UPDATED December 15, 2015 // Antidepressant use during the second or third trimester of pregnancy, particularly use of selective serotonin reuptake inhibitors (SSRIs), nearly doubles the risk of the child's developing autism spectrum disorder (ASD) by age 7 years, new research shows.
The study also showed that maternal history of depression is associated with an increased risk for ASD, albeit the risk is smaller.
"In our multivariate analysis, we found that treatment of depression with antidepressants in the second and/or third trimester of pregnancy was independently associated with an 87% increase risk of having a child with autistic spectrum disorder," Anick Bérard, PhD, of the University of Montreal's Faculty of Pharmacy, in Montreal, Canada, told Medscape Medical News.
"We further found that a history of maternal depression was an independent risk factor for having a child with ASD, increasing the risk by 20%."
The study was published online December 14 in JAMA Pediatrics.
Crossing the Placenta
For the study, the investigators evaluated data on 145,456 pregnancies from the Quebec Pregnancy Cohort. They analyzed antidepressant exposure during pregnancy and outcomes in the children from the time of conception to age 10 years.
Diagnoses of ASD included childhood autism, atypical autism, Asperger's syndrome, or a pervasive developmental disorder.
For the study, a child having ASD was defined as the child's receiving at least one diagnosis of ASD between the time of birth and last date of follow-up; 1054 children (0.7%) were diagnosed with ASD at the mean age of follow-up, which was 6.24 years. Boys with ASD outnumbered girls by a ratio of about 4:1, which the authors note is consistent with rates reported in the general population.
After adjusting for various potential confounders, including sociodemographic and psychiatric covariables, such as maternal age and poverty, the use of any antidepressants in the second and/or third trimester was associated with a significantly increased risk for ASD (adjusted hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.15 - 3.04).
Use of SSRIs in the second and/or third trimester was associated with a higher risk (HR, 2.17; 95% CI, 1.20 - 3.93). The risk was significant after adjusting for maternal history of depression (HR, 2.17; 95% CI, 1.20 - 3.93).
The combined use of drugs from two or more antidepressant drug classes was associated with the highest risk of having a child with ASD (HR, 4.39; 95% CI,1.44 - 13.32).
No increased risk for ASD was observed with the use of antidepressants during the first trimester.
In discussing possible mechanisms, Dr Bérard noted that SSRIs are known to cross the placenta and are found in amniotic fluid.
"The increased risk associated with SSRIs makes sense, because we know serotonin is essential for brain cell development, and we know that SSRIs cross the placental barrier," she explained.
"Serotonin inhibition during brain cell development is therefore likely to have an impact on cognitive function in general, and in the case of this study, it appears to affect the risk for ASD."
Although previous studies have also suggested an increased risk for ASD in association with maternal use of antidepressants, this study is the first to stratify the risk according to drug class and trimester exposure, Dr Bérard noted.
It was estimated that approximately 6% to 10% of pregnant women in the Quebec cohort were treated with antidepressants. Dr Bérard noted that higher rates have been reported in the United States.
"The US data show rates can be as high as 15% or more, depending on the practice," she said.
Dr Bérard noted that research has shown that 80% to 85% of depressed pregnant women have mild to moderate depression ― similar to rates in the general population. In those cases, more treatment options are available, including nonpharmacologic ones.
"I believe [US physicians] may overestimate the benefit and minimize the risks of use of antidepressants in pregnancy, and women may not even be aware of the risks because the information isn't disseminated to them.
"We would never advocate not treating depression, but particularly in pregnancy when the depression is mild, it's important to consider that antidepressants are just one treatment option," Dr Bérard said.
Balancing Risks and Benefits
In an accompanying editorial, autism expert Bryan H. King, MD, agreed but added that the data on the many potential causes of autism cloud the issue of the risk associated with antidepressant use.
"It does seem a given that nonpharmacologic approaches will be first line in pregnancy, for any condition," he told Medscape Medical News.
"[However,] the issue of weighing risks and benefits is very complicated, and this study only looks at autism," said Dr King, who is professor and vice chair of psychiatry and behavioral sciences and director of Seattle Children's Autism Center, Seattle Children's Hospital, in Washington.
Dr King noted that the increased risk observed in the study "cannot be uncoupled from a possible genetic risk for autism that might be shared with that for depression, [and] this study does not look at risks to the mother and child from untreated depression or anxiety," he said.
In his editorial, Dr King noted that several studies have shown a potential overlap in risk factors for depression and ASD, including a recent study showing genetic overlap in some patients with both depression and ASD.
In addition, he cited another recent study involving a large cohort in Finland in which exposure to SSRIs during pregnancy was found to be associated with various benefits. For children born of mothers who had been exposed to SSRIs, there was less risk of being born preterm and there were fewer cases of cesarean delivery compared with children whose mothers had not been exposed to psychotropic medications but who had been diagnosed with psychiatric illness. However, exposure to antidepressants in utero was associated with lower Apgar scores and an increased need if monitoring.
As data mount on the risks of the treatment as well as nontreatment of depression with antidepressants in pregnancy, "it makes no more sense to suggest that antidepressants should always be avoided than to say that they should never be stopped," Dr King wrote.
Importantly, clinicians should work to keep patients aware of the risks and benefits.
"I think it is worth being reminded that clinicians and their patients know how severe the depression that they are treating is or was, and they also know the degree to which medication has been helpful," Dr King said.
"This knowledge should frame the discussion of risks of changing what presumably is an effective treatment, and of potential illness exacerbation for both mother and fetus, against risks of possible adverse developmental outcomes that might accrue from medication exposure."
Nada Stotland, MD, professor of psychiatry with Rush University, in Chicago, added her concern that the study may unnecessarily raise alarm among patients and parents alike.
"The study doesn't prove any causation, and what concerns me is that having a child with autism is a very hard situation to be in, and parents always seem to look to something they did or something to blame that may have caused it, such as vaccinations," she told Medscape Medical News.
"So these are two very vulnerable populations ― parents of children with autism, and women with depression in pregnancy, and we have to be extremely careful about clarifying what the study really shows."
Dr Stotland also noted what she said were methodologic weaknesses in the study, such as details of patient treatment and severity of depression.
"The findings go back to whether this changes anything, and the answer is no."
The study received funding from the Canadian Institutes of Health Research and the Quebec Training Network in Perinatal Research. Dr Bérard’s has served as a consultant for plaintiffs in litigation involving antidepressants and birth defects. Dr King has disclosed no relevant financial relationships.
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Cite this: Antidepressants in Pregnancy Linked to Increased Autism Risk - Medscape - Dec 14, 2015.