Expert Reviews ajog.

org

OBSTETRICS
A review of sleep-promoting medications used in pregnancy
Michele L. Okun, PhD; Rebecca Ebert, BA; Bandana Saini, PhD

management of health conditions in

Approximately 4% of adults who have symptoms of insomnia resort to various hypnotic or pregnancy.10 This was a commendable
sedating medications for acute symptom relief. Although typically a common practice for effort and will likely address all classes of
nonpregnant adults, this is not the case for the thousands of pregnant women who also medications that may be used by preg-
report substantial sleep issues. Unfortunately, a paucity of randomized controlled trials in nant women, not just hypnotic/sedatives
this population, scant empiric evidence regarding the appropriateness of prescribing alone. This prototype likely will retrieve
options, and the concern of subsequent teratogenicity restricts the ability of clinicians to most of its information from the seminal
make informed decisions. We synthesized the current research regarding hypnotics and book by Briggs et al.11 This compilation
sedating medications used (both on- and off-label) during pregnancy and their associ- reviews every medication ever reported to
ation with adverse outcomes. Medications that we investigated included benzodiaze- be used in pregnancy. The downside to
pines, hypnotic benzodiazepine receptor agonists, antidepressants, and antihistamines. this book is that it is >2000 pages and
Overall, the examined studies showed no correlation of increased risk of congenital is designed for clinical practice. As
malformations. However, benzodiazepines and hypnotic benzodiazepine receptor ago- the dissemination of the incidence of
nists may increase rates of preterm birth, low birthweight, and/or small-for-gestational- sleep disturbances expands, an apprecia-
age infants. The small number of studies and the small number of subjects prohibit any tion of the health risks associated with
definitive interpretation regarding the consequences of the use of hypnotic or sedating disturbed sleep also grows. Based on this,
medications in pregnancy. Additional case reports, randomized clinical trials, and we proffer that the literature currently
epidemiologic studies are needed urgently. lacks a concise, easily obtainable review
regarding the usage and possible terato-
Key words: benzodiazepine, hypnotics, medication, pregnancy, sleep genic effects of sedative/hypnotic medi-
cations during pregnancy. Although
pregnancy risk categories denoted by the

S ymptoms of insomnia are prevalent

in adults. Approximately 50% of
adults report difculty initiating or
maintaining sleep or having unrefresh-
ing sleep (ie, symptoms of insomnia),
whereas upwards of 20% of adults meet
diagnostic criteria for insomnia.1 Given
these numbers, it is not surprising that a
signicant number of adults (4%) report
frequent use of hypnotic or sedating
medications to combat the symptoms of
insomnia.2,3 A variety of medications are
prescribed commonly (on and off label
for their sleep promoting effects), which
From the University of Pittsburgh (Drs Okun and
Ebert), Pittsburgh, PA; the University of Sydney
(Dr Saini), Sydney, Australia; and the University
of Colorado at Colorado Springs (Dr Okun),
Colorado Springs, CO.
Received July 31, 2014; revised Oct. 1, 2014;
accepted Oct. 28, 2014.
The authors report no conict of interest.
Corresponding author: Michele L. Okun, PhD.
mokun@uccs.edu
0002-9378/$36.00
2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2014.10.1106
includes benzodiazepines, hypnotic
benzodiazepine receptor agonists, anti-
depressants, and antihistamines.
Many of the adults who take hypnotic
or sedating medications are likely preg-
nant women, because pregnant women
have symptoms of insomnia more often
than their nonpregnant counterparts.4,5
Further, because one-half of the annual
6 million pregnancies in the United
States are unplanned, many women un-
intentionally may have exposed their
fetus to a hypnotic/sedative medication.6
As a result, hypnotic or sedating medi-
cation use during pregnancy is quite
common.7 Despite their frequent use,
clinicians are often reluctant to prescribe
medications to pregnant women for fear
of teratogenic effects.8,9
This is exemplied in a recent article
that noted that the Centers for Disease
Control and Prevention deemed it critical
to understand the existing evidence about
medication use as it relates to associated
pregnancy risks. The Centers for Disease
Control and Prevention solicited experts
in the eld to draft a prototype to
inform clinical decision-making for the
regulatory authorities such as the US
Food and Drug Administration (FDA)
and the Australia Therapeutic Goods
Administration (TGA) pregnancy risk
categories can be used, a concise and up-
to-date reference on sedative/hypnotic
use during pregnancy does not exist.
Previous reviews on medication safety
during the perinatal period are not spe-
cic to sedative/hypnotic medica-
tions.10,12 They often do not refer to
newly developed drugs nor cover all drug
categories, specically medications that
fall into the sedative/hypnotic class. Given
the wide prevalence of sleep disorders and
medication use in pregnancy, the aim of
this review was to describe comprehen-
sively the existing body of research to
understand the use and impact of hyp-
notic/sedating drugs (both on-and off-
label) during pregnancy and their
possible consequences for maternal and
fetal outcomes.
Methods
Search strategy
We exhaustively searched PubMed and
found articles based on key search terms:

