Implantacion

The Ne w E n g l a nd Jo ur n a l o f Me d ic i ne

Review Article

Mechanisms of Disease

I MPLANTATION AND THE S URVIVAL OF E ARLY P REGNANCY
ERROL R. NORWITZ, M.D., PH.D., DANNY J. SCHUST, M.D., AND SUSAN J. FISHER, PH.D.

H

UMAN reproduction entails a fundamental paradox: although it is critical to the survival of the species, the process is relatively inefficient. Maximalfecundity (the probability of conception during one menstrual cycle) is approximately 30 percent.1 Only 50 to 60 percent of all conceptions advance beyond 20 weeks of gestation.2 Of the pregnancies that are lost, 75 percent represent a failure of implantation and are therefore not clinically recognized as pregnancies.2 Failed implantation is also a major limiting factor in assisted reproduction.3 Abetter understanding of the molecular mechanisms responsible for implantation and placentation may improve clinicians’ ability to treat disorders related to these processes, including infertility and early pregnancy loss.
NORMAL IMPLANTATION
Early Embryonic Development

Very few specimens exist that document the first weeks of embryonic development in humans. In some cases, information about aparticular stage of development comes from a single specimen. Other crucial events, such as the initial adhesion of the blastocyst to the uterine epithelium, have never been observed. Therefore, much of our understanding of early human development is inferred from studies in animals. Given that the cellular interactions culminating in implantation and placentation vary greatly even among primates, therelevance of this information is unclear. Nevertheless, certain important steps that have been identified in implantation and placentation in ani-

From the Divisions of Maternal–Fetal Medicine and Reproductive Endocrinology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston (E.R.N., D.J.S.); and Department ofStomatology, University of California, San Francisco (S.J.F.). Address reprint requests to Dr. Norwitz at the Division of Maternal–Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, or at enorwitz@partners.org.

mals probably apply to humans. This review emphasizes those steps for which data already exist.Fertilization occurs in the fallopian tube within 24 to 48 hours after ovulation. The initial stages of development, from fertilized ovum (zygote) to a mass of 12 to 16 cells (morula), occur as the embryo, encased in a nonadhesive protective coating known as the zona pellucida, passes through the fallopian tube. The morula enters the uterine cavity approximately two to three days after fertilization.The appearance of a fluid-filled inner cavity within the mass of cells marks the transition from morula to blastocyst and is accompanied by cellular differentiation: the surface cells become the trophoblast (and give rise to extraembryonic structures, including the placenta), and the inner cell mass gives rise to the embryo. Within 72 hours after entering the uterine cavity, the embryo hatchesfrom the zona, thereby exposing its outer covering of syncytial (multinucleate) trophoblasts. Implantation occurs approximately six or seven days after conception (fertilization). Insofar as it is analogous to the events that occur in several primate species,4 implantation in humans probably includes three stages. The initial adhesion of the blastocyst to the uterine wall, called apposition, isunstable. Microvilli on the apical surface of syncytiotrophoblasts interdigitate with microprotrusions from the apical surface of the uterine epithelium, known as pinopodes (Fig. 1). Apposition, and consequently implantation, occurs most commonly in the upper posterior (fundal) wall of the uterus. The next stage, stable adhesion, is characterized by increased physical interaction between the...