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OBSTETRICS

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

Approximately 4% of adults who have symptoms of insomnia resort to various hypnotic or sedating medications for acute symptom relief. Although typically a common practice for nonpregnant adults, this is not the case for the thousands of pregnant women who also report substantial sleep issues. Unfortunately, a paucity of randomized controlled trials in this population, scant empiric evidence regarding the appropriateness of prescribing options, and the concern of subsequent teratogenicity restricts the ability of clinicians to make informed decisions. We synthesized the current research regarding hypnotics and sedating medications used (both on- and off-label) during pregnancy and their association with adverse outcomes. Medications that we investigated included benzodiazepines, hypnotic benzodiazepine receptor agonists, antidepressants, and antihistamines. Overall, the examined studies showed no correlation of increased risk of congenital malformations. However, benzodiazepines and hypnotic benzodiazepine receptor agonists may increase rates of preterm birth, low birthweight, and/or small-for-gestationalage infants. The small number of studies and the small number of subjects prohibit any definitive interpretation regarding the consequences of the use of hypnotic or sedating medications in pregnancy. Additional case reports, randomized clinical trials, and epidemiologic studies are needed urgently. Key words: benzodiazepine, hypnotics, medication, pregnancy, sleep

S

ymptoms of insomnia are prevalent in adults. Approximately 50% of adults report difficulty initiating or maintaining sleep or having unrefreshing 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 significant 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 conflict of interest. Corresponding author: Michele L. Okun, PhD. [email protected] 0002-9378/$36.00 ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.10.1106

includes benzodiazepines, hypnotic benzodiazepine receptor agonists, antidepressants, and antihistamines. Many of the adults who take hypnotic or sedating medications are likely pregnant 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 unintentionally may have exposed their fetus to a hypnotic/sedative medication.6 As a result, hypnotic or sedating medication 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 exemplified 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 field to draft a prototype to inform clinical decision-making for the

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management of health conditions in pregnancy.10 This was a commendable effort and will likely address all classes of medications that may be used by pregnant women, not just hypnotic/sedatives alone. This prototype likely will retrieve most of its information from the seminal book by Briggs et al.11 This compilation reviews every medication ever reported to be used in pregnancy. The downside to this book is that it is >2000 pages and is designed for clinical practice. As the dissemination of the incidence of sleep disturbances expands, an appreciation of the health risks associated with disturbed sleep also grows. Based on this, we proffer that the literature currently lacks a concise, easily obtainable review regarding the usage and possible teratogenic effects of sedative/hypnotic medications during pregnancy. Although pregnancy risk categories denoted by 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 upto-date reference on sedative/hypnotic use during pregnancy does not exist. Previous reviews on medication safety during the perinatal period are not specific to sedative/hypnotic medications.10,12 They often do not refer to newly developed drugs nor cover all drug categories, specifically 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 comprehensively the existing body of research to understand the use and impact of hypnotic/sedating drugs (both on-and offlabel) 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:

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ajog.org pregnancy and sleep with various medications or drug classes (hypnotics, sedatives, benzodiazepine, nonbenzodiazepine, melatonin, antidepressants, antihistamines, ramelteon, zolpidem, zopiclone, zaleplon, alprazolam, clonazepam lorazepam, medazepam, nitrazepam, temazepam, tofisopam., mirtazapine, trazodone, diphenhydramine, doxylamine, hydroxyzine, pheniramines). These search terms, which allowed for 30 different searches, resulted in 1452 articles. Our primary focus was to summarize 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, neonatal studies, reviews, inaccessible full texts, non-English publications, or for-medication doses that fell outside of the FDA-specified hypnotic/sedative doses. These exclusions removed a substantial number from our potential article pool and resulted in 1055 articles. After removing duplicate articles from the multiple searches, we had 399 articles to review. Of these 399 articles, we scanned the titles and abstracts and narrowed inclusion further by excluding articles in which prescription reason or dose was specified outside of the sedative realm. This resulted in a total of 16 articles to use. The Preferred Reporting Items for Systematic Reviews and Metaanalyses format for the literature search process is diagrammed in the Figure. Data abstraction In our review, we categorized the articles by drug class. We examined 6 articles on benzodiazepines, 5 articles on hypnotic benzodiazepine receptor agonist (HBRA) drugs, 2 articles on both benzodiazepines and HBRA drugs, 2 articles on antidepressants, and 1 article on antihistamines. We extracted the key data through the research findings that were presented in the articles with the use of a tabulation method. The summary table for all articles describes extracted data under the fields: author, date of publication, location(s) of study, type of study, population size, drug(s) studied, outcomes/results, and key findings.

