Are Selective Serotonin Reuptake Inhibitors (SSRIs) safe during pregnancy?

Safety of SSRIs During Pregnancy

SSRIs can be used during pregnancy when the benefits outweigh the risks, with sertraline being the preferred first-line option due to its established safety profile. 1

Risk-Benefit Assessment

The decision to use SSRIs during pregnancy requires careful consideration of:

1. Risks of untreated depression:

   • Premature birth
   • Decreased breastfeeding initiation
   • High risk of depression relapse (when medication is discontinued)
   • Adverse effects on maternal and fetal wellbeing 1

2. SSRI-associated risks:

   • Neonatal adaptation syndrome with third trimester exposure
   • Small increased risk of persistent pulmonary hypertension of the newborn (PPHN)
   • Potential cardiac malformations (particularly with paroxetine)
   • Possible association with speech delay and ADHD 1

Safety Profile of Specific SSRIs

• Sertraline: Preferred first-line option due to established safety profile 1
• Citalopram: Generally considered safe during pregnancy 1
• Paroxetine: FDA classified as pregnancy category D due to concerns about congenital cardiac malformations 1
• Fluoxetine: Associated with a small but higher risk for birth defects 2, with animal studies showing increased stillbirths and decreased pup weight at high doses 3

Third Trimester Considerations

Neonatal adaptation syndrome may occur with third trimester SSRI exposure, characterized by:

• Respiratory distress, cyanosis, apnea
• Seizures, temperature instability
• Feeding difficulties, vomiting, hypoglycemia
• Hypotonia, hypertonia, hyperreflexia
• Tremor, jitteriness, irritability, constant crying 3

These symptoms typically resolve within days to weeks and are consistent with either direct SSRI effects or a discontinuation syndrome 3.

PPHN Risk

Meta-analyses have shown a link between late pregnancy SSRI exposure and PPHN, with a number needed to harm of 286-351 1. The absolute risk increase is small but should be considered in treatment decisions.

Neurodevelopmental Outcomes

Converging evidence from multiple study designs suggests that observed associations between prenatal antidepressant exposure and neurodevelopmental problems (such as autism spectrum disorder and ADHD) are largely due to confounding factors rather than direct medication effects 4.

Breastfeeding Considerations

SSRIs are excreted in breast milk at varying levels:

• Paroxetine: Infant to maternal plasma concentration ratio <0.10
• Sertraline and Fluvoxamine: <10% of maternal daily dose in breast milk 1

Monitor breastfed infants for irritability, poor feeding, or sleep disturbances, with particular caution for premature or low birth weight infants 1.

Clinical Recommendations

1. For women requiring pharmacological treatment during pregnancy:

   • Sertraline is the preferred first-line option
   • Citalopram is an acceptable alternative
   • Avoid paroxetine if possible due to cardiac malformation risk

2. For women exposed to SSRIs during pregnancy:

   • Offer prenatal diagnosis through ultrasound examinations and fetal echocardiography 2
   • Monitor neonates for adaptation syndrome, particularly with third trimester exposure
   • Arrange early follow-up after initial hospital discharge 1

3. For women already on SSRI treatment who become pregnant:

   • Continuing treatment is often recommended as stopping antidepressants during pregnancy is associated with high risk of depression relapse 1
   • Consider tapering or switching therapy only on a case-by-case basis if appropriate for the individual 2

The evidence suggests that while SSRIs carry some risks during pregnancy, these risks are generally small in absolute terms, and untreated depression itself poses significant risks to both mother and child.