Conceiving complexity: Biological mechanisms underpinning the lasting effect of pregnancy on multiple sclerosis outcomes

Multiple sclerosis (MS) is an autoimmune, demyelinating disease with the highest incidence in women of childbearing age. The effect of pregnancy on disease activity and progression is a primary concern for women with MS and their clinical teams. It is well established that inflammatory disease activity is naturally suppressed during pregnancy, followed by an increase postpartum. However, the long-term effect of pregnancy on disease progression is less understood. Having had a pregnancy before MS onset has been associated with an older age at first demyelinating event, an average delay of 3.4 years. After MS onset, there is conflicting evidence about the impact of pregnancy on long-term outcomes. The study with the longest follow-up to date showed that pregnancy was associated with a 0.36-point lower disability score after 10-years of disease in 1830 women. Understanding the biological mechanism by which pregnancy induces long-term beneficial effects on MS outcomes could provide mechanistic insights into the elusive determinants of secondary progression. Here, we review potential biological processes underlying this effect, including evidence that acute sex hormone exposure induces lasting changes to neurobiological and DNA methylation patterns, and how sustained methylation changes in immune cells can alter immune composition and function long-term.