SAN DIEGO – The risk of autism spectrum disorders is more than doubled among children born to mothers with systemic lupus erythematosus, according to the first-ever controlled study to address the question.
That being said, women with SLE can be reassured that despite this elevated relative risk, the absolute risk that their child will be diagnosed with an autism spectrum disorder (ASD) is low – less than 1 in 50 – Dr. Evelyne Vinet said at the annual meeting of the American College of Rheumatology.
The increased risk of ASD in children born to women with SLE documented in this large study was not mediated by in utero exposure to medications for SLE, including antimalarials, immunosuppressive agents, corticosteroids, and antidepressants. Use of those drugs in pregnancy wasn’t associated with any increased risk. In light of this, further research is warranted into a highly promising alternative hypothesis: that in utero exposure to SLE-related autoantibodies, such as anti-DNA and antiphospholipid antibodies, may play a causative role, said Dr. Vinet, a rheumatologist at McGill University, Montreal.
Dr. Evelyne Vinet
Children born to mothers with SLE also had an increased likelihood of being diagnosed with attention-deficit/hyperactivity disorder in this study. However, in contrast to the situation with ASD, the increased risk of ADHD appeared to result from exposure to medications in utero – specifically, antidepressants and possibly immunosuppressives – rather than to maternal SLE per se, she added.
Dr. Vinet presented an analysis of the OSLER (Offspring of Systemic Lupus Erythematosus Mothers Registry) database, the world’s largest cohort of children born to mothers with SLE. OSLER includes all women with a diagnosis of SLE hospitalized for childbirth in the province of Quebec since 1989. This study included 509 women who had 719 children after they had been diagnosed with SLE, as well as 5,824 controls matched for age and year of delivery along with their 8,493 children. The mean maternal age was 30.3 years. The children were followed out to a mean age of 9.1 years.
ASD was diagnosed in 1.4% of children born to mothers with SLE, compared with 0.6% of control children. The mean age at diagnosis of ASD was noticeably lower in the offspring of mothers with SLE: 3.8 years, compared with 5.7 years in the control children.
Women with SLE had higher rates of hypertension, asthma, and diabetes than did controls at the time of delivery. They also had higher rates of obstetric complications, including preterm birth, small for gestational age, and gestational diabetes. In a multivariate analysis adjusted for these variables, maternal SLE remained independently associated with a 2.3-fold increased risk of diagnosis of an ASD in offspring.
Complete and reliable records of prescription drug use during pregnancy were available only for the roughly 20% of mothers belonging to the provincial medication public assistance program. Of the 18 cases of ASD diagnosed in the children of 1,925 mothers covered by the program, only one occurred among the 155 offspring of SLE mothers; that child had been exposed to corticosteroids in utero. Of the 17 cases of ASD diagnosed in the control group, 16 had no exposures to the medications under scrutiny, and one involved in utero exposure to an anticonvulsant.
The OSLER database doesn’t include information about maternal autoantibody levels, but Dr. Vinet and her coinvestigators have made the collection of such data a top priority in light of recent studies in animal models of SLE by other investigators. Those studies showed that SLE-related autoantibodies, including n-methyl-d-aspartate receptor antibodies and antiphospholipid antibodies, as well as interleukin-6 and other cytokines, alter fetal brain development and induce behavioral anomalies suggestive of autism, such as withdrawal, in the mouse offspring.
In addition, French investigators recently reported that 3 of 36 children born to mothers with antiphospholipid syndrome developed ASD, although Dr. Vinet noted that this small but intriguing study lacked a control group (Semin. Arthritis Rheum. 2013 Aug. 1 [doi: 10.1016/j.semarthrit.2013.07.001]).
ADHD was diagnosed in 9.9% of the children of mothers with SLE in the OSLER database, compared with 6.1% of controls. It was diagnosed when the children were older: at a mean age of 12.5 years, compared with 7.8 years in the controls. In a multivariate analysis adjusted for in utero drug exposures, the association between ADHD and maternal SLE was no longer significant. However, in utero exposure to antidepressant medication, regardless of whether or not a mother had SLE, was associated with a hefty 3.7-fold increase in ADHD in the offspring. Because of the relatively small number of mothers on antidepressant medication, Dr. Vinet is now collaborating with investigators in other Canadian provinces having more comprehensive maternal medication exposure data to take a closer look at this tentative link between in utero drug exposure and ADHD.