ORIGINAL ARTICLE
Epidemiology and Comorbidities of Polycystic Ovary Syndrome in an Indigent Population Susan M. Sirmans, PharmD, BCPS,* Roy C. Parish, PharmD,*Þ Sandra Blake, PhD,þ and Xiaojun Wang, BSþ
Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. The aims of this study were to provide an estimate of the prevalence of PCOS in clinical practice; compare the risk of established cardiovascular risk factors, cardiovascular disease, and other comorbid conditions in women with PCOS to that of age- and race-matched controls; and explore the total costs of care that can be attributed to PCOS. Methods: Louisiana Medicaid claims data were used to identify women with PCOS or its defining features and a control group in a ratio of 1:3. The prevalence of PCOS, cardiovascular risk factors (diabetes, dyslipidemia, dysmetabolic syndrome, glucose intolerance, hypertension, and obesity), key comorbidities (anxiety, bipolar disorders, depression, eating disorders, infertility, obstructive sleep apnea), and diagnosed cardiovascular disease were measured. Results: During 2010, the prevalence of PCOS was 0.88%. Women with PCOS were more likely to have a diagnosis of diabetes (odds ratio [OR], 4.35; 95% confidence interval [CI], 3.63Y5.21), dyslipidemia (OR, 3.56; 95% CI, 3.04Y4.19), dysmetabolic syndrome (OR, 23.46; 95% CI, 13.64Y40.36), glucose intolerance (OR, 5.46; 95% CI, 3.10Y9.60), hypertension (OR, 2.76; 95% CI, 2.41Y3.18), obesity (OR, 5.79; 95% CI, 5.07Y6.62), infertility (OR, 23.42; 95% CI, 10.63Y51.61), obstructive sleep apnea (OR, 6.47; 95% CI, 3.62Y11.55), anxiety (OR, 1.76; 95% CI, 1.53Y2.04), bipolar disorders (OR, 1.94; 95% CI, 1.55Y2.44), and depression (OR, 2.22; 95% CI, 1.94Y2.54) than did controls. Average total costs of care for the year was $5551 in the PCOS group and $3496 in the control group. After controlling for the effects of other variables, the average total cost of care for PCOS was $637 higher than that of the control group. Other variables that contributed significantly to the total costs of care included race, age, acute myocardial infarction, transient ischemic attack, peripheral artery disease, anxiety, depression, bipolar disorders, hypertension, diabetes, and dyslipidemia. Conclusions: Although the clinical burden of PCOS is high, it is diagnosed less frequently in clinical practice compared with systematic screening studies. This is concerning considering that PCOS is associated with cardiovascular risk factors and other comorbidities. Mean total costs of care for the PCOS group was higher than the mean total costs of
From the *School of Pharmacy, The University of Louisiana at Monroe, Baton Rouge; †Department of Internal Medicine, School of Medicine, Louisiana State University Health Sciences Center, Shreveport; and ‡Office of Outcomes Research, College of Pharmacy, The University of Louisiana at Monroe, Baton Rouge, LA. Received April 12, 2013, and in revised form February 25, 2014. Accepted for publication February 26, 2014. Reprints: Susan M. Sirmans, PharmD, BCPS, School of Pharmacy, The University of Louisiana at Monroe, 3849 N Blvd, Baton Rouge, LA 70806. E-mail: [email protected]. Supported by existing funds from the Tom and Mayme Scott Endowed Chair. Author disclosure statement: No competing financial interests exist. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.jinvestigativemed.com). Copyright * 2014 by The American Federation for Medical Research ISSN: 1081-5589 DOI: 10.1097/01.JIM.0000446834.90599.5d
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care for the control group. Polycystic ovary syndrome is independently associated with an increase in mean total costs of care. Key Words: polycystic ovary syndrome, cardiovascular risk factors, anxiety, bipolar disorders, depression, eating disorders, infertility, obstructive sleep apnea (J Investig Med 2014;62: 868Y874)
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olycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenism and oligo-ovulation or anovulation. Women typically present with complaints of irregular menstruation, hirsutism, and infertility. It is also associated with an increased risk for cardiovascular disease (CVD),1Y8 glucose intolerance, diabetes,9,10 and a clustering of cardiovascular risk factors.11 A number of other comorbidities have been identified in the literature, including depression,12 anxiety,13 bipolar disorder,14 eating disorders,15 and obstructive sleep apnea.16,17 Therefore, comprehensive management of women with PCOS focuses not only on the patient’s presenting concerns but also on the identification and treatment of CVD risk factors and other comorbidities. Polycystic ovary syndrome prevalence estimates from systematic screening of women in experimental protocols using the National Institutes of Health criteria indicate that PCOS is a common endocrinopathy affecting 4% to 10% of women of reproductive age.18,19 More recently, March et al.20 have provided prevalence estimates from a large birth cohort that vary depending on which of the 3 diagnostic criteria is used. Investigators traced women of approximately 30 years of age from a birth cohort of 2199 consecutive female babies born at the Queen Elizabeth Hospital in Adelaide, South Australia during January 1973 to December 1975. Structured interviews conducted by trained research nurses were completed in 728 participants who lived in the Adelaide area. Of these, 277 met the criteria for clinical examination. Using the National Institutes of Health criteria, PCOS prevalence was estimated to be 8.7%. The prevalence estimate using the criteria recommended by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) was reported to be 11.9%. Under the Androgen Excess Society recommendations, the prevalence was 10.2%. When the presence of polycystic ovaries for those who did not undergo ultrasound evaluation was imputed, these estimates rose to 17.8% for the ESHRE/ ASRM criteria and 12.0% for the Androgen Excess Society criteria. Other studies provide population-based estimates of PCOS using the ESHRE/ASRM criteria of 15% to 20%.21Y23 Overweight and obese women are particularly hard hit with prevalence estimates reaching 28.3%.24 The financial burden of PCOS is significant. In 2004, it was estimated that, in the United States, more than 4 million women were affected by PCOS, using a prevalence estimate of 6.6%. The estimated costs of screening for PCOS and treatment of menstrual dysfunction, infertility, type 2 diabetes, and
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hirsutism in women with PCOS during their reproductive years exceeded 4 billion dollars annually. These conservative estimates would be expected to be even greater when considering the costs of treatment of cardiovascular risk factors and comorbidities. Increasing the costs further would be those related to the management of diabetes and other cardiovascular risk factors in postmenopausal women with PCOS. Screening for PCOS was estimated to cost approximately $740 per woman with PCOS and accounted for only 2.3% of the overall economic burden.25 However, evidence suggests that, in contemporary clinical practice, PCOS is underrecognized. Review of records from a large managed care organization revealed a period prevalence of PCOS for women aged 20 to 39 years of 2.2%, much lower than that identified in systematic screenings.26 In addition, March et al.20 reported that 68% to 69% of women with PCOS did not have the diagnosis before their screening of the cohort. On the basis of these data, it seems that a substantial number of women with PCOS who are at increased risk for cardiovascular and other comorbidities are being overlooked. Our study provides an estimate of the rate at which indigent women receive a diagnosis of PCOS or its defining clinical features in routine clinical practice. We also examined the association of probable PCOS with established cardiovascular risk factors and reported comorbid conditions as compared with that of age- and race-matched controls. Finally, we explored the relationships between comorbidities and the annual total costs of care for PCOS.
