It is estimated that up to 95% of women experience some type of sleep disorder during pregnancy. While for many women insomnia is relatively benign and may respond to simple interventions, other women experience more severe insomnia that has a significant impact on their quality of life and ability to function. Sedative-hypnotic agents, such as Ambien (zolpidem), are commonly used for the short-term treatment of insomnia and are often prescribed to pregnant women. However, information on the reproductive safety of these drugs has been relatively scarce.
Insomnia, especially when severe, may be associated with worse pregnancy outcomes and may increase the risk for depression during pregnancy and the postpartum period. Treating insomnia involves understanding the underlying causes of insomnia and choosing medications that target the causes of insomnia. For example, if insomnia appears to be related to untreated anxiety, one can choose treatments that target anxiety, including cognitive-behavioral therapy for anxiety, SSRI and SNRI antidepressants, and benzodiazepines.
Here is a review of non-benzodiazepine sedative-hypnotic drugs.
Sedative-Hypnotic Drugs
Non-benzodiazepine Z-Drugs
- Ezopiclone (Lunesta)
- Zaleplon (Sonata)
- Zolpidem (Ambien, Ambien CR, Intermezzo)
Sleep disorders during pregnancy
Sleep problems are common during pregnancy
- Sleep increases in the 1st trimester, decreases in the 3rd trimester
- Sleep disturbance is common: 13% in the first trimester, 19% in the 2nd, 66% in the 3rd
- Up to 73.5% of women report insomnia: mild 50.5%, moderate 15.7% and severe 3.8%.
What causes insomnia during pregnancy?
- Symptoms related to pregnancy: frequency, heartburn, fetal movements
- Sleep apnea (up to 26% in Q3)
- Restless legs syndrome
- Worry
- Depression
Should insomnia be treated during pregnancy?
Untreated insomnia during pregnancy
Other negative effects of insomnia during pregnancy
- Increased HPA axis activity, inflammation
- Increased risk of gestational diabetes
- Increased risk of caesarean section
- Preterm delivery, lower birth weight
Maternal use of sedative-hypnotic drugs during pregnancy
Effect on pregnancy outcomes:
- Increased risk of caesarean section
- Increased risk of preterm birth, LBW, SGA
- Respiratory depression in the infant
Effect of medication against the underlying condition (insomnia, anxiety, depression)
Certain complications are more common in women with these underlying disorders
Risk of major malformations – Two studies
Wikner (2011)
- Swedish Medical Birth Registry
- 1341 exposed to Z-drug
- Zopiclone 692, Zolpidem 603, Zalepion 32, more than two 25
- Overlap with cohort from the Wikner 2007 study
- As a drug class – No increase in overall MCM risk
- 42 infants (3.1%) in the z drug group had malformation
- Statistically significant increase in risk of intestinal malformations based on only 4 infants – Further evaluation needed
- It did not look at individual drugs
Wang (2010)
- Taiwan
- 2497 exposed to zolpidem – 12 with MCM (0.48%)
- No increase in the risk of malformations
- Worse outcomes – LBW, preterm birth, SGA, C-section
Study restrictions
- Insufficient number of exposures to zopiclone and zaleplon
- No data on frequency of use: as needed versus daily use
- High rates of polypharmacy
- Mothers using Z-drugs tended to be older, more likely to smoke
Alternative cure
- Cognitive behavioral therapy for insomnia
- Doxylamine (in Diclegis and Unisom)
- Benzodiazepines – More data to support reproductive safety
- SSRIs and SNRIs to treat anxiety, depression
- Tricyclic antidepressants – TCA sedatives imipramine, amitriptyline in low doses. Risk of hypotension.
Clinical Recommendations
Currently, we have more information on the reproductive safety of zolpidem compared to zalepion and zopiclone. Some, but not all, studies have shown worse pregnancy outcomes in women using Z-drugs during pregnancy, including an increased risk of low birth weight, small for gestational age, preterm delivery, cesarean section, and NICU admission. It is important to note, however, that these results may be affected by the underlying disorder. Notably, insomnia during pregnancy has also been associated with an increased risk for low birth weight, preterm delivery, and cesarean section.
Although these studies are reassuring and show no increased risk of major malformation in infants exposed to Z-drugs during pregnancy, these results must be interpreted with caution. None of the studies documented how often the drug was used, and it is difficult to determine exactly when the drug was used (during the first trimester versus later in pregnancy). Z-drugs are usually used as needed and for shorter periods of time. Given these limited exposures, it may be difficult to accurately estimate the risk of major malformations.
Based on the limited data we have, we continue to recommend other approaches to managing sleep problems during pregnancy. CBT for insomnia is an effective treatment but is less commonly used. Doxylamine, which is used to manage nausea, is a sedative and may provide some relief. In women with anxiety and/or depression, treating the underlying illness may also improve sleep.
Ruta Nonacs, MD PhD
Z-Drugs and Pregnancy 21 NOV by Ruta Nonacs
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