Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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The author describes the idiosyncrasies of sleep in women, including changes that occur with the biological life cycles of menstruation, pregnancy, and menopause. Each phase increases the risk of sleep disturbance in unique ways that require distinct management. New research is revealing novel aspects of sleep pathology in women.
• Although women sleep better than men, 46% complain of trouble sleeping almost every night.
• Several sleep-related disorders, including restless legs syndrome, insomnia, and sleep-related eating disorder, are more prevalent and severe in women.
New research is revealing novel aspects of sleep pathology in women (22). Old studies had shown that snoring women had more strokes (41). In a study of 71,779 female nurses 40 through 65 years of age without previously diagnosed vascular disease followed for 8 years, the authors found that the age-adjusted relative risk of stroke was 1.60 (95% CI, 1.21 to 2.12) for occasional snorers and 1.88 (95% CI, 1.29 to 2.74) for habitual snorers. The study did not identify patients with sleep apnea, but as habitual snoring is a common marker of obstructive sleep apnea, it remains inescapable to assume that obstructive sleep apnea was the background risk factor for vascular disease. Research results show that women with sleep apnea are indeed at higher risk of stroke than men, but the mechanisms of this phenomenon remain elusive (18).
• The menstrual cycle, pregnancy, and menopause are the principal modifying factors that increase the risk of sleep disturbance.
• The cause of poor sleep quality in menopause is likely multifactorial.
In general, women sleep better than men (10). They have more deep sleep, a slower age-related decline in delta activity (the marker of deep sleep), and twice as many sleep spindles (31; 28). And yet, only 40% of women sleep well almost every night, and 46% of women complain of trouble sleeping almost every night (63). Women go through phases in their life cycle that increase the risk of sleep disturbance. The menstrual cycle, pregnancy, and menopause are the principal modifying factors.
Menstrual cycle. Menstrual-related hypersomnia is characterized by recurrent episodes of sleepiness in association with the menstrual cycle (04). The condition generally occurs within the first months following menarche. Episodes of hypersomnia last 1 week and resolve with the occurrence of menses. Oral contraceptives eliminate sleepiness, suggesting a hormonal imbalance underlying this form of hypersomnia.
Both subjective and objective sleep changes occur during the menstrual cycle. In women with premenstrual symptoms or painful menstrual cramps, decreased sleep quality in the premenstrual phase and menstruation are common. Increased sleep spindle activity has been noted from the follicular to luteal phase, suggesting progesterone effect. Luteal phase changes include reduced rapid eye movement sleep. Short sleep duration is associated with irregular menstrual cycles, and menstrual-related disorders should be considered when assessing women's sleep complaints (07).
Pregnancy. Thirty percent of pregnant women rarely or never get a good night’s sleep whereas 84% experience a sleep problem a few nights per week compared to 67% of women overall. Forty percent report symptoms of sleep disorders, including snoring, sleep apnea, or restless legs syndrome (63). More information about sleep disorders during pregnancy is covered in the “Pregnancy” section below.
There is an increased association between women with higher Epworth Sleepiness Scale (EDS) scores and planned cesarean delivery. Severe EDS (> 16) was associated with gestational diabetes in pregnant women in a small sample size (13). Future studies in larger samples need to confirm the association of severe EDS and gestational diabetes.
Postpartum. Eighty-four percent of women experience insomnia a few nights per week following delivery. Forty-two percent rarely or never get a good night’s sleep whereas 19% experience postpartum blues or depression (33). After parturition, sleep apnea improves significantly, both in REM (64 ± 11 to 22 ± 4 events per hour) and nonREM sleep (65 ± 18 to 18 ± 4 events per hour) (27).
Menopause. Postmenopausal sleep complaints increase to reach 35% to 60% of all women. In the absence of hormone replacement therapy, the risk of developing sleep apnea increases (11); in fact, in postmenopausal women, sleep apnea severity tends to equal that in men. Menopausal hot flashes display a circadian variation, with peak frequency in late evening, and are related to a change of unknown etiology in the central thermoregulatory response. Eighty percent of peri- and postmenopausal women with severe hot flashes have chronic insomnia (69). In another study of 206 menopausal women, the overall prevalence of insomnia was 4 to 5 times a week in 62% of the women, with 68.9% complaining of hot flashes (39). In a later study, the same authors found that hot flashes were associated with insomnia and polysomnographic alterations suggestive of insomnia. Hot flashes were more frequent among women with insomnia disorders (25.5%) and isolated insomnia symptoms (23.0%) when compared with good sleepers (12.6%) (p=0.01) (40).
Sleep apnea. Outside pregnancy, sleep apnea syndrome of moderate to severe intensity (Apnea Hypopnea Index [AHI], more than 15 respiratory events/hour of sleep) is found in 9% of 50- to 70-year-old women (73). For mild cases (AHI, more than five events per hour), the ratio changes to 15% of men and 10% of women. Gender differences in sleep apnea are related to anatomical differences, with more upper body fat distribution in men and increased ventilation and upper airway muscle activity caused by the hormonal action of progesterone in women (46). In general, the risk of sleep apnea increases after menopause, presumably when the influence of progesterone declines and the anatomical differences with men become less marked; the risk in women tends to approach that in men until the age of 65 years, which is the age when the prevalence of sleep apnea peaks in women. A prospective study evaluated differences in the clinical characteristics of women and men with obesity hypoventilation syndrome in a large cohort of patients with obstructive sleep apnea (06). Among 1973 consecutive patients, 617 women were diagnosed with obstructive sleep apnea, and 144 patients (96 women) suffered from obesity hypoventilation syndrome. The prevalence of obesity hypoventilation syndrome among women and men was 15.6% and 4.5%, respectively (P < 0.001), indicating that post-menopausal women with obstructive sleep apnea have the highest prevalence of obesity hypoventilation syndrome.