428 American Journal of Obstetrics & Gynecology APRIL 2015

ajog.org Obstetrics Expert Reviews
pregnancy and sleep with various medi-
cations or drug classes (hypnotics, seda- FIGURE
tives, benzodiazepine, nonbenzodiazepine, PRISMA diagram shows the selection of articles
melatonin, antidepressants, antihista-
mines, ramelteon, zolpidem, zopiclone,
zaleplon, alprazolam, clonazepam loraze-
pam, medazepam, nitrazepam, temaze-
pam, tosopam., mirtazapine, trazodone,
diphenhydramine, doxylamine, hydroxy-
zine, pheniramines). These search terms,
which allowed for 30 different searches,
resulted in 1452 articles.
Our primary focus was to summa-
rize comprehensively the current
literature on medications that are used
for sedative or hypnotic purposes by
pregnant women. Thus, we excluded
results that were animal studies, neo-
natal studies, reviews, inaccessible full
texts, non-English publications, or
for-medication doses that fell outside
of the FDA-specied hypnotic/sedative
doses. These exclusions removed a
substantial number from our potential
article pool and resulted in 1055 arti-
cles. After removing duplicate articles
from the multiple searches, we had
399 articles to review. Of these 399
articles, we scanned the titles and ab-
stracts and narrowed inclusion further
by excluding articles in which pre-
scription reason or dose was specied Adapted from Moher et al.82
outside of the sedative realm. This Okun. Sleep drugs in pregnancy. Am J Obstet Gynecol 2015.
resulted in a total of 16 articles to use.
The Preferred Reporting Items for
Systematic Reviews and Metaanalyses
format for the literature search process Based on this information, we compared pregnancy categories by the FDA and the
is diagrammed in the Figure. and collected the results to focus in on TGA are outlined in Tables 1 and 2.
general conclusions of the safety of
Data abstraction each drug and/or drug class during
In our review, we categorized the articles pregnancy. Results
by drug class. We examined 6 articles on All studies included here reported on
benzodiazepines, 5 articles on hypnotic Drug categories pregnant women. Most of the studies
benzodiazepine receptor agonist After the notable cases of thalidomide- were retrospective cohort studies. Most
(HBRA) drugs, 2 articles on both ben- caused fetal malformations in the of the data emanated from Sweden, the
zodiazepines and HBRA drugs, 2 articles 1960s, most countries require all drugs United States, and the United Kingdom,
on antidepressants, and 1 article on an- to be classied into pregnancy cate- with a few studies from Taiwan, Hungary,
tihistamines. We extracted the key data gories that denote risk of unwanted ef- and Canada. Prospective comparative
through the research ndings that were fects. Three of the most widely accepted and prospective cohort (matched pairs)
presented in the articles with the use of a international pregnancy classications studies were the second most common
tabulation method. The summary table include the FASS (Swedish Catalogue of study design.
for all articles describes extracted data Approved Drugs), the US FDA, and the Because most data came from regis-
under the elds: author, date of publi- Australian systems, which vary slightly tries, in some cases it is not clear whether
cation, location(s) of study, type of because of differences in safety data a drug was used off-label for sleep and/or
study, population size, drug(s) studied, interpretation.13 The categorization of insomnia, particularly for antidepressant
outcomes/results, and key ndings. drugs into risk classes for use in drugs. Further, in cases of self-report, the

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TABLE 1
Use in pregnancy drug risk categories
Use in pregnancy drug Classes
classification Food and Drug Administration (United States)
Category A Adequate and well-controlled studies have failed to
demonstrate a risk to the fetus in the first trimester of
pregnancy, and there is no evidence of risk in later
trimesters.
Category B Animal reproduction studies have failed to
demonstrate a risk to the fetus, and there are no
adequate and well-controlled studies in pregnant
women.
Category C Animal reproduction studies have shown an adverse
effect on the fetus; there are no adequate and
well-controlled studies in humans, but potential
benefits may warrant the use of the drug in pregnant
women despite potential risks.
Category D There is positive evidence of human fetal risk based on
adverse reaction data from investigational or
marketing experience or studies in humans, but
potential benefits may warrant the use of the drug in
pregnant women despite potential risks.
Category X Studies in animals or humans have demonstrated fetal
abnormalities, and/or there is positive evidence of
human fetal risk based on adverse reaction data from
investigational or marketing experience; the risks that
are involved in the use of the drug in pregnant women
clearly outweigh potential benefits.
Therapeutic Goods Administration (Australia)
These consist of drugs that have been taken by a large
number of pregnant women and women of
childbearing age without any proven increase in the
frequency of malformations or other direct or indirect
harmful effects on the fetus that have been observed.
B1: These are drugs that have been taken by only a
limited number of pregnant women and women of
childbearing age without an increase in the frequency
of malformation or other direct or indirect harmful
effects on the human fetus that have been observed.
B2: These are drugs that have been taken by only a
limited number of pregnant women and women of
childbearing age without an increase in the frequency
of malformation or other direct or indirect harmful
effects on the human that have been observed; studies
in animals are inadequate or may be lacking, but
available data show no evidence of an increased
occurrence of fetal damage.
B3: These are drugs that have been taken by only a
limited number of pregnant women and women of
childbearing age without an increase in the frequency
of malformation or other direct or indirect harmful
effects on the human fetus that have been observed;
studies in animals have shown evidence of an
increased occurrence of fetal damage, the significance
of which is considered uncertain in humans.
These are drugs that, owing to their pharmacologic
effects, have caused or may be suspected of causing
harmful effects on the human fetus or neonate without
causing malformations; these effects may be
reversible (accompanying texts should be consulted for
further details).
These are drugs that have caused, are suspected to
have caused, or may be expected to cause an
increased incidence of human fetal malformations or
irreversible damage; these drugs may also have
adverse pharmacologic effects (accompanying texts
should be consulted for further details).
These are drugs that have such a high risk of causing
permanent damage to the fetus that they should not be
used in pregnancy or when there is a possibility of
pregnancy.

Okun. Sleep drugs in pregnancy. Am J Obstet Gynecol 2015.

use of other drugs or substances often
was not available.
Benzodiazepines
Benzodiazepines are a class of psycho-
active medications that enhance the
effect of the neurotransmitter gamma-
aminobutyric acid (GABA) at the
GABAA receptor, which results in seda-
tive,hypnotic (sleep-inducing),anxio-
lytic (antianxiety), anticonvulsant, and
muscle relaxant properties.14 As a class,
they are not major teratogens, but there
remains uncertainty as to whether they
cause cleft palate in a small number of
babies and whether neurobehavioral ef-
fects occur as a result of prenatal expo-
sure.15 Benzodiazepines and HBRA
drugs cross the placenta and have the
potential to accumulate in the embryo/
fetus and therefore may cause adverse

