These findings suggest that controlling gestational weight gain should be a priority following GDM diagnosis to optimize pregnancy outcomes and improve maternal postnatal glucose homeostasis. The period after diagnosis of GDM (often 28 weeks gestation) is not too late to offer lifestyle advice or intervention to improve weight management and pregnancy outcomes.

Determining effective means of preventing Multiple Sclerosis (MS) relies on testing preventive strategies in trial populations. However, because of the low incidence of MS, demonstrating that a preventive measure has benefit requires either very large trial populations or an enriched population with a higher disease incidence. Risk scores which incorporate genetic and environmental data could be used, in principle, to identify high-risk individuals for enrolment in preventive trials. Here we discuss the concepts of developing predictive scores for identifying individuals at high risk of MS. We discuss the empirical efforts to do so using real cohorts, and some of the challenges-both theoretical and practical-limiting this work. We argue that such scores could offer a means of risk stratification for preventive trial design, but are unlikely to ever constitute a clinically-helpful approach to predicting MS for an individual.

Objective Higher childhood Body Mass Index (BMI) during early life is thought to be a causal risk factor for Multiple Sclerosis (MS). We used longitudinal mendelian randomisation (MR) to determine whether there is a critical window during which BMI influences MS risk. Methods Summary statistics for childhood BMI and for MS susceptibility were obtained from recent large GWAS. We generated exposure instruments for BMI during four non-overlapping epochs (< 3 months, 3 months - 1.5 years, 2 - 5 years, and 7 - 8 years) and performed MR using the inverse-variance weighted method with standard sensitivity analyses. Results At all time epochs other than birth, genetically-elevated BMI was associated with an increased liability to MS: Birth (OR 0.81, 95%CI 0.50-1.31, NSNPs=7, p=0.39), Infancy (OR 1.18, 95%CI 1.04-1.33, NSNPs=18, p=0.01), Early childhood (OR 1.31, 95%CI 1.03-1.66, NSNPs=4, p=0.03), Later childhood (OR 1.34, 95% CI 1.08-1.66, NSNPs=4, p=0.01). There was no evidence that horizontal pleiotropy was biasing the IVW estimates at any of these points. There was evidence of an upwards trend in MS risk from birth to 8 years (Mann-Kendall test, tau = 0.636, 2-sided p-value =0.005). Conclusion We provide novel evidence using longitudinal MR that genetically-determined higher BMI during early life (from 3 months) increases MS risk, and that the magnitude of this effect increases towards late childhood and adolescence.

Objective Higher body mass index (BMI) during early life is thought to be a causal risk factor for multiple sclerosis (MS). We used longitudinal Mendelian randomisation (MR) to determine whether there is a critical window during which BMI influences MS risk. Methods Summary statistics for childhood BMI (n ~ 28,000 children) and for MS susceptibility were obtained from recent large genome-wide association studies (GWAS) (n = 14,802 MS, 26,703 controls). We generated exposure instruments for BMI during four non-overlapping age epochs (< 3 months, 3 months–1.5 years, 2–5 years, and 7–8 years) and performed MR using the inverse variance weighted method with standard sensitivity analyses. Multivariable MR was used to account for effects mediated via later-life BMI. Results For all age epochs other than birth, genetically determined higher BMI was associated with an increased liability to MS: Birth [Odds Ratio (OR) 0.81, 95% Confidence Interval (CI) 0.50–1.31, Number of Single-Nucleotide Polymorphisms (NSNPs) = 7, p = 0.39], Infancy (OR 1.18, 95% CI 1.04–1.33, NSNPs = 18, p = 0.01), Early childhood (OR 1.31, 95% CI 1.03–1.66, NSNPs = 4, p = 0.03), Later childhood (OR 1.34, 95% CI 1.08–1.66, NSNPs = 4, p = 0.01). Multivariable MR suggested that these effects may be mediated by effects on adult BMI. Conclusion We provide evidence using MR that genetically determined higher BMI during early life is associated with increased MS risk. This effect may be driven by shared genetic architecture with later-life BMI.

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