Progesterone is an essential hormone in the occurrence and maintenance of pregnancy. Progesterone administration has also been shown to be neuroprotective in a variety of clinical situations, including traumatic brain injury (TBI). Sex steroid hormones, including progesterone, are critically involved in axonal myelination, forming the basis of white matter connectivity in the central nervous system (CNS). Progesterone and its metabolites not only promote the viability and regeneration of neurons, but also act on myelinating glial cell oligodendrocytes in the CNS and play an important role in the formation of myelin sheaths. Progesterone has also been shown to increase myelination and enhance maturation of immature oligodendrocytes progenitor cells to mature oligodendrocytes, which are more resistant to hypoxic/ischemic injury. Therapeutic administration of progesterone has also been demonstrated to prevent preterm birth. Thus, there are two potential mechanisms by which pre-natal progesterone therapy may improve neurodevelopmental outcomes in neonates with CHD: 1) a direct neuroprotective effect, and 2) decreasing the occurrence of pre-term birth.