Median delay of CIS was more than 3 years

Multiple Sclerosis is often diagnosed in women of childbearing age, which is why pregnancy and MS is an ongoing clinical concern. This report, which was first published Sept. 14, looks at the role that pregnancy or childbirth may have in the onset of the first symptoms of MS. BreakingMED is republishing the report as part of its year-end clinical review series.

Pregnancy or childbirth delayed the onset of clinically isolated syndrome (CIS), an initial episode of symptoms suggesting multiple sclerosis (MS), a retrospective cohort study found.

Women with previous pregnancy or childbirth had a later onset of CIS compared with women who had never been pregnant (HR 0.68, 95% CI 0.62-0.75; P<0.001), with a median delay of 3.3 years (95% CI 2.5-4.1), reported Ai-Lan Nguyen, of the Royal Melbourne Hospital in Australia, and coauthors in JAMA Neurology.

Women who had given birth also had a later CIS onset compared with women who had never given birth (HR 0.68, 95% CI 0.61-0.75; P<0.001), with a median delay of 3.4 years (95% CI 1.6-5.2). Higher gravidity or parity numbers were not associated with a dose-response effect with respect to delay in CIS onset.

These findings add to the conflicting literature about the association of pregnancy with MS risk, noted Jennifer Graves, MD, PhD, MAS, of the University of California San Diego, La Jolla, in an accompanying editorial.

“Excluding the possibility of reverse causation is difficult methodologically, but the ability of pregnancy to suppress relapses is on par with potent disease-modifying therapies,” she wrote.

“Just as pregnancy may prevent subsequent relapses in a woman’s MS course, it may forestall the first relapse,” she added. “Although pregnancy is unlikely to fully prevent MS, becoming pregnant when a woman would otherwise have had her first attack could forestall the first detectable demyelinating event or MS diagnosis.”

Reproductive factors, including puberty and pregnancy, alter disease course in MS. Pediatric MS increases at about age 13, near puberty, and pregnancy suppresses relapses, particularly in the second and third trimesters. Exclusive breastfeeding has also been associated with decreased relapse rates.

Prior work on having children and MS or CIS risk has led to an interesting divide in the literature. A 2012 study found a protective dose effect of having multiple pregnancies in women, and no association in men between number of offspring and the onset of first demyelinating event.

A 2011 study of reproductive history and MS risk found that for both sexes, parents had a lower risk of MS compared with childless persons, concluding, “Similar findings in women and men argue against a biologic role of pregnancy in the etiology of MS… reverse causality (i.e., reduced reproductive activity in persons with yet-undiagnosed MS) might explain the observed associations.” A 2014 study also found similar risk in both sexes, “which contradicts biologic impact of pregnancy on MS risk and argues in favor of reverse causality, i.e. that fecundity is affected by yet-undiagnosed MS.”

“Despite the association of partner pregnancies with lower MS risk in men, there is biological plausibility that pregnancy could forestall the first clinically recognized attack of MS in women,” Graves observed. “The same biological mechanisms by which pregnancy reduces the relapse rate could suppress or postpone the first relapse event.”

In this study, Nguyen and colleagues collected reproductive history of 2,557 adult women from September 2016 to June 2019 who were treated in four MS clinics in two countries — Czech Republic and Australia — and enrolled in the MSBase international registry. Women with a history of disease-modifying therapy use during CIS were excluded.

Gravida was defined as any pregnancy, including miscarriage and induced abortion, parity as childbirth after gestational age of more than 20 weeks.

The primary outcome was age at CIS onset — first clinical episode of central nervous system demyelination or symptom onset — in those with any gravida or parity exposure compared with those who had never been pregnant and those who had never given birth. Secondary analysis considered whether there was a dose-response association between gravidity or parity and CIS onset timing.

“Concern remains that reverse causation could support the association of gravidity and parity status with MS risk, but Nguyen et al tried to mitigate this issue by using age at onset (not risk) of CIS as the primary outcome measure and to treat pregnancy as a time-dependent variable,” the editorialist observed.

Mean age at CIS onset was 31.5. Of these women, before CIS onset, 1,188 (46%) had at least one pregnancy and 1,100 (43%) had at least one childbirth. Mean age at first pregnancy was 23.3 and at first childbirth was 23.8.

Expanded Disability Status Scale (EDSS) scores obtained within 12 months of symptom onset were available for 28% of participants, and ranged from 0 (no disability) to 6.5 (requires two walking aids to walk 20 meters without resting), with median of 1.5 (no disability; minimal signs in more than one functional system).

Dose response of gravidity and parity number was not seen in analysis comparing those having one, two, or three pregnancies, and comparing one, two, or three childbirths.

“One possible explanation for the lack of a dose response is that pregnancy may delay CIS onset through epigenetic mechanisms,” Nguyen and co-authors observed. “Numerous DNA methylation changes occur by the 10th week of pregnancy. Therefore, the duration of the pregnancy (gravidity versus parity) may be less important than the occurrence of the pregnancy.”

“Epigenetic changes that occur during pregnancy may persist beyond the pregnancy itself and for several years,” they added. “If a genetic locus is demethylated and remains so, then it will remain unchanged with a second or third pregnancy and may therefore explain the absence of a dose response and the absence of any difference between gravidity and parity in the present cohort.”

Limitations of the study include possible reverse causality, and other confounders may have affected results. In addition, socioeconomic status was not included in the analysis. Data about men and partner pregnancies also were not included.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was supported by MS Research Australia, the Australian Government Research Training Program, and NHMRC.

Nguyen reported receiving grants from MS Research Australia during the conduct of the study; grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Merck Serono; personal fees from Teva and Novartis; and nonfinancial support from Roche and Genzyme-Sanofi outside the submitted work.

Graves reported receiving grants from Octave and Biogen; personal fees from Alexion, Bristol Myers Squibb, and Genentech; and support from Novartis for clinical trial steering committee participation outside the submitted work.

Cat ID: 130

Topic ID: 82,130,730,130,36,41,192,925