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Abstract

Sleep disturbances and disorders are common during pregnancy, and they can be risk factors for a number of serious pregnancy-related sleep disorders. These include postpartum depression, pregnancy-induced hypertension, gestational diabetes, and intrauterine growth retardation. In addition, certain chronic sleep disorders, such as narcolepsy, are quite challenging to manage in the context of pregnancy and during lactation, particularly with medications that can be teratogenic. This review discusses 4 common sleep disorders and their impacts on pregnancy, and suggests ways to deal with these disorders that improves maternal and fetal outcomes safely. The review discusses diagnosis and treatment of obstructive sleep apnea, restless legs syndrome, insomnia, and narcolepsy in pregnancy.

Introduction

Changes in sleep patterns during pregnancy are common. These changes include decreased rapid eye movement (REM) sleep, increased non-REM sleep, increased night-time arousals secondary to nocturia, acid reflux, leg cramps, and contractions, as well as other anatomical and physiologic changes.¹ These changes lead to differences in the quantity and quality of sleep that pregnant women obtain. Additionally, complaints about sleep are common during pregnancy. In a large internet-based survey, 2427 women completed multiple questionnaires about their sleep.² Throughout pregnancy these women were noted to experience poor quality sleep (76%), daytime sleepiness (49%), insufficient sleep time (38%), and frequent night-time awakenings (100%).² Additionally the respondents reported symptoms of insomnia (57%), sleep-disordered breathing (19%), and restless legs syndrome (RLS; 24%), among other symptoms. Managing these sleep complaints as well as preexisting sleep disorders and newly diagnosed sleep disorders during pregnancy can be challenging. This review discusses the management of common sleep disorders during pregnancy.

Managing Obstructive Sleep Apnea in Pregnancy

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete (apnea) or partial (hypopnea) upper-airway obstruction during sleep.³ Blood oxygen desaturations typically coincide with these events and usually result in a brief arousal from sleep. Events typically last between 10 and 30 s, but longer events can occur as well. Excessive daytime sleepiness (EDS), snoring, and poor daytime function are common presenting complaints. OSA with associated daytime sleepiness occurs in 3%–7% of adult men and in 2%–5% of adult women.³ The exact prevalence of OSA in pregnancy is unknown. However, several studies have shown that the prevalence of sleep-disordered breathing during pregnancy is between 10% and 27%, and it seems to increase with gestational age.⁴ Older age and obesity— which are known risk factors for sleep-disordered breathing outside of pregnancy—are associated with sleep-disordered breathing early in pregnancy.⁴

During pregnancy physiologic changes occur that increase the risk of OSA, including gestational weight gain, nasal congestion, pharyngeal edema, tracheal shortening, abdominal mass loading, and decreased lung volumes.⁴ In a prospective observational study by Louis et al., 175 pregnant women underwent an overnight home-sleep study, and the prevalence of OSA was found to be 15.4%.⁵ The OSA group was found to have higher body mass indexes (BMIs: 46.8 ± 12.2 vs. 38.1 ± 7.5 kg/m²; p = 0.002) and more chronic hypertension (55.6 vs. 32.4%; p = 0.02).

Screening for OSA in pregnancy

Diagnosing OSA in pregnancy can be difficult because symptoms, such as EDS, frequent night-time arousals, and fatigue, are also symptoms of pregnancy itself. However, patients who are habitual snorers, are overweight or obese prior to pregnancy, have hypertension, and/or are considered to be of advanced maternal age (35+ years old) should likely be assessed for OSA.⁴ In addition to having a higher suspicion for OSA for women with certain comorbidities, the use of common screening questionnaires that are used for OSA may also have a place in pregnancy. The efficacies of the Berlin and Stop-Bang questionnaires for detecting OSA across pregnancy were both evaluated.⁶ Tantrakul et al. evaluated 72 pregnant women recruited from a high-risk antenatal clinic and assessed the predictive value of both questionnaires per trimester. Overall OSA prevalence was 31.9% (23 patients). The prevalence of OSA by trimesters was as follows: first, 30.4%; second, 33.33%; and third 32%.⁶ The Berlin questionnaire was positive in 26.4% of the total pregnant women group, with higher positive rates in the OSA group than in the non-OSA group (56.5% vs. 12.2%; p < 0.001).⁶ Similarly, the Stop-Bang questionnaire was positive in 19 (26.4%) pregnant women across all trimesters and the rates of positive Stop-Bang questionnaires were higher in the OSA group than in the non-OSA group (60.9% vs. 10.2%; p < 0.001). However, neither questionnaire was particularly effective in predicting OSA in high-risk pregnancies during the first trimester. Both questionnaires had similar predictive values in high-risk pregnancies during the second trimester (Berlin positive predictive value [PPV]: 85.7%; negative predictive value [NPV]: 88.2%; area under the curve [AUC]: 0.84; p = 0.007; 95% confidence interval [CI]: 0.67–1.00; Stop-Bang PPV: 83.3%; NPV: 83.3%; AUC: 0.78; p = 0.03; 95% CI: 0.56–1.00) and the third trimester (Berlin PPV: 100%; NPV: 85%; AUC: 0.81; p = 0.013; 95% CI: 0.56–1.00; Stop-Bang PPV: 71.4%; NPV: 83.3%; AUC: 0.75; p = 0.04; 95% CI: 0.53–0.97).⁶

Complications from OSA during pregnancy

OSA can result in multiple complications for mothers and neonates. In a recent population-based cohort study, >600,000 women from a 10-year period with OSA either in the year prior to pregnancy or during pregnancy were identified from hospital records.⁷ The researchers found that OSA was significantly associated with hypertension during pregnancy (adjusted relative risk [adjRR]: 1.43; 95% CI: 1.18–1.73), unplanned delivery (relative risk [RR]: 1.15; 95% CI: 1.07–1.23), preterm birth (RR: 1.5; 95% CI: 1.21–1.84), 5 min Apgar scores <7 (RR: 1.60; 95% CI: 1.07–2.38), admission to a neonatal intensive care unit/special care nursery (RR: 1.26; 95% CI: 1.11–1.44), and large-for-gestational-age infants (RR: 1.27; 95% CI 1.04–1.55).⁷

