Previous Pregnancy May Lead to Later-Onset Clinically Isolated Syndrome

Ai-Lan Nguyen, MBBS

Newly published data from a multicenter cohort study suggest there is an association between previous pregnancies and childbirths and the timing of clinically isolated syndrome (CIS) onset but did not appear to show an association between having more pregnancies or childbirths and later CIS onset.¹

Ai-Lan Nguyen, MBBS, neurologist, Royal Melbourne Hospital, and colleagues gathered data on gravida, defined as any pregnancy including pregnancy that ended in miscarriage and induced abortion, and parity, defined as childbirth after gestational age of more than 20 weeks, including livebirth and stillbirth in 2557 women before CIS onset.

Of these women, 1188 (46%) had at least 1 pregnancy and 1100 (43%) had at least 1 childbirth. Investigators found that later-onset CIS was more common in women with previous pregnancies and childbirths compared to those who had never been pregnant (hazard risk [HR], 0.68; 95% CI, 0.62–0.75; P <.001), with a median delay of 3.3 years (95% CI, 2.5–4.1). Of the 2557 total participants, 71 (3%) had their first demyelinating event during pregnancy.

Having 1 (HR, 0.70; 95% CI 0.61–0.79), 2 (HR, 0.67; 95% CI, 0.60–0.76), or 3 or more pregnancies (HR, 0.66; 95% CI, 0.58–0.75) delayed the onset of CIS compared with no pregnancies (P <.001).

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Prior to the study, there was no consensus on whether pregnancy can delay the first episode of demyelination or CIS despite multiple research attempts to unveil this information. Jennifer Graves, MD, PhD, neurologist, associate professor of neurosciences, UC San Diego Health, wrote in a related editorial that “although specific genes on the X chromosome may play a modest role in MS susceptibility and severity, reproductive factors, including sex steroid hormone production and pregnancy, have long been recognized to alter the disease course in MS.”²

Reproductive history including duration of each pregnancy, date of delivery, and length of breastfeeding were all incorporated into the study. Researchers also pulled preexisting data such as date of CIS onset, date of birth, sex, date of clinical onset, and Expanded Disability Status Scale (EDSS) score from MSBase.

Nguyen and colleagues also found that having 1 (HR, 0.70; 95% CI, 0.62–0.79), 2 (HR, 0.66; 95% CI, 0.58–0.74), or 3 or more childbirths (HR, 0.69; 95% CI, 0.58–0.81) all delayed the onset of CIS compared with no pregnancies (P <.001).

The mean age at CIS onset was 31.5 years (standard deviation [SD], 9.7) while the mean age at first pregnancy and first childbirth was 23.3 (SD, 4.5) and 23.8 years (SD, 4.5), respectively.

Graves continued to note that “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.”

Three sensitivity analyses were performed. In the first, left censoring occurred at age 18 years instead of 16 years. In the second sensitivity analysis, analyses were stratified according to changing diagnostic criteria for clinically definite multiple sclerosis (CDMS). In the third sensitivity analysis, patients treated with DMT during CIS, before MS diagnosis, were included. All of the sensitivity analysis confirmed the results of the primary analysis. Additionally, a higher gravidity and parity number were no associated with a change in CIS onset.

Investigators noted that further studies are needed to help explain the mechanisms behind the associations between pregnancy and onset of MS.

REFERENCES

1. Nguyen A, Vodehnalova K, Klinicik T, et al. Association of pregnancy with the onset of clinically isolated syndrome. JAMA Neurol. Published September 14, 2020. doi: 10.1001/jamaneurol.2020.3324.

2. Graves JS. Do pregnancies forestall the onset of MS? JAMA Neurol. Published September 14, 2020. doi: 10.1001/jamaneurol.2020.3332.