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FIGURE

PRISMA diagram shows the selection of articles

Adapted from Moher et al.82 Okun. Sleep drugs in pregnancy. Am J Obstet Gynecol 2015.

Based on this information, we compared and collected the results to focus in on general conclusions of the safety of each drug and/or drug class during pregnancy. Drug categories After the notable cases of thalidomidecaused fetal malformations in the 1960s, most countries require all drugs to be classified into ‘pregnancy categories’ that denote risk of unwanted effects. Three of the most widely accepted international pregnancy classifications include the FASS (Swedish Catalogue of Approved Drugs), the US FDA, and the Australian systems, which vary slightly because of differences in safety data interpretation.13 The categorization of drugs into risk classes for use in

pregnancy categories by the FDA and the TGA are outlined in Tables 1 and 2.

Results All studies included here reported on pregnant women. Most of the studies were retrospective cohort studies. Most of the data emanated from Sweden, the United States, and the United Kingdom, with a few studies from Taiwan, Hungary, and Canada. Prospective comparative and prospective cohort (matched pairs) studies were the second most common study design. Because most data came from registries, in some cases it is not clear whether a drug was used off-label for sleep and/or insomnia, particularly for antidepressant drugs. Further, in cases of self-report, the

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TABLE 1

Use in pregnancy drug risk categories Use in pregnancy drug classification

Classes Food and Drug Administration (United States)

Therapeutic Goods Administration (Australia)

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.

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.

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.

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.

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.

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).

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.

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).

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.

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 psychoactive medications that enhance the effect of the neurotransmitter gamma-

aminobutyric acid (GABA) at the GABAA receptor, which results in sedative,hypnotic (sleep-inducing),anxiolytic (antianxiety), anticonvulsant, and muscle relaxant properties.14 As a class, they are not major teratogens, but there remains uncertainty as to whether they

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cause cleft palate in a small number of babies and whether neurobehavioral effects occur as a result of prenatal exposure.15 Benzodiazepines and HBRA drugs cross the placenta and have the potential to accumulate in the embryo/ fetus and therefore may cause adverse

ajog.org effects.16 We identified 12 articles that discussed the safety of sedative benzodiazepine and HBRA drug use in pregnant 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 anxiolytic 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 nationalbased 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, nitrazepam, medazepam, tofisopam, alprazolam and clonazepam) as a drug class and congenital malformations. The results showed no statistically significant increased risk for congenital malformations resultant of the use of or exposure to the 5 benzodiazepines that were evaluated. Specifically, the authors report that. among women who used benzodiazepines, 57 women (0.25%) delivered a baby with congenital malformations compared with 75 women (0.20%) who delivered a healthy baby. Only alprazolam was suspected of teratogenicity on the basis of their data. However, the rate of congenital abnormalities did not appear to be higher in 2 series of infants who were born to women who were treated with alprazolam during the first 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 populationbased sample, they found that 2746

Obstetrics infant cases (12.0%), 4130 infant population 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 significant findings 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 first trimester, only 1 infant had any malformations. Results showed no significant increased risk of abnormality in infants who were born to mothers who received clonazepam monotherapy. St. Clair and Schirmer20 focused on women with first-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 abnormalities. Although alprazolam is known to cross the placenta, rates of congenital abnormalities and spontaneous abortions in women using alprazolam in the first trimester were not significantly 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

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Hypnotic benzodiazepine receptor agonists The Z-drugs are a group of nonbenzodiazepine 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 commonly 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 benzodiazepine receptor component of the g-GABAAereceptor complex, is indicated 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 classifies zolpidem as a category C drug; the TGA classifies 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 nonbenzodiazepine hypnotic agent that is used in the treatment of insomnia. It is a cyclopyrrolone, which increases the normal transmission of the neurotransmitter 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 absorbed 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 suggest no teratogenicity. The final HBRA is

