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Opioids in Pregnancy
Opioids in Pregnancy
Contents
Summary................................................................................................................................................1
Background............................................................................................................................................2
Answer...................................................................................................................................................3
Codeine..............................................................................................................................................3
Dihydrocodeine..................................................................................................................................5
Fentanyl..............................................................................................................................................5
Oxycodone.........................................................................................................................................6
Morphine............................................................................................................................................6
Tapentadol.........................................................................................................................................7
Tramadol............................................................................................................................................7
Limitations..............................................................................................................................................8
References..............................................................................................................................................8
Prepared by......................................................................................................................................10
Contact.............................................................................................................................................10
Date Prepared..................................................................................................................................10
Checked by.......................................................................................................................................10
Date of check....................................................................................................................................10
Search strategy.................................................................................................................................10
Summary
If possible, avoid all drugs during the first trimester. Non-pharmacological interventions should be
considered first line.
Paracetamol remains the analgesic of choice for mild to moderate pain relief.
Opioid analgesics can 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.
There are 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.
Indiscriminate use should be avoided.
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Medicines Q&As
The largest amounts of data available for a specific opioid used during pregnancy are for codeine. Overall,
data are conflicting but do suggest that therapeutic doses of codeine are unlikely to pose substantial harm
to the foetus. The lowest effective dose should be used for the shortest period of time. Codeine should
not be used in mothers who are known to be CYP2D6 ultra-rapid metabolisers.
Limited data are available for the use of oxycodone, tramadol and morphine during pregnancy and very
limited data are available for dihydrocodeine. The data that are available do not suggest that these agents
put the foetus at increased risk of congenital malformations. No data are yet available for the effects of
tapentadol during pregnancy.
In utero exposure to tramadol has been associated with severe withdrawal effects requiring medical
management.
Opioids used near to term may cause neonatal respiratory depression and long-term use may lead to
withdrawal symptoms (neonatal abstinence syndrome) in the neonate. Withdrawal symptoms include
tremors, irritability, sneezing, vomiting and occasionally seizures.
Administration of opioids during labour 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.
Short term therapeutic use of opioids must be evaluated differently to that of opiate abuse or substitution
therapy for opiate abuse.
Opioids may exacerbate constipation, which may already be a problem in the pregnant woman.
Background
In general, the use of medicines should be avoided during pregnancy, especially during the first trimester.
Organogenesis occurs between the 3rd and 8th weeks of gestation, during the embryonic period. Before the 3 rd
week, exposure of the embryo to medicines either leads to a spontaneous abortion or development without
abnormalities (‘all- or nothing effect’) (1). Later exposure may affect growth and functional maturation of different
organs. For example, the heart is most sensitive during the 3 rd and 4th weeks of gestation, the brain and skeleton
are sensitive from the 3rd week through to the end of pregnancy and external genitalia are sensitive during the 8 th
and 9th weeks. Approximately 2-3% of all birth defects result from drugs other than alcohol (1).
Pain is common during pregnancy, due to weight gain, postural changes, relaxation of ligaments caused by
hormonal changes and pelvic floor dysfunction. It has been suggested that two-thirds of pregnant women
experience low back pain and 20% experience pelvic pain, both of which could be improved by exercise and
acupuncture (2). Chronic pain, if not well managed, can lead to depression, anxiety and hypertension, which in
turn can impact on the physical and psychological well-being of the mother (3).
If analgesics such as paracetamol or ibuprofen are not controlling pain experienced during pregnancy, stronger
analgesics such as opioids may be necessary. There are a number of opioid analgesics licensed for use in the
UK for the treatment of moderate to severe pain (4). Opioids may exacerbate constipation, nausea and vomiting
which may already be a problem in the pregnant woman. The risk and tolerability of adverse effects must be
balanced against the pain that the pregnant woman is experiencing. What data are there to support the safety of
opioid analgesics when used during pregnancy?
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Medicines Q&As
Answer
Opioid analgesics can be used at any stage of pregnancy for the short-term treatment of moderate to severe pain,
but prolonged use may cause tolerance and dependency in the mother and withdrawal symptoms in the neonate
(neonatal abstinence syndrome) if they are used regularly (1;3;5). Opioids also cause nausea and constipation
which may be exacerbated in pregnancy (3). The use of any opioid during pregnancy, particularly around the time
of delivery, has a risk of causing neonatal respiratory depression (5;6). Many studies about opioid use during
pregnancy focus on delivery and do not provide information regarding their potential teratogenicity.
