Epigenetics may play a central, but yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy. We investigated changes in the methylome in isolated circulating CD4+ T cells in non-pregnant and pregnant women, during the 1st and 2nd trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with thousands of methylation differences, particularly during the 2nd trimester, where the majority of sites were hypermethylated, indicating transcriptional repression. Using a network-based modular approach disclosed several genes and pathways related to T cell signalling and activation. The pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. The directionality of the changes was also in line with the previously observed effect of pregnancy on the disease activity, with a negative correlation for multiple sclerosis and rheumatoid arthritis that improves during pregnancy, and a positive correlation for systemic lupus erythematosus, a disease that instead worsens. In summary, this systems medicine approach supports the importance of the methylome in immune regulation of CD4+ T cells during pregnancy. Samples included twelve (n=12) non-pregnant women, elven (n=11) 1st trimester pregnant women and twelve (n=12) Overall design: Methylation changes during pregnancy was analyzed in CD4+ T cells were isolated from peripheral blood using positive selection from pregnant and non-pregnant women. Genomic DNA was extracted from all samples and bisulphite converted. The converted DNA was hybridized to the Ilumina Infinium 45K Human Methylation BeadChip v1.2