Sleep Breath DOI 10.1007/s11325-014-1099-1
ORIGINAL ARTICLE
Central sleep apnea in pregnant women with sleep disordered breathing Ghada Bourjeily & Katherine M. Sharkey & Jeffrey Mazer & Robin Moore & Susan Martin & Richard Millman
Received: 22 July 2014 / Revised: 8 December 2014 / Accepted: 9 December 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Physiologic changes in the cardiac, respiratory, and renal systems in pregnancy likely impact ventilatory control. Though obstructive sleep apnea and snoring are common in the pregnant population, the predisposition to central respiratory events during sleep and the prevalence of such events is less well studied. The aim of this study was to assess the presence of central apneas during sleep in pregnant women and nonpregnant controls suspected of sleep disordered breathing. Methods Twenty-five pregnant women referred for polysomnography for sleep disordered breathing were compared with non-pregnant controls matched for age, body mass index, gender, and apnea hypopnea index (AHI). Central apnea index was defined as the number of central apneas per hour of sleep, and mixed apnea index was defined as the number of mixed apneas per hour of sleep. G. Bourjeily (*) Department of Medicine, The Warren Alpert Medical School of Brown University, The Miriam Hospital, 146 West River St., Suite 11C, Providence, RI 02904, USA e-mail: [email protected] K. M. Sharkey : R. Millman The Warren Alpert Medical School of Brown University, Sleep Disorders Center, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903, USA J. Mazer The Warren Alpert Medical School of Brown University, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906, USA R. Moore Department of Medicine, Sleep Disorders Center, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903, USA S. Martin Women’s Medicine Collaborative, Department of Medicine, The Miriam Hospital, 146 West River St., Suite 1F, Providence, RI 02904, USA
Results Sixty-four percent of pregnant women had a respiratory disturbance index >5 events per hour of sleep. Mean body mass index was 44.1±6.9 kg/m2 pregnant compared to 44.0± 7.3 kg/m2 in controls. The total number of central apneas observed during sleep in the pregnant group consisted of two central apneas in one patient, and of 98 central apneas in 11 patients in the control group (p=0.05). Median central apnea index was low in both groups (pregnant 0, interquartile range (IQR) 0, 0 vs. non-pregnant 0, IQR 0, 0.2, p=0.04). Mixed apnea index was similarly low in both groups. Conclusion Despite some physiologic changes of pregnancy that impact ventilatory control, the prevalence of central sleep apnea was low in our sample of overweight pregnant women with sleep-disordered breathing. Keywords Sleep-disordered breathing . Pregnancy . Central sleep apnea . Obstructive sleep apnea . Obesity . Ventilatory control
Introduction Sleep-disordered breathing in pregnancy has gained significant attention in the recent literature. The bulk of available research has focused on snoring and obstructive sleep apnea. Numerous studies have shown a high prevalence of sleepdisordered breathing in this population, up to 35 % in some studies [1–3]. Recent data also have shown a significant association between sleep-disordered breathing and adverse pregnancy outcomes. Pregnant women with habitual snoring [1, 2] or obstructive sleep apnea [4, 3] have an elevated risk of gestational hypertension; similarly, women with gestational hypertension are at a higher risk of having sleep-disordered breathing than normotensive pregnant women [5, 6]. Pregnant women with habitual snoring [1, 7, 8] and obstructive sleep apnea [4] also have an elevated risk of gestational diabetes
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compared to controls. Furthermore, women with gestational diabetes have a higher incidence of sleep-disordered breathing compared to controls [9]. The association of sleep-disordered breathing with adverse fetal and neonatal outcomes has been less consistent, with results varying depending on definitions of outcomes, confounders, methods used to define sleepdisordered breathing, and populations being studied [10, 11]. Central sleep apnea in pregnant women has not been as well studied. Central sleep apnea is due to a temporary failure of the pontomedullary pacemaker that generates the breathing rhythm, resulting in a lack of brainstem inspiratory neural output [12]. During non-rapid eye movement (NREM) sleep, respiration is critically dependent on chemical influences, namely that of the arterial carbon dioxide tension (PaCO2). Central apnea results if arterial PaCO2 drops below a highly sensitive “apneic threshold” [13], which is usually 4–5 mmHg below resting PaCO2. Hence, central apnea mainly occurs as a result of hyperpnea resulting in a ventilatory overshoot and a PaCO2 level that is below the apnea threshold, leading to central apnea. This phenomenon is then followed by a rise in arterial carbon dioxide which in turn restores the breathing rhythm [14]. This cascade of events then reoccurs as hyperpnea persists. During wakefulness, hyperventilation is not followed by apneas, since a short-term potentiation of the central respiratory motor output persists following cessation of the ventilatory stimulus, causing ventilation to slowly return to eupneic levels [15]. However, during sleep, a possible reduction in the CO2 drive to breathe overrides this protective mechanism, unmasking a sensitive apnea threshold. Ventilatory control mechanisms are different in men and women [16], with ventilation in pregnancy being influenced by unique stimuli compared to the general non-pregnant population (see Fig. 1 for the proposed physiologic model). Progesterone, a respiratory drive stimulant that rises six- to eightfold during the course of pregnancy [17], likely plays an important role. Progesterone increases the sensitivity of the
Fig. 1 Physiological changes of pregnancy and ventilatory control