430 American Journal of Obstetrics & Gynecology APRIL 2015

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effects.16 We identied 12 articles that
discussed the safety of sedative benzo-
diazepine and HBRA drug use in preg-
nant women. A summary of the research
on benzodiazepines is listed in Table 3.
We want to highlight that the reason for
the use of the drugs in the pregnant
women is not denoted. Given that the
main effect of this class of drugs is
sedation, a large proportion of the
women may have been taking them for
sleep-related issues. However, for drugs
such as diazepam and clonazepam, the
reason for use may have been the anxi-
olytic or antiepileptic effect.
Most of the evidence that pertains
to the effects of benzodiazepines on
maternal/fetal outcomes comes from
Europe. The Hungarian Congenital
Abnormality Registry is a national-
based registry of cases with congenital
abnormalities. The evaluated dataset
included 22,865 cases (69.7% of all
reported informative offspring) and
38,151 (68.8%) control subjects. All
analyses were controlled for maternal
age, birth order, acute and chronic
maternal disorders, and other drug uses.
Eros et al17 examined the association
between benzodiazepines (ie, nitraze-
pam, medazepam, tosopam, alprazo-
lam and clonazepam) as a drug class and
congenital malformations. The results
showed no statistically signicant in-
creased risk for congenital malforma-
tions resultant of the use of or exposure
to the 5 benzodiazepines that were
evaluated. Specically, the authors
report that. among women who used
benzodiazepines, 57 women (0.25%)
delivered a baby with congenital mal-
formations compared with 75 women
(0.20%) who delivered a healthy baby.
Only alprazolam was suspected of tera-
togenicity on the basis of their data.
However, the rate of congenital abnor-
malities did not appear to be higher in
2 series of infants who were born
to women who were treated with al-
prazolam during the rst trimester of
pregnancy.17
In another study by this group, Czeizel
et al18 evaluated the teratogenicity of
short-term (3-week) diazepam use in
pregnancy. Using the same population-
based sample, they found that 2746
Obstetrics
infant cases (12.0%), 4130 infant popu-
lation control subjects, (10.8%) and 97
infant patient control subjects (11.9%)
were born to mothers who were treated
with diazepam during pregnancy. They
concluded that short-term diazepam use
during pregnancy did not present any
detectable risk to the fetus.18 For both
studies, the authors note that some of the
statistically signicant ndings may be
due to chance error caused by multiple
comparisons.
Malformation rates that resulted
from clonazepam (benzodiazepine)
exposure were studied by Lin et al.19
The medical records of 28,565 infants
from Massachusetts were surveyed as
part of a hospital-based malformation
surveillance program to identify those
who had been exposed prenatally to
clonazepam. Of the 43 mothers who
used clonazepam alone, the treatment
indication included seizures (1/43
mothers; 2.3%), migraine headaches
(1/43 mothers; 2.3%), and psychiatric
diagnoses that included depression,
bipolar disorder, panic attacks, anxiety,
and obsessive-compulsive disorder
(41/43 mothers; 95.3%). Among 33
infants who were exposed during the
rst trimester, only 1 infant had any
malformations. Results showed no
signicant increased risk of abnor-
mality in infants who were born to
mothers who received clonazepam
monotherapy.
St. Clair and Schirmer20 focused on
women with rst-trimester exposure to
the benzodiazepine, alprazolam, who
were tracked prospectively throughout
pregnancy. In a sample of 411 women, 5
still births, 42 spontaneous abortions,
and 88 induced abortions were observed.
Among the 276 live births that were
tracked, 13 infants had congenital ab-
normalities. Although alprazolam is
known to cross the placenta, rates of
congenital abnormalities and sponta-
neous abortions in women using al-
prazolam in the rst trimester were not
signicantly higher compared with the
general population. No dose effect was
observed in cases of malformation. The
authors concluded that further research
is required, given the relatively small
sample size.20
APRIL 2015 American Journal of Obstetrics & Gynecology
Expert Reviews
Hypnotic benzodiazepine receptor
agonists
The Z-drugs are a group of non-
benzodiazepine drugs with effects
similar to benzodiazepines, (they act on
the GABAA receptor) that are used in the
treatment of insomnia.21,22 Since their
introduction and in response to safety
concerns, there has been a reduction in
the prescription of benzodiazepine
hypnotics in favor of the Z-drugs.23,24
The Z-drugs are now the most com-
monly prescribed hypnotic agents
worldwide. This is also true among
pregnant women.25 Unfortunately, there
still remains a paucity of published data
on the effects of the Z-drugs during
pregnancy.
Zolpidem, an agonist at the benzodi-
azepine receptor component of the
g-GABAAereceptor complex, is indi-
cated for short-term treatment (
4
weeks) of insomnia.21,26 Empiric data
have demonstrated adverse effects on
fetal development in animals; thus, the
FDA currently classies zolpidem as a
category C drug; the TGA classies it as a
B3 drug (Table 2). Zolpidem reduces the
onset time to sleep and prolongs its
duration in patients with insomnia.27
It appears to have minimal next-day
effects on cognition and psychomotor
performance when administered at
bedtime.28 Zopiclone is another non-
benzodiazepine hypnotic agent that is
used in the treatment of insomnia. It is
a cyclopyrrolone, which increases the
normal transmission of the neuro-
transmitter GABA in the central nervous
system, as benzodiazepines do, but in
a different way. Currently, it is not
available in the United States.29 After
oral administration, the drug is absor-
bed rapidly, with a bioavailability of
approximately 80% and an elimination
half-life that ranges from 3.5-6.5 hours.30
It has a smaller rebound insomnia effect
than benzodiazepines, minimal abuse
potential, and no teratogenic effects in
pregnant animals.29 Eszopiclone is the
active dextrorotatory stereoisomer of
zopiclone. It is currently available in the
United States and is an option during
pregnancy. Similar to zopiclone, there are
no human studies, but animal data sug-
gest no teratogenicity. The nal HBRA is
431
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Analyses controlled for infant gender,

