last active contact to establish when a participant resided in a a total of 15,005 women were included in the final analyses. Five given surveillance area. The complete file was then matched to imputed data sets were created and then analyzed using standard the Vital Status records. Using all names that a participant reg- methods for multiply-imputed data, as implemented in the mim istered with the DMV to find matches within the Vital Status package in STATA. These procedures ensure that SEs, confidence records substantially reduces the likelihood that cases were intervals, and P values properly reflect the extra variability from missed due to incomplete identifier information. Surveillance the imputation of missing variables. efforts identified one or more members of greater than 80% of All analyses were conducted using STATA (version 10). CHDS families. If a participant did not match to either the DMV or Vital Status files, then the participant was defined as alive at the last active follow-up year. Results Primary cause of death was provided by the Vital Status files. Mortality was determined for overall
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