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Pharmacological Approaches
toManaging Common Sleep Disorders
LauraPalagini
23.1 Introduction
Women’s sleep patterns during pregnancy and the postpartum period are inuenced
by a variety of factors, including anatomical, endocrinological, physiological, psychological, behavioral, socio-economic, and cultural elements (Pengo etal. 2018).
These alterations can signicantly impact sleep duration, quality, patterns, and
respiratory function during sleep, thereby increasing the likelihood of sleep disturbances in pregnant women during the peripartum phase (Baglioni et al. 2020;
Garbazza etal. 2020; Palagini etal. 2022). Research indicates that nearly 80% of
women report experiencing sleep disruptions during this period. The most prevalent
issues across all three trimesters include reduced sleep duration, diminished sleep
quality, and insomnia (Baglioni etal. 2020; Palagini etal. 2022), which often persist
and may worsen in the postpartum phase (Sivertsen et al. 2015). Additionally,
women may experience nightmares, sleep-disordered breathing, and restless legs
syndrome (Pengo etal. 2018; Garbazza etal. 2020). Accumulating evidence suggests that insomnia and sleep disruptions during pregnancy may be linked to adverse
gestational and birth outcomes (Okun et al. 2011), the necessity for emergency
cesarean sections (Paine etal. 2020), and the development of gestational diabetes.
Notably, insomnia and poor sleep quality during the peripartum period have been
identied as potential risk factors for peripartum psychopathology, including mood
disorders, postpartum blues, and psychosis (Swanson etal. 2020; Palagini et al.
2023; Sharma etal. 2023; Palagini etal. 2024a, b, c). Furthermore, maternal sleep
patterns during pregnancy may inuence infant sleep patterns, with disrupted maternal sleep correlating with poorer infant sleep, which can subsequently affect
23
L. Palagini (*)
Department of Neuroscience, Psychiatric Section, University of Pisa, Azienda Ospedaliera
Universitaria Pisana (AUOP), Pisa, Italy
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
F. Uguz, L. Orsolini (eds.), Perinatal Psychopharmacology,
https://doi.org/10.1007/978-3-031-99720-4_23
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496
maternal sleep in the postpartum period (Baglioni etal. 2020). Sleep during the
perinatal period is regarded as a family concern, with potential short-term effects on
the mental health of both the child and the entire family, as well as long-term implications for the child’s susceptibility to mental health issues in adulthood (Baglioni
etal. 2020). In this context, it is essential to evaluate and address sleep disturbances
during the peripartum period. The management of these numerous conditions often
necessitates the use of pharmacotherapy, which complicates the decision-making
process concerning the timing and selection of treatment, as well as the most suitable approach for both the mother and her unborn child, particularly in light of drug
safety and pharmacodynamic considerations. This chapter examines the physiological changes and the occurrence of sleep disorders. It will also discuss prescribing
decision-making process during the peripartum with a focus on sleep disorders.
L. Palagini
23.2 Peripartum-Related Physiological Changes
andtheOccurrence ofSleep Disorders
Pregnancy induces signicant physiological changes that markedly impact sleep
patterns. The hormonal uctuations that occur during this period, including
increased levels of various hormones, play a crucial role in altering both the circadian and homeostatic mechanisms governing sleep, thereby modifying sleep architecture. Notably, alterations in melatonin, cortisol, and gonadal steroids such as
estrogen and progesterone, along with pituitary hormones like gonadotropins, prolactin, and growth hormone, can inuence sleep quality. Research indicates that
non-rapid eye movement (NREM) sleep is enhanced by progesterone and prolactin,
while rapid eye movement (REM) sleep is diminished by progesterone and augmented by estrogens. Specically, progesterone exerts a sleep-promoting effect on
brain gamma-aminobutyric acid (GABA) receptors, leading to increased NREM
sleep and potentially explaining the daytime drowsiness and fatigue often experienced during the rst trimester, when progesterone levels are on the rise. Additionally,
the elevated respiratory rate associated with progesterone may help prevent airway
obstruction, thereby reducing the risk of sleep disorder breathing (SDB).