TABLE 2 parity, maternal educational level, and
Food and Drug Administration (United States) and Therapeutic Goods maternal morbidity. They found a
Administration (Australia) drug categorizationsa signicantly increased incidence of low
Pregnancy categoryb birthweight (LBW) infants (7.61% vs
Prescription drugs used as sedative/hypnotics United States Australia 5.19%; odds ratio [OR], 1.39; 95%
condence interval [CI], 1.17e1.64;
Benzodiazepines
P < .001), preterm deliveries (10.01% vs
Alprazolam D B3 6.30%; OR, 1.49; 95% CI, 1.28e1.74;
Clonazepam D B3 P < .001), small-for-gestational-age in-
Diazepam D C fants (19.94% vs 15.06%; OR, 1.34; 95%
CI, 1.20e1.49; P < .001), and cesarean
Lorazepam D C
deliveries (46.86% vs 33.46%; OR, 1.74;
Medazepam Not available Not available 95% CI, 1.59e1.90; P < .001). However,
Nitrazepam D C consistent with the benzodiazepine
Temazepam X C literature, there was no signicant dif-
ference between the 2 groups in the
Tofisopam Not available Not available
rates of congenital anomalies (0.48%
Nonbenzodiazepines vs 0.65%; P .329). Last, Juric et al25
Zaleplon C Not available conducted a prospective case-controlled
study of 45 pregnant women with a
Zolpidem C B3
psychiatric disorder (depression, bipo-
Zopiclone C C lar, or anxiety) who received zolpidem
Eszopiclone C C therapy and 45 psychiatrically matched
pregnant women who were not re-
Antidepressants
ceiving zolpidem therapy. Although
Mirtazapine C B3 rates of preterm delivery and LBW were
Trazodone C Not available 26.7% and 15.6%, respectively, in the
Amitriptyline C C zolpidem-exposed group vs 13.3% and
4.4% in the matched comparator group,
Antihistamines these rates were not statistically different.
Diphenhydramine B A Furthermore, no congenital abnormal-
Doxylamine. A A ities were observed in any of the infants
who were delivered. The use of HBRA
Hydroxyzine C A
drugs for sleep concerns, concurrent
Pheniramines Not available A with other psychotropic medications, in
a b
For common sedative/hypnotics that are used during pregnancy; See Table 1 for an explanation of the categories. psychiatric patients is extremely com-
Okun. Sleep drugs in pregnancy. Am J Obstet Gynecol 2015. mon. The additive effects of multiple
medications cannot be underscored
here. We reviewed 3 studies that provide
critical, yet limited, information on the
zaleplon which is also an agonist at the Although she was in and out of the consequences of multiple medication
GABAA a1 subreceptor site.31 Much less hospital before her delivery and experi- use during pregnancy.
is known about zaleplon because fewer enced withdrawal symptoms, she pro- As mentioned, zopiclone is not avail-
studies have been conducted. Presently, ceeded to deliver a full-term healthy baby able in the United States; thus, the only
there are no studies that are evaluating with no observable withdrawal symp- published report is from a Canadian
zaleplon use in pregnancy. toms. Further examination of cord blood group. Diav-Citrin et al34 evaluated 40
A summary of the limited research samples indicated that indeed zolpidem pregnant women who received zopiclone
on HBRA drugs is listed in Table 3. had crossed the placenta. Another study therapy during pregnancy and consulted
Three papers focused on zolpidem. The that focused on zolpidem was a retro- the Motherisk Program from 1993-1997.
rst was a case-study of a woman who spective cohort study by Wang et al.33 This cohort of women and a matched-
was addicted to the medication.32 The With access to a sample of 14,982 control group who did not receive
woman reported discontinuation at 29 Taiwanese mothers, they evaluated zopiclone therapy were telephoned after
weeks gestation; however, it was antici- whether zolpidem use of >90 days dur- delivery and asked about birth defects,
pated that fetal exposure was approxi- ing pregnancy was associated with maternal characteristics, pregnancy
mately 1000 mg over at least a month. adverse maternal and fetal outcomes. outcomes, and offspring characteristics.

432 American Journal of Obstetrics & Gynecology APRIL 2015


TABLE 3
Summary of publications and key findings on the use of hypnotics during pregnancy
Study Study design/population
Benzodiazepines
Ban et al38 (2014; Retrospective cohort design/Neonates of
United Kingdom) women who used either benzodiazepine or
nonbenzodiazepine hypnotic without
concomitant antidepressant in the first
trimester: 1159 infants with exposure to
diazepam; 379 infant with exposure to
temazepam; 19,193 infants with no drug
exposure
Czeizel et al18 (2003; Matched case-population control pair analysis/
Hungary) Neonates of women who, while pregnant, self-
reported or medically verified use of diazepam
for a short period (approximately 3 weeks):
38,151 population-control neonates without
congenital abnormalities; 22,865 neonates with
congenital abnormalities; 812 neonates with
Down syndrome (patient controls)
Eros et al17 (2002; Retrospective matched case-control study
Hungary) /Women who were pregnant while using
benzodiazepines who delivered infants with
congenital abnormalities (n 57) and pregnant
APRIL 2015 American Journal of Obstetrics & Gynecology
women controls who used benzodiazepines
who gave birth to infants without defects (n
75) whose cases were found in the dataset of
the nationwide Hungarian Case-Control
Surveillance of Congenital Abnormalities from
1980-1996
Lin et al19 (2004; Retrospective cohort study/52 of 28,565 total
Boston, MA, United infants were exposed to clonazepam (43
States) monotherapy, 33 during the first trimester) as
found in surveying medical records over a 32-
month period as part of a hospital-based
malformation surveillance program
Reis and Kallen37 Retrospective population-based cohort study/
(2013; Sweden) All infants born to mothers who used
benzodiazepines alone (n 606)
433
Okun. Sleep drugs in pregnancy. Am J Obstet Gynecol 2015.
ajog.org
Drug used (US
category/AUS category) Outcomes/results Key findings
Diazepam (D, C); Rate of major congenital abnormalities: No significant increased risk
temazepam (X, C) 2.7% among women with no for congenital malformations
depression/anxiety; 2.7% among
women who used diazepam; 2.9%
among women who used temazepam
Diazepam (D, C) Higher rate of limb deficiencies, rectal- No significant increased risk
anal atresia/stenosis, cardiovascular for congenital malformations
malformations and multiple congenital among the 3 groups
abnormalities after diazepam use during
the second and third months of
gestation; however, the evaluation of
only medically recorded diazepam use
did not indicate a higher use of
diazepam in any congenital abnormality
group
Nitrazepam (D, C), Rates of congenital abnormalities were No significant increased risk
medazepam (not not significantly different from national for congenital malformations
available), tofisopam (not average found
available), alprazolum (D,
B3), clonazepam (D, B3)
Obstetrics
Clonazepam (D, B3) 1/33 infants exposed to clonazepam No significant increased risk
Expert Reviews
monotherapy during the first trimester for major malformations
had major malformations
Benzodiazepinesa 37 infants with relative severe No significant increased risk
malformation; 13 with cardiovascular of malformations
defect (rates of congenital abnormalities
not significantly different from national
average)
(continued)