central chemoreflex response to CO2 [18, 19], resulting in chronic hyperventilation. Hence, it is possible that respiratory instability occurs in gravidas. However, it is also possible that due to the ongoing respiratory drive stimulation expected with increasing levels of progesterone, respiratory drive stimulation may persist despite a reduction in PaCO2. The 20 % increase in oxygen consumption, and the rise in metabolic rate, and carbon dioxide production that occur in response to the growing conception products are also likely stimulants of ventilation during pregnancy [20] and may protect against the development of central sleep apneas. However, it is also possible that these same factors may lead to ventilatory overshoot and instability. Bicarbonate secretion increases in pregnancy [21], partially compensating for the physiologic hyperventilation. The end result of all these changes is a physiologic bicarbonate level of 18–22 [21], pH of 7.42–7.46, and a PaCO2 range of 26–32 [22]. Hence, it remains unclear how these physiologic changes impact ventilatory control and the prevalence of central apneic events during sleep in pregnancy. Small polysomnographic studies assessing pregnant women with and without gestational hypertension [5] and healthy asymptomatic pregnant women [23, 24] show a low prevalence of central sleep apnea. However, there are no available data on the prevalence of central apneas in women with sleepdisordered breathing being referred for polysomnography. Hence, the authors intended to examine the presence of central sleep apneas in pregnant women suspected of sleep-disordered breathing compared to matched non-pregnant controls.
Materials and methods Participants This study received an approval from the Institutional Review Board and was Health Insurance Portability and Accountability
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Act (HIPAA) compliant, and all pregnant subjects signed a consent form prior to enrollment in the study. Methods have also been described elsewhere [25, 26]. This study is a secondary analysis of a study performed to analyze differences in airflow limitation during sleep [25]. Briefly, pregnant patients were recruited from an obstetric medicine consultative practice. Women in any trimester of pregnancy with a suspicion for sleep-disordered breathing (witnessed apneas, snoring, daytime sleepiness) who were referred for an in-laboratory polysomnography were recruited. Women were excluded only if they were unable to sign the informed consent. Non-pregnant controls consisted of women referred for polysomnography for clinical suspicion of sleep-disordered breathing who we matched for gender, age, body mass index (BMI), and apnea hypopnea index (AHI). Matching for AHI was performed based on AHI severity categories (30).
central if there was no evidence of ventilatory effort on thoracoabdominal sensors. Apneas were determined to be obstructive when there was evidence of an associated ventilatory effort. Mixed apneas were defined as apneas with an initial central component followed by an obstructive component. Hypopneas were defined as a ≥30 % drop in airflow on the pressure transducer signal for more than 10 s associated with at least 4 % desaturation (recommended definition) [27]. Respiratory effort-related arousal was defined as an arousal preceded by flattening of the nasal pressure signal. Apnea hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of sleep, and the respiratory disturbance index (RDI) as the number of apneas, hypopneas, and respiratory effort-related arousals per hour of sleep. The central apnea index (CAI) was defined as the total number of central apneas divided by the total number of hours of sleep. Mixed apnea index was defined as the number of mixed apneas per hour of sleep.
Polysomnography Statistical analysis In laboratory polysomnography data included electrooculograms from bilateral canthi, electroencephalography, submental electromyogram, bilateral tibial electromyogram, electrocardiographic monitoring, pulse oximetry, body position, snoring, and nasal pressure transducer on a DC channel per American Academy of Sleep Medicine (AASM) recommendations. Piezoelectric strain sensors were used to measure chest/abdominal movement for earlier studies, and inductance plethysmography was used for later studies per laboratory protocol. A thermal sensor (SleepSense Nasal/Oral Thermocouple sensor, S. L.P. Inc., Elgin, IL, USA) was inserted under the nares with an oral piece adjusted over the mouth and used to detect absence of airflow. A nasal air pressure transducer (Pro-Tech Pressure Transducer Airflow —PTAF 2 or Pro-tech PTAF Lite-Respironics, Andover, MA) was used for the scoring of hypopnea. Low-frequency filter for nasal airflow was standardized at 0.1 Hz and highfrequency filter at 15 Hz, with a sampling rate of 100 Hz. The SomnoStar Pro (Viasys Inc., Yorba Linda, CA) and XLTEC (Natus, Inc., San Carlos, CA) data acquisition systems were used to record polysomnographic data. Patients were encouraged to sleep in the supine position and were awakened in the morning by technicians per clinical protocol. Polysomnography data were scored according to the American Academy of Sleep Medicine recommendations published in 2007 [27] by a registered polysomnography technician, blinded to pregnancy status (RM). Apneas were defined as a drop in peak thermal sensor excursion of at least 90 % from baseline lasting at least 90 % of the whole event, with the event lasting for at least 10 s. Central apneas and mixed apneas were scored both in rapid eye movement (REM) and non-rapid eye movement sleep (NREM); those within 10 s of an arousal were excluded. Apneas were defined as
Standard statistical analysis was performed using Microsoft Excel® and SAS 9.2. Normal probability plots were assessed for the reported variables. Shapiro Wilk test was also performed to assess normality of data. Descriptive data were then reported as mean and standard deviation or as medians and interquartile range, depending on whether data were parametric or non-parametric. As some of the sleep data were nonnormally distributed, all polysomnography data were reported as median and interquartile range. Paired t test was used for comparison of cases and controls.