A large, retrospective cross-sectional analysis evaluated a national sample of maternal hospital discharges (55,781,965 pregnancy-related discharges) between 1999 and 2009, and found the overall rate of OSA to be 3.0/10,000.⁸ The rate climbed from 0.7 in 1998 to 7.3 in 2009 (an annual increase of 24%). OSA was significantly associated with increased preeclampsia, cesarean delivery, gestational hypertension, and gestational diabetes, as well as, with eclampsia, cardiomyopathy, hospital stay >5 days, postoperative wounds (in this study defined by International Classification of Diseases, 9th edition, codes as follows: 674.1, disruption of cesarean section; 674.3, other complications of obstetrical surgical wounds; 998.3, disruption of operation wounds; 998.5, postoperative infection not elsewhere classified), pulmonary edema and 5-fold higher odds of dying prior to discharge from the hospital (95% CI: 2.4–11.5).⁸

When looking specifically at OSA and gestational diabetes, Reutrakul et al. found that pregnant women with gestational diabetes had a higher prevalence of OSA (73% vs. 27%; p = 0.01) and higher Apnea Hypoapnea Indices (AHIs) than pregnant woman without gestational diabetes (AHI median: 8.2 vs. 2.0, p = 0.05).⁹ The adjusted odds ratio [adjOR] was 6.6 (95% CI: 1.15–37.96).⁹

Treatment of OSA in pregnancy

There is not a specific guideline for treating OSA during pregnancy. However treatment options for pregnant women with OSA are similar to the therapies used in the general population, including continuous positive airway pressure (CPAP), positional therapy, and oral appliances. Any patient with suspected or diagnosed OSA should be referred to a sleep specialist to determine the best treatment options for that patient. However, oral appliances that reposition the mandible or tongue may not be as effective in pregnant woman because of the need for multiple fittings and possibly refitting because of weight gain during pregnancy.¹⁰ Other therapies, such as airway surgeries and weight loss, are likely less applicable when considering the altered risk–benefit ratio (risk to the fetus) as well as the rapid weight gain, rather than weight loss seen during gestation.¹⁰

CPAP is safe during pregnancy, but it has been suggested that Auto-CPAP over a fixed-pressure CPAP should be considered due to the physiologic and anatomical changes in pregnancy that may result in higher pressure requirements as gestation progresses.¹⁰ Guilleminault et al. evaluated the effects of nasal CPAP in 12 nonobese pregnant women.¹¹ The patients' average AHI was 21 and 7 of the patients had preexisting OSA, while the other 5 were diagnosed after pregnancy (average ∼10 weeks' gestational age). The patients did well clinically on CPAP, but 6 of them did require pressure changes at 24–26 weeks' gestational age.¹¹ However some of the patients did report morning nasal congestion with CPAP use. In the general population, compliance (>4 h/night for 70% of the nights) with CPAP is mixed (29%–83%), and it is not clear if the rates of compliance in pregnant women would be similar.¹

Given that a supine position could worsen OSA in about half of the general population (53%–56% of patients with OSA),¹ lateral-recumbent or head-elevated positions are recommended. It is possible that pregnant patients may also have position-dependent OSA, so positional therapy could be an alternative that is less-invasive than CPAP. Positional therapy includes wearing something around one's waist or back (i.e., tennis balls or foam in a backpack or fanny pack) as well as newer devices, such as sleep-position trainers, that incorporate vibrations while a patient is in a supine position that continue until the patient changes position.¹

One study looked at positional therapy specifically for OSA in pregnancy. In that study 55 women in the immediate postpartum period were enrolled and their upper airway cross-sectional area measured both when laying supine and with the upper body elevated at a 45° angle.¹² Thirty women underwent polysomnography (PSG) in both body positions. Elevation of the upper body significantly reduced apnea AHI from 7.7 ± 2.2/h to 4.5 ± 1.4/h (p = 0.031).¹² Moderate-to-severe OSA (AHI >15/h) was diagnosed in 20% of postpartum patients and was treated successfully by an elevated body position in half of them. A position-dependent increase in cross-sectional area and a decrease in AHI were correlated (r = 0.42; p = 0.022).¹² There is also a case report of a pregnant woman with OSA with an AHI of 18/h whose AHI dropped to 2.3/h with a 45° elevation in body position.¹³

OSA certainly has the potential to lead to negative outcomes for patients and fetuses, so screening for and treating OSA is an important part of the gestational period.

Although most sleep apnea is obstructive in pregnancy as well as in the general population, there are specific physiologic changes in pregnancy that could lead to central apnea (CA). An increase in progesterone may lead to increased pH, decreased arterial partial pressure of carbon dioxide, and increased oxygen consumption because of hyperventilation and ventilator instability. This, in turn, may lead to respiratory instability and ventilatory overshoot and CAs.¹⁴ Bourjeily et al. conducted PSGs on 25 pregnant women and 25 matched controls.¹⁴ CAs were absent in almost all of the pregnant women except for 1 who had 2 CAs on her PSG while, among the controls, 98 CAs in 11 women were recorded. The overall CA Index/h was normal in both groups.¹⁴ There also have been case reports of central sleep apnea in pregnancy in the setting of a Chiari 1 malformation due to direct compression of the brainstem. Treatment during pregnancy is with an adaptive servoventilaton device, and postpartum such patients might need surgical decompression of the base of the skull.¹⁵