Studies evaluating the safety of opioid analgesics during pregnancy are limited and there are no prospective,
comparative studies (7). There may be confounders such as doses used, maternal diseases and other
medications (6). However, therapeutic doses of opioids have been used for many years by pregnant women and
have not been linked to an increased risk of major or minor malformations (7).
Effects of opioids on longer-term neurodevelopmental outcome following in utero exposure is unknown (8). The
use of opioids during pregnancy is not usually an indication for additional foetal monitoring unless there are other
risk factors involved; the need should be decided on a case-by-case basis (8-13).
Codeine
Women with CYP2D6 polymorphisms, and their babies, may be at greater risk of toxicity with codeine (3).
Codeine is converted to morphine in the liver by the CYP2D6 enzyme. Those who are extensive or ultra-rapid
metabolisers will have an excessive amount of morphine in their blood which can lead to side effects such as
confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite.
Codeine use is contra-indicated in all people who are known to be CYP2D6 ultra-rapid metabolisers (15;16).
There are inconsistent reports of malformations occurring after exposure to codeine during the first trimester (12).
While some studies found no association with congenital defects, others suggested an increased risk of a variety
of anomalies, including cardiovascular malformations, cleft lip and palate, respiratory tract malformations, inguinal
hernia and pyloric stenosis (6;12;17). However, these have not been substantiated in large epidemiological
studies in Europe and the USA (18). The absence of a consistent pattern and methodological limitations with
possible bias in these studies mean that it is not possible to state that codeine was definitely the causative agent
(6;12;17;18).
There are a number of case control studies and surveillance studies for the use of codeine immediately
before and during pregnancy which have conflicting outcomes. Maternal recall of medication use prior to and
during pregnancy may be required and this may be subject to recall bias. There is just one prospective cohort
study.
3
Medicines Q&As
In large study based on data from the US National Birth Defects Prevention Study, 454 of 17,449 cases of
infants with various birth defects (2.6%) were exposed to opioid analgesics between 1 month before and 3
months after conception compared with 134 of 6,701 controls (2.0%) (17). Codeine was one of the most
commonly used opioids (34.5%). Statistically significant associations with maternal opioid use (mainly
codeine or hydrocodone) were found among infants with congenital heart defects (CHD) (OR 1.4, 95% CI
1.1 to 1.7) as well as for spina bifida (OR 2.0, 95% CI 1.3 to 3.2). There were also statistically significant
associations between maternal opioid use and infants with hydrocephaly (OR 2.0, 95% CI 1.0 to 3.7),
glaucoma or anterior chamber eye defects (OR 2.6, 95% CI 1.0 to 6.6) and gastroschisis (OR 1.8, 95% CI
1.1 to 2.9). The investigators could not conclude whether one medication would be preferable to another in
terms of risk for birth defects. They also state that these findings are consistent with other studies, but these
are over 25 years old, published between 1979 and 1986. There are many limitations to this study. Sample
sizes for the individual CHD categories are at the borderline required to observe these effects. Exposure
information relied on maternal recall of medication use from 3 months prior to conception to end of
pregnancy, with data collected from any time between 6 weeks and 2 years post-delivery (average 9-11
months). Control infants were live births without major birth defects. Medication doses were not collected,
nor were the use of multi-ingredient preparations. The investigators did not stratify patients for any other risk
factors such as anaesthesia use during surgery (the most commonly reported use for opioids was surgical
procedures).
The UK Teratology Information Service (UKTIS) has data on 120 pregnancy outcomes where maternal use of
codeine was reported (12). Of the 94 pregnancies where codeine was used in therapeutic doses, there were 81
live births, of which 62 normal healthy infants. Fifteen were born with neonatal problems and four had minor
congenital malformations; all had been exposed to other medications during pregnancy, including other
analgesics, antidepressants, corticosteroids and anti-infectives. No baby had a major congenital malformation
(0/81, 0%), which is lower than the background rate in the general population (2-3%). More than 240mg of
codeine was taken in another 16 pregnancies; of the 15 infants born, one had a minor congenital anomaly.
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Medicines Q&As
Neonatal abstinence syndrome
The neonatal abstinence syndrome is rare in mothers who are not addicts and there are few case reports.
The mother of one infant used a codeine-containing cough medicine 3 weeks prior to delivery and started
using codeine-containing analgesics 2 weeks before delivery (48mg codeine/day) (6).