Results Patient characteristics The study compared 25 matched case–control pairs. As expected, there were no significant differences in age and BMI in matched cases and controls (Table 1). Mean gestational age at the time of polysomnography was 26.6±7.6 weeks in the pregnant group. None of the women in the study had a history of heart disease, cerebrovascular disease, or prior diagnosis of central sleep apnea. Eight percent of pregnant women had pregestational diabetes (type II) and 16 % had chronic hypertension. Twenty-four of 25 patients in each group reported habitual snoring. One patient in each group was unsure of snoring. Women in the pregnant group tended to have a higher Epworth Sleepiness Scale score than the control group (p= 0.07). In the pregnant group, prenatal vitamins were the most common medication recorded (19/25), followed by a beta blocker (6/25). One patient received trazodone and another received acetazolamide—but not for the treatment of central
Sleep Breath Table 1
Demographics of cases and controls Pregnant cases
Non-pregnant controls
Age (years) BMI (kg/m2) Gestational age at PSG (weeks) Gestational hypertension (%)
31.1±5.8 44.1±6.9 26.6±7.9 24 %
31.4±5.8 44.0±7.3 – –
Gestational diabetes (%) Epworth Sleepiness Scale score (range: 0–24)
36 % 12 (IQR 7, 16)
– 9 (IQR 3, 13.5)
BMI body mass index, PSG polysomnography, IQR interquartile range
sleep apnea. In the non-pregnant group, 11/25 patients were receiving an anti-depressant medication (selective serotonin reuptake inhibitor, selective serotonin and norepinephrine reuptake inhibitor, or bupropion), 6/25 a benzodiazepine, and 2/25 trazodone. Four patients in the pregnant group and three in the control group were on asthma medications. Polysomnography The difference in time in bed in pregnant women compared to non-pregnant controls was not statistically significant. Pregnant women slept on average close to 45 min less than non-pregnant controls (see Table 2). Arousal index was similar in cases and controls. There were no significant differences in sleep efficiency between pregnant and non-pregnant women. Sleep apnea severity based on apnea hypopnea index and respiratory disturbance index was similar in both groups. Nearly 32 % of women in both groups had OSA defined by AHI≥5 events per hour of sleep and 64 % had OSA defined by RDI≥5 events per hour of sleep.
Central apneas were rare in both groups of young women. The total number of central apneas in the pregnant group occurring during sleep consisted of two central apneas in one subject in the pregnant group, and a total of 98 central apneas in 11 subjects in the non-pregnant group, resulting in a median central apnea index of 0, interquartile range (IQR) 0–0, and 0, IQR 0–0.2, p=0.04 in the pregnant and control groups respectively (Table 2). The prevalence of mixed apneas was also rare in both groups. There were a total of two mixed apneas in the pregnant group and three in the control group. There were too few events in the pregnant group to compare the prevalence of these events in the rapid eye movement and non-rapid eye movement sleep.
Discussion Despite physiologic changes of pregnancy that may predispose to central respiratory events, the prevalence of central sleep apnea is rare in young, overweight women with sleepdisordered breathing. The current study adds to the existing literature by informing about the occurrence of one of the breathing-related sleep disorders in pregnancy. Though central apneas occurred more frequently in non-pregnant controls, the clinical significance of such a finding is not clear as central sleep apnea index was very low in both groups. The low prevalence of central events during sleep may be genderrelated as women are in general protected from central sleep apnea. However, our study does refute the hypothesis that pregnant women are more likely to develop central sleep apnea due to chronic hyperventilation. Progesterone is a strong respiratory stimulant and the hormone has been used therapeutically in a variety of respiratory conditions, including central sleep apnea [28, 29].