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TABLE 2

Food and Drug Administration (United States) and Therapeutic Goods Administration (Australia) drug categorizationsa Pregnancy categoryb Prescription drugs used as sedative/hypnotics

United States

Australia

Alprazolam

D

B3

Clonazepam

D

B3

Diazepam

D

C

Lorazepam

D

C

Medazepam

Not available

Not available

Nitrazepam

D

C

Temazepam

X

C

Tofisopam

Not available

Not available

Zaleplon

C

Not available

Zolpidem

C

B3

Benzodiazepines

Nonbenzodiazepines

Zopiclone

C

C

Eszopiclone

C

C

Mirtazapine

C

B3

Trazodone

C

Not available

Amitriptyline

C

C

Diphenhydramine

B

A

Doxylamine.

A

A

Hydroxyzine

C

A

Not available

A

Antidepressants

Antihistamines

Pheniramines a

b

For common sedative/hypnotics that are used during pregnancy; See Table 1 for an explanation of the categories.

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

zaleplon which is also an agonist at the GABAA a1 subreceptor site.31 Much less is known about zaleplon because fewer studies have been conducted. Presently, there are no studies that are evaluating zaleplon use in pregnancy. A summary of the limited research on HBRA drugs is listed in Table 3. Three papers focused on zolpidem. The first was a case-study of a woman who was addicted to the medication.32 The woman reported discontinuation at 29 weeks gestation; however, it was anticipated that fetal exposure was approximately 1000 mg over at least a month.

Although she was in and out of the hospital before her delivery and experienced withdrawal symptoms, she proceeded to deliver a full-term healthy baby with no observable withdrawal symptoms. Further examination of cord blood samples indicated that indeed zolpidem had crossed the placenta. Another study that focused on zolpidem was a retrospective cohort study by Wang et al.33 With access to a sample of 14,982 Taiwanese mothers, they evaluated whether zolpidem use of >90 days during pregnancy was associated with adverse maternal and fetal outcomes.

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Analyses controlled for infant gender, parity, maternal educational level, and maternal morbidity. They found a significantly increased incidence of low birthweight (LBW) infants (7.61% vs 5.19%; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.17e1.64; P < .001), preterm deliveries (10.01% vs 6.30%; OR, 1.49; 95% CI, 1.28e1.74; P < .001), small-for-gestational-age infants (19.94% vs 15.06%; OR, 1.34; 95% CI, 1.20e1.49; P < .001), and cesarean deliveries (46.86% vs 33.46%; OR, 1.74; 95% CI, 1.59e1.90; P < .001). However, consistent with the benzodiazepine literature, there was no significant difference between the 2 groups in the rates of congenital anomalies (0.48% vs 0.65%; P ¼ .329). Last, Juric et al25 conducted a prospective case-controlled study of 45 pregnant women with a psychiatric disorder (depression, bipolar, or anxiety) who received zolpidem therapy and 45 psychiatrically matched pregnant women who were not receiving zolpidem therapy. Although rates of preterm delivery and LBW were 26.7% and 15.6%, respectively, in the zolpidem-exposed group vs 13.3% and 4.4% in the matched comparator group, these rates were not statistically different. Furthermore, no congenital abnormalities were observed in any of the infants who were delivered. The use of HBRA drugs for sleep concerns, concurrent with other psychotropic medications, in psychiatric patients is extremely common. The additive effects of multiple medications cannot be underscored here. We reviewed 3 studies that provide critical, yet limited, information on the consequences of multiple medication use during pregnancy. As mentioned, zopiclone is not available in the United States; thus, the only published report is from a Canadian group. Diav-Citrin et al34 evaluated 40 pregnant women who received zopiclone therapy during pregnancy and consulted the Motherisk Program from 1993-1997. This cohort of women and a matchedcontrol group who did not receive zopiclone therapy were telephoned after delivery and asked about birth defects, maternal characteristics, pregnancy outcomes, and offspring characteristics.