A second mother consumed 90-120mg codeine/day for the last 10 days of pregnancy. Both babies were
born with Apgar scores 8-10 and in good health. Typical symptoms of narcotic withdrawal were noted in all
the infants (6).
A third infant, born at 34 weeks with Apgar scores of 9 and 10 (1 and 5 minutes) developed a tremor and
became restless and irritable at 24 hours (20). At 36 hours he had a convulsion and by 48 hours there was
widespread hypertonia and loose stools. Symptoms took a week to settle. It transpired that the mother had
taken at least 90mg/day of codeine for the last 2 months before delivery.
Overall, data are conflicting and insufficient to exclude risks (6;12;14;17;19). All studies contained confounders
such as lack of detail on doses used, reasons for use and other medication exposures. One study found an
associated between codeine use and an increased rate of Caesarean section, although underlying maternal
medical conditions may have been a cause. The use of codeine during pregnancy as an analgesic can be
justified when paracetamol alone is not sufficient (12;21). Use of codeine near term, as with other opioids, may
cause neonatal withdrawal syndromes (tremor, jitteriness, poor feeding) and respiratory depression (12). Little
information is available on the outcome of neonates who have neonatal withdrawal symptoms (20). Codeine
should not be used in mothers who are known to be CYP2D6 ultra-rapid metabolisers.
Dihydrocodeine
No epidemiological studies of congenital anomalies in infants born to women exposed to dihydrocodeine during
pregnancy have been located (6;9). Most data published were confined to the use of dihydrocodeine during
labour and, as with other opioids, the use of dihydrocodeine near term or during labour has been associated with
respiratory depression in the neonate (6;9).
The UKTIS has prospective follow-up data on 93 cases of women exposed to dihydrocodeine during pregnancy
up to June 2011 (9). In 67 of these cases, dihydrocodeine was used therapeutically and 50 babies were born, of
which 42 were classed as normal infants. In the seven babies with neonatal problems at birth and the one who
was born with a congenital abnormality, the mothers had taken other medications during pregnancy, including
antidepressants, benzodiazepines, illicit drugs and alcohol. There were 10 elective terminations, six spontaneous
abortions and one intrauterine death. In 14 of the 93 pregnancies, dihydrocodeine was taken in overdose
(>240mg/day); eight healthy babies were born out of the 10 resulting live births. Of the two who were not healthy,
one developed deafness and the other had an immature right hip. The frequency of congenital malformations in
both groups (1/50 and 0/14) was not significantly higher than the background rate. Retrospective follow-up data
are available for 12 pregnancies following therapeutic exposure to dihydrocodeine (9). One baby was exposed to
a range of analgesics in the third trimester and born with hydrops fetalis, subsequently dying in the neonatal
period. All of the other eleven live births had been exposed to other medications during pregnancy, including
other analgesics, antidepressants, illicit drugs, warfarin and alcohol. Opioid withdrawal symptoms, irritation and
poor feeding occurred in those exposed in the third trimester.
Overall, the limited data that are available for the use of dihydrocodeine during pregnancy do not indicate an
increased risk of foetal toxicity (9). If an opioid is required during pregnancy, codeine would be the first choice as
there are more data available of its effects on the foetus. As with other opioids, neonatal respiratory depression
may occur on maternal exposure to dihydrocodeine near term (6;21).
Fentanyl
There are limited data regarding the use of fentanyl during pregnancy, most data are for its use during labour.
There are few case reports of infants exposed to fentanyl from transdermal patches.
Transdermal fentanyl (125mcg/hour) was used throughout pregnancy in one mother for cervical and lumbar
spine injuries sustained prior to conception (22). A healthy infant was born at 38 weeks (Apgar scores of 9
at 1 and 5 minutes) and was closely observed in the neonatal special care unit for 5 days. At 24 hours, the
infant was showing mild signs of opioid withdrawal: jitteriness, fisting, irritable and high-pitched crying. No
pharmacological intervention was required and by 96 hours she showed no signs of opioid withdrawal.
Follow-ups at six weeks and 31 months showed normal development.
A second mother was treated with transdermal fentanyl (25mcg/hour) prior to and during pregnancy for
chronic pain associated with systemic lupus erythematosus (23). A healthy baby was born at 39 weeks and
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Medicines Q&As
although not assessed formally for neonatal withdrawal, he did not appear to suffer with any symptoms. He
was meeting all developmental milestones at 8 months.