Table 2 Sleep and respiratory parameters in pregnant cases and non-pregnant-matched controls Sleep parameters Time in bed (min) Total sleep time (min) N1 (% of TST) N2 (% of TST) N3 (% of TST) REM (% of TST) Sleep efficiency (%) IQR interquartile range, TST total sleep time, N1 stage N1 sleep, N2 stage N2 sleep, N3 stage N3 sleep, REM rapid eye movement sleep, AHI apnea hypopnea index, RDI respiratory disturbance index, CAI central apnea index, MAI mixed apnea index
Arousal index (events per hour) Respiratory parameters (events per hour) AHI RDI CAI MAI
Pregnant cases median (IQR)
Non-pregnant controls median (IQR)
p value
389 (354, 413) 308 (195, 351) 6 (4, 11) 55 (51, 59) 23 (14, 30) 14 (9, 17) 78 (55, 87)
409 (379,424) 355 (302, 386) 7 (5, 14) 55 (44, 64) 22 (16, 29) 10 (6, 19) 85 (71, 91)
0.07 0.03 0.7 0.8 0.6 0.7 0.2
16 (11.9, 24.9)
18.6 (13.7, 22.9)
0.9
1.3 (0.2, 7.1) 7.8 (2.8,14) 0 (0, 0) 0 (0, 0)
3.1 (0.8, 5.9) 12.3 (6.7, 20.5) 0 (0, 0.2) 0 (0, 0)
0.3 0.2 0.04 0.5
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Medroxyprogesterone acetate administered to postmenopausal women with hypercapnic respiratory failure [30] has resulted in significant reductions in arterial carbon dioxide levels. Similar reductions in arterial carbon dioxide levels were observed in women with partial upper airway obstruction during sleep [31]. These reductions appeared to be more pronounced than those observed following continuous positive airway pressure therapy [31]. Studies by the same group suggest that administration of medroxyprogesterone acetate also increases volumes of inspiratory flow shapes in postmenopausal women [32]. Despite these clear effects of progesterone on ventilation and the subsequent physiologic reduction in PaCO2 in the pregnant population, the low prevalence of central apneas in pregnancy can be explained in different ways. The progressive rise in progesterone levels in pregnancy may lead to an adaptation of the central respiratory drive, with the physiologic PaCO2 in pregnancy remaining above the apneic threshold, hence leading to the low prevalence of central apneas in the pregnant group. It is also possible that the apnea threshold may shift during pregnancy in response to the physiologic reduction in PaCO2, thereby lowering PaCO2 threshold needed to induce an apnea compared with the threshold outside of pregnancy. Another possible explanation of our findings is the drop in serum bicarbonate which partially compensates for hypocapnia, lowering serum pH. Furthermore, the significant rise in cardiac output that reaches 45 % above preconception levels in singleton pregnancies [33] may also be protective. The role that the progressive rise in ventilatory and oxygen requirements by the conception products may play in ventilatory control has not been studied experimentally and is poorly understood. Thus, on one hand, high demands may result in a cascade of physiologic changes that constitute a ventilatory stimulus protecting against central apneic events. On the other hand, high demands could also lead to ventilatory instability, similar to that seen in chronic hypoxia models such as high altitude [34]. Findings from this study cannot be extrapolated to the pregnant population in general, as our sample was at risk for sleep-disordered breathing. A study by Trakada et al. [24] has assessed 11 healthy pregnant women with polysomnography around 36 weeks of gestation and again 4 to 6 months postpartum. The study showed a low AHI (0.35) close to term in pregnancy and reported that events consisted of either central apneas or hypopneas, without the presence of obstructive apneas. A comparable study by Brownell et al. showed similar findings [23]. Our data were similar but tested the prevalence of central apneas in a population with clinical signs and symptoms of sleep-disordered breathing, rather than a healthy population. Furthermore, the study by Trakada et al. has described an increase in apneic and hypopneic events in the postpartum period compared to the third trimester of pregnancy. The same study also reported an increase in the mean apnea and hypopnea duration in the postpartum period, where all apneic episodes were central in nature. It is possible,
therefore, that pregnancy does in fact carry a protective effect against central apnea which may be explained by the physiologic model detailed above (Fig. 1). This study, being a secondary analysis, has some limitations that include a small sample size. Timing of sleep study in relation to the menstrual cycle was not collected due to the retrospective nature of the control selection; however, progesterone levels in pregnancy are several folds higher than those observed throughout the menstrual cycle. Similarly, nonpregnant status was confirmed by record review in the control group. Weight matching between pregnant and non-pregnant women clearly has its limitations as the distribution of weight gained in pregnancy may impact sleep-disordered breathing differently than obesity. In summary, despite physiological changes expected in pregnant women such as hyperventilation, our results are reassuring in that this group of women does not appear to be predisposed to the development of clinically significant central sleep apnea. Conflict of interest The authors have no potential personal or financial conflicts of interest. Funding This study was funded by an award from the American College of Chest Physicians’ Chest Foundation for clinical research in women’s lung health.