METHODS Louisiana Medicaid provides reimbursement for the provision of health care to Louisiana’s low-income population. During the 2009Y2010 fiscal year, expenditures for medical claims and premium payments totaled 5.8 billion dollars for 1.3 million Louisianans, approximately 29% of the state population. To determine the point prevalence of PCOS, the Louisiana Medicaid claims that the database was queried to identify all women between the ages of 15 and 45 years who were Medicaid eligible on January 1, 2010. Women were excluded if there was evidence of adrenal cancer (International Classification of Diseases, Ninth Revision [ICD-9] codes 194.0, 198.7, 234.8), adrenal tumor (ICD-9 codes 227.0, 237.2, 239.7), adrenal hyperplasia (ICD-9 code 255.2), Cushing syndrome (ICD-9 code 255.0), hyperprolactinemia (ICD-9 code 253.1), ovarian tumor or cancer (ICD-9 codes 183.0, 198.6, 233.39, 220, 239.5, 236.2), pituitary tumor or cancer (ICD codes-9 codes 194.3, 198.89, 234.8, 227.3, 237.0, 239.7).26 Women were considered to have probable PCOS if they had at least 1 paid claim for a diagnosis of PCOS (ICD-9 code 256.4) on or before January 1, 2010. Women were also considered to have probable PCOS if they had at least 1 paid claim for oligomenorrhea (ICD-9 code 626.1) or amenorrhea (ICD-9 code 620.0) plus hyperandrogenism. Hyperandrogenism was defined by the diagnosis of hirsutism (ICD-9 code 704.1). To evaluate comorbidities and costs of care, the Louisiana Medicaid claims that the database was queried to identify continuously eligible women between the ages of 15 and 45 years with at least 1 paid claim for a diagnosis of PCOS (ICD-9 code 256.4) before or during the 2010 calendar year. Those younger than 15 years were excluded to avoid the potential overlap with other hyperandrogenic states such as congenital hyperandrogenemia; women older than 45 years were excluded to avoid overlap with the transition to menopause.26 Women who were pregnant during the 2010 calendar year and women receiving
PCOS Epidemiology and Comorbidities
care at a long-term care facility were excluded to avoid the potential for these situations to confound the evaluation of the costs of care for PCOS. Pregnancy was identified in women with ICD-9 codes 630Y679, V22, V23, V28 on medical claims or with a co-pay code on pharmacy claims data indicating that the recipient was eligible for a pregnancy co-pay exemption at the time of dispensing. Women were also excluded if there was evidence of adrenal cancer (ICD-9 codes 194.0, 198.7, 234.8), adrenal tumor (ICD-9 codes 227.0, 237.2, 239.7), adrenal hyperplasia (ICD-9 code 255.2), Cushing syndrome (ICD-9 code 255.0), hyperprolactinemia (ICD-9 code 253.1), ovarian tumor or cancer (ICD-9 codes 183.0, 198.6, 233.39, 220, 239.5, 236.2), pituitary tumor or cancer (ICD-9 codes 194.3, 198.89, 234.8, 227.3, 237.0, 239.7).26 Women were considered to have probable PCOS if they had at least 1 paid claim for a diagnosis of PCOS (ICD-9 code 256.4) on or before December 31, 2010. Women were also considered to have probable PCOS if they had at least 1 paid claim for oligomenorrhea (ICD-9 code 626.1) or amenorrhea (ICD-9 code 620.0) plus hyperandrogenism on or before December 31, 2010. Hyperandrogenism was defined by the diagnosis of hirsutism (ICD-9 code 704.1). A control group of women without PCOS between the ages of 15 and 45 years was identified from the Louisiana Medicaid claims database. For comparison of the prevalence of cardiovascular risk factors and other comorbidities, a case-control ratio of 1:3 was used. The control group was matched on race and age. Control subjects were excluded using the same exclusion criteria as those used for the probable PCOS group. Patient race/ethnicity was obtained from the eligibility data. The age was calculated as the age at the beginning of the study period. The presence of cardiovascular risk factors and comorbidities was identified in the control and PCOS subjects using the criteria defined in Supplemental Table 1 (Supplemental Digital Content 1, http://links.lww.com/JIM/A22). Odds ratios (ORs) for cardiovascular risk factors and comorbidities were also evaluated separately in the 2 groups with probable PCOS: the group with a PCOS diagnosis and the group with clinical features of PCOS but no diagnosis of PCOS. Differences in cardiovascular risk factors and comorbidities between the patients with a claim for PCOS and those patients with claims for the clinical features of PCOS but no diagnosis of PCOS were explored. The influence of age, race, comorbidities, and PCOS status on total costs of care was examined. This study received approval from the University of Louisiana at Monroe’s institutional review board.
Statistical Analysis Overall point prevalence and point prevalence, stratified by 5-year age categories on January 1, 2010, were determined using identified PCOS cases and age-eligible female membership of the Medicaid plan. The comorbidities of women with probable PCOS versus those of the control group were compared using categorical statistical analysis. The Breslow-Day test was used to determine whether the conditional ORs for the diagnosed PCOS group and the group with clinical features of PCOS were equal. The Breslow-Day test was also used to test the null hypothesis: the relationship between PCOS and comorbidities is the same for each value of racial/ethnic groups. Total costs of care were evaluated using stepwise multiple linear regression, with total costs as the dependent variable and CVD and comorbidities as the independent variables. Collinearity was evaluated to assess the suitability of the data for a linear regression model.
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FIGURE 1. Data extraction flow chart.
Analyses were conducted using Statistical Analysis System software version 9 (SAS Institute, Cary, NC). A 2-sided P value less than 0.05 was considered statistically significant.
RESULTS A total of 262,862 women who were Medicaid eligible and aged 15 to 45 years on January 1, 2010 were identified. Women meeting the exclusion criteria numbered 2958, bringing the total
870
to 259,904. Of these women, 2284 had a diagnosis of PCOS or oligomenorrhea/amenorrhea plus hirsutism on or before January 1, 2010. An outpatient claim for PCOS was identified for 1942 women. The other 342 women in the PCOS cohort were those women with claims for defining clinical characteristics of PCOS (oligomenorrhea/amenorrhea plus hirsutism) but did not have a PCOS claim. The point prevalence of probable PCOS in this population was 0.88%. Point prevalences for each of the predefined * 2014 The American Federation for Medical Research
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age groups are as follows: age of 15 to 19 years, 0.73%; age of 20 to 24 years, 0.86%; age of 25 to 29 years, 0.86%; age of 30 to 34 years, 1.21%; age of 35 to 39 years, 1.07%; and age of 40 to 45 years, 0.85%. Figure 1 is a flow chart for data extraction for the determination of comorbidites and total costs of care. The total number of women who were continuously eligible for Medicaid in 2010, eligible only for Medicaid, not in a long-term care facility in 2010, and aged 15 to 45 years old was 160,021. After excluding 23,720 women for pregnancy and another 1888 for adrenal tumor or cancer, adrenal hyperplasia, Cushing syndrome, ovarian tumor or cancer, pituitary tumor or cancer, and prolactinoma, the number eligible totaled 143,413. The total number of women with a diagnosis of PCOS or its defining characteristics was 1689: 1454 had a diagnosis of PCOS and 235 had the diagnoses of oligomenorrhea or amenorrhea plus hirsutism. The clinical characteristics of age- and race-matched women in the probable PCOS group and the control group are listed in Table 1. Comparison of the 2 groups shows that they were carefully matched for age and race. Women with a diagnosis of PCOS or its defining features were more likely than controls to have a diagnosis of cardiovascular risk factors, including diabetes (OR, 4.35; 95% confidence interval [CI], 3.63Y5.21), dyslipidemia (OR, 3.56; 95% CI, 3.04Y4.19), dysmetabolic syndrome (OR, 23.46; 95% CI, 13.64Y40.36), glucose intolerance (OR, 5.46; 95% CI, 3.10-9.60), hypertension (OR, 2.76; 95% CI, 2.41Y3.18), and obesity (OR, 5.79; 95% CI, 5.07Y6.62). Cardiovascular disease was diagnosed infrequently and did not differ between the 2 groups. Women with claims for PCOS or its defining features had greater odds of being infertile (OR, 23.42; 95% CI, 10.63Y51.61) or having obstructive sleep apnea (OR, 6.47; 95% CI, 3.62Y11.55) than did the controls. Psychiatric disorders also occurred more frequently in the probable PCOS group. The probable PCOS group had greater odds of having diagnosed anxiety (OR, 1.76; 95% CI, 1.53Y2.04), bipolar disorders (OR, 1.94; 95% CI, 1.55Y2.44), and depression (OR, 2.22; 95% CI, 1.94Y2.54). There was no difference in eating disorders between the probable PCOS group and the control group (OR, 1.31; 95% CI, 0.54Y3.20). White women with probable PCOS were less likely to have a diagnosis of infertility (OR, 7.65; 95% CI, 2.96Y19.80) compared with their black counterparts (OR, 113.00; 95% CI, 15.48Y825.56; P = 0.01). Black women with probable PCOS had greater odds of having a diagnosis of bipolar disorder (OR, 3.27; 95% CI, 2.11Y5.05) than did white women (OR, 1.64; 95% CI, 1.25Y2.17). Breslow-Day tests for homogeneity of the ORs by race revealed no significant difference in the other cardiovascular risk factors or comorbidities. Differences in comorbidities between the patients receiving a diagnosis of PCOS and those patients with clinical features of PCOS but no diagnosis were evaluated (Table 2). Women who received a diagnosis of PCOS were significantly more likely to have diagnoses of diabetes, dyslipidemia, dysmetabolic syndrome, glucose intolerance, hypertension, obesity, anxiety, bipolar disorder, depression, infertility, and obstructive sleep apnea but not eating disorders when compared with their corresponding ageand race-matched control group. Women with oligomenorrhea or amenorrhea plus hirsutism were significantly more likely to have diagnoses of diabetes, dyslipidemia, dysmetabolic syndrome, hypertension, obesity, anxiety, bipolar disorder, depression, and obstructive sleep apnea but not glucose intolerance or eating disorders when compared with their corresponding ageand race-matched control group. Women with diagnosed PCOS were significantly more likely to have a diabetes diagnosis than did those women with the defining clinical features of PCOS
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TABLE 1. Clinical Characteristics of Women With PCOS and Matched (Age and Race) Controls
Characteristic Mean age in 2010 Age group in 2010 15Y19 y 20Y24 y 25Y29 y 30Y34 y 35Y39 y 40Y45 y Race/ethnicity White Black Hispanic Other Cardiovascular risk factors Diabetes Dyslipidemia Dysmetabolic syndrome Glucose intolerance Hypertension Obesity Comorbidities Anxiety Bipolar disorders Depression Eating disorders Infertility Obstructive sleep apnea Diagnosed cardiovascular disease Acute myocardial infarction Chronic heart failure Coronary artery bypass surgery Coronary heart disease Ischemic stroke Percutaneous coronary intervention Peripheral artery disease Transient ischemic attack Unstable and stable angina
PCOS No PCOS Number (%) Number (%) (n = 1689) (n = 5067) 25.24 y
25.23 y
P 0.95
544 (32.2) 317 (18.8) 323 (19.1) 261 (15.4) 146 (8.6) 98 (5.8)
1,633 954 969 783 434 294
(32.2) (18.8) (19.1) (15.4) (8.6) (5.8)
0.99 0.96 1.00 1.00 0.92 1.00
790 (46.8) 806 (47.7) 31 (1.8) 62 (3.7)
2,379 2,418 94 176
(47.0) (47.7) (1.9) (3.5)
0.90 1.00 0.96 0.70 G0.0001 G0.0001 G0.0001
297 (17.6) 349 (20.7) 110 (6.5)
237 (4.7) 345 (6.8) 15 (0.3)
34 (2.0) 442 (26.2) 667 (39.5)
19 (0.4) G0.0001 576 (11.4) G0.0001 513 (10.1) G0.0001
347 (22.1) 131 (7.8) 438 (25.9) 7 (0.4) 53 (3.1) 36 (2.1)
648 210 690 15 7 17
(12.8) (4.1) (13.6) (0.3) (0.1) (0.3)
G0.0001 G0.0001 G0.0001 0.46 G0.0001 G0.0001
1 (0.06)
4 (0.08)
1.00
5 (0.3) 0 (0)
9 (0.17) 1 (0.02)
0.36 1.00
21 (1.2) 8 (0.5) 1 (0.06)
45 (0.89) 14 (0.3) 3 (0.06)
0.20 0.22 1.00
4 (0.2)
13 (0.3)
0.92
4 (0.2)
9 (0.2)
0.75
14 (0.8)
36 (0.7)
0.56
and no diagnosis of PCOS. Odds ratios for other comorbidities were not significantly different between the group with diagnosed PCOS and the group with diagnoses for the features of PCOS but no PCOS diagnosis. The mean total cost of care for the patients with probable PCOS was $5551 compared with $3496 for the control group.
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TABLE 2. Comparison of ORs for Comorbid Conditions in Women With Diagnosed PCOS and Those With Defining Features of PCOS Including Irregular Menses and Clinical Hyperandrogenism Compared With Their Respective Control Groups Oligomenorrhea/Amenorrhea + Hyperandrogenism Compared With Control
PCOS Compared With Control Cardiovascular Risk Factors Diabetes Dyslipidemia Dysmetabolic syndrome Glucose intolerance Hypertension Obesity Comorbidities Anxiety Bipolar disorders Depression Eating disorders Infertility Obstructive sleep apnea
P
OR (95% CI)
PCOS Compared With Oligomenorrhea /Amenorrhea + Hyperandrogenism
P
OR (95% CI)
P
4.87 (4.00Y5.93) 3.80 (3.18Y4.53) 26.49 (14.50Y48.37) 6.81 (3.53Y13.13) 2.85 (2.45Y3.32) 5.93 (5.13Y6.85)
PG PG PG PG PG PG
0.0001 0.0001 0.0001 0.0001 0.0001 0.0001
2.26 (1.40Y3.64) 2.64 (1.78Y3.91) 11.49 (3.18Y41.55) 2.53 (0.77Y8.38) 2.39 (1.69Y3.37) 5.01 (3.50Y7.17)
PG PG PG P= PG PG
0.0006 0.0001 0.0001 0.1547 0.0001 0.0001
0.0032 0.0979 0.2385 0.1477 0.3545 0.3929
1.76 (1.51Y2.05) 1.83 (1.43Y2.34) 2.18 (1.88Y2.52) 1.39 (0.53Y3.65) 21.7 (9.81Y48.0) 5.90 (3.15Y11.03)
PG PG PG P= PG PG
0.0001 0.0001 0.0001 0.59 0.0001 0.0001
1.80 (1.20Y2.70) 2.72 (1.53Y4.85) 2.55 (1.75Y3.70) 1 (0.10Y9.66) 27.4 (1.47Y511.4) 10.79 (2.23Y52.32)
P= PG PG P= P= PG
0.0041 0.0004 0.0001 0.1 0.0038 0.0013
0.9158 0.2137 0.4429 0.7946 0.4552 0.4812
The mean total costs of care for those women who received a diagnosis of PCOS was $5152, which was significantly less than the $8020 mean total cost of care for those women who had claims for the defining features of PCOS but no PCOS claims. Multiple linear regression analysis showed that race (others and not black, white, or Hispanic), age, PCOS, acute myocardial infarction, transient ischemic attack, peripheral artery disease, anxiety, depression, bipolar disorders, hypertension, diabetes, and dyslipidemia are linearly related to total costs of care in PCOS (Table 3). The mean total costs of care for the probable PCOS group was $637 higher than those of the control group after controlling the effects of other variables. Variables removed from the model due to lack of statistical significance included coronary artery disease, impaired glucose tolerance, unstable angina, obesity, chronic heart failure, infertility, eating disorder, ischemic stroke, black race, Hispanic race, and obstructive sleep apnea. Percutaneous coronary intervention and coronary bypass graft surgery were removed from the model because they were highly correlated with acute myocardial infarction.
Likewise, dysmetabolic syndrome was removed from the model because it was highly correlated with diabetes and hypertension.
DISCUSSION Evaluation of claims data for indigent women receiving health care indicates that the prevalence of diagnosed PCOS and clinically evident PCOS is much lower than that reported in screening studies. This is consistent with the data of Lo et al.,26 who reported a prevalence of 2.2% in primarily middle-income women aged to 20 to 39 years. We included in our PCOS cohort women with claims for oligomenorrhea or amenorrhea plus clinical signs of hyperandrogenism. Despite including women with clinical signs of PCOS but no diagnosis in the PCOS group, our reported prevalence of 0.88% is much lower than the 4% to 10% prevalence from screening studies commonly reported in the literature. Taken together, these data suggest that PCOS is underrecognized and underreported in the clinical setting.
