Title: GENDER DIFFERENCES IN SAUDI PATIENTS WITH OBSTRUCTIVE SLEEP APNEA

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1 Editorial Manager(tm) for Sleep and Breathing Manuscript Draft Manuscript Number: Title: GENDER DIFFERENCES IN SAUDI PATIENTS WITH OBSTRUCTIVE SLEEP APNEA Article Type: Original Article Keywords: obstructive sleep apnea; women; gender; Polysomnography Corresponding Author: Dr. Ahmed SO BaHammam, FRCP, FCCP Corresponding Author's Institution: College of Medicine, King Saud University First Author: Hadil Alotair, MRCP, FCCP Order of Authors: Hadil Alotair, MRCP, FCCP; Ahmed SO BaHammam, FRCP, FCCP Abstract: Obstructive sleep apnea (OSA) remains under recognized in women possibly due to differences in clinical presentation, difference in tolerance to symptoms and rate of usage and referral to sleep services. No reports have addressed OSA in women in Middle Eastern (Arab) population. Therefore, we conducted this study to assess the differences in demographics, clinical presentation and polysomnographic (PSG) findings between Saudi women and men diagnosed to have (OSA). The study group comprised 200 consecutive women and 202 consecutive men who were referred to the Sleep Disorders Centre. Demographic and clinical data were obtained by personal interviews. All-night in-laboratory polysomnography was performed on all patients. Women were significantly older than men (53.5 yr and 42.3 yr, respectively (ρ <0.001)). Similarly, their body mass index (BMI) was significantly higher than men (ρ<0.001). Insomnia was more common among women (42.5%) compared to men (25.2%) (p<0.001). Other sleep symptoms including witnessed apnea, and excessive daytime sleepiness did not show any statistical difference between the two groups. Women were more likely than men to be diagnosed with hypothyroidism, diabetes, hypertension, cardiac disease and asthma. Apnea hypopnea index (AHI) was statistically higher in men compared to women whereas no statistical difference was found in hypopnea index between the two groups. Most of apnea/hypopnea events in women occurred during rapid eye movement (REM) sleep and the mean duration of hypopnea and apnea was significantly lower in women (p=0.004). Sleep efficiency was lower in women (71.7%) vs. (78.3%) in men (p<0.001). Desaturation index

2 was higher in men (p 0.01), but no difference was found in lowest SaO2 or time with SaO2 <90%. Men accepted to try CPAP / BIPAP in the sleep disorders center and later used it at home more frequently than women. The present study showed differences between women and men patients with OSA. Clinicians need to be aware of these differences when assessing women for the possibility of OSA as they may be symptomatic at a lower AHI and have significant co-morbid conditions that can be adversely affected if their OSA was not timely managed.

3 Manuscript Click here to download Manuscript: Draft.Fin.SB.doc GENDER DIFFERENCES IN SAUDI PATIENTS WITH OBSTRUCTIVE SLEEP APNEA Hadil Alotair, MRCP, FCCP, Ahmed BaHammam, FRCP, FCCP Respiratory Medicine Section and Sleep Disorders Centre, College of Medicine, King Saud University Short running title: Gender Difference in Patients with Sleep Apnea CORRESPONDING AUTHOR: PROF. AHMED BAHAMMAM PROFESSOR OF MEDICINE DIRECTOR SLEEP DISORDERS CENTER, COLLEGE OF MEDICINE, DEPARTMENT OF MEDICINE 38, KING SAUD UNIVERSITY Box , Riyadh 11324, Saudi Arabia Telephone: Fax:

4 Introduction Obstructive Sleep Apnea (OSA) is the most common sleep related breathing disorder. For decades it was thought to be primarily a disease of males (1, 2, 3), however recent epidemiological studies have revealed a relatively high prevalence of OSA in women (2 % compared to 4 % in men) (4). Nevertheless, OSA remains under recognized in women possibly due to differences in clinical presentation, difference in tolerance to symptoms and rate of usage and referral to sleep services (5, 12). This clinical under diagnosis may have serious consequences, given the association of OSA with hypertension (6), cardiovascular (7) and cerebrovascular diseases (8, 9), motor vehicle and work related accidents in addition to poor quality of life and poor work or school performance (10). Furthermore, the Wisconsin Sleep Cohort Study suggested that there might be significantly higher 5 year mortality for women with sleep disordered breathing than women without that diagnosis (11). Therefore, we conducted this study to assess the differences in demographics, clinical presentation and polysomnographic (PSG) findings between Saudi women and men diagnosed in the Sleep Disorders Centre (SDC) to have OSA and to compare our results to published literature as no reports addressing this issue were published from other Middle Eastern countries that share common ethnic backgrounds despite the presence of important differences in prevalence and severity of OSA in various ethnic groups (12). 2

5 Materials and Methods Study group The study group comprised 200 consecutive women and 202 consecutive men who were referred to the Sleep Disorder Centre at KKUH, Riyadh, Saudi Arabia between January June Demographic and clinical data were obtained by personal interviews that included questions and response scales from the Wisconsin Sleep Cohort Study questionnaire (11). Epworth Sleepiness Scale (ESS) was used for subjective assessment of daytime sleepiness (13). Patients who were taking benzodiazepines or narcotics at the time of study were excluded. Study Protocol All-night in laboratory polysomnography was performed on all patients. This included four electroencephalogram (EEG) placements (C1-A4, C2-A3, O1- A4 and O2-A3), electro-oculogram (EOG), sub mental and leg electromyogram (EMGs) and electrocardiogram (ECG). Air flow was detected by thermistor and nasal prong pressure transducer, sleep position by position sensor, snoring by microphone, chest and abdominal wall by thoracic and abdominal belts. Arterial oxygen saturation was measured continuously by finger pulse oximeter. PSG recording was performed using Alice 5 diagnostic equipment from Respironics Inc, Murrysville, Pennsylvania, USA. Page by page analysis and scoring of the electronic raw data was done manually in accordance with established criteria (14, 15). Obstructive apnea was defined as absence of airflow for more than 10 seconds in the presence of continued respiratory effort. 3

6 Hypopnea was defined as a reduction in the airflow by 10% - 50% of baseline and lasting for more than 10 seconds. Apnea hypopnea index (AHI) score was defined as the number of apneas and hypopneas per hour of sleep and was calculated for total sleep time as well as during rapid eye movement sleep (AHI- REM) and during non-rem sleep (AHI-NREM). Hypopnea Index was defined as the number of hypopneas per hour of sleep. OSA was defined as AHI 5 events per hour of sleep (16). Arousal was defined as awakening from sleep for 3-15 sec marked by simultaneous activity on EEG, eye movement and EMG activation (15). Arousal index was calculated as the number of arousals per hour of sleep. Wake after sleep onset (WASO) was calculated as the total duration in minutes of pages scored as WAKE from sleep onset to the last sleep page. Restless leg syndrome (RLS) was defined as the presence of uncomfortable sensations in the extremities that is relieved with movement and increased with inactivity with nocturnal worsening (17). Desaturation index was defined as the number of desaturation events per hour of sleep. Sleep efficiency was calculated as total sleep time/time in bed X100. Sleep onset latency (SOL) was defined as time from lights out to the first epoch of any stage of sleep. Height and weight were recorded in the night of study. The study was approved by the ethics committee in our institution. In case of repeated PSG, only the patient s initial PSG was included in the analysis and in split night study, the diagnostic part was used. Split night study, during which the final portion of the (PSG) is used to titrate continuous positive 4