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TABLE 3

Summary of publications and key findings on the use of hypnotics during pregnancy Study

Study design/population

Drug used (US category/AUS category)

Outcomes/results

Key findings

Benzodiazepines Retrospective cohort design/Neonates of 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

Diazepam (D, C); temazepam (X, C)

Rate of major congenital abnormalities: 2.7% among women with no depression/anxiety; 2.7% among women who used diazepam; 2.9% among women who used temazepam

No significant increased risk for congenital malformations

Czeizel et al18 (2003; Hungary)

Matched case-population control pair analysis/ Neonates of women who, while pregnant, selfreported 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)

Diazepam (D, C)

Higher rate of limb deficiencies, rectalanal atresia/stenosis, cardiovascular malformations and multiple congenital 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

No significant increased risk for congenital malformations among the 3 groups

Eros et al17 (2002; Hungary)

Retrospective matched case-control study /Women who were pregnant while using benzodiazepines who delivered infants with congenital abnormalities (n ¼ 57) and pregnant women controls who used benzodiazepines who gave birth to infants without defects (n ¼ 75) whose cases were found in the dataset of the nationwide Hungarian Case-Control Surveillance of Congenital Abnormalities from 1980-1996

Nitrazepam (D, C), medazepam (not available), tofisopam (not available), alprazolum (D, B3), clonazepam (D, B3)

Rates of congenital abnormalities were not significantly different from national average

No significant increased risk for congenital malformations found

Lin et al19 (2004; Boston, MA, United States)

Retrospective cohort study/52 of 28,565 total infants were exposed to clonazepam (43 monotherapy, 33 during the first trimester) as found in surveying medical records over a 32month period as part of a hospital-based malformation surveillance program

Clonazepam (D, B3)

1/33 infants exposed to clonazepam monotherapy during the first trimester had major malformations

No significant increased risk for major malformations

Reis and Kallen37 (2013; Sweden)

Retrospective population-based cohort study/ All infants born to mothers who used benzodiazepines alone (n ¼ 606)

Benzodiazepinesa

37 infants with relative severe malformation; 13 with cardiovascular defect (rates of congenital abnormalities not significantly different from national average)

No significant increased risk of malformations

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Ban et al38 (2014; United Kingdom)

Summary of publications and key findings on the use of hypnotics during pregnancy (continued) Study

Study design/population

Drug used (US category/AUS category)

Outcomes/results

Key findings

Alprazolam (D, B3)

Among 411 pregnancies, 47 spontaneous abortions, and 88 elective abortions; of 276 live births: 263 infants without congenital abnormalities, 13 infants with congenital abnormalities

No increased risk in congenital malformations observed

Population-based retrospective cohort study/ Pregnant women (n ¼ 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

Benzodiazepines, hypnotic benzodiazepine receptor agonistsa,b

Increased risk for preterm birth; increased risk for low birthweight infants; slight increase in major congenital malformations in infants exposed early in pregnancy

Increased risk of low birthweight, preterm birth

Askew32 (2007; Wilmington, NC, United States)

Case-study/30-year-old pregnant white woman with a history of zolpidem abuse (n ¼ 1)

Zolpidem (C, B3)

Spontaneous vaginal delivery at 38 weeks’ gestation, neonate normal and healthy; cord blood sampling indicated zolpidem crosses the placenta

No adverse outcomes found; zolpidem found to cross the placenta

Ban et al38 (2014; United Kingdom)

Retrospective cohort design/Neonates of 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

Zopiclone (C, C)

Rate of major congenital abnormalities similar for both groups; approximately 2.7% among women with no depression/anxiety; 2.5% among women who used zopiclone

No significant increased risk for congenital malformations

Diav-Citrin et al29 (2000; Canada)

Matched pairs prospective cohort study/ 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 ¼ 40)

Zopiclone (C, C)

No differences in pregnancy outcome, delivery method, preterm delivery, and malformations found for women who used zopiclone vs those who did not; differences found in low birthweight and lower gestational age for infants born to mothers who used zopiclone

After adjustment for birthweight for gestational age, there was no increased risk of low birthweight and/or lower gestational age

Wikner et al 36 (2007; Sweden)

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Prospective cohort study/Pregnant women who reported first-trimester use of alprazolam and who were followed through delivery (n ¼ 411)