Central sleep apnea occurs in women with congestive heart failure (odds ratio 3.5 for women) but with much lower frequency than in men (43). Women with sleep apnea complain of headaches in the morning more frequently than men, perhaps related to allodynia (lowering of pain threshold) in women with migraines (95), a condition that is well known to affect women more often than men at all ages. On the other hand, men with sleep apnea have a higher risk of suffering motor vehicle accidents, a feared complication of sleep apnea syndrome.
In China, Chang and colleagues found that young women (35 years old and younger) with sleep apnea are at higher risk of stroke (18). Using a universal insurance claims database, Chang and colleagues identified a large cohort of patients with sleep apnea (AHI > 5/hr) using polysomnography. The authors compared the sex- and age-specific stroke risk with a control group. Stratified by age, the effects of sleep apnea on stroke risk in women decreased with age (adjusted HR 4.90, 95% CI 1.93 to 12.4 for subgroup aged 20 to 35 years; adjusted HR 1.64, 95% CI 1.01 to 2.65 for subgroup aged 36 to 50 years; adjusted HR 1.38, 95% CI 1.01 to 1.89 for subgroup aged 51 to 65 years).
Severe obstructive sleep apnea during REM sleep (REM AHI > 30) was associated with a thicker carotid intima (51). This was noted in the community-based "Sleep and Health in Women" (SHE) cohort study of 400 women. Study subjects underwent polysomnography and a high-frequency ultrasound of the common carotid artery to assess the individual thickness of the layers of the artery wall. After 10 years, the study of 201 of the original participants free of known atherosclerotic disease at baseline and without CPAP-treatment for obstructive sleep apnea and diabetes showed that severe obstructive sleep apnea during REM sleep (REM AHI > 30) was associated with a thicker intima.
In a study of 53 placentas, 10 women (19%) had obstructive sleep apnea, and the weight of their placentas was significantly higher compared with the placentas of the controls (526.1 ± 83.9 vs. 425.7 ± 95.5 g, p = 0.00) (48). The authors concluded that maternal obstructive sleep apnea is associated with increased placental weight correlating with obstructive sleep apnea severity and neonatal adiposity independently of maternal BMI. Placental leptin overexpression may mediate these findings.
Women with polycystic ovary syndrome have an increased risk for sleep-disordered breathing, which should be treated to mitigate health impacts (08). Women with polycystic ovary syndrome should be screened for sleep disordered breathing.
In a study of 774 women (40-67 years old) from 15 centers in seven countries [European Community Respiratory Health Survey (2010-2012)], middle-aged women with low serum estrogen and progesterone levels were more likely to snore and report symptoms of obstructive sleep apnea (82).
High-altitude periodic breathing. Women are more resistant to high-altitude periodic breathing than men. Males tend to have higher central apnea indices and start developing sleep-related periodic breathing at lower altitudes than women. Gender differences are maintained even after 10 days of acclimatization (52).
Restless legs syndrome. Restless legs syndrome is a frequently undiagnosed sensorimotor disorder that impairs sleep and reduces the quality of life. It is characterized by an urge to move the legs, usually with uncomfortable leg sensations, a worsening of symptoms at rest or inactivity, an aggravation of symptoms in the evening and at night, and relief with movement, walking, or stretching. Restless legs syndrome affects 5% to 10% of the general population, increases with age, and is more prevalent in women (09; 01). Blood pressure and heart rate rise with periodic limb movements, increasing the risk of hypertension and cardiovascular disease (72). Restless legs syndrome is more common in older women than in older men and appears with relative frequency during pregnancy. Restless legs syndrome affects one third of pregnant women during their third trimester and usually improves after delivery (64). The transient pregnancy restless legs syndrome form is a significant risk factor for the development of a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy. In a study, the authors found that mothers of children with ADHD had an increased risk of having restless legs syndrome (32). Another study found a possible association with serum iron level disturbances in pregnancy (60).
In a prospective study of 57,417 women (mean age 67 years) with physician-diagnosed restless legs syndrome from the Nurses' Health Study, researchers investigated total and cardiovascular disease mortality relative to those without restless legs syndrome (50). The authors found that participants with restless legs syndrome had a significantly higher risk of cardiovascular disease mortality (adjusted HR 1.43, 95% CI 1.02-2.00) relative to those without restless legs syndrome after adjustment for potential confounders. The authors concluded that women with restless legs syndrome had a higher cardiovascular disease mortality rate, which may not be fully explained by common co-occurring disorders of restless legs syndrome.
In a study of 136 participants with long-haul COVID-19 (89.7% females, age 46.9 ± 12.9 years) and 136 controls (65.4% females, age 49.2 ± 15.5), the prevalence of restless legs syndrome in females with long-haul COVID-19 was 5.7% pre-COVID-19 and 14.8% post-COVID-19 (P < .01) versus 6.7% in control females (90). The severity of restless legs syndrome was moderate in both groups. The authors concluded that the prevalence of restless legs syndrome significantly increased in the long-haul COVID-19 state, suggesting that immunological mechanisms may be at play in the production of restless legs syndrome symptoms.
