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23 Pharmacological Approaches toManaging Common Sleep Disorders
501
considered “intermediate,” lasting around 5 h (for an overview see Palagini and
Bianchini. 2022).
Currently, four studies involved brotizolam in pregnancy and postpartum
(Table 23.1). One study was conducted in animals and showed that brotizolam
does pass the placenta and the breast milk in animal (Bechtel 1983). A study was
conducted with 11 women in the peripartum period, while two additional studies
were presented as case reports (Nishimura etal. 2021; Saito et al. 2021; Saito
etal. 2021). These studies indicated that the Relative Infant Dose (RID) was less
than 10%, suggesting a relatively safe level, and the milk to plasma (M/P) ratio
was below 1.
Temazepam
Temazepam, classied as a 1,4-benzodiazepine, is a hydroxylated derivative of
diazepam (3-hydroxydiazepam) and exerts its effects on sleep through interaction
with GABAA receptors. Its half-life ranges from approximately 5–11h. Six studies
involved the use of temazepam during the perinatal period (Table23.1) (Kargas
etal. 1985; Lebedevs etal. 1992; Cooper etal. 2001; Kelly etal. 2012; Damen etal.
2014; Ban etal. 2014). Data on pregnancy are lacking. Globally the milk to plasma
(M/P) ratio was below 1. Two studies report negative outcomes: one with the interaction with diphenhydramine, the other one after using it during delivery (Kargas
etal. 1985; Cooper et al. 2001). In a large cohort study, risks of system-specic
major congenital anomalies were generally similar in children exposed to temazepam during the rst trimester of pregnancy compared to those not exposed to such
medications (Ban etal. 2014).
Triazolam
Triazolam is classied as a triazolobenzodiazepine. Its half-life is relatively
brief, ranging from approximately 2–3h, with recommended hypnotic doses
between 0.125 and 0.25mg administered at bedtime. Five studies involved triazolam in the perinatal period (Kitagawa etal. 1979; Sakai etal. 1996; Kelly
etal. 2012; Noh et al. 2022; Bagger etal. 2023) (Table23.1). Triazolam has
been shown to cross the placenta in animals (Kitagawa etal. 1979) but there are
no data on RID of M/P in humans. Two retrospective cohort studies showed risk
for malformation after exposure during the rst trimester comparable to that of
non-exposed population (Noh etal. 2022; Bagger etal. 2023). Other reports are
case discussions.
There are no data on other benzodiazepines sometimes prescribed for insomnia
such as Flurazepam, lormetazepam, or estazolam, related to the peripartum period.
Currently, there is inconclusive data on the use of hypnotic benzodiazepines in
insomnia during the peripartum.
Several meta-analyses and reviews have examined the effects of these medications during the peripartum period (Chaudhry and Susser 2018; Miller etal. 2020;
Grigoriadis etal. 2020; Huitfeldt etal. 2020; Uguz 2021; Wang etal. 2022; Andrade
etal. 2024).
502
A 28-year-old female patient with a diagnosis of
bipolar II disorder was administered brotizolam
during her pregnancy (from 28 to 40weeks of
M/P ratio for brotizolam: The value 3days after
delivery was 0.12 n/mL and 0.59 after 1month. The
RID value was 2.3% for brotizolam. No
abnormalities were found in breastfeeding infants
and brotizolam was found in the milk of rats as well
as in that of cows
whose mothers were receiving these medications
gestation) and while breastfeeding, in conjunction
L. Palagini
with sertraline, alprazolam, and trazodone. There
were no indications of pulmonary dysfunction or
congenital anomalies. The concentrations of
brotizolam in maternal serum were measured at
0.51ng/mL and 0.22ng/mL at 7.0 and 14.0h
post-dosing, respectively. Notably, brotizolam was
absent in both cord blood and infant serum at 9.2h
following maternal administration. The
concentration of brotizolam found in breast milk,
collected 7.1h after maternal dosing, was 0.12ng/
mL.The infant exhibited normal development, with
no observable drug-related adverse effects noted
during the 1-, 3-, and 6-month postpartum
evaluations
brotizolam 0.25mg
obstetrics department
The milk to plasma
(M/P) ratio and relative
infant dose (RID) were
computed
Compound Design of the study Main results
Hypnotic benzodiazepines
Bechtel (1983) Brotizolam Safety study in animals In animal studies brotizolam crossed the placenta,
Authors
Table 23.1 Studies on pharmacological options for insomnia during the peripartuma period
Brotizolam 11 pregnant women at
Nishimura etal.
