Confounding by Depression, Not SSRIs, Drives Most Pregnancy Risks

In the United States, 5% to 6% of pregnant patients are treated with a selective serotonin reuptake inhibitor (SSRI), most commonly for major depressive disorder (MDD), a disorder with a prevalence of about 12%.¹

A special communication published in JAMA Psychiatry by Katherine L. Wisner, MD, MS, of Children's National Hospital, and coauthors from the University of British Columbia, Weill Cornell Medical College, and Harvard Medical School reviews the accumulated evidence on MDD and SSRI treatment during pregnancy and concludes that the field's long-standing focus on drug risk has obscured a more consequential problem: undertreated maternal depression. The authors wrote that "the thrust of the field has shifted to prioritize treatment of MDD to optimize maternal health."¹

A Debate Reopened by a 2025 FDA Panel

The special communication is framed explicitly as a response to renewed public attention on SSRI safety in pregnancy. An FDA expert panel convened in July 2025 to evaluate the drug class, with commissioner Marty Makary telling the panel that "serotonin may play a crucial role in the development of organs of a baby in utero, specifically the heart, brain, and even the gut."²

Panelists discussed potential risks including cardiac birth defects, poor neonatal adaptation, and behavioral outcomes such as attention-deficit/hyperactivity disorder, though the panel ultimately concluded that additional research is needed.²

The American College of Obstetricians and Gynecologists (ACOG) pushed back at the time, calling SSRIs "life-changing and lifesaving" for pregnant patients who require treatment and describing some panelists' claims as "outlandish and unfounded." Kay Roussos-Ross, MD, told the panel that untreated maternal depression carries its own serious consequences, including relapse of mood symptoms, suicide, and overdose death.²

The new JAMA Psychiatry analysis effectively builds the evidentiary case behind ACOG's position.

Confounding by Depression Explains Much of the Earlier Signal

The authors' central argument rests on how MDD itself—not just the drug used to treat it—independently raises the risk of adverse pregnancy outcomes. Women with MDD have higher rates of preterm birth (odds ratio [OR], 1.46; 95% CI, 1.20-1.78), low birth weight (OR, 1.90; 95% CI, 1.31-2.74), cesarean delivery, and hyperemesis gravidarum (OR, 5.2; 95% CI, 4.3-6.3), independent of any antidepressant exposure. Depressive symptoms also confer a 3-fold higher risk of hypertension and preeclampsia.¹

Cardiac malformations serve as the authors' central case study. Unadjusted analyses found a 25% increased odds of cardiac defects with first-trimester SSRI exposure (OR, 1.25; 95% CI, 1.13-1.38). After adjusting for depression, that association fell to an OR of 1.12 (95% CI, 1.00-1.26), and after adjusting for depression plus other maternal characteristics, it effectively disappeared (OR, 1.06; 95% CI, 0.93-1.22).¹

A similar pattern held for autism spectrum disorder. An unadjusted hazard ratio of 1.81 fell to 1.06 after adjustment, and comparisons of siblings in which only one was exposed to an SSRI in utero produced a null estimate (hazard ratio, 0.86; 95% CI, 0.60-1.23).¹

The authors devote substantial attention to the risks of discontinuation, arguing that this side of the risk-benefit equation has been underexamined relative to studies of drug harm. In one perinatal psychiatry program, women who discontinued medication relapsed significantly more often than those who maintained treatment (hazard ratio, 5.0; 95% CI, 2.8-9.1).¹

A Danish cohort study found that women who discontinued antidepressants during pregnancy had an increased risk of psychiatric emergencies compared with a propensity-matched group that continued treatment (hazard ratio, 1.25; 95% CI, 1.00-1.55). A systematic review and meta-analysis found the relapse risk was substantially higher among women with severe or recurrent depression (risk ratio, 2.30; 95% CI, 1.58-3.35) than among those with mild or moderate illness.¹

To help clinicians communicate this trade-off, the authors include a fact box modeled on prior work. Of pregnant patients treated with medication for depression, 74 of 100 remained healthy, and the baseline rate of any birth defect (3 of 100) rose only marginally to 3.2 of 100 with antidepressant exposure, and the baseline rate of heart defects (1 of 100) rose to 1.1 of 100.¹

What Literature Already Showed

The JAMA Psychiatry findings are consistent with, though more assertive than, the prior literature on the topic. A 2022 review in Current Psychiatry Reports by Lindsay G. Lebin, MD, and Andrew M. Novick, MD, of the University of Colorado School of Medicine similarly found that perinatal SSRI exposure does not increase the risk of major malformations or gestational diabetes once underlying maternal illness is accounted for.³