Insomnia. Insomnia is defined as the repeated difficulty initiating and maintaining sleep. The difficulty sets in despite adequate opportunity to sleep and results in daytime impairment (04). Insomnia in women shows some variations mostly related to biological life cycles. The menstrual phase worsens sleep quality in 31% of menstruating women (56). Pregnant women frequently describe difficulty sleeping.
Insomnia complaints increase in menopause, an epoch in the life cycle that is associated with sleep complaints in 35% to 60% of women (97). Commonly associated disorders are pain syndromes, fibromyalgia, depression, restless legs syndrome, and nocturnal sleep-related eating disorder. Insomnia in menopause should be considered a multifactorial alteration in which aging plays an important role.
Lower sleep efficiency and more minutes awake after sleep onset were independently associated with higher circulating levels of proinflammatory factors in midlife women (66). Factors studied were interleukin-6 and von Willebrand factor antigen. The study comprised 295 peri- and postmenopausal women aged 40 to 60 years who completed 3 days of wrist actigraphy. The findings suggest that sleep disturbances are associated with greater circulating inflammation in midlife women.
Hypersomnia and excessive daytime sleepiness. In a study of sleep duration and obesity among 7094 community-dwelling Chinese adults the authors found that long sleep duration is associated with general obesity in Chinese women (93). On the contrary, among men long sleepers (≥ 9 h/d) presented lower risks of developing abdominal obesity compared with individuals who slept 7 to 8 hours/day. Menstruation-related hypersomnia may be an underrecognized disorder (88).
Sleep-related eating disorder. Sleep-related eating disorder refers to recurrent episodes of involuntary eating and drinking during partial arousals from sleep with adverse consequences. Episodes occur without control by the individual. The episodes are generally not recalled, but a small number of patients have some awareness and retain fragmented memory of the episodes. The diagnostic criteria set forth by the International Classification of Sleep Disorders (ICSD-2) include consumption of peculiar foods in bizarre combinations and at times with inedible substances, like frozen pizza, buttered cigarettes, raw bacon, cat food, coffee grounds, and cleaning solutions (04). In addition, there is sleep disruption with complaints of nonrestorative sleep, daytime fatigue, and somnolence. Sleep-related injuries may occur, and examples are burns, lacerations, poisoning, and injuries from inappropriate use of kitchen utensils or internal lesions from eating inedible substances. Patients may gain weight (mean weight gain 12.6 kg) (81) and become depressed. Sweets, pasta, peanut butter, milk, and dairy products are preferred items. Depending on the series reported, 60% to 83% of patients with sleep-related eating disorder are women (91). Sleep-related eating disorder is more common between the ages of 22 and 40 years. Episodes may occur nightly, sometimes several times per night.
The impact of nightshift work in women was investigated in a study conducted with face-to-face interviews (89). The study included 712 women diagnosed with incident invasive breast cancer before treatment and 742 age-matched controls. Night-shift work was associated with an increased risk of breast cancer (OR (95% CI): 1.34 (1.05 to 1.72)). Compared to women with a sleep duration of 6.1 to 8.9 hours per day, women who had shorter ((≤6.0 h/day) (OR (95% CI): 1.53 (1.10 to 2.12)) and longer (≥9.0 h/day) sleep duration ((OR (95% CI): 1.59 (1.17 to 2.17)) also had an increased risk of breast cancer. Daytime napping was associated with a reduced risk of breast cancer among night-shift workers (OR (95% CI): 0.57 (0.36 to 0.90)). The authors concluded that nightshift work and shorter and longer sleep duration are associated with an increased breast cancer risk.
Old age. In an actigraphic study of community-dwelling older women, longer sleep duration and greater sleep fragmentation were associated with poorer performance and impairment in some cognitive domains. Women with dementia may have driven the results of the study because disturbed sleep and cognitive performance are intrinsic to dementia (83).
Sleep disorders are common among women veterans with insomnia, sleep-disordered breathing, and insufficient sleep prevailing (57). Women veterans should be screened and treated for sleep-disordered breathing, and behavioral and life-style factors contributing to insufficient sleep should be addressed. High rates of psychiatric comorbidities, such as posttraumatic stress disorder and depression are contributing factors that complicate management.
In an analysis of sleep duration and risk of selected site-specific and groups of cancer among a large prospective cohort of women in California, the authors studied 101,609 adult females participating in the California Teachers Study (42). All sites of invasive cancer prospectively diagnosed from 1995 through 2011 were identified through linkage to the California Cancer Registry (n = 12,322). Site-specific cancers analyzed were breast (n = 5053), colorectal (n = 983), lung (n = 820), melanoma (n = 749), and endometrial (n = 957). Estrogen-mediated cancers, consisting of breast, endometrial, and ovarian cancer (n = 6458), were independently analyzed. Sleep duration was based on self-report of average time sleeping in the year prior to baseline. The authors found that site-specific cancers were generally near or below 1 for short sleepers (< 6 hours per night) and above 1 for long sleepers (10+ hours per night); confidence intervals, however, were wide. Compared to average sleepers (7 to 9 hours per night), long sleepers had an increased risk of the group of estrogen-mediated cancers (HR 1.22, 95% CI, 0.97 to 1.54, p (trend) = 0.04). The authors concluded that longer sleep may be associated with increased risk of estrogen-mediated cancers, but additional studies are warranted.
