USE OF HYPNOTIC BENZODIAZEPINE RECEPTOR AGONISTS (HBRAs) IN PREGNANCY

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 6,900 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. Data investigating these risks for zopiclone are provided by a single small study, and while a crude increased risk of preterm delivery was described, 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, 5-minute Apgar scores being less than seven, neonatal respiratory complications, hypoglycaemia and CNS complications.

No controlled studies assessing the risk of miscarriage, intrauterine death, neurodevelopmental impairment or carcinogenicity have been located in the literature. The risk of these effects following HBRA exposure in pregnancy is therefore largely unknown.

Management of gestational insomnia should firstly be attempted through good sleep hygiene and/or referral to cognitive-behavioural therapy where available. Pharmacotherapy should generally be reserved for cases where these methods are ineffective, or 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. 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.