St. Clair and Schirmer20 (1992; Kalamazoo, MI, United States)

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TABLE 3

Hypnotic benzodiazepine receptor agonists

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

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TABLE 3

Summary of publications and key findings on the use of hypnotics during pregnancy (continued) Study

Study design/population 25

Drug used (US category/AUS category)

Outcomes/results

Key findings

Zolpidem (C, B3)

Obstetric outcome and neonatal wellbeing; fetus able to metabolize and eliminate the medication; the rate of preterm delivery (26.7%) and low birthweight (15.6%) in the zolpidemexposed cohort not statistically greater than the nonexposed comparison group

No major malformations reported; no increased risk for preterm birth or low birthweight

Reis and Kallen37 (2013; Sweden)

Retrospective population-based cohort study/ All infants who were born to mothers who used hypnotic benzodiazepine receptor agonists alone (n ¼ 776)

Hypnotic benzodiazepine receptor agonistsb

22 infants seen to have relative severe malformation; 2 with cardiovascular defect; rates of congenital abnormalities not significantly different from national average.

No significant increased risk of malformations

Wang et al33 (2010; Taiwan)

Retrospective cohort study/Pregnant women who used zolpidem as treatment for insomnia (n ¼ 2497) compared with pregnant women not using zolpidem (n ¼ 12,485) who were selected from the Taiwan National Health Insurance Research Dataset (NHIRD) and birthcertificate registry

Zolpidem (C, B3)

Mothers who use zolpidem more likely to have gestational hypertension and anemia; higher risk of low birthweight and small-for-gestational-age infants; and preterm and cesarean delivery; no difference in rates of congenital abnormalities; no difference in firsttrimester use vs second- or thirdtrimester use; increase of the risk of adverse outcomes if drug is used for >90 days

Increased risk of low birthweight and/or small-forgestational age infants, preterm and/or cesarean delivery

Wikner et al36 (2007; Sweden)

Population-based retrospective cohort study/ Pregnant women (n ¼ 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

Zopiclone (C, C), zolpidem (C, B3), zaleplon (C, not available)

Rates of congenital abnormalities not significantly different from national average; tentative association with intestinal malformations, results possibly significantly confounded or because of chance

No significant increased risk for congenital malformations

Wilton et al35 (1998; United Kingdom)

Noninterventional observational cohort study/ 87 pregnant women who used either zolpidem or zopiclone

Zopiclone (C, C), zolpidem (C, B3)

Among the 87 women, 5 spontaneous abortions and no preterm births or congenital abnormalities

No significant increased risk for adverse delivery or infant outcomes

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

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Prospective 1:1 matched comparison/45 pregnant women with psychiatric disorder who used zolpidem and comparison group of psychiatrically matched women who did not use zolpidem

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Juric et al (2009; Atlanta, GA, United States)

The researchers found that zopiclone use was associated with a significantly lower mean birthweight (3245.9  676 g [zopiclone] vs 3624.2  536 g [control subjects]; P ¼ .01) and lower gestational age (38.3  2.7 weeks [zopiclone] vs 40.0  1.6 weeks [controls]; P ¼ .002] compared with those in the control group. Once the birthweight was corrected for gestational age the differences were no longer significant. There were no differences in the outcome of pregnancy, delivery method, assisted deliveries, and fetal distress and the presence of meconium at birth, preterm deliveries, or neonatal intensive care admissions between study and control groups.34 Similar to other studies, the current consensus is that this drug does not represent a major human teratogen.

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

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.

Fewer depressive symptoms compared with placebo; no assessment of delivery or infant outcomes Diphenhydramine increased sleep duration and sleep efficiency compared with placebo; diphenhydramine associated with lower Edinburg Postnatal Depression Scale scores Diphenhydramine (B, A) Randomly controlled trial of antidepressant, antihistamine, or placebo in treatment of insomnia in the third trimester/54 age-matched pregnant women at 26-30 weeks’ gestation Khazaie et al51 (2013; Iran)

Antihistamines

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a

No adverse pregnancy or infant outcomes observed Cases 1 & 2: remission of all symptoms; case 3: mirtazapine exacerbated insomnia Case report/3 pregnant women with severe nausea, insomnia, and loss of appetite with accompanying psychiatric disorders Uguz47 (2013; Turkey)

