USE OF CODEINE OR DIHYDROCODEINE IN PREGNANCY

Codeine is an opioid analgesic used in the treatment of mild-to-moderate pain and as an antitussive. Dihydrocodeine is a semisynthetic opioid also used in the treatment of mild-to-moderate pain and as an antitussive. There are no published pregnancy safety data specifically for dihydrocodeine; however, any fetal or neonatal effects are expected to be similar to those for codeine. UKTIS has collected prospective data on 99 pregnancies with therapeutic exposure to dihydrocodeine (including 23 live-born infants with first trimester exposure). When genetic conditions were excluded, no major malformations were observed among 82 live-born infants exposed at any time during pregnancy.

The available data do not provide robust evidence of an increase in risk of malformation with gestational codeine use but are conflicting and potentially confounded. The majority of the available prospective cohort studies (greater than 4,300 first trimester exposures) have not identified significant increased risks of congenital anomaly overall following fetal codeine exposure. While single studies have identified increased risks of specific malformations, most are methodologically limited and these findings require further confirmation.

Data regarding other pregnancy outcomes are limited. A prospective cohort study described small increased risks of stillbirth, small for gestational age and preterm delivery with gestational codeine exposure in early pregnancy. However, these results may have been impacted by unmeasured co-variable risk factors that were not adequately considered in the analysis. As such, these findings remain unconfirmed. There are no data regarding the risk of miscarriage or abnormal neurodevelopment following in utero codeine exposure. Increased use of codeine in pregnancy among mothers of children with neuroblastoma was found in a single study. However, this finding is heavily biased and the association requires further investigation.

There are theoretical concerns that maternal use of codeine near term may be associated with respiratory depression in the neonate. However, the only study which has investigated the risk of neonatal respiratory depression found no increased risk. There are a small number of published case reports of perinatal arterial stroke and neonatal withdrawal in infants of women who used codeine in the weeks before delivery. However, no epidemiological studies have investigated these associations. Neonatal monitoring for symptoms of withdrawal may be warranted following maternal use of codeine near term.

The Medicines and Healthcare products Regulatory Agency (MHRA) advise that the use of codeine by lactating mothers is contraindicated due to concerns of infant opiate toxicity following exposure to codeine or its metabolite, morphine, through breast milk. For further guidance on the use of codeine in breastfeeding we advise contact with the UK Drugs in Lactation Advisory Service (UKDILAS).

Exposure to codeine at any stage in pregnancy would not usually be regarded as an indication for any additional fetal monitoring. However, 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.