Increase in multiple sclerosis activity after assisted reproduction technology

Ann Neurol. 2012 Nov;72(5):682-94. doi: 10.1002/ana.23745. Epub 2012 Oct 3.


Objective: Our objective was to evaluate risk of exacerbations in multiple sclerosis (MS) patients undergoing assisted reproduction technology (ART) infertility treatment.

Methods: Sixteen patients with relapsing-remitting MS subjected to 26 ART treatment cycles receiving gonadotropin-releasing hormone (GnRH) agonists and recombinant follicle-stimulating hormone were studied prospectively. The baseline study period encompassed 12 months prior to the first cycle and 9 months after final ART cycle. Neurological examinations, brain magnetic resonance imaging (MRI), and immunology testing were conducted every 3 months. Anti-myelin-oligodendrocyte glycoprotein (MOG) antibody production, interleukin (IL)-4, IL-8, IL-10, IL-12, IL-17, interferon (IFN)-γ, and transforming growth factor (TGF)-β secretion by myelin basic protein- and MOG-peptide-specific T cells, as well as ex vivo isolated peripheral blood mononuclear cells (PBMCs), were studied using enzyme-linked immunospot. vascular endothelial growth factor (VEGF) production by PBMCs was assessed using enzyme-linked immunosorbent assay.

Results: ART was associated with a 7-fold increase in risk of MS exacerbation, and a 9-fold increase in risk of enhanced disease activity on MRI. Worsening was associated with higher number of cells producing IL-8, IL-12, IFN-γ, and TGF-β, as well as increased VEGF production by CD4(+) T cells and CXCL-12 plasma levels, all GnRH-mediated effects. A rise in 17-β estradiol production associated with ART increased anti-MOG antibody titers, as well as B-cell survival factor BAFF (B-cell activating factor) and antiapoptotic molecule Bcl-2 levels from purified CD19(+) B cells. Finally, ART facilitated PBMC transmigration across an in vitro blood-brain barrier model, an effect mediated by IL-8, VEGF, and CXCL-12.

Interpretation: Results indicate a significant increase in MS disease activity in patients receiving ART, a risk that neurologists should be aware of. Reproductive hormones appear to exert an important role in regulating immune responses during the course of autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies / therapeutic use
  • B-Cell Activating Factor / metabolism
  • Brain / pathology
  • Case-Control Studies
  • Cell Movement / drug effects
  • Cytokines / metabolism
  • Disability Evaluation
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Follicle Stimulating Hormone / adverse effects
  • Gonadotropin-Releasing Hormone / agonists
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Infertility / complications
  • Infertility / therapy*
  • Magnetic Resonance Imaging
  • Multiple Sclerosis / chemically induced*
  • Multiple Sclerosis / complications
  • Multiple Sclerosis / drug therapy
  • Multiple Sclerosis / metabolism
  • Myelin Basic Protein / immunology
  • Myelin Basic Protein / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / pharmacology
  • Recurrence
  • Reproductive Techniques, Assisted / adverse effects*
  • Retrospective Studies
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • Time Factors
  • Transfection
  • Vascular Endothelial Growth Factor A / metabolism


  • Antibodies
  • B-Cell Activating Factor
  • Cytokines
  • Immunosuppressive Agents
  • MBP protein, human
  • Myelin Basic Protein
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • TNFSF13B protein, human
  • Vascular Endothelial Growth Factor A
  • Gonadotropin-Releasing Hormone
  • Follicle Stimulating Hormone