That review did identify small but statistically significant increases in the risk of preeclampsia, postpartum hemorrhage, preterm delivery, persistent pulmonary hypertension of the newborn, and neonatal intensive care unit admissions associated with SSRI exposure, while cautioning that the absolute risk of these outcomes remains low. Lebin and Novick concluded that "recent evidence suggest[s] low absolute risk of clinically relevant negative outcomes with perinatal SSRI exposure when compared to untreated perinatal depression."³

The new special communication reports similarly low absolute risks for poor neonatal adaptation signs, which appear in up to 30% of newborns exposed to SSRIs in utero, are usually self-limited, and resolve within 2 weeks with supportive care. A cohort study examining neurodevelopmental disorders found a 2-fold greater unadjusted risk among SSRI-exposed offspring, but sibling comparisons produced null estimates for autism spectrum disorder, attention-deficit/hyperactivity disorder, and learning and intellectual disability.¹

An Overprescribing Debate Complicates the Picture

The renewed emphasis on maintaining SSRI treatment during pregnancy arrives alongside a separate federal push in the opposite direction for psychiatric medication broadly. In May 2026, HHS Secretary Robert F. Kennedy Jr. announced a Make America Healthy Again action plan targeting what officials described as a national psychiatric overprescribing crisis, noting that approximately 65 million Americans, including 4 million children, currently take psychiatric medications.⁴

A 45-expert task force convened by the American Society of Clinical Psychopharmacology reached near-unanimous agreement that psychopharmacology regimens require formal annual review, and the Centers for Medicare & Medicaid Services issued guidance allowing reimbursement for deprescribing services using FDA-approved tapering schedules. Perry Cohen, CEO of The TPG Family of Companies, said, "Long term use of SSRIs should be re-evaluated with each patient every 6 months."⁴

Neither the HHS action plan nor the FDA panel discussion specifically addressed pregnant patients, but the general deprescribing momentum could complicate counseling for pharmacists working with patients who are pregnant or planning pregnancy. The Wisner et al. analysis explicitly cautions against reflexive discontinuation in this population, noting that a third of women who continue SSRI treatment during pregnancy still screen positive for depression, underscoring that many patients are undertreated rather than overtreated.¹

Implications for Pharmacists

Pharmacists are often the first point of contact when a pregnant or newly pregnant patient asks whether to stop an antidepressant, and the special communication's emphasis on structured, absolute-risk communication is directly applicable at the counter. The authors recommend using fact boxes and absolute-risk framing (eg, 1 in 1000) rather than relative-risk statistics that can overstate small effects, and they note that changes in drug pharmacokinetics during pregnancy generally lower plasma concentrations, which may warrant dose adjustment and therapeutic drug monitoring.¹

The authors also flag a coverage change relevant to access. Obstetric care is currently reimbursed as a bundled fee covering pregnancy and delivery together, but unbundling planned for January 2027 is expected to allow coverage for the additional time needed to support benefit-harm discussions with patients.¹

Until then, the authors wrote, structured decision-making conversations "now rarely take place outside of specialized reproductive psychiatry settings," leaving general pharmacists, obstetric clinicians, and primary care prescribers to fill the gap.¹

REFERENCES

1. Wisner KL, Oberlander TF, Osborne LM, Huybrechts KF. Depression and SSRI Treatment During Pregnancy—Prioritizing Maternal Mental Health. JAMA Psychiatry. Published online August 12, 2026. doi:10.1001/jamapsychiatry.2026.2405

2. Gallagher A. FDA panel weighs risks, benefits of SSRI use during pregnancy. Drug Topics. July 24, 2025. Accessed August 13, 2026. https://www.drugtopics.com/view/fda-panel-weighs-risks-benefits-of-ssri-use-during-pregnancy

3. Lebin LG, Novick AM. Selective Serotonin Reuptake Inhibitors (SSRIs) in Pregnancy: An Updated Review on Risks to Mother, Fetus, and Child. Curr Psychiatry Rep. 2022;24(11):687-695. doi:10.1007/s11920-022-01372-x

4. Gallagher A. HHS designs action plan to address overprescribing of SSRIs. Drug Topics. May 14, 2026. Accessed August 13, 2026. https://www.drugtopics.com/view/hhs-designs-action-plan-to-address-overprescribing-of-ssris