Prenatal exposure to selective serotonin reuptake inhibitors, particularly during the first trimester, may "modestly" raise the risk of autism spectrum disorders, according to a preliminary study published online July 4 in Archives of General Psychiatry.
"The fraction of cases of [autism spectrum disorders] that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD," said Lisa A. Croen, Ph.D., of Kaiser Permanente Northern California, Oakland, and her associates.
"Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or the fetus of untreated mental health disorders," they noted.
"We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASD in offspring," the investigators added.
The study was a population-based case-control assessment of mothers’ antidepressant use during pregnancy and the later diagnosis of ASD in their children. The sample was drawn from the Childhood Autism Perinatal Study, and it included 298 children with ASD and 1,507 unaffected controls matched for age, sex, and area of residence within Northern California.
Twenty case mothers (6.7%) and 50 control mothers (3.3%) had at least one prescription for an antidepressant during the year before the birth of the child. Most of these prescriptions – for 5% of the case mothers and 2.3% of the control mothers – were for SSRIs.
After the data were adjusted to account for maternal age, race/ethnicity, and education level and for the child\'s birth weight and sex, "we found an approximately twofold increased risk of ASD associated with treatment with SSRIs ... and an approximately threefold increased risk associated with treatment during the first trimester," Dr. Croen and her colleagues said (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.73]).
Mothers of children later diagnosed as having ASD were twice as likely as other mothers to have had at least one antidepressant prescription during the year preceding the birth. In addition, mothers with a prescription for an antidepressant were more than twice as likely as other mothers to have a child who was later diagnosed as having ASD. No such associations were seen among women prescribed any non-SSRI antidepressants, but the number of women in that group was quite small.
The link between SSRIs and ASD risk remained robust in several further statistical analyses. It remained strong when the analysis was restricted to only term births, as well as when it was restricted to only cases in which only one child in the family was affected with ASD ("simplex" cases).
The correlation also remained strong regardless of the indication for which the mother took the drugs. Moreover, ASD risk did not correlate with a history of mental health disorders. These two findings indicate that the SSRIs themselves, not the underlying indications for taking the medications, were the relevant contributing factor, Dr. Croen and her associates said.
However, they cautioned that "despite the significant association, the number of women in this [study] population exposed to SSRIs was modest, and the proportion of children with ASD in this population that can be statistically attributed to SSRI exposure is quite low: 2.1% for exposure during the year before delivery, and 2.3% for exposure during the first trimester."
There are several biologically plausible explanations for this link between SSRI exposure and ASD. Many studies have implicated serotonin abnormalities and anomalies in serotoninergic pathways in autism. And several animal studies "suggest the possibility that prenatal exposure to SSRIs may operate directly on the developing brain, perhaps selectively in fetuses with abnormalities in serotonin-related genes," they said.
"To our knowledge, our study is the first to directly examine antidepressant use during pregnancy as a potential risk factor for childhood ASD. A substantial strength of our study is our reliance on data documented in medical records and thus recorded at the time of diagnosis or treatment, avoiding potential biases associated with the mothers’ recall after diagnosis of ASD in the children," the investigators wrote.
This study was supported by the Kaiser Permanente Community Benefit Clinician Research Fund, and the Centers for Disease Control and Prevention. No relevant financial disclosures were reported.