It looks as if the roots of multiple sclerosis might stretch further back than we thought. Maybe all the way to the womb.
In a sweeping population-based study published this week in JAMA Neurology, researchers report that people born large for gestational age or exposed to maternal diabetes during pregnancy face a higher risk of developing multiple sclerosis (MS) in adulthood. Conversely, those born small for gestational age appear to have a slightly lower risk.
In short, what the researchers uncovered suggests that susceptibility to the disease might begin as early as the prenatal period, long before the first neurological symptoms ever show up.
Methodology
The researchers combed through national registry data from Norway, tracking more than 1.1 million of the country’s citizens born between 1967 and 1989. Using merged birth, health, and demographic records, investigators followed the participants into adulthood and identified MS diagnoses from 2009 through 2019, when all participants were at least 18 years old.
While the data has long since established genetic risk of MS, environmental influences also play a role. Incidentally, the higher concordance rates seen among dizygotic twins have hinted that shared prenatal or perinatal exposures might make a difference.
Even so, few large-scale studies tackled specific adverse pregnancy outcomes.
To rectify that, the research team looked at several maternal and birth-related factors, including preterm delivery, abnormal fetal growth, hypertensive disorders of pregnancy, placental abruption, and maternal diabetes.
Results
After adjusting for a broad range of confounders, a pair of strong (and surprising ) links stood out:
- Adults born large for gestational age had a 13% higher risk of developing MS compared with those born at an appropriate weight.
- Meanwhile, individuals born small for gestational age showed a 12% lower risk.
- The strongest connection emerged for maternal diabetes. Offspring exposed to diabetes in utero appear to be more than twice as likely to be diagnosed with MS later in life.
Other adverse pregnancy outcomes didn’t appear to influence MS risk. The researchers failed to identify any noteworthy associations with preterm birth, hypertensive disorders of pregnancy – including preeclampsia – or placental abruption. These null findings persisted across multiple sensitivity analyses.
The authors emphasize that the results align with existing evidence linking childhood obesity and metabolic disease to MS risk. Being born large for gestational age often predicts higher body mass index in childhood, a known MS risk factor. Maternal diabetes could amplify that by altering fetal growth patterns and metabolic programming before birth.
Even so, researchers found the protective association among individuals born small for gestational age more surprising. Small size at birth is typically linked to poorer cardiometabolic outcomes later in life, conditions that themselves increase MS risk and worsen disease progression.
One possible explanation, the researchers advise, is that children born small for gestational age tend to have lower body mass in early life, when adiposity might exert a particularly strong influence on immune development and MS susceptibility.
Another hypothesis stems from immune system programming. Prenatal exposure to high glucose levels could induce lasting changes in immune regulation, setting the stage for autoimmune disease decades later.
On the other hand, metabolic exposures in utero could influence vitamin D metabolism or chronic low-grade inflammation, both of which remain MS risk factors.
Conclusions
The findings add to a growing body of evidence showing that early-life biology – alongside genetics and adolescent or adult exposures – shapes MS. And while earlier studies have tied prenatal vitamin D deficiency and childhood obesity to MS risk, this new research pushed that timeline back even further, implicating fetal growth patterns and maternal metabolic health.
For now, the results probably won’t do much to alter clinical practice. But they could help refine future research into MS prevention, shifting some attention toward pregnancy and early development as potential windows of vulnerability (and opportunity).
As the authors wrap up, understanding how early metabolic and growth-related exposures shape immune development could offer new insights into why MS emerges decades later. And it could explain how its risk might one day be curbed before we’ve even born.
Further Reading
MS Might Begin a Decade Earlier Than We Thought