Low-dose mirtazapine (C, B3) added onto selective serotonin reuptake inhibitors in the treatment

Fewer depressive symptoms with trazodone; no assessment of delivery or infant outcomes Trazodone: increased sleep duration and sleep efficiency compared with placebo; associated with lower Edinburg Postnatal Depression Scale scores Randomly controlled trial of antidepressant, antihistamine, or placebo in treatment of insomnia in the third trimester/54 age-matched pregnant women at 26-30 weeks’ gestation 51

Khazaie et al (2013; Iran)

Trazodone (C, not available)

Key findings

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Outcomes/results Drug used (US category/AUS category) Study design/population Study

Summary of publications and key findings on the use of hypnotics during pregnancy (continued)

TABLE 3

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Studies that evaluated multiple drugs Because medication use during pregnancy is not recommended, there is a paucity of data on specific drug types. Some investigators have used large epidemiologic studies to provide some information. We found 4 studies that compared both benzodiazepine and HBRA medication use in pregnant and nonpregnant populations: (1) an older report on “newly marketed drugs” that were taken during pregnancy assessed outcomes among 831 pregnancies in England.35 There were 87 women who took either zolpidem or zopiclone during their pregnancy. The authors reported 5 spontaneous abortions (3 and 2, respectively), no preterm births (PTBs), and no congenital abnormalities. (2) In contrast to the previous reports, a study by Wikner et al36 of 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 benzodiazepines or HBRA drugs, there was an increased risk of LBW infants and PTB. There were 1944 mothers (1979 infants) who reported the use of benzodiazepines and/or HBRA drugs at the first antenatal visit (early exposures); 390 women (401 infants) had a prescription for these medications from the antenatal care after the first visit (late

ajog.org exposures). Among women who were exposed in early pregnancy, the risk for LBW was significantly 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 significantly higher for LBW (OR, 1.89; 95% CI, 1.29e2.76) and for PTB (OR, 2.57; 95% CI, 1.92e3.43). Independent assessment of the 2 classes of drugs indicated that benzodiazepines conferred a slightly higher, but not statistically significant, risk of malformation compared 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, Selective 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, smoking, and body mass index. No statistically significant findings were noted among any of the groups. Women who took an SSRI only (n ¼ 10,511) had no significant risk for a major malformation (OR, 1.05; 95% CI, 0.94e1.17). Among a sample of 1000 mothers who took benzodiazepines only, no significant 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 malformations 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 significant 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 first 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 prescribed for their sedating effects. It is thought that all approved antidepressants work through modulation of monoamine neurotransmitters, which include norepinephrine, dopamine, and serotonin, all of which have been shown to exert prominent effects in the regulation of sleep-wakefulness and sleep architecture.39 Although the tricyclic antidepressants confer the greatest soporific 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 effects 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 antidepressants taken for sleep issues during pregnancy, outside the background of depression, are associated with adverse maternal or fetal outcomes. We are aware of only 2 studies that specifically addressed the problem of antidepressant use for pregnancy-related insomnia. The first 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 severe nausea, insomnia, and decreased appetite. Although this does not provide exact answers, it does provide some information. In case 1, a woman was being treated for panic disorder with the pharmacologic regimen of citalopram

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20 mg/d plus mirtazapine 7.5 mg/d until the end of the pregnancy. The baby’s 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 reported 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, insomnia, 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 newborn infant was healthy, with a birthweight 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 problems often occurs with antidepressant treatment.48,50 Further evaluation is needed. The second study conducted a randomized controlled trial of trazodone, diphenhydramine, or placebo in 54 agematched pregnant Persian women who were seeking treatment for sleep problems 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 Structured Clinical Interview for DSM DisorderseIV. Investigators observed significantly longer sleep durations and better sleep efficiency in the trazodone (P < .0001) and diphenhydramine (P < .0001) groups compared with the placebo group. There were no differences in sleep duration or sleep efficiency between the 2 medication groups. They found significantly lower EPDS scores in the trazodone (P ¼ .033) and diphenhydramine (P ¼ .047) groups, compared

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Obstetrics

with the placebo group. There were no differences in EPDS score between the 2 medication groups. Although this study is the first to assess medication use for insomnia in pregnancy, the investigators did not collect information on delivery or infant outcomes. Hence, there remains 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 antagonists, are prescribed widely or taken as over-the-counter formulations during 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 soporific, 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 antidepressants 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 evidence supports the utility of antihistamines for hyperemesis gravidarum, it is unclear at this point about whether pregnant women who use antihistamines for sleep problems use similar doses with similar frequency. There is clearly a need to further investigate these distinctions.

