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Obstetrics
Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast

https://doi.org/10.1016/j.ajog.2010.12.027Get rights and content

Objective

We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition.

Study Design

We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like-tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7.

Results

Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to-mesenchymal transition feature and tumorlike cell phenotype.

Conclusion

Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion.

Section snippets

Study design and patient population

In a case-control study design we analyzed maternal blood serum samples from 90 women enrolled prospectively at Yale–New Haven Hospital between May 2005 and January 2010. Our study group consisted of 45 consecutive singleton patients (gestational age [GA] median, 31; interquartile range, 28–34 weeks) who were admitted with a diagnosis of vaginal bleeding due to CPP. Blood specimens from 45 healthy women (GA, 31; interquartile range, 28–33 weeks) pregnant with singletons were matched for GA and

Clinical characteristics of women

We present the demographic, clinical, and pregnancy outcome characteristics of our cohort in Table. Women with CPP were significantly older, were of significantly higher gravidity and parity, and had a significantly higher number of prior CDs when compared to controls. The vast majority of the women with CPP experienced at least one episode of vaginal bleeding during pregnancy (episodes of bleeding: 1 [1-2]). The fetuses of both CPP and control women were of appropriate growth for GA. Women

Comment

Herein, we found that women with CPP have circulatory levels of sFlt-1, PlGF, and VEGF similar to those expected for GA. That the process of excessive myometrial invasion in the setting of CPP is characterized by significantly lower maternal serum levels of VEGF was an unexpected finding.

Following apposition and attachment of the blastocyst to the uterine wall, the process of normal placentation requires a symbiotic interaction between fetal and maternal tissues. This process includes among

Acknowledgments

We are indebted to the nurses, fellows, residents, and faculty at Yale–New Haven Hospital, the Department of Obstetrics and Gynecology and Reproductive Sciences, and to all patients who participated in the study.

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      Thus, vimentin remains a negative marker for all trophoblast cell populations. Only one report has recently linked vimentin to the invasive properties of trophoblast cells in pathological situations such as the placenta accreta spectrum [68]. Likewise, the cadherin-switch is considered part of the transition during which CT become invasive EVT and downregulation of E-cadherin expression levels has been proven along this process [10,11].

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    This work was supported by National Institutes of Health Grant no. R01 HD 047321 (I.A.B.) and the Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine. C.S.B. was supported by the Yale Women's Reproductive Health Research Career Development Center (K12 HD 1027766) and NIH RO3 HD 50249.

    The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.

    Cite this article as: Wehrum MJ, Buhimschi IA, Salafia C, et al. Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast. Am J Obstet Gynecol 2011;204:411.e1-11.

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