In a prospective study, the association between obstructive sleep apnea (OSA) and incident psoriasis and psoriatic arthritis was investigated in 71,598 women over an 11-year period (1997 to 2008) in the Nurses' Health Study (20). Over the follow-up period, there were 524 cases of psoriasis. The age-adjusted relative risk (RR) of psoriasis among women with obstructive sleep apnea was 2.19 (95% CI, 1.39 to 3.45). Further adjusting for night shift work, hypertension, cardiovascular disease, and type 2 diabetes, the multivariate RR was 1.91(95% CI, 1.20 to 3.05). Obstructive sleep apnea was not associated with an increased risk of psoriatic arthritis; however, the study showed that women with obstructive sleep apnea had a significantly increased risk of psoriasis.
Shorter sleep time assessed with actigraphy and poorer subjective sleep quality were associated with increased carotid atherosclerosis (carotid ultrasound-intima media thickness plaque) among midlife women (85). The associations persisted after adjusting for vascular risk factors.
In a polysomnographic study of 177 consecutive women (89 with gestational diabetes mellitus and 88 controls) in the third trimester of pregnancy, the authors found that obstructive sleep apnea (more than five episodes per hour) prevalence during the third trimester of pregnancy was not significantly different in patients with gestational diabetes mellitus than without gestational diabetes mellitus (02). Total sleep time showed an inverse relationship with insulin resistance in pregnant women. The results are interesting because obstructive sleep apnea increases the risk of type 2 diabetes and hyperinsulinemia whereas pregnancy increases the risk of obstructive sleep apnea.
Menstruation is controlled by hormonal changes, which in turn may affect sleep. Estrogen levels are higher in the follicular phase (between days 6 and 14 of the cycle) when the endometrium grows and thickens. Simultaneously, the ovarian follicles grow in response to the action of the follicle-stimulating hormone, but only one follicle will develop into a mature egg. On day 14, the ovary releases the egg in response to an increase in luteinizing hormone, a process that is known as ovulation. The luteal phase ensues as the egg travels via the fallopian tubes to the uterus where it finds a receptive lining facilitated by increasing levels of progesterone. When pregnancy fails to occur, estrogen and progesterone levels drop and the lining of the uterus is shed into the vagina during days 1 to 6 of the menstrual cycle, a phenomenon identified as menstruation. On average, the cycle is 28 days long with a range between 21 and 35 days.
Estrogen decreases REM sleep in rats, but in humans, exogenous exposure to estrogen increases REM sleep (55). Progesterone increases the latency to REM sleep and decreases the proportion of REM sleep. Progesterone is related to decreased upper airway muscle activity (26). In the luteal phase, when the influence of progesterone is maximum, upper airway muscle activity decreases and the tongue muscle activity increases, improving the opening of the upper airway during that portion of the cycle (77). Measurements of upper airway resistance have shown a lower resistance in the luteal phase.
Menopause officially ensues 1 year following cessation of menstrual periods, but hormonal changes begin 7 to 10 years before the final menses. Estradiol and progesterone secretion decrease whereas follicle-stimulating hormone and luteinizing hormone increase. The cause of poor sleep quality in menopause is likely multifactorial. Women have greater susceptibility than men to develop depression. In addition, psychosocial factors such as responsibilities towards home, children, spouse, and jobs, as well as lifestyle changes imposed by retirement coupled with increased life expectancy contribute to sleeplessness in the postmenopausal years. Loss of estrogen and progesterone lead to difficulty with sleep maintenance, but the main significant finding is fragmentation of nocturnal sleep by arousals and awakenings. In one study, sleep duration and wake after sleep onset did not vary by menopause transition (58). Elevated beta EEG power in NREM sleep was apparent among women who transitioned to post-menopause, suggesting that the menopausal transition is associated with physiological hyperarousal during sleep, and this was independent of self-reported hot flashes.
Sleep alterations caused by the aging process interact with sleep disturbances precipitated by menopausal changes. Aging is associated with advanced sleep onset and core temperature phases, at a time when light as a Zeitgeber becomes less influential in maintaining the circadian cycle. Weakening of circadian and homeostatic processes contribute to sleep disturbances. In post-menopause, older women experience a phase advancement of 1.1 hours in melatonin acrophase.
Restless legs syndrome is a dysfunction of the dopamine system. Primary restless legs syndrome is idiopathic and may be familial with a genetic background (75), whereas secondary restless legs syndrome occurs with iron deficiency, renal failure, pregnancy, and advanced peripheral neuropathy of any etiology. Iron is a cofactor necessary for the production of dopamine, and its deficiency is indicated by ferritin levels in blood of less than 50 ng/ml.
Triggering factors of sleep-related eating disorders are hypoglycemic states, Kleine-Levin syndrome, reflux esophagitis, peptic ulcer disease, and zolpidem administration (62). Cessation of smoking or drinking alcohol has also been reported as a triggering event (81). Sleep-related eating disorders should be considered a final common pathway emerging from a broad range of clinical disorders. The episodes appear in all stages of sleep and, therefore, may occur at any time during the night.