434 American Journal of Obstetrics & Gynecology APRIL 2015
TABLE 3
Summary of publications and key findings on the use of hypnotics during pregnancy (continued)
Study Study design/population
St. Clair and Prospective cohort study/Pregnant women who
Schirmer20 (1992; reported first-trimester use of alprazolam and
Kalamazoo, MI, who were followed through delivery (n 411)
United States)
Wikner et al 36 (2007; Population-based retrospective cohort study/
Sweden) Pregnant women (n 390) who gave birth to
401 infants, as identified by the Swedish
Medical Birth Register, who were exposed to
benzodiazepines and/or hypnotic
benzodiazepine receptor agonists during late
pregnancy
Hypnotic benzodiazepine
receptor agonists
Askew32 (2007; Case-study/30-year-old pregnant white
Wilmington, NC, woman with a history of zolpidem abuse (n 1)
United States)
Ban et al38 (2014; Retrospective cohort design/Neonates of
United Kingdom) women who used either benzodiazepine or
non-benzodiazepine hypnotic without
concomitant antidepressant in the first
trimester: 406 infants with exposure to
zopiclone; 19,193 infants with no drug
exposure
Diav-Citrin et al29 Matched pairs prospective cohort study/
(2000; Canada) Pregnant women who had used zopiclone with
age-matched women with no teratogenic
exposure during pregnancy for smoking and
alcohol consumption and who were chosen
from those who consulted the Motherisk
Program between 1993 and 1997 (n 40)
Okun. Sleep drugs in pregnancy. Am J Obstet Gynecol 2015.
Expert Reviews
Drug used (US
category/AUS category) Outcomes/results Key findings
Alprazolam (D, B3) Among 411 pregnancies, 47 No increased risk in
spontaneous abortions, and 88 elective congenital malformations
abortions; of 276 live births: 263 infants observed
without congenital abnormalities, 13
infants with congenital abnormalities
Benzodiazepines, Increased risk for preterm birth; Increased risk of low
hypnotic benzodiazepine increased risk for low birthweight birthweight, preterm birth
receptor agonistsa,b
Obstetrics
infants; slight increase in major
congenital malformations in infants
exposed early in pregnancy
Zolpidem (C, B3) Spontaneous vaginal delivery at 38 No adverse outcomes found;
weeks gestation, neonate normal and zolpidem found to cross the
healthy; cord blood sampling indicated placenta
zolpidem crosses the placenta
Zopiclone (C, C) Rate of major congenital abnormalities No significant increased risk
similar for both groups; approximately for congenital malformations
2.7% among women with no
depression/anxiety; 2.5% among
women who used zopiclone
Zopiclone (C, C) No differences in pregnancy outcome, After adjustment for
delivery method, preterm delivery, and birthweight for gestational
malformations found for women who age, there was no increased
used zopiclone vs those who did not; risk of low birthweight and/or
differences found in low birthweight and lower gestational age
lower gestational age for infants born to
mothers who used zopiclone
(continued)
ajog.org

TABLE 3
Summary of publications and key findings on the use of hypnotics during pregnancy (continued)
Study Study design/population
25
Juric et al (2009; Prospective 1:1 matched comparison/45
Atlanta, GA, United pregnant women with psychiatric disorder who
States) used zolpidem and comparison group of
psychiatrically matched women who did not
use zolpidem
Reis and Kallen37 Retrospective population-based cohort study/
(2013; Sweden) All infants who were born to mothers who used
hypnotic benzodiazepine receptor agonists
alone (n 776)
Wang et al33 (2010; Retrospective cohort study/Pregnant women
Taiwan) who used zolpidem as treatment for insomnia
(n 2497) compared with pregnant women not
using zolpidem (n 12,485) who were
selected from the Taiwan National Health
Insurance Research Dataset (NHIRD) and birth-
certificate registry
APRIL 2015 American Journal of Obstetrics & Gynecology
Wikner et al36 (2007; Population-based retrospective cohort study/
Sweden) Pregnant women (n 1318) who gave birth to
1341 infants and who used hypnotic
benzodiazepine receptor agonists drugs from
July 1, 1995, through 2007 who were identified
by the Swedish Medical Birth Registry
Wilton et al35 (1998; Noninterventional observational cohort study/
United Kingdom) 87 pregnant women who used either zolpidem
or zopiclone
Antidepressants
Okun. Sleep drugs in pregnancy. Am J Obstet Gynecol 2015.
435
ajog.org
Drug used (US
category/AUS category) Outcomes/results Key findings
Zolpidem (C, B3) Obstetric outcome and neonatal well- No major malformations
being; fetus able to metabolize and reported; no increased risk
eliminate the medication; the rate of for preterm birth or low
preterm delivery (26.7%) and low birthweight
birthweight (15.6%) in the zolpidem-
exposed cohort not statistically greater
than the nonexposed comparison group
Hypnotic benzodiazepine 22 infants seen to have relative severe No significant increased risk
receptor agonistsb malformation; 2 with cardiovascular of malformations
defect; rates of congenital abnormalities
not significantly different from national
average.
Zolpidem (C, B3) Mothers who use zolpidem more likely Increased risk of low
to have gestational hypertension and birthweight and/or small-for-
anemia; higher risk of low birthweight gestational age infants,
and small-for-gestational-age infants; preterm and/or cesarean
and preterm and cesarean delivery; no delivery
difference in rates of congenital
abnormalities; no difference in first-
trimester use vs second- or third-
trimester use; increase of the risk of
adverse outcomes if drug is used for
>90 days
Zopiclone (C, C), Rates of congenital abnormalities not No significant increased risk
zolpidem (C, B3), significantly different from national for congenital malformations
Obstetrics
zaleplon (C, not available) average; tentative association with
intestinal malformations, results
possibly significantly confounded or
because of chance
Zopiclone (C, C), Among the 87 women, 5 spontaneous No significant increased risk
Expert Reviews
zolpidem (C, B3) abortions and no preterm births or for adverse delivery or infant
congenital abnormalities outcomes
(continued)
Expert Reviews Obstetrics ajog.org