(2021)
once daily
Saito etal. (2021) Brotizolam Case report oral
23 Pharmacological Approaches toManaging Common Sleep Disorders
Adverse outcomes, specically sedation was
identied in only 1.6% (2 of 124) of infants and was
Mean milk to plasma (M/P) ratio 0. 18ng/mL
Perinatal fetal mortality was related to the interaction
A 38-year-old female patient diagnosed with
dissociative disorder received treatment with
brotizolam. The concentration ratios of the drug in
both cord blood and maternal serum were found to
be 0.33 for brotizolam. In breast milk, concentrations
of brotizolam were undetectable. The newborn
exhibited no congenital defects and did not show any
of diphenhydramine and temazepam
signicant withdrawal symptoms following delivery
Temazepam was identied in every fetal serum
sample analyzed. The fetal to maternal (F:M) drug
concentration ratio for temazepam was found to be
0.38, remaining consistent between 60 and 120min
following oral administration to the mother.
Additionally, the F:M ratios exhibited variations
correlated with the gestational age of the fetus,
showing an increase as gestational age progressed
for temazepam
not associated with temazepam. Mothers reporting
503
(continued)
adverse outcomes in themselves were more likely to
be taking concomitantly a greater number of central
nervous system depressants
brotizolam 0.25mg
once daily she was also
in treatment with
sulpiride, periciazine,
alprazolam in the
Saito etal. (2021) Brotizolam Case report oral
postpartum
Kargas etal. (1985) Temazepam A case report of
women 10–20mg of
pregnant woman
temazepam
Temazepam 10 breastfeeding
Lebedevs etal.
(1992)
surgical termination of
pregnancy between 12
and 17weeks.
Temazepam 10mg,
approximately 1h
Cooper etal. (2001) Temazepam 37 women undergoing
pre-operatively
women during
breastfeeding
Temazepam and or
Kelly etal. (2012) Temazepam Retrospective study 124
other benzodiazpeines
504
A 38-week-old female neonate, delivered through a
spontaneous vaginal birth facilitated by a midwife at
home, was admitted to neonatal intensive care unit
following an episode of apnea, bradycardia, and
hypotonia 1 h after delivery. Cervical dilation was
slow, prompting the midwife to administer 20mg of
temazepam to mitigate maternal fatigue during the
Overall major congenital anomaly prevalence was
rst stage of labor. Three and a half hours post-
temazepam, the mother delivered a female infant.
Breastfeeding commenced immediately after birth.
However, 1 h later, the infant was discovered to be
nonbreathing. Initial laboratory tests indicated a
venous serum lactate of 8.6mmol/L was noted.
Capillary blood gas analysis revealed a pH of 7.35,
pCO2 of 31mmHg. Screening of urine was positive
for benzodiazepines and a supratherapeutic
temazepam plasma level of 145 μg/L (20–100 μg/L)
was found 6 h since maternal temazepam intake.
Three days later the neonate was fully recovered and
2.9% in 379 children with temazepam. When
could be discharged from the NICU
L. Palagini
compared with 2.7% in 351,785 children with no
diagnosed depression/anxiety nor medication
exposure, the adjusted odds ratio was 1.07
(0.49–2.37) for temazepam. Risks of system-specic
major congenital anomaly were generally similar in
children exposed and not exposed to such
medications
temazepam during
Compound Design of the study Main results
(continued)
Damen etal. (2014) Temazepam Case report 20mg of
Authors
Table 23.1
delivery for therapeutic
rest
children exposed to
with temazepam during
the rst trimester
compared with 351,785
children with no
Ban etal. (2014) Temazepam Retrospective study 379
diagnosed depression/
anxiety nor medication
exposure
23 Pharmacological Approaches toManaging Common Sleep Disorders
Among those exposed to triazolam, the risk for
overall malformation with triazolam was 0.91 and
Sedation was not associated with triazolam (1 case).
the tragic suicide of her mother, who ingested a
minimum of 20 triazolam tablets and subsequently
hanged herself 7h prior to the birth. The infant was
born with cesarean section at 33weeks of gestation.
