INTRODUCTION

Multiple sclerosis (MS) is a chronic progressive disease of the central nervous system (CNS) and two-thirds of the patients are women of childbearing age (1).These patients have a clinically isolated syndrome (CIS) defined by a distinct first neurological event with demyelination involved the optic nerve, cerebellum, brainstem, cerebrum or spinal cord (2).

The precise etiology of MS is unknown, although epidemiological studies reported that both genetic and environmental factors are important (3). The risk factors of MS are female gender, smoking, nonexclusive breast feeding, high Epstein-Barr virus antibody levels, having had infectious mononucleosis (4).

The Vitamin D deficiency is one of the environmental factors affecting MS development. Vitamin D is absorbed by the skin when it is exposed to ultraviolet (UV) or sunlight. The vitamin D insufficiency levels during pregnancy affect the immune status of the fetus and the MS risk (5). Likewise, the gene-environment interactions can be the cause of the development of MS (6).

Some studies showed that ‘month of birth’ affected on the risk of MS. Born in the winter reduced MS risk of neonates (7-9) and in those born in the spring there was an increased MS risk (8, 10, 11), although these results were not consistant. Interestingly, in studies that conducted in northern hemisphere, MS birth was lower in autumn (12), while in  southern hemisphere the risk of MS was higher in autumn (November–December), and the risk has fallen in the spring (May–June) (13). Hence, time of born within a year may affect the risk of MS later in life.

Abundant studies have been done for assessing the association between the month of birth and risk of MS, the pooled findings have shown inconsistencies due to differences in statistical methods, sample sizes, and ethnic groups. Besides, they have reported different months to be significantly influential on the risk of MS. Therefore, in this meta-analysis we assessed the effect of birth month on MS based on studies that reported observed vs. expected odds ratio by month, during 2000-2020.

MATERIALS AND METHODS

Data Sources

     This meta-analysis is conducted to estimate the association between month of birth and MS. We utilized PRISMA statement as a guide to enhance quality reporting of the review (14). Relevant studies that published in major international electronic bibliographic databases of PubMed, Scopus and Web of Science were systematically searched to October 2020. In addition, hand searches were also performed in order to identify additional relevant studies.

Search strategy

MeSH heading approach was used to perform the search strategy, identifying additional terms in the title, keywords, affiliations (scleroses; birth; birthed; births; months; month; sclerosis; multiple; MS and multiple scleroses). All off title and next abstracts were checked to find out articles with the most relevance. In the next step, the full texts of related articles were assessed to decide upon the articles to be included in meta-analysis. In the final step, cross-referring was done for increasing search sensitivity.

Inclusion and exclusion criteria

Papers that reported observed vs. expected MS birth odds ratio by month, original researches in English language, and conducted in 2000-2020 period were considered as eligible for inclusion in current study. Articles with lack of reports about the association between month of birth and MS, and duplicate articles as well as animal studies, case reports, case series, comments, editorials, and reports were excluded.

Data Extraction

Relevant studies were assessed by two independent authors (YV and SK), after that eligible studies were included, tiny disagreements were resolved with more caution by all authors. Data extraction form was used to extract the data. Data extraction form contained the following information: first author, years of publication, population, number of patients, observed vs. expected MS birth odds ratio (OR) and their associated 95% confidence intervals (CI) for each month of winter: December, January, February; spring: March, April, May; summer: June, July, August; and autumn: September, October, November.

Quality assessment

The methodological methods of included studies were assessed by Newcastle-Ottawa Scale (15). Eventually, articles were classified in two groups, high quality studies that gained more than 7 points and low quality studies that gained less than 7 points (Ranged from 1 to 9 points).

Statistical analysis

It was attempted to extract the results regarding the association between month of birth and MS, from the Meta-analyses. We used I² statistics to assess the heterogeneity of the included studies. Whenever the heterogeneity was high in studies (I² = 25 and more), the random effects model was used (April, May, June, November); while for lower heterogeneity the fixed model was used (I²= less than 25) (January, February, March, July, August, and September, October, and December). All meta-analyses were performed using Stata software version 12 (Stata Corp, College Station, TX, USA).

RESULTS

     In the initial search we enrolled 93 records according to search strategy. We have screened articles by title, abstract and full text, while duplicates were removed; and in final step 15 studies were considered for inclusion in the analysis. Figure 1 shows the diagram of included studies. The 15 analyzed studies offer data from 15 different populations, including 181602 patients with MS. Overall, excess risk of MS by birth months according to observed vs. expected MS birth odds ratio was observed in 9 populations;  and in 7 populations,  lower risk of MS by birth month was designed (Table 1).

The pooled observed vs. expected MS birth odds ratio for 12 months is shown in table 2. According to results from pooled meta-analysis the excess risk of MS by birth months was observed for April and June, while the lower risks of MS by birth months were attributed to January and November (Table2).

The Forrest plot for excess risk month is shown in figure 2. The observed vs. expected MS birth odds ratio for April and June was 1.03 (1.00 – 1.06) and 1.02 (1.00 – 1.05), respectively. The significance heterogeneity was observed for the two investigated months.   The Frost plot of lower risk months is shown in figure 3. The observed vs. expected MS birth odds ratio for January and November was 0.98 (0.96 – 0.99) and 0.96 (0.93 – 1.01), respectively. A significant heterogeneity was observed in studies that reported OR for November, but no evidence of heterogeneity was found for January. 

The trend of MS birth by month was shown in figure 4. According to the line trend more people with MS were born in May and fewer were born in November.

Acknowledgement

This research has not received any specific fund.

Conflict of interest statement

The authors declare that have no conflict of interest.