The researchers found that zopiclone use

was associated with a signicantly lower

Fewer depressive symptoms

Fewer depressive symptoms

compared with placebo; no
mean birthweight (3245.9  676 g

infant outcomes observed

assessment of delivery or

assessment of delivery or
No adverse pregnancy or
[zopiclone] vs 3624.2  536 g [control
with trazodone; no
subjects]; P .01) and lower gestational
infant outcomes

infant outcomes
age (38.3  2.7 weeks [zopiclone] vs
Key findings

40.0  1.6 weeks [controls]; P .002]

compared with those in the control
group. Once the birthweight was cor-
rected for gestational age the differences
were no longer signicant. There were
no differences in the outcome of preg-
Cases 1 & 2: remission of all symptoms;
placebo; associated with lower Edinburg

duration and sleep efficiency compared

The study did not specify which drug was used, only that the class was benzodizepines; b The study did not specify which drugs were evaluated, only that the class was non-benzodiazepine hypnotic agents.
Trazodone: increased sleep duration

nancy, delivery method, assisted de-

and sleep efficiency compared with

Postnatal Depression Scale scores

Postnatal Depression Scale scores

Diphenhydramine increased sleep
case 3: mirtazapine exacerbated

liveries, and fetal distress and the

associated with lower Edinburg

with placebo; diphenhydramine presence of meconium at birth, preterm
deliveries, or neonatal intensive care
admissions between study and control
Outcomes/results

groups.34 Similar to other studies, the

current consensus is that this drug does
not represent a major human teratogen.
insomnia
Summary of publications and key findings on the use of hypnotics during pregnancy (continued)

Studies that evaluated multiple drugs

Because medication use during preg-
nancy is not recommended, there is a
Low-dose mirtazapine (C,
category/AUS category)

paucity of data on specic drug types.

B3) added onto selective

Diphenhydramine (B, A)

Some investigators have used large

serotonin reuptake

epidemiologic studies to provide some

Trazodone (C, not

inhibitors in the
Drug used (US

information. We found 4 studies that

compared both benzodiazepine and
treatment
available)

HBRA medication use in pregnant and

nonpregnant populations: (1) an older
report on newly marketed drugs that
were taken during pregnancy assessed
insomnia in the third trimester/54 age-matched

insomnia in the third trimester/54 age-matched

outcomes among 831 pregnancies in

pregnant women at 26-30 weeks gestation

pregnant women at 26-30 weeks gestation

nausea, insomnia, and loss of appetite with
Randomly controlled trial of antidepressant,

Randomly controlled trial of antidepressant,

Case report/3 pregnant women with severe

England.35 There were 87 women who

antihistamine, or placebo in treatment of

antihistamine, or placebo in treatment of

took either zolpidem or zopiclone dur-

accompanying psychiatric disorders

ing their pregnancy. The authors re-

ported 5 spontaneous abortions (3 and
2, respectively), no preterm births
Study design/population

(PTBs), and no congenital abnormal-

ities. (2) In contrast to the previous re-
ports, a study by Wikner et al36 of
Okun. Sleep drugs in pregnancy. Am J Obstet Gynecol 2015.

873,879 infants who born to 859,455

mothers who were registered in the
Swedish Medical Birth Register (July 1,
1995 to Dec. 31, 2004) noted that,
among women who used benzodiaze-
pines or HBRA drugs, there was an
Khazaie et al (2013;

Uguz47 (2013; Turkey)

Khazaie et al51 (2013;

increased risk of LBW infants and PTB.

There were 1944 mothers (1979 infants)
51

who reported the use of benzodiaze-

Antihistamines

pines and/or HBRA drugs at the rst

antenatal visit (early exposures); 390
TABLE 3

Iran)

Iran)

