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 (1)
- is recommended as the first-line medication for mild-to-moderate pain
- is considered safe for use throughout pregnancy.
- non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen
- non-steroidal anti-inflammatory (NSAID) may be an additional option for some pregnant women in their first or second trimesters (1)
- NSAIDs should not be used in the third trimester.
- 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)
- weak opioids
- a weak opioid may be appropriate to use with paracetamol where pain control with paracetamol and/or an NSAID (in the first or second trimester only) is not achieved.
- lowest effective dose should be used for the shortest possible time
- management of severe and/or chronic pain (1)
- the treatment choice for severe and chronic pain in pregnancy will be based on the maternal condition, the severity of pain, and any known fetal adverse effects from in utero medication exposure. Pain management should be reviewed regularly for these women
- non-pharmacological interventions such as physiotherapy should be used to help manage pain and minimise the dose of medications during pregnancy
- maternal complications
- opioids may exacerbate constipation, nausea and vomiting, which may already be a problem in pregnant women
- neonatal withdrawal
- complications from neonatal withdrawal may occur with the use of opioid analgesics in pregnancy.
- use of any opioid during pregnancy, particularly if it has been used long term and/or around the time of delivery, confers a risk of neonatal respiratory depression
- the neonatology team should be informed if pregnant women have been receiving long-term opioids
- symptoms
- symptoms of neonatal withdrawal from opioids include:
- difficulty breathing
- extreme drowsiness (sleepiness)
- poor feeding
- irritability
- sweating
- tremors
- vomiting
- diarrhoea
- these symptoms will most often appear two days after birth and may last more than two weeks
- choose the most appropriate opioid
- weak opioids
- weak opioids are codeine, dihydrocodeine and tramadol
- consider weak opioids (with paracetamol) first for mild to moderate pain taking into account the risk to the fetus
- strong opioids
- examples of strong opioids are morphine, buprenorphine, fentanyl and oxycodone
- strong opioids may be required for more severe pain and may be considered after evaluating the risk of fetal adverse effects from in utero exposure. Their use needs to be reviewed regularly.
- 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 (1,3)
- codeine has often been the weak opioid of choice in pregnancy because there are more data available regarding its use in human pregnancy compared to other weak opioids
- use of codeine at any stage in pregnancy would not usually warrant any additional fetal monitoring
- if clinically indicated, codeine should be used at the lowest effective dose for the shortest possible duration.
- 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
- codeine is contraindicated for use during breastfeeding (1)
- risk of malformations (1)
- most data on the use of codeine in pregnancy (any trimester), whilst limited, do not suggest an increase in risk of fetal malformations. A possible association with respiratory and cardiac malformations has been reported following first trimester exposure to codeine
- UK Teratology Information Service (UKTIS) codeine monograph has further information and guidance
- neonatal respiratory depression
- using codeine (as with all opioid analgesics) near the end of the third trimester may cause neonatal respiratory depression and long-term use may cause neonatal withdrawal symptoms
- Dihydrocodeine (1,3,4)
- has an analgesic efficacy similar to codeine
- higher doses may provide some additional pain relief compared with codeine, but this may be at the cost of more nausea and vomiting (1)
- use of dihydrocodeine at any stage in pregnancy would not usually warrant any additional fetal monitoring (1)
- if clinically indicated, dihydrocodeine should be used at the lowest effective dose for the shortest possible duration.
