By Risa Kerslake
Obstructive sleep apnea (OSA) research in women reveals a startling statistic: Up to one in five have sleep apnea,1 but at least eight out of 10 remain undiagnosed.2 It’s numbers like these that have neurologist-sleep specialist Heidi D. Riney, MD, DABPN, concerned. “We know untreated sleep apnea increases the risk for cardiovascular disease, a leading killer of women,” says Riney, who is chief medical officer at sleep diagnostics company Nox Health. “Therefore, failing to accurately diagnose, treat, and manage sleep apnea can have a profound negative impact on women’s health.”
A 2024 post hoc analysis of the MERGE trial, which examined how PAP therapy affects energy and vitality in patients with mild OSA, found that women with mild OSA experienced significantly worse daytime symptoms compared to their male counterparts. Up to 73% of women in the study experienced problematic levels of daytime fatigue, and up to 40% of women with moderate to severe OSA didn’t present with the textbook symptoms of excessive daytime sleepiness, snoring, and witnessed apneas.3
Women with sleep apnea complain of symptoms such as fatigue, low energy, and lack of motivation, explains Alison J. Wimms, PhD, director of clinical research in the medical affairs team at ResMed and leader of the post hoc analysis after the MERGE trial. “Female patients have told me stories of how hard it was to get a sleep test and how often they felt dismissed by their doctor who would say it was menopause or that it was normal to be tired—to take iron.”
Traditional home sleep tests (HST) can’t always capture these differences. Women have lower loop gain, less airway collapsibility, a lower arousal threshold,4 and shorter obstructive events5 during non-REM sleep than their male counterparts. Sex-specific analysis, as well as technologies that better record and score events, could improve diagnostic accuracy for women.
OSA Symptoms in Women
The “typical” sleep apnea symptoms in men may not apply to women. Both men and women experience snoring, but women may be more reluctant to report it. Women’s snoring is often quieter too, Wimms says. Also, women tend to report fatigue, while men report witnessed apneas. Women aren’t being recognized as there’s still “a lack of association between OSA and females,” Wimms says.
Women’s tendency to have less airway collapsibility is likely due to less fatty tissue in the upper airway, according to Wimms, and because respiration is influenced by female sex hormones.6 Often, instead of complete closure of the upper airway, women have hypopneas(partial closure) and flow limitation (upper airway resistance).
In addition to those symptoms, Susan Redline, MD, MPH, a professor of sleep medicine at Brigham and Women’s Hospital and Harvard Medical School, says women are more likely than men to report symptoms of insomnia. A 2021 review refers to this combination of sleep disorders as comorbid insomnia and sleep apnea (COMISA).7 “Women have a higher prevalence of insomnia than men. Although the literature is limited, women may more likely have a COMISA phenotype and be at increased risk for this more serious morbidity.”
When an apnea event occurs, women may more easily wake up than men, which may be why they experience more sleep disruption, insomnia, and brain fog, explains Redline.
Another observation Redline and her colleagues have begun to make is that women—especially Black women—are more likely to have shorter apneas than men but have a brisk heart rate response at the end of apneas or hypopneas. Cardiovascular response may even occur without a significant desaturation.
High heart rate responses in association with apneas are linked with mortality and increased risk of developing cardiovascular diseases.8 Despite not having desaturations and having less airway collapsibility and shorter events, this cardiac autonomic response may be putting women at risk, explains Redline.
“We need to have a much more flexible approach, and that may need to be sex-specific—or at least sensitive to the fact that there are different manifestations of apneas and hypopneas,” says Redline.
HST Limitations
The International Classification of Sleep Disorders, Third Edition, outlines diagnostic criteria for OSA in adults to require frequent respiratory events shown in in-lab polysomnography (PSG) or HST.9
The apnea-hypopnea index (AHI) is the number of apneas and hypopneas that occur per hour of sleep and are used for PSG. The respiratory event index (REI) measures respiratory events per unit of time for HST. So while arousals are typically scored from PSG readings, they don’t show up in a conventional HST where electroencephalography (EEG) isn’t recorded. Women, and others who predominantly have hypopneas that end in arousals, are more likely to be underdiagnosed using HSTs, resulting in so-called false negatives, explains Jón S. Ágústsson, PhD, vice president of artificial intelligence and data science at Nox Research.
HSTs were designed to identify patients who have a high pretest probability of having sleep apnea—those who have the classic sleep apnea symptomatology, says Riney, including longer apnea events and oxygen desaturations. “Women tend to have shorter respiratory events broken up with cortical arousals as opposed to pronounced oxygen desaturations, which may be missed with home sleep testing,” she says.
Because of these limitations in specificity, negative HSTs should be followed up with an in-lab PSG.10 “I like the term ‘misdiagnosis.’ That’s what home tests can do inadvertently. Patients might get this inconclusive result, which is falsely labeled as negative, and may not pursue further testing. This misperception regarding the severity of their diagnosis or even the presence of a diagnosis may lead to women not pursuing therapy, which can ultimately lead to negative health outcomes,” says Riney.
Another concern with HST is that it may not tell you how much of a sleep period was spent in REM versus non-REM. And women have more REM-related apnea, says Redline, possibly because there’s more neuromuscular collapsibility during REM. HSTs also may be a false negative in cases of insufficient REM sleep.
