Essential Reads: The Use of Sedative-Hypnotic Drugs During Pregnancy

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.  Sedative-hypnotic agents, such as Ambien (zolpidem), are commonly used for the short-term treatment of insomnia, and are frequently prescribed to pregnant women.  However, information regarding the reproductive safety of these medications has been relatively sparse.

Insomnia, especially when severe, may be associated with worse pregnancy outcomes and may increase risk for depression during pregnancy and the postpartum period.  The treatment of insomnia involves understanding of the underlying causes of insomnia and choosing medications which target the causes of insomnia. For example, if insomnia appears to be related to untreated anxiety, one might select treatments that target anxiety, including cognitive-behavioral therapy for anxiety, SSRI and SNRI antidepressants, and benzodiazepines.

The following is a review of non-benzodiazepine sedative-hypnotic medications.

Sedative-Hypnotic Medications

Non-Benzodiazepine Z-Drugs

• Eszopiclone (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?

• Pregnancy-associated symptoms: urinary frequency, heartburn, fetal movements
• Sleep apnea (up to 26% in 3rd trimester)
• Restless leg syndrome
• Anxiety
• Depression

Should insomnia during pregnancy be treated?

Untreated insomnia during pregnancy

Other negative effects of insomnia during pregnancy

• Increased activity of HPA axis, inflammation
• Increased risk of gestational diabetes
• Increased risk of C-section
• Preterm birth, lower birth weight

Maternal use of Sedative-Hypnotic Drugs During Pregnancy 

Impact on pregnancy outcomes:

• Increased risk of caesarean section
• Increased risk of preterm birth, LBW, SGA
• Respiratory depression in the infant

Impact of medication vs. underlying condition (insomnia, anxiety, depression)

Some complications more common in women with these underlying disorders

Risk of Major Malformations – Two Studies

Wikner (2011)

• Swedish birth medical registry
• 1341 exposed to Z-drug
• Zopiclone 692, Zolpidem 603, Zalepion 32, more than two 25
• Overlapping with cohort from Wikner study 2007
• As a class of medications – No increase in overall risk of MCMs
• 42 infants (3.1%) in the z-drug group had a malformation
• Statistically significant increase in risk for intestinal malformations based on only 4 infants – Needs further evaluation
• Did not look at individual medications

Wang (2010) 

• Taiwan
• 2497 exposed to Zolpidem – 12 with MCM (0.48%)
• No increase in risk of malformations
• Worse outcomes – LBW, preterm birth, SGA, caesarean birth

Limitations of studies

• Inadequate number of exposures to zopiclone and zaleplon
• No data on frequency of use: as needed vs. daily
• High rates of polypharmacy
• Mothers using Z-drugs tended to be older, more likely smokers

Alternative Treatments

• Cognitive behavioral therapy for insomnia
• Doxylamine (in Diclegis and Unisom)
• Benzodiazepines – More data to support reproductive safety
• SSRIs and SNRIs for treatment of anxiety, depression
• Tricyclic antidepressants – Sedating TCAs imipramine, amitriptyline at low doses.  Risk of hypotension.

Clinical Recommendations

At the present time, 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 among women using Z-drugs during pregnancy, including increased risk for low birth weight, small for gestational age, preterm birth, caesarean section, and NICU admission.  It is important to note, however, that these outcomes may be influenced by the underlying disorder.  Specifically, insomnia during pregnancy has also been associated with increased risk for low birth weight, preterm birth, and caesarean section.  

 While these studies are reassuring and do not show any increase in risk of major malformations in infants exposed to Z-drugs during pregnancy, these results must be interpreted cautiously.  None of the studies document how frequently the medication is used, and it is difficult to exactly specify when the medication was used (during the first trimester vs. later in pregnancy). Z-drugs are typically used as needed and for shorter periods of time.  Given these limited exposures, it may be difficult to accurately assess the risk of major malformations.  

Based on the limited data we have, we continue to recommend other approaches to the management of sleep problems during pregnancy.  CBT for insomnia is an effective treatment but less commonly used.  Doxylamine, which is used for managing nausea, is sedating and may provide some relief.  In women with anxiety and/or depression, treating the underlying lillness may also improve sleep.

Ruta Nonacs, MD PhD

Z-Drugs and Pregnancy NOV 21 by Ruta Nonacs

References:

Bais B, Molenaar NM, Bijma HH, et al. Prevalence of benzodiazepines and benzodiazepine-related drugs exposure before, during and after pregnancy: A systematic review and meta-analysis. J Affect Disord. 2020;269:18-27. doi:10.1016/j.jad.2020.03.014

Björkstedt SM, Kautiainen H, Tuomi U, Gissler M, Pennanen P, Eriksson JG, Lain.  Maternal use of sedative drugs and its effects on pregnancy outcomes: a Finnish birth cohort study.  Sci Rep. 2021 Feb 24;11(1):4467. doi: 10.1038/s41598-021-84151-7.  Free article.

Dominguez JE, Street L, Louis J. Management of Obstructive Sleep Apnea in Pregnancy. Obstet Gynecol Clin North Am. 2018;45(2):233-247. 

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Reichner CA. Insomnia and sleep deficiency in pregnancy. Obstet Med. 2015;8(4):168-171. https://doi.org/10.1177/1753495X15600572

Srivanitchapoom P, Pandey S, Hallett M. Restless legs syndrome and pregnancy: a review. Parkinsonism Relat Disord. 2014;20(7):716-722.  https://doi.org/10.1016/j.parkreldis.2014.03.027

Silvestri, R. & Arico, I. Sleep disorders in pregnancy. Sleep Sci. 2019; 12: 232–239. https://doi.org/10.5935/1984-0063.20190098 (2019).

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(3):369-374.   https://doi.org/10.1038/clpt.2010.97

Wikner BN, Källén B. Are hypnotic benzodiazepine receptor agonists teratogenic in humans?. J Clin Psychopharmacol. 2011;31(3):356-359. https://doi.org/10.1097/JCP.0b013e3182197055