The TGA is working with sponsors of certain inhaled or injected general anaesthetic agents and sedative medicines to update information about the potential risk of deficits in learning and behavioural development in children, which may be associated with repeated or prolonged exposure to these products during late pregnancy or early childhood.
Inhaled or injected general anaesthetics and sedatives are medicines used to prevent pain and awareness during surgery. A wide variety of drugs are used in modern anaesthetic practice.
This concern applies to all general anaesthetic agents and sedative medicines that block N-methyl-D-aspartate (NMDA) receptors or potentiate gamma-aminobutyric acid (GABA) activity. These medicines include:
- desflurane
- isoflurane
- sevoflurane
- thiopentone
- ketamine
- midazolam
- propofol
- phenobarbitone injection
- nitrous oxide
- methoxyflurane.
The TGA has assessed the safety of certain general anaesthetic agents and sedative medicines in response to concerns raised from animal studies published in the scientific literature about possible effects on early brain development in babies and young children.
As part of its investigation, the TGA sought advice from the Advisory Committee on Medicines (ACM) at its December 2017 meeting. The ACM meeting statement can be found on the TGA website.
The ACM advised that there was good evidence from animal studies that general anaesthetic agents and certain sedative medicines used during anaesthesia had effects on the developing brain, including cell death. Some evidence suggested that these changes were greatest with longer exposure (several hours of exposure to a general anaesthetic).
However, the relevance of these finding to humans is not clear. Studies that are available in humans are not conclusive. Where an association between surgery and developmental outcomes was found, this association may have been confounded by a number of factors such as complications arising from the surgery itself or the underlying illness necessitating surgery. The effect of dose and duration of anaesthesia was not clear.
There is evidence that a single, relatively brief exposure to anaesthesia in otherwise healthy children is unlikely to cause any significant long-lasting effects (clinically detectable deficits) in cognitive function or behaviour.
Information for consumers
This potential concern only applies to unborn and young children in relation to repeated or prolonged (greater than 3 hours) use of anaesthetic agents or sedative medicines.
Surgeries in young children and pregnant women should not be delayed or avoided when there is any possibility that delay may result in an adverse outcome or harm.
Three of Australia's leading Children's Hospitals have published a fact sheet for parents and carers about this potential concern.
You should discuss any concerns you have about the potential risks associated with anaesthesia or sedation with your health professional.
Information for health professionals
Before using general anaesthetics and sedatives for a surgical procedure in pregnant women or young children, you should consider discussing the potential effects of these agents on neurodevelopment and learning. You should also be prepared to address questions raised by parents and carers about this issue.
These potential risks should obviously be balanced with any adverse outcomes likely to be associated with delaying or avoiding surgery. The timing of any non-urgent procedures should be discussed with patients.
The TGA is working with sponsors to update Product Information to include the following information:
- Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation drug administration or other factors such as the surgery or underlying illness.
- Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy. These studies have demonstrated that anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate gamma-aminobutyric acid activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes. The clinical significance of these non-clinical findings is yet to be determined.
Advice about the benefits and risks of anaesthesia in infants has recently been published by the Sydney Children's Hospital Network. In their statement, The Sydney Children's Hospital Network also provides advice when obtaining consent for general anaesthesia and sedation.
Additionally, in late 2016, the US Food and Drug Administration (FDA) published the findings of its review of this issue. The FDA found that repeated or prolonged exposure (over 3 hours) to these agents during late pregnancy or early childhood (under the age of 3 years) may cause an increased risk of long-term deficits in learning and behavioural development in children.
Reporting problems
Consumers and health professionals are encouraged to report problems with medicines or vaccines. Your report will contribute to the TGA's monitoring of these products.
The TGA cannot give advice about an individual's medical condition. You are strongly encouraged to talk with a health professional if you are concerned about a possible adverse event associated with a medicine or vaccine.