TABLE 3. Multiple Linear Regression Analysis Showing Predictors of Total Costs of Care in Women With PCOS Variable Intercept Race-other (not black, white, or Hispanic) Age PCOS Acute myocardial infarction Transient attack Peripheral artery disease Anxiety Depression Bipolar disorders Hypertension Diabetes Dyslipidemia
872
Coefficient Estimate
Standard Error
P
1652.16 2145.53 36.02 636.65 16,710.00 24,866.00 8567.94 1030.98 1740.74 3729.01 2146.05 3023.66 1917.17
442.28 657.40 16.45 286.61 4423.87 2743.38 2392.71 379.82 363.72 567.97 382.41 487.32 445.87
0.0002 0.0011 0.0285 0.0264 0.0002 G0.0001 0.0003 0.0067 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001
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We also report that diagnosed PCOS and its defining characteristics are associated with an increased risk for cardiovascular risk factors independent of age and race. However, PCOS was not associated with an increase of cardiovascular events in this relatively young population of women. Other reports have also failed to establish a link between PCOS and CVD in premenopausal women.27 However, recent studies report that PCOS is associated with premature subclinical CVD including coronary artery calcification,2,3 aortic calcification,2 and increased carotid intima-media wall thickness.28 In addition, the evaluation of postmenopausal women from the Women’s Ischemic Syndrome Evaluation study indicated that women with the clinical characteristics of PCOS, including a history of irregular menstruation and elevated serum androgen concentrations, had more frequent angiographic CAD and lower cardiovascular event-free survival. Lower event-free survival remained significant after controlling for diabetes, waist circumference, hypertension, and angiographic CAD.29 Our results confirm reports that women with PCOS are at greater risk for mental health disorders including depression, anxiety, and bipolar disease. During systematic screening for depression using Beck Depression Inventory and Primary Care Evaluation of Mental Disorders Patient Health Questionnaire, Hollinrake et al.30 determined that 35% of women with PCOS had depression compared with 10.7% in the control group. The OR for depressive disorders after controlling for body mass index (BMI), family history of depression, and history of infertility was 4.23 (95% CI, 2.96Y5.5).30 A recent meta-analysis reported an increased risk for elevated depression scores in PCOS with an OR of 4.03 (95% CI, 2.96Y6.41).31 Results from systematic screening for anxiety disorders have also been reported. The prevalence of anxiety disorders was reported by Hollinrake et al.30 and Jedel et al.32 as 14.5% in women with PCOS compared with 0.9% in controls. Prevalence estimates of anxiety in PCOS vary widely, ranging from 14.5% to 61%. In addition, a meta-analysis indicates that PCOS is associated with an increased prevalence of anxiety symptoms (OR, 6.88; 95% CI, 2.5Y18.9).13 Bipolar disorder, identified in the Mini International Neuropsychiatric Interview, has been reported in 11.1% of women with PCOS receiving care in an outpatient endocrine clinic.33 Using the Mood Disorders Questionnaire, others report that 26.9 % of premenopausal women with PCOS meet the criteria for bipolar disorder.14 This compares with the prevalence estimates of bipolar disorder in the general population of 0.5 to 2%.34 Our data indicate that women with oligomenorrhea or amenorrhea plus hirsutism but with no diagnosis of PCOS had a higher prevalence of bipolar disorder. It is possible that some of these women developed the clinical features of PCOS secondary to medications used in the treatment of bipolar disorder and, therefore, were not diagnosed with PCOS. Binge eating disorder (BED) has also been evaluated in women with PCOS. Kerchner et al.35 reported that 23.3% of women with PCOS have BED. Screening of women with PCOS and controls revealed that BED was present in 12.6% of women with PCOS compared with 1.9% in controls.30 When comparing comorbidities between the women with diagnosed PCOS and those with defining clinical features of PCOS but no PCOS diagnosis, women with diagnosed PCOS had a greater likelihood of diabetes. Whether this represents a true difference between the groups or whether the group with diagnosed PCOS was more likely to be screened for diabetes is not clear. However, it is important to point out that the American Diabetes Association considers women with PCOS to be a highrisk group and recommends that all overweight and obese women with PCOS be screened for diabetes.36 Therefore, it
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is not possible to rule out the possibility that the difference observed in the OR reflects a screening bias. The use of administrative databases, that is, claims data, for health services research has grown significantly in the last 15 to 20 years. There are acknowledged limitations in their use such as the following: (1) a limited amount of clinical information, (2) undercoding due to the limited number of diagnoses on a claim, and (3) data may be incomplete when a claim is not needed for payment, such as in prepaid plans (which is not the case with Louisiana Medicaid). Our study had limitations consistent with those outlined previously. We relied on the clinician to provide accurate and complete coding for each visit. The study design did not involve extrapolation of diagnosis codes from the patients’ medical records. Evidence of the diagnosis of PCOS came strictly from the Medicaid claims database. Likewise, we used claims data to identify subjects who had clinical features of PCOS but did not have a claim for PCOS in the defined period. Without access to patient medical records, we were not able to verify the accuracy of the diagnosis nor were we able to ensure that a diagnosis had not been missed. Without access to patients’ BMI, we were not able to match the probable PCOS and control groups on BMI. In addition, we were unable to determine which, if any, women developed PCOS or its defining clinical features secondary to concomitant drug therapy used in the treatment of bipolar disorder. Our study design does not allow us to determine the reasons why PCOS is underdiagnosed. Certainly, the limited number of diagnoses included on the medical claim forms may play a role. Another potential reason may be that providers consider making the diagnosis of PCOS as a low priority considering other presenting problems. It is possible that some providers do not recognize the presenting symptoms as PCOS or do not have the resources necessary to make the diagnosis. However, for this study, claims data offer many advantages. First, the data source contains records for a large population. Therefore, adequate numbers of patients can be found even when studying a less common diagnosis such as PCOS. Also, the data were existing and housed in a data warehouse so that the costs associated with accessing large amounts of patient data are minimized. Another advantage was the study was unobtrusive to the patient.
CONCLUSIONS In conclusion, we found that the identification of PCOS in standard clinical practice was made with less frequency than that observed in systematic screenings using standardized diagnostic criteria. Although the population evaluated was of low socioeconomic status, similar results have been reported in a racially/ ethnically diverse and more affluent population.26 Furthermore, PCOS was associated with increased odds of cardiovascular risk factors in primarily young women. However, clinically apparent CVD was uncommon and similar between the 2 groups. Largescale longitudinal studies are needed to evaluate whether the observed extended risk profile results in a significant increase in CVD as the population ages. Polycystic ovary syndrome is also associated with higher odds of mental health disorders. Early diagnosis of PCOS is important because it identifies women at increased risk for symptomatic and asymptomatic disorders amenable to pharmacologic and nonYpharmacologic therapies. Polycystic ovary syndrome and certain comorbidities such as race, age, acute myocardial infarction, transient ischemic attack, peripheral artery disease, anxiety, depression, bipolar disorders, hypertension, diabetes, and dyslipidemia are independently associated with increased total costs of care.
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REFERENCES 1. Christian RC, Dumesic DA, Behrenbeck T, et al. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:2562Y2568. 2. Talbott EO, Zborowski JV, Rager JR, et al. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89:5454Y5461. 3. Shroff R, Kerchner A, Maifeld M, et al. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab. 2007;92:4609Y4614. 4. Talbott EO, Zborowski JV, Rager J, et al. Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Vasc Health Risk Manag. 2008;4:453Y462.
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19. Azziz R, Woods KS, Reyna R, et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89:2745Y2749. 20. March WA, Moore VM, Willson KJ, et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544Y551. 21. Mehrabian F, Khani B, Kelishadi R, et al. The prevalence of polycystic ovary syndrome in Iranian women based on different diagnostic criteria. Endokrynol Pol. 2011;62(3):238Y242. 22. Tehrani FR, Simbar M, Tohidi M, et al. The prevalence of polycystic ovary syndrome in a community sample of Iranian population: Iranian PCOS prevalence study. Reprod Biol Endocrinol. 2011;9:39. 23. Yildiz BO, Bozdag G, Yapici Z, et al. Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum Reprod. 2012;27(10):3067Y3073.
5. Guzick DS, Talbot EO, Sutton-Tyrrell K. Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am J Obstet Gynecol. 1996;174:1224Y1232.
24. Alvarez-Blasco F, Botella-Carretero JI, San Millan JL, et al. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med. 2006;166:2081Y2086.
6. Carmina E, Orio F, Palomba S, et al. Endothelial dysfunction in PCOS: role of obesity and adipose hormones. Am J Med. 2006;119:356.
25. Azziz R, Marin C, Hoq L, et al. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J Clin Endocrinol Metab. 2005;90:4650Y4658.
7. Vryonidou A, Papatheodorou A, Tavridou A, et al. Association of hyperandrogenemic and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:2740Y2746. 8. Orio Jr F, Palomba S, Cascella T, et al. Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004; 89(9):4588Y4593. 9. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141Y146. 10. Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165Y169. 11. Sirmans SM, Weidman-Evans E, Everton V, et al. Polycystic ovary syndrome and chronic inflammation: pharmacotherapeutic implications. Ann Pharmacother. 2012;46:403Y418. 12. Dokras A. Mood and anxiety disorders in women with PCOS. Steroids. 2012;77:338Y341. 13. Dokras A, Clifton S, Futterweit W, et al. Increased prevalence of anxiety symptoms in women with polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril. 2012;97(1):225Y230. 14. Klipstein KG, Goldberg JF. Screening for bipolar disorder in women with polycystic ovary syndrome: a pilot study. J Affect Disord. 2006;91(2, 3):205Y209. 15. McCluskey S, Evans C, Lacey JH, et al. Polycystic ovary syndrome and bulimia. Fertil Steril. 1991;55(2):287Y291. 16. Fogel RB, Malhotra A, Pillar G, et al. Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86:1175Y1180. 17. Vgontzas AN, Legre RS, Bixler EO, et al. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance. J Clin Endocrinol Metab. 2001;86:517Y520. 18. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83:3078Y3082.
