opioids in pregnancy

Analgesia in pregnancy

Medications used in therapeutic doses for acute and chronic pain appear to be relatively safe in pregnancy (1,2)

• to minimize fetal risk, initiate drug interventions at the lowest effective dose, especially in late pregnancy, and select analgesics only after careful review of a woman's medical or medication history
  • women should avoid using NSAIDs after 32 weeks' gestation, owing to the possibility of antiplatelet or prolonged bleeding effects (2)
  • opioids should also be used with caution, especially in higher doses in late pregnancy when the infant should be observed carefully in the neonatal period for any signs of withdrawal (neonatal abstinence syndrome) (2)

Some brief guidance concerning the use of different analgesics available in primary care during pregnancy is provided below (1):

• paracetamol
  • not known to be harmful
    
    
• non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen
  • most manufacturers advise avoiding the use of NSAIDs during pregnancy or avoiding them unless the potential benefit outweighs the risk
    • should be avoided during the third trimester because use is associated with a risk of closure of fetal ductus arteriosus in utero and possibly persistent pulmonary hypertension of the newborn
    • onset of labour may be delayed and its duration may be increased
    • studies have failed to show consistent evidence of increased teratogenic effects in either humans or animals following therapeutic doses during the first trimester (2)
      
      
• codeine and opiate (opioid) based analgesia (1,2)
  • opiates (opioids) may depress neonatal respiration
  • withdrawal effects may occur in neonates of dependent mothers
  • gastric stasis and risk of inhalation pneumonia in mother during labour
  • codeine (3,4)
    • preferred if a weak opioid is required in pregnancy (3)
    • can be used short term in all trimesters of pregnancy - however, use of codeine near the end of the third trimester may cause neonatal respiratory depression and long-term use may cause withdrawal symptoms in the baby
    • the Royal College of Obstetricians and Gynaecologists (RCOG) suggest that codeine can be taken during all stages of pregnancy, using the lowest effective dose for the shortest possible time (4). It should also be noted that codeine is metabolised to morphine
    • there is limited data on the use of codeine in human pregnancy - but does not provide robust evidence of an increase in risk of foetal malformations (3)
    Dihydrocodeine (3,4)
    • no adequate data on the safety of dihydrocodeine in human pregnancy though it has been used without apparent adverse effects in practice for a number of years
    • any risks are expected to be similar to those for codeine (3)
    • if a weak opioid is required in pregnancy, codeine would be preferable to dihydrocodeine (3)
  • summary risks associated with use of opioid based analgesia in pregnancy if used in the first trimester (5)
  • a population based cohort study concluded that " findings suggest that prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although clinicians should be aware of the potential for a small increase in the risk of oral clefts and counsel patients about this risk"
  • use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester
  • relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14).
    
• aspirin
  • high doses of aspirin may be related to intrauterine growth restriction and teratogenic effects
  • impaired platelet function with risk of haemorrhage, and delayed onset and increased duration of labour with increased blood loss, can occur if used during delivery
  • avoid analgesic doses if possible in last few weeks (low doses probably not harmful)
  • with high doses
    • associated conditions include closure of fetal ductus arteriosus in utero and possibly persistent pulmonary hypertension of newborn
  • kernicterus may occur in jaundiced neonates
  • although aspirin has not been associated with other congenital anomalies, it has been associated with increased risk of vascular disruption, in particular gastroschisis, although this remains unproven. Overall, large trials demonstrate low-dose aspirin's relative safety and generally positive effects on reproductive outcomes (2)
    
    
• drugs used in opioid addiction e.g. buprenorphine and methadone
  • seek specialist advice
  • acute withdrawal of opioids should be avoided in pregnancy because it can cause fetal death
  • opioid substitution therapy is recommended during pregnancy because it carries a lower risk to the fetus than continued use of illicit drugs
  • if a woman who is stabilised on methadone or buprenorphine for treatment of opioid dependence becomes pregnant, therapy should be continued [buprenorphine is not licensed for use in pregnancy]
  • many pregnant patients choose a withdrawal regimen, but withdrawal during the first trimester should be avoided because it is associated with an increased risk of spontaneous miscarriage
  • withdrawal of methadone or buprenorphine should be undertaken gradually during the second trimester; for example, the dose of methadone may be reduced by 2-3 mg every 3-5 days
  • if illicit drug use occurs, the patient should be re-stabilised at the optimal maintenance dose and consideration should be given to stopping the withdrawal regimen.
  • further withdrawal of methadone or buprenorphine in the third trimester is not recommended because maternal withdrawal, even if mild, is associated with fetal distress, stillbirth, and the risk of neonatal mortality
  • drug metabolism can be increased in the third trimester
  • may be necessary to either increase the dose of methadone or change to twice-daily consumption (or a combination of both strategies) to prevent withdrawal symptoms from developing
  • neonate should be monitored for respiratory depression and signs of withdrawal if the mother is prescribed high doses of opioid substitute.
    • signs of neonatal withdrawal from opioids usually develop 24-72 hours after delivery but symptoms may be delayed for up to 14 days, so monitoring may be required for several weeks
    • symptoms include a high-pitched cry, rapid breathing, hungry but ineffective suckling, and excessive wakefulness; severe, but rare symptoms include hypertonicity and convulsions

Review recommendations are summarised (3):

• if possible, avoid all opioids during the first trimester. Non-pharmacological interventions should be considered first line.
• paracetamol remains the analgesic of choice for mild to moderate pain relief with NSAIDS as possible alternatives or adjuncts in the 1st or 2nd trimester only
• opioid analgesics, at their lowest effective dose, may be used at any stage of pregnancy for the short-term treatment of moderate to severe pain when other analgesics are not effective or not clinically indicated
• consider weak opioids, such as codeine, first for mild to moderate pain taking into account risk to the foetus
• inadequate data on human pregnancy exposure to opioids to rule out teratogenic risks completely, although the limited data available do not indicate substantial teratogenic effects
• a lack of adverse published data does not infer safety in pregnancy
• administration of opioids during labour or near term has been associated with neonatal respiratory depression. Abuse or prolonged use has also been associated with withdrawal symptoms including tremors, irritability, diarrhoea, vomiting and poor feeding
• opioids may exacerbate constipation, nausea and vomiting, which may already be a problem in the pregnant woman

The respective summary of product characteristics (SPCs) must be consulted before prescribing one of the drugs listed above.

Reference:

• British National Formulary (accessed 28/12/2013)
• Babb M et al. Treating pain during pregnancy.Can Fam Physician. 2010 Jan;56(1):25, 27.
• NHS Specialist Pharmacy Service (April 2020).Can opioids be used for pain relief during pregnancy?
• Bisson DL, Newell SD, Laxton C et al. Antenatal and postnatal analgesia. BJOG 2018; 1(26):e115-e124.
• Bateman BT et al. Association of first trimester prescription opioid use with congenital malformations in the offspring: population based cohort study. BMJ 2021;372:n102http://dx.doi.org/10.1136/bmj.n102

Last edited 02/2021