Several studies aimed to disentangle whether pregnancy influences the growth of uterine fibroids but results were inconsistent. In this study, we speculated that fibroid enlargement during pregnancy may not be linear and we hypothesized that this phenomenon may mainly occur during initial pregnancy. To test this hypothesis, we set up a prospective cohort study of women with fibroids undergoing IVF. Cases were women achieving a viable pregnancy. Controls were the subsequent women with fibroids but failing to become pregnant. Twenty-five cases and 25 controls were recruited. The total number of fibroids in the two groups was 46 and 41, respectively. The mean ± SD diameter of the fibroids was 17 ± 10 and 20 ± 11 mm, respectively (p = 0.18). A statistically significant enlargement emerged exclusively in pregnant women. The median (Interquartile Range) modification of the diameter of the lesions in cases and controls was +34% (+6%/+65%) and +2% (-6%/+12%), respectively (p<0.001). The median (Interquartile Range) modification of the volume of the lesions was +140% (+23%/+357%) and 0% (-18%/+37%), respectively (p<0.001). In pregnant women, we failed to document any significant correlation between the magnitude of the growth and ovarian responsiveness to hyper-stimulation, suggesting that steroids hormones are not the unique factors involved. In conclusion, fibroids undergo a rapid and remarkable growth during initial pregnancy. Reasons behind this phenomenon remain to be clarified. The early rise in steroids hormones during early pregnancy may not be sufficient to explain the process. Other pregnancy-related hormones and proteins may play also key roles.