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ACR2013: As well as neonatal lupus and heart block, new research suggests that children born to women with lupus may face higher risks for autism and attention deficit hyperactivity disorder.
As well as neonatal lupus and heart block, new research from Canada suggests that children born to women with systemic lupus erythematosus (SLE) may face a higher risk for autism and attention deficit hyperactivity disorder (ADHD).
The risk for autism spectrum disorders (ASDs) appears to be twice as high for children of women who have SLE than for those of healthy women, possibly because of exposure to autoimmune antibodies, according to Evelyne Vinet MD, assistant professor in the department of rheumatology at McGill University Health Center in Montreal. The risk for AHDH seems to be related to medication exposure,
“Recent studies do suggest an increased risk of learning disabilities in children of SLE mothers, possibly due to exposure to antibodies and cytokines in the womb,” Vinet said in an interview during the 2013 annual meeting of the American College of Rheumatology (ACR) in San Diego.
Previous studies in mice found that females with a lupus-like disorder have N-methyl-D-aspartate receptor (NMDR) antibodies that seem to alter fetal brain development and lead to behavioral problems in their offspring, she noted, as evidenced by prior work by Betty Diamond MD and colleagues at the Feinstein Institute for Medical Research in New York .
“We don’t know whether autism per se may be autoimmune," Vinet explained. "We do know that 10% to 15% of autistic kids have IGg antibodies and mothers also have other autoimmune diseases. IGg only crosses the blood-brain barrier except when there is a lot of inflammation.”
NMDR antibodies target brain receptors in males and cause behavioral disorders in their offspring, she noted, and autism does predominantly affect boys. Investigations are underway to determine whether the blood-brain barrier in SLE fetuses may be more permeable.
Vinet’s own research and that of Diamond's group also indicates an approximate 20% predominance of males born to SLE mothers, largely because most pregnancies lost in lupus are female.
In the current studies, the McGill team conducted analyses of the population-based Offspring of Systemic Lupus Erythematosus mothers Registry (OSLER) -- the first studies to look at ASDs and ADHD in women with lupus.
The OSLER cohort includes all Canadian women with one or more hospitalizations for childbirth after an SLE diagnosis, identified through universal health care databases between 1989 and 2009.
Vinet’s team analyzed ASD and ADHD diagnoses among 719 children born to 509 mothers with lupus and 8,493 children of 5,824 randomly-selected women who did not have SLE (average age >30), all followed for over nine years. Each SLE mother was matched 1:4 with healthy controls, based on age and year of delivery, the child’s sex, birth order, obstetrical complications, and demographics.
Children born to mothers with SLE had more than twice as many ASD diagnoses compared with those born to non-lupus mothers (1.4 % vs. 0.6 %, respectively) and they were diagnosed almost two years earlier (an average 3.8 years vs. 5.7 years), Vinet reported at the ACR meeting.
The risk for ADHD was 9.9% among the offspring of women with SLE compared with 6.1% among controls – a substantial risk, according to a multivariate analysis. In contrast to ASDs, there was an older age for an ADHD diagnosis (mean 12.5 years vs. 7.8 years, respectively).
To look at medication links, Vinet and co-investigators isolated 1,925 children whose mothers had public drug coverage. They found that drug exposure was rare among children with ASD.
Of the 18 ASD cases, only two children -- one born to a mother with lupus and another born to a control subject -- were exposed to medication, a corticosteroid and an anticonvulsant, respectively.
In contrast, the ADHD offspring had been exposed to medications in utero. However, only antidepressants appear to be significantly associated with ADHD risk (HR 3.70, 95% CI 1.38, 9.94), with a lesser risk for cyclophosphamide.
“Though the risk of ASDs was two-fold greater in children of women with lupus, the absolute risk is actually small," says Vinet. “For attention deficit, there seems to be a stronger risk.”
The earlier age at ASD diagnosis may relate to more frequent monitoring of SLE patients for neonatal lupus or lupus flares, so autism-like behaviors may be noticed earlier. ASDs usually appear earlier in life and are often more obvious, and women may also be more anxious about their infants because of their own disease, Vinet adds.
ADHD is typically diagnosed later in children, but reasons for the age difference among children born to women with lupus are unclear, she said, and the researchers plan to investigate futher. The McGill team could not assess lupus-related autoantibodies; Vinet hopes the finding will spur others to address the question.
“Although our findings are preliminary, they do provide some evidence-based answers to help women and their doctors,” Vinet concluded. “We also hope our studies will help clinicians advise women with lupus about their medications if they thinking of having children.”