**3. Implantation and Placentation**

Implantation is critical to survival of a species, but this process in humans has a surprisingly high failure rate. Maximal fecundity (the likelihood of getting pregnant each cycle) peaks at 30% [2,14]. Only 50% of conceptions advance beyond 20 weeks of gestation and, of all unsuccessful pregnancies, 75% represent a failure of implantation [2,14–16]. Even among eutherian (placental) mammals, humans are unique. Among other features, human pregnancy has the most invasive type of placentation (hemochorial), early recognition of the fetal allograft by the maternal immune system, and a long gestational length [9,11].

The factors regulating implantation have been reviewed in detail elsewhere [2,7,17]. Briefly, as in other mammals, human implantation likely involves three steps: (i) apposition (initial adhesion, which is unstable), (ii) attachment (stable adhesion), and (iii) invasion, which occurs in two phases or waves. The 'first wave' of trophoblast invasion occurs between days 7 and 10 post-conception, starting shortly after the blastocyst hatches out of the zona pellucida. During this time, the blastocyst actively invades the tissues of the uterus. By day 10 postconception, the blastocyst is completely buried within the endometrial lining. For the next few weeks, the placenta is not yet hemochorial [18] and the blastocyst is fed by secretions from the endometrial glands (histiotrophic support) under conditions that are both hypoxic and hypoglycemic. Indeed, high levels of oxygen or glucose at this stage will damage the developing embryo. At 8–10 weeks of gestation, the placental extravillous cytotrophoblast cells (EVCTs) change their adhesion molecule expression and stream out of the placental villi to invade the full thickness of the decidualized endometrium (decidua) and the inner third of the myometrium. These cells invade the maternal spiral arteries, attracted in part by the high oxygen tension [19] and by active recruitment by uterine natural killer (uNK) cells and macrophages [8,17,20], and remodel these vessels by destroying the muscle layer and replacing the endothelial lining with a pseudo-endothelium of fetal origin. This process—known as the 'second wave' of trophoblast invasion—is usually complete by 18 weeks of gestation and is critical for the establishment of the definitive uteroplacental circulation. Interestingly, the initiation of vascular remodeling precedes the trophoblast invasion of the spiral arteries and is likely initiated by resident uNK cells [21,22]. As pregnancy progresses, the 120–140 small, tortuous maternal spiral arteries that supply each placenta need to dilate enormously to accommodate

the increasing demands of the fetoplacental unit. The placenta is a high-volume, low-resistance organ. At term, almost one-fifth of the maternal cardiac output (approximately 800mL) passes through the placenta every minute. If this remodeling of the maternal spiral arteries from narrow lumen, tortuous vessels with a thick muscle layer to wide, thin-walled, funnel-shaped vessels is not adequate—a pathological hallmark known as shallow endovascular invasion [1,8]—the feto- placental unit will outgrow its blood supply, resulting in placental dysfunction and ultimately in clinical disease.
