Obstructive Sleep Apnoea in Women: What Do We Know and What Don't We Know?

Approximately 1 billion adults globally have obstructive sleep apnoea (OSA) with the highest numbers estimated in China, followed by the USA, Brazil, and India [1]. While epidemiological studies have historically reported higher OSA prevalence in men than pre-menopausal women, this gap narrows substantially between the sexes after menopause [2]. Furthermore, women are generally underrepresented in most randomised controlled trials studying OSA. Clinical bias and the knowledge gap of their gender-specific OSA symptom profile, which often differs from that of men with OSA, varying with age and physiological status, such as menopause and pregnancy [3-6] also result in women likely being underdiagnosed and therefore being left untreated. There are economic benefits of earlier OSA intervention [4, 7] because OSA is associated with a significant social welfare cost—it is estimated that about 23.5 million Americans with OSA remain undiagnosed, accounting for about 80% of cases, incurring about $149.6 billion annually due to greater health care utilisation, increased motor vehicle and workplace accidents, and reduced productivity [8]. Women with OSA showed lower employment rates compared to men with OSA (54.7% vs. 74.5%), higher rates of disability pension (20.6% vs. 11.1%), greater net cost differences increasing from 8259 EUR (approx. $9607) to 13,730 EUR (approx. $15,971) per year for women versus 4217 EUR (approx. $4905) to 8749 EUR (approx. $10,177) per year for men, and significantly higher morbidity, mortality, and social welfare costs than men [4]. After adjusting for comorbidities, women with OSA showed a 28% higher mortality risk compared to women controls (HR 1.28 [1.20–1.38]), while men with OSA showed a 3% higher risk without statistical significance (HR 1.03 [0.99–1.07]) [4]. There are unique diagnostic and therapeutic challenges given female OSA endotypes and phenotypes tend to differ from men. While men often present with ‘classic’ symptoms such as loud snoring, witnessed apnoeas, and excessive daytime sleepiness, women more commonly report ‘atypical’ symptoms such as fatigue, insomnia, morning headaches, and mood disturbances that may be misattributed to mental health conditions or chronic fatigue [5, 6]. Current OSA screening questionnaires (e.g., STOP-BANG, Epworth Sleepiness Scale [ESS]) lack the sensitivity to detect OSA in women because they mainly award points for the classic obese male sleepy OSA phenotype, leading to a falsely low assessment of the pretest probability for OSA [9]. For instance, only 36% of women with OSA in a Swedish cohort showed an abnormal ESS [10]. Women are often symptomatic at lower AHI compared to men and have a lower probability of receiving OSA treatment at follow-up visits than men, despite having a similar risk of developing hypertension and diabetes [5], having greater impairment of quality of life and higher healthcare expenditure compared to men with similar AHI levels [11, 12]. Current AASM treatment guidelines do not strongly emphasise CPAP or oral appliance as first-line therapy for mild OSA compared to the recommendations for moderate or severe OSA. It is important to note that the current PSG criteria to diagnose OSA are likely suboptimal to accurately assess OSA in pre-menopausal women as they tend to have a lower upper airway collapsibility, a lower arousal threshold, more frequent hypopnoeas than apnoeas, less supine dominance of OSA, a higher REM-related OSA compared to men [2, 13] and less oxygen desaturation during Non-REM sleep, making PSG interpretation more challenging in women. While REM-AHI is typically higher in women than in men, because the non-REM-AHI is lower, the total AHI is often lower in women than in men [2], likely contributing to underdiagnosis in women. This is especially true if the PSG is ended prematurely toward the end of the study, that is, early in the morning, when generally the longest REM period tends to occur. Underdiagnosis may also occur if facilities use a set split-night AHI criteria of AHI > 5/h when the diagnostic AHI may be inappropriately low during the first half of the night because the REM-heavy second half of the night was used for the titration portion. REM-related OSA is an important PSG-phenotype as it has been linked to an increased risk of hypertension and diabetes [14, 15]. The anatomical predisposition for OSA differs between men and women. Women have a shorter diaphragm, which may explain their predominance of OSA in REM, a state when the accessory respiratory muscles are paralysed and breathing is solely diaphragm related [12, 16], whereas the smaller upper airway in women increases tracheal traction, reducing the likelihood of collapse in NREM. This anatomical difference may explain the finding of an observational study showing greater success of mandibular advancement devices in controlling OSA in women, regardless of OSA severity [17], however, there are insufficient data at this time to be certain of this finding. Obesity has long been known to be associated with OSA in both genders, but current data are insufficient to determine whether the effect of weight loss in reducing OSA severity is greater in men than in women. The effect of weight loss on OSA severity in the two sexes is challenging to study, given differences in the regional distribution of adipose tissues. Men have more central obesity, which likely explains the greater lingual fat content contributing to greater tongue weight in men than in women [18], and lingual fat is an important concept for obesity and OSA. Reproductive hormones play a role in the pathogenesis of OSA impacting the upper airway patency, contractility of the genioglossus muscle, airway collapsibility, and fluid shifts [19, 20]. OSA prevalence increases after menopause as both oestrogen (which affects the upper airway dilator muscles) and progesterone (a prominent respiratory stimulant) decrease during menopause, and therefore, increase upper airway collapsibility contributing to OSA and AHI increases in menopause [21]. There are insufficient data as to whether hormone replacement therapy in women with OSA affects AHI severity. Current data indicate worse cardiovascular (CV) outcomes with comorbid insomnia and sleep apnoea (COMISA) compared to OSA alone [22]. COMISA is a more common presentation in women than in men. Even at lower AHI, COMISA is associated with a higher burden of CV comorbidities and lower CPAP adherence compared to the sleepy OSA group [23]. Women may have a more negative critical pressure (Pcrit), that is, less collapsible upper airway; therefore, the pressure required to reopen the airway is lower than in men. The current auto-titrating PAP algorithm was likely designed to titrate airflow limitation and target Pcrit in men with OSA rather than women, which may explain the poor PAP pressure tolerance noted in women. One study comparing an auto-titrating PAP algorithm that was specifically designed for women (with higher sensitivity to airflow limitation and slower pressure rise in response to airflow limitation) to a standard auto-titrating algorithm showed better control of airflow limitation in women [24]. COMISA may be related to flow limitation along with low arousal threshold; therefore, correcting flow limitation and snoring may be as important as addressing hypopnoeas and apnoeas in women. In summary, the unique OSA phenotypes and endotypes in women make diagnosis and treatment of OSA challenging (Figure 1). Undoubtedly, there is an urgent need to develop modified, gender-sensitive OSA screening tools in women given the striking gender disparities in health outcomes, mortality, and socio-economic consequences [25]. OSA risk changes across different stages of women's lives. Insomnia should raise suspicion for OSA in women in the absence of daytime sleepiness, loud snoring, witnessed apnoeas, or nocturnal gasping. There is a need to develop adjusted PSG diagnostic criteria, as women often present with REM-predominant OSA, non-desaturating OSA, and less prominent airflow limitation with a high arousal index that does not meet current hypopnoea criteria due to lower upper airway collapsibility, but may benefit from therapy to improve quality of life and reduce CV risk. Lastly, there is a need to develop female-specific algorithms for auto-titrating CPAP with higher sensitivity to airflow limitations and a slower pressure rise given in women to improve tolerance. Nancy Collop is on advisory boards of Apnimed, ZOLL Respicardia, Incannex, and has received priori grants from ZOLL Respicardia and NIH Recover study. Ee Rah Sung declares no conflicts of interest. Data derived from public domain resources.