Furthermore, progesterone’s thermogenic properties raise core body temperature,
and its relaxing effect on smooth muscles—including those in the gastrointestinal
tract, ureters, and bladder—can disrupt sleep, resulting in more frequent awakenings and diminished sleep quality. Estrogen, which is secreted by the placenta and
peaks before delivery, has stimulating effects on the nervous system and is known
to reduce REM sleep. Its elevated levels during pregnancy can lead to vasodilation
and nasal congestion, which may further contribute to SDB.Additionally, estrogen
promotes the production of prolactin. Collectively, all these factors may contribute
to the development of insomnia, SDB, and restless legs syndrome (RLS).
23 Pharmacological Approaches toManaging Common Sleep Disorders
497
23.3 Most Common Sleep Disorders During Peripartum
23.3.1 Insomnia
23.3.1.1 Epidemiology andClinical Features During
thePeripartum Period
Insomnia disorder is currently recognized as a 24-h sleep-wake disorder (APA
2022), marked by symptoms that manifest both at night and during the day. This
condition can be classied as episodic, lasting from 1 month to 3 months, or persistent, extending beyond 3 months; transient-episodic forms often progress to chronic
insomnia. It is the most prevalent sleep disturbance, affecting nearly one-third of the
general population and approximately 10% of the European population (APA 2022;
Riemann etal. 2023). The frequency, severity, and pattern of insomnia symptoms
may uctuate during pregnancy, with studies indicating that it impacts over 38% of
pregnant women, rising to 42.4% during the third trimester (Swanson etal. 2020;
Sedov etal. 2021; Salari etal. 2021). Symptoms of insomnia tend to increase in the
rst 6 months following childbirth. Notably, 50% of these women continue to experience insomnia 2 years postpartum, and 15% may develop a long-term insomnia
disorder (Sivertsen etal. 2015). Insomnia as a disorder may affect around 22–23%
of perinatal women (Palagini etal. 2024a, b, c).
23.3.1.2 Pathophysiology
The diathesis-stress model, often referred to as the “3-P” model, serves as the most
heuristic framework for understanding insomnia, particularly in the context of pregnancy and the postpartum period (Swanson etal. 2020; Palagini etal. 2021). This
model delineates three categories of factors: Predisposing, Precipitating, and
Perpetuating. Numerous physiological and psychosocial transformations occurring
during the perinatal period signicantly inuence the onset and continuation of
insomnia, as outlined by the diathesis-stress model of chronic insomnia, which
highlights the interplay of predisposing factors, triggering events, and sustaining
behaviors (Palagini etal. 2024a, b, c).
Numerous predisposing factors for insomnia arise during pregnancy. In the rst
trimester, hormonal changes may play a signicant role in the onset of insomnia.
Additional risk factors during this period include being over the age of 30, experiencing premenstrual syndrome, having no previous pregnancies, being a single
mother, suffering from affective disorders prior to pregnancy, experiencing perinatal
depression, and dealing with various physical symptoms. As pregnancy progresses
into the second trimester, a reduction in melatonin levels, alongside hormonal
changes characterized by increased estrogen, may contribute to insomnia. Physical
discomforts such as snoring, heartburn, vivid dreams, and pain in the back, neck,
and joints can also heighten the risk of developing insomnia. In the third trimester,
hormonal inuences from estrogen, cortisol, growth hormone, melatonin, and
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L. Palagini
oxytocin can disrupt sleep patterns, leading to sleep fragmentation, RLS, and
SDB.Physical discomfort continues to be a signicant factor in the development of
insomnia. Additionally, irregular uterine contractions and fetal movements toward
the end of pregnancy may further exacerbate insomnia (Swanson et al. 2020;
Palagini etal. 2022). Postpartum, factors contributing to insomnia include abrupt
hormonal shifts, breastfeeding, cesarean delivery, sleep deprivation during labor
and the peripartum period, and the irregular sleep patterns of the infant.
Chronodisruption is frequently observed during the postpartum phase, which may
further facilitate the onset of insomnia.