The differential diagnosis of sleep-related eating disorders should be made with the night-eating syndrome that refers to eating during nocturnal awakenings with total recall and control of the events.
Overnight ambulatory unassisted polysomnography is a reasonable test to use in the third trimester of pregnancy at home in women who snore, report sleepiness, and show hypertension. The aim would be to objectively demonstrate and measure clinically significant sleep apnea. A sleep Apnea Hypopnea Index (AHI) of five events per hour of sleep or more might lead to the indication of continuous positive airway pressure (CPAP) treatment.
The presenting complaint of restless legs syndrome and sleep-related eating disorder may be fatigue, nonrestorative sleep, or insomnia. It is important to reach a correct diagnosis because there is specific treatment in most cases. Referral to a sleep disorders center and in many instances overnight polysomnography are recommended, not only to reach a correct diagnosis but also to identify comorbid sleep-related conditions that may act as precipitating factors.
Periodic limb movements are repetitive movements of the legs, sometimes of the arms, occurring at 5- to 90-second intervals, often associated with arousals that reduce the quality of nocturnal sleep. The presence of periodic limb movements on the polysomnogram supports the diagnosis of restless legs syndrome.
Periodic limb movements can be used as an accessory diagnostic criterion in difficult to diagnose patients with restless legs syndrome (25). They may give information on restless legs syndrome severity and on the amount of sleep instability and fragmentation.
The Insomnia Symptoms Questionnaire (ISQ) is a short and cost-effective tool that can be quickly employed in large observational studies or in clinical practice where perinatal women are seen. It was evaluated in 143 pregnant women at 12-week gestation (67), and it was compared to traditional measures of sleep from sleep diaries, actigraphy, and the Pittsburgh Sleep Quality Index. The results showed that ISQ identified 12.6% of the sample as meeting a case definition of insomnia, consistent with established diagnostic criteria. The ISQ had high specificity (most greater than 85%), but sensitivity varied according to which sleep measure was used as the validating criterion. The authors concluded that insomnia is a health problem for many pregnant women at all stages in pregnancy and that the data support the validity and reliability of the ISQ to identify insomnia in pregnant women.
Recommendations to improve hot flashes include regulating the core body temperature, cooling ambient temperature, dressing in layers, drinking cold liquids, avoiding caffeine and nicotine, and losing weight. Estrogen replacement and administration of gabapentin or clonidine along with relaxation techniques have been recognized as effective remedies. Hormone replacement therapy users report better quality of sleep than nonusers, even 3 years after hormone replacement therapy, perhaps through modulation of the reticular activating system. Women should be aware that significant risks are associated with hormone replacement therapy, including increased risk of breast cancer, stroke, heart disease, and vascular dementia (34; 65; 80).
Nonpharmacologic therapy of restless legs syndrome and periodic limb movements rests on abstention from nicotine, caffeine, and alcohol as well as discontinuation of medications that exacerbate restless legs syndrome (sedating antihistamines, dopamine-receptor antagonists, and antidepressants except bupropion). Leg massages, hot baths, stretching, and walking alleviate the symptoms. Iron replacement should be added when appropriate. The goal of therapy is to maintain ferritin levels above 50 ng/ml. Treatment consists of ferrous sulfate 325 mg plus 100 mg of vitamin C, 1 hour before or up to 2 hours after a meal, 3 times daily. In severe iron deficiency expressed by a ferritin level in blood under 10 ng/ml, consideration should be given to administration of iron via intravenous infusions of 100 to 125 mg at least 2 days apart (71). Pharmacologic options are dopamine agonists such as pramipexole (92) and ropinirole, as drugs of choice, followed by gabapentin and low-potency opioids (87). Levodopa preparations are also effective but with continued use may cause augmentation, a peculiar worsening of symptoms earlier in the day. In consequence, levodopa preparations should be limited to transient situations such as long flights, car drives, and shows with forced confinement to a seat. Dopamine agonists are safe, but some individuals develop excessive somnolence and compulsive behaviors, including hypersexuality and pathologic gambling (86).
For nonpregnant women, the general approach to treatment of insomnia starts with the investigation of possible physical factors affecting the quality of sleep, including sleep apnea, restless legs syndrome, and periodic limb movements. When these conditions are suspected, referral to a sleep specialist and performance of polysomnography are indicated. Cognitive behavioral therapy alone or in combination with pharmacologic treatment with antidepressants, anxiolytics, or hypnotics is effective and most often should be preceded by a consultation with a sleep specialist. Preliminary findings support the notion that telephone-delivered cognitive behavioral therapy for treatment of chronic insomnia may be useful (05). Some individuals with insomnia may also benefit from pamphlet-delivered cognitive behavioral therapy with brief telephone support.
CBT-Meno (cognitive behavior therapy for menopausal symptoms) sessions (including psychoeducation, and cognitive and behavioral strategies for vasomotor and depressive symptoms, anxiety, sleep difficulties, and sexual concerns) were particularly effective in improving self-reported vasomotor symptoms, depressive symptoms, sleep difficulties, and sexual concerns (36). The results suggest that this protocol is effective in targeting commonly reported menopausal symptoms.
