Weighing the Evidence: Response to the FDA’s Recent Panel on Antidepressant Use in Pregnancy.

On Monday, the US Food and Drug Administration convened an expert panel to discuss the use and safety of selective serotonergic reuptake inhibitors (SSRIs) during pregnancy.  Considerable medical research supports the reproductive safety of SSRIs and other antidepressants during pregnancy, yet FDA leadership and invited panel members seemed to raise only concerns about the use of this class of medications during pregnancy without adequate discussion of the morbidity and mortality associated with untreated or incompletely treated perinatal psychiatric illness.

Many organizations, including the American College of Obstetricians and Gynecologists (ACOG), have publicly criticized the panel’s unbalanced approach to this complicated and nuanced topic.  The discussion focused largely on the risks of SSRIs during pregnancy but ignored or diminished the risks associated with untreated depression in the mother.  Furthermore, the FDA panel did not include leaders in the field of reproductive psychiatry but rather relied mostly on the opinions and comments of individuals who are longstanding outspoken critics of the use of psychiatric medications.  Only one of the ten panelists was a clinician — an obstetrician and psychiatrist — who treats women with psychiatric disorders during pregnancy.

The use of psychiatric medications during pregnancy has long been a polarizing issue.  Although we have more and more data to support the reproductive safety of many different types of psychiatric medications, we continue to encounter opponents to the use of these medications during pregnancy.  However, more concerning than the voice of a single individual who shares an opinion about a subject that affects so many, is when an organization such as the FDA represents such an unbalanced view to the public as evidence; that is when patients are put at risk.  

“For pregnant people who need SSRIs, they are life-changing and lifesaving. Mental health conditions are already the most frequent cause of pregnancy-related death. Unfortunately, the many outlandish and unfounded claims made by the panelists regarding SSRIs will only serve to incite fear and cause patients to come to false conclusions that could prevent them from getting the treatment they need.”  Steven J. Fleischman, MD, MBA, FACOG, President of ACOG.

Mood and anxiety disorders are common in women, and many women will grapple with the difficult decision of whether or not to use medications during pregnancy. Some women may experience benefit with non-pharmacologic interventions; however, a substantial proportion of women, especially those with recurrent or severe illness, will require medication to mitigate the experience and sequalae of untreated perinatal psychiatric illness.  Working collaboratively with their respective clinicians, they will consider the risks associated with taking a particular medication during pregnancy, while at the same time, acknowledging that to forgo treatment may also put their well-being and the safety of the pregnancy at risk.

No medication is without risk; however, we want to emphasize that during pregnancy untreated illness in the mother also carries significant risk.  Potential consequences include poor prenatal care, increased risk of substance use, higher rates of complications (e.g., preterm birth, low birth weight), compromised maternal-infant bonding, progression to postpartum depression, and, in severe cases, self-harm or suicide.  

Decisions regarding the use of medications is a collaborative process involving the patient and her health care providers.  This process depends on a thoughtful and thorough review of the most accurate, balanced, and evidence-based information available.  Careful consideration must be given to both the potential risks associated with the use of a specific medication, while at the same time considering the possible consequences of untreated illness in the mother. With this approach,  the patient is able to make well-informed and individualized decisions regarding her care, supporting the well-being of both the mother and her child.

Risk of Depression During Pregnancy

In the United States, epidemiologic studies indicate that 10% to 20% of women experience clinically significant depressive symptoms during pregnancy (antenatal depression).   Higher rates of depression have been documented among the following populations of women with:

• • History of depression or anxiety disorder prior to pregnancy
  • Lower income or socioeconomic status
  • Lack of partner support or being a single parent
  • Intimate partner violence
  • Chronic medical conditions (e.g., epilepsy)
  • High obstetric risk or a history of adverse pregnancy outcomes
  • Minority racial or ethnic background: According to a recent study, Non-Hispanic Black individuals had higher risk of perinatal depression, higher rates of comorbid anxiety, and were more likely to have moderate to severe depression compared to Non-Hispanic White individuals.  
  • Low and middle income countries: Meta-analyses and systematic reviews report a pooled prevalence of up to 25.5% in low- and middle–income countries

It would be dangerous to conclude that depression occurring in pregnancy will resolve spontaneously and can therefore be ignored or left untreated. While mild emotional ups and downs may occur, especially during the first trimester, clinical depression generally does not remit without intervention. Research consistently shows that without treatment, depression during pregnancy can persist or worsen, increasing risks for both mother and child. 

Risk of Relapse After Discontinuing Antidepressants

The decision to use an antidepressant for the treatment of depression is highly personal, and the decision to maintain or discontinue treatment during pregnancy is based on multiple factors, including illness history, severity of illness, prior attempts to discontinue treatment, and personal preference.  Most women elect to discontinue antidepressants during pregnancy.  Large population-based studies indicate that about 75% of women who have taken an  antidepressant in the year prior to pregnancy will elect to discontinue antidepressant use during pregnancy.

Especially for women with severe or recurrent depressive illness, discontinuation of antidepressants during pregnancy is associated with high rates of relapse.  A pivotal 2006 study from the MGH Center for Women’s Mental Health demonstrated that 68% of women with a history of major depression who discontinued their antidepressant experienced a relapse during pregnancy, compared with only 26% of women who continued their medication. 

In a recent pooled analysis of ten different studies, the frequency of relapse after antidepressant discontinuation varied widely, ranging from 15% to 68%, with four studies reporting a relapse rate above 60%.  When the researchers stratified the population according to severity of illness, they observed that women with severe depression experienced a 67.6% risk of relapse who discontinued medication , compared to much  lower rates in women with milder illness.

All studies reported that the highest relapse rates occurred during the first trimester. Women who continue their medication still face a risk of relapse, but the rate is significantly lower, generally in the 20% to 30% range.