Comment This review has summarized research studies that examined various medications 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 purposes 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 difficult to make clear interpretations regarding sleeppromoting/hypnotic medication use in pregnancy. It is likely that a primary reason for the sparse information is based on current ethical issues regarding studying pregnant women. During the 1970s, the Department of Health and Human Services responded to considerable concern about the potential harm to human fetuses 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 prescribe 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-benefits ratio of the pregnancy risk classifications and to use the information wisely in decision making. Findings by drug class Benzodiazepines and HBRA drugs. There are slightly mixed findings on the safety of benzodiazepines and HBRA drugs during pregnancy. Overall, the studies that we examined showed no correlation of increased risk of congenital

438 American Journal of Obstetrics & Gynecology APRIL 2015

ajog.org malformations. However, benzodiazepines and HBRA drugs may increase rates of PTB, LBW, and/or small-forgestational-age infants. Specifically, based on the available research, it would seem that zopiclone is relatively (the key word here is relatively) safer than zolpidem. Currently, no specific 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 benzodiazepines in pregnancy category B3, they are considerably rated in a somewhat higher risk category in the US system, where they are often categorized in the D group. This is due to the differences in which the regulatory authorities 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 findings.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 find out they are pregnant should not abruptly stop the drug, because she may experience significant rebound sleep symptoms. 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 antidepressants 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 antidepressant.46 However, SSRIs have been associated with LBW and PTB.46 Other fetal

ajog.org syndromes such as respiratory, motor, central nervous system, and gastrointestinal symptoms have been noted in approximately 10-30% of newborn infants (SSRI neonatal behavior syndrome) 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 significant risk for adverse outcomes.60,61 It is also important to emphasize that some SSRIs are soporific; others can disrupt sleep.41 Thus, it is important for both clinician and patient to understand all the potential benefits/risks when pharmacotherapy 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 classification that indicates better safety ratings when compared with other sedating medications. Nonetheless, we identified 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 significant risk for adverse pregnancy outcomes, many of these studies hold little statistical power because of their small sample sizes. Thus, as with all medications, the clinical significance of drug use during pregnancy must be considered. Clinical relevance Sleep complaints, which include difficulty 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 reflux, dyspnea, frequent micturition, discomfort, and neurohormonal changes.63 Thus, it is not a surprise that women may resort to the use of sedatives/hypnotics to help treat

Obstetrics developing or preexisting sleep issues during pregnancy. Although depression,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 significantly notable risk for malformations were observed. There was, however, 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 significant 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 benefits 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 complaints in the postpartum period with behavioral change and education, but the data are limited.78,79 Likewise, sparse empiric data are available about the effects of exercise on pregnancy-related sleep problems.80,81 According to the Office of Research on Women’s Health, there is currently no prescription protocol 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

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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 problems during pregnancy. ACKNOWLEDGMENT The authors thank Ms Linda Willrich for her assistance.