In another study, 117 postmenopausal women (56.34 ± 5.41 years) with peri- or postmenopausal onset of chronic insomnia were randomized to three treatment conditions: sleep hygiene education control, sleep restriction therapy, and cognitive-behavioral therapy for insomnia (45). Cognitive-behavioral therapy for insomnia and sleep restriction therapy reduced depressive symptoms, dysfunctional beliefs about sleep, and pre-sleep somatic hyperarousal in postmenopausal women, with cognitive-behavioral therapy for insomnia producing superior results.
In a randomized, double-blind, placebo-controlled clinical trial, three groups of 20 postmenopausal women were studied with the objective of evaluating the efficacy of venlafaxine and citalopram compared to placebo in the treatment of sleep disturbances in healthy postmenopausal women (24). The patients took venlafaxine 75 mg/daily (group I) or citalopram 20 mg/d (group II) or placebo (group III). Each patient filled out Pittsburgh sleep quality index (PSQI) and Pittsburgh and Beck depression questionnaires. The frequency and severity of daily hot flashes were measured through diaries. Citalopram and venlafaxine were equally more effective than placebo in reducing sleep disturbance and severity of hot flashes, whereas citalopram was more effective in reducing frequency of hot flashes than venlafaxine. Venlafaxine was more effective than citalopram in the treatment of depression in postmenopausal women. In another study of 546 peri- and postmenopausal women with insomnia and bothersome hot flashes, the authors concluded that cognitive behavioral therapy is a first-line treatment in healthy midlife women with insomnia symptoms and moderately bothersome hot flashes (38).
The treatment of sleep-related eating disorders includes elimination of triggering factors and treatment of underlying disorders such as sleep apnea. Topiramate is effective in doses of 100 to 200 mg at bedtime. Alternative therapies are dopamine agonists, opiates, clonazepam, bupropion, trazodone, and levodopa.
In a study of 55 early postpartum women, Zaremba and colleagues found that 45 degrees upper body elevation increased upper airway cross-sectional area and mitigated sleep apnea (96). They concluded that elevated body position might improve respiratory safety in women early after delivery.
Using data from 25,389 patients with a diagnosis of obstructive sleep apnea (OSA) selected from the Danish National Patient Registry for the period 1999 to 2009, the authors studied all-cause mortality from obstructive sleep apnea in middle-aged and elderly males and females who were treated, or not, with CPAP (44). They found that female patients with obstructive sleep apnea had a lower mortality than males, irrespective of whether they received CPAP treatment. CPAP treatment improved survival (HR= 0.62 (P< 0.001)), and this effect was dependent on gender Survival was increased by CPAP in males 40 to 59 years of age and males greater than 60 years of age, but no such effect was observed in females. The authors concluded that CPAP therapy is associated with reduced all-cause mortality in middle-aged and elderly males, but no significant effect was found in females.
The findings of a meta-analysis of 15 studies compared with placebo revealed that hormone therapy improved self-reported sleep outcomes but not sleep parameters measured by polysomnography (70). Subgroup analyses showed that 17β-estradiol and conjugated equine estrogens improved sleep quality, whereas transdermal administration was more beneficial than oral administration (P < 0.00001). The combination of estrogen and progesterone had a beneficial effect on sleep disturbance (P < 0.00001), whereas estrogen monotherapy did not. The results also showed that estrogen/micronized progesterone and estrogen/medroxyprogesterone acetate could alleviate sleep disturbance. The authors concluded that hormone therapy has some beneficial effect on sleep disturbance, whereas the formulations and routes of administration influence the effect size.
• Sleep apnea affects 10% of pregnant women, particularly those who are obese, with the incidence reaching a peak in the third trimester of pregnancy.
• The notion of a pathogenic link between sleep apnea and preeclampsia opens opportunities for prevention and treatment.
Thirty percent of pregnant women rarely or never get a good night’s sleep whereas 84% experience a sleep problem a few nights per week compared to 67% of women overall. Forty percent report symptoms of sleep disorders, including snoring, sleep apnea, or restless legs syndrome (63). The diagnosis of insomnia during pregnancy has increased over time, disparately affecting women of low socioeconomic status. A diagnosis of insomnia is an independent predictor of severe maternal morbidity (47).
Women experience significant sleep disruption, inadequate sleep, and high rates of symptoms of sleep disorder throughout pregnancy. In a study of 2427 women, subjects completed an internet-based survey that included the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, vitality scale of the Short Form 36 Health Survey (SF-36) along with the Insomnia Severity Index (ISI), Berlin questionnaire, International Restless Legs Syndrome (IRLS) question set, and a short version of the Pregnancy Symptoms Inventory (PSI) (61). Across all months of pregnancy, women experienced poor sleep quality (76%), insufficient nighttime sleep (38%), and significant daytime sleepiness (49%). All women reported frequent nighttime awakenings (100%), and most women took daytime naps (78%). Symptoms of insomnia (57%), sleep-disordered breathing (19%), and restless legs syndrome (24%) were commonly observed. There was no difference across the month of pregnancy for insomnia, sleep-disordered breathing, daytime sleepiness, or fatigue. Frequent urination (83%) and difficulty finding a comfortable sleep position (79%) contributed to disturbed sleep. The authors of the study suggest that all women should be screened and treated for sleep disturbances throughout pregnancy, especially given the risks of inadequate sleep and sleep disorders on fetal, pregnancy, and postpartum negative outcomes.
