Keywords

Insomnia

Menarche and Adolescence

Insomnia is more common in females than males throughout life. The gender distinction first becomes apparent around menarche (Tanner stage 4) with a 3.6-fold increase in girls (3.4–12.2%) vs boys with a 2.1-fold increase (4.3–9.1%) from Tanner stage 1–5 [1]. Insomnia symptoms may cycle with menses, in part relating to the hormonal fluctuations. In girls with dysmenorrhea, sleep disturbance is common, typically associated with abdominal cramps and pain. Mood disorders, with greater predominance in woman, also increase at menarche. Dysmenorrhea is also associated with a higher frequency of depression that may also contribute insomnia complaints [2].

Child-Bearing Years

Pregnancy

Insomnia is common during pregnancy , with an increasing incidence from first to third trimester. It ranges from 13% in the first trimester, 19% in the second and 66% by the third trimester. The severity of insomnia complaints ranges from mild (50.5%), moderate (15.7%) to severe (8.8%). The most common feature is difficulty maintaining sleep (69.9%). Early morning waking (34.8%) and difficulty falling asleep (23.7%) are also frequent concerns [3,4,5,6,7,8]. A recent study noted an association of demographic markers (age, race/ethnicity, BMI, insurance status and smoking history) to be associated with sleep continuity [9].

The symptoms identified with sleep disturbance vary by trimester. In first trimester nausea, nocturia and back pain are most common, while fetal activity, heartburn, leg cramps and shortness of breath occur more so in third trimester [5,6,7]. Hormonal changes through pregnancy also lower the arousal threshold and increase sleep fragmentation [10, 11].

While sleep symptoms occur to some degree in most women, the reporting of insomnia as a problem may be more likely in those with preexisting mood and anxiety disorders. Smoking may also contribute [7, 9, 12].

Insomnia and sleep deprivation contribute to an increased inflammatory state with potential adverse effects for the mother and fetus. An increased risk of gestational diabetes, elevated blood pressure and depression has also been reported. Increased pain perception in labor, longer labor duration, increased Caesarian sections and preterm labor and delivery have been associated with insomnia and sleep deprivation [13,14,15].

Insomnia treatment decisions must the relative risk of sleep disturbance for mother vs potential fetal harm. Physical discomfort, such as nocturia and back pain, should be addressed. Behavioral measures are generally a first line treatment for insomnia, including good sleep routines and protection of time in bed for adequate sleep hours. Avoiding naps, or limiting the duration is important to minimize disruption of the sleep-wake cycle. Relaxation techniques, appropriate exercise, prenatal yoga and massage may be considered. Formal cognitive behavioral therapy for insomnia has also been shown to help [16].

Benzodiazepines and selective benzodiazepine agonists are the most common prescriptions for insomnia. Fetal risks are possible as these agents do cross the placenta. These risks may include congenital malformations, preterm birth, low birthweight. While study results vary, many did not find evidence of increased risk. Of those that did indicate risk, many did not include data on other confounding variables such as tobacco, alcohol, other medical history. Third trimester use has been associated with floppy infant syndrome and withdrawal. Although, otherwise healthy infants exposed to long term use during pregnancy did show problems with neurobehavioral development or IQ [17, 18]. Several studies have also found that diphenhydramine use in early pregnancy, did not increase risk for cardiac conditions, birth defects or other major malformations [19, 20].

Post-Partum

Pharmacologic treatment for insomnia during the post-partum period is another concern, particularly with lactation. The interrupted sleep may contribute to post-partum depression, and increased stress from the daytime demands of the infant. Many medications are found in breast milk, with potentially sedating effects on the infant. An early study on benzodiazepine usage during lactation reported low doses of these agents in breast milk. These were not found to have significant impact on the infant [17].

In conclusion, insomnia is a common condition in the general population and in pregnant and postpartum women. Symptoms should be addressed for the potential impact on maternal and fetal health. Nonpharmacologic approaches would be a first consideration when possible. The risk vs benefit of pharmacologic interventions must be carefully considered.

Menopause and Beyond

There is an increase in sleep disturbance and insomnia during the menopausal transition reported in 40–60% of women. The 2005 National Institutes of Health State-of -the-Science Conference Statement recognized sleep disturbance as a central symptom of menopause [21]. The prevalence of insomnia ranges from 16–42% in pre-menopause, 39–47% in peri-menopause and 35–60% in post-menopause. Symptoms include increased sleep fragmentation, nocturnal awakenings, and poor sleep quality, that may be associated with nocturia and incontinence or vasomotor symptoms (hot flashes, night sweats). There is an association with increased age, medical comorbidities and weight gain [21, 22]. Lower melatonin levels, with related circadian changes, also contribute to less stable sleep quality and timing [23, 24]. Those with baseline depressive symptoms, daytime sleepiness and treatment with CNS active medications have a higher risk for the development of insomnia [25]. The health risks associated with insomnia and sleep deprivation, including cardiovascular disease and metabolic syndrome are also increased [26].

