Search strategy

We exhaustively searched PubMed and found articles based on key search terms: 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 .

PRISMA diagram shows the selection of articles

Adapted from Moher et al.

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

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. 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 thalidomide-caused 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. 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 .

Benzodiazepines

Benzodiazepines are a class of psychoactive medications that enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA _A receptor, which results in sedative,hypnotic (sleep-inducing),anxiolytic (antianxiety), anticonvulsant, and muscle relaxant properties. 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 effects occur as a result of prenatal exposure. Benzodiazepines and HBRA drugs cross the placenta and have the potential to accumulate in the embryo/fetus and therefore may cause adverse effects. 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 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 al 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.

In another study by this group, Czeizel et al evaluated the teratogenicity of short-term (3-week) diazepam use in pregnancy. Using the same population-based sample, they found that 2746 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. 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. 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 Schirmer 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.

Hypnotic benzodiazepine receptor agonists

The Z-drugs are a group of nonbenzodiazepine drugs with effects similar to benzodiazepines, (they act on the GABA _A receptor) that are used in the treatment of insomnia. 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. The Z-drugs are now the most commonly prescribed hypnotic agents worldwide. This is also true among pregnant women. 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 γ-GABA _A –receptor complex, is indicated for short-term treatment (≤4 weeks) of insomnia. 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. It appears to have minimal next-day effects on cognition and psychomotor performance when administered at bedtime. 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. 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. It has a smaller rebound insomnia effect than benzodiazepines, minimal abuse potential, and no teratogenic effects in pregnant animals. 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 zaleplon which is also an agonist at the GABA _A α1 subreceptor site. 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. 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. 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. 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], 1.17–1.64; P < .001), preterm deliveries (10.01% vs 6.30%; OR, 1.49; 95% CI, 1.28–1.74; P < .001), small-for-gestational-age infants (19.94% vs 15.06%; OR, 1.34; 95% CI, 1.20–1.49; P < .001), and cesarean deliveries (46.86% vs 33.46%; OR, 1.74; 95% CI, 1.59–1.90; 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 = .329). Last, Juric et al 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 al evaluated 40 pregnant women who received zopiclone therapy during pregnancy and consulted the Motherisk Program from 1993-1997. This cohort of women and a matched-control group who did not receive zopiclone therapy were telephoned after delivery and asked about birth defects, maternal characteristics, pregnancy outcomes, and offspring characteristics. 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 = .01) and lower gestational age (38.3 ± 2.7 weeks [zopiclone] vs 40.0 ± 1.6 weeks [controls]; P = .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. Similar to other studies, the current consensus is that this drug does not represent a major human teratogen.

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. 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 al 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 exposures). Among women who were exposed in early pregnancy, the risk for LBW was significantly higher (OR, 1.30; 95% CI, 1.06–1.59), as was the risk for PTB (OR, 1.48; 95% CI, 1.26–1.75). Among those who were exposed in late pregnancy, the risk was significantly higher for LBW (OR, 1.89; 95% CI, 1.29–2.76) and for PTB (OR, 2.57; 95% CI, 1.92–3.43). 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. In a more recent extension of the previous study, Reis and Kallen, 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 = 10,511) had no significant risk for a major malformation (OR, 1.05; 95% CI, 0.94–1.17). Among a sample of 1000 mothers who took benzodiazepines only, no significant risk of major malformations was noted (OR, 1.10; 95% CI, 0.79–1.54). Of the 776 mothers who took HBRA drugs only, again no risk of major malformations was noted (OR, 0.86; 95% CI, 0.57–1.72). (4) Finally, in a very recent study conducted on 374,196 singleton births between 1990 and 2010 in the United Kingdom, Ban et al found no significant risk of major congenital anomalies among women who used either diazepam (2.7%), 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, 0.63–1.64) for diazepam, 1.07 (95% CI, 0.49–2.37) for temazepam, 0.96 (95% CI, 0.42–2.20) for zopiclone and 1.01 (95% CI, 0.90–1.14) 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. Although the tricyclic antidepressants confer the greatest soporific properties, SSRIs are also used commonly for sedating purposes because they cause fewer side-effects. 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 cohorts and effects of antidepressants on pregnancy outcomes. 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. Uguz 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 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. 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. It is well appreciated that sleep problems are comorbid with depression or anxiety disorders and that the alleviation of sleep problems often occurs with antidepressant treatment. Further evaluation is needed.

The second study conducted a randomized controlled trial of trazodone, diphenhydramine, or placebo in 54 age-matched pregnant Persian women who were seeking treatment for sleep problems in the early third trimester. 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 Disorders–IV. 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 = .033) and diphenhydramine ( P = .047) groups, compared 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. They are extremely effective at the treatment of hyperemesis gravidarum, which purports a 4-fold increased risk of adverse fetal outcomes. 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.

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. 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. 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.