Pain Research and Treatment / 2015 / Article / Tab 2

Review Article

Pain Management in Pregnancy: Multimodal Approaches

Table 2

Specific drugs and indications in each trimester.

DrugFirst trimester
(weeks 1–12)
Second trimester
(weeks 13–28)
Third trimester
(weeks 28–40)
LaborPostpartum and lactation

Acetaminophen
Risk factor: B when taken orally (C for intravenous use)
650 mg every 4–6 hours or 1 g every 6 hours.
Use with caution
Strong evidence against increased risk of miscarriage [20], serious birth defects [21], IQ, or physical growth [22].
Associated with small increased risk of cryptorchidism in boys [23] and childhood asthma [24].
Use with caution
Associated with small increased risk of cryptorchidism in boys [23] and childhood asthma [24].
Use with caution
Associated with increased risk of childhood asthma [24].
Safe to use
No increased risk of hemorrhage if the drug is given to the mother at term in standard doses [16].
Safe to use
The American Academy of Pediatrics (AAP) considers acetaminophen to usually be safe during lactation [25].
Weak association with early infant exposure (first 6 months) with increased risk of childhood asthma [26]; more research is required.

Nonsteroidal anti-inflammatory drugs (NSAIDs)
See individual drugs in the class for more detailed information, as risks vary per drug.
Studies are mixed on prenatal and early pregnancy use of NSAIDs and risk of miscarriage. Nakhai-Pour et al. [27] showed the association with NSAIDs as a class; however, Edwards and colleagues [28] did not find this association. A more recent study, with more than 65,000 women also did not find an increased risk of spontaneous abortion following exposure to NSAIDs [29].
One prospective study in pregnant patients with inflammatory rheumatic disease did not show a significant association with major birth defects nor harmful long-term effects caused by intrauterine exposure to these drugs when taken early to mid-pregnancy [30]. On the other hand, Ericson and Källén observed an increase in cardiac malformations in women with rheumatic disease exposed to NSAIDs in the first trimester [31]. There was no drug specificity for cardiac defects.
One prospective study in pregnant patients with inflammatory rheumatic disease did not show a significant association with major birth defects nor harmful long-term effects caused by intrauterine exposure to these drugs when taken early to mid-pregnancy [30].Do not use.
NSAIDs are generally linked to premature closure of the ductus arteriosus when taken in the third trimester of pregnancy, which in some cases may result in primary pulmonary hypertension of the newborn [16].
Large doses taken by mothers in the week before delivery can increase risk of intracranial hemorrhage in premature neonates [16].
The use of NSAIDs as tocolytics has been associated with an increased risk of neonatal complications, such as patient ductus arteriosus necrotizing enterocolitis and intraventricular hemorrhage [16].NSAIDs in general seem to be safe during breastfeeding [16].

(i) Aspirin
Risk factor: D
60–100 mg daily is generally not associated with adverse outcomes.
Use only if clearly indicated
Three studies including 11,000 NSAID-exposed pregnancies did not find a significant increase in the frequency of congenital malformations, nor was there an effect upon infant survival compared with unexposed pregnancies [32, 33].
Low-dose aspirin therapy (81 mg/day) is generally free of maternal or neonatal complications [34].
Weak evidence for increased associations with gastroschisis [35] and IQ/attention decrements in children [22].
Use only if clearly indicated
In one study, aspirin was dose-dependently associated with congenital cryptorchidism, particularly during the second trimester [36].
Do not use, especially if there is increased risk of premature delivery
The use of high-dose aspirin close to delivery has been shown to increase the incidence of clotting abnormalities, in addition to neonatal and perinatal bleeding such as hemorrhage in the CNS in the newborn [16]. Severe neonatal bleeding has been reported after premature delivery [37].
Premature closure of the ductus arteriosus can result when using a full-dose aspirin in this period. Persistent pulmonary hypertension of the newborn (PPHN) is a potential complication of this closure.
Use only if clearly indicatedUse only if clearly indicated
Data has suggested that low dose aspirin, 81 mg/day, is generally considered safe; however, aspirin should be used with caution. Doses above 150 mg are contraindicated.

(ii) Ibuprofen
Risk factor: C (prior to 28 weeks of gestation)/D (≥28 weeks of gestation)
400 mg every 4–6 hours as needed.
Use with cautionUse with cautionDo not use
Linked to premature closure of the ductus arteriosus, resulting in persistent pulmonary hypertension of the newborn (PPHN) [16].
Use with cautionSafe for breastfeeding women to use.
AAP classifies ibuprofen as usually compatible with breastfeeding [25].

(iii) Ketorolac
Risk factor: C (prior to 28 weeks of gestation)/D (≥28 weeks of gestation)
Single IV dose: 30 mg. Weight <50 kg: 15 mg.
Use with cautionUse with cautionDo not use
Linked to premature closure of the ductus arteriosus, resulting in persistent pulmonary hypertension of the newborn (PPHN) [16].
Use with cautionUse with caution
AAP classifies ketorolac as usually compatible with breastfeeding [25].