Managing Restless Legs Syndrome in Pregnancy

RLS, also known as Willis–Ekbom disorder, is a sleep-related movement disorder. Its pathophysiology is not fully elucidated, but there is some evidence to suggest dysregulation of dopaminergic neurotransmission in the basal ganglia as well as iron deficiency in the brain due to misregulation of transferrin receptors on tyrosine hydroxylase neurons.^16,17 The cardinal characteristics of RLS include: (1) an irresistible, urge to move the limbs (primarily the legs); (2) uncomfortable, indescribable sensations that often accompany the urge to move; (3) symptoms that worsen in the evening or at night; and (4) symptoms that worsen with prolonged sedentary periods. The diagnosis is made clinically by history and examination without the need to rely on PSG as long as all 4 characteristics are present and other causes have been ruled out by the evaluating physician or sleep specialist.¹⁸ Regardless of regional prevalence (which varies widely worldwide), RLS is always female-preponderant with a female/male ratio of roughly 2:1.¹⁹ This higher prevalence among women is driven primarily by the dramatic, 2–3-fold, increase in the RLS incidence in pregnancy.²⁰

RLS that occurs only during pregnancy is called gestational RLS (gRLS). Women who experience gRLS and have family histories of RLS are at an increased risk of developing RLS (odds ratio [OR]: 1.92; 95% CI: 1.16–3.19).²⁰

The reported prevalence of gRLS varies between 10% and 38%,^21,22 depending on the method of diagnosis (patient surveys vs. face-to-face visits with clinicians), geographic location of the cohort studied, and during what trimester of pregnancy the women were in when they were included in the study. Table 1 lists the key prevalence studies chronologically.^21,23–38

Table 1.

gRLS Prevalence Studies

Study, year & ref.	Country	Trimester	Method of diagnosis	Prevalence
Suzuki et al., 2003²³	Japan	All trimesters	Questionnaire	19.9%
Manconi et al., 2004²⁴	Italy	At delivery	Clinician interview	26%
Alves et al., 2010²¹	Brazil	All trimesters	Clinician interview	13.5%
Facco et al., 2010²⁵	USA	All trimesters	Questionnaires	17.5% (31.2% in 3rd trimester)
Neau et al., 2010²⁶	France	All trimesters	Questionnaires	24%
Balendran et al., 2011²⁷	Australia	Third trimester	Clinician interview	22.5%
Uglane et al., 2011²⁸	Norway	At delivery	Questionnaires	34%
Chen et al., 2012²⁹	Taiwan	All trimesters	Clinician interview	10.4%
Sarberg et al., 2012³⁰	Sweden	All trimesters	Questionnaires	17.0% in 1st trimester 27.1% in 2nd trimester 29.6% in 3rd trimester
Hubner et al., 2013³¹	Switzerland	All trimesters	Clinician interview	12%
Minar et al., 2013³²	Slovakia	Third trimester	Questionnaires	31.3%
Ramirez et al., 2013³³	Peru	All trimesters	Clinician interview	18.4%
Vandat et al., 2013³⁴	Iran	3rd trimester	Clinician interview	17.8%
Neyal et al., 2015³⁵	Turkey	Third trimester	Clinician interview	38%
Shang et al., 2015³⁶	China	All trimesters	Clinician interview	11.2%
Liu et al., 2016³⁷	China	All trimesters	Clinician interview	12.3%
Morker et al., 2016³⁸	USA	2nd & 3rd trimesters	Clinician interview	20.2%

gRLS, gestational restless legs syndrome; RLS, restless legs syndrome.

Note: The questionnaire used in all studies was the International Restless Legs Syndrome Study Group standardized survey form with 4 diagnostic criteria & a severity scale. Clinician interviews were face-to-face RLS–focused history gathering.

The severity of gRLS also contributes to this wide variation in its prevalence. Some investigators included both mild and moderate/severe RLS based on the International Restless Legs Syndrome Study Group's severity scale. Most, however, only reported moderate/severe RLS, as mild RLS is rarely clinically significant.³⁹

Risk factors for gRLS include personal history of “growing pains” (OR: 2.85; 95% CI: 1.08–7.57)²⁷ or past history of RLS (OR: 12.9; 95% CI: 3.34–49.87),⁴⁰ family history of RLS (OR: 8.43; 95% CI: 2.32–30.57),^40,41 or gRLS in previous pregnancies (OR: 53.7; 95% CI: 6.72–429.8).⁴⁰ Other risk factors include smoking,³¹ snoring in the first trimester,³⁰ and obesity.⁴²

Complications of gRLS

There is an association between pregnancy-induced hypertension (PIH) and history of RLS. This raises the concern that gRLS is a risk factor for PIH. The data here are not as robust as with OSA but, according to 1 study, middle-age women with RLS were 2 times more likely to have had PIH (OR: 1.9; 95% CI: 1.1–3.6). The odds increased with increasing symptom frequency (adjOR for RLS with symptoms ≥3 times/week: 3.8; 95% CI: 1.9–7.6; p for trend = 0.003).⁴³ The prevalence of gRLS increases in certain cohorts with PIH,³⁷ and gRLS remains a significant risk factor for PIH even after adjusting for smoking, obesity, gravidity, parity, age, and alcohol consumption (OR: 1.35; 95% CI: 1.02–1.79).⁴⁴ Preeclampsia has been reported to be more prevalent in women with gRLS than age-, BMI-, and gestational age– matched controls (17.5% vs. 3%; p = 0.03).³³

Another pregnancy related-complication associated with gRLS is a 2-fold increase in the rate of preterm births even in the absence of other risk factors.⁴⁵ A multicenter study of 1000 women showed that gRLS was associated with increased odds of PIH and preeclampsia. The adjORs were 1.26 (95% CI: 0.65–2.46; p = 0.487) and 2.15 (95% CI: 0.97–4.75; p = 0.060), respectively. Also gRLS significantly impacted gestational age at birth (–0.7 week [95% CI: −1.1 to −0.2]; p = 0.021) and neonatal birth weight (coefficient: −149.5 g [95% CI: −276.9 to −22.5]; p = 0.005). This association persisted after adjusting for preeclampsia, diabetes, and smoking.⁴⁶