7 airway pressure (CPAP), was considered for patients with AHI of 20 to 40 events per hour or more and those who had prolonged obstructive respiratory events or severe oxygen desaturation. Patients who could not tolerate CPAP due to the inconvenience of high pressure or were known to have carbon dioxide retention were given Bi-level Positive Pressure Ventilation (BiPAP). CPAP was considered accepted if the patient described the machine as being good and completed the titration trial. Those who refused the titration trial or continued but still not feeling happy with the machine were considered as not accepting it. Later, those who accepted to use the machine during split night study were followed-up and the number of patients who attended the sleep clinic and used CPAP/BIPAP at home was recorded. Statistical Analysis: Data are expressed in the text and tables as mean ± standard deviation (SD). For continuous variables t-test was used if the distribution was normal. When normality test failed, Mann-Whitney rank sum test was used. Chi-square test was used for comparison of proportions. Results were considered statistically significant at the value of p Standard statistical soft ware (Sigma stat, version3; SPSS Chicago, Illinois, USA) was used for the analysis. 5

8 Results Demographic and clinical data of 200 women and 202 men diagnosed to have OSA was recorded. No difference was found in ESS between the two groups (table 1). Presenting Complaints Snoring was the presenting complaint of 75.2% of women compared to 86.6% of men (p<0.001). On the other hand, insomnia was more common among women (42.5%) compared to men (25.2%) (p<0.001). Other sleep symptoms including witnessed apnea, and excessive daytime sleepiness did not show any statistical difference between the two groups (table 2). More women reported symptoms of (RLS) than men (54.5% vs. 37.2%, p<0.001). Medical symptoms of heartburn, choking, headaches, palpitation, dry mouth and ankle swelling were found more frequently among women than men (table 2). In addition, the women in our study group were more likely than men to be diagnosed with hypothyroidism, diabetes, hypertension, cardiac disease and asthma (table 2). Polysomnographic Findings AHI and AHI-NREM were statistically higher in men compared to women whereas no statistical difference was found in hypopnea index between the two groups (table 3). Most of apnea/hypopnea events in women occurred during REM sleep and the mean duration of hypopnea and apnea was significantly lower in women (p=0.004). Likewise sleep efficiency was lower in women 6

9 (71.7%) vs. (78.3%) in men (p<0.001). Women had a longer sleep latency compared to men (p<0.005). There was no difference in Arousal Index between women and men but wakefulness after sleep onset (WASO) was higher in women (p<0.001). Desaturation index was higher in men (p< 0.01), but no difference was found in lowest SaO2 or time with SaO2 <90%. Compliance with Treatment Men accepted to try CPAP / BIPAP in the sleep disorders center and later used it at home more frequently than women (table 4). 7

10 Discussion The influence of gender on the severity of OSA and the distribution of sleep events during the sleep cycle has been reported in few studies (18-21) but none was conducted in the Arab population in the Middle East. It has been recently suggested that ethnicity could alter the risk and severity of OSA. It is not only due to cultural and social factors but also to differences in genetics, craniofacial structure, upper airway anatomy and pattern of fat deposition (12, 22). The present study found important differences in demographic, clinical and PSG findings between Saudi men and women which can at least partly explain the possible under recognition of sleep apnea in women. Furthermore, this study showed that Saudi women were older and had more severe AHI than Caucasian women despite similar BMI (Table 5). This could be due to older age at presentation, differences in tolerance of symptoms and delay in referral to sleep services, however, the role of genetic factors and differences in craniofacial structures and upper airway anatomy need to be explored. Women in our study are older than men. Other clinic-based studies reported similar age difference at presentation (23, 24). The prevalence of OSA peaks at around 55 years in men and at around 65 for women (24). This can be related to post menopausal status as the risk of sleep disordered breathing was shown to be at least 2.5 times higher in post than premenopausal women (26), and it approximates that of men at the time of menopause (27). Obesity is a known predisposing factor for OSA; the females in our study had higher BMI than 8