During the third trimester of pregnancy, there is decreased total sleep time and increased insomnia and nocturnal awakenings as well as increased daytime sleepiness. Many women report more difficulty falling asleep and maintaining sleep. Sleep is commonly disrupted by general physical discomfort, frequent urination, back and neck pain, vivid dreams, nasal congestion, leg cramps, fetal movements, and uterine contractions. Women with severely disrupted sleep (Wake After Sleep Onset (WASO) score of 15% or more) may have longer labors and are 5.2 times more likely to have C-sections (33).
Snoring increases during pregnancy (53). As many as 14% of pregnant women snore, compared to 4% of non-pregnant women, and 7% report witnessed apneic spells. Predictably, snoring is more common in obese pregnant women than in nonobese pregnant women (76); and for obvious anatomical reasons, symptoms of sleep apnea increase significantly from the first trimester to the month of delivery. In the few studies that have been conducted, predictors of sleep apnea were high Body Mass Index (BMI) and change in neck circumference. In a survey of over 500 pregnant women, snoring was reported every day during the last week of pregnancy in 23% of women, as compared to 4% of the same women prior to pregnancy (30). Snorers were more likely to develop hypertension and preeclampsia during pregnancy, as well as growth retardation of the fetus. Comorbid insomnia/habitual snoring were associated with adverse outcomes even after accounting for confounders in a study of pregnant women who reported disturbed sleep (68).
Pregnancy may be associated with sleep apnea. During the third trimester of pregnancy, reduced functional respiratory residual capacity due to weight gain and changes in the shape of the diaphragm and thorax increase the incidence and severity of sleep apnea. Up to 10% of pregnant women are at risk for development of sleep apnea (76), and overweight women and women with a metabolic syndrome are at particular high risk. In a study, 17 women with gestational hypertension were compared to 33 women without hypertension; overnight polysomnography was performed to evaluate for the presence of sleep apnea (17). Those with gestational hypertension were more likely to have sleep apnea (adjusted odds ratio 7.5). A 2011 study of Taiwanese women compared 791 women who had polysomnographically diagnosed sleep apnea to a larger group of women without sleep apnea (19). Pregnant women with sleep apnea showed an increased risk of having preterm and low birth weight infants, with a higher rate of preeclampsia and cesarean sections. Edema in preeclampsia may contribute to development of sleep apnea by causing upper airway obstruction (12).
An emergent body of literature has reported a distinct association between sleep apnea and preeclampsia (21). Preeclamptic toxemia is characterized by hypertension, proteinuria, and edema. Preeclampsia may affect 7% to 10% of all pregnancies in the United States (35) and constitutes a major cause of fetal and maternal morbidity and mortality. Sleep apnea in pregnancy may cause placental hypoxia. It has been hypothesized that placental ischemia is the triggering event in preeclampsia (94). Placental ischemia precipitates a cascade of active factors from the placenta that generate profound effects on the maternal cardiovascular system, causing hypertension and endothelial dysfunction. At the very least, sleep apnea is a significant contributing factor for the development of preeclampsia, in particular in pregnant women who are at high risk.
A study carried out in Buenos Aires, Argentina investigated with a questionnaire the relationship between snoring, witnessed sleep apneas, and pregnancy-induced hypertension in 456 women (74). The authors found that 156 (35%) of 447 women with singleton pregnancies snored at some point during pregnancy. Snoring was related to pregnancy-induced hypertension and preeclampsia combined, with an adjusted odds ratio of 1.82 (95% CI: 1.16-2.84; p < 0.01). The results were independent of BMI before pregnancy, weight gain during pregnancy, neck circumference, smoking, alcohol use, and age. The authors also found that daytime sleepiness was more prevalent in snoring women and concluded that snoring and witnessed sleep apneas were independently related to pregnancy-induced hypertension.
In a study of 17 women with preeclamptic toxemia and 25 matched women with uncomplicated pregnancy, subjects underwent a nocturnal ambulatory sleep study (using Watch_PAT100) and noninvasive evaluation of endothelial function utilizing the reactive hyperemia test (using Endo_PAT 2000) (94). The authors found that endothelial dysfunction and sleep apnea coexisted in women with preeclamptic toxemia compared with controls and suggested that endothelial dysfunction and sleep-disordered breathing were associated with each other without proving causality.
Although the ultimate study has not been done in pregnant women, it stands to reason that the clinical protocols used to treat sleep apnea in adult nonpregnant women should be considered also in pregnant women. Guilleminault and colleagues conducted a study based on the premise that a significant overlap exists between risk factors for preeclampsia and sleep-disordered breathing (37). The work was a prospective, longitudinal investigation designed to characterize sleep-related breathing patterns in pregnant women with risk factors of preeclampsia and to describe the effects of early nasal CPAP therapy in these patients. Twelve pregnant women with risk factors of preeclampsia underwent polysomnography to identify sleep-related breathing abnormalities and measure baseline blood pressure. Patients with sleep apnea underwent nasal CPAP titration and were treated with optimal pressures. In addition, they received periodic assessments of CPAP compliance and tolerance, sleep quality, and blood pressure control until delivery or onset of preeclampsia. Additional CPAP retitration was performed between weeks 20 and 22 of pregnancy. Based on the results of the study, the authors concluded that early application of nasal CPAP in pregnant women alleviated sleep-related breathing disturbances but was not sufficient to prevent negative pregnancy outcomes. Obesity and prior preeclampsia were associated with the worst complications. In their view, nasal CPAP applications could be beneficial to decrease severity of outcomes, particularly if individualized to risk factors, like hypertension at the onset of pregnancy.
