Are Trintellix (vortioxetine) and hydroxyzine classified as Pregnancy Category C?

Pregnancy Classification Status

Yes, both Trintellix (vortioxetine) and hydroxyzine were historically classified as Pregnancy Category C under the old FDA classification system, though this system has been discontinued since 2015.

Understanding the FDA Pregnancy Category System

The FDA pregnancy category system (A, B, C, D, X) was phased out in 2015 and replaced with more detailed narrative descriptions. However, understanding the historical Category C designation remains clinically relevant 1:

Category C Definition:

• Either animal studies have revealed adverse effects on the fetus and there are no controlled studies in women, OR
• Studies in women and animals are not available
• Drugs should be given only if potential benefits justify the potential risk to the fetus 1

Trintellix (Vortioxetine) in Pregnancy

Current FDA labeling does not use the old letter categories but provides detailed risk information 2:

Key Safety Information:

• Limited human data on Trintellix use during pregnancy to inform drug-associated risks
• Animal studies at ≥15 times the maximum recommended human dose (MRHD) showed decreased fetal body weight and delayed ossification
• No malformations were seen at doses up to 77 times the MRHD in rats and 58 times in rabbits 2

Critical Clinical Considerations:

• Third trimester exposure may lead to neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) 2
• Use in the month before delivery may be associated with increased risk of postpartum hemorrhage 2
• Women who discontinued antidepressants during pregnancy were more likely to experience relapse of major depression 2

Emerging Research Concerns:

Recent animal studies (2025) demonstrate that gestational vortioxetine exposure at clinically relevant doses caused significant maternal and fetal toxicity, including reduced fetal brain dimensions, cortical and hippocampal thinning, and disrupted neurodevelopmental pathways 3. Another 2024 study showed prenatal exposure induced depressive- and anxiety-like behaviors in offspring with reduced neurotransmitter levels 4.

However, human case series data (2021) from 17 pregnancies with first-trimester vortioxetine exposure resulted in 12 live births with no malformations, though sample size was very small 5.

Hydroxyzine in Pregnancy

Hydroxyzine has more established historical Category C classification and specific contraindications 6, 7:

Critical Guideline Recommendations:

• Hydroxyzine is specifically contraindicated during early stages of pregnancy in U.K. manufacturer's Summary of Product Characteristics 7
• It is best to avoid all antihistamines in pregnancy, especially during the first trimester, although none has been shown to be teratogenic in humans 7
• Administration has been associated with development of cleft palate 6

Safety Data:

A prospective controlled study (1997) of 53 women exposed to hydroxyzine during organogenesis found no significant differences in pregnancy outcomes, rates of major or minor anomalies, birth weight, or neonatal distress compared to controls 8. However, this does not override the guideline recommendations for avoidance.

Clinical Decision Algorithm

For both medications, the decision framework should be:

1. Preconception Planning:

   • Attempt gradual discontinuation before pregnancy if feasible without severe functional impairment
   • Consider switching to medications with better safety profiles (e.g., certain SSRIs with more robust human data)

2. During Pregnancy:

   • For hydroxyzine: Avoid use, especially in first trimester; if antihistamine needed, chlorphenamine is often chosen in U.K. due to long safety record 7
   • For Trintellix: Weigh risks of untreated depression against limited human safety data and concerning animal studies; monitor closely if continued

3. Third Trimester Considerations:

   • If continuing Trintellix, prepare for potential neonatal monitoring for PPHN and drug discontinuation syndrome 2
   • Avoid use in month before delivery if possible due to postpartum hemorrhage risk

4. Monitoring Requirements:

   • Neonates exposed to Trintellix in third trimester require monitoring for respiratory distress, feeding difficulties, temperature instability, and other complications 2

Important Caveats

• The old FDA pregnancy category system provides less nuanced information than current labeling
• Category C does not mean "safe" or "unsafe" - it indicates insufficient data to make definitive conclusions
• Individual risk-benefit assessment must consider severity of maternal condition, available alternatives, and timing of exposure
• For hydroxyzine specifically, the contraindication in early pregnancy per U.K. guidelines suggests higher concern than generic Category C classification implies 7