Article In Brief
New findings suggest pregnancy and childbirth delayed the onset of clinically isolated syndrome, a precursor condition to multiple sclerosis.
Pregnancy and childbirth delayed the onset of clinically isolated syndrome (CIS), a precursor condition to multiple sclerosis (MS), researchers reported in a paper in the September 14 online edition of JAMA Neurology.
The findings help crystallize a possible connection that MS researchers have attempted to better understand for years.
“This work supports the notion that pregnancy plays an immunomodulatory role in women predisposed to developing CIS,” said lead researchers Ai-Lan Nguyen, MBBS, a neurologist, researcher and PhD candidate at Royal Melbourne Hospital.
Researchers have been studying the association between pregnancy and childbirth and MS risk for years, often yielding mixed messages. Previous studies used a range of definitions for pregnancy and a variety of ways of analyzing data. Most of them looked at MS rather than CIS as the endpoint. But because of pre-MS symptoms, they were susceptible to reverse causality, with the symptoms affecting pregnancy likelihood.
In this study, researchers looked at CIS, the first episode of neurological symptoms of at least 24 hours that’s caused by inflammation or demyelination, using an international multiple sclerosis registry with data that was prospectively collected. Using time to CIS development as the endpoint—rather than the gross risk of MS development—is a critical difference in this study, Dr. Nguyen said.
“It is unlikely that pregnancy alone can prevent a woman from developing CIS or MS,” she said. “We know from the literature that there are likely to be other factors that play a more important role in the risk of MS, such as genetic predisposition, low vitamin D, smoking or Epstein Barr virus infection. Therefore, the relationship between pregnancy and CIS will be better elucidated by exploring the delay in symptom onset, rather than absolute risk.”
A total of 2,557 women were included in the study. Researchers examined gravida—any pregnancy, including those ending in miscarriage and abortion, parity, or childbirth—after more than 20 weeks of gestation. They assessed these as both yes or no variables and as ordinal variables, looking at the number of pregnancies and childbirths.
Women with previous pregnancies and childbirths had a later onset of CIS than those who had never been pregnant (HR = 0.68; p< 0.001). The median delay was 3.3 years. Women who had given birth also had a later CIS onset compared with those who did not, with a similar median delay, 3.4 years.
The number of pregnancies and childbirths did not contribute to the delay, researchers found. Those who had had one pregnancy or three or more pregnancies had a delayed onset of CIS compared with those who had no pregnancies, and a similar observation was made with the number of childbirths. Also, a higher pregnancy or childbirth number was not associated with a later onset of CIS.
“One possible explanation for the lack of a dose-response is that pregnancy may delay CIS onset through epigenetic mechanisms, such as DNA methylation changes or histone modifications,” researchers wrote. This is an understudied area, they said, but recent studies have shown that DNA methylation changes occur by the 10th week of pregnancy, and so the mere occurrence of pregnancy, rather than its duration, could be the determining factor.
Patients who had received disease-modifying therapy during their CIS were excluded from the study to reduce the chance that prodromal factors could have been at play in affecting pregnancy and childbirth.
Researchers also pointed out that a recent study found that estrogens bring about more tolerogenic traits in T cells in relapsing-remitting MS patients during pregnancy, through epigenetic means. These epigenetic changes could remain in place through a second or third pregnancy, they said.
Rhonda Voskuhl, MD, director of the multiple sclerosis program at the University of California, Los Angeles, praised the study, saying “the highest level of rigor” was used to address reverse causality.
“Alternative influences to observations are inherent to retrospective epidemiologic studies,” she said. “Despite this limitation, such studies are extremely important as a foundation for causal research at both the preclinical and clinical trial level. Also, a protective biologic effect of pregnancy and some degree of reverse causality are not mutually exclusive.”
That both pregnancy and childbirth delayed CIS suggests that it’s pregnancy itself, and not post-partum biology or breastfeeding, that is protective, she said.
“MS is both an autoimmune disease and a neurodegenerative disease,” she said. “Autoimmune mechanisms are thought to be critical in CIS and MS susceptibility and onset, while neurodegenerative mechanisms play a clear role in disability progression. A delay in CIS onset with pregnancy is likely due to an anti-inflammatory effect of pregnancy hormones of a given type and dose”—such as estriol or progesterone— “or epigenetic effects of pregnancy, which may be independent or mediated by estrogens.”
This study, she said, shows the value of a “bedside-to-bench-to-bedside” research approach, with basic research rooted in clinical observations, boosting its relevance.
“In the case of pregnancy, the protective effect on relapses and CIS are invaluable clues given to the scientific community to disentangle, identify causality, and discover novel treatments,” Dr. Voskuhl said.
“Further studies on the role of pregnancy on disability progression are also warranted as a foundation toward neuroprotective treatment discovery. To this end, estrogens and estrogen receptor ligands have been widely shown to have anti-inflammatory and neuroprotective properties in a type and dose-dependent manner. The current study moves the needle toward investment in research to capitalize on clinical observations of the protective effect of pregnancy in MS.”
Kristen Krysko, MD, a fellow in neurology at the University of California San Francisco who has studied multiple sclerosis and pregnancy, cautioned that “it is possible that prodromal symptoms before the first clinical demyelinating event could affect childbearing decisions, so it is impossible to exclude reverse causation even when using CIS as an outcome, as the disease process has likely already begun even before CIS onset.”
The precise mechanisms at work need more study, she said.
“Multiple factors may contribute including hormonal changes during pregnancy including high levels of estriol and progesterone, as well as a shift to an anti-inflammatory state during pregnancy to promote fetal tolerance,” she said.
“Additionally, I found it interesting that the authors postulate that epigenetic changes during pregnancy may contribute, and this requires further exploration.”
Further study, she said, “may identify potential modifiable factors that could delay onset of MS, which could also potentially be targeted as an MS treatment in women…. this study is a step in the right direction to better understand the relationship between pregnancy and onset of MS.”
Jennifer Graves, MD, PhD, associate professor of neuroscience at the University of California, San Diego, who wrote an accompanying editorial, said the study adds to the ongoing exploration in the literature about the link between pregnancy and MS.
“Is it influencing the disease course before the first relapse?” she said. “In my opinion, these data suggest that similar to how pregnancy reduces relapse rate later in disease, pregnancy may be forestalling the first attack of multiple sclerosis.”
“As pregnancy suppresses relapses in women who are already diagnosed, it’s very plausible that the same biological mechanisms could be preventing the observation of a first large attack,” she said.
Many factors could be contributing to this, she said, including high levels of progesterone and a shift during pregnancy from a T helper cell 1 to a T helper cell 2 phenotype.
But in the end, she said, “we need to understand specific biological mechanisms at play and if there is a potential therapeutic target,” she said. “Can we bottle pregnancy?”
In one clinical trial—led by Dr. Voskuhl—the pregnancy estrogen, estriol, showed some benefit in year one at reducing relapses but didn’t meet the primary endpoint at year two, she noted.
“Maybe estriol plays a role but it doesn’t appear to capture the full effect of pregnancy. What’s the other big player? Should we go for progesterone? Should we go for other possible biological targets?” Dr. Graves said.
“We need larger, multi-site studies—consortium efforts—to capture what’s happening biologically across the trimesters of pregnancy and to link these biological changes to the relapse control. Then we identify the best target and turn that into something we truly can bottle as a therapeutic for MS.”
Dr. 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 of the submitted work.