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ORIGINAL ARTICLE
Central sleep apnea in pregnant women with sleep disordered breathing Ghada Bourjeily & Katherine M. Sharkey & Jeffrey Mazer & Robin Moore & Susan Martin & Richard Millman
Received: 22 July 2014 / Revised: 8 December 2014 / Accepted: 9 December 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Physiologic changes in the cardiac, respiratory, and renal systems in pregnancy likely impact ventilatory control. Though obstructive sleep apnea and snoring are common in the pregnant population, the predisposition to central respiratory events during sleep and the prevalence of such events is less well studied. The aim of this study was to assess the presence of central apneas during sleep in pregnant women and nonpregnant controls suspected of sleep disordered breathing. Methods Twenty-five pregnant women referred for polysomnography for sleep disordered breathing were compared with non-pregnant controls matched for age, body mass index, gender, and apnea hypopnea index (AHI). Central apnea index was defined as the number of central apneas per hour of sleep, and mixed apnea index was defined as the number of mixed apneas per hour of sleep. G. Bourjeily (*) Department of Medicine, The Warren Alpert Medical School of Brown University, The Miriam Hospital, 146 West River St., Suite 11C, Providence, RI 02904, USA e-mail: [email protected] K. M. Sharkey : R. Millman The Warren Alpert Medical School of Brown University, Sleep Disorders Center, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903, USA J. Mazer The Warren Alpert Medical School of Brown University, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906, USA R. Moore Department of Medicine, Sleep Disorders Center, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903, USA S. Martin Women’s Medicine Collaborative, Department of Medicine, The Miriam Hospital, 146 West River St., Suite 1F, Providence, RI 02904, USA
Results Sixty-four percent of pregnant women had a respiratory disturbance index >5 events per hour of sleep. Mean body mass index was 44.1±6.9 kg/m2 pregnant compared to 44.0± 7.3 kg/m2 in controls. The total number of central apneas observed during sleep in the pregnant group consisted of two central apneas in one patient, and of 98 central apneas in 11 patients in the control group (p=0.05). Median central apnea index was low in both groups (pregnant 0, interquartile range (IQR) 0, 0 vs. non-pregnant 0, IQR 0, 0.2, p=0.04). Mixed apnea index was similarly low in both groups. Conclusion Despite some physiologic changes of pregnancy that impact ventilatory control, the prevalence of central sleep apnea was low in our sample of overweight pregnant women with sleep-disordered breathing. Keywords Sleep-disordered breathing . Pregnancy . Central sleep apnea . Obstructive sleep apnea . Obesity . Ventilatory control
Introduction Sleep-disordered breathing in pregnancy has gained significant attention in the recent literature. The bulk of available research has focused on snoring and obstructive sleep apnea. Numerous studies have shown a high prevalence of sleepdisordered breathing in this population, up to 35 % in some studies [1–3]. Recent data also have shown a significant association between sleep-disordered breathing and adverse pregnancy outcomes. Pregnant women with habitual snoring [1, 2] or obstructive sleep apnea [4, 3] have an elevated risk of gestational hypertension; similarly, women with gestational hypertension are at a higher risk of having sleep-disordered breathing than normotensive pregnant women [5, 6]. Pregnant women with habitual snoring [1, 7, 8] and obstructive sleep apnea [4] also have an elevated risk of gestational diabetes
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compared to controls. Furthermore, women with gestational diabetes have a higher incidence of sleep-disordered breathing compared to controls [9]. The association of sleep-disordered breathing with adverse fetal and neonatal outcomes has been less consistent, with results varying depending on definitions of outcomes, confounders, methods used to define sleepdisordered breathing, and populations being studied [10, 11]. Central sleep apnea in pregnant women has not been as well studied. Central sleep apnea is due to a temporary failure of the pontomedullary pacemaker that generates the breathing rhythm, resulting in a lack of brainstem inspiratory neural output [12]. During non-rapid eye movement (NREM) sleep, respiration is critically dependent on chemical influences, namely that of the arterial carbon dioxide tension (PaCO2). Central apnea results if arterial PaCO2 drops below a highly sensitive “apneic threshold” [13], which is usually 4–5 mmHg below resting PaCO2. Hence, central apnea mainly occurs as a result of hyperpnea resulting in a ventilatory overshoot and a PaCO2 level that is below the apnea threshold, leading to central apnea. This phenomenon is then followed by a rise in arterial carbon dioxide which in turn restores the breathing rhythm [14]. This cascade of events then reoccurs as hyperpnea persists. During wakefulness, hyperventilation is not followed by apneas, since a short-term potentiation of the central respiratory motor output persists following cessation of the ventilatory stimulus, causing ventilation to slowly return to eupneic levels [15]. However, during sleep, a possible reduction in the CO2 drive to breathe overrides this protective mechanism, unmasking a sensitive apnea threshold. Ventilatory control mechanisms are different in men and women [16], with ventilation in pregnancy being influenced by unique stimuli compared to the general non-pregnant population (see Fig. 1 for the proposed physiologic model). Progesterone, a respiratory drive stimulant that rises six- to eightfold during the course of pregnancy [17], likely plays an important role. Progesterone increases the sensitivity of the
Fig. 1 Physiological changes of pregnancy and ventilatory control
