Sex-specific differences in presenting symptoms of obstructive sleep apnea

ABSTRACT

Objectives:

Scant data from India are available on the gender differences in presenting features of Obstructive Sleep Apnea (OSA) in India. This study aims to compare male and female patients with OSA for general characteristics and presenting symptoms.

Methodology:

Retrospective study was done in OSA patients diagnosed in our sleep lab. History, biochemical reports, and polysomnography variables were retrieved from the sleep registry and were compared between males and females.

Results:

Out of 514 patients of OSA (367 males; 147 females). Females were older (55.97 ± 9.73 v/s 50.2 + 12.70 years, P<0.001) and more obese (BMI 35.26 ± 7.17 v/s 29.58 ± 5.49 Kg/m²; P<0.001). Waist and hip circumference were significantly higher in the female patients (P = 0.009 and <0.001 respectively). Morning headache, nocturia, fatigability (P < 0.001), and depression (P = 0.005) was more common in females (P = 0.036). Hypersomnia was more commonly seen in males (P < 0.001). Mean diastolic blood pressure was significantly higher in males, although no difference was seen in Systolic BP. Females had higher mean Fasting Blood glucose (FBS) (P = 0.02). Apnea hypopnea index was significantly higher in females {P = 0.01}.

Conclusion:

Women with OSA are more obese, elderly, and with higher fasting blood glucose than males at the time of diagnosis. Females have a higher prevalence of symptoms like fatigability, depression, nocturia and early morning headache and had more severe AHI than males.

INTRODUCTION

Obstructive sleep apnea (OSA) is caused by episodic nocturnal collapse of the upper airway and results in excessive daytime sleepiness, mood disturbances, and deterioration in functional status. OSA is also an independent risk factor for hypertension, diabetes mellitus, metabolic syndrome, and other cardiovascular disease such as stroke and myocardial infarction.[1,2,3]

OSA has often been regarded as a male predominant disease. Sleep-disordered breathing was seen in 24% of young middle-aged men and 9% of women and 70% of older men and 56% of older women.[4] The male-to-female ratio of OSA varies between 3:1 to 5:1 in the general population.[5]

Reasons for differences between males and females in symptoms, characteristics, and severity of OSA are not fully explained yet, but multiple factors may contribute. Inherent differences in a) distribution of fat, b) length and collapsibility of the upper airway, c) neurochemical control mechanisms, d) arousal response, and e) sex hormones may contribute to the disparity in prevalence between the two genders.[6] In general, men tend to have more severe and predominately position-dependent OSA than women.

It has often been postulated that women do not show the “classical” symptoms of OSA and thus may be under diagnosed. Women often present with headache, and fatigue rather than classical daytime sleepiness; they are more likely to be misdiagnosed with depression or other diseases.[7]

Differences in sleep architecture have also been reported in both genders.[8,9,10] In a study done in patients with OSA, women had longer sleep latencies, greater amounts of slow wave sleep, and fewer awakenings during the night than men despite no significant differences in age, respiratory disturbance index, or oxygen saturation.[11]

This study aims to compare male and female patients with OSA with respect to general characteristics, symptoms, biochemical parameters, and polysomnography variables.

MATERIALS AND METHODS

This is a retrospective chart analysis of 514 Indian adults (age >18 years) who were diagnosed with OSA from June 2015 to December 2019 from the sleep disorders clinic. From the sleep registry, we retrieved complete clinical, biochemical, and polysomnographic data. Only those patients were eligible for the study who were diagnosed with OSA {defined as apnea hypopnea index (AHI) ≥5 events per hour}.

Polysomnography: All patients underwent overnight Level I polysomnography (PSG) {Philips Respironics Alice 6} at our Hospital sleep laboratory. The following parameters were monitored during PSG: electroencephalogram (EEG): frontal, central, and occipital, electrooculogram (EOG), electromyogram (EMG- chin and anterior tibialis), nasal and oral airflow, body position and electrocardiogram. Additionally, thoracic and abdominal movements were recorded by inductance plethysmography (zRIP). Scoring of events was done according to AASM scoring manual version 2012.[12] OSA was classified into three categories based on AHI: mild (5–14.9) to moderate (AHI 15–29.9) and severe (AHI ≥30). If the patient had AHI ≥15, patient was titrated according to AASM titration guidelines 2008.[13] T90 was defined as the percentage of sleep time spent with sPO2 <90% during the diagnostic study.

