Infertility Treatments Increase Multiple Sclerosis Activity

Fran Lowry

October 10, 2012

October 10, 2012 — Results of a small prospective study indicate that there is a significant increase in multiple sclerosis (MS) disease activity after assisted reproduction technology (ART), suggesting that female patients with MS of childbearing age should be made aware of the risk.

The study, led by Jorge Correale, MD, from the Raul Carrea Institute for Neurological Research, Buenos Aires, Argentina, was published online October 3 in the Annals of Neurology .

"There have been previous retrospective series from France and Germany showing that ART increases the number of exacerbations in MS patients," Dr. Correale told Medscape Medical News. "The differences with our investigation are that it is a prospective study, we have MRI [magnetic resonance imaging] data, and we have a homogenous cohort that only used an GnRH [gonadotropin-releasing hormone] agonist, not an antagonist. Furthermore, we investigated the immunological mechanisms involved."

Dr. Jorge Correale

In the study, Dr. Correale and his group analyzed clinical, radiologic, and immune response data in 16 patients with relapsing-remitting MS who underwent 26 cycles of ART.

The participants received 100 to 450 IU of GnRH agonists daily and 150 to 225 IU of recombinant follicle-stimulating hormone daily for 7 to 10 days, as well as vaginal progesterone as luteal phase support.

No patients were receiving immunomodulatory support at baseline.

The infertility treatments stopped once a pregnancy occurred or if financial concerns necessitated that they be stopped.

The 26 ART attempts resulted in 7 pregnancies (27%), 3 embryonic losses, and 1 twin and 3 singleton deliveries. Two of 5 live-born infants were premature.

Seventy-five percent of the patients experienced disease exacerbation after infertility treatment. MS relapses were reported in 58% of the cycles during the 3-month period after ART treatment.

Additionally, ART was associated with a 7-fold increase in risk for an MS exacerbation, along with a 9-fold increase of greater MS disease activity as seen on MRI.

None of the 16 patients had sustained a relapse or had shown MRI activity in the 9 months before starting ART, Dr. Correale noted.

Of disease worsenings, 73% were new, and 27% corresponded to worsening of preexisting symptoms.

The immunologic mechanisms involved in these exacerbations included an increase in proinflammatory cytokines interleukin-8, interleukin-12, interferon-gamma, and transforming growth factor-beta by CD4+ T cells (a GnRH-mediated effect); increased production of antibodies against myelin proteins; and the transit of deleterious cells from the peripheral blood to the central nervous system.

"All these effects are mediated by different hormones, suggesting the possibility that hormones regulate the immune system," Dr. Correale noted.

In addition, he and his team used an in vitro model of the blood-brain barrier to demonstrate that ART facilitated the penetration of deleterious peripheral blood cells into the central nervous system, an effect that was modulated by the induction of the molecules interleukin-8, vascular endothelial growth factor, and chemokind (C-X-C motif) ligand 12.

"Patients under ART should be advised about the possibility of increasing activity of the disease," Dr. Correale said.

Long-Term Adverse Effects?

Barbara S. Giesser, MD, vice chair in the Department of Neurology at David Geffen School of Medicine, University of California, Los Angeles, and a spokesperson for the American Association of Neurology, agreed that such counseling should be an important part of the dialogue between physician and patient.

"The primary people who get MS are young women in their reproductive years, so if they choose to undergo assisted reproductive technology, they need to be aware that the literature suggests that there is an increased risk for relapse and an increased chance for new inflammatory lesions on their MRI," Dr. Giesser said.

What is not known from this study, because it is too short, is whether there will be long-term adverse sequelae from the therapy, Dr. Giesser said.

"There are no data right now to suggest that such a relapse will be potentially dangerous down the road, that it would increase long-term disability," she noted. "But practitioners need to know about this, because most of the people who get MS are young, premenopausal women and they have questions about reproduction and pregnancy, menopause and the menstrual cycle. Now, thanks to this very nicely done study, we can answer some questions about ART."

The study was sponsored by the Institute for Neurological Research Dr. Raul Carrera, Foundation against Neurological Disease in Childhood, Buenos Aires, Argentina. Dr. Correale has disclosed the following financial relationships: board membership, consultancy, and speaking fees for Merck Serono Argentina, Merck Serono LATAM, Novartis Argentina, Biogen Idec Argentina, Biogen-Idec LATAM; speaking fees for TEVAIVAX Argentina; paid educational presentations for Merck Serono Argentina, Merck Serono LATAM, Novartis Argentina, Biogen Idec Argentina, Biogen Idec LATAM, TEVAIVAX Argentina; and travel expenses for Merck Serono Argentina. Dr. Giesser have disclosed no relevant financial relationships.

Ann Neurol. Published online October 3, 2012. Abstract