Women with gRLS report more sleep disruptions⁴⁷ and significantly higher Epworth Sleepiness Scale scores (10.6 ± 3.9 vs. 7.6 ± 3.1; p < .01)³³ than women without gRLS. Women with gRLS also are more likely to report OSA symptoms, including fatigue and witnessed pauses in breathing.⁴⁸ Women with preconception moderate or severe RLS that persists during pregnancy are at a higher risk for perinatal depression with an adjOR (for past psychiatric illness) of 2.87; 95% CI: 1.4–5.9 at 17 weeks of gestation; an OR: 2.03 95% CI: 1.09–3.79 at 32 weeks of gestation; and an OR: 1.94; 95% CI: 0.99–3.81 at 6 weeks' postpartum.⁴⁹

Finally, the risk of chronic RLS later on in life is increased by 4-fold (OR: 3.95: 95% CI: 1.71–9.11)⁵⁰ in patients with transient gRLS.

Treatment

All of the medications approved for the treatment of RLS are either unsafe or their safety is unknown in pregnancy.^51–54

See Table 2 for a list of medications and their impacts on pregnancy; this table was adapted from Oyiengo et al.⁵⁵

Table 2.

RLS Medications & Their Safety in Pregnancy and Lactation^*

Medications	Pregnancy safety	Lactation safety
Pramipexole	Based on animal studies no anticipated increase in fetal malformations if taken by pregnant women Human safety data are limited & without evidence of malformations	No human studies assessing levels in breast Risk of milk reduction due to impact on prolactin
Ropinirole	Based on animal studies no anticipated increase in fetal malformations if taken by pregnant women Human safety data are limited to 1 case report	No human studies assessing levels in breast Risk of milk reduction due to impact on prolactin
Levodopa	High-dose treatment in animals causes adverse pregnancy & fetal outcomes Human safety data are limited & without evidence of malformations Placental perfusion could be theoretically affected by levodopa	Risk of milk reduction due to impact on prolactin
Opioids	Neonatal withdrawal & an increase in pulmonary-valve stenosis reported; latter not confirmed in other studies	Small amounts secreted in breast milk could lead to newborn sedation
Gabapentin	Based on some animal studies there is an increase in fetal malformations Human safety data are limited & mixed	Level in milk probably too low to cause any adverse outcomes in breastfed infants
Carbamazepine	Carbamazepine increases risk of neural-tube defects, craniofacial abnormalities & developmental delays	Carbamazepine usually compatible with breastfeeding per the AAP & WHO because of low transfer to breastfeeding infants
Clonidine (approved, but for off-label use)	Based on animal studies no anticipated increase in fetal malformations if taken by pregnant women Human safety data are limited to possible behavioral effects, such as hyperactivity & sleep disturbances in prenatally exposed children	Risk of milk reduction due to impact on prolactin
Pregabalin	High-dose treatment in animals causes adverse pregnancy & fetal outcomes Human safety data are limited	No safety data
Rotigotine	No data on teratogenicity available	No safety data available Risk of milk reduction due to impact on prolactin
Clonazepam	Not thought to increase teratogenicity risk when used in pregnancy	1 case report of clonazepam exposure via breast milk causing neonatal apnea, cyanosis, & hypotonia Another case series of 11 neonates did not report any adverse effects

RLS, restless legs syndrome, AAP, American Academy of Pediatrics; WHO, World Health Organization.

Adapted from ref. 55.

Given that low iron stores, in the form of serum ferritin levels,^24,35 and iron deficiency⁴⁰ have been shown to correlate with gRLS, iron supplementation has been the mainstay of treatment of gRLS. There have been a few case series showing safety and efficacy of a variety of iron formulations in the treatment of gRLS. Intravenous (IV) ferric carboxymaltose given to 19 anemic (hemoglobin [Hbg] <11 g/dL) women with gRLS significantly reduced their RLS severity, Periodic Leg Movements during Sleep indices, and subjective sleep quality. All of these women had moderate-to-severe gRLS and were in the third trimester with serum ferritin levels <35 μg/L.⁵⁶

Similarly in a case series of 2 women with gRLS, with ferritin levels <50 μg/L and who were in the third trimester, IV iron sucrose given twice 2 weeks apart, significantly reduced RLS severity and improved the patients' quality of life (QoL).⁵⁷ Also 5 doses of iron sucrose in a young woman with chronic RLS just before conception elevated her ferritin level sufficiently to keep her from experiencing gRLS. This woman was anemic (Hbg <11 g/dL) and had a ferritin level of 15 μg/L prior to treatment.⁵⁸

Iron supplementation seems to be effective in women who are relatively iron-deficient, but it is less clear what to do for those who have normal iron reserves. There are several studies that have shown no significant differences in mean ferritin levels among women with gRLS and gestation age-matched controls.^31,59 Other researchers also have failed to show any difference in mean iron levels or iron supplementation during pregnancy.^31,34,36,59

The current consensus statement on the evaluation and treatment for gRLS recommends the following steps:⁶⁰

(1) Make an accurate diagnosis with a clinical interview in order to rule out mimics of RLS. These include ankle edema, compression neuropathies, leg cramps, ligament and tendon sprains, positional discomfort, and the sensation of the legs “going to sleep.”⁶⁰

(2) Have the patient avoid triggers and change modifiable risk factors: Supplement orally or IV to raise serum ferritin to >75 μg/L. Screen for OSA and treat, if present, with an auto-titrating CPAP machine. Have the patient avoid serotoninergic medications, antihistamines, antiemetics, caffeine, alcohol, and tobacco, as well as avoiding periods of prolonged immobility.⁶⁰

