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

Risks of SSRIs in Pregnancy

SSRIs during pregnancy carry specific but generally modest risks including neonatal adaptation syndrome (affecting ~30% of exposed newborns), a possible small increased risk of preterm birth, and uncertain associations with persistent pulmonary hypertension of the newborn (PPHN), while recent evidence provides reassurance against substantial risks of autism spectrum disorder or ADHD. 1, 2

Neonatal Adaptation Syndrome

The most common and clinically significant risk is neonatal adaptation syndrome, occurring in approximately one-third of infants exposed to SSRIs in the third trimester. 2

• Symptoms include crying, irritability, jitteriness, tremors, poor feeding, hypertonia, tachypnea, sleep disturbance, hypoglycemia, and occasionally seizures 2
• These symptoms typically appear within hours to days after birth and are self-limiting, resolving within 1-4 weeks without intervention in most cases 1, 2
• Severely affected infants may require pharmacological intervention, with short-term chlorpromazine providing measurable symptom relief 2, 3
• Infants exposed to SSRIs in utero should be monitored for at least 48 hours after birth with early follow-up arranged after hospital discharge 2, 3

Persistent Pulmonary Hypertension of the Newborn (PPHN)

The FDA revised its 2006 advisory in 2011, stating that conflicting findings make it unclear whether SSRIs during pregnancy cause PPHN. 1

• A meta-analysis found a link between late pregnancy SSRI exposure and PPHN, with a number needed to harm of 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 4, 5
• Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN, though other studies do not show significant association 5

Preterm Birth Risk

Antidepressant use during pregnancy may increase the risk of preterm delivery compared with untreated women who have depression. 1

• Meta-analysis demonstrates women treated with SSRIs had significantly higher risk of preterm birth compared to controls (adjusted OR 1.24,95% CI 1.09-1.41) 6
• This increased risk remained significant even when comparing depressed women on SSRIs with depressed women not on SSRIs (OR 1.17,95% CI 1.10-1.25) 6

Congenital Malformations

Avoid paroxetine specifically, which has FDA pregnancy category D classification due to cardiac malformation concerns. 3

• Overall SSRI use shows a small increased risk of major congenital anomalies (RR 1.11,95% CI 1.03-1.19) and congenital heart defects (RR 1.24,95% CI 1.11-1.37) 7
• However, when restricted to women with psychiatric diagnoses, no significantly increased risk was observed (MCAs RR 1.04, CHD RR 1.06), suggesting confounding by indication 7
• Sertraline shows no increased risk of cardiac malformations in large population-based studies 3
• Fluoxetine and paroxetine show small but higher risk for birth defects compared to other SSRIs 8, 7

Neurodevelopmental Outcomes

Recent evidence provides reassurance that antidepressant use during pregnancy is unlikely to substantially increase the risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). 1

• Several recent reviews have not identified adverse neurodevelopmental outcomes among infants born to women treated with SSRIs during pregnancy 3
• Studies have suggested associations between antidepressant use and lower Apgar scores, ADHD, and speech delay, although high-quality evidence is lacking 1

Critical Clinical Context

Untreated depression during pregnancy carries significant documented risks including premature birth, decreased breastfeeding initiation, and potential harm to the mother-infant relationship. 1, 2, 3

• Women who discontinue antidepressant medication during pregnancy show a significant increase in relapse of major depression compared to those who continue treatment 4, 5
• The risks of SSRI treatment must be balanced against the substantial risks of untreated maternal depression to both mother and infant 3, 9, 10

Preferred SSRI Selection

Sertraline should be considered first-line therapy due to minimal excretion in breast milk, low infant-to-maternal plasma concentration ratios, and no demonstrated increased risk of cardiac malformations. 3

• Use the lowest effective dose throughout pregnancy 2, 3
• Continue SSRI treatment during pregnancy at the lowest effective dose when clinically indicated, as withdrawal may have harmful effects on the mother-infant dyad 2, 3
• Sertraline and paroxetine transfer to breast milk in lower concentrations than other antidepressants, making them preferred during breastfeeding 1, 3