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Blood Vessel Evolution in Early Pregnancy is Focus in Miscarriage Study

Variations in the way blood vessels are formed during the earliest stages of pregnancy are found more often in women with a history of repeat miscarriages. That's the finding of a study from Greece that examined these origins in a group of women who had a history of recurrent pregnancy loss.1

Even more specifically, variations in the genes responsible for the production of these blood vessels may be the culprit, although it hasn't yet been confirmed. "It is possible that women with a "bad" haplotype (combination of disadvantageous variants of these genes) are probably genetically prone to … recurrent miscarriage," explained Dimitrios Papazoglou, PhD, in the Second Department of Internal Medicine at the Medical School of Alexandroupolis in Greece, in an interview with Priority Healthcare.

Papazoglou was the study's chief researcher.

Blood Vessel Formation After Fertilization
During the time between fertilization of the egg and its implantation in the uterus, a substance produced by the body known as vascular endothelial growth factor, or VEGF, is responsible for directing the formation of blood vessels that allow the uterus to become receptive to the arriving egg. VEGF also controls the creation of new blood vessels in the placenta from which the developing fetus takes in nutrients from the mother.2

When this process goes awry, miscarriage theoretically, is the result, the researchers speculated. "Recurrent spontaneous abortions are a frequent reproductive problem, with three or more affecting 1% to 2%, and two or more affecting up to 5% of women of reproductive age," wrote Papazoglou and his colleagues. While this process of vascularization is essential to a normal pregnancy, it's not known if abnormal changes in the development of these blood vessels is a common cause of recurrent miscarriage, Papazoglou's team added.

Are VEGF Problems Linked to Miscarriage?
To determine that, Papazoglou and his colleagues compared a group of 52 women with a history of at least three miscarriages to a group of 82 women who each had had at least two live births and no miscarriages in the past. All of the women in the latter group had reached menopause "to exclude possible future miscarriages after inclusion in the study," the researchers wrote.

The investigators conducted a range of tests in each woman to determine how often common variations in the VEGF gene occurred, and whether they might be responsible for recurrent miscarriage. In the final analysis, Papazoglou and his team found that the women with a history of repeat miscarriage tended to have a higher prevalence of a gene variation related to VEGF. This variation resulted in a lower production of VEGF.

Since it's known that VEGF controls the development of blood vessels in the uterus at the earliest stages of development, "it could be suggested that the reduced ability of normal tissues to [take up] VEGF under stressful conditions demanding tissue revascularization [the process by which new blood vessels are formed] or tissue development (i.e., placenta formation) leads to the formation of a vascular network with an abnormally high apoptotic tendency," wrote Papazoglou and his team. (Apoptosis (ap-ahp-TOE-sis) is the medical term for cell death). 

An Early Step Toward Therapeutic Strategies
What does this mean for women who may be more susceptible to miscarriage? The study "allows further insight into the natural history of this syndrome and allows further characterization of susceptible women," the study authors wrote, in conclusion. While this may someday lead to strategies to help prevent recurrent miscarriage, Papazoglou stresses that that is years away. "Promising preliminary results regarding the inhibition of VEGF have been described in the field of oncology," he said. For instance, previous studies have suggested that consuming alcohol increases levels of VEGF leading to the production of blood vessels that cancer tumors feed off of to grow.3,4

[But] it is very simplistic (and possibly dangerous) and has no rationale to say, 'Let's augment VEGF levels in one or another way' in an infertile or pregnant woman," he said.

He adds that this study simply confirmed an association between lower levels of VEGF and miscarriage, not any definite cause. But that may be discovered in future research. "These results have to be confirmed by other researchers on a larger number of participating subjects of various populations," he said.

1. Papazoglou D, Galazios G, Papatheodorou K et al. Vascular endothelial growth factor gene polymorphisms and idiopathic recurrent pregnancy loss. Fertil Steril 2005 Apr;83(4):959-63.
2. Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PG. Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online 2004 Dec;9(6):692-715.
3. Gu JW, Bailey AP, Sartin A, Makey I, Brady AL. Ethanol stimulates tumor progression and expression of vascular endothelial growth factor in chick embryos. Cancer 2005 Jan 15;103(2):422-31.
4. Gu JW, Elam J, Sartin A, Li W, Roach R, Adair TH. Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis. Am J Physiol Regul Inegr Comp Physiol 2001 Jul;281(1):R365-72.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications. 

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