(3) Nonpharmacologic measures include yoga, massage, stretching, pneumatic compression devices for the ankles and feet, and moderate exercise and relaxation.⁶⁰

(4) If all else fails and pharmacologic agents must be used, low-dose pramipexole or ropinirole⁵⁴ during pregnancy and low-dose gabapentin (300–900 mg) during lactation may be used.⁶⁰

Treatment of RLS is not as much of a concern during breastfeeding as it is during pregnancy, as gRLS almost always precipitously improves or resolves after delivery. Eighty-seven percent of women with gRLS report resolution of symptoms within 1 month postpartum²⁸ (a third in <2 weeks),⁶¹ and the remainder report 50% or more reduction in severity scores.²⁸

In conclusion, RLS is quite common in pregnancy and is a risk factor for several pregnancy-related morbidities. With simple screening and early identification, treatment is possible with nonpharmacologic methods and, in rare cases, medication doses that minimize teratogenicity. If there is concern about whether a provider is making the correct diagnosis or if a patient's symptoms are refractory to nonpharmacologic treatments, a sleep specialist should be consulted.

Managing Insomnia in Pregnancy

Insomnia is defined as a persistent difficulty with sleep initiation, duration, consolidation, or quality that occurs despite having adequate time and circumstances for sleep, and that results in some of kind of daytime dysfunction.³ While chronic insomnia occurs in ∼10% of the population, the prevalence of transient insomnia is higher (30%–35%).³ In pregnancy, there are a variety of factors that contribute to the development of insomnia, which include hormonal, metabolic, and physiologic changes, as well as psychologic factors.⁶² Common physical symptoms, such as nausea, backache, and more-frequent urination, are all known to disrupt sleep.⁶³ The majority of pregnant women experience symptoms of insomnia at some point during pregnancy, particularly during the third trimester.⁶⁴ Difficulty with falling asleep and/or difficulty with maintaining sleep as nonrefreshing sleep are among some of the most commonly reported sleep issues.⁶³ Table 3 summarizes sleep disorders in pregnancy.

Table 3.

Summary of Sleep Disorders in Pregnancy

Disorder	Diagnostic tool	Treatment	Concerns in pregnancy
OSA	PSG	CPAP Oral appliance	Increases in prevalence & associated with adverse maternal & fetal outcomes
RLS	History & examination	Dopamine agonists Gabapentin Iron supplementation Massaging Folic acid	Increases in prevalence & might be associated with adverse maternal outcomes Management of medications in pregnancy & lactation
Insomnia, including CSWD	History & physical examination Sleep diaries	CBT Some sedative hypnotics	Increases in prevalence & might be associated with PPD & other adverse maternal outcomes Management of medications in pregnancy & lactation
Narcolepsy & other primary hypersomnias	PSG & MSLT	Modafinil/armodafinil Scheduled napping	Management of medications in pregnancy & lactation

OSA, obstructive sleep apnea, PSG, polysomnography; CPAP, continuous positive airway pressure; RLS, restless legs syndrome; CSWD, circadian rhythm sleep–wake disorder; CBT, cognitive–behavioral therapy, PPD, postpartum depression; MSLT, multiple sleep latency test.

Insomnia has been noted to worsen during the third trimester. A study of 370 pregnant women assessed their insomnia using the Insomnia Severity Index (ISI).⁶⁵ Higher scores on the ISI suggest more-severe insomnia, with scores between 8 and 28 suggesting some level of insomnia. The study revealed that 73.5% of women experienced some degree of insomnia during pregnancy.

Diagnosing insomnia

Typically, insomnia is diagnosed by a self-reported sleep history. Practitioners may utilize sleep diaries to determine patients' usual bedtimes and wake times as well as latency to sleep onset and number of nocturnal awakenings.⁶⁴ Sleep diaries along with actigraphy can also be used to characterize patients' sleeping difficulties better, particularly helping to assess whether their insomnia is predominantly an issue with falling asleep, staying asleep, or both. The Insomnia Symptom Questionnaire was recently validated among pregnant women^63,66; therefore it can be used as a reasonable screening tool for insomnia.⁶⁶

Complications of insomnia during pregnancy

Women have frequent night-time arousals and reduced sleep efficiency during pregnancy, which results in chronic sleep loss. Chronic sleep loss during pregnancy has been shown to result in adverse pregnancy outcomes, including prenatal depression, gestational diabetes, preeclampsia, increased length of labor, need for cesarean delivery, and preterm birth.⁶⁷ Insomnia is also a risk for postpartum depression (PPD).⁶⁸ Dorheim et al. found that women who developed PPD but were not depressed during pregnancy had higher insomnia scores during pregnancy than women who did not develop PPD.⁶⁸

Treatment

Given the potential negative consequences of insomnia during pregnancy, managing a patient's insomnia is important. Nonpharmacologic treatments, such as sleep hygiene and education, are typically thought to be first-line along with cognitive–behavioral therapy for insomnia rather than pharmacologic options due to their potential risk for the fetus.⁶⁹ However if nonmedical therapies fail for patients with moderate insomnia, then antihistamines, such as doxylamine or diphenhydramine, can be considered. Based on animal and human studies, these drugs are not expected to be teratogenic.⁶⁹ There are, however, some concerns with first-trimester use and minor birth defects.⁷⁰ Breastfeeding is not recommended by the manufacturers of these over-the-counter hypnotics, but no reports of adverse effects exist in the medical literature.

