Maternal Rheumatoid Arthritis Linked to Epilepsy in Offspring

Pauline Anderson

November 22, 2016

Children whose mothers — but not fathers — have rheumatoid arthritis (RA) are at increased risk for epilepsy, a new study has shown.

The risk is particularly high in children whose mothers had RA at the time of pregnancy compared with those who had preclinical RA at that time.

"Our findings suggest that factors related to autoimmunity could be involved in the development of some types of epilepsy," said lead author Ane L. Rom, PhD, Research Unit, Women's and Children's Health, The Juliane Marie Centre, Copenhagen University Hospital, Denmark.

"If the epilepsy has an autoimmune etiology, specific treatment against the cause — for example, antibodies — might be used for these patients instead of conventional antiepileptic drugs. However, much more research is warranted in this area."

The study was published online November 16 in Neurology.

Dr Rom and colleagues were interested in determining the epilepsy risk in offspring of parents with RA after recent research showed that having an autoimmune disease was associated with a 5-fold increased risk for epilepsy and that having RA was associated with a 3-fold increased risk for epilepsy.

Also, it's well known that parental autoimmune diseases increase the risk for autoimmune diseases in the offspring, said Dr Rom.

"The study is important since no other has investigated whether autoimmune diseases in the parent, in this case RA, influences the risk of epilepsy in the offspring later in life," said Dr Rom. "It's also important to understand how epilepsy develops."

National Registries

Researchers followed a nationwide cohort of more than 1.9 million children for a mean of 16 years. Using linked Danish national registries, they collected information on parental RA, first diagnosis of epilepsy among offspring, and various potentially important covariates.

During follow-up, almost 31,500 children were diagnosed with epilepsy and more than 19,000 children were exposed to parental RA.

The study found that compared with offspring of mothers without RA, young children (aged 29 days to 4 years) who were exposed to maternal RA had an increased risk for epilepsy (hazard ratio [HR] 1.34; 95% confidence interval [CI], 1.13 - 1.60). In contrast, offspring exposed to paternal RA were not at increased risk for early childhood epilepsy.

Older children (aged 5 to 15 years) who were exposed to maternal RA also had an increased risk for epilepsy (HR, 1.27; 95% CI, 1.07 - 1.51), while those exposed to paternal RA were not. Neither maternal nor paternal RA was associated with adolescent or adulthood epilepsy.

Among younger children exposed to maternal clinical RA in fetal life, the risk for epilepsy was higher (HR, 1.90; 95% CI, 1.26 - 2.86) than for younger children exposed to maternal preclinical RA (HR, 1.26; 95% CI, 1.03 - 1.52). Risks were also higher for maternal clinical RA than maternal preclinical RA exposure for late childhood epilepsy.

According to Dr Rom, this points to an effect of the disease rather than of specific RA therapies because women with preclinical RA are typically not yet being treated for RA. "The specific influence of RA treatments needs, however, further investigation."

Adjustments for many potential confounders, including parity, paternal age, birth weight, gestational age at birth, Apgar score, maternal epilepsy, maternal smoking, and maternal education, did not affect the associations.

Although the precise mechanism behind the association between maternal RA and childhood epilepsy is unknown, researchers believe it may involve the production of antibodies and the increased synthesis and release of specific cytokines and chemokines with increased inflammatory microglial response in the brain.

Autoimmune factors may affect the development of the fetus, resulting in an increased risk for epilepsy in children of mothers with RA, said Dr Rom. "This would explain why an increased risk of epilepsy was not found in offspring of fathers with RA."

It's also possible that genetics plays a role in the association.

Maternal RA isn't the only autoimmune disorder that may increase risks for brain disorders in offspring. For example, said Dr Rom, some studies have suggested an association between maternal diabetes and autism spectrum disorders in their children.

Although the authors didn't explore specific epilepsy syndromes, they used age at diagnosis of epilepsy as a proxy for the different types. Since the epilepsy risk following maternal RA exposure was different among younger and older children, the risk for specific epilepsy subtypes may be differently influenced by maternal RA.

Dr Rom stressed that even though the children in the study were up to 90% more likely to develop epilepsy if their mother had RA at the time of birth, "this in absolute numbers translates to 3% of the children, so 97% of the children born to mothers with RA will not develop epilepsy."

Growing Literature

According to an accompanying editorial, the new study "adds to the growing literature that maternal autoimmune diseases influence the development of the fetal brain and increase the risk of childhood neurologic disease."

Although the study "provides insight" into the associations between maternal RA and childhood epilepsy, it does not help explain the precise pathophysiologic mechanisms, Russell C. Dale, MRCP, PhD, Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Australia, and J. Nicholas Brenton, MD, the University of Virginia, Charlottesville, write.

Assuming the mechanism is immunologic, there are several possible explanations for the increased risk for neurologic disease in the offspring of mothers with autoimmune disease, they note. "In general, the fetus is more vulnerable to immune-mediated brain disease as the fetal blood–brain barrier, though functionally effective, is more vulnerable to environmental factors."

Regardless of the mechanism, many unanswered questions remain, note Dr Dale and Dr Brenton.

"Does an inflammatory insult on the fetal brain result in permanent alteration of neuronal development? Or could this fetal exposure result in a persistent immune activation of the CNS that is potentially exacerbated after birth by environmental triggers?"

These "biological uncertainties" raise the question as to whether this fetal immune priming could be modified using immune suppression or modulation ex utero, they say.

The study was supported by the US National Institutes of Health, Danish Council for Independent Research, and Augustinus Foundation. Dr Rom has disclosed no relevant financial relationships. Dr Dale has received speaker honoraria from Biogen Idec and Bristol-Myers Squibb, is an editorial advisory board member for MSARD, is an editorial board member for Neurology: Neuroimmunology & Neuroinflammation and European Journal of Paediatric Neurology, received publishing royalties from Biogen and Bristol-Myers Squibb, and received research support from the National Health and Medical Research Council, Tourette Syndrome Association, and Multiple Sclerosis Research Australia. Dr Brenton has disclosed no relevant financial relationships.

Neurology. Published online November 16, 2016. Abstract, Editorial

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