Safety of SSRIs in Pregnancy

Primary Recommendation

SSRIs should be continued during pregnancy at the lowest effective dose when clinically indicated, with sertraline as the first-line agent due to its favorable safety profile and minimal breast milk excretion. 1

The decision to continue SSRI therapy during pregnancy must weigh the well-documented risks of untreated maternal depression—including premature birth, decreased breastfeeding initiation, and harm to the mother-infant relationship—against the relatively small absolute risks associated with SSRI exposure. 1, 2

Risk-Benefit Framework

Risks of Untreated Depression

Untreated depression during pregnancy is associated with premature birth, decreased initiation of breastfeeding, and potential harmful effects on the mother-infant relationship. 3, 2
Women who discontinue antidepressant medication during pregnancy show a significant increase in relapse of major depression compared to those who continue treatment. 3, 4
The established benefits of treating depression with an antidepressant must be carefully weighed against potential SSRI risks on a case-by-case basis. 4

Congenital Malformations

Avoid paroxetine specifically, which has FDA pregnancy category D classification due to cardiac malformation concerns. 1
No increased risk of cardiac malformations has been demonstrated with first-trimester sertraline use in large population-based studies. 1
Studies addressing individual SSRIs indicate a small but higher risk for birth defects with maternal fluoxetine and paroxetine use, though the excess in absolute risk is small. 5
Most studies have not shown an increase in the overall risk of major malformations, though several studies have suggested SSRIs may be associated with a small increased risk for cardiovascular malformations. 6

Persistent Pulmonary Hypertension of the Newborn (PPHN)

Late pregnancy SSRI exposure has a possible association with PPHN, with the number needed to harm being 286-351. 1, 3
PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. 7, 4
Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including sertraline) in pregnancy and PPHN, though other studies do not show a significant statistical association. 4

Neonatal Adaptation Syndrome

Clinical Presentation

SSRIs used during pregnancy can cause neonatal adaptation syndrome in approximately one-third of exposed newborns. 3
Third-trimester SSRI use may lead to neonatal signs including irritability, jitteriness, tremors, feeding difficulty, sleep disturbance, respiratory distress, crying, restlessness, shivering, poor sucking, hypertonia, tachypnea, hypoglycemia, and seizures. 1, 3
Symptoms typically appear within hours to days after birth and usually resolve within 1-2 weeks. 1, 3
There is debate whether symptoms represent serotonin syndrome (characterized by changes in mental status, autonomic hyperactivity, and neuromuscular abnormalities) or SSRI withdrawal (manifesting with anxiety, headache, nausea, fatigue, and low mood). 3

Management of Neonatal Effects

Infants exposed to SSRIs in utero should be monitored for at least 48 hours after birth. 3
Clinicians should arrange for early follow-up after initial hospital discharge for infants exposed to SSRIs, and monitor infants for signs of drug toxicity or withdrawal over the first week of life. 1
In severely affected infants with persistent symptoms, a short-term course of chlorpromazine has provided measurable relief. 1, 3

Specific SSRI Selection

First-Line: Sertraline

Sertraline should be considered first-line therapy due to minimal excretion in breast milk and low infant-to-maternal plasma concentration ratios. 1
Sertraline is minimally excreted in breast milk, providing the infant with less than 10% of the maternal daily dose, and can be continued during breastfeeding. 1, 3
Sertraline and paroxetine are the most commonly prescribed antidepressants during breastfeeding, with both considered suitable first-line agents. 1
Start with low doses of sertraline, 25-50 mg daily, and slowly titrate upward while carefully monitoring the newborn. 1

Second-Line: Citalopram

If SSRI treatment is indicated, consider citalopram as an alternative if sertraline is not tolerated or ineffective. 1

Avoid: Paroxetine

Paroxetine should be avoided due to FDA pregnancy category D classification and documented cardiac malformation concerns. 1
Paroxetine has been associated with significant risks of major malformation, particularly cardiac defects, when used during pregnancy. 8

Practical Management Algorithm

For Women Already on SSRIs Who Become Pregnant

Continue SSRI treatment at the lowest effective dose rather than discontinuing, as withdrawal of medication may have harmful effects on the mother-infant dyad. 1
If currently on paroxetine, consider switching to sertraline in early pregnancy if clinically appropriate. 1
Use the lowest effective dose throughout pregnancy and postpartum. 1

For Women Requiring New SSRI Treatment During Pregnancy

Start sertraline as first-line therapy at 25-50 mg daily. 1
Titrate slowly while monitoring maternal symptoms and fetal wellbeing. 1
Continue treatment through pregnancy rather than discontinuing. 1

Prenatal Monitoring

Pregnant women exposed to any SSRI in early pregnancy should be offered options for prenatal diagnosis through ultrasound examinations and fetal echocardiography to detect the presence of birth defects. 5

Postpartum and Breastfeeding

Women already taking sertraline should breastfeed and continue the medication rather than discontinue either, as the benefits of breastfeeding for both mother and infant are well-documented, and untreated maternal anxiety/depression poses significant risks to the mother-infant dyad. 1
Sertraline can be continued during breastfeeding due to minimal excretion in breast milk. 1

Long-Term Neurodevelopmental Outcomes

Several recent reviews have not identified adverse neurodevelopmental outcomes among infants born to women treated with SSRIs during pregnancy. 1
Evidence for a possible association between in utero exposure to SSRIs and alterations in neurobehavioral development is currently weak. 8

Critical Clinical Pitfalls to Avoid

Do not discontinue SSRIs abruptly during pregnancy due to high risk of maternal depression relapse, which carries its own substantial risks to both mother and infant. 1, 3
Do not avoid treatment altogether due to fear of medication risks, as untreated maternal depression carries substantial documented risks to both mother and infant. 1
Do not use paroxetine as a first-line agent during pregnancy due to documented cardiac malformation risks. 1
Do not fail to monitor exposed neonates for at least 48 hours after birth and arrange early follow-up. 3

What are the safety concerns of using Selective Serotonin Reuptake Inhibitors (SSRIs) during pregnancy?

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