If a patient's insomnia is more severe, then treatment with a sedating antidepressant or sedative-hypnotic may be considered. However there are limited safety data on the sedative hypnotics during pregnancy. Zolpidem is considered safe in pregnancy, with no known teratogenicity but with potentials of low birth weight and preterm delivery.⁷¹ This drug is also considered safe in breastfeeding by the American Academy of Pediatrics.⁵⁵ No conclusive data on teratogenicity or breastfeeding safety exist for zaleplon. The amount of it that passes through to breast milk is miniscule though and is not likely to cause serious adverse effects.^55,72 The available human data suggest no teratogenicity with zopiclone or eszopiclone but there have been reports of withdrawal in infants after birth with chronic maternal use. Safety in breastfeeding has not been established.⁵⁵

Sedating antidepressants such as the tricyclic antidepressants (TCAs) might be better alternatives when patients have comorbid depression with their insomnia.⁶⁹ Based on case reports, and on animal and human studies, the 3 antidepressants used for insomnia—amitriptyline, trazodone, and doxepin—are not expected to be teratogenic; human data on doxepin, however, are scant.⁷³ Doxepin is contraindicated in breastfeeding while the other drugs do pass in breast milk in small amounts, but there are no reports of their impact on infants.⁵⁵ Low-dose benzodiazepines (i.e., lorazepam) might also be considered if a patient also has issues with anxiety; however caution must be used due to the potential risk for withdrawal and toxicity for the infant postpartum as well as an increased risk of cleft palate. When combined with diphenhydramine, benzodiazepines have been rarely reported to lead to fetal death.⁵⁵ Occasional use seems to be compatible with breastfeeding.⁵⁵ Finally ramelteon, a melatonin receptor agonist, is associated with teratogenicity but no human data on either pregnancy or breastfeeding are available.⁵⁵

Fifty-four pregnant women were assigned to take trazodone, diphenhydramine, or placebo, and their sleep quality was measured by actigraphy.⁷⁴ Depressive symptoms were assessed at 2 and 6 weeks after delivery. Both the trazodone group and the diphenhydramine group had significantly lower depression scores than the placebo group. The researchers found no significant differences in depressive symptoms between the trazodone and diphenhydramine groups, compared to the placebo group.⁷⁴

Acupuncture has been evaluated as a possible treatment for insomnia during pregnancy. The theory behind acupuncture's potential use in pregnancy is that acupuncture has been shown to increase serum melatonin levels. As there are alterations in melatonin levels with pregnancy da Silva et al. evaluated acupuncture's efficacy in insomnia during pregnancy.⁷⁵ The study specifically looked at the effects of acupuncture along with sleep-hygiene therapy, compared to patients only treated with sleep-hygiene therapy.⁷⁵ Sleep-hygiene instructions included things such as avoiding stimulants, heavy meals, and liquids before bed; having a set bedtime routine; bathing before bed; and using relaxation techniques.⁷⁵ The researchers assessed the severity of the women's insomnia, using a 0–10 scale. The women were followed for 8 weeks and interviewed 5 times. This was a small study with only 30 patients, and 8 of the women dropped out during the study. The patients receiving acupuncture had a larger reduction of their insomnia rating (5.1) than the control group, most of whom had no change (p = 0.0028).⁷⁵ The insomnia scores decreased by at least 50% in 9 of the patients (75%) in the study group and in 3 (30%) of the control group. This study had a very small sample size, but the results are promising for future research in acupuncture's role in insomnia during pregnancy.

Other complementary and alternative medicine interventions have not been well-studied in insomnia during pregnancy. Mindfulness meditation has some proven benefit in chronic insomnia but not much data exist for pregnant women with insomnia.⁷⁶ Hypnotherapy also has modest benefit in chronic insomnia but has not been studied in pregnancy for insomnia.⁷⁷ Not much exists in the peer-reviewed literature on Pranic healing and related interventions in insomnia in pregnant women.

Sometimes insomnia could be a complaint of an underlying circadian sleep–wake disorder (CSWD). Preliminary evidence in pregnancy has shown that shift-work disorder, the most prevalent CSWD, might be associated with small-for-gestational-age and low-birth-weight infants, preterm delivery, and fetal loss. Of note these studies did not control for sleep duration, stress, and other comorbidities that occur with shift-work disorder.^78–80

There are no systematic studies on the management of CSWD in pregnancy. In the general population, however, full-spectrum white light, or blue or green light, at specific times during a person's circadian cycle can help manage the symptoms of CSWD and realign one's circadian rhythms. Additionally, behavioral modification of one's sleep–wake pattern in the form of judiciously scheduled naps and relatively consistent bedtime and risetime may also help in CSWD treatment.⁸¹

Insomnia is a common problem during pregnancy and it can be difficult to treat because of both the physiologic reasons for difficulty with falling and staying asleep as well as the limitations on medications that can be tried.

Managing Narcolepsy in Pregnancy

Narcolepsy is a chronic neurologic condition characterized primarily by severe EDS. The third edition of the International Classification of Sleep Disorders defines narcolepsy as such: Narcolepsy is a disorder primarily characterized by EDS and signs of REM-sleep dissociation, the most specific of which is cataplexy. Narcolepsy with cataplexy is called narcolepsy type 1 and narcolepsy without cataplexy is called narcolepsy type 2.³

Although narcolepsy leads to significantly increased morbidity, mortality remains uncertain, especially among women.^82,83 One thing is certain: Narcolepsy, mainly because of excessive EDS,⁸⁴ is a profoundly disabling condition^85,86 with a hefty economic and QoL burden.^87–92 Narcolepsy is also associated with major societal stigma, leading to more QoL issues.⁹³

Narcolepsy is a rare disorder (prevalence 26–50/100,000),⁹⁴ and the illness itself is not associated with significant adverse pregnancy outcomes.⁹⁵ For these 2 reasons there is very little written on management of narcolepsy in pregnancy. A retrospective survey in a cohort of 54 Czech and Slovak women with narcolepsy (42 with type 1 and 12 with type 2), who had delivered (collectively) a total of 110 children, showed that the women (37) who had narcolepsy symptoms while pregnant had an insignificant increase of minor complications than women (17) who developed narcolepsy after pregnancy.⁹⁵ The only complication that reached significance was lower-leg edema (21.5% vs. 6.2%; p = 0.042).⁹⁵ There was also no significant increase in complications when the entire group was compared to the general Czech population. Only 1 woman in this cohort was taking medications during gestation and lactation.⁹⁵

