Is tramadol (ultram) safe for use during the second trimester of pregnancy?

Tramadol Use in Second Trimester: Not Recommended

Tramadol should be avoided during the second trimester of pregnancy due to documented embryotoxicity, fetotoxicity, and risk of neonatal withdrawal syndrome, despite the absence of proven teratogenicity. 1

FDA Classification and Animal Data

• The FDA classifies tramadol as Pregnancy Category C, indicating demonstrated embryotoxic and fetotoxic effects in animal studies at maternally toxic doses 1
• Animal studies showed decreased fetal weights, skeletal ossification delays, and increased supernumerary ribs in mice (≥120 mg/kg), rats (≥25 mg/kg), and rabbits (≥75 mg/kg) 1
• Importantly, no teratogenic effects (structural malformations) were observed in animal progeny up to high doses, but embryo/fetal toxicity was consistently present 1

Human Evidence of Risk

Congenital Malformation Data

• A large Swedish registry study (1997-2013) of 1,751 women exposed to tramadol in early pregnancy demonstrated a significantly increased risk of congenital malformations 2
• The adjusted odds ratio for relatively severe malformations was 1.33 (95% CI 1.05-1.70), with specific increases in cardiovascular defects (OR 1.56,95% CI 1.04-2.29) and pes equinovarus/clubfoot (OR 3.63,95% CI 1.61-6.89) 2
• This represents a moderate but real teratogenic risk that extends beyond the first trimester concern 2

Neonatal Withdrawal Syndrome

• Tramadol freely crosses the placenta with umbilical vein to maternal vein ratios of 0.83, ensuring significant fetal exposure 1, 3
• Chronic use during pregnancy carries a serious risk of neonatal abstinence syndrome requiring phenobarbital treatment and prolonged hospitalization (9+ days) 4
• The FDA label explicitly warns that neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth have been reported in post-marketing surveillance 1

FDA Contraindications for Labor and Delivery

• The FDA drug label states tramadol "should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks" 1
• Safe use in pregnancy has not been established according to the manufacturer 1
• The effect on later growth, development, and functional maturation of the child remains unknown 1

Clinical Decision Algorithm

If pain control is needed in the second trimester:

1. First-line alternatives: Consider acetaminophen (paracetamol) as the safest analgesic throughout pregnancy
2. Second-line for moderate pain: Short-term NSAIDs (ibuprofen, diclofenac) can be used for 7-10 days in the second trimester without substantial fetal risk, though they must be discontinued by 32 weeks 5
3. For severe pain requiring opioids: If opioid analgesia is absolutely necessary, other options with better-established safety profiles should be considered, though all opioids carry risks

Critical Pitfalls to Avoid

• Do not assume second trimester is "safe" for tramadol simply because organogenesis is complete—the Swedish data shows malformation risk persists, and fetal toxicity continues throughout pregnancy 2, 1
• Do not prescribe for chronic use without planning for neonatal monitoring and potential withdrawal treatment, as this requires minimum 3-day hospitalization and possible phenobarbital therapy 4
• Avoid the misconception that tramadol is "safer than other opioids"—while it has dual mechanism of action, the placental transfer is extensive and neonatal effects are well-documented 1, 4

Breastfeeding Considerations (Post-Delivery Context)

• The UK guideline suggests tramadol can be used "with caution" during breastfeeding, but infants must be observed for increased sleepiness, respiratory depression, sedation, and decreased alertness 5
• Use should be restricted to inpatient settings with total dose limitations 5
• Breast milk concentrations can reach significant levels (1,254 ng/mL tramadol documented), with neonatal oral fluid showing even higher concentrations of the active metabolite O-desmethyltramadol 6