[49] In rats and mice, the HPA axis expresses important differences from that found in humans. For example, the major product of HPA axis activation in humans is cortisol, while that in most rodents is corticosterone.[50] Moreover, the development of the fetal adrenal gland in rats and mice is markedly different with major relative deficiencies in important enzymes and preference for different substrates. In these species, EMD 1214063 the response to stress may lead to fundamentally different means of pregnancy failure, including a decreased level of circulating progesterone.[51] While

rodent models may not be ideal for the examination of the role of HPA axis in normal pregnancy, evolving rodent models may be of interest in understanding the interaction of the HPA axis and stress in parental behavior.[52] Sheep have been used as a model of maternal[53] and fetal HPA axis function during pregnancy. In this animal model, it is the development and activation of the fetal HPA that is the primary driver of parturition,[54] and stresses such as hypoxia activate the HPA axis in sheep and lead to preterm labor.[55] The maternal–fetal interface in humans includes close contact

between maternal and fetal cells not only within the placenta and uterus[8] but also within the maternal and fetal circulations, as cellular traffic has been shown in either direction.[56, 57] The expression of proteins unique to the mother on fetal cells has raised a decades-long Epacadostat debate over the critical pathways and mechanisms needed to assure both immune tolerance

C-X-C chemokine receptor type 7 (CXCR-7) and protection of the fetus from infection.[58] Humans can mount an immune response against fetal antigens during pregnancy,[59] and it is clear that there is an intricate interaction between maternal immune cells and trophoblast.[60, 61] This interaction may be of benefit to the evolving conceptus[62] or may be involved in early pregnancy loss or other adverse pregnancy outcomes.[63] Activation of local innate immunity within the myometrium is thought to play a role in parturition[64] and in premature uterine contractions.[65] In humans, certain pathogens are more deleterious during pregnancy as compared to the non-pregnant state,[66] while others are not,[67] and the role of the placenta as a safe harbor for evolving pathogens has been described.[68] Some infection syndromes that occur in humans occur only under contrived conditions in animals.[69] Moreover, some organisms, such as CMV, are different in different hosts.[70] Both the peculiarities of the immune response and the infectious agent must be taken into consideration when using an animal model to understand the function of the immune response during pregnancy.