More Evidence Supports Birth Month Effect in MS

A new systematic review and meta-analysis provides robust evidence that babies born in the spring have a higher risk for multiple sclerosis (MS) and those born in the fall have a lower risk.

The analysis showed an MS birth rate about 10% above expected for the month of April and a rate approximately 10% below expected for October and November.

The results confirm the effect of birth month previously reported and extend the evidence pointing to maternal exposure to vitamin D during pregnancy as a culprit in raising risks for this autoimmune disease, said study author Sreeram Ramagopalan, MD, Queen Mary University of London, United Kingdom.

"To me, the month of birth is just a marker for maternal vitamin D status; that's the key driver behind the risk. We believe as a team of researchers that vitamin D supplementation during pregnancy will help to reduce MS incidence," Dr. Ramagopalan told Medscape Medical News.

The study was published online November 14 in the Journal of Neurology, Neurosurgery and Psychiatry.

Northern Populations

The authors searched PubMed and Web of Science for studies published after 2000 that included both MS and healthy control groups, provided data on month or season of birth for each population, and geographic location and compared the relative risk for MS for each month of birth vs controls.

The review included 10 studies with a total of 151,978 MS births.

Taking all studies together, there was a significant increase in the ratio of observed MS births to expected MS births (O:E) in April (O:E, 1.05; P = .05) and a decreased ratio in October (O:E, 0.95; P = .04) and November (O:E, 0.92; P = .01).

A "population conservative" analysis that excluded studies where patient data may have overlapped, found a significant relationship only for November. According to Dr. Ramagopalan, this is likely because the analysis excluded studies of populations at a latitude greater than 52 degrees N.

The authors carried out a "geographically conservative" analysis that examined the effect of month of birth in studies of populations above latitude 52 degrees N, where from October to March there's no ultraviolet light of appropriate wavelength (290 to 315 nm) for the cutaneous synthesis of vitamin D, so residents would be expected to have significant variation in vitamin D levels during the year.

The analysis showed significantly more MS births in April (O:E, 1.08; P = .001) and May (O:E, 1.11; P = .007) and significantly fewer in October (O:E, 0.94; P = .006) and November (O:E, 0.89; P = .004).

Dr. Ramagopalan noted that the effect sizes in studies with these more northern populations, including parts of Canada and northern Europe (such as Scotland and Scandinavian countries), are much stronger than for countries below that latitude.

"So the month of birth probably plays a role predominantly in countries of high latitude," he said.

Robust Effect

This is the first study to demonstrate a significant interaction between the month-of-birth effect and latitude, the authors note.

An overall conservative analysis excluded all the studies that were not included in the population and the geographically conservative analyses.

This analysis included only 78,488 participants but again showed a significantly higher observed-to-expected MS birth ratio in April (O:E, 1.08; P = .004) and May (O:E, 1.09; P = .002) and a significantly lower ratio in October (O:E, 0.95; P = .03) and November (O:E, 0.90; P = .03).

This analysis is probably the most appropriate, said the authors, because it excluded both potential duplicate datasets and studies performed in areas with low variation in UV exposure during the year.

Individual studies have come to the same conclusions, but they were of relatively small size, perhaps only 10,000 participants, and although they had a effect, it was small and could have been due to chance.

"It's all a question of sample size. By putting everything together in this analysis, it's a statistically robust effect. It's not a chance finding, and it's consistent across many different countries," said Dr. Ramagopalan.

Dr. Ramagopalan hopes the study will raise awareness about the growing problem of vitamin deficiency, and perhaps prompt women to consider taking vitamin D during pregnancy.

The review could still have a possible publication bias or selection bias and the potential remains for some data duplications that could have influenced the results. The lack of studies from the Southern Hemisphere is another limitation because demonstration of the reversal of the month of birth effect would have strengthened confidence in the findings, said the authors.

Commenting on the study for Medscape Medical News, Anne-Louise Ponsonby, PhD, Murdoch Children's Research Institute, Victoria, Australia, agreed that it confirms past work that also reported an excess prevalence of MS among people born from April to May and a nadir during October and November in the Northern Hemisphere, but it also extends this work.

"It provides new findings that indicate this season of birth effect is stronger as latitude increases," she said in an email.. "This is consistent with a role of ambient UVR [ultraviolet radiation] levels affecting maternal vitamin D levels."

Although this review didn't include studies in the Southern Hemisphere, Dr. Ponsonby's research team in Australia found a similar, but reciprocal, pattern in Australia (BMJ. 2010;340:c1640).

"In that study, the month of birth effects were accounted for by ambient UVR levels in the first trimester. There was an inverse association between ambient ultraviolet radiation in the first trimester and risk of MS. This persisted even after adjusting for region of birth, demonstrating the importance, again, of the seasonal pattern," she said.

This work was supported by MS Society of Great Britain and Northern Ireland. The authors are variously supported by an Association of British Neurologists/MS Society of Great Britain Clinical Research Fellowship, the Medical Research Council, National MS Society, MS Society of Great Britain and Northern Ireland, AIMS2CURE, and the Roan Charitable Trust. Dr. Ramagopalan has disclosed no relevant financial relationships. Disclosures for other authors are available with the article.

J Neurol Neurosurg Psychiatry. Published online November 14, 2012. Abstract