Is promethazine (phenothiazine) safe to use during pregnancy?

Promethazine Safety in Pregnancy

Promethazine is considered safe for use during pregnancy and is endorsed by the American College of Obstetricians and Gynecologists (ACOG) as a first-line pharmacologic antiemetic therapy when non-pharmacologic treatments fail. 1

Safety Profile and Classification

• Promethazine is FDA-approved as a first-line pharmacologic treatment for nausea and vomiting in pregnancy (NVP) according to ACOG guidelines. 1

• The FDA classifies promethazine as Pregnancy Category C, meaning animal studies have shown adverse effects but adequate human studies are lacking, though the benefits may be acceptable despite potential risks. 2

• No increased risk of congenital defects has been reported with promethazine use in human observational data. 3

• Large birth registries, case-control studies, and cohort studies have confirmed the safety of both first-generation antihistamines (including promethazine) during the first trimester, with no significant increase in congenital malformations. 4

Treatment Algorithm Position

First-line approach:

• Begin with non-pharmacologic interventions: dietary modifications, avoidance of triggers, ginger, and vitamin B6 (pyridoxine 10-25 mg every 8 hours). 1

When non-pharmacologic approaches fail:

• Promethazine is recommended as a first-line pharmacologic option alongside doxylamine and dimenhydrinate. 1
• The doxylamine-pyridoxine combination is often preferred as the initial antiemetic due to FDA approval specifically for pregnancy. 3

If first-line therapy fails:

• Escalate to metoclopramide rather than increasing promethazine doses, as metoclopramide has similar efficacy but fewer adverse events (less drowsiness, dizziness, and dystonia). 1, 3
• A randomized study in hospitalized hyperemesis gravidarum patients showed promethazine and metoclopramide had equivalent efficacy, but promethazine caused significantly more side effects and treatment discontinuations. 3

Important Caveats and Precautions

Timing considerations:

• The most critical period for concern about congenital malformations is the first trimester during organogenesis, though promethazine has demonstrated safety during this period. 4

Specific warnings:

• Promethazine administered within two weeks of delivery may inhibit platelet aggregation in the newborn, requiring caution in late pregnancy. 1, 2
• Extrapyramidal side effects can occur—withdraw the drug immediately if these symptoms develop. 3
• Common side effects include drowsiness, dizziness, and anticholinergic effects. 1, 2

Contraindications:

• Absolutely contraindicated in pediatric patients less than 2 years of age due to respiratory depression risk. 2

Dosing

• Promethazine 12.5-25 mg orally or rectally every 4-6 hours as needed for nausea and vomiting. 5, 6
• For severe hyperemesis gravidarum: 25 mg suppository every 12 hours or 5-10 mg every 6-8 hours orally. 7

Common Pitfalls to Avoid

• Do not continue escalating promethazine doses when side effects emerge—switch to metoclopramide instead for better tolerability. 3
• Do not use epinephrine to treat hypotension associated with promethazine overdose, as promethazine can reverse epinephrine's vasopressor effect. 2
• Avoid combining with other anticholinergic agents or MAO inhibitors due to increased risk of drug interactions and extrapyramidal effects. 2