Diagnosing narcolepsy

When narcolepsy is suspected, the patient should be referred to a sleep specialist for a full evaluation and the required sleep studies, which include an overnight PSG to rule out other causes of daytime sleepiness, such as OSA, followed by a nap study known as a mean sleep latency test (MSLT). Narcolepsy is diagnosed when a patient has daily periods of an irrepressible need to sleep or daytime lapses into sleep for at least 3 months.³⁹ The patient must have a mean sleep latency of 8 minutes or less with 2 or more sleep-onset REM periods (SOREMPs) during the MSLT. A SOREMP (within 15 min of sleep onset) on any preceding nocturnal PSG may replace one of the SOREMPs on the MSLT.³⁹ Patients with narcolepsy with cataplexy (type 1) have low levels of cerebrospinal fluid hypocretin, but this is not something that is checked routinely.^96,97

Complications/consequences of narcolepsy during pregnancy

A larger multinational cohort of 249 women with narcolepsy (414 pregnancies) in 12 European countries was surveyed, and the results were similar to the abovementioned study.⁹⁸ This cohort was divided into 216 women with narcolepsy type 1 and 33 with narcolepsy type 2. Of the 216 with type 1 narcolepsy, 155 had symptoms during pregnancy, 56 developed symptoms afterward, and 5 did not indicate when their symptoms started. Of the 33 with type 2 narcolepsy, 21 had symptoms during pregnancy and 12 developed it afterward. The total numbers of children born to women with type 1 was 371 and 55 for those with type 2. Totals of 311 children were born to mothers experiencing symptoms of narcolepsy and 108 to those whose symptoms developed after childbirth. Narcolepsy medication was used in 11.9% of pregnancies in women with narcolepsy type 1 and in 7.7% of pregnancies in those with type 2.⁹⁸ There was a significantly higher prevalence of anemia and impaired glucose metabolism among women who had symptoms during pregnancy vs. those who developed it afterward (p < 0.05). There have been case reports of women with cataplexy during labor having successful cesarean deliveries.⁹⁸

In addition to the health concerns about narcolepsy, there are also social consequences. In 1 study having narcolepsy, particularly narcolepsy type 1, in the general population, was associated with an annual cost (both direct and indirect) of $10,376 ± $10,966 per person in a cohort of 100 Italians with the condition. Irresistible EDS in the general population was associated with work absences and higher indirect costs. Poorer symptom control and unemployment was associated with depression which, itself, predicted poorer QoL.⁹⁹ Untreated narcolepsy (for ∼2 years from conception to end of breastfeeding) could lead to unemployment and, as a result, a higher financial burden and poorer QoL.^100–102 Another factor to consider is the elevated rate of accidents, particularly motor vehicle accidents. Several studies have shown a trend toward a higher accident risk among all people with narcolepsy. A study using the divided-attention driving test on a simulator compared 21 patients with OSA to 21 controls and 16 patients with narcolepsy. Patients with narcolepsy and patients with OSA performed significantly worse than controls (p = 0.001).¹⁰³

Patients with narcolepsy, especially those under age 40, were more likely to report car accidents due to falling asleep than controls in a German survey.¹⁰² The same group of researchers, however, did not find a significant difference between a small cohort of patients with narcolepsy and controls while using the simulator. Stimulant medication, however, significantly reduced the rate of errors in some of the patients with narcolepsy.¹⁰⁴ A 2007 prospective cross-sectional internet-linked survey on driving behaviors of large cohort of 40,000 showed that patients with narcolepsy were at a significantly higher RR of accidents due to EDS than patients without narcolepsy (OR: 3.99 [2.48–6.42]; p < 0.0001). Patients with narcolepsy were also at a significantly higher risk of near-miss accidents (OR: 1.95 [1.53–2.49]; p < 0.0001).¹⁰⁵

Treatment

Medications used to treat narcolepsy are mostly of unknown safety profiles in pregnancy.¹⁰⁶ Amphetamines, such as methylphenidate, can lead to prematurity, growth restriction, and neonatal withdrawal but animal data and limited human data do not support teratogenicity.^108,109 Modafinil/armodafinil has limited human data, and animal data do not support teratogenicity. There is an ongoing registry maintained by the original manufacturer.^55,108 Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors are used for cataplexy and other REM intrusions into wakefulness.¹⁰⁶ These drugs are not associated with any significant birth defects, except perhaps decreased birth weight and transient neonatal abnormalities.⁵⁵ The safety of TCAs¹⁰⁹ (for cataplexy, sleep paralysis and hypnagogic hallucinations) in pregnancy is not well-established. There have been case reports of neonatal withdrawal and cardiac abnormalities.^110,111 There are no available studies to support the safety of sodium oxybate, which is used for cataplexy and hypersomnia in pregnancy.¹⁰⁶ Hence, there needs to be a way to balance the disability of the illness over the period of gestation and lactation and safety of the fetus.

Guidelines on how to manage narcolepsy and cataplexy medications in pregnant women do not exist. This is an area, however, that sorely needs attention, as most pregnant women might not have the luxury of risking accidents, loss of jobs, and higher economic burdens due to the profound and misunderstood disability of EDS. A pregnancy registry created by Teva Pharmaceutical Industries, Ltd., collects data on pregnant women who take modafinil and armodafinil. The company has not, to date, published any findings.