(iv) Naproxen
Risk factor: C
500 mg every 12 hours.
Use with caution
One study found an association between naproxen use and orofacial clefts [38]. However, the risk for these defects appears to be small [16].
Use with cautionDo not use
Linked to premature closure of the ductus arteriosus, resulting in persistent pulmonary hypertension of the newborn (PPHN) [16].
Use with cautionSafe for breastfeeding women to use.
AAP classifies naproxen as usually compatible with breastfeeding [25].

(v) Celecoxib
Risk factor: C (prior to 28 weeks of gestation)/D (≥28 weeks of gestation).
200 mg twice daily.
Use with cautionUse with cautionDo not use
Linked to premature closure of the ductus arteriosus, resulting in persistent pulmonary hypertension of the newborn (PPHN) [16].
Use with cautionUse only if clearly indicated
There is inadequate evidence to fully determine infant risk. Should only be used if the possible benefit outweighs the possible risk.

Opioids
See individual drugs in the class for more detailed information, as risks vary per drug.
Use with caution
In general, short-term, episodic use of opiates appears to be safe in pregnancy [16].
Few studies have evaluated opioid teratogenicity in the first trimester. Overall opinion is that there is minimal risk [39]. However, one study [40] showed an association with congenital heart defects, spina bifida, and gastroschisis. This study is limited by recall-bias.
Opioid abuse and use of chronic opioids during pregnancy is associated with neonatal abstinence syndrome (NAS) [41].
Use with caution
In general, short-term, episodic use of opiates appears to be safe in pregnancy [16].
Opioid abuse as well as use of chronic opioids during pregnancy is associated with neonatal abstinence syndrome (NAS) [41].
Use with caution
In general, short-term, episodic use of opiates appears to be safe in pregnancy [16].
Opioid abuse as well as use of chronic opioids during pregnancy is associated with neonatal abstinence syndrome (NAS) [41].
Onset of withdrawal signs is sooner in infants exposed to opioids with shorter half-lives, such as morphine and oxycodone.
Use with caution
Maternal opioids pass readily into fetal circulation and can cause fetal respiratory depression.
Opioids should be avoided when delivery of a premature neonate is expected.
Use with caution
The short-term use of opiates during breastfeeding appears to be safe.
Infants should be closely monitored for signs of respiratory depression [16, 25].

(i) Morphine
Risk factor: C
15 mg, 30 mg tabs; 10 mg, 20 mg/5 mL elixir
Use with caution
No reports linking the therapeutic use of morphine with major congenital defects have been reported [16].
Use with caution
Onset of withdrawal signs is sooner in infants exposed to opioids with shorter half-lives, such as morphine.
Use with caution
Onset of withdrawal signs is sooner in infants exposed to opioids with shorter half-lives, such as morphine.
Use with cautionUse with caution
AAP classifies morphine as usually compatible with breastfeeding [25].

(ii) Fentanyl
Risk factor: C
Intramuscular, intravenous, intrabuccal, transdermal, or epidural
Use with cautionUse with cautionUse with cautionUse with cautionUse with caution
AAP classifies fentanyl as usually compatible with breastfeeding [25].

(iii) Hydrocodone
Risk factor: C
Use with cautionUse with cautionUse with cautionUse with cautionUse with caution
Appears to be safe in breastfeeding as very little hydrocodone is transferred to the milk [42]. However, there is inadequate evidence to fully determine infant risk. Should only be used if the possible benefit outweighs the possible risk.

(iv) Codeine
Risk factor: C
Use with caution
Birth defects (including some heart defects) have been reported with maternal use of codeine in the first trimester of pregnancies [16, 40]. However, in another study, no effects were observed on infant survival or congenital malformation rate [33].
Use with cautionUse with cautionUse with caution
The use of codeine during labor may produce neonatal respiratory depression [16].
Use with caution.
AAP has classified codeine as usually compatible with breastfeeding [16]. However, toxicity has been reported [43].
The recommendation is to avoid long-term consumption of codeine-containing products during breastfeeding. Short-term therapy, such as 1-2 days, with close monitoring of the infant for symptoms of opioid toxicity is recommended [16].

(v) Methadone
Risk factor: C
Oral, subcutaneous, intramuscular, or intravenous
Use with caution
Methadone has been shown to have a favorable risk/benefit ratio if the user is a part of a comprehensive opioid dependence maintenance program during pregnancy.
Methadone-maintenance has been associated with longer gestation and increased birth weights in comparison to nonmaintenance controls [44].
If maintenance medication is necessary, treatment should begin with the lowest effective dose [45].
Use with caution
Clearance of methadone increases during the second and third trimester, which may cause withdrawal symptoms and necessitate dose adjustment [46].
Onset of withdrawal signs is longer in infants exposed to opioids like methadone.
Use with caution
Clearance of methadone increases during the second and third trimester, which may cause withdrawal symptoms and necessitate dose adjustment [46].
Onset of withdrawal signs is longer in infants exposed to opioids like methadone.
Use with cautionUse with caution
Breastfeeding is likely safe, based on studies that show transfer to milk is extremely low [16, 47].
AAP classifies methadone as usually compatible with breastfeeding [25].