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26. Lo JC, Feigenbaum SL, Yand J, et al. Epidemiology and adverse cardiovascular risk profile of diagnosed polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:1357Y1363. 27. Pierpoint T, McKeigue PM, Isaacs AJ, et al. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol. 1998;51:581Y586. 28. Talbott EO, Zborowski JV, Boudreaux MY, et al. The relationship between C-reactive protein and carotid intima-media wall thickness in middle-aged women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89(12):6061Y6067. 29. Shaw LJ, Bairey Merz CN, Azziz R, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health-National Heart, Lung, and Blood Institute Sponsored Women’s Ischemia Syndrome Evaluation. J Clin Endocrinol Metab. 2008;93:1276Y1284. 30. Hollinrake E, Abreu A, Maifeld M, et al. Increased risk of depressive disorders in women with polycystic ovary syndrome. Fertil Steril. 2007;87:1369Y1376. 31. Dokras A, Clifton S, Futterweit W, et al. Increased risk for abnormal depression scores in women with polycystic ovary syndrome: a systematic review and meta-analysis. Obstet Gynecol. 2011;117(1):145Y152. 32. Jedel E, Gustafson D, Waern M, et al. Sex steroids, insulin sensitivity and sympathetic nerve activity in relation to affective symptoms in women with polycystic ovary syndrome. Psychoneuroendocrinology. 2011;36:1470Y1479. 33. Rassi A, Veras AB, dos Reis M, et al. Prevalence of psychiatric disorders in patients with polycystic ovary syndrome. Compr Psychiatry. 2010;51:599Y602. 34. Merikangas KR, Spence A, Kupfer DJ. Linkage studies of bipolar disorder: methodologic and analytic issues. Arch Gen Psychiatry. 1989;46:1137Y1141. 35. Kerchner A, Lester W, Stuart SP, et al. Risk of depression and other mental health disorders in women with polycystic ovary syndrome: a longitudinal study. Fertil Steril. 2009;91:207Y212. 36. American Diabetes Association. Standards of medical care in diabetesV2013. Diabetes Care. 2013;36(suppl 1):S11YS66.
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Epidemiology and Comorbidities of Polycystic Ovary Syndrome in an Indigent Population Susan M. Sirmans, PharmD, BCPS,* Roy C. Parish, PharmD,*Þ Sandra Blake, PhD,þ and Xiaojun Wang, BSþ
Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. The aims of this study were to provide an estimate of the prevalence of PCOS in clinical practice; compare the risk of established cardiovascular risk factors, cardiovascular disease, and other comorbid conditions in women with PCOS to that of age- and race-matched controls; and explore the total costs of care that can be attributed to PCOS. Methods: Louisiana Medicaid claims data were used to identify women with PCOS or its defining features and a control group in a ratio of 1:3. The prevalence of PCOS, cardiovascular risk factors (diabetes, dyslipidemia, dysmetabolic syndrome, glucose intolerance, hypertension, and obesity), key comorbidities (anxiety, bipolar disorders, depression, eating disorders, infertility, obstructive sleep apnea), and diagnosed cardiovascular disease were measured. Results: During 2010, the prevalence of PCOS was 0.88%. Women with PCOS were more likely to have a diagnosis of diabetes (odds ratio [OR], 4.35; 95% confidence interval [CI], 3.63Y5.21), dyslipidemia (OR, 3.56; 95% CI, 3.04Y4.19), dysmetabolic syndrome (OR, 23.46; 95% CI, 13.64Y40.36), glucose intolerance (OR, 5.46; 95% CI, 3.10Y9.60), hypertension (OR, 2.76; 95% CI, 2.41Y3.18), obesity (OR, 5.79; 95% CI, 5.07Y6.62), infertility (OR, 23.42; 95% CI, 10.63Y51.61), obstructive sleep apnea (OR, 6.47; 95% CI, 3.62Y11.55), anxiety (OR, 1.76; 95% CI, 1.53Y2.04), bipolar disorders (OR, 1.94; 95% CI, 1.55Y2.44), and depression (OR, 2.22; 95% CI, 1.94Y2.54) than did controls. Average total costs of care for the year was $5551 in the PCOS group and $3496 in the control group. After controlling for the effects of other variables, the average total cost of care for PCOS was $637 higher than that of the control group. Other variables that contributed significantly to the total costs of care included race, age, acute myocardial infarction, transient ischemic attack, peripheral artery disease, anxiety, depression, bipolar disorders, hypertension, diabetes, and dyslipidemia. Conclusions: Although the clinical burden of PCOS is high, it is diagnosed less frequently in clinical practice compared with systematic screening studies. This is concerning considering that PCOS is associated with cardiovascular risk factors and other comorbidities. Mean total costs of care for the PCOS group was higher than the mean total costs of
From the *School of Pharmacy, The University of Louisiana at Monroe, Baton Rouge; †Department of Internal Medicine, School of Medicine, Louisiana State University Health Sciences Center, Shreveport; and ‡Office of Outcomes Research, College of Pharmacy, The University of Louisiana at Monroe, Baton Rouge, LA. Received April 12, 2013, and in revised form February 25, 2014. Accepted for publication February 26, 2014. Reprints: Susan M. Sirmans, PharmD, BCPS, School of Pharmacy, The University of Louisiana at Monroe, 3849 N Blvd, Baton Rouge, LA 70806. E-mail: [email protected]. Supported by existing funds from the Tom and Mayme Scott Endowed Chair. Author disclosure statement: No competing financial interests exist. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.jinvestigativemed.com). Copyright * 2014 by The American Federation for Medical Research ISSN: 1081-5589 DOI: 10.1097/01.JIM.0000446834.90599.5d
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care for the control group. Polycystic ovary syndrome is independently associated with an increase in mean total costs of care. Key Words: polycystic ovary syndrome, cardiovascular risk factors, anxiety, bipolar disorders, depression, eating disorders, infertility, obstructive sleep apnea (J Investig Med 2014;62: 868Y874)
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olycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenism and oligo-ovulation or anovulation. Women typically present with complaints of irregular menstruation, hirsutism, and infertility. It is also associated with an increased risk for cardiovascular disease (CVD),1Y8 glucose intolerance, diabetes,9,10 and a clustering of cardiovascular risk factors.11 A number of other comorbidities have been identified in the literature, including depression,12 anxiety,13 bipolar disorder,14 eating disorders,15 and obstructive sleep apnea.16,17 Therefore, comprehensive management of women with PCOS focuses not only on the patient’s presenting concerns but also on the identification and treatment of CVD risk factors and other comorbidities. Polycystic ovary syndrome prevalence estimates from systematic screening of women in experimental protocols using the National Institutes of Health criteria indicate that PCOS is a common endocrinopathy affecting 4% to 10% of women of reproductive age.18,19 More recently, March et al.20 have provided prevalence estimates from a large birth cohort that vary depending on which of the 3 diagnostic criteria is used. Investigators traced women of approximately 30 years of age from a birth cohort of 2199 consecutive female babies born at the Queen Elizabeth Hospital in Adelaide, South Australia during January 1973 to December 1975. Structured interviews conducted by trained research nurses were completed in 728 participants who lived in the Adelaide area. Of these, 277 met the criteria for clinical examination. Using the National Institutes of Health criteria, PCOS prevalence was estimated to be 8.7%. The prevalence estimate using the criteria recommended by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) was reported to be 11.9%. Under the Androgen Excess Society recommendations, the prevalence was 10.2%. When the presence of polycystic ovaries for those who did not undergo ultrasound evaluation was imputed, these estimates rose to 17.8% for the ESHRE/ ASRM criteria and 12.0% for the Androgen Excess Society criteria. Other studies provide population-based estimates of PCOS using the ESHRE/ASRM criteria of 15% to 20%.21Y23 Overweight and obese women are particularly hard hit with prevalence estimates reaching 28.3%.24 The financial burden of PCOS is significant. In 2004, it was estimated that, in the United States, more than 4 million women were affected by PCOS, using a prevalence estimate of 6.6%. The estimated costs of screening for PCOS and treatment of menstrual dysfunction, infertility, type 2 diabetes, and
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hirsutism in women with PCOS during their reproductive years exceeded 4 billion dollars annually. These conservative estimates would be expected to be even greater when considering the costs of treatment of cardiovascular risk factors and comorbidities. Increasing the costs further would be those related to the management of diabetes and other cardiovascular risk factors in postmenopausal women with PCOS. Screening for PCOS was estimated to cost approximately $740 per woman with PCOS and accounted for only 2.3% of the overall economic burden.25 However, evidence suggests that, in contemporary clinical practice, PCOS is underrecognized. Review of records from a large managed care organization revealed a period prevalence of PCOS for women aged 20 to 39 years of 2.2%, much lower than that identified in systematic screenings.26 In addition, March et al.20 reported that 68% to 69% of women with PCOS did not have the diagnosis before their screening of the cohort. On the basis of these data, it seems that a substantial number of women with PCOS who are at increased risk for cardiovascular and other comorbidities are being overlooked. Our study provides an estimate of the rate at which indigent women receive a diagnosis of PCOS or its defining clinical features in routine clinical practice. We also examined the association of probable PCOS with established cardiovascular risk factors and reported comorbid conditions as compared with that of age- and race-matched controls. Finally, we explored the relationships between comorbidities and the annual total costs of care for PCOS.