As in other populations, caution with long term pharmacologic agents is recommended. Non-pharmacologic treatments are often successful, particularly with cognitive behavioral therapy and sleep restriction as appropriate. Sleep hygiene education alone was less likely to be effective [27]. A randomized clinical trial of yoga also demonstrated improvements in sleep quality [28].

Insomnia prevalence continues to increase with age, maintaining a female predominance. The overall insomnia prevalence in the elderly may be up to 42%. This is characterized by trouble with both sleep initiation and maintenance. Comorbidities and related medications pose increased risks, especially associated with depression and chronic pulmonary symptoms [29,30,31]. In general, lifestyle (regular physical activity, Tai Chi, weight training) and behavioral measures are first line treatments including cognitive-behavioral therapy for insomnia (CBT-I) where studies have shown resolution and sustained response for up to 2 years [32]. Pharmacologic treatment should be reserved for those unresponsive to behavioral approaches, with goals for voiding medications with long half-life, low dose and frequent reassessment of response and side effects.

Restless Legs Syndrome and Periodic Limb Movement Disorder

Menarche and Adolescence

Restless Legs Syndrome (RLS) is about twice as common in women than men. With noted hormonal and iron metabolism mechanisms, a gender difference in RLS incidence would be expected around the time of menses as noted in an epidemiologic study in Chinese children. The female predominance is noted in the mid-pubertal, Tanner 3 and above, group. These children reported more problems with daytime function, behavioral issues and health quality [33].

Child-Bearing Years

Restless legs syndrome (RLS) is more common in pregnant women than the general population, which may partially explain the overall predominance in women. Women with pre-existing RLS symptoms generally report worsening symptoms during pregnancy, that may also increase with parity. For women developing RLS during pregnancy, the risk for subsequent chronic RLS later in life may be fourfold higher than women without pregnancy related RLS [34]. The overall prevalence during pregnancy is 21%, with increasing prevalence from first to third trimester. The prevalence of RLS then decreases to 4% postpartum [35]. The disturbance is characterized by poor sleep quality, poor daytime function and excessive sleepiness. Symptoms generally range from moderate to severe, consistent with symptoms 2–3 times/week up to 4 or more times/week [36]. Suggested mechanisms for the increased RLS include iron deficiency and increases in prolactin, estrogen and progesterone. Both iron and hormonal changes persist in early post-partum, which does not align with the rapid symptom improvement in symptoms soon after delivery [37]. Maternal and fetal health risks relating to untreated restless legs include gestational hypertension, preeclampsia and gestational diabetes, preterm birth and low birth weight [38]. The impact of periodic limb movement in sleep (PLMS) is less clear. A recent study of women in third trimester noted high prevalence (25% with PLMS index >15 per hour. There were no associated symptoms nor evidence of increased pregnancy related hypertension [39].

The high frequency and potential health risks of RLS during pregnancy warrant screening for this condition throughout pregnancy. Patients with RLS prior to pregnancy should also reconsider treatment options during pregnancy. These include low impact exercise, avoidance of exacerbating factors (alcohol, caffeine and nicotine), iron stores (ferritin and iron levels, and possible oral iron supplementation. If medication is required, it should be used at the lowest dose and for shortest duration [40].

Menopause and Beyond

There are further increases in RLS prevalence during menopausal transition and beyond, but the mechanisms for this are unclear. Hormonal influences are likely in the early transition, though aging and other medical comorbidities are more likely reasons for increased risk of RLS later in menopause. These patients may also be more susceptible due to comorbid iron deficiency and renal failure, as well as from medications particularly certain antidepressants and antipsychotics (dopamine antagonists) [41,42,43]. Postmenopausal women identify substantial impact on their quality of life due to RLS symptoms, and possible comorbid PLMs [44].

Periodic limb movements in sleep are commonly noted in older women. However, in the absence of concomitant RLS, the need for treatment is less clear. Definitive symptoms attributed to PLMs are required to support treatment indications. Pharmacologic treatment for both RLS and PLMD must be monitored closely with existing medications. Such medications may also exacerbate PLMD and weaning, where appropriate, may be the first line therapy [45].

Obstructive Sleep Apnea (OSA)

Child-Bearing Years

Gender differences in the presentation of OSA create diagnostic challenges for women. While women may report apnea, they are more likely, than men, to describe insomnia, restless legs, depression, nightmares, palpitations, and hallucinations [46]. The risk for developing sleep apnea is strongly related to BMI and with aging. While both men and women have increased risk for cardiovascular disease, atrial fibrillation and hypertension, women have a higher risk for developing heart failure [47,48,49].