women (401 infants) had a prescription

Study

for these medications from the ante-

a

natal care after the rst visit (late

436 American Journal of Obstetrics & Gynecology APRIL 2015

ajog.org
exposures). Among women who were
exposed in early pregnancy, the risk for
LBW was signicantly higher (OR, 1.30;
95% CI, 1.06e1.59), as was the risk for
PTB (OR, 1.48; 95% CI, 1.26e1.75).
Among those who were exposed in late
pregnancy, the risk was signicantly
higher for LBW (OR, 1.89; 95% CI,
1.29e2.76) and for PTB (OR, 2.57; 95%
CI, 1.92e3.43). Independent assess-
ment of the 2 classes of drugs indicated
that benzodiazepines conferred a
slightly higher, but not statistically sig-
nicant, risk of malformation com-
pared with HBRA drugs. They further
state that these medications do not
appear to have a strong teratogenic
potential.36 In a more recent extension
of the previous study, Reis and Kallen, 37
using the same Swedish Medical Birth
Registry, examined infant outcomes and
congenital malformations of women
who used benzodiazepines only, Selec-
tive serotonin reuptake inhibitors
(SSRIs) only, benzodiazepine receptor
agonists only, or various combinations
of said drugs. Their overall goal was to
determine whether there was an
increased additive risk for congenital
abnormalities among infants whose
mothers took a combination of SSRIs
and either a benzodiazepine or a HBRA.
Analyses included a total of 290,672
women and controlled for potential
confounders such as the year the infant
was born, maternal age, parity, smok-
ing, and body mass index. No statisti-
cally signicant ndings were noted
among any of the groups. Women who
took an SSRI only (n 10,511) had no
signicant risk for a major malforma-
tion (OR, 1.05; 95% CI, 0.94e1.17).
Among a sample of 1000 mothers who
took benzodiazepines only, no signi-
cant risk of major malformations was
noted (OR, 1.10; 95% CI, 0.79e1.54).
Of the 776 mothers who took HBRA
drugs only, again no risk of major mal-
formations was noted (OR, 0.86; 95%
CI, 0.57e1.72). (4) Finally, in a very
recent study conducted on 374,196
singleton births between 1990 and 2010
in the United Kingdom, Ban et al38
found no signicant risk of major
congenital anomalies among women
who used either diazepam (2.7%),
Obstetrics
temazepam (2.9%) or zopiclone (25%)
when compared with women who took
no medication in the rst trimester. The
ORs resemble those of similar studies
with adjusted ORs of 1.02 (95% CI,
0.63e1.64) for diazepam, 1.07 (95% CI,
0.49e2.37) for temazepam, 0.96 (95%
CI, 0.42e2.20) for zopiclone and 1.01
(95% CI, 0.90e1.14) for unmedicated
depression/anxiety.
Antidepressants
Antidepressants, aside from the main
indication of depression, are often pre-
scribed for their sedating effects. It is
thought that all approved antidepres-
sants work through modulation of
monoamine neurotransmitters, which
include norepinephrine, dopamine, and
serotonin, all of which have been shown
to exert prominent effects in the regu-
lation of sleep-wakefulness and sleep
architecture.39 Although the tricyclic
antidepressants confer the greatest sop-
oric properties, SSRIs are also used
commonly for sedating purposes
because they cause fewer side-effects.39
The effects of antidepressants on sleep
in nonpregnant individuals, and the ef-
fects of antidepressants on pregnancy
outcomes, are beyond the scope of this
article. There are several reviews for the
interested reader: antidepressant effects
on sleep in nonpregnant cohorts40,41 and
effects of antidepressants on pregnancy
outcomes.8,42-46 Currently, whether an-
tidepressants taken for sleep issues dur-
ing pregnancy, outside the background
of depression, are associated with
adverse maternal or fetal outcomes.
We are aware of only 2 studies that
specically addressed the problem of
antidepressant use for pregnancy-related
insomnia. The rst article is a case report
of 3 women who were diagnosed with a
psychiatric disorder. Uguz47 evaluated
the effects of a low-dose combination of
mirtazapine with SSRIs in 3 pregnant
women with major depression or panic
disorder that included symptoms of se-
vere nausea, insomnia, and decreased
appetite. Although this does not provide
exact answers, it does provide some in-
formation. In case 1, a woman was being
treated for panic disorder with the
pharmacologic regimen of citalopram
APRIL 2015 American Journal of Obstetrics & Gynecology
Expert Reviews
20 mg/d plus mirtazapine 7.5 mg/d until
the end of the pregnancy. The babys
weight was 2950 g, and no neonatal
complications were reported. Case 2
involved a depressed woman who was
given mirtazapine 15 mg/d in addition
to sertraline 50 mg/d. The patient re-
ported a considerable improvement
in all depressive symptoms, especially
insomnia, and decreased appetite and
weight in the next week. The delivery
was by elective cesarean. The baby had a
birthweight of 2800 g; no medical
problems were observed, except mild
tachypnea, which resolved within 2
days.47 Last, case 3 concerned a woman
with complaints of depressive mood,
psychomotor agitation, anhedonia, in-
somnia, nausea, and loss of appetite.
Sertraline 50 mg/d and mirtazapine
7.5 mg/d were initiated. After 4 weeks
of treatment, mirtazapine was stopped
because the symptoms of insomnia and
nausea remained/increased. The new-
born infant was healthy, with a birth-
weight of 3030 g.47 It is well appreciated
that sleep problems are comorbid with
depression or anxiety disorders48,49
and that the alleviation of sleep prob-
lems often occurs with antidepressant
treatment.48,50 Further evaluation is
needed.
The second study conducted a ran-
domized controlled trial of trazodone,
diphenhydramine, or placebo in 54 age-
matched pregnant Persian women who
were seeking treatment for sleep prob-
lems in the early third trimester.51 The
outcome of the study was depressive
symptoms that were assessed by the
Edinburg Postnatal Depression Scale
(EPDS). Importantly, none of women,
on entry into the study, had a sleep or
mood disorder as assessed by the Struc-
tured Clinical Interview for DSM
DisorderseIV. Investigators observed
signicantly longer sleep durations and
better sleep efciency in the trazodone
(P < .0001) and diphenhydramine
(P < .0001) groups compared with the
placebo group. There were no differ-
ences in sleep duration or sleep efciency
between the 2 medication groups. They
found signicantly lower EPDS scores in
the trazodone (P .033) and diphen-
hydramine (P .047) groups, compared
437
Expert Reviews Obstetrics
with the placebo group. There were no
differences in EPDS score between the 2
medication groups. Although this study
is the rst to assess medication use for
insomnia in pregnancy, the investigators
did not collect information on delivery
or infant outcomes. Hence, there re-
mains a gap in the knowledge as to
whether medications that were used for
pregnancy-related sleep problems confer
any (or additional) risk.
Antihistamines
Antihistamines, or H1 receptor antag-
onists, are prescribed widely or taken
as over-the-counter formulations dur-
ing pregnancy, primarily for the
treatment of nausea and vomiting or
relief of cold and allergy symptoms.52
They are extremely effective at the
treatment of hyperemesis gravidarum,
which purports a 4-fold increased risk
of adverse fetal outcomes.53 They are
also highly soporic, which makes
them desirable for pregnancy-related
sleep disturbances. It is not surprising
that approximately 92% of pregnant
women report that they occasionally
self-treat with over-the-counter sleep
aids, in particular diphenhydramine
and doxylamine.54
Similar to the literature on antide-
pressants and sleep in pregnancy, there
is only one published study that has
evaluated the use of antihistamines for
pregnancy-related sleep problems in
pregnancy.51 However, as stated earlier,
the investigators did not report any data
on delivery or infant outcomes. Much
of our current understanding relies on
large-scale studies. Two studies that are
reported here evaluated the relationship
between antihistamine exposures in
early pregnancy and found no increased
risk for cardiac effects, birth defects, or
major malformations. However, there
was no mention of their use for sleep
disturbances.37,52 Although the evi-
dence supports the utility of antihista-
mines for hyperemesis gravidarum, it is
unclear at this point about whether
pregnant women who use antihista-
mines for sleep problems use similar
doses with similar frequency. There is
clearly a need to further investigate
these distinctions.
438 American Journal of Obstetrics & Gynecology APRIL 2015
Comment
This review has summarized research