In a parallel study conducted in Sao Paulo, Brazil, Poyares and colleagues evaluated the possible benefit of CPAP applications in pregnant women with chronic snoring and hypertension early in pregnancy (78). Subjects were randomized to receive either CPAP with standard prenatal care (treatment group) or standard prenatal care alone (control group) with routine obstetric follow-up. In the treatment group (n=7), blood pressure was noted to decrease significantly as compared to the control group, with associated decreases in doses of antihypertensive medications at 6 months of gestation. All treated patients experienced uncomplicated pregnancies and delivered infants with higher APGAR scores compared to those of controls. The authors concluded that in pregnant women with hypertension and chronic snoring, nasal CPAP applications during the first 8 weeks of pregnancy combined with standard prenatal care are associated with better blood pressure control and improved pregnancy outcomes.
Offspring of mothers with sleep disordered breathing may have a smaller mean head circumference at birth (-0.95 ± 0.70 vs. -0.30 ± 0.71, P = 0.004) and a distinctive pattern of catchup growth by the end of the first year of life (14). Offspring may also exhibit increased mean adiposity at birth and a distinctive pattern of increased triceps thickness at 3 years of age. The findings suggest that isolated maternal sleep disordered breathing during pregnancy may affect longitudinal head circumference growth and adiposity acquisition in the fetus including the first 3 years of life.
In one study of 686 Asian pregnant women, 43.1% had poor sleep quality and 11.2% were diagnosed as short sleepers; 19.1% were diagnosed with gestational diabetes mellitus (15). Poor sleep quality and short nocturnal sleep duration were independently associated with increased risk of gestational diabetes mellitus (poor sleep, adjusted OR = 1.75, 95% confidence interval [CI] 1.11 to 2.76; short sleep, adjusted OR = 1.96, 95% CI 1.05 to 3.66). The authors concluded that Asian women with poor sleep quality or short nocturnal sleep duration during pregnancy exhibited a higher prevalence of abnormal glucose regulation.
In a study of 192 pregnant women with a median BMI of 35.14 kg/m2 using home sleep testing at 11.14 and 15.35 gestational weeks, respectively, sleep-disordered breathing and insulin resistance were associated in early pregnancy (79). There was a dose-response association between respiratory event index severity and insulin resistance.
Twenty percent to 25% of women experience restless legs syndrome during pregnancy, generally in the second half (84). Symptoms stop soon after delivery, but the occurrence of restless legs syndrome may herald a recurrence later in life. In a Brazilian study the prevalence of restless legs syndrome during pregnancy was 13.5%, and 90% of the cases started with symptoms during pregnancy. It occurred especially during the third trimester (03). In another study women who presented restless legs in a previous pregnancy had a significant 4-fold increased risk of developing chronic restless legs syndrome (16).
In a study of possible risk factors for developing restless legs syndrome in pregnant women, the authors found significantly lower hemoglobin levels with signs of hypochromic anemia typical of iron deficiency in restless legs syndrome-positive respondents to a questionnaire, although oral iron supplementation was significantly higher in this group (60). The overall severity of symptoms correlated inversely with hemoglobin level. They concluded that serum iron level disturbances may play an important role in the pathophysiology of secondary restless legs syndrome in pregnant women.
A systematic review of the prevalence of restless legs syndrome in the third trimester of pregnancy was conducted up to 2019 by Darvishi and colleagues (23). Ten articles capturing 2431 subjects within the age range of 25 to 39 years revealed a prevalence of restless legs syndrome in the third trimester of pregnancy of 22.9% (95% CI:14.7%-33.8%). The prevalence increased as the age of the subjects advanced (P < 0.05).
Opiates are the safest pharmacologic choice for treatment of restless legs syndrome during pregnancy.
Medications to treat insomnia are generally unsafe during pregnancy. In the classification developed by the United States Food and Drug Administration, drugs are classified according to their known adverse effect on the fetus both in animals and humans (59). Common hypnotics such as eszopiclone, zaleplon, and zolpidem are categorized as class C drugs; benzodiazepines are categorized as class D; and diphenhydramine occasionally used to induce sleep is categorized as class B. Pregnant women who develop severe insomnia should resort to nonpharmacologic measures, such as improving sleep hygiene, exercising as recommended by the obstetrician, and avoiding the supine position in sleep. The snore shirt may be of help. It consists of a T-shirt with three soft cylinders or tennis balls sewed to the back. The discomfort produced when turning on the back, forces the individual to sleep on her side. Naps during the day are acceptable if short and not too close to bedtime.
In a study, acupuncture was shown to significantly improve the sleep quality in pregnant women, possibly through increasing melatonin secretion (29). Acupuncture may be recommended as a low-cost, low-risk treatment alternative.
Obese parturients are prone to anesthetic complications such as aspiration of gastric contents, difficult monitoring, positioning, airway management, and challenging neuraxial techniques. A thorough pre-cesarean delivery preparation should include an evaluation by an anesthesiologist for women with a body mass index over 40 kg/m2. Regional anesthesia should ideally be used in all obese parturients unless contraindicated (54).
The information in this article has been adapted from articles that originally appeared in Practical Neurology (2009; vol. 8, numbers 5 and 9).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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