central chemoreflex response to CO2 [18, 19], resulting in chronic hyperventilation. Hence, it is possible that respiratory instability occurs in gravidas. However, it is also possible that due to the ongoing respiratory drive stimulation expected with increasing levels of progesterone, respiratory drive stimulation may persist despite a reduction in PaCO2. The 20 % increase in oxygen consumption, and the rise in metabolic rate, and carbon dioxide production that occur in response to the growing conception products are also likely stimulants of ventilation during pregnancy [20] and may protect against the development of central sleep apneas. However, it is also possible that these same factors may lead to ventilatory overshoot and instability. Bicarbonate secretion increases in pregnancy [21], partially compensating for the physiologic hyperventilation. The end result of all these changes is a physiologic bicarbonate level of 18–22 [21], pH of 7.42–7.46, and a PaCO2 range of 26–32 [22]. Hence, it remains unclear how these physiologic changes impact ventilatory control and the prevalence of central apneic events during sleep in pregnancy. Small polysomnographic studies assessing pregnant women with and without gestational hypertension [5] and healthy asymptomatic pregnant women [23, 24] show a low prevalence of central sleep apnea. However, there are no available data on the prevalence of central apneas in women with sleepdisordered breathing being referred for polysomnography. Hence, the authors intended to examine the presence of central sleep apneas in pregnant women suspected of sleep-disordered breathing compared to matched non-pregnant controls.
Materials and methods Participants This study received an approval from the Institutional Review Board and was Health Insurance Portability and Accountability
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Act (HIPAA) compliant, and all pregnant subjects signed a consent form prior to enrollment in the study. Methods have also been described elsewhere [25, 26]. This study is a secondary analysis of a study performed to analyze differences in airflow limitation during sleep [25]. Briefly, pregnant patients were recruited from an obstetric medicine consultative practice. Women in any trimester of pregnancy with a suspicion for sleep-disordered breathing (witnessed apneas, snoring, daytime sleepiness) who were referred for an in-laboratory polysomnography were recruited. Women were excluded only if they were unable to sign the informed consent. Non-pregnant controls consisted of women referred for polysomnography for clinical suspicion of sleep-disordered breathing who we matched for gender, age, body mass index (BMI), and apnea hypopnea index (AHI). Matching for AHI was performed based on AHI severity categories (30).
central if there was no evidence of ventilatory effort on thoracoabdominal sensors. Apneas were determined to be obstructive when there was evidence of an associated ventilatory effort. Mixed apneas were defined as apneas with an initial central component followed by an obstructive component. Hypopneas were defined as a ≥30 % drop in airflow on the pressure transducer signal for more than 10 s associated with at least 4 % desaturation (recommended definition) [27]. Respiratory effort-related arousal was defined as an arousal preceded by flattening of the nasal pressure signal. Apnea hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of sleep, and the respiratory disturbance index (RDI) as the number of apneas, hypopneas, and respiratory effort-related arousals per hour of sleep. The central apnea index (CAI) was defined as the total number of central apneas divided by the total number of hours of sleep. Mixed apnea index was defined as the number of mixed apneas per hour of sleep.
Polysomnography Statistical analysis In laboratory polysomnography data included electrooculograms from bilateral canthi, electroencephalography, submental electromyogram, bilateral tibial electromyogram, electrocardiographic monitoring, pulse oximetry, body position, snoring, and nasal pressure transducer on a DC channel per American Academy of Sleep Medicine (AASM) recommendations. Piezoelectric strain sensors were used to measure chest/abdominal movement for earlier studies, and inductance plethysmography was used for later studies per laboratory protocol. A thermal sensor (SleepSense Nasal/Oral Thermocouple sensor, S. L.P. Inc., Elgin, IL, USA) was inserted under the nares with an oral piece adjusted over the mouth and used to detect absence of airflow. A nasal air pressure transducer (Pro-Tech Pressure Transducer Airflow —PTAF 2 or Pro-tech PTAF Lite-Respironics, Andover, MA) was used for the scoring of hypopnea. Low-frequency filter for nasal airflow was standardized at 0.1 Hz and highfrequency filter at 15 Hz, with a sampling rate of 100 Hz. The SomnoStar Pro (Viasys Inc., Yorba Linda, CA) and XLTEC (Natus, Inc., San Carlos, CA) data acquisition systems were used to record polysomnographic data. Patients were encouraged to sleep in the supine position and were awakened in the morning by technicians per clinical protocol. Polysomnography data were scored according to the American Academy of Sleep Medicine recommendations published in 2007 [27] by a registered polysomnography technician, blinded to pregnancy status (RM). Apneas were defined as a drop in peak thermal sensor excursion of at least 90 % from baseline lasting at least 90 % of the whole event, with the event lasting for at least 10 s. Central apneas and mixed apneas were scored both in rapid eye movement (REM) and non-rapid eye movement sleep (NREM); those within 10 s of an arousal were excluded. Apneas were defined as
Standard statistical analysis was performed using Microsoft Excel® and SAS 9.2. Normal probability plots were assessed for the reported variables. Shapiro Wilk test was also performed to assess normality of data. Descriptive data were then reported as mean and standard deviation or as medians and interquartile range, depending on whether data were parametric or non-parametric. As some of the sleep data were nonnormally distributed, all polysomnography data were reported as median and interquartile range. Paired t test was used for comparison of cases and controls.
