Insight: Research Edition

Fall 2006

Researcher Investigates Growth-Restricted Pregnancies

At the University of Colorado’s Health Sciences Center – Perinatal Research Facility in Denver, sheep are helping researchers understand some of the intricacies of fetal development, including how and why things go wrong. Dr. Russell Anthony, Colorado State University’s Hill Professor of Animal Biotechnology in the College’s Department of Biomedical Sciences, leads the collaborative effort between Colorado State University and the University of Colorado, capitalizing on both schools’ strengths to more quickly push forward innovative research into growth-restricted pregnancies.

“More recently, our research has shifted from molecular/cellular aspects toward placental/fetal interactions, primarily in growth-restricted pregnancies,” said Dr. Anthony, who has a joint appointment in the Department of Pediatrics at UCHSC and also is a faculty member with the College’s Animal Reproduction and Biotechnology Laboratory. “In the United States, 8 to 10 percent of babies suffer from clinical fetal growth restriction. Worldwide the number is closer to 17 percent. In 80 percent of these growth-restricted infants, the underlying cause is a functional failure of the placenta to grow, develop and provide groceries to the baby in utero.”

One of the focuses of Dr. Anthony’s research is placental insufficiency. His research team is investigating the early stages of placental development, trying to understand what is going wrong that leads to low birth-weight babies who are small for their gestational age.

“Intrauterine growth restriction is a clinical diagnosis where the size of the head is maintained but the abdomen and trunk are proportionately smaller, displaying asymmetric growth,” said Dr. Anthony. “And we are not only concerned about the developing infant. In the last 15 to 20 years, epidemiologists have been able to demonstrate that infants born at low birth weight have a higher predisposition to coronary heart disease, type 2 diabetes and hypertension as adults. We are finding that fetal organ systems, if not nourished at the right time, can suffer impaired development that can create lifelong health concerns.”

Some causes of growth-restricted pregnancies, such as smoking, drug abuse and high altitude, are apparent. But, Dr. Anthony noted, most growth-restricted pregnancies are idiopathic cases with no apparent external or environmental cause.

“We are using sheep as a model and have developed various ways to set up growth-restricted pregnancies where we can assess oxygen, glucose and amino acids transfer to the fetus, and examine uterine and umbilical or fetal organ blood flow,” said Dr. Anthony. “We are trying to look at the same end points that are examined in human cases, while we monitor pregnancies and verify that what we are seeing is truly mimicking what we know about growth-restricted pregnancies in humans.”

Using sheep as a model, researchers can take the next step, going further and looking at things that can’t be done in humans. Researchers can put catheters into the fetus mid-gestation and not disrupt the pregnancy. With the catheters, they are able to look at nutrient transfer, oxygen transfer, and other markers of fetal growth and development.

Collaborating with researchers in Italy, where ultrasound monitoring of pregnancies is more routine, the CSU and UC team has good guidance on what to look at and where to focus. They are also looking at stable isoptomers of amino acids and glucose that can be tracked across the placenta into the fetus.

“A lot of development of methodology is done here at CSU,” said Dr. Anthony. “As we develop new approaches, we transfer that technology to Denver. There are a lot of things we can do here much more cost-effectively than there. For example, the CSU team has a grant to look at a gene called periattachment factor. It is expressed early in gestation and during the period of maternal recognition of pregnancy in cattle and sheep. The gene also is expressed later in gestation and researchers are working to determine the role it plays then as well. They are using in vivo RNA interference to examine the function of this protein, and that technology may be applied to growth-restricted pregnancies in the future.

“We also do a lot of cross-training of researchers and physicians from both institutions. The physicians get a good appreciation of how basic research is impacting clinical practice, and our graduate students get to see the big picture of why the work they are doing is so important.”

Dr. Anthony hopes that through the work of the CSU-CU team, scientists can better understand the aspects of placental development that are problematic, including key developmental mechanisms, and begin to look at early treatments that may prevent or reduce conditions leading to growth-restricted pregnancies and the associated long-term health risks.