TwinLife: TWIN Longitudinal Investigation of FEtal discordance

Lifelong health is in part set during intrauterine life. An adverse intrauterine environment can induce persistent epigenetic changes that are thought to cause long-term health effects. There is an urgent need for human studies that can identify the epigenetic alterations that underlie the impact of intrauterine adversity on disease, in particular cardiovascular disease (CVD) and neurodevelopmental impairment (NDI). This study will focus on identical twin pairs who shared a single placenta i.e., monochorionic (MC) twins. Every year, over 600 MC twins are born in The Netherlands and they are at high risk of experiencing an adverse intrauterine environment. In one third of pairs, one fetus has significantly less access to nutrients and resources during pregnancy than its co-twin, conditions known to be linked to increased CVD risk and impaired neurodevelopment in adults. Thus, although genetically identical, great differences in intrauterine exposure exist within twin pairs, providing an unique natural experiment allowing a robust assessment of the development of cardiac- and neurodevelopmental risk factors in childhood and probe the underlying epigenetic mechanisms. Instead of relying on commonly used blood samples, this study will examine altered epigenetic regulation in mesenchymal stromal cells (MSCs), an enhanced proxy for other tissues involved in CVD and NDI. These multipotent cells are known to display metabolic changes in newborns exposed to an adverse intrauterine environment and can be differentiated into other cell types. The hypothesis is that twins discordant for pregnancy complications display a distinct epigenetic signature in MSCs. This signature contributes to cellular metabolic alterations and is associated with future cardiovascular and neurodevelopmental outcome in childhood and beyond. Our results will not only address an unmet clinical need in the high-risk group of MC twins, but may also advance early-life CVD prevention strategies and underpin their efficacy in the general population.

The hypothesis is that twins discordant for pregnancy complications display a distinct epigenetic signature in MSCs. This signature contributes to cellular metabolic alterations and is associated with future cardiovascular and neurodevelopmental outcome in childhood and beyond.

Prenatal; birth; 6 months; follow-up at 2, 5 and 8 years