Effects of Untreated Antenatal Depression in the Mother

Depression during pregnancy is a strong and consistent predictor of postpartum depression (PPD). Women with antenatal depression are about four times as likely to experience PPD compared to those without depression during pregnancy. In women with a prior history of depression or high risk for PPD, studies suggest that continuing or initiating antidepressant therapy during pregnancy can reduce the rate of postpartum depressive episodes by up to 40–74%, compared to placebo or discontinuation.

There is an accumulating body of literature indicating that untreated depression in the mother may have negative consequences for the pregnancy and the developing fetus.  Recent meta-analyses and systematic reviews consistently demonstrate that antenatal depression increases the risk for:

• • Preterm birth
  • Low birth weight and intrauterine growth restriction
  • Increased neonatal intensive care admissions

In addition, women who are depressed are more likely to smoke, drink alcohol, and use illicit drugs.  All of these factors are associated with worse pregnancy outcomes and can affect fetal neurodevelopment.

More recent studies actually show that depression during pregnancy (in the absence of antidepressant treatment) can actually change the architecture of the fetal brain. Researchers have observed alterations in the microstructure of the right amygdala, a brain region associated with stress reactivity and vulnerability to mood and anxiety disorders.

There is also evidence that what happens in utero, while the fetus is developing, may predispose a child to certain illnesses later on in life.  There is a growing consensus that untreated depression and/or stress in the mother is associated with dysregulation of the maternal hypothalamic-pituitary-adrenal (HPA) axis.  Fetal exposure to elevated levels of maternal stress hormones and inflammation leads to dysregulation of the fetal HPA axis that may lead to long-standing alterations in the fetal HPA axis, making the child more susceptible to depression or anxiety as an adult.

Importantly, untreated depression may also increase risk for self-harm and suicidal behaviors.  In the United States, suicide remains one of the leading causes of death in the perinatal period. 

What Are the Risks Associated with SSRI Exposure During Pregnancy?

The use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy has been the subject of extensive research, particularly regarding their potential association with adverse pregnancy outcomes, congenital malformations, and long-term neurodevelopmental risks. While some studies have reported associations between prenatal SSRI exposure and risk for certain malformation or increased autism risk, larger and better-controlled studies adjusting for confounding factors—including maternal age, BMI, socioeconomic status, and psychiatric illness— have generally found little or no increased risk.

A major methodological issue is confounding by indication: women who take medications during pregnancy often have more severe psychiatric symptoms, which themselves increase risk for adverse outcomes. Comparing SSRI-exposed women to those without psychiatric illness overestimates medication risk; the most meaningful comparisons are among women with similar psychiatric histories.

Because randomized controlled trials investigating drug safety cannot be conducted in pregnant populations, all evidence comes from observational studies, which can never fully eliminate confounding. Still, the bulk of data suggests that when confounding is addressed, SSRIs during pregnancy appear to confer minimal risk.

• • Pregnancy Loss (Miscarriage): Large meta-analyses indicate that after accounting for confounding factors including maternal depression severity, SSRI use in pregnancy is not causally linked to an increased risk of miscarriage.
  • Congenital Malformations: Large population-based studies carried out in the United States and five Nordic countries have found no substantial increase in the overall prevalence of congenital malformations among infants with prenatal exposure to SSRIs in utero.
  • Adverse Pregnancy Outcomes: Some studies have found a modest association between SSRI use and adverse outcomes like preterm birth, low birth weight, and lower Apgar scores. However, these outcomes are also more common in women with untreated depression, making it difficult to separate the effects of medication from underlying illness.
  • Persistent Pulmonary Hypertension of the Newborn (PPHN): SSRI exposure, especially in late pregnancy, has been linked to a slightly higher risk of PPHN; however, the absolute risk is small (about 0.3%, or 3 per 1000 births).
  • Neurodevelopmental Issues: Large-scale studies have found no significant increase in the overall risk of neurodevelopmental disorders in children exposed to SSRIs in utero compared to unexposed children. Some imaging studies report subtle, transient differences in brain structure, but no clear evidence links these changes to functional impairment.
  • Risk of Autism Spectrum Disorders: While early research suggested a potential association between prenatal SSRI exposure and autism spectrum disorder (ASD), more recent, well-controlled studies emphasize that the observed risk is likely due to underlying maternal illness rather than direct medication effect.  More succinctly, there is no robust evidence for a causal link between prenatal SSRI exposure and risk for autism.
  • Poor Neonatal Adaptation: Multiple studies have demonstrated an association between prenatal SSRI exposure and poor neonatal adaptation.  While about 25% to 30% of exposed children may present with poor neonatal adaptation, these symptoms are transient and there is no evidence of long-term effects.  

Collaborative Decision-Making

When considering the use of medications during pregnancy, women are often faced with complex and deeply personal decisions.  This process is guided by a careful risk-benefit analysis, where women, together with their healthcare providers, weigh the potential benefits of treatment against possible risks associated with a particular medication. This decision-making process is informed by the best available scientific evidence, illness and treatment history, and the values and preferences of each woman. Recognizing that untreated psychiatric illness in the mother also carries significant risks for both maternal and infant well-being, we advocate for open dialogue, shared decision-making, and individualized care plans that support the health of both mother and child.

Primum non Nocere – first, do no harm —is a guiding principle for all who care for patients. Unfortunately, the recent FDA panel did not provide a balanced discussion of antidepressant use during pregnancy, overlooking both the complexity of these decisions and the wealth of data gathered over the past 25 years. This one-sided conversation has created unnecessary confusion for patients and healthcare providers and, most importantly, put patients—who must ultimately make these decisions—at risk. The panel’s discussion undermines the agency’s mission to protect and promote public health. Our patients deserve better.