METHODS Louisiana Medicaid provides reimbursement for the provision of health care to Louisiana’s low-income population. During the 2009Y2010 fiscal year, expenditures for medical claims and premium payments totaled 5.8 billion dollars for 1.3 million Louisianans, approximately 29% of the state population. To determine the point prevalence of PCOS, the Louisiana Medicaid claims that the database was queried to identify all women between the ages of 15 and 45 years who were Medicaid eligible on January 1, 2010. Women were excluded if there was evidence of adrenal cancer (International Classification of Diseases, Ninth Revision [ICD-9] codes 194.0, 198.7, 234.8), adrenal tumor (ICD-9 codes 227.0, 237.2, 239.7), adrenal hyperplasia (ICD-9 code 255.2), Cushing syndrome (ICD-9 code 255.0), hyperprolactinemia (ICD-9 code 253.1), ovarian tumor or cancer (ICD-9 codes 183.0, 198.6, 233.39, 220, 239.5, 236.2), pituitary tumor or cancer (ICD codes-9 codes 194.3, 198.89, 234.8, 227.3, 237.0, 239.7).26 Women were considered to have probable PCOS if they had at least 1 paid claim for a diagnosis of PCOS (ICD-9 code 256.4) on or before January 1, 2010. Women were also considered to have probable PCOS if they had at least 1 paid claim for oligomenorrhea (ICD-9 code 626.1) or amenorrhea (ICD-9 code 620.0) plus hyperandrogenism. Hyperandrogenism was defined by the diagnosis of hirsutism (ICD-9 code 704.1). To evaluate comorbidities and costs of care, the Louisiana Medicaid claims that the database was queried to identify continuously eligible women between the ages of 15 and 45 years with at least 1 paid claim for a diagnosis of PCOS (ICD-9 code 256.4) before or during the 2010 calendar year. Those younger than 15 years were excluded to avoid the potential overlap with other hyperandrogenic states such as congenital hyperandrogenemia; women older than 45 years were excluded to avoid overlap with the transition to menopause.26 Women who were pregnant during the 2010 calendar year and women receiving
PCOS Epidemiology and Comorbidities
care at a long-term care facility were excluded to avoid the potential for these situations to confound the evaluation of the costs of care for PCOS. Pregnancy was identified in women with ICD-9 codes 630Y679, V22, V23, V28 on medical claims or with a co-pay code on pharmacy claims data indicating that the recipient was eligible for a pregnancy co-pay exemption at the time of dispensing. Women were also excluded if there was evidence of adrenal cancer (ICD-9 codes 194.0, 198.7, 234.8), adrenal tumor (ICD-9 codes 227.0, 237.2, 239.7), adrenal hyperplasia (ICD-9 code 255.2), Cushing syndrome (ICD-9 code 255.0), hyperprolactinemia (ICD-9 code 253.1), ovarian tumor or cancer (ICD-9 codes 183.0, 198.6, 233.39, 220, 239.5, 236.2), pituitary tumor or cancer (ICD-9 codes 194.3, 198.89, 234.8, 227.3, 237.0, 239.7).26 Women were considered to have probable PCOS if they had at least 1 paid claim for a diagnosis of PCOS (ICD-9 code 256.4) on or before December 31, 2010. Women were also considered to have probable PCOS if they had at least 1 paid claim for oligomenorrhea (ICD-9 code 626.1) or amenorrhea (ICD-9 code 620.0) plus hyperandrogenism on or before December 31, 2010. Hyperandrogenism was defined by the diagnosis of hirsutism (ICD-9 code 704.1). A control group of women without PCOS between the ages of 15 and 45 years was identified from the Louisiana Medicaid claims database. For comparison of the prevalence of cardiovascular risk factors and other comorbidities, a case-control ratio of 1:3 was used. The control group was matched on race and age. Control subjects were excluded using the same exclusion criteria as those used for the probable PCOS group. Patient race/ethnicity was obtained from the eligibility data. The age was calculated as the age at the beginning of the study period. The presence of cardiovascular risk factors and comorbidities was identified in the control and PCOS subjects using the criteria defined in Supplemental Table 1 (Supplemental Digital Content 1, http://links.lww.com/JIM/A22). Odds ratios (ORs) for cardiovascular risk factors and comorbidities were also evaluated separately in the 2 groups with probable PCOS: the group with a PCOS diagnosis and the group with clinical features of PCOS but no diagnosis of PCOS. Differences in cardiovascular risk factors and comorbidities between the patients with a claim for PCOS and those patients with claims for the clinical features of PCOS but no diagnosis of PCOS were explored. The influence of age, race, comorbidities, and PCOS status on total costs of care was examined. This study received approval from the University of Louisiana at Monroe’s institutional review board.
Statistical Analysis Overall point prevalence and point prevalence, stratified by 5-year age categories on January 1, 2010, were determined using identified PCOS cases and age-eligible female membership of the Medicaid plan. The comorbidities of women with probable PCOS versus those of the control group were compared using categorical statistical analysis. The Breslow-Day test was used to determine whether the conditional ORs for the diagnosed PCOS group and the group with clinical features of PCOS were equal. The Breslow-Day test was also used to test the null hypothesis: the relationship between PCOS and comorbidities is the same for each value of racial/ethnic groups. Total costs of care were evaluated using stepwise multiple linear regression, with total costs as the dependent variable and CVD and comorbidities as the independent variables. Collinearity was evaluated to assess the suitability of the data for a linear regression model.
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FIGURE 1. Data extraction flow chart.
Analyses were conducted using Statistical Analysis System software version 9 (SAS Institute, Cary, NC). A 2-sided P value less than 0.05 was considered statistically significant.