Innovation in Recording Arousals
The American Academy of Sleep Medicine recommends scoring arousal-based hypopneas when possible and states that arousal-based hypopneas cause significant and potentially dangerous sleep apnea symptoms. These have also been established to have hemodynamic effects, which can have cardiovascular consequences.9
Nox is developing a technology called BodySleep 2.0, a deep neural network that scores wake, REM, and non-REM epochs, as well as arousal events in HST without EEG, to give a more accurate AHI and decrease inconclusive results.11 “The arousal detection of the Nox BodySleep 2.0 was motivated by known physiology,” says Ágústsson.
Riney adds, “There are gender disparities currently in accurately diagnosing sleep apnea in women with home sleep testing. The ability to have Body Sleep 2.0 allows us the goal of having conclusive testing in the home to tackle these gender disparities to get women to a timelier and accurate diagnosis.”
Sleep techs refer to the respiratory signals when scoring both sleep and arousals. Therefore, Ágústsson and his team predicted the information required to score both sleep states and arousals are in the respiratory inductance plethysmography (RIP) signals.
RIP has historically been used to detect respiratory effort, but recently, with patented technology, they can measure changes in breathing, as well as arousals and sleep states, according to Ágústsson. “The key physiology that distinguishes REM sleep and wake is that during REM the intercostal muscles of the rib cage are paralyzed, and we see this in how the chest RIP signal changes compared to the abdominal RIP signal,” Ágústsson says.
Using Sleep Biomarkers
Another technology showing promise for diagnostic accuracy for women is the SleepImage System, a software as a medical device that can utilize electrocardiogram or photoplethysmogram data for analysis and calculations of sleep and, in conjunction with SpO2, calculate sleep apnea events.
“When looking at women who may have a lower threshold to arouse from sleep and without a defined drop in oxygenation, the ability in the SleepImage System to identify subcortical arousals causing fragmentation adds an important layer of sleep-related biomarkers that aid in more accurate diagnosis,” says Solveig Magnusdottir, MD, MSc, MBA chief medical officer at SleepImage. The SleepImage System uses cardiopulmonary coupling analysis to qualify hypopneas based on arousal; it doesn’t depend on desaturation alone.
Measuring sleep, rather than just breathing events, is an important difference between the SleepImage HST and traditional level III HST, according to Edmund Shaw, MBA, vice president of marketing at SleepImage. These metrics, which include sleep fragmentation, sleep continuity, sleep quality, total sleep time, and wake after sleep onset, support clinicians when evaluating the effects of sleep apnea events.
In research published in 2019, Magnusdottir and her team recruited 110 participants who had been diagnosed with chronic insomnia. “When objectively testing this cohort for sleep apnea with a level III HSAT, measuring respiratory event index, 27 (24.5%) individuals were reclassified with moderate-severe sleep apnea, with an REI over 15, indicating COMISA, rather than just insomnia,” she explains.12
Additionally, using the SleepImage System analysis, the team identified another 10 women with moderate-severe OSA (AHI>15), for a total of 37 (33.6%) patients.12
“Sleep apnea in women is under-recognized and may be related to both gender differences in symptom presentation and a systematic bias where men are labeled as more likely to have sleep apnea and women, insomnia,” Magnusdottir says.
References
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2. Gurubhagavatula I, Baldassari C, Das A, et al. Obstructive sleep apnea national indicator report. Count on Sleep/American Academy of Sleep Medicine. 4 Apr 2023.
3. Wimms AJ, Kelly JL, Turnbull CD, et al; MERGE Trial Investigators. Mild obstructive sleep apnoea in females: post hoc analysis of the MERGE randomised controlled trial. ERJ Open Res. 2024 Feb 5;10(1):00574-2023.
4. Won CHJ, Reid M, Sofer T, Azarbarzin A, et al. Sex differences in obstructive sleep apnea phenotypes, the multi-ethnic study of atherosclerosis. Sleep. 2020 May 12;43(5):zsz274.
5. Ware JC, McBrayer RH, Scott JA. Influence of sex and age on duration and frequency of sleep apnea events. Sleep. 2000 Mar 15;23(2):165-70.
6. LoMauro A, Aliverti A. Sex and gender in respiratory physiology. Eur Respir Rev. 2021 Nov 8;30(162):210038.
7. Ragnoli B, Pochetti P, Raie A, Malerba M. Comorbid insomnia and obstructive sleep apnea (COMISA): Current concepts of patient management. Int J Environ Res Public Health. 2021 Sep 1;18(17):9248.
8. Azarbarzin A, Zinchuk A, Wellman A, et al. Cardiovascular benefit of continuous positive airway pressure in adults with coronary artery disease and obstructive sleep apnea without excessive sleepiness. Am J Respir Crit Care Med. 2022 Sep 15;206(6):767-74.
9. Malhotra RK, Kirsch DB, Kristo DA, et al; American Academy of Sleep Medicine Board of Directors. Polysomnography for obstructive sleep apnea should include arousal-based scoring: An American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2018 Jul 15;14(7):1245-7.
10. Caples SM, Anderson WM, Calero K, et al. Use of polysomnography and home sleep apnea tests for the longitudinal management of obstructive sleep apnea in adults: an American Academy of Sleep Medicine clinical guidance statement. J Clin Sleep Med. 2021 Jun 1;17(6):1287-93.
11. Sigurdur Jonsson, Hrafnkell Zahawi, Eydis Arnardottir, et al. 0311 Artificial intelligence (AI) to predict arousals in home sleep testing (HST) without electroencephalography (EEG). Sleep. 2024 May;47(suppl 1):A134.
12. Hilmisson H, Sveinsdottir E, Lange N, Magnusdottir S. Insomnia symptoms in primary care: A prospective study focusing on prevalence of undiagnosed co-morbid sleep disordered breathing. Eur J Intern Med. 2019 May;63:19-26.
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