Highlight
- Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression in pregnancy, but their fetal safety profile remains debated.
- FDA panelists and external experts emphasize that the risks of untreated perinatal depression—including maternal mortality—may outweigh the potential adverse effects of SSRIs on fetal development.
- Current evidence shows associations between SSRIs and some adverse neonatal outcomes, but causality is confounded by underlying depression and methodological limitations.
- Shared decision-making and individualized risk-benefit assessment remain cornerstones of care for pregnant individuals with depression.
Background
Depression affects approximately 10–20% of pregnant individuals in the United States, making it one of the most common complications of pregnancy. Untreated perinatal depression is associated with significant maternal and fetal risks, including preterm birth, low birth weight, compromised maternal-infant bonding, substance use, poor prenatal care adherence, and increased maternal mortality through suicide and overdose. SSRIs are among the most commonly prescribed pharmacologic treatments for depression during pregnancy due to their favorable efficacy and tolerability profiles. Yet, concerns persist about their safety for the developing fetus, prompting the recent FDA panel review.
Study Overview and Methodological Design
Most data on SSRI safety in pregnancy derive from large-scale observational cohort studies, population registries, case-control studies, and meta-analyses. Randomized controlled trials (RCTs) are lacking due to ethical constraints in assigning pregnant women to drug exposure. Key study outcomes include rates of spontaneous abortion, congenital malformations, preterm birth, low birth weight, neonatal adaptation syndrome, persistent pulmonary hypertension of the newborn (PPHN), and neurodevelopmental disorders such as autism spectrum disorder (ASD) or attention deficit hyperactivity disorder (ADHD). Critical issues in study design include confounding by indication (i.e., distinguishing effects of the medication from effects of the underlying depression), selection bias, and inconsistent adjustment for important covariates such as maternal age, severity of illness, and comorbid substance use.
Key Findings
Panelists cited data showing associations between prenatal SSRI exposure and a spectrum of adverse neonatal outcomes:
- Spontaneous abortion: Some studies suggest a modestly increased risk with SSRIs, but recent meta-analyses adjusting for depression indicate negligible or no significant increase compared to unexposed depressed controls (MGH Center for Women’s Health, 2021).
- Congenital malformations: The absolute risk increase appears small. While some SSRIs (notably paroxetine) have been linked to cardiac defects, the overall risk for major congenital anomalies remains low and inconsistent across studies (Mayo Clinic, 2025).
- Preterm birth: Evidence is mixed. A recent 2024 study (Amit G et al., npj Women’s Health) found that preterm birth risk was higher in women with untreated depression than in those treated with SSRIs, suggesting that the underlying disorder may drive risk more than the medication.
- Neurodevelopmental outcomes: Early studies suggested links between prenatal SSRI exposure and increased ASD or ADHD risk, but more rigorous analyses controlling for maternal psychiatric history often attenuate or eliminate these associations (MGH Center for Women’s Health, 2023). The risk for depression in offspring is also debated, with heritability and environmental factors being major confounders.
- Neonatal adaptation syndrome and PPHN: There is a recognized, albeit rare, risk of transient neonatal adaptation symptoms (jitteriness, irritability, respiratory distress) and a slight increase in PPHN risk, though absolute rates are low.
Notably, 12% of women on SSRIs remain depressed during pregnancy, highlighting the need for optimal dosing, monitoring, and consideration of adjunctive non-pharmacologic treatments.
Mechanistic Insights and Pathophysiological Context
SSRIs act by increasing synaptic serotonin levels via inhibition of its reuptake. Serotonin is a critical neurotransmitter in fetal neurodevelopment, influencing cell migration, differentiation, and organogenesis in the heart, brain, and gut. It is biologically plausible that altering serotonergic signaling during key developmental windows could impact organogenesis or neurodevelopment. Animal studies confirm that SSRIs cross the placenta and can affect fetal brain development, but translation to human outcomes is less clear due to species differences and the complexity of human psychiatric disease.
Clinical Implications
The central clinical dilemma is balancing the known, substantial risks of untreated depression against the potential—largely small and inconsistently demonstrated—risks of SSRI exposure. Professional societies such as the American College of Obstetricians and Gynecologists (ACOG) and the American Psychiatric Association advocate for individualized, shared decision-making that accounts for depression severity, prior medication response, patient preference, and comorbidities. For women with moderate to severe depression or a history of relapse off antidepressants, continuing SSRIs during pregnancy is often warranted. Psychotherapy should be considered for mild cases or as adjunctive therapy. Routine preconception counseling and informed consent regarding the risks and benefits of all treatment options are essential.
Limitations and Controversies
Existing evidence is hampered by the non-randomized nature of most studies, residual confounding, and heterogeneous outcome definitions. Some clinicians and panelists argue for stronger FDA warning labels to better inform pregnant women and prescribers, especially regarding risks such as preeclampsia, preterm birth, and neonatal withdrawal. Others, including ACOG and noted perinatal psychiatrists, caution that overemphasizing medication risks without equal attention to untreated depression can deter necessary treatment and increase harm. Labeling inconsistencies among SSRIs (e.g., Lexapro vs. Zoloft) further complicate counseling. Data on long-term neurodevelopmental outcomes remain limited and require ongoing surveillance.
Expert Commentary or Guideline Positioning
Leading experts, including Dr. Tiffany Moore Simas and Dr. Kay Roussos-Ross, stress that untreated perinatal depression is the leading cause of preventable maternal mortality and that SSRIs remain among the most studied and safest options when indicated. ACOG’s July 2025 statement reaffirms that the benefits of SSRI access often outweigh the potential risks when used judiciously. Dr. Joseph Goldberg highlights the challenge of disentangling medication effects from disease effects, noting the absence of robust evidence for changing current warning labels. Emphasis is placed on comprehensive, compassionate counseling and the need for consistent, evidence-based medication guides.
Conclusion
The FDA panel’s review underscores the complexity of treating depression during pregnancy. While SSRIs may confer small risks for certain adverse outcomes, untreated depression carries greater and more immediate dangers for both mother and child. Current evidence supports a nuanced, individualized approach emphasizing shared decision-making, careful risk assessment, and patient education. Continued research, including large-scale prospective cohort studies and registry-based surveillance, is needed to clarify long-term effects and optimize perinatal mental health care.
References
- Amit G, et al. “Antidepressant use in pregnancy and risk of preterm birth: a population-based study.” npj Women’s Health. 2024; doi:10.1038/s44294-024-00008-0 .
- ACOG. “Statement on the Benefit of Access to SSRIs During Pregnancy.” July 21, 2025. https://www.acog.org/news/news-releases/2025/07/statement-on-benefit-of-access-to-ssris-during-pregnancy.
- Mayo Clinic. “Antidepressants: Safe during pregnancy?” July 22, 2025. https://www.mayoclinic.org/healthy-lifestyle/pregnancy-week-by-week/in-depth/antidepressants/art-20046420.
- MGH Center for Women’s Mental Health. Multiple publications. https://womensmentalhealth.org/
- March of Dimes. “Antidepressants don’t increase risk of preterm birth; untreated depression does.” April 11, 2024. https://www.marchofdimes.org/our-work/research/blog/antidepressants-dont-increase-risk-preterm-birth-untreated-depression-does-ucsf-prc