There are only a few articles published on this topic. A survey of 34 sleep physicians from 13 countries revealed that, depending on the medication, 59%–73% of physicians advised their patients who had narcolepsy and were trying to conceive to stop their stimulants and anticataplexy medications. Another 5%–15% of the physicians advised a reduction in the dose, and 19%–28% did not advise any change in dosing.¹¹² During actual pregnancy and breastfeeding, 70%–94% of the physicians advised stopping the medications, 3%–19% advised reductions in doses; and 0%–11% advised no changes in dosing.¹¹² Medication advice also depended on the trimester of the pregnancy. Approximately 50% of the responding physicians (from 40% to 55%, depending on the medication) stopped the medications throughout the 3 trimesters; 33%–43% stopped medication only during the first trimester; and 4%–12% stopped the medications during the first 2 trimesters.¹¹²

Three pregnancies (9%) had fetal malformations or pregnancy complications in the surveyed physicians' patient populations. Only 2 of these pregnant patients were receiving medication to treat narcolepsy. One patient was taking both modafinil and sodium oxybate and had a very preterm infant who survived and thrived with proper care. The other patient was taking amphetamines and underwent an abortion because of major cardiac malformations in her fetus. Eight women who were taking stimulants delivered term and healthy infants.¹¹²

A Danish pregnancy registry, designed to collect outcomes data in women taking attention-deficit hyperactivity disorder drugs, reported increased miscarriages and abortions in women taking modafinil, methylphenidate, or atomoxetine (a medication not used in narcolepsy). There was higher likelihood of induced abortions on maternal request (OR: 4.70; 95% CI: 3.77–5.85), induced abortions for special indications (OR: 2.99; 95% CI: 1.34–6.67), and miscarriages (OR: 2.07; 95%CI: 1.51–2.84).^113,114

There are no data on therapeutic use of amphetamines during pregnancy, but recreational abuse of amphetamines is associated with pregnancy-induced hypertension; intrauterine growth restriction; miscarriages; and neurologic, cardiovascular, and limb teratogenicity.^115,116

Antidepressants are the primary class of medications used to treat cataplexy. The cumulative results from 12 European pregnancy registries revealed that first-trimester exposure to SSRIs was associated with a higher risk of congenital abnormalities. The overall adjOR for congenital heart defects (CHD) was 1.41 (95% CI: 1.07–1.86). Individual drugs were associated with similar ORs. Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR: 2.46; 95% CI: 1.06–5.68), gastroschisis (adjOR: 2.42; 95% CI: 1.10–5.29), renal dysplasia (adjOR: 3.01; 95% CI: 1.61–5.61), and clubfoot (adjOR: 2.41; 95% CI: 1.59–3.65).¹¹⁷ A Danish registry study looking at only severe CHD reported a 4-fold increase in the risk with SSRIs (adjOR: 4.03; 95% CI: 1.75–9.26).¹¹⁸

Other studies looking at TCAs and SSRIs have not shown this increased risk.^119–121 The largest of these studies was a U.S.-based cohort study utilizing a Medicaid database with close to 1,000,000 women. An adjOR of 1.06 (95% CI: 0.93–1.22) was revealed. Of note all these studies were performed in women with depression and not narcolepsy.¹²²

No information is available on the use of sodium oxybate in pregnancy save for its use as an anesthetic during labor.

The current recommendations, as supported by the existing data, are to stop all medications for narcolepsy and cataplexy during pregnancy and to rely on naps, short-term disability, public transportation, and family members if possible. However, the reality is that narcolepsy can cause disabling sleepiness in some pregnant women, and not all patients can afford the economic and lifestyle limitations that narcolepsy causes. While there is not another diagnosis that parallels that of narcolepsy directly, the current authors have found that there are some similarities in the difficulties that pregnant women with epilepsy experience. A look at the epilepsy literature can offer some help as a potential guide for managing medications in pregnant women with narcolepsy even though the impact of epilepsy and narcolepsy on the lives of those who have it is quite different. While imperfect, the basic principles are applicable and could serve as a good starting point for ways to treat these patients during pregnancy. Some suggestions could be:

(1) Have a clear and detailed discussion with the patients during preconception about the risk vs. benefits of taking the medications used to treat narcolepsy and cataplexy.¹²³

(2) If it is feasible to manage EDS with naps, have flexible work hours, go on short-term disability and rely on others for transportation, then patients should stop the medications used to treat narcolepsy and cataplexy altogether, at least for the first trimester and ideally for as long as possible during pregnancy and lactation. Patients with type 1 narcolepsy should be warned of the potential of labor-induced cataplexy.^98,106

(3) Prenatal vitamins and folic acid at 0.4–4 mg per day should be recommended to mitigate the potential of teratogenicity if the patient is to continue on medications.¹²⁴

(4) If stimulant medications are required, then use the minimal effective dose, and use it sparingly,^125,126 preferably after the first trimester.

(5) Perform a targeted anatomical ultrasound (a “level II ultrasound”) at 20 weeks.¹²⁴

Finally, type 1 and type 2 narcolepsy can become more disabling in pregnancy because of the need to stop stimulant and anticataplexy medications. With careful planning and a referral to a well-informed sleep specialist, however, narcolepsy can be easily managed during this important life period with little harm to the mother and her infant.

Conclusions

Managing sleep disorders during pregnancy can be challenging because of how the disorders can change over the course of the pregnancy. Additionally there are limitations to some of the conventional therapies and medications that are commonly used to treat sleep disorders in nonpregnant patients. Practitioners should be assessing their pregnant patients frequently for sleep issues.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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Managing Sleep Disorders During Pregnancy

Abstract

Introduction

Managing Obstructive Sleep Apnea in Pregnancy

Screening for OSA in pregnancy

Complications from OSA during pregnancy

Treatment of OSA in pregnancy

Managing Restless Legs Syndrome in Pregnancy

Complications of gRLS

Treatment

Managing Insomnia in Pregnancy

Diagnosing insomnia

Complications of insomnia during pregnancy

Treatment

Managing Narcolepsy in Pregnancy

Diagnosing narcolepsy

Complications/consequences of narcolepsy during pregnancy

Treatment

Conclusions

Footnotes

Author Disclosure Statement

References