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New protein chips are a window on the womb

Medicine@Yale, 2006 - July Aug


A rapid, reliable test to make preterm births safer for mother and child

Preterm birth is the leading cause of death and disease in newborns worldwide, but it is difficult to prevent or to manage because premature labor can result from several causes, including infection and intrauterine inflammation. It is well known that inflammation is damaging to babies, but inflammation itself has many causes. Sometimes infection leads to inflammation, but as often as not, other biological processes are at work.

Because of this complexity, obstetricians treating mothers at risk for preterm birth must decide within a brief time window whether to prescribe anti-inflammatory agents, antibiotics or both, while they simultaneously weigh whether aiming for a quick delivery or slowing down labor with drugs will be better for the baby. Physicians find their way through this clinical thicket by counting white blood cells (WBCs) in a sample of amniotic fluid or culturing a sample. However, these tests take time, and they provide a crude and unreliable measure of inflammation.

But new work using cutting edge protein-chip technology by the husband-and-wife research team of Catalin S. Buhimschi, M.D., and Irina Buhimschi, M.D., both assistant professors in the Department of Obstetrics, Gynecology and Reproductive Sciences, may soon make doctors’ decisions surrounding preterm birth faster, easier and healthier for both mother and child.

Irina Buhimschi says that relying on WBC counts or cultures to manage premature labor allows for “educated guesses” at best, and in 2000 she began exploring the newly emerging field of proteomics—the study of the structure and function of proteins—to find a better way. She settled on a technique known as SELDI (surface enhanced laser desorption ionization), in which a biological sample, such as amniotic fluid, is placed on a small aluminum strip coated with chemicals that bind proteins (see photo). The strip is then inserted into equipment that determines which proteins in the sample are most abundant and rapidly generates a protein profile, a graph in which the most plentiful proteins are represented as peaks.

The Buhimschis put SELDI technology to use in a study reported in the February 2005 issue of BJOG, a British journal of obstetrics and gynecology, in which they analyzed samples of amniotic fluid that had been obtained during the 1990s from 77 women with symptoms of preterm labor and placed in cold storage. Seventeen of these patients, called the “normal group” in the study, had low WBC counts and normal culture results when the samples were drawn, and these women eventually had normal deliveries. Sixty other women had preterm deliveries, but in a vivid illustration of the complexity of premature labor, only 21 (the “disease group”) had high WBC counts and cultures indicating infection; the remainder had low levels of WBCs and negative cultures, or had inconclusive test results—negative on one and positive on the other.

When the Buhimschis applied a statistical technique known as mass restricted (MR) analysis to the disease group’s SELDI-derived protein profiles, four peaks emerged that were not present in the normal group. To test whether these proteins, all of which are involved in inflammatory pathways, could serve as reliable biomarkers to manage preterm labor, the researchers devised an “MR score,” assigning one point for the presence of any of the peaks in a sample. They then scored 24 additional amniotic samples, this time without knowing what the patient’s outcome had been, and found that the MR score predicted with great accuracy which women had preterm births, and what the nature of their test results had been.

In a more recent study, presented at the February meeting of the Society for Maternal-Fetal Medicine, the Buhimschis tested fresh samples of amniotic fluid taken from women with symptoms of preterm labor and found that their MR scores not only predicted preterm births but when those births would occur. “An MR score of 2 indicates the median time for delivery is four days,” says Catalin Buhimschi. “If all four biomarkers for inflammation are present, delivery occurs within hours. Our test has more clinical value because we can obtain results in half an hour.”

The Buhimschis hope this latest work, which won the 2006 March of Dimes Award for Best Research in Prematurity, will add momentum to their efforts to move their technique into clinical practice, and they are now exploring the use of SELDI for the diagnosis and management of other prenatal conditions, such as preeclampsia.

In a scientific bonus, one of the proteins the Buhimschis identified with SELDI has never been associated with preterm inflammation. “In addition to its diagnostic power,” Catalin Buhimschi says, “SELDI also opens the window for new studies to understand the biology of the process of inflammation.”