Fluoxetine Safety During Pregnancy
Fluoxetine can be used during pregnancy when clinically indicated, as it does not increase the risk of major congenital malformations, though third-trimester exposure requires careful monitoring for neonatal adaptation complications.
Risk of Major Malformations
No increased risk of major malformations overall. The FDA label states there was no evidence of teratogenicity in animal studies at doses up to 1.5-3.6 times the maximum recommended human dose, and fluoxetine is classified as Pregnancy Category C 1.
Meta-analysis confirms safety regarding major malformations. A systematic review of 21 studies found an odds ratio of 1.12 (95% CI 0.98 to 1.28) for major malformations with first-trimester fluoxetine exposure, which is not statistically significant 2.
Cardiac malformation concerns are likely confounded. While some cohort studies suggested an increased risk of cardiac defects (OR 1.6,95% CI 1.31 to 1.95), case-control studies showed no increased risk (OR 0.63,95% CI 0.39 to 1.03), and this apparent risk has been demonstrated in depressed women who deferred SSRI therapy, indicating ascertainment bias rather than true drug effect 2.
Third-Trimester Considerations
Neonatal adaptation syndrome is the primary concern with late pregnancy exposure. The FDA label warns that neonates exposed to fluoxetine late in the third trimester may develop complications requiring prolonged hospitalization, respiratory support, and tube feeding 1.
Clinical manifestations include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying 1.
These symptoms typically resolve within 1-2 weeks. The American Academy of Pediatrics notes that signs usually appear within hours to days after birth and resolve spontaneously, though in one case with paroxetine, symptoms persisted through 4 weeks 3.
Third-trimester exposure increases perinatal complications. Women taking fluoxetine in the third trimester have higher rates of premature delivery (RR 4.8), admission to special-care nurseries (RR 2.6), and poor neonatal adaptation (RR 8.7) compared to first/second trimester exposure only 4.
Clinical Management Algorithm
When depression requires treatment during pregnancy:
Continue fluoxetine at the lowest effective dose if already well-controlled, as the FDA states it should be used "only if the potential benefit justifies the potential risk to the fetus" 1.
Do not discontinue abruptly, as untreated maternal depression poses significant risks to both mother and fetus. The FDA notes that women who discontinued antidepressants during pregnancy were more likely to experience relapse of major depression 1.
For third-trimester exposure, arrange enhanced monitoring:
Consider citalopram or sertraline as alternatives if initiating new therapy during pregnancy, as these have more consistent safety data 5.
Important Caveats
Persistent pulmonary hypertension of the newborn (PPHN) remains controversial. The FDA label notes one retrospective study showing approximately six-fold higher risk with SSRI exposure after 20 weeks gestation, though this is the only study investigating this risk and lacks corroborative evidence 1.
The risk-benefit calculation favors treatment in most cases. Untreated maternal depression carries substantial risks including poor prenatal care, inadequate nutrition, substance abuse, and postpartum complications that may outweigh medication risks 1, 5.
Distinguish between serotonin syndrome and withdrawal in neonates. Both can present with overlapping symptoms, though serotonin syndrome typically includes the triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities 3.