11 men. Several previous studies have shown that women with OSA are much more obese than men (4, 18, 23, and 28). Walker et al compared men and women of similar age at presentation and with the same severity of apnea, and found that women had higher BMI (29). In the Wisconsin Sleep Cohort Study, women had higher BMI than men at each level of Respiratory Distress Index (11). Obesity in general is more common in women than men. In the United States about 24.9% of women versus 19.9% of men had BMI > 30 (30). Likewise, in Saudi Arabia, women are significantly more obese than men with a prevalence of 44% and 26.4%, respectively (31). Insomnia was more commonly reported as presenting complaint in women than men (42.5% vs. 25.2%, p<0.001). This is in accordance with previous studies that showed that women with OSA or upper airway resistance syndrome more commonly describe their sleep problem as insomnia. Ambrogetti et al (32) and Pillar et al (33) found that women report symptoms of fatigue, insomnia more frequently than men. Shepertycky et al in their study group of 260 patients found that 1:5 of women with OSA had presenting complaint of insomnia compared to 1:20 in men (19). In our study, 1:2.3 of women and 1:4 of men presented with insomnia either alone or in addition to other symptoms. These findings point out to the importance of assessing women who present with insomnia for the possibility of OSA as this could be one of the causes for clinical under recognition of OSA in women. More men presented with snoring than women, which could be due to differences in fat distribution and upper airway anatomy and function in addition to cultural factors that make women less likely to reveal loud snoring than men. However, similar to 9

12 other studies (19, 23) no difference was noted in the rest of OSA classical symptoms namely witnessed apnea and excessive daytime sleepiness. Comorbid medical conditions namely hypertension (HTN), diabetes (DM), bronchial asthma and cardiac diseases were more prevalent in women than men at the time of diagnosis. Previous reports did not show gender related difference with regard to DM, HTN (6, 34), however, COPD was reported by some investigators to be more prevalent in women (28, 35). Shepertychy et al found in their study population that women were more often taking asthma puffs and labeled as COPD compared to men, however no explanation for this could be found (19). The lower prevalence of cardiac diseases among men in our study group could be explained by their relatively younger age (mean=42.3 years). In our study, hypothyroidism was more commonly diagnosed in women with OSA than men and this is in agreement with previous reports that found women < 50 years old with hypothyroidism have the highest relative risk of OSA (19, 36). Depression was reported more frequently by women than men. Young et al noted that women more often than men reported depression, anxiety and morning headache (23). In the present study, RLS symptoms were reported more commonly by women. This is probably related to the fact that they were older than men and had higher prevalence of DM. It seems that RLS affect more women than men in older age groups (37, 38). Our results concurred with previous reports that found OSA to be less severe in women compared to men (18, 20, 24, and 39). However, women tend to have higher REM related apnea and hypopneas than men. This was studied by 10

13 O Conner who found that women have most of their sleep events during REM sleep and 62% of women were categorized as REM related apnea group compared to 24% of men. This difference was not age or weight dependent (20). So it appears that women can be symptomatic at lower AHI (11). Possible explanation is the clustering of apneas and hypopneas mainly in REM sleep (27). The disruption of which can cause reduced sleep latency, as measured by multiple sleep latency test (40, 41). This is important to remember when assessing women with OSA since AHI does not necessarily correlate with symptoms and a lower AHI should not preclude the institution of therapy. Several theories tried to explain the reason for the higher REM compared to NREM sleep respiratory events in women. One possible mechanism is gender-related differences in upper airway function during sleep in which airway protection mechanisms disappear during REM sleep in women (42). Female hormones (especially progesterone) may play a role in increasing upper airway muscle activity during wakefulness and NREM sleep (43). Furthermore, there are important gender differences in central ventilatory control. Women have a lower apnea threshold, compared to men and they are less likely to exhibit apneas during NREM sleep despite inspiratory flow limitation (44-46). Oxygen desaturation was less severe in women than men possibly due to higher hypopnea/apnea ration and shorter apnea duration in women. This could be related to decreased collapsibility of upper airways and increased hypoxic and hypercapnic chemo sensitivity in women (18, 36, 47). 11