The infant experienced respiratory distress and
required the administration of pulmonary articial
surfactant. Following extubation, she experienced
apneic episodes, necessitating supplemental oxygen
and aminophylline treatment. The triazolam
concentration measured in the cord blood was
2.30ng/ml. The infant was discharged from the
neonatal intensive care unit at 2months of age and
demonstrated normal developmental progress by
Mothers reporting adverse outcomes in themselves
4months of post-conceptional age
were more likely to be taking concomitantly a
greater number of central nervous system
depressants
for cardiac defect 1.12, which was comparable with
505
(continued)
non-exposed population
Triazolam Safety study in animals In animal studies triazolam crossed the placenta
Sakai etal. (1996) Triazolam Case report A female infant was delivered prematurely following
Kitagawa etal.
(1979)
case with triazolam
Kelly etal. 2012 Triazolam Retrospective study 1
population-based cohort
study exposure to
triazolam and other
benzodiazepines during
the rst trimester
3,094,227 women
Noh etal. (2022) Triazolam Retrospective
506
The estimated apparent elimination half-life of
zolpidem, derived from plasma concentrations, was
found to be 2.6h. At the 3-h mark, the quantity of
zolpidem present in breast milk varied from 0.76 to
414 women (52%) were treated with therapeutic rest.
The most frequently used (n=206) medication for
therapeutic rest was a combination of paracetamol,
triazolam, and codeine. No signicant difference in
neonatal admission, or neonatal resuscitation,
between women treated with or without therapeutic
rest
3.88 micrograms, accounting for 0.004 to 0.019% of
the administered dose. No detectable levels of
zolpidem (below 0.5ng/ml) were observed in the
L. Palagini
milk during subsequent sampling intervals. The
concentration ratio of zolpidem in breast milk to that
in plasma at 3h was determined to be 0.13.
Furthermore, the apparent clearance of zolpidem
from breast milk, calculated based on the total
amount excreted in milk relative to its plasma
concentration, was 1.48ml/h. these ndings indicate
that the excretion of zolpidem in human milk is
minimal (below 0.02%), with the majority occurring
within the initial 3h post-administration drug intake
Compound Design of the study Main results
(continued)
Bagger etal. (2023) Triazolam Retrospective cohort
Authors
Table 23.1
study 800 nulliparous
singleton pregnant
women in the latent
phase of labor
presenting at the labor
ward women who were
treated with therapeutic
rest Triazolam vs
women who were not
women were treated
Z-DRUGS
Pons etal. (1989) Zolpidem Five lactating, healthy
with a single 20mg
tablet of zolpidem
3–4days after the
delivery of a full-term
baby. The drug was
administered at 20.00h,
30min after dinner, and
milk samples were
collected before and 3,
13, and 16h. venous
blood 5ml was taken
before and 1.5, 3, 13,
and 16h after zolpidem
administration.
23 Pharmacological Approaches toManaging Common Sleep Disorders
(continued)
zolpidem misuse experienced a spontaneous vaginal
delivery at 38weeks of gestation. The total fetal
exposure to zolpidem remains uncertain; however, it
is estimated to be no less than 1000mg over a
duration of at least 1 month. Typical peak plasma
concentrations following a single administration of
5mg and 10mg of zolpidem are reported to be
between 29–113ng/ml (mean 59ng/ml) and
58–272ng/ml (mean 121ng/ml), respectively. A
sample of cord blood was collected for zolpidem
analysis, yielding a concentration of 41ng/ml.
Notably, despite the detection of zolpidem in the
cord blood, the neonate exhibited activity and
alertness following a normal delivery. There were no
signs of withdrawal symptoms, and both the mother
and the neonate were discharged after a 48-h
monitoring period. This case report illustrates that
zolpidem is capable of crossing the human placenta,
These ndings indicate a convergence on anxiety-
related behaviors in the effects of prenatal exposure
to diazepam and alprazolam but not of zolpidem
as evidenced by the cord blood analysis
507
to zolpidem
Zolpidem Rats prenatal exposure
Cannizzaro etal.
