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 that is 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 106 pregnancies with therapeutic exposure to dihydrocodeine (including 26 live-born infants with first- trimester exposure). When genetic conditions were excluded, no major malformations were observed among 88 live-born infants exposed at any time during pregnancy.

The available data do not provide robust evidence of an increased risk of malformations following gestational codeine use, but findings are conflicting and potentially confounded. The majority of available prospective cohort studies (more than 4,300 first-trimester exposures) and a meta-analysis have not identified an increased risk of congenital anomalies overall following fetal codeine exposure. While single studies have identified increased risks of specific malformations, most were methodologically flawed, likely introducing bias; therefore, higher-quality studies are required to confirm or refute these findings.

Data regarding other pregnancy outcomes are limited, and there is no robust evidence that codeine use in pregnancy increases the risk of stillbirth, small for gestational age, or preterm delivery. 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 to investigate 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) advises that codeine is contraindicated in breastfeeding women due to concerns about 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 contacting 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.