WEST PALM BEACH, Florida Women who have no history of a full-term pregnancy show an earlier onset of progressive multiple sclerosis (MS) compared with those who have had pregnancies, and the apparent onset-delaying effect appears to increase with the number of pregnancies, new research suggests.

The results add to speculation on the effects of pregnancy in MS.

"Our results suggest that a higher number of full-term pregnancies than average is associated with later onset of progressive MS, while having no full-term pregnancies is associated with significantly younger age at progressive MS onset," first author Burcu Zeydan, MD, an assistant professor of radiology in the Center for MS and Autoimmune Neurology at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News.

The study was presented here at the 5th annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2020.

The findings, which also link early menopause with faster disease progression, offer important insights into the broader effects of pregnancy on MS, commented ACTRIMS president Jeffrey A. Cohen, MD, who is the director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research, Cleveland Clinic, Ohio.

"We know pregnancy affects the short term disease activity relapses tend to quiet down during pregnancy but what has been somewhat conflicting is whether it affects the long-term prognosis or is just a temporary effect," he told Medscape Medical News.

"So that is the main interest in this study, and it does indicate that pregnancy affects the long-term prognosis and provides some insight into the mechanism by which it might do that."

While being female is in fact considered the most important risk factor for MS susceptibility, pregnancy has been suggested to have a protective role in disease progression. However, more research is needed on the nature of the effect and its mechanisms.

For this study, Zeydan and colleagues evaluated data on 202 patients (134 women, 68 men) with MS who were part of a Mayo Clinic survey.

They found that women who had no full-term pregnancies (n = 32), had an earlier onset of progressive MS (mean age 41.4 12.6 years) compared with women giving birth to one or more children (n = 95; 47.1 9.7 years; P = .012).

In addition, the mean age of progressive MS onset increased with a dose-effect trend according to the number of full pregnancies (no children, 41.4 12.6 years; 1-3 children: 46.4 9.2 years; 4 or more children: 52.6 12.9 years; P = .002).

A look at a subgroup of patients with secondary progressive MS also showed an earlier mean age of onset among women who had no full pregnancies(n = 19; 41.5 9.2 years) compared with women who had one or more full pregnancies (n = 57; 47.3 10.6 years; P = .049).

The later disease onset associated with pregnancy was also seen in relapsing-remitting MS: Mean age of onset was earlier women with no pregnancies (27.5 7.0 years) compared with those with one or more children (33.0 9.4 years;P = .021).

The mean duration of time from relapsing-remitting MS to secondary progressive MS was also shorter among women with premature or early menopause (n = 26; 12.9 9.0 years) compared with those who had menopause at a normal age (n = 39; 17.8 10.3 years).

The pattern was similar for women experiencing the onset of secondary progressive MS after menopause, with a shorter progression among those with early menopause (P = .012).

The trends of later onset with more pregnancies was also observed with the mean age of onset of secondary progressive MS (no full pregnancies: onset at 41.5 9.2 years; 1-3 pregnancies: onset 46.2 9.9 years; 4 or more pregnancies: onset 52.6 12.9 years; P = .010).

And likewise, the later mean age of onset of relapsing-remitting MS was seen with additional pregnancies (no full pregnancies: 27.5 7.0 years; 1-3 pregnancies: 32.4 9.3 years; 4 or more pregnancies: 35.8 9.8 years;P = .012).

"The dose effect was clearly a surprise (having no full-term pregnancies vs 1-3 vs 4 or more)," Zeydan said.

"In addition to the significant difference between having no vs 1 or more full-term pregnancies, the clear dose-effect consolidates our results related to the association between the number of pregnancies and age at progressive MS onset."

The study also showed that women with premature or early menopause had a shorter duration of progression from relapsing-remitting MS to secondary progressive MS (n = 26; 12.9 9.0 years) compared with women who experienced menopause at a normal age (n = 39; 17.8 10.3 years).

The patterns in early menopause are consistent with previous observations regarding menopause and MS progression, Cohen said.

"When women go through menopause, estradiol and pregnancy-related factors further decline and we know this coincides temporally with the development of progressive MS in women," he noted.

Compared with men, women with premature or early menopause furthermore had a longer duration from relapsing-remitting MS to secondary progressive MS (P = .008), and women with secondary progressive MS also had also had an earlier age of relapsing-remitting MS onset than men (P = .018).

The mechanisms of pregnancy could include a complex interaction between estrogen and factors such as astrocyte and microglia function, Zeydan explained.

"Estrogen, through various mechanisms of eliminating toxicity of highly activated neurons including preventing pro-inflammatory molecule release, supporting mitochondria function thereby eliminating energy failure, and promoting remyelination helps neuronal plasticity and delays neurodegeneration, which is closely related to the progressive phase of MS," she said.

"One could easily make the probable association, while yet to be proven, that our findings may relate to these mechanisms," Zeydan said.

The logical question of whether hormone replacement or some type of therapy that could mimic the effects of pregnancy could also benefit in delaying MS onset remain to be seen, Zeydan said.

"While we believe that is possible, particularly for delaying the onset of progressive phase, definitive evidence is lacking at this time," Zeydan said. "However, our study ultimately may lead to such a trial."

In the meantime, the findings provide additional insights that may be beneficial in sharing with patients regarding pregnancy, she said.

"As the contemporary problem in MS care is to delay or prevent progressive MS onset, our findings may suggest that how we counsel women with MS who are planning to get pregnant, or contemplating surgically induced menopause, or how we consider hormone therapies during perimenopause, may impact the course of their disease."

Zeydan cautions, however, that "our findings do not confirm causality beyond an association."

"More studies are needed in this important issue in a disease that affects women three times more than men," she stressed.

Zeydan has disclosed no relevant financial relationships. Cohen reports personal compensation for consulting for Adamas, Convelo, MedDay, Mylan, and Population Council; and serving as an editor of Multiple Sclerosis Journal.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2020: Abstract P135. Presented February 27, 2020.

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Pregnancy Linked to Later Onset of Progressive MS - Medscape