Pregnancy and childbirth, while often viewed as positive milestones, are signicant life stressors that can trigger insomnia (Swanson etal. 2020). During the perinatal period, these stressors can exacerbate maladaptive cognitive and emotional
regulation strategies (Swanson et al. 2020). Extensive research has established
hyperarousal as a critical factor in chronic insomnia (Riemann etal. 2015; Riemann
etal. 2023), characterized by heightened physiological, cognitive, and emotional
arousal. This hyperarousal is believed to interact with detrimental cognitive beliefs
and negative behaviors, further sustaining insomnia. The allostatic load hypothesis
has been suggested in the context of pregnancy and the postpartum period.
Consequently, insomnia and chronic sleep deprivation serve as both triggers and
outcomes of stress, potentially leading to a state of stress overload that may result in
adverse pregnancy outcomes, including peripartum psychopathology and persistent
insomnia (Palagini etal. 2014, 2023, 2024a, b, c).
23.3.1.3 Insomnia Treatment inthePeripartum
Assessment and effective management are crucial in preventing potential adverse
outcomes during pregnancy and the recurrence of chronic insomnia. Research indicates that a signicant number of pregnant women refrain from seeking treatment
for insomnia, often believing it will resolve on its own post-delivery or due to concerns regarding the impact of medication on the fetus (Bacaro et al. 2020; Baglioni
etal. 2020). Consequently, it is imperative to evaluate and address sleep disturbances from the onset of pregnancy. The National Institute for Health and Clinical
Excellence (NICE) guidelines on antenatal and postnatal mental health, published
in 2018, advocate for psychological therapies to be prioritized as the rst-line treatment for mild to moderate conditions whenever feasible. The criteria for prescribing
psychotropic medications should be stringent, with such medications being considered only when psychological interventions fail to alleviate symptoms (NICE 2018).
For chronic insomnia, Cognitive Behavioral Therapy for Insomnia (CBT-I) is recognized internationally as the primary treatment option (Riemann etal. 2023). CBT-I
typically encompasses various behavioral strategies, including psychoeducation
and sleep hygiene, relaxation techniques, stimulus control therapy, sleep restriction
therapy, and cognitive strategies such as cognitive restructuring related to sleep.
Within the framework of CBT-I, psychoeducation often involves imparting “sleep
hygiene rules” that address health practices and environmental factors (such as
light, noise, and temperature) that can either facilitate or hinder sleep. Relaxation
23 Pharmacological Approaches toManaging Common Sleep Disorders
499
therapy focuses on alleviating physical tension and intrusive thoughts at bedtime.
Behavioral strategies include sleep restriction, which limits time spent in bed to the
actual amount of sleep achieved, and stimulus control therapy, which provides
behavioral guidelines to help re-establish a positive association with the bed and
bedroom environment. A systematic review and meta-analysis conducted by Zheng
etal. (2023) evaluated the effectiveness of CBT-I among pregnant women. This
analysis encompassed eight randomized controlled trials with a total of 743 participants. The ndings indicated that CBT-I led to a notable improvement in insomnia
symptoms among perinatal women when compared to the control group. The
National Institute for Health and Clinical Excellence (NICE) guideline on antenatal
and postnatal mental health from 2018 advises that pharmacological treatment
should be considered for women who do not respond to nonpharmacological therapies and exhibit severe insomnia symptoms, particularly when no alternatives are
available and the benets outweigh the risks (Kay-Stacey and Attarian 2017). The
US Food and Drug Administration (FDA) has classied various medications based
on their risk levels during pregnancy and lactation. However, in 2015, the FDA
discontinued this classication system, replacing the ABCDX categories with the
FDA Pregnancy and Lactation Labeling Rule (PLLR). This new regulation provides
prescribers with essential information for informed decision-making, advocating
for a shared decision-making approach when treating pregnant or lactating women.
It includes three categories: (1) pregnancy, encompassing labor and delivery; (2)
lactation; and (3) female individuals of reproductive potential Miller etal. (2020)
proposed an algorithm for treating insomnia or other sleep conditions during pregnancy. Uguz (2021) introduced a safety scoring system for the administration of
psychotropic medications during lactation, which is based on six safety parameters.
The total score can range from 0 to 10, with higher scores indicating a more favorable safety prole.
