USE OF HYPNOTIC BENZODIAZEPINE RECEPTOR AGONISTS (HBRAs) IN PREGNANCY

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(Date of issue: February 2018, Version: 1)

This is a UKTIS monograph for use by health care professionals. For case-specific advice please contact UKTIS on 0344 892 0909. To report an exposure please download and complete a pregnancy reporting form. Please encourage all women to complete an online reporting form.

A corresponding patient information leaflet on zolpidem use in pregnancy is available at www.medicinesinpregnancy.org.

Summary

Hypnotic benzodiazepine receptor agonists (HBRAs) including zolpidem and zopiclone are licensed for the short-term treatment of debilitating or distressing insomnia.

Controlled studies describe the outcomes of more than 6,600 unique pregnancies where mothers used HBRAs in pregnancy, with more than 4,500 having been confirmed to have been exposed in the first trimester. For specific HBRAs, studies collectively describe more than 3,000 zolpidem-exposed and 1,600 zopiclone-exposed pregnancies, with confirmed first trimester exposure in more than 1,000 and 1,500 respectively. Of note, the majority of the available data are provided by studies which utilised general population unexposed pregnancies in their control groups and, as such, the possibility of data confounding cannot be excluded.

The available data do not currently provide evidence that gestational use of HBRAs as a class, or zolpidem/zopiclone specifically, is associated with an increased risk of congenital malformation overall. Individual studies investigating HBRAs as a class or HBRA/benzodiazepine use have identified possible associations with intestinal malformations, pyloric stenosis and, separately, oesophageal, anal or small gut atresia as a composite outcome. However, further research is required to confirm these observations.

Increased risks of small for gestational age and preterm delivery have been identified for both HBRAs as a class and for zolpidem specifically. Additionally, one small study identified higher rates of both of these outcomes following zopiclone use in pregnancy, but this did not reach statistical significance, mainly due to the small study sample size. Adverse neonatal effects of HBRA use in late pregnancy have also been described and these have included increased rates of neonatal complications overall, five minute Apgar scores being less than seven, neonatal respiratory complications, hypoglycaemia and CNS complications.

No controlled studies assessing the risk of spontaneous abortion, intrauterine death, neurodevelopmental impairment or carcinogenicity have been located in the literature. The risk of these effects following HBRA exposure in pregnancy is therefore unknown.
Management of gestational insomnia should firstly be attempted through sleep hygiene improvement and/or referral to cognitive-behavioural therapy where available. Pharmacotherapy should generally be reserved for cases where these methods are insufficient or the insomnia is moderate to severe and impacting daily life. Alternative pharmacological treatment options such as sedating antihistamines, antidepressants or short-acting benzodiazepines may be preferable to the use of HBRAs for the management of insomnia in pregnancy. Discussion with UKTIS is advised in all cases.

Exposure to HBRAs at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Due to the evidence indicating a possible association between HBRA use and impaired fetal growth, enhanced monitoring may be considered on a case-by-case basis following prolonged HBRA use in pregnancy. Although data confounding cannot be excluded, neonatal monitoring may be warranted following maternal HBRA use prior to delivery. Where multiple CNS acting medications have been used around the time of delivery, synergistic effects may be expected. Other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

This document is regularly reviewed and updated. Only use full UKTIS monographs downloaded directly from TOXBASE.org to be sure you are using the most up-to-date version. The summaries of these monographs are openly available on UKTIS.org.

This is a summary of the full UKTIS monograph for health care professionals and should not be used in isolation. The full UKTIS monograph and access to any hyperlinked related documents is available to health care professionals at www.toxbase.org.

If you have a patient with exposure to a drug or chemical and require assistance in making a patient-specific risk assessment, please telephone UKTIS on 0344 892 0909 to discuss the case with a teratology specialist.

If you would like to report a pregnancy to UKTIS please click here to download our pregnancy reporting form. Please encourage all women to complete an online reporting form.

Disclaimer: Every effort has been made to ensure that this monograph was accurate and up-to-date at the time of writing, however it cannot cover every eventuality and the information providers cannot be held responsible for any adverse outcomes of the measures recommended. The final decision regarding which treatment is used for an individual patient remains the clinical responsibility of the prescriber. This material may be freely reproduced for education and not for profit purposes within the UK National Health Service, however no linking to this website or reproduction by or for commercial organisations is permitted without the express written permission of this service. This document is regularly reviewed and updated. Only use UKTIS monographs downloaded directly from TOXBASE.org or UKTIS.org to ensure you are using the most up-to-date version.