What factors affect teratogenicity?

There are a number of general principles that affect teratogenicity that can be useful for you to consider when considering potential risk.

Timing of exposure

Extensive damage during the pre-embryonic phase (conception to 17 days) is thought to result in failure to implant and miscarriage, while minor damaged will be repaired by division of undifferentiated cells, with subsequent normal development. You will need to take care if there is uncertainty around dates, or if the drug has a long half-life. The embryonic phase (days 18-55) is the highest risk period for exposure and damage during this period is most likely to result in malformations During the foetal period (56 to birth), organs continue to develop and some remain susceptible to damage, such as the cerebral cortex, and kidney. Functional abnormalities (e.g. deafness) may also occur. Use in the final semester may also result in pharmacological effects to the neonate, for example bradycardia with atenolol, respiratory depression with opiates. Long term exposure of the foetus to maternal drug therapy may also lead to withdrawal symptoms after birth. Examples of this include benzodiazepines, opiates, and antidepressants (Shaefer et al 1997)

Dose

Teratogenic effects are generally dose dependant; hence there is a general recommendation that you should prescribe the lowest effective dose in pregnancy

Multiple drug therapy

Risk of teratogenicity may be increased if the number of drugs taken concomitantly is increased.

Maternal pharmacokinetic changes

Significant changes in drug distribution may occur because of an increase of up to 50% in blood volume, and a mean increase of 8 litres in body water. Kidney function also changes, with an increase in glomerular filtration rate of 50%, which may affect drugs that are excreted predominantly by the kidneys. You may need to carry out more frequent monitoring for drugs with narrow therapeutic indices (e.g. carbamazepine, phenytoin, lithium, digoxin) (Anderson 2005, Pavek et al 2009)

What are the key principles for reducing risk in pregnancy?

• Assess risk benefit – the risk of exposure of the foetus must be balanced against the risk of uncontrolled disease if therapy is stopped
• Consider non-drug treatments where possible and only prescribe drugs if essential • If possible avoid all drug use during the first trimester • Avoid new drugs – there is usually little information available on their safety in pregnancy
• Avoid multiple drug therapy
• Avoid known teratogens in women of child bearing age - if this is not possible, the potential risks should be discussed with the patient
• Use the lowest effective dose for as short a period as possible
• Consider the need for therapeutic drug monitoring and dose alteration for drugs with narrow therapeutic index

Sources of information

The BNF gives brief information on use in pregnancy under individual drug monographs. The SPC may give more information, but will tend to err on the side of caution for medico-legal reasons. You can obtain detailed information from the UK Teratology Information Service 0844 892 0909, and online through TOXBASE® (www.toxbase.org)

Balancing the risks and benefits of drugs in pregnancy