Guidelines concerning the treatment of insomnia highlight various sleeppromoting agents. These include GABA modulator compounds such as benzodiazepines and related medications known as Z drugs, as well as melatonin receptor
agonists like prolonged-release melatonin (2 mg) and ramelteon. Additionally,
antagonists targeting the arousal-promoting system are noted, including dual orexin
receptor antagonists (DORAs) such as daridorexant, suvorexant, and lemborexant.
Most of sedating antidepressants with antihistaminic and anti-5HT properties,
including low doses of trazodone, are considered off-label in insomnia treatment.
However, other classes of medications, including various antidepressants, antihistamines, neuroleptics, and mood stabilizers, are not recommended for the treatment
of insomnia (Riemann etal. 2023; Palagini etal. 2023).
Sleep-Promoting Agents inthePeripartum Period
GABA, a four-carbon non-proteinogenic amino acid, serves as the primary inhibitory neurotransmitter found in signicant concentrations across various regions of
the mammalian brain. GABAA receptors are distinguished by numerous allosteric
binding sites, including those for benzodiazepines. Ligands that engage with these
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L. Palagini
binding sites trigger a conformational alteration in GABAA receptors, thereby
inuencing their functionality. GABAergic neurons are crucial in modulating the
sleep-wake cycle through cortico-medullary pathways. These neurons may affect
both rapid eye movement (REM) and non-REM (NREM) sleep, particularly during
slow wave sleep (SWS) (for an overview see Palagini and Bianchini 2022).
Furthermore, the activation of GABAA receptors plays a signicant role in sleep
regulation, with GABAergic activity originating from the ventrolateral preoptic
nucleus (VLPO) of the hypothalamus exerting inhibitory control over the ascending
arousal network. This network is supported by various wake-promoting circuits,
including the cholinergic basal forebrain, histaminergic tuberomammillary nucleus,
serotonergic dorsal raphe, and noradrenaline-producing locus coeruleus, with
orexin neurons providing excitatory projections to the thalamus and neocortex (for
an overview see Palagini and Bianchini 2022). Reduced levels of GABA or dysfunctional GABAergic transmission are linked to the development and persistence
of both acute and chronic insomnia and are associated with hyperarousal in insomnia cases (for an overview see Palagini etal. 2022). The GABAA receptor, a pentameric ligand-gated ion channel made up of ve transmembrane glycoprotein
subunits (two α, two β, and one γ), each with distinct isoforms [α1–6, β1–3, and
γ1–3], binds GABA at the extracellular site. Hypnotic benzodiazepines and Z-drugs
interact at the junction of the α and γ subunits of the GABAA receptor, functioning
as positive allosteric modulators that facilitate a conformational change in the subunit structure. This process increases the binding site’s afnity for GABA, thereby
enhancing its effects (for an overview see Palagini etal. 2022). Most hypnotic benzodiazepines exhibit a high afnity for the α1, α2, α3, and α5 receptor subtypes. In
contrast, Z-drugs demonstrate a comparatively lower afnity for these subunits
(Palagini and Bianchini 2022). For instance, zolpidem does not bind to the α5 subunit, and its afnity for the α1 and α2, α3 GABAA receptor subtypes is approximately 10 times and 100 times lower than that of triazolam, respectively (for an
overview see Palagini and Bianchini 2022). The subsequent sections will discuss
commonly prescribed hypnotic benzodiazepines (such as brotizolam, temazepam,
and triazolam) and Z-drugs (including zolpidem, zopiclone, eszopiclone, and
zaleplon), with particular emphasis on their implications during pregnancy and the
postpartum period. Estazolam, urazepam, and lormetazepam have been recommended for the treatment of insomnia over the past years; therefore, data regarding
these benzodiazepines will also be analyzed during the peripartum period (Wang et
al 2022). Conversely, although lorazepam is not typically classied as a hypnotic
benzodiazepine, it is often used in managing insomnia in pregnant patients (Uguz
2021). Data regarding lorazepam will be discussed elsewhere.
Hypnotic Benzodiazepines
Brotizolam
Brotizolam (8-bromo-6-(o-chlorophenyl)-1-methyl-4H triazolo[3,4-c]thieno[2,3e]-1,4-diazepine) is classied as a thieno-triazolo diazepine derivative that interacts
with α1-containing GABAA receptors. The drug has an elimination half-life that is