14 Women in our study had higher WASO compared to men with significantly longer sleep latency and lower sleep efficiency which is different from healthy middle age women who sleep better than men with higher sleep efficiency (37). This indicates a more disturbed sleep in women even when their AHI is lower than that of men. Nevertheless, insomnia in general is more prevalent in women at all ages and it increases further with age and post menopausal status (48). Compliance with treatment was significantly less in women than men; this could reflect social and cultural factors that make women reluctant to readily accept CPAP machine usage at night. In a study done in an urban public hospital in Illinois, women were 2.49 times more likely to be non-adherent to OSA treatment than men (49). There are few limitations of our study that need to be addressed. The data obtained during personal interviews could have been affected by the level of education of the patient and this could be reflected on her or his understanding of the words used. In addition, the presence of a family member or a spouse during the interview could have an effect on the response to some of the questions. The interviewer was obviously not blinded and this could have resulted in bias. In summary, this is the first study in Middle Eastern Arab population that compared the clinical and the polysomnographic findings of women and men with OSA. We found that Saudi Women with OSA were older, more obese and presented with insomnia more frequently than Saudi men. They were more likely to be diagnosed with diabetes, hypertension, cardiac diseases, hypothyroidism 12

15 and asthma at presentation. Despite lower AHI in women, most of their respiratory events occurred during REM stage and their sleep efficiency was lower than men. Clinicians need to be aware of these differences when assessing women for the possibility of OSA as they may be symptomatic at a lower AHI and have significant co-morbid conditions that can be adversely affected if their OSA was not timely managed. 13

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23 Table 1. Study group demographics. Women Men p-value No Age (year) <0.001 BMI <0.001 AHI ESS score BMI: Body Mass Index AHI: Apnea Hypopnea Index ESS: Epworth Sleepiness Scale 21

24 Table 2: Symptoms and comorbidities of patients. Women (%) Men (%) p-value Presenting complaints Snoring <0.001 Witnessed apnea Excessive daytime sleepiness Insomnia <0,001 Other symptoms Restless leg symptoms <0.001 Heart burn Choking on awakening Headache on awakening Palpitations <0.001 Ankle swelling <0.001 Dry mouth Comorbidities Cardiac disease Hypertension <0.001 Asthma <0.001 Depression Hypothyroidism <0.001 Diabetes mellitus <

25 Table 3: Polysomnographic findings. Women Men Parameter (n=153) (n = 154) p-value Mean ± SD Mean ±SD Sleep efficiency (%) 71.7 ± ±18.5 <0.001 Sleep latency (min.) 27.1 ± ± Arousal index 53.6 ± ± AHI TST 49.3± ±36.2 <0.011 AHI- NREM 47.3± ±33.1 <0.001 AHI- REM 60.9± ± Hypopnea Index 43± ± Hypopnea/apnea mean duration 17.3± ± WASO 38.1± ±34.5 <0.001 Desaturation index 33.2± ± Lowest SaO ± ± Time with SaO 2 <90% 27.8± ± AHI: Apnea hypopnea index TST: Total sleep time NREM: Non-rapid eye movement REM: Rapid eye movement WASO: Wakefulness after sleep onset SaO2: Oxygen Saturation 23

26 Table 4: Compliance with Treatment. Women % (n = 148) Men % (n = 169) p-value ACCEPT CPAP (%) Used CPAP(%) CPAP: continuous positive airway pressure. 24

27 Table 5: Comparison of demographics of women with OSA in the present study compared to previously published data. Present study Mohsenin et al (24) Shepertycky et al (19). O Connor et al (20) Vagiakis et al (21) n=200 n=52 n=130 n=206 n=166 Age BMI AHI ESS n = Number of women with OSA 25