High birth weight and risk of multiple sclerosis: A multicentre study in Argentina

Multiple sclerosis (MS) is now recognized as a multifactorial disease in which genetic and environmental factors intervene. Considerable efforts have been made to identify external risk factors present in childhood, adolescence and youth, though only a few perinatal risk factors have been positively associated with MS. Previously, we found an association between high birth weight and MS in male patients in a small study in Argentina. The present research was designed to further assess the association between high birth weight and MS in a larger sample of patients, using an extensive and validated general population database as control.

We present an analytical observational, multicentre, population-based, and case-control study. A total of 637 patients (cases) with confirmed MS diagnosis attending five MS specialized centres in Argentina were included. Birth weight (BW) data was recalled by the patient's mother, which is a validated approach. A two-way comparison was performed. First, we used the standard categories of high, adequate and low BW in grams. Then, we applied the weight percentile distribution to provide reproducible results for further research. For a proper assessment and comparison of variables, we adopted the guidelines of the American Academy of Pediatrics for neonate classification according to gestational weeks and to BW in grams. The neonate's BW distribution of the general population was used as control. For the purposes of the study, we adapted Urquía's et al. curves, which are based on an extensive database of all the live births registered in the country from 2003 to 2007. To measure the magnitude of the proportional differences between low, adequate and high BW, the odds ratio (OR) and their 95% confidence interval (CI) were estimated. The mean BW and percentile values for each sex were compared using a z-Normal test. The respective MS patients and general population BW distribution curves by sex were compared between each other.

Cases and controls were comparable in their demographic, geographic and environmental characteristics. Males showed higher BW than females both in the MS patients and the general population groups. When we applied the sex stratified analysis separately, we found that males in the MS group showed an almost seven times higher risk of high birth weight than males from the general population (OR 6.58 [95% CI 4.81-8.99]). Female patients showed an almost five times higher risk of high BW than their respective controls (OR 4.5 [95% CI 3.06-6.58]). The comparison based on the BW percentile distribution confirmed that MS patients showed higher BW than the general population. This result reached statistical significance from the 75^th percentile onwards for both sexes.

In summary, our findings suggested that high BW could be one of the earliest risk factors for MS in life. If this results were reproduced in other centres, high birth weight would emerge as a novel and very early risk factor, potentially modifiable in utero or immediately postpartum, representing a unique opportunity to prevent the disease in future generations.