Anthropometry and general examination: The waist was defined as the point midway between the iliac crest and lower costal margin. Waist measurement was done during normal breath out with tape snugly fitted and horizontal to the floor while the subject was standing. Hip circumference was measured around the widest portion of the hips with tape snugly fitted and horizontal to the floor while the subject stood with arms at the sides, and feet close together. Neck circumference was measured at the level of the cricothyroid membrane with tape while a patient was in a standing position. Blood Pressure was measured after 10 min of sitting position. The first reading was discarded. The average of the second and third readings was taken. Weight was measured by SECA weighing machine and height was measured by an SECA stadiometer. BMI was calculated as {weight (kg)/height (m) ²}. Hypertension was defined, if the patient’s blood pressure (BP) was >140/90 or if the patient was already taking antihypertensive medications. The frequency of urination and timing was assessed after the onset of sleep. Nocturia was defined as having a history of urination more than once after sleep onset.

History of morning headache, and insomnia (initiation, maintenance, or terminal) was taken from patients. The history of depression diagnosed by a psychiatrist was asked. Excessive daytime sleepiness was defined as Epworth Sleepiness score (ESS) ≥11.

All patients underwent blood testing in the morning after overnight fasting for fasting blood glucose (FBS) and lipid profile (total cholesterol, triglyceride, low-density lipids, very low-density lipid, heavy density lipid). FBS was done by the hexokinase method using an automated chemistry analyzer (AU680, Beckman Coulter).

Ethics and permissions

The protocol of this study was reviewed and approved by the Institutional Human Ethics Committee (IHEC) of AIIMS Bhopal (IHEC-LOP/2018/MD0014).

Data analysis

The data was compiled and cleaned using Microsoft Excel. It was then analyzed using SPSS version 25. Binary and ordinal variables were described using frequency and percentages. Differences or associations were assessed using Chi-square tests. Continuous data were expressed with mean values and standard deviations and compared using independent t-tests. The significance level (alpha) was set at 0.05 for P values.

RESULTS

During the study period, 514 Indian adults (367 males; 147 females) were diagnosed with OSA (AHI ≥5) in a referral sleep lab in central India. The mean age was significantly higher in females (55.97 ± 9.73 years) compared to males (50.2 + 12.70 years). Females were more obese with (BMI of 35.26 ± 7.17 v/s 29.58 ± 5.49 Kg/m²; P value <0.001). Waist and hip circumference were significantly higher in the female patients (P = 0.009 and <0.001 respectively), whereas neck circumference was higher in males (P = 0.002). The features are depicted in Tables 1 and 2.

Table 1.

Gender distribution of patients according to history and Laboratory parameters

Parameter	Levels	Female (%)	Male (%)	Total (%)	*P	P (adjusted for age and BMI)
Shortness of Breath (n=513)	Present	41 (27.9%)	63 (17.2%)	104 (20.3%)	0.007	0.058
Loud snoring	Present	126 (85.7%)	339 (92.4%)	465 (90.5%)	0.02	0.001
Fatiguability	Present	95 (64.6%)	151 (41.1%)	246 (47.9%)	<0.001	<0.001
Forgetfulness	Present	5 (3.4%)	12 (3.3%)	17 (3.3%)	0.94	0.834
Hypersomnia	Present	90 (61.2%)	210 (57.2%)	300 (58.4%)	0.405	0.438
Insomnia	Present	21 (14.3%)	30 (8.2%)	51 (9.9%)	0.036	0.089
Witnessed Apnea	Present	90 (61.2%)	230 (62.7%)	320 (62.3%)	0.76	0.168
Morning Headache	Present	87 (59.2%)	108 (29.4%)	195 (37.9%)	<0.001	<0.001
Epworth Sleepiness Scale (n=513)	<11	107 (72.8%)	235 (64.2%)	342 (66.7%)	0.062	<0.001
	≥11	40 (27.2%)	131 (35.8%)	171 (33.3%)
Nocturnal urination Frequency (n=513)	<2	85 (58.2%)	281 (76.6%)	366 (71.3%)	<0.001	0.039
	≥2 (Nocturia)	61 (41.8%)	86 (23.4%)	147 (28.7%)
Hypertension	Present	54 (36.7%)	141 (38.4%)	195 (37.9%)	0.722	0.060
Diabetes Mellitus	Present	34 (27.2%)	41 (12.5%)	75 (16.6%)	<0.001	0.047
Depression (n=513)	Present	33 (22.6%)	59 (16.1%)	92 (17.9%)	0.082	0.005
PaCO2 in ABG (n=447)	<45	102 (80.3%)	288 (90%)	390 (87.2%)	0.006	0.083
	≥45	25 (19.7%)	32 (10%)	57 (12.8%)
HCO3 (n=447)	<27	93 (73.8%)	284 (88.5%)	377 (84.3%)	<0.001	0.007
	≥27	33 (26.2%)	37 (11.5%)	70 (15.7%)
Status of Thyroid (n=459)	Euthyroid	71 (53%)	277 (85.2%)	348 (75.8%)	<0.001	<0.001
	Hypothyroid	63 (47%)	48 (14.8%)	111 (24.2%)
Severity of OSA	Mild	9 (6.1%)	27 (7.4%)	36 (7%)	0.804	0.767
	Moderate	25 (17%)	56 (15.3%)	81 (15.8%)
	Severe	113 (76.9%)	284 (77.4%)	397 (77.2%)

*P value statistically significant at <0.05; **Cross Tabulations or Chi-square; ***n=514 unless otherwise state

Table 2.

