A mother’s use of selective serotonin reuptake inhibitors during pregnancy doesn’t appear to raise the risk of autism spectrum disorders in her offspring, according to a report published online Dec. 18 in the New England Journal of Medicine.
In a cohort study of all 626,875 singleton live births that occurred in Denmark between 1996 and 2005, fetal exposure to maternal SSRI use did not significantly increase the risk that the child would be diagnosed as having an autism spectrum disorder during 5-14 years of follow-up, said Dr. Anders Hviid of the department of epidemiology research, Statens Serum Institut, Copenhagen, and his associates.
This large nationwide study had the statistical power to rule out all but a small increase in relative risk, they noted.
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Pregnant women who use SSRIs did not significantly increase the risk that the child would be diagnosed as having an autism spectrum disorder, experts said.
Dr. Hviid and his colleagues undertook this study because a recent California case-control study reported that the risk of autism spectrum disorder increased by a factor of two among offspring of women who used antidepressants, particularly SSRIs, during pregnancy, and that this risk was increased by a factor of more than three if the woman used an SSRI during the first trimester (Arch. Gen. Psychiatry 2011;68:1104-12). Evidence from other studies also seemed to bolster this association.
In addition, a causal association is biologically plausible, because people with autism spectrum disorders are known to have increased levels of circulating serotonin, and because serotonin appears to play an important role in early brain development. "Manipulation of serotonin homeostasis can alter neuroanatomical and neurophysiological development and produce enduring behavioral changes in animal models," Dr. Hviid and his associates said.
The investigators analyzed data from the Danish national birth registry, national prescription registry, and national registry of psychiatric diagnoses to assess the 626,875 children, including those who were born to 6,068 mothers who used SSRIs during pregnancy. A total of 3,892 cases of autism spectrum disorder were diagnosed.
In an initial analysis, autism was strongly associated with maternal psychiatric diagnoses and with the use of drugs other than SSRIs during pregnancy. This suggested possible confounding by indication, meaning that any association found between SSRI use and autism might be due to the mother’s underlying psychiatric disorder rather than to the medication she took for it.
During 42,400 person-years of follow-up, there were 52 cases of autism spectrum disorder among the offspring of women who took SSRIs during pregnancy. "In unadjusted analyses, we did find a significantly increased risk of autism spectrum disorder in association with the use of SSRIs during pregnancy.
"In fully adjusted analyses, however, the risk was no longer significant. This was primarily due to adjustment for a number of psychiatric diagnoses [in the mother], which is consistent with the presence of confounding by indication in the unadjusted analysis," the investigators said (N. Engl. J. Med. 2013;369:2406-15 [doi:10.1056/NEJMoa1301449]).
In a further analysis, the researchers found that SSRI use before but not during pregnancy was associated with an increased risk of subsequent autism spectrum disorders in the offspring, similarly suggesting that any association arose from the mother’s underlying psychiatric disorder rather than from the medication.
A sensitivity analysis restricted to the 574,020 pregnancies for which complete information was available yielded the same results as the main analysis: SSRI use during pregnancy did not raise the risk of autism spectrum disorders in the offspring.
One of the strengths of this study was that it was large enough to include 52 cases of autism spectrum disorder, which is more than three times the number of cases assessed in previous studies of this issue.
However, this study was limited in that the prevalence of SSRI use during pregnancy was only 0.97% in this cohort, whereas the prevalence in the United States is estimated to be 5.6%. Similarly, the prevalence of autism spectrum disorders in this cohort was only 0.62%, while it is estimated to be 1.14% in the United States "Thus, our findings may not be generalizable to other countries," Dr. Hviid and his associates said.
This study was funded by the Danish Health and Medicines Authority. No financial conflicts of interest were reported.