Results Patient characteristics The study compared 25 matched case–control pairs. As expected, there were no significant differences in age and BMI in matched cases and controls (Table 1). Mean gestational age at the time of polysomnography was 26.6±7.6 weeks in the pregnant group. None of the women in the study had a history of heart disease, cerebrovascular disease, or prior diagnosis of central sleep apnea. Eight percent of pregnant women had pregestational diabetes (type II) and 16 % had chronic hypertension. Twenty-four of 25 patients in each group reported habitual snoring. One patient in each group was unsure of snoring. Women in the pregnant group tended to have a higher Epworth Sleepiness Scale score than the control group (p= 0.07). In the pregnant group, prenatal vitamins were the most common medication recorded (19/25), followed by a beta blocker (6/25). One patient received trazodone and another received acetazolamide—but not for the treatment of central
Sleep Breath Table 1
Demographics of cases and controls Pregnant cases
Non-pregnant controls
Age (years) BMI (kg/m2) Gestational age at PSG (weeks) Gestational hypertension (%)
31.1±5.8 44.1±6.9 26.6±7.9 24 %
31.4±5.8 44.0±7.3 – –
Gestational diabetes (%) Epworth Sleepiness Scale score (range: 0–24)
36 % 12 (IQR 7, 16)
– 9 (IQR 3, 13.5)
BMI body mass index, PSG polysomnography, IQR interquartile range
sleep apnea. In the non-pregnant group, 11/25 patients were receiving an anti-depressant medication (selective serotonin reuptake inhibitor, selective serotonin and norepinephrine reuptake inhibitor, or bupropion), 6/25 a benzodiazepine, and 2/25 trazodone. Four patients in the pregnant group and three in the control group were on asthma medications. Polysomnography The difference in time in bed in pregnant women compared to non-pregnant controls was not statistically significant. Pregnant women slept on average close to 45 min less than non-pregnant controls (see Table 2). Arousal index was similar in cases and controls. There were no significant differences in sleep efficiency between pregnant and non-pregnant women. Sleep apnea severity based on apnea hypopnea index and respiratory disturbance index was similar in both groups. Nearly 32 % of women in both groups had OSA defined by AHI≥5 events per hour of sleep and 64 % had OSA defined by RDI≥5 events per hour of sleep.
Central apneas were rare in both groups of young women. The total number of central apneas in the pregnant group occurring during sleep consisted of two central apneas in one subject in the pregnant group, and a total of 98 central apneas in 11 subjects in the non-pregnant group, resulting in a median central apnea index of 0, interquartile range (IQR) 0–0, and 0, IQR 0–0.2, p=0.04 in the pregnant and control groups respectively (Table 2). The prevalence of mixed apneas was also rare in both groups. There were a total of two mixed apneas in the pregnant group and three in the control group. There were too few events in the pregnant group to compare the prevalence of these events in the rapid eye movement and non-rapid eye movement sleep.
Discussion Despite physiologic changes of pregnancy that may predispose to central respiratory events, the prevalence of central sleep apnea is rare in young, overweight women with sleepdisordered breathing. The current study adds to the existing literature by informing about the occurrence of one of the breathing-related sleep disorders in pregnancy. Though central apneas occurred more frequently in non-pregnant controls, the clinical significance of such a finding is not clear as central sleep apnea index was very low in both groups. The low prevalence of central events during sleep may be genderrelated as women are in general protected from central sleep apnea. However, our study does refute the hypothesis that pregnant women are more likely to develop central sleep apnea due to chronic hyperventilation. Progesterone is a strong respiratory stimulant and the hormone has been used therapeutically in a variety of respiratory conditions, including central sleep apnea [28, 29].
