It is estimated that up to 95% of women experience some type of sleep disturbance during pregnancy.  While for many women the insomnia is relatively benign and may respond to simple interventions, other women experience more severe insomnia which has a significant impact on their quality of life and ability to function.  While zolpidem (Ambien), a sedative-hypnotic agent used for the short-term treatment of insomnia, is commonly prescribed in pregnant women, the information regarding its reproductive safety has been sparse.

Up until very recently only animal studies, case reports, and two very small cohort studies were available regarding zolpidem use and pregnancy.  The first study included 18 women and did not find any association between zolpidem use and risk of congenital anomalies.  The second study included 45 pregnant women with psychiatric illness treated with zolpidem and found that in the zolpidem-exposed group, as compared to unexposed controls, there was an increased risk of preterm delivery (26.7% vs. 15.6%) and low birth weight (13.3% vs. 4.4%).

A recent study, published in Clinical Pharmacology & Therapeutics, adds to the limited data available regarding the use of zolpidem (Ambien) during pregnancy.    In this study, Wang and colleagues conducted a population-based study in Taiwan comparing rates of adverse pregnancy outcomes between mothers who received zolpidem during pregnancy and those who did not.  They linked two large data sets: the Taiwan National Health Insurance Program and the national birth certificate registry for a one year period in 2005.

During this period there were 218,776 singleton births to mothers utilizing prenatal care.  Of these, 10,343 women were prescribed zolpidem during pregnancy, but they defined women who had been prescribed zolpidem for at least  30 days during pregnancy as those who had received zolpidem treatment (n=2984).  Thus the percentage of pregnant women treated with zolpidem was calculated to be 4.72%, which is slightly lower than the reported prevalence in the general adult female population in Taiwan (5.24%).  Women were excluded from the analysis if they had a mental health disorder (n=446), or hypertension, diabetes or coronary heart disease prior to conceiving (n=41).  Data from a total of 2,497 mothers who had received zolpidem treatment were analyzed.  An age-matched comparison group of 12,485 was extracted from the remaining women in the database using the same exclusion criteria.

Of the total sample the mean age was 29.7 years old, and on average the mothers who received zolpidem had lower educational levels, higher rates of gestational hypertension and anemia, and greater parity.   After adjusting for these factors, the authors observed that zolpidem-exposed women had higher rates of adverse pregnancy outcomes including lower birth weight (adjusted odds ratio (OR) =1.39), preterm delivery (OR=1.49), small for gestational age babies (OR=1.34), and were more likely to have a caesarean section (OR=1.74).  There was no observed increase in congenital anomalies in the exposed group.  The risk of adverse pregnancy outcomes was the highest in women who took zolpidem for more than 90 days.

The authors hypothesize, drawing from findings from animal studies, that zolpidem and other GABAergic agonists may cause the pituitary to release higher levels of vasopressin and oxytocin which may result in uterine vasoconstriction in the mother.  Also, GABAergic agonists that penetrate the CNS may cause respiratory depression by depressing the central ventilatory drive.  Both of these mechanisms might result in decreased blood flow to the uterus and may thus influence fetal growth.

While this report suggests an increased risk of certain adverse outcomes, the results are difficult to interpret.  The study excludes women with a formal psychiatric diagnosis; however, they do not assess symptoms of depression or anxiety during pregnancy.  It is likely that many of the women who require a sleeping aid during pregnancy experience insomnia as a symptom of an underlying mood or anxiety disorder.  Multiple studies have shown that certain adverse outcomes– preterm delivery, low birth weight, and small for gestational age babies– occur at higher rates in women with depression and anxiety in the absence of medication exposure.  Thus, do these results reflect the adverse effects of exposure to zolpidem?  Or are they related to an underlying mood or anxiety disorder?

Furthermore, the authors were not unable to account for the effect of insomnia severity, which may directly affect the pregnancy, nor were they able to assess the degree of adherence to the prescription medication.  Data regarding other variables which may affect pregnancy outcomes, including alcohol use, smoking status, and use of non-prescription medications were not collected.

Despite the prevalence of sleep problems in pregnancy, there are few guidelines to help clinician choose appropriate interventions.  Improving sleep hygiene and cognitive-behavioral interventions may be helpful in many cases, but some women may require pharmacologic treatment.  In light of these findings, the authors suggest the prescription of zolpidem be avoided for pregnant women when possible.  All women who present with insomnia should be screened for underlying mood or anxiety disorders.  By addressing these symptoms first, sleep problems may diminish or resolve.  Other pharmacologic options for the treatment of insomnia during pregnancy include benzodiazepines and tricyclic antidepressants.

April Hirschberg, MD

Wang LH,  Lin HC, Lin CC , Chen YH & Lin HC. Increased Risk of Adverse Pregnancy Outcomes in Women Receiving Zolpidem During Pregnancy. Clin Pharm Ther 88:3, 369-374 (2010).

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. Br J Obstet Gynaecol. 105, 882-889 (1998).

Juric S, Newport DJ, Ritchie JC, Galanti M & Stowe ZN. Zolpidem (Ambien) in pregnancy: placental passage and outcome. Arch Womens Ment Health 12, 441-446 (2009).

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