Preterm labor (PTL) is an important cause of preterm delivery. The trigger initiating the process toward overt labor and parturition is poorly understood and the molecular basis remains an enigma. It recently emerged that the overall occurrence of PTL in pregnant women with congenital heart disease (CHD) is increased. In this review, we present data on pregnancy in women with CHD and the opportunities this provides for research on the initiating mechanisms of inappropriately premature contractions. This may provide means for early detection of women at high risk of PTL in the general population, with models using cervical length, novel biomarkers, and maternal factors. We discuss human embryonic development of the heart and the uterus and the molecular pathways shared by the cardio- and uteromyocytes. We propose 2 hypotheses for the co-occurrence of maternal CHD and PTL; one based on a shared genetic origin and the other on a shared epigenetic origin.