- 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)
- see UKTIS dihydrocodeine monograph has further information and guidance
- risk of malformations (1)
- are no adequate data on the safety of dihydrocodeine in human pregnancy though it has been used without apparent adverse effects for several years. Any risks are expected to be similar to those for codeine
- neonatal respiratory depression (1)
- use of dihydrocodeine (as with all opioid analgesics) near the end of the third trimester may cause neonatal respiratory depression and long-term use may cause neonatal withdrawal symptoms
- Tramadol (1)
- used to treat moderate-to-severe pain
- produces analgesia via two mechanisms: an opioid effect and an enhancement of serotonergic and adrenergic pathways
- has fewer of the typical opioid side-effects (respiratory depression, constipation and addiction potential) though psychiatric reactions have been reported
- use of tramadol at any stage in pregnancy would not usually be considered as medical grounds for termination of pregnancy
- if clinically indicated, tramadol should be used at the lowest effective dose for the shortest possible duration
- risk of malformations
- most data regarding risks of congenital malformation following first trimester tramadol exposure, though limited, are reassuring
- possible associations between first trimester exposure and infant cardiovascular defects and a foot defect called talipes equinovarus have been identified. However, these are not confirmed by larger studies
- UKTIS tramadol monograph has further information and guidance
- neonatal respiratory depression
- use of tramadol (as with all opioid analgesics) near the end of the third trimester may cause neonatal respiratory depression and long-term use may cause neonatal withdrawal symptoms
- other complications
- the largest and most methodologically robust study available does not indicate an increased risk of miscarriage following gestational tramadol exposure
- a single cohort study found no increased risk of preterm delivery
- Strong opioids (1)
- Buprenorphine
- is a semi-synthetic opioid that only partially activates opiate receptors
- use of buprenorphine at any stage in pregnancy would not usually be considered as medical grounds for termination of pregnancy
- pregnancies complicated by severe pain may require additional fetal monitoring, this should be assessed on a case-by-case basis
- if clinically indicated, buprenorphine should be used at the lowest effective dose for the shortest possible duration
- risk of malformations
- are limited data on the use of buprenorphine in human pregnancies, which do not indicate associations with congenital malformations. However, data are too limited to fully exclude increased risks
- UKTIS buprenorphine monograph has further information and guidance
- neonatal respiratory depression
- use of buprenorphine (as with all opioid analgesics) near the end of the third trimester may cause neonatal respiratory depression and long-term use may cause neonatal withdrawal symptoms
- due to the long half-life of buprenorphine, neonatal monitoring for several days after birth should be considered
- other complications
- available data on buprenorphine exposure in human pregnancy do not indicate associations with stillbirth, preterm delivery or low infant birth weight. However, data are too limited to fully exclude increased risks
- Fentanyl
- is a very potent opioid analgesic and is available in a range of medicinal products including transdermal patches
- use of fentanyl at any stage in pregnancy would not usually be considered as medical grounds for termination of pregnancy
- need for additional fetal monitoring or prenatal investigations should be decided on a case-by-case basis
- if clinically indicated, fentanyl should be used at the lowest effective dose for the shortest possible duration
- risk of malformations
- safety of fentanyl in human pregnancy has not been established and the very limited data available are insufficient to assess the risk of teratogenicity
- UKTIS fentanyl monograph has further information and guidance
- neonatal respiratory depression
- use of fentanyl (as with all opioid analgesics) near the end of the third trimester may cause neonatal respiratory depression and long-term use may cause neonatal withdrawal symptoms
- other complications
- limited data available do not currently raise concerns about other adverse pregnancy outcomes
- Morphine
- remains the most used opioid analgesic for severe pain although it frequently causes nausea and vomiting
- RCOG guidance suggests that morphine can be taken during all stages of pregnancy at the lowest effective dose for the shortest possible duration
- risk of malformations
- is no robust evidence of an increased malformation risk, a possible association with childhood strabismus (a visual defect) has been suggested
- association is not confirmed because the data for morphine use in human pregnancy are inadequate with conflicting studies that are often confounded by other factors
- UKTIS morphine monograph has further information and guidance
- neonatal respiratory depression
- use of morphine (as with all opioid analgesics) near the end of the third trimester may cause neonatal respiratory depression and long-term use may cause neonatal withdrawal symptoms
- other complications
- some studies have suggested a possible association between morphine use in pregnancy with altered fetal growth in utero and an increased risk of preterm delivery
- however, data are extremely limited in relation to low birth weight, preterm delivery, stillbirth and neurodevelopmental outcomes
- Oxycodone
- has an efficacy and side-effect profile similar to that of morphine
- is commonly used as a second-line medication if morphine is not tolerated or does not control the pain
- use of oxycodone at any stage in pregnancy would not usually be considered as medical grounds for termination of pregnancy
- if clinically indicated, oxycodone should be used at the lowest effective dose for the shortest possible duration
- risk of malformations
- is no indication that the use of oxycodone in early pregnancy increases malformation rates, but the available data are insufficient to exclude an increase in risk
- UKTIS oxycodone monograph has further information and guidance
- neonatal respiratory depression
- use of oxycodone (as with all opioid analgesics) near the end of the third trimester may cause neonatal respiratory depression and long-term use may cause neonatal withdrawal symptoms
- other complications
- the UKTIS mentions one study of over 2,000 exposed pregnancies which found that oxycodone exposure in the first and second trimesters was associated with a small increased risk of preterm delivery (absolute risk ~10% vs. background risk ~7%).
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.
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