Comparison of means of clinical, biochemical andpolysomnography parameters

Parameter	Gender of Patient	n	Mean±SD	P	P (adjusted for Age and BMI)
Age	Female	147	55.97±9.73	<0.001	N.A.
	Male	367	50.2±12.70
BMI	Female	147	35.26±7.17	<0.001
	Male	367	29.58±5.49
Systolic Blood Pressure (mm Hg)	Female	147	135.4±22.474	0.271	0.569
	Male	367	133.12±17.611
Diastolic Blood Pressure (mm Hg)	Female	147	80.54±12.145	<0.001	<0.001
	Male	367	84.92±11.33
Neck Circumference (inches)	Female	147	15.039±1.1345	0.002	<0.001
	Male	367	16.818±6.7204
Waist circumference (inches)	Female	147	43.126±6.3623	0.009	<0.001
	Male	367	41.693±5.3136
Hip circumference (inches)	Female	147	45.861±5.8124	<0.001	0.030
	Male	367	41.601±4.6177
Fasting Blood Sugar (n=453)	Female	125	129.53±107.023	0.020	0.026
	Male	328	106.51±33.085
Serum Cholesterol level (n=483)	Female	138	174.67±44.339	0.162	0.913
	Male	345	180.67±41.864
Serum Triglycerides (n=482)	Female	138	135.43±52.302	0.002	0.062
	Male	344	155.38±89.242
Serum HDL (n=467)	Female	134	44.22±11.674	0.445	0.198
	Male	333	42.42±26.079
Serum LDL (n=463)	Female	134	101.95±38.509	0.044	0.657
	Male	329	110.48±42.324
AHI	Female	147	67.194±39.5737	0.084	0.010
	Male	367	60.783±33.0313
Lowest sPO2 (n=513)	Female	147	74.299±18.8303	0.021	0.609
	Male	366	78.34±14.8871
T90 (%) (n=503)	Female	146	17.695±28.8824	0.02	0.688
	Male	357	11.482±21.5332
PAP Pressure advised (n=393)	Female	108	12.81±3.836	0.017	0.828
	Male	285	11.82±3.565

*P value statistically significant at <0.05; **Cross Tabulations or Chi-square; ***n=514 unless otherwise state

Multivariable analysis of all the parameters was done after adjusting for age and BMI.

Early morning headache, nocturia, and fatigability (P < 0.001), and depression (P = 0.005) were more common in females. Insomnia was more common in females (P = 0.036), but it was not significant after adjusting for age and BMI. Hypersomnia (assessed by ESS) was more commonly seen in males. Mean diastolic blood pressure (DBP) was significantly higher in males, although no difference was seen in systolic BP. Higher mean FBS (P = 0.02) and diabetes mellitus (defined by FBS >125) were more commonly seen in females. ABG values were available for 447 individuals. Raised bicarbonate (defined as HCO₃ ≥27 mmol/L) was more common in females (P = 0.007). In our cohort, 47% of the female study population had hypothyroidism on presentation compared to only 14.8% male study population (P < 0.001). A higher prevalence of Obesity Hypoventilation Syndrome (OHS){defined by PaCO₂ ≥45 mm Hg} was seen in females (19.7% v/s 10%).

In the polysomnography parameters, mean AHI was higher in females although nadir oxygen and time spent during sleep study with SpO2 <90% (T90) was similar in both groups.

In our study, 393 patients underwent titration study; the mean Positive airway pressure (PAP) prescribed was similar in both groups.

DISCUSSION

Previous studies have estimated the male-to-female ratio at 3:1 to 5:1 in the general population.[7,14] In our clinical study done at a referral sleep center, the ratio of male to female was 2.5:1 (367 males; 147 females).