Transdermal fentanyl (100mcg/hour) was used throughout pregnancy by a third mother to treat herniated
disks (24). She also required additional fentanyl during the 12 hours leading up to labour (35mcg every 6
minutes by patient-controlled analgesia and 50mcg IV four times). A healthy baby girl was born by
Caesarean section (Apgar scores 8 and 9) but her neonatal abstinence syndrome scores rose rapidly,
indicating opioid withdrawal. This was treated with oral morphine every 4 hours, with daily dose increases
until day 4. Morphine withdrawal was slowly done over a few weeks, due to irritability of the baby, but was
stopped on day 29. No development follow-up was available for the baby.
Overall, the data are too limited to make an evidence-based assessment of the risks associated with fentanyl use
during pregnancy. As with other opioids, respiratory depression in the newborn is a potential complication if
fentanyl is used near to delivery, and neonatal withdrawal may occur after chronic long-term exposure (6).
Oxycodone
Data regarding the use of oxycodone during pregnancy come from a few studies and case reports.
Overall, data regarding the safety of oxycodone during pregnancy are relatively limited, with one study showing
an increased in pulmonary valve stenosis that has not been reported elsewhere. As per other opioids, respiratory
depression and neonatal withdrawn are potential complications if oxycodone is used during pregnancy; neonatal
abstinence syndrome has been reported in one study.
Morphine
No reports linking therapeutic morphine use to major congenital defects have been found (6). Limited data from
the Boston Collaborative Perinatal Project did not suggest an association between congenital anomalies and
gestational exposure to morphine. The frequency of congenital abnormalities was no greater than expected in the
70 infants exposed to morphine during the first trimester or of the 448 infant exposed to morphine anytime during
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Medicines Q&As
pregnancy (6). A possible association with inguinal hernia was observed but causality has not been confirmed
(6).
There are few case reports of infants exposed to morphine in utero. A review described six case reports of
morphine exposure from weeks 18 to 30 of gestation, and one report of morphine exposure throughout
pregnancy. Five healthy infants were born to women receiving intrathecal or epidural morphine (4mg/day in three
women, 35-60mg/kg/week in one woman, dose not stated in one woman). The sixth baby was born at 33 weeks
following in utero exposure to oral morphine (60mg twice a day from week 18 of gestation, increased to
360mg/day from week 23), paracetamol (from week 23) and amitriptyline and ketamine (from week 32). The baby
required ventilator support for 12 hours and special neonatal care, but had no signs of opioid withdrawal or
malformations (27).
The UKTIS has prospective data on therapeutic exposures of 30 pregnancies to morphine (8). Of the 24 live
births, 19 were normal infants and of the five that had been exposed to other medications including other
analgesics, antibiotics, corticosteroids and anti-emetics, four infants had neonatal problems and one had a minor
congenital malformation. No major congenital malformations were reported. Three elective terminations and
three spontaneous abortions occurred in the first trimester.
Overall, the data available do not suggest that the use of morphine during pregnancy increases the risk of foetal
toxicity but are too limited to state that no increased risk exists (8). As with other opioids, neonatal respiratory
depression may occur on maternal exposure to morphine near term as it has been observed in neonates exposed
to morphine during labour (6;21) . Long term use has been associated with neonatal withdrawal syndrome;
symptoms seen included tremors, irritability, sneezing, diarrhoea, vomiting and occasionally seizures (21).
Tapentadol
No data were identified describing the use of tapentadol during human pregnancy and it may be prudent to use
another opioid first (6). As with other opioids, use close to delivery could cause respiratory depression in the
newborn.
Tramadol
No epidemiological studies on the effects of tramadol use in human pregnancy have been located (6;10). There
are some case reports of tramadol withdrawal symptoms in the neonate; some have been published with scant
information (see below) (28-32). No congenital malformations were reported in the case studies and all babies
apart from one were born with Apgar scores of 9-10.
An infant exposed to tramadol during pregnancy displayed signs of withdrawal 24 hours after birth, with
nausea, vomiting, poor feeding and tremor, followed by hypertonicity, myoclonus and generalised tonic-
clonic seizures (28). Withdrawal symptoms subsided following phenobarbitone therapy.
Four infants born following in utero exposure to tramadol 200-450mg/day, during the third trimester in 3
cases and throughout pregnancy in the third, all exhibited signs of withdrawal symptoms (clonus,
convulsions, crying, hyper-excitability); one was born with an Apgar score of 0 and required resuscitation
(29;33).
