Fewer Pregnancies, Premature Menopause Linked to Early Onset of Progressive MS

Women who have never given birth are more likely to develop early onset of progressive multiple sclerosis, according to a new study, which also found that a woman’s number of pregnancies showed a positive effect in delaying the disease.

In addition, entering menopause earlier, before the age of 46, is linked with earlier onset of progressive MS, the researchers found.

The study, “Reproductive history and progressive multiple sclerosis risk in women,” was published in the journal Brain Communications.

Being a woman is one of the strongest risk factors for developing multiple sclerosis (MS). Estimates suggest that, after puberty, women are two to three times more likely than men to develop MS.

Furthermore, women are more prone both to develop relapsing-remitting MS (RRMS) at a younger age than men and to have more frequent relapses. Conversely, men with RRMS tend to accumulate more disability and in a faster way than women. Thus, men usually enter the progressive MS phase earlier than women. Of note, RRMS can be followed by a progressive phase of the disease called secondary progressive MS (SPMS).

Yet, after the onset of progressive MS, women accumulate disability faster than their male counterparts, reaching the levels of severity seen in men.

Overall, this suggests that both hormonal and environmental factors play a role in the gender differences seen in MS.

The transition from RRMS to SPMS typically occurs in the fifth decade of life, which is when menopause occurs for most women.

Since delaying the onset of SPMS will delay severe disability, researchers at the Mayo Clinic now decided to investigate whether a woman’s reproductive history influences her MS disease course.

The team conducted a case-control study involving 137 post-menopausal women with MS, followed at the Mayo Clinic. A control group of 396 postmenopausal women without MS had participated in the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2). Of note, an oophorectomy is a surgical procedure to remove one or both of the ovaries.

Data showed that the number of pregnancies, including those that went full-term, was significantly lower in women with MS compared with control women.

Moreover, even a lower number of viable pregnancies showed a positive effect in delaying MS, when compared with none at all. Researchers found that the onset of RRMS was delayed in those women (mean age of 33 years) who had one or more viable pregnancies, compared with those (mean age of 27.5 years) who had never had a live birth (nulliparous).

Notably, while nulliparous is the medical term for a woman who has never given birth, it also applies to women who have given birth to a stillborn baby, or a baby who was otherwise not able to survive outside the womb.

Women with four or more viable pregnancies had a mean age of 35.8 years at onset of RRMS, compared with 32.4 years in women with one to three pregnancies.

Age for a woman’s first menstruation (menarche) was not associated with the onset of progressive MS or RRMS, neither to the number or type of pregnancies.

Regarding SPMS, women who had never given birth were younger at the onset of disease (mean age 41.9 years) compared with women with at least one full-term pregnancy, whose disease onset occurred at a mean age of 47.1 years.

A significant dose-dependent relation between the number of viable pregnancies and age in progressive MS was observed by the researchers.

“There seems to be an association between the number of pregnancies and the onset of progressive MS,” Burcu Zeydan, MD, researcher at the Mayo Clinic and the study’s lead author, said in a press release. “The higher the number of pregnancies, the later the progressive MS onset.”

The researchers said their study had practical and important “potential implications on how women with MS can be counseled.”

“For example, a pregnancy decision can potentially be reinforced in women with MS who may be doing well, but had previously chosen to avoid pregnancy due to concerns about a negative impact of pregnancies in the future,” the researchers wrote.

The team also investigated the link between menopause and MS. The age at which women reached menopause was similar between women with MS (median age of 49 years) and controls (median age of 50 years).

However, non-natural menopause was more frequent among women with MS (40.7%) than control women (30.1%).

Among women with progressive MS — both primary progressive MS and SPMS — 36% had menopause before its onset. In this group, age at menopause was significantly associated with the age at progressive MS onset.

In the SPMS group, women who entered menopause at the age of 45 or younger progressed faster from onset of relapses to progressive disease when compared with women who started menopause after 45 years old.

Among women with severe disability, as shown by an expanded disability status scale (EDSS) score of six or higher, 52% were already in menopause. Among these patients, age at menopause showed a significant association with the age at which they reached severe disability scores in EDSS. The association remained for both natural and non-natural menopause groups.

Taken together, the results showed that “premature/early menopause or nulliparity were associated with earlier onset of progressive multiple sclerosis with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability,” the researchers wrote.

“Although causality remains uncertain, our results suggest a beneficial impact of estrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counseling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy,” they added.

The researchers also emphasized that “any decision about premature non-natural menopause should be discussed with the patient as a potentially harmful intervention,” as well as the possible use of menopausal hormone therapies to delay the onset of progressive MS in the setting of premature or early menopause.