Table 2 Sleep and respiratory parameters in pregnant cases and non-pregnant-matched controls Sleep parameters Time in bed (min) Total sleep time (min) N1 (% of TST) N2 (% of TST) N3 (% of TST) REM (% of TST) Sleep efficiency (%) IQR interquartile range, TST total sleep time, N1 stage N1 sleep, N2 stage N2 sleep, N3 stage N3 sleep, REM rapid eye movement sleep, AHI apnea hypopnea index, RDI respiratory disturbance index, CAI central apnea index, MAI mixed apnea index
Arousal index (events per hour) Respiratory parameters (events per hour) AHI RDI CAI MAI
Pregnant cases median (IQR)
Non-pregnant controls median (IQR)
p value
389 (354, 413) 308 (195, 351) 6 (4, 11) 55 (51, 59) 23 (14, 30) 14 (9, 17) 78 (55, 87)
409 (379,424) 355 (302, 386) 7 (5, 14) 55 (44, 64) 22 (16, 29) 10 (6, 19) 85 (71, 91)
0.07 0.03 0.7 0.8 0.6 0.7 0.2
16 (11.9, 24.9)
18.6 (13.7, 22.9)
0.9
1.3 (0.2, 7.1) 7.8 (2.8,14) 0 (0, 0) 0 (0, 0)
3.1 (0.8, 5.9) 12.3 (6.7, 20.5) 0 (0, 0.2) 0 (0, 0)
0.3 0.2 0.04 0.5
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Medroxyprogesterone acetate administered to postmenopausal women with hypercapnic respiratory failure [30] has resulted in significant reductions in arterial carbon dioxide levels. Similar reductions in arterial carbon dioxide levels were observed in women with partial upper airway obstruction during sleep [31]. These reductions appeared to be more pronounced than those observed following continuous positive airway pressure therapy [31]. Studies by the same group suggest that administration of medroxyprogesterone acetate also increases volumes of inspiratory flow shapes in postmenopausal women [32]. Despite these clear effects of progesterone on ventilation and the subsequent physiologic reduction in PaCO2 in the pregnant population, the low prevalence of central apneas in pregnancy can be explained in different ways. The progressive rise in progesterone levels in pregnancy may lead to an adaptation of the central respiratory drive, with the physiologic PaCO2 in pregnancy remaining above the apneic threshold, hence leading to the low prevalence of central apneas in the pregnant group. It is also possible that the apnea threshold may shift during pregnancy in response to the physiologic reduction in PaCO2, thereby lowering PaCO2 threshold needed to induce an apnea compared with the threshold outside of pregnancy. Another possible explanation of our findings is the drop in serum bicarbonate which partially compensates for hypocapnia, lowering serum pH. Furthermore, the significant rise in cardiac output that reaches 45 % above preconception levels in singleton pregnancies [33] may also be protective. The role that the progressive rise in ventilatory and oxygen requirements by the conception products may play in ventilatory control has not been studied experimentally and is poorly understood. Thus, on one hand, high demands may result in a cascade of physiologic changes that constitute a ventilatory stimulus protecting against central apneic events. On the other hand, high demands could also lead to ventilatory instability, similar to that seen in chronic hypoxia models such as high altitude [34]. Findings from this study cannot be extrapolated to the pregnant population in general, as our sample was at risk for sleep-disordered breathing. A study by Trakada et al. [24] has assessed 11 healthy pregnant women with polysomnography around 36 weeks of gestation and again 4 to 6 months postpartum. The study showed a low AHI (0.35) close to term in pregnancy and reported that events consisted of either central apneas or hypopneas, without the presence of obstructive apneas. A comparable study by Brownell et al. showed similar findings [23]. Our data were similar but tested the prevalence of central apneas in a population with clinical signs and symptoms of sleep-disordered breathing, rather than a healthy population. Furthermore, the study by Trakada et al. has described an increase in apneic and hypopneic events in the postpartum period compared to the third trimester of pregnancy. The same study also reported an increase in the mean apnea and hypopnea duration in the postpartum period, where all apneic episodes were central in nature. It is possible,
therefore, that pregnancy does in fact carry a protective effect against central apnea which may be explained by the physiologic model detailed above (Fig. 1). This study, being a secondary analysis, has some limitations that include a small sample size. Timing of sleep study in relation to the menstrual cycle was not collected due to the retrospective nature of the control selection; however, progesterone levels in pregnancy are several folds higher than those observed throughout the menstrual cycle. Similarly, nonpregnant status was confirmed by record review in the control group. Weight matching between pregnant and non-pregnant women clearly has its limitations as the distribution of weight gained in pregnancy may impact sleep-disordered breathing differently than obesity. In summary, despite physiological changes expected in pregnant women such as hyperventilation, our results are reassuring in that this group of women does not appear to be predisposed to the development of clinically significant central sleep apnea. Conflict of interest The authors have no potential personal or financial conflicts of interest. Funding This study was funded by an award from the American College of Chest Physicians’ Chest Foundation for clinical research in women’s lung health.
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