Depression and Pregnancy: Clarifying the Role of SSRIs During Pregnancy

Pregnancy-related depression poses a dilemma: while untreated maternal illness carries significant risks, worries about SSRI fetal safety, such as congenital defects and neonatal adaptation syndrome, may discourage necessary treatment. To assist patients in making well-informed, well-rounded decisions, pharmacists must evaluate the strongest available data.

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The relationship between SSRIs and pregnancy has been the subject of some research. After controlling for maternal and clinical factors, a large US Medicaid cohort study of 949,504 pregnancies—of which 64,389 involved women who were exposed to SSRIs during the first trimester—found no statistically significant increase in the overall number of congenital heart defects.¹ Compared to previous, smaller studies, this well-controlled, large study offers strong assurance.

Additionally, first-trimester SSRI use was linked to a 26% higher relative risk for cardiovascular malformation, according to a systematic meta-analysis of 18 cohort studies, including over 65,000 pregnancies exposed to SSRIs.² Atrial septal defects were among the specified elevations, whereas ventricular septal defects were also elevated but not as strong. Crucially, the absolute risk corresponds to only a few extra cases per 10,000 births due to low baseline rates. While the risk for paroxetine may increase from 10 to 24 per 10,000, there is no discernible increase for other SSRIs, such as citalopram and sertraline.²

Neonatal Adaptation Syndrome

Exposure to SSRIs later in pregnancy may raise the risk of poor neonatal adaptation syndrome (PNAS). A 2013 systematic review found a 5-times higher chance for PNAS symptoms in exposed neonates.³ These can include tremors, respiratory distress, feeding difficulty, and irritability, typically appearing within 48 hours of birth.

One prospective cohort of 2793 mother-infant pairs reported that 56% of SSRI-exposed infants experienced PNAS.³ Respiratory symptoms and tremors were significantly more common, though most cases resolved within 2-5 days without long-term effects.³ Pharmacists should reassure patients that PNAS, while common, is transient and often clinically mild.

Untreated Maternal Depression

When discussing risk-benefit with pregnant patients, pharmacists must also highlight the substantial risks of untreated depression. A landmark prospective cohort of 201 women found that those who discontinued antidepressants during pregnancy had a 68% relapse rate, compared with only 26% among those who maintained therapy, with a hazard ratio of 5.0.⁴ Relapse was associated with poor prenatal care adherence, preterm labor, low birth weight, and even suicide.

Untreated depression also increases the risk of postpartum depression, impaired bonding, and negative cognitive or behavioral outcomes in the child.⁴ These effects often extend beyond the prenatal window, influencing long-term developmental and family health.

SSRI Counseling

Pharmacists play a critical role in guiding patients through the complexities of antidepressant use during pregnancy. One of the most important responsibilities is translating statistical risk into meaningful, patient-friendly language. For example, while studies may cite a 26% relative increase in the risk of certain birth defects, pharmacists should clarify that this corresponds to only a few additional cases per 10,000 births, helping to alleviate unnecessary anxiety.² Medication selection is another key area where pharmacists contribute; recommending SSRIs with lower associated fetal risks, such as sertraline or citalopram, over higher-risk options like paroxetine can help optimize both maternal mental health and fetal safety.^1,2

In addition, pharmacists are essential in care coordination, working closely with prescribers to manage potential drug-drug interactions, especially in patients taking medications that are CYP2D6 substrates or inhibitors.¹ They can also assist in developing tapering strategies when treatment discontinuation becomes clinically necessary, minimizing the risk of relapse and withdrawal symptoms.⁴ Pharmacists should also encourage appropriate postnatal planning by educating both patients and caregivers on the signs of PNAS while emphasizing that these symptoms are typically mild and self-limiting.³ Through these interventions, pharmacists serve as a bridge between evidence-based medicine and patient-centered care, empowering pregnant individuals to make informed, confident decisions about their mental health treatment.

Conclusion

Robust clinical data show that SSRIs are not associated with a significant overall increase in congenital heart defects, and the modest relative risk increase observed in some studies corresponds to a very small absolute risk.^1,2 PNAS is common among exposed neonates but generally self-resolves without intervention.³ In contrast, untreated depression leads to relapse in up to 68% of patients, with far-reaching consequences for both mother and child.⁴ Pharmacists, as accessible and trusted providers, have a critical role in guiding pregnant patients through evidence-based decisions about antidepressant use, balancing risks, alleviating fear, and improving outcomes for both generations.

REFERENCES

1. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant Use in Pregnancy and the Risk of Cardiac Defects. New England Journal of Medicine. 2014;370(25):2397-2407. doi:10.1056/nejmoa1312828

2. Zhang TN, Gao SY, Shen ZQ, et al. Use of selective serotonin-reuptake inhibitors in the first trimester and risk of cardiovascular-related malformations: a meta-analysis of cohort studies. Scientific Reports. 2017;7(1). doi10.1038/srep43085

3. Grigoriadis S, VonderPorten EH, Mamisashvili L, et al. Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence. J Clin Psychiatry. 2013;74(4):e293-e308. doi:10.4088/JCP.12r07966

4. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507. doi:10.1001/jama.295.5.499