In this study, we found that women with OSA have different presenting symptoms, anthropometric and biochemical features than male patients with OSA. Many hypotheses have been given explaining the diversity in ratio including the lack of classic symptomatology in females. Previous studies also showed that complaints like difficulty in initiating sleep, fatigue, morning headaches, insomnia, depression, and the use of sedatives were all more frequent in women than in men.[7,15,16]

In our study, females with OSA were older compared to male patients. This late presentation appears to be multifactorial: 1) It is known that after menopause, the probability of OSA increases significantly, and thus male:female ratio decreases compared to patients in the younger age group. This is postulated due to the waning of the protective effect of estrogen post-menopause. 2) In third-world countries, females often neglect their health for various socioeconomic reasons and that is also an important factor for their late presentation. 3) Our study shows that females present with different symptoms; headache, depression, nocturia, and fatigability were found more frequently than males. Since these symptoms are not considered classical of OSA, medical care providers fail to respond to these symptoms and this could also lead to a delay in getting diagnosed.

Obesity has long been known to be associated with OSA, and body mass index (BMI) correlates positively with the severity of the disease for both males and females.[17] National Family Health Survey 2020 data shows that 22.9% and 24% of Indian males and females are overweight respectively.[18] Clinical studies have indicated that women with OSA tend to be more obese than men with the same level of OSA.[19] In our study, neck circumference was significantly higher in the males whereas waist and hip circumference was higher in the female study population compared to their counterparts. This disparity may be explained by differences in fat distribution in men and women. Men have a more android (upper body) fat distribution compared to gynoid (lower body) fat distribution seen in females.[20] Non-obese patients with OSA have more neck fat in the anterolateral segments in comparison to non-obese subjects without OSA.[21] This finding led to a hypothesis that men are more prone to OSA simply due to increased deposition of fat around the airway. Davidson and Patel suggested that waist and neck circumferences are better markers for OSA than BMI due to differential fat deposition.[22]

In Sleep Heart Health Study, Baldwin et al.[23] observed that although women reported feeling sleepy at similar rates to men, they were less likely to have an excessive daytime sleepiness (EDS) { defined by Epworth Sleepiness Scale score ≥11}. In our study, EDS was more commonly seen in male patients (35.8% vs 27.2%) and insomnia was more commonly seen in females. It is important to note that contrary to the lower prevalence of EDS, females reported more often fatigability. Often sleepiness and fatigability are confused with each other; it is very important to differentiate between these two symptoms.

Nocturia has been associated with severe OSA; nocturia is more frequently reported in females with OSA than males.[24] Early morning Headache appears to be due to consequences of OSA-related repeated apneas, hypoxemia, and hypercapnia leading to cerebral vasodilation. Early morning headaches were also more commonly seen in females in our study; similar findings were seen in a cross-sectional study done in Poland.[25] Sleep fragmentation and insomnia are also more common in females and thus might contribute to headache pathophysiology.

Although there was no difference in witnessed apnea, but the history of loud snoring was more commonly seen in males. Valipour et al.[26] also noted that loud snoring and apneic episodes were more common in males.

It is conventionally thought that OSA is in general more severe in male patients presenting to a sleep clinic, but in our study, higher mean AHI was found in females. Prevalence of hypercapnia and hypercarbia was significantly higher in females in our study indicating a higher prevalence of Obesity Hypoventilation Syndrome (OHS) in females (19.7% v/s 10%). Similar findings of higher prevalence of OHS in females were published by Bahammam AS et al.[27] (15.6% vs 4.5%; P < 0.001).

OHS directly correlates with BMI, as females had higher BMI in both these studies can partially explain the higher prevalence of OHS in females.

In our previous work, we found that females with OSA were more likely to have metabolic syndrome than males with OSA.[3] In the current study, diastolic BP was found to be higher in males, but there was no difference in systolic BP. We also found that women had significantly higher levels of fasting blood sugar at the time of diagnosis. Previous studies have shown that OSA preferentially leads to 1) impaired fasting glucose levels in females and 2) to hypertension in males.[28,29] This difference in complications of OSA in both genders is interesting and needs further evaluation.

Limitations

It was a retrospective analysis done at a single center. Ours is a referral center, the possibility of referral bias cannot be ruled out and these findings cannot be extrapolated to the general population.

CONCLUSION

Women with OSA are more obese, elderly, and with higher fasting blood sugar than males at the time of diagnosis. Females have a prevalence of symptoms like fatigability, depression, nocturia, and early morning headache and had more severe AHI than males.

Abbreviation List

• AHI (Apnea Hypopnea Index)

• Body Mass Index (BMI)

• Continuous Positive Airway Pressure (CPAP)

• Diastolic Blood Pressure (DBP)

• Excessive Daytime Sleepiness (EDS)

• Epworth Sleepiness Scale (ESS)

• Fasting Blood Sugar (FBS)

• Metabolic syndrome (MS)

• National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III)

• Non-Obese OSA (NOOSA)

• Obstructive Sleep Apnea (OSA)

• Obesity hypoventilation Syndrome (OHS)

• Polysomnography (PSG)

• Systolic Blood Pressure (SBP).

Ethical approval

All procedures performed in studies involving human participants were by the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.