RESULTS A total of 262,862 women who were Medicaid eligible and aged 15 to 45 years on January 1, 2010 were identified. Women meeting the exclusion criteria numbered 2958, bringing the total
870
to 259,904. Of these women, 2284 had a diagnosis of PCOS or oligomenorrhea/amenorrhea plus hirsutism on or before January 1, 2010. An outpatient claim for PCOS was identified for 1942 women. The other 342 women in the PCOS cohort were those women with claims for defining clinical characteristics of PCOS (oligomenorrhea/amenorrhea plus hirsutism) but did not have a PCOS claim. The point prevalence of probable PCOS in this population was 0.88%. Point prevalences for each of the predefined * 2014 The American Federation for Medical Research
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age groups are as follows: age of 15 to 19 years, 0.73%; age of 20 to 24 years, 0.86%; age of 25 to 29 years, 0.86%; age of 30 to 34 years, 1.21%; age of 35 to 39 years, 1.07%; and age of 40 to 45 years, 0.85%. Figure 1 is a flow chart for data extraction for the determination of comorbidites and total costs of care. The total number of women who were continuously eligible for Medicaid in 2010, eligible only for Medicaid, not in a long-term care facility in 2010, and aged 15 to 45 years old was 160,021. After excluding 23,720 women for pregnancy and another 1888 for adrenal tumor or cancer, adrenal hyperplasia, Cushing syndrome, ovarian tumor or cancer, pituitary tumor or cancer, and prolactinoma, the number eligible totaled 143,413. The total number of women with a diagnosis of PCOS or its defining characteristics was 1689: 1454 had a diagnosis of PCOS and 235 had the diagnoses of oligomenorrhea or amenorrhea plus hirsutism. The clinical characteristics of age- and race-matched women in the probable PCOS group and the control group are listed in Table 1. Comparison of the 2 groups shows that they were carefully matched for age and race. Women with a diagnosis of PCOS or its defining features were more likely than controls to have a diagnosis of cardiovascular risk factors, including diabetes (OR, 4.35; 95% confidence interval [CI], 3.63Y5.21), dyslipidemia (OR, 3.56; 95% CI, 3.04Y4.19), dysmetabolic syndrome (OR, 23.46; 95% CI, 13.64Y40.36), glucose intolerance (OR, 5.46; 95% CI, 3.10-9.60), hypertension (OR, 2.76; 95% CI, 2.41Y3.18), and obesity (OR, 5.79; 95% CI, 5.07Y6.62). Cardiovascular disease was diagnosed infrequently and did not differ between the 2 groups. Women with claims for PCOS or its defining features had greater odds of being infertile (OR, 23.42; 95% CI, 10.63Y51.61) or having obstructive sleep apnea (OR, 6.47; 95% CI, 3.62Y11.55) than did the controls. Psychiatric disorders also occurred more frequently in the probable PCOS group. The probable PCOS group had greater odds of having diagnosed anxiety (OR, 1.76; 95% CI, 1.53Y2.04), bipolar disorders (OR, 1.94; 95% CI, 1.55Y2.44), and depression (OR, 2.22; 95% CI, 1.94Y2.54). There was no difference in eating disorders between the probable PCOS group and the control group (OR, 1.31; 95% CI, 0.54Y3.20). White women with probable PCOS were less likely to have a diagnosis of infertility (OR, 7.65; 95% CI, 2.96Y19.80) compared with their black counterparts (OR, 113.00; 95% CI, 15.48Y825.56; P = 0.01). Black women with probable PCOS had greater odds of having a diagnosis of bipolar disorder (OR, 3.27; 95% CI, 2.11Y5.05) than did white women (OR, 1.64; 95% CI, 1.25Y2.17). Breslow-Day tests for homogeneity of the ORs by race revealed no significant difference in the other cardiovascular risk factors or comorbidities. Differences in comorbidities between the patients receiving a diagnosis of PCOS and those patients with clinical features of PCOS but no diagnosis were evaluated (Table 2). Women who received a diagnosis of PCOS were significantly more likely to have diagnoses of diabetes, dyslipidemia, dysmetabolic syndrome, glucose intolerance, hypertension, obesity, anxiety, bipolar disorder, depression, infertility, and obstructive sleep apnea but not eating disorders when compared with their corresponding ageand race-matched control group. Women with oligomenorrhea or amenorrhea plus hirsutism were significantly more likely to have diagnoses of diabetes, dyslipidemia, dysmetabolic syndrome, hypertension, obesity, anxiety, bipolar disorder, depression, and obstructive sleep apnea but not glucose intolerance or eating disorders when compared with their corresponding ageand race-matched control group. Women with diagnosed PCOS were significantly more likely to have a diabetes diagnosis than did those women with the defining clinical features of PCOS
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TABLE 1. Clinical Characteristics of Women With PCOS and Matched (Age and Race) Controls
Characteristic Mean age in 2010 Age group in 2010 15Y19 y 20Y24 y 25Y29 y 30Y34 y 35Y39 y 40Y45 y Race/ethnicity White Black Hispanic Other Cardiovascular risk factors Diabetes Dyslipidemia Dysmetabolic syndrome Glucose intolerance Hypertension Obesity Comorbidities Anxiety Bipolar disorders Depression Eating disorders Infertility Obstructive sleep apnea Diagnosed cardiovascular disease Acute myocardial infarction Chronic heart failure Coronary artery bypass surgery Coronary heart disease Ischemic stroke Percutaneous coronary intervention Peripheral artery disease Transient ischemic attack Unstable and stable angina
PCOS No PCOS Number (%) Number (%) (n = 1689) (n = 5067) 25.24 y
25.23 y
P 0.95
544 (32.2) 317 (18.8) 323 (19.1) 261 (15.4) 146 (8.6) 98 (5.8)
1,633 954 969 783 434 294
(32.2) (18.8) (19.1) (15.4) (8.6) (5.8)
0.99 0.96 1.00 1.00 0.92 1.00
790 (46.8) 806 (47.7) 31 (1.8) 62 (3.7)
2,379 2,418 94 176
(47.0) (47.7) (1.9) (3.5)
0.90 1.00 0.96 0.70 G0.0001 G0.0001 G0.0001
297 (17.6) 349 (20.7) 110 (6.5)
237 (4.7) 345 (6.8) 15 (0.3)
34 (2.0) 442 (26.2) 667 (39.5)
19 (0.4) G0.0001 576 (11.4) G0.0001 513 (10.1) G0.0001
347 (22.1) 131 (7.8) 438 (25.9) 7 (0.4) 53 (3.1) 36 (2.1)
648 210 690 15 7 17
(12.8) (4.1) (13.6) (0.3) (0.1) (0.3)
G0.0001 G0.0001 G0.0001 0.46 G0.0001 G0.0001
1 (0.06)
4 (0.08)
1.00
5 (0.3) 0 (0)
9 (0.17) 1 (0.02)
0.36 1.00
21 (1.2) 8 (0.5) 1 (0.06)
45 (0.89) 14 (0.3) 3 (0.06)
0.20 0.22 1.00
4 (0.2)
13 (0.3)
0.92
4 (0.2)
9 (0.2)
0.75
14 (0.8)
36 (0.7)
0.56
and no diagnosis of PCOS. Odds ratios for other comorbidities were not significantly different between the group with diagnosed PCOS and the group with diagnoses for the features of PCOS but no PCOS diagnosis. The mean total cost of care for the patients with probable PCOS was $5551 compared with $3496 for the control group.
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TABLE 2. Comparison of ORs for Comorbid Conditions in Women With Diagnosed PCOS and Those With Defining Features of PCOS Including Irregular Menses and Clinical Hyperandrogenism Compared With Their Respective Control Groups Oligomenorrhea/Amenorrhea + Hyperandrogenism Compared With Control
PCOS Compared With Control Cardiovascular Risk Factors Diabetes Dyslipidemia Dysmetabolic syndrome Glucose intolerance Hypertension Obesity Comorbidities Anxiety Bipolar disorders Depression Eating disorders Infertility Obstructive sleep apnea
P
OR (95% CI)
PCOS Compared With Oligomenorrhea /Amenorrhea + Hyperandrogenism
P
OR (95% CI)
P
4.87 (4.00Y5.93) 3.80 (3.18Y4.53) 26.49 (14.50Y48.37) 6.81 (3.53Y13.13) 2.85 (2.45Y3.32) 5.93 (5.13Y6.85)
PG PG PG PG PG PG
0.0001 0.0001 0.0001 0.0001 0.0001 0.0001
2.26 (1.40Y3.64) 2.64 (1.78Y3.91) 11.49 (3.18Y41.55) 2.53 (0.77Y8.38) 2.39 (1.69Y3.37) 5.01 (3.50Y7.17)
PG PG PG P= PG PG
0.0006 0.0001 0.0001 0.1547 0.0001 0.0001
0.0032 0.0979 0.2385 0.1477 0.3545 0.3929
1.76 (1.51Y2.05) 1.83 (1.43Y2.34) 2.18 (1.88Y2.52) 1.39 (0.53Y3.65) 21.7 (9.81Y48.0) 5.90 (3.15Y11.03)
PG PG PG P= PG PG
0.0001 0.0001 0.0001 0.59 0.0001 0.0001
1.80 (1.20Y2.70) 2.72 (1.53Y4.85) 2.55 (1.75Y3.70) 1 (0.10Y9.66) 27.4 (1.47Y511.4) 10.79 (2.23Y52.32)
P= PG PG P= P= PG
0.0041 0.0004 0.0001 0.1 0.0038 0.0013
0.9158 0.2137 0.4429 0.7946 0.4552 0.4812
The mean total costs of care for those women who received a diagnosis of PCOS was $5152, which was significantly less than the $8020 mean total cost of care for those women who had claims for the defining features of PCOS but no PCOS claims. Multiple linear regression analysis showed that race (others and not black, white, or Hispanic), age, PCOS, acute myocardial infarction, transient ischemic attack, peripheral artery disease, anxiety, depression, bipolar disorders, hypertension, diabetes, and dyslipidemia are linearly related to total costs of care in PCOS (Table 3). The mean total costs of care for the probable PCOS group was $637 higher than those of the control group after controlling the effects of other variables. Variables removed from the model due to lack of statistical significance included coronary artery disease, impaired glucose tolerance, unstable angina, obesity, chronic heart failure, infertility, eating disorder, ischemic stroke, black race, Hispanic race, and obstructive sleep apnea. Percutaneous coronary intervention and coronary bypass graft surgery were removed from the model because they were highly correlated with acute myocardial infarction.