studies that examined various medica-
tions that often are used to promote
sleep in pregnant women and resultant
maternal and/or fetal adverse outcomes.
The literature we looked at covered a
comprehensive time frame, and to the
best of our knowledge, is the only review
to collate information on outcomes that
resulted from exposure to sedating drugs
or drugs used for sleep concerns as per
indication or for on- and off-label pur-
poses in pregnant women. Our review
indicates that only a handful of studies
have been conducted, with several
examining a small number of subjects.
Thus, it is difcult to make clear in-
terpretations regarding sleep-
promoting/hypnotic medication use in
pregnancy.
It is likely that a primary reason for the
sparse information is based on current
ethical issues regarding studying preg-
nant women. During the 1970s, the
Department of Health and Human Ser-
vices responded to considerable concern
about the potential harm to human fe-
tuses if pregnant women were enrolled in
research studies. Thus, investigators
historically have shied away from
recruiting pregnant women because of
their status as a special or vulnerable
population.55 This response has led to
large gaps, for instance, in knowledge
about the health of pregnant women as
related to metabolic activity and drug
interactions.6,55 The resistance to pre-
scribe clinically perpetuates the lack of
information that enters the published
arena because few case or cohort reports
are written.6,55 However, given that
pregnant women often report disturbed
sleep, it is important to understand
clearly the risk-to-benets ratio of the
pregnancy risk classications and to use
the information wisely in decision
making.
Findings by drug class
Benzodiazepines and HBRA drugs. There
are slightly mixed ndings on the safety
of benzodiazepines and HBRA drugs
during pregnancy. Overall, the studies
that we examined showed no correla-
tion of increased risk of congenital
ajog.org
malformations. However, benzodiaze-
pines and HBRA drugs may increase
rates of PTB, LBW, and/or small-for-
gestational-age infants. Specically,
based on the available research, it would
seem that zopiclone is relatively (the key
word here is relatively) safer than zolpi-
dem. Currently, no specic research has
been done on zaleplon exclusively.
Zopiclone and zolpidem both have
pregnancy drug risk category C in the
United States; however, in Australia,
zolpidem is categorized as B3. Although
the Australian system rates many ben-
zodiazepines in pregnancy category B3,
they are considerably rated in a some-
what higher risk category in the US
system, where they are often categorized
in the D group. This is due to the dif-
ferences in which the regulatory au-
thorities view data, particularly data
from animal studies. The B3 listing of
zolpidem in Australia contains a proviso
that the drug is not recommended for
use and that alternative treatments
should be considered because of lack
of data. In terms of benzodiazepines,
based on the research that we found,
there is an overall small risk of congenital
malformations from benzodiazepine
exposure, although a larger study used
the Swedish Birth Cohort indicated
contrary ndings.36
When considering fetal abnormalities,
it could be deduced that benzodiazepines
are safer than HBRA drugs. Although
long-term use of benzodiazepine or
nonbenzodiazepine drugs is not a
recommendation, women who nd out
they are pregnant should not abruptly
stop the drug, because she may experi-
ence signicant rebound sleep symp-
toms. A planned cessation should be
staged in these instances.56
Antidepressants. There currently is a
paucity of published data from studies
that have investigated the effects of an-
tidepressants on pregnancy outcomes
when they are only prescribed for sleep
disturbances (if at all). The consensus
from the available studies shows no
increased risks of major malformation as
a consequence of taking an antidepres-
sant.46 However, SSRIs have been asso-
ciated with LBW and PTB.46 Other fetal
ajog.org
syndromes such as respiratory, motor,
central nervous system, and gastroin-
testinal symptoms have been noted in
approximately 10-30% of newborn in-
fants (SSRI neonatal behavior syn-
drome) when antidepressants were used
in latter stages of pregnancy.45,57-59
Still, it must be highlighted that these
women were diagnosed with major
depressive disorder, which confers an
independent and signicant risk for
adverse outcomes.60,61 It is also impor-
tant to emphasize that some SSRIs are
soporic; others can disrupt sleep.41
Thus, it is important for both clinician
and patient to understand all the
potential benets/risks when pharma-
cotherapy is considered.
Antihistamines. Antihistamines are one
of the most commonly used medications
because of their wide availability as an
over-the-counter medication. Although
they commonly are prescribed for nausea
and vomiting during pregnancy, they are
recognized for their sedating effects.52 As
a result, this class of drugs was ascribed a
drug classication that indicates better
safety ratings when compared with other
sedating medications. Nonetheless, we
identied only one published study that
empirically evaluated antihistamines that
were used for pregnancy-related sleep
problems. The only outcome assessed
was depressive symptoms. Although the
available reports indicate that, as a class,
antihistamines confer no statistically sig-
nicant risk for adverse pregnancy out-
comes, many of these studies hold little
statistical power because of their small
sample sizes. Thus, as with all medica-
tions, the clinical signicance of drug use
during pregnancy must be considered.
Clinical relevance
Sleep complaints, which include dif-
culty initiating or maintaining sleep,
sleep fragmentation, and poor sleep
quality, are common in pregnancy,
particularly during late gestation.4,5,62
Problems may arise because of varying
factors such as reux, dyspnea, frequent
micturition, discomfort, and neurohor-
monal changes.63 Thus, it is not a sur-
prise that women may resort to the use
of sedatives/hypnotics to help treat
Obstetrics
developing or preexisting sleep issues
during pregnancy. Although depres-
sion,46,64 stress,65-67 and socioeconomic
status68,69 are recognized contributors to
adverse pregnancy outcomes, it is only in
the last several years that evidence that is
suggestive of a link between disturbed
sleep and adverse pregnancy outcomes
has been acknowledged.70-76 These
emerging data strongly support the need
to further investigate the consequences
of pregnancy-related sleep disturbances
on pregnancy outcomes and the impact
of sedative/hypnotic medications that
are used to treat these complaints.
Future considerations
Among the 16 articles that we examined,
no congenital malformations nor a
signicantly notable risk for malforma-
tions were observed. There was, how-
ever, evidence that benzodiazepines and
HBRA drugs conferred risk for increased
rates of PTB, cesarean delivery, and
small-for-gestational-age and/or LBW
infants.17,19,33,34,36,37,77 In the review of
3 studies with small sample sizes, neither
antidepressants nor antihistamines, when
taken during pregnancy, were found to
have any signicant adverse effects on
mother or child. However, none of the
studies that we described noted that the
use was for sleep complaints. It should
be recommended that women consult
with their prenatal care provider as to
the risk and benets that are associated
with any sleep-promoting medications.
To avoid these potential teratogenic
effects, clinicians could consider using
nonpharmacologic treatments for sleep
complaints, such as cognitive behavioral
treatment for insomnia, exercise, or
meditation. There has been moderate
success in the treatment of sleep com-
plaints in the postpartum period with
behavioral change and education, but the
data are limited.78,79 Likewise, sparse
empiric data are available about the ef-
fects of exercise on pregnancy-related
sleep problems.80,81 According to the
Ofce of Research on Womens Health,
there is currently no prescription proto-
col in existence for the treatment of sleep
problems during pregnancy. A resultant
conclusion was made that it is time to
invest in and to explore treatment
APRIL 2015 American Journal of Obstetrics & Gynecology
Expert Reviews
modalities for pregnant women.6 We
proffer that additional research that
consists of both pharmacotherapy and
nonpharmacologic interventions is
needed for the treatment of sleep prob-
lems during pregnancy. -
ACKNOWLEDGMENT
The authors thank Ms Linda Willrich for her
assistance.
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