The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1(-/-) female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1(+/-) embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1(-/-) uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1(-/-) female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans.

Influenza is a major health problem worldwide. Both seasonal influenza and pandemics take a major toll on the health and economy of our country. The present review focuses on the virology and complex immunology of this RNA virus in general and in relation to pregnancy. The goal is to attempt to explain the increased morbidity and mortality seen in infection during pregnancy. We discuss elements of innate and adaptive immunity as well as placental cellular responses to infection. In addition, we delineate findings in animal models as well as human disease. Increased knowledge of maternal and fetal immunologic responses to influenza is needed. However, enhanced understanding of nonimmune, pregnancy-specific factors influencing direct interaction of the virus with host cells is also important for the development of more effective prevention and treatment options in the future.

Normal pregnancy is associated with an increase in uteroplacental blood flow in part due to growth and remodeling of the maternal uterine vasculature. In this study, we characterized the effect of diabetic pregnancy on vascular growth of the maternal uterine vasculature and on the passive mechanical properties of the uterine resistance arteries. Diabetes was induced in pregnant rats by injection of streptozotocin and confirmed by development of hyperglycemia. Fetuses of diabetic rats were significantly smaller and placentas larger compared to controls. Pregnancy-induced axial elongation of the mesometrial uterine vasculature was not altered by diabetes. Vascular wall thickness was unchanged between groups. Wall distensibility was increased and the rate constant of an exponential function fitted to stress-strain curve was significantly reduced demonstrating decreased wall stiffness in diabetic uterine radial arteries compared to controls. We conclude that experimental diabetes in rat pregnancy does not compromise the growth of maternal uterine vasculature but alters passive mechanical properties of the uterine radial arteries.

Nonchromosomal pregnancy failure is a common but poorly understood phenomenon. Because recent data have suggested that epigenetic abnormalities such as abnormal placental DNA methylation may play a role in human pregnancy failure, we undertook experiments to test whether decidual and/or placental DNA methylation abnormalities are present in a mouse model of pregnancy failure. A large number of studies have shown that crosses between CBA/J female mice and DBA/2 males result in pregnancies with a high rate of failure/resorption, whereas other crosses with CBA/J females produce normal pregnancies. Although the CBA/J × DBA/2 mouse has frequently been used as a model for miscarriage, a detailed explanation for the pregnancy failure phenotype is lacking. We performed timed matings between CBA/J female and DBA/2 male mice as well as between DBA/2 female and CBA/J male mice. Decidual caps were isolated at Embryonic Day (E) 9.5 from both crosses, and a microarray-based method was used to comparatively assess genomic methylation at approximately 16,000 loci on mouse chromosome 7. In comparison with decidual caps from DBA/2 × CBA/J pregnancies, CBA/J × DBA/2 decidual caps were characterized by widely and apparently randomly disturbed methylation. In another set of analogous experiments, genomic methylation of placental DNA from E8.5 pregnancies was assessed using the same microarray-based method. This analysis revealed that in contrast to the decidua, placental DNA methylation from CBA/J × DBA/2 pregnancies was indistinguishable from that of normal controls. We conclude that abnormal DNA methylation in the uterine decidua likely plays a role in the CBA/J × DBA/2 model of pregnancy failure. To our knowledge, these experiments are the first to demonstrate that epigenetic abnormalities of the decidua are associated with pregnancy failure, and they set the stage for future efforts to understand the role of DNA methylation at the maternal-fetal interface.

Attempting to improve IVF pregnancy rates by permitting multiple embryo transfers results in sharply increased rates of multiple gestation and preterm delivery. This practice yields a greater frequency of adverse perinatal outcomes and substantially increased healthcare spending. Better efforts to encourage SET are necessary to normalize healthcare expenditures considering the frequency of very high cost sequela associated with IVF where multiple embryo transfers occur.