Pregnancy

Snoring is not unusual during pregnancy, resulting from changes in upper airway dimensions, increased resistance and increased negative pharyngeal pressure during inspiration. These are also the mechanisms that promote OSA during pregnancy [50]. The OSA risk is higher in women with pre-existing hypertension and diabetes [51]. Untreated OSA during pregnancy may increase health risks for both the mother and fetus. Screening women of child bearing age for pre-existing sleep apnea, as well as for the onset of OSA symptoms during pregnancy is necessary.

A recent study, using a modified STOP-Bang questionnaire, found 15.4% intermediate and 3% at high risk for OSA. The STOP-Bang had a 62.5% sensitivity and 82.1% specificity for preclampsia [52]. A prospective study of nulliparous women, found a low prevalence of sleep apnea but increased risk for gestational diabetes and hypertension in those with apnea [53, 54]. The risk for older mothers with increased BMI and OSA is higher for both assisted vaginal delivery and cesarean [55].

Findings regarding fetal risks of untreated maternal sleep apnea vary, often relating to maternal health confounders. Several studies indicate an increased risk for intrauterine growth restriction and low birth weight, and preterm delivery [54,55,56,57]. Infants of mothers who are older, with higher BMI and OSA have greater risk for preterm birth, low birth weight, low Apgar scores, stillbirth, and increased NICU admissions [55]. Follow up after pregnancy should include formal assessment of apnea, which may resolve post-partum.

Information on CPAP efficacy and adherence varies across studies which are also limited by small sample size. As a noninvasive approach, this would be the most appropriate treatment for the pregnant woman. It has been shown to reduce apnea related pregnancy risks, and specifically reduce or treat pre-eclampsia and eclampsia [58].

Menopause and Beyond

The risk for sleep apnea increases during the perimenopausal phase, with an odds ratio for AHI >15 per hour (moderate sleep apnea) increasing from 1.1 premenopause to 3.5 perimenopause. These findings persist when controlled for weight gain. Mechanisms may relate to changes in upper airway anatomy and muscle tone, fat tissue distribution, sex hormones and leptin. The protective hormonal effects on upper airway tone diminish with decreased estrogen and progesterone. Leptin, a hormone which suppresses hunger and stimulates breathing, also decreases during this time, which adds to increased risk for OSA. Apnea severity has also be shown to increase with increasing BMI and neck circumference. The increase in OSA may also contribute to cardiovascular risk, cognitive functional decline and depression at this time of life [59]. A study of early menopausal women found that those with OSA had more cognitive concerns than those without OSA [60].

While hormonal factors contribute to these findings, there is insufficient data to support hormone supplement as a treatment. Usual treatment options include weight loss, PAP therapy, oral appliances, position modification (as appropriate) and upper airway stimulation [61].

Sleep apnea prevalence increases in elderly men and women, reported in up to 56% of women. Much of this change is attributed to the increased incidence during the menopausal years [62]. Patients are less likely to be obese, though other health risks of untreated apnea are also prevalent in this age group including hypertension, heart disease and stroke [63, 64].Untreated apnea also complicates potential neurocognitive impairment, nocturia and decreased quality of life [63]. The increased mortality risk is less clear than in younger age groups [64].

Sleepiness Disorders/Hypersomnias

Menarche and Adolescence

Narcolepsy symptoms may begin in childhood, more commonly identified during the teen years and early adulthood. Despite current efforts to increase awareness, a delay in diagnosis of many years is not uncommon, as well as misdiagnosis. Sleepiness, generally the first presenting symptom, may manifest differently in young children, sometimes as hyperactivity. “Catapletic facies” occurs more often at disease onset and may not be triggered by emotion. It is characterized by repetitive mouth opening with tongue protrusion and ptosis [65]. Untreated, narcolepsy symptoms may result in deterioration in school performance, social isolation and poor quality of life.

Sleep testing results including a nap series (multiple sleep latency test, MSLT) may result in false negatives particularly regarding the MSLT findings in this age group [66, 67]. Screening tools also need better validation in the adolescent and younger populations [68]. The more recent role of hypocretin deficiency has helped to distinguish between several related conditions including Narcolepsy type 1 (with cataplexy) and type 2 (without cataplexy) and idiopathic hypersomnia. However, cerebrospinal fluid assessments are not readily available in clinical practice.

Management includes behavioral measures with adequate hours in bed nightly and planned naps. Medications include modafinil, methylphenidate, amphetamines for sleepiness [69]. Cataplexy and sleepiness may also be treated with sodium oxybate, recently FDA approved for children ages 7 and up [70]. In Europe, pitolisant, an H-3 receptor inverse agonist has been used for both sleepiness and cataplexy, recently available for sleepiness in the United States.