Likewise, dysmetabolic syndrome was removed from the model because it was highly correlated with diabetes and hypertension.
DISCUSSION Evaluation of claims data for indigent women receiving health care indicates that the prevalence of diagnosed PCOS and clinically evident PCOS is much lower than that reported in screening studies. This is consistent with the data of Lo et al.,26 who reported a prevalence of 2.2% in primarily middle-income women aged to 20 to 39 years. We included in our PCOS cohort women with claims for oligomenorrhea or amenorrhea plus clinical signs of hyperandrogenism. Despite including women with clinical signs of PCOS but no diagnosis in the PCOS group, our reported prevalence of 0.88% is much lower than the 4% to 10% prevalence from screening studies commonly reported in the literature. Taken together, these data suggest that PCOS is underrecognized and underreported in the clinical setting.
TABLE 3. Multiple Linear Regression Analysis Showing Predictors of Total Costs of Care in Women With PCOS Variable Intercept Race-other (not black, white, or Hispanic) Age PCOS Acute myocardial infarction Transient attack Peripheral artery disease Anxiety Depression Bipolar disorders Hypertension Diabetes Dyslipidemia
872
Coefficient Estimate
Standard Error
P
1652.16 2145.53 36.02 636.65 16,710.00 24,866.00 8567.94 1030.98 1740.74 3729.01 2146.05 3023.66 1917.17
442.28 657.40 16.45 286.61 4423.87 2743.38 2392.71 379.82 363.72 567.97 382.41 487.32 445.87
0.0002 0.0011 0.0285 0.0264 0.0002 G0.0001 0.0003 0.0067 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001
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We also report that diagnosed PCOS and its defining characteristics are associated with an increased risk for cardiovascular risk factors independent of age and race. However, PCOS was not associated with an increase of cardiovascular events in this relatively young population of women. Other reports have also failed to establish a link between PCOS and CVD in premenopausal women.27 However, recent studies report that PCOS is associated with premature subclinical CVD including coronary artery calcification,2,3 aortic calcification,2 and increased carotid intima-media wall thickness.28 In addition, the evaluation of postmenopausal women from the Women’s Ischemic Syndrome Evaluation study indicated that women with the clinical characteristics of PCOS, including a history of irregular menstruation and elevated serum androgen concentrations, had more frequent angiographic CAD and lower cardiovascular event-free survival. Lower event-free survival remained significant after controlling for diabetes, waist circumference, hypertension, and angiographic CAD.29 Our results confirm reports that women with PCOS are at greater risk for mental health disorders including depression, anxiety, and bipolar disease. During systematic screening for depression using Beck Depression Inventory and Primary Care Evaluation of Mental Disorders Patient Health Questionnaire, Hollinrake et al.30 determined that 35% of women with PCOS had depression compared with 10.7% in the control group. The OR for depressive disorders after controlling for body mass index (BMI), family history of depression, and history of infertility was 4.23 (95% CI, 2.96Y5.5).30 A recent meta-analysis reported an increased risk for elevated depression scores in PCOS with an OR of 4.03 (95% CI, 2.96Y6.41).31 Results from systematic screening for anxiety disorders have also been reported. The prevalence of anxiety disorders was reported by Hollinrake et al.30 and Jedel et al.32 as 14.5% in women with PCOS compared with 0.9% in controls. Prevalence estimates of anxiety in PCOS vary widely, ranging from 14.5% to 61%. In addition, a meta-analysis indicates that PCOS is associated with an increased prevalence of anxiety symptoms (OR, 6.88; 95% CI, 2.5Y18.9).13 Bipolar disorder, identified in the Mini International Neuropsychiatric Interview, has been reported in 11.1% of women with PCOS receiving care in an outpatient endocrine clinic.33 Using the Mood Disorders Questionnaire, others report that 26.9 % of premenopausal women with PCOS meet the criteria for bipolar disorder.14 This compares with the prevalence estimates of bipolar disorder in the general population of 0.5 to 2%.34 Our data indicate that women with oligomenorrhea or amenorrhea plus hirsutism but with no diagnosis of PCOS had a higher prevalence of bipolar disorder. It is possible that some of these women developed the clinical features of PCOS secondary to medications used in the treatment of bipolar disorder and, therefore, were not diagnosed with PCOS. Binge eating disorder (BED) has also been evaluated in women with PCOS. Kerchner et al.35 reported that 23.3% of women with PCOS have BED. Screening of women with PCOS and controls revealed that BED was present in 12.6% of women with PCOS compared with 1.9% in controls.30 When comparing comorbidities between the women with diagnosed PCOS and those with defining clinical features of PCOS but no PCOS diagnosis, women with diagnosed PCOS had a greater likelihood of diabetes. Whether this represents a true difference between the groups or whether the group with diagnosed PCOS was more likely to be screened for diabetes is not clear. However, it is important to point out that the American Diabetes Association considers women with PCOS to be a highrisk group and recommends that all overweight and obese women with PCOS be screened for diabetes.36 Therefore, it
PCOS Epidemiology and Comorbidities
is not possible to rule out the possibility that the difference observed in the OR reflects a screening bias. The use of administrative databases, that is, claims data, for health services research has grown significantly in the last 15 to 20 years. There are acknowledged limitations in their use such as the following: (1) a limited amount of clinical information, (2) undercoding due to the limited number of diagnoses on a claim, and (3) data may be incomplete when a claim is not needed for payment, such as in prepaid plans (which is not the case with Louisiana Medicaid). Our study had limitations consistent with those outlined previously. We relied on the clinician to provide accurate and complete coding for each visit. The study design did not involve extrapolation of diagnosis codes from the patients’ medical records. Evidence of the diagnosis of PCOS came strictly from the Medicaid claims database. Likewise, we used claims data to identify subjects who had clinical features of PCOS but did not have a claim for PCOS in the defined period. Without access to patient medical records, we were not able to verify the accuracy of the diagnosis nor were we able to ensure that a diagnosis had not been missed. Without access to patients’ BMI, we were not able to match the probable PCOS and control groups on BMI. In addition, we were unable to determine which, if any, women developed PCOS or its defining clinical features secondary to concomitant drug therapy used in the treatment of bipolar disorder. Our study design does not allow us to determine the reasons why PCOS is underdiagnosed. Certainly, the limited number of diagnoses included on the medical claim forms may play a role. Another potential reason may be that providers consider making the diagnosis of PCOS as a low priority considering other presenting problems. It is possible that some providers do not recognize the presenting symptoms as PCOS or do not have the resources necessary to make the diagnosis. However, for this study, claims data offer many advantages. First, the data source contains records for a large population. Therefore, adequate numbers of patients can be found even when studying a less common diagnosis such as PCOS. Also, the data were existing and housed in a data warehouse so that the costs associated with accessing large amounts of patient data are minimized. Another advantage was the study was unobtrusive to the patient.
CONCLUSIONS In conclusion, we found that the identification of PCOS in standard clinical practice was made with less frequency than that observed in systematic screenings using standardized diagnostic criteria. Although the population evaluated was of low socioeconomic status, similar results have been reported in a racially/ ethnically diverse and more affluent population.26 Furthermore, PCOS was associated with increased odds of cardiovascular risk factors in primarily young women. However, clinically apparent CVD was uncommon and similar between the 2 groups. Largescale longitudinal studies are needed to evaluate whether the observed extended risk profile results in a significant increase in CVD as the population ages. Polycystic ovary syndrome is also associated with higher odds of mental health disorders. Early diagnosis of PCOS is important because it identifies women at increased risk for symptomatic and asymptomatic disorders amenable to pharmacologic and nonYpharmacologic therapies. Polycystic ovary syndrome and certain comorbidities such as race, age, acute myocardial infarction, transient ischemic attack, peripheral artery disease, anxiety, depression, bipolar disorders, hypertension, diabetes, and dyslipidemia are independently associated with increased total costs of care.
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Copyright © 2014 American Federation for Medical Research. Unauthorized reproduction of this article is prohibited.
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