Cesarean scar ectopic pregnancy: nuances in diagnosis and treatment

Hypoxia inducible factor (HIF) is a transcription factor that acts in low-oxygen conditions. The cellular response to HIF activation is transcriptional upregulation of a large group of genes. Some target genes promote anaerobic metabolism to reduce oxygen consumption, while others "alleviate" hypoxia by acting non-cell-autonomously to extend and modify the surrounding vasculature. Although hypoxia is often thought of as being a pathological phenomenon, the mammalian embryo in fact develops in a low-oxygen environment, and in this context HIF has additional responsibilities. This review describes how low oxygen and HIF affect gene expression, cell behavior, and ultimately morphogenesis of the embryo and placenta. 2009 Elsevier Inc. All rights reserved.

Establishment of the human placenta requires that fetal cytotrophoblast stem cells in anchoring chorionic villi become invasive. These cytotrophoblasts aggregate into cell columns and invade both the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta. Cytotrophoblasts colonizing spiral arterioles replace maternal endothelium as far as the first third of the myometrium. We show here that differentiating cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace. Cytotrophoblasts in cell columns show reduced E-cadherin staining and express VE-(endothelial) cadherin, platelet-endothelial adhesion molecule-1, vascular endothelial adhesion molecule-1, and alpha-4-integrins. Cytotrophoblasts in the uterine interstitium and maternal vasculature continue to express these receptors, and, like endothelial cells during angiogenesis, also stain for alphaVbeta3. In functional studies, alphaVbeta3 and VE-cadherin enhance, while E-cadherin restrains, cytotrophoblast invasiveness. Cytotrophoblasts expressing alpha4 integrins bound immobilized VCAM-1 in vitro, suggesting that this receptor-pair could mediate cytotrophoblast-endothelium or cytotrophoblast-cytotrophoblast interactions in vivo, during endovascular invasion. In the pregnancy disorder preeclampsia, in which endovascular invasion remains superficial, cytotrophoblasts fail to express most of these endothelial markers (Zhou et al., 1997. J. Clin. Invest. 99:2152-2164.), suggesting that this adhesion phenotype switch is required for successful endovascular invasion and normal placentation.

In 2011, 1 in 3 women who gave birth in the United States did so by cesarean delivery. Cesarean birth can be lifesaving for the fetus, the mother, or both in certain cases. However, the rapid increase in cesarean birth rates from 1996 through 2011 without clear evidence of concomitant decreases in maternal or neonatal morbidity or mortality raises significant concern that cesarean delivery is overused. Variation in the rates of nulliparous, term, singleton, vertex cesarean births also indicates that clinical practice patterns affect the number of cesarean births performed. The most common indications for primary cesarean delivery include, in order of frequency, labor dystocia, abnormal or indeterminate (formerly, nonreassuring) fetal heart rate tracing, fetal malpresentation, multiple gestation, and suspected fetal macrosomia. Safe reduction of the rate of primary cesarean deliveries will require different approaches for each of these, as well as other, indications. For example, it may be necessary to revisit the definition of labor dystocia because recent data show that contemporary labor progresses at a rate substantially slower than what was historically taught. Additionally, improved and standardized fetal heart rate interpretation and management may have an effect. Increasing women's access to nonmedical interventions during labor, such as continuous labor and delivery support, also has been shown to reduce cesarean birth rates. External cephalic version for breech presentation and a trial of labor for women with twin gestations when the first twin is in cephalic presentation are other of several examples of interventions that can contribute to the safe lowering of the primary cesarean delivery rate.