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27. Greenblatt DJ, Roth T. Zolpidem for insomnia. Expert Opin Pharmacother 2012;13: 879-93. 28. Kleykamp BA, Griffiths RR, McCann UD, Smith MT, Mintzer MZ. Acute effects of zolpidem extended-release on cognitive performance and sleep in healthy males after repeated nightly use. Exp Clin Psychopharmacol 2012;20:28-39. 29. Diav-Citrin O, Okotore B, Lucarelli K, Koren G. Zopiclone use during pregnancy. Can Fam Physician 2000;46:63-4. 30. Fernandez C, Martin C, Gimenez F, Farinotti R. Clinical pharmacokinetics of zopiclone. Clin Pharmacokinet 1995;29:431-41. 31. Patat A, Paty I, Hindmarch I. Pharmacodynamic profile of Zaleplon, a new nonbenzodiazepine hypnotic agent. Hum Psychopharmacol 2001;16:369-92. 32. Askew JP. Zolpidem addiction in a pregnant woman with a history of second-trimester bleeding. Pharmacotherapy 2007;27:306-8. 33. Wang LH, Lin HC, Lin CC, Chen YH, Lin HC. Increased risk of adverse pregnancy outcomes in women receiving zolpidem during pregnancy. Clin Pharmacol Ther 2010;88:369-74. 34. Diav-Citrin O, Okotore B, Lucarelli K, Koren G. Pregnancy outcome following firsttrimester exposure to zopiclone: a prospective controlled cohort study. Am J Perinatol 1999;16: 157-60. 35. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. BJOG 1998;105:882-9. 36. Wikner BN, Stiller CO, Bergman U, Asker C, Kallen B. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf 2007;16: 1203-10. 37. Reis M, Kallen B. Combined use of selective serotonin reuptake inhibitors and sedative/hypnotics during pregnancy: risk of relatively severe congenital malformations or cardiac defects: a register study. BMJ Open 2013;3. 38. Ban L, West J, Gibson JE, et al. First trimester exposure to anxiolytic and hypnotic drugs and the risks of major congenital anomalies: a United Kingdom population-based cohort study. PLoS One 2014;9:e100996. 39. Winokur A, Gary KA, Rodner S, Rae-Red C, Fernando AT, Szuba MP. Depression, sleep physiology, and antidepressant drugs. Depress Anxiety 2001;14:19-28. 40. McCall C, McCall WV. What is the role of sedating antidepressants, antipsychotics, and anticonvulsants in the management of insomnia? Curr Psychiatry Rep 2012;14: 494-502. 41. Holshoe JM. Antidepressants and sleep: a review. Perspect Psychiatr Care 2009;45: 191-7. 42. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant

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ajog.org women taking fluoxetine. N Engl J Med 1996;335:1010-5. 43. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006;295:499-507. 44. Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry 2009;54:242-6. 45. Huang H, Coleman S, Bridge JA, Yonkers K, Katon W. A meta-analysis of the relationship between antidepressant use in pregnancy and the risk of preterm birth and low birth weight. Gen Hosp Psychiatry 2014;36:13-8. 46. Wisner KL, Sit DK, Hanusa BH, et al. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry 2009;166:557-66. 47. Uguz F. Low-dose mirtazapine added to selective serotonin reuptake inhibitors in pregnant women with major depression or panic disorder including symptoms of severe nausea, insomnia and decreased appetite: three cases. J Matern Fetal Neonatal Med 2013;26:1066-8. 48. Argyropoulos SV, Wilson SJ. Sleep disturbances in depression and the effects of antidepressants. Int Rev Psychiatry 2005;17:237-45. 49. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996;39:411-8. 50. Armitage R. The effects of antidepressants on sleep in patients with depression. Can J Psychiatry 2000;45:803-9. 51. Khazaie H, Ghadami MR, Knight DC, Emamian F, Tahmasian M. Insomnia treatment in the third trimester of pregnancy reduces postpartum depression symptoms: a randomized clinical trial. Psychiatry Res 2013;210: 901-5. 52. Gilboa SM, Strickland MJ, Olshan AF, Werler MM, Correa A. Use of antihistamine medications during early pregnancy and isolated major malformations. Birth Defects Res A Clin Mol Teratol 2009;85:137-50. 53. Fejzo MS, Magtira A, Schoenberg FP, et al. Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 2013;170: 71-6. 54. Black RA, Hill DA. Over-the-counter medications in pregnancy. Am Fam Physician 2003;67:2517-24. 55. Blehar MC, Spong C, Grady C, Goldkind SF, Sahin L, Clayton JA. Enrolling pregnant women: issues in clinical research. Womens Health Issues 2013;23:e39-45. 56. Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of couseling. J Psychiatry Neurosci 2001;22:44-8. 57. Austin MP, Karatas JC, Mishra P, Christl B, Kennedy D, Oei J. Infant neurodevelopment following in utero exposure to antidepressant medication. Acta Paediatr 2013;102:1054-9.

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