Askew (2007) Zolpidem Case report A 30-year-old Caucasian female with a history of
(2002)
508
The incidence of preterm delivery and low birth
weight in the group exposed to zolpidem was
The ndings indicate that the adjusted odds ratios
(ORs) for negative pregnancy outcomes—Including
low-birth-weight infants, preterm births, small-for-
gestational-age infants, and cesarean sections—were
recorded at 26.7% and 15.6%, respectively,
compared to 13.3% and 4.4% in the matched control
group; however, these differences were not
statistically signicant. The ratio of zolpidem
concentrations in umbilical cord blood to maternal
plasma in six pairs varied between 0.48 and 2.75.
Zolpidem is capable of crossing the human placenta
and is rapidly eliminated from fetal circulation.
Although pregnant women with psychiatric disorders
receiving zolpidem may experience less favorable
obstetric outcomes, it remains uncertain whether this
is attributable to the medication itself
signicantly elevated among mothers who
L. Palagini
underwent zolpidem treatment during pregnancy
when compared to the randomly selected control
group (1.39 (95% condence interval
(CI)=1.17–1.64), 1.49 (95% CI=1.28–1.74), 1.34
(95% CI=1.20–1.49), and 1.74 (95%
CI=1.59–1.90), respectively). In summary, the data
suggest that the likelihood of experiencing adverse
pregnancy outcomes is greater in women who were
treated with zolpidem during their pregnancy
compared to those who were not
Compound Design of the study Main results
(continued)
Juric etal. (2009) Zolpidem Forty-ve women
Authors
Table 23.1
taking zolpidem during
pregnancy were studied
in comparison with
non-exposed patients
based study Taiwan
National Health
Insurance Research
Dataset (NHIRD) and
birth-certicate registry.
In total, the data from
2497 mothers who
Wang etal. (2010) Zolpidem Nationwide population-
received zolpidem
treatment during
pregnancy and those
from 12,485 randomly
selected mothers who
did not receive the drug
were included in the
analysis.
23 Pharmacological Approaches toManaging Common Sleep Disorders
(continued)
5mg each night to aid her sleep. Breastmilk
concentrations were assessed on three occasions
following childbirth: On day one, 8.2h post-dose,
the concentration measured was 12.8 mcg/L; on day
two, 9h after the dose, the concentration was
recorded at 6.4 mcg/L; and on day three, 2.2h
post-dose, the concentration reached 26.5 mcg/L. the
authors calculated the maximum daily dose for the
infant to be 4 mcg/kg, based on the measurement
defects has been reported, linked to her dependence
on zolpidem and the consumption of high doses
The use of hypnotic benzodiazepine receptor
agonists did not correlate with an elevated risk of
congenital malformations. However, a statistically
signicant increased risk for other intestinal
malformations, excluding atresias and stenosis, was
identied, albeit based on a limited sample of only
four infants
during the rst trimester of her pregnancy
obtained on day three
509
registry indicated that
1318 women reported
the use of Z drugs
during early pregnancy
Zolpidem Swedish medical birth
Wikner and Källén
(2011)
Zolpidem Case report A woman was administered zolpidem at a dosage of
Saito etal. (2022a, b,
Sharma etal. (2011) Zolpidem Case report A case of a female patient with fetal neural tube
c, d)
510
5mg of zolpidem throughout their pregnancy and
the postpartum period. One of the women exhibited
a breastmilk concentration of zolpidem measuring
10.1 mcg/L, recorded 6.5h following a dose on the
sixth day postpartum. The second woman displayed
varying milk zolpidem concentrations, with levels
between 0.6 mcg/L at 18.1h post-dose on the second
day postpartum and 4.8 mcg/L at 10.1h post-dose on
the third day postpartum. Additionally, a third
woman, who took a 5mg dose as needed, showed a
milk concentration of 3.4 mcg/L at 17.2h after a
dose on the rst day postpartum. By the seventh day,
105h after a dose, zolpidem was no longer
detectable in the breastmilk. Three infants were
breastfed by mothers who were administered
L. Palagini
zolpidem at a dosage of 5mg daily (n=2) or on an
as-needed basis (n=1). The breastfeeding frequency
for these infants ranged from four to six times per
day. Notably, all infants exhibited undetectable
serum levels of zolpidem, measured at less than 0.05
mcg/L
Zopidem Three case series Two pregnant women administered daily doses of
Compound Design of the study Main results
(continued)
Saito etal. (2022a, b,
c, d)
Authors
Table 23.1