Child-Bearing Years

Narcolepsy diagnosed in the pregnant patient, or those planning pregnancy, must balance symptom management for the mother and risk to the fetus. These matters may extend to postpartum and lactation. There are no current practice parameters, and study findings vary.

A retrospective case-control study of 25 patients with Type 1 narcolepsy (narcolepsy with cataplexy) and 75 controls found similar pregnancy outcomes, although a higher prevalence of gestational diabetes, heavier birth weight and longer duration of breastfeeding was reported in the patients [71]. Another retrospective study of 249 pregnancies in narcoleptic patients with and without cataplexy found that patients with cataplexy had higher weight gain, impaired glucose metabolism, anemia, a higher rate of caesarian sections and more (not severe) neonatal care adverse events. Difficulty in care of the newborn might also be anticipated due to maternal narcolepsy symptoms. Most patients had successful vaginal deliveries. Cataplexy rarely interfered with delivery [72].

A treatment survey of experienced sleep medicine clinicians (34 responses) reveals that practices vary by provider and country. Most providers discontinued medications at conception with reduced or unchanged dosing during lactation. Medications for narcolepsy treatment do cross the placenta and many are secreted in breast milk. A low risk of teratogenic effects of medications is reported, but with limited data [73].

Menopause and Beyond

In older women, conditions of sleepiness (known or newly recognized) include narcolepsy, idiopathic hypersomnia and hypersomnia due to other medical conditions. A careful history should distinguish the latter from other primary sleepiness conditions. The cognitive impairments include fatigue, tiredness, memory problems, poor concentration and coordination difficulties that may raise additional challenges in the elderly. Untreated patients have reduced quality of life, an increased risk for motor vehicle accidents and other injury [74]. Treatment often begins with optimizing other medical conditions and related medications, especially those with sedating features. Behavioral measures include protected sleep time and planned daytime naps and good sleep hygiene, as well as attention to social and occupational need. Careful assessment of stimulant use, in those already treated and when considering new medication, is necessary. These may include modafinil and other stimulants and sodium oxybate , or selected SSRIs for cataplexy [75,76,77].

Circadian Disorders

Menopause and Beyond

Advanced sleep phase disorder (ASPD), is thought to be rare in younger adults, though more likely to present in the elderly (both men and women), ranging from 1% and 7% of the population [78, 79]. Predisposing factors may include reduced light exposure (situational or relating to medical conditions such as cataracts) and a shortening of the circadian period with age. Specific light exposure in the evening hours may be effective in some individuals [80]. The role of morning melatonin to shift bedtime later is unclear and may cause daytime sleepiness [81].

Another circadian rhythm noted in the elderly is irregular sleep-wake disorder (ISWD). The incidence, prevalence and gender differences are not clear. It is more likely to occur in those with dementia, as well as traumatic brain injury and mental retardation. Treatment generally focuses on behavioral measures with a multicomponent plan for light exposure, physical and social activity, meal times to support wakefulness, then low light and less stimulation later in the day. Naps are avoided [81, 82]. The response to melatonin is inconsistent, though may be more effective in the patient with a documented melatonin deficiency [83].

Parasomnias

Menopause and Beyond

REM sleep parasomnias include REM behavior disorder (RBD) and nightmare disorder. While rare, RBD is more frequent in middle and older adults, more common in men than in women (2:1) [84]. The risks of this condition relate to injury to the person or partner and treatment measures focus on environmental safety and medications in more severe cases. Monitoring for subsequent neurodegenerative disease is recommended as this condition is currently viewed as a prodromal manifestation.

Nightmare disorder may occur at any age, though is more prominent in women for most life stages. There is little data on prevalence overall and much of the literature is based on post-traumatic stress disorder and treatment response. Behavioral approaches may include image rehearsal therapy and relaxation techniques. Prazosin has been used for PTSD with good response, but the effectiveness for nightmare disorder is less clear [85].

Conclusion

The discussion of sleep disorders as an impactful field has been growing since the last edition of this book. There is a growing interest in the need for personalized medicine. This concept certainly suits the recognition of sleep disorders by gender, and in woman the additional impact of different life stages. While there are still many layers to further explore, the basic conclusions support that untreated sleep disorders have a sizeable impact on women’s health, and potentially the growing fetus. As studies offer better understanding of these disorders, and treatment options expand, the health care provider must stay current on the dialogue and consider sleep disorders screening as a basic element of good patient care beginning in childhood and well into the 80s and 90s. Subsequent chapters review these conditions in more detail to further expand the reader’s understanding that sleep disorders are not just sleep apnea, and even sleep apnea has many evolving layers.