FDA panel debates label change on SSRI use during pregnancy

A US Food and Drug Administration (FDA) panel convened on Monday to explore the impact of selective serotonin reuptake inhibitors (SSRIs) on fetal development, with some panel members proposing that the labeling for SSRIs be changed to include a warning about adverse maternal and fetal risks during pregnancy.

At times, members of the FDA expert roundtable on SSRIs and pregnancy disagreed on the effectiveness of SSRIs in treating anxiety and depression, whether they should be used in pregnancy, and if mental health disorders should be treated with medication during pregnancy in the same way a physical problem like hypertension or diabetes would be treated.

FDA Commissioner Marty Makary told those in attendance that as many as one in four middle-aged women are taking antidepressants, and up to 5% of women in pregnancy are on an antidepressant.

While antidepressants can be an effective treatment for depression, “we have to stop and look at the bigger picture,” Makary said.

“We are losing the broader battle of addressing mental health in the United States,” he said. “In some respects, we’re going backwards.”

Makary claimed there has been a nationwide increase in depression as antidepressant use has increased, an increase in diabetes as insulin use has increased, and an increase in pain when pain medication use increased during the opioid epidemic.

“I’m not suggesting that these medications—or any medications—are causative of mass explosions of these disease from an epidemic standpoint,” he said, “but we have to start talking about root causes.”

Healthy relationships, community, natural light exposure, “other modalities and co-factors,” and novel therapies also need to be explored, he noted.

Makary said the session was being convened because SSRIs may be unique due to serotonin interacting with maternal physiology and fetal organ development.

“Serotonin may play a crucial role in the development of organs of a baby in utero,” including the heart, brain, and gut, Makary said. He also noted that some studies have linked SSRIs to cases of postpartum hemorrhage, pulmonary hypertension, cardiac birth defects, and “cognitive downstream effects in the baby.”

Another issue stems from women on SSRIs not knowing they are pregnant and needing to wean off the medications during early pregnancy, Makary said.

Informed decision-making

Anick Bérard, of the University of Montreal and CHU Sainte-Justine, said depression and anxiety is very common during pregnancy, and needs to be treated “the same way we treat hypertension, diabetes, nausea, vomiting, and even migraine.”

About 6% of pregnant women in the US and Canada take antidepressants, and most of them are SSRIs, Bérard noted. The incidence of anxiety and depression doubled at the beginning of the COVID-19 pandemic and has since decreased, “but is still widely prevalent,” she said.

The use of SSRIs in pregnancy has been studied for over 30 years, Bérard said. Among antidepressants, paroxetine and fluoxetine have been linked with an increased risk of spontaneous abortion, congenital malformations, prematurity, low birth weight, cardiac defects, autism, and attention-deficit/hyperactivity disorder.

Bérard acknowledged the situation is complex. Many women have mild or moderate symptoms of depression, there is no randomized controlled trial looking at the efficacy of SSRIs in pregnancy, and untreated depression and anxiety can increase the risk for postpartum depression.

“The importance of informed decision-making in pregnant women is essential,” she said. “Pregnant women will be the ones making the decision, and they will be acknowledging the risks and the benefits for themselves if it is well explained to them.”

SSRI exposure in utero

Jay Gingrich, director of the institute for developmental sciences at Columbia University Irving Medical Center, discussed recent research from his group that found higher anxiety and depression symptoms in adolescents who were exposed to SSRIs in utero.

“I like to think it’s reasonable to say that while SSRI treatment during pregnancy may improve maternal well-being, we haven’t yet found any evidence that it improves the outcomes of the offspring,” Gingrich said.

“There may be evidence that it actually worsens the outcome, which is not something we would have expected,” he said.

Nonpharmacological therapies such as psychotherapy and transcranial magnetic stimulation “can be extremely effective for mild-to-moderate depression and anxiety,” Gingrich said.

Untreated anxiety, depression

Kay Roussos-Ross, director of the perinatal mood disorders program at the University of Florida College of Medicine, said that unrecognized, untreated, and undertreated anxiety and depression can have a significant impact on maternal and fetal health as well as the health of the mother during pregnancy. These can include preterm delivery, preclampsia, small for gestational age infants, and increased risk for substance use and suicide, among others.

“One of the leading causes of maternal death in the United States is mental health, including suicide and overdose deaths,” she said.

Psychotherapy and SSRIs are “tools that we have in our armamentarium to make a positive impact in the lives of mothers and infants,” she explained.

“Just like we would not withhold medications for preeclampsia, or medications for diabetes in pregnancy, or blood thinners in pregnancy when women have blood clots, we should not neglect treating mental health concerns,” Roussos-Ross said.

FDA labeling

Several panel members proposed changing the labeling on SSRIs to describe maternal and fetal risks associated with use during pregnancy.

Adam Urato, chief of maternal-fetal medicine at MetroWest Medical Center in Framingham, Mass., said he believes pregnant women “aren’t being properly informed on this issue, particularly with SSRI antidepressants.”

“The public needs better information, and the FDA must strengthen the warnings,” he said.

Urato said he thinks SSRIs should have a boxed warning describing maternal, fetal, and pregnancy complications.

Josef Witt-Doerring, a psychiatrist at Taperclinic, said SSRI labels should be updated “to reflect what the science is showing.”

“[T]he first part is getting the correct information in the label. The second problem is, how do we get it in a format that’s readily available and easily digestible so people can hear it,” he said.

Roussos-Ross said there is “robust data” on SSRI exposure for hundreds of thousands of patients in different countries.

“The panel has raised concerns related to SSRI use in pregnancy, but when we review the literature and account for the confounding variables, comparing patients with depression who are untreated versus patients who are with depression and medications, we actually see the risks are very similar between the two groups,” she said.

More research needed

Bérard said there are efforts from the Tri-Council in Canada and the Centers for Disease Control (CDC) in the US to safely include pregnant women in randomized controlled trials, but acknowledged “we might never have them.”

If pregnant women were included in a randomized controlled trial, she said a study evaluating women with mild-to-moderate depression receiving SSRIs and women receiving psychotherapy or an exercise program “would be appropriate to do.”

“Doing randomized controlled trials on pregnant women, I think, is something we should really look at,” Roussos-Ross said. “The physiology in women is different, the metabolism of drugs is different.”

“Women are able to choose and should have the autonomy to choose if they would like to participate in research to further the field and to help other women as well, and to have the information that’s needed regarding the safety of meds,” she added.

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FDA panel debates label change on SSRI use during pregnancy

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