Withdrawal symptoms (high pitched crying, trembling and shortened sleeping hours) occurred in an infant
born at 36 weeks following exposure to tramadol 400mg/day (reduced to 200mg/day during the last weeks
of pregnancy) (30). A reducing dose of opium tincture was used over 13 days to control symptoms.
An infant was with withdrawal symptoms after being exposed to tramadol 300mg daily throughout pregnancy
(31). Withdrawal symptoms first occurred after 24 hours and were fully developed by 48 hours; the baby
also experienced tachypnoea, tachycardia and a light single convulsion. These were treated with diazepam
(2.5mg IV stat then 1mg tds orally until day 7) and phenobarbitone (10mg/kg until day 13).
A 34-week neonate showed symptoms of tramadol withdrawal within 48 hours of delivery, with jitteriness,
myoclonic movements and irritability (32). The mother had used tramadol 600-800mg/day. The baby was
treated with oral clonidine (1microgram/kg every 8 hours) until day 32, then tapered off over the subsequent
7 days.
The UKTIS has prospective data on pregnancy outcomes of 51 pregnancies exposed to tramadol at various
stages (10). Of the 39 prospective therapeutic exposures, the frequency of congenital malformations in live-born
infants (4/31) was not significantly higher than the background rate, although data were inadequate to exclude an
increase in rates of malformations overall, or specific malformations.
7
Medicines Q&As
Overall, based on experimental animal models and limited human data, the use of tramadol in pregnancy is not
expected to increase the risk of congenital anomalies. However, severe neonatal withdrawal symptoms have
been reported following tramadol using during pregnancy and infants should be closely monitored for symptoms,
which may require medical management. Symptoms may not arise until 24 hours after birth.
Limitations
Data on exposure of human pregnancies to codeine were inconsistent. Limitations on methodologies
with possible bias did not allow causal relationship of anomalies to be established.
Data available for all opioids in this Q&A were inadequate to rule out risks completely.
Evidence of pregnancy outcomes of drug exposure is usually based on case control or cohort studies
due to ethical grounds. Limitations of these studies included other factors which need to be considered,
such as concurrent maternal diseases and other drug therapies that may have been taken. Prospective
data may also subject to reporting bias.
Opioids other than codeine, dihydrocodeine, morphine, oxycodone, tapentadol and tramadol have not
been considered in this Q&A.
This Q&A only provides guidance on the therapeutic use of opiates as analgesics and not as substitution
therapy for opioid abuse. Opioids in these two distinctive clinical indications with regard to their toxicity in
pregnancy should be evaluated differently.
This Q&A does not discuss the following:
o opioid-containing combination analgesics
o use in mothers with long-term serious conditions including renal impairment or liver disease
o long-term developmental effects of opioids on infants exposed in utero.
References
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Medicines Q&As
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(33) Anon. Tramadol withdrawal symptoms in infants exposed in utero. Prescrire Int 2012; 21(125):71-72.
Prepared by
Alexandra Denby, Regional MI Manager, London MI Service (Northwick Park)
Contact
nwlh-tr.medinfo@nhs.net
Date Prepared
September 2014
Checked by
Lekha Shah, Pharmacist, London MI Service (Northwick Park)
Date of check
October 2014
Search strategy
Embase: (PREGNANCY AND [MORPHINE OR CODEINE OR TRAMADOL OR DIHYDROCODEINE] AND
exp PAIN/dt) [Limit to: English Language and Humans and Publication Year 2012-Current]].
Embase: (PREGNANCY AND [MORPHINE OR CODEINE OR TRAMADOL OR DIHYDROCODEINE]) [Limit
to: English Language and Humans and Publication Year 2012-Current]].
Embase: [OXYCODONE/ OR FENTANYL OR TAPENTADOL] AND PREGNANCY [Limit to: English
Language and Humans and Publication Year 2004-Current]].
Medline: ([MORPHINE OR CODEINE OR TRAMADOL OR dihydrocodeine.af] AND PREGNANCY [Limit to:
English Language and Humans and Publication Year 2012-Current])
Medline: [*OXYCODONE/ OR *FENTANYL OR tapentadol.af] AND *PREGNANCY OUTCOME
Medline: [*OXYCODONE/ OR *FENTANYL OR tapentadol.af] AND PREGNANCY [Limit to: English
Language and Humans]
Medline: ([MORPHINE OR CODEINE OR TRAMADOL OR dihydrocodeine.af] AND *PREGNANCY
OUTCOME [Limit to: English Language and Humans]
In-house Database/resources
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